Liver and diabetes. A vicious circle

Hepatology Research

Volumn 43, Issue 1, 2013, Pages 51-64

  Loria, Paola ^a   Lonardo, Amedeo ^a   Anania, Frank ^b  

^a UNIVERSITY OF MODENA AND REGGIO EMILIA   (Italy)

^b EMORY UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Cholangiocarcinoma; Cirrhosis; Epidemiology; Hepatocellular carcinoma; Management; Natural history

Indexed keywords

2,4 THIAZOLIDINEDIONE DERIVATIVE; GLITAZONE DERIVATIVE;

ADIPOSE TISSUE; APOPTOSIS; AUTOPHAGY; CARCINOGENESIS; DISEASE COURSE; ENDOPLASMIC RETICULUM STRESS; FATTY LIVER; FIBROGENESIS; FIBROSIS; HEART MUSCLE; HUMAN; HYPOTHALAMUS; INFLAMMATION; INSULIN RESISTANCE; INTESTINE FLORA; LIPOTOXICITY; LIVER CANCER; LIVER CELL; LIVER CIRRHOSIS; LIVER INJURY; MICROBIOME; NON INSULIN DEPENDENT DIABETES MELLITUS; NONALCOHOLIC FATTY LIVER; NONHUMAN; PATHOGENESIS; PRIMARY TUMOR; PRIORITY JOURNAL; REVIEW; RISK FACTOR; SKELETAL MUSCLE; STEATOSIS;

EID: 84872671526     PISSN: 13866346     EISSN: 1872034X     Source Type: Journal    
DOI: 10.1111/j.1872-034X.2012.01031.x     Document Type: Review

References (142)

1. Nolan CJ, Damm P, Prentki M. Type 2 diabetes across generations: from pathophysiology to prevention and management. Lancet 2011; 378: 169-81.
2. Perseghin G, Mazzaferro V, Sereni LP etal. Contribution of reduced insulin sensitivity and secretion to the pathogenesis of hepatogenous diabetes: effect of liver transplantation. Hepatology 2000; 31: 694-703.
3. Trombetta M, Spiazzi G, Zoppini G, Muggeo M. Review article: type 2 diabetes and chronic liver disease in the Verona diabetes study. Aliment Pharmacol Ther 2005; 22 (Suppl 2): 24-7.
4. Chitturi S, Wong VW, Farrell G. Nonalcoholic fatty liver in Asia: firmly entrenched and rapidly gaining ground. J Gastroenterol Hepatol 2011; 26 (Suppl 1): 163-72.
5. Musso G, Gambino R, Cassader M, Pagano G. Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann Med 2011; 43: 617-49.
6. Ariza X, Castellote J, Lora-Tamayo J etal. Risk factors for resistance to ceftriaxone and its impact on mortality in community, healthcare and nosocomial spontaneous bacterial peritonitis. J Hepatol 2012; 56: 825-32.
7. Centers for Disease Control and Prevention (CDC). Use of hepatitis B vaccination for adults with diabetes mellitus: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2011; 60: 1709-11. PubMed PMID: 22189894.
8. Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: mayo clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 1980; 55: 434-8.
9. Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest 2005; 115: 1343-51.
10. Kotronen A, Yki-Järvinen H. Fatty liver. A novel component of the metabolic syndrome. Arterioscler Thromb Vasc Biol 2008; 28: 27-38.
11. Kantartzis K, Gastaldelli A, Magkos F, Lavoie JM. Diabetes and non-alcoholic Fatty liver disease. Exp Diabetes Res 2012; 2012: 404632.
12. Loria P, Carulli L, Bertolotti M, Lonardo A. Endocrine and liver interaction: the role of endocrine pathways in NASH. Nat Rev Gastroenterol Hepatol 2009; 6: 236-47.
13. Day CP, James OF. Steatohepatitis: a tale of two "hits"? Gastroenterology 1998; 114: 842-5.
14. Rhee EJ, Lee WY, Cho YK, Kim BI, Sung KC. Hyperinsulinemia and the development of nonalcoholic Fatty liver disease in nondiabetic adults. Am J Med 2011; 124: 69-76.
15. Wanless IR, Shiota K. The pathogenesis of nonalcoholic steatohepatitis and other fatty liver diseases: a four-step model including the role of lipid release and hepatic venular obstruction in the progression to cirrhosis. Semin Liver Dis 2004; 24: 99-106.
16. Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology 2010; 52: 1836-46.
17. Tiikkainen M, Bergholm R, Vehkavaara S etal. 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: 701-7.
18. Petersen KF, Dufour S, Befroy D, Lehrke M, Hendler RE, Shulman GI. Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes. Diabetes 2005; 54: 603-8.
19. Kotronen A, Juurinen L, Tiikkainen M, Vehkavaara S, Yki-Järvinen H. Increased liver fat, impaired insulin clearance, and hepatic and adipose tissue insulin resistance in type 2 diabetes. Gastroenterology 2008; 135: 122-30.
20. Monetti M, Levin MC, Watt MJ etal. Dissociation of hepatic steatosis and insulin resistance in mice overexpressing DGAT in the liver. Cell Metab 2007; 6: 69-78.
21. Lonardo A, Lombardini S, Scaglioni F etal. Hepatic steatosis and insulin resistance: does etiology make a difference? J Hepatol 2006; 44: 190-6.
22. Kantartzis K, Peter A, Machicao F etal. Dissociation between fatty liver and insulin resistance in humans carrying a variant of the patatin-like phospholipase 3 gene. Diabetes 2009; 58: 2616-23.
23. Kantartzis K, Machicao F, Machann J etal. The DGAT2 gene is a candidate for the dissociation between fatty liver and insulin resistance in humans. Clin Sci (Lond) 2009; 116: 531-7.
24. Amaro A, Fabbrini E, Kars M etal. Dissociation between intrahepatic triglyceride content and insulin resistance in familial hypobetalipoproteinemia. Gastroenterology 2010; 139: 149-53.
25. Stefan N, Staiger H, Häring HU. Dissociation between fatty liver and insulin resistance: the role of adipose triacylglycerol lipase. Diabetologia 2011; 54: 7-9.
26. de la Monte SM, Longato L, Tong M, Wands JR. Insulin resistance and neurodegeneration: roles of obesity, type 2 diabetes mellitus and non-alcoholic steatohepatitis. Curr Opin Investig Drugs 2009; 10: 1049-60.
27. Karmi A, Iozzo P, Viljanen A etal. Increased brain fatty acid uptake in metabolic syndrome. Diabetes 2010; 59: 2171-7.
28. Das UN. Obesity: genes, brain, gut, and environment. Nutrition 2010; 26: 459-73.
29. Martínez de Morentin PB, Varela L, Fernø J, Nogueiras R, Diéguez C, López M. Hypothalamic lipotoxicity and the metabolic syndrome. Biochim Biophys Acta 2010; 1801: 350-61.
30. Bäckhed F, Ding H, Wang T etal. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci U S A 2004; 101: 15718-23.
31. Cani PD, Delzenne NM. Interplay between obesity and associated metabolic disorders: new insights into the gut microbiota. Curr Opin Pharmacol 2009; 9: 737-43.
32. Vijay-Kumar M, Aitken JD, Carvalho FA etal. Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science 2010; 328: 228-31.
33. Sandoval DA, Seeley RJ. Medicine. The microbes made me eat it. Science 2010; 328: 179-80.
34. Serino M, Luche E, Gres S etal. Metabolic adaptation to a high-fat diet is associated with a change in the gut microbiota. Gut 2012; 61: 543-53.
35. Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature 1998; 395: 763-70.
36. Halaas JL, Gajiwala KS, Maffei M etal. Weight-reducing effects of the plasma protein encoded by the obese gene. Science 1995; 269: 543-6.
37. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature 1994; 372: 425-32. Erratum in: Nature 1995;374:479.
38. Arita Y, Kihara S, Ouchi N etal. Paradoxical decrease of an adiposespecific protein, adiponectin, in obesity. Biochem Biophys Res Commun 1999; 257: 79-83.
39. Steppan CM, Bailey ST, Bhat S etal. The hormone resistin links obesity to diabetes. Nature 2001; 409: 307-12.
40. Masaki T, Yoshimatsu H, Chiba S etal. Tumor necrosis factor-alpha regulates in vivo expression of the rat UCP family differentially. Biochim Biophys Acta 1999; 1436: 585-92.
41. Mohamed-Ali V, Goodrick S, Rawesh A etal. Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo. J Clin Endocrinol Metab 1997; 82: 4196-200.
42. Guerre-Millo M. Adipose tissue hormones. J Endocrinol Invest 2002; 250: 855-61.
43. Fliers E, Kreier F, Voshol PJ etal. White adipose tissue: getting nervous. J Neuroendocrinol 2003; 15: 1005-10.
44. Leclercq IA, Da Silva Morais A, Schroyen B, Van Hul N, Geerts A. Insulin resistance in hepatocytes and sinusoidal liver cells: mechanisms and consequences. J Hepatol 2007; 47: 142-56.
45. Rabøl R, Petersen KF, Dufour S, Flannery C, Shulman GI. Reversal of muscle insulin resistance with exercise reduces postprandial hepatic de novo lipogenesis in insulin resistant individuals. Proc Natl Acad Sci U S A 2011; 108: 13705-9.
46. Straznicky NE, Lambert EA, Grima MT etal. The effects of dietary weight loss with or without exercise training on liver enzymes in obese metabolic syndrome subjects. Diabetes Obes Metab 2012; 14: 139-48.
47. Stanhope KL, Schwarz JM, Keim NL etal. Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans. J Clin Invest 2009; 119: 1322-34.
48. Dekker MJ, Su Q, Baker C, Rutledge AC, Adeli K. Fructose: a highly lipogenic nutrient implicated in insulin resistance, hepatic steatosis, and the metabolic syndrome. Am J Physiol Endocrinol Metab 2010; 299: E685-94.
49. Lim JS, Mietus-Snyder M, Valente A, Schwarz JM, Lustig RH. The role of fructose in the pathogenesis of NAFLD and the metabolic syndrome. Nat Rev Gastroenterol Hepatol 2010; 7: 251-64.
50. Ouyang X, Cirillo P, Sautin Y etal. Fructose consumption as a risk factor for non-alcoholic fatty liver disease. J Hepatol 2008; 48: 993-9.
51. Abdelmalek MF, Suzuki A, Guy C etal. Nonalcoholic Steatohepatitis Clinical Research Network. Increased fructose consumption is associated with fibrosis severity in patients with nonalcoholic fatty liver disease. Hepatology 2010; 51: 1961-71.
52. Yuan H, Shyy JY, Martins-Green M. Second-hand smoke stimulates lipid accumulation in the liver by modulating AMPK and SREBP-1. J Hepatol 2009; 51: 535-47.
53. Zein CO, Unalp A, Colvin R, Liu YC, McCullough AJ. Nonalcoholic Steatohepatitis Clinical Research Network. Smoking and severity of hepatic fibrosis in nonalcoholic fatty liver disease. J Hepatol 2011; 54: 753-9.
54. Azzalini L, Ferrer E, Ramalho LN etal. Cigarette smoking exacerbates nonalcoholic fatty liver disease in obese rats. Hepatology 2010; 51: 1567-76.
55. Willi C, Bodenmann P, Ghali WA, Faris PD, Cornuz J. Active smoking and the risk of type 2 diabetes: a systematic review and meta-analysis. JAMA 2007; 298: 2654-64.
56. Baliunas DO, Taylor BJ, Irving H etal. Alcohol as a risk factor for type 2 diabetes: a systematic review and meta-analysis. Diabetes Care. 2009; 32: 2123-32.
57. Moriya A, Iwasaki Y, Ohguchi S etal. Alcohol consumption appears to protect against non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2011; 33: 378-88.
58. Catalano D, Martines GF, Tonzuso A, Pirri C, Trovato FM, Trovato GM. Protective role of coffee in non-alcoholic fatty liver disease (NAFLD). Dig Dis Sci 2010; 55: 3200-6.
59. Lin WY, Xaiver Pi-Sunyer F, Chen CC etal. Coffee consumption is inversely associated with type 2 diabetes in Chinese. Eur J Clin Invest 2011; 41: 659-66.
60. Boggs DA, Rosenberg L, Ruiz-Narvaez EA, Palmer JR. Coffee, tea, and alcohol intake in relation to risk of type 2 diabetes in African American women. Am J Clin Nutr 2010; 92: 960-6.
61. Mozaffarian D, Cao H, King IB etal. Transpalmitoleic acid, metabolic risk factors, and new-onset diabetes in U.S. adults: a cohort study. Ann Intern Med 2010; 153: 790-9.
62. Considine RV, Nyce MR, Allen LE etal. Protein kinase C is increased in the liver of humans and rats with noninsulin-dependent diabetes mellitus: an alteration not due to hyperglycemia. J Clin Invest 1995; 95: 2938-44.
63. Samuel VT, Liu ZX, Wang A etal. Inhibition of protein kinase Cepsilon prevents hepatic insulin resistance in nonalcoholic fatty liver disease. J Clin Invest 2007; 117: 739-45.
64. Kumashiro N, Erion DM, Zhang D etal. Cellular mechanism of insulin resistance in nonalcoholic fatty liver disease. Proc Natl Acad Sci U S A 2011; 108: 16381-5.
65. Gupta NA, Mells J, Dunham RM etal. Glucagon-like peptide-1 receptor is present on human hepatocytes and has a direct role in decreasing hepatic steatosis in vitro by modulating elements of the insulin signaling pathway. Hepatology 2010; 51: 1584-92.
66. Dey D, Basu D, Roy SS, Bandyopadhyay A, Bhattacharya S. Involvement of novel PKC isoforms in FFA induced defects in insulin signaling. Mol Cell Endocrinol 2006; 246: 60-4.
67. Roden M. Mechanisms of disease: hepatic steatosis in type 2 diabetes - pathogenesis and clinical relevance. Nat Clin Pract Endocrinol Metab 2006; 2: 335-48.
68. Al-Haddad M, Khashab M, Zyromski N etal. Risk factors for hyperechogenic pancreas on endoscopic ultrasound: a case-control study. Pancreas 2009; 38: 672-5.
69. Choi CW, Kim GH, Kang DH etal. Associated factors for a hyperechogenic pancreas on endoscopic ultrasound. World J Gastroenterol 2010; 16: 4329-34.
70. Stefan N, Fritsche A, Weikert C etal. Plasma fetuin-A levels and the risk of type 2 diabetes. Diabetes 2008; 57: 2762-7.
71. Wieckowska A, Papouchado BG, Li Z, Lopez R, Zein NN, Feldstein AE. Increased hepatic and circulating interleukin-6 levels in human nonalcoholic steatohepatitis. Am J Gastroenterol 2008; 103: 1372-9.
72. Lonardo A, Carulli N, Loria P. HCV and diabetes. A two-question-based reappraisal. Dig Liver Dis 2007; 39: 753-61.
73. Yamaguchi K, Itoh Y, Yokomizo C etal. Blockade of interleukin-6 signaling enhances hepatic steatosis but improves liver injury in methionine choline-deficient diet-fed mice. Lab Invest 2010; 90: 1169-78.
74. Yamaguchi K, Yang L, McCall S etal. Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with non-alcoholic steatohepatitis. Hepatology 2007; 45: 1366-74.
75. Walter P, Ron D. The unfolded protein response: from stress pathway to homeostatic regulation. Science 2011; 334: 1081-6.
76. Lee JY, Cho HK, Kwon YH. Palmitate induces insulin resistance without significant intracellular triglyceride accumulation in HepG2 cells. Metabolism 2010; 59: 927-34.
77. Akazawa Y, Cazanave S, Mott JL etal. Palmitoleate attenuates palmitate-induced Bim and PUMA up-regulation and hepatocyte lipoapoptosis. J Hepatol 2010; 52: 586-93.
78. Mantzaris MD, Tsianos EV, Galaris D. Interruption of triacylglycerol synthesis in the endoplasmic reticulum is the initiating event for saturated fatty acid-induced lipotoxicity in liver cells. FEBS J 2011; 278: 519-30.
79. Schattenberg JM, Singh R, Wang Y etal. JNK1 but not JNK2 promotes the development of steatohepatitis in mice. Hepatology 2006; 43: 163-72.
80. Puri P, Mirshahi F, Cheung O etal. Activation and dysregulation of the unfolded protein response in non-alcoholic fatty liver disease. Gastroenterology 2008; 134: 568-76.
81. Malhi H, Gores GJ. Molecular mechanisms of lipotoxicity in nonalcoholic fatty liver disease. Semin Liver Dis 2008; 28: 360-9.
82. Schröder M, Sutcliffe L. Consequences of stress in the secretory pathway: the ER stress response and its role in the metabolic syndrome. Methods Mol Biol 2010; 648: 43-62.
83. Lee AH, Glimcher LH. Intersection of the unfolded protein response and hepatic lipid metabolism. Cell Mol Life Sci 2009; 66: 2835-50.
84. Soon RK Jr, Yan JS, Grenert JP, Maher JJ. Stress signaling in the methionine-choline-deficient model of murine fatty liver disease. Gastroenterology 2010; 139: 1730-9, 1739.e1.
85. Singh R, Kaushik S, Wang Y etal. Autophagy regulates lipid metabolism. Nature 2009; 458: 1131-5.
86. Wang Y, Singh R, Xiang Y, Czaja MJ. Macroautophagy and chaperone-mediated autophagy are required for hepatocyte resistance to oxidant stress. Hepatology 2010; 52: 266-77.
87. Czaja MJ. Autophagy in health and disease. 2. Regulation of lipid metabolism and storage by autophagy: pathophysiological implications. Am J Physiol Cell Physiol 2010; 298: C973-8.
88. Romeo S, Kozlitina J, Xing C etal. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2008; 40: 1461-5.
89. Browning JD, Kumar KS, Saboorian MH, Thiele DL. Ethnic differences in the prevalence of cryptogenic cirrhosis. Am J Gastroenterol 2004; 99: 292-8.
90. Lonardo A, Trande P. Are there any sex differences in fatty liver? A study of glucose metabolism and body fat distribution. J Gastroenterol Hepatol 2000; 15: 775-82.
91. Marchesini G, Brizi M, Bianchi G etal. Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes 2001; 50: 1844-50.
92. Wong VW, Hui AY, Tsang SW etal. Prevalence of undiagnosed diabetes and postchallenge hyperglycaemia in Chinese patients with non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2006; 24: 1215-22.
93. Gastaldelli A, Kozakova M, Højlund K etal.; RISC Investigators. Fatty liver is associated with insulin resistance, risk of coronary heart disease, and early atherosclerosis in a large European population. Hepatology 2009; 49: 1537-44.
94. Fraser A, Harris R, Sattar N, Ebrahim S, Davey Smith G, Lawlor DA. Alanine aminotransferase, gamma-glutamyltransferase, and incident diabetes: the British Women's Heart and Health Study and meta-analysis. Diabetes Care 2009; 32: 741-50.
95. Speliotes EK, Massaro JM, Hoffmann U etal. Fatty liver is associated with dyslipidemia and dysglycemia independent of visceral fat: the Framingham Heart Study. Hepatology 2010; 51: 1979-87.
96. Bedogni G, Gastaldelli A, Manco M etal. Relationship between fatty liver and glucose metabolism: a cross-sectional study in 571 obese children. Nutr Metab Cardiovasc Dis 2012; 22: 120-6.
97. Vozarova B, Stefan N, Lindsay RS etal. High alanine aminotransferase is associated with decreased hepatic insulin sensitivity and predicts the development of type 2 diabetes. Diabetes 2002; 51: 1889-95.
98. Lee DH, Ha MH, Kim JH etal. Gamma-glutamyltransferase and diabetes - a 4year follow-up study. Diabetologia 2003; 46: 359-64.
99. Monami M, Bardini G, Lamanna C etal. Liver enzymes and risk of diabetes and cardiovascular disease: results of the Firenze Bagno a Ripoli (FIBAR) study. Metabolism 2008; 57: 387-92.
100. Hanley AJ, Williams K, Festa A, Wagenknecht LE, D'Agostino RB Jr, Haffner SM. Liver markers and development of the metabolic syndrome: the insulin resistance atherosclerosis study. Diabetes 2005; 54: 3140-7.
101. Goessling W, Massaro JM, Vasan RS, D'Agostino RB Sr, Ellison RC, Fox CS. Aminotransferase levels and 20-year risk of metabolic syndrome, diabetes, and cardiovascular disease. Gastroenterology 2008; 135: 1935-44.
102. Adams LA, Waters OR, Knuiman MW, Elliott RR, Olynyk JK. NAFLD as a risk factor for the development of diabetes and the metabolic syndrome: an eleven-year follow-up study. Am J Gastroenterol 2009; 104: 861-7.
103. Ryu S, Chang Y, Woo HY etal. Longitudinal increase in gamma-glutamyltransferase within the reference interval predicts metabolic syndrome in middle-aged Korean men. Metabolism 2010; 59: 683-9.
104. Balkau B, Lange C, Vol S, Fumeron F, Bonnet F, Group Study D.E.S.I.R. Nine-year incident diabetes is predicted by fatty liver indices: the French D.E.S.I.R. study. BMC Gastroenterol 2010; 10: 56-66.
105. Ekstedt M, Franzén LE, Mathiesen UL etal. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 2006; 44: 865-73.
106. Arase Y, Suzuki F, Ikeda K, Kumada H, Tsuji H, Kobayashi T. Multivariate analysis of risk factors for the development of type 2 diabetes in non-alcoholic fatty liver disease. J Gastroenterol 2009; 44: 1064-70.
107. Sung KC, Kim SH. Interrelationship between fatty liver and insulin resistance in the development of type 2 diabetes. J Clin Endocrinol Metab 2011; 96: 1093-7.
108. Bae JC, Rhee EJ, Lee WY etal. Combined effect of nonalcoholic fatty liver disease and impaired fasting glucose on the development of type 2 diabetes: a 4-year retrospective longitudinal study. Diabetes Care 2011; 34: 727-9.
109. Musso G, Gambino R, Cassader M, Pagano G. A meta-analysis of randomized trials for thetreatment of nonalcoholic fatty liver disease. Hepatology 2010; 52: 79-104.
110. Rakoski MO, Singal AG, Rogers MA, Conjeevaram H. Meta-analysis: insulin sensitizers for the treatment of non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2010; 32: 1211-21.
111. Boettcher E, Csako G, Pucino F, Wesley R, Loomba R. Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2012; 35: 66-75.
112. Arrese M. Burning hepatic fat: therapeutic potential for liver-specific hyromimetics in the treatment of nonalcoholic fatty liver disease. Hepatology 2009; 49: 348-51.
113. Lonardo A, Bellentani S, Ratziu V, Loria P. Insulin resistance in non-alcoholic steatohepatitis: necessary but not sufficient - death of a dogma from analysis of therapeutic studies? Expert Rev Gastroenterol Hepatol 2011; 5: 279-89.
114. Takeshita Y, Takamura T, Hamaguchi E etal. Tumor necrosis factor-alpha-induced production of plasminogen activator inhibitor 1 and its regulation by pioglitazone and cerivastatin in a nonmalignant human hepatocyte cell line. Metabolism 2006; 55: 1464-72.
115. Estep JM, Baranova A, Hossain N etal. Expression of cytokine signaling genes in morbidly obese patients with nonalcoholic steatohepatitis and hepatic fibrosis. Obes Surg 2009; 19: 617-24.
116. Civera M, Urios A, Garcia-Torres ML etal. Relationship between insulin resistance, inflammation and liver cell apoptosis in patients with severe obesity. Diabetes Metab Res Rev 2010; 26: 187-92.
117. Chiang DJ, Pritchard MT, Nagy LE. Obesity, diabetes mellitus and liver fibrosis. Am J Physiol Gastrointest Liver Physiol 2011; 300: G697-702.
118. El-Serag HB. Hepatocellular carcinoma. N Engl J Med 2011; 365: 1118-27.
119. Petta S, Craxì A. Hepatocellular carcinoma and non-alcoholic fatty liver disease: from a clinical to a molecular association. Curr Pharm Des 2010; 16: 741-52.
120. Starley BQ, Calcagno CJ, Harrison SA. Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology 2010; 51: 1820-32.
121. Stocks T, Rapp K, Bjørge T etal. Blood glucose and risk of incident and fatal cancer in the metabolic syndrome and cancer project (me-can): analysis of six prospective cohorts. PLoS Med 2009; 6: e1000201.
122. Peyrou M, Bourgoin L, Foti M. PTEN in liver diseases and cancer. World J Gastroenterol 2010; 16: 4627-33.
123. Lonardo A, Loria P. Insulin resistance, type 2 diabetes and chronic liver disease. A deadly trio. Clin Med Endocrinol Diabetes 2009; 2: 1-8.
124. Donadon V, Balbi M, Valent F, Avogaro A. Glycated hemoglobin and antidiabetic strategies as risk factors for hepatocellular carcinoma. World J Gastroenterol 2010; 16: 3025-32.
125. Nkontchou G, Cosson E, Aout M etal. Impact of metformin on the prognosis of cirrhosis induced by viral hepatitis C in diabetic patients. J Clin Endocrinol Metab 2011; 96: 2601-8.
126. Chang CH, Lin JW, Wu LC, Lai MS, Chuang LM, Chan KA. Association of thiazolidinediones with liver cancer and colorectal cancer in type 2 diabetes mellitus. Hepatology 2012; 55: 1462-72.
127. Adams LA, Sanderson S, Lindor KD, Angulo P. The histological course ofnonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies. J Hepatol 2005; 42: 132-8.
128. Adams LA, Lymp JF, St Sauver J etal. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 2005; 129: 113-21.
129. Adams LA, Harmsen S, St Sauver JL etal. Nonalcoholic fatty liver disease increases risk of death among patients with diabetes: a community-based cohort study. Am J Gastroenterol 2010; 105: 1567-73.
130. Saito K, Inoue S, Saito T etal. Augmentation effect of postprandial hyperinsulinaemia on growth of human hepatocellular carcinoma. Gut 2002; 51: 100-4.
131. El-Serag HB, Tran T, Everhart JE. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology 2004; 126: 460-8.
132. Younossi ZM, Gramlich T, Matteoni CA, Boparai N, McCullough AJ. Nonalcoholic ftty liver disease in patients with type 2 diabetes. Clin Gastroenterol Hepatol 2004; 2: 262-5. Erratum in: Clin Gastroenterol Hepatol. 2004; 2: 522.
133. Hamaguchi M, Kojima T, Takeda N etal. The metabolic syndrome as a predictor of nonalcoholic fatty liver disease. Ann Intern Med 2005; 143: 722-8.
134. Tsochatzis E, Papatheodoridis GV, Manesis EK, Kafiri G, Tiniakos DG, Archimandritis AJ. Metabolic syndrome is associated with severe fibrosis in chronic viral hepatitis and nonalcoholic steatohepatitis. Aliment Pharmacol Ther 2008; 27: 80-9.
135. Paradis V, Zalinski S, Chelbi E etal. Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liver fibrosis: a pathological analysis. Hepatology 2009; 49: 851-9.
136. Ertle J, Dechêne A, Sowa JP etal. Nonalcoholic fatty liver disease progresses to HCC in the absence of apparent cirrhosis. Int J Cancer 2011; 128: 2436-43.
137. Porepa L, Ray JG, Sanchez-Romeu P, Booth GL. Newly diagnosed diabetes mellitus as a risk factor for serious liver disease. CMAJ 2010; 182: E526-31.
138. Emerging Risk Factors Collaboration, Seshasai SR, Kaptoge S, Thompson A etal. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med 2011; 364: 829-41.
139. Stepanova M, Rafiq N, Younossi ZM. Components of metabolic syndrome are independent predictors of mortality in patients with chronic liver disease: a population-based study. Gut 2010; 59: 1410-5.
140. Michelini E, Lonardo A, Ballestri S etal. Is cholangiocarcinoma another complication of insulin resistance: a report of three cases. Metab Syndr Relat Disord 2007; 5: 194-202.
141. Borena W, Strohmaier S, Lukanova A etal. Metabolic risk factors and primary liver cancer in a prospective study of 578, 700 adults. Int J Cancer 2011. doi: 10.1002/ijc.26338. [Epub ahead of print].
142. Welzel TM, Graubard BI, Zeuzem S, El-Serag HB, Davila JA, McGlynn KA. Metabolic syndrome increases the risk of primary liver cancer in the United States: a study in the SEERMedicare database. Hepatology 2011; 54: 463-71.