Digestive and Liver Disease
Volume 42, Issue 5 , Pages 310-319 , May 2010

Insulin resistance, adipose depots and gut: Interactions and pathological implications

  • Amalia Gastaldelli

      Affiliations

    • Institute of Clinical Physiology, Stable Isotope Laboratory, CNR-National Research Council, Pisa, Italy
    • Corresponding Author InformationCorresponding author. Tel.: +39 050 3152679; fax: +39 050 3152166.
    • ,
  • Andrea Natali

      Affiliations

    • Department of Internal Medicine, University of Pisa, Italy
    • ,
  • Roberto Vettor

      Affiliations

    • Department of Medical and Surgical Sciences, University of Padova, Italy
    • ,
  • Stefano Ginanni Corradini

      Affiliations

    • Division of Gastroenterology, Department of Clinical Medicine, University “Sapienza” of Rome, Italy

Received 12 January 2010 ,Accepted 17 January 2010.

References 

  1. DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol. 1979;237:E214–E223
  2. Bergman RN, Ider YZ, Bowden CR, et al. Quantitative estimation of insulin sensitivity. Am J Physiol. 1979;236:E667–E677
  3. Wallace TM, Levy JC, Matthews DR. Use and abuse of homa modeling. Diabetes Care. 2004;27:1487–1495
  4. Quon MJ. Quicki is a useful and accurate index of insulin sensitivity. J Clin Endocrinol Metab. 2002;87:949–951
  5. Mari A, Pacini G, Murphy E, et al. A model-based method for assessing insulin sensitivity from the oral glucose tolerance test. Diabetes Care. 2001;24:539–548
  6. Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care. 1999;22:1462–1470
  7. Mari A, Pacini G, Brazzale AR, et al. Comparative evaluation of simple insulin sensitivity methods based on the oral glucose tolerance test. Diabetologia. 2005;48:748–751
  8. Randle PJ. Regulatory interactions between lipids and carbohydrates: the glucose fatty acid cycle after 35 years. Diabetes Metab Rev. 1998;14:263–283
  9. Roden M, Price TB, Perseghin G, et al. Mechanism of free fatty acid-induced insulin resistance in humans. J Clin Invest. 1996;97:2859–2865
  10. Boden G, Jadali F, White J, et al. Effects of fat on insulin-stimulated carbohydrate metabolism in normal men. J Clin Invest. 1991;88:960–966
  11. Boden G, Lebed B, Schatz M, et al. Effects of acute changes of plasma free fatty acids on intramyocellular fat content and insulin resistance in healthy subjects. Diabetes. 2001;50:1612–1617
  12. Schmitz-Peiffer C. Signalling aspects of insulin resistance in skeletal muscle: mechanisms induced by lipid oversupply. Cell Signal. 2000;12:583–594
  13. Boden G, Cheung P, Stein TP, et al. Ffa cause hepatic insulin resistance by inhibiting insulin suppression of glycogenolysis. Am J Physiol. 2002;283:E12–E19
  14. Bergman RN, Mittelman SD. Central role of the adipocyte in insulin resistance. J Basic Clin Physiol Pharmacol. 1998;9:205–221
  15. Boden G, Chen X, Rosner J, et al. Effects of a 48-h fat infusion on insulin secretion and glucose utilization. Diabetes. 1995;44:1239–1242
  16. 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
  17. Groop LC, Bonadonna RC, DelPrato S, et al. Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus. Evidence for multiple sites of insulin resistance. J Clin Invest. 1989;84:205–213
  18. Bugianesi E, Gastaldelli A, Vanni E, et al. Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms. Diabetologia. 2005;48:634–642
  19. Gastaldelli A, Cusi K, Pettiti M, et al. Relationship between hepatic/visceral fat and hepatic insulin resistance in nondiabetic and type 2 diabetic subjects. Gastroenterology. 2007;133:496–506
  20. Gastaldelli A, Toschi E, Pettiti M, et al. Effect of physiological hyperinsulinemia on gluconeogenesis in nondiabetic subjects and in type 2 diabetic patients. Diabetes. 2001;50:1807–1812
  21. Gastaldelli A, Casolaro A, Pettiti M, et al. Effect of pioglitazone on the metabolic and hormonal response to a mixed meal in type ii diabetes. Clin Pharmacol Ther. 2007;81:205–212
  22. Gastaldelli A, Baldi S, Pettiti M, et al. Influence of obesity and type 2 diabetes on gluconeogenesis and glucose output in humans: a quantitative study. Diabetes. 2000;49:1367–1373
  23. Paquot N, Scheen AJ, Dirlewanger M, et al. Hepatic insulin resistance in obese non-diabetic subjects and in type 2 diabetic patients. Obes Res. 2002;10:129–134
  24. Carey DG, Jenkins AB, Campbell LV, et al. 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. 1996;45:633–638
  25. Boden G, Shulman GI. Free fatty acids in obesity and type 2 diabetes: defining their role in the development of insulin resistance and beta-cell dysfunction. Eur J Clin Invest. 2002;32(Suppl. 3):14–23
  26. Ekberg K, Landau B, Wajngot A, et al. Contributions by kidney and liver to glucose production in the postabsorptive state and after 60h of fasting. Diabetes. 1999;48:292–298
  27. DeFronzo R. The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes. 1988;37:667–687[Lilly lecture 1987]
  28. Natali A, Toschi E, Camastra S, et al. Determinants of postabsorptive endogenous glucose output in non-diabetic subjects. European group for the study of insulin resistance (egir). Diabetologia. 2000;43:1266–1272
  29. 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;38:387–395
  30. Sindelar DK, Chu CA, Venson P, et al. Basal hepatic glucose production is regulated by the portal vein insulin concentration. Diabetes. 1998;47:523–529
  31. Wallace TM, Matthews DR. The assessment of insulin resistance in man. Diabet Med. 2002;19:527–534
  32. Houten SM, Watanabe M, Auwerx J. Endocrine functions of bile acids. EMBO J. 2006;25:1419–1425
  33. Cani PD, Delzenne NM. Gut microflora as a target for energy and metabolic homeostasis. Curr Opin Clin Nutr Metab Care. 2007;10:729–734
  34. Gupta S, Stravitz RT, Dent P, et al. Down-regulation of cholesterol 7alpha-hydroxylase (cyp7a1) gene expression by bile acids in primary rat hepatocytes is mediated by the c-jun n-terminal kinase pathway. J Biol Chem. 2001;276:15816–15822
  35. Qiao L, Han SI, Fang Y, et al. Bile acid regulation of c/ebpbeta, creb, and c-jun function, via the extracellular signal-regulated kinase and c-jun nh2-terminal kinase pathways, modulates the apoptotic response of hepatocytes. Mol Cell Biol. 2003;23:3052–3066
  36. Kawamata Y, Fujii R, Hosoya M, et al. A G protein-coupled receptor responsive to bile acids. J Biol Chem. 2003;278:9435–9440
  37. Maruyama T, Miyamoto Y, Nakamura T, et al. Identification of membrane-type receptor for bile acids (m-bar). Biochem Biophys Res Commun. 2002;298:714–719
  38. Makishima M, Okamoto AY, Repa JJ, et al. Identification of a nuclear receptor for bile acids. Science. 1999;284:1362–1365
  39. Parks DJ, Blanchard SG, Bledsoe RK, et al. Bile acids: natural ligands for an orphan nuclear receptor. Science. 1999;284:1365–1368
  40. Wang H, Chen J, Hollister K, et al. Endogenous bile acids are ligands for the nuclear receptor fxr/bar. Mol Cell. 1999;3:543–553
  41. Goodwin B, Jones SA, Price RR, et al. A regulatory cascade of the nuclear receptors fxr, shp-1, and lrh-1 represses bile acid biosynthesis. Mol Cell. 2000;6:517–526
  42. Lu TT, Makishima M, Repa JJ, et al. Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Mol Cell. 2000;6:507–515
  43. Watanabe M, Houten SM, Wang L, et al. Bile acids lower triglyceride levels via a pathway involving fxr, shp, and srebp-1c. J Clin Invest. 2004;113:1408–1418
  44. Watanabe M, Houten SM, Mataki C, et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature. 2006;439:484–489
  45. Pellicciari R, Sato H, Gioiello A, et al. Nongenomic actions of bile acids. Synthesis and preliminary characterization of 23- and 6,23-alkyl-substituted bile acid derivatives as selective modulators for the G-protein coupled receptor tgr5. J Med Chem. 2007;50:4265–4268
  46. Thomas C, Auwerx J, Schoonjans K. Bile acids and the membrane bile acid receptor tgr5—connecting nutrition and metabolism. Thyroid. 2008;18:167–174
  47. Katsuma S, Hirasawa A, Tsujimoto G. Bile acids promote glucagon-like peptide-1 secretion through tgr5 in a murine enteroendocrine cell line stc-1. Biochem Biophys Res Commun. 2005;329:386–390
  48. Backhed F, Ding H, Wang T, et al. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci USA. 2004;101:15718–15723
  49. Backhed F, Manchester JK, Semenkovich CF, et al. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc Natl Acad Sci USA. 2007;104:979–984
  50. Tsai F, Coyle WJ. The microbiome and obesity: is obesity linked to our gut flora?. Curr Gastroenterol Rep. 2009;11:307–313
  51. Cani PD, Amar J, Iglesias MA, et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes. 2007;56:1761–1772
  52. Pappo I, Becovier H, Berry EM, et al. Polymyxin b reduces cecal flora, TNF production and hepatic steatosis during total parenteral nutrition in the rat. J Surg Res. 1991;51:106–112
  53. Creely SJ, McTernan PG, Kusminski CM, et al. Lipopolysaccharide activates an innate immune system response in human adipose tissue in obesity and type 2 diabetes. Am J Physiol. 2007;292:E740–E747
  54. Turnbaugh PJ, Ley RE, Mahowald MA, et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006;444:1027–1031
  55. Ley RE, Backhed F, Turnbaugh P, et al. Obesity alters gut microbial ecology. Proc Natl Acad Sci USA. 2005;102:11070–11075
  56. Ley RE, Turnbaugh PJ, Klein S, et al. Microbial ecology: human gut microbes associated with obesity. Nature. 2006;444:1022–1023
  57. Samuel BS, Gordon JI. A humanized gnotobiotic mouse model of host-archaeal-bacterial mutualism. Proc Natl Acad Sci USA. 2006;103:10011–10016
  58. Kalliomaki M, Collado MC, Salminen S, et al. Early differences in fecal microbiota composition in children may predict overweight. Am J Clin Nutr. 2008;87:534–538
  59. Unger RH. The physiology of cellular liporegulation. Annu Rev Physiol. 2003;65:333–347
  60. Yki-Jarvinen H. Ectopic fat accumulation: an important cause of insulin resistance in humans. J R Soc Med. 2002;95(Suppl. 42):39–45
  61. Despres JP, Lemieux I. Abdominal obesity and metabolic syndrome. Nature. 2006;444:881–887
  62. Ravussin E, Smith SR. Increased fat intake, impaired fat oxidation, and failure of fat cell proliferation result in ectopic fat storage, insulin resistance, and type 2 diabetes mellitus. Ann N Y Acad Sci. 2002;967:363–378
  63. Scherer PE. Adipose tissue: from lipid storage compartment to endocrine organ. Diabetes. 2006;55:1537–1545
  64. Marchesini G, Brizi M, Bianchi G, et al. Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes. 2001;50:1844–1850
  65. Angulo P. Nonalcoholic fatty liver disease. New Engl J Med. 2002;346:1221–1231
  66. Vettor R, Milan G, Rossato M, et al. Review article: adipocytokines and insulin resistance. Aliment Pharmacol Ther. 2005;22(Suppl. 2):3–10
  67. Goldstein BJ. Insulin resistance as the core defect in type 2 diabetes mellitus. Am J Cardiol. 2002;90:3G–10G
  68. Rajala MW, Scherer PE. Minireview: the adipocyte—at the crossroads of energy homeostasis, inflammation, and atherosclerosis. Endocrinology. 2003;144:3765–3773
  69. Yamauchi T, Kamon J, Minokoshi Y, et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating amp-activated protein kinase. Nat Med. 2002;8:1288–1295
  70. Fu Y, Luo N, Klein RL, et al. Adiponectin promotes adipocyte differentiation, insulin sensitivity, and lipid accumulation. J Lipid Res. 2005;46:1369–1379
  71. Kim JY, van de Wall E, Laplante M, et al. Obesity-associated improvements in metabolic profile through expansion of adipose tissue. J Clin Invest. 2007;117:2621–2637
  72. Jacob S, Machann J, Rett K, et al. Association of increased intramyocellular lipid content with insulin resistance in lean nondiabetic offspring of type 2 diabetic subjects. Diabetes. 1999;48:1113–1119
  73. Kelley DE, Goodpaster BH. Skeletal muscle triglyceride. An aspect of regional adiposity and insulin resistance. Diabetes Care. 2001;24:933–941
  74. 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
  75. Greco AV, Mingrone G, Giancaterini A, et al. Insulin resistance in morbid obesity: reversal with intramyocellular fat depletion. Diabetes. 2002;51:144–151
  76. Fabris R, Nisoli E, Lombardi AM, et al. Preferential channeling of energy fuels toward fat rather than muscle during high free fatty acid availability in rats. Diabetes. 2001;50:601–608
  77. Gastaldelli A. Abdominal fat: does it predict the development of type 2 diabetes?. Am J Clin Nutr. 2008;87:1118–1119
  78. Zhang C, Rexrode KM, van Dam RM, et al. Abdominal obesity and the risk of all-cause, cardiovascular, and cancer mortality: sixteen years of follow-up in us women. Circulation. 2008;117:1658–1667
  79. Winter Y, Rohrmann S, Linseisen J, et al. Contribution of obesity and abdominal fat mass to risk of stroke and transient ischemic attacks. Stroke. 2008;39:3145–3151
  80. Pischon T, Boeing H, Hoffmann K, et al. General and abdominal adiposity and risk of death in europe. New Engl J Med. 2008;359:2105–2120
  81. Barzilai N, She L, Liu BQ, et al. Surgical removal of visceral fat reverses hepatic insulin resistance. Diabetes. 1999;48:94–98
  82. Bajaj M, Suraamornkul S, Hardies LJ, et al. Plasma resistin concentration, hepatic fat content, and hepatic and peripheral insulin resistance in pioglitazone-treated type ii diabetic patients. Int J Obes Relat Metab Disord. 2004;28:783–789
  83. Ferrannini E, Sironi AM, Iozzo P, et al. Intra-abdominal adiposity, abdominal obesity, and cardiometabolic risk. Eur Heart J Suppl. 2008;10:B4–B10
  84. Gastaldelli A, Miyazaki Y, Pettiti M, et al. Separate contribution of diabetes, total fat mass, and fat topography to glucose production, gluconeogenesis, and glycogenolysis. J Clin Endocrinol Metab. 2004;89:3914–3921
  85. Hwang JH, Stein DT, Barzilai N, et al. Increased intrahepatic triglyceride is associated with peripheral insulin resistance: in vivo MR imaging and spectroscopy studies. Am J Physiol. 2007;293:E1663–E1669
  86. Bjorntorp P. Metabolic difference between visceral fat and subcutaneous abdominal fat. Diabetes Metab. 2000;26:10–12
  87. Bergman RN. Non-esterified fatty acids and the liver: why is insulin secreted into the portal vein?. Diabetologia. 2000;43:946–952
  88. Nielsen S, Guo Z, Johnson CM, et al. Splanchnic lipolysis in human obesity. J Clin Invest. 2004;113:1582–1588
  89. Fabbrini E, Magkos F, Mohammed BS, et al. Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity. Proc Natl Acad Sci USA. 2009;106:15430–15435
  90. Lewis GF, Carpentier A, Adeli K, et al. Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes. Endocr Rev. 2002;23:201–229
  91. Despres JP. Is visceral obesity the cause of the metabolic syndrome?. Ann Med. 2006;38:52–63
  92. Abate N, Garg A, Peshock RM, et al. Relationships of generalized and regional adiposity to insulin sensitivity in men. J Clin Invest. 1995;96:88–98
  93. Fontana L, Eagon JC, Trujillo ME, et al. Visceral fat adipokine secretion is associated with systemic inflammation in obese humans. Diabetes. 2007;56:1010–1013
  94. Marceau P, Biron S, Hould FS, et al. Liver pathology and the metabolic syndrome x in severe obesity. J Clin Endocrinol Metab. 1999;84:1513–1517
  95. Seppala-Lindroos A, Vehkavaara S, Hakkinen AM, 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
  96. Sanyal AJ, Campbell-Sargent C, Mirshahi F, et al. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology. 2001;120:1183–1192
  97. Musso G, Gambino R, Durazzo M, et al. Adipokines in nash: postprandial lipid metabolism as a link between adiponectin and liver disease. Hepatology. 2005;42:1175–1183
  98. Donnelly KL, Smith CI, Schwarzenberg SJJ, et al. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest. 2005;115:1343–1351
  99. Petersen KF, Dufour S, Befroy D, et al. Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes. Diabetes. 2005;54:603–608
  100. Bugianesi E, Pagotto U, Manini R, et al. Plasma adiponectin in nonalcoholic fatty liver is related to hepatic insulin resistance and hepatic fat content, not to liver disease severity. J Clin Endocrinol Metab. 2005;90:3498–3504
  101. Pagano C, Soardo G, Esposito W, et al. Plasma adiponectin is decreased in nonalcoholic fatty liver disease. Eur J Endocrinol/Eur Fed Endocr Soc. 2005;152:113–118
  102. Marra F, Gastaldelli A, Svegliati Baroni G, et al. Molecular basis and mechanisms of progression of non-alcoholic steatohepatitis. Trends Mol Med. 2008;14:72–81
  103. Marra F. Leptin and liver tissue repair: do rodent models provide the answers?. J Hepatol. 2007;46:12–18

PII: S1590-8658(10)00017-4

doi: 10.1016/j.dld.2010.01.013

Digestive and Liver Disease
Volume 42, Issue 5 , Pages 310-319 , May 2010

Article Tools

* Image Usage & Resolution