Gastroenterology
Volume 134, Issue 5 , Pages 1369-1375 , May 2008

Liver, Muscle, and Adipose Tissue Insulin Action Is Directly Related to Intrahepatic Triglyceride Content in Obese Subjects

  • Kevin M. Korenblat

      Affiliations

    • Center for Human Nutrition, Washington University School of Medicine, St Louis, Missouri
    • Division of Gastroenterology, Washington University School of Medicine, St Louis, Missouri
  • ,
  • Elisa Fabbrini

      Affiliations

    • Center for Human Nutrition, Washington University School of Medicine, St Louis, Missouri
    • Department of Medical Pathophysiology, University of Rome “La Sapienza,” Rome, Italy
  • ,
  • B. Selma Mohammed

      Affiliations

    • Center for Human Nutrition, Washington University School of Medicine, St Louis, Missouri
  • ,
  • Samuel Klein

      Affiliations

    • Center for Human Nutrition, Washington University School of Medicine, St Louis, Missouri
    • Corresponding Author InformationAddress requests for reprints to: Samuel Klein, MD, Center for Human Nutrition, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8031, St Louis, Missouri 63110. fax: (314) 362-8230.

Received 9 September 2007 ,Accepted 18 January 2008.

References 

  1. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med. 2002;346:1221–1231
  2. Marchesini G, Bugianesi E, Forlani G, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology. 2003;37:917–923
  3. Ioannou GN, Weiss NS, Boyko EJ, et al. Elevated serum alanine aminotransferase activity and calculated risk of coronary heart disease in the United States. Hepatology. 2006;43:1145–1151
  4. Adams LA, Lymp JF, St Sauver J, et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology. 2005;129:113–121
  5. Ruhl CE, Everhart JE. Determinants of the association of overweight with elevated serum alanine aminotransferase activity in the United States. Gastroenterology. 2003;124:71–79
  6. Chitturi S, Abeygunasekera S, Farrell GC, et al. NASH and insulin resistance: insulin hypersecretion and specific association with the insulin resistance syndrome. Hepatology. 2002;35:373–379
  7. Pagano G, Pacini G, Musso G, et al. Nonalcoholic steatohepatitis, insulin resistance, and metabolic syndrome: further evidence for an etiologic association. Hepatology. 2002;35:367–372
  8. Groop LC, Saloranta C, Shank M, et al. The role of free fatty acid metabolism in the pathogenesis of insulin resistance in obesity and noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 1991;72:96–107
  9. Gastaldelli A, Cusi K, Pettiti M, et al. Relationship between hepatic/visceral fat and hepatic insulin resistance in nondiabetics and type 2 diabetic subjects. Gastroenterology. 2007;133:496–506
  10. 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
  11. Sanyal AJ, Campbell-Sargent C, Mirshahi F, et al. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology. 2001;120:1183–1192
  12. 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
  13. Marchesini G, Brizi M, Bianchi G, et al. Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes. 2001;50:1844–1850
  14. Selzer ML. The Michigan alcoholism screening test: the quest for a new diagnostic instrument. Am J Psychiatry. 1971;127:1653–1658
  15. Frimel TN, Deivanayagam S, Bashir A, et al. Assessment of intrahepatic triglyceride content using magnetic resonance spectroscopy. J Cardiometab Syndr. 2007;2:136–138
  16. Jensen MD, Heiling VJ. Heated hand vein blood is satisfactory for measurements during free fatty acid kinetic studies. Metabolism. 1991;40:406–409
  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. Patterson BW, Zhao G, Klein S. Improved accuracy and precision of gas chromatography/mass spectrometry measurements for metabolic tracers. Metabolism. 1998;47:706–712
  19. Patterson BW, Zhao G, Elias N, et al. Validation of a new procedure to determine plasma fatty acid concentration and isotopic enrichment. J Lipid Res. 1999;40:2118–2124
  20. Mittendorfer B, Liem O, Patterson BW, et al. What does the measurement of whole-body fatty acid rate of appearance in plasma by using a fatty acid tracer really mean?. Diabetes. 2003;52:1641–1648
  21. 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
  22. 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
  23. Amarapurka DN, Amarapurkar AD, Patel ND, et al. Nonalcoholic steatohepatitis (NASH) with diabetes: predictors of liver fibrosis. Ann Hepatol. 2006;5:30–33
  24. Villanova N, Moscatiello S, Ramilli S, et al. Endothelial dysfunction and cardiovascular risk profile in nonalcoholic fatty liver disease. Hepatology. 2005;42:473–480
  25. Horowitz JF, Klein S. Whole body and abdominal lipolytic sensitivity to epinephrine is suppressed in upper body obese women. Am J Physiol Endocrinol Metab. 2000;278:E1144–E1152
  26. Cassader M, Gambino R, Musso G, et al. Postprandial triglyceride-rich lipoprotein metabolism and insulin sensitivity in nonalcoholic steatohepatitis patients. Lipids. 2001;36:1117–1124
  27. Petersen KF, Dufour S, Savage DB, et al. Inaugural article: the role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome. Proc Natl Acad Sci U S A. 2007;104:12587–12594
  28. Savage DB, Petersen KF, Shulman GI. Disordered lipid metabolism and the pathogenesis of insulin resistance. Physiol Rev. 2007;87:507–520
  29. Cai D, Yuan M, Frantz DF, et al. Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med. 2005;11:183–190
  30. Stefan N, Hennige AM, Staiger H, et al. Alpha2-Heremans-Schmid glycoprotein/fetuin-A is associated with insulin resistance and fat accumulation in the liver in humans. Diabetes Care. 2006;29:853–857
  31. Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313–1321
  32. Neuschwander-Tetri BA, Brunt EM, Wehmeier KR, et al. Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand rosiglitazone. Hepatology. 2003;38:1008–1017
  33. Szczepaniak LS, Nurenberg P, Leonard D, et al. Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab. 2005;288:E462–E468
  34. Petersen KF, Dufour S, Feng J, et al. Increased prevalence of insulin resistance and nonalcoholic fatty liver disease in Asian-Indian men. Proc Natl Acad Sci U S A. 2006;103:18273–18277
  35. Adiels M, Taskinen MR, Packard C, et al. Overproduction of large VLDL particles is driven by increased liver fat content in man. Diabetologia. 2006;49:755–765
  36. Kelley DE, McKolanis TM, Hegazi RA, et al. Fatty liver in type 2 diabetes mellitus: relation to regional adiposity, fatty acids, and insulin resistance. Am J Physiol Endocrinol Metab. 2003;285:E906–E916
  37. Westerbacka J, Corner A, Tiikkainen M, et al. Women and men have similar amounts of liver and intra-abdominal fat, despite more subcutaneous fat in women: implications for sex differences in markers of cardiovascular risk. Diabetologia. 2004;47:1360–1369
  38. Fishbein MH, Mogren C, Gleason T, et al. Relationship of hepatic steatosis to adipose tissue distribution in pediatric nonalcoholic fatty liver disease. J Pediatr Gastroenterol Nutr. 2006;42:83–88
  39. Bergman RN, Finegood DT, Ader M. Assessment of insulin sensitivity in vivo. Endocrinol Rev. 1985;6:45–86

 The authors report that no conflicts of interests exist.

 Supported by National Institutes of Health grants DK 37948, DK 56341 (Clinical Nutrition Research Unit), RR-00036 (General Clinical Research Center), and RR-00954 (Biomedical Mass Spectrometry Resource) and by DK 52574 (Washington University Digestive Diseases Research Core Center) and an American Gastroenterological Association Roche Junior Faculty Clinical Research Award in Hepatology (to K.M.K.).

PII: S0016-5085(08)00181-9

doi: 10.1053/j.gastro.2008.01.075

Gastroenterology
Volume 134, Issue 5 , Pages 1369-1375 , May 2008