Skip to main content

Advertisement

Log in

The Role of Adipose Tissue and Lipotoxicity in the Pathogenesis of Type 2 Diabetes

  • Published:
Current Diabetes Reports Aims and scope Submit manuscript

Abstract

The widespread epidemics of obesity and type 2 diabetes mellitus (T2DM) suggest that both conditions are closely linked. An increasing body of evidence has shifted our view of adipose tissue from a passive energy depot to a dynamic “endocrine organ” that tightly regulates nutritional balance by means of a complex crosstalk of adipocytes with their microenvironment. Dysfunctional adipose tissue, particularly as observed in obesity, is characterized by adipocyte hypertrophy, macrophage infiltration, impaired insulin signaling, and insulin resistance. The result is the release of a host of inflammatory adipokines and excessive amounts of free fatty acids that promote ectopic fat deposition and lipotoxicity in muscle, liver, and pancreatic β cells. This review focuses on recent work on how glucose homeostasis is profoundly altered by distressed adipose tissue. A better understanding of this relationship offers the best chance for early intervention strategies aimed at preventing the burden of T2DM.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  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.

Download references

Acknowledgments

Dr. Kenneth Cusi is supported by the American Diabetes Association, the Burroughs Wellcome Fund, the Veterans Affairs Medical Research Fund, and by Award Number UL 1RR025767 from the National Center for Research Resources. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources of the National Institutes of Health.

Disclosure

No potential conflict of interest relevant to this article was reported.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Kenneth Cusi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cusi, K. The Role of Adipose Tissue and Lipotoxicity in the Pathogenesis of Type 2 Diabetes. Curr Diab Rep 10, 306–315 (2010). https://doi.org/10.1007/s11892-010-0122-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11892-010-0122-6

Keywords

Navigation