Gastroenterology
Volume 135, Issue 1 , Pages 122-130 , July 2008

Increased Liver Fat, Impaired Insulin Clearance, and Hepatic and Adipose Tissue Insulin Resistance in Type 2 Diabetes

  • Anna Kotronen

      Affiliations

    • Department of Medicine, Division of Diabetes, University of Helsinki, Helsinki, Finland
    • Minerva Medical Research Institute, Helsinki, Finland
    • Corresponding Author InformationAddress requests for reprints to: Anna Kotronen, MB, PhD, Department of Medicine, Division of Diabetes, University of Helsinki, P.O. Box 700, room C418B, FIN - 00029 HUCH, Helsinki, Finland. fax: 358-9-471 71992
    • ,
  • Leena Juurinen

      Affiliations

    • Department of Medicine, Division of Diabetes, University of Helsinki, Helsinki, Finland
    • Minerva Medical Research Institute, Helsinki, Finland
    • ,
  • Mirja Tiikkainen

      Affiliations

    • Department of Medicine, Division of Diabetes, University of Helsinki, Helsinki, Finland
    • ,
  • Satu Vehkavaara

      Affiliations

    • Department of Medicine, Division of Diabetes, University of Helsinki, Helsinki, Finland
    • ,
  • Hannele Yki–Järvinen

      Affiliations

    • Department of Medicine, Division of Diabetes, University of Helsinki, Helsinki, Finland

Received 17 December 2007 ,Accepted 13 March 2008.

References 

  1. Thamer C, Tschritter O, Haap M, et al. Elevated serum GGT concentrations predict reduced insulin sensitivity and increased intrahepatic lipids. Horm Metab Res. 2005;37:246–251
  2. Vozarova B, Stefan N, Lindsay RS, et al. High alanine aminotransferase is associated with decreased hepatic insulin sensitivity and predicts the development of type 2 diabetes. Diabetes. 2002;51:1889–1895
  3. Perry IJ, Wannamethee SG, Shaper AG. Prospective study of serum gamma-glutamyltransferase and risk of NIDDM. Diabetes Care. 1998;21:732–737
  4. Lee DH, Jacobs DR, Gross M, et al. Gamma-glutamyltransferase is a predictor of incident diabetes and hypertension: the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Clin Chem. 2003;49:1358–1366
  5. Ohlson LO, Larsson B, Bjorntorp P, et al. Risk factors for type 2 (non-insulin-dependent) diabetes mellitus (Thirteen and one-half years of follow-up of the participants in a study of Swedish men born in 1913). Diabetologia. 1988;31:798–805
  6. Hanley AJ, Williams K, Festa A, et al. Insulin resistance atherosclerosis study (Elevations in markers of liver injury and risk of type 2 diabetes: the insulin resistance atherosclerosis study). Diabetes. 2004;53:2623–2632
  7. Sattar N, McConnachie A, Ford I, et al. Serial metabolic measurements and conversion to type 2 diabetes in the west of Scotland coronary prevention study: specific elevations in alanine aminotransferase and triglycerides suggest hepatic fat accumulation as a potential contributing factor. Diabetes. 2007;56:984–991
  8. Kotronen A, Westerbacka J, Bergholm R, et al. Liver fat in the metabolic syndrome. J Clin Endocrinol Metab. 2007;92:3490–3497
  9. Yki-Jarvinen H. Fat in the liver and insulin resistance. Ann Med. 2005;37:347–356
  10. Kotronen A, Juurinen L, Hakkarainen A, et al. Liver fat is increased in type 2 diabetic patients and underestimated by serum alanine aminotransferase compared with equally obese nondiabetic subjects. Diabetes Care. 2008;31:165–169
  11. Ferrannini E, Wahren J, Faber OK, et al. Splanchnic and renal metabolism of insulin in human subjects: a dose-response study. Am J Physiol. 1983;244:E517–E527
  12. Meistas MT, Margolis S, Kowarski AA. Hyperinsulinemia of obesity is due to decreased clearance of insulin. Am J Physiol. 1983;245:E155–E159
  13. Sonnenberg GE, Hoffman RG, Mueller RA, et al. Splanchnic insulin dynamics and secretion pulsatilities in abdominal obesity. Diabetes. 1994;43:468–477
  14. Peiris AN, Mueller RA, Smith GA, et al. Splanchnic insulin metabolism in obesity (Influence of body fat distribution). J Clin Invest. 1986;78:1648–1657
  15. Letiexhe MR, Scheen AJ, Gerard PL, et al. Insulin secretion, clearance, and action on glucose metabolism in cirrhotic patients. J Clin Endocrinol Metab. 1993;77:1263–1268
  16. Polonsky KS, Gumbiner B, Ostrega D, et al. Alterations in immunoreactive proinsulin and insulin clearance induced by weight loss in NIDDM. Diabetes. 1994;43:871–877
  17. 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
  18. Genuth SM. Metabolic clearance of insulin in man. Diabetes. 1972;21:1003–1012
  19. Frost DP, Srivastava MC, Jones RH, et al. The kinetics of insulin metabolism in diabetes mellitus. Postgrad Med J. 1973;49(Suppl 7):949–954
  20. Stimmler L, Mashiter K, Snodgrass GJ, et al. Insulin disappearance after intravenous injection and its effect on blood glucose in diabetic and non-diabetic children and adults. Clin Sci. 1972;42:337–344
  21. Orskov H, Christensen NJ. Plasma disappearance rate of injected human insulin in juvenile diabetic, maturity-onset diabetic and nondiabetic subjects. Diabetes. 1969;18:653–659
  22. Strang BD, Bertics SJ, Grummer RR, et al. Relationship of triglyceride accumulation to insulin clearance and hormonal responsiveness in bovine hepatocytes. J Dairy Sci. 1998;81:740–747
  23. Goto T, Onuma T, Takebe K, et al. The influence of fatty liver on insulin clearance and insulin resistance in non-diabetic Japanese subjects. Int J Obes Relat Metab Disord. 1995;19:841–845
  24. Kotronen A, Vehkavaara S, Seppala-Lindroos A, et al. Effect of liver fat on insulin clearance. Am J Physiol Endocrinol Metab. 2007;293:E1709–E1715
  25. 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
  26. Olefsky JM, Kolterman OG, Scarlett JA. Insulin action and resistance in obesity and noninsulin-dependent type II diabetes mellitus. Am J Physiol. 1982;243:E15–E30
  27. 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
  28. Turk D, Alzaid A, Dinneen S, et al. The effects of non-insulin-dependent diabetes mellitus on the kinetics of onset of insulin action in hepatic and extrahepatic tissues. J Clin Invest. 1995;95:755–762
  29. 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
  30. Staehr P, Hother-Nielsen O, Levin K, et al. Assessment of hepatic insulin action in obese type 2 diabetic patients. Diabetes. 2001;50:1363–1370
  31. Basu R, Basu A, Johnson CM, et al. Insulin dose-response curves for stimulation of splanchnic glucose uptake and suppression of endogenous glucose production differ in nondiabetic humans and are abnormal in people with type 2 diabetes. Diabetes. 2004;53:2042–2050
  32. Alzaid AA, Dinneen SF, Turk DJ, et al. Assessment of insulin action and glucose effectiveness in diabetic and nondiabetic humans. J Clin Invest. 1994;94:2341–2348
  33. Lillioja S, Mott DM, Howard BV, et al. Impaired glucose tolerance as a disorder of insulin action (Longitudinal and cross-sectional studies in Pima Indians). N Engl J Med. 1988;318:1217–1225
  34. Duckworth WC, Hamel FG, Peavy DE. Hepatic metabolism of insulin. Am J Med. 1988;85:71–76
  35. Tiikkainen M, Hakkinen AM, Korsheninnikova E, et al. Effects of rosiglitazone and metformin on liver fat content, hepatic insulin resistance, insulin clearance, and gene expression in adipose tissue in patients with type 2 diabetes. Diabetes. 2004;53:2169–2176
  36. Juurinen L, Tiikkainen M, Hakkinen AM, et al. Effects of insulin therapy on liver fat content and hepatic insulin sensitivity in patients with type 2 diabetes. Am J Physiol Endocrinol Metab. 2007;292:E829–E835
  37. Angulo P, Hui JM, Marchesini G, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007;45:846–854
  38. Ryysy L, Hakkinen AM, Goto T, et al. Hepatic fat content and insulin action on free fatty acids and glucose metabolism rather than insulin absorption are associated with insulin requirements during insulin therapy in type 2 diabetic patients. Diabetes. 2000;49:749–758
  39. 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
  40. Yki-Jarvinen H, Young AA, Lamkin C, et al. Kinetics of glucose disposal in whole body and across the forearm in man. J Clin Invest. 1987;79:1713–1719
  41. Rizza RA, Mandarino LJ, Gerich JE. Dose-response characteristics for effects of insulin on production and utilization of glucose in man. Am J Physiol. 1981;240:E630–E639
  42. Jones CN, Pei D, Staris P, et al. Alterations in the glucose-stimulated insulin secretory dose-response curve and in insulin clearance in nondiabetic insulin-resistant individuals. J Clin Endocrinol Metab. 1997;82:1834–1838
  43. Savage PJ, Flock EV, Mako ME, et al. C-Peptide and insulin secretion in Pima Indians and Caucasians: constant fractional hepatic extraction over a wide range of insulin concentrations and in obesity. J Clin Endocrinol Metab. 1979;48:594–598
  44. Thomsen C, Becker U, Winkler K, et al. Quantification of liver fat using magnetic resonance spectroscopy. Magn Reson Imaging. 1994;12:487–495
  45. 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
  46. 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
  47. Sutinen J, Hakkinen AM, Westerbacka J, et al. Increased fat accumulation in the liver in HIV-infected patients with antiretroviral therapy-associated lipodystrophy. AIDS. 2002;16:2183–2193
  48. Lukaski HC, Johnson PE, Bolonchuk WW, et al. Assessment of fat-free mass using bioelectrical impedance measurements of the human body. Am J Clin Nutr. 1985;41:810–817
  49. Miles J, Glasscock R, Aikens J, et al. A microfluorometric method for the determination of free fatty acids in plasma. J Lipid Res. 1983;24:96–99
  50. Nurjhan N, Campbell PJ, Kennedy FP, et al. Insulin dose-response characteristics for suppression of glycerol release and conversion to glucose in humans. Diabetes. 1986;35:1326–1331
  51. 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
  52. Campbell PJ, Mandarino LJ, Gerich JE. Quantification of the relative impairment in actions of insulin on hepatic glucose production and peripheral glucose uptake in non-insulin-dependent diabetes mellitus. Metabolism. 1988;37:15–21
  53. Groop LC, Bonadonna RC, Shank M, et al. Role of free fatty acids and insulin in determining free fatty acid and lipid oxidation in man. J Clin Invest. 1991;87:83–89
  54. Jensen MD, Nielsen S. Insulin dose response analysis of free fatty acid kinetics. Metabolism. 2007;56:68–76
  55. Mandarino LJ, Campbell PJ, Gottesman IS, et al. Abnormal coupling of insulin receptor binding in noninsulin-dependent diabetes. Am J Physiol. 1984;247:E688–E692
  56. Thiebaud D, Jacot E, DeFronzo RA, et al. The effect of graded doses of insulin on total glucose uptake, glucose oxidation, and glucose storage in man. Diabetes. 1982;31:957–963
  57. Wiesenthal SR, Sandhu H, McCall RH, et al. Free fatty acids impair hepatic insulin extraction in vivo. Diabetes. 1999;48:766–774
  58. 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
  59. Yki-Jarvinen H, Puhakainen I, Saloranta C, et al. Demonstration of a novel feedback mechanism between FFA oxidation from intracellular and intravascular sources. Am J Physiol. 1991;260:E680–E689
  60. Arner P. Human fat cell lipolysis: biochemistry, regulation and clinical role. Best Pract Res Clin Endocrinol Metab. 2005;19:471–482
  61. Yki-Jarvinen H. Glucose toxicity. Endocr Rev. 1992;13:415–431
  62. Bajaj M, Suraamornkul S, Pratipanawatr T, et al. Pioglitazone reduces hepatic fat content and augments splanchnic glucose uptake in patients with type 2 diabetes. Diabetes. 2003;52:1364–1370
  63. Matthews DR, Hosker JP, Rudenski AS, et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412–419
  64. Katz A, Nambi SS, Mather K, et al. Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab. 2000;85:2402–2410
  65. Monzillo LU, Hamdy O. Evaluation of insulin sensitivity in clinical practice and in research settings. Nutr Rev. 2003;61:397–412
  66. Wallace TM, Levy JC, Matthews DR. Use and abuse of HOMA modeling. Diabetes Care. 2004;27:1487–1495

 Supported by research grants from the Academy of Finland, the Sigrid Juselius Foundation, and Novo Nordisk Foundation. This work is part of the project “Hepatic and adipose tissue and functions in the metabolic syndrome” (www.hepadip.org), which is supported by the European Commission as an Integrated Project under the 6th Framework Programme (Contract LSHM-CT-2005-018734).

PII: S0016-5085(08)00457-5

doi: 10.1053/j.gastro.2008.03.021

Gastroenterology
Volume 135, Issue 1 , Pages 122-130 , July 2008

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