research topics on type 1 diabetes

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Type 1 diabetes articles from across Nature Portfolio

Type 1 diabetes (also known as diabetes mellitus) is an autoimmune disease in which immune cells attack and destroy the insulin-producing cells of the pancreas. The loss of insulin leads to the inability to regulate blood sugar levels. Patients are usually treated by insulin-replacement therapy.

Latest Research and Reviews

Characterization of the gut bacterial and viral microbiota in latent autoimmune diabetes in adults

• Casper S. Poulsen
• Mette K. Andersen

Islet autoantibodies as precision diagnostic tools to characterize heterogeneity in type 1 diabetes: a systematic review

Felton et al. conduct a systematic review to determine the utility of islet autoantibodies as biomarkers of type 1 diabetes heterogeneity. They find that islet autoantibodies are most likely to be useful for patient stratification prior to clinical diagnosis.

• Jamie L. Felton
• Maria J. Redondo
• Paul W. Franks

Dynamic associations between glucose and ecological momentary cognition in Type 1 Diabetes

• Z. W. Hawks
• L. T. Germine

Generative deep learning for the development of a type 1 diabetes simulator

Mujahid et al. develop a type 1 diabetes patient simulator using a conditional sequence-to-sequence deep generative model. Their approach captures causal relationships between insulin, carbohydrates, and blood glucose levels, producing virtual patients with similar responses to real patients in open and closed-loop insulin therapy scenarios.

• Omer Mujahid
• Ivan Contreras

High dose cholecalciferol supplementation causing morning blood pressure reduction in patients with type 1 diabetes mellitus and cardiovascular autonomic neuropathy

• João Felício
• Lorena Moraes
• Karem Felício

Does minimed 780G TM insulin pump system affect energy and nutrient intake?: long-term follow-up study

• Yasemin Atik-Altinok
• Yelda Mansuroglu
• Damla Goksen

News and Comment

Reply to ‘slowly progressive insulin dependent diabetes mellitus in type 1 diabetes endotype 2’.

• Noel G. Morgan

Slowly progressive insulin-dependent diabetes mellitus in type 1 diabetes endotype 2

• Tetsuro Kobayashi
• Takashi Kadowaki

METTL3 restrains autoimmunity in β-cells

Activation of innate immunity has been linked to the progression of type 1 diabetes. A study now shows that overexpression of METTL3, a writer protein of the m 6 A machinery that modifies mRNA, restrains interferon-stimulated genes when expressed in pancreatic β-cells, identifying it as a promising therapeutic target.

• Balasubramanian Krishnamurthy
• Helen E. Thomas

Type 1 diabetes mellitus: a brave new world

One hundred years after the Nobel prize was bestowed on Banting and McLeod for the ‘discovery’ of insulin, we are again seeing major evolutions in the management of type 1 diabetes mellitus, with the prospect of achieving disease control beyond mere management now becoming real. Here, we discuss the latest, most notable developments.

• Pieter-Jan Martens
• Chantal Mathieu

β-cells protected from T1DM by early senescence programme

• Olivia Tysoe

Antivirals in the treatment of new-onset T1DM

• Claire Greenhill

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Research Gaps Around Type 1 Diabetes

A large body of research on Type 2 diabetes has helped to develop guidance, informing how patients are diagnosed, treated, and manage their lifestyle. In contrast, Type 1 diabetes, often mistakenly associated only with childhood, has received less attention.

In this Q&A, adapted from the  April 17 episode of Public Health On Call , Stephanie Desmon speaks to Johns Hopkins epidemiologists  Elizabeth Selvin , PhD '04, MPH, and  Michael Fang , PhD, professor and assistant professor, respectively, in the Department of Epidemiology, about recent findings that challenge common beliefs about type 1 diabetes. Their conversation touches on the misconception that it’s solely a childhood condition, the rise of adult-onset cases linked to obesity, and the necessity for tailored approaches to diagnosis and care. They also discuss insulin prices and why further research is needed on medications like Ozempic in treating Type 1 diabetes.

I want to hear about some of your research that challenges what we have long understood about Type 1 diabetes, which is no longer called childhood diabetes. 

MF: Type 1 diabetes was called juvenile diabetes for the longest time, and it was thought to be a disease that had a childhood onset. When diabetes occurred in adulthood it would be type 2 diabetes. But it turns out that approximately half of the cases of Type 1 diabetes may occur during adulthood right past the age of 20 or past the age of 30.

The limitations of these initial studies are that they've been in small clinics or one health system. So, it's unclear whether it's just that particular clinic or whether it applies to the general population more broadly. 

We were fortunate because the CDC has collected new data that explores Type 1 diabetes in the U.S. Some of the questions they included in their national data were, “Do you have diabetes? If you do, do you have Type 1 or Type 2? And, at what age were you diagnosed?”

With these pieces of information, we were able to characterize how the age of diagnosis of Type 1 diabetes differs in the entire U.S. population.

Are Type 1 and Type 2 diabetes different diseases?

ES:  They are very different diseases and have a very different burden. My whole career I have been a Type 2 diabetes epidemiologist, and I’ve been very excited to expand work with Type 1 diabetes.

There are about 1.5 million adults with Type 1 diabetes in the U.S., compared to 21 million adults with Type 2 diabetes. In terms of the total cases of diabetes, only 5 to 10 percent have Type 1 diabetes. Even in our largest epidemiologic cohorts, only a small percentage of people have Type 1 diabetes. So, we just don't have the same national data, the same epidemiologic evidence for Type 1 diabetes that we have for Type 2. The focus of our research has been trying to understand and characterize the general epidemiology and the population burden of Type 1 diabetes.

What is it about Type 1 that makes it so hard to diagnose?

MF: The presentation of symptoms varies by age of diagnosis. When it occurs in children, it tends to have a very acute presentation and the diagnosis is easier to make. When it happens in adulthood, the symptoms are often milder and it’s often misconstrued as Type 2 diabetes. 

Some studies have suggested that when Type 1 diabetes occurs in adulthood, about 40% of those cases are misdiagnosed initially as Type 2 cases. Understanding how often people get diagnosed later in life is important to correctly diagnose and treat patients. 

Can you talk about the different treatments?

MF:  Patients with Type 1 diabetes are going to require insulin. Type 2 diabetes patients can require insulin, but that often occurs later in the disease, as oral medications become less and less effective.

ES: Because of the epidemic of overweight and obese in the general population, we’re seeing a lot of people with Type 1 diabetes who are overweight and have obesity. This can contribute to issues around misdiagnosis because people with Type 1 diabetes will have signs and will present similarly to Type 2 diabetes. They'll have insulin resistance potentially as a result of weight gain metabolic syndrome. Some people call it double diabetes—I don't like that term—but it’s this idea that if you have Type 1 diabetes, you can also have characteristics of Type 2 diabetes as well.

I understand that Type 1 used to be considered a thin person's disease, but that’s not the case anymore.  MF:  In a separate paper, we also explored the issue of overweight and obesity in persons with Type 1 diabetes. We found that approximately 62% of adults with Type 1 diabetes were either overweight or obese, which is comparable to the general U.S. population.

But an important disclaimer is that weight management in this population [with Type 1 diabetes] is very different. They can't just decide to go on a diet, start jogging, or engage in rigorous exercise. It can be a very, very dangerous thing to do.

Everybody's talking about Ozempic and Mounjaro—the GLP-1 drugs—for diabetes or people who are overweight to lose weight and to solve their diabetes. Where does that fit in with this population?

ES: These medications are used to treat Type 2 diabetes in the setting of obesity. Ozempic and Mounjaro are incretin hormones. They mediate satiation, reduce appetite, slow gastric emptying, and lower energy intake. They're really powerful drugs that may be helpful in Type 1 diabetes, but they're  not approved for the management of obesity and Type 1 diabetes. At the moment, there aren't data to help guide their use in people with Type 1 diabetes, but I suspect they're going to be increasingly used in people with Type 1 diabetes.

MF:   The other piece of managing weight—and it's thought to be foundational for Type 1 or Type 2—is dieting and exercising. However, there isn’t good guidance on how to do this in persons with Type 1 diabetes, whereas there are large and rigorous trials in Type 2 patients. We’re really just starting to figure out how to safely and effectively manage weight with lifestyle changes for Type 1 diabetics, and I think that's an important area of research that should continue moving forward.

ES: Weight management in Type 1 diabetes is complicated by insulin use and the risk of hypoglycemia, or your glucose going too low, which can be an acute complication of exercise. In people with Type 2 diabetes, we have a strong evidence base for what works. We know modest weight loss can help prevent the progression and development of Type 2 diabetes, as well as weight gain. In Type 1, we just don't have that evidence base.

Is there a concern about misdiagnosis and mistreatment? Is it possible to think a patient has Type 2 but they actually have Type 1? 

MF: I think so. Insulin is the overriding concern. In the obesity paper, we looked at the percentage of people who said their doctors recommended engaging in more exercise and dieting. We found that people with Type 1 diabetes were less likely to receive the same guidance from their doctor. I think providers may be hesitant to say, “Look, just go engage in an active lifestyle.”

This is why it's important to have those studies and have that guidance so that patients and providers can be comfortable in improving lifestyle management.

Where is this research going next?

ES:  What's clear from these studies is that the burden of overweight and obesity is substantial in people with Type 1 diabetes and it's not adequately managed. Going forward, I think we're going to need clinical trials, clear clinical guidelines, and patient education that addresses how best to tackle obesity in the setting of Type 1 diabetes.

It must be confusing for people with Type 1 diabetes who are   hearing about people losing all this weight on these drugs, but they go to their doctor who says, “Yeah, but that's not for you.”

ES: I hope it's being handled more sensitively. These drugs are being used by all sorts of people for whom they are not indicated, and I'm sure that people with Type 1 diabetes are accessing these drugs. I think the question is, are there real safety issues? We need thoughtful discussion about this and some real evidence to make sure that we're doing more good than harm.

MF:  Dr. Selvin’s group has published a paper, estimating that about 15% of people with Type 1 diabetes are on a GLP-1. But we don't have great data on what potentially can happen to individuals.

The other big part of diabetes that we hear a lot about is insulin and its price. Can you talk about your research on this topic?

MF:  There was a survey that asked, “Has there been a point during the year when you were not using insulin because you couldn’t afford it?” About 20% of adults under the age of 65 said that at some point during the year, they couldn't afford their insulin and that they did engage in what sometimes is called “cost-saving rationing” [of insulin].

Medicare is now covering cheaper insulin for those over 65, but there are a lot of people for whom affordability is an issue. Can you talk more about that? 

MF:  The fight is not over. Just because there are national and state policies, and now manufacturers have been implementing price caps, doesn't necessarily mean that the people who need insulin the most are now able to afford it. 

A recent study in the  Annals of Internal Medicine looked at states that adopted or implemented out-of-pocket cost caps for insulin versus those that didn't and how that affected insulin use over time. They found that people were paying less for insulin, but the use of insulin didn't change over time. The $35 cap is an improvement, but we need to do more.

ES: There are still a lot of formulations of insulin that are very expensive. $35 a month is not cheap for someone who is on insulin for the rest of their lives.

• Overweight and Obesity in People With Type 1 Diabetes Nearly Same as General Population
• The Impacts of COVID-19 on Diabetes and Insulin
• Why Eli Lilly’s Insulin Price Cap Announcement Matters

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New advances in type 1 diabetes

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• Savitha Subramanian , professor of medicine ,
• Farah Khan , clinical associate professor of medicine ,
• Irl B Hirsch , professor of medicine
• University of Washington Diabetes Institute, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, WA, USA
• Correspondence to: I B Hirsch ihirsch{at}uw.edu

Type 1 diabetes is an autoimmune condition resulting in insulin deficiency and eventual loss of pancreatic β cell function requiring lifelong insulin therapy. Since the discovery of insulin more than 100 years ago, vast advances in treatments have improved care for many people with type 1 diabetes. Ongoing research on the genetics and immunology of type 1 diabetes and on interventions to modify disease course and preserve β cell function have expanded our broad understanding of this condition. Biomarkers of type 1 diabetes are detectable months to years before development of overt disease, and three stages of diabetes are now recognized. The advent of continuous glucose monitoring and the newer automated insulin delivery systems have changed the landscape of type 1 diabetes management and are associated with improved glycated hemoglobin and decreased hypoglycemia. Adjunctive therapies such as sodium glucose cotransporter-1 inhibitors and glucagon-like peptide 1 receptor agonists may find use in management in the future. Despite these rapid advances in the field, people living in under-resourced parts of the world struggle to obtain necessities such as insulin, syringes, and blood glucose monitoring essential for managing this condition. This review covers recent developments in diagnosis and treatment and future directions in the broad field of type 1 diabetes.

Introduction

Type 1 diabetes is an autoimmune condition that occurs as a result of destruction of the insulin producing β cells of the pancreatic islets, usually leading to severe endogenous insulin deficiency. 1 Without treatment, diabetic ketoacidosis will develop and eventually death will follow; thus, lifelong insulin therapy is needed for survival. Type 1 diabetes represents 5-10% of all diabetes, and diagnosis classically occurs in children but can also occur in adulthood. The burden of type 1 diabetes is expansive; it can result in long term complications, decreased life expectancy, and reduced quality of life and can add significant financial burden. Despite vast improvements in insulin, insulin delivery, and glucose monitoring technology, a large proportion of people with type 1 diabetes do not achieve glycemic goals. The massive burden of type 1 diabetes for patients and their families needs to be appreciated. The calculation and timing of prandial insulin dosing, often from food with unknown carbohydrate content, appropriate food and insulin dosing when exercising, and cost of therapy are all major challenges. The psychological realities of both acute management and the prospect of chronic complications add to the burden. Education programs and consistent surveillance for “diabetes burnout” are ideally available to everyone with type 1 diabetes.

In this review, we discuss recent developments in the rapidly changing landscape of type 1 diabetes and highlight aspects of current epidemiology and advances in diagnosis, technology, and management. We do not cover the breadth of complications of diabetes or certain unique scenarios including psychosocial aspects of type 1 diabetes management, management aspects specific to older adults, and β cell replacement therapies. Our review is intended for the clinical reader, including general internists, family practitioners, and endocrinologists, but we acknowledge the critical role that people living with type 1 diabetes and their families play in the ongoing efforts to understand this lifelong condition.

Sources and selection criteria

We did individual searches for studies on PubMed by using terms relevant to the specific topics covered in this review pertaining to type 1 diabetes. Search terms used included “type 1 diabetes” and each individual topic—diagnosis, autoantibodies, adjuvant therapies, continuous glucose monitoring, automated insulin delivery, immunotherapies, diabetic ketoacidosis, hypoglycemia, and under-resourced settings. We considered all studies published in the English language between 1 January 2001 and 31 January 2023. We selected publications outside of this timeline on the basis of relevance to each topic. We also supplemented our search strategy by a hand search of the references of key articles. We prioritized studies on each highlighted topic according to the level of evidence (randomized controlled trials (RCTs), systematic reviews and meta-analyses, consensus statements, and high quality observational studies), study size (we prioritized studies with at least 50 participants when available), and time of publication (we prioritized studies published since 2003 except for the landmark Diabetes Control and Complications Trial and a historical paper by Tuomi on diabetes autoantibodies, both from 1993). For topics on which evidence from RCTs was unavailable, we included other study types of the highest level of evidence available. To cover all important clinical aspects of the broad array of topics covered in this review, we included additional publications such as clinical reviews as appropriate on the basis of clinical relevance to both patients and clinicians in our opinion.

Epidemiology

The incidence of type 1 diabetes is rising worldwide, possibly owing to epigenetic and environmental factors. Globally in 2020 an estimated 8.7 million people were living with type 1 diabetes, of whom approximately 1.5 million were under 20 years of age. 2 This number is expected to rise to more than 17 million by 2040 ( https://www.t1dindex.org/#global ). The International Diabetes Federation estimates the global prevalence of type 1 diabetes at 0.1%, and this is likely an underestimation as diagnoses of type 1 diabetes in adults are often not accounted for. The incidence of adult onset type 1 diabetes is higher in Europe, especially in Nordic countries, and lowest in Asian countries. 3 Adult onset type 1 diabetes is also more prevalent in men than in women. An increase in prevalence in people under 20 years of age has been observed in several western cohorts including the US, 4 5 Netherlands, 6 Canada, 7 Hungary, 8 and Germany. 9

Classically, type 1 diabetes presents over the course of days or weeks in children and adolescents with polyuria, polydipsia, and weight loss due to glycosuria. The diagnosis is usually straightforward, with profound hyperglycemia (often >300 mg/dL) usually with ketonuria with or without ketoacidemia. Usually, more than one autoantibody is present at diagnosis ( table 1 ). 10 The number of islet autoantibodies combined with parameters of glucose tolerance now forms the basis of risk prediction for type 1 diabetes, with stage 3 being clinical disease ( fig 1 ). 11 The originally discovered autoantibody, islet cell antibody, is no longer used clinically owing to variability of the assay despite standardisation. 12

Autoantibody characteristics associated with increased risk of type 1 diabetes 10

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Natural history of type 1 diabetes. Adapted with permission from Insel RA, et al. Diabetes Care 2015;38:1964-74 11

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Half of all new cases of type 1 diabetes are now recognized as occurring in adults. 13 Misclassification due to misdiagnosis (commonly as type 2 diabetes) occurs in nearly 40% of people. 14 As opposed to typical childhood onset type 1 diabetes, progression to severe insulin deficiency, and therefore its clinical presentation in adults, is variable. The term latent autoimmune diabetes of adults (LADA) was introduced 30 years ago to identify adults who developed immune mediated diabetes. 15 An international consensus defined the diagnostic criteria for LADA as age >30 years, lack of need for insulin use for at least six months, and presence of islet cell autoantibodies. 16 However, debate as to whether the term LADA should even be used as a diagnostic term persists. The American Diabetes Association (ADA) Standards of Care note that for the purpose of classification, all forms of diabetes mediated by autoimmune β cell destruction are included in the classification of type 1 diabetes. 17 Nevertheless, they note that use of the term LADA is acceptable owing to the practical effect of heightening awareness of adults likely to have progressive autoimmune β cell destruction and thereby accelerating insulin initiation by clinicians to prevent diabetic ketoacidosis.

The investigation of adults with suspected type 1 diabetes is not always straightforward ( fig 2 ). 18 Islet cell autoantibodies such as glutamic acid decarboxylase antibody (GADA), tyrosine phosphatase IA2 antibody, and zinc transporter isoform 8 autoantibody act as markers of immune activity and can be detected in the blood with standardized assays ( table 1 ). The presence of one or more antibodies in adults with diabetes could mark the progression to severe insulin deficiency; these individuals should be considered to have type 1 diabetes. 1 Autoantibodies, especially GADA, should be measured only in people with clinically suspected type 1 diabetes, as low concentrations of GADA can be seen in type 2 diabetes and thus false positive measurements are a concern. 19 That 5-10% of cases of type 1 diabetes may occur without diabetes autoantibodies is also now clear, 20 and that the diabetes autoantibodies disappear over time is also well appreciated. 21

Flowchart for investigation of suspected type 1 diabetes in adults, based on data from white European populations. No single clinical feature in isolation confirms type 1 diabetes. The most discriminative feature is younger age at diagnosis (<35 years), with lower body mass index (<25), unintentional weight loss, ketoacidosis, and glucose >360 mg/dL at presentation. Adapted with permission from Holt RIG, et al. Diabetes Care 2021;44:2589-625 1

Genetic risk scoring (GRS) for type 1 diabetes has received attention to differentiate people whose classification is unclear. 22 23 24 Developed in 2019, the T1D-GRS2 uses 67 single nucleotide polymorphisms from known autoimmune loci and can predict type 1 diabetes in children of European and African ancestry. Although GRS is not available for routine clinical use, it may allow prediction of future cases of type 1 diabetes to allow prevention strategies with immune intervention (see below).

A major change in the type 1 diabetes phenotype has occurred over the past few decades, with an increase in obesity; the reasons for this are complex. In the general population, including people with type 1 diabetes, an epidemic of sedentary lifestyles and the “westernized diet” consisting of increased processed foods, refined sugars, and saturated fat is occurring. In people with type 1 diabetes, the overall improvement in glycemic control since the report of the Diabetes Control and Complications Trial (DCCT) in 1993 (when one or two insulin injections a day was standard therapy) has resulted in less glycosuria so that the typical patient with lower body weight is uncommon in high income countries. In the US T1D Exchange, more than two thirds of the adult population were overweight or obese. 25

Similarly, obesity in young people with type 1 diabetes has also increased over the decades. 26 The combination of autoimmune insulin deficiency with obesity and insulin resistance has received several descriptive names over the years, with this phenotype being described as double diabetes and hybrid diabetes, among others, 26 27 but no formal nomenclature in the diabetes classification exists. Many of these patients have family members with type 2 diabetes, and some patients probably do have both types of diabetes. Clinically, minimal research has been done into how this specific population responds to certain antihyperglycemic oral agents, such as glucagon-like peptide 1 (GLP-1) receptor agonists, given the glycemic, weight loss, and cardiovascular benefits seen with these agents. 28 These patients are common in most adult diabetes practices, and weight management in the presence of insulin resistance and insulin deficiency remains unclear.

Advances in monitoring

The introduction of home blood glucose monitoring (BGM) more than 45 years ago was met with much skepticism until the report of the DCCT. 29 Since then, home BGM has improved in accuracy, precision, and ease of use. 30 Today, in many parts of the world, home BGM, a static measurement of blood glucose, has been replaced by continuous glucose monitoring (CGM), a dynamic view of glycemia. CGM is superior to home BGM for glycemic control, as confirmed in a meta-analysis of 21 studies and 2149 participants with type 1 diabetes in which CGM use significantly decreased glycated hemoglobin (HbA 1c ) concentrations compared with BGM (mean difference −0.23%, 95% confidence interval −3.83 to −1.08; P<0.001), with a greater benefit if baseline HbA 1c was >8% (mean difference −0.43%, −6.04 to −3.30; P<0.001). 31 This newer technology has also evolved into a critical component of automated insulin delivery. 32

CGM is the standard for glucose monitoring for most adults with type 1 diabetes. 1 This technology uses interstitial fluid glucose concentrations to estimate blood glucose. Two types of CGM are available. The first type, called “real time CGM”, provides a continuous stream of glucose data to a receiver, mobile application, smartwatch, or pump. The second type, “intermittently scanned CGM,” needs to be scanned by a reader device or smartphone. Both of these technologies have shown improvements in HbA 1c and amount of time spent in the hypoglycemic range compared with home BGM when used in conjunction with multiple daily injections or “open loop” insulin pump therapy. 33 34 Real time CGM has also been shown to reduce hypoglycemic burden in older adults with type 1 diabetes ( table 2 ). 36 Alerts that predict or alarm with both hypoglycemia and hyperglycemia can be customized for the patient’s situation (for example, a person with unawareness of hypoglycemia would have an alert at a higher glucose concentration). Family members can also remotely monitor glycemia and be alerted when appropriate. The accuracy of these devices has improved since their introduction in 2006, so that currently available sensors can be used without a confirmation glucose concentration to make a treatment decision with insulin. However, some situations require home BGM, especially when concerns exist that the CGM does not match symptoms of hypoglycemia.

Summary of trials for each topic covered

Analysis of CGM reports retrospectively can assist therapeutic decision making both for the provider and the patient. Importantly, assessing the retrospective reports and watching the CGM in real time together offer insight to the patient with regard to insulin dosing, food choices, and exercise. Patients should be encouraged to assess their data on a regular basis to better understand their diabetes self-management. Table 3 shows standard metrics and targets for CGM data. 52 Figure 3 shows an ambulatory glucose profile.

Standardized continuous glucose monitoring metrics for adults with diabetes 52

Example of ambulatory glucose profile of 52 year old woman with type 1 diabetes and fear of hypoglycemia. CGM=continuous glucose monitoring; GMI=glucose management indicator

Improvements in technology and evidence for CGM resulting in international recommendations for its widespread use have resulted in greater uptake by people with type 1 diabetes across the globe where available and accessible. Despite this, not everyone wishes to use it; some people find wearing any device too intrusive, and for many the cost is prohibitive. These people need at the very least before meal and bedtime home BGM.

A next generation implantable CGM device (Sensionics), with an improved calibration algorithm that lasts 180 days after insertion by a healthcare professional, is available in both the EU and US. Although fingerstick glucose calibration is needed, the accuracy is comparable to that of other available devices. 53

Advances in treatments

The discovery of insulin in 1921, resulting in a Nobel Prize, was considered one of the greatest scientific achievements of the 20th century. The development of purified animal insulins in the late 1970s, followed by human insulin in the early 1980s, resulted in dramatic reductions in allergic reactions and lipoatrophy. Introduction of the first generation of insulin analogs, insulin lispro in the mid-1990s followed by insulin glargine in the early 2000s, was an important advance for the treatment of type 1 diabetes. 54 We review the next generation of insulin analogs here. Table 4 provides details on available insulins.

Pharmacokinetics of commonly used insulin preparations

Ultra-long acting basal insulins

Insulin degludec was developed with the intention of improving the duration of action and achieving a flatter profile compared with the original long acting insulin analogs, insulin glargine and insulin detemir. Its duration of action of 42 hours at steady state means that the profile is generally flat without significant day-to-day variability, resulting in less hypoglycemia compared with U-100 glargine. 39 55

When U-100 insulin glargine is concentrated threefold, its action is prolonged. 56 U-300 glargine has a different kinetic profile and is delivered in one third of the volume of U-100 glargine, with longer and flatter effects. The smaller volume of U-300 glargine results in slower and more gradual release of insulin monomers owing to reduced surface area in the subcutaneous space. 57 U-300 glargine also results in lesser hypoglycemia compared with U-100 glargine. 58

Ultra-rapid acting prandial insulins

Rapid acting insulin analogs include insulin lispro, aspart, and glulisine. With availability of insulin lispro, the hope was for a prandial insulin that better matched food absorption. However, these newer insulins are too slow to control the glucose spike seen with ingestion of a high carbohydrate load, leading to the development of insulins with even faster onset of action.

The first available ultra-rapid prandial insulin was fast acting insulin aspart. This insulin has an onset of appearance approximately twice as fast (~5 min earlier) as insulin aspart, whereas dose-concentration and dose-response relations are comparable between the two insulins ( table 4 ). 59 In adults with type 1 diabetes, mealtime and post-meal fast acting aspart led to non-inferior glycemic control compared with mealtime aspart, in combination with basal insulin. 60 Mean HbA 1c was 7.3%, 7.3%, and 7.4% in the mealtime faster aspart, mealtime aspart, and post‐meal faster aspart arms, respectively (P<0.001 for non-inferiority).

Insulin lispro-aabc is the second ultra-rapid prandial insulin. In early kinetic studies, insulin lispro-aabc appeared in the serum five minutes faster with 6.4-fold greater exposure in the first 15 minutes compared with insulin lispro. 61 The duration of exposure of the insulin concentrations in this study was 51 minutes faster with lispro-aabc. Overall insulin exposure was similar between the two groups. Clinically, lispro-aabc is non-inferior to insulin lispro, but postprandial hyperglycemia is lower with the faster acting analog. 62 Lispro-aabc given at mealtime resulted in greater improvement in post-prandial glucose (two hour post-prandial glucose −31.1 mg/dL, 95% confidence interval −41.0 to −21.2; P<0.001).

Both ultra-rapid acting insulins can be used in insulin pumps. Lispro-aabc tends to have more insertion site reactions than insulin lispro. 63 A meta-analysis including nine studies and 1156 participants reported increased infusion set changes on rapid acting insulin analogs (odds ratio 1.60, 95% confidence interval 1.26 to 2.03). 64

Pulmonary inhaled insulin

The quickest acting insulin is pulmonary inhaled insulin, with an onset of action of 12 minutes and a duration of 1.5-3 hours. 65 When used with postprandial supplemental dosing, glucose control is improved without an increase in hypoglycemia. 66

Insulin delivery systems

Approved automated insulin delivery systems.

CGM systems and insulin pumps have shown improvement in glycemic control and decreased risk of severe hypoglycemia compared with use of self-monitoring of blood glucose and multiple daily insulin injections in type 1 diabetes. 67 68 69 Using CGM and insulin pump together (referred to as sensor augmented pump therapy) only modestly improves HbA 1c in patients who have high sensor wear time, 70 71 but the management burden of diabetes does not decrease as frequent user input is necessary. Thus emerged the concept of glucose responsive automated insulin delivery (AID), in which data from CGM can inform and allow adjustment of insulin delivery.

In the past decade, exponential improvements in CGM technologies and refined insulin dosing pump algorithms have led to the development of AID systems that allow for minimization of insulin delivery burden. The early AID systems reduced hypoglycemia risk by automatically suspending insulin delivery when glucose concentrations dropped to below a pre-specified threshold but did not account for high glucose concentrations. More complex algorithms adjusting insulin delivery up and down automatically in response to real time sensor glucose concentrations now allow close replication of normal endocrine pancreatic physiology.

AID systems (also called closed loop or artificial pancreas systems) include three components—an insulin pump that continuously delivers rapid acting insulin, a continuous glucose sensor that measures interstitial fluid glucose at frequent intervals, and a control algorithm that continuously adjusts insulin delivery that resides in the insulin pump or a smartphone application or handheld device ( fig 4 ). All AID systems that are available today are referred to as “hybrid” closed loop (HCL) systems, as users are required to manually enter prandial insulin boluses and signal exercise, but insulin delivery is automated at night time and between meals. AID systems, regardless of the type used, have shown benefit in glycemic control and cost effectiveness, improve quality of life by improving sleep quality, and decrease anxiety and diabetes burden in adults and children. 72 73 74 Limitations to today’s HCL systems are primarily related to pharmacokinetics and pharmacodynamics of available analog insulins and accuracy of CGM in extremes of blood glucose values. The iLet bionic pancreas, cleared by the US Food and Drug Administration (FDA) in May 2023, is an AID system that determines all therapeutic insulin doses for an individual on the basis of body weight, eliminating the need for calculation of basal rates, insulin to carbohydrate ratios, blood glucose corrections, and bolus dose. The control algorithms adapt continuously and autonomously to the individual’s insulin needs. 38 Table 5 lists available AID systems.

Schematic of closed loop insulin pump technology. The continuous glucose monitor senses interstitial glucose concentrations and sends the information via Bluetooth to a control algorithm hosted on an insulin pump (or smartphone). The algorithm calculates the amount of insulin required, and the insulin pump delivers rapid acting insulin subcutaneously

Comparison of commercially available hybrid closed loop systems 75

Unapproved systems

Do-it-yourself (DIY) closed loop systems—DIY open artificial pancreas systems—have been developed by people with type 1 diabetes with the goal of self-adjusting insulin by modifying their individually owned devices. 76 These systems are built by the individual using an open source code widely available to anyone with compatible medical devices who is willing and able to build their own system. DIY systems are used by several thousand people across the globe but are not approved by regulatory bodies; they are patient-driven and considered “off-label” use of technology with the patient assuming full responsibility for their use. Clinicians caring for these patients should ensure basic diabetes skills, including pump site maintenance, a knowledge of how the chosen system works, and knowing when to switch to “manual mode” for patients using an artificial pancreas system of any kind. 76 The small body of studies on DIY looping suggests improvement in HbA 1c , increased time in range, decreased hypoglycemia and glucose variability, improvement in night time blood glucose concentrations, and reduced mental burden of diabetes management. 77 78 79 Although actively prescribing or initiating these options is not recommended, these patients should be supported by clinical teams; insulin prescription should not be withheld, and, if initiated by the patient, unregulated DIY options should be openly discussed to ensure open and transparent relationships. 78

In January 2023, the US FDA cleared the Tidepool Loop app, a DIY AID system. This software will connect the CGM, insulin pump, and Loop algorithm, but no RCTs using this method are available.

β cell replacement therapies

For patients with type 1 diabetes who meet specific clinical criteria, β cell replacement therapy using whole pancreas or pancreatic islet transplantation can be considered. Benefits of transplantation include immediate cessation of insulin therapy, attainment of euglycemia, and avoidance of hypoglycemia. Additional benefits include improved quality of life and stabilization of complications. 80 Chronic immunosuppression is needed to prevent graft rejection after transplantation.

Pancreas transplantation

Whole pancreas transplantation, first performed in 1966, involves complex abdominal surgery and lifelong immunosuppressive therapy and is limited by organ donor availability. Today, pancreas transplants are usually performed simultaneously using two organs from the same donor (simultaneous pancreas-kidney transplant (SPKT)), sequentially if the candidate has a living donor for renal transplantation (pancreas after kidney transplant (PAKT)) or on its own (pancreas transplantation alone). Most whole pancreas transplants are performed with kidney transplantation for end stage diabetic kidney disease. Pancreas graft survival at five years after SPKT is 80% and is superior to that with pancreas transplants alone (62%) or PAKT (67%). 81 Studies from large centers where SPKT is performed show that recipients can expect metabolic improvements including amelioration of problematic hypoglycemia for at least five years. 81 The number of pancreas transplantations has steadily decreased in the past two decades.

Islet transplantation

Islet transplantation can be pursued in selected patients with type 1 diabetes marked by unawareness of hypoglycemia and severe hypoglycemic episodes, to help restore the α cell response critical for responding to hypoglycemia. 82 83 Islet transplantation involves donor pancreas procurement with subsequent steps to isolate, purify, culture, and infuse the islets. Multiple donors are needed to provide enough islet cells to overcome islet cell loss during transplantation. Survival of the islet grafts, limited donor supply, and lifelong need for immunosuppressant therapy remain some of the biggest challenges. 84 Islet transplantation remains experimental in the US and is offered in a few specialized centers in North America, some parts of Europe, and Australia. 85

Disease modifying treatments for β cell preservation

Therapies targeting T cells, B cells, and cytokines that find use in a variety of autoimmune diseases have also been applied to type 1 diabetes. The overarching goal of immune therapies in type 1 diabetes is to prevent or delay the loss of functional β cell mass. Studies thus far in early type 1 diabetes have not yet successfully shown reversal of loss of C peptide or maintenance of concentrations after diagnosis, although some have shown preservation or slowing of loss of β cells. This suggests that a critical time window of opportunity exists for starting treatment depending on the stage of type 1 diabetes ( fig 1 ).

Teplizumab is a humanized monoclonal antibody against the CD3 molecule on T cells; it is thought to modify CD8 positive T lymphocytes, key effector cells that mediate β cell death and preserves regulatory T cells. 86 Teplizumab, when administered to patients with new onset of type 1 diabetes, was unable to restore glycemia despite C peptide preservation. 87 However, in its phase II prevention study of early intervention in susceptible individuals (at least two positive autoantibodies and an abnormal oral glucose tolerance test at trial entry), a single course of teplizumab delayed progression to clinical type 1 diabetes by about two years ( table 2 ). 43 On the basis of these results, teplizumab received approval in the US for people at high risk of type 1 diabetes in November 2022. 88 A phase III trial (PROTECT; NCT03875729 ) to evaluate the efficacy and safety of teplizumab versus placebo in children and adolescents with new diagnosis of type 1 diabetes (within six weeks) is ongoing. 89

Thus far, targeting various components of the immune response has been attempted in early type 1 diabetes without any long term beneficial effects on C peptide preservation. Co-stimulation blockade using CTLA4-Ig abatacept, a fusion protein that interferes with co-stimulation needed in the early phases of T cell activation that occurs in type 1 diabetes, is being tested for efficacy in prevention of type 1 diabetes ( NCT01773707 ). 90 Similarly, several cytokine directed anti-inflammatory targets (interleukin 6 receptor, interleukin 1β, tumor necrosis factor ɑ) have not shown any benefit.

Non-immunomodulatory adjunctive therapies

Adjunctive therapies for type 1 diabetes have been long entertained owing to problems surrounding insulin delivery, adequacy of glycemic management, and side effects associated with insulin, especially weight gain and hypoglycemia. At least 50% of adults with type 1 diabetes are overweight or obese, presenting an unmet need for weight management in these people. Increased cardiovascular risk in these people despite good glycemic management presents additional challenges. Thus, use of adjuvant therapies may tackle these problems.

Metformin, by decreasing hepatic glucose production, could potentially decrease fasting glucose concentrations. 91 It has shown benefit in reducing insulin doses and possibly improving metabolic control in obese/overweight people with type 1 diabetes. A meta-analysis of 19 RCTs suggests short term improvement in HbA 1c that is not sustained after three months and is associated with higher incidence of gastrointestinal side effects. 92 No evidence shows that metformin decreases cardiovascular morbidity in type 1 diabetes. Therefore, owing to lack of conclusive benefit, addition of metformin to treatment regimens is not recommended in consensus guidelines.

Glucagon-like peptide receptor agonists

Endogenous GLP-1 is an incretin hormone secreted from intestinal L cells in response to nutrient ingestion and enhances glucose induced insulin secretion, suppresses glucagon secretion, delays gastric emptying, and induces satiety. 93 GLP-1 promotes β cell proliferation and inhibits apoptosis, leading to expansion of β cell mass. GLP-1 secretion in patients with type 1 diabetes is similar to that seen in people without diabetes. Early RCTs of liraglutide in type 1 diabetes resulted in weight loss and modest lowering of HbA 1c ( table 2 ). 49 50 Liraglutide 1.8 mg in people with type 1 diabetes and higher body mass index decreased HbA 1c , weight, and insulin requirements with no increased hypoglycemia risk. 94 However, on the basis of results from a study of weekly exenatide that showed similar results, these effects may not be sustained. 51 A meta-analysis of 24 studies including 3377 participants showed that the average HbA 1c decrease from GLP-1 receptor agonists compared with placebo was highest for liraglutide 1.8 mg daily (−0.28%, 95% confidence interval −0.38% to−0.19%) and exenatide (−0.17%, −0.28% to 0.02%). The estimated weight loss from GLP-1 receptor agonists compared with placebo was −4.89 (−5.33 to−4.45)  kg for liraglutide 1.8 mg and −4.06  (−5.33 to−2.79) kg for exenatide. 95 No increase in severe hypoglycemia was seen (odds ratio 0.67, 0.43 to 1.04) but therapy was associated with higher levels of nausea. GLP-1 receptor agonist use may be beneficial for weight loss and reducing insulin doses in a subset of patients with type 1 diabetes. GLP-1 receptor agonists are not a recommended treatment option in type 1 diabetes. Semaglutide is being studied in type 1 diabetes in two clinical trials ( NCT05819138 ; NCT05822609 ).

Sodium-glucose cotransporter inhibitors

Sodium-glucose cotransporter 2 (SGLT-2), a protein expressed in the proximal convoluted tubule of the kidney, reabsorbs filtered glucose; its inhibition prevents glucose reabsorption in the tubule and increases glucose excretion by the kidney. Notably, the action of these agents is independent of insulin, so this class of drugs has potential as adjunctive therapy for type 1 diabetes. Clinical trials have shown significant benefit in cardiovascular and renal outcomes in type 2 diabetes; therefore, significant interest exists for use in type 1 diabetes. Several available SGLT-2 inhibitors have been studied in type 1 diabetes and have shown promising results with evidence of decreased total daily insulin dosage, improvement in HbA 1c , lower rates of hypoglycemia, and decrease in body weight; however, these effects do not seem to be sustained at one year in clinical trials and seem to wane with time. Despite beneficial effects, increased incidence of diabetic ketoacidosis has been observed in all trials, is a major concern, and is persistent despite educational efforts. 96 97 98 Low dose empagliflozin (2.5 mg) has shown lower rates of diabetic ketoacidosis in clinical trials ( table 2 ). 47 Favorable risk profiles have been noted in Japan, the only market where SGLT-2 inhibitors are approved for adjunctive use in type 1 diabetes. 99 In the US, SGLT-2 inhibitors are approved for use in type 2 diabetes only. In Europe, although dapagliflozin was approved for use as adjunct therapy to insulin in adults with type 1 diabetes, the manufacturer voluntarily withdrew the indication for the drug in 2021. 100 Sotagliflozin is a dual SGLT-1 and SGLT-2 inhibitor that decreases renal glucose reabsorption through systemic inhibition of SGLT-2 and decreases glucose absorption in the proximal intestine by SGLT-1 inhibition, blunting and delaying postprandial hyperglycemia. 101 Studies of sotagliflozin in type 1 diabetes have shown sustained HbA 1c reduction, weight loss, lower insulin requirements, lesser hypoglycemia, and more diabetic ketoacidosis relative to placebo. 102 103 104 The drug received authorization in the EU for use in type 1 diabetes, but it is not marketed there. Although SGLT inhibitors are efficacious in type 1 diabetes management, the risk of diabetic ketoacidosis is a major limitation to widespread use of these agents.

Updates in acute complications of type 1 diabetes

Diabetic ketoacidosis.

Diabetic ketoacidosis is a serious and potentially fatal hyperglycemic emergency accompanied by significant rates of mortality and morbidity as well as high financial burden for healthcare systems and societies. In the past decade, increasing rates of diabetic ketoacidosis in adults have been observed in the US and Europe. 105 106 This may be related to changes in the definition of diabetic ketoacidosis, use of medications associated with higher risk, and admission of patients at lower risk. 107 In a US report of hospital admissions with diabetic ketoacidosis, 53% of those admitted were between the ages of 18 and 44, with higher rates in men than in women. 108 Overall, although mortality from diabetic ketoacidosis in developed countries remains low, rates have risen in people aged >60 and in those with coexisting life threatening illnesses. 109 110 Recurrent diabetic ketoacidosis is associated with a substantial mortality rate. 111 Frequency of diabetic ketoacidosis increases with higher HbA 1c concentrations and with lower socioeconomic status. 112 Common precipitating factors include newly diagnosed type 1 diabetes, infection, poor adherence to insulin, and an acute cardiovascular event. 109

Euglycemic diabetic ketoacidosis refers to the clinical picture of an increased anion gap metabolic acidosis, ketonemia, or significant ketonuria in a person with diabetes without significant glucose elevation. This can be seen with concomitant use of SGLT-2 inhibitors (currently not indicated in type 1 diabetes), heavy alcohol use, cocaine use, pancreatitis, sepsis, and chronic liver disease and in pregnancy 113 Treatment is similar to that for hyperglycemic diabetic ketoacidosis but can require earlier use and greater concentrations of a dextrose containing fluid for the insulin infusion in addition to 0.9% normal saline resuscitation fluid. 114

The diagnosis of diabetic ketoacidosis has evolved from a gluco-centric diagnosis to one requiring hyperketonemia. By definition, independent of blood glucose, a β-hydroxybutyrate concentration >3 mmol/L is required for diagnosis. 115 However, the use of this ketone for assessment of the severity of the diabetic ketoacidosis is controversial. 116 Bedside β-hydroxybutyrate testing during treatment is standard of care in many parts of the world (such as the UK) but not others (such as the US). Concerns have been raised about accuracy of bedside β-hydroxybutyrate meters, but this is related to concentrations above the threshold for diabetic ketoacidosis. 116

Goals for management of diabetic ketoacidosis include restoration of circulatory volume, correction of electrolyte imbalances, and treatment of hyperglycemia. Intravenous regular insulin infusion is the standard of care for treatment worldwide owing to rapidity of onset of action and rapid resolution of ketonemia and hyperglycemia. As hypoglycemia and hypokalemia are more common during treatment, insulin doses are now recommended to be reduced from 0.1 u/kg/h to 0.05 u/kg/h when glucose concentrations drop below 250 mg/dL or 14 mM. 115 Subcutaneous rapid acting insulin protocols have emerged as alternative treatments for mild to moderate diabetic ketoacidosis. 117 Such regimens seem to be safe and have the advantages of not requiring admission to intensive care, having lower rates of complications related to intravenous therapy, and requiring fewer resources. 117 118 Ketonemia and acidosis resolve within 24 hours in most people. 115 To prevent rebound hyperglycemia, the transition off an intravenous insulin drip must overlap subcutaneous insulin by at least two to four hours. 115

Hypoglycemia

Hypoglycemia, a common occurrence in people with type 1 diabetes, is a well appreciated effect of insulin treatment and occurs when blood glucose falls below the normal range. Increased susceptibility to hypoglycemia from exogenous insulin use in people with type 1 diabetes results from multiple factors, including imperfect subcutaneous insulin delivery tools, loss of glucagon within a few years of diagnosis, progressive impairment of the sympatho-adrenal response with repeated hypoglycemic episodes, and eventual development of impaired awareness. In 2017 the International Hypoglycemia Study Group developed guidance for definitions of hypoglycemia; on the basis of this, a glucose concentration of 3.0-3.9 mmol/L (54-70 mg/dL) was designated as level 1 hypoglycemia, signifying impending development of level 2 hypoglycemia—a glucose concentration <3 mmol/L (54 mg/dL). 119 120 At approximately 54 mg/dL, neuroglycopenic hypoglycemia symptoms, including vision and behavior changes, seizures, and loss of consciousness, begin to occur as a result of glucose deprivation of neurons in the central nervous system. This can eventually lead to cerebral dysfunction at concentrations <50 mg/dL. 121 Severe hypoglycemia (level 3), denoting severe cognitive and/or physical impairment and needing external assistance for recovery, is a common reason for emergency department visits and is more likely to occur in people with lower socioeconomic status and with the longest duration of diabetes. 112 Prevalence of self-reported severe hypoglycemia is very high according to a global population study that included more than 8000 people with type 1 diabetes. 122 Severe hypoglycemia occurred commonly in younger people with suboptimal glycemia according to a large electronic health record database study in the US. 123 Self- reported severe hypoglycemia is associated with a 3.4-fold increase in mortality. 124 125

Acute consequences of hypoglycemia include impaired cognitive function, temporary focal deficits including stroke-like symptoms, and memory deficits. 126 Cardiovascular effects including tachycardia, arrhythmias, QT prolongation, and bradycardia can occur. 127 Hypoglycemia can impair many activities of daily living, including motor vehicle safety. 128 In a survey of adults with type 1 diabetes who drive a vehicle at least once a week, 72% of respondents reported having hypoglycemia while driving, with around 5% reporting a motor vehicle accident due to hypoglycemia in the previous two years. 129 This contributes to the stress and fear that many patients face while grappling with the difficulties of ongoing hypoglycemia. 130

Glucagon is highly efficacious for the primary treatment of severe hypoglycemia when a patient is unable to ingest carbohydrate safely, but it is unfortunately under-prescribed and underused. 131 132 Availability of nasal, ready to inject, and shelf-stable liquid glucagon formulations have superseded the need for reconstituting older injectable glucagon preparations before administration and are now preferred. 133 134 Real time CGM studies have shown a decreased hypoglycemic exposure in people with impaired awareness without a change in HbA 1c . 34 135 136 137 138 CGM has shown benefit in decreasing hypoglycemia across the lifespan, including in teens, young adults, and older people. 36 139 Although CGM reduces the burden of hypoglycemia including severe hypoglycemia, it does not eliminate it; overall, such severe level 3 hypoglycemia rates in clinical trials are very low and hard to decipher in the real world. HCL insulin delivery systems integrated with CGM have been shown to decrease hypoglycemia. Among available rapid acting insulins, ultra-rapid acting lispro (lispro-aabc) seems to be associated with less frequent hypoglycemia in type 1 diabetes. 140 141

As prevention of hypoglycemia is a crucial aspect of diabetes management, formal training programs to increase awareness and education on avoidance of hypoglycemia, such as the UK’s Dose Adjustment for Normal Eating (DAFNE), have been developed. 142 143 This program has shown fewer severe hypoglycemia (mean 1.7 (standard deviation 8.5) episodes per person per year before training to 0.6 (3.7) episodes one year after training) and restoration of recognition of hypoglycemia in 43% of people reporting unawareness. Clinically relevant anxiety and depression fell from 24.4% to 18.0% and from 20.9% to 15.5%, respectively. A structured education program with cognitive and psychotherapeutic aspects for changing hypoglycemia related behaviors, called the Hypoglycemia Awareness Restoration Program despite optimized self-care (HARPdoc), showed a positive effect on changing unhelpful beliefs around hypoglycemia and improved diabetes related and general distress and anxiety scores. 144

Management in under-resourced settings

According to a recent estimate from the International Diabetes Federation, 1.8 million people with type 1 diabetes live in low and middle income countries (LMICs). 2 In many LMICs, the actual burden of type 1 diabetes remains unknown and material resources needed to manage type 1 diabetes are lacking. 145 146 Health systems in these settings are underequipped to tackle the complex chronic disease that is type 1 diabetes. Few diabetes and endocrinology specialist physicians are available owing to lack of specific postgraduate training programs in many LMICs; general practitioners with little to no clinical experience in managing type 1 diabetes care for these patients. 146 This, along with poor availability and affordability of insulin and lack of access to technology, results in high mortality rates. 147 148 149 In developed nations, low socioeconomic status is associated with higher levels of mortality and morbidity for adults with type 1 diabetes despite access to a universal healthcare system. 150 Although global governments have committed to universal health coverage and therefore widespread availability of insulin, it remains very far from realization in most LMICs. 151

Access to technology is patchy and varies globally. In the UST1DX, CGM use was least in the lowest fifth of socioeconomic status. 152 Even where technology is available, successful engagement does not always occur. 153 In a US cohort, lower CGM use was seen in non-Hispanic Black children owing to lower rates of device initiation and higher rates of discontinuation. 154 In many LMICs, blood glucose testing strips are not readily available and cost more than insulin. 151 In resource limited settings, where even diagnosis, basic treatments including insulin, syringes, and diabetes education are limited, use of CGM adds additional burden to patients. Need for support services and the time/resources needed to download and interpret data are limiting factors from a clinician’s perspective. Current rates of CGM use in many LMICs are unknown.

Inequities in the availability of and access to certain insulin formulations continue to plague diabetes care. 155 In developed countries such as the US, rising costs have led to insulin rationing by around 25% of people with type 1 diabetes. 156 LMICs have similar trends while also remaining burdened by disproportionate mortality and complications from type 1 diabetes. 155 157 With the inclusion of long acting insulin analogs in the World Health Organization’s Model List of Essential Medicines in 2021, hope has arisen that these will be included as standard of care across the world. 158 In the past, the pricing of long acting analogs has limited their use in resource poor settings 159 ; however, their inclusion in WHO’s list was a major step in improving their affordability. 158 With the introduction of lower cost long acting insulin biosimilars, improved access to these worldwide in the future can be anticipated. 160

Making insulin available is not enough on its own to improve the prognosis for patients with diabetes in resource poor settings. 161 Improved healthcare infrastructure, better availability of diabetes supplies, and trained personnel are all critical to improving type 1 diabetes care in LMICs. 161 Despite awareness of limitations and barriers, a clear understanding of how to implement management strategies in these settings is still lacking. The Global Diabetes Compact was launched in 2021 with the goal of increasing access to treatment and improving outcomes for people with diabetes across the globe. 162

Emerging technologies and treatments

Monitoring systems.

The ability to measure urinary or more recently blood ketone concentrations is an integral part of self-management of type 1 diabetes, especially during acute illness, intermittent fasting, and religious fasts to prevent diabetic ketoacidosis. 163 Many people with type 1 diabetes do not adhere to urine or blood ketone testing, which likely results in unnecessary episodes of diabetic ketoacidosis. 164 Noting that blood and urine ketone testing is not widely available in all countries and settings is important. 1 Regular assessment of patients’ access to ketone testing (blood or urine) is critical for all clinicians. Euglycemic diabetic ketoacidosis in type 1 diabetes is a particular problem with concomitant use of SGLT-2 inhibitors; for this reason, these agents are not approved for use in these patients. For sick day management (and possibly for the future use of SGLT-2 inhibitors in people with type 1 diabetes), it is hoped that continuous ketone monitoring (CKM) can mitigate the risks of diabetic ketoacidosis. 165 Like CGM, the initial CKM device measures interstitial fluid β-hydroxybutyrate instead of glucose. CKM use becomes important in conjunction with a hybrid closed loop insulin pump system and added SGLT-2 inhibitor therapy, where insulin interruptions are common and hyperketonemia is frequent. 166

Perhaps the greatest technological challenge to date has been the development of non-invasive glucose monitoring. Numerous attempts have been made using strategies including optics, microwave, and electrochemistry. 167 Lack of success to date has resulted in healthy skepticism from the medical community. 168 However, active interest in the development of non-invasive technology with either interstitial or blood glucose remains.

Insulin and delivery systems

In the immediate future, two weekly basal insulins, insulin icodec and basal insulin Fc, may become available. 169 Studies of insulin icodec in type 1 diabetes are ongoing (ONWARDS 6; NCT04848480 ). How these insulins will be incorporated in management of type 1 diabetes is not yet clear.

Currently available AID systems use only a single hormone, insulin. Dual hormone AID systems incorporating glucagon are in development. 170 171 Barriers to the use of dual hormone systems include the need for a second chamber in the pump, a lack of stable glucagon formulations approved for long term subcutaneous delivery, lack of demonstrated long term safety, and gastrointestinal side effects from glucagon use. 74 Similarly, co-formulations of insulin and amylin (a hormone co-secreted with insulin and deficient in people with type 1 diabetes) are in development. 172

Immunotherapy for type 1 diabetes

As our understanding of the immunology of type 1 diabetes expands, development of the next generation of immunotherapies is under active pursuit. Antigen specific therapies, peptide immunotherapy, immune tolerance using DNA vaccination, and regulatory T cell based adoptive transfer targeting β cell senescence are all future opportunities for drug development. Combining immunotherapies with metabolic therapies such as GLP-1 receptor agonists to help to improve β cell mass is being actively investigated.

The quest for β cell replacement methods is ongoing. Transplantation of stem cell derived islets offers promise for personalized regenerative therapies as a potentially curative method that does away with the need for donor tissue. Since the first in vivo model of glucose responsive β cells derived from human embryonic stem cells, 173 different approaches have been attempted. Mesenchymal stromal cell treatment and autologous hematopoietic stem cells in newly diagnosed type 1 diabetes may preserve β cell function without any safety signals. 174 175 176 Stem cell transplantation for type 1 diabetes remains investigational. Encapsulation, in which β cells are protected using a physical barrier to prevent immune attack and avoid lifelong immunosuppression, and gene therapy techniques using CRISPR technology also remain in early stages of investigation.

Until recently, no specific guidelines for management of type 1 diabetes existed and management guidance was combined with consensus statements developed for type 2 diabetes. Table 6 summarizes available guidance and statements from various societies. A consensus report for management of type 1 diabetes in adults by the ADA and European Association for the Study of Diabetes became available in 2021; it covers several topics of diagnosis and management of type 1 diabetes, including glucose monitoring, insulin therapy, and acute complications. Similarly, the National Institute for Health and Care Excellence also offers guidance on management of various aspects of type 1 diabetes. Consensus statements for use of CGM, insulin pump, and AID systems are also available.

Guidelines in type 1 diabetes

Conclusions

Type 1 diabetes is a complex chronic condition with increasing worldwide prevalence affecting several million people. Several successes in management of type 1 diabetes have occurred over the years from the serendipitous discovery of insulin in 1921 to blood glucose monitoring, insulin pumps, transplantation, and immunomodulation. The past two decades have seen advancements in diagnosis, treatment, and technology including development of analog insulins, CGM, and advanced insulin delivery systems. Although we have gained a broad understanding on many important aspects of type 1 diabetes, gaps still exist. Pivotal research continues targeting immune targets to prevent or delay onset of type 1 diabetes. Although insulin is likely the oldest of existing modern drugs, no low priced generic supply of insulin exists anywhere in the world. Management of type 1 diabetes in under resourced areas continues to be a multifaceted problem with social, cultural, and political barriers.

Glossary of abbreviations

ADA—American Diabetes Association

AID—automated insulin delivery

BGM—blood glucose monitoring

CGM—continuous glucose monitoring

CKM—continuous ketone monitoring

DCCT—Diabetes Control and Complications Trial

DIY—do-it-yourself

FDA—Food and Drug Administration

GADA—glutamic acid decarboxylase antibody

GLP-1—glucagon-like peptide 1

GRS—genetic risk scoring

HbA1c—glycated hemoglobin

HCL—hybrid closed loop

LADA—latent autoimmune diabetes of adults

LMIC—low and middle income country

PAKT—pancreas after kidney transplant

RCT—randomized controlled trial

SGLT-2—sodium-glucose cotransporter 2

SPKT—simultaneous pancreas-kidney transplant

Questions for future research

What future new technologies can be helpful in management of type 1 diabetes?

How can newer insulin delivery methods benefit people with type 1 diabetes?

What is the role of disease modifying treatments in prevention and delay of type 1 diabetes?

Is there a role for sodium-glucose co-transporter inhibitors or glucagon-like peptide 1 receptor angonists in the management of type 1 diabetes?

As the population with type 1 diabetes ages, how should management of these people be tailored?

How can we better serve people with type 1 diabetes who live in under-resourced settings with limited access to medications and technology?

How patients were involved in the creation of this manuscript

A person with lived experience of type 1 diabetes reviewed a draft of the manuscript and offered input on important aspects of their experience that should be included. This person is involved in large scale education and activism around type 1 diabetes. They offered their views on various aspects of type 1 diabetes, especially the use of adjuvant therapies and the burden of living with diabetes. This person also raised the importance of education of general practitioners on the various stages of type 1 diabetes and the management aspects. On the basis of this feedback, we have highlighted the burden of living with diabetes on a daily basis.

Series explanation: State of the Art Reviews are commissioned on the basis of their relevance to academics and specialists in the US and internationally. For this reason they are written predominantly by US authors

Contributors: SS and IBH contributed to the planning, drafting, and critical review of this manuscript. FNK contributed to the drafting of portions of the manuscript. All three authors are responsible for the overall content as guarantors.

Competing interests: We have read and understood the BMJ policy on declaration of interests and declare the following interests: SS has received an honorarium from Abbott Diabetes Care; IBH has received honorariums from Abbott Diabetes Care, Lifescan, embecta, and Hagar and research support from Dexcom and Insulet.

Provenance and peer review: Commissioned; externally peer reviewed.

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Clinical Research in Type 1 Diabetes

Determinants, etiology, progression, prevention, and treatment of Type 1 Diabetes in children and adults.

The Clinical Research in Type 1 Diabetes program includes studies across the lifespan that address the etiology, pathogenesis, prevention and treatment (medical- and self-management) of type 1 diabetes in youth and adults. The program also supports research on hypoglycemia in T1D, including clinical studies and basic research using healthy individuals to understand the physiologic mechanisms of hypoglycemia. The program includes investigator-initiated clinical or behavioral studies, large, multi-center clinical trials that are conducted under cooperative agreements or contracts, and secondary analyses of ongoing clinical trials in diabetes and endocrinology.

NIDDK Program Staff

• Beena Akolkar, Ph.D. Clinical research in the prevention and immunopathogenesis of Type 1 Diabetes and the genetics and genomics of Type 1 and Type 2 Diabetes
• Guillermo A. Arreaza-Rubín, M.D. Diabetes and endocrine disease bioengineering and glucose sensing
• Miranda Broadney, M.D., M.P.H. Pediatrics, Pediatric Endocrinology, Clinical Management of Diabetes Mellitus, Insulin Resistance, Pediatric Obesity
• Maureen Monaghan Center, Ph.D., CDCES Health Psychology, Behavioral Science, Clinical Management of Diabetes
• Ellen Leschek, M.D. Type 1 and type 2 diabetes clinical research
• Hanyu Liang, M.D., Ph.D. Hepatic Metabolism; Insulin Resistance; Type 2 Diabetes; Obesity; Bariatric Surgery
• Lisa M. Spain, Ph.D. Disease-modifying clinical trials in type 1 diabetes, etiology and pathogenesis of type 1 diabetes
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Mentored patient-oriented research career development award (parent k23 independent clinical trial required), mentored patient-oriented research career development award (parent k23 independent clinical trial not allowed), rare diseases clinical research consortia (rdcrc) for the rare diseases clinical research network (rdcrn) (u54 clinical trial optional), adaptation of diabetes control technologies for older adults with t1d (r01 clinical trial optional), diabetes research centers (p30 clinical trial optional), related links.

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Type 1 Research Highlights

While the Association’s priority is to improve the lives of all people affected by diabetes, type 1 diabetes is a critical focus of the organization. In fact, in 2016, 37 percent of our research budget was dedicated to projects relevant to type 1 diabetes. Read more about the critical research made possible by the American Diabetes Association.

Smart Insulin Patch

American Diabetes Association Pathway to Stop Diabetes Scientist Zhen Gu, PhD, recently published a paper describing the development of an innovative "smart insulin" patch that imitates the body's beta cells by both sensing blood glucose levels and releasing insulin.

A Possible Trigger for Type 1 Diabetes

In order to prevent or reverse the development of type 1 diabetes, it is essential to understand why and how the immune system attacks the body’s own cells. Association-funded Researcher Thomas Delong, PhD, found a possible answer to these questions.

Enhancing Survival of Beta Cells for Successful Transplantation

Islet transplantation has long offered hope as a curative measure for type 1 diabetes. However, more than 80% of transplanted islets die within one week after transplantation. Research efforts are working to improve their survival and the promise of stem cells to reverse diabetes.

Explore: Type 1 Research Highlights

Investments in type 1 diabetes research

The CDC estimates that nearly 1.6 million Americans have it, including about 187,000 children and adolescents. The American Diabetes Association funds a productive research portfolio that offers significant progress and hope for improved outcomes for people with type 1 diabetes.

Identifying type 1 diabetes before beta cell loss

Dr. Hessner is investigating so-called “biomarkers,” which are components in blood or tissue samples that can be measured to predict which individuals are most likely to develop type 1 diabetes. 

Beta cell replacement

Both type 1 and type 2 diabetes result from a complete or partial loss of beta cell number and function. Finding a way to successfully replace functional beta cell is key to efforts to one day cure diabetes.

Enhancing survival of beta cells for successful transplantation

Islet transplantation has long offered hope as a curative measure for type 1 diabetes. However, more than 80% of transplanted islets die within one week after transplantation. Research efforts are working to improve their survival and the promise of stem cells to reverse diabetes.


New insight into how diabetes leads to blindness

New research is uncovering how diabetes changes the kinds of proteins that are made in the eye. These changes may lead to diabetic retinopathy, a leading cause of blindness. This information is allowing researchers to identify new targets for therapies that could delay or prevent the development of diabetic retinopathy.

Donate Today and Change Lives!

Type 1 Diabetes Research

Through the JDRF – Beyond Type 1 Alliance , Beyond Type 1 has partnered with JDRF—the world’s biggest nonprofit funder of type 1 diabetes research —to educate our community on the important role research plays in the lives of everyone affected by type 1 diabetes (T1D). It was diabetes research that led to the discovery of insulin in 1921. It was research that led to the creation of the first insulin pump in 1963, and research that led to the modern analog insulins used by many living with T1D today. Without research, we wouldn’t have continuous glucose monitors (CGMs), hybrid closed loop systems, or treatment for the complications that arise from living with diabetes. And it is research that will some day lead to the cure for type 1 diabetes.

Cure Research: The most promising cures for Type 1 diabetes will need to address two challenges: the loss of insulin-producing beta cells, and the immune system’s attack on those beta cells.

Vertex VX-880 Clinical Results Lead To Insulin-Independence

Explaining the Research: What Will It Take to Cure Diabetes?

Vertex Acquires ViaCyte, Combining Resources Toward a T1D Cure

Beta Cell Replacement Therapy: A Pathway to a Cure for Type 1 Diabetes?

New Documentary: ‘The Human Trial’ is a Quest to Cure Type 1 Diabetes

Beta Cell Therapies

Immunotherapies

Improving lives: a future cure is not enough for people living with t1d today. research also focuses on improving lives through glucose control and treating complications..

Glucose Control Therapies

Complications Treatment Research

Learn more about t1d research and the importance of trial participation.

Research Trials

Research News

Research Funding

To learn more about all the great T1D research being funded by JDRF,  visit their research and impact page here.

WRITTEN BY BT1 Editorial Team, POSTED 02/13/21, UPDATED 01/03/23

Bionic boy -, diabetes and the ketogenic diet -, why beyond type 1 matters: an interview with nick jonas -, the isolated caregiver—a mom’s story -, diabetes + exercise -.

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Kendall EK , Olaker VR , Kaelber DC , Xu R , Davis PB. Association of SARS-CoV-2 Infection With New-Onset Type 1 Diabetes Among Pediatric Patients From 2020 to 2021. JAMA Netw Open. 2022;5(9):e2233014. doi:10.1001/jamanetworkopen.2022.33014

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Association of SARS-CoV-2 Infection With New-Onset Type 1 Diabetes Among Pediatric Patients From 2020 to 2021

• 1 Center for Artificial Intelligence in Drug Discovery, Case Western Reserve University School of Medicine, Cleveland, Ohio
• 2 The Center for Clinical Informatics Research and Education, The MetroHealth System, Cleveland, Ohio
• 3 Center for Community Health Integration, Case Western Reserve University School of Medicine, Cleveland, Ohio

Incidence of new-onset type 1 diabetes (T1D) increased during the COVID-19 pandemic, 1 and this increase has been associated with SARS-CoV-2 infection. 2 The US Centers for Disease Control and Prevention reported that pediatric patients with COVID-19 were more likely to be diagnosed with diabetes after infection, although types 1 and 2 were not separated. 3 Therefore, whether COVID-19 was associated with new-onset T1D among youths remains unclear. This cohort study assessed whether there was an increase in new diagnoses of T1D among pediatric patients after COVID-19.

Data were obtained using TriNetX Analytics Platform, a web-based database of deidentified electronic health records of more than 90 million patients, from the Global Collaborative Network, which includes 74 large health care organizations across 50 US states and 14 countries with diverse representation of geographic regions, self-reported race, age, income, and insurance types. 4 The MetroHealth System institutional review board deemed the study exempt because it was determined to be non–human participant research. The study followed the STROBE reporting guideline.

The study population comprised pediatric patients in 2 cohorts: (1) patients aged 18 years or younger with SARS-CoV-2 infection between March 2020 and December 2021 and (2) patients aged 18 years or younger without SARS-CoV-2 infection but with non–SARS-CoV-2 respiratory infection during the same period. SARS-CoV-2 infection was defined as described in prior studies. 5 These cohorts were subdivided into groups aged 0 to 9 years and 10 to 18 years.

Cohorts were propensity score matched (1:1 using nearest-neighbor greedy matching) for demographics and family history of diabetes ( Table ). Risk of new diagnosis of T1D within 1, 3, and 6 months after infection were compared between matched cohorts using hazard ratios (HRs) and 95% CIs. Statistical analyses were conducted in the TriNetX Analytics Platform. Further details and analyses from the TriNetX database are given in the eMethods in the Supplement .

The Table shows population characteristics before and after matching. The study population included 1 091 494 pediatric patients: 314 917 with COVID-19 and 776 577 with non–COVID-19 respiratory infections. The matched cohort included 571 256 pediatric patients: 285 628 with COVID-19 and 285 628 with non–COVID-19 respiratory infections. By 6 months after COVID-19, 123 patients (0.043%) had received a new diagnosis of T1D, but only 72 (0.025%) were diagnosed with T1D within 6 months after non–COVID-19 respiratory infection. At 1, 3, and 6 months after infection, risk of diagnosis of T1D was greater among those infected with SARS-CoV-2 compared with those with non–COVID-19 respiratory infection (1 month: HR, 1.96 [95%CI, 1.26-3.06]; 3 months: HR, 2.10 [95% CI, 1.48-3.00]; 6 months: HR, 1.83 [95% CI, 1.36-2.44]) and in subgroups of patients aged 0 to 9 years, a group unlikely to develop type 2 diabetes, and 10 to 18 years ( Figure ). Similar increased risks were observed among children infected with SARS-CoV-2 compared with other control cohorts at 6 months (fractures: HR, 2.09 [95% CI, 1.41- 3.10]; well child visits: HR, 2.10 [95% CI, 1.61- 2.73]).

In this study, new T1D diagnoses were more likely to occur among pediatric patients with prior COVID-19 than among those with other respiratory infections (or with other encounters with health systems). Respiratory infections have previously been associated with onset of T1D, 6 but this risk was even higher among those with COVID-19 in our study, raising concern for long-term, post–COVID-19 autoimmune complications among youths. Study limitations include potential biases owing to the observational and retrospective design of the electronic health record analysis, including the possibility of misclassification of diabetes as type 1 vs type 2, and the possibility that additional unidentified factors accounted for the association. Results should be confirmed in other populations. The increased risk of new-onset T1D after COVID-19 adds an important consideration for risk-benefit discussions for prevention and treatment of SARS-CoV-2 infection in pediatric populations.

Accepted for Publication: August 6, 2022.

Published: September 23, 2022. doi:10.1001/jamanetworkopen.2022.33014

Open Access: This is an open access article distributed under the terms of the CC-BY License . © 2022 Kendall EK et al. JAMA Network Open .

Corresponding Author: Rong Xu, PhD, Sears Tower T303, Center for Artificial Intelligence in Drug Discovery ( [email protected] ); Pamela B. Davis, MD, PhD, Sears Tower T402, Center for Community Health Integration ( [email protected] ), Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH 44106.

Author Contributions : Ms Kendall and Ms Olaker had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Kendall, Xu, Davis.

Acquisition, analysis, or interpretation of data: Kendall, Olaker, Kaelber, Xu.

Drafting of the manuscript: Kendall, Olaker.

Critical revision of the manuscript for important intellectual content: Kendall, Kaelber, Xu, Davis.

Statistical analysis: Kendall, Olaker, Xu.

Obtained funding: Xu.

Administrative, technical, or material support: All authors.

Supervision: Kaelber, Xu, Davis.

Conflict of Interest Disclosures: Dr Kaelber reported receiving grants from the National Institutes of Health during the conduct of the study. No other disclosures were reported.

Funding/Support : This study was supported by grants AG057557 (Dr Xu), AG061388 (Dr Xu), AG062272 (Dr Xu), and AG076649 (Drs Xu and Davis) from the National Institute on Aging; grant R01AA029831 (Drs Xu and Davis) from the National Institute on Alcohol Abuse and Alcoholism; grant UG1DA049435 from the National Institute on Drug Abuse, and grant 1UL1TR002548-01 from the Clinical and Translational Science Collaborative of Cleveland.

Role of the Funder/Sponsor : The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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• Type 1 diabetes

What is type 1 diabetes? A Mayo Clinic expert explains

Learn more about type 1 diabetes from endocrinologist Yogish Kudva, M.B.B.S.

I'm Dr. Yogish C. Kudva an endocrinologist at Mayo Clinic. In this video, we'll cover the basics of type 1 diabetes. What is it? Who gets it? The symptoms, diagnosis, and treatment. Whether you're looking for answers for yourself or someone you love. We are here to give you the best information available. Type 1 diabetes is a chronic condition that affects the insulin making cells of the pancreas. It's estimated that about 1.25 million Americans live with it. People with type 1 diabetes don't make enough insulin. An important hormone produced by the pancreas. Insulin allows your cells to store sugar or glucose and fat and produce energy. Unfortunately, there is no known cure. But treatment can prevent complications and also improve everyday life for patients with type 1 diabetes. Lots of people with type 1 diabetes live a full life. And the more we learn and develop treatment for the disorder, the better the outcome.

We don't know what exactly causes type 1 diabetes. We believe that it is an auto-immune disorder where the body mistakenly destroys insulin producing cells in the pancreas. Typically, the pancreas secretes insulin into the bloodstream. The insulin circulates, letting sugar enter your cells. This sugar or glucose, is the main source of energy for cells in the brain, muscle cells, and other tissues. However, once most insulin producing cells are destroyed, the pancreas can't produce enough insulin, meaning the glucose can't enter the cells, resulting in an excess of blood sugar floating in the bloodstream. This can cause life-threatening complications. And this condition is called diabetic ketoacidosis. Although we don't know what causes it, we do know certain factors can contribute to the onset of type 1 diabetes. Family history. Anyone with a parent or sibling with type 1 diabetes has a slightly increased risk of developing it. Genetics. The presence of certain genes can also indicate an increased risk. Geography. Type 1 diabetes becomes more common as you travel away from the equator. Age, although it can occur at any age there are two noticeable peaks. The first occurs in children between four and seven years of age and the second is between 10 and 14 years old.

Signs and symptoms of type 1 diabetes can appear rather suddenly, especially in children. They may include increased thirst, frequent urination, bed wetting in children who previously didn't wet the bed. Extreme hunger, unintended weight loss, fatigue and weakness, blurred vision, irritability, and other mood changes. If you or your child are experiencing any of these symptoms, you should talk to your doctor.

The best way to determine if you have type 1 diabetes is a blood test. There are different methods such as an A1C test, a random blood sugar test, or a fasting blood sugar test. They are all effective and your doctor can help determine what's appropriate for you. If you are diagnosed with diabetes, your doctor may order additional tests to check for antibodies that are common in type 1 diabetes in the test called C-peptide, which measures the amount of insulin produced when checked simultaneously with a fasting glucose. These tests can help distinguish between type 1 and type 2 diabetes when a diagnosis is uncertain.

If you have been diagnosed with type 1 diabetes, you may be wondering what treatment looks like. It could mean taking insulin, counting carbohydrates, fat protein, and monitoring your glucose frequently, eating healthy foods, and exercising regularly to maintain a healthy weight. Generally, those with type 1 diabetes will need lifelong insulin therapy. There are many different types of insulin and more are being developed that are more efficient. And what you may take may change. Again, your doctor will help you navigate what's right for you. A significant advance in treatment from the last several years has been the development and availability of continuous glucose monitoring and insulin pumps that automatically adjust insulin working with the continuous glucose monitor. This type of treatment is the best treatment at this time for type 1 diabetes. This is an exciting time for patients and for physicians that are keen to develop, prescribe such therapies. Surgery is another option. A successful pancreas transplant can erase the need for additional insulin. However, transplants aren't always available, not successful and the procedure can pose serious risks. Sometimes it may outweigh the dangers of diabetes itself. So transplants are often reserved for those with very difficult to manage conditions. A successful transplant can bring life transforming results. However, surgery is always a serious endeavor and requires ample research and concentration from you, your family, and your medical team.

The fact that we don't know what causes type 1 diabetes can be alarming. The fact that we don't have a cure for it even more so. But with the right doctor, medical team and treatment, type 1 diabetes can be managed. So those who live with it can get on living. If you would like to learn even more about type 1 diabetes, watch our other related videos or visit mayoclinic.org. We wish you well.

Type 1 diabetes, once known as juvenile diabetes or insulin-dependent diabetes, is a chronic condition. In this condition, the pancreas makes little or no insulin. Insulin is a hormone the body uses to allow sugar (glucose) to enter cells to produce energy.

Different factors, such as genetics and some viruses, may cause type 1 diabetes. Although type 1 diabetes usually appears during childhood or adolescence, it can develop in adults.

Even after a lot of research, type 1 diabetes has no cure. Treatment is directed toward managing the amount of sugar in the blood using insulin, diet and lifestyle to prevent complications.

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Type 1 diabetes symptoms can appear suddenly and may include:

• Feeling more thirsty than usual
• Urinating a lot
• Bed-wetting in children who have never wet the bed during the night
• Feeling very hungry
• Losing weight without trying
• Feeling irritable or having other mood changes
• Feeling tired and weak
• Having blurry vision

When to see a doctor

Talk to your health care provider if you notice any of the above symptoms in you or your child.

The exact cause of type 1 diabetes is unknown. Usually, the body's own immune system — which normally fights harmful bacteria and viruses — destroys the insulin-producing (islet) cells in the pancreas. Other possible causes include:

• Exposure to viruses and other environmental factors

The role of insulin

Once a large number of islet cells are destroyed, the body will produce little or no insulin. Insulin is a hormone that comes from a gland behind and below the stomach (pancreas).

• The pancreas puts insulin into the bloodstream.
• Insulin travels through the body, allowing sugar to enter the cells.
• Insulin lowers the amount of sugar in the bloodstream.
• As the blood sugar level drops, the pancreas puts less insulin into the bloodstream.

The role of glucose

Glucose — a sugar — is a main source of energy for the cells that make up muscles and other tissues.

• Glucose comes from two major sources: food and the liver.
• Sugar is absorbed into the bloodstream, where it enters cells with the help of insulin.
• The liver stores glucose in the form of glycogen.
• When glucose levels are low, such as when you haven't eaten in a while, the liver breaks down the stored glycogen into glucose. This keeps glucose levels within a typical range.

In type 1 diabetes, there's no insulin to let glucose into the cells. Because of this, sugar builds up in the bloodstream. This can cause life-threatening complications.

Risk factors

Some factors that can raise your risk for type 1 diabetes include:

• Family history. Anyone with a parent or sibling with type 1 diabetes has a slightly higher risk of developing the condition.
• Genetics. Having certain genes increases the risk of developing type 1 diabetes.
• Geography. The number of people who have type 1 diabetes tends to be higher as you travel away from the equator.
• Age. Type 1 diabetes can appear at any age, but it appears at two noticeable peaks. The first peak occurs in children between 4 and 7 years old. The second is in children between 10 and 14 years old.

Complications

Over time, type 1 diabetes complications can affect major organs in the body. These organs include the heart, blood vessels, nerves, eyes and kidneys. Having a normal blood sugar level can lower the risk of many complications.

Diabetes complications can lead to disabilities or even threaten your life.

• Heart and blood vessel disease. Diabetes increases the risk of some problems with the heart and blood vessels. These include coronary artery disease with chest pain (angina), heart attack, stroke, narrowing of the arteries (atherosclerosis) and high blood pressure.

Nerve damage (neuropathy). Too much sugar in the blood can injure the walls of the tiny blood vessels (capillaries) that feed the nerves. This is especially true in the legs. This can cause tingling, numbness, burning or pain. This usually begins at the tips of the toes or fingers and spreads upward. Poorly controlled blood sugar could cause you to lose all sense of feeling in the affected limbs over time.

Damage to the nerves that affect the digestive system can cause problems with nausea, vomiting, diarrhea or constipation. For men, erectile dysfunction may be an issue.

• Kidney damage (nephropathy). The kidneys have millions of tiny blood vessels that keep waste from entering the blood. Diabetes can damage this system. Severe damage can lead to kidney failure or end-stage kidney disease that can't be reversed. End-stage kidney disease needs to be treated with mechanical filtering of the kidneys (dialysis) or a kidney transplant.
• Eye damage. Diabetes can damage the blood vessels in the retina (part of the eye that senses light) (diabetic retinopathy). This could cause blindness. Diabetes also increases the risk of other serious vision conditions, such as cataracts and glaucoma.
• Foot damage. Nerve damage in the feet or poor blood flow to the feet increases the risk of some foot complications. Left untreated, cuts and blisters can become serious infections. These infections may need to be treated with toe, foot or leg removal (amputation).
• Skin and mouth conditions. Diabetes may leave you more prone to infections of the skin and mouth. These include bacterial and fungal infections. Gum disease and dry mouth also are more likely.
• Pregnancy complications. High blood sugar levels can be dangerous for both the parent and the baby. The risk of miscarriage, stillbirth and birth defects increases when diabetes isn't well-controlled. For the parent, diabetes increases the risk of diabetic ketoacidosis, diabetic eye problems (retinopathy), pregnancy-induced high blood pressure and preeclampsia.

There's no known way to prevent type 1 diabetes. But researchers are working on preventing the disease or further damage of the islet cells in people who are newly diagnosed.

Ask your provider if you might be eligible for one of these clinical trials. It is important to carefully weigh the risks and benefits of any treatment available in a trial.

• Summary of revisions: Standards of medical care in diabetes — 2022. Diabetes Care. 2022; doi:10.2337/dc22-Srev.
• Papadakis MA, et al., eds. Diabetes mellitus. In: Current Medical Diagnosis & Treatment 2022. 61st ed. McGraw Hill; 2022. https://accessmedicine.mhmedical.com. Accessed May 4, 2022.
• What is diabetes? National Institute of Diabetes and Digestive and Kidney Diseases. https://www.niddk.nih.gov/health-information/diabetes/overview/what-is-diabetes. Accessed May 4, 2022.
• Levitsky LL, et al. Epidemiology, presentation, and diagnosis of type 1 diabetes mellitus in children and adolescents. https://www.uptodate.com/contents/search. Accessed May 4, 2022.
• Diabetes mellitus (DM). Merck Manual Professional Version. https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/diabetes-mellitus-and-disorders-of-carbohydrate-metabolism/diabetes-mellitus-dm. Accessed May 4, 2022.
• AskMayoExpert. Type 1 diabetes mellitus. Mayo Clinic; 2021.
• Robertson RP. Pancreas and islet transplantation in diabetes mellitus. https://www.uptodate.com/contents/search. Accessed May 4, 2022.
• Levitsky LL, et al. Management of type 1 diabetes mellitus in children during illness, procedures, school, or travel. https://www.uptodate.com/contents/search. Accessed May 4, 2022.
• Hyperglycemia (high blood glucose). American Diabetes Association. https://www.diabetes.org/healthy-living/medication-treatments/blood-glucose-testing-and-control/hyperglycemia. Accessed May 4, 2022.
• Diabetes and DKA (ketoacidosis). American Diabetes Association. https://www.diabetes.org/diabetes/dka-ketoacidosis-ketones. Accessed May 4, 2022.
• Insulin resistance & prediabetes. National Institute of Diabetes and Digestive and Kidney Diseases. https://www.niddk.nih.gov/health-information/diabetes/overview/what-is-diabetes/prediabetes-insulin-resistance. Accessed May 4, 2022.
• Blood sugar and insulin at work. American Diabetes Association. https://www.diabetes.org/tools-support/diabetes-prevention/high-blood-sugar. Accessed May 4, 2022.
• Inzucchi SE, et al. Glycemic control and vascular complications in type 1 diabetes. https://www.uptodate.com/contents/search. Accessed May 4, 2022.
• Diabetes and oral health. American Diabetes Association. https://www.diabetes.org/diabetes/keeping-your-mouth-healthy. Accessed May 4, 2022.
• Drug treatment of diabetes mellitus. Merck Manual Professional Version. https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/diabetes-mellitus-and-disorders-of-carbohydrate-metabolism/drug-treatment-of-diabetes-mellitus. Accessed May 4, 2022.
• Weinstock DK, et al. Management of blood glucose in adults with type 1 diabetes mellitus. https://www.uptodate.com/contents/search. Accessed May 7, 2022.
• FDA proves first automated insulin delivery device for type 1 diabetes. U.S. Food and Drug Administration. https://www.fda.gov/news-events/press-announcements/fda-approves-first-automated-insulin-delivery-device-type-1-diabetes. Accessed May 4, 2022.
• Boughton CK, et al. Advances in artificial pancreas systems. Science Translational Medicine. 2019; doi:10.1126/scitranslmed.aaw4949.
• Hypoglycemia (low blood sugar). American Diabetes Association. https://www.diabetes.org/healthy-living/medication-treatments/blood-glucose-testing-and-control/hypoglycemia. Accessed May 4, 2022.
• Diabetes in the workplace and the ADA. U.S. Equal Opportunity Employment Commission. https://www.eeoc.gov/laws/guidance/diabetes-workplace-and-ada. Accessed May 4, 2022.
• Cardiovascular disease and risk management: Standards of medical care in diabetes — 2022. Diabetes Care. 2022; doi:10.2337/dc22-S010.
• Diabetes technology. Standards of Medical Care in Diabetes — 2022. 2022; doi:10.2337/dc22-S007.
• FDA authorizes a second artificial pancreas system. JDRF. https://www.jdrf.org/blog/2019/12/13/jdrf-reports-fda-authorizes-second-artificial-pancreas-system/. Accessed May 4, 2022.
• Classification and diagnosis of diabetes: Standards of medical care in diabetes — 2022. Diabetes Care. 2022; doi:10.2337/dc22-S002.
• Retinopathy, neuropathy, and foot care: Standards of medical care in diabetes — 2022. Diabetes Care. 2022; doi:10.2337/dc22-S012.
• Glycemic targets: Standards of medical care in diabetes — 2022. Diabetes Care. 2022; doi:10.2337/dc22-S012.
• Pharmacologic approaches to glycemic treatment: Standards of medical care in diabetes — 2022. Diabetes Care. 2022; doi:10.2337/dc22-S009.
• Facilitating behavior change and well-being to improve health outcomes: Standards of medical care in diabetes — 2022. Diabetes Care. 2022; doi:10.2337/dc22-S005.
• Centers for Disease Control and Prevention. Use of hepatitis B vaccination for adults with diabetes mellitus: Recommendations of the Advisory Committee on Immunization Practices (ACIP). Morbidity and Mortality Weekly Report. 2011;60:1709.
• Management of diabetes in pregnancy: Standards of medical care in diabetes — 2022. Diabetes Care. 2022; doi:10.2337/dc22-S015.
• Older adults: Standards of medical care in diabetes — 2022. Diabetes Care. 2022; doi:10.2337/dc22-S013.
• FDA approves first-of-its-kind automated insulin delivery and monitoring system for use in young pediatric patients. U.S. Food and Drug Administration. https://www.fda.gov/news-events/press-announcements/fda-approves-first-its-kind-automated-insulin-delivery-and-monitoring-system-use-young-pediatric#:~:text=Today, the U.S. Food and,by individuals aged 2 to. Accessed May 8, 2022.
• What you need to know: Getting a COVID-19 vaccine. American Diabetes Association. https://www.diabetes.org/coronavirus-covid-19/vaccination-guide. Accessed June 1, 2022.

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Home > Books > Pediatric Endocrinology

Major Topics in Type 1 Diabetes

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Florida Institute of Technology , United States of America

Published 14 November 2015

Doi 10.5772/59335

ISBN 978-953-51-2204-3

eBook (PDF) ISBN 978-953-51-4214-0

Copyright year 2015

Number of pages 182

Type 1 diabetes (TD1) is one of the most common endocrine disorders in children and can occur at any age. Incidences of T1D have steadily increased worldwide, and it is largely considered an autoimmune disorder resulting from the specific destruction of pancreatic beta-cells producing insulin. However, T1D pathophysiology is still not completely understood, and although insulin and other therapies...

Type 1 diabetes (TD1) is one of the most common endocrine disorders in children and can occur at any age. Incidences of T1D have steadily increased worldwide, and it is largely considered an autoimmune disorder resulting from the specific destruction of pancreatic beta-cells producing insulin. However, T1D pathophysiology is still not completely understood, and although insulin and other therapies ameliorate the manifestations of the disease, no cure is currently available. This book has been written by widely acknowledged experts, with each chapter providing unique information on emerging aspects of T1D. Because a large body of information has been available regarding T1D, this book highlights lesser explored topics linked to the subject using important and recent knowledge that presages directions for further research. Current possibilities to forestall diabetic complications are also explored.

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JDRF Celebrates Research Award Winners and Recognizes Type 1 Diabetes Research Leaders

New York, April 18, 2024— JDRF, the leading global type 1 diabetes (T1D) research and advocacy organization, proudly presented awards to five outstanding leaders in T1D research whose impact has pushed JDRF’s mission forward. Award recipients include:

• Linda DiMeglio, M.D. and Moshe Phillip, M.D., co-recipients, George Eisenbarth Award for Type 1 Diabetes Prevention
• Colin Dayan, M.D., Ph.D., JDRF Rumbough Award
• Kirstine Bell, Ph.D., Dr. Robert Goldstein Award
• Viral Shah, M.D., Mary Tyler Moore and S. Robert Levine, M.D., Excellence in Clinical Research Award

“Since our inception, JDRF’s mission has been focused on accelerating research and breakthroughs to cure, prevent, and treat type 1 diabetes and its complications. Our progress has been driven by the exceptional work and commitment of T1D researchers across the globe,” said JDRF Chief Scientific Officer Sanjoy Dutta, Ph.D. “It’s an honor to recognize and celebrate these dedicated individuals for their leadership and clinical implementation in research and the tangible impacts they have had on their fields and the millions of people who live with or are at risk of T1D.”

George Eisenbarth Award for Type 1 Diabetes Prevention

Named after esteemed researcher George Eisenbarth, M.D., Ph.D., who provided the foundation for predicting T1D and identifying novel approaches toward prevention and cures, this award recognizes researchers who have made great contributions to preventing T1D.

Dr. Moshe Phillip and Dr. Linda DiMeglio have led the development of international consensus guidance for monitoring of T1D in its early stages prior to clinical diagnosis. As chair and vice chair of this effort, they helped convene a broad range of global experts and co-led the writing of the guidance document, which will provide actionable information for healthcare providers to monitor early-stage T1D in the clinical setting.

Dr. Phillip is the director of the Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes at Schneider Children’s Medical Center, Petah Tikva, where he has served since 1997, and leads the Diabetes Technologies Center at the institute. Under Dr. Phillip’s leadership, the institute was leading the first multinational multicenter study with automatic insulin delivery (AID) outside of a hospital. Dr. Phillip is currently engaged in studies for national screening of diabetes in the general population and in family members. He remains active in clinical and applied research, focusing on childhood diabetes and growth.

In addition to maintaining an active clinical practice, Dr. DiMeglio serves as the Edwin Letzter Professor of Pediatrics at Indiana University School of Medicine and Chief of the Division of Pediatric Endocrinology and Diabetology at Riley Children’s Health. She began her career with a JDRF career development award to support one of her first research projects on insulin pump therapy in very young children with diabetes. Now, she directs local and national research teams focused on preventing T1D, preserving beta cell function, and improving metabolic control and quality of life for persons living with the disease.

JDRF Rumbough Award

The JDRF David Rumbough Award acknowledges an individual who has made outstanding contributions in the field of T1D that have significantly accelerated the JDRF mission.

For over 20 years, Dr. Colin Dayan has been a leader in T1D immunotherapy research, and his work has been central to JDRF’s research strategy and overall mission. He is leading efforts to bring teplizumab, the first disease-modifying therapy approved by the U.S. Food and Drug Administration that can delay clinical T1D in individuals in early stages, to Europe and the UK to expand treatment options available in these areas. He is a leading member of the JDRF-funded UK T1D Research Consortium, through which he has brought the research community together to accelerate critical research, leverage collective resources, and collaborate to improve T1D clinical trial delivery. Currently, Professor Dayan serves as chair of Clinical Diabetes and Metabolism and head of section at Cardiff University School of Medicine and as part-time senior clinical researcher in the Nuffield Department of Medicine at the University of Oxford.

Dr. Robert Goldstein Award

Named for Dr. Robert Goldstein, who played a key role in developing JDRF’s Research department and served as chief scientific officer for JDRF International and JDRF Canada for decades, this award recognizes early career T1D researchers who show great promise for future work in the field.

Dr. Kirstine Bell is a diabetes educator, dietitian, and the principal research fellow at the Charles Perkins Centre at the University of Sydney. She leads the Australian T1D National Screening Pilot, a national feasibility, acceptability, and cost-effectiveness program to determine the optimal method for routine, publicly funded national screening program for all Australian children. She has served in a critical role as a co-first author on the 2022 ISPAD Clinical Practice Consensus Guideline: Stages of T1D in children and adolescents.

Mary Tyler Moore and S. Robert Levine, M.D., Excellence in Clinical Research Award

This award was established in honor of the late actress, Mary Tyler Moore, who served as chairman of JDRF International from 1984 until her passing in 2017, and her husband, Dr. Levine, who remains committed to JDRF’s mission. The award recognizes leaders and innovators of outstanding clinical and translational T1D research.

Dr. Viral Shah is currently leading a JDRF-funded trial to examine the effects of semaglutide, a GLP-1 agonist, in people with T1D and hybrid closed-loop systems, and he recently published the first report on use of the GLP1-GIP agonist Mounjaro in T1D that demonstrated promising results. His research has also shown the association between time in range and retinopathy progression in T1D, which provides necessary evidence to support future therapy development.

Dr. Shah is a professor of medicine in endocrinology and metabolism and the director of diabetes clinical research at the Center for Diabetes and Metabolic Diseases at Indiana University whose research focuses on improving glycemic control and reducing complications in people with T1D.

JDRF Research award recipients were recognized at a ceremony in New York City earlier in April 2024.

JDRF recognizes and appreciates all of the dedicated researchers who are committed to finding cures and improving the lives of those living with T1D.

JDRF’s mission is to accelerate life-changing breakthroughs to cure, prevent and treat T1D and its complications. To accomplish this, JDRF has invested more than $2.5 billion in research funding since our inception. We are an organization built on a grassroots model of people connecting in their local communities, collaborating regionally and globally for efficiency and broader fundraising impact, and uniting on a global stage to pool resources, passion, and energy. We collaborate with academic institutions, policymakers, and corporate and industry partners to develop and deliver a pipeline of innovative therapies to people living with T1D. Our staff and volunteers throughout the United States and our five international affiliates are dedicated to advocacy, community engagement, and our vision of a world without T1D. For more information, please visit jdrf.org or follow us on Twitter (@JDRF), Facebook (@myjdrf), and Instagram (@jdrfhq).

About Type 1 Diabetes (T1D)

T1D is an autoimmune condition that causes the pancreas to make very little insulin or none at all. This leads to dependence on insulin therapy and the risk of short or long-term complications, which can include highs and lows in blood sugar; damage to the kidneys, eyes, nerves, and heart; and even death if left untreated. Globally, it impacts nearly 9 million people. Many believe T1D is only diagnosed in childhood and adolescence, but diagnosis in adulthood is common and accounts for nearly 50% of all T1D diagnoses. The onset of T1D has nothing to do with diet or lifestyle. While its causes are not yet entirely understood, scientists believe that both genetic factors and environmental triggers are involved. There is currently no cure for T1D.

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The Future: Diabetes Youth and Parent Group

Diabetic ketoacidosis (DKA) is a life-threatening yet avoidable acute complication of type 1 diabetes. Alarmingly, five or more episodes of DKA increase the risk of premature mortality by 23% 1 . In young people, the psychological burden from living with diabetes has been shown to be highly predictive of frequent DKA, particularly for youth from economically challenged homes 2 . According to the University of Chicago Medicine’s 2018-19 Community Health Needs Assessment, 43% of children under the age of 18 in our surrounding communities live at poverty level, vastly limiting their access to the resources and support necessary for managing a chronic illness 3 .

Teenagers with diabetes widely report feelings of isolation from their peer group. The resulting loneliness is a compounded concern because it may lead to poor diabetes self-management. Evidence indicates that interventions that provide support, education and resources for children and families undergoing the challenges of living with diabetes result in improved consistency in treatment regimens, improved glycemic control 4 and a decreased necessity for repeated hospitalizations.

In 2018, the inpatient diabetes care and education specialists at UChicago Medicine, along with pediatric endocrine, psychology, and child life and social work team members took action. They decided that a peer group could be of great benefit to the hospital population of young people with type 1diabetes and their families. Preliminary research showed there were no type 1 diabetes groups for support in surrounding pediatric hospitals on the South Side of Chicago, in neighboring suburbs or in Northwest Indiana.

The team collaboratively resolved not to call the service a “support group” due to any preconceived associations the term may carry that could discourage their target teenage demographic. The interdisciplinary group, worked to develop a format that would assist in providing a service addressing the psychosocial and educational challenges of living with a chronic illness. They established the group’s goals: providing free psychological, emotional and educational support to youth and families with type 1 diabetes and for attendees to meet others who have the same condition. Outcomes they hoped their effort would garner were to improve glycemic control, decrease hospitalizations for DKA and above all bolster quality of life for parents and their children.

The team identified a population of patients with type 1 diabetes at UChicago Medicine Comer Children’s Hospital and surveyed both children and parents regarding their interest in a group. More than 100 responses were received — 30% from youths old enough to respond and 70% from parents of younger children. The response was overwhelming, showing that 91% were interested in attending and had many topics they wanted to discuss.

In July 2019, the first group meeting was held, welcoming youths of any age. The young people held a contest to name the group and chose The Future: Diabetes Youth and Parent Group . The meetings were initially held in person once a quarter, but moved to a virtual platform during the peak of the pandemic. The group now meets every other month and alternate between virtual and in-person meetings. The group has also expanded to youth with type 2 diabetes.

There are separate programs for parents and children. For parents, there are informal open discussions with diabetes experts, including CDCES, a dietitian, an endocrinologist, a psychologist, a child life specialist, a social worker, and guest speakers such as technology specialists. For children, there are informal games, contests, crafts, prizes, and guest speakers who are living with diabetes (Dexcom Warriors and JDRF Youth Ambassadors). The group is funded and supported by the Kovler Diabetes Center and Center for Clinical Professional Practice.

Response has been enthusiastic. Groups have ranged from four to nine families per session. Parents have commented that input from the group’s professional team has helped guide them in making decisions regarding their child’s diabetes, that they appreciate the support the other parents offer, and that they value the technology updates. Children have mentioned that this is their only opportunity to meet others who are going through similar situations related to diabetes, and that they enjoy the chance to win prizes.

Among the four children who attended all three consecutive in-person meetings, only one was admitted to the hospital for DKA between the first session in July 2019 and October 2020. This is significant compared to the experiences of other high-risk young people who expressed interest in attending but did not come to any groups or attended only one session. There were a total of thirteen admissions for DKA among those youth.

The Diabetes Youth and Parent Group team welcomes parents and children to join their Zoom and in-person sessions. To receive additional details, please contact [email protected] .

Bernadine Holland is a registered nurse and certified diabetes care and education specialist. Bernadine welcomes daily opportunities to empower patients by assisting them in building skills to manage their diabetes confidently, consistently and serenely.

1. Sperling, Mark, A. Recurrent DKA-for whom the bell tolls. Nature Reviews/Endocrinology. 2016:doi:10.1038/nendo.2016.137

2. Sperling, Mark, A. Recurrent DKA-for whom the bell tolls. Nature Reviews/Endocrinology. 2016:doi:10.1038/nendo.2016.137

3. Community Health Needs Assessment 2018-2019, UChicago Medicine: 22

4. Delameter, Alan M., de Wit, Maartje, McDarby, Vincent. Malik, Jamil, A., Hillard, Marisa, E., Northam, Elisabeth, Acerini, Carlo, L.ISPAD Clinical Practice Consensus Guidelines 2018: Psychological care for children and adolescents with Type 1 diabetes. Pediatric Diabetes. 2018: 19(Supp. 27): 237-49.

Kovler Diabetes Center

UChicago Medicine offers a patient-centered, science-based approach for managing insulin-dependent Type 1 diabetes, complex Type 2 diabetes, gestational, pre-diabetes and monogenic diabetes. 

The Future: Diabetes Youth & Parent Group

The Future: Diabetes Youth and Parent Group is a free group open to any youth with diabetes, as well as parents and caregivers. We offer a supportive, interactive experience for all participants.

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Type 1 diabetes

Linda a dimeglio.

Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA;

Carmella Evans-Molina

Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA;

Richard A Oram

Institute of Biomedical and Clinical Science, University of Exeter Medical School, and The Academic Kidney Unit, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK

Contributors

Type 1 diabetes is a chronic autoimmune disease characterised by insulin deficiency and resultant hyperglycaemia. Knowledge of type 1 diabetes has rapidly increased over the past 25 years, resulting in a broad understanding about many aspects of the disease, including its genetics, epidemiology, immune and β-cell phenotypes, and disease burden. Interventions to preserve β cells have been tested, and several methods to improve clinical disease management have been assessed. However, wide gaps still exist in our understanding of type 1 diabetes and our ability to standardise clinical care and decrease disease-associated complications and burden. This Seminar gives an overview of the current understanding of the disease and potential future directions for research and care.

Introduction

At first consideration, type 1 diabetes pathophysiology and management might seem straightforward; however, the more that is learnt about the disease, the less it seems is truly known. Improved understanding of the disease’s pathogenesis has not led to a single unifying Koch’s postulate for all cases. What once seemed like a single autoimmune disorder, with roots in T-cell mediated attack of insulin-producing β cells, is now recognised to result from a complex interplay between environmental factors and microbiome, genome, metabolism, and immune systems that vary between individual cases.

Despite known genetic underpinnings, most people who are diagnosed with type 1 diabetes do not have a relative with the disease or even the highest risk combination of HLA alleles, making attempts at primary disease prevention difficult. Although survival and patient health have improved considerably, particularly in the past 25 years, a cure for type 1 diabetes remains elusive. 1 , 2 Additionally, despite advances in technology, glycaemic control for most people with type 1 diabetes is not optimised, and many cannot access modern therapies because of the high costs of even basic care.

In 1984, George Eisenbarth developed a conceptual model for the pathogenesis of type 1 diabetes that is still used nowadays ( figure 1 ). 3 The model plots β-cell mass against age, highlighting an event sequence starting with predisposing genetic risk, then a precipitating environmental trigger that causes islet-specific auto-immunity, followed by β-cell loss, dysglycaemia, clinical diabetes, and rapid progression to complete β-cell loss. Although useful, this model does not address the increasingly apparent complexity of type 1 diabetes pathogenesis. Additionally, the disease pathogenesis is shown by a single line of disease course over time; however, at all stages of the disease heterogeneity exists that is not well understood.

Key events of the Eisenbarth model 3 over the course of the disease (measured in years) are shown by dotted lines at different time points. Challenges to this model, taking into account the increasing complexity of type 1 diabetes, include the following: precipitating immune events that might occur prenatally (A); large variation in starting β-cell mass and function, defects in one or both could be developmentally programmed (B); initiation of autoimmunity is measured by autoantibodies, but other immunological abnormalities probably precede the presence of detectable pancreatic antibodies (C); the patient’s environment could affect their entire disease course (D); β-cell loss could relapse or remit (E); dysglycaemia occurs before clinical diagnosis (F); decline in β-cell function might not mirror decline in β-cell mass—methods to measure β-cell mass have not been established (G); and residual C-peptide is detectable in many people who have long duration type 1 diabetes (H). Furthermore, progression through stages A–C is heterogeneous, and will be affected by immune, genetic, environment, and key demographic features (ie, age, body-mass index). Adapted from Atkinson et al. 4

This Seminar provides a review of type 1 diabetes and the status of research in the field. We focus on developments from the past 5 years that highlight the heterogeneity and complexity of the disease.

A diagnosis of diabetes is based on a fasting blood glucose concentration above 7·0 mmol/L (126 mg/dL), a random blood glucose concentration above 11·1 mmol/L (200 mg/dL) with symptoms, or an abnormal result from an oral glucose tolerance test. 5 In the absence of symptoms, abnormal glycaemia must be present on two different occasions. A diagnosis of diabetes can also be made on the basis of a glycated haemoglobin (HbA 1c ) concentration above 48 mmol/mol (6·5%). However, since dysglycaemia progression can be rapid in patients with type 1 diabetes, HbA 1c is less sensitive for diagnosis than fasting or stimulated blood glucose measurements. 5

Children with type 1 diabetes commonly present with symptoms of polyuria, polydipsia, and weight loss; approximately a third present with diabetic ketoacidosis. 6 The onset of type 1 diabetes can be more variable in adults, who might not present with the classic symptoms seen in children. Although traditional definitions classified type 1 diabetes as juvenile onset, the disease can occur at any age, with up to 50% of cases occurring in adulthood. 7 As many as 50% of adults with type 1 diabetes might be initially misclassified as having type 2 diabetes. 8 Similarly, in conjunction with the epidemic of childhood obesity, type 2 diabetes is increasingly common in adolescents (particularly in non-white individuals), and monogenic diabetes (eg, maturity diabetes onset of the young) accounts for 1–6% of childhood diabetes cases. 9 – 11

Although low C-peptide concentration as a marker of severe endogenous insulin deficiency is useful to guide both classification and treatment in cases of diabetes assessed over 3 years after clinical diagnosis, 12 no single clinical feature can perfectly distinguish type 1 from non-type 1 diabetes at diagnosis. Classification depends on an appreciation of other risk factors for type 1 versus other subtypes and the integration of clinical features (eg, age of diagnosis and body-mass index) with biomarkers (eg, pancreatic autoantibodies). 13

Over 90% of people with newly diagnosed type 1 diabetes have measurable antibodies against specific β-cell proteins, including insulin, glutamate decarboxylase, islet antigen 2, zinc transporter 8, and tetraspanin-7. 14 Birth cohort studies 15 , 16 of individuals with a high genetic risk for diabetes have shown a peak incidence of first autoantibody development before age 2 years. Most people with a single autoantibody do not progress to type 1 diabetes, but seroconversion to the presence of two or more serum autoantibodies in children is associated with an 84% risk of clinical type 1 diabetes by the age of 18 years ( figure 2A ). 16 The high risk of progression in the presence of multiple autoantibodies has led to a redefining of type 1 diabetes stages. In this new paradigm, a preclinical stage 1 case of type 1 diabetes is defined as the presence of two or more autoantibodies, while stages 2 and 3 are defined as the progression of metabolic abnormalities from abnormal glycaemia to overt diabetes, diagnosed by standard criteria ( figure 2B ). 18 Since the progression from islet autoantibody positivity to clinical diabetes could take months or years, defining multiple auto-antibody positivity as stage 1 allows targeting of immune interventions to a realistic primary outcome and facilitates early life intervention studies. 19

(A) The probability of developing diabetes in childhood stratified by the number of islet antibodies. In a study by Zeigler and colleagues, 16 13 377 children were identified as at risk in the newborn or infant period on the basis of high-risk HLA genotypes or having a relative with type 1 diabetes, or both, and were followed-up regularly. The numbers at risk are the number of children receiving follow-up at ages 0, 5, 10, 15, and 20 years. Adapted from Ziegler et al 16 with permission of the American Medical Association. (B) Type 1 diabetes progression and stages of type 1 diabetes. Stage 1 is the start of type 1 diabetes, marked by individuals having two or more diabetes-related autoantibodies and normal blood sugar concentrations. In stage 2, individuals have dysglycaemia without symptoms. Stage 3 is the time of clinical diagnosis. Reproduced from Greenbaum et al, 17 with permission from the American Diabetes Association. T1D=type 1 diabetes.

Type 1 diabetes is a heritable polygenic disease with identical twin concordance of 30–70%, 20 sibling risk of 6–7%, and a risk of 1–9% for children who have a parent with diabetes. 21 The overall lifetime risk varies greatly by country and geographical region but overall is around one in 250 people. 22 The disease is slightly more common in men and boys than in women and girls. 23 Two HLA class 2 haplotypes involved in anti gen presentation, HLA DRB1*0301-DQA1*0501-DQ* {"type":"entrez-nucleotide","attrs":{"text":"B10201","term_id":"2091320","term_text":"B10201"}} B10201 ( DR3 ) and HLA DRB1*0401-DQA1*0301-DQB1*0301 (DR4-DQ8) , are linked to approximately 50% of disease heritability and are prevalent in white people. 24 Other haplotypes are known to reduce type 1 diabetes risk, including DRB1*1501-DQA1*0102-DQB1–0602 ( DR15-DQ6 ). 24 The mechanisms by which these HLA haplotypes interact and alter risk are not completely understood. Different HLA associations in other racial groups are recognised but remain poorly characterised. 24 Genome-wide association studies have identified over 60 additional non-HLA loci associated with the risk of type 1 diabetes. These variants have been predominantly associated with the immune system and highlight pathways that are important in disease development—eg, insulin gene expression in the thymus, regulation of T-cell activation, and viral responses. 24 These HLA and non-HLA genetic associations could identify potential targets for future disease-modifying therapies or subgroups of patients who could benefit from specific immune interventions.

Historically, people at high risk of type 1 diabetes have been identified for research by HLA risk or familial risk, or both. 25 By contrast, individual non-HLA loci cannot be used to predict type 1 diabetes or discriminate it from other types of diabetes. Combined measurement of HLA and non-HLA loci into genetic risk scores could offer improved prediction of the risk of developing type 1 diabetes and discrimination of type 1 from type 2 diabetes. 26 , 27 Furthermore, the continuing fall of genotyping costs could facilitate future population-level disease prediction by use of genetic risk scores. 19 , 28

Epidemiology

Globally, type 1 diabetes is increasing both in incidence and prevalence, with overall annual increases in incidence of about 2–3% per year. 29 , 30 US data 31 suggest an overall annualised incidence from 2001 to 2015 of about 22·9 cases per 100 000 people among those younger than 65 years; data from other regions suggest similar incidences. 32 The greatest observed increases in incidence of type 1 diabetes are among children younger than 15 years, particularly in those younger than 5 years. 33 These increases cannot be explained by genetic changes, implicating environmental or behavioural factors, or both. Many environmental exposures are associated with type 1 diabetes, including infant and adult diet, vitamin D sufficiency, early-life exposure to viruses associated with islet inflammation (eg, enteroviruses), and decreased gut-microbiome diversity. 34 Obesity is associated with increasing presentation of type 1 diabetes, with β-cell stress potentially providing a mechanistic underpinning. 34 , 35 The large differences in the incidence of type 1 diabetes in genetically similar populations that are separated by socioeconomic borders 36 and the increasing incidence of type 1 diabetes in genetically low-risk individuals 37 highlight the importance of environmental risk factors regardless of genetic background risk. Further work is being done to understand the role of gene–environment interactions in the pathogenesis of type 1 diabetes, the role of different loci and pathways at different stages of the disease, and whether loci that are independent of disease risk could have a role in disease progression after development of autoimmunity. 38 – 40 Some data 31 , 41 suggest that the observed incidence could be declining in adults or potentially even levelling off across all age ranges; worldwide registry data will eventually reveal if this pattern is indeed true. 42

The incidence of type 1 diabetes varies by country and by region within countries. 31 At northern latitudes, people born in the spring are more likely to develop the disease than those born in the other seasons. 43 The peak incidence of diagnosis is seen in children aged 10–14 years. 31 , 32 Although many people present with type 1 diabetes in adulthood, 44 the higher incidence of type 2 diabetes in adulthood compared with type 1 diabetes and the flawed criteria for distinguishing these forms of disease make assessment of the incidence of type 1 diabetes in adults very difficult. 23 , 45 Most people living with type 1 diabetes are adults. 46

The immune phenotype of type 1 diabetes

The pathogenesis of type 1 diabetes results from a complex interaction between the pancreatic β-cell and innate and adaptive immune systems ( figure 3 ). 47 The question of whether a trigger for the immune response against β cells exists or whether the immune response is a random stochastic event has been a subject of considerable speculation and controversy. Several viral infections are associated with type 1 diabetes, with enterovirus being one of the most commonly associated infections. Enteroviral major capsid protein VP1 and RNA have been detected in islets from people with recent-onset type 1 diabetes, 48 along with hyper-expression of the class 1 major histo compatibility complex 49 and other indices of viral infection. One possibility is that some people with type 1 diabetes have an atypical, chronic viral infection of β cells, leading to chronic inflammation and the development of autoimmunity. The viral hypothesis has been difficult to test, although both antiviral therapy and the development of vaccines targeting enteroviruses are being pursued for this purpose.

The development of type 1 diabetes is thought to be initiated by the presentation of β-cell peptides by antigen-presenting cell (APCs). APCs bearing these autoantigens migrate to the pancreatic lymph nodes where they interact with autoreactive CD4+ T lymphocytes, which in turn mediate the activation of autoreactive CD8+T cells (A). These activated CD8+ T cells return to the islet and lyse β cells expressing immunogenic self-antigens on major histocompatibility complex class I surface molecules (B). β-cell destruction is further exacerbated by the release of proinflammatory cytokines and reactive oxygen species from innate immune cells (macrophages, natural killer cells, and neutrophils; C). This entire process is amplified by defects in regulatory T lymphocytes, which do not effectively suppress autoimmunity (D). Activated T cells within the pancreatic lymph node also stimulate B lymphocytes to produce autoantibodies against β-cell proteins. These autoantibodies can be measured in circulation and are considered a defining biomarker of type 1 diabetes (E).

In the field, much effort has been given to the study of the adaptive immune system in type 1 diabetes by use of assays of peripheral lymphocytes selected for autoreactivity to islet antigens. Increased frequency of islet-specific autoreactive CD8+ T lymphocytes and decreased regulatory immune function have been associated with type 1 diabetes. 50 Experiments, such as the transfer of type 1 diabetes following non-T-cell depleted allogeneic bone-marrow transplantation, 51 development of type 1 diabetes in an individual with B-lymphocyte and antibody deficiency, 52 and inherited genetic defects of T-lymphocyte function causing type 1 diabetes 53 highlight the crucial role of T cells in the pathophysiology of type 1 diabetes. 54 Almost all studies of peripheral autoimmunity in people with type 1 diabetes show overlap of phenotypes seen in the general population, and the proportion of islet autoreactive cells present in the periphery is often tiny (only a few cells among millions of non-autoreactive cells). As a result, connecting the population of autoreactive immune cells that is detectable in blood to the disease process in islets has been difficult. A key development has been the isolation of T lymphocytes that are reactive to β-cell antigen peptides from islets of organ donors with type 1 diabetes. 55 – 57

Histopathologically, these processes are observed as insulitis or immune-infiltrated (insulitic) islets. 58 CD8+ T lymphocytes are the most common immune cells within insulitic lesions, with CD4+ T cells present in lower numbers. Distinct patterns of insulitis that stratify with the aggressiveness of β-cell loss and age of diagnosis have been identified in insulitic islets. 59 Although insulitis is common and intense in animal models of type 1 diabetes, it is much rarer and more variable in human beings ( figure 3 ). 60

The β-cell phenotype of type 1 diabetes

At diagnosis, people with type 1 diabetes have reduced β-cell function compared with healthy controls. 61 With amelioration of hyperglycaemia, these β cells can have a partial recovery of insulin secretory function, leading to a so-called honeymoon period after diagnosis with minimal or no exogenous insulin needed. Over time, many of these residual cells are lost. However, analysis of pancreatic sections from individuals with long-term type 1 diabetes show the presence of residual β cells decades after diagnosis. 62 , 63 When sensitive C-peptide measure ments are performed, 30–80% of people with long-term type 1 diabetes are found to be insulin microsecretors. 64 – 67 So, although endogenous β-cell quantity and function decline with longer disease duration, this decline does not progress to a complete loss of all β cells. 64 – 67 This finding is noteworthy because in the Diabetes Control and Complications Trial 68 , 69 persistent C-peptide secretion was associated with reduced development of retinopathy, nephropathy, and hypoglycaemia. Additionally, the persistence of C-peptide secretion in people with long-term type 1 diabetes could improve glucagon responses to hypoglycaemia. 70 Moreover, the presence of residual C-peptide secretion after the diagnosis of disease could also increase the possibility of an improved effect of interventions targeted at rescuing or augmenting the survival of this residual pool of β cells. Analyses of pancreatic specimens from the Network of Pancreatic Organ Donors repository have not found evidence of either increased neogenesis or proliferation in pancreatic cells from donors with type 1 diabetes. 63 Thus, the mechanisms underlying the persistence of residual β cells in people with long-term type 1 diabetes remain unclear. Identifying pathways that have allowed these cells to escape the autoimmune attack could yield insight into new therapeutic approaches.

β-cell abnormalities might also contribute to type 1 diabetes pathogenesis, leading to the notion of so-called β-cell suicide. β-cell HLA class I overexpression is common in pancreatic sections from cadaveric donors with type 1 diabetes. This overexpression serves as a homing signal for cytotoxic T lymphocytes. 49 However, whether this signal is a primary β-cell defect or a response to a stimulus (eg, a viral infection) is not yet known. Additionally, evidence also exists for increased β-cell endoplasmic reticulum stress linked with accelerated β-cell death. 71 , 72 Endoplasmic reticulum stress in β cells has also been associated with alterations in mRNA splicing and errors in protein translation and folding; the resultant protein products have been proposed as potential immunogenic neoantigens. 73

In addition to these defects in the β-cell compartment, alterations in non-endocrine islet cells and the exocrine pancreas have also been described ( figure 4 ). These defects include abnormalities in the islet extracellular matrix 74 , 75 and in islet innervation and vascularity. 76 – 78 Data have also placed a renewed emphasis on the role of exocrine pancreatic pathology in type 1 diabetes. Compared with healthy individuals, people with type 1 diabetes have a decreased pancreatic weight and volume that continues to decrease with disease duration. 79 , 80 This finding could be explained by developmental defects, or pancreatic atrophy in response to loss of the paracrine and pro-growth effects of insulin or chronic inflammation, or even autoimmune-mediated exocrine destruction. These possibilities are all topics of active investigation.

(A) Type 1 diabetes is characterised by a variety of abnormalities that involve both the islet and the exocrine pancreas. The hallmark of type 1 diabetes is loss of insulin-producing β cells and immune infiltration of islets. However, the presence of insulitis, even within an individual pancreas, can be highly variable. (B) Immunofluorescent image of an insulitic islet from a cadaveric donor with long-term type 1 diabetes. Insulin is shown in blue and CD8+ T cells surrounding the islet are shown in yellow. (C) Haematoxylin and eosin staining of an islet from a cadaveric donor that exhibits a classic pattern of insulitis. The islet is circled with a yellow dotted line. The infiltrating immune cells are circled in red and indicated by arrows. (D) Haematoxylin and eosin staining of an islet, circled in yellow dotted line, from a cadaveric donor with long-term type 1 diabetes without any discernible immune infiltrate. By contrast with the islet in (C), this islet has evidence of peri-islet fibrosis as shown circled in red and indicated by arrows. Images B–D courtesy of M Campbell-Thompson, University of Florida, Gainesville, FL, USA.

Management of clinical disease

Methods of managing type 1 diabetes continue to improve, and although progress is generally slow and incremental, occasionally it is punctuated by rapid change. One such moment of change happened in 1993 with the publication of the Diabetes Control and Complication Trial. 81 This trial and the follow-up observational Epidemiology of Diabetes Interventions and Complications trial convincingly showed that achieving and maintaining glucose concentrations as close to those seen in people without diabetes as possible leads to a reduction in microvascular and cardiovascular type 1 diabetes complications. 82

Although insulin remains the mainstay of therapy, new insulin analogues with varying onsets and durations of action are widely available. Optimal glycaemic control requires multiple-dose insulin regimens that mimic physiological insulin release, with basal insulin for overnight and between-meal control, plus bolus doses of rapid-acting insulin analogues to cover ingested carbohydrate loads and treat hyperglycaemia. Insulin can be taken by injection (with an insulin pen if available) or, preferably for many people, with an insulin pump. 83 Ultra-rapid inhaled insulin is also available, but little enthusiasm for this preparation exists because of its fixed dosing (four or eight unit increments only), issues with consistent delivery, cost, and the need for pulmonary function testing. 84 A faster-acting subcutaneously-administered insulin (via injection or infusion) has also recently become available for clinical use. Appropriate insulin use requires frequent dosing adjustments for ingested carbohydrates, physical activity, and illness or stress.

While pramlintide is the only non-insulin medication approved for improved glycaemic control in patients with type 1 diabetes, metformin, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, and sodium-glucose co-transporter-2 (SGLT2) inhibitors have also been used of-label; however, fewer than 5% of patients use these medications. 85 Metformin, an insulin sensitiser, is the most commonly prescribed drug for people with type 1 diabetes who have insulin resistance but it has not been shown to be effective in people younger than 18 years who are overweight or obese and have type 1 diabetes. 86 Use of SGLT2 inhibitors is restricted in part because of early reports of euglycaemic diabetic ketoacidosis in people with type 1 diabetes treated with these compounds. A 2018 meta-analysis of these inhibitors suggests they are safe, 87 but more data are needed.

Glucagon therapy is also poised to undergo a resurgence in management of type 1 diabetes. Although only an emergency kit has been commercially available up until now for cases of severe hypoglycaemia leading to seizure or loss of consciousness, nasal and stable liquid formulations are being developed. The nasal formulation will be available as a rapid rescue therapy only, 88 whereas the stable liquid formulation could also be used in small doses for exercise and in dual hormone (ie, insulin and glucagon) closed-loop systems. 89 , 90

In the past 13 years, continuous glucose monitoring (CGM) and intermittently viewed CGM devices for at-home patient use with minimally invasive devices have become available, which have similar accuracy to capillary blood glucose monitors. 91 Both CGM and intermittently viewed CGM allow examination of glucose concentration patterns over time and, although CGM devices still need periodic calibration, they obviate the need for frequent capillary blood glucose measurements. CGM is more sophisticated than intermittently viewed CGM because it can give the user a warning on the basis of absolute or projected glucose values. When CGM is incorporated into hybrid closed-loop insulin-pump systems that automatically regulate basal infusion rates, but that require manual delivery of meal boluses by trained wearers to cover estimated carbohydrate intakes, substantial improvements in glucose variability and overall glycaemic control are seen ( figure 5 ). 93 Combined use of automated insulin delivery and CGM offers the prospect of an artificial pancreas with little input from the user. The substantial advances that have been made in pump and sensor technology and the increase in the number of trials to test their efficacy show that partially or fully automated systems could become a reality.

Sensor glucose profiles from 124 people with type 1 diabetes, of which 30 were adolescents (14–21 years; A) and 94 were adults (22–75 years; B), before (during run-in phase) and during the study phase using the Medtronic MiniMed 670 g hybrid closed-loop system (Medtronic, Northridge CA, USA) under clinical trial conditions. Median and IQR of sensor glucose values are given as a green line and band for the run-in phase, and a pink line and band for the study phase, respectively. In the run-in phase, the hybrid closed-loop system was in manual mode, with participants making all treatment decisions except for the pump automatically suspending before senor glucose concentrations became too low. In the study phase, the hybrid closed-loop system was in auto mode. Participants had less variability in their blood glucose concentration during auto mode. Reproduced from Garg et al, 92 with permission from Mary Ann Liebert.

Guidelines from the American Diabetes Association, International Society for Pediatric and Adolescent Diabetes, and Candian Diabetes Association suggest a HbA 1c target of less than 53 mmol/mol (7·0%) for adults and less than 58 mmol/mol (7·5%) in paediatric patients with type 1 diabetes; 94 – 96 however, most individuals do not achieve these targets. Although setting more aggressive targets is associated with achieving lower HbA 1c , 97 these targets should be individualised on the basis of many factors including comorbidities, patient capability and attitude, and available care resources 98 —eg, even lower targets are often prescribed for pregnant women and women anticipating pregnancy than those prescribed to other patients. 99 Higher targets might be appropriate for people with hypoglycaemia unawareness, history of severe hypoglycaemia, advanced complications, and short life expectancy. For optimal outcomes, people with diabetes should be cared for by a multidisciplinary care team, including diabetes educators, nurse practitioners, nurses, nutritionists, physician assistants, exercise physiologists, social workers, and psychologists. To optimise glycaemic control, clinical care with skilled and structured patient education and training sessions should be provided—including information on insulin adjustments, carbohydrate counting, and optimal use of available technology. 100

People with type 1 diabetes also risk developing other autoimmune diseases, sometimes as part of a poly-glandular autoimmune syndrome. A study 101 from the Type 1 Diabetes Exchange clinic registry noted the prevalence of autoimmune disease was 27% in a population of over 25 000 people with type 1 diabetes with a mean age of 23 years. The most common autoimmune disease is autoimmune thyroiditis (ie, Hashimoto thyroid itis and Graves’ disease) followed by coeliac disease. Other associated conditions include collagen-vascular diseases (eg, rheumatoid arthritis and lupus), autoimmune gastritis or pernicious anaemia, vitiligo, and Addison’s disease. Guidelines for the care of people with diabetes include periodic screening for these diseases, particularly thyroid and coeliac diseases. 102

Complications of type 1 diabetes

The discovery of insulin in 1922 transformed type 1 diabetes from a terminal to a treatable disease. Despite the advances in care discussed previously, the disease continues to be associated with substantial medical, psychological, and financial burden. Hypoglycaemia and ketoacidosis are persistent potentially life-threatening complications. Severe hypoglycaemic events requiring treatment assistance from another person occur at rates of 16–20 per 100 person-years; hypoglycaemic events leading to loss of consciousness or seizure occur at a rate of 2–8 per 100 person-years. 103 – 105 Recurrent hypoglycaemia results in an increased likelihood of hypoglycaemia unawareness and subsequent severe hypoglycaemic events, since recurrent hypoglycaemia reduces the glucose concentration that triggers the counter-regulatory responses to return to euglycaemia. 106 Hypoglycaemia unawareness can improve with edu cation, support, and glucose targets that are aimed at avoiding biochemical hypoglycaemia, while maintaining overall metabolic control. 107

Hypoglycaemic events are associated with adverse effects on cognitive function, 108 , 109 and are associated with 4–10% of type 1 diabetes-related deaths. 110 – 112 Observational studies suggest poor diabetes control does not reduce the risk of severe hypoglycaemia. 113 Notably, rates of severe hypoglycaemic events have been decreasing over time 104 and with CGM and other advanced diabetes technologies HbA 1c can be lowered into the target range without increasing the risk of severe hypoglycaemia. 114 Treatment in hospital for diabetic ketoacidosis occurs at a rate of 1–10 per 100 patient-years in paediatric populations with established type 1 diabetes, and accounts for 13–19% of type 1 diabetes-related mortality. 105 , 110 , 111 Incidence of diabetic ketoacidosis is higher among women than among men, and among people with higher HbA 1c levels than other people with type 1 diabetes.

Microvascular complications of the disease manifest primarily as retinopathy, neuropathy, and nephropathy, but also can affect cognitive function, the heart, and other organs. Hyperglycaemia is the primary risk factor for microvascular disease, and reducing HbA 1c through intensive diabetes management, particularly early during disease, is associated with striking (about 70%) reductions in incidence and slower progression of microvascular disease. However, differences in HbA 1c do not fully explain the variation in the incidence of complications and the severity of disease between individuals. Variability in glucose concentrations (both during the day and longer term) and glycosylation rates also probably have a role in interindividual differences. 115 , 116 Type 1 diabetes during puberty also appears to accelerate the development of complications. 117

Macrovascular complications of type 1 diabetes include atherosclerosis and thrombosis in the heart, peripheral arteries, and brain. By contrast with microvascular complications, the risk of cardiovascular complications does not appear to be as attenuated by intensive blood sugar control. Diabetic nephropathy, whether manifesting as microalbuminuria, macroalbuminuria, or a reduced glomerular filtration rate progressively augments the overall risk of macrovascular complications. 118 Cardiovascular disease remains the major cause of premature morbidity and mortality, with data 119 , 120 suggesting an 8–13-year shorter life expectancy for people with type 1 diabetes than for healthy individuals.

People with diabetes might also have both chronic and acute neurocognitive changes that include decline in cognitive function with detrimental effects on psychomotor speed, cognitive flexibility, attention, and visual perception. 121 , 122 Although the pathophysiology of neurocognitive changes is poorly understood, their development has been linked with both microvascular and macrovascular changes and changes in brain structure, neuronal loss, and cerebral atrophy. 123 , 124 Risk factors include developing diabetes early in life, chronic hyperglycaemia, and repeated hypoglycaemia.

In the past 25 years, among people with type 1 diabetes the risks of microvascular and macrovascular compli-cations have substantially decreased and outcomes have improved. 125 , 126 These improvements have been largely driven by better glycaemic control and improved management of associated risk factors—eg, hypertension and hyperlipidaemia. Several studies 127 – 130 have identified additional non-glycaemic risk factors for the development of complications. Genetic studies have not yielded strong associations between specific gene variants and complication status. Low levels of education and income have been associated with high risks of both micro-vascular and macrovascular complications. 127 Sex also appears to modify risk, since women with type 1 diabetes have been shown to have higher rates of all-cause premature mortality and vascular events than do men with type 1 diabetes. 128 In the past 5 years, new technologies have been designed to attempt to better predict future risk and complications by combining risk factors into probability models. Two examples are the QDiabetes 129 and QRISK3 130 web calculators that were developed with a prospective general practice dataset of 803 044 people with diabetes (44 440 with type 1 diabetes). These calculators can be used to predict 10-year risk for microvascular and macrovascular complications. However, continued work is needed in this area to combine prediction models with disease-specific bio- markers and disease-modifying therapies that can prevent sequelae.

An additional noteworthy complication of type 1 diabetes is the patient-reported burden of adverse also their family, friends, and caregivers. 131 Fear of hypoglycaemia is a prevalent issue, particularly for the families of very young children with type 1 diabetes. 132 Furthermore, poor quality of life is predictive of subsequent poor glycaemic control. 133

Disease-modifying therapies

For over 30 years, most efforts to cure type 1 diabetes have focused on altering the immune system’s attack on β cells. This approach began with trials of ciclosporin, an immunosuppressant that was given to inhibit T-cell activation. Although ciclosporin was unable to induce a durable disease remission, insulin requirements of patients decreased during active treatment, generating enthusiasm that immune modulation could treat type 1 diabetes. 134 – 136 Subsequently, other strategies have been tested in both primary and secondary prevention paradigms. Most efforts have focused broadly on tolerance induction by use of antigens or modulation of T-lymphocyte, B-lymphocyte, and cytokine responses. Some primary prevention studies have also used dietary approaches. 137 , 138

Antigen-based trials have used various forms of glutamate decarboxylase (GAD) protein, which have shown mixed but mostly negative results. 139 – 141 The Diabetes Prevention Trial—Type 1, tested whether oral or parental insulin prevented the development of type 1 diabetes in people who were autoantibody positive. Neither approach reduced diabetes development, but subgroup analyses suggested a benefit of oral insulin in individuals with the highest titres of insulin auto-antibodies. 142 , 143 Based on this finding, the Type 1 Diabetes TrialNet Network completed a trial 144 of low-dose oral insulin in a second cohort of individuals who were autoantibody positive with similar insulin autoantibody profiles, but this trial was also negative. Negative results were also observed in another trial investigating intranasal insulin. 145

Personalised strategies for tolerance induction are now also being pursued. One study tested repeated intradermal doses of a specific proinsulin peptide fragment in people with the HLA DRB1*0401 genotype, 146 for whom this peptide was identified to be specifically immunogenic. Clinical trials at diagnosis have also tested approaches aimed at modulating T-cell and B-cell responses. Despite many attempts at immune intervention, only four categories of drugs have shown efficacy in preserving C-peptide secretion in recent onset type 1 diabetes in randomised placebocontrolled trials. These drugs include a monoclonal antibody against the B-cell CD20 receptor (rituximab), 147 monoclonal antibodies against the T-cell CD3 receptor (teplizumab 148 , 149 and otelixizumab 150 ), cytotoxic T-lymphocyte protein 4 (CTLA4)-immunoglobulin-mediated co-stimulatory blockade with abatacept, 151 and alefacept, 152 which is a fusion protein that binds CD2 and targets CD4+ and CD8+ effector memory T cells. Although the phase 2 trials of these drugs met their primary or secondary endpoints, defined as an improvement in the C-peptide area-under-the-curve response during a mixed meal tolerance test, no drug has yet been able to induce insulin independence or progressed to a positive phase 3 trial that was translatable into clinical care. This gap in translating results from trials into clinical practice could highlight the need for alternative strategies. Combinatorial approaches that modulate multiple aspects of the immune response could result in better efficacy. For example, low-dose anti-thymocyte globulin in combination with granulocyte colony-stimulating factor has shown early and sustained efficacy in pilot studies 153 , 154 and is being tested in a phase 2 study () in recent-onset type 1 diabetes. Another approach is to intervene earlier in the disease process, at a time when greater β-cell mass remains. To this end, abatacept () and teplizumab () are being tested in stage 1 and stage 2 type 1 diabetes through the TrialNet Network. Even modest preservation of β-cell function could have long-term benefits, and better glycaemic control early in the disease course could mitigate the likelihood of complications. 155 – 157

One potential future therapy for type 1 diabetes is with replacement of β cells from an external source. Pancreas transplants have been performed for over 50 years and have become a standard-of-care treatment in individuals who have developed end-stage renal failure and require kidney transplantation. 158 Simultaneous kidney and pancreas transplantation in experienced centres can offer an up to 80% chance of insulin independence for over 5 years, but there is substantial surgical risk, and the requirement of immunosuppression. 159 Islet transplantation is a low-risk procedure, with donor islets infused into the liver via the portal vein. Shapiro and colleagues’ landmark work, by use of a steroid free Edmonton Protocol, 160 showed that islet transplantation could achieve insulin independence and offered an example of a successful and low-risk cell-based therapy. However, only a minority of islet transplant recipients achieve durable insulin independence. Moreover, morbidity associated with immunosuppression and limitations in the supply of donor islets restricts the number of people who can benefit from islet transplantation. 161 Currently, islet transplantation is used in a small subset of patients who have extremely severe hypoglycaemic unawareness. Even if insulin independence is not achieved, severe life-threatening hypoglycaemia can be prevented with minimal islet transplant function. 162 , 163

Cell therapy as a potential cure for type 1 diabetes remains a field of great interest. 2 Considerable effort has been focused on protocols to generate functional and glucose-responsive β cells from human embryonic stem cells or induced pluripotent stem cells from living donors. This approach offers the possibility of a limitless source of β cells that could be delivered in a semipermeable device that would permit functional insulin secretion but avoid the need for immuno-suppression. 164 Several small molecules, growth factors, hormones, and nutrients have been shown to promote modest β-cell neogenesis and proliferation. However, most positive results come from animal models and have been difficult to replicate in human studies. While stem-cell-based therapies and neogenesis are a source of hope for potential cures, they are not realistic treatments in the immediate future. 2

Other novel approaches include autologous haemopoietic stem-cell transplantation 165 , 166 and autologous T-regulatory cell administration. 167 – 169 In response to growing evidence highlighting an active role for the β cell in disease pathogenesis, several ongoing trials are testing drugs that have successfully targeted β-cell stress responses in mouse models of diabetes. 170

Conclusions

Over the past 50 years, people with type 1 diabetes and their medical-care providers have been tantalised with optimism and subsequently disappointed at the seemingly unobtainable cure on the horizon. However, this long journey has been punctuated by several pivotal successes, including the discovery of insulin in 1922, the first pancreatic transplantation in 1966, 171 the first insulin-pump studies, the first immunomodulatory trial in 1986, 136 and the first definitive evidence linking glycaemic control with complication status in 1993. 81 The past 25 years has brought an upsurge of technological advances, including designer insulin analogues, smart insulin pumps, continuous glucose sensors, and closed-loop insulin delivery systems.

Clinicians, investigators, and patients have gained a better appreciation of the true complexity of type 1 diabetes, and humility in the face of many unsuccessful trials aimed at inducing a durable disease remission. While scientists continue to untangle the complicated pathogenesis of the disease, patients and health-care providers should focus on advocating for improved access to modern advances in diabetes care, especially for affordable insulin analogues and technologies that can reduce the burden of managing this chronic disease. When insulin was discovered, the University of Toronto freely licensed the right to manufacture the drug; yet, people in resource-limited environments continue to die because they have no access to insulin. 172

Additionally, crucial research must continue into strategies to prevent disease onset and preserve or restore β-cell function. These approaches offer the promise of ameliorating or eliminating disease complications, and greatly improving outcomes for those who have the disease. Continued development of new low-cost, low-burden, and highly effective therapies to improve glycaemic control is also needed. These approaches could include investigation into the effects of different dietary composition on glycaemic outcomes, and the safety and efficacy of open-source patient-designed artificial pancreas innovations. Given observed differences in care, health-care providers must be committed to initiatives for continuous quality improvement, with a focus on increasing uptake and implementation of best standards of care. A greater focus on patient-centred outcomes has been present in trials, and further exploration of these important endpoints is also crucial. If stakeholders in the field concentrate on the areas that are most likely to have a long-term effect, management of type 1 diabetes is poised to undergo further radical transformation.

Search strategy and selection criteria

We searched MEDLINE for publications in English published between Jan 1, 2014, and March 1, 2018, using the term “type 1 diabetes” and MEDLINE subheadings and selected papers on the basis of our opinion of their scientific importance. Research published since the 2014 Lancet Seminar on this topic was given particular attention. We provide an overview of type 1 diabetes focusing on updating the reader on recent advances and controversies.

Acknowledgments

This work was partly supported by grants from the National Institutes of Health, JDRF, the Veteran’s Administration, Diabetes UK, the Leona M and Harry B Helmsley Charitable Trust, the BIRAX Regenerative Medicine Initiative, the Ball Brothers Foundation, George and Francis Ball Foundation, Sigma Beta Sorority, Cryptic Masons Medical Research Foundation, and the Luke Weise Research Fund. We thank W Tamborlane, C Matthews, and J Kushner for their review of a draft of this Seminar. We thank M Campbell-Thompson, F Syed, and T Weinzerl for assistance with figures. And we thank T Lewallen and M Wales for administrative support.

Declaration of interests

LAD reports personal fees from Eli Lilly, and grants from Medtronic, Sanofi, Xeris, Caladrius, Dexcom, and Janssen outside the submitted work. RAO holds a UK Medical Research Council institutional Confidence in Concept grant to develop a 10 SNP biochip type 1 diabetes genetic test in collaboration with Randox. CE-M declares no competing interests.

Contributor Information

Linda A DiMeglio, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA;

Carmella Evans-Molina, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA;

Richard A Oram, Institute of Biomedical and Clinical Science, University of Exeter Medical School, and The Academic Kidney Unit, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.

New study focuses on the placenta for clues to the development of gestational diabetes

A new study led by the Harvard Pilgrim Health Care Institute has identified that a deficit in the placental expression of the gene insulin-like growth factor 1 (IGFBP1) and low IGFBP1 circulating levels are associated with insulin resistance during pregnancy, highlighting a potential risk factor for the development of gestational diabetes.

The study, "Placental IGFBP1 levels during early pregnancy and the risk of insulin resistance and gestational diabetes," appears in the April 16, 2024 edition of Nature Medicine .

Gestational diabetes, a disease that can lead to multiple pregnancy and delivery complications, is the most common pregnancy metabolic complication, affecting 1 in 7 pregnancies. Existing research has shown that excess insulin resistance in pregnancy contributes to gestational diabetes, but the exact causes of this resistance remain unclear.

"The placenta -- the major driver of changes in insulin physiology in pregnancy -- is likely a key source of hormones involved in the development of gestational diabetes," says Marie-France Hivert, Harvard Medical School associate professor of population medicine at the Harvard Pilgrim Health Care Institute and lead author of the study. "Our goal was to discover novel placental factors that are implicated in gestational diabetes, by studying all proteins expressed in placenta tissues, across the human genome. We identified placental insulin-like growth factor 1 (IGFBP1) as a secreted placental factor that is likely implicated in regulation of glucose in human pregnancy."

The study builds on Dr. Hivert's extensive research into the determinants of gestational diabetes using genetics and other omics approaches, and their interaction with lifestyle and environmental factors. The study team conducted genome-wide RNA sequencing on maternal-facing placental tissue samples, and measured identified proteins in blood collected in multiple pregnancy cohorts with diverse backgrounds.

The team identified 14 genes whose placental RNA expression levels were associated with insulin resistance, finding the strongest association with gene IGFBP1. By measuring the IGFBP1 protein levels in circulation, they found that IGFBP1 levels rise over the course of pregnancy and are 5 times higher in pregnant people compared to outside of pregnancy, arguing for the placenta being one of the major sources of this protein during pregnancy. Results also show that low levels of circulating IGFBP1 in early pregnancy could predict who is likely to develop gestational diabetes in late second trimester of pregnancy. Finally, the team found that the trajectory of IGFBP1 levels across pregnancy differs in people who have a subtype of gestational diabetes characterized by insulin resistance previously shown more likely to develop pregnancy complications.

"Identifying a novel protein that characterizes a subtype of gestational diabetes is one additional step towards developing precision medicine for gestational diabetes," adds Dr. Hivert. "It's possible that measuring IGFBP1 in the first trimester could help identify people at risk of developing gestational diabetes early in pregnancy, potentially offering a window for prevention. We hope to conduct future research to address whether this protein plays a causal role in gestational glycemic regulation."

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Materials provided by Harvard Pilgrim Health Care Institute . Note: Content may be edited for style and length.

Journal Reference :

• Marie-France Hivert, Frédérique White, Catherine Allard, Kaitlyn James, Sana Majid, François Aguet, Kristin G. Ardlie, Jose C. Florez, Andrea G. Edlow, Luigi Bouchard, Pierre-Étienne Jacques, S. Ananth Karumanchi, Camille E. Powe. Placental IGFBP1 levels during early pregnancy and the risk of insulin resistance and gestational diabetes . Nature Medicine , 2024; DOI: 10.1038/s41591-024-02936-5

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Type 1 diabetes is a challenging condition to manage since it includes many facets such as treatment with insulin, technical devices, physiological and behavioral factors. Regular exercise is a cornerstone in diabetes treatment, but management of different forms of physical activity could be difficult for ...

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The unexpected health benefits of Ozempic and Mounjaro

Research is showing that these new weight-loss drugs can help treat conditions from addiction to kidney disease—and may even be contributing to a boom of “Ozempic babies.”

Casey Arnold, who lives in a suburb of Houston, spent years trying to quit smoking. She’d tried nicotine patches. That failed. She tried quitting cold turkey but that made her short tempered. On other occasions the idea of quitting made her so anxious, she smoked more to ease her fears.

By the time she permanently gave up cigarettes in the winter of 2023, at age 55, she’d been smoking for four decades and was up to two packs a day. But this time it was a new type of weight loss drug that helped her quit.

GLP-1, short for glucagon-like peptide 1, is a natural hormone that stimulates the production and release of insulin, slows digestion, curbs appetite, and blunts the brain’s focus on food. GLP-1 agonist drugs, like exanetide, tirzepatide and semaglutide, mimic this hormone. They were originally developed as diabetes treatments, but as more people began taking them, researchers observed these medications are effective for many more conditions than just diabetes and weight loss.

The FDA recently approved semaglutide, the active ingredient of Wegovy, for the treatment of obesity and for reducing the risk of heart attack and stroke in patients with obesity and heart disease . But as the number of people taking these drugs grows, physicians and researchers are learning about unanticipated health benefits for conditions where treatments have been limited, such as addiction, heart failure, and kidney disease.

( Ozempic is a serious drug with serious risks. Here’s what to know. )

Arnold quit smoking while participating in a clinical trial examining the potential of GLP-1 agonists as a treatment for smoking addiction.

“It was totally opposite of when I tried to quit in my previous years,” Arnold says. “I was shocked at how calm I was, compared to how I used to think about quitting.” Instead of anxiety and rage, she felt at peace, and her cravings faded.

“It’s just been an avalanche across the different patient populations,” says Mark Petrie , a cardiologist at the University of Glasgow, whose research focuses on the use of GLP-1 agonists in patients with heart failure. “It’s just good news all around.”

Heart failure with preserved ejection fraction

More than six million Americans are living with heart failure , a condition where the heart progressively loses the ability to pump enough blood to the rest of the body. Of these patients, approximately half have a type known as heart failure with preserved ejection fraction , in which the heart can pump normally but is too stiff to fill up with blood.

In a study published last year , researchers tested semaglutide as a treatment for heart failure with preserved ejection fraction in patients who were not diabetic. The result: patients who received the drug showed fewer symptoms and reported a better quality of life, compared to those who received the placebo. Patients who received the drug had lower levels of C-reactive protein, which is a marker for inflammation.

“This is a big finding,” says James de Lemos, a cardiologist at UT Southwestern Medical Center, in Dallas, Texas, who was not associated with the study. The study was too small to determine if semaglutide can reduce the risk of hospitalization or death but given the stark improvement in patient quality of life, it’s promising.

Although some of these benefits are likely due to weight loss, that’s just part of what makes this treatment effective.

These medications are also cardioprotective and reduce inflammation, which is known to be a driver of heart failure, says Amanda Vest , a cardiologist at the Cleveland Clinic, who specializes in treating patients with heart failure. “We must continue to think more expansively than just about the number on the scale,” Vest says.

For patients with the other major type of heart failure—heart failure with reduced ejection fraction—there is less evidence, so far, that these drugs are effective. More trials are in the works to determine which types of patients will benefit from the use of these medications.

Kidney disease

An estimated 850 million people worldwide are living with chronic kidney disease ,   but there are few effective treatments. Historically, the main strategy has been to stall kidney failure for as long as possible and then move the patient to dialysis or wait for a kidney transplant. But nine out of 10 patients die of complications before reaching that point.

For patients with severe chronic kidney disease, “you are looking at a mortality rate that’s 10 to 20 percent a year,” says Katherine Tuttle , a nephrologist at the University of Washington Medicine. “This is on par with the worst malignancies.”

As a couple of recent studies have shown , the GLP-1 agonist dulaglutide helps patients who suffer from chronic kidney disease and diabetes. In a recent trial looking at the effect of semaglutide on patients with chronic kidney disease and type 2 diabetes, the treatment was so effective at delaying the progression of chronic kidney disease that the clinical trial was stopped early so that all the trial patients could benefit from the drug.

“It’s the only semaglutide trial that was stopped early for efficacy,” says Tuttle, who is on the executive committee for the trial. “To stop a trial early for efficacy, the bar is set really high,” which includes strong enough evidence for its efficacy that it would be no longer considered ethical to continue giving patients the placebo.

( New obesity drugs are coming. Here's how they could change everything. )

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As Tuttle notes, the effects on the kidneys is only partially due to reductions in risk factors such as blood pressure, blood sugar, and weight. Other benefits are likely to result from reduced inflammation.

“They have a profound anti-inflammatory effect,” Tuttle says. “Our field is really under recognizing the importance of inflammation, particularly in kidney damage caused by diabetes.”

Results from the trial will be published later this year.

Effects on fertility

For a growing number of patients on GLP-1 agonists, such as Ozempic or Mounjaro, one surprising side effect has been unexpected pregnancy, which for some patients, has come after years of struggling with infertility. Although more research is needed to explore the link between GLP-1 agonists and pregnancy, it’s become enough of a phenomenon that ‘Ozempic babies’ has become a trending phrase. Meanwhile, experts think there are several factors responsible.

The first factor is the fact that GLP-1 agonists cause a delayed gastric emptying, which can cause oral contraception pills to be absorbed by the body at a slower rate. “These drugs are altering that particular part of the drug absorption phase,” says Archana Sadhu , an endocrinologist at Houston Methodist Hospital, adding that this effect can be particularly prominent during dosage increases. This means that oral birth control may not be as effective.

The second factor is the link between polycystic ovarian syndrome (PCOS)—the leading cause of infertility in women—and insulin resistance.

“Insulin resistance will dysregulate the ovarian cycle,” Sadhu says. Insulin resistance can lead to infertility by disrupting hormones such as estrogen and testosterone, which are related to fertility; and it can affect the release of eggs from the ovaries. When patients start taking GLP-1 agonists, this reduces their insulin resistance, which boosts fertility.

However, the effects of these drugs on pregnancy are still unknown, which means that it’s important for patients to talk with their doctors about any plans for becoming pregnant, as well as strategies for contraception, which may include adding in a second method to augment oral contraceptive pills, or switching to a different method.

Treating addiction

Since Ozempic and Mounjaro have been become more common, patients have been reporting several unexpected side effects, such as a diminished desire to smoke or drink. Although more research is needed, it’s thought that the part of the brain that is responsible for food cravings overlaps with the part of the brain that is responsible for cravings for substances of abuse, says Luba Yammine, an addiction researcher at UTHealth Houston.

For doctors working in the field, earlier versions of these GLP-1 drugs showed tremendous potential as anti-addiction medications.

“We have far fewer medications available” for treating addiction and many patients report difficulties accessing these, says Christian Hendershot, an addiction researcher at the University of North Carolina School of Medicine. The field also receives less research funding compared with other diseases.

For Yammine, she first became interested in studying the effect of GLP-1 agonists on addiction while working in primary care, where she had several patients who were smokers with diabetes. Yammine would counsel her patients on quitting smoking, prescribing nicotine patches or the medication buproprion, to help them quit. But most of the time these strategies failed.

“It’s hard to quit smoking, period,” Yammine says. “The vast majority of smokers want to quit, but even with the use of these therapies, many of them are not successful.”

To help these smokers with their diabetes she would prescribe GLP-1 agonist medications, only to discover when they returned for a follow-up that they had quit smoking. When she asked them what happened, their answer was that suddenly their cravings vanished. “That was a very interesting finding,” Yammine says.

This happened often enough that Yammine decided to explore the impact of these GLP-1 receptor agonists on addiction through a clinical trial.

Yammine and her collaborators led a pilot study , in which 46 percent of the participants who received exanetide, plus nicotine patches and smoking cessation counseling, were able to quit, compared to 26 percent of participants who received nicotine patches, counseling, and a placebo. Yammine and her collaborators are now following up with a larger trial. They are also planning a separate trial with semaglutide.

For the patients in the study who received exanetide, their post-cessation weight was 5.6 pounds lower than those who received the placebo, a side effect that can help offset the weight gain that is often associated with quitting smoking.  

“This weight gain is very problematic,” Yammine says, adding that many patients are either afraid to quit or relapse due to concerns about weight gain, while it can also put them at heightened risk for developing weight-related conditions, such as type 2 diabetes.

For Arnold, who was enrolled in a follow up trial that Yammine is conducting, the months in which she was participating in the trial was characterized both by a calmness surrounding her efforts to quit, as well as minimal weight gain. Since the trial has ended, she’s been able to maintain her efforts to quit smoking, although she gained a little weight. “I don’t have cravings,” Arnold says. “It’s this weight gain that is bothering me.”

Arnold, who works for an HVAC company, would really like to go back on exanetide, but as is the case with so many other patients who have experienced benefits from GLP-1 receptor agonists, she’s finding that it’s too expensive to do so. Just one month’s supply costs about $1,000, and without FDA approval for its use as an anti-addiction drug, most health insurance companies won’t pay for it.

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Type 2 diabetes is not one-size-fits-all: Subtypes affect complications and treatment options

by Lili Grieco-St-Pierre and Jennifer Bruin, The Conversation

You may have heard of Ozempic, the "miracle drug" for weight loss, but did you know that it was actually designed as a new treatment to manage diabetes? In Canada, diabetes affects approximately 10% of the general population . Of those cases, 90% have type 2 diabetes.

This metabolic disorder is characterized by persistent high blood sugar levels , which can be accompanied by secondary health challenges, including a higher risk of stroke and kidney disease .

Locks and keys

In type 2 diabetes , the body struggles to maintain blood sugar levels in an acceptable range. Every cell in the body needs sugar as an energy source, but too much sugar can be toxic to cells. This equilibrium needs to be tightly controlled and is regulated by a lock and key system.

In the body's attempt to manage blood sugar levels and ensure that cells receive the right amount of energy, the pancreatic hormone, insulin, functions like a key. Cells cover themselves with locks that respond perfectly to insulin keys to facilitate the entry of sugar into cells.

Unfortunately, this lock and key system doesn't always perform as expected. The body can encounter difficulties producing an adequate number of insulin keys, and/or the locks can become stubborn and unresponsive to insulin.

All forms of diabetes share the challenge of high blood sugar levels; however, diabetes is not a singular condition; it exists as a spectrum. Although diabetes is broadly categorized into two main types, type 1 and type 2, each presents a diversity of subtypes, especially type 2 diabetes.

These subtypes carry their own characteristics and risks, and do not respond uniformly to the same treatments .

To better serve people living with type 2 diabetes, and to move away from a "one size fits all" approach, it is beneficial to understand which subtype of type 2 diabetes a person lives with. When someone needs a blood transfusion, the medical team needs to know the patient's blood type. It should be the same for diabetes so a tailored and effective game plan can be implemented.

This article explores four unique subtypes of type 2 diabetes, shedding light on their causes, complications and some of their specific treatment avenues.

Severe insulin-deficient diabetes

Insulin is produced by beta cells , which are found in the pancreas. In the severe insulin-deficient diabetes (SIDD) subtype, the key factories—the beta cells—are on strike. Ultimately, there are fewer keys in the body to unlock the cells and allow entry of sugar from the blood.

SIDD primarily affects younger, leaner individuals, and unfortunately, increases the risk of eye disease and blindness , among other complications. Why the beta cells go on strike remains largely unknown, but since there is an insulin deficiency, treatment often involves insulin injections.

Severe insulin-resistant diabetes

In the severe insulin-resistant diabetes (SIRD) subtype, the locks are overstimulated and start ignoring the keys. As a result, the beta cells produce even more keys to compensate. This can be measured as high levels of insulin in the blood, also known as hyperinsulinemia.

This resistance to insulin is particularly prominent in individuals with higher body weight. Patients with SIRD have an increased risk of complications such as fatty liver disease . There are many treatment avenues for these patients but no consensus about the optimal approach ; patients often require high doses of insulin.

Mild obesity-related diabetes

Mild obesity-related (MOD) diabetes represents a nuanced aspect of type 2 diabetes, often observed in individuals with higher body weight. Unlike more severe subtypes, MOD is characterized by a more measured response to insulin. The locks are "sticky," so it is challenging for the key to click in place and open the lock. While MOD is connected to body weight, the comparatively less severe nature of MOD distinguishes it from other diabetes subtypes.

To minimize complications, treatment should include maintaining a healthy diet, managing body weight, and incorporating as much aerobic exercise as possible. This is where drugs like Ozempic can be prescribed to control the evolution of the disease, in part by managing body weight.

Mild age-related diabetes

Mild age-related diabetes (MARD) happens more often in older people and typically starts later in life. With time, the key factory is not as productive, and the locks become stubborn. People with MARD find it tricky to manage their blood sugar, but it usually doesn't lead to severe complications.

Among the different subtypes of diabetes, MARD is the most common .

Unique locks, varied keys

While efforts have been made to classify diabetes subtypes, new subtypes are still being identified, making proper clinical assessment and treatment plans challenging.

In Canada, unique cases of type 2 diabetes were identified in Indigenous children from Northern Manitoba and Northwestern Ontario by Dr. Heather Dean and colleagues in the 1980s and 90s. Despite initial skepticism from the scientific community, which typically associated type 2 diabetes with adults rather than children, clinical teams persisted in identifying this as a distinct subtype of type 2 diabetes, called childhood-onset type 2 diabetes.

Childhood-onset type 2 diabetes is on the rise across Canada, but disproportionately affects Indigenous youth. It is undoubtedly linked to the intergenerational trauma associated with colonization in these communities . While many factors are likely involved, recent studies have discovered that exposure of a fetus to type 2 diabetes during pregnancy increases the risk that the baby will develop diabetes later in life .

Acknowledging this distinct subtype of type 2 diabetes in First Nations communities has led to the implementation of a community-based health action plan aimed at addressing the unique challenges faced by Indigenous Peoples. It is hoped that partnered research between communities and researchers will continue to help us understand childhood-onset type 2 diabetes and how to effectively prevent and treat it.

A mosaic of conditions

Type 2 diabetes is not uniform; it's a mosaic of conditions, each with its own characteristics. Since diabetes presents so uniquely in every patient, even categorizing into subtypes does not guarantee how the disease will evolve . However, understanding these subtypes is a good starting point to help doctors create personalized plans for people living with the condition.

While Indigenous communities, lower-income households and individuals living with obesity already face a higher risk of developing type 2 diabetes than the general population, tailored solutions may offer hope for better management. This emphasizes the urgent need for more precise assessments of diabetes subtypes to help customize therapeutic strategies and management strategies. This will improve care for all patients, including those from vulnerable and understudied populations.

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