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New Aspects of Diabetes Research and Therapeutic Development

Both type 1 and type 2 diabetes mellitus are advancing at exponential rates, placing significant burdens on health care networks worldwide. Although traditional pharmacologic therapies such as insulin and oral antidiabetic stalwarts like metformin and the sulfonylureas continue to be used, newer drugs are now on the market targeting novel blood glucose–lowering pathways. Furthermore, exciting new developments in the understanding of beta cell and islet biology are driving the potential for treatments targeting incretin action, islet transplantation with new methods for immunologic protection, and the generation of functional beta cells from stem cells. Here we discuss the mechanistic details underlying past, present, and future diabetes therapies and evaluate their potential to treat and possibly reverse type 1 and 2 diabetes in humans.

Significance Statement

Diabetes mellitus has reached epidemic proportions in the developed and developing world alike. As the last several years have seen many new developments in the field, a new and up to date review of these advances and their careful evaluation will help both clinical and research diabetologists to better understand where the field is currently heading.

I. Introduction

Diabetes mellitus, a metabolic disease defined by elevated fasting blood glucose levels due to insufficient insulin production, has reached epidemic proportions worldwide (World Health Organization, 2020 ). Type 1 and type 2 diabetes (T1D and T2D, respectively) make up the majority of diabetes cases with T1D characterized by autoimmune destruction of the insulin-producing pancreatic beta cells. The much more prevalent T2D arises in conjunction with peripheral tissue insulin resistance and beta cell failure and is estimated to increase to 21%–33% of the US population by the year 2050 (Boyle et al., 2010 ). To combat this growing health threat and its cardiac, renal, and neurologic comorbidities, new and more effective diabetes drugs and treatments are essential. As the last several years have seen many new developments in the field of diabetes pharmacology and therapy, we determined that a new and up to date review of these advances was in order. Our aim is to provide a careful evaluation of both old and new therapies ( Fig. 1 ) in a manner that we hope will be of interest to both clinical and bench diabetologists. Instead of the usual encyclopedic approach to this topic, we provide here a targeted and selective consideration of the underlying issues, promising new treatments, and a re-examination of more traditional approaches. Thus, we do not discuss less frequently used diabetes agents, such as alpha-glucosidase inhibitors; these were discussed in other recent reviews (Hedrington and Davis, 2019 ; Lebovitz, 2019 ).

Pharmacologic targeting of numerous organ systems for the treatment of diabetes. Treatment of diabetes involves targeting of various organ systems, including the kidney by SGLT2 inhibitors; the liver, gut, and adipose tissue by metformin; and direct actions upon the pancreatic beta cell. Beta cell compounds aim to increase secretion or mass and/or to protect from autoimmunity destruction. Ultimately, insulin therapy remains the final line of diabetes treatment with new technologies under development to more tightly regulate blood glucose levels similar to healthy beta cells. hESC, human embryonic stem cell.

II. Diabetes Therapies

A. metformin.

Metformin is a biguanide originally based on the natural product galegine, which was extracted from the French lilac (Bailey, 1992 ; Rojas and Gomes, 2013 ; Witters, 2001 ). A closely related biguanide, phenformin, was also used initially for its hypoglycemic actions. Based on its successful track record as a safe, effective, and inexpensive oral medication, metformin has become the most widely prescribed oral agent in the world in treating T2D (Rojas and Gomes, 2013 ; He and Wondisford, 2015 ; Witters, 2001 ), whereas phenformin has been largely bypassed due to its unacceptably high association with lactic acidosis (Misbin, 2004 ). Unlike sulfonylureas, metformin lowers blood glucose without provoking hypoglycemia and improves insulin sensitivity (Bailey, 1992 ). Despite these well known beneficial metabolic actions, metformin’s mechanism of action and even its main target organ remain controversial. In fact, metformin has multiple mechanisms of action at the organ as well as the cellular level, which has hindered our understanding of its most important molecular effects on glucose metabolism (Witters, 2001 ). Adding to this, a specific receptor for metformin has never been identified. Metformin has actions on several tissues, although the primary foci of most studies have been the liver, skeletal muscle, and the intestine (Foretz et al., 2014 ; Rena et al., 2017 ). Metformin and phenformin clearly suppress hepatic glucose production and gluconeogenesis, and they improve insulin sensitivity in the liver and elsewhere (Bailey, 1992 ). The hepatic actions of metformin have been the most exhaustively studied to date, and there is little doubt that these actions are of some importance. However, several of the studies remain highly controversial, and there are still open questions.

One of the first reported specific molecular targets of metformin was mitochondrial complex I of the electron transport chain. Inhibition of this complex results in reduced oxidative phosphorylation and consequently decreased hepatic ATP production (El-Mir et al., 2008 ; Evans et al., 2005 ; Owen et al., 2000 ). As is the case in many other studies of metformin, however, high concentrations of the drug were found to be necessary to depress metabolism at this site (El-Mir et al., 2000 ; He and Wondisford, 2015 ; Owen et al., 2000 ). Also controversial is whether metformin works by activating 5′ AMP-activated protein kinase (AMPK), a molecular energy sensor that is known to be a major metabolic sensor in cells, or if not AMPK directly, then one of its upstream regulators such as liver kinase B2 (Zhou et al., 2001 ). Although metformin was shown to activate AMPK in several excellent studies, other studies directly contradicted the AMPK hypothesis. Most dramatic were studies showing that metformin’s actions to suppress hepatic gluconeogenesis persisted despite genetic deletion of the AMPK’s catalytic domain (Foretz et al., 2010 ). More recent studies identified additional or alternative targets, such as cAMP signaling in the liver (Miller et al., 2013 ) or glycogen synthase kinase-3 (Link, 2003 ). Other work showed that the phosphorylation of acetyl-CoA carboxylase and acetyl-CoA carboxylase 2 are involved in regulating lipid homeostasis and improving insulin sensitivity after exposure to metformin (Fullerton et al., 2013 ).

Although there are strong data to support each of these pathways, it is not entirely clear which signaling pathway(s) is most essential to the actions of metformin in hepatocytes. Metformin clearly inhibits complex I and concomitantly decreases ATP and increases AMP. The latter results in AMPK activation, reduced fatty acid synthesis, and improved insulin receptor activation, and increased AMP has been shown to inhibit adenylate cyclase to reduce cAMP and thus protein kinase A activation. Downstream, this reduces the expression of phosphoenolpyruvate carboxykinase and glucose 6-phosphatase via decreased cAMP response element-binding protein, the cAMP-sensitive transcription factor. Decreased PKA also promotes ATP-dependent 6-phosphofructokinase, liver type activity via fructose 2,6-bisphosphate and reduces gluconeogenesis, as fructose-bisphosphatase 1 is inhibited by fructose 2,6-bisphosphate, along with other mechanisms (Rena et al., 2017 ; Pernicova and Korbonits, 2014 ).

More recent work has shown that metformin at pharmacological rather than suprapharmacological doses increases mitochondrial respiration and complex 1 activity and also increases mitochondrial fission, now thought to be critical for maintaining proper mitochondrial density in hepatocytes and other cells. This improvement in respiratory activity occurs via AMPK activation (Wang et al., 2019 ).

Although the liver has historically been the major suspected site of metformin action, recent studies have suggested that the gut instead of the liver is a major target, a concept supported by the increased efficacy of extended-release formulations of metformin that reside for a longer duration in the gut after their administration (Buse et al., 2016 ). An older, but in our view an important observation, is that the intravenous administration of metformin has little or no effect on blood glucose, whereas, in contrast, orally administered metformin is much more effective (Bonora et al., 1984 ). Recent imaging studies using labeled glucose have shown directly that metformin stimulates glucose uptake by the gut in patients with T2D to reduce plasma glucose concentrations (Koffert et al., 2017 ; Massollo et al., 2013 ). Additionally, it is possible that metformin may exert its effect in the gut by inducing intestinal glucagon-like peptide-1 (GLP-1) release (Mulherin et al., 2011 ; Preiss et al., 2017) to potentiate beta cell insulin secretion and by stimulating the central nervous system (CNS) to exert control over both blood glucose and liver function. Indeed, CNS effects produced by metformin have been proposed to occur via the local release of GLP-1 to activate intestinal nerve endings of ascending nerve pathways that are involved in CNS glucose regulation (Duca et al., 2015 ). Lastly, several papers have now implicated that metformin may act by altering the gut microbiome, suggesting that changes in gut flora may be critical for metformin’s actions (McCreight et al., 2016 ; Wu et al., 2017 ; Devaraj et al., 2016 ). A new study proposed that activation of the intestinal farnesoid X receptor may be the means by which microbiota alter hyperglycemia (Sun et al., 2018 ). However, these studies will require more mechanistic detail and confirmation before they can be fully accepted by the field. In addition to the action of metformin on gut flora, the production of imidazole propionate by gut microbes in turn has been shown to interfere with metformin action through a p38-dependent mechanism and AMPK inhibition. Levels of imidazole propionate are especially higher in patients with T2D who are treated with metformin (Koh et al., 2020 ).

In summary, the combined contribution of these various effects of metformin on multiple cellular targets residing in many tissues may be key to the benefits of metformin treatment on lowering blood glucose in patients with type 2 diabetes (Foretz et al., 2019 ). In contrast, exciting new work showing metformin leads to weight loss by increasing circulating levels of the peptide hormone growth differentiation factor 15 and activation of brainstem glial cell-derived neurotropic factor family receptor alpha like receptors to reduce food intake and energy expenditure works independently of metformin’s glucose-lowering effect (Coll et al., 2020 ).

B. Sulfonylureas and Beta Cell Burnout

The class of compounds known as sulfonylureas includes one of the oldest oral antidiabetic drugs in the pharmacopoeia: tolbutamide. Tolbutamide is a “first generation” oral sulfonylurea secretagogue whose clinical usefulness is due to its prompt stimulation of insulin release from pancreatic beta cells. “Second generation” sulfonylureas include drugs such as glyburide, gliclazide, and glipizide. Sulfonylureas act by binding to a high affinity sulfonylurea binding site, the sulfonylurea receptor 1 subunit of the K(ATP) channel, which closes the channel. These drugs mimic the physiologic effects of glucose, which closes the K(ATP) channel by raising cytosolic ATP/ADP. This in turn provokes beta cell depolarization, resulting in increased Ca 2+ influx into the beta cell (Ozanne et al., 1995 ; Ashcroft and Rorsman, 1989 ; Nichols, 2006 ). Importantly, sulfonylureas, and all drugs that directly increase insulin secretion, are associated with hypoglycemia, which can be severe, and which limits their widespread use in the clinic (Yu et al., 2018 ). Meglitinides are another class of oral insulin secretagogues that, like the sulfonylureas, bind to sulfonylurea receptor 1 and inhibit K(ATP) channel activity (although at a different site of action). The rapid kinetics of the meglitinides enable them to effectively blunt the postprandial glycemic excursions that are a hallmark (along with elevated fasting glucose) of T2D (Rosenstock et al., 2004). However, the need for their frequent dosing (e.g., administration before each meal) has limited their appeal to patients.

The efficacy of sulfonylureas is known to decrease over time, leading to failure of the class for effective long-term treatment of T2D (Harrower, 1991 ). More broadly, it is now widely accepted that the number of functional beta cells in humans declines during the progression of T2D. Thus, one would expect that due to this decline, all manner of oral agents intended to target the beta cell and increase its cell function (and especially insulin secretion) will fail over time (RISE Consortium, 2019 ), a process referred to as “beta cell failure” (Prentki and Nolan, 2006 ). Currently, treatments that can expand beta cell mass or improve beta cell function or survival over time are not yet available for use in the clinic. As a result, treatments that may be able to help patients cope with beta cell burnout such as islet cell transplantation, insulin pumps, or stem cell therapy are alternatives that will be discussed below.

C. Ca 2+ Channel Blockers and Type 1 Diabetes

Strategies to treat and prevent T1D have historically focused on ameliorating the toxic consequences of immune dysregulation resulting in autoimmune destruction of pancreatic beta cells. More recently, a concerted focus on alleviating the intrinsic beta cell defects (Sims et al., 2020 ; Soleimanpour and Stoffers, 2013 ) that also contribute to T1D pathogenesis have been gaining traction at both the bench and the bedside. Several recent preclinical studies suggest that Ca 2+ -induced metabolic overload induces beta cell failure (Osipovich et al., 2020 ; Stancill et al., 2017 ; Xu et al., 2012 ), with the potential that excitotoxicity contributes to beta cell demise in both T1D and T2D, similar to the well known connection between excitotoxicity and, concomitantly, increased Ca 2+ loading of the cells and neuronal dysfunction. Indeed, the use of the phenylalkylamine Ca 2+ channel blocker verapamil has been successful in ameliorating beta cell dysfunction in preclinical models of both T1D and T2D (Stancill et al., 2017 ; Xu et al., 2012 ). Verapamil is a well known blocker of L-type Ca 2+ channels, and, in normally activated beta cells, it limits Ca 2+ entry into the beta cell (Ohnishi and Endo, 1981 ; Vasseur et al., 1987 ). This would be expected to, in turn, alter the expression of many Ca 2+ influx–dependent beta cell genes (Stancill et al., 2017 ), and the evidence to date suggests it is likely that verapamil preserves beta cell function in diabetes models by repressing thioredoxin-interacting protein (TXNIP) expression and thus protecting the beta cell. This is somewhat surprising given the physiologic role of Ca 2+ is to acutely trigger insulin secretion; this process would be expected to be inhibited by L-type Ca 2+ channel blockers (Ashcroft and Rorsman, 1989 ; Satin et al., 1995 ).

Hyperglycemia is a well known inducer of TXNIP expression, and a lack of TXNIP has been shown to protect against beta cell apoptosis after inflammatory stress (Chen et al., 2008a ; Shalev et al., 2002 ; Chen et al., 2008b ). Excitingly, the use of verapamil in patients with recent-onset T1D improved beta cell function and improved glycemic control for up to 12 months after the initiation of therapy, suggesting there is indeed promise for targeting calcium and TXNIP activation in T1D. Use of verapamil for a repurposed indication in the preservation of beta cell function in T1D is attractive due its well known safety profile as well as its cardiac benefits (Chen et al., 2009 ). Although the long-term efficacy of verapamil to maintain beta cell function in vivo is unclear, a recently described TXNIP inhibitor may also show promise in suppressing the hyperglucagonemia that also contributes to glucose intolerance in T2D (Thielen et al., 2020 ). As there is a clear need for increased Ca 2+ influx into the beta cell to trigger and maintain glucose-dependent insulin secretion (Ashcroft and Rorsman, 1990 ; Satin et al., 1995 ), it remains to be seen how well regulated insulin secretion is preserved in the presence of L-type Ca 2+ channel blockers like verapamil in the system. One might speculate that reducing but not fully eliminating beta cell Ca 2+ influx might reduce TXNIP levels while preserving enough influx to maintain glucose-stimulated insulin release. Alternatively, these two phenomena may operate on entirely different time scales. At present, these issues clearly will require further investigation.

D. GLP-1 and the Incretins

Studies dating back to the 1960s revealed that administering glucose in equal amounts via the peripheral circulation versus the gastrointestinal tract led to dramatically different amounts of glucose-induced insulin secretion (Elrick et al., 1964 ; McIntyre et al., 1964 ; Perley and Kipnis, 1967 ). Gastrointestinal glucose administration greatly increased insulin secretion versus intravenous glucose, and this came to be known as the “incretin effect” (Nauck et al., 1986a ; Nauck et al., 1986b ). Subsequent work showed that release of the gut hormone GLP-1 mediated this effect such that food ingestion induced intestinal cell hormone secretion. GLP-1 so released would then circulate to the pancreas via the blood to prime beta cells to secrete more insulin when glucose became elevated because these hormones stimulated beta cell cAMP formation (Drucker et al., 1987 ). The discovery that a natural peptide corresponding to GLP-1 could be found in the saliva of the Gila monster, a desert lizard, hastened progress in the field, and ample in vitro studies subsequently confirmed that GLP-1 potentiated insulin secretion in a glucose-dependent manner. GLP-1 has little or no significant action on insulin secretion in the absence of elevated glucose (such as might typically correspond to the postprandial case or during fasting), thus minimizing the likelihood of hypoglycemia provoked by GLP-1 in treated patients (Kreymann et al., 1987 ). Although not completely understood, the glucose dependence of GLP-1 likely reflects the requirement for adenine nucleotides to close glucose-inhibited K(ATP) channels and thus subsequently activate Ca 2+ influx–dependent insulin exocytosis. Besides potentiating GSIS at the level of the beta cell, glucagon-like peptide-1 receptor (GLP-1R) agonists also decrease glucagon secretion from pancreatic islet alpha cells, reduce gastric emptying, and may also increase beta cell proliferation, among other cellular actions (reviewed in Drucker, 2018 ; Muller et al., 2019).

Intense interest in the incretins by basic scientists, clinicians, and the pharma community led to the rapid development of new drugs for treating primarily T2D. These drugs include a range of GLP-1R agonists and inhibitors of the incretin hormone degrading enzyme dipeptidyl peptidase 4 (DPP4), whose targeting increases the half-lives of GLP-1 and gastric inhibitory polypeptide (GIP) and thereby increases protein hormone levels in plasma. GLP-1R agonists have been associated with not only a lowering of plasma glucose but also weight loss, decreased appetite, reduced risk of cardiovascular events, and other favorable outcomes (Gerstein et al., 2019; Hernandez et al., 2018; Husain et al., 2019; Marso et al., 2016a; Marso et al., 2016b ; Buse et al., 2004). Regarding their untoward actions, although hypoglycemia is not a major concern, there have been reports of pancreatitis and pancreatic cancer from use of GLP-1R agonists. However, a recent meta-analysis covering four large-scale clinical trials and over 33,000 participants noted no significantly increased risk for pancreatitis/pancreatic cancer in patients using GLP-1R agonists (Bethel et al., 2018).

Ongoing and future developments in the use of proglucagon-derived peptides such as GLP-1 and glucagon include the use of combined GLP-1/GIP, glucagon/GLP-1, and agents targeting all three peptides in combination (reviewed in Alexiadou and Tan, 2020 ). Although short-term infusions of GLP-1 with GIP failed to yield metabolic benefits beyond those seen with GLP-1 alone (Bergmann et al., 2019 ), several GLP-1/GIP dual agonists are currently in development and have shown promising metabolic results in clinical trials (Frias et al., 2017 ; Frias et al., 2020 ; Frias et al., 2018 ). At the level of the pancreatic islet, beneficial effects of dual GLP-1/GIP agonists may be related to imbalanced and biased preferences of these agonists for the gastric inhibitory polypeptide receptor over the GLP-1R (Willard et al., 2020 ) and possibly were not simply to dual hormone agonism in parallel. Dual glucagon/GLP-1 agonist therapy has also been shown to have promising metabolic effects in humans (Ambery et al., 2018 ; Tillner et al., 2019 ). Oxyntomodulin is a natural dual glucagon/GLP-1 receptor agonist and proglucagon cleavage product that is also secreted from intestinal enteroendocrine cells, which has beneficial effects on insulin secretion, appetite regulation, and body weight in both humans and rodents (Cohen et al., 2003 ; Dakin et al., 2001 ; Dakin et al., 2002 ; Shankar et al., 2018 ; Wynne et al., 2005 ). Interestingly, alpha cell crosstalk to beta cells through the combined effects of glucagon and GLP-1 is necessary to obtain optimal glycemic control, suggesting a potential pathway for therapeutic dual glucagon/GLP-1 agonism within the islets of patients with T2D (Capozzi et al., 2019a ; Capozzi et al., 2019b ). Although the early results appear promising, more studies will be necessary to better understand the mechanistic and clinical impacts of these multiagonist agents.

E. DPP4 Inhibitors

Inhibition of DPP4, the incretin hormone degrading enzyme, is one of the most common T2D treatments to increase GLP-1 and GIP plasma hormone levels. These DPP4 inhibitors or “gliptins” are generally used in conjunction with other T2D drugs such as metformin or sulfonylureas to obtain the positive benefits discussed above (Lambeir et al., 2008 ). DPP4 is a primarily membrane-bound peptidase belonging to the serine peptidase/prolyl oligopeptidase gene family, which cleaves a large number of substrates in addition to the incretin hormones (Makrilakis, 2019 ). DPP4 inhibitors provide glucose-lowering benefits while being generally well tolerated, and the variety of available drugs (including sitagliptin, saxagliptin, vildagliptin, alogliptin, and linagliptin) with slightly different dosing frequency, half-life, and mode of excretion/metabolism allows for use in multiple patient populations (Makrilakis, 2019 ). This includes the elderly and individuals with renal or hepatic insufficiency (Makrilakis, 2019 ).

Although hypoglycemia is not a concern for DPP4 inhibitor use, other considerations should be made. DPP4 inhibitors tend to be more expensive than metformin or other second-line oral drugs in addition to having more modest glycemic effects than GLP-1R agonists (Munir and Lamos, 2017 ). Finally, meta-analysis of randomized and observational studies concluded that heart failure in patients with T2D was not associated with use of DPP4 inhibitors; however, this study was limited by the short follow-up and lack of high-quality data (Li et al., 2016 ). Thus, the US Food and Drug Administration (FDA) did recommend assessing risk of heart failure hospitalization in patients with pre-existing cardiovascular disease, prior heart failure, and chronic kidney disease when using saxagliptin and alogliptin (Munir and Lamos, 2017 ).

F. Sodium Glucose Cotransporter 2 Inhibitors

A recent development in the field of T2D drugs are sodium glucose cotransporter 2 (SGLT2) inhibitors, which have an interesting and very different mechanism of action. Within the proximal tubule of the nephron, SGLT2 transports ingested glucose into the lumen of the proximal tubule between the epithelial layers, thereby reclaiming glucose by this reabsorption process (reviewed in Vallon, 2015 ). SGLT2 inhibitors target this transporter and increase glucose in the tubular fluid and ultimately increase it in the urine. In patients with diabetes, SGLT2 inhibition results in a lowering of plasma glucose with urine glucose content rising substantially (Adachi et al., 2000 ; Vallon, 2015 ). These drugs, although they are relatively new, have become an area of great interest for not only patients with T2D (Grempler et al., 2012 ; Imamura et al., 2012 ; Meng et al., 2008 ; Nomura et al., 2010 ) but also for patients with T1D (Luippold et al., 2012 ; Mudaliar et al., 2012 ). Part of their appeal also rests on reports that their use can lead to a statistically significant decline in cardiac events that are known to occur secondarily to diabetes, possibly independently of plasma glucose regulation (reviewed in Kurosaki and Ogasawara, 2013 ). Although the long-term consequences of their clinical use cannot yet be determined, raising the glucose content of the urogenital tract leads to an increased risk of urinary tract infections and other related infections in some patients (Kurosaki and Ogasawara, 2013 ).

Another recent concern about the use of SGLT2 inhibitors has been the development of normoglycemic diabetic ketoacidosis (DKA). Despite the efficacy of SGLT2 inhibitors, observations of hyperglucagonemia in patients with euglycemic DKA has led to a number of recent studies focused on SGLT2 actions on pancreatic islets. Initial studies of isolated human islets treated with small interfering RNA directed against SGLT2 and/or SGLT2 inhibitors demonstrated increased glucagon release. These studies were complemented by the finding of elevations in glucagon release in mice that were administered SGLT2 inhibitors in vivo (Bonner et al., 2015 ). Insights into the possible mechanistic links between SGLT2 inhibition, DKA frequency, and glucagon secretion in humans may relate to the observation of heterogeneity in SGLT2 expression, as SGLT2 expression appears to have a high frequency of interdonor and intradonor variability (Saponaro et al., 2020 ). More recently, both insulin and GLP-1 have been demonstrated to modulate SGLT2-dependent glucagon release through effects on somatostatin release from delta cells (Vergari et al., 2019 ; Saponaro et al., 2019 ), suggesting potentially complex paracrine effects that may affect the efficacy of these compounds.

On the other hand, several recent studies question that the development of euglycemic DKA after SGLT2 inhibitor therapy may be through alpha cell–dependent mechanisms. Three recent studies found no effect of SGLT2 inhibitors to promote glucagon secretion in mouse and/or rat models and could not detect SGLT2 expression in human alpha cells (Chae et al., 2020 ; Kuhre et al., 2019 ; Suga et al., 2019 ). A fourth study demonstrated only a brief transient effect of SGLT2 inhibition to raise circulating glucagon concentrations in immunodeficient mice transplanted with human islets, which returned to baseline levels after longer exposures to SGLT2 inhibitors (Dai et al., 2020 ). Furthermore, SGLT2 protein levels were again undetectable in human islets (Dai et al., 2020 ). These results could suggest alternative islet-independent mechanisms by which patients develop DKA, including alterations in ketone generation and/or clearance, which underscore the additional need for further studies both in molecular models and at the bedside. Nevertheless, SGLT2 inhibitors continue to hold promise as a valuable therapy for T2D, especially in the large segment of patients who also have superimposed cardiovascular risk (McMurray et al., 2019; Wiviott et al., 2019; Zinman et al., 2015).

G. Thiazolidinediones

Once among the most commonly used oral agents in the armamentarium to treat T2D, thiazolidinediones (TZDs) were clinically popular in their utilization to act specifically as insulin sensitizers. TZDs improve peripheral insulin sensitivity through their action as peroxisome proliferator-activated receptor (PPAR) γ agonists, but their clinical use fell sharply after studies suggested a connection between cardiovascular toxicity with rosiglitazone and bladder cancer risk with pioglitazone (Lebovitz, 2019 ). Importantly, an FDA panel eventually removed restrictions related to cardiovascular risk with rosiglitazone in 2013 (Hiatt et al., 2013 ). Similarly, concerns regarding use of bladder cancer risk with pioglitazone were later abated after a series of large clinical studies found that pioglitazone did not increase bladder cancer (Lewis et al., 2015 ; Schwartz et al., 2015 ). However, usage of TZDs had already substantially decreased and has not since recovered.

Although concerns regarding edema, congestive heart failure, and fractures persist with TZD use, there have been several studies suggesting that TZDs protect beta cell function. In the ADOPT study, use of rosiglitazone monotherapy in patients newly diagnosed with T2D led to improved glycemic control compared with metformin or sulfonylureas (Kahn et al., 2006). Later analyses revealed that TZD-treated subjects had a slower deterioration of beta cell function than metformin- or sulfonylurea-treated subjects (Kahn et al., 2011). Furthermore, pioglitazone use improved beta cell function in the prevention of T2D in the ACT NOW study (Defronzo et al., 2013; Kahn et al., 2011). Mechanistically, it is unclear if TZDs lead to beneficial beta cell function through direct effects or through indirect effects of reduced beta cell demand due to enhanced peripheral insulin sensitivity. Indeed, a beta cell–specific knockout of PPAR γ did not impair glucose homeostasis, nor did it impair the antidiabetic effects of TZD use in mice (Rosen et al., 2003 ). However, other reports demonstrated PPAR-responsive elements within the promoters of both glucose transporter 2 and glucokinase that enhance beta cell glucose sensing and function, which could explain beta cell–specific benefits for TZDs (Kim et al., 2002 ; Kim et al., 2000 ). Furthermore, TZDs have been shown to improve beta cell function by upregulating cholesterol transport (Brunham et al., 2007 ; Sturek et al., 2010 ). Additionally, use of TZDs in the nonobese diabetic (NOD) mouse model of T1D augmented the beta cell unfolded protein response and prevented beta cell death, suggesting potential benefits for TZDs in both T1D and T2D (Evans-Molina et al., 2009 ; Maganti et al., 2016 ). With a now refined knowledge of demographics in which to avoid TZD treatment due to adverse effects, together with genetic approaches to identify candidates more likely to respond effectively to TZD therapy (Hu et al., 2019 ; Soccio et al., 2015 ), it remains to be seen if TZD therapy will return to more prominent use in the treatment of diabetes.

H. Insulin and Beyond: The Use of “Smart” Insulin and Closed Loop Systems in Diabetes Treatment

Due to recombinant DNA technology, numerous insulin analogs are now available in various forms ranging from fast acting crystalline insulin to insulin glargine; all of these analogs exhibit equally effective insulin receptor binding. Most are generated by altering amino acids in the B26–B30 region of the molecule (Kurtzhals et al., 2000 ). The American Diabetes Association delineates these insulins by their 1) onset or time before insulin reaches the blood stream, 2) peak time or duration of maximum blood glucose–lowering efficacy, and 3) the duration of blood glucose–lowering time. Insulin administration is independent of the residuum of surviving and/or functioning beta cells in the patient and remains the principal pharmacological treatment of both T1D and T2D. The availability of multiple types of delivery methods, i.e., insulin pens, syringes, pumps, and inhalants, provides clinicians with a solid and varied tool kit with which to treat diabetes. The downsides, however, are that 1) hypoglycemia is a constant threat, 2) proper insulin doses are not trivial to calculate, 3) compliance can vary especially in children and young adults, and 4) there can be side effects of a variety of types. Nonetheless, insulin therapy remains a mainstay treatment of diabetes.

To eliminate the downsides of insulin therapy, research in the past several decades has worked toward generating glucose-sensitive or “smart” insulin molecules. These molecules change insulin bioavailability and become active only upon high blood glucose using glucose-binding proteins such as concanavalin A, glucose oxidase to alter pH sensitivity, and phenylboronic acid (PBA), which forms reversible ester linkages with diol-containing molecules including glucose itself (reviewed in Rege et al., 2017 ). Indeed, promising recent studies included various PBA moieties covalently bonded to an acylated insulin analog (insulin detemir, which contains myristic acid coupled to Lys B29 ). The detemir allows for binding to serum albumin to prolong insulin’s half-life in the circulation, and PBA provided reversible glucose binding (Chou et al., 2015 ). The most promising of the PBA-modified conjugates showed higher potency and responsiveness in lowering blood glucose levels compared with native insulin in diabetic mouse models and decreased hypoglycemia in healthy mice, although the molecular mechanisms have not yet been determined (Chou et al., 2015 ).

An additional active area of research includes structurally defining the interaction between insulin and the insulin receptor ectodomain. Importantly, a major conformational change was discovered that may be exploited to impair insulin receptor binding under hypoglycemic conditions (Menting et al., 2013 ; Rege et al., 2017 ). Challenges in the design, testing, and execution of glucose-responsive insulins may be overcome by the adaptation of novel modeling approaches (Yang et al., 2020 ), which may allow for more rapid screening of candidate compounds.

Technologies have also progressed in the field of artificial pancreas design and development. Currently two “closed loop” systems are now available: Minimed 670G from Medtronic and Control-IQ from Tandem Diabetes Care. Both systems use a continuous glucose monitor, insulin pump, and computer algorithm to predict correct insulin doses and administer them in real time. Such algorithm systems also take into account insulin potency, the rate of blood glucose increase, and the patient’s heart rate and temperature to adjust insulin delivery levels during exercise and after a meal. In addition, so-called “artificial pancreas” systems have also been clinically tested, which use both insulin and glucagon and as such result in fewer reports of hypoglycemic episodes (El-Khatib et al., 2017 ). These types of systems will continue to become more popular as the development of room temperature–stable glucagon analogs continue, such as GVOKE by Xeris Pharmaceuticals (currently available in an injectable syringe) and Baqsimi, a nasally administered glucagon from Eli Lilly.

I. Present and Future Therapies: Beta Cell Transplantation, Replication, and Immune Protection

1. islet transplantation.

The idea to use pancreatic allo/xenografts to treat diabetes remarkably dates back to the late 1800s (Minkowski, 1892 ; Pybus, 1924 ; Williams, 1894 ). Before proceeding to the discovery of insulin (together with Best, MacLeod, and Collip), Frederick Banting also postulated the potential for transplantation of pancreatic tissue emulsions to treat diabetes in dog models in a notebook entry in 1921 (Bliss, 1982 ). Decades later, Paul Lacy, David Scharp, and colleagues successfully isolated intact functional pancreatic islets and transplanted them into rodent models (Kemp et al., 1973 ). These studies led to the initial proof of concept studies for humans, with the first successful islet transplant in a patient with T1D occurring in 1977 (Sutherland et al., 1978 ). A rapid expansion of islet transplantation, inspired by these original studies led to key observations of successfully prolonged islet engraftment by the “Edmonton protocol” whereby corticosteroid-sparing immunosuppression was applied, and islets from at least two allogeneic donors were used to achieve insulin independence (Shapiro et al., 2000 ). More recent work has focused on improving upon the efficiency and long-term engraftment of allogeneic transplants leading to more prolonged graft function (to the 5-year mark) and successful transplantation from a single islet donor (Hering et al., 2016; Hering et al., 2005 ; Rickels et al., 2013 ). Critical to these efforts to improve the success rate was the recognition that the earlier generation of immunosuppressive agents to counter tissue rejection was toxic to islets (Delaunay et al., 1997 ; Paty et al., 2002 ; Soleimanpour et al., 2010 ) and that more appropriate and less toxic agents were needed (Hirshberg et al., 2003 ; Soleimanpour et al., 2012 ).

Certainly, islet transplantation as a therapeutic approach for patients with T1D has been scrutinized due to several challenges, including (but not limited to) the lack of available donor supply to contend with demand, limited long-term functional efficacy of islet allografts, the potential for re-emergence of autoimmune islet destruction and/or metabolic overload-induced islet failure, and significant adverse effects of prolonged immunosuppression (Harlan, 2016 ). Furthermore, although islet transplantation is not currently available for individuals with T2D, simultaneous pancreas-kidney transplantation in T2D had similar favorable outcomes to simultaneous pancreas-kidney transplantation in T1D; therefore, islet-kidney transplantation may eventually be a feasible option to treat T2D, as patients will already be on immunosuppressors (Sampaio et al., 2011 ; Westerman et al., 1983 ). An additional significant obstacle is the tremendous expense associated with islet transplantation therapy. Indeed, the maintenance, operation, and utilization of an FDA-approved and Good Manufacturing Practice–compliant islet laboratory can lead to operating costs at nearly $150,000 per islet transplant, which is not cost effective for the vast majority of patients with T1D (Naftanel and Harlan, 2004 ; Wallner et al., 2016 ). At present, the focus has been to obtain FDA approval for islet allo-transplantation as a therapy for T1D to allow for insurance compensation (Hering et al., 2016; Rickels and Robertson, 2019 ). In the interim, the islet biology, stem cell, immunology, and bioengineering communities have continued the development of cell-based therapies for T1D by other approaches to overcome the challenges identified during the islet transplantation boom of the 1990s and 2000s.

2. Pharmacologic Induction of Beta Cell Replication

Besides transplantation, progress in islet cell biology and especially in developmental biology of beta cells over several decades raised the additional possibility that beta cell mass reduction in diabetes might be countered by increasing beta cell number through mitogenic means. A key method to expand pancreatic beta cell mass is through the enhancement of beta cell replication. Although the study of pancreatic beta cell replication has been an area of intense focus in the beta cell biology field for several decades, only recently has this seemed truly feasible. Seminal studies identified that human beta cells are essentially postmitotic, with a rapid phase of growth occurring in the prenatal period that dramatically tapers off shortly thereafter (Gregg et al., 2012 ; Meier et al., 2008 ). The plasticity of rodent beta cells is considerably higher than that of human beta cells (Dai et al., 2016 ), which has led to a renewed focus on validation of pharmacologic agents to enhance rodent beta cell replication using isolated and/or engrafted human islets (Bernal-Mizrachi et al., 2014 ; Kulkarni et al., 2012 ; Stewart et al., 2015 ). Indeed, a large percentage of agents that were successful when applied to rodent systems were largely unsuccessful at inducing replication in human beta cells (Bernal-Mizrachi et al., 2014 ; Kulkarni et al., 2012 ; Stewart et al., 2015 ). However, several recent studies have begun to make significant progress on successfully pushing human beta cells to replicate.

Several groups have reported successful human beta cell proliferation, both in vitro and in vivo, in response to inhibitors of the dual specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A). These inhibitors include harmine, INDY, GNF4877, 5-iodotubericidin, leucettine-42, TG003, AZ191, CC-401, and more specific, recently developed DYRK1A inhibitors (Ackeifi et al., 2020 ). Although DYRK1A is conclusively established as the important mediator of human beta cell proliferation, comprehensively determining other cellular targets and if additional gene inhibition amplifies the proliferative response is still in process. New evidence from Wang and Stewart shows dual specificity tyrosine phosphorylation-regulated kinase 1B to be an additional mitogenic target and also describes variability in the range of activated kinases within cells and/or levels of inhibition for the many DYRK1A inhibitors listed above (Ackeifi et al., 2020 ). Interestingly, opposite to these human studies, earlier mouse studies from the Scharfmann group demonstrated that Dyrk1a haploinsufficiency leads to decreased proliferation and loss of beta cell mass (Rachdi et al., 2014b ). In addition, overexpression of Dyrk1a in mice led to beta cell mass expansion with increased glucose tolerance (Rachdi et al., 2014a ).

Although important differences in beta cell proliferative capacity have been shown between human and rodent species, there are also significant differences in the mitogenic capacity of beta cells from juvenile, adult, and pregnant individuals. This demonstrates that proliferative stimuli appear to act within the complex islet, pancreas, and whole-body environments unique to each time point. For example, the administration of the hormones platelet-derived growth factor alpha or GLP-1 result in enhanced proliferation in juvenile human beta cells yet are ineffective in adult human beta cells (Chen et al., 2011 ; Dai et al., 2017 ). This has been shown to be due to a loss of platelet-derived growth factor alpha receptor expression as beta cells age but appears to be unrelated to GLP-1 receptor expression levels (Chen et al., 2011 ). Indeed, the GLP-1 receptor is highly expressed in adult beta cells, and GLP-1 secretion increases insulin secretion, as detailed previously; however, the induction of proliferative factors such as nuclear factor of activated T cells, cytoplasmic 1; forkhead box protein 1; and cyclin A1 is only seen in juvenile islets (Dai et al., 2017 ). Human studies using cadaveric pancreata from pregnant donors also showed increased beta cell mass, yet lactogenic hormones from the pituitary or placenta (prolactin, placental lactogen, or growth hormone) are unable to stimulate proliferation in human beta cells despite their ability to produce robust proliferation in mouse beta cells (reviewed in Baeyens et al., 2016 ). Experiments overexpressing mouse versus human signal transducer and activator of transcription 5, the final signaling factor inducing beta cell adaptation, in human beta cells allows for prolactin-mediated proliferation revealing fundamental differences in prolactin pathway competency in human (Chen et al., 2015 ). Overcoming the barrier of recapitulating human pregnancy’s effect on beta cells through isolating placental cells or blood serum during pregnancy may result in the discovery of a factor(s) that facilitates the increase in beta cell mass observed during human pregnancy.

Mechanisms that stimulate beta cell proliferation have also been discovered from studying genetic mutations that result in insulinomas, spontaneous insulin-producing beta cell adenomas. The most common hereditary mutation occurs in the multiple endocrine neoplasia type 1 (MEN1) gene. Indeed, administration of a MEN1 inhibitor in addition to a GLP-1 agonist (which cannot induce proliferation alone) is able to increase beta cell proliferation in isolated human islets through synergistic activation of KRAS proto-oncogene, GTPase downstream signals (Chamberlain et al., 2014 ). Interestingly, MEN1 mutations are uncommon in sporadic insulinomas, yet assaying genomic and epigenetic changes in a large cohort of non-MEN1 insulinomas found alterations in trithorax and polycomb chromatin modifying genes that were functionally related to MEN1 (Wang et al., 2017 ). Stewart and colleagues hypothesized that changes in histone 3 lysine 27 and histone 3 lysine 4 methylation status led to increased enhancer of zeste homolog 2 and lysine demethylase 6A, decreased cyclin-dependent kinase inhibitor 1C, and thereby increased beta cell proliferation, among other phenotypes. They also proposed that these findings help to explain why increased proliferation always occurs despite broad heterogeneity of mutations found between individual insulinomas (Wang et al., 2017 ).

Although factors that induce proliferation are continuing to be discovered, there are drawbacks that still limit their clinical application. Harmine and other DYRK1A inhibitors are not beta cell specific, nor have all their cellular targets been determined (Ackeifi et al., 2020 ). Targeting other pathways to induce human beta cell proliferation such as modulation of prostaglandin E2 receptors (i.e., inhibition of prostaglandin E receptor 3 alone or in combination with prostaglandin E receptor 4 activation) showed promising increases in proliferative rate yet suffers from the same lack of specificity (Carboneau et al., 2017 ). Induction of proliferation may also come at the expense of glucose sensing as in insulinomas, which have an increased expression of “disallowed genes” and alterations in glucose transporter and hexokinase expression (Wang et al., 2017 ). A further untoward consequence that must be avoided is the production of cancerous cells through unchecked proliferation. Finally, increasing beta cell mass through low rates of proliferation may increase the pool of functional insulin-secreting cells in T2D, but without additional measures, these beta cells will still ultimately be targeted for immune cell destruction in T1D.

3. Beta Cell Stress Relieving Therapies

Metabolic, inflammatory, and endoplasmic reticulum (ER) stress contribute to beta cell dysfunction and failure in both T1D and T2D. Although reduction of metabolic overload of beta cells by early exogenous insulin therapy or insulin sensitizers can temporarily reduce loss of beta cell mass/function early in diabetes, a focus on relieving ER and inflammatory stress is also of interest to preserve beta cell health.

ER stress is a well known contributor to beta cell demise both in T1D and T2D (Laybutt et al., 2007 ; Marchetti et al., 2007 ; Marhfour et al., 2012 ; Tersey et al., 2012 ) and a target of interest in the prevention of beta cell loss in both diseases. Preclinical studies suggest that the use of chemical chaperones, including 4-phenylbutyric acid and tauroursodeoxycholic acid (TUDCA), to alleviate ER stress improves beta cell function and insulin sensitivity in mouse models of T2D (Cnop et al., 2017 ; Ozcan et al., 2006 ). Furthermore, TUDCA has been shown to preserve beta cell mass and reduce ER stress in mouse models of T1D (Engin et al., 2013 ). Interestingly, TUDCA has shown promise at improving insulin action in obese nondiabetic human subjects, yet beta cell function and insulin secretion were not assessed (Kars et al., 2010 ). A clinical trial regarding the use of TUDCA for humans with new-onset T1D is also ongoing ( {"type":"clinical-trial","attrs":{"text":"NCT02218619","term_id":"NCT02218619"}} NCT02218619 ). However, a note of caution regarding use of ER chaperones is that they may prevent low level ER stress necessary to potentiate beta cell replication during states of increased insulin demand (Sharma et al., 2015 ), suggesting that the broad use of ER chaperone therapies should be carefully considered.

The blockade of inflammatory stress has long been an area of interest for treatments of both T1D and T2D (Donath et al., 2019 ; Eguchi and Nagai, 2017 ). Indeed, use of nonsteroidal anti-inflammatory drugs (NSAIDs), which block cyclooxygenase, have been observed to improve metabolic control in patients with diabetes since the turn of the 20th century (Williamson, 1901 ). Salicylates have been shown to improve insulin secretion and beta cell function in both obese human subjects and those with T2D (Fernandez-Real et al., 2008; Giugliano et al., 1985 ). However, another NSAID, salsalate, has not been shown to improve beta cell function while improving other metabolic outcomes (Kim et al., 2014 ; Penesova et al., 2015 ), possibly suggesting distinct mechanisms of action for anti-inflammatory compounds. The regular use of NSAIDs to enhance metabolic outcomes is also often limited to the tolerability of long-term use of these agents due to adverse effects. Recently, golilumab, a monoclonal antibody against the proinflammatory cytokine tumor necrosis factor alpha, was demonstrated to improve beta cell function in new-onset T1D, suggesting that targeting the underlying inflammatory milieu may have benefits to preserve beta cell mass and function in T1D (Quattrin et al., 2020). Taken together, both new and old approaches to target beta cell stressors still remain of long-term interest to improve beta cell viability and function in both T1D and T2D.

3. New Players to Induce Islet Immune Protection

Countless researchers have expended intense industry to determine T1D disease etiology and treatments focused on immunotherapy and tolerogenic methods. Multiple, highly comprehensive reviews are available describing these efforts (Goudy and Tisch, 2005 ; Rewers and Gottlieb, 2009 ; Stojanovic et al., 2017 ). Here we will focus on the protection of beta cells through programmed cell death protein-1 ligand (PD-L1) overexpression, major histocompatibility complex class I, A, B, C (HLA-A,B,C) mutated human embryonic stem cell–derived beta cells, and islet encapsulation methods.

Cancer immunotherapies that block immune checkpoints are beneficial for treating advanced stage cancers, yet induction of autoimmune diseases, including T1D, remains a potential side effect (Stamatouli et al., 2018 ; Perdigoto et al., 2019 ). A subset of these drugs target either the programmed cell death-1 protein on the surface of activated T lymphocytes or its receptor PD-L1 (Stamatouli et al., 2018 ; Perdigoto et al., 2019 ). PD-L1 expression was found in insulin-positive beta cells from T1D but not insulin-negative islets or nondiabetic islets, leading to the hypothesis that PD-L1 is upregulated in an attempt to drive immune cell attenuation (Osum et al., 2018 ; Colli et al., 2018 ). Adenoviral overexpression of PD-L1 specifically in beta cells rescued hyperglycemia in the NOD mouse model of T1D, but these animals eventually succumbed to diabetes by the study’s termination (El Khatib et al., 2015 ). A more promising report from Ben Nasr et al. ( 2017 ) demonstrated that pharmacologically or genetically induced overexpression of PD-L1 in hematopoietic stem and progenitor cells inhibited beta cell autoimmunity in the NOD mouse as well as in vitro using human hematopoietic stem and progenitor cells from patients with T1D.

As mentioned above, islet transplantation to treat T1D is limited by islet availability, cost, and the requirement for continuous immunosuppression. Islet cells generated by differentiating embryonic or induced pluripotent stem (iPS) cells could circumvent these limitations. Ideally, iPS-derived beta cells could be manipulated to eliminate the expression of polymorphic HLA-A,B,C molecules, which were found to be upregulated in T1D beta cells (Bottazzo et al., 1985 ; Richardson et al., 2016 ). These molecules allow peptide presentation to CD8+ T cells or cytotoxic T lymphocytes and may lead to beta cell removal. Interestingly, remaining insulin-positive cells in T1D donor pancreas are not HLA-A,B,C positive (Nejentsev et al., 2007; Rodriguez-Calvo et al., 2015 ). However, current differentiation protocols are still limited in their ability to produce fully glucose-responsive beta cells without transplantation into animal models to induce mature characteristics. Additionally, use of iPS-derived beta cells will still lead to concerns regarding DNA mutagenesis resulting from the methods used to obtain pluripotency or teratoma formation from cells that have escaped differentiation.

Encapsulation devices would protect islets or stem cells from immune cell infiltration while allowing for the proper exchange of nutrients and hormones. Macroencapsulation uses removable devices that would help assuage fears surrounding mutation or tumor formation; indeed, the first human trial using encapsulated hESC-derived beta cells will be completed in January 2021 ( {"type":"clinical-trial","attrs":{"text":"NCT02239354","term_id":"NCT02239354"}} NCT02239354 ). Macroencapsulation of islets prior to transplantation using various alginate-based hydrogels has historically been impeded by a strong in vivo foreign body immune response (Desai and Shea, 2017 ; Doloff et al., 2017 ; Pueyo et al., 1993 ). More recently, chemically modified forms of alginate that avoid macrophage recognition and fibrous deposition have been successfully used in rodents and for up to 6 months in nonhuman primates (Vegas et al., 2016 ). Indeed, Bochenek et al. ( 2018 ) successfully transplanted alginate protected islets for 4 months without immunosuppression in the bursa omentalis of nonhuman primates demonstrating the feasibility for this approach to be extended to humans. It remains to be seen if these devices will be successful for long-term use, perhaps decades, in patients with diabetes.

III. Summary

Although existing drug therapies using classic oral antidiabetic drugs like sulfonylureas and metformin or injected insulin remain mainstays of diabetes treatment, newer drugs based on incretin hormone actions or SGLT2 inhibitors have increased the pharmacological armamentarium available to diabetologists ( Fig. 1 ). However, the explosion of progress in beta cell biology has identified potential avenues that can increase beta cell mass in sophisticated ways by employing stem cell differentiation or enhancement of beta cell proliferation. Taken together, there should be optimism that the increased incidence of both T1D and T2D is being matched by the creativity and hard work of the diabetes research community.

Abbreviations

Authorship contributions.

Wrote and contributed to the writing of the manuscript: Satin, Soleimanpour, Walker

This work was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [Grant R01-DK46409] (to L.S.S.), [Grant R01-DK108921] (to S.A.S.), and [Grant P30-DK020572 pilot and feasibility grant] (to S.A.S.), the Juvenile Diabetes Research Foundation (JDRF) [Grant CDA-2016-189] (to L.S.S. and S.A.S.), [Grant SRA-2018-539] (to S.A.S.), and [Grant COE-2019-861] (to S.A.S.), and the US Department of Veterans Affairs [Grant I01 BX004444] (to S.A.S.). The JDRF Career Development Award to S.A.S. is partly supported by the Danish Diabetes Academy and the Novo Nordisk Foundation.

https://doi.org/10.1124/pharmrev.120.000160

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Recent Advances

ADA-funded researchers use the money from their awards to conduct critical diabetes research. In time, they publish their findings in order to inform fellow scientists of their results, which ensures that others will build upon their work. Ultimately, this cycle drives advances to prevent diabetes and to help people burdened by it. In 2018 alone, ADA-funded scientists published over 200 articles related to their awards!

Identification of a new player in type 1 diabetes risk

Type 1 diabetes is caused by an autoimmune attack of insulin-producing beta-cells. While genetics and the environment are known to play important roles, the underlying factors explaining why the immune system mistakenly recognize beta-cells as foreign is not known. Now, Dr. Delong has discovered a potential explanation. He found that proteins called Hybrid Insulin Peptides (HIPs) are found on beta-cells of people with type 1 diabetes and are recognized as foreign by their immune cells. Even after diabetes onset, immune cells are still present in the blood that attack these HIPs.

Next, Dr. Delong wants to determine if HIPs can serve as a biomarker or possibly even targeted to prevent or treat type 1 diabetes. Baker, R. L., Rihanek, M., Hohenstein, A. C., Nakayama, M., Michels, A., Gottlieb, P. A., Haskins, K., & Delong, T. (2019). Hybrid Insulin Peptides Are Autoantigens in Type 1 Diabetes. Diabetes , 68 (9), 1830–1840.

Understanding the biology of body-weight regulation in children

Determining the biological mechanisms regulating body-weight is important for preventing type 2 diabetes. The rise in childhood obesity has made this even more urgent. Behavioral studies have demonstrated that responses to food consumption are altered in children with obesity, but the underlying biological mechanisms are unknown. This year, Dr. Schur tested changes in brain and hormonal responses to a meal in normal-weight and obese children. Results from her study show that hormonal responses in obese children are normal following a meal, but responses within the brain are reduced. The lack of response within the brain may predispose them to overconsumption of food or difficulty with weight-loss.

With this information at hand, Dr. Schur wants to investigate how this information can be used to treat obesity in children and reduce diabetes.

Roth, C. L., Melhorn, S. J., Elfers, C. T., Scholz, K., De Leon, M. R. B., Rowland, M., Kearns, S., Aylward, E., Grabowski, T. J., Saelens, B. E., & Schur, E. A. (2019). Central Nervous System and Peripheral Hormone Responses to a Meal in Children. The Journal of Clinical Endocrinology and Metabolism , 104 (5), 1471–1483.

A novel molecule to improve continuous glucose monitoring

To create a fully automated artificial pancreas, it is critical to be able to quantify blood glucose in an accurate and stable manner. Current ways of continuously monitoring glucose are dependent on the activity of an enzyme which can change over time, meaning the potential for inaccurate readings and need for frequent replacement or calibration. Dr. Wang has developed a novel molecule that uses a different, non-enzymatic approach to continuously monitor glucose levels in the blood. This new molecule is stable over long periods of time and can be easily integrated into miniaturized systems.

Now, Dr. Wang is in the process of patenting his invention and intends to continue research on this new molecule so that it can eventually benefit people living with diabetes.

Wang, B. , Chou, K.-H., Queenan, B. N., Pennathur, S., & Bazan, G. C. (2019). Molecular Design of a New Diboronic Acid for the Electrohydrodynamic Monitoring of Glucose. Angewandte Chemie (International Ed. in English) , 58 (31), 10612–10615.

Addressing the legacy effect of diabetes

Several large clinical trials have demonstrated the importance of tight glucose control for reducing diabetes complications. However, few studies to date have tested this in the real-world, outside of a controlled clinical setting. In a study published this year, Dr. Laiteerapong found that indeed in a real-world setting, people with lower hemoglobin A1C levels after diagnosis had significantly lower vascular complications later on, a phenomenon known as the ‘legacy effect’ of glucose control. Her research noted the importance of early intervention for the best outcomes, as those with the low A1C levels just one-year after diagnosis had significantly lower vascular disease risk compared to people with higher A1C levels.

With these findings in hand, physicians and policymakers will have more material to debate and determine the best course of action for improving outcomes in people newly diagnosed with diabetes.

Laiteerapong, N. , Ham, S. A., Gao, Y., Moffet, H. H., Liu, J. Y., Huang, E. S., & Karter, A. J. (2019). The Legacy Effect in Type 2 Diabetes: Impact of Early Glycemic Control on Future Complications (The Diabetes & Aging Study). Diabetes Care , 42 (3), 416–426.

A new way to prevent immune cells from attacking insulin-producing beta-cells

Replacing insulin-producing beta-cells that have been lost in people with type 1 diabetes is a promising strategy to restore control of glucose levels. However, because the autoimmune disease is a continuous process, replacing beta-cells results in another immune attack if immunosorbent drugs are not used, which carry significant side-effects. This year, Dr. Song reported on the potential of an immunotherapy he developed that prevents immune cells from attacking beta-cells and reduces inflammatory processes. This immunotherapy offers several potential benefits, including eliminating the need for immunosuppression, long-lasting effects, and the ability to customize the treatment to each patient.

The ability to suppress autoimmunity has implications for both prevention of type 1 diabetes and improving success rates of islet transplantation.

Haque, M., Lei, F., Xiong, X., Das, J. K., Ren, X., Fang, D., Salek-Ardakani, S., Yang, J.-M., & Song, J . (2019). Stem cell-derived tissue-associated regulatory T cells suppress the activity of pathogenic cells in autoimmune diabetes. JCI Insight , 4 (7).

A new target to improve insulin sensitivity

The hormone insulin normally acts like a ‘key’, traveling through the blood and opening the cellular ‘lock’ to enable the entry of glucose into muscle and fat cells. However, in people with type 2 diabetes, the lock on the cellular door has, in effect, been changed, meaning insulin isn’t as effective. This phenomenon is called insulin resistance. Scientists have long sought to understand what causes insulin resistance and develop therapies to enable insulin to work correctly again. This year, Dr. Summers determined an essential role for a molecule called ceramides as a driver of insulin resistance in mice. He also presented a new therapeutic strategy for lowering ceramides and reversing insulin resistance. His findings were published in one of the most prestigious scientific journals, Science .

Soon, Dr. Summers and his team will attempt to validate these findings in humans, with the ultimate goal of developing a new medication to help improve outcomes in people with diabetes.

Chaurasia, B., Tippetts, T. S., Mayoral Monibas, R., Liu, J., Li, Y., Wang, L., Wilkerson, J. L., Sweeney, C. R., Pereira, R. F., Sumida, D. H., Maschek, J. A., Cox, J. E., Kaddai, V., Lancaster, G. I., Siddique, M. M., Poss, A., Pearson, M., Satapati, S., Zhou, H., … Summers, S. A. (2019). Targeting a ceramide double bond improves insulin resistance and hepatic steatosis. Science (New York, N.Y.) , 365 (6451), 386–392.

Determining the role of BPA in type 2 diabetes risk

Many synthetic chemicals have infiltrated our food system during the period in which rates of diabetes has surged. Data has suggested that one particular synthetic chemical, bisphenol A (BPA), may be associated with increased risk for developing type 2 diabetes. However, no study to date has determined whether consumption of BPA alters the progression to type 2 diabetes in humans. Results reported this year by Dr. Hagobian demonstrated that indeed when BPA is administered to humans in a controlled manner, there is an immediate, direct effect on glucose and insulin levels.

Now, Dr. Hagobian wants to conduct a larger clinical trial including exposure to BPA over a longer period of time to determine precisely how BPA influences glucose and insulin. Such results are important to ensure the removal of chemicals contributing to chronic diseases, including diabetes.

Hagobian, T. A. , Bird, A., Stanelle, S., Williams, D., Schaffner, A., & Phelan, S. (2019). Pilot Study on the Effect of Orally Administered Bisphenol A on Glucose and Insulin Response in Nonobese Adults. Journal of the Endocrine Society , 3 (3), 643–654.

Investigating the loss of postmenopausal protection from cardiovascular disease in women with type 1 diabetes

On average, women have a lower risk of developing heart disease compared to men. However, research has shown that this protection is lost in women with type 1 diabetes. The process of menopause increases rates of heart disease in women, but it is not known how menopause affects women with type 1 diabetes in regard to risk for developing heart disease. In a study published this year, Dr. Snell-Bergeon found that menopause increased risk markers for heart disease in women with type 1 diabetes more than women without diabetes.

Research has led to improved treatments and significant gains in life expectancy for people with diabetes and, as a result, many more women are reaching the age of menopause. Future research is needed to address prevention and treatment options.

Keshawarz, A., Pyle, L., Alman, A., Sassano, C., Westfeldt, E., Sippl, R., & Snell-Bergeon, J. (2019). Type 1 Diabetes Accelerates Progression of Coronary Artery Calcium Over the Menopausal Transition: The CACTI Study. Diabetes Care , 42 (12), 2315–2321.

Identification of a potential therapy for diabetic neuropathy related to type 1 and type 2 diabetes

Diabetic neuropathy is a type of nerve damage that is one of the most common complications affecting people with diabetes. For some, neuropathy can be mild, but for others, it can be painful and debilitating. Additionally, neuropathy can affect the spinal cord and the brain. Effective clinical treatments for neuropathy are currently lacking. Recently, Dr. Calcutt reported results of a new potential therapy that could bring hope to the millions of people living with diabetic neuropathy. His study found that a molecule currently in clinical trials for the treatment of depression may be valuable for diabetic neuropathy, particularly the type affecting the brain.

Because the molecule is already in clinical trials, there is the potential that it can benefit patients sooner than later.

Jolivalt, C. G., Marquez, A., Quach, D., Navarro Diaz, M. C., Anaya, C., Kifle, B., Muttalib, N., Sanchez, G., Guernsey, L., Hefferan, M., Smith, D. R., Fernyhough, P., Johe, K., & Calcutt, N. A. (2019). Amelioration of Both Central and Peripheral Neuropathy in Mouse Models of Type 1 and Type 2 Diabetes by the Neurogenic Molecule NSI-189. Diabetes , 68 (11), 2143–2154.

ADA-funded researcher studying link between ageing and type 2 diabetes

One of the most important risk factors for developing type 2 diabetes is age. As a person gets older, their risk for developing type 2 diabetes increases. Scientists want to better understand the relationship between ageing and diabetes in order to determine out how to best prevent and treat type 2 diabetes. ADA-funded researcher Rafael Arrojo e Drigo, PhD, from the Salk Institute for Biological Studies, is one of those scientists working hard to solve this puzzle.

Recently, Dr. Arrojo e Drigo published results from his research in the journal Cell Metabolism . The goal of this specific study was to use high-powered microscopes and novel cellular imaging tools to determine the ‘age’ of different cells that reside in organs that control glucose levels, including the brain, liver and pancreas. He found that, in mice, the cells that make insulin in the pancreas – called beta-cells – were a mosaic of both old and young cells. Some beta-cells appeared to be as old as the animal itself, and some were determined to be much younger, indicating they recently underwent cell division.

Insufficient insulin production by beta-cells is known to be a cause of type 2 diabetes. One reason for this is thought to be fewer numbers of functional beta-cells. Dr. Arrojo e Drigo believes that people with or at risk for diabetes may have fewer ‘young’ beta-cells, which are likely to function better than old ones. Alternatively, if we can figure out how to induce the production of younger, high-functioning beta-cells in the pancreas, it could be a potential treatment for people with diabetes.

In the near future, Dr. Arrojo e Drigo’s wants to figure out how to apply this research to humans. “The next step is to look for molecular or morphological features that would allow us to distinguish a young cell from and old cell,” Dr. Arrojo e Drigo said.

The results from this research are expected to provide a unique insight into the life-cycle of beta-cells and pave the way to novel therapeutic avenues for type 2 diabetes.

Watch a video of Dr. Arrojo e Drigo explaining his research!

Arrojo E Drigo, R. , Lev-Ram, V., Tyagi, S., Ramachandra, R., Deerinck, T., Bushong, E., … Hetzer, M. W. (2019). Age Mosaicism across Multiple Scales in Adult Tissues. Cell Metabolism , 30 (2), 343-351.e3.

Researcher identifies potential underlying cause of type 1 diabetes

Type 1 diabetes occurs when the immune system mistakenly recognizes insulin-producing beta-cells as foreign and attacks them. The result is insulin deficiency due to the destruction of the beta-cells. Thankfully, this previously life-threatening condition can be managed through glucose monitoring and insulin administration. Still, therapies designed to address the underlying immunological cause of type 1 diabetes remain unavailable.

Conventional approaches have focused on suppressing the immune system, which has serious side effects and has been mostly unsuccessful. The American Diabetes Association recently awarded a grant to Dr. Kenneth Brayman, who proposed to take a different approach. What if instead of suppressing the whole immune system, we boost regulatory aspects that already exist in the system, thereby reigning in inappropriate immune cell activation and preventing beta-cell destruction? His idea focused on a molecule called immunoglobulin M (IgM), which is responsible for limiting inflammation and regulating immune cell development.

In a paper published in the journal Diabetes , Dr. Brayman and a team of researchers reported exciting findings related to this approach. They found that supplementing IgM obtained from healthy mice into mice with type 1 diabetes selectively reduced the amount of autoreactive immune cells known to target beta-cells for destruction. Amazingly, this resulted in reversal of new-onset diabetes. Importantly, the authors of the study determined this therapy is translatable to humans. IgM isolated from healthy human donors also prevented the development of type 1 diabetes in a humanized mouse model of type 1 diabetes.

The scientists tweaked the original experiment by isolating IgM from mice prone to developing type 1 diabetes, but before it actually occurred. When mice with newly onset diabetes were supplemented with this IgM, their diabetes was not reversed. This finding suggests that in type 1 diabetes, IgM loses its capacity to serve as a regulator of immune cells, which may be contribute to the underlying cause of the disease.

Future studies will determine exactly how IgM changes its regulatory properties to enable diabetes development. Identification of the most biologically optimal IgM will facilitate transition to clinical applications of IgM as a potential therapeutic for people with type 1 diabetes.    Wilson, C. S., Chhabra, P., Marshall, A. F., Morr, C. V., Stocks, B. T., Hoopes, E. M., Bonami, R.H., Poffenberger, G., Brayman, K.L. , Moore, D. J. (2018). Healthy Donor Polyclonal IgM’s Diminish B Lymphocyte Autoreactivity, Enhance Treg Generation, and Reverse T1D in NOD Mice. Diabetes .

ADA-funded researcher designs community program to help all people tackle diabetes

Diabetes self-management and support programs are important adjuncts to traditional physician directed treatment. These community-based programs aim to give people with diabetes the knowledge and skills necessary to effectively self-manage their condition. While several clinical trials have demonstrated the value of diabetes self-management programs in terms of improving glucose control and reducing health-care costs, whether this also occurs in implemented programs outside a controlled setting is unclear, particularly in socially and economically disadvantaged groups.

Lack of infrastructure and manpower are often cited as barriers to implementation of these programs in socioeconomically disadvantaged communities. ADA-funded researcher Dr. Briana Mezuk addressed this challenge in a study recently published in The Diabetes Educator . Dr. Mezuk partnered with the YMCA to evaluate the impact of the Diabetes Control Program in Richmond, Virginia. This community-academic partnership enabled both implementation and evaluation of the Diabetes Control Program in socially disadvantaged communities, who are at higher risk for developing diabetes and the complications that accompany it.

Dr. Mezuk had two primary research questions: (1) What is the geographic and demographic reach of the program? and (2) Is the program effective at improving diabetes management and health outcomes in participants? Over a 12-week study period, Dr. Mezuk found that there was broad geographic and demographic participation in the program. The program had participants from urban, suburban and rural areas, most of which came from lower-income zip codes. HbA1C, mental health and self-management behaviors all improved in people taking part in the Greater Richmond Diabetes Control Program. Results from this study demonstrate the value of diabetes self-management programs and their potential to broadly improve health outcomes in socioeconomically diverse communities. Potential exists for community-based programs to address the widespread issue of outcome disparities related to diabetes.  Mezuk, B. , Thornton, W., Sealy-Jefferson, S., Montgomery, J., Smith, J., Lexima, E., … Concha, J. B. (2018). Successfully Managing Diabetes in a Community Setting: Evidence from the YMCA of Greater Richmond Diabetes Control Program. The Diabetes Educator , 44 (4), 383–394.

Using incentives to stimulate behavior changes in youth at risk for developing diabetes

Once referred to as ‘adult-onset diabetes’, incidence of type 2 diabetes is now rapidly increasing in America’s youth. Unfortunately, children often do not have the ability to understand how everyday choices impact their health. Could there be a way to change a child’s eating behaviors? Davene Wright, PhD, of Seattle Children’s Hospital was granted an Innovative Clinical or Translational Science award to determine whether using incentives, directed by parents, can improve behaviors related to diabetes risk. A study published this year in Preventive Medicine Reports outlined what incentives were most desirable and feasible to implement. A key finding was that incentives should be tied to behavior changes and not to changes in body-weight.

With this information in hand, Dr. Wright now wants to see if incentives do indeed change a child’s eating habits and risk for developing type 2 diabetes. She is also planning to test whether an incentive program can improve behavior related to diabetes management in youth with type 1 diabetes. Jacob-Files, E., Powell, J., & Wright, D. R. (2018). Exploring parent attitudes around using incentives to promote engagement in family-based weight management programs. Preventive Medicine Reports , 10 , 278–284.

Determining the genetic risk for gestational diabetes

Research has identified more than 100 genetic variants linked to risk for developing type 2 diabetes in humans. However, the extent to which these same genetic variants might affect a woman’s probability for getting gestational diabetes has not been investigated.

Pathway to Stop Diabetes ® Accelerator awardee Marie-France Hivert, MD, of Harvard University set out to answer this critical question. Dr. Hivert found that indeed genetic determinants of type 2 diabetes outside of pregnancy are also strong risk factors for gestational diabetes. This study was published in the journal Diabetes .

The implications? Because of this finding, doctors in the clinic may soon be able to identify women at risk for getting gestational diabetes and take proactive steps to prevent it. Powe, C. E., Nodzenski, M., Talbot, O., Allard, C., Briggs, C., Leya, M. V., … Hivert, M.-F. (2018). Genetic Determinants of Glycemic Traits and the Risk of Gestational Diabetes Mellitus. Diabetes , 67 (12), 2703–2709.

Research Projects

The Division of Diabetes Translation (DDT) conducts and supports studies, often in collaboration with partners, to develop and apply sound science to reduce the burden of diabetes and to address the research needs of DDT programs and the diabetes community.

Analyses from various studies, such as LEAD and SEARCH, to help improve diabetes surveillance and guide decision-making.

Research, including the Diabetes Prevention Program Outcome Study (DPPOS), that evaluates the success of diabetes interventions and strategies.

Reviews of the effect of type 2 diabetes-related health policies on various populations, such as the NEXT-D2 study.

Collection of the most recent publications and access to archived ones.

• US Diabetes Surveillance System
• Chronic Kidney Disease Surveillance System
• Vision and Eye Health Surveillance System
• Diabetes State Burden Toolkit
• Diabetes Prevention Impact Toolkit

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• Chronic Kidney Disease
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• Heart Disease and Stroke
• Overweight & Obesity

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Clinical Trials

Displaying 175 studies

The purpose of this study is to identify immune mediated diabetes in patients treated with PD 1 inhibitors, and characterizing its clinical course, laboratory features and possible risk factors. 

The purpose of this study is to determine the longitudinal effect of diabetes-associated variation in TCF7L2 on a-cell function and the contribution of a-cell function to longitudinal glucose tolerance and EGP in non-diabetic subjects.  

The purpose of this study is to identify potentially modifiable barriers to hyperglycemia management in hospitalized diabetic patients. Both general hospitalized diabetic patients and first time renal transplant patients will be studied.

The purpose of this study is to establish a biobank of blood samples to study the relationship between diabetes mellitus and other pancreatic conditions.

The objective of this study is to gain understanding of how patients with diabetes mellitus (DM) dispose of hazardous waste items (e.g., needles, used glucometer strips, unused insulin) with the goal of providing education regarding safe practices

The goal of this study is to understand how and why insulin resistant individuals respond differently to exercise as compared with insulin sensitive individuals at the skeletal muscle and gene expression level.

The purpose of this study is to compare the effectiveness and safety of an automated insulin delivery (AID) study system using a Model Predictive Control (MPC) algorithm versus Sensor Augmented Pump (SAP) (which may or may not include PLGS; to be referred to as SAP) therapy in people with type 1 diabetes. A Pilot Phase involving up to 7 participants using the study system for 10-14 days will be conducted prior to the crossover trial.

The purpose of this study is to determine if a 6 month supply (1 meal//day) of healthy food choices readily available in the patients home and self management training including understanding how foods impact diabetes, improved food choices and how to prepare those foods, will improve glucose control, and if there will be lasting behavior change modification after the program.

The objectives of this study are to determine whether the InPen® alters the glycemic control and variability in adolescents and emerging adults with type 1 diabetes, and to determine if InPen® use alters the perceived burden of diabetes cares, diabetes distress scores, transition readiness scores, and parental experience of child illness scale (11-13).

The goal of this study is to determine the role of postprandial glucagon suppression and insulin secretion in the progression of glucose intolerance in people with diabetes-associated variation in TCF7L2.

The purpose of this study is to use the well-characterized Diabetes Control and Complications Trial (DCCT) cohort of 1,400 patients to determine the long-term effects of prior separation of glycemic levels on micro- and macrovascular outcomes.

The purpose of this study is to establish a cohort of new onset diabetes patients.

Patients age 25 to 75 who are in the care of one of the primary care physicians at Mayo Clinic in Jacksonville, Florida or Montage Health in Monterey, California and have a recent HbA1c in the range of 7.5% to 13% will be prospectively identified and eligible for participation in this randomized, crossover clinical trial examining the effect of medically tailored meal delivery on glycemic control. Eligible patients who sign informed consent will be randomized in a 1:1 fashion to treatment sequence AB or treatment sequence BA.  In the first study phase, participants randomized to sequence AB will receive 3 ...

The purpose of this study is to determine if patient’s own Continuous Glucose Monitoring (CGMs) worn in the non-ICU hospital setting have adequate accuracy for blood glucose monitoring when compared to point-of-care capillary glucose measurement, and to determine if alerts given by CGMs worn in the non-ICU hospital would prevent episodes of hyperglycemia and hypoglycemia.

The obectives of this study are to identify insulin resistance (IR)-specific chromatin signatures in mature adipocytes and myotubes, and to identify IR-specific chromatin signatures in progenitor cells from adipose tissue (AT) and skeletal muscle (SM).

The purpose of this study is to demonstrate that a morning injection of Toujeo compared to Lantus will provide better glycemic control, as shown  by Continuous Glucose Monitoring (CGM), in adult patients with type 1 diabetes mellitus.

The purpose of this study is to identify changes to the metabolome (range of chemicals produced in the body) and microbiome (intestine microbe environment) that are unique to Roux-en-Y gastric bypass surgery and assess the associated effect on the metabolism of patients with type 2 diabetes.

The primary aim of this study is to compare the outcome measures of adult ECH type 2 diabetes patients who were referred to onsite pharmacist services for management of their diabetes to similar patients who were not referred for pharmacy service management of their diabetes. A secondary aim of the study is to assess the Kasson providers’ satisfaction level and estimated pharmacy service referral frequency to their patients. A tertiary aim of the study is to compare the hospitalization rates of type 2 diabetes rates who were referred to onsite pharmacist services for management of their diabetes to similar patients ...

To explore the feasibility of conducting a family centered wellness coaching program for patients at high risk for developing diabetes, in a primary care setting.

To determine engagement patterns.

To describe characteristics of families who are likely to participate.

To identify barriers/limitations to family centered wellness coaching.

To assess whether a family centered 8 week wellness coaching intervention for primary care patients at high risk for diabetes will improve self-care behaviors as measured by self-reported changes in physical activity level and food choices.

This study is being done to understand metformin's mechanisms of action regarding glucose production, protein metabolism, and mitochondrial function.

The purpose of this study is to assess the effectiveness of Revita® DMR for improving HbA1c to ≤ 7% without the need of insulin in subjects with T2D compared to sham and to assess the effectiveness of DMR versus Sham on improvement in Glycemic, Hepatic and Cardiovascular endpoints.

The purpose of this study is to identify risk factors for ICI associated diabetes mellitus and to assess the severity and natural course of this immune related adverse effect.

The purpose of this study is to evaluate the impact of a digital storytelling intervention derived through a community-based participatory research (CBPR) approach on type 2 diabetes mellitus (T2D) outcomes among Hispanic adults with poorly controlled type 2 diabetes mellitus (T2D) in primary care settings through a randomized clinical trial.

The purpose of  this study is to learn more about if the medication, Entresto, could help the function of the heart and kidneys.

The purpose of this study is to assess the impact of a whole food plant-based diet on blood sugar control in diabetic patients versus a control group on the American Diabetics Association diet before having a total hip, knee, or shoulder replacement surgery.

The purpose of this study is to evaluate 6 weeks of home use of the Control-IQ automated insulin delivery system in individuals with type 2 diabetes.

This study will evaluate whether bile acids are able to increase insulin sensitivity and enhance glycemic control in T2DM patients, as well as exploring the mechanisms that enhance glycemic control. These observations will provide the preliminary data for proposing future therapeutic as well as further mechanistic studies of the role of bile acids in the control of glycemia in T2DM.

The purpose of this study is to determine if Inpatient Stress Hyperglycemia is an indicator of future risk of developing type 2 Diabetes Mellitus.

The purpose of this study is to collect blood samples for biomarker assessment in type 1 diabetes prior to and at specific time points during closed loop control.

The purpose of this study is to assess the effectiveness of a digital storytelling intervention derived through a community based participatory research (CBPR) approach on self-management of type 2 diabetes (T2D) among Somali adults. 

The GRADE Study is a pragmatic, unmasked clinical trial that will compare commonly used diabetes medications, when combined with metformin, on glycemia-lowering effectiveness and patient-centered outcomes.

Hypothesis: Increased contact with the diabetes care team throughout pregnancy will lead to improved glucose control during pregnancy.

The overall goal of this proposal is to determine the effects of acute hyperglycemia and its modulation by Glucagon-like Peptide-1 (GLP-1) on myocardial perfusion in type 2 diabetes (DM). This study plan utilizes myocardial contrast echocardiography (MCE) to explore a) the effects of acute hyperglycemia on myocardial perfusion and coronary flow reserve in individuals with and without DM; and b) the effects of GLP-1 on myocardial perfusion and coronary flow reserve during euglycemia and hyperglycemia in DM. The investigators will recruit individuals with and without DM matched for age, gender and degree of obesity. The investigators will measure myocardial perfusion ...

The purpose of this study is to test the hypothesis that patients with T2DM will have greater deterioration in BMSi and in cortical porosity over 3 yrs as compared to sex- and age-matched non-diabetic controls; and identify the circulating hormonal (e.g., estradiol [E2], testosterone [T]) and biochemical (e.g., bone turnover markers, AGEs) determinants of changes in these key parameters of bone quality, and evaluate the possible relationship between existing diabetic complications and skeletal deterioration over time in the T2DM patients.

The purpose of this study is to serve as a comparator group to a group of patients that will be managed with AP for varying periods of time during pregnancy.

The purpose of this study is to determine the effect of endogenous GLP-1 secretion on islet function in people with Typr 2 Diabetes Mellitus (T2DM).

GLP-1 is a hormone made by the body that promotes the production of insulin in response to eating. However, there is increasing evidence that this hormone might help support the body’s ability to produce insulin when diabetes develops. 

The purpose of this study is to assess whether psyllium is more effective in lowering fasting blood sugar and HbA1c, and to evaluate the effect of psyllium compared to wheat dextrin on the following laboratory markers:  LDL-C, inflammatory markers such as ceramides and hsCRP, and branch chain amino acids which predict Diabetes Mellitus (DM).

The purpose of this study is to evaluate glucose variability in patients with type 1 diabetes (T1D) and insulin antibodies, to evaluate the clinical significance of insulin antibodies, and to establish an in vitro assay that would detect antibodies to insulin and insulin analogs.

This clinical trial will identify exercise-related and emotional stress related effects on glycemic control in patients with type 1 diabetes using sensor-augmented pump (SAP) therapy.

This study will test the efficacy of BKR-017 (colon-targeted 500 mg butyrate tablets) on insulin sensitivity, glucose control and triglycerides in type-1 diabetes subjects.

The purpose of this research is to test the safety and effectiveness of the interoperable Artificial Pancreas System Smartphone App (iAPS) in managing blood sugars in pregnant patients with type 1 diabetes.

This observational study is conducted to determine how the duodenal layer thicknesses (mucosa, submucosa, and muscularis) vary with several factors in patients with and without type 2 diabetes.

This mixed methods study aims to answer the question: "What is the work of being a patient with type 2 diabetes mellitus?" .

The objective of this study is to evaluate the EWIS in patients with type 1 diabetes on insulin pump therapy.

This study is a multi-center, non-randomized, prospective single arm study with type 1 patients with diabetes on insulin pump therapy with Continuous Glucose Monitoring (CGM).

A total of up to 300 subjects will be enrolled at up to 20 investigational centers in the US in order to have 240 subjects meeting eligibility criteria. Each subject will wear their own MiniMed™ 670G insulin system. Each subject will be given 12 infusion sets to wear (each infusion set for at least 174 hours, or ...

The purpose of this study is to use the USS Virginia Closed-Loop system for overnight insulin delivery in adults with Type 1 Diabetes (T1DM) in an outpatient setting to evaluate the system's ability to significantly improve blood glucose levels. This protocol will test the feasibility of "bedside" closed-loop control - an approach comprised of standard sensor-augmented pump therapy during the day using off-the-shelf devices and overnight closed-loop control using experimental devices in an outpatient setting. The rationale for this study is as follows: we anticipate that closed-loop control may ultimately be adopted by patients with T1DM in a selective manner. ...

The purpose of this study is to assess penile length pre- and post-completion of RestoreX® traction therapy compared to control groups (no treatment) among men with type II diabetes.

The overall objective of this study is to perform baseline and repeat assessments over time of the metabolic and immunologic status of individuals at risk for type 1 diabetes (T1D) to:

• characterize their risk for developing T1D and identify subjects eligible for prevention trials;
• describe the pathogenic evolution of T1D; and
• increase the understanding of the pathogenic factors involved in the development of T1D.

Our goal in this pilot study is to test and develop a novel method that will accurately measure, in vivo, glucagon kinetics in healthy humans and generate preliminary data in type 1 diabetes (T1DM) subjects under overnight fasted conditions.

This trial is a multi-center, adaptive, randomized, double-blind, placebo- and active- controlled, parallel group, phase 2 study in subjects with Type 2 Diabetes Mellitus to evaluate the effect of TTP399 on HbA1c following administration for 6 months.

The purpose of this study is to find the inheritable changes in genetic makeup that are related to the development of type 2 diabetes in Latino families.

The objective of this early feasibility study is to assess the feasibility and preliminary safety of the Endogenex Divice for endoscopic duodenal mucosal regeneration in patients with type 2 diabetes (T2D) inadequately controlled on 2-3 non-insulin glucose-lowering medications. 

The purpose of this research is to create a single registry for type 1 diabetes at Mayo Rochester and affiliated Mayo sites.

The purpose of this study is to evaluate if breathing pure oxygen overnight affects insulin sensitivity in participants with diabetes.   

The purpose of this study is to determine the impact of patient decision aids compared to usual care on measures of patient involvement in decision-making, diabetes care processes, medication adherence, glycemic and cardiovascular risk factor control, and use of resources in nonurban practices in the Midwestern United States.

The purpose of this study is to assess a novel informatics approach that incorporates the use of patient’s diabetes self-care data into the design and delivery of individualized education interventions to improve diabetes control.

The purpose of this study is to assess the glycemic variability in patients with complex diabetes admitted in the hospital using a glycemic sensor.

The study purpose is to understand patients’ with the diagnosis of Diabetes Mellitus type 1 or 2 perception of the care they receive in the Diabetes clinic or Diabetes technology clinic at Mayo Clinic and to explore and to identify the healthcare system components patients consider important to be part of the comprehensive regenerative care in the clinical setting.

However, before we can implement structural changes or design interventions to promote comprehensive regenerative care in clinical practice, we first need to characterize those regenerative practices occurring today, patients expectations, perceptions and experiences about comprehensive regenerative care and determine the ...

The purpose of this study is to estimate the risk of diabetes related complications after total pancreatectomy.  We will contact long term survivors after total pancreatectomy to obtain data regarding diabetes related end organ complications.

The multi-purpose of this study is to examine the effectiveness of “InsulisiteGuider” in patients with type 1 diabetes (T1D) through a two-group randomized controlled trial, to characterize the RNA biomarkers in skin epithelial cells isolated from the continuous subcutaneous insulin infusion (CSII) cannulas from T1D patients, and to characterize RNA biomarkers in the blood and saliva of TID patients.

The purpose of this study is to understand nighttime glucose regulation in humans and find if the pattern is different in people with Type 2 diabetes

Can QBSAfe be implemented in a clinical practice setting and improve quality of life, reduce treatment burden and hypoglycemia among older, complex patients with type 2 diabetes?

Questionnaire administered to diabetic patients in primary care practice (La Crosse Mayo Family Medicine Residency /Family Health Clinic) to assess patient’s diabetic knowledge. Retrospective chart review will also be done to assess objective diabetic control based on most recent hemoglobin A1c.    

Exendin-(9,39) has been shown to have effects on beta-cell function, and after gastric bypass, to accelerate gastrointestinal transit. - infused at rates of 300pmol/kg/min. Given that gastrointestinal transit is typically delayed by Glucagon-Like Peptide-1 (GLP-1) and also that this hormone causes decreased food intake through increased satiation, it is reasonable to expect an effect of Exendin-9,39 on appetite. This may help explain the effects of gastric bypass on food intake. To examine the effect of Exendin on food intake we propose a dose-response study to determine whether the compound has effects in a dose-dependent fashion. We will examine the presence ...

The purpose of this study is to evaluate the dose-dependent effects of TAK-954 on gastric emptying time of solids in participants with diabetic or idiopathic gastroparesis assessed by scintigraphy.

This study is being done to determine the roles that several molecules play in the repair of injured cells that line your blood vessels.

This purpose of this study is to determine if activation of a person's immune system in the small intestine could be a contributing cause of Type 1 Diabetes.

The purpose of this project is to collect data over the first year of clinical use of the FDA approved 670G closed loop insulin delivery system among patients with type 1 diabetes. The goal is to evaluate how this newly approved system impacts both clinical and patient-reported outcomes.

It is unknown how patient preferences and values impact the comparative effectiveness of second-line medications for Type 2 diabetes (T2D). The purpose of this study is to elicit patient preferences toward various treatment outcomes (e.g., hospitalization, kidney disease) using a participatory ranking exercise, use these rankings to generate individually weighted composite outcomes, and estimate patient-centered treatment effects of four different second-line T2D medications that reflect the patient's value for each outcome. 

The purpose of this mixed-methods study is to deploy the tenets of Health and Wellness Coaching (HWC) through a program called BeWell360 model , tailored to the needs of Healthcare Workers (HCWs) as patients living with poorly-controlled Type 2 Diabetes (T2D). The objective of this study is to pilot-test this novel, scalable, and sustainable BeWell360 model that is embedded and integrated as part of primary care for Mayo Clinic Employees within Mayo Clinic Florida who are identified as patients li)ving with poorly-controlled T2D. 

The primary goal of this study protocol is to determine the candidate ratio of pramlintide and insulin co-infusion in individuals with type 1 diabetes (T1DM) to enable stable glucose control during the overnight post-absorptive and in the postprandial periods.

The purpose of this trial is to assess the performance of an Artificial Pancreas (AP) device using the Portable Artificial Pancreas System (pAPS) platform for subjects with type 1 diabetes using an insulin pump and rapid acting insulin. This proposed study is designed to compare closed-loop control with or without optimization of initialization parameters related to basal insulin infusion rates and insulin to carbohydrate (I:C) ratios for meals and snacks. The study consists of an evaluation of the Artificial Pancreas device system during two 24-27.5-hour closed-loop phases in an outpatient/hotel environment. Prior to the closed-loop phases, each subject will undergo ...

The study is being done to find out if low blood sugar (hypoglycemia) can be reduced in people with type 1 diabetes (T1D) 65 years and older with use of automated insulin delivery (AID) system.

The device systems used in this study are approved by the Food and Drug Administration (FDA) for diabetes management. We will be collecting data about how they are used, how well they work, and how safe they are.

This study aims to identify an early stage biomarker for type 1 diabetes. In vitro evidence identified a significant enrichment of the chemokine CXCL10 in β-cell derived EXO upon exposure to diabetogenic pro-inflammatory cytokines. The study also aims to test protocols for efficient isolation of plasma-derived EXO from small volumes of sample, develop an assay for the sensitive detection of CXCL10 in plasma-derived EXO, and characterization of plasma-derived EXO through assessment of concentration, size, and content (proteomics).

The study is designed to understand the confidence and competence level of patients with type 1 diabetes mellitus in their ability to make changes to their insulin pump.

The investigators will determine whether people with high muscle mitochondrial capacity produce higher amount of reactive oxygen species (ROS) on consuming high fat /high glycemic diet and thus exhibit elevated cellular oxidative damage. The investigators previously found that Asian Indian immigrants have high mitochondrial capacity in spite of severe insulin resistance. Somalians are another new immigrant population with rapidly increasing prevalence of diabetes. Both of these groups traditionally consume low caloric density diets, and the investigators hypothesize that when these groups are exposed to high-calorie Western diets, they exhibit increased oxidative stress, oxidative damage, and insulin resistance. The investigators will ...

The purpose of this study is to gather preliminary data to better understand acute effects of exercise on glucose metabolism. We will address if subjects with Type 1 Diabetes (T1D) are more insulin sensitive during and following a short bout of exercise compared to healthy controls. We will also determine insulin dependent and insulin independent effects on exercise in people with and without type 1 diabetes.

The purpose of this study is to retrospectively and prospectively compare maternal and fetal/newborn clinical outcomes in age-matched pregnant patients with T1D and healthy controls and to assess the relationship between glycemic variability and pregnancy outcomes in the current era.

The purpose of this research is to find out how genetic variations in GLP1R, alters insulin secretion, in the fasting state and when blood sugars levels are elevated. Results from this study may help us identify therapies to prevent or reverse type 2 diabetes mellitus.

The objective for thisstudy is to characterize the impact of glycemic excursions on cognition in Type 1 Diabetes (T1D) and determine mediators and moderators of this relationship. This study will allow us to determine how glycemic excursions impact cognition, as well as to identify mediators and moderators of this relationship that could lead to novel interventions.

The purpose of this study is to compare the effectiveness and safety of an automated insulin delivery (AID) system using a model predictive control (MPC) algorithm versus Sensor-Augmented Pump/Predictive Low Glucose Suspend (SAP/PLGS) therapy with different stress assessments over a 4-week period.

Muscle insulin resistance is a hallmark of upper body obesity (UBO) and Type 2 diabetes (T2DM). It is unknown whether muscle free fatty acid (FFA) availability or intramyocellular fatty acid trafficking is responsible for muscle insulin resistance, although it has been shown that raising FFA with Intralipid can cause muscle insulin resistance within 4 hours. We do not understand to what extent the incorporation of FFA into ceramides or diacylglycerols (DG) affect insulin signaling and muscle glucose uptake. We propose to alter the profile and concentrations of FFA of healthy, non-obese adults using an overnight, intra-duodenal palm oil infusion vs. ...

The objectives of this study are to identify circulating extracellular vesicle (EV)-derived protein and RNA signatures associated with Type 2 Diabetes (T2D), and to identify changes in circulating EV cargo in patients whose T2D resolves after sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB).

This research study is being done to develop educational materials that will help patients and clinicians talk about diabetes treatment and management options.

The purpose of this study is to assess the effectiveness and safety of treatment with various dose levels of TAK-906 in adult participants with gastroparesis compared with placebo during 12 weeks of treatment.

To understand why patients with indigestion with or without diabetes have gastrointestinal symptoms and in particular to understand where the symptoms are related to increased sensitivity to nutrients.

The purpose of this study is to evaluate whether or not a 6 month supply (1 meal//day) of healthy food choices readily available in the patient's home and self management training including understanding of how foods impact diabetes, improved food choices and how to prepare those foods, improve glucose control.  In addition, it will evaluate whether or not there will be lasting behavior change modification after the program.

To determine if the EndoBarrier safely and effectively improves glycemic control in obese subjects with type 2 diabetes.

The primary objective of this study is to determine if continuous glucose monitoring (CGM) can reduce hypoglycemia and improve quality of life in older adults with type 1 diabetes (T1D).

The purpose of this study is to compare the rate of progression from prediabetes at 4 months to frank diabetes at 12 months (as defined by increase in HbA1C or fasting BS to diabetic range based on the ADA criteria) after transplantation in kidney transplant recipients on Exenatide SR + SOC vs. standard-of-care alone.

The purpose of this study evaluates a subset of people with isolated Impaired Fasting Glucose with Normal Glucose Tolerance (i.e., IFG/NGT) believed to have normal β-cell function in response to a glucose challenge, suggesting that – at least in this subset of prediabetes – fasting glucose is regulated independently of glucose in the postprandial period. To some extent this is borne out by genetic association studies which have identified loci that affect fasting glucose but not glucose tolerance and vice-versa.

The purpose of this study is to learn more about how the body stores dietary fat. Medical research has shown that fat stored in different parts of the body can affect the risk for diabetes, heart disease and other major health conditions.

The purpose of this study is to see why the ability of fat cells to respond to insulin is different depending on body shape and how fat tissue inflammation is involved.

The purpose of this study is to determine the mechanism(s) by which common bariatric surgical procedures alter carbohydrate metabolism. Understanding these mechanisms may ultimately lead to the development of new interventions for the prevention and treatment of type 2 diabetes and obesity.

Increased accumulation of fat into the muscles is associated with what is called insulin-resistant state, which is a pre-diabetic state. The purpose of this research is to find out how fat circulating in the blood following fat consumption is taken up by the muscles in healthy people as well as people that are insulin-resistant. The investigators are specifically interested in how a hormone called insulin is involved in this process. Findings from this research will contribute to our understanding of why insulin-resistant people have increased accumulation of fat in their muscles, and ultimately help to design appropriate interventions to prevent ...

The purpose of this study is to evaluate the effects of improving glycemic control, and/or reducing glycemic variability on gastric emptying, intestinal barrier function, autonomic nerve functions, and epigenetic changes in subjects with type 1 diabetes mellitus (T1DM) and  type 2 diabetes mellitus (T2DM) who are switched to intensive insulin therapy as part of clinical practice.

This study is designed to compare an intensive lifestyle and activity coaching program ("Sessions") to usual care for diabetic patients who are sedentary. The question to be answered is whether the Sessions program improves clinical or patient centric outcomes. Recruitment is through invitiation only.

This is a study to evaluate a new Point of Care test for blood glucose monitoring.

Women with gestational diabetes mellitus (GDM) are likely to have insulin resistance that persists long after pregnancy, resulting in greater risk of developing type 2 diabetes mellitus (T2DM). The study will compare women with and without a previous diagnosis of GDM to determine if women with a history of GDM have abnormal fatty acid metabolism, specifically impaired adipose tissue lipolysis. The study will aim to determine whether women with a history of GDM have impaired pancreatic β-cell function. The study will determine whether women with a history of GDM have tissue specific defects in insulin action, and also identify the effect of a ...

The purpose of this study is to determine the metabolic effects of Colesevelam, particularly for the ability to lower blood sugar after a meal in type 2 diabetics, in order to develop a better understanding of it's potential role in the treatment of obesity.

The purpose of this study is to test whether markers of cellular aging and the SASP are elevated in subjects with obesity and further increased in patients with obesity and Type 2 Diabetes Mellitus (T2DM) and to relate markers of cellular aging (senescence) and the SASP to skeletal parameters (DXA, HRpQCT, bone turnover markers) in each of these groups.

The purpose of this study is to determine the changes in tissue function that occur in the first year postpartum in women with and without gestational diabetes mellitus.

The Early Detection Initiative for pancreatic cancer is a multi-center randomized controlled trial to determine if algorithm-based screening in patients with new onset hyperglycemia and diabetes can result in earlier detection of pancreatic ductal adenocarcinoma.

The purpose of this study is assess the feasibility, effectiveness, and acceptability of Diabetes-REM (Rescue, Engagement, and Management), a comprehensive community paramedic (CP) program to improve diabetes self-management among adults in Southeast Minnesota (SEMN) treated for servere hypoglycemia by the Mayo Clinic Ambulance Services (MCAS).

Muscle insulin resistance is a hallmark of upper body obesity (UBO) and Type 2 diabetes (T2DM). It is unknown whether muscle free fatty acid (FFA) availability or intramyocellular fatty acid trafficking is responsible for the abnormal response to insulin. Likewise, we do not understand to what extent the incorporation of FFA into ceramides or diacylglycerols (DG) affect insulin signaling and muscle glucose uptake. We will measure muscle FFA storage into intramyocellular triglyceride, intramyocellular fatty acid trafficking, activation of the insulin signaling pathway and glucose disposal rates under both saline control (high overnight FFA) and after an overnight infusion of intravenous ...

The purpose of this study is to improve our understanding of why gastrointestinal symptoms occur in diabetes mellitus patients and identify new treatment(s) in the future.  

These symptoms are often distressing and may impair glycemic control. We do not understand how diabetes mellitus affects the GI tracy. In 45 patients undergoing sleeve gastrectomy, we plan to compare the cellular composition of circulating peripheral mononuclear cells, stomach immune cells, and interstitial cells of Cajal in the stomach. 

Muscle insulin resistance is a hallmark of upper body obesity (UBO) and Type 2 diabetes (T2DM), whereas lower body obesity (LBO) is characterized by near-normal insulin sensitivity. It is unknown whether muscle free fatty acid (FFA) availability or intramyocellular fatty acid trafficking differs between different obesity phenotypes. Likewise, we do not understand to what extent the incorporation of FFA into ceramides or diacylglycerols (DG) affect insulin signaling and muscle glucose uptake. By measuring muscle FFA storage into intramyocellular triglyceride, intramyocellular fatty acid trafficking, activation of the insulin signaling pathway and glucose disposal rates we will provide the first integrated examination ...

The goal of this study is to evaluate the presence of podocytes (special cells in the kidney that prevent protein loss) in the urine in patients with diabetes or glomerulonephritis (inflammation in the kidneys). Loss of podocyte in the urine may be an earlier sign of kidney injury (before protein loss) and the goal of this study is to evaluate the association between protein in the urine and podocytes in the urine.

The objective of the study is to assess efficacy and safety of a closed loop system (t:slim X2 with Control-IQ Technology) in a large randomized controlled trial.

Using stem cell derived intestinal epithelial cultures (enteroids) derived from obese (BMI> 30) patients and non-obese and metabolically normal patients (either post-bariatric surgery (BS) or BS-naïve with BMI < 25), dietary glucose absorption was measured. We identified that enteroids from obese patients were characterized by glucose hyper-absorption (~ 5 fold) compared to non-obese patients. Significant upregulation of major intestinal sugar transporters, including SGLT1, GLU2 and GLUT5 was responsible for hyper-absorptive phenotype and their pharmacologic inhibition significantly decreased glucose absorption. Importantly, we observed that enteroids from post-BS non-obese patients exhibited low dietary glucose absorption, indicating that altered glucose absorption ...

The purpose of this study is to evaluate the effectiveness and safety of brolucizumab vs. aflibercept in the treatment of patients with visual impairment due to diabetic macular edema (DME).

The purpose of this study is to determine if a blood test called "pancreatic polypeptide" can help distinguish between patients with diabetes mellitus with and without pancreatic cancer.

The purpose of this study is to create a prospective cohort of subjects with increased probability of being diagnosed with pancreatic cancer and then screen this cohort for pancreatic cancer

The purpose of this study is to develop a better blood test to diagnose early kidney injury in type 1 diabetes.

Although vitreous hemorrhage (VH) from proliferative diabetic retinopathy (PDR) can cause acute and dramatic vision loss for patients with diabetes, there is no current, evidence-based clinical guidance as to what treatment method is most likely to provide the best visual outcomes once intervention is desired. Intravitreous anti-vascular endothelial growth factor (anti-VEGF) therapy alone or vitrectomy combined with intraoperative PRP each provide the opportunity to stabilize or regress retinal neovascularization. However, clinical trials are lacking to elucidate the relative time frame of visual recovery or final visual outcome in prompt vitrectomy compared with initial anti-VEGF treatment. The Diabetic Retinopathy Clinical Research ...

The purpose of this study is to demonstrate feasibility of dynamic 11C-ER176 PET imaging to identify macrophage-driven immune dysregulation in gastric muscle of patients with DG. Non-invasive quantitative assessment with PET can significantly add to our diagnostic armamentarium for patients with diabetic gastroenteropathy.

What are the effects of transient insulin deprivation on brain structure, blood flow, mitochondrial function, and cognitive function in T1DM patients? What are the effects of transient insulin deprivation on circulating exosomes and metabolites in T1DM patients?

The purpose of this study is to identify novel genetic variants that predispose to Type 1 Diabetes.

The purpose of this study is to evaluate the effects of multiple dose regimens of RM-131 on vomiting episodes, stomach emptying and stomach paralysis symptoms in patients with Type 1 and Type 2 diabetes and gastroparesis.

The purpose of this study is to demonstrate the safety and effectiveness of the Hybrid Closed Loop system (HCL) in adult and pediatric patients with type 1 diabetes in the home setting. A diverse population of patients with type 1 diabetes will be studied. The study population will have a large range for duration of diabetes and glycemic control, as measured by glycosylated hemoglobin (A1C). They will be enrolled in the study regardless of their prior diabetes regimen, including using Multiple Daily Injections (MDI), Continuous Subcutaneous Insulin Infusion (CSII) or Sensor-Augmented Pump therapy (SAP)

The purpose of this study is to evaluate the safety of utilizing insulin lispro-aabc in the MiniMed™ 780G System to support product and system labeling.

The objective of the study is to assess the efficacy and safety of home use of a Control-to-Range (CTR) closed-loop (CL) system.

The purpose of this 3-month extension study (DCLP3 Extension) following a primary trial (DCLP3 or NCT03563313) to assess effectiveness and safety of a closed loop system (t:slim X2 with Control-IQ Technology) in a large randomized controlled trial.

The goal of this work is to identify an early stage biomarker for type 1 diabetes. In vitro evidence using rodent models has identified a significant enrichment of the chemokine CXCL10 in β-cell derived sEV upon exposure to diabetogenic pro-inflammatory cytokines. The aims of this project will focus on 1) testing protocols for efficient isolation of plasma-derived sEV from small volumes of sample, 2) development of an assay for the sensitive detection of CXCL10 in plasma-derived sEV, and 3) characterization of plasma-derived sEV through assessment of concentration, size, and content (proteomics). The study plans to include children that ...

The purpose of this study is to assess key characteristics of bone quality, specifically material strength and porosity, in patients who have type 2 diabetes. These patients are at an unexplained increased risk for fractures and there is an urgent need to refine clinical assessment for this risk.

This study aims to measure the percentage of time spent in hyperglycemia in patients on insulin therapy and evaluate diabetes related patient reported outcomes in kidney transplant recipients with type 2 diabetes. It also aimes to evaluate immunosuppression related patient reported outcomes in kidney transplant recipients with type 2 diabetes.

The purpose of this study is to look at how participants' daily life is affected by their heart failure. The study will also look at the change in participants' body weight. This study will compare the effect of semaglutide (a new medicine) compared to "dummy" medicine on body weight and heart failure symptoms. Participants will either get semaglutide or "dummy" medicine, which treatment participants get is decided by chance. Participants will need to take 1 injection once a week. 

The objectives of this study are to evaluate the safety of IW-9179 in patients with diabetic gastroparesis (DGP) and the effect of treatment on the cardinal symptoms of DGP.

The purpose of this study is to understand why patients with indigestion, with or without diabetes, have gastrointestinal symptoms and, in particular, to understand where the symptoms are related to increased sensitivity to nutrients.Subsequently, look at the effects of Ondansetron on these patients' symptoms.

The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, and exploratory effectiveness of nimacimab in patients with diabetic gastroparesis.

The purpose of this study is to assess the safety and tolerability of intra-arterially delivered mesenchymal stem/stromal cells (MSC) to a single kidney in one of two fixed doses at two time points in patients with progressive diabetic kidney disease. 

Diabetic kidney disease, also known as diabetic nephropathy, is the most common cause of chronic kidney disease and end-stage kidney failure requiring dialysis or kidney transplantation.  Regenerative, cell-based therapy applying MSCs holds promise to delay the progression of kidney disease in individuals with diabetes mellitus.  Our clinical trial will use MSCs processed from each study participant to test the ...

The purpose of this study is to evaluate whether or not semaglutide can slow down the growth and worsening of chronic kidney disease in people with type 2 diabetes. Participants will receive semaglutide (active medicine) or placebo ('dummy medicine'). This is known as participants' study medicine - which treatment participants get is decided by chance. Semaglutide is a medicine, doctors can prescribe in some countries for the treatment of type 2 diabetes. Participants will get the study medicine in a pen. Participants will use the pen to inject the medicine in a skin fold once a week. The study will close when ...

The purpose of this study is to prospectively assemble a cohort of subjects >50 and ≤85 years of age with New-onset Diabetes (NOD):

• Estimate the probability of pancreatic ductal adenocarcinoma (PDAC) in the NOD Cohort;
• Establish a biobank of clinically annotated biospecimens including a reference set of biospecimens from pre-symptomatic PDAC and control new-onset type 2 diabetes mellitus (DM) subjects;
• Facilitate validation of emerging tests for identifying NOD subjects at high risk for having PDAC using the reference set; and
• Provide a platform for development of an interventional protocol for early detection of sporadic PDAC ...

The study is being undertaken to understand how a gastric bypass can affect a subject's diabetes even prior to their losing significant amounts of weight. The hypothesis of this study is that increased glucagon-like peptide-1 (GLP-1) secretion explains the amelioration in insulin secretion after Roux-en-Y Gastric Bypass (RYGB) surgery.

The purpose of this study is to assess the effectiveness and safety of D-PLEX administered concomitantly over a period of 90 days (3 months)with the standard of care (SOC) IV prophylactic antibiotic treatment vs. SOC in prevention of post-cardiac surgery sternal infections.

Diabetics are at risk for invasive pneumococcal infections and are more likely to have severe outcomes with infection compared to the general population. The pneumococcal (PPSV23) vaccination is recommended for all people with type 1 diabetes, but whether the vaccine is beneficial for this population has not been established.  The purpose of this study is to determine if children with type 1 diabetes have adequate immune response to the PPSV23 vaccination and to assess factors affecting immune response through a pre and post vaccination blood sample.

The primary purpose of this study is to prospectively assess symptoms of bloating (severity, prevalence) in patients with diabetic gastroparesis.

The purpose of this study is to track the treatment burden experienced by patients living with Type 2 Diabetes Mellitus (T2DM) experience as they work to manage their illness in the context of social distancing measures. 

To promote social distancing during the COVID-19 pandemic, health care institutions around the world have rapidly expanded their use of telemedicine to replace in-office appointments where possible.1 For patients with diabetes, who spend considerable time and energy engaging with various components of the health care system,2,3 this unexpected and abrupt transition to virtual health care may signal significant changes to ...

The purpose of this study is to collect device data to assist in the development of a Personalized Closed Loop (PCL) system.

Assessment of glucose metabolism and liver fat after 12 week dietary intervention in pre diabetes subjects. Subjects will be randomized to either high fat (olive oil supplemented),high carb/high fiber (beans supplemented) and high carb/low fiber diets. Glucose metabolism will be assessed by labeled oral glucose tolerance test and liver fat by magnetic resonance spectroscopy pre randomization and at 8 and 12 week after starting dietary intervention.

To study the effect of an ileocolonic formulation of ox bile extract on insulin sensitivity, postprandial glycemia and incretin levels, gastric emptying, body weight and fasting serum FGF-19 (fibroblast growth factor) levels in overweight or obese type 2 diabetic subjects on therapy with DPP4 (dipeptidyl peptidase-4) inhibitors (e.g. sitagliptin) alone or in combination with metformin.

The objectives of this study are to evaluate the effectiveness and safety of PB in the treatment of patients with hereditary nephrogenic diabetes insipidus, to evaluate the effectiveness and safety of PB in polyuric patients with autosomal dominant polycystic kidney disease treated with tolvaptan, and to evaluate the effectiveness and safety of PB in polyuric patients previously treated with lithium.

The primary purpose of this study is to evaluate the impact of dapagliflozin, as compared with placebo, on heart failure, disease specific biomarkers, symptoms, health status and quality of life in patients with type 2 diabetes or prediabetes and chronic heart failure with preserved systolic function.

The purpose of this study is to look at the relationship of patient-centered education, the Electronic Medical Record (patient portal) and the use of digital photography to improve the practice of routine foot care and reduce the number of foot ulcers/wounds in patients with diabetes.

Diabetes mellitus is a common condition which is defined by persistently high blood sugar levels. This is a frequent problem that is most commonly due to type 2 diabetes. However, it is now recognized that a small portion of the population with diabetes have an underlying problem with their pancreas, such as chronic pancreatitis or pancreatic cancer, as the cause of their diabetes. Currently, there is no test to identify the small number of patients who have diabetes caused by a primary problem with their pancreas.

The goal of this study is to develop a test to distinguish these ...

The purpose of this study is to compare incidence rates of complete hard-to-heal diabetic foot ulcer healing in Medicare beneficiaries following application of the 3C Patch® plus usual care (i.e., care consistent with the International Working Group on the Diabetic Foot guidelines), tested against a historical control group of similar patients that received usual care during a randomized controlled trial.

The purpose of this study is to measure and characterize specific immune cell abnormalities found in patients who have type 1 diabetes and may or may not be on the waiting list for either a pancreas alone or a pancreas and kidney transplant.

The MADIT S-ICD trial is designed to evaluate if subjects with a prior myocardial infarction, diabetes mellitus and a relatively preserved ejection fraction of 36-50% will have a survival benefit from receiving a subcutaneous implantable cardioverter defibrillator (S-ICD) when compared to those receiving conventional medical therapy.

The purpose of this study is to demonstrate the performance of the Guardian™ Sensor (3) with an advanced algorithm in subjects age 2 - 80 years, for the span of 170 hours (7 days).

A research study to enhance clinical discussion between patients and pharmacists using a shared decision making tool for type 2 diabetes or usual care.

While the potential clinical uses of pulsed electromagnetic field therapy (PEMF) are extensive, we are focusing on the potential benefits of PEMF on vascular health. We are targeting, the pre diabetic - metabolic syndrome population, a group with high prevalence in the American population. This population tends to be overweight, low fitness, high blood pressure, high triglycerides and borderline high blood glucose.

The purpose of this study is to evaluate the safety and efficacy of oral Pyridorin 300 mg BID in reducing the rate of progression of nephropathy due to type 2 diabetes mellitus.

The purpose of this study is to evaluate the effect of Aramchol as compared to placebo on NASH resolution, fibrosis improvement and clinical outcomes related to progression of liver disease (fibrosis stages 2-3 who are overweight or obese and have prediabetes or type 2 diabetes).

The purpose of this study is to assess the effects of a nighttime rise in cortisol on the body's glucose production in type 2 diabetes.

As the global epidemic of obesity and diabetes mellitus spreads, an exponential rise in incident chronic kidney disease (CKD) complicated by end stage renal disease (ESRD) is predicted, leaving healthcare systems overwhelmed worldwide. Hence, there is urgent need for novel therapies to slow the progression of DKD and optimize the health of this patient population. The purpose of this study is to examine the effect of a supplement on mesenchymal stem cells, physical body function (or frailty), kidney function, and total clearance of senescent cells in individuals with CKD. At present, we are enrolling participants with CKD, with a subset ...

The goal of this study is to evaluate a new format for delivery of a culturally tailored digital storytelling intervention by incorporating a facilitated group discussion following the videos, for management of type II diabetes in Latino communities.

The purpose of this study is to evaluate the ability of appropriately-trained family physicians to screen for and identify Diabetic Retinopathy using retinal camera and, secondarily, to describe patients’ perception of the convenience and cost-effectiveness of retinal imaging.

To compare the effect of senolytic drugs on cellular senescence, physical ability or frailty, and adipose tissue-derived MSC functionality in patients with chronic kidney disease. Primary Objectives: To assess the efficacy of a single 3-day treatment regimen with dasatinib and quercetin (senolytic drugs) on clearing senescent adipose-derived MSC in patients with CKD. To assess the efficacy of a single 3-day treatment regimen with dasatinib and quercetin (senolytic drugs) on improving adipose-derived MSC functionality in patients with CKD. Secondary Objective: To assess the short-term effect of a single 3-day treatment regimen with dasatinib and quercetin (senolytic drugs) on ...

This protocol is being conducted to determine the mechanisms responsible for insulin resistance, obesity and type 2 diabetes.

The purpose of this study is to develop a blood test to distinguish various causes of diabetes by evaluating patients who have developed diabetes within the last 3 years, but we will also enroll a small number of patients with long-term diabetes and normal blood sugars for comparison. 

Diabetes mellitus is a common condition which is defined by persistently high blood sugar levels.  This is a frequent problem that is most commonly due to type 2 diabetes.  However, it is now recognized that a small portion of the population with diabetes have an underlying problem with their pancreas, such as ...

The primary purpose of this study is to evaluate the impact of dapagliflozin, as compared with placebo, on heart failure disease-specific biomarkers, symptoms, health status, and quality of life in patients who have type 2 diabetes and chronic heart failure with reduced systolic function.

Hypothesis: We hypothesize that patients from the Family Medicine Department at Mayo Clinic Florida who participate in RPM will have significantly reduced emergency room visits, hospitalizations, and hospital contacts.  

Aims, purpose, or objectives: In this study, we will compare the RPM group to a control group that does not receive RPM. The primary objective is to determine if there are significant group differences in emergency room visits, hospitalizations, outpatient primary care visits, outpatient specialty care visits, and hospital contacts (inbound patient portal messages and phone calls). The secondary objective is to determine if there are ...

The purpose of this research is to determine if CGM (continuous glucose monitors) used in the hospital in patients with COVID-19 and diabetes treated with insulin will be as accurate as POC (point of care) glucose monitors. Also if found to be accurate, CGM reading data will be used together with POC glucometers to dose insulin therapy.

The purpose of this study is to evaluate the effect of fenofibrate compared with placebo for prevention of diabetic retinopathy (DR) worsening or center-involved diabetic macular edema (CI-DME) with vision loss through 4 years of follow-up in participants with mild to moderately severe non-proliferative DR (NPDR) and no CI-DME at baseline.

The purpose of this study is to use multiple devices to measure blood sugar changes and the reasons for these changes in healthy and diabetic children.

The purpose of this study is gain the adolescent perspective on living with type 1 diabetes.

The purpose of this study is to assess painful diabetic peripheral neuropathy after high-frequency spinal cord stimulation.

The purpose of this study is to understand the day-to-day variability in stomach emptying and gastrointestinal (GI) transit in patients with digestive symptoms. This information will be useful for interpreting the results of stomach emptying studies in future.

The purpose of this study is to see if there is a connection between bad experiences in the patient's childhood, either by the patient or the parent, and poor blood sugar control, obesity, poor blood lipid levels, and depression in patients with type 1 diabetes.

The purpose of this study is to examine the evolution of diabetic kindey injury over an extended period in a group of subjects who previously completed a clinical trial which assessed the ability of losartan to protect the kidney from injury in early diabetic kidney disease. We will also explore the relationship between diabetic kidney disease and other diabetes complications, including neuropathy and retinopathy.

The objectives of this study are to determine if the 1-year graft success rate following DMEK performed with corneas from donors without diabetes is superior to the graft success rate with cornea donors with diabetes, to determine if the 1-year central endothelial cell loss (ECL) following DMEK performed with corneas from donors without diabetes is superior to the central ECL when corneas from donors with diabetes are used, nd to explore the relationship of severity of diabetes in the donor, as measured by eye bank-determined diabetes risk categorization scores, post-mortem hemoglobin A1c (HbA1c), and skin advanced glycation endproducts (AGE) and ...

The purpose of this study is to evaluate the effietiveness of remdesivir (RDV) in reducing the rate of of all-cause medically attended visits (MAVs; medical visits attended in person by the participant and a health care professional) or death in non-hospitalized participants with early stage coronavirus disease 2019 (COVID-19) and to evaluate the safety of RDV administered in an outpatient setting.

The purpose of this study is to determine whether short-term treatment with Fisetin reduces the rate of death and long term complications related to COVID-19.

This study (SE2030) will establish a platform of data to build the perfect stress echo test, suitable for all patients, anywhere, anytime, also quantitative and operator independent.

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Olefsky JM. Prospects for Research in Diabetes Mellitus. JAMA. 2001;285(5):628–632. doi:10.1001/jama.285.5.628

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Prospects for Research in Diabetes Mellitus

Author Affiliation: Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, and Department of Veterans Affairs, San Diego.

Diabetes mellitus is the sixth leading cause of death in the United States, and morbidities resulting from diabetes-related complications such as retinopathy, kidney disease, and limb amputation cause a huge burden to the national health care system. Identification of the genetic components of type 1 and type 2 diabetes is the most important area of research because elucidation of the diabetes genes will influence all efforts toward a mechanistic understanding of the disease, its complications, and its treatment, cure, and prevention. Also, the link between obesity and type 2 diabetes mandates a redoubled effort to understand the genetic and behavioral contributions to obesity.

Diabetes mellitus affects between 6% and 7% of the US population equating to about 16 million people. It is projected that there will be 800 000 new cases per year and a total of 23 million affected people within 10 years. 1 Diabetes occurs in all populations and age groups but is increasing in prevalence in the elderly and in blacks, Hispanics, Native Americans, and Asians. 2 Although deaths due to cancer, stroke, and cardiovascular disease are declining, the death rates due to diabetes have increased by about 30% in the past 12 years ( Figure 1 ), and life expectancy for persons with diabetes is approximately 15 years less than in those who do not have diabetes. Diabetes is the sixth leading cause of death in the United States and accounted for more than 193 000 deaths in the US in 1997. However, this is an underestimate because diabetes contributes substantially to many deaths that are ultimately ascribed to other causes, such as cardiovascular disease. 3

Due to its complications, diabetes causes an enormous national burden of morbidity. For example, diabetic retinopathy is the leading cause of blindness in adults aged 20 through 74 years, 4 and diabetic kidney disease accounts for 40% of all new cases of end-stage renal disease. 5 Diabetes is the leading cause for amputation of limbs in the country. 6 Heart disease and strokes occur 2 to 4 times more frequently in adults with diabetes than in those who are healthy. Diabetes causes special problems during pregnancy, and the rate of congenital malformations can be 5 times higher in the offspring of women with diabetes. In aggregate diabetes mellitus costs $105 billion annually and involves 1 of every 10 US health care dollars and 1 of every 4 Medicare dollars. 7 (pp746-757)

Diabetes mellitus refers to a number of disorders that share the cardinal characteristic feature of elevated blood glucose levels. The 2 most common general categories of this disease are termed type 1 and type 2 diabetes. 8 Research has enormously increased our understanding of type 1 and type 2 diabetes, but much more remains to be done.

Documentation that elevated blood glucose levels are a direct cause of long-term complications of diabetes has been a major accomplishment. The Diabetes Control and Complications Trial (DCCT) 9 and the United Kingdom Prospective Diabetes Study (UKPDS) 10 both showed that control of blood glucose levels as close to normal as possible prevents and retards development of diabetic retinopathy, nephropathy, neuropathy, and macrovascular disease. The fact that each increment of improved control of blood glucose levels reduces complications has focused clinical and research efforts to elucidate disease mechanisms and to design new therapies. This insight coincided with the development of home glucose monitoring systems that make it possible to measure blood glucose levels throughout the day and coincided with the availability of new insulin preparations; insulin delivery devices, such as insulin pumps; and oral antidiabetic agents. 11

Likewise, fetal malformations and perinatal morbidity are now known to be due to elevated maternal glucose levels, and blood glucose control before and after conception can reduce these risks to normal. 7 (pp863-870) As a consequence, intensive efforts are now being made to diagnose and control glucose levels in pregnant women with diabetes. Although these advances have certainly helped improve the lives of patients, they do not provide an answer because most patients with diabetes do not obtain adequate blood glucose control.

Type 1 diabetes accounts for 5% to 10% of diabetes, usually occurs in children or young adults, and was formerly termed insulin-dependent diabetes mellitus (IDDM) or juvenile-onset diabetes . 12 This disease is caused by autoimmune destruction of the pancreatic β cells that secrete insulin. 12 The process involves a smoldering destructive process that can persist for several years and ultimately leads to failure of insulin secretion. This autoimmune process is due to genetic and environmental factors, and many genes contribute to the pathogenesis. During the preclinical phase, a variety of autoimmune antibodies directed against β-cell antigens serve as markers for the prediabetic state, allowing for early detection and possible prevention strategies. Patients with type 1diabetes require insulin therapy for survival, but blood glucose is still difficult to control, and most patients ultimately develop devastating complications of this disease. The present need is for improved means of treating type 1 diabetes until it is practical to prevent its development.

New methods to achieve tight glucose control are needed that are practical and can be administered to all persons with type 1 diabetes, including methods of insulin delivery, better forms of insulin, and practical, affordable methods of noninvasive self monitoring that can be coupled to patient-specific insulin treatment regimens. Cure of diabetes will require permanent replacement of lost β-cell function, which could involve islet cell transplantation, regeneration of β cells, or development of immortalized insulin secreting cell line. The ultimate aim in preventing disease onset will require a major multidisciplinary effort to identify the genes that predispose to type 1 diabetes and to identify the interacting environmental factors that trigger the disease. A thorough understanding of the cellular and molecular causes of the autoimmune destructive process will also be necessary.

Type 2 diabetes accounts for 90% to 95% of all patients with diabetes and is increasing in prevalence, especially in minority populations. 13 Type 2 diabetes is a heterogeneous, polygenic disorder, and the responsible genes have been identified in selected subtypes of this disease. 7 (pp691-705) Multiple diabetes genes exist, and more than 1 gene is likely to be involved in an individual patient. Some of the known environmental factors are obesity, a sedentary lifestyle, and aging. Obesity probably is the major environmental factor contributing to the increasing incidence of type 2 diabetes, and some of the hormonal, genetic, and environmental factors that predispose to obesity have been identified.

Insulin resistance is a characteristic metabolic defect in the great majority of patients with type 2 diabetes, and this defect can be demonstrated in the prediabetic state many years prior to the development of hyperglycemia. 14 As a consequence of insulin resistance, the β cell produces increased amounts of insulin, and, if sufficient, the compensatory hyperinsulinemia maintains glucose levels within the normal range ( Figure 2 ). In those individuals destined to develop diabetes, β-cell function eventually declines, and relative insulin insufficiency occurs. 15 Thus, insulin resistance combined with β-cell failure leads to the decompensated hyperglycemic diabetic state.

A number of the molecular steps in the insulin action cascade have been identified, and several components of the β-cell insulin secretion pathway have been elucidated. Researchers are beginning to understand the complex heterogeneous, genetic determinants of type 2 diabetes susceptibility. Efforts to understand genetic variation, gene expression profiling, and the interaction between genetic factors and environmental triggers must be intensified. This information will reveal new targets for pharmacologic intervention. Researchers also must continue work to understand the basic mechanisms that cause insulin resistance and limitation of compensatory insulin secretion. Truly effective treatments for type 2 diabetes will only come about when drugs are developed to target and correct the 2 underlying defects.

Obesity is the major environmental risk factor promoting the rise in type 2 diabetes incidence, and obesity is an increasing problem in the United States. The genetic and environmental factors that control food intake and energy expenditure must be identified so that we can improve the ability to effect beneficial lifestyle changes and eventually develop drugs to treat obese patients who are refractory to lifestyle modifications.

Much has been learned about the basic biology, epidemiology, and treatment of diabetes, and extraordinary opportunities exist to understand, treat, cure, and prevent diabetes. Coupled with these opportunities are substantial challenges and hurdles. The Diabetes Research Working Group 3 has identified several research areas that present unique opportunities for major advances and changes that will have to be made in the scientific infrastructure to implement this research endeavor.

Identification of the genetic components of types 1 and 2 diabetes is the single most important area of research because elucidation of the diabetes genes (alleles) will influence all efforts toward a mechanistic understanding of the disease, its complications, and its treatment, cure, and prevention. Completion of the Human Genome Project, the identification of a large number of single nucleotide polymorphisms—which will make genome-wide association studies for complex multigenic diseases feasible—the availability of new technologies such as DNA gene chips and genetic manipulation of animals have provided a solid foundation for rapid and tremendous advances in the study of diabetes genetics.

The new knowledge and technology are available for application to diabetes research, and a rigorous, multidisciplinary, well-funded effort is needed to achieve these goals. Increased funding for individual scientists should be a cornerstone of this approach, but new enhancements to the scientific infrastructure are equally important. A multidisciplinary approach will require coordination of many centers and different disciplines to identify the diabetes genes. This will necessitate the establishment and availability of repositories of DNA samples from phenotypically well-characterized diabetes patients spanning a number of ethnic groups. A coordinating and planning agency should be established to bring together and integrate the efforts of the National Institutes of Health and of nongovernment organizations such as the American Diabetes Association and Juvenile Diabetes Foundation International so that information is broadly disseminated as rapidly as possible. Once the diabetes genes are identified, it will be necessary to deal with the ethical, legal, and social issues involved in the availability of such information.

Since type 1 diabetes is an autoimmune disease, the mechanisms underlying this process must be thoroughly understood. Expanded efforts are needed to identify the environmental triggers and how they interact with the genetic predispositions. The basic cell biology of the immune destructive process must be solved, and the specific β-cell autoantigens must be identified. Hopefully this will lead to development of highly specific immunosuppressive agents that will produce relatively few adverse effects.

Insulin resistance and impaired insulin secretion are the key metabolic defects in type 2 diabetes. Increased efforts are necessary to dissect the molecular components involved in insulin signaling, insulin secretion, and β-cell growth and development. This research coupled with the efforts to identify the diabetes genes, will provide a mechanistic understanding of the specific defects in these pathways in type 2 diabetes, which should lead to the development of more specific, and more effective, pharmaceutical agents directed against defined molecular targets.

It is also essential to redouble efforts to understand the genetic and behavioral contributions to obesity. Excess body weight is a widespread and increasing problem in the United States and contributes to the high and increasing incidence of type 2 diabetes. A thorough understanding of basic mechanisms will enhance development of new methods of prevention and treatment. To facilitate the country's ability to make rapid progress in these areas of scientific opportunity, the Diabetes Research Working Group has recommended changes in the infrastructure. These include the following:

Create new mechanisms and modify existing programs to maximize recruitment, training, and career development of diabetes investigators.

Substantially strengthen and enhance National Institutes of Health–sponsored diabetes centers by increasing the funding levels and expanding their mission.

Create new regional centers for advanced technologies required for metabolic and functional imaging studies, such as nuclear magnetic resonance and positron emission tomography.

Enhance efforts to develop and characterize small- and large-animal models of type 1 and type 2 diabetes and establish regional centers for these animal models.

Expand procurement of human tissues, DNA samples, and organs for diabetes research.

If aggressive efforts across the broad front of diabetes research are accompanied by increased research funding in the areas of exceptional opportunity, the future does indeed look promising and it is likely that major accomplishments over the next 25 years will change the picture of diabetes prevention, treatment, and cure. ( Figure 3 )

For patients with type 1 diabetes, the procedures of cadaveric islet cell transplants will be largely perfected so that this can be performed either without the need for immunosuppression or with the use of specific highly focused immunosuppressive agents that will produce minimal adverse effects. However, that supply of freshly isolated human islets will be insufficient to provide transplants for all patients with type 1 diabetes. Replenishable sources of β cells for replacement could be derived from xenografts, possibly from genetically modified animals, or by creating a relatively inexhaustible, functional insulin secreting β–cell line. Such cell lines will be developed by learning to expand and grow large amounts of β cells from progenitor cells or by genetically engineering immortalized β cells.

Identification of the genes that predispose to type 1 diabetes will make it possible to identify individuals destined to develop the disease. Coupled with the elucidation of the basic immunologic mechanisms that cause autoimmune β-cell destruction and the development of specific targeted treatments to interrupt this process, the prevention of type 1 diabetes will become a reality. On the way to reaching these goals, substantial advances in glucose monitoring and insulin delivery mechanisms, which will lead to patient-specific treatment algorithms, will improve the outlook for patients with type 1 diabetes.

The genes responsible for the predisposition to type 2 diabetes and the mechanisms by which environmental factors bring out this predisposition will be identified. In parallel with this genetic information, identification of the cellular defects responsible for insulin resistance and impaired insulin secretion in type 2 diabetes will lead to development of new drugs that will be specific for defined molecular targets and that will be relatively free of unwanted adverse effects. This should include new ways to prevent or treat obesity. Once the predisposing diabetes genes are identified, it will be a straightforward matter to genotype individuals for diabetes susceptibility. The availability of new pharmaceutical treatments, together with the ability to predict diabetes susceptibility will provide a sound basis for early intervention and will lead to the prevention of type 2 diabetes in susceptible individuals. If an appropriate health care delivery system can disseminate these new therapeutic modalities to all diabetic patients, then control or prevention of diabetes will be a reality. In this event, the burden of diabetes complications will gradually diminish and ultimately disappear. Advances in methods of gene therapy may make genetic interventions a reality for this disorder.

The surest way to treat diabetic complications is to prevent them by glycemic control in patients with established diabetes or preferably by prevention of diabetes. While moving toward these goals over the next 25 years, it is critical to improve treatment and prevention of the microvascular and macrovascular complications of diabetes because these complications account for the excessive morbidity and mortality associated with this disease.

All of these predictions are fully achievable if adequate resources (financial and human) are applied to the field of diabetes. With appropriate effort, future generations could be freed from the scourge of diabetes.

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Open Access

Peer-reviewed

Research Article

Whole transcriptome sequencing analyses of islets reveal ncRNA regulatory networks underlying impaired insulin secretion and increased β-cell mass in high fat diet-induced diabetes mellitus

Contributed equally to this work with: Jinfang Ma, Rui Gao, Qingxing Xie

Roles Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Validation, Writing – original draft

Affiliations Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China, Center for Diabetes and Metabolism Research, West China Hospital, Sichuan University, Chengdu, China

Roles Data curation, Formal analysis, Validation, Writing – review & editing

Affiliation Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom

Roles Data curation, Formal analysis, Investigation, Writing – review & editing

Roles Formal analysis, Validation, Writing – review & editing

Roles Funding acquisition, Project administration, Supervision, Writing – review & editing

* E-mail: [email protected]

• Jinfang Ma, 
• Rui Gao, 
• Qingxing Xie, 
• Xiaohui Pan, 
• Nanwei Tong

• Published: April 1, 2024
• https://doi.org/10.1371/journal.pone.0300965
• Reader Comments

Our study aims to identify novel non-coding RNA-mRNA regulatory networks associated with β-cell dysfunction and compensatory responses in obesity-related diabetes.

Glucose metabolism, islet architecture and secretion, and insulin sensitivity were characterized in C57BL/6J mice fed on a 60% high-fat diet (HFD) or control for 24 weeks. Islets were isolated for whole transcriptome sequencing to identify differentially expressed (DE) mRNAs, miRNAs, IncRNAs, and circRNAs. Regulatory networks involving miRNA–mRNA, lncRNA–mRNA, and lncRNA–miRNA–mRNA were constructed and functions were assessed through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses.

Despite compensatory hyperinsulinemia and a significant increase in β-cell mass with a slow rate of proliferation, HFD mice exhibited impaired glucose tolerance. In isolated islets, insulin secretion in response to glucose and palmitic acid deteriorated after 24 weeks of HFD. Whole transcriptomic sequencing identified a total of 1324 DE mRNAs, 14 DE miRNAs, 179 DE lncRNAs, and 680 DE circRNAs. Our transcriptomic dataset unveiled several core regulatory axes involved in the impaired insulin secretion in HFD mice, such as miR-6948-5p/ Cacna1c , miR-6964-3p/ Cacna1b , miR-3572-5p/ Hk2 , miR-3572-5p/ Cckar and miR-677-5p/ Camk2d . Additionally, proliferative and apoptotic targets, including miR-216a-3p/ FKBP5 , miR-670-3p/ Foxo3 , miR-677-5p/ RIPK1 , miR-802-3p/ Smad2 and ENSMUST00000176781 / Caspase9 possibly contribute to the increased β-cell mass in HFD islets. Furthermore, competing endogenous RNAs (ceRNA) regulatory network involving 7 DE miRNAs, 15 DE lncRNAs and 38 DE mRNAs might also participate in the development of HFD-induced diabetes.

Conclusions

The comprehensive whole transcriptomic sequencing revealed novel non-coding RNA-mRNA regulatory networks associated with impaired insulin secretion and increased β-cell mass in obesity-related diabetes.

Citation: Ma J, Gao R, Xie Q, Pan X, Tong N (2024) Whole transcriptome sequencing analyses of islets reveal ncRNA regulatory networks underlying impaired insulin secretion and increased β-cell mass in high fat diet-induced diabetes mellitus. PLoS ONE 19(4): e0300965. https://doi.org/10.1371/journal.pone.0300965

Editor: Michael Bader, Max Delbruck Centrum fur Molekulare Medizin Berlin Buch, GERMANY

Received: January 7, 2024; Accepted: March 7, 2024; Published: April 1, 2024

Copyright: © 2024 Ma et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All the sequencing data generated in this study are publicly available from the NCBI database ( https://www.ncbi.nlm.nih.gov/ ) with accession number PRJNA1061374.

Funding: This study was supported by a grant from 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University (NT, ZYGD 18017). There was no additional external funding received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Type 2 diabetes mellitus (T2DM) primarily arises from a combination of insulin resistance and basal hyperinsulinemia [ 1 ], and its global prevalence is on the rise [ 2 ].

This metabolic disorder results from the multifaceted interplay among genetic elements, environmental influences, and the combined effects these have on the epigenome [ 3 , 4 ]. While genetic susceptibility holds considerable sway, substantial attention has also focused on environmental contributors, such as excess nutrition in recent years. Although the cause-and-effect relationship between insulin resistance and hyperinsulinemia remains a subject of debate [ 5 ], numerous findings indicated overnutrition promoted insulin resistance and hyperinsulinemia [ 6 – 9 ]. It serves as a precursor to T2DM, followed by a progressive decline in β-cell function and a decrease in the mass of functional β-cell [ 10 ]—two critical factors contributing to the development of T2DM. To replicate the human condition of obesity-induced diabetes, high-fat diet, in particular, have been extensively studied for their potential contribution to the development and progression of T2DM [ 11 , 12 ].

Non-coding RNAs (ncRNAs) are RNA molecules that do not encode proteins, but they interact with protein-coding genes and plays significant roles in various key biological processes [ 13 – 15 ]. Increasing evidence indicated that ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), are crucial regulators in multiple facets of T2DM pathogenesis, such as insulin synthesis, glucose metabolism and homeostasis [ 15 – 20 ]. For example, the downregulation of miR146a enhances NFkB -mediated inflammatory events and induces β-cell apoptosis [ 21 ], and altered miR-124a expression also contributes to β-cell dysfunction in T2DM [ 22 ]. In addition, diminished expression levels of lncRNAs TTC28-AS1 and SNHG17 have been reported to be associated with T2DM susceptibility, showing significant correlation to metabolic features [ 23 ], while overexpression of lncRNA-p3134 maintains β-cell mass by providing a protective effect against glucotoxicity-mediated apoptosis [ 24 ]. Besides, hsa_circ_0054633 and hsa_circ_0071106 have also been found as diagnostics biomarkers of pre-diabetes and T2DM [ 25 – 27 ]. Recent research findings propose that lncRNAs and circRNAs may serve as miRNA "sponges" or "decoys," engaging in competitive binding with miRNAs, thereby diminishing the regulatory influence of these miRNAs on their intended mRNA targets [ 15 , 28 , 29 ]. Due to the competitiveness, these lncRNAs and circRNAs are also called competing endogenous RNAs (ceRNAs). While a growing body of recent research has centred on the regulation of ceRNAs interactions, especially in cancer, the number of functionally well-annotated ncRNAs related to T2DM remains limited. Moreover, the intricate network of how ncRNAs and mRNAs mutually regulate each other in a model of obesity-related diabetes is yet to be fully elucidated. However, the existing studies mentioned above were derived from analyzing peripheral blood samples and β-cell lines, or were solely profiled in a microarray focusing on a single type of ncRNA. Furthermore, acute toxic injuries in β-cells, such as fatty acid-induced dysfunction, might not serve as an ideal research model for understanding the natural progression of T2DM in humans.

In recent years, whole transcriptome analysis through total RNA sequencing has emerged as an efficient tool for providing a comprehensive view of the transcriptome’s complexity. In our present study, we utilised whole transcriptome sequencing data to establish ncRNA networks within islet tissue, encompassing miRNA–mRNA, lncRNA–mRNA and lncRNA–miRNA–mRNA interactions, using a diet-induced obesity and diabetes mellitus model. Our study aims to correlate transcriptomic features with phenotypes, and systematically unveil pathogenic pathways underlying islet dysfunction and diabetes progression, thereby identifying novel therapeutic targets associated with T2DM.

Materials and methods

Five-week-old male C57BL/6J mice were purchased from GemPharmatech Co., Ltd. (Jiangsu). The mice were given ad libitum access to water and food, and were housed in a 12 h light/ dark cycle at an ambient temperature of 22±2°C. Following 1 weeks of acclimatization, the mice were fed either a high-fat diet (HFD) comprising 60% fat, 20% protein and 20% carbohydrate (D12492, Jiangsu Synergetic Bioengineering Co., Ltd.) or a chow diet (CD) that contained 10% fat, 20% protein and 70% carbohydrate (D12450 J, Jiangsu Synergetic Bioengineering Co., Ltd.). After 24 weeks of dietary intervention, intraperitoneal glucose tolerance tests (IPGTT), intraperitoneal insulin tolerance tests (IPITT) and glucose stimulated insulin secretion test (GSIS) were performed in both HFD and CD mice. Following a one-week recovery period, the body weights of all mice were measured, and serum samples were collected. Islets were then isolated from both HFD and CD mice for further sequencing at the end of the dietary intervention.

Daily health checks were conducted throughout the study to promptly address any signs of distress. Experimental protocols adhered to the "3Rs" principle, minimizing animal usage and maximizing welfare. Cervical dislocation was employed for humane euthanasia of mice. This rapid method was executed by trained personnel to ensure immediate loss of consciousness and death. All procedures were carried out in accordance with the National Institutes of Health Guidelines for the Care and Use of Animals (IACUC) and had been approved by the Institutional Animal Care and Use Committee at Sichuan University.

In vivo dynamic physiological tests

IPGTT: Mice underwent a 16 h fasting period before receiving an intraperitoneal (i.p.) injection of D-glucose (2 g/kg). Tail blood glucose levels were measured at 0, 15, 30, 60, 90, and 120 min after the injection using a glucometer (Roche, Basel, Switzerland).

Mice underwent a 16 h fasting period prior to an i.p. injection of D-glucose (2 g/kg). At 0, 15, 30, and 120 min post-injection, 25 μL of blood was collected from the tail vein to measure insulin levels subsequently.

Mice were fasted for 6h before receiving an i.p. injection of insulin (0.75 U/kg). Tail blood glucose levels were measured at 0, 15, 30, 45, 60, and 90 min post-insulin injection with a glucometer.

In vivo biochemical measurements

Serum samples were obtained by centrifuging the blood samples at 5000 rpm for 30 min and stored at -80°C. Serum insulin levels were measured using an Ultra-sensitive Mouse Insulin ELISA Kit (Crystal Chem, Chicago, IL). Serum total cholesterol (TC), triglyceride (TG), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and low-density lipoprotein-cholesterol (LDL-C) were determined after a 16 h fasting period using an automatic biochemical analyzer (HITACHI 7100, Hitachi Koki Co. Ltd., Japan).

Immunohistochemistry of pancreatic tissues

Immunohistochemical staining was performed to examine pancreatic islet cells according to standard protocols. In brief, pancreatic tissues were fixed overnight with 4% paraformaldehyde (PFA). The fixed tissue samples were embedded in paraffin, sliced into sections, and subsequently subjected to baking, dewaxing, and hydration. Then, slides were heated in IHCTek epitope retrieval solution for 30 min and permeabilized with 0.25% Triton X-100 in PBS for 10 min. The samples were then blocked with 5% goat serum in PBS and incubated overnight at 4°C with anti-insulin (1:500 dilution, Servicebio, Wuhan, China) or anti-glucagon antibody (1:500 dilution, Servicebio) or anti-Ki67 (1:1000 dilution, Servicebio). After thorough PBS washes, the slides were incubated for 1 h at room temperature with a mixture of Alexa Fluor 555- or Alexa Fluor 488-conjugated secondary antibodies (1:500 dilution, Servicebio). All sections were counterstained and mounted using ProLong Gold antifade reagent with DAPI (Servicebio). Negative controls were obtained by omitting the primary antibodies. Images were then captured using a Nikon microscope (Eclipse C1).

TUNEL staining of pancreatic tissues

The sliced pancreatic tissues were first dried in a 60°C oven for 30 min and then dewaxed with xylene (5 min × 3 times) followed by dehydration using a series of ethanol washes (100% ethanol, 95% ethanol, and 70% ethanol; each repeated three times). The sections were then incubated with protein kinase K for another 30 min. After rinsing with PBS, the terminal deoxyribonucleotide transferase TdT and luciferase-labeled dUTP were added, and the reaction was incubated at 37°C for 1 h. The sections were subsequently incubated with HRP-specific antibodies for 1 h at 37°C in an incubator. Finally, 3,3’-Diaminobenzidine (DAB) was added as the substrate, and the reaction was allowed to proceed at room temperature for 10 min. Following the staining of nuclei with hematoxylin, images were captured using a Nikon microscope (Eclipse C1), and the number of cells was manually counted.

Hematoxylin-eosin (HE) staining of liver tissues

The sliced liver tissues were prepared as previously described [ 30 ], and they were subsequently immersed in a 5% hematoxylin aqueous solution and stained for 5 min. After rinsing with running water, the stained samples were incubated in a hematoxylin differentiation solution for 15 s, followed by treatment with hematoxylin scott tap bluing for 15 s. The sections were rinsed again with running water, immersed in eosin (0.5%) staining for 3 min, and subjected to a final rinse with running water. The samples were then dehydrated, cleared, mounted, and examined.

Oil red O staining

For assessing lipid droplet formation, frozen sections of liver tissue were stained with Oil Red O for 30 minutes and subsequently counter-stained with haematoxylin for 1 minute. The stained frozen sections were then washed, dehydrated, and mounted for imaging.

Islet isolation

Islets were isolated from both HFD and CD mice with pancreas extraction following intra-ductal injection with collagenase P (Roche, Basel, Switzerland) in Hank’s Balanced Salt Solution (Sigma). After three rounds of hand selection under a light microscope, islets were collected for further experiments.

In vitro insulin secretion measurements

Insulin secretion was performed by static incubation as described earlier [ 12 ]. Briefly, islets were isolated from 4–5 mice per group and cultured overnight. On the following day, groups consisting of 20 size-matched islets were pre-incubated in a custom-made KRB buffer (pH 7.4) for 1 hour. Subsequently, these islets were exposed to either 2 or 20 mmol/L glucose, optionally combined with 0.5 mM palmitate acid (PA), for an additional hour at 37°C under 5% CO2. After this treatment, supernatants were harvested, and islets were lysed in an acid ethanol solution. Insulin within both supernatants and contents were measured by ELISA kits (Mercodia, Sweden). The secreted insulin was calculated as percentage of total contents per hour.

RNA sequencing

Total RNA was isolated from handpicked islets of both HFD and CD mice (each group consisted of three biological replicates, with each replicate derived from the islets of 3 mice) using TRIzol (Invitrogen, Carlsbad, CA, USA). RNA degradation and contamination were monitored on 1% agarose gels. Subsequently, the quality of the isolated RNA samples was evaluated using an Agilent Bioanalyzer 2100 (Agilent Technologies, Santa Clara, CA, USA), and the quantity was measured using a NanoDrop ND-2000 (NanoDrop Technologies, USA). Only RNA sample meeting high-quality standards (OD260/280 = 1.8~2.2, OD260/230≥2.0, RIN≥8.0, 28S:18S≥1.0, >5μg) were utilized to construct sequencing libraries.

RNA purification, reverse transcription, library construction, and sequencing were all carried out at Shanghai Majorbio Bio-pharm Biotechnology Co., Ltd. (Shanghai, China), adhering to the manufacturer’s instructions from Illumina (San Diego, CA). For RNA-seq transcriptome strand library preparation, 1 μg of total RNA was utilized following the TruSeqTM Stranded Total RNA Library Prep Kit protocol by Illumina. Shortly, ribosomal RNA (rRNA) depletion instead of poly(A) purification was performed using the Ribo-off rRNA Depletion kit. Subsequently, the RNA underwent fragmentation using a fragmentation buffer. Thereafter, first-strand cDNA synthesis took place with random hexamer primers. The RNA template was then removed, and a replacement strand was synthesized, incorporating dUTP in lieu of dTTP to generate ds cDNA. The presence of dUTP effectively quenched the second strand during amplification since polymerase bypassing this nucleotide was inhibited. AMPure XP beads were employed to separate ds cDNA from the second strand reaction mixture. To prevent self-ligation during adapter ligation, a single ’A’ nucleotide was added to the 3’ ends of these blunt fragments. Finally, multiple indexing adapters were ligated to the ends of the ds cDNA. Libraries were size-selected for cDNA target fragments ranging between 200–300 bp on a 2% Low Range Ultra Agarose, followed by PCR amplification for 15 cycles using Phusion DNA polymerase (NEB). Upon quantification with TBS380, the paired-end RNA-seq sequencing library was sequenced on an Illumina NovaSeq6000 sequencer (2 × 150bp read length). In parallel, for small RNA library preparation, a total of 3 μg of total RNA per sample was used as input material. Sequencing libraries were constructed using the TruSeq TM Small RNA Sample Prep Kit from Illumina according to the manufacturer’s guidelines. Activated 5’ and 3’ adaptors were ligated to the total RNA, respectively. The adaptor-ligated RNA was subsequently converted into first-strand cDNA via reverse transcription utilizing reverse transcriptase and random primer. A PCR reaction was conducted with primers complementary to the two adaptors for 11–12 cycles. Fragments of the appropriate size were isolated through a 6% Novex TBE PAGE gel. Once quantified with TBS380, the single-end RNA-seq sequencing library was sequenced on an Illumina NovaSeq 6000 sequencer. For the longRNA-seq dataset, each of the six samples produced over 17.04 gigabases (Gb) of high-quality (Clean) data, amounting to a collective total of 107.84 Gb with a consistently high Q30 base percentage exceeding 94.78%. In contrast, for the smallRNA-seq experiment, we obtained a total of 73.65 million (M) raw sequencing reads across the six samples, with every individual sample yielding more than 11.07 M raw reads. These samples maintained a robust Q30 base call rate of at least 94.99%.

The quality of the sequencing data was evaluated with fastx_toolkit (Version 0.0.14) and fastp (Version 0.19.5). Subsequently, reads were aligned to the mouse reference genome (GRCm39) using Bowtie2 (Version 2.2.9) and HISAT2 (Version 2.1.0). The mapped reads from the two libraries were then assembled using StringTie (Version 1.3.3b) and cufflinks (Version 2.2.1). Gene expression levels were quantified by RSEM (Version 1.3.1) and were normalized by the method of transcripts Per Million reads (TPM). Differentially expressed mRNA transcripts (DEMs) between HFD and CD groups were identified based on criteria of log 2 FC > 1 or < -1 and P-value < 0.05, performed by DEseq2 package (Version 1.10.1).

Identification of miRNAs

Mapped small RNA tags were first employed to identify known miRNAs using the miRBase22.0 database ( http://www.mirbase.org/ ). The modified miRDeep2 software ( https://www.mdc-berlin.de/content/mirdeep2-documentation ) was utilized to retrieve potential miRNAs and generate their secondary structures. Custom scripts were employed to derive both the miRNA counts and the base bias at the first position of identified miRNAs with specific lengths, as well as at each position across all identified miRNAs, respectively. Subsequently, the small RNA tags were aligned against both the Rfam database and the Repbase database, filtered ribosomal RNA (rRNA), transfer RNA (tRNA), small nuclear RNA (snRNA), small nucleolar RNA (snoRNA) and other ncRNA and repeats. The miRDeep2 software was further used to predict novel miRNAs based on Dicer cleavage sites and the minimum free energy of the unannotated small RNA tags from previous steps. The expression levels of each miRNA were calculated using the transcripts per million reads (TPM) method. Significant DE miRNAs were extracted with |log2FC| >1 and P-value < 0.05.

Identification of lncRNAs

We initially refer to the known lncRNAs catalogued in NONCODE ( http://www.noncode.org/index.php ). Subsequently, we discarded transcripts that overlapped with known protein-coding genes on the same strand, transcripts with length shorter than 200 nt, the open reading frame (ORF) longer than 300 nt, and an exon number of less than 2. Next, we employed the Coding Potential Calculator (CPC), Coding-Non-Coding index (CNCI), and Coding Potential Assessment Tool (CPAT) to filter out transcripts demonstrating coding potential (with CPC score < 0.5; CNCI score < 0; CPAT score < 0.5). Furthermore, the remaining transcripts harboring known protein domains were eliminated by Pfam Scan according to Pfam HMM. The surviving transcripts were thus classified as reliably expressed lncRNAs, which were further categorized into intergenic, sense exon overlap, antisense, sense intron overlap, and bidirectional lncRNA types. To identify DE lncRNAs between two distinct groups, the expression levels of each lncRNA were calculated based on the transcripts per million reads (TPM) method. RSEM was utilized for quantifying lncRNA abundances. Fundamentally, differential expression analysis was conducted using DESeq2, LncRNAs with |log2FC| ≥ 1 and P-value < 0.05 were considered significantly differentially expressed.

Identification of circRNAs

The CIRI (CircRNA Identifier) and find_circ tools were employed to identify circRNAs. Subsequently, the identified circRNAs were categorized into exon, intron, and intergenic circRNAs. For the purpose of identifying DE circRNAs between two different groups, the expression level of each circRNA was calculated based on the reads per million mapped reads (RPM) method. Essentially, differential expression analysis was carried out using DEGseq, where circRNAs with |log2 FC| ≥ 1 and P-value < 0.05 were deemed significantly differentially expressed.

Quantitative real-time PCR

To validate the reliability of the RNA-sequencing data, quantitative real-time PCR (qRT-PCR) was conducted. RNA was extracted from islets using the AxyPrep Total RNA Mini Kit (Axygen, Corning, New York, USA) according to the manufacturer’s instructions. cDNA was synthesized from 0.5 μg of RNA using oligo(dT) and random hexamer primers with reverse transcriptase (Takara RT Kit). Quantitative PCR was performed using the CFX96 system (Bio-Rad) and SYBR Green Master Mix (Bio-Rad). The primer sequences are provided in Table 1 .

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https://doi.org/10.1371/journal.pone.0300965.t001

GO and COG analysis

Gene Ontology (GO) analysis was employed to investigate the primary function of the differential expressed mRNAs. GO categories, derived from the Gene Ontology ( http://www.geneontology.org/ ). describe attributes of gene products and provide the gene regulatory network based on biological processes, molecular functions and cellular components.

The Clusters of Orthologous Groups (COGs) were constructed by applying the criterion of consistency of genome-specific best hits to the results of an exhaustive comparison of all protein sequences from the genomes of bacteria, archaea and eukaryotes [ 31 ]. This COGs database ( http://www.ncbi.nlm.nih.gov/COG ) was then employed to facilitate applied to functional and phylogenetic annotation of the sequenced genomes in our study.

KEGG pathway analysis

Pathway analyses of differentially expressed mRNAs were conducted using the latest Kyoto Encyclopedia of Genes and Genomes (KEGG) database ( https://www.genome.jp/kegg/ ), allowing us to identify the specific biological pathways in which the significantly enriched mRNAs were involved.

Prediction of miRNA target gene

To predict the differentially expressed mRNAs targeted by the differentially expressed miRNAs, the miRanda ( http://www.miranda.org/ ) algorithms were employed to identify miRNA binding sites. The mRNAs associated with the differentially expressed miRNA were annotated using both the GO and the KEGG pathway databases.

Target gene prediction and functional analysis of lncRNAs

To investigate the functions of the identified lncRNAs, we predicted their cis-target genes (neighboring genes). We accomplished this by selecting coding genes located within a 10,000 bp range both upstream and downstream of the identified lncRNAs using a Python script. Subsequently, we annotated the genes associated with the differentially expressed lncRNAs using the GO and the KEGG pathway databases.

Overview of the processes used to identify ceRNA interaction pairs

Based on the expression levels of mRNAs, miRNAs, and lncRNAs or circRNAs, Pearson’s correlation coefficient and p value were calculated for miRNA-target (predicted via miRanda). Pairs with negative correlations and p -value < 0.05 were selected for further analyses and the co-expression relationships were visualized using Cytoscape (v3.10.0).

Statistical analysis

GraphPad Prism 8.0 (San Diego, CA, USA) was utilized to perform statistical analyses. Data are expressed as mean ± standard error of the mean (SEM). We used two-tailed unpaired t -tests for comparison between two groups, one-way ANOVA and two-way ANOVA with repeated measures for comparison involving three or more groups, followed by Bonferroni’s post-hoc test. A two-tailed p-value < 0.05 was considered statistically significant.

General characteristics and impaired glucose homeostasis and islet function in HFD mice

The long-term HFD is recognized for inducing a mouse model for obesity-related diabetes. To demonstrate the comprehensive metabolic characteristics in this HFD model, we investigated the profile of general characteristics, glucose metabolism, islet secretion, and architecture in C57BL/6J mice fed either a 60% HFD or a chow diet (CD) over a 24-week period. Severe obesity and hyperinsulinemia were observed in HFD mice, as compared to the CD mice ( Fig 1A and 1B ). Moreover, S1 Fig demonstrates that the HFD induced fatty liver, hyperlipidemia, and hepatic toxicity. This is manifested by cytoplasmic ballooning and lipid accumulation observed through HE staining and Oil Red O staining ( S1A and S1B Fig ), along with significantly elevated plasma levels of TC (p < 0.0001), TG (p<0.01), LDL-C (p<0.001), AST (p<0.0001), and ALT (p<0.001) shown in S1C–S1G Fig .

(A) The average body weights of high-fat diet (HFD) and chow diet (CD) mice. (n≥ 23 mice /group). (B) The average serum insulin levels of HFD and CD mice. (n≥14 mice /group). (C-D) Blood glucose (C) and the corresponding plasma insulin concentration (D) during IPGTT. (n≥10 mice/group). (E) Blood glucose during IPITT. (N≥20 mice/group). (F) Insulin secretion in islets isolated from HFD and CD mice. (n = 7 samples/group, n = 3–4 mice/group). (G) Representative immunofluorescence staining of pancreatic islets from HFD and CD mice. Red indicates glucagon-positive cells, and green indicates insulin-positive cells. (H) Islet size distributions analyzed by morphometry (N = 4 mice/group). (I) Representative immunofluorescence staining showing Ki67+ Ins+ cells in pancreatic sections. Red indicates insulin-positive cells, and green indicates Ki67-positive cells. (J) Quantification of the percentage of Ki67+ Ins+ cells in total Ins+ cells. (n = 9 islets/group, n = 3 mice/group). (K) Apoptotic signals at the pancreatic islets of HFD and CD mice. Green indicates insulin-positive cells, and red indicates apoptosis signals detected by the TUNEL method. (L) Quantification of the percentage TUNEL+ apoptotic cell in total Ins+ cells. (n = 5 islets/group, n = 3 mice/group). Data presented as mean ± SEM. *p<0.05, **p<0.01, ***p<0.005, **** p<0.001.

https://doi.org/10.1371/journal.pone.0300965.g001

To evaluate islet function, we performed IPGTT, GSIS and IPITT. The results revealed that HFD mice displayed a marked deterioration in glucose tolerance compared to CD mice, as evidenced by significantly elevated peak and a slower decay of plasma glucose level following glucose administration ( Fig 1C ). Besides, throughout GSIS, HFD mice consistently displayed significantly higher insulin levels compared to CD mice at every measured time point, despite CD mice showing an appropriate insulin secretory response to the glucose challenge ( Fig 1D ). ITTs were subsequently conducted to evaluate systemic insulin sensitivity, and our finding showed a marked insulin resistance following 24 weeks of HFD treatment. The blood glucose levels in HFD mice were significantly higher at 0, 15, 30, 45, 60, and 90 min post-insulin injection ( Fig 1E ), compared to CD mice.

We also evaluated insulin secretion in intact islets isolated from HFD mice or CD mice, under conditions of low and high glucose concentrations, and in the presence and absence of PA. The insulin secretion of islets from HFD mice was notably lower than that from CD mice, regardless of whether stimulatory glucose or PA was present, suggesting impairment of β-cell function. When comparing the fold increase in insulin secretion due to 20 mM glucose stimulation alone, we observed a reduction from 3.91-fold in CD mice to 2.2-fold in HFD mice. Similarly, upon 0.5 mM PA treatment alone, the fold increase dropped from 1.98 in CD mice to 1.74 in HFD mice. The potentiating effect of PA on glucose-stimulated insulin secretion was also found to be impaired in HFD mice (2.52-fold in HFD versus 4.53-fold in CD), which consistent with the previous research [ 32 ] ( Fig 1F ).

Immunofluorescent staining and TUNEL assays were performed to examine proliferative and apoptotic changes in the islet from HFD mice. Our observation revealed a notable increase in the prevalence of large-sized islets (6000–8999 um 2 ) in HFD group ( Fig 1G and 1H , 7.99% in HFD versus 1.18% in CD) and a higher percentage of Ki67+ Ins+ β-cells within HFD islet ( Fig 1I and 1J , 1.06% in HFD versus 0.19% in CD). However, as marked by TUNEL assay, no apoptotic signals (red in the nucleus) were observed in β-cells from both HFD and CD mice ( Fig 1K and 1L ), suggesting that neither diet led to a significant level of apoptosis.

Hence, our data confirmed the occurrence of impaired glucose homeostasis and compromised islet function in the HFD mice, suggesting the successful establishment of a diet-induced obesity and diabetes mouse model.

Whole transcriptomic profiles and pathway of islets in diet-induced diabetes

Islets obtained from C57BL/6Jmice fed a 60% HFD or a CD for 24 weeks were isolated for whole transcriptome sequencing ( Fig 2A ). Following data processing, a total of 1324 differentially expressed mRNAs (DEMs) were identified between the two groups ( S1 Table ). Among these, 379 showed significant upregulation with a log2 FC≥1, while 945 were notably downregulated with a log2 FC≤-1, as illustrated in the volcano plot ( Fig 2B ). Heatmap and hierarchical clustering analyses in Fig 2C presented 1324 differentially expressed mRNAs between HFD and CD group. Notably, the expression patterns of DEMs among the three samples within each group showed remarkable similarity, suggesting high reproducibility ( Fig 2C ). To validate our transcriptomic data, we randomly chose 6 DEMs for assessment via qRT-PCR in a separate set of islet samples derived from both HFD and CD mice. The results showed similar expression patterns to those observed in RNA-sequencing data ( Fig 2D ).

(A) Schematic of the experimental design for whole transcriptome sequencing. Created with BioRender.com. (B) A volcano plot of the DEMs between the HFD and CD groups. The numbers of upregulated (red dots) and downregulated (blue dots) genes are marked in the graph. (C) Heatmap and hierarchical clustering analyses of the 1324 differentially expressed mRNAs. (D) Random selection of 6 DEMs for the validation of islet transcriptomic data. Data presented as mean ± SEM. *p<0.05, **p<0.01. (E) COG function classification of the DEMs. (F) GO enrichment analysis of DEMs. (G) KEGG enrichment analysis of DEMs. Abbreviations: DEMs, differentially expressed mRNAs; COG, Cluster of Orthologous Groups; GO, gene ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes.

https://doi.org/10.1371/journal.pone.0300965.g002

To elucidate the molecular mechanisms contributing to the changes in these DEMs during diabetes progression, functional analyses were conducted. The Cluster of Orthologous Groups (COG) database was utilized to classify the DEMs, revealing predominant functional clusters related to crucial cellular processes such as intracellular trafficking, vesicular transport mechanisms, and secretion (COG category U). Additionally, there was a notable concentration of DEMs associated with posttranslational modification, protein turnover, and chaperone functions within COG category O ( Fig 2E ).

The GO enrichment analysis revealed significant enrichment of DEMs in biological processes such as pancreas morphogenesis and exocrine pancreas development, which are crucial pathways related to β-cell differentiation and formation ( Fig 2F ). We also mapped the DEMs in the KEGG database, resulting in 318 enriched pathways. Notably, the pathways of pancreatic secretion and calcium signaling, which are associated with the islet function and progression of diabetes, were significantly enriched, featuring among the top 20 pathways ( Fig 2G ).

A total of 14 differentially expressed (DE) miRNAs (8 upregulated and 6 downregulated) and 179 DE lncRNAs (80 upregulated and 99 downregulated) were also identified (Figs 3A and 4A ), and details regarding these DE miRNAs and DE lncRNAs can be found in S2 and S3 Tables, respectively. The upregulated miRNAs included miR-135b-5p, mmu-miR-153-3p, mmu-miR-5121, mmu-miR-670-3p, mmu-miR-677-5p, mmu-miR-6948-5p, mmu-miR-6964-3p and 12_4382, while the downregulated annotated miRNAs were mmu-miR-1188-5p, mmu-miR-216a-3p, mmu-miR-217-3p, mmu-miR-3572-5p, mmu-miR-6969-3p and mmu-miR-802-3p. These differentially expressed miRNAs were identified through hierarchical clustering analysis shown in Fig 3B . Among differentially expressed (DE) lncRNAs, the most significantly upregulated annotated transcripts included: chr7:140134538–140137224 with the corresponding lncRNA gene ID ENSMUSG00000025464 and gene name Paox; MSTRG.581.10 linked to ENSMUSG00000084799 and gene Ino80dos; chr18:68340371–68342443 associated with ENSMUSG00000007480 and Mc5r; chr4:98115993–98118843 related to ENSMUSG00000028565 and Nfia; and chr7:101899953–101901847 connected to ENSMUSG00000030649 and Anapc15. On the contrary, the most downregulated annotated lncRNAs were chr4:138206284–138207058 from ENSMUSG00000028760 (Eif4g3); ENSMUST00000186785 corresponding to ENSMUSG00000073538 (E330020D12Rik); ENSMUST00000138164 tied to ENSMUSG00000085510 (Mir217hg); chr12:38869930–38870479 linked with ENSMUSG00000004151 (Etv1); and NR_168300.1 which is affiliated with ENSMUSG00000100627 (A830008E24Rik). These differentially expressed lncRNAs were identified via hierarchical clusteringanalysis ( Fig 4B ).

(A-B) Differentially expressed miRNAs were exhibited by volcanoplot and clustering analysis. (C) miRNAs-mRNAs regulatory network analysis of DE miRNAs and DE mRNAs. The diamond represents DE miRNAs, and ellipses represent DE mRNAs. Target mRNAs associated with key pathways have been color-coded for clarity: red for pancreatic secretion pathway; blue for type 2 diabetes mellitus pathway; yellow for calcium signaling pathway. To denote involvement in multiple pathways, mRNAs are marked green if they participate in both calcium signaling and type 2 diabetes mellitus pathways, orange for those involved in calcium signaling and insulin secretion pathways, pink for mRNAs implicated in all three pathways (calcium signaling, type 2 diabetes mellitus, and insulin secretion), and brown for targets participating in pancreatic secretion, calcium signaling, and insulin secretion pathways. (D) GO enrichment analysis of DE miRNAs-targeted DE mRNAs. (E) KEGG enrichment analysis of DE miRNAs-targeted DE mRNAs.

https://doi.org/10.1371/journal.pone.0300965.g003

(A-B) Differentially expressed lncRNAs were exhibited by volcanoplot and clustering analysis. (C) LncRNA-cis target genes regulatory network analysis of DE lncRNAs and DE mRNAs. The diamond represents DE lncRNAs, and ellipses represent their corresponding differentially expressed potential cis target genes. (D) GO enrichment analysis of the corresponding differentially expressed potential cis target genes of DE lncRNAs. (E) KEGG enrichment analysis of the corresponding differentially expressed potential cis target genes of DE lncRNAs.

https://doi.org/10.1371/journal.pone.0300965.g004

Moreover, a total of 680 DE circRNAs were discovered, consisting of 357 upregulated circRNAs (347 annotated and 10 non-annotated) and 323 downregulated circRNAs (311 annotated and 12 non-annotated). These findings were illustrated through volcano plot and hierarchical clustering analysis ( S2A and S2B Fig ). The most highly downregulated circRNAs were 19_58662180_58719032, 7_130721154_130721279, 7_130674581_130681275, 6_41353742_41420524 and 19_58668512_58669244 (circRNA id). Conversely, the most highly upregulated circRNAs included 7_142232409_142233415, 7_130655793_130671489, 7_142232398_142233422, 9_108208070_108212380 and 7_142233169_142233457 (circRNA id). Detailed information regarding all DE circRNAs were presented in S4 Table .

The sponge and target regulatory elements of DE miRNA in islets

Considering the ability of a single miRNA to target multiple mRNAs and conversely, multiple miRNAs regulating a single mRNA [ 33 , 34 ], we conducted a target analysis between DE miRNA and DE mRNA pairs. Using the miRanda software, 238 targeted DE mRNAs of the 14 DE miRNAs were predicted, and these mRNAs are expected to be specially regulated by the corresponding miRNAs, as depicted in the network of Fig 3C .

Based on GO enrichment analysis of the targeted DE mRNAs regulated by DE miRNAs, several significant enrichments were observed across categories of molecular functions (MF), cellular components (CC), and biological processes (BP). Remarkably enriched among the MF category were heparan sulfate binding, zymogen binding, alpha-amylase activity, alpha-amylase activity (releasing maltohexaose), and lipoteichoic acid binding category. Within the CC category, collagen-containing extracellular matrix, and extracellular matrix were significantly enriched. The most notably enriched BP category was the induction of bacterial agglutination ( Fig 3D ).

We then conducted KEGG enrichment analysis to identify the principal biochemical metabolic pathways and signal transduction pathways related to specific mRNA. Among the top 20 pathways, pancreatic secretion, calcium signaling pathway, type 2 diabetes mellitus, and insulin secretion are the significantly enriched pathway associated with in diabetes progression ( Fig 3E ).

Of particular note, certain DE mRNAs enriched in calcium signaling pathway and type 2 diabetes mellitus pathway play a fundamental in the process of insulin secretion. Specifically, compared to the control group, the expression of Cacna1c and Cacna1b , which was reported to be downregulated in hypertriglyceridemia subjects with decreased insulin secretion [ 35 ], was decreased in HFD mice. Additionally, HFD resulted in the downregulation of Hk2 , a glycolytic enzyme gene known to promotes insulin secretion [ 36 ], and Cckar , a crucial receptor stimulating insulin secretion [ 37 ]. Furthermore, Camk2d , a protein coding gene belonging to the calcium/calmodulin-dependent protein kinase subfamily, which plays a key role in GSIS [ 38 ], also exhibited reduced expression in the HFD islets. Taken together, the reduced expression of Cacna1c , Cacna1b , Hk2 , Cckar , and Camk2d may to some extent account for the defective insulin secretion observed in HFD mice. Our subsequent bioinformatics analysis identified a few core regulatory axes, including miR-6948-5p/ Cacna1c , miR-6964-3p/ Cacna1b , miR-216a-3p/ Cacna1b , miR-6948-5p/ Cacna1b , miR-670-3p/ Cacna1b , miR-3572-5p/ Hk2 , miR-3572-5p/ Cckar , miR-670-3p/ Camk2d and miR-677-5p/ Camk2d ( Fig 3C ). Therefore, miR-6948-5p, miR-6964-3p, miR-216a-3p, miR-670-3p, miR-3572-5p, and miR-677-5p exhibit potential regulatory roles in β-cell function within the context of T2DM. The miRNA–mRNA network involved in insulin secretion pathway is depicted schematically in Fig 6A.

Our study also identified several pairs of DE miRNAs and their target mRNAs which linked to the regulation of β-cell mass. Specifically, the FK506-binding protein 51 (encoded by FKBP5 gene) emerged as a crucial regulator for T2DM, with its inhibition known to protect β-cell survival via AKT/FOXO1 signaling [ 39 ]. Our results revealed that FKBP5 was downregulated in HFD mice compared with CD group, indicating a pro-survival mechanism mediated by inhibition of FKBP5 against inflammatory stress in T2DM. In addition, Foxo3 , a key mediator of apoptosis [ 40 ], was found to be downregulated in HFD mice. Moreover, our results indicated a decreased expression of RIPK1 in the HFD group compared to control mice. Previous evidence suggested that RIPK1 -deficient β-cells are protected from TNFα -induced cell death and caspase activation [ 41 ]. Hence, the reduced expression of FKBP5 , Foxo3 , and RIPK1 in our study highlights a potential mechanism against β-cell apoptosis. Previous research have shown that the loss of Smad2 enhances the expression of proliferative genes in β-cell [ 42 ]. Consistently, we also observed a significant decrease in Smad2 expression level in HFD islets. To sum up, the decreased expression of FKBP5 , Foxo3 , RIPK1 and Smad2 participated in the pathway regulating β-cell mass in HFD mice. Based on this, our target prediction suggested that miR-216a-3p/ FKBP5 , miR-1188-5p/ FKBP5 , miR-670-3p/ Foxo3 , miR-677-5p/ RIPK1 , miR-802-3p/ Smad2 could represent key regulatory axes, and these miRNAs may serve as potential novel therapeutic targets to promote β-cell mass in T2DM. Fig 6B provided a schematic representation of the miRNA-mRNA network involved in β-cell mass.

The target regulatory elements of DE lncRNA in islets

Using the DE lncRNA data, we proceeded to predict the target genes for the DE IncRNAs among the differentially expressed mRNAs (mRNAs that were misregulated in the HFD). In our analysis, we observed that 9 out of the 179 DE lncRNAs displayed significant correlation with 10 DE mRNAs in close genomic proximity (cis-correlation), as depicted in Fig 4C . While most of these DE lncRNAs correlated with a single cis-located mRNA, two lncRNAs, namely chr8:94166252–94173140 and ENSMUST00000176781, were found to be potentially associated with two cis target mRNAs each ( Fig 4C ). These putative target genes were further subjected to GO and KEGG pathway analyses to explore their possible functional connections with the DE lncRNAs.

Based on GO enrichment analysis of the targeted DE mRNAs of DE lncRNAs, the most remarkably enriched term was IgM binding within the MF category. Within the Cellular Component (CC) and Biological Process (BP) categories, the most enriched terms were keratohyalin granule and mammary gland bud morphogenesis, respectively ( Fig 4D ).

The function of the predicted target DE mRNAs of the identified DE lncRNAs was also assessed through KEGG pathway analysis. The top 20 most enriched pathways, as depicted in Fig 4E , notably included apoptosis—multiple species. As regards to the apoptosis pathway, caspase9 was identified as the predicted mRNA regulated by ENSMUST00000176781 . The reduced expression of caspase9 in HFD islets potentially inhibits apoptosis in β-cell [ 43 , 44 ], facilitating increased β-cell mass. Therefore, lncRNA ENSMUST00000176781 might represent a novel therapeutic target to promote β-cell mass increase in T2D (Fig 6B).

Characterization of lncRNA–miRNA–mRNA network reveals potential functional ceRNAs in islets

In addition to mRNAs, several studies have suggested that lncRNAs and circRNAs could also be targeted by miRNAs. These ncRNAs, known as ceRNAs, function by regulating other RNA transcripts through the competition for shared miRNAs [ 29 ]. To gain a better understanding of how mRNA expression is regulated by lncRNAs/circRNAs through their interaction with miRNAs, we constructed a ceRNA regulatiory network involving 7 DE miRNAs, 15 DE lncRNAs and 38 DE mRNAs. While numerous DE circRNAs were identified, a ceRNA molecular network involving circRNA–miRNA–mRNA interactions could not be constructed.

The lncRNA–miRNA–mRNA network was constructed and visualized using “ggalluvial” R package and then imported into the Cytoscape software, enabling the assembly of the regulatory ceRNA network ( Fig 5A and 5B ). This ceRNA network comprises three parts, each centered on 12_4382, miR-1188-5p, miR-216a-3p, miR-3572-5p, miR-670-3p, miR-677-5p, and miR-6964-3p.

(A) Sankey diagram for the ceRNA network in islets. Each rectangle represents a gene, and the connection degree of each gene is displayed based on the size of the rectangle. (B) A ceRNA visual network including 38 DE mRNAs, 15 DE lncRNAs, and 7 DE miRNAs. The diamond represents DE miRNAs, ellipses represent DE mRNAs, and triangles represent DE lncRNAs. (C) GO enrichment analysis of the DE mRNAs in ceRNA network. (D) KEGG enrichment analysis of the DE mRNAs in ceRNA network.

https://doi.org/10.1371/journal.pone.0300965.g005

Thirty-eight mRNAs in the lncRNA–miRNA–mRNA network were subjected to GO and KEGG pathway enrichment analyses. Fig 5C highlighted significantly enriched terms by the mRNAs in the ceRNA network, including chloride ion binding within the MF category, axon terminus in the CC category, and carbohydrate catabolic process in the BP category ( Fig 5C ). As presented in Fig 5D , KEGG pathway enrichment analysis showcased the top 20 pathways related to these genes. We specifically looked into calcium signaling pathway, T2DM pathway, and insulin secretion pathway, all closely associated with diabetes. In miRNA-mRNA networks, the reduced expression of Hk2 , regulated by miR-3572-5p, may also be influenced by lncRNAs Gm12295 (gene id:ENSMUSG00000085162, transcript id: XR_003949565.2), Gm26911 (gene id:ENSMUSG00000097834, transcript id: XR_003956483.2), Gm13657 (gene id:ENSMUSG00000086813, transcript id: XR_004941126.1), Gm49519 (gene id: ENSMUSG00000115756, transcript id: ENSMUST00000227732), and Gm15834 (gene id: ENSMUSG00000085054, transcript id: XR_003947829.2). Similarly, the lowered level of Camk2d expression, which regulated by miR-677-5p, might be affected by lncRNA 5031434O11Rik (gene id: ENSMUSG00000097885, transcript id: ENSMUST00000180616), Gm50100 (gene id: ENSMUSG00000117696, transcript id: XR_001782685.2), E530011L22Rik (gene id: ENSMUSG00000097820, transcript id: ENSMUST00000181325) and Gm34237 (gene id: ENSMUSG00000113330, transcript id: ENSMUST00000220575). In addition, lncRNA Gm44756 (gene id: ENSMUSG00000108432, transcript id: chr7:43938056–43976573) might exerts an effect on the downregulation of Cacna1b by competing for the corresponding miR-6964-3p. The depiction in Fig 6A highlights the changes in the expression of these ceRNAs within the three established lncRNA–miRNA–mRNA networks, offering insight into the impaired insulin secretion observed during the diabetic progression in HFD mice.

(A) The schematic representation illustrating the physiology and key ceRNAs involved in impaired insulin secretion of HFD β-cell. mRNAs are colored in red, miRNAs are colored in green, and lncRNAs are colored in blue. The expression change in HFD mice were indicated with arrows. Created with BioRender.com. (B) The diagrammatic representation depicted an overview of LncRNA/miRNA-mRNA change toward increased β-cell mass of HFD mice. mRNAs are colored in red, miRNAs are colored in green, and lncRNA is colored in blue. The expression change in HFD mice were indicated with arrows. Created with BioRender.com.

https://doi.org/10.1371/journal.pone.0300965.g006

The development of T2DM is a multifaceted process influenced by interaction between genetic inheritance, environmental exposures, obesity, and sedentary lifestyles [ 15 , 45 , 46 ]. Long-term overnutrition is a key contributor to the development of T2DM. To simulate the impact of high energy intake on diabetic progression, we developed an obesity-related diabetic mouse model through a 24-week HFD. As compared to CD mice, those on HFD displayed substantial impairments in glucose regulation, compromised islet function, and exhibited signs of liver steatosis. Through whole transcriptomic sequencing of pancreatic islets in both the 24-week HFD and CD mice, DE miRNA, IncRNAs, cirRNA and their targeted DE mRNAs identified in our study reveal association with reduced insulin secretion, increased β-cell mass, and several other biological progresses. Additionally, our research sheds light on the potential role of non-coding RNA-mediated networks in β-cells, encompassing interactions such as miRNA–mRNA, lncRNA–mRNA, and lncRNA–miRNA–mRNA in the development of T2DM.

Insulin is one of the most important anabolic hormone responsible for regulating glucose and energy homeostasis [ 47 ]. Since Anderson et al. [ 48 ] and Grodsky et al. [ 49 ] first provided pivotal evidence for the canonical model of GSIS around 1950s, significant efforts and progress have led to the identification of critical components within the β-cell metabolic signaling machinery for GSIS. Although the crucial physiological role of glucokinase ( GK ) in β-cell glucose sensing has been extensively documented [ 50 ], Hexokinase ( HK ), another glycolytic enzyme in β-cell has received relatively less attention. Interestingly, studies have reported that the upregulation of HK in β-cells causes a leftward shift of the normal concentration-dependent activation of GSIS, essentially reducing the threshold for glucose sensing [ 51 ]. In our study, we observed that several lncRNAs (Gm12295, Gm26911, Gm13657, Gm49519, and Gm15834) were upregulated in HFD islets and computationally predicted to bind miR-3572-5p, which might influence HK2 expression. The potential downregulation of HK2 in HFD mice could theoretically elevate the threshold for β-cell glucose sensing, potentially contributing to impaired insulin secretion, particularly under low glucose conditions.

β-cells exhibit electrical excitability, with voltage-gated Ca 2+ channels (Ca v channels) playing a pivotal role in the process of insulin secretion [ 52 ]. Beyond their crucial function in regulating insulin exocytosis, Ca v channels in β-cell significantly contribute to cell development, survival, and growth [ 52 , 53 ]. Inappropriate regulation of Ca V channels within β-cell can lead to cellular dysfunction and, in severe cases, may result increased mortality rates associated with both type 1 and type 2 diabetes [ 52 , 54 ]. Cacna1b encodes a subunit responsible for high voltage-gated Ca 2+ channel activity which acts as a source of Ca 2+ required for excitation-secretion coupling [ 55 ]. Meanwhile, Camk2d encodes Ca 2+ calmodulin-dependent protein kinase II, which also plays a significant role in mediating the effect of Ca 2+ cations on insulin exocytosis [ 56 ]. Our data revealed dysregulation of lncRNA–miRNA–mRNA axes, such as Gm44756/miR-6964-3p/ Cacna1b and 5031434O11Rik-Gm50100-E530011L22Rik-Gm34237/miR-677-5p/ Camk2d , could be responsible for the defective Ca 2+ influx and reduced granule release in HFD islets. Taken together, these lncRNAs/miRNAs-associated ceRNA crosstalks provide new insights into the regulation of insulin secretion and offers potential therapeutic targets for addressing impaired glucose homeostasis.

The balance between pancreatic β-cell apoptosis and proliferation is vital for maintaining the β-cell mass [ 57 ]. In response to insulin resistance triggered by overnutrition, β-cells are able to compensate by increasing mass through enhanced proliferation and hypertrophy. While previous studies by Mosser et al . reported rapid β-cell proliferation occurs within 3 days of HFD feeding [ 58 ], our immunofluorescent findings demonstrated a slower rate of proliferation even at 24 weeks of HFD ( Fig 1G and 1I ). Consistently, our whole transcriptomic sequencing data revealed downregulation of several DE mRNAs which targeted by DE miRNAs or DE lncRNAs in HFD islets, such as FKBP5 , Foxo3 , RIPK1 , Smad2 and Caspase9 . The reduced expression of these genes could protect β-cell from inflammatory stress and apoptosis, and enhance proliferation, further contributing to the observed increase in β-cell mass.

The novelty of our study is constructing a ncRNA-associated network to investigate the functional and morphological changes in islets of diet-induced obesity and diabetes model. The whole transcriptomic sequencing and comprehensive analyses that we conducted regarding the interactions of miRNA–mRNA, lncRNA–mRNA, and lncRNA–miRNA–mRNA could provide valuable insights into the underlying mechanisms associated with overnutrition, β-cell dysfunction, and compensatory responses in the context of T2DM. Understanding these interactions is crucial in identifying potential therapeutic targets for more effective T2DM management.

The limitations of the study are acknowledged as follows: Our study showed the development of NAFLD and insulin resistance in HFD model, but we haven’t performed a whole transcriptomic sequencing on liver cells in HFD mice to investigate the associated pathways. Given that liver can regulate β-cell function through various metabolic processes and non-coding RNAs [ 59 , 60 ], conducting liver RNA sequencing simultaneously could offer additional valuable insights into the interplay between the liver and the islets. Furthermore, the predicted targets of DE miRNAs should be further confirmed using methods such as dual luciferase reporter assays, RNA-binding protein immunoprecipitation, and validation at the protein level. In addition, conducting gain- and loss-of-function experiments in future studies is crucial to provide direct experimental evidence of their functional impact. These steps would provide more concrete evidence and strengthen the outcomes of our study.

Supporting information

S1 fig. hfd induced fatty liver, hyperlipidemia, and hepatic toxicity..

(A-B) Representative images of H&E (A) and Oil-red O staining (B) of liver sections. Original magnification ×50 and ×200. (C-G) The average serum TC, TG, LDL, AST and ALT levels of HFD and CD mice. (n≥ 14 mice /group). Data presented as mean ± SEM. **p<0.01, ***p<0.005, **** p<0.001.

https://doi.org/10.1371/journal.pone.0300965.s001

S2 Fig. The expressional pattern of differentially expressed circRNAs from HFD and CD islets.

(A) Differentially expressed circRNAs were exhibited by volcanoplot. (B) Differentially expressed circRNAs were exhibited by clustering analysis.

https://doi.org/10.1371/journal.pone.0300965.s002

S1 Table. Differentially expressed mRNAs.

https://doi.org/10.1371/journal.pone.0300965.s003

S2 Table. Differentially expressed miRNAs.

https://doi.org/10.1371/journal.pone.0300965.s004

S3 Table. Differentially expressed lncRNAs.

https://doi.org/10.1371/journal.pone.0300965.s005

S4 Table. Differentially expressed circRNAs.

https://doi.org/10.1371/journal.pone.0300965.s006

Acknowledgments

We thank Dr Andrei Tarasov (University of Ulster and University of Oxford) for helpful discussions and comments.

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Elements and Minerals in Type 2 Diabetes Mellitus

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Trace elements are essential for the biological, chemical and molecular activities of cell. These agents play a key role in biochemical reactions by acting as cofactors for enzymes. The use of trace elements including copper, zinc, selenium, and magnesium is an important procedure in the management of type 2 ...

Keywords : Trace elements, Minerals, Saliva, Type II Diabetes, Ferroptosis, Apoptosis, Autophagy, Cell Death

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Lipidome characterisation and sex-specific differences in type 1 and type 2 diabetes mellitus

• Maria Barranco-Altirriba 1 , 2 , 3 , 4 ,
• Núria Alonso 5 , 6 , 7 ,
• Ralf J. M. Weber 8 , 9 , 10 ,
• Gavin R. Lloyd 8 , 9 , 10 ,
• Marta Hernandez 11 ,
• Oscar Yanes 5 , 12 ,
• Jordi Capellades 5 , 13 ,
• Andris Jankevics 14 , 15 ,
• Catherine Winder 8 , 9 , 16 ,
• Mireia Falguera 17 ,
• Josep Franch-Nadal 5 , 18 ,
• Warwick B Dunn 8 , 9 , 16 ,
• Alexandre Perera-Lluna 2 , 3 , 4 ,
• Esmeralda Castelblanco 19 , 20 &
• Didac Mauricio 1 , 5 , 21 , 22  

Cardiovascular Diabetology volume  23 , Article number:  109 ( 2024 ) Cite this article

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In this study, we evaluated the lipidome alterations caused by type 1 diabetes (T1D) and type 2 diabetes (T2D), by determining lipids significantly associated with diabetes overall and in both sexes, and lipids associated with the glycaemic state.

An untargeted lipidomic analysis was performed to measure the lipid profiles of 360 subjects (91 T1D, 91 T2D, 74 with prediabetes and 104 controls (CT)) without cardiovascular and/or chronic kidney disease. Ultra-high performance liquid chromatography-electrospray ionization mass spectrometry (UHPLC-ESI-MS) was conducted in two ion modes (positive and negative). We used multiple linear regression models to (1) assess the association between each lipid feature and each condition, (2) determine sex-specific differences related to diabetes, and (3) identify lipids associated with the glycaemic state by considering the prediabetes stage. The models were adjusted by sex, age, hypertension, dyslipidaemia, body mass index, glucose, smoking, systolic blood pressure, triglycerides, HDL cholesterol, LDL cholesterol, alternate Mediterranean diet score (aMED) and estimated glomerular filtration rate (eGFR); diabetes duration and glycated haemoglobin (HbA1c) were also included in the comparison between T1D and T2D.

A total of 54 unique lipid subspecies from 15 unique lipid classes were annotated. Lysophosphatidylcholines (LPC) and ceramides (Cer) showed opposite effects in subjects with T1D and subjects with T2D, LPCs being mainly up-regulated in T1D and down-regulated in T2D, and Cer being up-regulated in T2D and down-regulated in T1D. Also, Phosphatidylcholines were clearly down-regulated in subjects with T1D. Regarding sex-specific differences, ceramides and phosphatidylcholines exhibited important diabetes-associated differences due to sex. Concerning the glycaemic state, we found a gradual increase of a panel of 1-deoxyceramides from normoglycemia to prediabetes to T2D.

Conclusions

Our findings revealed an extensive disruption of lipid metabolism in both T1D and T2D. Additionally, we found sex-specific lipidome changes associated with diabetes, and lipids associated with the glycaemic state that can be linked to previously described molecular mechanisms in diabetes.

Introduction

Diabetes mellitus (DM) is characterized by chronic hyperglycaemia that leads to heterogenous disturbances of metabolism [ 1 ] and its continuing rise is a major concern in society [ 2 ]. DM is one of the main risk factors for cardiovascular disease and other conditions [ 3 ]. Therefore, a better understanding of diabetes pathophysiology has become a subject of major interest in research.

Lipid disruption has been associated with many human diseases, leading to the rise in the relevance of lipidomics, an emerging field involving the study of lipids and factors that interact with lipids [ 4 ]. The association between lipids and DM has been widely recognised. Advanced lipoprotein analyses have shown a reduction in serum concentrations of triglycerides (TG), cholesterol, and apolipoprotein (Apo)B-containing lipoproteins when comparing subjects at the onset of T1D and after achieving optimal glycaemic control [ 5 ]. In addition, epidemiological studies have shown a close relationship between low-density lipoprotein cholesterol (LDL-cholesterol) and high-density lipoprotein cholesterol (HDL-cholesterol) concentrations in T2D. However, the complexity of the associations between diabetes and lipid metabolites is underestimated in these studies since lipoproteins contain a great variety of lipids that remain unanalysed, highlighting the crucial role lipidomics can play [ 6 ].

The association between lipid species and T1D still needs to be fully understood. Most of the studies have focused on biomarker discovery for T1D risk during childhood [ 7 ]. One study reported several lipid species significantly altered in subjects at the onset of T1D and after achieving glycaemic control [ 8 ]. On the other hand, the number of studies focused on lipidomic changes associated with T2D risk is higher [ 9 , 10 , 11 , 12 ]. Lipidome differences between normoglycemic, prediabetic and T2D subjects have also been described [ 13 ], as well as lipid species significantly associated with T2D complications, such as diabetic retinopathy [ 14 ], diabetic neuropathy [ 15 ] or diabetic nephropathy [ 16 ].

Nevertheless, to the best of our knowledge, there is a lack of studies comparing the lipidome of subjects with T1D and T2D. Moreover, some studies have shown evidence that the risk of diabetes complications differs between the sexes [ 17 ]; however, the underlying mechanisms behind these sex-specific differences are poorly understood.

In the present study, we extensively investigated the serum lipidome of T1D, T2D, and non-diabetic subjects through an untargeted lipidomics analysis using Ultra High-Performance Liquid Chromatography-Mass Spectrometry (UHPLC-MS). Our objectives were to identify lipid subspecies that differ between (1) subjects with T1D and with T2D, (2) subjects with T1D and non-diabetic subjects, (3) subjects with T2D and non-diabetic subjects, (4) to determine sex-specific differences in each of the above-mentioned comparisons, and (5) compare the lipidome between normoglycemia, prediabetes and T2D.

Participants

In this study, 536 participants including 156 with T1D, 159 with T2D, and 221 without diabetes and matched by sex and BMI, were selected from previous cohorts, at the University Hospitals Arnau de Vilanova (Lleida, Spain), Germans Trias i Pujol (Badalona, Spain), Clinic (Barcelona, Spain), and the Primary Care Center Mollerussa (Lleida, Spain) [ 18 , 19 , 20 , 21 ] (Additional File1 - Figure S1 ). The inclusion criteria for all groups were: aged between 20 and 85 years, the absence of established chronic kidney disease (defined as calculated glomerular filtration rate < 60 mL/min and/or urine albumin/creatinine ratio > 299 mg/g), and absence of known clinical cardiovascular events or associated revascularization procedures, including coronary heart disease, cerebrovascular disease, or peripheral vascular disease (including the diagnosis of diabetic foot disease).

Age, sex, tobacco exposure and pharmacological treatment were recorded. Diabetes duration was acquired from the medical records. Subjects were considered to have hypertension or dyslipidaemia if they were under anti-hypertensive or lipid-lowering treatment, respectively. Anthropometric data, weight, height, waist circumference, BMI, and blood pressure were obtained using standard methods. The standard biochemical analysis included glucose and glycated hemoglobin (HbA1c), lipid profile, and estimated glomerular filtration rate calculated according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation [ 22 ]. The dietary pattern was assessed using the alternate Mediterranean Diet score (aMED), as described previously [ 23 ]. This score includes monounsaturated-to-saturated fat ratio, legumes, vegetables, nuts, fruits, nuts, cereals, fish, meat and wine. This score ranges from 0 to 9, with higher scores indicative of a higher adherence to the MedDiet.

Blood samples were collected in the fasting state and blood tests were conducted using standard laboratory methods [ 18 ]. Urine tests were performed in subjects with diabetes following standard laboratory methods. Subjects with normoglycemia and prediabetes were classified using the American Diabetes Association criteria (glycated haemoglobin (HbA1c) < 5.7% or fasting plasma glucose ≤ 100 mg/dL for normoglycemia; and HbA1c between 5.7% and < 6.5% or fasting plasma glucose between 101 mg/dL and < 126 mg/dL for prediabetes) [ 24 ].

Blood samples for the lipidomic analyses were collected in the fasting state with EDTA tubes, processed immediately after extraction, and stored at − 80 °C at the biobanks of the participant centres until determination.

From the 536 samples, 23 were discarded due to technical problems, and for the present study, the lipid profiles of 360 participants, 91 with T1D, 91 with T2D and 178 without diabetes were selected from the full cohort (Additional File 1 - Figure S1 ). Serum samples for all the selected participants were collected by University Hospital Arnau of Vilanova (Lleida, Spain) and the Mollerussa Primary Health care area (Lleida, Spain), as part of previously published studies [ 18 , 19 , 20 ]. The acquisition, processing and storage of these samples were performed in the same facility, and the geographic location of the subjects was the same, thus avoiding any variability due to sample origin that might be present in the full cohort (Additional File 1 - Figure S1 ).

Sample preparation

Due to the large number of samples in the full cohort, samples were randomly assigned to one of 6 batches. To reduce the impact of technical factors, the sample order within each batch was randomized before sample preparation, and then again prior to measurement of the lipid profile by UHPLC-ESI-MS/MS. All serum samples were defrosted on ice, and each sample was aliquoted (50 µL) to create a pooled quality control (QC) representative of all samples in the study. The pooled QC was vortexed, further aliquoted (50 µL), and stored at -80 °C until the analysis of each of the 6 batches of QC samples. Lipid extraction was performed by mixing 50 µL of biological sample or QC with 150 µL isopropanol (LC-MS grade), vortexed for 20 s, and centrifuged at 22,000 g for 20 min at 4 °C. 120 µL of the supernatant was transferred to a low recovery vial and transferred to the LC sample manager at 4 °C.

Ultra-high-performance liquid chromatography-mass spectrometry

Samples were maintained at 4 °C and analysed by applying UHPLC-MS methods using a Dionex UltiMate 3000 Rapid Separation LC system (Thermo Fisher Scientific, MA, USA) coupled with a heated electrospray Q Exactive Focus mass spectrometer (Thermo Fisher Scientific, MA, USA). Non-polar extracts were analysed on a Hypersil GOLD column (100 × 2.1 mm, 1.9 μm; Thermo Fisher Scientific, MA, USA). Mobile phase A consisted of 10 mM ammonium formate and 0.1% formic acid in 60% acetonitrile/water and mobile phase B consisted of 10 mM ammonium formate and 0.1% formic acid in 90% propan-2-ol/water. Flow rate was set for 0.40 mL/min with the following gradient: t = 0.0, 20% B; t = 0.5, 20% B, t = 8.5, 100% B; t = 9.5, 100% B; t = 11.5, 20% B; t = 14.0, 20% B, all changes were linear with curve = 5. The column temperature was set to 55 °C and the injection volume was 2µL. Data were acquired in positive and negative ionization mode separately within the mass range of 150–2000 m/z at resolution 70,000 (FWHM at m/z 200). Ion source parameters were: sheath gas = 50 arbitrary units, Aux gas = 13 arbitrary units, sweep gas 3 arbitrary units, spray voltage 3.5 kV (positive ion mode) and 3.1 kV (negative ion mode), Capillary temp = 263 °C, and Aux gas heater = 425 °C. Data dependent MS2 in ‘Discover mode’ was applied for the MS/MS spectral acquisition with the following settings: resolution at 17,500 (FWHM at m/z 200), isolation width 3.0 m/z , stepped normalised collision energy at 20, 50 and 80%. Spectra were acquired at three mass ranges 200–400 m/z , 400–700 m/z and 700–1500 m/z on the pooled QC samples. Thermo ExactiveTune (2.8 SP1 build 2806) software was used to control the instrument in both cases, with data acquired in profile mode. Quality control samples were acquired in both profile and dependent scan mode at the start of the run (i.e., 7 QCs MS1 only, 3 QCs with MS2) and then every seventh injection with two QC samples at the end of the analytical batch. Preparation blank samples were analysed between QCs 5 and 6 and at the end of the analytical batch.

Mass spectrometry raw data processing

Raw data acquired in each analytical batch were converted from the instrument-specific format to a mzML file format using the open access ProteoWizard (version 3.0.11417) msconvert tool [ 25 ]. Deconvolution was performed by the R package XCMS (version 1.46.0, running in the Galaxy workflow environment) [ 26 ]. Isotopologue Parameter Optimization (IPO - version 1.0.0) [ 27 ] was used to optimise the XCMS peak picking parameters. A data matrix of metabolite features (m/z-retention time pairs) versus samples was constructed with peak areas provided.

Assessment of data quality and peak matrix filtering

The first five QCs for each batch were used to equilibrate the analytical system and therefore subsequently removed before the data was processed and analysed. Data matrices were corrected for run-order drift in intensity for each lipid feature separately using the Quality Control-Robust Spline Correction (QC-RSC) algorithm [ 28 ] in the R environment using the pmp package [ 29 ]. Principal Component Analysis (PCA) was used to identify and remove (PCs 1 and 2, Hotelling T 2 p  < 0.05) suspected outlier (QC) samples within each batch to ensure robust correction. Blank samples at the start and end of a run were used to remove features from non-biological origins. Any feature with an average QC intensity less than 20 times the average intensity of the blanks was removed. Any sample with > 50% missing values was excluded from further analysis. Metabolite features with RSD > 30% and present in less than 90% of the QC samples were deleted from the dataset. Features with a < 50% detection rate over all samples were also removed. All data preparation steps were undertaken in R using the structToolbox package [ 30 , 31 ].

Statistical analysis

After removing the observations with missing values in the variables included in the models (Additional File 1 - Figure S1 ), the clinical data of participants was summarised as mean (standard deviation) for continuous variables and as frequency (percentage) for categorical data, using the compareGroups R package [ 32 ].

Analysis of the UHPLC-ESI-MS/MS data was conducted in the R environment [ 33 ]. Prior to the statistical analysis, Probabilistic Quotient Normalization (PQN) [ 34 ], using the mean of the QC samples as a reference, was applied. Data were log-transformed to reduce skewness.

Multiple linear regression models were used to assess the association between each metabolite and T1D, T2D, and non-diabetic controls (CT). Three different comparisons were performed: T1D against T2D, T1D against CT, and T2D against CT. The models were adjusted by sex, age, hypertension, dyslipidaemia, body mass index, glucose, smoking, systolic blood pressure, TG, HDL cholesterol, LDL cholesterol, alternate Mediterranean diet score and estimated glomerular filtration rate (eGFR); diabetes duration and glycated haemoglobin (HbA1c) were also included in the T1D and T2D comparison.

Regarding the sex-specific differences related to diabetes, the same linear models were used, but an interaction term between diabetes and sex (basal level: men) was added. Using this configuration, the p-value and regressor (β Men ) associated with the diabetes variable were assigned to men. The effect of diabetes in women (β Women ) was computed by summing the regressor of the diabetes variable and the interaction between diabetes and sex. The standard error of the effect was computed, the t-value was obtained by dividing β Women by its standard error, and the p-value associated with diabetes in women was computed using this t-value.

Concerning the lipid alterations associated with the glycaemic state, we considered the following categories: normoglycemia, prediabetes and T2D. The models were adjusted using the confounding factors mentioned above, and a numeric variable defining the glycaemic state: 0, normoglycemia; 1, prediabetes; 2, T2D.

In all analyses, False Discovery Rate (FDR) correction was performed, and a corrected p-value of < 0.05 was considered significant. For each comparison, we present significant p-values that correspond to lipids when not considering the interaction effect between diabetes and sex (all subjects), p-values for men, p-values for women, and p-values for the glycaemic state.

A description of each analysis is shown in Additional File 1 (Table S1 ). LipidSearch was used to annotate lipid species. Annotations with grades A or B were mapped to XCMS-detected features based on an absolute ppm error less than 5 and an absolute retention time tolerance of less than 5 s.

Clinical and biological parameters

The baseline characteristics for each group according to diabetes status are shown in Table  1 . Subjects with T1D had longer diabetes duration, and higher HDL-cholesterol in comparison with subjects with T2D. On the other hand, subjects with T2D were older, had a higher BMI, higher HbA1c, and higher frequency of hypertension and dyslipidaemia. In Additional File 1 (Table S2 ), the baseline characteristics for each comparison are shown.

Data are mean (SD) for continuous variables and number (%) for categorical variables. For continuous variables, the p-values are obtained using a student’s t-test and for categorical variables, a chi-squared test. BMI, body mass index; DM, diabetes mellitus; HbA1c, glycated haemoglobin; sBP, systolic blood pressure; dBP, diastolic blood pressure; TG, triglycerides; HDL, high-density lipoprotein; LDL, low-density lipoprotein; aMED, alternate Mediterranean diet score; eGFR, estimated glomerular filtration rate.

Lipid markers of diabetes mellitus

Table  2 shows the overall number of lipidomic features that were significantly different in the comparisons (corrected p-value lower than 0.05), and of those, the number that were annotated using LipidSearch. When comparing T1D and T2D subjects, 30 lipid species (positive and negative ion modes combined) obtained a corrected p-value lower than 0.05 both in males and females (all subjects), 16 lipids were found in females and 17 in males. In the comparison between T1D and CT, 35 lipids were statistically significant in all subjects, 11 lipids in women only, and 16 in men only. Finally, when comparing T2D vs. CT, 15 lipids were significantly different in all subjects, 10 in women only, and 10 in men only. Overall, 54 unique lipid species from 15 classes were determined as significant features across all comparisons.

UpSet plots depicting the number of unique and shared (i.e., intersections) significant lipidomic features in the different comparisons in positive and negative acquisition modes are shown in Additional File 1 (Figures S2 and S3 ), respectively.

Figure 1 shows the lipid classes that differ in the comparisons according to diabetes status. When comparing both diabetic conditions, lysophosphatidylcholines (LPC) and ceramides (Cer) were more importantly altered than other lipid classes (Fig.  1 A). In a similar way, LPCs, phosphatidylcholines (PC), phosphatidylethanolamines (PE) and TGs were especially altered in T1D (Fig.  1 B), as well as Cer in T2D (Fig.  1 C). Additional File 2 (Table S3 ) reports the mass-to-charge ratio (mz) and retention time (rt) for each lipid ion significantly associated with one of these conditions in at least one of the analyses. Moreover, the range of corrected p-values, ionization mode and the list of analyses corresponding to the significant corrected p-value is also shown in Additional File 2 (Table S3 )

Figure  1 . Manhattan plots of the minus logarithm of the corrected p-values (y axis) for each of the lipid classes (x axis) obtained in the analysis of A ) T1D vs. T2D, B ) T1D vs. CT and C ) T2D vs. CT. Corrected p-values are shown for the features that had been annotated using LipidSearch and fulfilled the quality criteria described in the Methods section. The dashed line indicates the threshold of significance ( \(0.05\) ). AcCa, acylcarnitine; Cer, ceramide; ChE, cholesterol esther; Co, coenzyme; DG, diacylglycerol, dMePE, dimethylphosphatidylethanolamine; Hex1Cer, hexosylceramides; Hex2Cer, dihexosylceramides; Hex3Cer, trihexosylceramides; LdMePE, lysodimethylphosphatidylethanolamine; LPA, Lysophosphatidic acid; LPC, lysophosphatidylcholine; LPE, lysophosphatidylethanolamine; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PI, phosphatidylinositol; SM, sphingomyelin; ST, sterol; StE, Stigmasteryl ester; TG, triacylglycerol; ZyE, Zymosteryl ester

In Figure  2 , the fold-changes and significance level of the lipids significantly altered in at least one of the analyses are shown.

Fold-change values and statistical significance obtained for each lipid determined as being significantly different in at least one of the nine analyses conducted. Statistical significance is indicated using asterisks: corrected p-value (p) < 0.05 (*), p  < 0.01 (**), p  < 0.001 (***), p  < 0.0001 (****). Bars in the right side of each panel indicate a positive fold-change value, while bars in the left indicate a negative one. A positive fold-change indicates that the lipid is increased in the first group (e.g. in T1D vs. T2D, TG(18:1_18:1_18:2) is significantly increased in T1D with respect to T2D). The different colours in the background of the plot show the different lipid classes. In the left, the names of the lipid subspecies are shown. The nomenclatures of the type 16:1e indicate that the fatty acid (FA) of the glycerophospholipid is linked to the glycerol moiety by an ether bond, therefore, the mentioned glycerophospholipid is an ether-glycerophospholipid

In general, TGs, sphingomyelins (SMs), PCs, diacylglycerols (DGs) and ceramide lipids were down-regulated in subjects with T1D, while phosphatidylethanolamines (PE) lysophosphatidylethanolamines (LPEs) and LPCs were mainly up-regulated when compared to CT. On the other hand, some LPCs were down-regulated in T2D subjects and ceramide lipids were mostly up-regulated with respect to controls. Results comparing T1D and T2D support the observed opposing effects seen in comparisons against the control group. A generalized opposite disruption of ceramide lipids and LPCs in subjects with T1D and subjects with T2D could be detected. Contrary to LPCs, ceramide lipids were mainly upregulated in T2D with respect to T1D. Specifically, the ceramide lipids increased in T2D were 1-deoxyceramides (i.e., Cer(m18:1_22:0), Cer(m18:0_22:0), Cer(m18:1_23:0), Cer(m18:0_23:0), Cer(m18:0_24:1) and Cer(m18:0_24:0)) (Fig.  2 ).

Several sex-specific lipidomic differences were detected, as shown in Fig.  2 . These alterations are further illustrated in Figs.  3 and 4 for T2D and controls comparison and T1D and controls comparison, respectively.

Boxplots of lipids that are significantly associated with T2D in men or women. The nomenclatures of the type 16:1e indicate that the fatty acid (FA) of the glycerophospholipid is linked to the glycerol moiety by an ether bond, therefore, the mentioned glycerophospholipid is an ether-glycerophospholipid

Boxplots of 20 selected lipids significantly associated with T1D in men or women

In general, our results showed that PC levels were higher in normoglycemic women than their male counterparts.

Figure  5 shows lipids significantly associated with a numeric variable that describes glycaemic stag, by considering the prediabetes stage. Although Co(Q10) was not statistically significant (q-value = 0.07), the boxplot shown in Fig.  5 shows a gradual decrease through the glycaemic progression.

Boxplots of lipids significantly associated with the numeric variable defined as 0 for normoglycemia, 1 for prediabetes and 2 for T2D

Our results show a consistent alteration of ceramides, revealing a gradual increase of these lipids in the stage of prediabetes to T2D.

Through an untargeted lipidomic serum profiling approach, we investigated the lipidomic alterations in type 1 and type 2 diabetes; the sex-specific differences in these diseases and the glycaemic state by considering the prediabetes stage. The results reported in the present study have revealed 54 lipid species belonging to 15 different lipid classes potentially implicated in well-known mechanisms involved in type 1 and type 2 diabetes.

Lysophosphatidylcholine acyltransferase (LCAT) activity

Our results have revealed a panel of LPCs significantly increased in T1D, specifically LPC(26:0), LPC(20:1), LPC(18:1) and LPC(18:2). These findings are in agreement with other studies, where LPC(18:3) has been consistently found to be positively associated with T1D or in those at risk [ 7 ]. The mechanisms behind this increase are unclear; however, SMs have been described as inhibitors of LCAT, enzyme responsible of LPCs and cholesteryl esters synthesis from PCs [ 35 ]. In our study, SM(d18:2_22:2) was significantly reduced in T1D subjects, which could be a potential explanation for an enhanced activity of LCAT and a subsequent increase of LPC levels. Furthermore, we observed a general decrease of a set of PC species in subjects with T1D. This aligns with some studies that showed a negative association between PC levels and T1D risk [ 36 , 37 ], and concurs with the suspected enhancement of LCAT activity. The potential consequences of these changes should also be considered. Serum levels of LPC(18:1) and LPC(18:2) were found to be significantly higher in children with T1D after a diabetes ketoacidosis or a hypoglycaemic episode [ 38 ], suggesting an association between certain diabetes complications and LPCs.

Although non-significant, our results showed a reduction of LPC levels in T2D compared to controls, and a significant reduction of LPC(20:1) and LPC(18:2) when compared to subjects with T1D. Moreover, PC(18:0_22:5) and PC(18:0_20:3) were significantly increased in subjects with T2D versus controls. Our results are aligned with other studies that showed a positive association between PCs and T2D risk [ 39 ], and suggested a reduction of LCAT activity in T2D [ 40 , 41 ] and a negative correlation between LCAT activity and HbA1c [ 40 , 41 , 42 ]. A potential mechanism behind this relationship is the non-enzymatic glycation of apolipoprotein A-I in HDL particles due to hyperglycemia [ 40 , 42 ].

Polyunsaturated fatty acids (PUFAs)

Our findings also showed a general down-regulation of TG and DG containing PUFAs in subjects with T1D when compared to controls and subjects with T2D. The decrease of oleic (16:1) and palmitoleic (18:1) acids, as well as a reduction in the synthesis of omega-6 and omega-3 PUFAs in T1D has been previously described. This reduction is caused by decreased activity of Δ6 desaturase and the stearoyl-CoA desaturases (SCD). mRNA transcription of these desaturases is activated by the protein SREBP-1c, the expression and activation of which is modulated by insulin and therefore, reduced in T1D [ 43 ]. This mechanism could be an explanation for the significant reduction of PUFA-containing TGs and DGs in subjects with T1D. This becomes even more feasible if we consider that all the TGs and DGs found to be significantly reduced in our study, contain at least one of the previously mentioned fatty acids (16:1, 18:2, 18:3 and 20:5).

Ether lipids

Peroxisomal defects causing decreased levels of serum ether lipids have been associated with neurodegenerative diseases, cancer, obesity, hypertension [ 44 ] and T2D [ 45 ]. Plasmalogen PEs containing PUFA have been associated with lower risk of T2D [ 46 ]. However, in the present study, PE(20:0p_18:2) was significantly increased in subjects with T1D and T2D when compared to controls, and PE(16:0p_18:1) and PE(16:1e_18:1) were significantly increased in subjects with T1D. On the other hand, previous studies have revealed reduced levels of ether PCs in lean subjects with T2D [ 45 ] and in HDL particles of subjects with T2D [ 9 ], as well as inverse associations between ether PCs and T2D risk [ 39 ]. Moreover, ether PCs have been positively associated with longevity [ 47 ]. Although our results do not show a significant association between ether PCs and diabetes, we have found lower levels of ether LPCs (LPC(18:1e) and LPC(18:2e)) in subjects with T2D, supporting the previously hypothesized peroxisomal defect associated with T2D.

Phosphatidylethanolamines and Lysophosphatidylethanolamines

Regarding phosphatidylethanolamines (PEs), we showed an increase of PE(18:0_20:3) and PE(16:0_18:2) in subjects with T2D. Previous work has reported increased serum levels of PEs in T2D obese subjects. The mechanism proposed to explain this alteration was a higher abundance of PEs in VLDL particles compared to HDL particles, and a relative increase of VLDL particles in obese T2D subjects [ 45 ]. Furthermore, another study showed enrichment of PE(38:5), PE(38:6), and PE(40:7) in HDL particles in patients with T2D and CHD [ 9 ]. This could explain the increase in PEs observed in the present study, since the lipid species observed in lipidomics mainly stem from circulant lipoproteins. Additionally, PEs have been described as modulators of inflammation and apoptosis [ 47 ]. In line with this, our results revealed two PE species, PE(18:0_18:1) and PE(18:1_18:2), significantly increased in subjects with T1D, and interestingly one of their metabolic products LPE(18:1) also increased in T1D. On the other hand, PE(18:0_22:6) was significantly decreased in subjects with T1D, as well as one of its plausible products, LPE(22:6).

Sphingolipids

The direct inhibition of the insulin-signalling pathway caused by sphingolipids has been widely described. Ceramides accumulation interferes in the insulin-stimulated activation of protein kinase B (Akt/PKB), which decreases glucose uptake in skeletal muscles and activates gluconeogenesis and glycogenolysis in the liver. On the other hand, several studies support the theory that elevated intracellular levels of sphingolipids may hinder mitochondrial respiratory chain activity, thus causing alterations in mitochondrial metabolism [ 48 ]. Our results revealed an increase of a set of 1-deoxyceramides, Cer(m18:1_22:0), Cer(m18:0_22:0), Cer(m18:1_23:0), Cer(m18:0_23:0), Cer(m18:0_24:1), Cer(m18:0_24:0), in subjects with T2D compared to subjects with T1D and controls. Moreover, this significant association is maintained when comparing normoglycemia, prediabetes and T2D, showing a gradual increase with the glycaemic state. Related to this, it is quite relevant that we found coenzyme Q10, Co(Q10), to be significantly decreased in subjects with T2D compared to controls. Co(Q10) has a key role in the electron transport chain of the mitochondria and its deficiency in subjects with T2D has been previously described [ 49 ]. This concurs with our results and is probably related to the above-mentioned mitochondrial dysfunction. Even though this molecule has not been found significantly associated in the prediabetes analysis (q-value = 0.07), the corrected p-value is close to significance. The plot of its progression has been added to the main manuscript, and it is possible to see a non-linear gradual decrease from normoglycemia to T2D.

Sex-specific metabolic changes in type 1 and type 2 diabetes

It has been shown that women have a steeper age-related increase of ceramide levels [ 50 ]. The loss of oestrogens during and after menopause has been proposed as the main mechanism behind this pattern [ 50 , 51 ], but other processes have been proposed, such as the differences in sex steroids or the higher levels of oxidative stress in post-menopausal women [ 51 ]. Moreover, pre-menopausal women have better cardiovascular health and CVD outcomes than men, but this tendency changes during and after menopause. Ceramides might have a key role in this process, due to the strong relationship between oestrogens and sphingolipid metabolism and the association of ceramides with apoptosis, oxidative stress, inflammation and endothelial dysfunction [ 52 ]. Further, menopause has been associated with an increased risk of T2D [ 53 ]. In our study, the age of the female subgroup with T2D was 57.3 (SD: 10.6) years. Therefore, we might assume that in a large proportion of the subjects, menopause was playing a role in the lipidomic differences observed. We found one 1-deoxyceramide, Cer(m18:1_20:0), significantly associated with T2D in women but not in men, and in general, the fold-changes and the significance level of the significant 1-deoxyceramides in T2D were higher in women than in men (Fig.  2 ). Diabetes has been shown to attenuate the protective effect of the female sex in the development of cardiac diseases and nephropathy [ 54 ]. The specific lipids that differ between sexes found in the present study could explain the greater impact of T2D complications in post-menopausal women.

Our results also revealed a greater T1D-associated alteration of ceramide metabolism in men, specifically, Cer(d18:1_20:0) and Cer(d18:1_18:0) were significantly decreased only in men. Reduced levels of very long chain ceramide species have been associated with the development of macroalbuminuria [ 55 ], while male sex has been reported as a risk factor for the development of macroalbuminuria associated with T1D [ 56 ]. Moreover, we revealed a panel of LPCs significantly increased only in men. It has been shown that LPA and LPCs accumulate in the kidney and promote renal inflammation and tubulo-interstitial fibrosis in diabetic rodent models. Six species of LPAs and LPCs were found to be significantly enriched in the urine, but not in plasma, of people with T2D with nephropathy [ 57 ]. The mentioned sex-related lipidic differences could help to explain the worse prognosis of T1D-related diabetic nephropathy in men compared to women.

Strengths and limitations

Our study has several strengths, such as the large number of covariables used in our linear models to minimize confounding, the untargeted approach that allows for a more comprehensive characterisation of the lipidome in people with diabetes, and the consideration of sex-specific lipid differences associated with diabetes. There are also some limitations. First, our findings have not been validated in an independent cohort, and secondly, the observational nature of our study does not allow us to make causal inference. Therefore, further research is required to assess diabetes progression and its complications. Interestingly, our study shows the need to investigate this matter in a sex-specific manner.

In conclusion, we detected a panel of lipids associated with T1D and T2D, sex-specific differences in lipid metabolism disruption associated with diabetes and lipids associated with the glycaemic state, by considering the prediabetes stage. A large part of the lipids reported in this study have previously been linked to T1D, T2D and/or their complications in the literature, thus confirming their role in diabetes. Regarding sex-specific differences, we reported several lipid species associated with T2D only in women that have been previously related to menopause. This could help explain an unfavourable prognosis of T2D in women of older age compared to their male counterparts. In a similar way, we have shown a set of lipids associated with T1D only in men that have been previously linked to diabetic nephropathy, potentially explaining the worse prognosis of diabetic nephropathy in men. Our findings point to the need of establishing sex-specific strategies in the management and research on diabetes mellitus and its associated comorbidities and suggest the importance of lipidomics in advancing personalized medicine.

Data availability

No datasets were generated or analysed during the current study.

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Acknowledgements

We want to particularly acknowledge the participants, and the IGTP-HUGTP (B.0000643) and IRBLleida Biobank (B.0000682) integrated in the PLATAFORMA BIOBANCOS (PT20/00050 and PT20/00021, respectively). The authors are also thankful to the COST Action EpiLipidNET, CA19105 - Pan-European Network in Lipidomics and EpiLipidomics. The first author gratefully acknowledges the Universitat Politècnica de Catalunya and Banco Santander for the financial support of her predoctoral grant. We would like to thank Joana Rossell and Minerva Granado-Casas for her feedback during the revision process. The authors acknowledge Amanda Prowse (Lochside Medical Communications Ltd.) for support in editing the paper.

This work was funded by Spanish Ministry of Health, Instituto de Salud Carlos III (Madrid, Spain) grants PI15/0625 (to DM and EC), PI17/01362 (to NA), PI18/0328 (to DM), FEDER “Una manera de hacer Europa”, and by Fundació La Marató de TV3 2016 (303/C/2016) (201602.30.31) (to NA). Spanish Ministry of Economy and Competitiveness, grant PID2021-122952OB-I00 funded by AEI 10.13039/501100011033 and by ERDF A way of making Europe, Instituto de Salud Carlos III (grant AC22/00035); and the CERCA Programme / Generalitat de Catalunya (to AP). This research was supported by CIBER-Consorcio Centro de Investigación Biomèdica en Red-CIBERDEM (leading group CB15/00071) and Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III, Ministry of Science and Innovation. Institut de Recerca de l’Hospital de la Santa Creu i Sant Pau is accredited by the Generalitat de Catalunya as Centre de Recerca de Catalunya (CERCA). B2SLab is certified as 2021 SGR 01052.

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Maria Barranco-Altirriba & Didac Mauricio

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Núria Alonso, Oscar Yanes, Jordi Capellades, Josep Franch-Nadal & Didac Mauricio

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Núria Alonso

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School of Biosciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK

Ralf J. M. Weber, Gavin R. Lloyd, Catherine Winder & Warwick B Dunn

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Jordi Capellades

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Josep Franch-Nadal

Division of Endocrinology, Metabolism and Lipid Research, Department of Internal Medicine, Washington University School of Medicine, 63110, St. Louis, MO, USA

Esmeralda Castelblanco

Unitat de Suport a la Recerca Barcelona, Institut Universitari d’Investigació en Atenció Primària Jordi Gol i Gurina, 08007, Barcelona, Spain

Institut d’Investigació Biomèdica Sant Pau (IR Sant Pau), 08041, Barcelona, Spain

Didac Mauricio

Faculty of Medicine, University of Vic, Vic, Spain

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Contributions

DM, NA and EC conceived and designed the study; WD, CW, MH, MF, JF, OY, JC participated in data acquisition, RW, GL and AJ participated in lipidomic data processing; MB and AP contributed to statistical analysis and the design of figures and tables; MB and EC drafted the manuscript; DM, AP, EC, MB, RW and GL contributed to expert review, data interpretation and literature review; DM, AP and EC supervised the study; DM, EC, NA contributed with funding acquisition. All authors have reviewed and agree to the published version of the manuscript. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Correspondence to Esmeralda Castelblanco or Didac Mauricio .

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This study was approved by the local ethics committee of the University Hospital Germans Trias i Pujol (PI-15-147), following the principles of the Declaration of Helsinki. All participants provided written informed consent.

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Competing interests

Prof. Mauricio is a co-author of this study and an Editorial Board member of the Cardiovascular diabetology journal. He was not involved in handling this manuscript during the submission and the review processes.

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12933_2024_2202_MOESM1_ESM.pdf

Additional File 1: Figure S1. Flow chart of the participants recruitment. Table S1. Description of the analyses performed. Table S2. Baseline characteristics for each comparison. Figure S2. Upset plot of the positive acquisition mode results. Figure S3. Upset plot of the negative acquisition mode results.

12933_2024_2202_MOESM2_ESM.xlsx

Additional File 2: Table S3. Mass-to-charge ratio (mz) and retention time (rt) for each lipid ion significantly associated with T1D and/or T2D in at least one of the analyses.

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Barranco-Altirriba, M., Alonso, N., Weber, R.J.M. et al. Lipidome characterisation and sex-specific differences in type 1 and type 2 diabetes mellitus. Cardiovasc Diabetol 23 , 109 (2024). https://doi.org/10.1186/s12933-024-02202-5

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Association of indoleamine 2,3 dioxygenase, brain derived neurotrophic factor and cellular senescence in type 2 diabetes mellitus with depression: a clinical approach

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• Published: 05 April 2024
• Volume 51 , article number  481 , ( 2024 )

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• Prasanth Subramanian   ORCID: orcid.org/0000-0002-2996-8408 1 ,
• Venkataraman Prabhu   ORCID: orcid.org/0000-0002-5192-6511 1 ,
• Mohanraj Nehru   ORCID: orcid.org/0000-0001-8566-7688 1 ,
• Rajapriya Palanirasu   ORCID: orcid.org/0000-0002-4315-7409 2 &
• Rajiv Janardhanan   ORCID: orcid.org/0000-0002-3904-3900 1  

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Background and aim

Type 2 diabetes mellitus (T2DM) and depression are often linked. Several studies have reported the role of molecular markers either in diabetes or depression. The present study aimed at molecular level profiling of Indoleamine-2,3-dioxygenase (IDO), brain-derived neurotrophic factor (BDNF) and cellular senescence in patients with type 2 diabetes with and without depression compared to individuals with healthy controls.

A total of 120 individuals diagnosed with T2DM were enlisted for the study, with a subset of participants with and without exhibiting depression. The gene expression analysis was done using quantitative real-time PCR.

Indoleamine 2,3 dioxygenase (p < 0.001) and senescence genes (p < 0.001) were significantly upregulated, while brain derived neurotrophic factor (p < 0.01) was significantly downregulated in T2DM patients comorbid with and without depression when compared to healthy controls.

Indoleamine 2,3 dioxygenase, Brain derived neurotrophic factor and cellular senescence may play a role in the progression of the disease. The aforementioned discoveries offer significant contributions to our understanding of the molecular mechanisms that underlie T2DM with depression, potentially aiding in the advancement of prediction and diagnostic methods for this particular ailment.

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Prasanth Subramanian, Venkataraman Prabhu, Mohanraj Nehru & Rajiv Janardhanan

Department of Transfusion Medicine, HLA and Transport Immunology, Dr Rela Institute and Medical Centre, Chromepet, Chennai, Tamil Nadu, India

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Study conception and design was performed by PS and VP. Material preparation, and data collection were performed by PS and MN. Analysis was performed by PS and RP. The first draft of the manuscript was written by PS and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Venkataraman Prabhu .

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Subramanian, P., Prabhu, V., Nehru, M. et al. Association of indoleamine 2,3 dioxygenase, brain derived neurotrophic factor and cellular senescence in type 2 diabetes mellitus with depression: a clinical approach. Mol Biol Rep 51 , 481 (2024). https://doi.org/10.1007/s11033-024-09435-3

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Received : 04 December 2023

Accepted : 11 March 2024

Published : 05 April 2024

DOI : https://doi.org/10.1007/s11033-024-09435-3

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The Effects of Exercise during Pregnancy on Gestational Diabetes Mellitus, Preeclampsia, and Spontaneous Abortion among Healthy Women-A Systematic Review and Meta-Analysis

Affiliations.

• 1 Department of Sports Science and Clinical Biomechanics, University of Southern Denmark, 5230 Odense, Denmark.
• 2 The Parker Institute, Bispebjerg and Frederiksberg Hospital, 2000 Frederiksberg, Denmark.
• 3 Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
• 4 Metodekonsulent Callesen, 8600 Silkeborg, Denmark.
• 5 Department Physiotherapy and Occupational Therapy, Copenhagen University Hospital, Herlev and Gentofte, 2100 Copenhagen, Denmark.
• 6 Research Unit OPEN, Department of Clinical Research, University of Southern Denmark, 5230 Odense, Denmark.
• PMID: 37372656
• PMCID: PMC10298745
• DOI: 10.3390/ijerph20126069

The aim was to compare the effects of different exercise modalities (aerobic, resistance, aerobic and resistance combined, or mind-body exercise) on gestational diabetes mellitus (GDM), preeclampsia, spontaneous abortion, withdrawal from the study, and adverse events in healthy pregnant women. A systematic search was conducted in February 2022 using MEDLINE, EMBASE, Cochrane library, and SPORT Discus to identify eligible randomized trials. The meta-analysis of 18 studies that examined exercise compared to no exercise showed a reduced risk of GDM (RR: 0.66 (95% CI: 0.50 to 0.86)). No subgroup differences were found regarding modality, intensity, or supervision. Exercise did not reduce the risk of preeclampsia (nine studies, RR: 0.65 (95% CI: 0.42 to 1.03)); however, in subgroup analyses, mind-body exercise and low-intensity exercise seemed to be effective in reduction of preeclampsia. There was no effect of exercise on withdrawal or adverse events found. No studies reported on spontaneous abortion, therefore, exercise during pregnancy is beneficial and safe. In the prevention of GDM, any modality and intensity seem equally effective. Subgroup analyses support an association between mind-body exercise and physical activity with low intensity and reduced risk of preeclampsia, but more high-quality randomized studies are needed. PROSPERO: CRD42022307053.

Keywords: exercise; gestational diabetes mellitus; meta-analysis; preeclampsia; pregnancy; spontaneous abortion.

Publication types

• Meta-Analysis
• Systematic Review
• Research Support, Non-U.S. Gov't
• Abortion, Spontaneous* / epidemiology
• Diabetes, Gestational* / epidemiology
• Diabetes, Gestational* / prevention & control
• Exercise Therapy
• Pre-Eclampsia* / epidemiology

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