The Role of Adipose Tissue and Lipotoxicity in the Pathogenesis of Type 2 Diabetes (original) (raw)

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  1. Cusi K: The epidemic of type 2 diabetes mellitus: its links to obesity, insulin resistance and lipotoxicity. In Diabetes and Exercise. Edited by Regensteiner J, Stewart K, Veves A. Totowa, NJ: Humana Press; 2009:3–54.
  2. • Cusi K: Lessons learned from studying families genetically predisposed to type 2 diabetes mellitus. Curr Diab Rep 2009, 9:200–207. This is a comprehensive summary of the metabolic defects that precede T2DM prior to the developemnt of acquired defects such as obesity or hyperglycemia.
  3. Buchanan TA: (How) can we prevent type 2 diabetes? Diabetes 2007, 56:1502–1507.
    Article PubMed CAS Google Scholar
  4. Vaag A, Poulsen P: Twins in metabolic and diabetes research: what do they tell us? Curr Opin Clin Nutr Metab Care 2007, 10:591–596.
    Article PubMed CAS Google Scholar
  5. Shaw JE, Sicree RA, Zimmet PZ: Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract 2009, 87:4–14.
    Article PubMed Google Scholar
  6. Flegal KM, Carroll MD, Ogden CL, Curtin LR: Prevalence and trends in obesity among US adults, 1999-2008. JAMA 2010, 303:235–241.
    Article PubMed CAS Google Scholar
  7. Ogden CL, Carroll MD, Curtin LR, et al.: Prevalence of high body mass index in US children and adolescents, 2007-2008. JAMA 2010, 303:242–249.
    Article PubMed CAS Google Scholar
  8. Baker J, Olsen L, Sorensen T: Childhood body-mass index and the risk of coronary heart disease in adulthood. N Engl J Med 2007, 357:2329–2337.
    Article PubMed CAS Google Scholar
  9. Franks PW, Hanson RL, Knowler WC, et al.: Childhood obesity, other cardiovascular risk factors, and premature death. N Engl J Med 2010, 362:485–493.
    Article PubMed CAS Google Scholar
  10. Kashyap S, Belfort R, Gastaldelli A, et al.: A sustained increase in plasma free fatty acids impairs insulin secretion in nondiabetic subjects genetically predisposed to develop type 2 diabetes. Diabetes 2003, 52:2461–2474.
    Article PubMed CAS Google Scholar
  11. Mathew M, Tay C, Belfort R, et al.: A 48-hour elevation in plasma FFA, but not hyperglycemia, impairs insulin secretion in lean Mexican-American subjects genetically predisposed to T2DM. Diabetes 2007, 56(Suppl 1):A674.
    Google Scholar
  12. Hotamisligil GS, Erbay E: Nutrient sensing and inflammation in metabolic diseases. Nat Rev Immunol 2008, 8:923–934.
    Article PubMed CAS Google Scholar
  13. Gregor MF, Yang L, Fabbrini E, et al.: Endoplasmic reticulum stress is reduced in tissues of obese subjects after weight loss. Diabetes 2009, 58:693–700.
    Article PubMed CAS Google Scholar
  14. Rutkowski JM, Davis KE, Scherer PE: Mechanisms of obesity and related pathologies: the macro- and microcirculation of adipose tissue. FEBS J 2009, 276:5738–5746.
    Article PubMed CAS Google Scholar
  15. • Lefterova MI, Lazar MA: New developments in adipogenesis. Trends Endocrinol Metab 2009, 20:107–114. This is a comprehensive review of the mechanisms that control adipocyte development in health and disease.
  16. Khan T, Muise ES, Iyengar P, et al.: Metabolic dysregulation and adipose tissue fibrosis: role of collagen VI. Mol Cell Biol 2009, 29:1575–1591.
    Article PubMed CAS Google Scholar
  17. Ye J: Emerging role of adipose tissue hypoxia in obesity and inuslin resistance. Int J Obes 2009, 33:54–66.
    Article CAS Google Scholar
  18. Muniyappa R, Iantorno M, Quon MJ: An integrated view of insulin resistance and endothelial dysfunction. Endocrinol Metab Clin North Am 2008, 37:685–711.
    Article PubMed CAS Google Scholar
  19. Cusi K, Maezono K, Osman A, et al.: Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle. J Clin Invest 2000, 105:311–320.
    Article PubMed CAS Google Scholar
  20. Kashyap SR, Belfort R, Cersosimo E, et al.: Chronic low-dose lipid infusion in healthy patients induces markers of endothelial activation independent of its metabolic effects. J Cardiometab Syndr 2008, 3:141–146.
    Article PubMed Google Scholar
  21. Mathew M, Tay E, Cusi K: Elevated plasma free fatty acids increase cardiovascular risk by inducing plasma biomarkers of endothelial activation, myeloperoxidase and PAI-1 in healthy subjects. Cardiovasc Diabetol 2010, 9:1–9.
    Article CAS Google Scholar
  22. • Furuhashi M, Hotamisligil GS: Fatty acid-binding proteins: role in metabolic diseases and potential as drug targets. Nat Rev Drug Discov 2008, 7:489–503. This is a careful crafted description of the multiple roles of fatty acid–binding proteins to regulate whole-body energy homeostasis in humans.
  23. •• Yeop Han C, Kargi AY, Omer M, et al.: Differential effect of saturated and unsaturated free fatty acids on the generation of monocyte adhesion and chemotactic factors by adipocytes. Diabetes 2010, 59:386–396. This is a provocative study highlighting the complex crosstalk between different types of fatty acids and macrophage recruitment by adipocytes.
  24. Wueest S, Rapold R, Schumann D, et al.: Deletion of Fas in adipocytes relieves adipose tissue inflammation and hepatic manifestations of obesity in mice. J Clin Invest 2010, 120:191–202.
    PubMed CAS Google Scholar
  25. Gulli G, Ferrannini E, Stern M, et al.: The metabolic profile of NIDDM is fully established in glucose-tolerant offspring of two Mexican-American NIDDM parents. Diabetes 1992, 41:1575–1586.
    Article PubMed CAS Google Scholar
  26. Perseghin G, Ghosh S, Gerow K, Shulman G: Metabolic defects in lean nondiabetic offspring of NIDDM parents. A cross-sectional study. Diabetes 1997, 46:1001–1009.
    CAS Google Scholar
  27. Virkamaki A, Korsheninnikova E, Seppala-Lindroos A, et al.: Intramyocellular lipid Is associated with resistance to in vivo Insulin actions on glucose uptake, antilipolysis, and early insulin signaling pathways in human skeletal muscle. Diabetes 2001, 50:2337–2343.
    Article PubMed CAS Google Scholar
  28. Brassard P, Frisch F, Lavoie F, et al.: Impaired plasma nonesterified fatty acid tolerance is an early defect in the natural history of type 2 diabetes. J Clin Endocrinol Metab 2008, 93:837–844.
    Article PubMed CAS Google Scholar
  29. McGarry J: What if Minkowski had been ageusic? An alternative angle on diabetes. Science 1992, 258:766–770.
    Article PubMed CAS Google Scholar
  30. Yang X, Jansson PA, Nagaev I, et al.: Evidence of impaired adipogenesis in insulin resistance. Biochem Biophys Res Commun 2004, 317:1045–1051.
    Article PubMed CAS Google Scholar
  31. Civitarese A, Jenkinson C, Richardson D, et al.: Adiponectin receptors gene expression and insulin sensitivity in non-diabetic Mexican Americans with or without a family history of type 2 diabetes. Diabetologia 2004, 47:816–820.
    Article PubMed CAS Google Scholar
  32. Muhlhausler B, Smith SR: Early-life origins of metabolic dysfunction: role of the adipocyte. Trends Endocrinol Metab 2009, 20:51–57.
    Article PubMed CAS Google Scholar
  33. Isganaitis E, Jimenez-Chillaron J, Woo M, et al.: Accelerated postnatal growth increases lipogenic gene expression and adipocyte size in low-birth weight mice. Diabetes 2009, 58:1192–1200.
    Article PubMed CAS Google Scholar
  34. Bogacka I, Xie H, Bray GA, Smith SR: The effect of pioglitazone on peroxisome proliferator-activated receptor-gamma target genes related to lipid storage in vivo. Diabetes Care 2004, 27:1660–1667.
    Article PubMed CAS Google Scholar
  35. Kim J, van de Wall E, Laplante M, et al.: Obesity-associated improvements in metabolic profile through expansion of adipose tissue. J Clin Invest 2007, 117:2621–2630.
    Article PubMed CAS Google Scholar
  36. Cusi K, Kashyap S, Belfort R, et al.: Effects on insulin secretion and action of short-term reduction of plasma free fatty acids with acipimox in non-diabetic subjects genetically predisposed to type 2 diabetes. Am J Physiol Endocrinol Metab 2007, 292:E1775–E1781.
    Article PubMed CAS Google Scholar
  37. Gastaldelli A, Ferrannini E, Miyazaki Y, et al.: Beta cell dysfunction and glucose intolerance: results from the San Antonio Metabolism (SAM) study. Diabetologia 2004, 47:31–39.
    Article PubMed CAS Google Scholar
  38. DeFronzo R, Banerji M, Bray G, et al.: Determinants of glucose tolerance in impaired glucose tolerance at baseline in the Actos Now for Prevention of Diabetes (ACT NOW) study. Diabetologia 2010, 53:435–445.
    Article PubMed CAS Google Scholar
  39. Butler A, Janson J, Bonner-Weir S, et al.: B-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 2003, 52:102–110.
    Article PubMed CAS Google Scholar
  40. Federici M, Hribal M, Perego L, et al.: High glucose causes apoptosis in cultured human pancreatic islets of Langerhans: a potential role for regulation of specific Bcl family genes toward an apoptotic cell death program. Diabetes 2001, 50:1290–1301.
    Article PubMed CAS Google Scholar
  41. Unger R, Zhou Y: Lipotoxicity of beta-cells in obesity and in other causes of fatty acid spillover. Diabetes 2001, 50(Suppl 1):S118–S121.
    Article PubMed CAS Google Scholar
  42. Poitout V, Robertson RP: Glucolipotoxicity: fuel excess and beta-cell dysfunction. Endocr Rev 2008, 29:351–366.
    Article PubMed CAS Google Scholar
  43. Delghingaro-Augusto V, Nolan C, Gupta D, et al.: Islet beta cell failure in the 60% pancreatectomised obese hyperlipidaemic Zucker fatty rat: severe dysfunction with altered glycerolipid metabolism without steatosis or a falling beta cell mass. Diabeteologia 2009, 52:1122–1132.
    Article CAS Google Scholar
  44. Kashyap SR, Belfort R, Berria R, et al.: Discordant effects of a chronic physiological increase in plasma FFA on insulin signaling in healthy subjects with or without a family history of type 2 diabetes. Am J Physiol Endocrinol Metab 2004, 287:E537–E546.
    Article PubMed CAS Google Scholar
  45. Pratipanawatr W, Pratipanawatr T, Cusi K, et al.: Skeletal muscle insulin resistance in normoglycemic subjects with a strong family history of type 2 diabetes is associated with decreased insulin-stimulated insulin receptor substrate-1 tyrosine phosphorylation. Diabetes 2001, 50:2572–2578.
    Article PubMed CAS Google Scholar
  46. Petersen KF, Dufour S, Befroy D, et al.: Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med 2004, 350:664–671.
    Article PubMed CAS Google Scholar
  47. Belfort R, Mandarino L, Kashyap S, et al.: Dose-response effect of elevated plasma free fatty acid on insulin signaling. Diabetes 2005, 54:1640–1648.
    Article PubMed CAS Google Scholar
  48. Szendroedi J, Roden M: Ectopic lipids and organ function. Curr Opin Lipidol 2009, 20:50–56.
    Article PubMed CAS Google Scholar
  49. • Reyna SM, Ghosh S, Tantiwong P, et al.: Elevated toll-like receptor 4 expression and signaling in muscle from insulin-resistant subjects. Diabetes 2008, 57:2595–2602. This is a careful description of the potential role of TLR4 in insulin-resistant states in humans.
  50. De Filippis E, Alvarez G, Berria R, et al.: Insulin-resistant muscle is exercise resistant: evidence for reduced response of nuclear-encoded mitochondrial genes to exercise. Am J Physiol Endocrinol Metab 2008, 294:E607–E614.
    Article PubMed CAS Google Scholar
  51. • Liu L, Shi X, Bharadwaj KG, et al.: DGAT1 expression increases heart triglyceride content but ameliorates lipotoxicity. J Biol Chem 2009, 284:36312–36323. This is an elegant study serving as proof of concept that increasing triglyceride synthesis and accumulation by overexpression of DGAT1 in the heart may alleviate lipotoxicity by shifting toxic lipid metabolites from harmful metabolic pathways.
    Google Scholar
  52. Liu L, Shi X, Choi CS, et al.: Paradoxical coupling of triglyceride synthesis and fatty acid oxidation in skeletal muscle overexpressing DGAT1. Diabetes 2009, 58:2516–2524.
    Article PubMed CAS Google Scholar
  53. Patti ME, Butte AJ, Crunkhorn S, et al.: Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1. Proc Natl Acad Sci U S A 2003, 100:8466–8471.
    Article PubMed CAS Google Scholar
  54. Hojlund K, Mogensen M, Sahlin K, Beck-Nielsen H: Mitochondrial dysfunction in type 2 diabetes and obesity. Endocrinol Metab Clin North Am 2008, 37:713–731.
    Article PubMed CAS Google Scholar
  55. Abdul-Ghani MA, DeFronzo RA: Mitochondrial dysfunction, insulin resistance, and type 2 diabetes mellitus. Curr Diab Rep 2008, 8:173–178.
    Article PubMed CAS Google Scholar
  56. Holloszy JO: Skeletal muscle "mitochondrial deficiency" does not mediate insulin resistance. Am J Clin Nutr 2009, 89:463S–466S.
    Article PubMed CAS Google Scholar
  57. • Chavez AO, Kamath S, Jani R, et al.: Effect of short-term free fatty acids elevation on mitochondrial function in skeletal muscle of healthy individuals. J Clin Endocrinol Metab 2010, 95:422–429. This is a valuable contribution showing a deleterious effect of elevated plasma FFAs on mitochondrial function in healthy human subjects.
  58. Handschin C, Spiegelman BM: The role of exercise and PGC-1α in inflammation and chronic disease. Nature 2008, 454:463–469.
    Article PubMed CAS Google Scholar
  59. Richardson DK, Kashyap S, Bajaj M, et al.: Lipid infusion decreases the expression of nuclear encoded mitochondrial genes and increases the expression of extracellular matrix genes in human skeletal muscle. J Biol Chem 2005, 280:10290–10297.
    Article PubMed CAS Google Scholar
  60. Liang H, Balas B, Tantiwong P, et al.: Whole body overexpression of PGC-1α has opposite effects on hepatic and muscle insulin sensitivity. Am J Physiol Endocrin Metab 2009, 296:E945–E954.
    Article CAS Google Scholar
  61. Choi CS, Befroy DE, Codella R, et al.: Paradoxical effects of increased expression of PGC-1α on muscle mitochondrial function and insulin-stimulated muscle glucose metabolism. Proc Natl Acad Sci U S A 2008, 105:19926–19931.
    Article PubMed Google Scholar
  62. Roden M, Stingl H, Chandramouli V, et al.: Effects of free fatty acid elevation on postabsorptive endogenous glucose production and gluconeogenesis in humans. Diabetes 2000, 49:701–707.
    Article PubMed CAS Google Scholar
  63. Boden G, Cheung P, Stein TP, et al.: FFA cause hepatic insulin resistance by inhibiting insulin suppression of glycogenolysis. Am J Physiol Endocrinol Metab 2002, 283:E12–E19.
    PubMed CAS Google Scholar
  64. Ortiz-Lopez C, Orsak B, Darland C, et al.: Abnormal glucose metabolism is common in NASH patients and associated with more severe hepatic and adipose tissue insulin resistance and hepatocyte necroinflammation. Diabetes 2010, (Suppl 1):59.
  65. • Greenfield V, Cheung O, Sanyal A: Recent advances in nonalcoholic fatty liver disease. Curr Opin Gastroenterol 2008, 24:320–327. This is an excellent review on the mechanisms and clinical dilemmas on the management of NAFLD.
  66. • Cusi K: Nonalcoholic fatty liver disease in type 2 diabetes mellitus. Curr Opin Endocrinol Diabetes Obes 2009, 16:141–149. This is a comprehensive review on the role of T2DM in the development of NAFLD, reviewing the molecular mechanisms, diagnosis, and treatments.
  67. • Cusi K: Role of liver insulin resistance and lipotoxicity in NASH. Clin Liver Dis 2009, 13:545–563. This is an overview on the systemic effects of ectopic fat accumulation, insulin resistance, and lipotoxicity in the development of NASH.
  68. Chan DC, Watts GF, Gan S, et al.: Nonalcoholic fatty liver disease as the transducer of hepatic oversecretion of very-low-density lipoprotein-apolipoprotein B-100 in obesity. Arterioscler Thromb Vasc Biol 2010, 30:1043–1050.
    Article PubMed CAS Google Scholar
  69. Minehira K, Young SG, Villanueva CJ, et al.: Blocking VLDL secretion causes hepatic steatosis but does not affect peripheral lipid stores or insulin sensitivity in mice. J Lipid Res 2008, 49:2038–2044.
    Article PubMed CAS Google Scholar
  70. Wouters K, van Gorp PJ, Bieghs V, et al.: Dietary cholesterol, rather than liver steatosis, leads to hepatic inflammation in hyperlipidemic mouse models of nonalcoholic steatohepatitis. Hepatology 2008, 48:474–486.
    Article PubMed Google Scholar
  71. • Huang W, Metlakunta A, Dedousis N, et al.: Depletion of liver Kupffer cells prevents the development of diet-induced hepatic steatosis and insulin resistance. Diabetes 2010, 59:347–357. This is a provocative study about the role of the immune system in the development of NAFLD.
  72. Estall JL, Ruas JL, Choi CS, et al.: PGC-1α negatively regulates hepatic FGF21 expression by modulating the heme/Rev-Erb(alpha) axis. Proc Natl Acad Sci U S A 2009, 106:22510–22515.
    Article PubMed Google Scholar
  73. Belfort R, Harrison SA, Brown K, et al.: A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 2006, 355:2297–2307.
    Article PubMed CAS Google Scholar
  74. Gastaldelli A, Harrison SA, Belfort-Aguilar R, et al.: Importance of changes in adipose tissue insulin resistance to histological response during thiazolidinedione treatment of patients with nonalcoholic steatohepatitis. Hepatology 2009, 50:1087–1093.
    Article PubMed CAS Google Scholar
  75. •• Semple R, Sleigh A, Murgatroyd P, et al.: Postreceptor insulin resistance contributes to human dyslipidemia and hepatic steatosis. J Clin Invest 2009, 119:315–322. This study proposes from observations in humans that there is a selective insulin resistance to glucose metabolism but not to lipid metabolism in the developemnt of insulin resistance and steatosis in humans.
  76. • Li ZZ, Berk M, McIntyre TM, Feldstein AE: Hepatic lipid partitioning and liver damage in nonalcoholic fatty liver disease: role of stearoyl-CoA desaturase. J Biol Chem 2009, 284:5637–5644. This is an excellent study on the potential role of SCD1 as a regulator of fat metabolism and fatty liver in human disease.
  77. Listenberger L, Han X, Lewis S, et al.: Triglyceride accumulation protects againstfatty acid-induced lipotoxicity. Proc Natl Acad Sci 2003, 100:3077–3082.
    Article PubMed CAS Google Scholar
  78. • Choi S, Diehl A: Hepatic triglyceride synthesis and nonalcoholic fatty liver disease. Curr Opin Lipidol 2008, 19:295–300. This is a comprehensive review on the role of triglycerides and their manipulation in laboratory studies regarding the pathophysiology of NAFLD and NASH.

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