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Mechanisms linking obesity to insulin resistance and type 2 diabetes

Abstract

Obesity is associated with an increased risk of developing insulin resistance and type 2 diabetes. In obese individuals, adipose tissue releases increased amounts of non-esterified fatty acids, glycerol, hormones, pro-inflammatory cytokines and other factors that are involved in the development of insulin resistance. When insulin resistance is accompanied by dysfunction of pancreatic islet β-cells — the cells that release insulin — failure to control blood glucose levels results. Abnormalities in β-cell function are therefore critical in defining the risk and development of type 2 diabetes. This knowledge is fostering exploration of the molecular and genetic basis of the disease and new approaches to its treatment and prevention.

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Figure 1: Relationship between insulin sensitivity and insulin release in health and disease.
Figure 2: Simplified model outlining potential cellular mechanisms of β-cell adaptation to insulin resistance.
Figure 3: Interaction of genes and the environment in individuals who maintain normal glucose tolerance and those who develop type 2 diabetes.
Figure 4: Model of the critical role of impaired insulin release in linking obesity with insulin resistance and type 2 diabetes.

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References

  1. Hedley, A. A. et al. Prevalence of overweight and obesity among US children, adolescents, and adults, 1999–2002. J. Am. Med. Assoc. 291, 2847–2850 (2004).

    Article  CAS  Google Scholar 

  2. World Health Organization Consultation on Obesity 1–253 (World Health Organization, Geneva, 2000).

  3. 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 27, 1047–1053 (2004).

    PubMed  Google Scholar 

  4. Reaven, G. M. Role of insulin resistance in human disease. Diabetes 37, 1595–1607 1988).

    CAS  PubMed  Google Scholar 

  5. Perley, M. & Kipnis, D. M. Plasma insulin responses to glucose and tolbutamide of normal weight and obese diabetic and nondiabetic subjects. Diabetes 15, 867–874 (1966).

    CAS  PubMed  Google Scholar 

  6. Polonsky, K. S., Given, B. D. & Van Cauter, E. Twenty-four-hour profiles and patterns of insulin secretion in normal and obese subjects. J. Clin. Invest. 81, 442–448 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Kahn, S. E. et al. Quantification of the relationship between insulin sensitivity and B-cell function in human subjects. Evidence for a hyperbolic function. Diabetes 42, 1663–1672 (1993).

    CAS  PubMed  Google Scholar 

  8. Kahn, S. E. The importance of β-cell failure in the development and progression of type 2 diabetes. J. Clin. Endocrinol. Metab. 86, 4047–4058 (2001).

    CAS  PubMed  Google Scholar 

  9. Moran, A. et al. Insulin resistance during puberty: results from clamp studies in 357 children. Diabetes 48, 2039–2044 (1999).

    CAS  PubMed  Google Scholar 

  10. Buchanan, T. A., Metzger, B. E., Freinkel, N. & Bergman, R. N. Insulin sensitivity and B-cell responsiveness to glucose during late pregnancy in lean and moderately obese women with normal glucose tolerance or mild gestational diabetes. Am. J. Obstet. Gynecol. 162, 1008–1014 (1990).

    CAS  PubMed  Google Scholar 

  11. DeFronzo, R. A. Glucose intolerance of aging. Evidence for tissue insensitivity to insulin. Diabetes 28, 1095–1101 (1979).

    CAS  PubMed  Google Scholar 

  12. Goodyear, L. J. & Kahn, B. B. Exercise, glucose transport, and insulin sensitivity. Annu. Rev. Med. 49, 235–261 (1998).

    CAS  PubMed  Google Scholar 

  13. Chen, M., Bergman, R. N. & Porte, D. Insulin resistance and β-cell dysfunction in aging: the importance of dietary carbohydrate. J. Clin. Endocrinol. Metab. 67, 951–957 (1988).

    CAS  PubMed  Google Scholar 

  14. Wellen, K. E. & Hotamisligil, G. S. Inflammation, stress, and diabetes. J. Clin. Invest. 115, 1111–1119 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Scherer, P. E. Adipose tissue: from lipid storage compartment to endocrine organ. Diabetes 55, 1537–1545 (2006).

    CAS  PubMed  Google Scholar 

  16. Shoelson, S. E., Lee, J. & Goldfine, A. B. Inflammation and insulin resistance. J. Clin. Invest. 116, 1793–1801 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Yang, Q. et al. Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature 436, 356–362 (2005).

    ADS  CAS  PubMed  Google Scholar 

  18. Kadowaki, T. et al. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J. Clin. Invest. 116, 1784–1792 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Fain, J. N., Madan, A. K., Hiler, M. L., Cheema, P. & Bahouth, S. W. Comparison of the release of adipokines by adipose tissue, adipose tissue matrix, and adipocytes from visceral and subcutaneous abdominal adipose tissues of obese humans. Endocrinology 145, 2273–2282 (2004).

    CAS  PubMed  Google Scholar 

  20. Mooney, R. A. et al. Suppressors of cytokine signaling-1 and -6 associate with and inhibit the insulin receptor. A potential mechanism for cytokine-mediated insulin resistance. J. Biol. Chem. 276, 25889–25893 (2001).

    CAS  PubMed  Google Scholar 

  21. Perreault, M. & Marette, A. Targeted disruption of inducible nitric oxide synthase protects against obesity-linked insulin resistance in muscle. Nature Med. 7, 1138–1143 (2001).

    CAS  PubMed  Google Scholar 

  22. Weisberg, S. P. et al. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112, 1796–1808 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Xu, H. et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J. Clin. Invest. 112, 1821–1830 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Reaven, G. M., Hollenbeck, C., Jeng, C. Y., Wu, M. S. & Chen, Y. D. Measurement of plasma glucose, free fatty acid, lactate, and insulin for 24 h in patients with NIDDM. Diabetes 37, 1020–1024 (1988).

    CAS  PubMed  Google Scholar 

  25. Boden, G. Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes 46, 3–10 (1997).

    CAS  PubMed  Google Scholar 

  26. Roden, M. et al. Mechanism of free fatty acid-induced insulin resistance in humans. J. Clin. Invest. 97, 2859–2865 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Santomauro, A. T. et al. Overnight lowering of free fatty acids with Acipimox improves insulin resistance and glucose tolerance in obese diabetic and nondiabetic subjects. Diabetes 48, 1836–1841 (1999).

    CAS  PubMed  Google Scholar 

  28. Randle, P. J., Garland, P. B., Hales, C. N. & Newsholme, E. A. The glucose fatty-acid cycle: its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet i, 785–789 (1963).

    Google Scholar 

  29. Shulman, G. I. Cellular mechanisms of insulin resistance. J. Clin. Invest. 106, 171–176 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Carey, D. G., Jenkins, A. B., Campbell, L. V., Freund, J. & Chisholm, D. J. Abdominal fat and insulin resistance in normal and overweight women: direct measurements reveal a strong relationship in subjects at both low and high risk of NIDDM. Diabetes 45, 633–638 (1996).

    CAS  PubMed  Google Scholar 

  31. Cnop, M. et al. The concurrent accumulation of intra-abdominal and subcutaneous fat explains the association between insulin resistance and plasma leptin concentrations: distinct metabolic effects of two fat compartments. Diabetes 51, 1005–1015 (2002).

    CAS  PubMed  Google Scholar 

  32. Kahn, S. E. The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes. Diabetologia 46, 3–19 (2003).

    CAS  PubMed  Google Scholar 

  33. Fujimoto, W. Y. et al. Preventing diabetes — applying pathophysiological and epidemiological evidence. Br. J. Nutr. 84 (Suppl. 2), S173–S176 (2000).

    CAS  PubMed  Google Scholar 

  34. Maeda, K. et al. Analysis of an expression profile of genes in the human adipose tissue. Gene 190, 227–235 (1997).

    CAS  PubMed  Google Scholar 

  35. Motoshima, H. et al. Differential regulation of adiponectin secretion from cultured human omental and subcutaneous adipocytes: effects of insulin and rosiglitazone. J. Clin. Endocrinol. Metab. 87, 5662–5667 (2002).

    CAS  PubMed  Google Scholar 

  36. Reynisdottir, S., Dauzats, M., Thorne, A. & Langin, D. Comparison of hormone-sensitive lipase activity in visceral and subcutaneous human adipose tissue. J. Clin. Endocrinol. Metab. 82, 4162–4166 (1997).

    CAS  PubMed  Google Scholar 

  37. Montague, C. T. & O'Rahilly, S. The perils of portliness: causes and consequences of visceral adiposity. Diabetes 49, 883–888 (2000).

    CAS  PubMed  Google Scholar 

  38. Kim, S. P., Ellmerer, M., Van Citters, G. W. & Bergman, R. N. Primacy of hepatic insulin resistance in the development of the metabolic syndrome induced by an isocaloric moderate-fat diet in the dog. Diabetes 52, 2453–2460 (2003).

    CAS  PubMed  Google Scholar 

  39. Kloppel, G., Lohr, M., Habich, K., Oberholzer, M. & Heitz, P. U. Islet pathology and the pathogenesis of type 1 and type 2 diabetes mellitus revisited. Surv. Synth. Pathol. Res. 4, 110–125 (1985).

    CAS  PubMed  Google Scholar 

  40. Butler, A. E. et al. β-cell deficit and increased β-cell apoptosis in humans with type 2 diabetes. Diabetes 52, 102–110 (2003).

    CAS  PubMed  Google Scholar 

  41. Chen, C., Hosokawa, H., Bumbalo, L. M. & Leahy, J. L. Mechanism of compensatory hyperinsulinemia in normoglycemic insulin-resistant spontaneously hypertensive rats. Augmented enzymatic activity of glucokinase in β-cells. J. Clin. Invest. 94, 399–404 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Liu, Y. Q., Jetton, T. L. & Leahy, J. L. β-cell adaptation to insulin resistance. Increased pyruvate carboxylase and malate-pyruvate shuttle activity in islets of nondiabetic Zucker fatty rats. J. Biol. Chem. 277, 39163–39168 (2002).

    CAS  PubMed  Google Scholar 

  43. Kahn, S. E. et al. Increased β-cell secretory capacity as mechanism for islet adaptation to nicotinic acid-induced insulin resistance. Diabetes 38, 562–568 (1989).

    CAS  PubMed  Google Scholar 

  44. Kahn, S. E. et al. Effect of exercise on insulin action, glucose tolerance and insulin secretion in aging. Am. J. Physiol. 258, E937–E943 (1990).

    CAS  PubMed  Google Scholar 

  45. Dobbins, R. L. et al. A fatty acid-dependent step is critically important for both glucose — and non-glucose — stimulated insulin secretion. J. Clin. Invest. 101, 2370–2376 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Prentki, M., Joly, E., El-Assaad, W. & Roduit, R. Malonyl-CoA signaling, lipid partitioning, and glucolipotoxicity: role in β-cell adaptation and failure in the etiology of diabetes. Diabetes 51 (Suppl. 3), S405–S413 (2002).

    CAS  PubMed  Google Scholar 

  47. Bergman, R. N. et al. Why visceral fat is bad: mechanisms of the metabolic syndrome. Obesity 14 (Suppl. 1), 16S–19S (2006).

    CAS  PubMed  Google Scholar 

  48. Itoh, Y. et al. Free fatty acids regulate insulin secretion from pancreatic β cells through GPR40. Nature 422, 173–176 (2003).

    ADS  CAS  PubMed  Google Scholar 

  49. Drucker, D. J. The biology of incretin hormones. Cell Metab. 3, 153–165 (2006).

    CAS  PubMed  Google Scholar 

  50. Verdich, C. et al. The role of postprandial releases of insulin and incretin hormones in meal-induced satiety — effect of obesity and weight reduction. Int. J. Obes. Relat. Metab. Disord. 25, 1206–1214 (2001).

    CAS  PubMed  Google Scholar 

  51. Berthoud, H. R. & Jeanrenaud, B. Acute hyperinsulinemia and its reversal by vagotomy after lesions of the ventromedial hypothalamus in anesthetized rats. Endocrinology 105, 146–151 (1979).

    CAS  PubMed  Google Scholar 

  52. Ahren, B., Taborsky, G. J. & Porte, D. Neuropeptidergic versus cholinergic and adrenergic regulation of islet hormone secretion. Diabetologia 29, 827–836 (1986).

    CAS  PubMed  Google Scholar 

  53. Hull, R. L. et al. Dietary-fat-induced obesity in mice results in beta cell hyperplasia but not increased insulin release: evidence for specificity of impaired beta cell adaptation. Diabetologia 48, 1350–1358 (2005).

    CAS  PubMed  Google Scholar 

  54. Sorenson, R. L. & Brelje, T. C. Adaptation of islets of Langerhans to pregnancy: beta-cell growth, enhanced insulin secretion and the role of lactogenic hormones. Horm. Metab. Res. 29, 301–307 (1997).

    CAS  PubMed  Google Scholar 

  55. Bonner-Weir, S., Deery, D., Leahy, J. L. & Weir, G. C. Compensatory growth of pancreatic β-cells in adult rats after short-term glucose infusion. Diabetes 38, 49–53 (1989).

    CAS  PubMed  Google Scholar 

  56. Steil, G. M. et al. Adaptation of β-cell mass to substrate oversupply: enhanced function with normal gene expression. Am. J. Physiol. Endocrinol. Metab. 280, E788–E796 (2001).

    CAS  PubMed  Google Scholar 

  57. Rhodes, C. J. Type 2 diabetes — a matter of β-cell life and death? Science 307, 380–384 (2005).

    ADS  CAS  PubMed  Google Scholar 

  58. Bernal-Mizrachi, E., Wen, W., Stahlhut, S., Welling, C. M. & Permutt, M. A. Islet β cell expression of constitutively active Akt1/PKBα induces striking hypertrophy, hyperplasia, and hyperinsulinemia. J. Clin. Invest. 108, 1631–1638 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Hennige, A. M. et al. Upregulation of insulin receptor substrate-2 in pancreatic β cells prevents diabetes. J. Clin. Invest. 112, 1521–1532 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Kiba, T. et al. Ventromedial hypothalamic lesion-induced vagal hyperactivity stimulates rat pancreatic cell proliferation. Gastroenterology 110, 885–893 (1996).

    CAS  PubMed  Google Scholar 

  61. Røder, M. E., Porte, D. & Kahn, S. E. Disproportionately elevated proinsulin levels reflect the degree of impaired B-cell secretory capacity in patients with non-insulin dependent diabetes mellitus. J. Clin. Endocrinol. Metab. 83, 604–608 (1998).

    PubMed  Google Scholar 

  62. Garvey, W. T., Olefsky, J. M., Griffen, J., Hamman, R. F. & Kolterman, O. G. The effect of insulin treatment on insulin secretion and insulin action in type II diabetes mellitus. Diabetes 34, 222–234 (1985).

    CAS  PubMed  Google Scholar 

  63. Kahn, S. E., Bergman, R. N., Schwartz, M. W., Taborsky, G. J. & Porte, D. Short-term hyperglycemia and hyperinsulinemia improve insulin action but do not alter glucose action in normal humans. Am. J. Physiol. 262, E518–E523 (1992).

    CAS  PubMed  Google Scholar 

  64. Sako, Y. & Grill, V. E. A 48-hour lipid infusion in the rat time-dependently inhibits glucose-induced insulin secretion and B cell oxidation through a process likely coupled to fatty acid oxidation. Endocrinology 127, 1580–1589 (1990).

    CAS  PubMed  Google Scholar 

  65. Zhou, Y. P. & Grill, V. E. Long-term exposure of rat pancreatic islets to fatty acids inhibits glucose-induced insulin secretion and biosynthesis through a glucose fatty acid cycle. J. Clin. Invest. 93, 870–876 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Carpentier, A. et al. Acute enhancement of insulin secretion by FFA in humans is lost with prolonged FFA elevation. Am. J. Physiol. 276, E1055–E1066 (1999).

    CAS  PubMed  Google Scholar 

  67. Utzschneider, K. M. et al. Impact of differences in fasting glucose and glucose tolerance on the hyperbolic relationship between insulin sensitivity and insulin responses. Diabetes Care 29, 356–362 (2006).

    PubMed  Google Scholar 

  68. Ward, W. K. et al. Insulin resistance and impaired insulin secretion in subjects with histories of gestational diabetes mellitus. Diabetes 34, 861–869 (1985).

    CAS  PubMed  Google Scholar 

  69. Ehrmann, D. A. et al. Insulin secretory defects in polycystic ovary syndrome. Relationship to insulin sensitivity and family history of non-insulin-dependent diabetes mellitus. J. Clin. Invest. 96, 520–527 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Kahn, S. E. et al. Exercise training delineates the importance of B-cell dysfunction to the glucose intolerance of human aging. J. Clin. Endocrinol. Metab. 74, 1336–1342 (1992).

    CAS  PubMed  Google Scholar 

  71. Cavaghan, M. K., Ehrmann, D. A., Byrne, M. M. & Polonsky, K. S. Treatment with the oral antidiabetic agent troglitazone improves β cell responses to glucose in subjects with impaired glucose tolerance. J. Clin. Invest. 100, 530–537 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Jensen, C. C. et al. β-cell function is the major determinant of oral glucose tolerance in four ethnic groups in the United States. Diabetes 51, 2170–2178 (2002).

    CAS  PubMed  Google Scholar 

  73. Knowles, N. G., Landchild, M. A., Fujimoto, W. Y. & Kahn, S. E. Insulin and amylin release are both diminished in first-degree relatives of subjects with type 2 diabetes. Diabetes Care 25, 292–297 (2002).

    CAS  PubMed  Google Scholar 

  74. Weyer, C., Bogardus, C., Mott, D. M. & Pratley, R. E. The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J. Clin. Invest. 104, 787–794 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Festa, A., Williams, K., D'Agostino, R., Wagenknecht, L. E. & Haffner, S. M. The natural course of β-cell function in nondiabetic and diabetic individuals: the Insulin Resistance Atherosclerosis Study. Diabetes 55, 1114–1120 (2006).

    CAS  PubMed  Google Scholar 

  76. O'Rahilly, S. & Farooqi, I. S. Genetics of obesity. Phil. Trans. R. Soc. B 361, 1095–1105 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Barroso, I. Genetics of type 2 diabetes. Diabet. Med. 22, 517–535 (2005).

    CAS  PubMed  Google Scholar 

  78. Andrulionyte, L., Zacharova, J., Chiasson, J. L. & Laakso, M. Common polymorphisms of the PPAR-γ2 (Pro12Ala) and PGC-1a (Gly482Ser) genes are associated with the conversion from impaired glucose tolerance to type 2 diabetes in the STOP-NIDDM trial. Diabetologia 47, 2176–2184 (2004).

    CAS  PubMed  Google Scholar 

  79. Kaiyala, K. J. et al. Reduced β-cell function contributes to impaired glucose tolerance in dogs made obese by high-fat feeding. Am. J. Physiol. 277, E659–E667 (1999).

    CAS  PubMed  Google Scholar 

  80. Hales, C. N. & Barker, D. J. Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia 35, 595–601 (1992).

    CAS  PubMed  Google Scholar 

  81. Leung, N. et al. Prolonged increase of plasma non-esterified fatty acids fully abolishes the stimulatory effect of 24 hours of moderate hyperglycaemia on insulin sensitivity and pancreatic beta-cell function in obese men. Diabetologia 247, 204–213 (2004).

    Google Scholar 

  82. Schwartz, M. W., Woods, S. C., Porte, D., Seeley, R. J. & Baskin, D. G. Central nervous system control of food intake. Nature 404, 661–671 (2000).

    CAS  PubMed  Google Scholar 

  83. Otani, K. et al. Reduced β-cell mass and altered glucose sensing impair insulin-secretory function in βIRKO mice. Am. J. Physiol. Endocrinol. Metab. 286, E41–E49 (2004).

    MathSciNet  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported in part by the US Department of Veterans Affairs and the NIH. S.E.K. is the recipient of an American Diabetes Association Distinguished Clinical Scientist Award.

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Kahn, S., Hull, R. & Utzschneider, K. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 444, 840–846 (2006). https://doi.org/10.1038/nature05482

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