Carbohydrate Metabolism and the Liver: Actual Aspects from Physiology and Disease

Zusammenfassung

Die Leber spielt eine Hauptrolle in der Aufrechterhaltung des Blutglukosespiegels innerhalb eines Normalbereiches. Dies wird durch ein in den Hepatozyten lokalisiertes System aus Enzymen gewährleistet, das für den Glukoseabbau bzw. für die Glukosesynthese verantwortlich ist. Die Steuerung dieses Systems erfolgt durch Mediatoren und Hormone, von denen Insulin eine Schlüsselrolle innehat. Beim Typ-2-Diabetes, aber auch bei verschiedenen Lebererkrankungen kommt es zu eine Störung des hepatischen Glukosestoffwechsels, die durch eine vermehrte hepatische Nüchtern-Glukoseproduktion und eine verminderte Glukoseaufnahme in der Postprandialphase gekennzeichnet ist. Als zentrales pathophysiologisches Element hierbei ist eine Insulinresistenz anzusehen. Die genaue Kenntnis der physiologischen Glukosehomeostase als auch der Mechanismen, die zu einer Insulinresistenz führen, sind entscheidende Vorraussetzung zur Entwicklung neuer Therapieansätze beim Diabetes mellitus wie auch bei Lebererkrankungen, die mit einer Insulinresistenz assoziiert sind. Experimente an genetisch manipulierten Mäusen haben in den letzten Jahren wesentlich zum Verständnis des Kohlenhydratstoffwechsels und seiner Störungen beigetragen. So konnten eine Reihe von Enzymen, Transkriptionsfaktoren und Mediatoren identifiziert werden, die von wesentlicher Bedeutung für die Aufrechterhaltung der hepatischen Glukosehomeostase sind. Zudem bieten solche Mäuse die Möglichkeit, den Glukosestoffwechsel an Modellen von Lebererkrankungen zu erforschen. In der folgenden Übersicht werden daher einige Mausmodelle vorgestellt und im Kontext mit der Situation beim Menschen diskutiert, bei denen durch genetische Manipulation Enzyme der Glukoneogenese, hepatische Transkriptionsfaktoren, IGF-1, hepatische Insulinrezeptoren, Adipokine oder Hepatitis C core Antigen über- bzw. vermindert exprimiert wurden.

Abstract

The liver plays a unique role in controlling carbohydrate metabolism by maintaining glucose concentrations in a normal range. This is achieved by a tightly regulated system of enzymes and kinases regulating either glucose breakdown or synthesis in hepatocytes. This process is under the control of glucoregulatory mediators among which insulin plays a key role. In type 2 diabetes, as well as in liver disease, alterations in hepatic glucose metabolism like an increased post-absorptive glucose production together with diminished glucose uptake following carbohydrate ingestion occur, implying insulin resistance as a central pathological principle. Knowledge of the processes involved in maintaining glucose homeostasis as well as insulin resistance is a prerequisite to develop new therapeutic approaches in diabetes as well as in liver disease. In the recent years, genetically-altered mouse models that have helped to identify enzymes, transcription factors and mediators that are essential for maintaining glucose homeostasis in the liver and provide a valuable tool to study carbohydrate metabolism in liver disease. In this current review, genetically manipulated animals either overexpressing or lacking key gluconeogenic enzymes, hepatic transcription factors, IGF-1, hepatic insulin receptors, adipokines and hepatitis C core antigen will be discussed in the context of human disease.

Schlüsselwörter

hepatischer Glukosestoffwechsel - Insulin - IGF-1 - Insulinresistenz - NAFLD - Hepatitis C - hepatogenische Diabetes

Key words

hepatic glucose production - insulin - IGF-1 - insulin resistance - NAFLD - hepatitis C - hepatogenous diabetes

References

• 1 Rothman D L, Magnusson I, Katz L D. et al . Quantitation of hepatic glycogenolysis and gluconeogenesis in fasting humans with 13C NMR.  Science. 1991;  254 573-576
• 2 Toffolo G, Campioni M, Basu R. et al . A minimal model of insulin secretion and kinetics to assess hepatic insulin extraction.  Am J Physiol Endocrinol Metab. 2006;  290 E169-E176
• 3 Giacca A, Fisher S J, Shi Z Q. et al . Importance of peripheral insulin levels for insulin-induced suppression of glucose production in depancreatized dogs.  J Clin Invest. 1992;  90 1769-1777
• 4 Lewis G F, Zinman B, Groenewoud Y. et al . Hepatic glucose production is regulated both by direct hepatic and extrahepatic effects of insulin in humans.  Diabetes. 1996;  45 454-462
• 5 Ferrannini E, Galvan A Q, Gastaldelli A. et al . Insulin: new roles for an ancient hormone.  Eur J Clin Invest. 1999;  29 842-852
• 6 Duong D T, Waltner-Law M E, Sears R. et al . Insulin inhibits hepatocellular glucose production by utilizing liver-enriched transcriptional inhibitory protein to disrupt the association of CREB-binding protein and RNA polymerase II with the phosphoenolpyruvate carboxykinase gene promoter.  J Biol Chem. 2002;  277 32 234-32 242
• 7 Hall R K, Yamasaki T, Kucera T. et al . Regulation of phosphoenolpyruvate carboxykinase and insulin-like growth factor-binding protein-1 gene expression by insulin. The role of winged helix/forkhead proteins.  J Biol Chem. 2000;  275 30 169-30 175
• 8 O’Brien R M, Granner D K. Regulation of gene expression by insulin.  Physiol Rev. 1996;  76 1109-1161
• 9 Lewis G F, Vranic M, Giacca A. Role of free fatty acids and glucagon in the peripheral effect of insulin on glucose production in humans.  Am J Physiol. 1998;  275 E177-E186
• 10 Obici S, Zhang B B, Karkanias G. et al . Hypothalamic insulin signaling is required for inhibition of glucose production.  Nat Med. 2002;  8 1376-1382
• 11 Cherrington A D, Edgerton D, Sindelar D K. The direct and indirect effects of insulin on hepatic glucose production in vivo.  Diabetologia. 1998;  41 987-996
• 12 Sindelar D K, Chu C A, Venson P. et al . Basal hepatic glucose production is regulated by the portal vein insulin concentration.  Diabetes. 1998;  47 523-529
• 13 Edgerton D S, Lautz M, Scott M. et al . Insulin’s direct effects on the liver dominate the control of hepatic glucose production.  J Clin Invest. 2006;  116 521-527
• 14 Fisher S J, Kahn C R. Insulin signaling is required for insulin’s direct and indirect action on hepatic glucose production.  J Clin Invest. 2003;  111 463-468
• 15 Okamoto H, Obici S, Accili D. et al . Restoration of liver insulin signaling in Insr knockout mice fails to normalize hepatic insulin action.  J Clin Invest. 2005;  115 1314-1322
• 16 Michael M D, Kulkarni R N, Postic C. et al . Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction.  Mol Cell. 2000;  6 87-97
• 17 Buettner C, Patel R, Muse E D. et al . Severe impairment in liver insulin signaling fails to alter hepatic insulin action in conscious mice.  J Clin Invest. 2005;  115 1306-1313
• 18 Cherrington A D. The role of hepatic insulin receptors in the regulation of glucose production.  J Clin Invest. 2005;  115 1136-1139
• 19 Girard J. Insulin’s effect on the liver: “direct or indirect?” continues to be the question.  J Clin Invest. 2006;  116 302-304
• 20 Jungermann K, Gardemann A, Beuers U. et al . Regulation of liver metabolism by the hepatic nerves.  Adv Enzyme Regul. 1987;  26 63-88
• 21 Pocai A, Obici S, Schwartz G J. et al . A brain-liver circuit regulates glucose homeostasis.  Cell Metab. 2005;  1 53-61
• 22 Magnusson I, Rothman D L, Katz L D. et al . Increased rate of gluconeogenesis in type II diabetes mellitus. A 13C nuclear magnetic resonance study.  J Clin Invest. 1992;  90 1323-1327
• 23 Reaven G M, Chen Y D, Golay A. et al . Documentation of hyperglucagonemia throughout the day in nonobese and obese patients with non-insulin-dependent diabetes mellitus.  J Clin Endocrinol Metab. 1987;  64 106-110
• 24 Pilkis S J, Granner D K. Molecular physiology of the regulation of hepatic gluconeogenesis and glycolysis.  Annu Rev Physiol. 1992;  54 885-909
• 25 Sun Y, Liu S, Ferguson S. et al . Phosphoenolpyruvate carboxykinase overexpression selectively attenuates insulin signaling and hepatic insulin sensitivity in transgenic mice.  J Biol Chem. 2002;  277 23 301-23 307
• 26 Trinh K Y, O’Doherty R M, Anderson P. et al . Perturbation of fuel homeostasis caused by overexpression of the glucose-6-phosphatase catalytic subunit in liver of normal rats.  J Biol Chem. 1998;  273 31 615-31 620
• 27 Barzilai N, Rossetti L. Role of glucokinase and glucose-6-phosphatase in the acute and chronic regulation of hepatic glucose fluxes by insulin.  J Biol Chem. 1993;  268 25 019-25 025
• 28 Burchell A, Cain D I. Rat hepatic microsomal glucose-6-phosphatase protein levels are increased in streptozotocin-induced diabetes.  Diabetologia. 1985;  28 852-856
• 29 Valera A, Pujol A, Pelegrin M. et al . Transgenic mice overexpressing phosphoenolpyruvate carboxykinase develop non-insulin-dependent diabetes mellitus.  Proc Natl Acad Sci USA. 1994;  91 9151-9154
• 30 Christ B, Nath A, Bastian H. et al . Regulation of the expression of the phosphoenolpyruvate carboxykinase gene in cultured rat hepatocytes by glucagon and insulin.  Eur J Biochem. 1988;  178 373-379
• 31 Yoon J C, Puigserver P, Chen G. et al . Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1.  Nature. 2001;  413 131-138
• 32 Puigserver P, Rhee J, Donovan J. et al . Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction.  Nature. 2003;  423 550-555
• 33 Christ B, Yazici E, Nath A. Phosphatidylinositol 3-kinase and protein kinase C contribute to the inhibition by interleukin 6 of phosphoenolpyruvate carboxykinase gene expression in cultured rat hepatocytes.  Hepatology. 2000;  31 461-468
• 34 Metzger S, Goldschmidt N, Barash V. et al . Interleukin-6 secretion in mice is associated with reduced glucose-6-phosphatase and liver glycogen levels.  Am J Physiol. 1997;  273 E262-E267
• 35 Inoue H, Ogawa W, Ozaki M. et al . Role of STAT-3 in regulation of hepatic gluconeogenic genes and carbohydrate metabolism in vivo.  Nat Med. 2004;  10 168-174
• 36 Dentin R, Pegorier J P, Benhamed F. et al . Hepatic glucokinase is required for the synergistic action of ChREBP and SREBP-1c on glycolytic and lipogenic gene expression.  J Biol Chem. 2004;  279 20 314-20 326
• 37 Dentin R, Benhamed F, Hainault I. et al . Liver-specific inhibition of ChREBP improves hepatic steatosis and insulin resistance in ob/ob mice.  Diabetes. 2006;  55 2159-2170
• 38 Valera A, Bosch F. Glucokinase expression in rat hepatoma cells induces glucose uptake and is rate limiting in glucose utilization.  Eur J Biochem. 1994;  222 533-539
• 39 Ferre T, Riu E, Bosch F. et al . Evidence from transgenic mice that glucokinase is rate limiting for glucose utilization in the liver.  FASEB J. 1996;  10 1213-1218
• 40 Ferre T, Pujol A, Riu E. et al . Correction of diabetic alterations by glucokinase.  Proc Natl Acad Sci USA. 1996;  93 7225-7230
• 41 Yakar S, Liu J L, Fernandez A M. et al . Liver-specific igf-1 gene deletion leads to muscle insulin insensitivity.  Diabetes. 2001;  50 1110-1118
• 42 Fernandez A M, Kim J K, Yakar S. et al . Functional inactivation of the IGF-I and insulin receptors in skeletal muscle causes type 2 diabetes.  Genes Dev. 2001;  15 1926-1934
• 43 Haluzik M, Yakar S, Gavrilova O. et al . Insulin resistance in the liver-specific IGF-1 gene-deleted mouse is abrogated by deletion of the acid-labile subunit of the IGF-binding protein-3 complex: relative roles of growth hormone and IGF-1 in insulin resistance.  Diabetes. 2003;  52 2483-2489
• 44 Yakar S, Setser J, Zhao H. et al . Inhibition of growth hormone action improves insulin sensitivity in liver IGF-1-deficient mice.  J Clin Invest. 2004;  113 96-105
• 45 O’Connell T, Clemmons D R. IGF-I/IGF-binding protein-3 combination improves insulin resistance by GH-dependent and independent mechanisms.  J Clin Endocrinol Metab. 2002;  87 4356-4360
• 46 Desbriere R, Vuaroqueaux V, Achard V. et al . 11beta-hydroxysteroid dehydrogenase type 1 mRNA is increased in both visceral and subcutaneous adipose tissue of obese patients.  Obesity (Silver Spring). 2006;  14 794-798
• 47 Masuzaki H, Paterson J, Shinyama H. et al . A transgenic model of visceral obesity and the metabolic syndrome.  Science. 2001;  294 2166-2170
• 48 Paulsen S K, Pedersen S B, Jorgensen J O. et al . Growth hormone (GH) substitution in GH-deficient patients inhibits 11beta-hydroxysteroid dehydrogenase type 1 messenger ribonucleic acid expression in adipose tissue.  J Clin Endocrinol Metab. 2006;  91 1093-1098
• 49 Thieringer R, Hermanowski-Vosatka A. Inhibition of 11beta-HSD1 as a novel treatment for the metabolic syndrome: do glucocorticoids play a role?.  Expert Rev Cardiovasc Ther. 2005;  3 911-924
• 50 Wang M. Inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 for the treatment of metabolic syndrome.  Curr Opin Investig Drugs. 2006;  7 319-323
• 51 Naunyn B. Glycosurie und Diabetes durch experimentelle Insulte und Krankheiten der Leber. E. N Handbuch Spez Path Terap Wien; A. Holder 1898: 38-49
• 52 Buzzelli G, Chiarantini E, Cotrozzi G. et al . Estimate of prevalence of glucose intolerance in chronic liver disease. Degree of agreement among some diagnostic criteria.  Liver. 1988;  8 354-359
• 53 Creutzfeldt W, Frerichs H, Sickinger K. Liver diseases and diabetes mellitus.  Prog Liver Dis. 1970;  3 371-407
• 54 Gentile S, Turco S, Guarino G. et al . Effect of treatment with acarbose and insulin in patients with non-insulin-dependent diabetes mellitus associated with non-alcoholic liver cirrhosis.  Diabetes Obes Metab. 2001;  3 33-40
• 55 Holstein A, Hinze S, Thiessen E. et al . Clinical implications of hepatogenous diabetes in liver cirrhosis.  J Gastroenterol Hepatol. 2002;  17 677-681
• 56 Bianchi G, Marchesini G, Zoli M. et al . Prognostic significance of diabetes in patients with cirrhosis.  Hepatology. 1994;  20 119-125
• 57 Vannini P, Forlani G, Marchesini G. et al . The euglycemic clamp technique in patients with liver cirrhosis.  Horm Metab Res. 1984;  16 341-343
• 58 Muller M J, Willmann O, Rieger A. et al . Mechanism of insulin resistance associated with liver cirrhosis.  Gastroenterology. 1992;  102 2033-2041
• 59 Kruszynska Y, Williams N, Perry M. et al . The relationship between insulin sensitivity and skeletal muscle enzyme activities in hepatic cirrhosis.  Hepatology. 1988;  8 1615-1619
• 60 Taylor R, Heine R J, Collins J. et al . Insulin action in cirrhosis.  Hepatology. 1985;  5 64-71
• 61 Nolte W, Hartmann H, Ramadori G. Glucose metabolism and liver cirrhosis.  Exp Clin Endocrinol Diabetes. 1995;  103 63-74
• 62 Siegel E G, Seidenstucker A, Gallwitz B. et al . Insulin secretion defects in liver cirrhosis can be reversed by glucagon-like peptide-1.  J Endocrinol. 2000;  164 13-19
• 63 Misbin R I, Merimee T J, Lowenstein J M. Insulin removal by isolated perfused rat liver.  Am J Physiol. 1976;  230 171-177
• 64 Navalesi R, Pilo A, Ferrannini E. Insulin kinetics after portal and peripheral injection of (125I) insulin: II. Experiments in the intact dog.  Am J Physiol. 1976;  230 1630-1636
• 65 Kruszynska Y T, Home P D, McIntyre N. Relationship between insulin sensitivity, insulin secretion and glucose tolerance in cirrhosis.  Hepatology. 1991;  14 103-111
• 66 Raddatz D, Rossbach C, Buchwald A. et al . Fasting hyperglucagonemia in patients with transjugular intrahepatic portosystemic shunts (TIPS).  Exp Clin Endocrinol Diabetes. 2005;  113 268-274
• 67 Perseghin G, Mazzaferro V, Sereni L P. et al . Contribution of reduced insulin sensitivity and secretion to the pathogenesis of hepatogenous diabetes: effect of liver transplantation.  Hepatology. 2000;  31 694-703
• 68 White M F. The insulin signalling system and the IRS proteins.  Diabetologia. 1997;  40 (Suppl 2) S2-17
• 69 Saltiel A R, Pessin J E. Insulin signaling pathways in time and space.  Trends Cell Biol. 2002;  12 65-71
• 70 Yin M J, Yamamoto Y, Gaynor R B. The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta.  Nature. 1998;  396 77-80
• 71 Aguirre V, Werner E D, Giraud J. et al . Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action.  J Biol Chem. 2002;  277 1531-1537
• 72 Lin Y, Berg A H, Iyengar P. et al . The hyperglycemia-induced inflammatory response in adipocytes: the role of reactive oxygen species.  J Biol Chem. 2005;  280 4617-4626
• 73 Furukawa S, Fujita T, Shimabukuro M. et al . Increased oxidative stress in obesity and its impact on metabolic syndrome.  J Clin Invest. 2004;  114 1752-1761
• 74 Ozcan U, Cao Q, Yilmaz E. et al . Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes.  Science. 2004;  306 457-461
• 75 Ozawa K, Miyazaki M, Matsuhisa M. et al . The endoplasmic reticulum chaperone improves insulin resistance in type 2 diabetes.  Diabetes. 2005;  54 657-663
• 76 Houstis N, Rosen E D, Lander E S. Reactive oxygen species have a causal role in multiple forms of insulin resistance.  Nature. 2006;  440 944-948
• 77 Hirosumi J, Tuncman G, Chang L. et al . A central role for JNK in obesity and insulin resistance.  Nature. 2002;  420 333-336
• 78 Gao Z, Zhang X, Zuberi A. et al . Inhibition of insulin sensitivity by free fatty acids requires activation of multiple serine kinases in 3T3-L1 adipocytes.  Mol Endocrinol. 2004;  18 2024-2034
• 79 Yu C, Chen Y, Cline G W. et al . Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle.  J Biol Chem. 2002;  277 50 230-50 236
• 80 Shoelson S E, Lee J, Yuan M. Inflammation and the IKK beta/I kappa B/NF-kappa B axis in obesity- and diet-induced insulin resistance.  Int J Obes Relat Metab Disord. 2003;  27 (Suppl 3) S49-52
• 81 Cai D, Yuan M, Frantz D F. et al . Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB.  Nat Med. 2005;  11 183-190
• 82 Yamauchi T, Kamon J, Ito Y. et al . Cloning of adiponectin receptors that mediate antidiabetic metabolic effects.  Nature. 2003;  423 762-769
• 83 Maeda N, Shimomura I, Kishida K. et al . Diet-induced insulin resistance in mice lacking adiponectin/ACRP30.  Nat Med. 2002;  8 731-737
• 84 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
• 85 Hui J M, Hodge A, Farrell G C. et al . Beyond insulin resistance in NASH: TNF-alpha or adiponectin?.  Hepatology. 2004;  40 46-54
• 86 Xu A, Wang Y, Keshaw H. et al . The fat-derived hormone adiponectin alleviates alcoholic and non-alcoholic fatty liver diseases in mice.  J Clin Invest. 2003;  112 91-100
• 87 Kaser S, Moschen A, Cayon A. et al . Adiponectin and its receptors in non-alcoholic steatohepatitis.  Gut. 2005;  54 117-121
• 88 Kaser S, Foger B, Waldenberger P. et al . Transjugular intrahepatic portosystemic shunt (TIPS) augments hyperinsulinemia in patients with cirrhosis.  J Hepatol. 2000;  33 902-906
• 89 Harle P, Straub R H. Leptin is a link between adipose tissue and inflammation.  Ann N Y Acad Sci. 2006;  1069 454-462
• 90 Petersen K F, Oral E A, Dufour S. et al . Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy.  J Clin Invest. 2002;  109 1345-1350
• 91 Aleffi S, Petrai I, Bertolani C. et al . Upregulation of proinflammatory and proangiogenic cytokines by leptin in human hepatic stellate cells.  Hepatology. 2005;  42 1339-1348
• 92 Leclercq I A, Farrell G C, Schriemer R. et al . Leptin is essential for the hepatic fibrogenic response to chronic liver injury.  J Hepatol. 2002;  37 206-213
• 93 McCullough A J, Bugianesi E, Marchesini G. et al . Gender-dependent alterations in serum leptin in alcoholic cirrhosis.  Gastroenterology. 1998;  115 947-953
• 94 Nolte W, Wirtz M, Rossbach C. et al . TIPS implantation raises leptin levels in patients with liver cirrhosis.  Exp Clin Endocrinol Diabetes. 2003;  111 435-442
• 95 Liangpunsakul S, Chalasani N. Relationship between unexplained elevations in alanine aminotransferase and serum leptin in U.S. adults: results from the Third National Health and Nutrition Examination Survey (NHANES III).  J Clin Gastroenterol. 2004;  38 891-897
• 96 Bethanis S K, Theocharis S E. Leptin in the field of hepatic fibrosis: A pivotal or an incidental player?.  Dig Dis Sci. 2006;  Epub ahead of print. doi: 10.1007/s10620-006-9126-0
• 97 Steppan C M, Bailey S T, Bhat S. et al . The hormone resistin links obesity to diabetes.  Nature. 2001;  409 307-312
• 98 Rajala M W, Qi Y, Patel H R. et al . Regulation of resistin expression and circulating levels in obesity, diabetes, and fasting.  Diabetes. 2004;  53 1671-1679
• 99 Rangwala S M, Rich A S, Rhoades B. et al . Abnormal glucose homeostasis due to chronic hyperresistinemia.  Diabetes. 2004;  53 1937-1941
• 100 Rajala M W, Obici S, Scherer P E. et al . Adipose-derived resistin and gut-derived resistin-like molecule-beta selectively impair insulin action on glucose production.  J Clin Invest. 2003;  111 225-230
• 101 Muse E D, Obici S, Bhanot S. et al . Role of resistin in diet-induced hepatic insulin resistance.  J Clin Invest. 2004;  114 232-239
• 102 Way J M, Gorgun C Z, Tong Q. et al . Adipose tissue resistin expression is severely suppressed in obesity and stimulated by peroxisome proliferator-activated receptor gamma agonists.  J Biol Chem. 2001;  276 25 651-25 653
• 103 Engeli S, Bohnke J, Feldpausch M. et al . Regulation of 11beta-HSD genes in human adipose tissue: influence of central obesity and weight loss.  Obes Res. 2004;  12 9-17
• 104 Patel K, Muir A, McHutchison J G. et al . A link between leptin and steatosis in chronic hepatitis C? Time to weigh up the fats.  Am J Gastroenterol. 2003;  98 952-955
• 105 Savage D B, Sewter C P, Klenk E S. et al . Resistin/Fizz3 expression in relation to obesity and peroxisome proliferator-activated receptor-gamma action in humans.  Diabetes. 2001;  50 2199-2202
• 106 McTernan C L, McTernan P G, Harte A L. et al . Resistin, central obesity, and type 2 diabetes.  Lancet. 2002;  359 46-47
• 107 McTernan P G, McTernan C L, Chetty R. et al . Increased resistin gene and protein expression in human abdominal adipose tissue.  J Clin Endocrinol Metab. 2002;  87 2407
• 108 Lin S Y, Sheu W H, Chen W Y. et al . Stimulated resistin expression in white adipose of rats with bile duct ligation-induced liver cirrhosis: relationship to cirrhotic hyperinsulinemia and increased tumor necrosis factor-alpha.  Mol Cell Endocrinol. 2005;  232 1-8
• 109 Yagmur E, Trautwein C, Gressner A M. et al . Resistin serum levels are associated with insulin resistance, disease severity, clinical complications, and prognosis in patients with chronic liver diseases.  Am J Gastroenterol. 2006;  101 1244-1252
• 110 Bahr M J, Ockenga J, Boker K H. et al . Elevated resistin levels in cirrhosis are associated with the proinflammatory state and altered hepatic glucose metabolism but not with insulin resistance.  Am J Physiol Endocrinol Metab. 2006;  291 E199-206
• 111 Pagano C, Soardo G, Pilon C. et al . Increased serum resistin in nonalcoholic fatty liver disease is related to liver disease severity and not to insulin resistance.  J Clin Endocrinol Metab. 2006;  91 1081-1086
• 112 Hotamisligil G S, Peraldi P, Budavari A. et al . IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance.  Science. 1996;  271 665-668
• 113 Uysal K T, Wiesbrock S M, Marino M W. et al . Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function.  Nature. 1997;  389 610-614
• 114 Li Z, Yang S, Lin H. et al . Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease.  Hepatology. 2003;  37 343-350
• 115 Fried S K, Bunkin D A, Greenberg A S. Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid.  J Clin Endocrinol Metab. 1998;  83 847-850
• 116 Fernandez-Real J M, Vayreda M, Richart C. et al . Circulating interleukin 6 levels, blood pressure, and insulin sensitivity in apparently healthy men and women.  J Clin Endocrinol Metab. 2001;  86 1154-1159
• 117 Andreozzi F, Laratta E, Cardellini M. et al . Plasma interleukin-6 levels are independently associated with insulin secretion in a cohort of Italian-Caucasian nondiabetic subjects.  Diabetes. 2006;  55 2021-2024
• 118 Di Gregorio G B, Hensley L, Lu T. et al . Lipid and carbohydrate metabolism in mice with a targeted mutation in the IL-6 gene: absence of development of age-related obesity.  Am J Physiol Endocrinol Metab. 2004;  287 E182-187
• 119 Wallenius V, Wallenius K, Ahren B. et al . Interleukin-6-deficient mice develop mature-onset obesity.  Nat Med. 2002;  8 75-79
• 120 Allison M E, Wreghitt T, Palmer C R. et al . Evidence for a link between hepatitis C virus infection and diabetes mellitus in a cirrhotic population.  J Hepatol. 1994;  21 1135-1139
• 121 Mehta S H, Brancati F L, Sulkowski M S. et al . Prevalence of type 2 diabetes mellitus among persons with hepatitis C virus infection in the United States.  Ann Intern Med. 2000;  133 592-599
• 122 Mangia A, Schiavone G, Lezzi G. et al . HCV and diabetes mellitus: evidence for a negative association.  Am J Gastroenterol. 1998;  93 2363-2367
• 123 Shaheen M, Echeverry D, Oblad M G. et al . Hepatitis C, metabolic syndrome, and inflammatory markers: Results from the Third National Health and Nutrition Examination Survey (NHANES III).  Diabetes Res Clin Pract. 2006;  Epub ahead of print. doi: 10.106/j.diabres.2006.07.008
• 124 Hui J M, Sud A, Farrell G C. et al . Insulin resistance is associated with chronic hepatitis C virus infection and fibrosis progression (corrected).  Gastroenterology. 2003;  125 1695-1704
• 125 Tazawa J, Maeda M, Nakagawa M. et al . Diabetes mellitus may be associated with hepatocarcinogenesis in patients with chronic hepatitis C.  Dig Dis Sci. 2002;  47 710-715
• 126 Shintani Y, Fujie H, Miyoshi H. et al . Hepatitis C virus infection and diabetes: direct involvement of the virus in the development of insulin resistance.  Gastroenterology. 2004;  126 840-848
• 127 Tsutsumi T, Suzuki T, Moriya K. et al . Alteration of intrahepatic cytokine expression and AP-1 activation in transgenic mice expressing hepatitis C virus core protein.  Virology. 2002;  304 415-424
• 128 Aytug S, Reich D, Sapiro L E. et al . Impaired IRS-1/PI3-kinase signaling in patients with HCV: a mechanism for increased prevalence of type 2 diabetes.  Hepatology. 2003;  38 1384-1892
• 129 Marchesini G, Brizi M, Morselli-Labate A M. et al . Association of non-alcoholic fatty liver disease with insulin resistance.  Am J Med. 1999;  107 450-455
• 130 Marchesini G, Brizi M, Bianchi G. et al . Nonalcoholic fatty liver disease: a feature of the metabolic syndrome.  Diabetes. 2001;  50 1844-1850
• 131 Kraegen E W, Clark P W, Jenkins A B. et al . Development of muscle insulin resistance after liver insulin resistance in high-fat-fed rats.  Diabetes. 1991;  40 1397-1403
• 132 Kim J K, Fillmore J J, Chen Y. et al . Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance.  Proc Natl Acad Sci USA. 2001;  98 7522-7527
• 133 Friedman J. Fat in all the wrong places.  Nature. 2002;  415 268-269
• 134 Caldwell S H, Swerdlow R H, Khan E M. et al . Mitochondrial abnormalities in non-alcoholic steatohepatitis.  J Hepatol. 1999;  31 430-434
• 135 Bugianesi E, McCullough A J, Marchesini G. Insulin resistance: a metabolic pathway to chronic liver disease.  Hepatology. 2005;  42 987-1000
• 136 Tiikkainen M, Hakkinen A M, 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
• 137 Matsumoto M, Han S, Kitamura T. et al . Dual role of transcription factor FoxO1 in controlling hepatic insulin sensitivity and lipid metabolism.  J Clin Invest. 2006;  116 2464-2472