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Pathophysiology of Diabetes in Obesity

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Part of the book series: Contemporary Diabetes ((CDI))

Abstract

Obesity is diagnosed when the percentage of body fat is high in relation to the lean body mass or when the body mass index (BMI) is 30 kg/m2 or more, and individuals with a BMI between 25 and 29.9 kg/m2 are considered overweight. According to the Department of Health and Human Services, 60% of the US population in 2001 was either overweight or obese. Such prevalence is much higher among patients with type 2 diabetes, 80% of whom are either overweight or obese (1,2). The situation is almost equally dismal around the globe, including many developing countries, where the adverse health consequences of overweight and obesity have begun to replace undernutrition and infection as the main causes of early death and disability (3).

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References

  1. Mokdad AH, Bowman BA, Ford ES, et al. The continuing epidemics of obesity and diabetes in the United States. JAMA 2001;286:1195–1200.

    Article  PubMed  CAS  Google Scholar 

  2. Mokdad AH, Ford ES, Bowman BA, et al. Prevalence of obesity, diabetes and obesity-related health risk factors, 2001. JAMA 2003;289:76–79.

    Article  PubMed  Google Scholar 

  3. Caballero B. Obesity in developing countries: biological and ecological factors. J Nutr 2001;131:866S–870S.

    PubMed  CAS  Google Scholar 

  4. Must A, Spadano J, Coakley EH, et al. The disease burden associated with overweight and obesity. JAMA 1999;282:1523–1529.

    Article  PubMed  CAS  Google Scholar 

  5. Field AE, Coakley EH, Must A, et al. Impact of overweight on the risk of developing common chronic diseases during a 10-year period. Arch Intern Med 2001;161:1581–1586.

    Article  PubMed  CAS  Google Scholar 

  6. Colditz GA, Willet WC, Rotnitzky A, et al. Weight gain as a risk factor for clinical diabetes mellitus in women. Ann Intern Med 1995;122:481–486.

    PubMed  CAS  Google Scholar 

  7. Chan JM, Rimm EB, Colditz GA. Obesity, fat distribution and weight gain as risk factors for clinical diabetes in men. Diabetes Care 1994;17:961–969.

    Article  PubMed  CAS  Google Scholar 

  8. Felber JP. From obesity to diabetes: pathophysiological considerations. Int J Obes Relat Metab Disord 1992;16:937–952.

    PubMed  CAS  Google Scholar 

  9. Knowler WC, Barrett-Conner E, Fowler E, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393–403.

    Article  PubMed  CAS  Google Scholar 

  10. Helmrich SP, Ragland DR, Leung RW, et al. Physical activity and reduced occurrence of non-insulin dependent diabetes mellitus. N Engl J Med 1991;325:147–152.

    Article  PubMed  CAS  Google Scholar 

  11. Sjostrom CD, Lissner L, Wedel H, et al. Reduction in incidence of diabetes, hypertension and lipid disturbances after intentional weight loss induced by bariatric surgery: the SOS Intervention Study. Obes Res 1999;7:477–484.

    PubMed  CAS  Google Scholar 

  12. Dixon JB, O’Brien PE. Health outcomes of severely obese type 2 diabetic subjects 1 year after laparoscopic adjustable gastric banding. Diabetes Care 2002;25(2):358–363.

    Article  PubMed  Google Scholar 

  13. Bays H, DeFronzo RA, Ferranini E. Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia and atherosclerotic cardiovascular disease. Diabetes Care 1991;14:173–194.

    Article  Google Scholar 

  14. Reaven GM, Hollenbeck CB, Chen YD. Relationship between glucose tolerance, insulin secretion and insulin action in non-obese individuals with varying degrees of glucose tolerance. Diabetologia 1998;32:52–55.

    Google Scholar 

  15. Haffner SM, Miettinen H, Gaskill SP, et al. Decreased insulin action and insulin secretion predict the development of impaired glucose tolerance. Diabetologia 1996;39:1201–1207.

    Article  PubMed  CAS  Google Scholar 

  16. Martin BC, Warram JH, Krolewski AS. Role of glucose and insulin resistance in development of type 2 diabetes: results of a 25 year follow-up study. Lancet 1992;340:925–929.

    Article  PubMed  CAS  Google Scholar 

  17. Warram JH, Sigal RJ, Martin BC, et al. Natural history of impaired glucose tolerance: follow-up at the Joslin Clinic. Diabet Med 1996;13:S40–S45.

    Article  PubMed  CAS  Google Scholar 

  18. Weyer C, Bogardus C, Mott DM. The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J Clin Invest 1999;104:787–794.

    PubMed  CAS  Google Scholar 

  19. Boden G, Chen X. Effects of fat on glucose uptake and utilization in patients with non-insulin dependent diabetes. J Clin Invest 1995;96:1261–1268.

    PubMed  CAS  Google Scholar 

  20. Paolisso G, Tataranni PA, Foley JE, et al. A high concentration of fasting plasma non-esterified fatty acids is a risk factor for the development of NIDDM. Diabetologia 1995;38:1213–1217.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  22. Greco AV, Mingrone G, Giancaterini A, et al. Insulin resistance in morbid obesity: reversal with intramyocellular fat depletion. Diabetes 2002;51:144–151.

    Article  PubMed  CAS  Google Scholar 

  23. Seppala-Lindroos A, Vehkavaara S, Hakkinen A.-M., et al. Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men. J Clin Endocrinol Metab 2002;87:3023–3028.

    Article  PubMed  CAS  Google Scholar 

  24. Unger RH. Lipotoxicity in the pathogenesis of obesity-dependent NIDDM: genetic and clinical implications. Diabetes 1996;45:273–283.

    Article  Google Scholar 

  25. Shimabukuro M, Zhou YT, Leve M, Unger RH. Fatty acid induced β cell apoptosis. Proc Natl Acad Sci USA 1998;95:2498–2502.

    Article  PubMed  CAS  Google Scholar 

  26. Fruhbeck G, Gomez-Ambrosi J, Muruzabal FJ, Burrell MA. The adipocyte: a model for integration of endocrine and metabolic signaling in energy metabolism regulation. Am J Physiol 2001;280:E827–E847.

    CAS  Google Scholar 

  27. Yamauchi T, Kamon J, Waki H, et al. The fat derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 2001;7:941–946.

    Article  PubMed  CAS  Google Scholar 

  28. Nadler ST, Stoehr JP, Schueler KL, et al. The expression of adipogenic genes is decreased in obesity and diabetes mellitus. Proc Natl Acad Sci USA 2000;97:11,371–11,376.

    Article  PubMed  CAS  Google Scholar 

  29. Hotta K, Funahashi T, Bodkin NL, et al. Circulating concentrations of the adipocyte protein adiponectin are decreased in parallel with reduced insulin sensitivity during the progression to t ype 2 diabetes in rhesus monkeys. Diabetes 2001;50:1126–1133.

    Article  PubMed  CAS  Google Scholar 

  30. Maeda N, Shimomura I, Kishida K, et al. Diet-induced insulin resistance in mice lacking adiponectin/ACRP30. Nat Med 2002;8:731–737.

    Article  PubMed  CAS  Google Scholar 

  31. Weyer C, Funahashi T, Tanaka S, et al. Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab 2001;86:1930–1935.

    Article  PubMed  CAS  Google Scholar 

  32. Abbasi F, Chu JW, Mclaughlin T, et al. Obesity versus insulin resistance in modulation of plasma adiponectin concentration. Diabetes 2002;52(Suppl 1):A81.

    Google Scholar 

  33. Arita Y, Kihara S, Ouchi N, et al. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 1999;257:79–83.

    Article  PubMed  CAS  Google Scholar 

  34. Hotta K, Funahashi T, Arita Y, et al. Plasma concentration of a novel adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler Thromb Vasc Biol 2000;20:1595–1599.

    PubMed  CAS  Google Scholar 

  35. Monzillo LU, Hamdy O, Horton ES, et al. Effect of lifestyle modification on adipokine levels in obese subjects with insulin resistance. Obes Res 2003;11:1048–1054.

    PubMed  CAS  Google Scholar 

  36. Yang WS, Lee WJ, Funahashi T, et al. Weight reduction increases plasma levels of an adipose-derived anti-inflammatory protein, adiponectin. J Clin Endocrinol Metab 2001;86:3815–3819.

    Article  PubMed  CAS  Google Scholar 

  37. Lindsay RS, Funahashi T, Hanson RL, et al. Adiponectin and development of type 2 diabetes in the Pima Indian population. Lancet 2002;360:57, 58.

    Article  PubMed  CAS  Google Scholar 

  38. Yokota T, Oritani K, Takahashi I, Ishikawa J, Matsuyama A, Ouchi N. Adiponectin, a new member of the family of soluble defense collagens, negatively regulated the growth of myelmonocytic progenitors and the functions of macrophages. Blood 2000;96:1723–1732.

    PubMed  CAS  Google Scholar 

  39. Matsuda M, Shimomura I, Sata M, et al. Role of adiponectin in preventing vascular stenosis: the missing link of adipo-vascular axis. J Biol Chem 2002;277:37,487–37,491.

    Article  PubMed  CAS  Google Scholar 

  40. Uzui H, Harpf A, Liu M, et al. Increased expression of membrane type 3-matrix metalloproteinase in human atherosclerotic plaque: role of activated macrophages and inflammatory cytokines. Circulation 2002;106(24):3024–3030.

    Article  PubMed  CAS  Google Scholar 

  41. Hotamisligil GS, Arner P, Caro JF, et al. Increased adipose tissue expression of tumor necrosis factoralpha in human obesity and insulin resistance. J Clin Invest 1995;95:2409–2415.

    PubMed  CAS  Google Scholar 

  42. Miyazaki Y, Pipek R, Mandarino LJ, DeFronzo RA. Tumor necrosis factor α and insulin resistance in obese type 2 diabetic patients. Int J Obes 2003;27:88–94.

    Article  CAS  Google Scholar 

  43. Zinman B, Hanley AJ, Harris SB, et al. Circulating tumor necrosis factor α concentrations in a native Canadian population with high rates if type 2 diabetes mellitus. J Clin Endocrinol Metab 1999;84:272–278.

    Article  PubMed  CAS  Google Scholar 

  44. Hotamisligil GS, Peraldi P, Budavari A, et al. IRS-1 mediated inhibition of insulin receptor tyrosine kinase activity in TNF-α and obesity induced insulin resistance. Science 1996;271:665–668.

    Article  PubMed  CAS  Google Scholar 

  45. Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS. Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature 1997;389:610–614.

    Article  PubMed  CAS  Google Scholar 

  46. Hofmann C, Lorenz K, Braithwaite SS, et al. Altered gene expression for tumor necrosis factor-alpha and its receptors during drug and dietary modulation of insulin resistance. Endocrinology 1994;134:264–270.

    Article  PubMed  CAS  Google Scholar 

  47. Sandler S, Bendtzen K, Eizirik DL, Welsh M. Interleukin-6 affects insulin secretion and glucose metabolism of rat pancreatic islets in vitro. Endocrinology 1990;126:1288–1294.

    Article  PubMed  CAS  Google Scholar 

  48. Pradhan AD, Manson JE, Rifai N, et al. C-reactive protein, interleukin 6 and the risk of developing type 2 diabetes. JAMA 2001;286:327–334.

    Article  PubMed  CAS  Google Scholar 

  49. Pickup JC, Chusney GD, Thomas SM, Burt D. Plasma interleukin 6, tumor necrosis factor and blood cytokine production in type 2 diabetes. Life Sci 2000;67:291–300.

    Article  PubMed  CAS  Google Scholar 

  50. Suzuki K, Nakaji S, Yamada M, et al. Systemic inflammatory response to exhaustive exercise: cytokine kinetics. Exerc Immunol Rev 2002;8:6–48.

    PubMed  Google Scholar 

  51. Starkie R, Ostrowski SR, Jauffred S, et al. Exercise and IL-6 infusion inhibit endotoxin-induced TNF-alpha production in humans. FASEB J 2003;17:884–886.

    PubMed  CAS  Google Scholar 

  52. Lonnqvist F, Arner P, Nordfors L, Schalling M. Overexpression of the obese (ob) gene in adipose tissue of human obese subjects. Nat Med 1995;1:950–993.

    Article  PubMed  CAS  Google Scholar 

  53. Van Heek M, Compton DS, France CF, et al. Diet-induced obese mice develop peripheral, but not central, resistance to leptin. J Clin Invest 1997;99:385–390.

    PubMed  Google Scholar 

  54. Considine RV, Sinha MK, Heiman ML, et al. Serum immunoreactive-leptin concentrations in normal-weight and obeses humans. N Engl J Med 1996;334:292–295.

    Article  PubMed  CAS  Google Scholar 

  55. Ceddia RB, William WN Jr, Curi R. Comparing effects of leptin and insulin on glucose metabolism in skeletal muscle: evidence for an effect of leptin on glucose uptake and decarboxylation. Int J Obes Rel Metab Disord 1999;23:75–82.

    Article  CAS  Google Scholar 

  56. Kamohara S, Burcelin R, Halaas JL, Freidman JM. Acute stimulation of glucose metabolism in mice by leptin treatment. Nature 1997;389:374–377.

    Article  PubMed  CAS  Google Scholar 

  57. Muoio DM, Dohm GL. Peripheral metabolic actions of leptin. Best Pract Res Clin Endocrinol Metab 2002;16:653–666.

    Article  PubMed  CAS  Google Scholar 

  58. Clement K, Vaisse C, Lahlou N, et al. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 1998;392:398–401.

    Article  PubMed  CAS  Google Scholar 

  59. Farooqui IS, Jebb SA, Langmack G, et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 1999;341:879–884.

    Article  Google Scholar 

  60. Mantzoros CS, Flier JS. Editorial: leptin as a therapeutic agent-trials and tribulations. J Clin Endocrinol Metab 2000;85:4000–4002.

    Article  PubMed  CAS  Google Scholar 

  61. Santos-Alvarez J, Goberna R, Sanchez-Margalet V: Human leptin stimulates proliferation and activation of human circulating monocytes. Cell Immunol 1999;194:6–11.

    Article  PubMed  CAS  Google Scholar 

  62. Giansford T, Willson TA, Metcalf D, et al. Leptin can induce proliferation, differentiation, and functional activation of hemopoietic cells. Proc Natl Acad Sci USA 1996;93:14,564–14,568.

    Article  Google Scholar 

  63. Yudkin JS. Abnormalities of coagulation and fibrinolysis in insulin resistance: evidence for a common antecedent? Diabetes Care 1999;22:C25–C30.

    Article  PubMed  Google Scholar 

  64. Alessi MC, Bastelica D, Morange P, et al. Plasminogen activator inhibitor 1, transforming growth factor-β1 and ABMI are closely associated in human adipose tissue during morbid obesity. Diabetes 2000;49:1374–1380.

    Article  PubMed  CAS  Google Scholar 

  65. Alessi MC, Peiretti F, Morange P, et al. Production of plasminogen activator inhibitor1 by human adipose tissue: possible link between visceral fat accumulation and vascular disease. Diabetes 1997;46:860–867.

    Article  PubMed  CAS  Google Scholar 

  66. Smith SR, Bai F, Charbonneau C, et al. A promoter genotype and oxidative stress potentially link resistin to human insulin resistance. Diabetes 2003;52:1611–1618.

    Article  PubMed  CAS  Google Scholar 

  67. Wang H, Chu WS, Hemphill C, Elbein SC. Human resistin gene: molecular scanning and evaluation of association with insulin sensitivity and type 2 diabetes in Caucasians. J Clin Endocrinol Metab 2002;87:2520–2524.

    Article  PubMed  CAS  Google Scholar 

  68. Vidal-Puig A, O’Rahilly S. Resistin: a new link between obesity and insulin resistance? Clin Endocrinol (Oxf) 2001;55:437–438.

    Article  CAS  Google Scholar 

  69. Kissebah AH, Peiris AN. Biology of regional body fat distribution: relationship to non-insulin-dependent diabetes mellitus. Diabetes Metab Rev 1989;5:83–109.

    Article  PubMed  CAS  Google Scholar 

  70. Despres JP, Lemieux S, Lamarche B, et al. The insulin resistance-dyslipidemic syndrome: contribution of visceral obesity and therapeutic implications. Int J Obes Related Metab Disord 1995;19(Suppl): S76–S86.

    Google Scholar 

  71. Lee JH, Bullen JW Jr, Stoyneva VL, Mantzoros CS. Circulating resistin in lean, obese and insulin-resistant mouse models: lack of association with insulinemia and glycemia. Am J Physiol Endocrinol Metab 2005;288:E625–E632.

    Article  PubMed  CAS  Google Scholar 

  72. Lee JH, Chan JL, Yiannakouris N, et al. Circulating resistin levels are not associated with obesity or insulin resistance in humans and are not regulated by fasting or leptin administration: cross-sectional and interventional studies in normal, insulin-resistant, and diabetic subjects. J Clin Endocrinol Metab 2003;88:4848–4856.

    Article  PubMed  CAS  Google Scholar 

  73. Albu JB, Kovera AJ, Johnson JA. Fat distribution and health in obesity. Ann NY Acad Sci 2000;904:491–501.

    Article  PubMed  CAS  Google Scholar 

  74. Zeirath JR, Livingston JN, Thorne J, et al. Regional difference in insulin inhibition of non-esterified fatty acid release from human adipocytes: relation to insulin receptor phosphorylation and intracellular signaling through the insulin receptor substrate-1-pathway. Diabetologia 1998;41:1343–1354.

    Article  Google Scholar 

  75. Arner P. Regional differences in protein production by human adipose tissue. Biochem Soc Trans 2001;29:72–75.

    Article  PubMed  CAS  Google Scholar 

  76. Motoshima H, Wu X, Sinha MK, et al. Differential regulation of adiponectin secretion from cultured human omental and subcutaneous adipocytes: effects of insulin and rosiglitazone. J Clin Endocrinol Metab 2002;87:5662–5667.

    Article  PubMed  CAS  Google Scholar 

  77. Sewter CP, Blows F, Vidal Puig A, O’Rahilly S. Regional differences in the response of human preadipocytes to PPARγ and RXRα agonists. Diabetes 2002;51:7218–7223.

    Google Scholar 

  78. Bouchard C, Depress JP, Mauriege P. Genetics and nongenetic determinants of regional fat distribution. Endocr Rev 1993;14:72–93.

    Article  PubMed  CAS  Google Scholar 

  79. Perusse L, Rice T, Chagnon YC, et al. genome-wide scan for abdominal fat assessed by computed tomography in the Quebec Family Study. Diabetes 2001;50:614–621.

    Article  PubMed  CAS  Google Scholar 

  80. Pan DA, Lillioja S, Kriketos AD, et al. Skeletal muscle triglyceride levels are inversely related to insulin action. Diabetes 1997;46:983–988.

    Article  PubMed  CAS  Google Scholar 

  81. Goodpaster BH, Thaete FL, Simoneau JA, Kelley DE. Subcutaneous abdominal fat and thigh muscle composition predict insulin sensitivity independently of visceral fat. Diabetes 1997;46:1579–1585.

    Article  PubMed  CAS  Google Scholar 

  82. Bajaj M, Surramornkul S, Pratipanawatr T, et al. Pioglitazone reduces hepatic fat content and augments splanchnic glucose uptake in patients with type 2 diabetes mellitus. Diabetes 2003;52:1364–1370.

    Article  PubMed  CAS  Google Scholar 

  83. Bajaj M, Surramonkul S, Piper P, et al. Decreased plasma adiponectin concentrations are closely related to hepatic fat content and hepatic insulin resistance in pioglitazone treated type 2 diabetic patients. J Clin Endocrinol Metab 2004;89:200–206.

    Article  PubMed  CAS  Google Scholar 

  84. Robbins DC, Horton ES, Tulp O, Sims EA. Familial partial lipodystrophy; complications of obesity in the non-obese? Metabolism 1982;31:445–452.

    Article  PubMed  CAS  Google Scholar 

  85. Oral EA, Simha V, Ruiz E, et al. Leptin replacement therapy for lipodystrophy. N Engl J Med 2002;346:57–78.

    Article  Google Scholar 

  86. Gavrilova O, Marcus-Samuels B, Graham D, et al. Surgical implantation of adipose tissue reverses diabetes in lipoatrophic mice. J Clin Invest 2000;105:271–278.

    Article  PubMed  CAS  Google Scholar 

  87. Weber RV, Buckley MC, Fried SK, Kral JG. Subcutaneous lipectomy causes a metabolic syndrome in hamsters. Am J Physiol 2000;279: R936–R943.

    CAS  Google Scholar 

  88. Weyer C, Foley JE, Bogardus PA, Tataranni REP. Enlarged subcutaneous abdominal adipocyte size, but not obesity itself, predicts type 2 diabetes independent of insulin resistance. Diabetologia 2000;43:1498–1506.

    Article  PubMed  CAS  Google Scholar 

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Soodini, G.R., Hamdy, O. (2006). Pathophysiology of Diabetes in Obesity. In: Mantzoros, C.S. (eds) Obesity and Diabetes. Contemporary Diabetes. Humana Press. https://doi.org/10.1007/978-1-59259-985-1_7

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