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Critical Reviews™ in Oncogenesis
SJR: 0.631 SNIP: 0.503 CiteScore™: 2

ISSN Imprimir: 0893-9675
ISSN En Línea: 2162-6448

Critical Reviews™ in Oncogenesis

DOI: 10.1615/CritRevOncog.2019030976
pages 213-222

Type 2 Diabetes: An Updated Overview

Asghar Ghasemi
Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Reza Norouzirad
Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Dezful University of Medical Sciences, Dezful, Iran


The prevalence of type 2 diabetes (T2D) is increasing worldwide. This study provides essential information about the classification, diagnosis, pathogenesis, treatment, and complications of T2D. Glucose homeostasis is controlled by the rates of endogenous glucose production (EGP) and glucose utilization. EGP is ~2 mg/kg/min in humans and is equal to the rate of basal glucose utilization. During fasting, ~75−85% of EGP occurs in the liver and the remainder in the kidney. Hepatic glucose production is the main determinant of fasting blood glucose concentration. In the fed state, when insulin secretion is stimulated and glucagon secretion is inhibited, EGP decreases and glucose uptake in splanchnic (liver and gut) and peripheral (primarily muscle) tissues increases. β-cell dysfunction and insulin resistance represent core pathophysiological defects in T2D. Although the pathogenesis of T2D was previously focused on dysfunctions of "ominous triumvirate" (liver, skeletal muscle, and β-cell), it has been extended to "ominous octet," which includes defects in adipocytes (increased lipolysis), gastrointestinal tract (incretin deficiency/resistance), pancreatic α-cells (hyperglucagonemia), kidneys (increased glucose reabsorption), and brain (insulin resistance); endothelial dysfunction, inflammation, increased oxidative stress, and hypoxia are also involved in the pathogenesis of T2D. In conclusion, diabetes is one of the leading causes of morbidity and mortality worldwide. More insights into the pathophysiology of T2D necessitate revising the treatment approaches from only glycemic control to a pathophysiological-based view. In addition, new emerging complications of T2D such as cancer warrant further attention.


  1. Bluher M. Obesity: global epidemiology and pathogenesis. Nat Rev Endocrinol. 2019;15(5):288-98.

  2. International Diabetes Federation. IDF diabetes atlas, 8th ed. Brussels, Belgium: International Diabetes Federation; 2017. Available from:

  3. Cho NH, Shaw JE, Karuranga S, Huang Y, da Rocha Fernandes JD, Ohlrogge AW, Malanda B. IDF Diabetes Atlas: global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract. 2018;138:271-81.

  4. WeismanA, Fazli GS, JohnsA, Booth GL. Evolving trends in the epidemiology, risk factors, and prevention of type 2 diabetes: a review. Can J Cardiol. 2018;34(5):552-64.

  5. American Diabetes Association. 2. Classification and diagnosis of diabetes: standards of medical care in diabetes-2019. Diabetes Care. 2019 Jan 1;42(Suppl 1):S13-28.

  6. Zaccardi F, Webb DR, Yates T, Davies MJ. Pathophysiology of type 1 and type 2 diabetes mellitus: a 90-year perspective. Postgrad Med J. 2016;92(1084):63-9.

  7. Zimmet P, Alberti KG, Magliano DJ, Bennett PH. Diabetes mellitus statistics on prevalence and mortality: facts and fallacies. Nat Rev Endocrinol. 2016;12(10):616-22.

  8. American Diabetes Association. 3. Prevention or delay of type 2 diabetes: standards of Medical Care in Diabetes-2019. Diabetes Care. 2019 Jan 1;42(Suppl 1):S29-33.

  9. Abdullah A, Peeters A, de Courten M, Stoelwinder J. The magnitude of association between overweight and obesity and the risk of diabetes: a meta-analysis of prospective cohort studies. Diabetes Res Clin Pract. 2010;89(3):309-19.

  10. Hruby A, Hu FB. The epidemiology of obesity: a big picture. Pharmacoeconomics. 2015;33(7):673-89.

  11. Burhans MS, Hagman DK, Kuzma JN, Schmidt KA, Kratz M. Contribution of adipose tissue inflammation to the development of type 2 diabetes mellitus. Compr Physiol. 2019;9(1):1-58.

  12. Defronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58(4):773-95.

  13. Al-Sofiani ME, Ganji SS, Kalyani RR. Body composition changes in diabetes and aging. J Diabetes Comp. 2019;33(6):451-9.

  14. Harding JL, Pavkov ME, Magliano DJ, Shaw JE, Gregg EW. Global trends in diabetes complications: a review of current evidence. Diabetologia. 2019;62(1):3-16.

  15. Lopez-Suarez A. Burden of cancer attributable to obesity, type 2 diabetes and associated risk factors. Metabolism. 2019;92:136-46.

  16. Schwartz MW, Seeley RJ, Tschop MH, Woods SC, Morton GJ, Myers MG, D'Alessio D. Cooperation between brain and islet in glucose homeostasis and diabetes. Nature. 2013;503(7474):59-66.

  17. Tirone TA, Brunicardi FC. Overview of glucose regulation. World J Surg. 2001;25(4):461-7.

  18. Gerich JE. Control of glycaemia. Baillieres Clin Endocrinol Metab. 1993;7(3):551-86.

  19. Rizza RA, Gerich JE, Haymond MW, Westland RE, Hall LD, Clemens AH, Service FJ. Control of blood sugar in insulin-dependent diabetes: comparison of an artificial endocrine pancreas, continuous subcutaneous insulin infusion, and intensified conventional insulin therapy. N Engl J Med. 1980;303(23):1313-8.

  20. Ghasemi A, Zahediasl S, Azizi F. Reference values for fasting serum glucose levels in healthy Iranian adult subjects. Clin Lab. 2011;57(5-6):343-9.

  21. Alsahli M, Shrayyef MZ, Gerich JE. Normal glucose homeostasis. In: Poretsky L, editor. Principles of diabetes mellitus. 3rd ed. Switzerland: Springer; 2017. p. 23-42.

  22. Cersosimo E, Triplitt C, Solis-Herrera C, Mandarino LJ, DeFronzo RA. Pathogenesis of type 2 diabetes mellitus. In: Endotext. South Dartmouth, MA: MDText. com, Inc.; 2000.

  23. Choukem SP, Gautier JF. How to measure hepatic insulin resistance? Diabetes Metab. 2008;34(6 Pt 2):664-73.

  24. Krentz A. Insulin resistance: a clinical handbook. John Wiley & Sons; 2002.

  25. DeFronzo RA. Current issues in the treatment of type 2 diabetes. Overview of newer agents: where treatment is going. Am J Med. 2010;123(3 Suppl):S38-48.

  26. Cersosimo E, Solis-Herrera C, Triplitt C. Inhibition of renal glucose reabsorption as a novel treatment for diabetes patients. J Bras Nefrol. 2014;36(1):80-92.

  27. Santoleri D, Titchenell PM. Resolving the paradox of hepatic insulin resistance. Cell Mol Gastroenterol Hepatol. 2019;7(2):447-56.

  28. Rachek LI. Free fatty acids and skeletal muscle insulin resistance. Prog Mol Biol Transl Sci. 2014;121:267-92.

  29. Abdul-Ghani MA, DeFronzo RA. Pathogenesis of insulin resistance in skeletal muscle. J Biomed Biotechnol. 2010;2010:476279.

  30. Muniyappa R, Lee S, Chen H, Quon MJ. Current approaches for assessing insulin sensitivity and resistance in vivo: advantages, limitations, and appropriate usage. Am J Physiol Endocrinol Metabol. 2008;294(1):E15-26.

  31. Reaven GM. The fourth musketeer-from Alexandre Dumas to Claude Bernard. Diabetologia. 1995;38(1):3-13.

  32. Paneni F, Costantino S, Cosentino F. Role of oxidative stress in endothelial insulin resistance. World J Diabetes. 2015;6(2):326-32.

  33. Rehman K, Akash MSH. Mechanism of generation of oxidative stress and pathophysiology of type 2 diabetes mellitus: how are they interlinked? J Cell Biochem. 2017;118(11):3577-85.

  34. Norouzirad R, Ghanbari M, Bahadoran Z, Abdollahifar MA, Rasouli N, Ghasemi A. Hyperoxia improves carbohydrate metabolism by browning of white adipocytes in obese type 2 diabetic rats. Life Sci. 2019;220:58-68.

  35. Norouzirad R, Gonzalez-Muniesa P, Ghasemi A. Hypoxia in obesity and diabetes: potential therapeutic effects of hyperoxia and nitrate. Oxid Med Cell Longev. 45 2017;2017:5350267.

  36. Rizza RA, Mandarino LJ, Gerich JE. Dose-response characteristics for effects of insulin on production 46 and utilization of glucose in man. Am J Physiol. 1981;240(6):E630-9.

  37. Brown MS, Goldstein JL. Selective versus total insulin resistance: a pathogenic paradox. Cell Metab. 2008;7(2):95-6. 47.

  38. Taylor R, Holman RR. Normal weight individuals who develop type 2 diabetes: the personal fat threshold. Clin Sci (Lond). 2015;128(7):405-10.

  39. Berridge MJ. Cell signalling biology. London, UK: Portland Press; 2014.

  40. Blaslov K, Naranda FS, Kruljac I, Renar IP. Treatment approach to type 2 diabetes: past, present and future. World J Diabetes. 2018;9(12):209-19.

  41. Kapur S, Bedard S, Marcotte B, Cote CH, Marette A. Expression of nitric oxide synthase in skeletal muscle: a novel role for nitric oxide as a modulator of insulin action. Diabetes. 1997;46(11):1691-700.

  42. Tessari P, Cecchet D, Cosma A, Vettore M, Coracina A, Millioni R, Iori E, Puricelli L, Avogaro A, Vedovato M. Nitric oxide synthesis is reduced in subjects with type 2 diabetes and nephropathy. Diabetes. 2010;59(9):2152-9. 52.

  43. Masaki N, Ido Y, Yamada T, Yamashita Y, Toya T, Takase B, Hamburg NM, Adachi T. Endothelial insulin resistance of freshly isolated arterial endothelial cells from radial sheaths in patients with suspected coronary artery disease. J Am Heart Assoc. 2019;8(6):e010816.

  44. Stumvoll M, Haring H, Fritsche A. For debate: Starling's curve of the pancreas-overuse of a concept? Horm Metab Res. 2003;35(7):391-5.

  45. Weir GC, Bonner-Weir S. Five stages of evolving beta-cell dysfunction during progression to diabetes. Diabetes. 2004;53(Suppl 3):S16-21.

  46. Del Prato S, Matsuda M, Simonson DC, Groop LC, Sheehan P, Leonetti F, Bonadonna RC, DeFronzo RA. Studies on the mass action effect of glucose in NIDDM and IDDM: evidence for glucose resistance. Diabetologia. 1997;40(6):687-97.

  47. American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: Standards of medical care in diabetes-2019. Diabetes Care. 2019;42(Suppl 1):S90-102.

  48. Sterrett JJ, Bragg S, Weart CW. Type 2 diabetes medication review. Am J Med Sci. 2016;351(4):342-55.

  49. Asmat U, Abad K, Ismail K. Diabetes mellitus and oxidative stress: a concise review. Saudi Pharm J. 2016;24(5):547-53.

  50. Park S, Kang HJ, Jeon JH, Kim MJ, Lee IK. Recent advances in the pathogenesis of microvascular complications in diabetes. Arch Pharm Res 2019;42(3):252-62.

  51. Avogaro A, Fadini GP. Microvascular complications in diabetes: a growing concern for cardiologists. Int J Cardiol. 2019.

  52. Kharroubi AT, Darwish HM. Diabetes mellitus: the epidemic of the century. World J Diabetes. 2015;6(6):850-67.

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