essay on type 2 diabetes mellitus

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.

• Chicago (A-D)
• Chicago (N-B)

IvyPanda. (2019, February 4). Type 2 Diabetes. https://ivypanda.com/essays/type-2-diabetes-2/

"Type 2 Diabetes." IvyPanda , 4 Feb. 2019, ivypanda.com/essays/type-2-diabetes-2/.

IvyPanda . (2019) 'Type 2 Diabetes'. 4 February.

IvyPanda . 2019. "Type 2 Diabetes." February 4, 2019. https://ivypanda.com/essays/type-2-diabetes-2/.

1. IvyPanda . "Type 2 Diabetes." February 4, 2019. https://ivypanda.com/essays/type-2-diabetes-2/.

Bibliography

IvyPanda . "Type 2 Diabetes." February 4, 2019. https://ivypanda.com/essays/type-2-diabetes-2/.

• Insulin Injection: Drug Properties and Injection Process
• Doctors' Reluctance to Prescribe Birth Control Pills to Early Adolescents
• Endocrine Disorders: The Diabetic
• The Diabetic Plate and Healthy Nutrition
• How to Self-Administer Insulin Injection
• The History of the Pill and Feminism
• Management of Patients With Diabetic Ketoacidosis
• Stontioum-90 in Plasma
• Diabetic Diet and Food Restrictions
• R-insulin: Article Critique
• Type I Diabetes: Pathogenesis and Treatment
• Human Body Organ Systems Disorders: Diabetes
• Informative Speech on Hyperthyroidism
• Are there Occasions in the Delivery of Health Care when Deception is Warranted?
• Xtra Mile: Roles of Medical Directors

• Reference Manager
• Simple TEXT file

People also looked at

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

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

• View all journals
• Explore content
• About the journal
• Publish with us
• Sign up for alerts
• Published: 23 July 2015

Type 2 diabetes mellitus

• Ralph A. DeFronzo 1 ,
• Ele Ferrannini 2 ,
• Leif Groop 3 ,
• Robert R. Henry 4 ,
• William H. Herman 5 ,
• Jens Juul Holst 6 ,
• Frank B. Hu 7 ,
• C. Ronald Kahn 8 ,
• Itamar Raz 9 ,
• Gerald I. Shulman 10 ,
• Donald C. Simonson 11 ,
• Marcia A. Testa 12 &
• Ram Weiss 13  

Nature Reviews Disease Primers volume  1 , Article number:  15019 ( 2015 ) Cite this article

47k Accesses

1072 Citations

125 Altmetric

Metrics details

• Diabetes complications
• Type 2 diabetes

Type 2 diabetes mellitus (T2DM) is an expanding global health problem, closely linked to the epidemic of obesity. Individuals with T2DM are at high risk for both microvascular complications (including retinopathy, nephropathy and neuropathy) and macrovascular complications (such as cardiovascular comorbidities), owing to hyperglycaemia and individual components of the insulin resistance (metabolic) syndrome. Environmental factors (for example, obesity, an unhealthy diet and physical inactivity) and genetic factors contribute to the multiple pathophysiological disturbances that are responsible for impaired glucose homeostasis in T2DM. Insulin resistance and impaired insulin secretion remain the core defects in T2DM, but at least six other pathophysiological abnormalities contribute to the dysregulation of glucose metabolism. The multiple pathogenetic disturbances present in T2DM dictate that multiple antidiabetic agents, used in combination, will be required to maintain normoglycaemia. The treatment must not only be effective and safe but also improve the quality of life. Several novel medications are in development, but the greatest need is for agents that enhance insulin sensitivity, halt the progressive pancreatic β-cell failure that is characteristic of T2DM and prevent or reverse the microvascular complications. For an illustrated summary of this Primer, visit: http://go.nature.com/V2eGfN

This is a preview of subscription content, access via your institution

Access options

Subscribe to this journal

Receive 1 digital issues and online access to articles

92,52 € per year

only 92,52 € per issue

Buy this article

• Purchase on Springer Link
• Instant access to full article PDF

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

Double or hybrid diabetes: A systematic review on disease prevalence, characteristics and risk factors

Jomana Khawandanah

Novel therapies with precision mechanisms for type 2 diabetes mellitus

Leigh Perreault, Jay S. Skyler & Julio Rosenstock

Heterogeneity and endotypes in type 1 diabetes mellitus

Maria J. Redondo & Noel G. Morgan

DeFronzo, R. A. Banting lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 58 , 773–795 (2009). A classic review of the aetiology of T2DM, with a therapeutic approach based on its pathophysiology.

Article   CAS   PubMed   PubMed Central   Google Scholar  

Abdul-Ghani, M. A., Tripathy, D. & DeFronzo, R. A. Contributions of β-cell dysfunction and insulin resistance to the pathogenesis of impaired glucose tolerance and impaired fasting glucose. Diabetes Care 29 , 1130–1139 (2006).

Article   CAS   PubMed   Google Scholar  

Gerstein, H. C. et al . Annual incidence and relative risk of diabetes in people with various categories of dysglycemia: a systematic overview and meta-analysis of prospective studies. Diabetes Res. Clin. Pract. 78 , 305–312 (2007).

Article   PubMed   Google Scholar  

Hawa, M. I. et al . Adult-onset autoimmune diabetes in Europe is prevalent with a broad clinical phenotype: action LADA 7. Diabetes Care 36 , 908–913 (2013).

Article   PubMed   PubMed Central   Google Scholar  

Gardner, D. S. & Tai, E. S. Clinical features and treatment of maturity onset diabetes of the young (MODY). Diabetes. Metab. Syndr. Obes. 5 , 101–108 (2012).

American Diabetes Association. Standards of medical care in diabetes. Diabetes Care 37 , S14–S80 (2014). A comprehensive overview of the standards of medical care published by the ADA.

Article   Google Scholar  

DeFronzo, R. A. & Abdul-Ghani, M. A. Preservation of β-cell function: the key to diabetes prevention. J. Clin. Endocrinol. Metab. 96 , 2354–2366 (2011).

Ferrannini, E., Gastaldelli, A. & Iozzo, P. Pathophysiology of prediabetes. Med. Clin. North Am. 95 , 327–339 (2011).

Garvey, W. T. et al . Prevention of type 2 diabetes in subjects with prediabetes and metabolic syndrome treated with phentermine and topiramate extended release. Diabetes Care 37 , 912–921 (2014).

Nathan, D. M. et al . Impaired fasting glucose and impaired glucose tolerance: implications for care. Diabetes Care 30 , 753–759 (2007).

DeFronzo, R. A. et al . Pioglitazone for diabetes prevention in impaired glucose tolerance. N. Engl. J. Med. 364 , 1104–1115 (2011). A large prospective study demonstrating the efficacy of thiazolidinediones in preventing the progression of IGT to T2DM.

Zinman, B. et al . Low-dose combination therapy with rosiglitazone and metformin to prevent type 2 diabetes mellitus (CANOE trial): a double-blind randomised controlled study. Lancet 376 , 103–111 (2010).

Dansinger, M. L., Tatsioni, A., Wong, J. B., Chung, M. & Balk, E. M. Meta-analysis: the effect of dietary counseling for weight loss. Ann. Intern. Med. 147 , 41–50 (2007).

Purcell, K. et al . The effect of rate of weight loss on long-term weight management: a randomised controlled trial. Lancet Diabetes Endocrinol. 2 , 954–962 (2014).

Ali, M. K., Echouffo-Tcheugui, J. & Williamson, D. F. How effective were lifestyle interventions in real-world settings that were modeled on the Diabetes Prevention Program? Health Aff. (Millwood) 31 , 67–75 (2012).

Tuomilehto, J. et al . Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N. Engl. J. Med. 344 , 1343–1350 (2001).

Inzucchi, S. E. et al . Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 35 , 1364–1379 (2012). ADA position statement on the treatment of T2DM, advocating a stepped care approach starting with metformin.

American Association of Clinical Endocrinologists. AACE Comprehensive Diabetes Algorithm 2013 Consensus Statement. Endocr. Pract. Suppl. 1 , 1–87 (2015). AACE position statement on the treatment of T2DM, advocating initial monotherapy or combination therapy based upon the starting HbA1c, and recommending various antidiabetic medications as initial therapy.

Google Scholar  

Pozzilli, P. et al . The A1C and ABCD of glycaemia management in type 2 diabetes: a physician's personalized approach. Diabetes Metab. Res. Rev. 26 , 239–244 (2010). The first published report by key opinion leaders recommending individualized therapy based on the age and body weight of patients, the presence or absence of complications, and duration and aetiology of disease.

International Diabetes Federation. IDF Diabetes Atlas 6th Edition. IDF [online] , (2013).

Hu, F. B. Globalization of diabetes: the role of diet, lifestyle, and genes. Diabetes Care 34 , 1249–1257 (2011). An important study emphasizing the role of diet, physical activity and genes — beyond obesity — in the diabetes epidemic that is engulfing Asian countries as they are exposed to westernization.

Chan, J. C. et al . Diabetes in Asia: epidemiology, risk factors, and pathophysiology. JAMA 301 , 2129–2140 (2009).

Ley, S. H., Hamdy, O., Mohan, V. & Hu, F. B. Prevention and management of type 2 diabetes: dietary components and nutritional strategies. Lancet 383 , 1999–2007 (2014).

Grøntved, A., Rimm, E. B., Willett, W. C., Andersen, L. B. & Hu, F. B. A prospective study of weight training and risk of type 2 diabetes mellitus in men. Arch. Intern. Med. 172 , 1306–1312 (2012).

Grøntved, A. & Hu, F. B. Television viewing and risk of type 2 diabetes, cardiovascular disease, and all-cause mortality: a meta-analysis. JAMA 305 , 2448–2455 (2011).

Cappuccio, F. P., D'Elia, L., Strazzullo, P. & Miller, M. A. Quantity and quality of sleep and incidence of type 2 diabetes: a systematic review and meta-analysis. Diabetes Care 33 , 414–420 (2009).

Pan, A., Schernhammer, E. S., Sun, Q. & Hu, F. B. Rotating night shift work and risk of type 2 diabetes: two prospective cohort studies in women. PLoS Med. 8 , e1001141 (2011).

Barnett, A. H., Eff, C., Leslie, R. D. & Pyke, D. A. Diabetes in identical twins. A study of 200 pairs. Diabetologia 20 , 87–93 (1981).

Wang, Y. C., McPherson, K., Marsh, T., Gortmaker, S. L. & Brown, M. Health and economic burden of the projected obesity trends in the USA and the UK. Lancet 378 , 815–825 (2011).

Wang, X. et al . Inflammatory markers and risk of type 2 diabetes: a systematic review and meta-analysis. Diabetes Care 36 , 166–175 (2013).

Li, S., Shin, H. J., Ding, E. L. & van Dam, R. M. Adiponectin levels and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA 302 , 179–188 (2009).

Ding, E. L. et al . Sex hormone-binding globulin and risk of type 2 diabetes in women and men. N. Engl. J. Med. 361 , 1152–1163 (2009).

Wang, T. J. et al . Metabolite profiles and the risk of developing diabetes. Nat. Med. 17 , 448–453 (2011).

Esteve, E., Ricart, W. & Fernández-Real, J.-M. Gut microbiota interactions with obesity, insulin resistance and type 2 diabetes: did gut microbiote co-evolve with insulin resistance? Curr. Opin. Clin. Nutr. Metab. Care 14 , 483–490 (2011).

Hu, F. B. et al . Diet, lifestyle, and the risk of type 2 diabetes mellitus in women. N. Engl. J. Med. 345 , 790–797 (2001).

Schellenberg, E. S., Dryden, D. M., Vandermeer, B., Ha, C. & Korownyk, C. Lifestyle interventions for patients with and at risk for type 2 diabetes. Ann. Intern. Med. 159 , 543–551 (2013). A comprehensive review of the effectiveness of lifestyle intervention in the treatment of T2DM, emphasizing that, although initially successful, most subjects with diabetes regain the majority of lost weight over the subsequent 3–5 years.

DeFronzo, R. A. Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links. The Claude Bernard Lecture 2009. Diabetologia 53 , 1270–1287 (2010). A comprehensive review describing the role of excess tissue lipid deposition in the development of insulin resistance, β-cell failure and atherosclerotic cardiovascular disease: that is, lipotoxicity.

Hemminki, K., Li, X., Sundquist, K. & Sundquist, J. Familial risks for type 2 diabetes in Sweden. Diabetes Care 33 , 293–297 (2010).

Groop, L. et al . Metabolic consequences of a family history of NIDDM (the Botnia study): evidence for sex-specific parental effects. Diabetes 45 , 1585–1593 (1996).

Lyssenko, V. et al . Predictors of and longitudinal changes in insulin sensitivity and secretion preceding onset of type 2 diabetes. Diabetes 54 , 166–174 (2005).

Grant, S. F. et al . Variant of transcription factor 7-like 2 ( TCF7L2 ) gene confers risk of type 2 diabetes. Nat. Genet. 38 , 320–323 (2006).

Lyssenko, V. et al . Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes. J. Clin. Invest. 117 , 2155–2163 (2007).

Sladek, R. et al . A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 445 , 881–885 (2007).

Saxena, R. et al . Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316 , 1331–1336 (2007).

Morris, A. P. et al . Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat. Genet. 44 , 981–990 (2012).

Flannick, J. et al . Loss-of-function mutations in SLC30A8 protect against type 2 diabetes. Nat. Genet. 46 , 357–363 (2014).

Lyssenko, V. et al . Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion. Nat. Genet. 41 , 82–88 (2009).

Rosengren, A. H. et al . Overexpression of alpha2A-adrenergic receptors contributes to type 2 diabetes. Science 327 , 217–220 (2010).

Tang, Y. et al . Genotype-based treatment of type 2 diabetes with an α2A-adrenergic receptor antagonist. Sci. Transl Med. 6 , 257ra139 (2014). These paper provides an example in which a genetic finding in an animal model of diabetes has been translated into a drug target in humans, the ADRA2A gene.

De Jesus, D. F. & Kulkarni, R. N. Epigenetic modifiers of islet function and mass. Trends Endocrinol. Metab. 25 , 628–636 (2014).

Ozcan, S. Minireview: microRNA function in pancreatic β cells. Mol. Endocrinol. 28 , 1922–1933 (2014).

Lyssenko, V. et al . Clinical risk factors, DNA variants, and the development of type 2 diabetes. N. Engl. J. Med. 359 , 2220–2232 (2008). This paper presents a genetic explanation for the development of T2DM.

Travers, M. E. et al . Insights into the molecular mechanism for type 2 diabetes susceptibility at the KCNQ1 locus from temporal changes in imprinting status in human islets. Diabetes 62 , 987–992 (2013).

Gulli, G., Ferrannini, E., Stern, M., Haffner, S. & DeFronzo, R. A. The metabolic profile of NIDDM is fully established in glucose-tolerant offspring of two Mexican-American NIDDM parents. Diabetes 41 , 1575–1586 (1992).

Martin, B. C. et al . Role of glucose and insulin resistance in development of type 2 diabetes mellitus: results of a 25-year follow-up study. Lancet 340 , 925–929 (1992).

Ferrannini, E. & Mari, A. β-cell function in type 2 diabetes. Metabolism 63 , 1217–1227 (2014).

Kahn, S. E., Cooper, M. E. & Del Prato, S. Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future. Lancet 383 , 1068–1083 (2014).

Muller, D. C., Elahi, D., Tobin, J. D. & Andres, R. Insulin response during the oral glucose tolerance test: the role of age, sex, body fat and the pattern of fat distribution. Aging (Milano) 8 , 13–21 (1996).

CAS   Google Scholar  

Nauck, M. A., Vardarli, I., Deacon, C. F., Holst, J. J. & Meier, J. J. Secretion of glucagon-like peptide-1 (GLP-1) in type 2 diabetes: what is up, what is down? Diabetologia 54 , 10–18 (2011).

Madsbad, S. The role of glucagon-like peptide-1 impairment in obesity and potential therapeutic implications. Diabetes Obes. Metab. 16 , 9–21 (2014).

Bays, H., Mandarino, L. & DeFronzo, R. A. Role of the adipocyte, free fatty acids, and ectopic fat in pathogenesis of type 2 diabetes mellitus: peroxisomal proliferator-activated receptor agonists provide a rational therapeutic approach. J. Clin. Endocrinol. Metab. 89 , 463–478 (2004).

Perry, R. J., Samuel, V. T., Petersen, K. F. & Shulman, G. I. The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes. Nature 510 , 84–91 (2014). An excellent review of the specific lipid varieties and the molecular events through which they cause insulin resistance in the liver.

Bensellam, M., Laybutt, D. R. & Jonas, J.-C. The molecular mechanisms of pancreatic β-cell glucotoxicity: recent findings and future research directions. Mol. Cell. Endocrinol. 364 , 1–27 (2012).

Ritzel, R. A., Meier, J. J., Lin, C.-Y., Veldhuis, J. D. & Butler, P. C. Human islet amyloid polypeptide oligomers disrupt cell coupling, induce apoptosis, and impair insulin secretion in isolated human islets. Diabetes 56 , 65–71 (2007).

Collins, S., Pi, J. & Yehuda-Shnaidman, E. Uncoupling and reactive oxygen species (ROS) — a double-edged sword for β-cell function? “Moderation in all things”. Best Pract. Res. Clin. Endocrinol. Metab. 26 , 753–758 (2012).

Cabrera, O. et al . The unique cytoarchitecture of human pancreatic islets has implications for islet cell function. Proc. Natl Acad. Sci. USA 103 , 2334–2339 (2006).

Hodson, D. J. et al . Lipotoxicity disrupts incretin-regulated human β cell connectivity. J. Clin. Invest. 123 , 4182–4194 (2013).

Brandhorst, H., Brandhorst, D., Brendel, M. D., Hering, B. J. & Bretzel, R. G. Assessment of intracellular insulin content during all steps of human islet isolation procedure. Cell Transplant. 7 , 489–495 (1998).

Rahier, J., Guiot, Y., Goebbels, R. M., Sempoux, C. & Henquin, J. C. Pancreatic β-cell mass in European subjects with type 2 diabetes. Diabetes Obes. Metab. 10 (Suppl. 4), 32–42 (2008). A post-mortem study demonstrating a decline in β-cell mass with preservation of α-cell mass in individuals with T2DM.

Marselli, L. et al . Are we overestimating the loss of beta cells in type 2 diabetes? Diabetologia 57 , 362–365 (2014).

Marchetti, P. et al . The endoplasmic reticulum in pancreatic beta cells of type 2 diabetes patients. Diabetologia 50 , 2486–2494 (2007).

Marchetti, P. & Masini, M. Autophagy and the pancreatic beta-cell in human type 2 diabetes. Autophagy 5 , 1055–1056 (2009).

Gupta, D. & Leahy, J. L. Islet amyloid and type 2 diabetes: overproduction or inadequate clearance and detoxification? J. Clin. Invest. 124 , 3292–3294 (2014).

Mezza, T. et al . Insulin resistance alters islet morphology in nondiabetic humans. Diabetes 63 , 994–1007 (2014). This work in human islets describes the impact of insulin resistance on the relative proportion of α-cells and β-cells, and the functional consequences — in terms of insulin and glucagon secretion — of this chronic adaptation.

Deng, S. et al . Structural and functional abnormalities in the islets isolated from type 2 diabetic subjects. Diabetes 53 , 624–632 (2004).

Igoillo-Esteve, M. et al . Palmitate induces a pro-inflammatory response in human pancreatic islets that mimics CCL2 expression by beta cells in type 2 diabetes. Diabetologia 53 , 1395–1405 (2010).

Giacca, A., Xiao, C., Oprescu, A. I., Carpentier, A. C. & Lewis, G. F. Lipid-induced pancreatic β-cell dysfunction: focus on in vivo studies. Am. J. Physiol. Endocrinol. Metab. 300 , E255–E262 (2010).

Halban, P. A. et al . β-cell failure in type 2 diabetes: postulated mechanisms and prospects for prevention and treatment. J. Clin. Endocrinol. Metab. 99 , 1983–1992 (2014).

Ferrannini, E. et al . Natural history and physiological determinants of changes in glucose tolerance in a non-diabetic population: the RISC Study. Diabetologia 54 , 1507–1516 (2011). This longitudinal study of non-diabetic subjects identifies baseline insulin resistance and β-cell dysfunction as predictors of future dysglycaemia.

Michaliszyn, S. F. et al . β-cell function, incretin effect, and incretin hormones in obese youth along the span of glucose tolerance from normal to prediabetes to type 2 diabetes. Diabetes 63 , 3846–3855 (2014).

Mari, A. et al . Mechanisms of the incretin effect in subjects with normal glucose tolerance and patients with type 2 diabetes. PLoS ONE 8 , e73154 (2013).

Holst, J. J., Knop, F. K., Vilsbøll, T., Krarup, T. & Madsbad, S. Loss of incretin effect is a specific, important, and early characteristic of type 2 diabetes. Diabetes Care 34 , S251–S257 (2011).

Camastra, S. et al . Long-term effects of bariatric surgery on meal disposal and β-cell function in diabetic and nondiabetic patients. Diabetes 62 , 3709–3717 (2013).

Ferrannini, E. The stunned β cell: a brief history. Cell Metab. 11 , 349–352 (2010).

Shulman, G. I. et al . Quantitation of muscle glycogen synthesis in normal subjects and subjects with non-insulin-dependent diabetes by 13C nuclear magnetic resonance spectroscopy. N. Engl. J. Med. 322 , 223–228 (1990). This study demonstrated that defects in insulin-stimulated muscle glycogen synthesis was the major factor responsible for whole-body insulin resistance in patients with T2DM.

Groop, L. C. et al . Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus. Evidence for multiple sites of insulin resistance. J. Clin. Invest. 84 , 205–213 (1989).

Guilherme, A., Virbasius, J. V., Puri, V. & Czech, M. P. Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Nat. Rev. Mol. Cell Biol. 9 , 367–377 (2008).

Gerich, J. E., Meyer, C., Woerle, H. J. & Stumvoll, M. Renal gluconeogenesis: its importance in human glucose homeostasis. Diabetes Care 24 , 382–391 (2001).

Honka, H. et al . Validation of [ 18 F]fluorodeoxyglucose and positron emission tomography (PET) for the measurement of intestinal metabolism in pigs, and evidence of intestinal insulin resistance in patients with morbid obesity. Diabetologia 56 , 893–900 (2013).

Meijer, R. I. et al . Insulin-induced microvascular recruitment in skin and muscle are related and both are associated with whole-body glucose uptake. Microcirculation 19 , 494–500 (2012).

Blázquez, E., Velázquez, E., Hurtado-Carneiro, V. & Ruiz-Albusac, J. M. Insulin in the brain: its pathophysiological implications for states related with central insulin resistance, type 2 diabetes and Alzheimer's disease. Front. Endocrinol. (Lausanne) 5 , 161 (2014).

Kleinridders, A., Ferris, H. A., Cai, W. & Kahn, C. R. Insulin action in brain regulates systemic metabolism and brain function. Diabetes 63 , 2232–2243 (2014).

Kulkarni, R. N. et al . Tissue-specific knockout of the insulin receptor in pancreatic β cells creates an insulin secretory defect similar to that in type 2 diabetes. Cell 96 , 329–339 (1999). An insightful study documenting that β-cell-specific insulin receptor knockout results in markedly impaired insulin secretion and overt diabetes, thereby providing a unifying mechanism whereby insulin resistance explains both the defects in insulin-stimulated tissue glucose uptake and decreased insulin secretion.

Oliveira, J. M., Rebuffat, S. A., Gasa, R. & Gomis, R. Targeting type 2 diabetes: lessons from a knockout model of insulin receptor substrate 2. Can. J. Physiol. Pharmacol. 92 , 613–620 (2014).

Samuel, V. T. & Shulman, G. I. Mechanisms for insulin resistance: common threads and missing links. Cell 148 , 852–871 (2012). An excellent review of the molecular mechanism responsible for insulin resistance in T2DM and obesity.

Magnusson, I., Rothman, D. L., Katz, L. D., Shulman, R. G. & Shulman, G. I. Increased rate of gluconeogenesis in type II diabetes mellitus. A 13C nuclear magnetic resonance study. J. Clin. Invest. 90 , 1323–1327 (1992). This study demonstrated that increased rates of hepatic glucose production in patients with poorly controlled T2DM could entirely be attributed to increased rates of gluconeogenesis.

Matsuda, M. et al . Glucagon dose-response curve for hepatic glucose production and glucose disposal in type 2 diabetic patients and normal individuals. Metabolism 51 , 1111–1119 (2002).

Samuel, V. T. et al . Fasting hyperglycemia is not associated with increased expression of PEPCK or G6Pc in patients with type 2 diabetes. Proc. Natl Acad. Sci. USA 106 , 12121–12126 (2009).

Baron, A. D., Schaeffer, L., Shragg, P. & Kolterman, O. G. Role of hyperglucagonemia in maintenance of increased rates of hepatic glucose output in type II diabetics. Diabetes 36 , 274–283 (1987).

DeFronzo, R. A., Ferrannini, E., Hendler, R., Wahren, J. & Felig, P. Influence of hyperinsulinemia, hyperglycemia, and the route of glucose administration on splanchnic glucose exchange. Proc. Natl Acad. Sci. USA 75 , 5173–5177 (1978).

Ferrannini, E. et al . The disposal of an oral glucose load in patients with non-insulin-dependent diabetes. Metabolism 37 , 79–85 (1988).

DeFronzo, R. A. et al . Characterization of renal glucose reabsorption in response to dapagliflozin in healthy subjects and subjects with type 2 diabetes. Diabetes Care 36 , 3169–3176 (2013).

Barrett, E. J., Wang, H., Upchurch, C. T. & Liu, Z. Insulin regulates its own delivery to skeletal muscle by feed-forward actions on the vasculature. Am. J. Physiol. Endocrinol. Metab. 301 , E252–E263 (2011).

Baron, A. D. Hemodynamic actions of insulin. Am. J. Physiol. 267 , E187–E202 (1994).

CAS   PubMed   Google Scholar  

Krüger, M. et al . Dissection of the insulin signaling pathway via quantitative phosphoproteomics. Proc. Natl Acad. Sci. USA 105 , 2451–2456 (2008).

Cusi, K. et al . Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle. J. Clin. Invest. 105 , 311–320 (2000). The first study in humans with T2DM to demonstrate impaired insulin signal transduction through the IRS1–PI3K pathway in muscle, with normal to increased insulin signalling through the MAPK pathway.

Krook, A. et al . Characterization of signal transduction and glucose transport in skeletal muscle from type 2 diabetic patients. Diabetes 49 , 284–292 (2000).

Copps, K. D. & White, M. F. Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2. Diabetologia 55 , 2565–2582 (2012).

Bouzakri, K. et al . IRS-1 serine phosphorylation and insulin resistance in skeletal muscle from pancreas transplant recipients. Diabetes 55 , 785–791 (2006).

Hiratani, K. et al . Roles of mTOR and JNK in serine phosphorylation, translocation, and degradation of IRS-1. Biochem. Biophys. Res. Commun. 335 , 836–842 (2005).

Krssak, M. et al . Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study. Diabetologia 42 , 113–116 (1999).

Petersen, K. F. et al . Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J. Clin. Invest. 109 , 1345–1350 (2002).

Petersen, K. F. et al . Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes. Diabetes 54 , 603–608 (2005).

Lara-Castro, C. & Garvey, W. T. Intracellular lipid accumulation in liver and muscle and the insulin resistance syndrome. Endocrinol. Metab. Clin. North Am. 37 , 841–856 (2008).

Yu, C. et al . Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle. J. Biol. Chem. 277 , 50230–50236 (2002).

Bezy, O. et al . PKCδ regulates hepatic insulin sensitivity and hepatosteatosis in mice and humans. J. Clin. Invest. 121 , 2504–2517 (2011).

Samuel, V. T. et al . Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. J. Biol. Chem. 279 , 32345–32353 (2004).

Samuel, V. T. et al . Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease. J. Clin. Invest. 117 , 739–745 (2007).

Choi, C. S. et al . Suppression of diacylglycerol acyltransferase-2 ( DGAT2 ), but not DGAT1 , with antisense oligonucleotides reverses diet-induced hepatic steatosis and insulin resistance. J. Biol. Chem. 282 , 22678–22688 (2007).

Morino, K. et al . Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents. J. Clin. Invest. 115 , 3587–3593 (2005).

Szendroedi, J. et al . Role of diacylglycerol activation of PKCθ in lipid-induced muscle insulin resistance in humans. Proc. Natl Acad. Sci. USA 111 , 9597–9602 (2014).

Larsen, P. J. & Tennagels, N. On ceramides, other sphingolipids and impaired glucose homeostasis. Mol. Metab. 3 , 252–260 (2014).

Turpin, S. M. et al . Obesity-induced CerS6-dependent C16:0 ceramide production promotes weight gain and glucose intolerance. Cell Metab. 20 , 678–686 (2014).

Cantley, J. L. et al . CGI-58 knockdown sequesters diacylglycerols in lipid droplets/ER-preventing diacylglycerol-mediated hepatic insulin resistance. Proc. Natl Acad. Sci. USA 110 , 1869–1874 (2013).

Patti, M.-E. & Corvera, S. The role of mitochondria in the pathogenesis of type 2 diabetes. Endocr. Rev. 31 , 364–395 (2010). Mitochondrial dysfunction as a causative factor in the development of insulin resistance in T2DM is reviewed.

Ritov, V. B. et al . Deficiency of subsarcolemmal mitochondria in obesity and type 2 diabetes. Diabetes 54 , 8–14 (2005).

Petersen, K. F. et al . Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science 300 , 1140–1142 (2003).

Petersen, K. F., Dufour, S., Befroy, D., Garcia, R. & Shulman, G. I. Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N. Engl. J. Med. 350 , 664–671 (2004).

Mogensen, M. et al . Mitochondrial respiration is decreased in skeletal muscle of patients with type 2 diabetes. Diabetes 56 , 1592–1599 (2007).

Petersen, K. F., Dufour, S. & Shulman, G. I. Decreased insulin-stimulated ATP synthesis and phosphate transport in muscle of insulin-resistant offspring of type 2 diabetic parents. PLoS Med. 2 , e233 (2005).

Wang, C.-H., Wang, C.-C., Huang, H.-C. & Wei, Y.-H. Mitochondrial dysfunction leads to impairment of insulin sensitivity and adiponectin secretion in adipocytes. FEBS J. 280 , 1039–1050 (2013).

Rains, J. L. & Jain, S. K. Oxidative stress, insulin signaling, and diabetes. Free Radic. Biol. Med. 50 , 567–575 (2011).

Morino, K. et al . Regulation of mitochondrial biogenesis by lipoprotein lipase in muscle of insulin-resistant offspring of parents with type 2 diabetes. Diabetes 61 , 877–887 (2012).

Romeo, G. R., Lee, J. & Shoelson, S. E. Metabolic syndrome, insulin resistance, and roles of inflammation — mechanisms and therapeutic targets. Arterioscler. Thromb. Vasc. Biol. 32 , 1771–1776 (2012).

Arkan, M. C. et al . IKK-β links inflammation to obesity-induced insulin resistance. Nat. Med. 11 , 191–198 (2005).

De Alvaro, C., Teruel, T., Hernandez, R. & Lorenzo, M. Tumor necrosis factor α produces insulin resistance in skeletal muscle by activation of inhibitor κB kinase in a p38 MAPK-dependent manner. J. Biol. Chem. 279 , 17070–17078 (2004).

Howard, J. K. & Flier, J. S. Attenuation of leptin and insulin signaling by SOCS proteins. Trends Endocrinol. Metab. 17 , 365–371 (2006).

Lebrun, P. & Van Obberghen, E. SOCS proteins causing trouble in insulin action. Acta Physiol. (Oxf.) 192 , 29–36 (2008).

Article   CAS   Google Scholar  

Uysal, K. T., Wiesbrock, S. M. & Hotamisligil, G. S. Functional analysis of tumor necrosis factor (TNF) receptors in TNF-α-mediated insulin resistance in genetic obesity. Endocrinology 139 , 4832–4838 (1998).

Ofei, F., Hurel, S., Newkirk, J., Sopwith, M. & Taylor, R. Effects of an engineered human anti-TNF-α antibody (CDP571) on insulin sensitivity and glycemic control in patients with NIDDM. Diabetes 45 , 881–885 (1996).

Kim, J. K. et al . Prevention of fat-induced insulin resistance by salicylate. J. Clin. Invest. 108 , 437–446 (2001).

Yuan, M. et al . Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of IKK β. Science 293 , 1673–1677 (2001).

Goldfine, A. B. et al . The effects of salsalate on glycemic control in patients with type 2 diabetes: a randomized trial. Ann. Intern. Med. 152 , 346–357 (2010).

Lumeng, C. N. & Saltiel, A. R. Inflammatory links between obesity and metabolic disease. J. Clin. Invest. 121 , 2111–2117 (2011).

Nishimura, S. et al . CD8 + effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat. Med. 15 , 914–920 (2009).

Feuerer, M. et al . Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat. Med. 15 , 930–939 (2009).

Bertola, A. et al . Identification of adipose tissue dendritic cells correlated with obesity-associated insulin-resistance and inducing Th17 responses in mice and patients. Diabetes 61 , 2238–2247 (2012).

Cai, D. et al . Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-κB. Nat. Med. 11 , 183–190 (2005).

Perry, R. J. et al . Hepatic acetyl CoA links adipose tissue inflammation to hepatic insulin resistance and type 2 diabetes. Cell 160 , 745–758 (2015).

Mori, M. A. et al . A systems biology approach identifies inflammatory abnormalities between mouse strains prior to development of metabolic disease. Diabetes 59 , 2960–2971 (2010).

Mauer, J. et al . Myeloid cell-restricted insulin receptor deficiency protects against obesity-induced inflammation and systemic insulin resistance. PLoS Genet. 6 , e1000938 (2010).

Shi, H. et al . TLR4 links innate immunity and fatty acid-induced insulin resistance. J. Clin. Invest. 116 , 3015–3025 (2006).

Ron, D. & Walter, P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat. Rev. Mol. Cell Biol. 8 , 519–529 (2007).

Boden, G. et al . Increase in endoplasmic reticulum stress-related proteins and genes in adipose tissue of obese, insulin-resistant individuals. Diabetes 57 , 2438–2444 (2008).

Eizirik, D. L., Cardozo, A. K. & Cnop, M. The role for endoplasmic reticulum stress in diabetes mellitus. Endocr. Rev. 29 , 42–61 (2008). A comprehensive review of ER stress and the UPR in the development of insulin resistance and obesity.

Gregor, M. F. et al . Endoplasmic reticulum stress is reduced in tissues of obese subjects after weight loss. Diabetes 58 , 693–700 (2009).

Ozawa, K. et al . The endoplasmic reticulum chaperone improves insulin resistance in type 2 diabetes. Diabetes 54 , 657–663 (2005).

Herschkovitz, A. et al . Common inhibitory serine sites phosphorylated by IRS-1 kinases, triggered by insulin and inducers of insulin resistance. J. Biol. Chem. 282 , 18018–18027 (2007).

Boden, G. Endoplasmic reticulum stress: another link between obesity and insulin resistance/inflammation? Diabetes 58 , 518–519 (2009).

Sengupta, S., Peterson, T. R. & Sabatini, D. M. Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress. Mol. Cell 40 , 310–322 (2010).

Shah, O. J., Wang, Z. & Hunter, T. Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies. Curr. Biol. 14 , 1650–1656 (2004).

Ozcan, U. et al . Loss of the tuberous sclerosis complex tumor suppressors triggers the unfolded protein response to regulate insulin signaling and apoptosis. Mol. Cell 29 , 541–551 (2008).

Park, S. W. et al . The regulatory subunits of PI3K, p85α and p85β, interact with XBP-1 and increase its nuclear translocation. Nat. Med. 16 , 429–437 (2010).

Stratton, I. M. et al . Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 321 , 405–412 (2000). A seminal UK Prospective Diabetes Study study unequivocally demonstrating that improved glycaemic control reduced the incidence of microvascular, and to a lesser extent, macrovascular complications in patients with T2DM.

Holman, R. R., Paul, S. K., Bethel, M. A., Matthews, D. R. & Neil, H. A. 10-year follow-up of intensive glucose control in type 2 diabetes. N. Engl. J. Med. 359 , 1577–1589 (2008). A long-term follow-up of the UK Prospective Diabetes Study showing that early intensive glycaemic control has a persistent impact on preventing both microvascular and macrovascular complications long after initiation of the intensified antidiabetic regimen has been discontinued: that is, the ‘legacy effect’.

Brownlee, M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes 54 , 1615–1625 (2005). A lucid discussion of the molecular pathways involved in the development of diabetic microvascular complications.

Giacco, F. & Brownlee, M. Oxidative stress and diabetic complications. Circ. Res. 107 , 1058–1070 (2010).

Coutinho, M., Gerstein, H. C., Wang, Y. & Yusuf, S. The relationship between glucose and incident cardiovascular events. A metaregression analysis of published data from 20 studies of 95,783 individuals followed for 12.4 years. Diabetes Care 22 , 233–240 (1999).

Taskinen, M.-R. & Borén, J. New insights into the pathophysiology of dyslipidemia in type 2 diabetes. Atherosclerosis 239 , 483–495 (2015). An up-to-date review of the pathogenesis of diabetic dyslipidaemia and its treatment.

Isomaa, B. et al . Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 24 , 683–689 (2001).

Adler, A. I. et al . Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ 321 , 412–419 (2000).

Williams, B. Treating hypertension in patients with diabetes: when to start and how low to go? JAMA 313 , 573–574 (2015). The optimal blood pressure goal in hypertensive patients with T2DM is discussed in light of the controversial results observed in the blood pressure arm of the ACCORD trial.

Lastra, G., Syed, S., Kurukulasuriya, L. R., Manrique, C. & Sowers, J. R. Type 2 diabetes mellitus and hypertension: an update. Endocrinol. Metab. Clin. North Am. 43 , 103–122 (2014).

International Expert Committee. International Expert Committee report on the role of the A1C assay in the diagnosis of diabetes. Diabetes Care 32 , 1327–1334 (2009).

[No authors listed.] Report of the Expert Committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 20 , 1183–1197 (1997). A reference publication by the ADA on the diagnosis and classification of diabetes mellitus.

Herman, W. H. Diabetes epidemiology: guiding clinical and public health practice: the Kelly West Award Lecture, 2006. Diabetes Care 30 , 1912–1919 (2007). A landmark lecture providing a comprehensive overview of the epidemiology of T2DM and the public health implications for diabetes prevention.

DECODE Study Group, European Diabetes Epidemiology Group. Is the current definition for diabetes relevant to mortality risk from all causes and cardiovascular and noncardiovascular diseases? Diabetes Care 26 , 688–696 (2003).

Engelgau, M. M., Narayan, K. M. & Herman, W. H. Screening for type 2 diabetes. Diabetes Care 23 , 1563–1580 (2000).

LeFevre, M. L. Behavioral counseling to promote a healthful diet and physical activity for cardiovascular disease prevention in adults with cardiovascular risk factors: U.S. Preventive Services Task Force Recommendation Statement. Ann. Intern. Med. 161 , 587–593 (2014).

Lindström, J. & Tuomilehto, J. The diabetes risk score: a practical tool to predict type 2 diabetes risk. Diabetes Care 26 , 725–731 (2003).

Tabaei, B. P. & Herman, W. H. A multivariate logistic regression equation to screen for diabetes: development and validation. Diabetes Care 25 , 1999–2003 (2002).

World Health Organization. Definition, diagnosis and classification of diabetes mellitus and its complications. report of a WHO consultation. Part 1: diagnosis and classification of diabetes mellitus (WHO, 1999).

Pan, X. R. et al . Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT Diabetes Study. Diabetes Care 20 , 537–544 (1997).

Knowler, W. C. et al . Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N. Engl. J. Med. 346 , 393–403 (2002).

Ramachandran, A. et al . The Indian Diabetes Prevention Programme shows that lifestyle modification and metformin prevent type 2 diabetes in Asian Indian subjects with impaired glucose tolerance (IDPP-1). Diabetologia 49 , 289–297 (2006).

Chiasson, J.-L. et al . Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet 359 , 2072–2077 (2002).

Kawamori, R. et al . Voglibose for prevention of type 2 diabetes mellitus: a randomised, double-blind trial in Japanese individuals with impaired glucose tolerance. Lancet 373 , 1607–1614 (2009).

Knowler, W. C. et al . Prevention of type 2 diabetes with troglitazone in the Diabetes Prevention Program. Diabetes 54 , 1150–1156 (2005).

Gerstein, H. C. et al . Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet 368 , 1096–1105 (2006).

Li, G. et al . The long-term effect of lifestyle interventions to prevent diabetes in the China Da Qing Diabetes Prevention Study: a 20-year follow-up study. Lancet 371 , 1783–1789 (2008).

Lindström, J. et al . Sustained reduction in the incidence of type 2 diabetes by lifestyle intervention: follow-up of the Finnish Diabetes Prevention Study. Lancet 368 , 1673–1679 (2006).

Knowler, W. C. et al . 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet 374 , 1677–1686 (2009). Long-term follow-up of body weight regain and diabetes incidence in patients with IGT in the Diabetes Prevention Program treated with lifestyle heavy, lifestyle light and metformin, showing that gradual weight regain is the norm and that 40–50% of patients with IGT develop diabetes despite successful weight loss.

DeFronzo, R. A., Eldor, R. & Abdul-Ghani, M. Pathophysiologic approach to therapy in patients with newly diagnosed type 2 diabetes. Diabetes Care 36 , S127–S138 (2013). A rational approach to the treatment of T2DM is presented based on its pathophysiology.

Raz, I. et al . Personalized management of hyperglycemia in type 2 diabetes: reflections from a Diabetes Care Editors’ Expert Forum. Diabetes Care 36 , 1779–1788 (2013).

Nakagami, T., Kawahara, R., Hori, S. & Omori, Y. Glycemic control and prevention of retinopathy in Japanese NIDDM patients. A 10-year follow-up study. Diabetes Care 20 , 621–622 (1997).

Lim, E. L. et al . Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol. Diabetologia 54 , 2506–2514 (2011).

Jazet, I. M. et al . Loss of 50% of excess weight using a very low energy diet improves insulin-stimulated glucose disposal and skeletal muscle insulin signalling in obese insulin-treated type 2 diabetic patients. Diabetologia 51 , 309–319 (2008).

Abdul-Ghani, M. A. et al . Initial combination therapy with metformin, pioglitazone and exenatide is more effective than sequential add-on therapy in subjects with new-onset diabetes. Results from the Efficacy and Durability of Initial Combination Therapy for Type 2 Diabetes (EDICT): a randomized trial. Diabetes Obes. Metab. 17 , 268–275 (2015). This prospective randomized trial using a combination of antidiabetic agents proven to reverse known pathophysiological abnormalities in T2DM demonstrated superiority of glycaemic control compared with the stepped approach of metformin followed by a sulfonylurea and then basal insulin recommended by most national diabetes organizations.

Harrison, L. B., Adams-Huet, B., Raskin, P. & Lingvay, I. β-cell function preservation after 3.5 years of intensive diabetes therapy. Diabetes Care 35 , 1406–1412 (2012).

Gram, J. et al . Pharmacological treatment of the pathogenetic defects in type 2 diabetes: the randomized multicenter South Danish Diabetes Study. Diabetes Care 34 , 27–33 (2011).

DeFronzo, R. A. et al . Combination of empagliflozin and linagliptin as second-line therapy in subjects with type 2 diabetes inadequately controlled on metformin. Diabetes Care 38 , 384–393 (2015).

Weng, J. et al . Effect of intensive insulin therapy on β-cell function and glycaemic control in patients with newly diagnosed type 2 diabetes: a multicentre randomised parallel-group trial. Lancet 371 , 1753–1760 (2008).

Hu, Y. et al . Short-term intensive therapy in newly diagnosed type 2 diabetes partially restores both insulin sensitivity and β-cell function in subjects with long-term remission. Diabetes Care 34 , 1848–1853 (2011). One of several recent studies demonstrating that intensive insulin therapy to correct the decompensated metabolic state in newly diagnosed patients with T2DM can lead to durable glycaemic control without or with a marked reduction in antidiabetic medications.

Xiang, A. H. et al . Effect of pioglitazone on pancreatic β-cell function and diabetes risk in Hispanic women with prior gestational diabetes. Diabetes 55 , 517–522 (2006).

Astrup, A. et al . Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide. Int. J. Obes. (Lond.) 36 , 843–854 (2012).

Cusi, K., Consoli, A. & DeFronzo, R. A. Metabolic effects of metformin on glucose and lactate metabolism in noninsulin-dependent diabetes mellitus. J. Clin. Endocrinol. Metab. 81 , 4059–4067 (1996).

Turner, R. C., Cull, C. A., Frighi, V. & Holman, R. R. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group. JAMA 281 , 2005–2012 (1999). A landmark UK Prospective Diabetes Study documenting the need for progressive add-on therapies in newly diagnosed patients with T2DM receiving initial therapy with metformin or with a sulfonylurea.

Brown, J. B., Conner, C. & Nichols, G. A. Secondary failure of metformin monotherapy in clinical practice. Diabetes Care 33 , 501–506 (2010).

Kahn, S. E. et al . Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N. Engl. J. Med. 355 , 2427–2443 (2006). A 5-year ADOPT study demonstrating long-term durable HbA1c reduction with rosiglitazone compared with a progressive rise in HbA1c observed with metformin and sulfonylureas, and a more rapid deterioration of glycaemic control with sulfonylureas compared with metformin.

Madiraju, A. K. et al . Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature 510 , 542–546 (2014).

Ferrannini, E. The target of metformin in type 2 diabetes. N. Engl. J. Med. 371 , 1547–1548 (2014).

[No authors listed.] Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 352 , 854–865 (1998).

Maedler, K. et al . Sulfonylurea induced β-cell apoptosis in cultured human islets. J. Clin. Endocrinol. Metab. 90 , 501–506 (2005).

Roumie, C. L. et al . Comparative effectiveness of sulfonylurea and metformin monotherapy on cardiovascular events in type 2 diabetes mellitus: a cohort study. Ann. Intern. Med. 157 , 601–610 (2012).

Simpson, S. H., Majumdar, S. R., Tsuyuki, R. T., Eurich, D. T. & Johnson, J. A. Dose–response relation between sulfonylurea drugs and mortality in type 2 diabetes mellitus: a population-based cohort study. CMAJ 174 , 169–174 (2006).

Simpson, S. H. et al . Mortality risk among sulfonylureas: a systematic review and network meta-analysis. Lancet Diabetes Endocrinol. 3 , 43–51 (2015). A review of the published literature that examines the relationship between sulfonylurea therapy and the development of adverse cardiovascular events.

Yki-Järvinen, H. Thiazolidinediones. N. Engl. J. Med. 351 , 1106–1118 (2004).

Eldor, R., DeFronzo, R. A. & Abdul-Ghani, M. In vivo actions of peroxisome proliferator-activated receptors: glycemic control, insulin sensitivity, and insulin secretion. Diabetes Care 36 , S162–S174 (2013). An exhaustive review of the mechanism of action, efficacy and side-effect profile of the thiazolidinedione class of antidiabetic medications.

Miyazaki, Y., He, H., Mandarino, L. J. & DeFronzo, R. A. Rosiglitazone improves downstream insulin receptor signaling in type 2 diabetic patients. Diabetes 52 , 1943–1950 (2003).

Gastaldelli, A. et al . Thiazolidinediones improve β-cell function in type 2 diabetic patients. Am. J. Physiol. Endocrinol. Metab. 292 , E871–E883 (2007).

DeFronzo, R. A. et al . Prevention of diabetes with pioglitazone in ACT NOW: physiologic correlates. Diabetes 62 , 3920–3926 (2013).

Kahn, S. E. et al . Effects of rosiglitazone, glyburide, and metformin on β-cell function and insulin sensitivity in ADOPT. Diabetes 60 , 1552–1560 (2011).

Dormandy, J. A. et al . Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 366 , 1279–1289 (2005). A large prospective study (PROactive) demonstrating that pioglitazone significantly reduced the second principal end point of myocardial infarction, stroke and cardiovascular death; the primary end point did not reach statistical significance because of the inclusion of peripheral arterial disease and leg revascularization, which is known to be refractory to medical intervention, including statin therapy.

Aronoff, S. et al . Pioglitazone hydrochloride monotherapy improves glycemic control in the treatment of patients with type 2 diabetes: a 6-month randomized placebo-controlled dose-response study. The Pioglitazone 001 Study Group. Diabetes Care 23 , 1605–1611 (2000).

Erdmann, E., Song, E., Spanheimer, R., van Troostenburg de Bruyn, A.-R. & Perez, A. Observational follow-up of the PROactive study: a 6-year update. Diabetes Obes. Metab. 16 , 63–74 (2014).

[No authors listed.] Takeda announces completion of the post-marketing commitment to submit data to the FDA, the EMA and the PMDA for pioglitazone containing medicines including ACTOS. Takeda [online] , (2014).

Levin, D. et al . Pioglitazone and bladder cancer risk: a multipopulation pooled, cumulative exposure analysis. Diabetologia 58 , 493–504 (2015).

Kjems, L. L., Holst, J. J., Vølund, A. & Madsbad, S. The influence of GLP-1 on glucose-stimulated insulin secretion: effects on β-cell sensitivity in type 2 and nondiabetic subjects. Diabetes 52 , 380–386 (2003).

Vilsbøll, T., Krarup, T., Madsbad, S. & Holst, J. J. Defective amplification of the late phase insulin response to glucose by GIP in obese Type II diabetic patients. Diabetologia 45 , 1111–1119 (2002).

Aroda, V. R. et al . Efficacy of GLP-1 receptor agonists and DPP-4 inhibitors: meta-analysis and systematic review. Clin. Ther. 34 , 1247–1258.e22 (2012).

Deacon, C. F. Dipeptidyl peptidase-4 inhibitors in the treatment of type 2 diabetes: a comparative review. Diabetes Obes. Metab. 13 , 7–18 (2011).

Balas, B. et al . The dipeptidyl peptidase IV inhibitor vildagliptin suppresses endogenous glucose production and enhances islet function after single-dose administration in type 2 diabetic patients. J. Clin. Endocrinol. Metab. 92 , 1249–1255 (2007).

Drucker, D. J. Incretin action in the pancreas: potential promise, possible perils, and pathological pitfalls. Diabetes 62 , 3316–3323 (2013). A comprehensive review of the effect of incretin hormones on pancreatic hormone secretion and pathology by one of the world's leading authorities.

White, W. B. et al . Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N. Engl. J. Med. 369 , 1327–1335 (2013).

Scirica, B. M. et al . Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N. Engl. J. Med. 369 , 1317–1326 (2013).

Cervera, A. et al . Mechanism of action of exenatide to reduce postprandial hyperglycemia in type 2 diabetes. Am. J. Physiol. Endocrinol. Metab. 294 , E846–E852 (2008).

Bunck, M. C. et al . Effects of exenatide on measures of β-cell function after 3 years in metformin-treated patients with type 2 diabetes. Diabetes Care 34 , 2041–2047 (2011). A landmark 3-year prospective study demonstrating the marked and durable improvement in β-cell function using the combined hyperglycaemic and euglycaemic insulin clamp techniques following exenatide treatment in patients with T2DM.

Klonoff, D. C. et al . Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years. Curr. Med. Res. Opin. 24 , 275–286 (2008).

Schwartz, S. & Kohl, B. A. Type 2 diabetes mellitus and the cardiometabolic syndrome: impact of incretin-based therapies. Diabetes Metab. Syndr. Obes. 3 , 227–242 (2010).

Eng, C., Kramer, C. K., Zinman, B. & Retnakaran, R. Glucagon-like peptide-1 receptor agonist and basal insulin combination treatment for the management of type 2 diabetes: a systematic review and meta-analysis. Lancet 384 , 2228–2234 (2014).

Egan, A. G. et al . Pancreatic safety of incretin-based drugs — FDA and EMA assessment. N. Engl. J. Med. 370 , 794–797 (2014).

Van de Laar, F. A. et al . Alpha-glucosidase inhibitors for type 2 diabetes mellitus. Cochrane Database Syst. Rev. 2 , CD003639 (2005).

Esposito, K. et al . Dipeptidyl peptidase-4 inhibitors and HbA1c target of <7% in type 2 diabetes: meta-analysis of randomized controlled trials. Diabetes Obes. Metab. 13 , 594–603 (2011).

Richter, B., Bandeira-Echtler, E., Bergerhoff, K. & Lerch, C. L. Dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes mellitus. Cochrane Database Syst. Rev. 2 , CD006739 (2008).

Abdul-Ghani, M. A., Norton, L. & DeFronzo, R. A. Role of sodium-glucose cotransporter 2 (SGLT 2) inhibitors in the treatment of type 2 diabetes. Endocr. Rev. 32 , 515–531 (2011). An excellent review of the mechanism of action, efficacy and safety of the recently approved SGLT2 inhibitor class of antidiabetic medications.

Wright, E. M., Loo, D. D. & Hirayama, B. A. Biology of human sodium glucose transporters. Physiol. Rev. 91 , 733–794 (2011).

Merovci, A. et al . Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J. Clin. Invest. 124 , 509–514 (2014).

Ferrannini, E. et al . Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J. Clin. Invest. 124 , 499–508 (2014).

Abdul-Ghani, M. A., DeFronzo, R. A. & Norton, L. Novel hypothesis to explain why SGLT2 inhibitors inhibit only 30–50% of filtered glucose load in humans. Diabetes 62 , 3324–3328 (2013).

Cherney, D. Z. I. et al . Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation 129 , 587–597 (2014).

Holman, R. R. et al . Three-year efficacy of complex insulin regimens in type 2 diabetes. N. Engl. J. Med. 361 , 1736–1747 (2009). A comparison of the efficacy and side-effect profile of commonly used complex insulin regimens for the treatment of patients with T2DM.

Gough, S. C. L. et al . Efficacy and safety of a fixed-ratio combination of insulin degludec and liraglutide (IDegLira) compared with its components given alone: results of a phase 3, open-label, randomised, 26-week, treat-to-target trial in insulin-naive patients with type 2 diabetes. Lancet Diabetes Endocrinol. 2 , 885–893 (2014).

Wilding, J. P. et al . Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin: a randomized trial. Ann. Intern. Med. 156 , 405–415 (2012).

Anderson, M., Powell, J., Campbell, K. M. & Taylor, J. R. Optimal management of type 2 diabetes in patients with increased risk of hypoglycemia. Diabetes Metab. Syndr. Obes. 7 , 85–94 (2014).

PubMed   PubMed Central   Google Scholar  

Schopman, J. E. et al . The incidence of mild and severe hypoglycaemia in patients with type 2 diabetes mellitus treated with sulfonylureas: a systematic review and meta-analysis. Diabetes Metab. Res. Rev. 30 , 11–22 (2014).

Desouza, C., Salazar, H., Cheong, B., Murgo, J. & Fonseca, V. Association of hypoglycemia and cardiac ischemia: a study based on continuous monitoring. Diabetes Care 26 , 1485–1489 (2003).

Gerstein, H. C. et al . Effects of intensive glucose lowering in type 2 diabetes. N. Engl. J. Med. 358 , 2545–2559 (2008). The ORIGIN trial demonstrated that physiological insulin replacement doses (30–40 units per day) in newly diagnosed patients with T2DM could control HbA1c without an increased risk of cardiovascular events; however, the risk of hypoglycaemia was significantly increased, and the study did not examine the effect of higher doses of insulin, which are usually required to normalize glycaemia in more long-standing diabetes, on cardiovascular risk or other potential side effects of insulin therapy.

Cushman, W. C. et al . Effects of intensive blood-pressure control in type 2 diabetes mellitus. N. Engl. J. Med. 362 , 1575–1585 (2010).

James, P. A. et al . 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 311 , 507–520 (2014).

Emdin, C. et al . Association of cardiovascular trial registration with positive study findings: Epidemiological Study of Randomized Trials (ESORT). JAMA Intern. Med. 175 , 304–307 (2015).

Testa, M. A. & Simonson, D. C. Health economic benefits and quality of life during improved glycemic control in patients with type 2 diabetes mellitus: a randomized, controlled, double-blind trial. JAMA 280 , 1490–1496 (1998). This was the first randomized trial to demonstrate that better glucose control improves QOL, cognitive function and general perceived health, and reduces symptom distress and absenteeism from work.

Testa, M. A. & Simonson, D. C. Assesment of quality-of-life outcomes. N. Engl. J. Med. 334 , 835–840 (1996).

Testa, M. A., Simonson, D. C. & Turner, R. R. Valuing quality of life and improvements in glycemic control in people with type 2 diabetes. Diabetes Care 21 , C44–C52 (1998).

Bode, B. W. et al . Patient-reported outcomes following treatment with the human GLP-1 analogue liraglutide or glimepiride in monotherapy: results from a randomized controlled trial in patients with type 2 diabetes. Diabetes Obes. Metab. 12 , 604–612 (2010).

Testa, M. A. et al . Comparative effectiveness of basal-bolus versus premix analog insulin on glycemic variability and patient-centered outcomes during insulin intensification in type 1 and type 2 diabetes: a randomized, controlled, crossover trial. J. Clin. Endocrinol. Metab. 97 , 3504–3514 (2012). This randomized trial demonstrated that patient satisfaction with treatment was more positively affected by improved QOL, reduced glucose variability and better glycaemic control with a basal-bolus regimen than negatively affected by the burden of additional injections.

Cotter, A. P., Durant, N., Agne, A. A. & Cherrington, A. L. Internet interventions to support lifestyle modification for diabetes management: a systematic review of the evidence. J. Diabetes Complications 28 , 243–251 (2014).

Rose, M. et al . The PROMIS Physical Function item bank was calibrated to a standardized metric and shown to improve measurement efficiency. J. Clin. Epidemiol. 67 , 516–526 (2014).

DeFronzo, R. A. & Triplitt, C. Novel agents for T2DM. Diabetes Spectr. 27 , 100–112 (2014). This article presents a more detailed review of novel antidiabetic agents that currently are being investigated in animals and humans for the treatment of T2DM.

Wong, A. K., Howie, J., Petrie, J. R. & Lang, C. C. AMP-activated protein kinase pathway: a potential therapeutic target in cardiometabolic disease. Clin. Sci. (Lond.) 116 , 607–620 (2009).

Agrawal, N. K. & Kant, S. Targeting inflammation in diabetes: newer therapeutic options. World J. Diabetes 5 , 697–710 (2014). Inflammation in insulin target tissues and β-cells is a now well-established pathogenetic abnormality T2DM. This article reviews the mechanism by which inflammation contributes to glucose intolerance in T2DM and potential interventions to suppress inflammation and improve insulin sensitivity and β-cell function.

Poy, M. N. et al . miR-375 maintains normal pancreatic α- and β-cell mass. Proc. Natl Acad. Sci. USA 106 , 5813–5818 (2009).

Burant, C. F. et al . TAK-875 versus placebo or glimepiride in type 2 diabetes mellitus: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet 379 , 1403–1411 (2012).

Assmann, A., Hinault, C. & Kulkarni, R. N. Growth factor control of pancreatic islet regeneration and function. Pediatr. Diabetes 10 , 14–32 (2009).

Vasavada, R. C. et al . Protein kinase C-ζ activation markedly enhances β-cell proliferation: an essential role in growth factor mediated β-cell mitogenesis. Diabetes 56 , 2732–2743 (2007).

Wiederkehr, A. & Wollheim, C. B. Mitochondrial signals drive insulin secretion in the pancreatic β-cell. Mol. Cell. Endocrinol. 353 , 128–137 (2012).

Wang, C. et al . Deficiency of APPL1 in mice impairs glucose-stimulated insulin secretion through inhibition of pancreatic beta cell mitochondrial function. Diabetologia 56 , 1999–2009 (2013).

Sivitz, W. I. & Yorek, M. A. Mitochondrial dysfunction in diabetes: from molecular mechanisms to functional significance and therapeutic opportunities. Antioxid. Redox Signal. 12 , 537–577 (2010).

Li, N., Stojanovski, S. & Maechler, P. Mitochondrial hormesis in pancreatic β cells: does uncoupling protein 2 play a role? Oxid. Med. Cell. Longev. 2012 , 740849 (2012).

Aquilano, K., Baldelli, S., Pagliei, B. & Ciriolo, M. R. Extranuclear localization of SIRT1 and PGC-1α: an insight into possible roles in diseases associated with mitochondrial dysfunction. Curr. Mol. Med. 13 , 140–154 (2013).

Matschinsky, F. M. et al . Glucokinase activators for diabetes therapy: May 2010 status report. Diabetes Care 34 , S236–S243 (2011).

Engel, S. S. Glycemic and lipid effects of the short-acting glucagon receptor antagonist MK-3577 in patients with type 2 diabetes. Diabetes Abstr. 61 , A266 (2012).

Gumbiner, B. Pronounced glucose (G) reduction in poorly controlled T2DM with MB07803, a novel fructose-1, 6-biphosphatase inhibitor (FBPasel) with reduced potential for acid-base disturbance versus the 1st generation FBPasel CS-917. Diabetes Abstr. 58 , LB4 (2009).

Kumashiro, N. et al . Targeting pyruvate carboxylase reduces gluconeogenesis and adiposity and improves insulin resistance. Diabetes 62 , 2183–2194 (2013).

Stark, R. et al . A role for mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M) in the regulation of hepatic gluconeogenesis. J. Biol. Chem. 289 , 7257–7263 (2014).

Harlan, D. M., Kenyon, N. S., Korsgren, O. & Roep, B. O. Current advances and travails in islet transplantation. Diabetes 58 , 2175–2184 (2009).

Motté, E. et al . Composition and function of macroencapsulated human embryonic stem cell-derived implants: comparison with clinical human islet cell grafts. Am. J. Physiol. Endocrinol. Metab. 307 , E838–E846 (2014).

Pagliuca, F. W. et al . Generation of functional human pancreatic β cells in vitro . Cell 159 , 428–439 (2014).

Blum, B. et al . Reversal of β cell de-differentiation by a small molecule inhibitor of the TGFβ pathway. eLife 3 , e02809 (2014).

Pickup, J. C. Banting Memorial Lecture 2014* Technology and diabetes care: appropriate and personalized. Diabet. Med. 32 , 3–13 (2015).

Peyser, T., Dassau, E., Breton, M. & Skyler, J. S. The artificial pancreas: current status and future prospects in the management of diabetes. Ann. NY Acad. Sci. 1311 , 102–123 (2014). This article presents an up-to-to-date status report on progress with the artificial pancreas (closed-loop system).

Klonoff, D. C. Afrezza inhaled insulin: the fastest-acting FDA-approved insulin on the market has favorable properties. J. Diabetes Sci. Technol. 8 , 1071–1073 (2014).

Eldor, R., Arbit, E., Corcos, A. & Kidron, M. Glucose-reducing effect of the ORMD-0801 oral insulin preparation in patients with uncontrolled type 1 diabetes: a pilot study. PLoS ONE 8 , e59524 (2013).

DeFronzo, R. A. Dissociation between metformin plasma exposure and its glucose-lowering effect: a novel gut-mediated mechanism of action. Diabetes 62 , a281 (2013).

DePaoli, A. M., Higgins, L. S., Henry, R. R., Mantzoros, C. & Dunn, F. L. Can a selective PPARγ modulator improve glycemic control in patients with type 2 diabetes with fewer side effects compared with pioglitazone? Diabetes Care 37 , 1918–1923 (2014).

Colca, J. R., Tanis, S. P., McDonald, W. G. & Kletzien, R. F. Insulin sensitizers in 2013: new insights for the development of novel therapeutic agents to treat metabolic diseases. Expert Opin. Investig. Drugs 23 , 1–7 (2014).

Suh, J. M. et al . Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer. Nature 513 , 436–439 (2014).

Gaich, G. et al . The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes. Cell Metab. 18 , 333–340 (2013).

Jeoung, N. H. & Harris, R. A. Role of pyruvate dehydrogenase kinase 4 in regulation of blood glucose levels. Korean Diabetes J. 34 , 274–283 (2010).

Povel, C. M. et al . Metabolic syndrome model definitions predicting type 2 diabetes and cardiovascular disease. Diabetes Care 36 , 362–368 (2013).

Pacini, G., Mari, A., Fouqueray, P., Bolze, S. & Roden, M. Imeglimin increases glucose-dependent insulin secretion and improves β-cell function in patients with type 2 diabetes. Diabetes Obes. Metab. 17 , 541–545 (2015).

Birch, A. M., Buckett, L. K. & Turnbull, A. V. DGAT1 inhibitors as anti-obesity and anti-diabetic agents. Curr. Opin. Drug Discov. Devel. 13 , 489–496 (2010).

Liu, L. et al . Upregulation of myocellular DGAT1 augments triglyceride synthesis in skeletal muscle and protects against fat-induced insulin resistance. J. Clin. Invest. 117 , 1679–1689 (2007).

Harrima, G., Greenwood, J. & Bhar, S. Acetyl-CoA carboxylase inhibition by NDI-630 inhibits fatty acid synthesis stimulates fatty acid oxidative, reduces body weight, improvise insulin sensitivity, and modulates dyslipidemia in rats. Diabetes Abstr. 62 , A161 (2013).

Tao, H., Zhang, Y., Zeng, X., Shulman, G. I. & Jin, S. Niclosamide ethanolamine-induced mild mitochondrial uncoupling improves diabetic symptoms in mice. Nat. Med. 20 , 1263–1269 (2014).

Perry, R. J. et al . Reversal of hypertriglyceridemia, fatty liver disease, and insulin resistance by a liver-targeted mitochondrial uncoupler. Cell Metab. 18 , 740–748 (2013).

Garvey, W. T. et al . Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study. Am. J. Clin. Nutr. 95 , 297–308 (2012).

Carlsson, L. M. et al . Bariatric surgery and prevention of type 2 diabetes in Swedish obese subjects. N. Engl. J. Med. 367 , 695–704 (2012). The effectiveness and safety of bariatric surgery in the treatment of obesity and T2DM is reviewed in this longest ongoing study on surgical intervention.

Neuschwander-Tetri, B. A. et al . Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 385 , 956–965 (2014).

Out, C., Groen, A. K. & Brufau, G. Bile acid sequestrants: more than simple resins. Curr. Opin. Lipidol. 23 , 43–55 (2012).

Cellitti, S. A novel GLP-1-FGF21 fusion protein for the treatment of diabetes and obesity. Keystone Symp. Obes. (2014).

Thareja, S., Aggarwal, S., Bhardwaj, T. R. & Kumar, M. Protein tyrosine phosphatase 1B inhibitors: a molecular level legitimate approach for the management of diabetes mellitus. Med. Res. Rev. 32 , 459–517 (2012).

Chakraborty, C., Doss, C. G., Bandyopadhyay, S. & Agoramoorthy, G. Influence of miRNA in insulin signaling pathway and insulin resistance: micro-molecules with a major role in type-2 diabetes. Wiley Interdiscip. Rev. RNA 5 , 697–712 (2014).

Tilg, H. & Moschen, A. R. Microbiota and diabetes: an evolving relationship. Gut 63 , 1513–1521 (2014).

Patel, S. R., Hakim, D., Mason, J. & Hakim, N. The duodenal–jejunal bypass sleeve (EndoBarrier Gastrointestinal Liner) for weight loss and treatment of type 2 diabetes. Surg. Obes. Relat. Dis. 9 , 482–484 (2013).

Bhatt, M. P., Lim, Y.-C. & Ha, K.-S. C-peptide replacement therapy as an emerging strategy for preventing diabetic vasculopathy. Cardiovasc. Res. 104 , 234–244 (2014).

Bhat, M., Pouliot, M., Couture, R. & Vaucher, E. The kallikrein–kinin system in diabetic retinopathy. Prog. Drug Res. 69 , 111–143 (2014).

PubMed   Google Scholar  

Hajhosseiny, R. et al . Have we reached the limits for the treatment of diabetic nephropathy? Expert Opin. Investig. Drugs 23 , 511–522 (2014).

Williams, M. E. et al . Effects of pyridoxamine in combined phase 2 studies of patients with type 1 and type 2 diabetes and overt nephropathy. Am. J. Nephrol. 27 , 605–614 (2007).

De Zeeuw, D. et al . The endothelin antagonist atrasentan lowers residual albuminuria in patients with type 2 diabetic nephropathy. J. Am. Soc. Nephrol. 25 , 1083–1093 (2014).

Boussageon, R. et al . Effect of intensive glucose lowering treatment on all cause mortality, cardiovascular death, and microvascular events in type 2 diabetes: meta-analysis of randomised controlled trials. BMJ 343 , d4169 (2011).

Colditz, G. A., Willett, W. C., Rotnitzky, A. & Manson, J. E. Weight gain as a risk factor for clinical diabetes mellitus in women. Ann. Intern. Med. 122 , 481–486 (1995).

Chan, J. M., Rimm, E. B., Colditz, G. A., Stampfer, M. J. & Willett, W. C. Obesity, fat distribution, and weight gain as risk factors for clinical diabetes in men. Diabetes Care 17 , 961–969 (1994).

Download references

Acknowledgements

The authors acknowledge grants from: the South Texas Veterans Healthcare System to R.A.D.; the National Institutes of Health (grants R01DK24092 to R.A.D.; DK58845 and P30 DK46200 to F.B.H.; R01 DK-040936, R01 DK-049230, R24 DK-085836, UL1 RR-045935, R01 DK-082659 and R24 DK085610 to G.I.S.; P30 DK036836 to C.R.K. Novo Nordisk Foundation for Basic Metabolic Research and the University of Copenhagen to G.I.S. and C.R.K.; DVA-Merit Review grant and VA San Diego Healthcare System to R.H.; National Institute for Diabetes and Digestive and Kidney Disease (grant P30DK092926) to W.H.; the Swedish Research Council (grants 2010–3490 and 2008–6589) and European Council (grants GA269045) to L.G.; Italian Ministry of University & Research (MIUR 2010329EKE) to E.F.; the Patient-Centered Outcomes Research Institute (PCORI) Program Award (CE1304-6756) to D.C.S. and M.A.T.; NovoNordisk Foundation to the NNF Center for Basic Metabolic Research to J.H. W.H. acknowledges the Michigan Center for Diabetes Translational Research and I.R. thanks R. Sprung for editorial assistance.

Author information

Authors and affiliations.

Diabetes Division, Department of Medicine, University of Texas Health Science Center, South Texas Veterans Health Care System and Texas Diabetes Institute, 701 S. Zarzamoro, San Antonio, 78207, Texas, USA

Ralph A. DeFronzo

CNR Institute of Clinical Physiology, Pisa, Italy

Ele Ferrannini

Department of Clinical Science Malmoe, Diabetes & Endocrinology, Lund University Diabetes Centre, Lund, Sweden

University of California, San Diego, Section of Diabetes, Endocrinology & Metabolism, Center for Metabolic Research, VA San Diego Healthcare System, San Diego, California, USA

Robert R. Henry

University of Michigan, Ann Arbor, Michigan, USA

William H. Herman

University of Copenhagen, Kobenhavn, Denmark

Jens Juul Holst

Department of Nutrition, Harvard T.H. Chan School of Public Health and Department of Epidemiology, Harvard T.H. Chan School of Public Health and Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

Frank B. Hu

Harvard Medical School and Joslin Diabetes Center, Boston, Massachusetts, USA

C. Ronald Kahn

Division of Internal Medicine, Diabetes Unit, Hadassah Hebrew University Hospital, Jerusalem, Israel

Howard Hughes Medical Institute and the Departments of Internal Medicine and Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut, USA

Gerald I. Shulman

Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

Donald C. Simonson

Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA

Marcia A. Testa

Department of Human Metabolism and Nutrition, Braun School of Public Health, Hebrew University, Jerusalem, Israel

You can also search for this author in PubMed   Google Scholar

Contributions

Introduction (R.R.H.); Epidemiology (F.B.H.); Mechanisms/pathophysiology (L.C.G., C.R.K., E.F., G.I.S. and R.A.D.); Diagnosis, screening and prevention (W.H.H.); Management (R.A.D.); Quality of life (D.C.S. and M.A.T.); Outlook (I.R., J.J.H. and R.W.); overview of Primer (R.A.D.).

Corresponding author

Correspondence to Ralph A. DeFronzo .

Ethics declarations

Competing interests.

The authors declare the following potential COI: (1) R.A.D.: Research Grant Support - AstraZeneca, Bristol Myers Squibb, Janssen; Speaker's Bureau - AstraZeneca, Novo Nordisk, Advisory Board/Consultant - AstraZeneca, Janssen, Novo Nordisk, Boehringer Ingelheim, Lexicon, Intarcia; (2) E.F.: Research Grant Support - Boehringer Ingelheim, Eli Lilly; Consultant/Speaker Bureau-Boehringer Ingelheim, Eli Lilly, Sanofi, Novo Nordisk, Janssen, AstraZeneca, Takeda, Medtronic, Intarcia; (3) C.R.K. serves as a consultant for Medimmune, Merck, Five Prime Therapeutics, CohBar, Antriabio, and Catabasis; (4) L.G. has no conflict of interest; (5) R.H. has received grant support from Hitachi, Janssen, Eli Lilly, Sanofi-Aventis and Viacyte and is a consultant/advisory board member for Alere, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Clin Met, Eisai, Elcelyx, Gilead, Intarcia, Isis, Janssen, Merck, Novo Nordisk, Sanofi-Aventis, and Vivus; (6) W.H.H. has no conflict of interest; (7) J.J.H. has received grant support from Novartis and Merck and is a consultant/advisory board member for Glaxo, Smith, Kline, Novo Nordisk, and Zealand Pharmaceuticals; (8) M.A.T. has no conflict of interest; (9) R.W. serves as a consultant for Medtronics and Kamada and is on the speaker's bureau for Medtronics and Novo Nordisk; (10) F.H. has received research support from California Walnut Commission and Metegenics; (11) G.I.S. serves on scientific advisory boards for Merck and Novartis and he has received research grant support from Gilead Pharmaceuticals; (12) D.C.S. has no conflict of interest; (13) I.R. – Advisory Board: Novo Nordisk, Astra Zeneca/BMS, MSD, Eli Lilly, Sanofi, Medscape Cardiology; Consultant: Astra Zeneca/BMS, Insuline; Speaker's Bureau: Eli Lilly, Novo Nordisk, Astra Zeneca/BMS, J&J, Sanofi, MSD, Novartis, Teva; Shareholder: Insuline, Labstyle.

PowerPoint slides

Powerpoint slide for fig. 1, powerpoint slide for fig. 2, powerpoint slide for fig. 3, powerpoint slide for fig. 4, powerpoint slide for fig. 5, powerpoint slide for fig. 6, powerpoint slide for fig. 7, powerpoint slide for fig. 8, rights and permissions.

Reprints and permissions

About this article

Cite this article.

DeFronzo, R., Ferrannini, E., Groop, L. et al. Type 2 diabetes mellitus. Nat Rev Dis Primers 1 , 15019 (2015). https://doi.org/10.1038/nrdp.2015.19

Download citation

Published : 23 July 2015

DOI : https://doi.org/10.1038/nrdp.2015.19

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

Quick links

• Explore articles by subject
• Guide to authors
• Editorial policies

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Type 2 Diabetes - Free Essay Examples And Topic Ideas

Type 2 Diabetes is a chronic condition that affects the way the body processes blood sugar (glucose). Essays could explore the risk factors, prevention strategies, and management of Type 2 Diabetes. Discussions on its socioeconomic impact and the challenges in managing this condition in various healthcare settings could also be enlightening. We have collected a large number of free essay examples about Type 2 Diabetes you can find at PapersOwl Website. You can use our samples for inspiration to write your own essay, research paper, or just to explore a new topic for yourself.

Type 2 Diabetes in America

As we know, America today has become more and more obese. Americans are eating more calories a day than ever before. With increased calorie consumption there is increased carbohydrate consumption. This increased carbohydrate consumption has led to an increase in diabetes in not only adults but children and adolescences as well. Previously type 2 diabetes was very uncommon in children but with the recent increase in calorie intake it has become more prevalent. Type 2 diabetes is preventable. Type 2 […]

A Problem of Hispanics with Diabetes

Introduction The health care industry changes each and every year. Making America a very diverse nation and with diversity many issues present itself in today's society. One of the main issues that is affecting society is the prevalence of Type 2 Diabetes in Hispanics. The purpose of this paper is to provide cultural information and awareness of this issue with ways to assist in the prevention of Diabetes. Knowledge about diabetes is very important and sometimes there is not enough […]

General Characteristic of Type II Diabetes

Type 2 Diabetes Background about the disease- Type 2 Diabetes is a disorder caused by an imbalance of insulin. It is the more common form of diabetes, mostly seen in adults but now increasingly observed in young adults as well. Also known as non-insulin-dependent diabetes, this lifelong disease causes your blood glucose level to rise above the normal range. Pathophysiology and causes- Type 2 diabetes stems from several factors. It can develop when your body becomes resistant to insulin or […]

We will write an essay sample crafted to your needs.

History and Types of Diabetes

The first sign of diabetes was discovered in 1500 B.C.E by the Egyptians. According to one study, ancient Indians were familiar with the condition and had even determined two types of the condition. They called it "honey urine" and tested for it by determining if the ants were drawn to the urine. The first mention of the word diabetes was by the Greeks. It means "to go through", it was named this because of its main symptom: the excessive passing […]

Growing Problem of Diabetes

As today's youth grows, health and physical activity haves slowly been shifted to the back of people's thoughts. Everyday life can become busy and the quickest and easiest option is to grab an unhealthy snack or meal for the family or as an individual. Proper nutrition and exercise are the main components to creating a better and healthier lifestyle. In today's society there is an overt disregard in the choices made as a part of a routine which include daily […]

The Basic Problem of Diabetes

Uncontrolled levels of blood glucose are the basic problem in patients admitted to our unit. Many are related to lack of knowledge and self-care in diabetes management, sedentary lifestyle, and food habits. This reveals that when assessing a patient in the hospital, a nurse must consider all factors and design a care plan accordingly. Nurses need to be non-judgmental and assess what factors may limit patients' abilities to follow lifestyle recommendations. According to the American Diabetes Association (ADA), uncontrolled blood […]

Characteristic of Type Two Diabetes

Diabetes is a very harsh form of a metabolic dysfunction which is tagged by an increased level of blood glucose. These increased levels of blood glucose could be from many things but two main things are the deficiency in the production of insulin and deficiency in the use of insulin to transport glucose from the blood into the tissue [insulin and insulin resistance]. There are two types of diabetes, type one and two that are the commonly known types in […]

Diabetes and its Main Types

Diabetes is a disorder of the endocrine system, which messes with the metabolism of carbohydrates, fats, and proteins. The metabolism is compromised because of a lack of insulin, either from destruction of the beta cells, which secrete insulin, or because of insulin resistance. Insulin is secreted by beta cells and it is what enables the cells to use glucose. Type 1 diabetes was formerly called juvenile diabetes because mostly kids were diagnosed with it. It is now changed to be […]

Why you should Learn about Diabetes

Auntie Jeanette is the second oldest out of ten children. She is a loving mother, auntie, and daughter. She is well-respected in the community and is known for her outstanding cooking. Every Thanksgiving and Christmas, she makes her famous collard greens with hamhocks, fried chicken, corn bread, and pasta salad. Everyone from all over would come just to eat her delicious food. Although this was very good food, it was not the healthiest choice. Consuming so much of these unhealthy […]

Adverse Health Effect of Environmental Heavy Metals on Diabetes

ABSTRACT Type 2 diabetes (T2D) and its complications constitute a major public health problem for both developed and developing countries due to the high rate of morbidity and mortality associated with the disease.  New evidence from both experimental and human studies has resulted in increased interest in analyzing the relationship between T2D and heavy metal exposures that are ubiquitous in the environment. Vellore district is a major leather- processing centre in Tamil Nadu, with an estimated 60,000 tannery workers. Tannery […]

What should you Know about Diabetes

What is diabetes? Diabetes is when your blood sugars, or blood glucose, is to high.  Your main source of energy is blood glucose, which comes from the food you eat.  Your pancreas creates a hormone called insulin.  Insulin helps all the glucose from the food you eat get into your body's cells and use it for energy.  But in some cases, the body doesn't create enough insulin, sometimes the body doesn't make any insulin at all.  If this is the […]

How is Low Carbohydrate Diet Beneficial to Diabetes

Abstract: This essay is about the global status of diabetes, what is diabetes, how insulin works, why people easy to have diabetes, what is carbohydrate and why low carbohydrate diet beneficial to the diabetes. With the development of society, people's living standards have gradually improved. The choice of food is gradually becoming more and more, also it has brought us many diseases. Diabetes, as one of the top ten death diseases in the world, has attracted the attention of people […]

Diabetes: One of the Hardest Illness

Diabetes is a standout amongst the most widely recognized maladies that can prompt passing if not treated right. In any case there are particular sorts of this ailment which is Type 1,Type 2, and Gestational diabetes. Diabetes is an illness that happens when your blood glucose, additionally called glucose, is too high. Blood glucose is your fundamental wellspring of significance and begins from the sustenance you eat. Diabetes is the sort of ailment that goes with conspicuous signs with in […]

An Issue of Nutrition and Diabetes

The article I've reviewed is called, "Nutrition Therapy Recommendations for the Management of Adults with Diabetes".  My decision to review this article is based upon interest in links with nutrition and chronic disease.  A National Center for Health Statistics study (Table 18) identified eight of the top ten killers in America as chronic diseases.  I've read multiple books that link the two and this article conducted a systematic review of 228 articles or studies.  The article goes fairly in depth […]

Connection between Genetics and Diabetes

Each single person has a specific set of genes; however, these genetics are greatly influenced by their families. Genetics can also be affected via one's environmental surroundings, as well. These genetics are associated with most diseases, such as cancer, kidney diseases, and psychologic diseases. Diabetes is no different. Genetics are not the only causative factor in diabetes, but it can alert healthcare members to look for this disease due to predisposition. According to the American Diabetes Association (2018), "Type 1 […]

Insulin-Dependent Diabetes Mellitus

Diabetes Mellitus 1, more specifically known as IDDM is a disorder concerning glucose homeostasis, which needs insulin therapy is generally seen in children. Diabetes is generally classified into 2 types IDDM (Insulin dependent diabetes mellitus) and the other NIDDM (Non-insulin dependent diabetes mellitus). Diabetes simply means an increase of glucose levels in the body as a result of the improper or no production of insulin from ones pancreatic ??-cells. The standard auto-immune response of type 1 diabetes is specific destruction […]

Diabetes and Renal Failure

Diabetes and Renal Failure Introduction This is a research article about prevalence of renal failure and its early detection among patients who have long standing diabetes mellitus. End stage renal disease significantly increases the risk of death and requires expert health care. Although diabetes is the most predominant cause of chronic renal disease, maximum individuals with diabetes are not investigated based on national guidelines. Chronic kidney disease warrants improved detection using standardized criteria to improve outcomes. Proper screening of diabetic […]

What are the Main Causes and Treatments of Diabetes

Diabetes is a chronic disease that can cause complications and death if left untreated. It is one of the most common chronic diseases in the world and affects nearly half of the global population. According to Koye et al. (2018), it is also a leading cause of disability worldwide, affecting more than 300 million people globally. Diabetes is one of the most common diseases in the United States, with more than 100 million adults affected by type 2 diabetes and over 6.3 […]

An Evolution of Diabetes

EVOLUTION Diabetes is a major public health problem with a rapid increase in prevalence globally. Twelve percent of all health care spending is related to diabetes. The diagnosis and treatment of diabetes has evolved extensively over the last century. Although there is still no cure for the disorder, diabetes is much more manageable due to advancement in medicine and technology. In the beginning of the 20th century, Edward Schafer concluded that the pancreas of diabetics was unable to produce insulin […]

Acute Coronary Syndrome

The condition is characterized by pains in the chest and it is typically confirmed inside the hospital or the emergency room. It is also manageable if immediately confirmed. Acute syndrome occurs when plaques inside a narrowed vessel of blood splits causing thrombus development. This will consequently lead to unexpected partial or full blockage. The thrombus may also dislodge from a broken plaque consequently blocking the blood vessels. Explain risk factors Acute coronary syndrome may occur gradually in the long run […]

Child and Adolescent Obesity in the United States

Child and adolescent obesity in the United States has nearly tripled sincethe 70s. About 1 out of every 5 children suffer from childhood obesity. It is the duty ofmothers and fathers to prevent and find solutions to child and adolescent obesity. Thispaper will seek to explain the many causes and current results which parents can execute.Child and adolescent obesity comprises of several likely causes such as poor diet and lowphysical activity including numerous adverse effects. Therefore, changes in familyhousehold structures […]

Treatment of Diabetes in Adolescents

Abstract Background: Diabetes is a significant public health challenge facing the US and several other countries around the world. It is mostly perceived as a lifestyle disease, although type 1 diabetes can be viewed as a congenital autoimmune disorder. Diabetes is increasingly becoming a problem among young adolescents in America, with high prevalence and incidence rates. This study sought to establish the impact of treatment of adolescents for diabetes on their maturity process, demand for independence, parent-adolescent conflict, and their […]

Importance of Nursing Theories

Nursing theories are important tools for the designing, understanding, and application of diabetes patient education (Anderson, Funnell, & Hernandez, 2005). Imogene King is one of the nursing theorists who has made significant contributions to nursing. King's Conceptual Framework and Theory of Goal Attainment (TGA) is valuable in the care of diabetes patients and adherence to treatment. In my unit most commonly-used nursing theories include, King's theory of goal attainment to the care of the adult with diabetes mellitus. TGA theory […]

An Issue of Diabetes and Self-Efficacy

Abstract While self-efficacy is a proven clinical predictor of metabolic and glycemic control among people with poorly controlled Type 1 and Type 2 diabetes (Abubakari et al., 2015), few healthcare systems integrate effective biochemical individual strategies for disease management. Customized clinical meal plans, personalized education, high-intensity interval training (HIIT), and targeted health coaching have demonstrated significant improvement in clinical biomarkers associated with Type 2 diabetes and metabolic syndrome (MetS), including HOMA-IR, triglyceride/HDL ratio, HgA1c, fasting insulin, fasting glucose, fasting triglycerides, […]

A Problem of Diabetes

Low socioeconomic status has previously been associated with type 2 diabetes. Health is not only affected by individual risk factors and behaviors, but also a range of economic circumstances. Primarily, this issue is caused by the underuse or reduced access to recommended preventive care in individuals from low socioeconomic backgrounds. Economic issues inherent in diabetes stem from the fact that economically disadvantaged individuals do not have the support for healthy behaviors. Furthermore, economically disadvantaged individuals may lack access to clinical […]

Importance of Speech about Diabetes

On 14th November this year on World Diabetes Day we witnessed an amazing talk by the keynote speaker Dr. Ronny Bell at the University of Florida. The title of the talk was 'Challenges and Opportunities in achieving diabetes health equity.' He spoke about important issues that often get lost and not given too much importance when we talk about diabetes. He mentioned that we all know about the complications, we all know about the emergencies, but what we often don't […]

My Work as a Nurse

I work at Overlake Hospital Medical Center on a Medical Surgical and Oncology Unit. As a bedside nurse, my job and responsibility not only centered around vigilant monitoring for physiological changes and immediate needs of patients but also centered around an emotional aspect of caring and advocating. Our 37-bed unit provides care for various medical-surgical conditions, chemotherapy infusion, blood transfusion, dialysis, oncology with hospice, and end of life care patients on a day to day basis. As a bedside nurse, […]

My Understanding of Diabetes

For this essay I'll be covering the topic of diabetes. I've always found diabetes as an interesting topic; maybe because it's a huge problem for most people in the United States. you might be wonder what diabetes is, Diabetes is a disease in which the body response to the hormone insulin is impaired or not fully functional, resluting  in complications with the metabolism. Having high glucose is also one of the main reasons people get diabetes. Having high glucose in […]

My Research on Diabetes

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 […]

Diabetes Type 2: a Chronic Disease

Diabetes type 2 is a chronic disease which is widespread around the world. According to Mayo Clinic, type 2 diabetes is the most common type of diabetes that occurs due to high blood sugar and the lack of ability of the body to use insulin properly or make enough of it. Diabetes type 2 does not have a cure. However, it can be prevented or delayed. The most common causes of diabetes relate to people's lifestyle and their genetics. Physical […]

Additional Example Essays

• A Research Paper on Alzheimer's Disease
• Professional Goals in Nursing Essay
• Moving to a New School
• David Zinczenko: “Don't Blame the Eater”
• Benefits of Swimming
• Why Violent Video Games Should Not Be Banned: Scientific Perspective
• GMO Disadvantages Essay

1. Tell Us Your Requirements

2. Pick your perfect writer

3. Get Your Paper and Pay

Hi! I'm Amy, your personal assistant!

Don't know where to start? Give me your paper requirements and I connect you to an academic expert.

short deadlines

100% Plagiarism-Free

Certified writers

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.

Customize your course in 30 seconds

Which class are you in.

• Travelling Essay
• Picnic Essay
• Our Country Essay
• My Parents Essay
• Essay on Favourite Personality
• Essay on Memorable Day of My Life
• Essay on Knowledge is Power
• Essay on Gurpurab
• Essay on My Favourite Season
• Essay on Types of Sports

Leave a Reply Cancel reply

Your email address will not be published. Required fields are marked *

Download the App

• Previous Article
• Next Article

Acknowledgments

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 .

Summary and Conclusion

• Split-Screen
• Article contents
• Figures & tables
• Supplementary Data
• Peer Review
• Open the PDF for in another window
• Cite Icon Cite
• Get Permissions

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

Download citation file:

• Ris (Zotero)
• Reference Manager

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.

Dualities of Interest

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.

Author Contributions

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.

Email alerts

• Online ISSN 2771-6880
• Print ISSN 2771-6872
• Diabetes Care
• Clinical Diabetes
• Diabetes Spectrum
• Standards of Medical Care in Diabetes
• Scientific Sessions Abstracts
• BMJ Open Diabetes Research & Care
• ShopDiabetes.org
• ADA Professional Books

Clinical Compendia

• Clinical Compendia Home
• Latest News
• DiabetesPro SmartBrief
• Special Collections
• DiabetesPro®
• Diabetes Food Hub™
• Insulin Affordability
• Know Diabetes By Heart™
• About the ADA
• Journal Policies
• For Reviewers
• Advertising in ADA Journals
• Reprints and Permission for Reuse
• Copyright Notice/Public Access Policy
• ADA Professional Membership
• ADA Member Directory
• Diabetes.org
• X (Twitter)
• Cookie Policy
• Accessibility
• Terms & Conditions
• Get Adobe Acrobat Reader
• © Copyright American Diabetes Association

This Feature Is Available To Subscribers Only

Sign In or Create an Account

An official website of the United States government

The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

• Publications
• Account settings

Preview improvements coming to the PMC website in October 2024. Learn More or Try it out now .

• Advanced Search
• Journal List
• World J Diabetes
• v.6(6); 2015 Jun 25

Diabetes mellitus: The epidemic of the century

Correspondence to: Akram T Kharroubi, PhD, Associate Professor of Biochemistry and Endocrinology, Dean of Faculty of Health Professions, Department of Medical Laboratory Sciences, Faculty of Health Professions, Al-Quds University, P.O. Box 51000, Abed Elhamaid Shoman Street, Beit Hanina-Jerusalem, Jerusalem 91000, Palestine. [email protected]

Telephone: +972-2-2791243 Fax: +972-2-2791243

The epidemic nature of diabetes mellitus in different regions is reviewed. The Middle East and North Africa region has the highest prevalence of diabetes in adults (10.9%) whereas, the Western Pacific region has the highest number of adults diagnosed with diabetes and has countries with the highest prevalence of diabetes (37.5%). Different classes of diabetes mellitus, type 1, type 2, gestational diabetes and other types of diabetes mellitus are compared in terms of diagnostic criteria, etiology and genetics. The molecular genetics of diabetes received extensive attention in recent years by many prominent investigators and research groups in the biomedical field. A large array of mutations and single nucleotide polymorphisms in genes that play a role in the various steps and pathways involved in glucose metabolism and the development, control and function of pancreatic cells at various levels are reviewed. The major advances in the molecular understanding of diabetes in relation to the different types of diabetes in comparison to the previous understanding in this field are briefly reviewed here. Despite the accumulation of extensive data at the molecular and cellular levels, the mechanism of diabetes development and complications are still not fully understood. Definitely, more extensive research is needed in this field that will eventually reflect on the ultimate objective to improve diagnoses, therapy and minimize the chance of chronic complications development.

Core tip: Diabetes mellitus is rising to an alarming epidemic level. Early diagnosis of diabetes and prediabetes is essential using recommended hemoglobin A1c criteria for different types except for gestational diabetes. Screening for diabetes especially in underdeveloped countries is essential to reduce late diagnosis. Diabetes development involves the interaction between genetic and non-genetic factors. Biomedical research continues to provide new insights in our understanding of the mechanism of diabetes development that is reviewed here. Recent studies may provide tools for the use of several genes as targets for risk assessment, therapeutic strategies and prediction of complications.

DEFINITION OF DIABETES MELLITUS

Diabetes mellitus is a group of metabolic diseases characterized by chronic hyperglycemia resulting from defects in insulin secretion, insulin action, or both. Metabolic abnormalities in carbohydrates, lipids, and proteins result from the importance of insulin as an anabolic hormone. Low levels of insulin to achieve adequate response and/or insulin resistance of target tissues, mainly skeletal muscles, adipose tissue, and to a lesser extent, liver, at the level of insulin receptors, signal transduction system, and/or effector enzymes or genes are responsible for these metabolic abnormalities. The severity of symptoms is due to the type and duration of diabetes. Some of the diabetes patients are asymptomatic especially those with type 2 diabetes during the early years of the disease, others with marked hyperglycemia and especially in children with absolute insulin deficiency may suffer from polyuria, polydipsia, polyphagia, weight loss, and blurred vision. Uncontrolled diabetes may lead to stupor, coma and if not treated death, due to ketoacidosis or rare from nonketotic hyperosmolar syndrome[ 1 - 3 ].

CLASSIFICATION OF DIABETES MELLITUS

Although classification of diabetes is important and has implications for the treatment strategies, this is not an easy task and many patients do not easily fit into a single class especially younger adults[ 1 , 4 - 6 ] and 10% of those initially classified may require revision[ 7 ]. The classical classification of diabetes as proposed by the American Diabetes Association (ADA) in 1997 as type 1, type 2, other types, and gestational diabetes mellitus (GDM) is still the most accepted classification and adopted by ADA[ 1 ]. Wilkin[ 8 ] proposed the accelerator hypothesis that argues “type 1 and type 2 diabetes are the same disorder of insulin resistance set against different genetic backgrounds”[ 9 ]. The difference between the two types relies on the tempo, the faster tempo reflecting the more susceptible genotype and earlier presentation in which obesity, and therefore, insulin resistance, is the center of the hypothesis. Other predictors of type 1 diabetes include increased height growth velocity[ 10 , 11 ] and impaired glucose sensitivity of β cells[ 12 ]. The implications of increased free radicals, oxidative stress, and many metabolic stressors in the development, pathogenesis and complications of diabetes mellitus[ 13 - 18 ] are very strong and well documented despite the inconsistency of the clinical trials using antioxidants in the treatment regimens of diabetes[ 19 - 21 ]. The female hormone 17-β estradiol acting through the estrogen receptor-α (ER-α) is essential for the development and preservation of pancreatic β cell function since it was clearly demonstrated that induced oxidative stress leads to β-cell destruction in ER-α knockout mouse. The ER-α receptor activity protects pancreatic islets against glucolipotoxicity and therefore prevents β-cell dysfunction[ 22 ].

TYPE 1 DIABETES MELLITUS

Autoimmune type 1 diabetes.

This type of diabetes constitutes 5%-10% of subjects diagnosed with diabetes[ 23 ] and is due to destruction of β cells of the pancreas[ 24 , 25 ]. Type 1 diabetes accounts for 80%-90% of diabetes in children and adolescents[ 2 , 26 ]. According to International Diabetes Federation (IDF), the number of youth (0-14 years) diagnosed with type 1 diabetes worldwide in 2013 was 497100 (Table ​ (Table1) 1 ) and the number of newly diagnosed cases per year was 78900[ 27 ]. These figures do not represent the total number of type 1 diabetes patients because of the high prevalence of type 1 diabetes in adolescence and adults above 14 years of age. One reported estimate of type 1 diabetes in the United States in 2010 was 3 million[ 28 , 29 ]. The number of youth in the United States younger than 20 years with type 1 diabetes was estimated to be 166984 in the year 2009[ 30 ]. The prevalence of type 1 diabetes in the world is not known but in the United States in youth younger than 20 years was 1.93 per 1000 in 2009 (0.35-2.55 in different ethnic groups) with 2.6%-2.7% relative annual increase[ 26 , 31 ]. Type 1 diabetes is mainly due to an autoimmune destruction of the pancreatic β cells through T-cell mediated inflammatory response (insulitis) as well as a humoral (B cell) response[ 25 ]. The presence of autoantibodies against the pancreatic islet cells is the hallmark of type 1 diabetes, even though the role of these antibodies in the pathogenesis of the disease is not clear. These autoantibodies include islet cell autoantibodies, and autoantibodies to insulin (IAA), glutamic acid decarboxylase (GAD, GAD65), protein tyrosine phosphatase (IA2 and IA2β) and zinc transporter protein (ZnT8A)[ 32 ]. These pancreatic autoantibodies are characteristics of type 1 diabetes and could be detected in the serum of these patients months or years before the onset of the disease[ 33 ]. Autoimmune type 1 diabetes has strong HLA associations, with linkage to DR and DQ genes. HLA-DR/DQ alleles can be either predisposing or protective[ 1 ]. This autoimmune type 1 diabetes is characterized by the absence of insulin secretion and is more dominant in children and adolescents.

Number of subjects with type 1 diabetes in children (0-14 years), with diabetes in adults (20-79 years) and with hyperglycemia (type 2 or gestational diabetes) in pregnancy (20-49 years)

Data extracted from International Diabetes Federation Diabetes Atlas, 6th ed, 2013.

In addition to the importance of genetic predisposition in type 1 diabetes, several environmental factors have been implicated in the etiology of the disease[ 9 , 33 ]. Viral factors include congenital rubella[ 34 , 35 ], viral infection with enterovirus, rotavirus, herpes virus, cytomegalovirus, endogenous retrovirus[ 36 , 37 ] and Ljungan virus. Other factors include low vitamin D levels[ 38 ], prenatal exposure to pollutants, improved hygiene and living conditions decreased childhood infections in countries with high socioeconomic status leading to increased autoimmune diseases (hygiene hypothesis), early infant nutrition such as using cow’s milk formula instead of breast feeding[ 39 ] in addition to insulin resistance in early childhood due to obesity or increased height growth velocity. The role of environmental factors remains controversial[ 40 ]. Recent evidence supported the causative effect of viral infections in diabetes[ 41 - 43 ].

Type 1 diabetes often develops suddenly and can produce symptoms such as polydipsia, polyuria, enuresis, lack of energy, extreme tiredness, polyphagia, sudden weight loss, slow-healing wounds, recurrent infections and blurred vision[ 27 ] with severe dehydration and diabetic ketoacidosis in children and adolescents. The symptoms are more severe in children compared to adults. These autoimmune type 1 diabetes patients are also prone to other autoimmune disorders such as Graves’ disease, Hashimoto’s thyroiditis, Addison’s disease, vitiligo, celiac sprue, autoimmune hepatitis, myasthenia gravis, and pernicious anemia[ 1 ]. The complete dependence on insulin of type 1 diabetes patients may be interrupted by a honeymoon phase which lasts weeks to months or in some cases 2-3 years. In some children, the requirement for insulin therapy may drop to a point where insulin therapy could be withdrawn temporarily without detectable hyperglycemia[ 44 ].

Idiopathic type 1 diabetes

A rare form of type 1 diabetes of unknown origin (idiopathic), less severe than autoimmune type 1 diabetes and is not due to autoimmunity has been reported. Most patients with this type are of African or Asian descent and suffer from varying degrees of insulin deficiency and episodic ketoacidosis[ 45 ].

Fulminant type 1 diabetes

This is a distinct form of type 1 diabetes, first described in the year 2000, and has some common features with idiopathic type 1 diabetes being non-immune mediated[ 46 , 47 ]. It is characterized by ketoacidosis soon after the onset of hyperglycemia, high glucose levels (≥ 288 mg/dL) with undetectable levels of serum C-peptide, an indicator of endogenous insulin secretion[ 48 ]. It has been described mainly in East Asian countries and accounted for approximately 20% of acute-onset type 1 diabetes patients in Japan (5000-7000 cases) with an extremely rapid and almost complete beta-cell destruction resulting in nearly no residual insulin secretion[ 48 , 49 ]. Both genetic and environmental factors, especially viral infection, have been implicated in the disease. Anti-viral immune response may trigger the destruction of pancreatic beta cells through the accelerated immune reaction with no detectable autoantibodies against pancreatic beta cells[ 48 , 50 ]. Association of fulminant type 1 diabetes with pregnancy has also been reported[ 51 ].

TYPE 2 DIABETES MELLITUS

The global prevalence of diabetes in adults (20-79 years old) according to a report published in 2013 by the IDF was 8.3% (382 million people), with 14 million more men than women (198 million men vs 184 million women), the majority between the ages 40 and 59 years and the number is expected to rise beyond 592 million by 2035 with a 10.1% global prevalence. With 175 million cases still undiagnosed, the number of people currently suffering from diabetes exceeds half a billion. An additional 21 million women are diagnosed with hyperglycemia during pregnancy. The Middle East and North Africa region has the highest prevalence of diabetes (10.9%), however, Western Pacific region has the highest number of adults diagnosed with diabetes (138.2 millions) and has also countries with the highest prevalence (Figure ​ (Figure1 1 )[ 27 ]. Low- and middle-income countries encompass 80% of the cases, “where the epidemic is gathering pace at alarming rates”[ 27 ]. Despite the fact that adult diabetes patients are mainly type 2 patients, it is not clear whether the reported 382 million adults diagnosed with diabetes also include type 1 diabetes patients.

Comparative prevalence of diabetes in adults (20-79 years) in countries with high prevalence (≥ 10%). Data extracted from International Diabetes Federation Diabetes Atlas, 6th ed, 2013.

More than 90%-95% of diabetes patients belong to this type and most of these patients are adults. The number of youth (less than 20 years) with type 2 diabetes in the United States in the year 2009 was 0.46 in 1000 and accounted for approximately 20% of type 2 diabetes in youth[ 26 ]. The increased incidence of type 2 diabetes in youth is mainly due to the change in the lifestyle of the children in terms of more sedentary life and less healthy food. Obesity is the major reason behind insulin resistance which is mainly responsible for type 2 diabetes[ 52 - 54 ]. The ADA recommends screening of overweight children and adolescence to detect type 2 diabetes[ 55 , 56 ]. The prevalence of obesity in children in on the rise[ 6 ] which is probably the main reason for the increased incidence of type 2 diabetes in the young (30.3% overall increase in type 2 diabetes in children and adolescence between 2001 and 2009)[ 26 ].

Insulin resistance in type 2 diabetes patients increases the demand for insulin in insulin-target tissues. In addition to insulin resistance, the increased demand for insulin could not be met by the pancreatic β cells due to defects in the function of these cells[ 18 ]. On the contrary, insulin secretion decreases with the increased demand for insulin by time due to the gradual destruction of β cells[ 57 ] that could transform some of type 2 diabetes patients from being independent to become dependent on insulin. Most type 2 diabetes patients are not dependent on insulin where insulin secretion continues and insulin depletion rarely occurs. Dependence on insulin is one of the major differences from type 1 diabetes. Other differences include the absence of ketoacidosis in most patients of type 2 diabetes and autoimmune destruction of β cells does not occur. Both type 1 and type 2 diabetes have genetic predisposition, however, it is stronger in type 2 but the genes are more characterized in type 1 (the TCF7L2 gene is strongly associated with type 2 diabetes)[ 58 ]. Due to the mild symptoms of type 2 diabetes in the beginning, its diagnosis is usually delayed for years especially in countries where regular checkup without symptoms is not part of the culture. This delay in diagnosis could increase the incidence of long-term complications in type 2 diabetes patients since hyperglycemia is not treated during this undiagnosed period.

In addition to diabetes, insulin resistance has many manifestations that include obesity, nephropathy, essential hypertension, dyslipidemia (hypertriglyceridemia, low HDL, decreased LDL particle diameter, enhanced postprandial lipemia and remnant lipoprotein accumulation), ovarian hyperandrogenism and premature adrenarche, non-alcoholic fatty liver disease and systemic inflammation[ 6 , 54 ]. The presence of type 2 diabetes in children and adolescence who are not obese[ 59 - 61 ], the occasional severe dehydration and the presence of ketoacidosis in some pediatric patients with type 2 diabetes[ 55 ] had led to the misclassification of type 2 to type 1 diabetes.

Some patients with many features of type 2 diabetes have some type 1 characteristics including the presence of islet cell autoantibodies or autoantibodies to GAD65 are classified as a distinct type of diabetes called latent autoimmune diabetes in adults (LADA)[ 62 ]. People diagnosed with LADA do not require insulin treatment. In a recent study, Hawa et al[ 63 ] reported 7.1% of European patients with type 2 diabetes with a mean age of 62 years, tested positive for GAD autoantibodies and the prevalence of LADA was higher in patients diagnosed with diabetes at a younger age. This classification of LADA as a distinct type of diabetes is still controversial[ 6 , 64 - 66 ].

Insulin resistance and signaling

Defects in the insulin-dependent substrate proteins IRS-1 and IRS-2 mediated signaling pathway are implicated in the development of metabolic disorders, mainly diabetes. This pathway mediates the cellular response to insulin and involves a large array of insulin-stimulated protein kinases including the serine/threonine kinase AKT and protein kinase C (PKC) that phosphorylate a large number of Ser/Thr residues in the insulin receptor substrate (IRS) proteins involved in the metabolic response to insulin[ 67 ]. In addition, other non-insulin dependent kinases including the AMP-activated protein kinase, c-Jun N-terminal protein kinase and G protein-coupled receptor kinase 2 that are activated under various conditions can phosphorylate the two insulin responsive substrates[ 67 - 71 ]. Disruption in the AKT and PKC kinases is central to the development of diabetes[ 72 ] and is associated with all major features of the disease including hyperinsulinemia, dyslipidemia and insulin resistance[ 73 ]. Replacing the wild type IRS-1 with a mutant version of the protein having alanine instead of tyrosine in three locations using genetic knock-in approach provided evidence to the central role of IRS-1 phosphorylation in the development of insulin resistance[ 74 ]. Using a similar approach to generate IRS-1 mutant with a single mutation involving a specific tyrosine residue, confirmed the role of IRS-1 phosphorylation in the development of insulin resistance pathogenesis[ 75 ]. The large cumulative evidence indicates a complex array of factors including environmental factors[ 76 ] and a wide range of cellular disturbances in glucose and lipid metabolism in various tissues[ 77 ] contribute to the development of insulin resistance. This condition generates complex cellular metabolic changes in a variety of tissues, mainly liver and muscles, that include the inability of the liver to transport and dispose glucose, control glucose production via gluconeogenesis, impaired storage of glucose as glycogen, de novo lipogenesis and hypertriglyceridemia[ 77 ]. Among the factors implicated in the development of insulin resistance, obesity is the most predominant risk factor leading to insulin insensitivity and diabetes which involves several mechanisms that participate in the pathogenesis of the disease[ 78 ]. Obesity-induced insulin resistance is directly linked to increased nutrient flux and energy accumulation in tissues that directly affect cell responsiveness to insulin[ 77 ]. However, it seems that other insulin-independent mechanisms are involved in the overall metabolic disturbances of glucose homeostasis and diabetes including activities in extra-hepatic tissues in addition to the central role of liver.

OTHER TYPES OF DIABETES MELLITUS

Monogenic diabetes.

Characterization of the genetic etiology of diabetes enables more appropriate treatment, better prognosis, and counseling[ 79 ]. Monogenic diabetes is due to a genetic defect in single genes in pancreatic β cells which results in disruption of β cell function or a reduction in the number of β cells. Conventionally, monogenic diabetes is classified according to the age of onset as neonatal diabetes before the age of six months or Maturity Onset Diabetes of the Young (MODY) before the age of 25 years. However, certain familial defects are manifested in neonatal diabetes, MODY or adult onset diabetes[ 2 , 9 , 80 ]. Others believe that classification of diabetes as MODY and neonatal diabetes is obsolete and monogenic diabetes is currently used relating specific genetic etiologies with their specific treatment implications[ 79 ]. Beta cell differentiation depends on the expression of the homeodomain transcription factor PDX1 where mutation in the gene results in early onset diabetes (MODY) and its expression decreases before the onset of diabetes[ 81 ]. The angiopoietin-like protein 8 (ANGPTL8) may represent a potential “betatrophin” that acts to promote the proliferation of beta cells, however, studies using mice lacking the ANGPTL8 active gene or overexpressed protein indicated that it did not seem to play a role in beta cells proliferation[ 82 ].

Mitochondrial diabetes is due to a point mutation in the mitochondrial DNA associated with deafness and maternal transmission of the mutant DNA can result in maternally-inherited diabetes[ 1 , 83 ].

Mutations that result in mutant insulin or the inability to convert proinsulin to insulin result in glucose intolerance in some of these cases. Genetic defects in the insulin receptor or in the signal transduction pathway of insulin have been demonstrated to result in hyperinsulinemia and modest hyperglycemia to severe diabetes[ 1 ].

Disease of the exocrine pancreas

Damage of the β cells of the pancreas due to diffused injury of the pancreas can cause diabetes. This damage could be due to pancreatic carcinoma, pancreatitis, infection, pancreatectomy, and trauma[ 1 ]. Atrophy of the exocrine pancreas leads to progressive loss of the β cells[ 84 ]. Accumulation of fat in the pancreas or pancreatic steatosis could lead to diabetes due to decreased insulin secretion but may require a long time before the damage to β cells occurs[ 85 ]. In most cases, extensive damage of the pancreas is required before diabetes occurs and the exocrine function of the pancreas is decreased in these patients[ 86 ]. Cirrhosis in cystic fibrosis may contribute to insulin resistance and diabetes[ 2 ].

Hormones and drugs

Diabetes has been found in patients with endocrine diseases that secrete excess hormones like growth hormone, glucocorticoids, glucagon and epinephrine in certain endocrinopathies like acromegaly, Cushing’s syndrome, glucagonoma, and pheochromocytoma, respectively[ 1 ]. Some of these hormones are used as drugs such as glucocorticoids to suppress the immune system and in chemotherapy and growth hormone to treat children with stunted growth.

Genetic syndromes

Diabetes has been detected in patients with various genetic syndromes such as Down syndrome, Klinefelter syndrome, Turner syndrome and Wolfram syndrome[ 1 ].

PREDIABETES

Individuals with prediabetes do not meet the criteria of having diabetes but are at high risk to develop type 2 diabetes in the future. According to the ADA Expert Committee, individuals are defined to have prediabetes if they have either impaired fasting plasma glucose (IFG) levels between 100-125 mg/dL (5.6-6.9 mmol/L) or impaired glucose tolerance test (IGT) with 2-h plasma glucose levels in the oral glucose tolerance test (OGTT) of 140-199 mg/dL (7.8-11.0 mmol/L). The World Health Organization (WHO) still adopts the range for IFG from 110-125 mg/dL (6.1-6.9 mmol/L). Prediabetes has been shown to correlate with increased cardiovascular mortality[ 87 , 88 ] and cancer[ 89 ]. The definition of prediabetes with the indicated cut off values is misleading since lower levels of glucose in the normal range are still correlated with cardiovascular disease in a continuous glycemic risk perspective[ 90 ]. In accordance with the recommendation of the ADA in 2009 to use hemoglobin A1c (HbA1c) to diagnose diabetes, ADA also recommended the use of an HbA1c (5.7%-6.4%) to diagnose prediabetes[ 91 ]. The number of people with IGT according to IDF was 316 million in 2013 (global prevalence 6.9% in adults) and is expected to rise to 471 million in 2030[ 27 ]. According to a report in 2014 by the Center for Disease Control and Prevention, 86 million Americans (1 out of 3) have prediabetes[ 92 ]. Four of the top ten countries with the highest prevalence of prediabetes are in the Middle East Arab States of the Gulf (Kuwait, Qatar, UAE and Bahrin with prevalence of 17.9%, 17.1%, 16.6% and 16.3%, respectively)[ 27 ]. The number of people diagnosed with prediabetes is different according to the method and criteria used to diagnose prediabetes. The number of people with prediabetes defined by IFG 100-125 mg/dL is 4-5 folds higher than those diagnosed using the WHO criteria of 110-125 mg/dL[ 93 ]. Diabetes and prediabetes diagnosed using an HbA1c criteria give different estimates compared to methods using FPG or OGTT. Higher percentages of prediabetes were diagnosed using HbA1c compared to FPG[ 94 - 96 ]. Prediabetes is associated with metabolic syndrome and obesity (especially abdominal or visceral obesity), dyslipidemia with high triglycerides and/or low HDL cholesterol, and hypertension[ 97 ]. Not all individuals with prediabetes develop diabetes in the future, exercise with a reduction of weight 5%-10% reduces the risk of developing diabetes considerably (40%-70%)[ 98 ]. Individuals with an HbA1c of 6.0%-6.5% have twice the risk of developing diabetes (25%-50%) in five years compared to those with an HbA1c of 5.5%-6.0%[ 99 ].

DIAGNOSTIC CRITERIA FOR DIABETES MELLITUS

Diabetes mellitus is diagnosed using either the estimation of plasma glucose (FPG or OGTT) or HbA1c. Estimation of the cut off values for glucose and HbA1c is based on the association of FPG or HbA1c with retinopathy. Fasting plasma glucose of ≥ 126 mg/dL (7.0 mmol/L), plasma glucose after 2-h OGTT ≥ 200 mg/dL (11.1 mmol/L), HbA1c ≥ 6.5% (48 mmol/mol) or a random plasma glucose ≥ 200 mg/dL (11.1 mmol/L) along with symptoms of hyperglycemia is diagnostic of diabetes mellitus. In addition to monitor the treatment of diabetes, HbA1c has been recommended to diagnose diabetes by the International Expert Committee in 2009[ 100 ] and endorsed by ADA[ 101 ], the Endocrine Society, the WHO[ 102 ] and many scientists and related organizations all over the world. The advantages and disadvantages of the different tests used to diagnose diabetes have been reviewed by Sacks et al[ 103 ]. The advantages of using HbA1c over FPG to diagnose diabetes include greater convenience and preanalytical stability, lower CV (3.6%) compared to FPG (5.7%) and 2h OGTT (16.6%), stronger correlation with microvascular complications especially retinopathy, and a marker for glycemic control and glycation of proteins which is the direct link between diagnosis of diabetes and its complications[ 104 - 109 ]. It is recommended to repeat the HbA1c test in asymptomatic patients within two weeks to reaffirm a single apparently diagnostic result[ 110 ].

A cut off value for HbA1c of ≥ 6.5% (48 mmol/mol) has been endorsed by many countries and different ethnic groups, yet ethnicity seems to affect the cut off values to diagnose diabetes[ 111 , 112 ]. Cut-off values of 5.5% (37 mmol/mol)[ 113 ] and 6.5% (48 mmol/mol)[ 114 ] have been reported in a Japanese study, 6.0% (42 mmol/mol) in the National Health and Nutrition Examination Survey (NHANES III), 6.2% (44 mmol/mol) in a Pima Indian study, 6.3% (45 mmol/mol) in an Egyptian study as reported by Davidson[ 105 ]; and three cut-off values for Chinese[ 112 ]. The Australians recommended the use of two cut-off values: ≤ 5.5% to “rule-out” and ≥ 7.0% to “rule-in” diabetes[ 115 ]. Variations in the prevalence of diabetes[ 94 , 116 - 119 ] and prediabetes[ 120 ] due to ethnicity have been documented. Most studies diagnosed less subjects with diabetes using HbA1c compared to FPG or OGTT[ 121 - 123 ]. Yet, other studies reported more subjects diagnosed with diabetes using HbA1c[ 96 , 124 - 126 ].

GESTATIONAL DIABETES

Hyperglycemia in pregnancy whether in the form of type 2 diabetes diagnosed before or during pregnancy or in the form gestational diabetes has an increased risk of adverse maternal, fetal and neonatal outcome. Mothers with gestational diabetes and babies born to such mothers have increased risk of developing diabetes later in life. Hyperglycemia in pregnancy is responsible for the increased risk for macrosomia (birth weight ≥ 4.5 kg), large for gestational age births, preeclampsia, preterm birth and cesarean delivery due to large babies[ 127 ]. Risk factors for gestational diabetes include obesity, personal history of gestational diabetes, family history of diabetes, maternal age, polycystic ovary syndrome, sedentary life, and exposure to toxic factors[ 3 ].

Diagnosis of type 2 diabetes before or during pregnancy is based on criteria mentioned before. Fasting plasma glucose ≥ 126 mg/dL (7.0 mmol/L) or 2-h plasma glucose ≥ 200 mg/dL (11.1 mmol/L) after a 75 g oral glucose load. However, gestational diabetes has been diagnosed at 24-28 wk of gestation in women not previously diagnosed with diabetes using two approaches: the first approach is based on the “one-step” International Association of the Diabetes and Pregnancy Study Groups (IADPSG) consensus[ 128 ] and recently adopted by WHO[ 129 ]. Gestational diabetes is diagnosed using this method by FPG ≥ 92 mg/dL (5.1 mmol/L), 1-h plasma glucose after a 75 g glucose load ≥ 180 mg/dL (10.0 mmol/L) or 2-h plasma glucose after a 75 g glucose load ≥ 153 mg/dL (8.5 mmol/L). This criteria is derived from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study[ 127 ] even though the HAPO study showed a continuous relationship between hyperglycemia and adverse short-term pregnancy outcome with no threshold reported[ 130 ]. The second approach is used in the United States and is based on the “two-step” NIH consensus[ 131 ]. In the first step 1-h plasma glucose after a 50 g glucose load under nonfasting state ≥ 140 mg/dL (7.8 mmol/L) is followed by a second step under fasting conditions after a 100 g glucose load for those who screened abnormal in the first step. The diagnosis of gestational diabetes is made when at least two of the four plasma glucose levels are met. The four plasma glucose levels according to Carpenter/Coustan criteria are: FPG ≥ 95 mg/dL (5.3 mmol/L); 1-h ≥ 180 mg/dL (10.0 mmol/L); 2-h ≥ 155 mg/dL (8.6 mmol/L); and 3-h ≥ 140 mg/dL (7.8 mmol/L)[ 1 ].

The use IADPSC criteria in comparison with the Carpenter/Coustan criteria was associated with a 3.5-fold increase in GDM prevalence as well as significant improvements in pregnancy outcomes, and was cost-effective[ 132 ]. In another retrospective cohort study of women diagnosed with gestational diabetes, Ethridge et al[ 133 ] have shown that newborns of women diagnosed with gestational diabetes by IADPSG approach have greater measures of fetal overgrowth compared with Carpenter-Coustan “two-step” approach neonates. A strategy of using fasting plasma glucose as a screening test and to determine the need for OGTT is valid[ 134 , 135 ]. According to Sacks[ 136 ], correlation of glucose concentrations and the risk of subsequent complications will eventually lead to universal guidelines.

The use of ADA/WHO cut off value of HbA1c ≥ 6.5% (48 mmol/mol) to diagnose gestational diabetes is not recommended by the “one step” IADPSC criteria or the “two-step” NIH criteria. Further investigation is required in light of recent reports on HbA1c in combination with OGTT and its usefulness to predict adverse effect of gestational diabetes or obviate the use OGTT in all women with gestational diabetes[ 137 - 141 ].

DIABETES AND GENETICS

Diabetes is a complex disease that involves a wide range of genetic and environmental factors. Over the past several years, many studies have focused on the elucidation of the wide spectrum of genes that played a role in the molecular mechanism of diabetes development[ 142 - 144 ]. However, despite the vast flow of genetic information including the identification of many gene mutations and a large array of single nucleotide polymorphisms (SNPs) in many genes involved in the metabolic pathways that affect blood glucose levels, the exact genetic mechanism of diabetes remains elusive[ 145 , 146 ]. Evidently, a major complication is the fact that a single gene mutation or polymorphism will not impose the same effect among different individuals within a population or different populations. This variation is directly or indirectly affected by the overall genetic background at the individual, family or population levels that are potentially further complicated by interaction with highly variable environmental modifier factors[ 147 , 148 ].

Molecular genetics and type 2 diabetes

One of the major focuses of biomedical research is to delineate the collective and broad genetic variants in the human genome that are involved in the development of diabetes. This major effort will potentially provide the necessary information to understand the molecular genetics of the different forms of diabetes including type 1, type 2 and monogenic neonatal diabetes among individuals of all populations and ethnic groups. Despite the fact that linkage and association studies allowed the identification and characterization of many candidate genes that are associated with type 2 diabetes[ 144 , 149 , 150 ], however, not all of these genes showed consistent and reproducible association with the disease[ 151 ]. Genome wide association studies (GWAS) in various populations identified 70 loci associated with type 2 diabetes and revealed positive linkage of many mutations and SNPs that influence the expression and physiological impact of the related proteins and risk to develop type 2 diabetes. One study involved several thousand type 2 diabetes patients and control subjects from the United Kingdom allowed the identification of several diabetes putative loci positioned in and around the CDKAL1 , CDKN2A/B , HHEX/IDE and SLC30A8 genes in addition to the contribution of a large number of other genetic variants that are involved in the development of the disease[ 152 ]. Two similar studies from the Finns and Swedish populations and the United States resulted in the identification of similar single nucleotide variants[ 153 ] that are linked to the risk of acquiring type 2 diabetes[ 154 , 155 ]. The study in the United States population included in addition to type 2 diabetes, the association of the identified SNPs with the level of triglycerides in the tested subjects[ 155 ]. These SNPs are located near several candidate genes including IGFBP2 and CDKAL1 and other genes in addition to several other variants that are located near or in genes firmly associated with the risk of acquiring type 2 diabetes. Other GWAS analysis studies were performed in the Chinese, Malays, and Asian-Indian populations which are distinct from the European and United States populations in addition to meta-analysis of data from other populations in the region revealed relevant findings among patients with European ancestry[ 156 ]. The results of the combined analysis showed significant association of SNPs in the CDKAL1 , CDKN2A/B , HHEX , KCNQ1 and SLC30A8 genes after adjustment with gender and body mass index. More recently, meta-analysis of GWAS data involving African American type 2 diabetes patients identified similar loci to the previous studies with the addition of two novel loci, HLA-B and INS-IGF[ 157 ]. These results provide strong evidence of common genetic determinants including common specific genes that are linked to diabetes. A small list of specific genetic markers seem strongly associated with the risk of developing type 2 diabetes including the TCF7L2 [ 158 ] and CAPN10 [ 159 , 160 ] genes which also play a significant role in the risk and pathogenesis of the disease[ 158 , 159 ]. The association of TCF7L2 gene variants with type 2 diabetes and its mechanism of action received special attention by several investigators[ 161 , 162 ]. Over expression of the protein was shown to decrease the sensitivity of beta islet cells to secrete insulin[ 163 , 164 ] and was more precisely involved in the regulation of secretary granule fusion that constitute a late event in insulin secretion pathway[ 165 ]. The role of TCF7L2 in insulin secretion was partially clarified[ 166 ] that involves modifying the effect of incretins on insulin secretion by lowering the sensitivity of beta cells to incretins. Several other genes have been found to be significantly associated with the risk of developing type 2 diabetes including a specific SNP in a hematopoietically-expressed homeobox ( HHEX ) gene[ 167 ]. The islet zinc transporter protein (SLC30A8)[ 168 ] showed positive correlation with the risk of developing type 2 diabetes where variant mutations in this gene seem protective against the disease which provides a potential tool for therapy[ 169 ]. More recently, a low frequency variant of the HNF1A identified by whole exome sequencing was associated with the risk of developing type 2 diabetes among the Latino population and potentially may serve as a screening tool[ 170 ]. Genetic variants and specific combined polymorphisms in the interleukin and related genes including interlukin-6 ( IL-6 ), tumor necrosis factor-α and IL-10 genes were found to be associated with greater risk of developing type 2 diabetes[ 171 ], in addition to genetic variants in the genes for IL12B , IL23R and IL23A genes[ 172 ]. In a study involving the hormone sensitive lipase responsible for lipolysis in adipose tissues, a deletion null mutation, which resulted in the absence of the protein from adipocytes, was reported to be associated with diabetes[ 173 ]. Nine specific rare variants in the peroxisome proliferator-activated receptor gamma ( PPARG ) gene that resulted in loss of the function of the protein in adipocytes differentiation, were significantly associated with the risk of developing type 2 diabetes[ 174 ]. In addition, certain SNPs in the alpha 2A adrenergic receptor ( ADRA2A ) gene, involved in the sympathetic nervous system control of insulin secretion and lipolysis, were found to be associated with obesity and type 2 diabetes[ 175 ]. Link analysis between the melatonin MT2 receptor ( MTNR1B ) gene, a G-protein coupled receptor, identified 14 mutant variants from 40 known variants revealed by exome sequencing, to be positively linked with type 2 diabetes[ 176 ]. The authors suggested that mutations in the MT2 gene could provide a tool with other related genes in modifying therapy for type 2 diabetes patients based on their specific genetic background to formulate personalized therapies which potentially may ensures the optimum response. Interestingly, mutations in the clock[ 177 , 178 ] and Bmal1 [ 179 ] transcription factor genes which are involved in beta cells biological clock affecting growth, survival and synaptic vesicle assembly in these cells, resulted in reduced insulin secretion and diabetes. Evidently, prominent metabolic functions involve the production of specific reactive metabolites, leading to oxidative stress, which affect lipids, proteins and other biological compounds leading to serious damage in various tissues and organs. Mutations and SNPs in the antioxidant genes, including superoxide dismutase, catalase and glutathione peroxidase, that decrease their activity are implicated in the risk and pathogenesis of type 2 diabetes[ 180 ]. The metabolic syndrome was shown to be associated with the development of type 2 diabetes in a population that is described as highly endogenous especially in individuals over 45 years of age[ 181 ]. Since consanguinity marriages is high in this population, screening for this syndrome among families could provide an informative marker on the risk of developing type 2 diabetes[ 181 ].

Molecular genetics of type 1 diabetes

Even though type 1 diabetes is basically described as an autoimmune disease that results in the destruction of pancreatic beta cells, however, single gene mutations and SNPs have been found to be associated with the susceptibility to this type of diabetes. Initially, two gene mutations were linked to the development of type 1 diabetes including the autoimmune regulator ( AIRE ) gene which affect the immune tolerance to self antigens leading to autoimmunity[ 182 ] and the FOXP3 gene which results in defective regulatory T cells[ 183 ]. In addition, a mutation in the histone deacetylase SIRTI gene predominantly expressed in beta cells involved in the regulation of insulin secretion[ 184 ] and played a role in modulating the sensitivity of peripheral tissues to insulin[ 185 ] was detected in type 1 diabetes patients[ 186 ]. Recently, additional mutations and SNPs in the CTLA-4 +49A/G and HLA-DQB1 and INS gene VNTR alleles were found to be associated with type 1 diabetes, which have the advantage of differentiating between Latent autoimmune type 1 diabetes and type 2 diabetes[ 187 ]. The HLA-DQB1, in combination with HLA-DR alleles and a polymorphism in PTPN22 gene seem to be associated with the age onset of late type 1 diabetes[ 188 , 189 ]. Two specific polymorphisms in the promoter region of a transmembrane protein (DC-SIGN) gene expressed in macrophages and played an important role of T- cell activation and inflammation were found to be protective against type 1 diabetes[ 190 ]. An innovative non-parametric SNP enrichment tool using summary GWAS DATA allowed the identification of association between several transcription factors and type 1 diabetes and are located in a type 1 diabetes susceptibility region[ 191 ]. Nine SNP variants in several genes associated with type 1 diabetes, not including the major histocompatibility gene region, were identified using extensive GWAS analysis[ 192 ]. Furthermore, several novel SNPs in a region in chromosome 16 located in the CLEC16A gene were shown to be associated with type 1 diabetes and seem to function through the reduced expression of DEX1 in B lymphoblastoid cells[ 193 ]. Since more than 40 regions in the human genome were identified to be associated with the susceptibility to type 1 diabetes[ 194 - 196 ], a weighted risk model was developed utilizing selected genes SNPs could be used for testing infants for these genetic markers that could provide insights in the susceptibility to type 1 diabetes development or safe prevention of the disease among young children[ 197 ].

Molecular genetics of monogenic diabetes

A large array of genes were identified to be involved in the development of monogenic diabetes[ 80 ] which represent about 2%-5% of diabetes patients. Monogenic diabetes results primarily from gene defects that lead to a decrease in beta cell number or function. Monogenic diabetes genes were identified using linkage studies or code for proteins that directly affected glucose homeostasis. The majority of genes responsible for monogenetic diabetes code for either transcription factors that participate in the control of nuclear gene expression or proteins that are located on the cell membrane, cytoplasm and endoplasmic reticulum, proteins involved in insulin synthesis and secretion, exocrine pancreatic proteins and autoimmune diabetes proteins[ 80 ]. The collective function of these proteins is their participation in glucose metabolism at different levels. Evidently, the hierarchy of a specific gene in the overall glucose metabolism pathway determines the onset of diabetes in the patient and whether it is neonataly expressed or have late onset expression (adulthood). Consequently, molecular defects in the structure and function of these genes lead to the disturbance of plasma glucose level, the primary pathological sign of diabetes. The molecular mechanism of permanent neonatal diabetes mellitus (PNDP) in addition to MODY explains the observed phenotype of monogenetic diabetes that involves loss of function of the expressed mutant protein. The first gene implicated in monogenic diabetes was the glucokinase ( GCK ) gene[ 198 ] which functions as a pancreatic sensor for blood glucose where more than 70 mutations in the gene were identified that affected its activity[ 199 ]. A recent study on GCK gene mutations causing neonatal and childhood diabetes showed that the majority of mutations resulted in the loss of the enzyme function primarily due to protein instability[ 148 , 150 ]. Two hepatocytes nuclear factor genes that code for the HNF4A and HNF1A transcription factors were closely associated with MODY1 and MODY2[ 148 , 149 ]. Definitely, a whole list of other genes involved in monogenic diabetes are either overlooked or included in the genetic determinants of type 1 and type 2 diabetes which will be identified and clarified through more careful future studies.

MOLECULAR GENETICS OF DIABETES COMPLICATIONS

In addition to the genetic determinants of diabetes, several gene mutations and polymorphisms have been associated with the clinical complications of diabetes. The cumulative data on diabetes patients with a variety of micro- and macrovascular complications support the presence of strong genetic factors involved in the development of various complications[ 200 ]. A list of genes have been reported that are associated with diabetes complications including ACE and AKR1B1 in nephropathy, VEGF and AKRB1 in retinopathy and ADIPOQ and GLUL in cardiovascular diseases[ 200 ]. A study on Chinese patients revealed a single SNP in the promoter region of the smooth muscle actin ( ACTA2 ) gene correlates with the degree of coronary artery stenosis in type 2 diabetes patients[ 201 ]. Furthermore, the alpha kinase 1 gene ( ALPK1 ) identified as a susceptibility gene for chronic kidney disease by GWAS[ 202 ], was demonstrated in type 2 diabetes patients[ 203 ]. Three additional genes have been strongly correlated with this risk of diabetic retinopathy (DR) including the vascular endothelial growth receptor, aldose reductase and the receptor for advanced glycation products genes[ 204 ] where specific polymorphisms in these genes seem to increase the risk of DR development in diabetes patients[ 204 ]. A significant differential proteome (involving 56 out of 252 proteins) is evident that characterizes vitreous samples obtained from diabetes patients with the complication in comparison to diabetes patients without the complication and control individuals[ 205 ]. Interestingly, a large portion of these proteins (30 proteins) belong to the kallikrein-kinin, coagulation and complement systems including complement C3, complement factor 1, prothrombin, alpha-1-antitrypsin and antithrombin III that are elevated in diabetic patients with retinopathy[ 205 ]. In addition, 2 single nucleotides polymorphisms in the human related B7-I gene seem to mediate podocyte injury in diabetic nephropathy[ 206 ]. Furthermore, increased concentration of the ligand of B7-1 correlates with the progression of end-stage renal disease (ESRD) in diabetes patients[ 206 ]. These results indicate that B7-I inhibition may serve as a potential target for diabetes nephropathy prevention and/or treatment. Recently, it was shown that direct correlation is evident between circulating levels of tumor necrosis factors 1 and 2 and increased risk of ESRD in American Indian patients[ 207 ]. The link between diabetes and proper bone development and health is evident. Studies using animal models with major significant reduction in insulin receptor (IR) in osteoprogenitor cells resulted in thin and rod-like weak bones with high risk of fractures[ 208 ]. Similar findings were observed in animal models with bone-specific IR knockdown animals which points to the central role of IR in the proper development of bones[ 208 ]. Type 2 diabetes is also associated with mitochondrial dysfunction in adipose tissues. Using knockout animal models of specific mitochondrial genes led to significant reduction in key electron transport complexes expression and eventually adipocytes death[ 209 ]. These animals exhibited Insulin resistance in addition to other complications that can potentially lead to cardiovascular disease[ 209 ].

Diabetes mellitus is the epidemic of the century and without effective diagnostic methods at an early stage, diabetes will continue to rise. This review focuses on the types of diabetes and the effective diagnostic methods and criteria to be used for diagnosis of diabetes and prediabetes. Evidently, diabetes is a complex disease with a large pool of genes that are involved in its development. The precise identification of the genetic bases of diabetes potentially provides an essential tool to improve diagnoses, therapy (more towards individualized patient targeted therapy) and better effective genetic counseling. Furthermore, our advanced knowledge of the association between medical genetics and the chronic complications of diabetes, will provide an additional advantage to delay or eradicate these complications that impose an immense pressure on patient’s quality of life and the significantly rising cost of health-care services.

Conflict-of-interest: The authors declare that there is no conflict of interest associated with this manuscript.

Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

Peer-review started: November 23, 2014

First decision: February 7, 2015

Article in press: April 14, 2015

P- Reviewer: Hegardt FG, Surani S, Traub M S- Editor: Gong XM L- Editor: A E- Editor: Wang CH