Advertisement

Pathogenesis of Type 2 Diabetes Mellitus

  • Marcia F. KalinEmail author
  • Marcus GoncalvesEmail author
  • Jennifer John-Kalarickal
  • Vivian FonsecaEmail author
Reference work entry

Abstract

Type 2 diabetes affects about 3% of the worldwide population and about 9% of the US population, and its prevalence is accelerating rapidly. Twin studies suggest that genetics account for 60–90% of the susceptibility to type 2 diabetes. Environmental factors, including physical inactivity, obesity, diet, and altered intestinal microbiota, account for the remaining risk. The earliest detectable defect in the development of type 2 diabetes is insulin resistance, which may occur in the muscle, fat, or liver. The primary cause of insulin resistance in type 2 diabetes appears to be a post-receptor defect. Because insulin resistance in type 2 diabetes is evident in several different actions of insulin, the primary defect likely involves an early step in the insulin signaling pathway, possibly phosphatidylinositol-3-kinase, the insulin receptor substrates IRS-1 or IRS-2, or the glucose transporter, Glut-4. During the natural course of diabetes, insulin levels rise with the increasing obesity and insulin resistance that precede the onset of diabetes, peak around the time of the onset of diabetes, and fall progressively thereafter. The progressive deterioration in insulin secretion results from β-cell loss and β-cell dysfunction. Possible contributors to β-cell loss or β-cell dysfunction include amyloid deposition in the pancreatic islet, β-cell dedifferentiation, glucotoxicity, and lipotoxicity. Other contributors to hyperglycemia in type 2 diabetes include a diminished incretin effect and increased hepatic glucose output.

Keywords

Pathogenesis Pathophysiology Type 2 diabetes 

References

  1. 1.
    Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 2004;27(5):1047–53.CrossRefPubMedGoogle Scholar
  2. 2.
    Centers for Disease Control and Prevention. National diabetes statistics report: estimates of diabetes and its burden in the United States. Atlanta: US Department of Health and Human Services; 2014.Google Scholar
  3. 3.
    Narayan KM, Boyle JP, Thompson TJ, Sorensen SW, Williamson DF. Lifetime risk for diabetes mellitus in the United States. JAMA. 2003;290(14):1884–90. doi:10.1001/jama.290.14.1884.CrossRefPubMedGoogle Scholar
  4. 4.
    Froguel P, Velho G. Genetic determinants of type 2 diabetes. Recent Prog Horm Res. 2001;56:91–105.CrossRefPubMedGoogle Scholar
  5. 5.
    Knowler WC, Pettitt DJ, Savage PJ, Bennett PH. Diabetes incidence in Pima Indians: contributions of obesity and parental diabetes. Am J Epidemiol. 1981;113(2):144–56.CrossRefPubMedGoogle Scholar
  6. 6.
    Narayan KM, Boyle JP, Thompson TJ, Gregg EW, Williamson DF. Effect of BMI on lifetime risk for diabetes in the U.S. Diabetes Care. 2007;30(6):1562–6. doi:10.2337/dc06-2544.CrossRefPubMedGoogle Scholar
  7. 7.
    Grundy SM. Metabolic complications of obesity. Endocrine. 2000;13(2):155–65. doi:10.1385/ENDO:13:2:155.CrossRefPubMedGoogle Scholar
  8. 8.
    Groop LC. Insulin resistance: the fundamental trigger of type 2 diabetes. Diabetes Obes Metab. 1999;1 Suppl 1:S1–7.CrossRefPubMedGoogle Scholar
  9. 9.
    Clark DO. Physical activity efficacy and effectiveness among older adults and minorities. Diabetes Care. 1997;20(7):1176–82.CrossRefPubMedGoogle Scholar
  10. 10.
    Hartstra AV, Bouter KE, Backhed F, Nieuwdorp M. Insights into the role of the microbiome in obesity and type 2 diabetes. Diabetes Care. 2015;38(1):159–65. doi:10.2337/dc14-0769.CrossRefPubMedGoogle Scholar
  11. 11.
    Vrieze A, Van Nood E, Holleman F, Salojarvi J, Kootte RS, Bartelsman JF, et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology. 2012;143(4):913–6. doi:10.1053/j.gastro.2012.06.031. e7.CrossRefPubMedGoogle Scholar
  12. 12.
    Martin BC, Warram JH, Krolewski AS, Bergman RN, Soeldner JS, Kahn CR. Role of glucose and insulin resistance in development of type 2 diabetes mellitus: results of a 25-year follow-up study. Lancet. 1992;340(8825):925–9.CrossRefPubMedGoogle Scholar
  13. 13.
    Saad MF, Knowler WC, Pettitt DJ, Nelson RG, Mott DM, Bennett PH. Sequential changes in serum insulin concentration during development of non-insulin-dependent diabetes. Lancet. 1989;1(8651):1356–9.CrossRefPubMedGoogle Scholar
  14. 14.
    DeFronzo RA, Ferrannini E, Simonson DC. Fasting hyperglycemia in non-insulin-dependent diabetes mellitus: contributions of excessive hepatic glucose production and impaired tissue glucose uptake. Metabolism. 1989;38(4):387–95.CrossRefPubMedGoogle Scholar
  15. 15.
    DeFronzo RA, Tripathy D. Skeletal muscle insulin resistance is the primary defect in type 2 diabetes. Diabetes Care. 2009;32 Suppl 2:S157–63. doi:10.2337/dc09-S302.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Samuel VT, Shulman GI. The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux. J Clin Invest. 2016;126(1):12–22. doi:10.1172/JCI77812.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Aeberli I, Hochuli M, Gerber PA, Sze L, Murer SB, Tappy L, et al. Moderate amounts of fructose consumption impair insulin sensitivity in healthy young men: a randomized controlled trial. Diabetes Care. 2013;36(1):150–6. doi:10.2337/dc12-0540.CrossRefPubMedGoogle Scholar
  18. 18.
    Dekker MJ, Su Q, Baker C, Rutledge AC, Adeli K. Fructose: a highly lipogenic nutrient implicated in insulin resistance, hepatic steatosis, and the metabolic syndrome. Am J Physiol Endocrinol Metab. 2010;299(5):E685–94. doi:10.1152/ajpendo.00283.2010.CrossRefPubMedGoogle Scholar
  19. 19.
    Moller DE, Flier JS. Insulin resistance – mechanisms, syndromes, and implications. N Engl J Med. 1991;325(13):938–48. doi:10.1056/NEJM199109263251307.CrossRefPubMedGoogle Scholar
  20. 20.
    Elbein SC, Sorensen LK, Taylor M. Linkage analysis of insulin-receptor gene in familial NIDDM. Diabetes. 1992;41(5):648–56.CrossRefPubMedGoogle Scholar
  21. 21.
    Kahn CR, Vicent D, Doria A. Genetics of non-insulin-dependent (type-II) diabetes mellitus. Annu Rev Med. 1996;47:509–31. doi:10.1146/annurev.med.47.1.509.CrossRefPubMedGoogle Scholar
  22. 22.
    Kono T, Barham FW. The relationship between the insulin-binding capacity of fat cells and the cellular response to insulin. Studies with intact and trypsin-treated fat cells. J Biol Chem. 1971;246(20):6210–6.PubMedGoogle Scholar
  23. 23.
    Klein HH, Matthaei S, Drenkhan M, Ries W, Scriba PC. The relationship between insulin binding, insulin activation of insulin-receptor tyrosine kinase, and insulin stimulation of glucose uptake in isolated rat adipocytes. Effects of isoprenaline. Biochem J. 1991;274(Pt 3):787–92.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Thies RS, Molina JM, Ciaraldi TP, Freidenberg GR, Olefsky JM. Insulin-receptor autophosphorylation and endogenous substrate phosphorylation in human adipocytes from control, obese, and NIDDM subjects. Diabetes. 1990;39(2):250–9.CrossRefPubMedGoogle Scholar
  25. 25.
    Cusi K, Maezono K, Osman A, Pendergrass M, Patti ME, Pratipanawatr T, et al. Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle. J Clin Invest. 2000;105(3):311–20. doi:10.1172/JCI7535.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Kruszynska YT, Olefsky JM. Cellular and molecular mechanisms of non-insulin dependent diabetes mellitus. J Invest Med. 1996;44(8):413–28.Google Scholar
  27. 27.
    Kelley DE, Mintun MA, Watkins SC, Simoneau JA, Jadali F, Fredrickson A, et al. The effect of non-insulin-dependent diabetes mellitus and obesity on glucose transport and phosphorylation in skeletal muscle. J Clin Invest. 1996;97(12):2705–13. doi:10.1172/JCI118724.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Ferrannini E, Gastaldelli A, Miyazaki Y, Matsuda M, Mari A, DeFronzo RA. Beta-cell function in subjects spanning the range from normal glucose tolerance to overt diabetes: a new analysis. J Clin Endocrinol Metab. 2005;90(1):493–500. doi:10.1210/jc.2004-1133.CrossRefPubMedGoogle Scholar
  29. 29.
    Porte Jr D, Kahn SE. Beta-cell dysfunction and failure in type 2 diabetes: potential mechanisms. Diabetes. 2001;50 Suppl 1:S160–3.CrossRefPubMedGoogle Scholar
  30. 30.
    Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes. 2003;52(1):102–10.CrossRefPubMedGoogle Scholar
  31. 31.
    Cinti F, Bouchi R, Kim-Muller JY, Ohmura Y, Sandoval PR, Masini M, et al. Evidence of beta-cell dedifferentiation in human type 2 diabetes. J Clin Endocrinol Metab. 2016;101(3):1044–54. doi:10.1210/jc.2015-2860.CrossRefPubMedGoogle Scholar
  32. 32.
    Westermark P. Amyloid in the islets of Langerhans: thoughts and some historical aspects. Ups J Med Sci. 2011;116(2):81–9. doi:10.3109/03009734.2011.573884.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Maloy AL, Longnecker DS, Greenberg ER. The relation of islet amyloid to the clinical type of diabetes. Hum Pathol. 1981;12(10):917–22.CrossRefPubMedGoogle Scholar
  34. 34.
    Clark A, de Koning EJ, Hattersley AT, Hansen BC, Yajnik CS, Poulton J. Pancreatic pathology in non-insulin dependent diabetes (NIDDM). Diabetes Res Clin Pract. 1995;28(Suppl):S39–47.CrossRefPubMedGoogle Scholar
  35. 35.
    Schneider HM, Storkel S, Will W. Amyloid of islets of Langerhans and its relation to diabetes mellitus (author's transl). Dtsch Med Wochenschr. 1980;105(33):1143–7. doi:10.1055/s-2008-1070828.CrossRefPubMedGoogle Scholar
  36. 36.
    Westermark P, Wilander E, Westermark GT, Johnson KH. Islet amyloid polypeptide-like immunoreactivity in the islet B cells of type 2 (non-insulin-dependent) diabetic and non-diabetic individuals. Diabetologia. 1987;30(11):887–92.PubMedGoogle Scholar
  37. 37.
    Lorenzo A, Razzaboni B, Weir GC, Yankner BA. Pancreatic islet cell toxicity of amylin associated with type-2 diabetes mellitus. Nature. 1994;368(6473):756–60. doi:10.1038/368756a0.CrossRefPubMedGoogle Scholar
  38. 38.
    Clark A, Edwards CA, Ostle LR, Sutton R, Rothbard JB, Morris JF, et al. Localisation of islet amyloid peptide in lipofuscin bodies and secretory granules of human B-cells and in islets of type-2 diabetic subjects. Cell Tissue Res. 1989;257(1):179–85.CrossRefPubMedGoogle Scholar
  39. 39.
    Buse JB, Weyer C, Maggs DG. Amylin replacement with pramlintide in type 1 and type 2 diabetes: a physiological approach to overcome barriers with insulin therapy. Clin Diab. 2002;20(3):137–44.CrossRefGoogle Scholar
  40. 40.
    Ludvik B, Thomaseth K, Nolan JJ, Clodi M, Prager R, Pacini G. Inverse relation between amylin and glucagon secretion in healthy and diabetic human subjects. Eur J Clin Invest. 2003;33(4):316–22.CrossRefPubMedGoogle Scholar
  41. 41.
    Macdonald IA. Amylin and the gastrointestinal tract. Diabet Med. 1997;14 Suppl 2:S24–8. doi:10.1002/(SICI)1096-9136(199706)14:2+<S24::AID-DIA399>3.0.CO;2-M.CrossRefPubMedGoogle Scholar
  42. 42.
    Johnson KH, O’Brien TD, Betsholtz C, Westermark P. Islet amyloid, islet-amyloid polypeptide, and diabetes mellitus. N Engl J Med. 1989;321(8):513–8. doi:10.1056/NEJM198908243210806.CrossRefPubMedGoogle Scholar
  43. 43.
    Azen SP, Peters RK, Berkowitz K, Kjos S, Xiang A, Buchanan TA. TRIPOD (TRoglitazone In the Prevention Of Diabetes): a randomized, placebo-controlled trial of troglitazone in women with prior gestational diabetes mellitus. Control Clin Trials. 1998;19(2):217–31.CrossRefPubMedGoogle Scholar
  44. 44.
    Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346(6):393–403. doi:10.1056/NEJMoa012512.CrossRefPubMedGoogle Scholar
  45. 45.
    Knowler WC, Hamman RF, Edelstein SL, Barrett-Connor E, Ehrmann DA, Walker EA, et al. Prevention of type 2 diabetes with troglitazone in the diabetes prevention program. Diabetes. 2005;54(4):1150–6.CrossRefPubMedGoogle Scholar
  46. 46.
    Investigators DT, Gerstein HC, Yusuf S, Bosch J, Pogue J, Sheridan P, 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. 2006;368(9541):1096–105. doi:10.1016/S0140-6736(06)69420-8.CrossRefGoogle Scholar
  47. 47.
    Chiasson JL, Gomis R, Hanefeld M, Josse RG, Karasik A, Laakso M. The STOP-NIDDM trial: an international study on the efficacy of an alpha-glucosidase inhibitor to prevent type 2 diabetes in a population with impaired glucose tolerance: rationale, design, and preliminary screening data. Study to prevent non-insulin-dependent diabetes mellitus. Diabetes Care. 1998;21(10):1720–5.CrossRefPubMedGoogle Scholar
  48. 48.
    Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006;355(23):2427–43. doi:10.1056/NEJMoa066224.CrossRefPubMedGoogle Scholar
  49. 49.
    Garvey WT, Olefsky JM, Griffin J, Hamman RF, Kolterman OG. The effect of insulin treatment on insulin secretion and insulin action in type II diabetes mellitus. Diabetes. 1985;34(3):222–34.CrossRefPubMedGoogle Scholar
  50. 50.
    Henry RR, Wallace P, Olefsky JM. Effects of weight loss on mechanisms of hyperglycemia in obese non-insulin-dependent diabetes mellitus. Diabetes. 1986;35(9):990–8.CrossRefPubMedGoogle Scholar
  51. 51.
    McGarry JD, Dobbins RL. Fatty acids, lipotoxicity and insulin secretion. Diabetologia. 1999;42(2):128–38. doi:10.1007/s001250051130.CrossRefPubMedGoogle Scholar
  52. 52.
    Tushuizen ME, Bunck MC, Pouwels PJ, Bontemps S, van Waesberghe JH, Schindhelm RK, et al. Pancreatic fat content and beta-cell function in men with and without type 2 diabetes. Diabetes Care. 2007;30(11):2916–21. doi:10.2337/dc07-0326.CrossRefPubMedGoogle Scholar
  53. 53.
    Meier JJ, Nauck MA. Is the diminished incretin effect in type 2 diabetes just an epi-phenomenon of impaired beta-cell function? Diabetes. 2010;59(5):1117–25. doi:10.2337/db09-1899.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;26(10):2929–40.CrossRefPubMedGoogle Scholar
  55. 55.
    Drucker DJ. Glucagon-like peptide-1 and the islet beta-cell: augmentation of cell proliferation and inhibition of apoptosis. Endocrinology. 2003;144(12):5145–8. doi:10.1210/en.2003-1147.CrossRefPubMedGoogle Scholar
  56. 56.
    Nauck M, Stockmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia. 1986;29(1):46–52.CrossRefPubMedGoogle Scholar
  57. 57.
    Meier JJ, Nauck MA. Is secretion of glucagon-like peptide-1 reduced in type 2 diabetes mellitus? Nat Clin Pract Endocrinol Metab. 2008;4(11):606–7. doi:10.1038/ncpendmet0946.CrossRefPubMedGoogle Scholar
  58. 58.
    Consoli A. Role of liver in pathophysiology of NIDDM. Diabetes Care. 1992;15(3):430–41.CrossRefPubMedGoogle Scholar
  59. 59.
    Girard J. The inhibitory effects of insulin on hepatic glucose production are both direct and indirect. Diabetes. 2006;55 Suppl 2:S65–9. doi:10.2337/db06-S009.CrossRefGoogle Scholar
  60. 60.
    Unger RH. Glucagon physiology and pathophysiology in the light of new advances. Diabetologia. 1985;28(8):574–8.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Endocrinology Service, Department of MedicineMemorial Sloan Kettering Cancer CenterNew YorkUSA
  2. 2.Section of EndocrinologyTullis Tulane Alumni Chair in Diabetes, Tulane University Health Sciences CenterNew OrleansUSA
  3. 3.EndocrinologyNortheast Georgia Diagnostic ClinicGainesvilleUSA

Personalised recommendations