Bedeutung der ektopen Fettablagerung in Leber und Skelettmuskulatur für die Pathogenese des Metabolischen Syndroms

Zusammenfassung

Die Insulinresistenz, das heißt das verminderte Ansprechen der an sich insulinempfindlichen Gewebe Leber und Skelettmuskel auf die Stoffwechselwirkungen von Insulin, ist ein wesentlicher pathogenetischer Faktor in der Entstehung der Erkrankungen des Metabolischen Syndroms. Vermehrt anfallende Fettmetaboliten in diesen Geweben stören die Übertragung des Insulinsignals vom Insulinrezeptor an der Zelloberfläche. Hierdurch wird die insulinabhängige Glucoseaufnahme in Muskelzellen vermindert und in der Leber kann die Glucosefreisetzung nicht mehr durch Insulin unterdrückt werden. Beides begünstigt einen Blutzuckeranstieg und somit das Auftreten eines Diabetes mellitus. Ursachen dieser ektopen Fettablagerung sind eine vermehrte Freisetzung von Fettsäuren aus dem Fettgewebe, eine verminderte Oxidation von Fett in der Muskulatur und auch eine gesteigerte Fettsynthese in der Leber. Medikamente, die die ektope Fettablagerung in Leber und Muskulatur vermindern, stellen einen neuen Therapieansatz in der Behandlung der mit dem Metabolischen Syndrom assoziierten Erkrankungen dar.

Summary

An impaired response of usually insulin sensitive tissues such as skeletal muscle and liver to the metabolic actions of insulin, also referred to as insulin resistance, is a hallmark feature of the metabolic syndrome. Importantly, skeletal muscle and liver insulin resistance are associated with ectopic fat deposition in these tissues. Increased intracellular fat metabolites have been shown to impair insulin signalling, thereby resulting in impaired insulin mediated glucose transport in skeletal muscle and diminished suppression of hepatic glucose production. Enhanced release of fatty acids from subcutaneous and visceral adipose tissue stores, impaired skeletal muscle fatty acid oxidation and increased hepatic fat synthesis are important contributors to the observed increase in ectopic fat deposition. Strategies targeted at repartitioning fat from muscle and liver represent a novel therapeutic approach to the metabolic syndrome and its associated diseases.

Schlüsselwörter

Insulinresistenz - Fettsäuren - Nicht-alkoholische Fettlebererkrankung

Key words

Insulin resistance - intramyocellular fat - non-alcoholic fatty liver disease - fatty acids

Literatur

• 1 Garg A. Acquired and inherited lipodystrophies.  N Engl J Med. 2004;  350 1220-1234
• 2 Hegele RA. Monogenic forms of insulin resistance: apertures that expose the common metabolic syndrome.  Trends Endocrinol Metab. 2003;  14 371-377
• 3 Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease.  Diabetes. 1988;  37 1595-1607
• 4 Angulo P. Nonalcoholic fatty liver disease.  N Engl J Med. 2002;  346 1221-1231
• 5 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
• 6 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
• 7 Krssak M, Falk PK, Dresner A. et al. . Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study.  Diabetologia. 1999;  42 113-116
• 8 Kim JK, Fillmore JJ, Chen Y. et al. . Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance.  Proc Natl Acad Sci U S A. 2001;  98 7522-7527
• 9 Shulman GI. Cellular mechanisms of insulin resistance.  J Clin Invest. 2000;  106 171-176
• 10 Samuel VT, Liu ZX, Qu X. et al. . Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease.  J Biol Chem. 2004;  279 32345-53
• 11 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
• 12 Diraison F, Moulin P, Beylot M. Contribution of hepatic de novo lipogenesis and reesterification of plasma non esterified fatty acids to plasma triglyceride synthesis during non-alcoholic fatty liver disease.  Diabetes Metab. 2003;  29 478-485
• 13 Hotamisligil GS. Inflammatory pathways and insulin action.  Int J Obes Relat Metab Disord. 2003;  27 53-55
• 14 Lehrke M, Lazar MA.. Inflamed about obesity.  Nat Medicine. 2004;  10 126-127
• 15 Hundal RS, Petersen KF, Mayerson AB. et al. . Mechanism by which high-dose aspirin improves glucose metabolism in type 2 diabetes.  J Clin Invest. 2002;  109 1321-1326
• 16 Unger RH, Zhou YT. Lipotoxicity of beta-cells in obesity and in other causes of fatty acid spillover.  Diabetes. 2001;  50 118-121
• 17 Ginsberg HN. Insulin resistance and cardiovascular disease.  J Clin Invest. 2000;  106 453-458
• 18 Wang RT, Koretz RL, Yee Jr. HF. Is weight reduction an effective therapy for nonalcoholic fatty liver?.  A systematic review. Am J Med. 2003;  115 554-559
• 19 Tiikkainen M, Bergholm R, Vehkavaara S. et al. . Effects of identical weight loss on body composition and features of insulin resistance in obese women with high and low liver fat content.  Diabetes. 2003;  52 701-707
• 20 Solga S, Alkhuraishe AR, Clark JM. et al. . Dietary composition and nonalcoholic fatty liver disease.  Dig Dis Sci. 2004;  49 1578-1583
• 21 Yki-Jarvinen H. Thiazolidinediones.  N Engl J Med. 2004;  351 1106-1118
• 22 Petersen KF, Oral EA, Dufour S. et al. . Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy.  J Clin Invest. 2002;  109 1345-1350
• 23 Cohen P, Miyazaki M, Socci ND. et al. . Role for stearoyl-CoA desaturase-1 in leptin-mediated weight loss.  Science. 2002;  297 240-243