type 2 diabetes essay

Type 2 Diabetes Essay

Introduction.

Diabetes is a health condition that is developed when sugar level in the blood increases above normal levels. The two major types of diabetes are type 1 diabetes and type 2 diabetes. Type 2 diabetes is more prevalent than type 1 diabetes. This essay discusses some of the most frequently asked questions about type 2 diabetes through a sample dialogue between a patient and a doctor.

Patient: What is type 2 Diabetes and how is it developed?

Doctor: Type 2 diabetes can be described as a complication in the metabolic processes characterized by a relative shortage of insulin and high levels of glucose in the blood (Barnett, 2011). It differs from type 1 diabetes where there is a complete deficiency of insulin caused by destruction of pancreatic islet cells.

In addition, type 2 diabetes is more common in adults unlike type 1 diabetes which is prevalent amongst young people. The typical symptoms of type 2 diabetes include: recurrent urination, excessive thirst, and persistent hunger (Wilson &Mehra, 1997).

Type 2 diabetes is caused by a mixture of lifestyle and hereditary factors. Even though some factors, like nutrition and obesity, are under individual control, others like femininity, old age, and genetics are not. Sedentary lifestyle, poor nutrition and stress are the major causes of Type 2 diabetes.

Particularly, excessive consumption of sugar and fats increases the risk of infection. Genetic factors have been linked to this condition. For instance, research indicates that if one identical twin is infected, there is a 90% probability of the other twin getting infected. Nutritional condition of a mother for the period of fetal growth can as well lead to this condition. Inadequate sleep is associated with Type 2 diabetes since it affects the process of metabolism (Hawley & Zierath, 2008).

Patient: How is type 2 Diabetes transmitted?

Doctor: Type 2 diabetes cannot be transmitted from one individual to another, since it is not caused by micro-organisms that can be spread. Instead, it is a health condition where the body is unable to create sufficient insulin to maintain the blood sugar level.

Nevertheless, a child from diabetic parents is likely to develop the complication due to genetic inheritance. According to Hanas & Fox (2007), there are some genes that may result in diabetes. As in 2011, research showed that there are more than thirty-six genes that increase the risk of type 2 diabetes infection.

These genes represent 10 per cent of the entire hereditary component of the complication. For instance, a gene referred to as TCF7L2 allele, increases the probability of diabetes occurrence by 1.5 times. It is the greatest threat amongst the genetic invariants. Children from diabetic parents are, therefore, likely to get infected since genes are transferrable from parents to the offspring.

Patient: How is type 2 Diabetes treated?

Doctor: The first step in the treatment of type 2 diabetes is consumption of healthy diet. This involves avoiding excessive consumption of foods that contain sugar and fats as they are likely to increase the levels of sugar in the blood. In addition, getting involved in physical activity and losing excessive weight are also important.

These management practices are recommended because they lower insulin resistance and improve the body cells’ response to insulin. Eating healthy food and physical activity also lower the level of sugar in the blood. There are also pills and other medications that can be injected when these lifestyle changes do not regulate the blood sugar (Roper, 2006).

Type2 diabetes pills function in different ways. Some pills work by lowering insulin resistance while some raise the level of insulin in the blood or decrease the rate of food digestion. Even though the non-insulin injected medicines for this condition work in complex ways, essentially, they lower the levels of blood glucose after injection.

Insulin injection treatment basically raises the insulin level in the blood. Another treatment for type 2 diabetes is weight loss surgery that is recommended for obese people. This treatment has been proved effective since most of the patients can maintain regular levels of sugar in their blood after surgery (Codario, 2011).

Multiple prescriptions can be applied in controlling the levels of blood sugar. Actually, combination treatment is a popular remedy for Type 2 diabetes. If a single therapy is not sufficient, a health care provider may prescribe two or more different kinds of pills.

For instance, individuals with type 2 diabetes have high fat levels in the blood and high blood pressure. Therefore, doctors can prescribe medicines for treatment of these conditions at the same time. The kind of medication prescribed depends on the health condition of the patient (Ganz, 2005).

Patient: What are the chances of survival?

Doctor: Diabetes is one of the major causes of deaths in the United States each year. Statistics indicates that it contributes to approximately 100,000 deaths every year. In the United States, there are over 20 million reported cases of diabetes, the majority being Type 2 diabetes. Proper remedy including change of lifestyle and medications is known to improve the health condition of a patient. If properly used together, lifestyle changes and medication can increase the chances of survival of a patient by up to 85 per cent (Rosenthal, 2009).

Barnett, H. (2011). Type 2 diabetes. Oxford: Oxford University Press.

Codario, A. (2011). Type 2 diabetes, pre-diabetes, and the metabolic syndrome. Totowa, N.J: Humana Press.

Ganz, M. (2005). Prevention of Type 2 Diabetes . Chichester: John Wiley & Sons.

Hanas, R., & Fox, C. (2007). Type 2 diabetes in adults of all ages. London: Class Health.

Hawley, A., & Zierath, R. (2008). Physical activity and type 2 diabetes: Therapeutic effects and mechanisms of action. Champaign, IL: Human Kinetics.

Roper, R. (2006). Type 2 diabetes: The adrenal gland disease : the cause of type 2 diabetes and a nutrition program that takes control! . Bloomington, IN: AuthorHouse.

Rosenthal, S. (2009). The Canadian type 2 diabetes sourcebook. Mississauga, Ont: J. Wiley & Sons Canada.

Wilson, L., & Mehra, V. (1997). Managing the patient with type II diabetes . Gaithersburg, Md: Aspen Publishers.

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Hypothesis and theory article, type 2 diabetes mellitus: a pathophysiologic perspective.

• Department of Medicine, Duke University, Durham, NC, United States

Type 2 Diabetes Mellitus (T2DM) is characterized by chronically elevated blood glucose (hyperglycemia) and elevated blood insulin (hyperinsulinemia). When the blood glucose concentration is 100 milligrams/deciliter the bloodstream of an average adult contains about 5–10 grams of glucose. Carbohydrate-restricted diets have been used effectively to treat obesity and T2DM for over 100 years, and their effectiveness may simply be due to lowering the dietary contribution to glucose and insulin levels, which then leads to improvements in hyperglycemia and hyperinsulinemia. Treatments for T2DM that lead to improvements in glycemic control and reductions in blood insulin levels are sensible based on this pathophysiologic perspective. In this article, a pathophysiological argument for using carbohydrate restriction to treat T2DM will be made.

Introduction

Type 2 Diabetes Mellitus (T2DM) is characterized by a persistently elevated blood glucose, or an elevation of blood glucose after a meal containing carbohydrate ( 1 ) ( Table 1 ). Unlike Type 1 Diabetes which is characterized by a deficiency of insulin, most individuals affected by T2DM have elevated insulin levels (fasting and/or post glucose ingestion), unless there has been beta cell failure ( 2 , 3 ). The term “insulin resistance” (IR) has been used to explain why the glucose levels remain elevated even though there is no deficiency of insulin ( 3 , 4 ). Attempts to determine the etiology of IR have involved detailed examinations of molecular and intracellular pathways, with attribution of cause to fatty acid flux, but the root cause has been elusive to experts ( 5 – 7 ).

Table 1 . Definition of type 2 diabetes mellitus.

How Much Glucose Is in the Blood?

Keeping in mind that T2DM involves an elevation of blood glucose, it is important to understand how much glucose is in the blood stream to begin with, and then the factors that influence the blood glucose—both exogenous and endogenous factors. The amount of glucose in the bloodstream is carefully controlled—approximately 5–10 grams in the bloodstream at any given moment, depending upon the size of the person. To calculate this, multiply 100 milligrams/deciliter × 1 gram/1,000 milligrams × 10 deciliters/1 liter × 5 liters of blood. The “zeros cancel” and you are left with 5 grams of glucose if the individual has 5 liters of blood. Since red blood cells represent about 40% of the blood volume, and the glucose is in equilibrium, there may be an extra 40% glucose because of the red blood cell reserve ( 8 ). Adding the glucose from the serum and red blood cells totals about 5–10 grams of glucose in the entire bloodstream.

Major Exogenous Factors That Raise the Blood Glucose

Dietary carbohydrate is the major exogenous factor that raises the blood glucose. When one considers that it is common for an American in 2021 to consume 200–300 grams of carbohydrate daily, and most of this carbohydrate is digested and absorbed as glucose, the body absorbs and delivers this glucose via the bloodstream to the cells while attempting to maintain a normal blood glucose level. Thinking of it in this way, if 200–300 grams of carbohydrates is consumed in a day, the bloodstream that holds 5–10 grams of glucose and has a concentration of 100 milligrams/deciliter, is the conduit through which 200,000–300,000 milligrams (200 grams = 200,000 milligrams) passes over the course of a day.

Major Endogenous Factors That Raise the Blood Glucose

There are many endogenous contributors that raise the blood glucose. There are at least 3 different hormones that increase glucose levels: glucagon, epinephrine, and cortisol. These hormones increase glucose levels by increasing glycogenolysis and gluconeogenesis ( 9 ). Without any dietary carbohydrate, the normal human body can generate sufficient glucose though the mechanism of glucagon secretion, gluconeogenesis, glycogen storage and glycogenolysis ( 10 ).

Major Exogenous Factors That Lower the Blood Glucose

A reduction in dietary carbohydrate intake can lower the blood glucose. An increase in activity or exercise usually lowers the blood glucose ( 11 ). There are many different medications, employing many mechanisms to lower the blood glucose. Medications can delay sucrose and starch absorption (alpha-glucosidase inhibitors), slow gastric emptying (GLP-1 agonists, DPP-4 inhibitors) enhance insulin secretion (sulfonylureas, meglitinides, GLP-1 agonists, DPP-4 inhibitors), reduce gluconeogenesis (biguanides), reduce insulin resistance (biguanides, thiazolidinediones), and increase urinary glucose excretion (SGLT-2 inhibitors). The use of medications will also have possible side effects.

Major Endogenous Factors That Lower the Blood Glucose

The major endogenous mechanism to lower the blood glucose is to deliver glucose into the cells (all cells can use glucose). If the blood glucose exceeds about 180 milligrams/deciliter, then loss of glucose into the urine can occur. The blood glucose is reduced by cellular uptake using glut transporters ( 12 ). Some cells have transporters that are responsive to the presence of insulin to activate (glut4), others have transporters that do not require insulin for activation. Insulin-responsive glucose transporters in muscle cells and adipose cells lead to a reduction in glucose levels—especially after carbohydrate-containing meals ( 13 ). Exercise can increase the glucose utilization in muscle, which then increases glucose cellular uptake and reduce the blood glucose levels. During exercise, when the metabolic demands of skeletal muscle can increase more than 100-fold, and during the absorptive period (after a meal), the insulin-responsive glut4 transporters facilitate the rapid entry of glucose into muscle and adipose tissue, thereby preventing large fluctuations in blood glucose levels ( 13 ).

Which Cells Use Glucose?

Glucose can used by all cells. A limited number of cells can only use glucose, and are “glucose-dependent.” It is generally accepted that the glucose-dependent cells include red blood cells, white blood cells, and cells of the renal papilla. Red blood cells have no mitochondria for beta-oxidation, so they are dependent upon glucose and glycolysis. White blood cells require glucose for the respiratory burst when fighting infections. The cells of the inner renal medulla (papilla) are under very low oxygen tension, so therefore must predominantly use glucose and glycolysis. The low oxygen tension is a result of the countercurrent mechanism of urinary concentration ( 14 ). These glucose-dependent cells have glut transporters that do not require insulin for activation—i.e., they do not need insulin to get glucose into the cells. Some cells can use glucose and ketones, but not fatty acids. The central nervous system is believed to be able to use glucose and ketones for fuel ( 15 ). Other cells can use glucose, ketones, and fatty acids for fuel. Muscle, even cardiac muscle, functions well on fatty acids and ketones ( 16 ). Muscle cells have both non-insulin-responsive and insulin-responsive (glut4) transporters ( 12 ).

Possible Dual Role of an Insulin-Dependent Glucose-Transporter (glut4)

A common metaphor is to think of the insulin/glut transporter system as a key/lock mechanism. Common wisdom states that the purpose of insulin-responsive glut4 transporters is to facilitate glucose uptake when blood insulin levels are elevated. But, a lock serves two purposes: to let someone in and/or to keep someone out . So, one of the consequences of the insulin-responsive glut4 transporter is to keep glucose out of the muscle and adipose cells, too, when insulin levels are low. The cells that require glucose (“glucose-dependent”) do not need insulin to facilitate glucose entry into the cell (non-insulin-responsive transporters). In a teleological way, it would “make no sense” for cells that require glucose to have insulin-responsive glut4 transporters. Cells that require glucose have glut1, glut2, glut3, glut5 transporters—none of which are insulin-responsive (Back to the key/lock metaphor, it makes no sense to have a lock on a door that you want people to go through). At basal (low insulin) conditions, most glucose is used by the brain and transported by non-insulin-responsive glut1 and glut3. So, perhaps one of the functions of the insulin-responsive glucose uptake in muscle and adipose to keep glucose OUT of the these cells at basal (low insulin) conditions, so that the glucose supply can be reserved for the tissue that is glucose-dependent (blood cells, renal medulla).

What Causes IR and T2DM?

The current commonly espoused view is that “Type 2 diabetes develops when beta-cells fail to secrete sufficient insulin to keep up with demand, usually in the context of increased insulin resistance.” ( 17 ). Somehow, the beta cells have failed in the face of insulin resistance. But what causes insulin resistance? When including the possibility that the environment may be part of the problem, is it possible that IR is an adaptive (protective) response to excess glucose availability? From the perspective that carbohydrate is not an essential nutrient and the change in foods in recent years has increased the consumption of refined sugar and flour, maybe hyperinsulinemia is the cause of IR and T2DM, as cells protect themselves from excessive glucose and insulin levels.

Insulin Is Already Elevated in IR and T2DM

Clinical experience of most physicians using insulin to treat T2DM over time informs us that an escalation of insulin dose is commonly needed to achieve glycemic control (when carbohydrate is consumed). When more insulin is given to someone with IR, the IR seems to get worse and higher levels of insulin are needed. I have the clinical experience of treating many individuals affected by T2DM and de-prescribing insulin as it is no longer needed after consuming a diet without carbohydrate ( 18 ).

Diets Without Carbohydrate Reverse IR and T2DM

When dietary manipulation was the only therapy for T2DM, before medications were available, a carbohydrate-restricted diet was used to treat T2DM ( 19 – 21 ). Clinical experience of obesity medicine physicians and a growing number of recent studies have demonstrated that carbohydrate-restricted diets reverse IR and T2DM ( 18 , 22 , 23 ). Other methods to achieve caloric restriction also have these effects, like calorie-restricted diets and bariatric surgery ( 24 , 25 ). There may be many mechanisms by which these approaches may work: a reduction in glucose, a reduction in insulin, nutritional ketosis, a reduction in metabolic syndrome, or a reduction in inflammation ( 26 ). Though there may be many possible mechanisms, let's focus on an obvious one: a reduction in blood glucose. Let's assume for a moment that the excessive glucose and insulin leads to hyperinsulinemia and this is the cause of IR. On a carbohydrate-restricted diet, the reduction in blood glucose leads to a reduction in insulin. The reduction in insulin leads to a reduction in insulin resistance. The reduction in insulin leads to lipolysis. The resulting lowering of blood glucose, insulin and body weight reverses IR, T2DM, AND obesity. These clinical observations strongly suggest that hyperinsulinemia is a cause of IR and T2DM—not the other way around.

What Causes Atherosclerosis?

For many years, the metabolic syndrome has been described as a possible cause of atherosclerosis, but there are no RCTs directly targeting metabolic syndrome, and the current drug treatment focuses on LDL reduction, so its importance remains controversial. A recent paper compared the relative importance of many risk factors in the prediction of the first cardiac event in women, and the most powerful predictors were diabetes, metabolic syndrome, smoking, hypertension and BMI ( 27 ). The connection between dietary carbohydrate and fatty liver is well-described ( 28 ). The connection between fatty liver and atherosclerosis is well-described ( 29 ). It is very possible that the transport of excess glucose to the adipose tissue via lipoproteins creates the particles that cause the atherosclerotic damage (small LDL) ( Figure 1 ) ( 30 – 32 ). This entire process of dietary carbohydrate leading to fatty liver, leading to small LDL, is reversed by a diet without carbohydrate ( 26 , 33 , 34 ).

Figure 1 . Key aspects of the interconnection between glucose and lipoprotein metabolism.

Reducing dietary carbohydrate in the context of a low carbohydrate, ketogenic diet reduces hyperglycemia and hyperinsulinemia, IR and T2DM. In the evaluation of an individual for a glucose abnormality, measure the blood glucose and insulin levels. If the insulin level (fasting or after a glucose-containing meal) is high, do not give MORE insulin—instead, use an intervention to lower the insulin levels. Effective ways to reduce insulin resistance include lifestyle, medication, and surgical therapies ( 23 , 35 ).

The search for a single cause of a complex problem is fraught with difficulty and controversy. I am not hypothesizing that excessive dietary carbohydrate is the only cause of IR and T2DM, but that it is a cause, and quite possibly the major cause. How did such a simple explanation get overlooked? I believe it is very possible that the reductionistic search for intracellular molecular mechanisms of IR and T2DM, the emphasis on finding pharmaceutical (rather than lifestyle) treatments, the emphasis on the treatment of high total and LDL cholesterol, and the fear of eating saturated fat may have misguided a generation of researchers and clinicians from the simple answer that dietary carbohydrate, when consumed chronically in amounts that exceeds an individual's ability to metabolize them, is the most common cause of IR, T2DM and perhaps even atherosclerosis.

While there has historically been a concern about the role of saturated fat in the diet as a cause of heart disease, most nutritional experts now cite the lack of evidence implicating dietary saturated fat as the reason for lack of concern of it in the diet ( 36 ).

The concept of comparing medications that treat IR by insulin-sensitizers or by providing insulin itself was tested in the Bari-2D study ( 37 ). Presumably in the context of consuming a standard American diet, this study found no significant difference in death rates or major cardiovascular events between strategies of insulin sensitization or insulin provision.

While lifestyle modification may be ideal to prevent or cure IR and T2DM, for many people these changes are difficult to learn and/or maintain. Future research should be directed toward improving adherence to all effective lifestyle or medication treatments. Future research is also needed to assess the effect of carbohydrate restriction on primary or secondary prevention of outcomes of cardiovascular disease.

Data Availability Statement

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.

Author Contributions

The author confirms being the sole contributor of this work and has approved it for publication.

Conflict of Interest

EW receives royalties from popular diet books and is founder of a company based on low-carbohydrate diet principles (Adapt Your Life, Inc.).

Publisher's Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

1. American Diabetes Association. Classification and diagnosis of diabetes. Diabetes Care . (2016) 39 (Suppl. 1):S13–22. doi: 10.2337/dc16-S005

PubMed Abstract | CrossRef Full Text | Google Scholar

2. Bogardus C, Lillioja S, Howard BV, Reaven G, Mott D. Relationships between insulin secretion, insulin action, and fasting plasma glucose concentration in nondiabetic and noninsulin-dependent diabetic subjects. J Clin Invest. (1984) 74:1238–46. doi: 10.1172/JCI111533

3. Reaven GM. Compensatory hyperinsulinemia and the development of an atherogenic lipoprotein profile: the price paid to maintain glucose homeostasis in insulin-resistant individuals. Endocrinol Metab Clin North Am. (2005) 34:49–62. doi: 10.1016/j.ecl.2004.12.001

4. DeFronzo RA, Ferrannini E. Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care. (1991) 14:173–94. doi: 10.2337/diacare.14.3.173

5. Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet. (2005) 365:1415–28. doi: 10.1016/S0140-6736(05)66378-7

6. Yaribeygi H, Farrokhi FR, Butler AE, Sahebkar A. Insulin resistance: review of the underlying molecular mechanisms. J Cell Physiol. (2019) 234:8152–61. doi: 10.1002/jcp.27603

7. Shulman GI. Cellular mechanisms of insulin resistance. J Clin Invest. (2000) 106:171–6. doi: 10.1172/JCI10583

8. Guizouarn H, Allegrini B. Erythroid glucose transport in health and disease. Pflugers Arch. (2020) 472:1371–83. doi: 10.1007/s00424-020-02406-0

9. Petersen MC, Vatner DF, Shulman GI. Regulation of hepatic glucose metabolism in health and disease. Nat Rev Endocrinol. (2017) 13:572–87. doi: 10.1038/nrendo.2017.80

10. Tondt J, Yancy WS, Westman EC. Application of nutrient essentiality criteria to dietary carbohydrates. Nutr Res Rev. (2020) 33:260–70. doi: 10.1017/S0954422420000050

11. Colberg SR, Hernandez MJ, Shahzad F. Blood glucose responses to type, intensity, duration, and timing of exercise. Diabetes Care. (2013) 36:e177. doi: 10.2337/dc13-0965

12. Mueckler M, Thorens B. The SLC2 (GLUT) family of membrane transporters. Mol Aspects Med. (2013) 34:121–38. doi: 10.1016/j.mam.2012.07.001

13. Bryant NJ, Govers R, James DE. Regulated transport of the glucose transporter GLUT4. Nat Rev Mol Cell Biol. (2002) 3:267–77. doi: 10.1038/nrm782

14. Epstein FH. Oxygen and renal metabolism. Kidney Int. (1997) 51:381–5. doi: 10.1038/ki.1997.50

15. Cahill GF. Fuel metabolism in starvation. Annu Rev Nutr. (2006) 26:1–22. doi: 10.1146/annurev.nutr.26.061505.111258

16. Murashige D, Jang C, Neinast M, Edwards JJ, Cowan A, Hyman MC, et al. Comprehensive quantification of fuel use by the failing and nonfailing human heart. Science. (2020) 370:364–8. doi: 10.1126/science.abc8861

17. Skyler JS, Bakris GL, Bonifacio E, Darsow T, Eckel RH, Groop L, et al. Differentiation of diabetes by pathophysiology, natural history, and prognosis. Diabetes. (2017) 66:241–55. doi: 10.2337/db16-0806

18. Westman EC, Yancy WS, Mavropoulos JC, Marquart M, McDuffie JR. The effect of a low-carbohydrate, ketogenic diet versus a low-glycemic index diet on glycemic control in type 2 diabetes mellitus. Nutr Metab. (2008) 5:36. doi: 10.1186/1743-7075-5-36

CrossRef Full Text | Google Scholar

19. Allen F. The treatment of diabetes. Boston Med Surg J. (1915) 172:241–7. doi: 10.1056/NEJM191502181720702

20. Osler W, McCrae T. The Principles and Practice of Medicine . 9th ed. New York and London: Appleton & Company (1923).

21. Lennerz BS, Koutnik AP, Azova S, Wolfsdorf JI, Ludwig DS. Carbohydrate restriction for diabetes: rediscovering centuries-old wisdom. J Clin Invest. (2021) 131:e142246. doi: 10.1172/JCI142246

22. Steelman GM, Westman EC. Obesity: Evaluation and Treatment Essentials . 2nd ed. Boca Raton: CRC Press, Taylor & Francis Group (2016). 340 p.

23. Athinarayanan SJ, Adams RN, Hallberg SJ, McKenzie AL, Bhanpuri NH, Campbell WW, et al. Long-term effects of a novel continuous remote care intervention including nutritional ketosis for the management of type 2 diabetes: a 2-year non-randomized clinical trial. Front Endocrinol. (2019) 10:348. doi: 10.3389/fendo.2019.00348

24. Lim EL, Hollingsworth KG, Aribisala BS, Chen MJ, Mathers JC, Taylor R. Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol. Diabetologia. (2011) 54:2506–14. doi: 10.1007/s00125-011-2204-7

25. Isbell JM, Tamboli RA, Hansen EN, Saliba J, Dunn JP, Phillips SE, et al. The importance of caloric restriction in the early improvements in insulin sensitivity after Roux-en-Y gastric bypass surgery. Diabetes Care. (2010) 33:1438–42. doi: 10.2337/dc09-2107

26. Bhanpuri NH, Hallberg SJ, Williams PT, McKenzie AL, Ballard KD, Campbell WW, et al. Cardiovascular disease risk factor responses to a type 2 diabetes care model including nutritional ketosis induced by sustained carbohydrate restriction at 1 year: an open label, non-randomized, controlled study. Cardiovasc Diabetol. (2018) 17:56. doi: 10.1186/s12933-018-0698-8

27. Dugani SB, Moorthy MV, Li C, Demler OV, Alsheikh-Ali AA, Ridker PM, et al. Association of lipid, inflammatory, and metabolic biomarkers with age at onset for incident coronary heart disease in women. JAMA Cardiol. (2021) 6:437–47. doi: 10.1001/jamacardio.2020.7073

28. Duwaerts CC, Maher JJ. Macronutrients and the adipose-liver axis in obesity and fatty liver. Cell Mol Gastroenterol Hepatol. (2019) 7:749–61. doi: 10.1016/j.jcmgh.2019.02.001

29. Zhang L, She Z-G, Li H, Zhang X-J. Non-alcoholic fatty liver disease: a metabolic burden promoting atherosclerosis. Clin Sci Lond Engl. (1979) 134:1775–99. doi: 10.1042/CS20200446

30. Horton TJ, Drougas H, Brachey A, Reed GW, Peters JC, Hill JO. Fat and carbohydrate overfeeding in humans: different effects on energy storage. Am J Clin Nutr. (1995) 62:19–29. doi: 10.1093/ajcn/62.1.19

31. Packard C, Caslake M, Shepherd J. The role of small, dense low density lipoprotein (LDL): a new look. Int J Cardiol. (2000) 74 (Suppl. 1):S17–22. doi: 10.1016/S0167-5273(99)00107-2

32. Borén J, Chapman MJ, Krauss RM, Packard CJ, Bentzon JF, Binder CJ, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. (2020) 41:2313–30. doi: 10.1093/eurheartj/ehz962

33. Yancy WS, Olsen MK, Guyton JR, Bakst RP, Westman EC. A low-carbohydrate, ketogenic diet versus a low-fat diet to treat obesity and hyperlipidemia: a randomized, controlled trial. Ann Intern Med. (2004) 140:769. doi: 10.7326/0003-4819-140-10-200405180-00006

34. Tendler D, Lin S, Yancy WS, Mavropoulos J, Sylvestre P, Rockey DC, et al. The effect of a low-carbohydrate, ketogenic diet on nonalcoholic fatty liver disease: a pilot study. Dig Dis Sci. (2007) 52:589–93. doi: 10.1007/s10620-006-9433-5

35. Pories WJ, Swanson MS, MacDonald KG, Long SB, Morris PG, Brown BM, et al. Who would have thought it? An operation proves to be the most effective therapy for adult-onset diabetes mellitus. Ann Surg. (1995) 222:339–50. doi: 10.1097/00000658-199509000-00011

36. Astrup A, Magkos F, Bier DM, Brenna JT, de Oliveira Otto MC, Hill JO, et al. Saturated fats and health: a reassessment and proposal for food-based recommendations: JACC state-of-the-art review. J Am Coll Cardiol. (2020) 76:844–57. doi: 10.1016/j.jacc.2020.05.077

37. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med . (2009) 360:2503–15. doi: 10.1056/NEJMoa0805796

Keywords: type 2 diabetes, insulin resistance, pre-diabetes, carbohydrate-restricted diets, hyperinsulinemia, hyperglycemia

Citation: Westman EC (2021) Type 2 Diabetes Mellitus: A Pathophysiologic Perspective. Front. Nutr. 8:707371. doi: 10.3389/fnut.2021.707371

Received: 09 May 2021; Accepted: 20 July 2021; Published: 10 August 2021.

Reviewed by:

Copyright © 2021 Westman. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Eric C. Westman, ewestman@duke.edu

This article is part of the Research Topic

Carbohydrate-restricted Nutrition and Diabetes Mellitus

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What Is Diabetes?

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Diabetes is a disease that occurs when your blood glucose, also called blood sugar, is too high. Glucose is your body’s main source of energy. Your body can make glucose, but glucose also comes from the food you eat.

Insulin is a hormone  made by the pancreas  that helps glucose get into your cells to be used for energy. If you have diabetes, your body doesn’t make enough—or any—insulin, or doesn’t use insulin properly. Glucose then stays in your blood and doesn’t reach your cells.

Diabetes raises the risk for damage to the eyes, kidneys, nerves, and heart. Diabetes is also linked to some types of cancer. Taking steps to prevent or manage diabetes may lower your risk of developing diabetes health problems.

What are the different types of diabetes?

The most common types of diabetes are type 1, type 2, and gestational diabetes.

Type 1 diabetes

If you have type 1 diabetes , your body makes little or no insulin. Your immune system  attacks and destroys the cells in your pancreas that make insulin. Type 1 diabetes is usually diagnosed in children and young adults, although it can appear at any age. People with type 1 diabetes need to take insulin every day to stay alive.

Type 2 diabetes

If you have type 2 diabetes , the cells in your body don’t use insulin properly. The pancreas may be making insulin but is not making enough insulin to keep your blood glucose level in the normal range. Type 2 diabetes is the most common type of diabetes. You are more likely to develop type 2 diabetes if you have risk factors , such as overweight or obesity , and a family history of the disease. You can develop type 2 diabetes at any age, even during childhood.

You can help delay or prevent type 2 diabetes  by knowing the risk factors and taking steps toward a healthier lifestyle, such as losing weight or preventing weight gain.

Gestational diabetes

Gestational diabetes is a type of diabetes that develops during pregnancy. Most of the time, this type of diabetes goes away after the baby is born. However, if you’ve had gestational diabetes, you have a higher chance of developing type 2 diabetes later in life. Sometimes diabetes diagnosed during pregnancy is type 2 diabetes.

Prediabetes

People with prediabetes  have blood glucose levels that are higher than normal but not high enough to be diagnosed with type 2 diabetes. If you have prediabetes, you have a higher risk of developing type 2 diabetes in the future. You also have a higher risk for heart disease than people with normal glucose levels.

Other types of diabetes

A less common type of diabetes, called monogenic diabetes , is caused by a change in a single gene . Diabetes can also come from having surgery to remove the pancreas, or from damage to the pancreas due to conditions such as cystic fibrosis or pancreatitis .

How common are diabetes and prediabetes?

More than 133 million Americans have diabetes or prediabetes. 1

As of 2019, 37.3 million people—or 11.3% of the U.S. population—had diabetes. 1 More than 1 in 4 people over the age of 65 had diabetes. Nearly 1 in 4 adults with diabetes didn’t know they had the disease. 2

About 90% to 95% of diabetes cases are type 2 diabetes. 3

In 2019, 96 million adults—38% of U.S. adults—had prediabetes. 4

What other health problems can people with diabetes develop?

Over time, high blood glucose can damage your heart , kidneys , feet , and eyes . If you have diabetes, you can take steps to lower your chances of developing diabetes health problems  by taking steps to improve your health  and learning how to manage the disease . Managing your blood glucose, blood pressure, and cholesterol levels can help prevent future health problems.

This content is provided as a service of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), part of the National Institutes of Health. NIDDK translates and disseminates research findings to increase knowledge and understanding about health and disease among patients, health professionals, and the public. Content produced by NIDDK is carefully reviewed by NIDDK scientists and other experts.

NIDDK would like to thank: Daniel Bessesen, M.D., University of Colorado; Domenico Accili, M.D., Columbia University

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• Type 2 diabetes

Type 2 diabetes is a condition that happens because of a problem in the way the body regulates and uses sugar as a fuel. That sugar also is called glucose. This long-term condition results in too much sugar circulating in the blood. Eventually, high blood sugar levels can lead to disorders of the circulatory, nervous and immune systems.

In type 2 diabetes, there are primarily two problems. The pancreas does not produce enough insulin — a hormone that regulates the movement of sugar into the cells. And cells respond poorly to insulin and take in less sugar.

Type 2 diabetes used to be known as adult-onset diabetes, but both type 1 and type 2 diabetes can begin during childhood and adulthood. Type 2 is more common in older adults. But the increase in the number of children with obesity has led to more cases of type 2 diabetes in younger people.

There's no cure for type 2 diabetes. Losing weight, eating well and exercising can help manage the disease. If diet and exercise aren't enough to control blood sugar, diabetes medications or insulin therapy may be recommended.

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Symptoms of type 2 diabetes often develop slowly. In fact, you can be living with type 2 diabetes for years and not know it. When symptoms are present, they may include:

• Increased thirst.
• Frequent urination.
• Increased hunger.
• Unintended weight loss.
• Blurred vision.
• Slow-healing sores.
• Frequent infections.
• Numbness or tingling in the hands or feet.
• Areas of darkened skin, usually in the armpits and neck.

When to see a doctor

See your health care provider if you notice any symptoms of type 2 diabetes.

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Type 2 diabetes is mainly the result of two problems:

• Cells in muscle, fat and the liver become resistant to insulin As a result, the cells don't take in enough sugar.
• The pancreas can't make enough insulin to keep blood sugar levels within a healthy range.

Exactly why this happens is not known. Being overweight and inactive are key contributing factors.

How insulin works

Insulin is a hormone that comes from the pancreas — a gland located behind and below the stomach. Insulin controls how the body uses sugar in the following ways:

• Sugar in the bloodstream triggers the pancreas to release insulin.
• Insulin circulates in the bloodstream, enabling sugar to enter the cells.
• The amount of sugar in the bloodstream drops.
• In response to this drop, the pancreas releases less insulin.

The role of glucose

Glucose — a sugar — is a main source of energy for the cells that make up muscles and other tissues. The use and regulation of glucose includes the following:

• Glucose comes from two major sources: food and the liver.
• Glucose is absorbed into the bloodstream, where it enters cells with the help of insulin.
• The liver stores and makes glucose.
• When glucose levels are low, the liver breaks down stored glycogen into glucose to keep the body's glucose level within a healthy range.

In type 2 diabetes, this process doesn't work well. Instead of moving into the cells, sugar builds up in the blood. As blood sugar levels rise, the pancreas releases more insulin. Eventually the cells in the pancreas that make insulin become damaged and can't make enough insulin to meet the body's needs.

Risk factors

Factors that may increase the risk of type 2 diabetes include:

• Weight. Being overweight or obese is a main risk.
• Fat distribution. Storing fat mainly in the abdomen — rather than the hips and thighs — indicates a greater risk. The risk of type 2 diabetes is higher in men with a waist circumference above 40 inches (101.6 centimeters) and in women with a waist measurement above 35 inches (88.9 centimeters).
• Inactivity. The less active a person is, the greater the risk. Physical activity helps control weight, uses up glucose as energy and makes cells more sensitive to insulin.
• Family history. An individual's risk of type 2 diabetes increases if a parent or sibling has type 2 diabetes.
• Race and ethnicity. Although it's unclear why, people of certain races and ethnicities — including Black, Hispanic, Native American and Asian people, and Pacific Islanders — are more likely to develop type 2 diabetes than white people are.
• Blood lipid levels. An increased risk is associated with low levels of high-density lipoprotein (HDL) cholesterol — the "good" cholesterol — and high levels of triglycerides.
• Age. The risk of type 2 diabetes increases with age, especially after age 35.
• Prediabetes. Prediabetes is a condition in which the blood sugar level is higher than normal, but not high enough to be classified as diabetes. Left untreated, prediabetes often progresses to type 2 diabetes.
• Pregnancy-related risks. The risk of developing type 2 diabetes is higher in people who had gestational diabetes when they were pregnant and in those who gave birth to a baby weighing more than 9 pounds (4 kilograms).
• Polycystic ovary syndrome. Having polycystic ovary syndrome — a condition characterized by irregular menstrual periods, excess hair growth and obesity — increases the risk of diabetes.

Complications

Type 2 diabetes affects many major organs, including the heart, blood vessels, nerves, eyes and kidneys. Also, factors that increase the risk of diabetes are risk factors for other serious diseases. Managing diabetes and controlling blood sugar can lower the risk for these complications and other medical conditions, including:

• Heart and blood vessel disease. Diabetes is associated with an increased risk of heart disease, stroke, high blood pressure and narrowing of blood vessels, a condition called atherosclerosis.
• Nerve damage in limbs. This condition is called neuropathy. High blood sugar over time can damage or destroy nerves. That may result in tingling, numbness, burning, pain or eventual loss of feeling that usually begins at the tips of the toes or fingers and gradually spreads upward.
• Other nerve damage. Damage to nerves of the heart can contribute to irregular heart rhythms. Nerve damage in the digestive system can cause problems with nausea, vomiting, diarrhea or constipation. Nerve damage also may cause erectile dysfunction.
• Kidney disease. Diabetes may lead to chronic kidney disease or end-stage kidney disease that can't be reversed. That may require dialysis or a kidney transplant.
• Eye damage. Diabetes increases the risk of serious eye diseases, such as cataracts and glaucoma, and may damage the blood vessels of the retina, potentially leading to blindness.
• Skin conditions. Diabetes may raise the risk of some skin problems, including bacterial and fungal infections.
• Slow healing. Left untreated, cuts and blisters can become serious infections, which may heal poorly. Severe damage might require toe, foot or leg amputation.
• Hearing impairment. Hearing problems are more common in people with diabetes.
• Sleep apnea. Obstructive sleep apnea is common in people living with type 2 diabetes. Obesity may be the main contributing factor to both conditions.
• Dementia. Type 2 diabetes seems to increase the risk of Alzheimer's disease and other disorders that cause dementia. Poor control of blood sugar is linked to a more rapid decline in memory and other thinking skills.

Healthy lifestyle choices can help prevent type 2 diabetes. If you've received a diagnosis of prediabetes, lifestyle changes may slow or stop the progression to diabetes.

A healthy lifestyle includes:

• Eating healthy foods. Choose foods lower in fat and calories and higher in fiber. Focus on fruits, vegetables and whole grains.
• Getting active. Aim for 150 or more minutes a week of moderate to vigorous aerobic activity, such as a brisk walk, bicycling, running or swimming.
• Losing weight. If you are overweight, losing a modest amount of weight and keeping it off may delay the progression from prediabetes to type 2 diabetes. If you have prediabetes, losing 7% to 10% of your body weight may reduce the risk of diabetes.
• Avoiding long stretches of inactivity. Sitting still for long periods of time can increase the risk of type 2 diabetes. Try to get up every 30 minutes and move around for at least a few minutes.

For people with prediabetes, metformin (Fortamet, Glumetza, others), a diabetes medication, may be prescribed to reduce the risk of type 2 diabetes. This is usually prescribed for older adults who are obese and unable to lower blood sugar levels with lifestyle changes.

More Information

• Diabetes prevention: 5 tips for taking control
• Professional Practice Committee: Standards of Medical Care in Diabetes — 2020. Diabetes Care. 2020; doi:10.2337/dc20-Sppc.
• Diabetes mellitus. Merck Manual Professional Version. https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/diabetes-mellitus-and-disorders-of-carbohydrate-metabolism/diabetes-mellitus-dm. Accessed Dec. 7, 2020.
• Melmed S, et al. Williams Textbook of Endocrinology. 14th ed. Elsevier; 2020. https://www.clinicalkey.com. Accessed Dec. 3, 2020.
• Diabetes overview. National Institute of Diabetes and Digestive and Kidney Diseases. https://www.niddk.nih.gov/health-information/diabetes/overview/all-content. Accessed Dec. 4, 2020.
• AskMayoExpert. Type 2 diabetes. Mayo Clinic; 2018.
• Feldman M, et al., eds. Surgical and endoscopic treatment of obesity. In: Sleisenger and Fordtran's Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management. 11th ed. Elsevier; 2021. https://www.clinicalkey.com. Accessed Oct. 20, 2020.
• Hypersmolar hyperglycemic state (HHS). Merck Manual Professional Version. https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/diabetes-mellitus-and-disorders-of-carbohydrate-metabolism/hyperosmolar-hyperglycemic-state-hhs. Accessed Dec. 11, 2020.
• Diabetic ketoacidosis (DKA). Merck Manual Professional Version. https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/diabetes-mellitus-and-disorders-of-carbohydrate-metabolism/diabetic-ketoacidosis-dka. Accessed Dec. 11, 2020.
• Hypoglycemia. Merck Manual Professional Version. https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/diabetes-mellitus-and-disorders-of-carbohydrate-metabolism/hypoglycemia. Accessed Dec. 11, 2020.
• 6 things to know about diabetes and dietary supplements. National Center for Complementary and Integrative Health. https://www.nccih.nih.gov/health/tips/things-to-know-about-type-diabetes-and-dietary-supplements. Accessed Dec. 11, 2020.
• Type 2 diabetes and dietary supplements: What the science says. National Center for Complementary and Integrative Health. https://www.nccih.nih.gov/health/providers/digest/type-2-diabetes-and-dietary-supplements-science. Accessed Dec. 11, 2020.
• Preventing diabetes problems. National Institute of Diabetes and Digestive and Kidney Diseases. https://www.niddk.nih.gov/health-information/diabetes/overview/preventing-problems/all-content. Accessed Dec. 3, 2020.
• Schillie S, et al. Prevention of hepatitis B virus infection in the United States: Recommendations of the Advisory Committee on Immunization Practices. MMWR Recommendations and Reports. 2018; doi:10.15585/mmwr.rr6701a1.
• Caffeine: Does it affect blood sugar?
• GLP-1 agonists: Diabetes drugs and weight loss
• Hyperinsulinemia: Is it diabetes?
• Medications for type 2 diabetes

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Essay on Diabetes for Students and Children

500+ words essay on diabetes.

Diabetes is a very common disease in the world. But people may never realize, how did they get diabetes and what will happen to them and what will they go through. It may not be your problem but you have to show respect and care for the one who has diabetes. It can help them and also benefited you to know more about it and have a better understanding of it. Diabetes is a metabolic disorder which is identified by the high blood sugar level. Increased blood glucose level damages the vital organs as well as other organs of the human’s body causing other potential health ailments.

Types of Diabetes

Diabetes  Mellitus can be described in two types:

Description of two types of Diabetes Mellitus are as follows

1) Type 1 Diabetes Mellitus is classified by a deficiency of insulin in the blood. The deficiency is caused by the loss of insulin-producing beta cells in the pancreas. This type of diabetes is found more commonly in children. An abnormally high or low blood sugar level is a characteristic of this type of Diabetes.

Most patients of type 1 diabetes require regular administration of insulin. Type 1 diabetes is also hereditary from your parents. You are most likely to have type 1 diabetes if any of your parents had it. Frequent urination, thirst, weight loss, and constant hunger are common symptoms of this.

2) Type 2 Diabetes Mellitus is characterized by the inefficiency of body tissues to effectively respond to insulin because of this it may be combined by insulin deficiency. Type 2 diabetes mellitus is the most common type of diabetes in people.

People with type 2 diabetes mellitus take medicines to improve the body’s responsiveness to insulin or to reduce the glucose produced by the liver. This type of diabetes mellitus is generally attributed to lifestyle factors like – obesity, low physical activity, irregular and unhealthy diet, excess consumption of sugar in the form of sweets, drinks, etc.

Get the huge list of more than 500 Essay Topics and Ideas

Causes of Diabetes

By the process of digestion, food that we eat is broken down into useful compounds. One of these compounds is glucose, usually referred to as blood sugar. The blood performs the job of carrying glucose to the cells of the body. But mere carrying the glucose to the cells by blood isn’t enough for the cells to absorb glucose.

This is the job of the Insulin hormone. Pancreas supply insulin in the human body. Insulin acts as a bridge for glucose to transit from blood to the body cells. The problem arises when the pancreas fails to produce enough insulin or the body cells for some reason do not receive the glucose. Both the cases result in the excess of glucose in the blood, which is referred to as Diabetes or Diabetes Mellitus.

Symptoms of Diabetes

Most common symptoms of diabetes are fatigue, irritation, stress, tiredness, frequent urination and headache including loss of strength and stamina, weight loss, increase in appetite, etc.

Levels of Diabetes

There are two types of blood sugar levels – fasting blood sugar level and postprandial blood sugar level. The fasting sugar level is the sugar level that we measure after fasting for at least eight hours generally after an overnight fast. Blood sugar level below 100 mg/dL before eating food is considered normal. Postprandial glucose level or PP level is the sugar level which we measure after two hours of eating.

The PP blood sugar level should be below 140 mg/dL, two hours after the meals. Though the maximum limit in both the cases is defined, the permissible levels may vary among individuals. The range of the sugar level varies with people. Different people have different sugar level such as some people may have normal fasting sugar level of 60 mg/dL while some may have a normal value of 90 mg/dL.

Effects of Diabetes

Diabetes causes severe health consequences and it also affects vital body organs. Excessive glucose in blood damages kidneys, blood vessels, skin resulting in various cardiovascular and skin diseases and other ailments. Diabetes damages the kidneys, resulting in the accumulation of impurities in the body.

It also damages the heart’s blood vessels increasing the possibility of a heart attack. Apart from damaging vital organs, diabetes may also cause various skin infections and the infection in other parts of the body. The prime cause of all type of infections is the decreased immunity of body cells due to their inability to absorb glucose.

Diabetes is a serious life-threatening disease and must be constantly monitored and effectively subdued with proper medication and by adapting to a healthy lifestyle. By following a healthy lifestyle, regular checkups, and proper medication we can observe a healthy and long life.

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Type 2 Diabetes - Free Essay Examples And Topic Ideas

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Diabetes is a type of illness which is metabolic in nature leading to deficiencies in insulin. There are 2 types of diabetes (Type 1 and Type 2). Type 1 Diabetes (5-10% with diabetes), is known to be dependent in insulin, and would usually occur during childhood. This type of diabetes is a result of an autoimmune obliteration of Pancreatic ??-cell function. Another is Type 2 or the non-insulin dependent, correlates for 90-95% of those people with the diabetes. The onset […]

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Type 2 diabetes

Affiliations.

• 1 Diabetes Research Centre, University of Leicester and the Leicester NIHR Biomedical Research Centre, Leicester General Hospital, Leicester, UK.
• 2 Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea.
• 3 Family Medicine Department, Korle Bu Teaching Hospital, Accra Ghana and Community Health Department, University of Ghana Medical School, Accra, Ghana.
• 4 Diabetes Research Centre, University of Leicester and the Leicester NIHR Biomedical Research Centre, Leicester General Hospital, Leicester, UK. Electronic address: [email protected].
• PMID: 36332637
• DOI: 10.1016/S0140-6736(22)01655-5

Type 2 diabetes accounts for nearly 90% of the approximately 537 million cases of diabetes worldwide. The number affected is increasing rapidly with alarming trends in children and young adults (up to age 40 years). Early detection and proactive management are crucial for prevention and mitigation of microvascular and macrovascular complications and mortality burden. Access to novel therapies improves person-centred outcomes beyond glycaemic control. Precision medicine, including multiomics and pharmacogenomics, hold promise to enhance understanding of disease heterogeneity, leading to targeted therapies. Technology might improve outcomes, but its potential is yet to be realised. Despite advances, substantial barriers to changing the course of the epidemic remain. This Seminar offers a clinically focused review of the recent developments in type 2 diabetes care including controversies and future directions.

Copyright © 2022 Elsevier Ltd. All rights reserved.

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• Diabetes Mellitus, Type 2* / drug therapy
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Connected content.

In a special series of the ADA Journals' podcast Diabetes Core Update , host Dr. Neil Skolnik interviews special guests and authors of this clinical compendium issue. Listen now at Special Podcast Series: Focus on Diabetes or view the interviews on YouTube at A Practice Guide to Diabetes-Related Eye Care .

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Thomas W. Gardner; Summary and Conclusion. ADA Clinical Compendia 1 July 2022; 2022 (3): 20. https://doi.org/10.2337/db20223-20

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Diabetes is a multifactorial disease process, and its long-term management requires the active involvement of people with diabetes and their families, as well as a large multidisciplinary care team to ensure optimal health, quality of life, and productivity. Keeping up with new medications, emerging technology, and evolving treatment recommendations can be challenging, and the language and care processes commonly used by practitioners in one discipline may be less familiar to other diabetes care professionals.

In the realm of diabetes-related eye care, our ability to prevent the progression of diabetes-related retinal disease and thereby preserve vision has never been greater. However, far too many people with diabetes still are not receiving appropriate screening to identify eye disease early and ensure its timely treatment.

It is our hope that this compendium has provided information and guidance to improve communication and encourage collaboration between eye care professionals and other diabetes health care professionals and allow them to more effectively cooperate to reduce barriers to care and improve both the ocular and systemic health of their shared patients.

Editorial and project management services were provided by Debbie Kendall of Kendall Editorial in Richmond, VA.

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B.A.C. is a consultant for Genentech and Regeneron. S.A.R. is a speaker for Allergan, Inc., and VSP Vision Care. No other potential conflicts of interest relevant to this compendium were reported.

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All authors researched and wrote their respective sections. Lead author T.W.G. reviewed all content and is the guarantor of this work.

The opinions expressed are those of the authors and do not necessarily reflect those of VSP Vision Care, Regeneron, or the American Diabetes Association. The content was developed by the authors and does not represent the policy or position of the American Diabetes Association, any of its boards or committees, or any of its journals or their editors or editorial boards.

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How do you get diabetes? Causes of Type 1 and Type 2, according to an expert.

D iabetes affects 37 million people in the U.S. The Centers for Disease Control and Prevention estimates another 96 million people – or 1 in 3 adults – have prediabetes , a condition where blood sugar levels are higher than normal but not high enough to be diagnosed with Type 2. 

Most people know of Type 1 and Type 2 diabetes, but not all know how their causes differ. We asked Dr. Rodica Busui, the president of Medicine and Science at the American Diabetes Association. Here’s what you need to know.

What causes diabetes?

Start the day smarter. Get all the news you need in your inbox each morning.

Diabetes is a chronic health condition. With Type 1 diabetes, your body can’t produce enough insulin and with Type 2 diabetes, it doesn’t use it properly.

But even beyond the two types, the effects and treatment associated with diabetes are different from person to person. It can also have serious complications if left untreated. This is why educating the public about diabetes is so crucial, says Busui.

“It can affect every single part of one body, and that’s important to understand – it cannot be taken lightly,” Busui says. 

How to prevent diabetes: Here are tips to control the condition, according to a doctor

What causes Type 1 diabetes?

Type 1 diabetes is an autoimmune disease where beta cells, a hormone located in the pancreas that creates insulin, are destroyed, Busui says. This destruction may happen quickly or over some time until a “critical mass” of beta cells is lost and the individual cannot survive without insulin from external sources. This is why many Type 1 diabetics undergo regular insulin injections . 

“It’s like your own body creates antibodies against your own structures, in this case, the beta cells,” Busui says.

Type 1 diabetes is more commonly diagnosed in children than Type 2. It can occur at any age – Busui says she’s diagnosed patients in their mid-60s with Type 1 and recent data suggests more than half of new Type 1 cases occur in adulthood.

Anyone can get Type 1 diabetes, Busui says. Type 1 symptoms , which include increased thirst and hunger, frequent urination, fatigue, blurry vision, slow-healing cuts and bruises and weight loss, often come on quicker than Type 2 diabetes. 

What causes Type 2 diabetes?

Type 2 diabetes is the more common form of diabetes. In Type 2, beta cell dysfunction has multiple, complex causes, including weight gain, lifestyle changes and lack of exercise. Family history, ethnicity and age can also play a role. 

These changes cause your body to stop using the insulin it makes properly. This is called insulin resistance – it’s harder for your body to bring blood glucose levels down. 

“The more we are insulin resistant … the more insulin is needed to take the same amount of glucose from the blood inside the cell to produce energy,” Busui says. “And because of that, the beta cells have to work overtime constantly, working nonstop. Eventually, they get exhausted and they cannot produce as much insulin.”

This can cause changes in the brain and warp your sense of satiety, or how full you are. Busui says this causes a “vicious cycle,” for those who dealing with obesity and diabetes.

Doctors are diagnosing more children with Type 2 diabetes than ever, an impact of the obesity epidemic in the U.S. and food insecurity, where many children don’t have access to fresh, healthy food. Children can also develop complications from Type 2 diabetes, Busui says. 

The Diabetes Dilemma: American can prevent (and control) Type 2 diabetes. So why aren’t we doing it?

Not everyone who has Type 2 diabetes needs insulin from an external source – many Type 2 diabetics’ bodies can still produce insulin. This is why early diagnosis is key and can help patients make lifestyle changes or start on medication to prevent further complications. But because Type 2 diabetes symptoms are much more subtle than Type 1, they may not be taken seriously enough to seek care. 

“If people ignore (high blood glucose levels) saying ‘Well, I don’t have a pain, I don’t want to do anything,’ then there is a progressive decrease,” Busui says. “The higher blood glucose then generates some changes in the body metabolism that will lead to all these toxic radicals that actually have an additional effect on the beta cells to make them less and less functional.”

The Diabetes Dilemma: Managing Type 2 diabetes is complicated.

Can eating too much sugar cause diabetes?

Consumption of sugary drinks is associated with a higher risk of Type 2 diabetes , studies show. But there are other risk factors including family history, age and ethnicity. Sugar-sweetened beverages are the largest source of added sugar in American diets. 

The American Diabetes Association recommends avoiding sugar-sweetened beverages and switching to water. The Dietary Guidelines for Americans advise no more than 10% of daily caloric intake be from added sugar.

Diabetes is one of the leading causes of death and disability in the country, but Busui says she has a “glass half full” outlook on where diabetes care and research are today. Part of that is providing greater education and access to care, especially for high-risk, historically underserved populations . 

“It’s truly remarkable how much progress we have made in discovering effective strategies, medications, technologies,” Busui says. 

The Diabetes Dilemma: Solutions exist to end the Type 2 diabetes dilemma but too few get the help they need

Diabetes treatment can be costly: The biggest cost is (surprisingly) not insulin

Just Curious for more? We've got you covered

USA TODAY is exploring the questions you and others ask every day. From "What is the healthiest bread?" to "How to treat dog flu" to "How much do nurses make?" , we're striving to find answers to the most common questions you ask every day. Head to our Just Curious section to see what else we can answer for you. 

Read more on diabetes in America

Diabetes runs deep in rural Mississippi: Locals have taken to growing their own solutions.

A diabetes disparity: Why Colorado's healthy lifestyle brand isn't shared by all

The steep cost of Type 2: When diabetes dragged her down, she chose to fight

More: America can prevent (and control) Type 2 diabetes. So why aren’t we doing it?

More: Solutions exist to end the Type 2 diabetes dilemma but too few get the help they need

This article originally appeared on USA TODAY: How do you get diabetes? Causes of Type 1 and Type 2, according to an expert.

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Treating a type 2 diabetic patient with impaired pancreatic islet function by personalized endoderm stem cell-derived islet tissue

• Jiaying Wu 1   na1 ,
• Tuo Li   ORCID: orcid.org/0000-0002-6691-7423 2   na1 ,
• Meng Guo 3   na1 ,
• Junsong Ji 4   na1 ,
• Xiaoxi Meng 5   na1 ,
• Tianlong Fu 1   na1 ,
• Tengfei Nie 1   na1 ,
• Tongkun Wei 1   na1 ,
• Ying Zhou 1 ,
• Weihua Dong 5 ,
• Ming Zhang 6 ,
• Yongquan Shi 2 ,
• Xin Cheng 1 ,
• Hao Yin 4 , 7 &

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Type 2 diabetes (T2D) typically starts with insulin resistance in peripheral tissues and proceeds with gradual loss of islet function due to the reduction in β-cell mass or dedifferentiation of β cells 1 , 2 . More than 30% of T2D patients eventually rely on exogenous insulin treatment. Cadaveric islet transplantation is an effective treatment for insulin-dependent diabetes 3 , 4 . Notably, improved metabolic control after islet transplantation is associated with better kidney allograft function and long-term survival 5 , 6 . However, the application of islet transplantation is severely hampered due to the critical shortage of donor organs.

The pancreatic progenitor (PP) cells or islet tissues, generated from human pluripotent stem cells (hPSCs), have been shown to survive, function and reverse hyperglycemia in diabetic animal models 7 , 8 , 9 . In addition, a recent clinical trial has shown that, when subcutaneously implanted into T1D patients, the hPSC-derived pancreatic endodermal cells encapsulated with non-immunoprotective devices were able to further mature into meal-responsive β-like cells and secrete insulin, albeit at the levels insufficient to achieve the independence of exogenous insulin 10 , 11 . Nevertheless, clinical applications of hPSC-derived cells are undermined by the complicated differentiation processes and the risk of having residual undifferentiated cells that may form teratomas in vivo. Recent studies have focused on identifying intermediate stem cell types, including the non-tumorigenic human endoderm stem cells (EnSCs) 12 , which appear to be more suitable as precursors for large-scale generation of islet cells.

Here, we report the intrahepatic implantation of islet tissue (E-islets) differentiated in vitro from autologous EnSCs in a T2D patient who had impaired insulin secretion. This is a pilot study of an investigator-initiated trial designed to investigate the safety and efficacy of E-islets for the treatment of insulin-dependent diabetic patients (Fig. 1a ). The patient was a 59-year-old man with a 25-year history of T2D who developed end-stage diabetic nephropathy and underwent kidney transplantation in June of 2017 and displayed poor glycemic control since November of 2019, characterized by blood glucose level ranging from 3.66–14.60 mmol/L, mean amplitude of glycemic excursion (MAGE) of 5.54 mmol/L, the time-in-the-tight-target-range (TITR, 3.9–7.8 mM) of 56.7%, with daily hyperglycemic events (> 10.0 mmol/L) of 0.7/d and hypoglycemic events (< 3.9 mmol/L) of 0.3/d (Supplementary Table S1 ). Due to the major concerns of hypoglycemia and the detrimental effect of poor glycemic control on the long-term survival of the donor kidney, the patient agreed to pursue transplantation with autologous E-islets.

a Brief scheme of major procedures involved in the generation and quality control of E-islets and the safety/effectiveness evaluations of E-islet transplantation. b – d E-islets reverse hyperglycemia in STZ-induced diabetic immunocompromised mice. Schematic illustration of kidney capsule transplantation of E-islets ( b ). Fasting blood glucose dynamics (blue line: sham group; red line: E-islet-transplanted group, c ). Secretion of human C-peptide after fasting and 30 min following an i.p. glucose bolus on days 90 and 180 post transplantation ( d ). e – g Immunogenicity of E-islets in humanized mice. Schematic illustration of the syngeneic and allogeneic kidney capsule transplantation of patient-specific E-islets into the NCG-hIL15 diabetic mice humanized with the patient’s and a volunteer’s PBMCs ( e ). Fasting blood glucose dynamics (blue line represents the control group with the patient E-islets transplanted into three diabetic mice humanized with the volunteer’s PBMCs; red line represents the group with the patient E-islets transplanted into three diabetic mice humanized with the patient’s PBMCs, f ). Secretion of human C-peptide after fasting and 30 min following an i.p. glucose bolus on days 7 and 14 post E-islet transplantation (U.D. undetectable, g ). h Clinical measurements of TITR, TIR and HbA1c, and the insulin dosage during 116 weeks. i Continuous interstitial glucose fluctuations derived from the CGM measurements at weeks 52 and 105 compared with pre-surgery levels. j – l Serum levels of fasting and meal-stimulated circulating glucose ( j ), C-peptide ( k ) and insulin ( l ) from MMTT assays.

E-islets were generated from the autologous EnSCs that are established under the culture condition modified from our previous reports 12 (see details in Supplementary methods), through two intermediate stages under GMP conditions. The morphology, purity, viability and microorganism contamination of EnSC-derived PPs, endocrine progenitor cells and E-islets were proven to meet the release criteria (Supplementary Figs. S1 – S3 and Table S6 ). E-islets displayed similar morphology (Supplementary Fig. S3a ), endocrine cell composition (Supplementary Fig. S3b, c, e, f ), gene expression patterns (Supplementary Fig. S3d–f ) and in vitro functionality (Supplementary Fig. S3g ) to human cadaveric islets, and showed functional efficacy in Streptozotocin (STZ)-induced diabetic mouse (Fig. 1b–d ) and monkey (Supplementary Fig. S4 ) models. The nontarget hepatic or intestinal lineages, when examined by either scRNA-seq (Supplementary Fig. S3f ) or FACS (Supplementary Fig. S3h ), were not detected. Neither tumor formation nor cystic/ductal structures that indicate cell proliferation were detected in the immunocompromised animals transplanted with either EnSCs or E-islets during the experiments (Supplementary Table S3 ). The patient-specific E-islets survived and functioned under the kidney capsules of the diabetic immunocompromised mice humanized with patient’s own PBMCs, but rejected by the ones humanized with PBMCs from an unrelated volunteer (Fig. 1e–g ; Supplementary Fig. S5 ), which suggests that patient’s immune system likely tolerates the autologous E-islets.

The patient underwent a percutaneous transhepatic portal vein transplantation with 1.2 million IEQs of E-islets delivered, conforming to the regulatory guidance from the clinical islet transplantation registration. At designated visits, examinations of endocrine function and diabetes-specific parameters by mixed-meal tolerance test (MMTT) were performed at baseline, 4, 8, 12, 16, 20, 24, 36 and 48 weeks and thereafter at specified time points (Supplementary Fig. S6a ). The glycemic control of the patient was measured with a 24-h real-time continuous glucose monitoring system (CGM).

During the 116-week follow-up period, no tumor formation was detected either by MRI on the upper abdomen or by the measurements of serum tumor-related antigen markers. The treatment-emergent adverse events included: (1) temporary abdominal distension and loss of appetite within 4–8 weeks, relieved with methionyltrichloride; (2) restorable weight loss < 5% (from 80 kg to 76 kg).

The three major clinical outcomes, the glycemic targets, the reduction of exogenous insulin and the levels of fasting and meal-stimulated circulating C-peptide/insulin were monitored throughout the first 116 weeks (Supplementary Tables S4 , S5 ). Marked changes in the patient’s glycemic control were observed as early as week 2 post transplantation, as the MAGE declined from 5.50 mmol/L to 3.60 mmol/L, and the TITR increased rapidly from 56.7% to 77.8% (Fig. 1h ; Supplementary Table S1 ). Over the same period, the time-above-range (TAR) decreased by 55% from baseline, while the events of severe hyperglycemia (> 13.9 mM) and hypoglycemia (< 3.9 mM) completely disappeared (Supplementary Fig. S7a, b and Table S1 ). During the period between weeks 4 and 12, a significant reduction in ambulatory mean glucose fluctuations (from 5.50 to 2.6 mmol/L) (Supplementary Table S1 ) and a steady rise in TITR (from 81% to 90%) were observed (Fig. 1h ; Supplementary Fig. S7c–e and Table S1 ). After week 32, the patient’s TITR had readily reached 99% and was maintained thereafter (Fig. 1h, i ; Supplementary Table S1 ), while MAGE, the gold standard of blood glucose variability, was reduced from 5.50 mM to 1.60 mM (Supplementary Figs. S6d , S7h–l and Table S1 ). Importantly, no episodes of hypoglycemia or severe hyperglycemia were observed during the whole follow-up period of 116 weeks post surgery (Supplementary Fig. S7 and Table S1 ). Additionally, MMTT revealed a trend of stabilization in glycemic variability after surgery, as manifested by the stable fasting glucose concentrations and the significant reductions in the post-meal glucose concentrations (maximum of 21.3 mM at baseline vs maximum of 9.1 mM at week 105) (Fig. 1j ; Supplementary Table S5 ). Consistently, the area under the curve (AUC) derived from the 5-point intravenous glucose values decreased to 40% of baseline (Supplementary Fig. S6b ), confirmed by the AUCs of the values acquired from CGM (Supplementary Fig. S6c ). The hemoglobin A1c levels decreased from 6.6% (baseline) to 5.5% (week 85) and 4.6% (week 113) (Fig. 1h ; Supplementary Table S1 ).

Notably, the insulin requirements were reduced gradually until complete withdrawal at the end of week 11 (Fig. 1h ), and the oral antidiabetic medications were tapered since week 44 and discontinued at weeks 48 (acarbose) and 56 (metformin) (Supplementary Fig. S6a ).

The average post-surgery fasting C-peptide level (0.68 nmol/L) increased by 3-fold when compared to pre-surgery level (Fig. 1k ; Supplementary Table. S5 ). Notably, the secretions of C-peptide (Fig. 1k ) and insulin (Fig. 1l ) measured by MMTT revealed significant elevations compared to those of the pre-surgery tests, as confirmed by the AUCs (Supplementary Fig. S6b ).

Collectively, we report the first-in-human tissue replacement therapy using autologous E-islets for a T2D patient with impaired islet function. The first 27-month data revealed significant improvements in glycemic control, and provided the first evidence that stem cell-derived islet tissues can rescue islet function in late-stage T2D patients. The grafts were well tolerated with no tumor formation or severe graft-related adverse events.

The precedent clinical trials using cadaveric islets or encapsulated hPSC-derived PPs 10 , 11 , along with our study, have provided encouraging evidence that islet tissue replacement is an effective cure for diabetic patients. Notably, the derivation of islet tissues from either hPSCs or EnSCs provides unprecedented new sources for tissue-replacement therapy. Despite the common proof-of-concept purpose, there are some distinctions among the published trials 10 , 11 and ours. First, EnSC-based islet regeneration system is unique, in that EnSCs are nontumorigenic in vivo 12 and amenable for efficient mass production of islets as they are endoderm-specific and developmentally closer to pancreatic lineages. Second, our pilot study chose a T2D rather than T1D patient, which not only precluded the interference from autoimmune conditions for the assessment of engraftment and functionality of E-islets but also extended the scope of indications for islet transplantation. As for the limitations of this study, we cannot completely rule out the possibility that the residual endogenous islets benefitted from the surgery and acquired functional improvements. Therefore, an increase in sample size and additional trials of T1D patients with complete loss of islet β cells will help draw definitive conclusions on the causative role of E-islets in the achievement of glycemic targets.

Future studies are warranted to address the pharmacodynamics of stem cell-derived islets as a drug, to extend the application of stem cell-derived islet transplantation to other subtypes of diabetes, and to generate “universal islets” as off-the-shelf products to cure diabetes without the need for immunosuppression.

Talchai, C. et al. Cell 150 , 1223–1234 (2012).

Chatterjee, S. et al. Lancet 389 , 2239–2251 (2017).

Shapiro, A. M. et al. N. Engl. J. Med. 355 , 1318–1330 (2006).

Marfil-Garza, B. A. et al. Lancet Diabetes Endocrinol. 10 , 519–532 (2022).

Lablanche, S. et al. Lancet Diabetes Endocrinol. 6 , 527–537 (2018).

Markmann, J. F. et al. Am. J. Transplant. 21 , 1477–1492 (2021).

Pagliuca, F. W. et al. Cell 159 , 428–439 (2014).

Rezania, A. et al. Nat. Biotechnol. 32 , 1121–1133 (2014).

Sneddon, J. B. et al. Cell Stem Cell 22 , 810–823 (2018).

Ramzy, A. et al. Cell Stem Cell 28 , 2047–2061 (2021).

Shapiro, A. M. J. et al. Cell Rep. Med. 2 , 100466 (2021).

Cheng, X. et al. Cell Stem Cell 10 , 371–384 (2012).

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Acknowledgements

This work was funded by the Strategic Priority Research Program of the CAS (XDA16020203); the National Basic Research Program of China (2017YFA0102702); the National Natural Science Foundation of China (82070798, 82270788, 81500447, 82071799); the Science and Technology Commission of Shanghai Municipality (21S11905200, 22ZR1477300); Shenkang Project (SHDC12021116, SHDC12020111).

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These authors contributed equally: Jiaying Wu, Tuo Li, Meng Guo, Junsong Ji, Xiaoxi Meng, Tianlong Fu, Tengfei Nie, Tongkun Wei.

Authors and Affiliations

Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China

Jiaying Wu, Tianlong Fu, Tengfei Nie, Tongkun Wei, Ying Zhou, Xin Cheng & Xiaoliang Xu

Department of Endocrinology, Shanghai Changzheng Hospital (Second Affiliated Hospital of Naval Medical University), Shanghai, China

Tuo Li & Yongquan Shi

National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, Shanghai, China

Organ Transplant Center, Shanghai Changzheng Hospital, Shanghai, China

Junsong Ji, Hao Yin, Xiaoyu Mou, Yifan Feng, Junfeng Dong, Duowen He, Yuanyu Zhao, Xue Zhou, Guoshan Ding & Zhiren Fu

Department of Interventional Radiology, Shanghai Changzheng Hospital, Shanghai, China

Xiaoxi Meng & Weihua Dong

Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

Islet Transplantation Training Base of Shanghai Endocrinology Clinical Quality Control Center, Shanghai, China

Department of Health Care, Department of Translational Medicine, Shanghai Changzheng Hospital, Shanghai, China

Department of Hepatic Surgery IV, Third Affiliated Hospital of Naval Medical University (Eastern Hepatobiliary Surgery Hospital), Shanghai, China

Shanghai Key Laboratory of Cell Engineering, Research Center of Translational Medicine, Naval Medical University, Shanghai, China

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Contributions

H.Y., X.C., Y.S., M.Z. and W.D. conceived and supervised the study. J.W., T.F., T.N., T.W., Y.Z. and X.X. were responsible for the generation and quality control of E-islets. T.L., M.G., J.J., X.M. and Clinical Group members performed E-islet transplantation and were responsible for clinical follow-up, safety monitoring and data collection. All authors analyzed and interpreted the data.

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Correspondence to Weihua Dong , Ming Zhang , Yongquan Shi , Xin Cheng or Hao Yin .

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Wu, J., Li, T., Guo, M. et al. Treating a type 2 diabetic patient with impaired pancreatic islet function by personalized endoderm stem cell-derived islet tissue. Cell Discov 10 , 45 (2024). https://doi.org/10.1038/s41421-024-00662-3

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DOI : https://doi.org/10.1038/s41421-024-00662-3

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2 Faculty of Medical Sciences Professional Services, Newcastle University, U.K.

Carmen Martin-Ruiz

3 BioScreening Core Facility, Campus for Ageing and Vitality, Faculty of Medical Sciences, Newcastle University, U.K.

Davide Romeres

4 Department of Endocrinology, University of Virginia, Charlottesville, VA, U.S.A.

Albert Koulman

5 Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Box 289, Cambridge Biomedical Campus, Cambridge, U.K.

Claire M. Meek

6 Wolfson Diabetes and Endocrine Centre, Cambridge Universities NHS Foundation Trust, Cambridge, U.K.

Benjamin Jenkins

Claudio cobelli.

7 Department of Woman and Child's Health, University of Padova, Italy

Rury R. Holman

8 Diabetes Trials Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, U.K.

Associated Data

All data will be made freely available on the Mendelay database accessible at https://data.mendeley.com/datasets/72bm99t7wm/draft?a=832a3c4e-964e-4b00-ab74-89ab564675a8 .

Weight loss in overweight or obese individuals with Type 2 diabetes (T2D) can normalize hepatic fat metabolism, decrease fatty acid oversupply to β cells and restore normoglycaemia. One in six people has BMI <27 kg/m 2 at diagnosis, and their T2D is assumed to have different aetiology. The Personal Fat Threshold hypothesis postulated differing individual thresholds for lipid overspill and adverse effects on β-cell function. To test this hypothesis, people with Type 2 diabetes and body mass index <27kg/m 2 ( n = 20) underwent repeated 5% weight loss cycles. Metabolic assessments were carried out at stable weight after each cycle and after 12 months. To determine how closely metabolic features returned to normal, 20 matched normoglycemic controls were studied once. Between baseline and 12 months: BMI fell (mean ± SD), 24.8 ± 0.4 to 22.5 ± 0.4 kg/m 2 ( P <0.0001) (controls: 21.5 ± 0.5); total body fat, 32.1 ± 1.5 to 27.6 ± 1.8% ( P <0.0001) (24.6 ± 1.5). Liver fat content and fat export fell to normal as did fasting plasma insulin. Post-meal insulin secretion increased but remained subnormal. Sustained diabetes remission (HbA 1c < 48 mmol/mol off all glucose-lowering agents) was achieved by 70% (14/20) by initial weight loss of 6.5 (5.5–10.2)%. Correction of concealed excess intra-hepatic fat reduced hepatic fat export, with recovery of β-cell function, glycaemic improvement in all and return to a non-diabetic metabolic state in the majority of this group with BMI <27 kg/m 2 as previously demonstrated for overweight or obese groups. The data confirm the Personal Fat Threshold hypothesis: aetiology of Type 2 diabetes does not depend on BMI. This pathophysiological insight has major implications for management.

Introduction

Type 2 diabetes affects at least 10.5% of the world population yet the underlying cause of this common condition remains unresolved [ 1 ]. The disease is regarded as being heterogenous, with causes involving obesity, genetics, the microbiome, inflammation, ageing and other factors. Aetiology in people with a normal body mass index (BMI) is believed to be different from that in obese people [ 2 ], and guidelines do not recommend weight loss for management [ 3 ]. Observation that people of any BMI between 27 and 45 kg/m 2 could return to normal metabolic control by losing a similar amount of weight [ 4 , 5 ] led to the Personal Fat Threshold hypothesis [ 6 ]. It postulated that the storage capacity of subcutaneous fat may vary markedly between individuals and that T2D occurs when an individual of any BMI can no longer store triglyceride safely, thus promoting excess liver fat accumulation, excess hepatic fat export and exposure of β cells to excess lipid [ 6 ].

The Personal Fat Threshold hypothesis postulates that people with T2D will exhibit the same pathophysiological mechanisms irrespective of BMI and may return to non-diabetic glucose control after weight loss. This is of profound importance as it would indicate that this common disease does not have heterogenous causative mechanisms dependent upon body weight. The question is also of major therapeutic importance as 1 in 6 of all newly-presenting T2D in the US and UK have a BMI <27 kg/m 2 [ 7 ] (personal communication Prof Sarah Wild).

The Reversal of Type 2 diabetes Upon Normalization of Energy intake in non-obese people (ReTUNE) Study was designed explicitly to test the Personal Fat Threshold hypothesis. The prior prediction of this hypothesis was that people with normal or near-normal BMI could achieve remission of T2D by weight loss and that this would be achieved with the same underlying pathophysiological changes [ 6 ]. The effect of stepwise weight loss in people with T2D and BMI 21–27 kg/m 2 was, therefore, examined to determine possible thresholds for correction of the underlying mechanisms, using application of MRI in conjunction with detailed pathophysiologic studies. Additionally, durability of remission was examined by re-study at 12 months.

Participant details

Participants with T2D of <6 years duration aged 20–70 years and not on insulin therapy were recruited between 31.5.18 and 2.11.21 with follow-up to 25.1.22. Clinical characteristics are listed in Table 1 . To determine how closely to normal the metabolic features of the T2D cohort became, normoglycaemic control participants with no first-degree family history of T2D were studied on one occasion only. Hence, BMI of the controls was matched to the post-weight loss BMI of the T2D cohort and they were also matched for sex and age. Both T2D and control groups were recruited by newspaper advertisement.

Mean ± SEM. Number stated is for the whole cohort of 13 female and 7 male participants. Male data are not shown for 24 weeks (third cycle) as n =3. The P -values for each time point vs. baseline are shown. For the control data, P refers to comparison with 52 week time point (P4).

All clinical studies were conducted at the Newcastle University Magnetic Resonance Centre. As monogenic and autoimmune diabetes are more common in this ‘normal’ weight group, testing was carried out after informed consent to ensure that other types of diabetes were excluded. Screening was carried out for monogenic diabetes ( www.diabetesgenes.org ) and islet cell antibodies (GAD (U/ml, positive >10.9), human islet cell IA2 (U/ml, positive >7.49) or ZnT8 (U/ml, positive >9.99)) in the UK national test centre [ 8 ]. The study design was single group analysis of change from baseline. The cohort of 20 participants with T2D of duration <6 years and not on insulin therapy underwent 2 cycles of 5% rapid weight loss. If the HbA 1c remained above 48 mmol/mol [ 9 ] and if the individual wished, a third cycle was undertaken. One person was in remission after the first cycle of weight loss and wished to remain at that weight. Each cycle consisted of 2–4 weeks low calorie diet (600 kcal/day of formula meal replacements plus up to 200 kcal/day of non-starchy vegetables) [ 4 ] followed by 4–6 weeks weight stability with advice about types and quantities of foods, predominantly following a Mediterranean style eating pattern. Studies were conducted at baseline on usual hypoglycaemic agent therapy then at 8, 16 and 24 weeks after weight loss and weight stability. The weight loss and weight maintenance phases were supervised by one-to-one contact with a research dietitian (A.C.B. or K.M.I.). To determine durability of change of metabolic state, studies were also conducted at 52 weeks with dietetic review at 9 months, with telephone advice if required.

The 10-year risk of heart attack or stroke at baseline and 52 weeks in the T2D cohort and in the controls was calculated using QRISK3 [ 10 ]. Diary-based total dietary intake over 3-day periods were evaluated using Intake 24 [ 11 ] during the 2 weeks prior to each study visit (baseline, 8, 16, 24 and 52 weeks). Average intake of macronutrients, fruit and vegetables during the study are shown in Supplementary Table S3.

Determination of liver fat content

Liver fat content was quantified by the three-point Dixon magnetic resonance (MR) method, with gradient-echo scans acquired during breath holding using a 3T Philips Achieva scanner with a sixteen-channel torso array (Philips, Netherlands) [ 12 ]. Homogenous regions of interest were selected on five image slices of liver.

Determination of visceral and subcutaneous fat content

Three-point Dixon MRI was also acquired at the level of the L2-L3 vertebral space to estimate subcutaneous and visceral fat (SAT, VAT). Thresholding and watershed analysis using ImageJ were applied to calculate VAT and SAT areas in cm 2 at L2-L3 from the proton density fat fraction map.

Determination of liver-derived lipoprotein triglyceride

A Sorvall MX150+ microcentrifuge (Thermo Scientific) with S140-AT rotor was used for lipoprotein separation. Chylomicrons were separated from plasma using a supernate solution of 1.006 g/ml at 12,000 rpm for 30 min. The VLDL-TG fraction was then separated at 140,000 rpm for 50 min with supernate solution of 1.006 g/ml. Triglyceride concentrations in the fractions were quantified using the standard method (Roche Diagnostics, U.K).

Determination of indices of de novo lipogeneis

Concentration of plasma triglyceride 48:1 and 50:1 were used as best estimates of rate of fasting de novo lipogenesis [ 13 ] measured by liquid chromatography hyphenated with high-resolution mass spectrometry detection (LC-MS) [ 14 ].

Calculation of insulin sensitivity and insulin secretion

Indices of insulin sensitivity (SI) and insulin secretion normalised to insulin sensitivity (DI) were estimated by mathematical modelling [ 15 ] after a standard meal of ordinary foodstuffs (587 kcal; 65% carbohydrate, 13% protein and 19% fat) following an overnight fast. Total cholesterol, HDL cholesterol and blood pressure were measured. HOMA2_IR was estimated using the Oxford Diabetes Trials Unit HOMA Calculator [ 16 ].

Plasma adipokine assay

Plasma adipokine levels were assessed using R&D sandwich ELISA kits (Bio-Techne, Abingdon, U.K.), in quadruplicate on a 384-well format. All colorimetric reactions were read at 450 nm with correction at 540 nm on a FLUOstar Omega spectrofluorometer (BMG–LABTECH) and evaluated by the corresponding software MARS Data Analysis Version 1.20. Four parameter logistic (4-PL) curve-fits were applied for all standard curves; concentration values were corrected against an internal control as well as the corresponding dilution factor for each biomarker.

Glucose was measured by the oxidase method (Yellow Springs Inc., U.S.A.). HbA 1c was quantified using HPLC (Tosoh Bioscience, U.K.). C-peptide, insulin, glucose, NEFA, VLDL triglyceride and other metabolites were analysed at a Clinical Pathology Accredited Laboratory (Newcastle upon Tyne Hospital NHS Foundation Trust, U.K.).

Statistical analysis

Power calculation: The study was powered on primary dual outcome measures of reversal to non-diabetic HbA 1c and change in HbA 1c from baseline to post-diet because the Personal Fat Threshold hypothesis depends upon improvement in glucose control. In the absence of prior information on a non-obese group, a clinically relevant reversal rate was taken as 50%. Twenty-one participants (not including dropouts or exclusion due to other specific diagnosis) were allowed to calculate a confidence interval of width 0.4, assuming an actual reversal rate of 50%, i.e. 50% (95% CI: 30% to 70 [DS1]%). Twenty four participants were recruited to allow for dropouts or exclusions. A type 1 error of 5% and power of 90% was used. The co-primary outcome was the change in HbA 1c from entry/pre-weight loss to post-weight loss. As no data existed on a non-obese group, data from the short duration group of the Counterbalance study (mean BMI: 34 kg/m 2 ) were used (a clinically relevant mean change in HbA 1c pre- and post-weight loss of 0.6% with SD = 0.8%) [ 26 ].

Analyses were conducted on all subjects with paired data before and after weight loss. For physiological parameters, the principal outcomes were HbA 1c change from baseline to <48 mmol/mol at CEP and at 12 months. Data are presented as mean ± SEM, mean ± SD or median (IQ range), if not normally distributed. Student paired or two-sample t- tests were used as appropriate for parametric data and the Wilcoxon-Rank test or Mann–Whitney U- test for paired or unpaired nonparametric data. Analyses were performed using Minitab 17 (Minitab, U.S.A.) and Stata, version 13.1 (StataCorp LP, College Station, Texas, U.S.A.). For the time series data, Benjamini–Hochberg testing was carried out using a false discovery rate of 0.1 to detect multiple testing errors as indicated in the tables. Three participants were recruited late due to COVID-19 and were studied only to the 24-week time point due to grant period constraint. Missing data are indicated in each of the figures and tables. A two-tailed P- value <0.05 was considered as significant.

Clinical and metabolic characteristics

Of 24 individuals screened, four were found to have non-T2D aetiology and excluded, two with glucokinase-deficient monogenic diabetes and two with Type 1 diabetes. At baseline, there were 20 individuals in the T2D cohort (13 females and 7 males) who were (mean ± SD) aged 59.0 ± 7.0 years, weighed 71.8 ± 12.6 kg, and had a mean BMI of 24.8 ± 1.7 (range 21.2–26.9) kg/m 2 ( Table 1 ). Of these, 16 were White European, three were South Asian and one was of Middle Eastern ethnicity. Mean diabetes duration was 2.8±1.9 years. Eleven had a first-degree family history of T2D and 12 were taking oral glucose-lowering agents (metformin 10, gliclazide 2). Twenty individuals in the control group (13 females and 7 males) were matched for weight following weight loss in the T2D group. They were aged 58.0 ± 10.5 years, weighed 61.5 ± 11.3 kg, and had a mean BMI of 21.5 ± 2.2 kg/m 2 ( Table 1 ). There were 17 White European, 2 of South Asian and 1 of Far Eastern ethnicity.

Weight loss

In the T2D group mean body weight decreased as per protocol at each step from 71.8 ± 2.8 kg ( Figure 1 and Table 1 ) and remained stable between the final weight loss cycle visit (cycle 2 or 3) and 12 months (63.1 ± 3.0 vs. 64.1 ± 2.8 kg, P =0.88). Total body fat mirrored this (32.1 ± 1.5% at baseline and 27.7 ± 1.8% at 12 months, P =0.0001, Figure 1 and Table 1 ) remaining greater than control in women (32.0 ± 0.9% vs. 27.5 ± 1.7%, P =0.037) but not in men (19.2 ± 1.8% vs. 19.2 ± 1.7%, P =0.983, Table 1 ).

Changes in mean (+SEM) BMI, weight, % body fat, waist circumference, visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) in the T2D group during the intervention at each time point. Numbers of participants and level of statistical significance vs. baseline are shown below each time point. The dotted line shows the mean control values for each parameter.

Physiological changes of remission

Median (interquartile range) liver fat content decreased from 4.0 (2.1–6.0)% to 1.8 (1.5–2.8)% at the clinical endpoint (CEP: achievement of HbA 1c <48 mmol/mol) ( n =14, P <0.001, Figure 2 ). It decreased further with increasing weight loss and at 12 months was 1.5 (1.4–1.8)% ( P =0.001 vs. baseline), comparable to control group levels (1.3 [1.0–1.8)%, P =0.452).

Median (IQR) liver fat, very low-density lipoprotein-1 (VLDL) triglyceride, plasma triglycerides with palmitic acid content reflecting rate of de novo lipogenesis, total plasma triglyceride, and Disposition Index at baseline, the co-primary end points of CEP (clinical end point; HbA 1c <48 mmol/mol) and at 12 months in the T2D group. Numbers of participants and level of statistical significance vs. baseline are shown below CEP and 12 months. Non-diabetic control data are also shown with the level of significance vs. T2D at 12 months below ‘Control’.

De novo lipogenesis

Median plasma 50:1 triglyceride decreased from baseline of 0.54 (0.37–0.77) to 0.22 (0.12–0.44) µmol/l ( P =0.002) at CEP. It remained low at 12 months (0.26 [0.22–0.35] µmol/l ( P =0.003 vs. baseline), and similar to control levels (0.25 [0.16–0.42], P =0.496, Figure 2 ). Plasma 48:1 triglyceride decreased from baseline of 0.30 (0.22–0.53) to 0.09 (0.06–0.33) µmol/l ( P =0.021) at CEP. It was 0.13 (0.07–0.19) µmol/l at 12 months ( P =0.007 vs. baseline) when it did not differ from control levels 0.14 (0.07–0.31) µmol/l ( P =0.426, Figure 2 ). The time course of change for both triglycerides is shown in Supplementary Figure S1.

VLDL and plasma total triglyceride

Median fasting plasma VLDL triglyceride was 0.35 (0.30–0.61) mmol/l at baseline and 0.22 (0.17–0.30) mmol/l at CEP ( P <0.033), similar to the control group (0.21 [0.15–0.29] mmol/l, P =0.555, Figure 2 and Table 3 ). At 12 months, it was 0.24 (0.17–0.32) mmol/l ( P <0.005 vs. baseline; P =0.792 vs. controls). Median fasting plasma total triglyceride decreased in parallel from 1.4 (1.1–1.7) to 1.0 (0.9–1.3) mmol/l at CEP ( P =0.023) and to 0.9 (0.7–1.1) mmol/l at 12 months ( P =0.001), when it was similar to the control group (0.8 [0.6–1.1] mmol/l, P =0.315).

Median (IQ range). Benjamini–Hochberg correction confirmed the significance of difference from baseline with one exception. † The P- values for each time point versus baseline are shown. The P- values for difference between Controls and the 12-month (P4) data for the type 2 diabetes participants are shown in the Controls column.

β-Cell function

Median fasting plasma insulin decreased from 36 (26–53) pmol/l to 25 (18–36) pmol/l at CEP ( P =0.001). It was 22 (15–31) pmol/l at 12 months ( P =0.001), similar to the control group (20 [11–32] pmol/l, P =0.716). Fasting C-peptide decreased from 0.58 (0.53–0.99) nmol/l at baseline to 0.48 (0.43–0.70) nmol/l at CEP ( P =0.001) and to 0.45 (0.35–0.58) at 12 months ( P =0.006), similar to the control group (0.45 [0.36–0.55] nmol/l, P =0.532). Meal-related insulin secretion corrected for insulin sensitivity (disposition index, DI) was 348 (166–423) dl/kg/min 2 per pmol/l at baseline and 583 (410–803) dl/kg/min 2 per pmol/l at CEP ( P =0.064), increasing to 624 (437–1342) dl/kg/min 2 per pmol/l at 12 months ( P =0.006 vs. baseline). At 12 months, it was within the range of the control group values (586–8728 dl/kg/min/pmol/l) but remained significantly lower than the median control group value (2652 [1546–4190] dl/kg/min/pmol/l, P <0.001) ( Figure 2 ). Supplementary Figure S1 shows the time course of change in major pathophysiological factors.

Insulin sensitivity and postprandial metabolism

Fasting insulin resistance, assessed as HOMA2_IR, reflecting insulin control of hepatic glucose output, decreased from 2.02 (1.44–3.30) to 1.32 (0.97–1.97) at CEP ( P =0.001) and to 0.88 (0.51–1.36) at 12 months ( P =0.001) when it did not differ significantly from the control group (0.67 [0.47–1.10], P =0.342). Mean meal related insulin sensitivity, modelled as SI, was 9.9 ± 1.4 at baseline and 16.6 ± 3.85 × 10 −5 dl/kg/min per pmol/l at CEP ( P =0.088), increasing at 12 months to 19.2 ± 4.0 × 10 −5 dl/kg/min per pmol/l ( P =0.022) but still significantly lower than the control group (36.3 ± 5.3 × 10 −5 dl/kg/min per pmol/l, P =0.015). Median AUC glucose decreased from 2162 (2024–2498) at baseline to 1644 (1486–2011) mmol/l min at CEP ( P =0.016) and 1795 (1559–1924) mmol/l min at 12 months ( P =0.011), remaining higher than the control group (1153 [1038–1232] mmol/l min, P <0.001). Mean fasting plasma NEFA at baseline and 12 months did not differ significantly (0.72 ± 0.04 vs. 0.57 ± 0.04mmol/l, P =0.155) and suppressed to a similar extent following the standard test meal (maximum suppression 0.13 ± 0.02 vs. 0.10 ± 0.01mmol/l, P =0.446) (Supplementary Table S1). Mean fasting plasma ketones (measured after each period of weight stability) did not change significantly (0.19 ± 0.02 at baseline vs. 0.30 ± 0.07 mmol/l at 12 months, P =0.150) and were not different from the control group (0.24 ± 0.03mmol/l, P =0.361, Table 2 ).

Mean ± SEM or median (IQR). Significance stated as paired analysis from baseline for each time point (all confirmed by Benjamini–Hochberg correction). The P- values for each time point versus baseline are shown. Significance of difference shown in control column is in comparison with the 52-week T2D time point.

Plasma adipokines

Median PAI-1 decreased from 8.64 (6.41–11.22) ng/ml at baseline to 6.32 (4.68–7.96) ng/ml at CEP ( P =0.009, compared with controls 4.87 [3.49–8.47] ng/ml, P =0.230). At 12 months (6.31 [4.63–9.36] ng/ml) it did not differ from control ( P =0.250). Median leptin decreased from 442 (266–744) to 296 (75–447) ng/ml at CEP ( P =0.002) when it did not differ from the control group (227 (162–290) ng/ml, P =0.517). It remained similar at 12 months (299 [123–513) ng/ml, P =0.001 vs. baseline and P =0.474 vs. controls). Median IL-6, FGF-21, GDF-15 and hsCRP values did not change significantly to CEP. IL-6 and hsCRP decreased significantly and adiponectin increased significantly at 12 months only ( Table 3 ).

Glucose control

HbA 1c decreased to <48 mmol/mol at CEP in 70% (14/20) of participants, declining from baseline of 54 ± 1mmol/mol to 46 ± 1 ( P <0.0001) at 12 months when BMI was 22.4 ± 0.5 kg/m 2 ( Figure 3 ). The mean change from baseline was −8.4 ± 1.6 mmol/mol at CEP and −7.4 ± 1.7 mmol/mol at 12 months. Oral glucose-lowering agents remained discontinued throughout the study in those achieving HbA 1c <48 mmol/mol and were restarted in one participant remaining >48 mmol/mol. The threshold of remission off all glucose-lowering agents was achieved with median weight loss of 6.5 (range: 5.5–10.2)%.

Change in mean (+SEM) HbA 1c and fasting plasma glucose values in the T2D group during weight stability following each weight loss cycle and also after longer term follow up at 12 months. Numbers of participants and significance level versus baseline are shown below each time point.

Mean fasting plasma glucose decreased from baseline of 7.4 ± 0.2 to 5.9 ± 0.1mmol/l ( P =0.001) at CEP and to 5.8 ± 0.2 mmol/l at 12 months ( P =0.0001 vs. baseline) ( Figure 3 ). The CEP was achieved following median (IQR) weight loss of 4.7 (3.4–9.2) kg, equating to 6.4 (5.4–11.1)% below baseline. The median time to first HbA 1c value <48 mmol/mol was 8 (8–10) weeks ( n =10 at 8 weeks, 3 at 16 weeks, and 1 at 52 weeks).

There were no significant baseline differences in HbA 1c between those achieving or not achieving the CEP, although all 6 who did not achieve CEP were taking an oral glucose-lowering agent at baseline compared with 6/14 of those who achieved CEP ( Table 2 ). In particular, there were no significant differences in BMI, sex, age, ethnicity or HOMA2_IR (Supplementary Table S2). Changes in composition of food intake during the study is shown in Supplementary Table S3.

Lipid-related and vascular factors

The ratio of total cholesterol/HDL cholesterol decreased from 3.4 ± 0.2 to 3.1 ± 0.1 at CEP ( P =0.021) and became similar to the control group at 12 months (2.8 ± 0.2 vs. 2.9 ± 0.2, P =0.758). Median systolic blood pressure was 131 (123–136) mmHg at baseline, 122 (115–136) mmHg at CEP ( P =0.052 vs. baseline) and 118 (112–125) mmHg at 12 months ( P =0.008 vs. baseline). Median diastolic blood pressure was 76 (64–81) mmHg at baseline, 72 (66–78) mmHg at CEP ( P =0.052) and 64 (59–67) mmHg at 12 months ( P =0.003). Antihypertensive agents were withdrawn after baseline tests were performed in the 4 participants receiving these agents but were required to be re-commenced in three participants. The 10-year cardiovascular disease risk (QRISK) decreased from 14.4 ± 1.5% at baseline to 8.1 ± 1.1% ( P <0.001) at 12 months, when it was similar to that of the control group (6.2 ± 1.2%, P =0.242).

Waist circumference decreased between baseline and 12 months from 90.0 ± 2.1 to 79.7 ± 2.0 cm ( P <0.001, Table 1 and Figure 1 ). Visceral adipose tissue (VAT) decreased by 37.4% and subcutaneous adipose tissue (SAT) by 26.5% ( P =0.001 for both, Table 1 and Figure 1 ). In women, VAT and SAT remained higher than control (70 ± 9 vs. 26 ± 6 cm 2 , P =0.001 and 159 ± 14 vs. 110 ± 16 cm 2 , P =0.034). In men after weight loss a non-significant similar trend was evident in waist circumference, VAT and SAT ( Table 1 ). MRI fat maps illustrating the change in VAT with weight loss compared with matched control participants are shown in Supplementary Figure S2.

The ReTUNE study confirms the Personal Fat Hypothesis predictions by showing that 70% of people with T2D with normal or near-normal BMI return to non-diabetic HbA 1c despite stopping all glucose-lowering agents after weight loss, with the same underlying pathophysiological changes as already demonstrated in overweight/obese people. These data introduce a frame shift of understanding of T2D with demonstration of homogenous aetiology irrespective of BMI. The return to normal levels of liver fat after dietary weight loss in T2D, first demonstrated by Petersen and colleagues [ 17 ], emphasises the tight relationship between liver fat content, hepatic insulin sensitivity and restraint of hepatic glucose output by insulin [ 18–20 ]. The Counterpoint and subsequent studies established that this normalization of physiology in overweight/obese people presenting with T2D was accompanied by recovery of β-cell function [ 4 , 5 , 21 , 22 ]. The stepwise induction of weight loss in the T2D group identified that the BMI threshold for return to non-diabetic HbA 1c values was crossed at a median of 23.1 kg/m 2 with a median 6.5% weight loss, less than the 9.9% weight loss required for the higher-BMI group studied in DiRECT [ 23 ].

Although liver fat content at baseline in the present study was within the usually accepted normal range derived from the Dallas Heart Study with mean BMI 30kg/m 2 [ 24 ], it is important to consider what is normal for people with lower BMI values. The differential between baseline liver fat content in the ReTUNE T2D group was three-fold greater than that in the control group, similar to that observed between groups of heavier people with T2D and controls [ 21 ]. Consistent with this, Petersen and colleagues have observed the 95% boundary for liver fat to be less than 2% in individuals with BMI under 25 kg/m 2 [ 25 ]. The proximal mediators of hepatic insulin resistance are the toxic lipid intermediaries (including ceramides and diacylglycerol) rather than stored triglyceride itself [ 26 ], and the former would be expected to fall more rapidly on initiation of negative energy balance. Close study of the initial time course of change in hepatic insulin resistance in the Counterpoint study using the same hypocaloric diet showed a 30% decrease in liver fat yet complete normalisation of directly measured hepatic insulin resistance within 7 days [ 4 ]. The Counterpoint study was designed to test the specific predictions of the Twin Cycle Hypothesis [ 27 ] that T2D was caused by excess fat inside liver and supplied to the β cells and that this the underlying mechanisms could be reversed to normal by weight loss, and hence the present study provides further confirmation of fat-dependent aetiology of the disease.

The >50% decrease in plasma triglycerides containing predominantly palmitic acid reflects decreased fasting de novo lipogenesis [ 13 ], as previously documented with weight loss in heavier people [ 4 , 5 , 21 , 28 ]. Palmitic acid is the most potent fatty acid in suppressing β-cell function [ 29 ]. Although functional β-cell mass has been shown to return completely to normal during 12 months of dietary weight loss-induced remission of T2D, first phase insulin secretion improves but does not normalise either in the present or previous studies [ 30 ]. Onset of T2D is likely to relate primarily to the β-cell functional insulin secretory capacity [ 31 ], confirmed in studies of remission and recurrence with weight regain in people with wide range of T2D duration [ 5 , 21 , 32 ]. But even in genetically lipid-susceptible β cells function will not be impaired if the β-cell lipid environment remains normal. The metabolic stress of chronic nutrient oversupply in vitro is particularly evident following exposure to palmitate, [ 33 ], the product of de novo lipogenesis which is markedly increased in states of muscle insulin resistance [ 34 ]. The fat overflow hypothesis and separately the concept that chronic excess fatty acid exposure could impair β-cell function are far from new [ 35–39 ]. Our present and previous studies demonstrate that these factors act in a coordinated fashion to cause T2D, and that effective weight loss across BMI range leads to a lower rate of continuous fatty acid delivery from plasma triglycerides to β cells [ 4 , 5 , 22 , 40 ].

The development of hyperglycaemia will add to this β-cell metabolic insult, contributing to the well-recognised longer-term deterioration in glycaemic control [ 41 ]. De-differentiation and loss of specialised function of β cells is consistent with recent studies [ 42–45 ] and re-differentiation would explain the observed recovery when endoplasmic reticulum stress is removed [ 42 , 43 , 45–47 ]. Markers of de-differentiation are expressed in β cells from human T2D pancreases [ 44 , 48 ]. There is no proof that de-differentiation is the sole process underlying β-cell dysfunction, but if the state of metabolic stress persists too long, irreversible loss of endocrine function results [ 5 , 49 ]. The response to weight loss could be used as a phenotyping tool to guide future genetic studies of two distinct characteristics: β-cell susceptibility to lipid induced dysfunction, and β-cell durability in avoiding irreversible loss of function despite chronic fat and glucose excess. The genetic basis of heterogeneity in subcutaneous fat storage capacity itself has been confirmed [ 50 ].

A secondary aim of ReTUNE was to examine whether raised plasma adipokine concentrations could identify people who were above their personal fat thresholds. Median PAI-1 and leptin were both found to be elevated in the T2D group and to decrease once HbA 1c became <48 mmol/mol but a larger study will be necessary to determine whether or not a combination of PAI-1 and leptin could be a reliable indicator.

The Personal Fat Threshold paper drew attention to the median BMI of the people with newly diagnosed T2D enrolled in UK Prospective Diabetes Study (UKPDS) of 27.5 kg/m 2 , with over one-third (36%) having a normal BMI (<25kg/m 2 ) [ 6 ]. When recruitment for UKPDS commenced in the 1970’s, 64% of the background population had a BMI less than 25 kg/m 2 [ 51 ] and the apparent lack of association of T2D with obesity at that time [ 52 ] is explicable by the small numbers of people with high BMI. Now that 28% of the UK adult population have a BMI greater than 30 kg/m 2 [ 53 ], the association of obesity with T2D is so prominent that a causal relationship has become widely assumed. Hence, the nature of T2D itself has been overlooked, and concepts of heterogeneity of aetiology in different weight groups have emerged [ 54 ]. This is partly based on the assumption that non-obese people with T2D have less insulin resistance and a greater β-cell defect compared with those who are obese [ 55 ]. However, when appropriate BMI-matched controls are used, there is no difference in these parameters between non-obese and obese people [ 56 ] and the β-cell response after test meals is similar in non-obese and obese T2D groups [ 57 ].

People with a BMI <27 kg/m 2 account for 16% of newly diagnosed T2D [ 7 ]. Demonstration of the value of weight loss in this group carries major health economic implications. The present and previous studies show that the majority of people presenting with T2D are heavier than their individual metabolism can tolerate [ 4 , 5 , 21 , 22 ]. However, in the lower BMI range exclusion is necessary of monogenic or autoimmune diabetes which can mimic T2D with 4/24 people (16%) found to have other specific causes of diabetes.

Limitations of the present study must be considered. The group studied was relatively small but the effect size was so large with highly statistically significant outcomes, and this detailed physiologic study was powered to test an a priori hypothesis. Also, the group characteristics were typical for people with T2D and BMI <27 kg/m 2 . Secondly, the ethnicity reflected that in the North East of England and was largely white European. Remission of T2D after weight loss has been documented in all ethnicities tested [ 58–61 ], although it would be expected that different ethnicities will have different personal fat thresholds. Thirdly, the possibility of achieving the necessary weight loss with diet may be doubted by many doctors, but the acceptability of the specific dietary approach has been confirmed [ 62 ] and its success in the wider population of people with T2D has led to a NHS England national programme for remission [ 63 ]. At present this is limited to those with BMI >27 kg/m 2 . Finally, follow-up beyond one year is required for this BMI group studied, although there was a notable stability of weight during the low intensity follow-up between 6 and 12 months which differed from the weight regain observed in people similarly managed with starting BMI >27 kg/m 2 [ 21 ].

The Personal Fat Threshold hypothesis explains the apparent weight-related heterogeneity in T2D with individual differences in capacity for fat storage in metabolically safe depots. However, the pathophysiologic mechanisms underlying T2D and its reversal are identical in people with normal or raised BMI.

Clinical perspectives

• The study tested the Personal Fat Threshold hypothesis that Type 2 diabetes in people of BMI <27 kg/m 2 could achieve remission by dietary weight loss, accompanied by the same underlying pathogenic mechanisms as in heavier people.
• The study group were shown to have raised liver fat, de novo lipogenesis and hepatic fat export compared with a matched non-diabetic control group and these parameters returned to normal resulting in improved β-cell function with 70% achieving remission lasting for 12 months.
• Recognising that Type 2 diabetes is directly caused by overnutrition, potentially reversible by dietary weight loss to below a personal threshold, is vital to direct clinical management as well as future research.

Supplementary Material

Acknowledgements.

The authors are grateful to Louise Ward, Tim Hodgson, and Dorothy Wallace, research radiographers, and Craig Parker, research technician, Newcastle University. The authors also thank Helen Pilkington, research nurse, Karen Bradley, research administrator, Susan McLellen, Alison Younghusband, Louise Burnip, Marie Appleton, and Mellissa Watts, laboratory technicians, Newcastle upon Tyne NHS Trust, and Ahmad Al-Mrabeh and Olivier Govaere of Newcastle University Translational and Clinical Research Institute. The authors are grateful to Dr Clive J Petry of Cambridge University for statistical analyses and to Dr Kevin Colclough and Professor Sian Ellard, Exeter University, for conduct of and advice about the screen for monogenic diabetes and islet autoantibody testing. R.R.H. is an Emeritus National Institute for Health and Care Research (NIHR) Senior Investigator.

Abbreviations

Data availability, competing interests.

R.T. reports grants from Diabetes UK, lecture fees from Novartis, Lilly and Jansen during the conduct of the study and is a member of the NHS England Advisory Board for the Type 2 Diabetes Path to Remission Programme. He was a member of the ADA/EASD/DUK Consensus Group for the Definition of Type 2 Diabetes Remission. C.L.M. is supported by the Diabetes UK Harry Keen Intermediate Clinical Fellowship (DUK-HKF 17/0005712) and the European Foundation for the Study of Diabetes - Novo Nordisk Foundation Future Leaders' Award (NNF19SA058974). AK and B.J. are supported by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (BRC) and the core metabolomic and lipidomic laboratory (CMAL). R.R.H reports research support from AstraZeneca, Bayer, and MSD; and personal fees from Anji Pharmaceuticals, Bayer, Novartis, and Novo Nordisk. All other authors declare no competing interests. R.T. is the guarantor of this work and takes full responsibility for the integrity of the data and the accuracy of the data analysis.

The study was funded by a grant from Diabetes UK (award number 17/0005645), and the formula diet was donated by The Hut Group, Manchester, U.K. Neither organization contributed in any way to the study design, data analysis, or interpretation.

Open Access

Open access for this article was enabled by the participation of Newcastle University in an all-inclusive Read & Publish agreement with Portland Press and the Biochemical Society under a transformative agreement with JISC.

CRediT Author Contribution

Roy Taylor: Conceptualization, Resources, Data curation, Supervision, Funding acquisition, Validation, Writing—original draft, Project administration, Writing—review & editing. Alison C. Barnes: Conceptualization, Investigation, Methodology, Project administration, Writing—review & editing. Kieren G. Hollingsworth: Resources, Software, Supervision, Funding acquisition, Investigation, Methodology, Writing—review & editing. Keaton M. Irvine: Data curation, Investigation, Project administration, Writing—review & editing. Alexandra S. Solovyova: Investigation, Methodology, Writing—review & editing. Lucy Clark: Investigation, Writing—review & editing. Tara Kelly: Investigation, Writing—review & editing. Carmen Martin-Ruiz: Data curation, Investigation, Methodology, Writing—review & editing. Davide Romeres: Software, Formal analysis, Writing—review & editing. Albert Koulman: Data curation, Investigation, Writing—review & editing. Claire M. Meek: Data curation, Investigation, Writing—review & editing. Benjamin Jenkins: Investigation, Writing—review & editing. Claudio Cobelli: Software, Investigation, Writing—review & editing. Rury R. Holman: Conceptualization, Supervision, Funding acquisition, Writing—review & editing.

Ethics Approval

The study was approved by the Newcastle Ethics Committee on 22.12.2017(17/NE/84) and conducted between 31.5.2018 and 7.1.2022. Informed consent was obtained after full explanation. It was registered as ISRCTN 15177113. The STROBE checklist is shown in the Supplementary Materials.