The pathogenesis, complications and therapeutic strategy for hepatitis C virus-associated insulin resistance in the era of anti-viral treatment

Reviews on Recent Clinical Trials

Volumn 5, Issue 3, 2010, Pages 147-157

  Kawaguchi, Takumi ^a   Taniguchi, Eitaro ^a   Itou, Minoru ^a   Sumie, Shuji ^a   Yamagishi, Sho ichi ^a   Sata, Michio ^a  

^a KURUME UNIVERSITY SCHOOL OF MEDICINE   (Japan)

Author keywords

Branched chain amino acids; Hepatitis c virus; Hepatocellular carcinoma; Incretin; Insulin resistance

Indexed keywords

ALPHA GLUCOSIDASE INHIBITOR; ANTIDIABETIC AGENT; ANTIVIRUS AGENT; BRANCHED CHAIN AMINO ACID; INCRETIN; INSULIN; INSULIN SENSITIZING AGENT; SULFONYLUREA DERIVATIVE;

DIET SUPPLEMENTATION; DIET THERAPY; DISEASE ASSOCIATION; GLUCOSE METABOLISM; HEPATITIS C; HEPATITIS C VIRUS; HUMAN; INSULIN RESISTANCE; LIVER CELL CARCINOMA; PRIORITY JOURNAL; PROGNOSIS; REVIEW; VIRUS PATHOGENESIS;

ANIMALS; ANTIVIRAL AGENTS; HEPACIVIRUS; HEPATITIS C, CHRONIC; HUMANS; HYPERINSULINISM; HYPOGLYCEMIC AGENTS; INSULIN; INSULIN RESISTANCE; PRACTICE GUIDELINES AS TOPIC; RISK FACTORS;

EID: 78649985219     PISSN: 15748871     EISSN: None     Source Type: Journal    
DOI: 10.2174/157488710792007257     Document Type: Review

References (188)

1. Choo QL, Kuo G, Weiner AJ, Overby LR, Bradley DW, Houghton M. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 1989; 244: 359-62.
2. Houghton M. The long and winding road leading to the identification of the hepatitis C virus. J Hepatol 2009; 51: 939-48.
3. Asselah T, Bieche I, Sabbagh A, et al. Gene expression and hepatitis C virus infection. Gut 2009; 58: 846-58.
4. Maheshwari A, Ray S, Thuluvath P J. Acute hepatitis C. Lancet 2008; 372: 321-32.
5. Seeff LB, Hoofnagle JH. Appendix: The national institutes of health consensus development conference management of hepatitis C 2002. Clin Liver Dis 2003; 7: 261-87.
6. Thein HH, Yi Q, Dore GJ, Krahn MD. Estimation of stage-specific fibrosis progression rates in chronic hepatitis C virus infection: a meta-analysis and meta-regression. Hepatology 2008; 48: 418-31.
7. Thompson ND, Perz JF, Moorman AC, Holmberg SD. Nonhospital health care-associated hepatitis B and C virus transmission: United States, 1998-2008. Ann Intern Med 2009; 150: 33-9.
8. Alter MJ, Margolis HS, Krawczynski K, et al. The natural history of community-acquired hepatitis C in the United States. The sentinel counties chronic non-a, non-b hepatitis study team. N Engl J Med 1992; 327: 1899-905.
9. Marcellin P. Hepatitis B and hepatitis C in 2009. Liver Int 2009; 29 (Suppl 1): 1-8.
10. Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet 1997; 349: 825-32.
11. Ali SS, Ali I S, Aamir AH, Jadoon Z, Inayatullah S. Frequency of hepatitis C infection in diabetic patients. J Ayub Med Coll Abbottabad 2007; 19: 46-9.
12. Bahtiyar G, Shin JJ, Aytaman A, Sowers JR, Mcfarlane SI. Association of diabetes and hepatitis C infection: epidemiologic evidence and pathophysiologic insights. Curr Diabetes Rep 2004; 4: 194-8.
13. Gray H, Wreghitt T, Stratton IM, Alexander GJ, Turner RC, O'rahilly S. High prevalence of hepatitis C infection in Afro-Caribbean patients with type 2 diabetes and abnormal liver function tests. Diabet Med 1995; 12: 244-9.
14. Kawaguchi T, Nagao Y, Tanaka K, et al. Causal relationship between hepatitis C virus core and the development of type 2 diabetes mellitus in a hepatitis C virus hyperendemic area: a pilot study. Int J Mol Med 2005; 16: 109-14.
15. Mehta SH, Brancati FL, Strathdee SA, et al. Hepatitis C virus infection and incident type 2 diabetes. Hepatology 2003; 38: 50-6.
16. Mehta SH, Brancati FL, Sulkowski MS, Strathdee SA, Szklo M, Thomas DL. Prevalence of type 2 diabetes mellitus among persons with hepatitis C virus infection in the United States. Ann Intern Med 2000; 133: 592-9.
17. Nwokediuko SC, Oli JM. Hepatitis C virus infection in Nigerians with diabetes mellitus. Niger J Clin Pract 2008; 11: 94-9.
18. Shaheen M, Echeverry D, Oblad MG, Montoya MI, Teklehaimanot S, Akhtar AJ. Hepatitis C, metabolic syndrome, and inflammatory markers: results from the Third National Health and Nutrition Examination Survey [NHANES III]. Diabetes Res Clin Pract 2007; 75: 320-6.
19. Simo R, Hernandez C, Genesca J, Jardi R, Mesa J. High prevalence of hepatitis C virus infection in diabetic patients. Diabetes Care 1996; 19: 998-1000.
20. Sporea I, Sirli R, Hogea C, Sink AA, Serban V. Diabetes mellitus and chronic HCV infection. Rom J Intern Med 2009; 47: 141-7.
21. Wilson C. Hepatitis C infection and type 2 diabetes in American- Indian women. Diabetes Care 2004; 27: 2116-9.
22. Akuta N, Suzuki F, Hirakawa M, et al. Amino acid substitutions in the hepatitis C virus core region of genotype 1b are the important predictor of severe insulin resistance in patients without cirrhosis and diabetes mellitus. J Med Virol 2009; 81: 1032-9.
23. Allison ME, Wreghitt T, Palmer CR, Alexander GJ. Evidence for a link between hepatitis C virus infection and diabetes mellitus in a cirrhotic population. J Hepatol 1994; 21: 1135-9.
24. Aytug S, Reich D, Sapiro LE, Bernstein D, Begum N. Impaired IRS-1/PI3-kinase signaling in patients with HCV: a mechanism for increased prevalence of type 2 diabetes. Hepatology 2003; 38: 1384-92.
25. Kawaguchi T, Ide T, Taniguchi E, et al. Clearance of HCV improves insulin resistance, beta-cell function, and hepatic expression of insulin receptor substrate 1 and 2. Am J Gastroenterol 2007; 102: 570-6.
26. Kawaguchi T, Yoshida T, Harada M, et al. Hepatitis C virus downregulates insulin receptor substrates 1 and 2 through up-regulation of suppressor of cytokine signaling 3. Am J Pathol 2004; 165: 1499-508.
27. Negro F. Insulin resistance and HCV: will new knowledge modify clinical management? J Hepatol 2006; 45: 514-9.
28. Romero-Gomez M. Insulin resistance and hepatitis C. World J Gastroenterol 2006; 12: 7075-80.
29. 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: 840-8.
30. Taura N, Ichikawa T, Hamasaki K, et al. Association between liver fibrosis and insulin sensitivity in chronic hepatitis C patients. Am J Gastroenterol 2006; 101: 2752-9.
31. Alberti KG, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009; 120: 1640-5.
32. Balsano C, Alisi A, Nobili V. Liver fibrosis and therapeutic strategies: the goal for improving metabolism. Curr Drug Targets 2009; 10: 505-12.
33. El-Serag HB. Hepatocellular carcinoma: recent trends in the United States. Gastroenterology 2004; 127: S27-34.
34. Negro F. Correction of insulin resistance in chronic hepatitis C patients not responding to the standard of care: more questions than answers. J Hepatol 2009; 50: 1271-2.
35. Sumie S, Kawaguchi T, Komuta M, et al. Significance of glucose intolerance and SHIP2 expression in hepatocellular carcinoma patients with HCV infection. Oncol Rep 2007; 18: 545-52.
36. Kawaguchi T, Sata M. Importance of hepatitis C virus-associated insulin resistance: therapeutic strategies for insulin sensitization. World J Gastroenterol 2010; 16: 1943-52.
37. Kawaguchi T, Sata M. Importance of hepatitis C virus-associated insulin resistance-therapeutic strategies for insulin sensitization. World J Gastroenterol 2010; 16: 1943-52.
38. Bianchi G, Marchesini G, Zoli M, Bugianesi E, Fabbri A, Pisi E. Prognostic significance of diabetes in patients with cirrhosis. Hepatology 1994; 20: 119-25.
39. Itou M, Kawaguchi T, Taniguchi E, et al. Altered expression of glucagon-like peptide-1 and dipeptidyl peptidase IV in patients with HCV-related glucose intolerance. J Gastroenterol Hepatol 2008; 23: 244-51.
40. Eguchi Y, Mizuta T, Ishibashi E, et al. Hepatitis C virus infection enhances insulin resistance induced by visceral fat accumulation. Liver Int 2009; 29: 213-20.
41. Hung CH, Lee CM, Chen CH, et al. Association of inflammatory and anti-inflammatory cytokines with insulin resistance in chronic hepatitis C. Liver Int 2009; 29: 1086-93.
42. Lu JY, Chuang LM, Yang WS, et al. Adiponectin levels among patients with chronic hepatitis B and C infections and in response to IFN-alpha therapy. Liver Int 2005; 25: 752-9.
43. Knobler H, Zhornicky T, Sandler A, Haran N, Ashur Y, Schattner A. Tumor necrosis factor-alpha-induced insulin resistance may mediate the hepatitis C virus-diabetes association. Am J Gastroenterol 2003; 98: 2751-6.
44. Maeno T, Okumura A, Ishikawa T, et al. Mechanisms of increased insulin resistance in non-cirrhotic patients with chronic hepatitis C virus infection. J Gastroenterol Hepatol 2003; 18: 1358-63.
45. Koike K, Miyoshi H. Oxidative stress and hepatitis C viral infection. Hepatol Res 2006; 34: 65-73.
46. Mitsuyoshi H, Itoh Y, Sumida Y, et al. Evidence of oxidative stress as a cofactor in the development of insulin resistance in patients with chronic hepatitis C. Hepatol Res 2008; 38: 348-53.
47. Vidali M, Tripodi MF, Ivaldi A, et al. Interplay between oxidative stress and hepatic steatosis in the progression of chronic hepatitis C. J Hepatol 2008; 48: 399-406.
48. Narita R, Abe S, Tabaru A, Otsuki M. Impact of steatosis on insulin secretion in chronic hepatitis C patients. Am J Gastroenterol 2007; 102: 2173-80.
49. Narita R, Abe S, Kihara Y, Akiyama T, Tabaru A, Otsuki M. Insulin resistance and insulin secretion in chronic hepatitis C virus infection. J Hepatol 2004; 41: 132-8.
50. Ferenci P, Bratusch-Marrain P, Waldhausl WK, Nowotny P, Korn A. Impaired plasma amino-acid clearance in patients with cirrhosis of the liver and portocaval shunt--its relation to insulin resistance. Eur J Clin Invest 1984; 14: 255-61.
51. Tanabe N, Ishii M, Sato Y, et al. Effects of collateral vessel occlusion on oral glucose tolerance test in liver cirrhosis. Dig Dis Sci 2000; 45: 581-6.
52. Muckenthaler MU. Fine tuning of hepcidin expression by positive and negative regulators. Cell Metab 2008; 8: 1-3.
53. Nishina S, Hino K, Korenaga M, et al. Hepatitis C virus-induced reactive oxygen species raise hepatic iron level in mice by reducing hepcidin transcription. Gastroenterology 2008; 134: 226-38.
54. Fujita N, Sugimoto R, Takeo M, et al. Hepcidin expression in the liver: relatively low level in patients with chronic hepatitis C. Mol Med 2007; 13: 97-104.
55. Nagashima M, Kudo M, Chung H, et al. Regulatory failure of serum prohepcidin levels in patients with hepatitis C. Hepatol Res 2006; 36: 288-93.
56. Lecube A, Hernandez C, Simo R. Glucose abnormalities in nonalcoholic fatty liver disease and chronic hepatitis C virus infection: the role of iron overload. Diabetes Metab Res Rev 2009; 25: 403-10.
57. Furutani M, Nakashima T, Sumida Y, et al. Insulin resistance/betacell function and serum ferritin level in non-diabetic patients with hepatitis C virus infection. Liver Int 2003; 23: 294-9.
58. Sumida Y, Kanemasa K, Fukumoto K, Yoshida N, Sakai K. Hepatic iron accumulation may be associated with insulin resistance in patients with chronic hepatitis C. Hepatol Res 2007; 37: 932-40.
59. Tsochatzis E, Manolakopoulos S, Papatheodoridis GV, et al. Serum HCV RNA levels and HCV genotype do not affect insulin resistance in nondiabetic patients with chronic hepatitis C: a multicentre study. Aliment Pharmacol Ther 2009; 30: 947-54.
60. Hsu CS, Liu CJ, Liu CH, et al. High hepatitis C viral load is associated with insulin resistance in patients with chronic hepatitis C. Liver Int 2008; 28: 271-7.
61. Moucari R, Asselah T, Cazals-Hatem D, et al. Insulin resistance in chronic hepatitis C: association with genotypes 1 and 4, serum HCV RNA level, and liver fibrosis. Gastroenterology 2008; 134: 416-23.
62. Yoneda M, Saito S, Ikeda T, et al. Hepatitis C virus directly associates with insulin resistance independent of the visceral fat area in nonobese and nondiabetic patients. J Viral Hepatitis 2007; 14: 600-7.
63. Delgado-Borrego A, Jordan SH, Negre B, et al. Reduction of insulin resistance with effective clearance of hepatitis C infection: results from the HALT-C trial. Clin Gastroenterol Hepatol 2010; 8(5): 458-62.
64. Kawaguchi T, Taniguchi E, Itou M, et al. Branched-chain amino acids improve insulin resistance in patients with hepatitis C virusrelated liver disease: report of two cases. Liver Int 2007; 27: 1287-92.
65. Kawaguchi Y, Mizuta T, Oza N, et al. Eradication of hepatitis C virus by interferon improves whole-body insulin resistance and hyperinsulinaemia in patients with chronic hepatitis C. Liver Int 2009; 29: 871-7.
66. Rui L, Yuan M, Frantz D, Shoelson S, White MF. SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2. J Biol Chem 2002; 277: 42394-8.
67. Persico M, Russo R, Persico E, et al. SOCS3 and IRS-1 gene expression differs between genotype 1 and genotype 2 hepatitis C virus- infected HepG2 cells. Clin Chem Lab Med 2009; 47: 1217-25.
68. Banerjee S, Saito K, Ait-Goughoulte M, Meyer K, Ray RB, Ray R. Hepatitis C virus core protein upregulates serine phosphorylation of insulin receptor substrate-1 and impairs the downstream akt/protein kinase B signaling pathway for insulin resistance. J Virol 2008; 82: 2606-12.
69. Pazienza V, Clement S, Pugnale P, et al. The hepatitis C virus core protein of genotypes 3a and 1b downregulates insulin receptor substrate 1 through genotype-specific mechanisms. Hepatology 2007; 45: 1164-71.
70. Cua IH, Hui JM, Kench JG, George J. Genotype-specific interac tions of insulin resistance, steatosis, and fibrosis in chronic hepatitis C. Hepatology 2008; 48: 723-31.
71. Liu CJ, Jeng YM, Chen PJ, et al. Influence of metabolic syndrome, viral genotype and antiviral therapy on superimposed fatty liver disease in chronic hepatitis C. Antivir Ther 2005; 10: 405-15.
72. Pazienza V, Vinciguerra M, Andriulli A, Mangia A. HCV core protein genotype 3a increases SOCS-7 expression through PPAR- {gamma} in Huh-7 cells. J Gen Virol 2010; 91(Pt 7): 1678-86.
73. Duseja A, Dhiman RK, Chawla Y, et al. Insulin resistance is common in patients with predominantly genotype 3 chronic hepatitis C. Dig Dis Sci 2009; 54: 1778-82.
74. Wang AY, Hickman IJ, Richards AA, Whitehead JP, Prins JB, Macdonald GA. High molecular weight adiponectin correlates with insulin sensitivity in patients with hepatitis C genotype 3, but not genotype 1 infection. Am J Gastroenterol 2005; 100: 2717-23.
75. Khattab M, Eslam M, Sharwae MA, Shatat M, Ali A, Hamdy L. Insulin resistance predicts rapid virologic response to peginterferon/ ribavirin combination therapy in hepatitis C genotype 4 patients. Am J Gastroenterol 2010; [Epub ahead of print]
76. Moucari R, Ripault MP, Martinot-Peignoux M, et al. Insulin resistance and geographical origin: major predictors of liver fibrosis and response to peginterferon and ribavirin in HCV-4. Gut 2009; 58: 1662-9.
77. Kawaguchi T, Yamagishi S, Sata M. Branched-chain amino acids and pigment epithelium-derived factor: novel therapeutic agents for hepatitis C Virus-associated insulin resistance. Curr Med Chem 2009: 16(36): 4843-57.
78. Camma C, Petta S, Di Marco V, et al. Insulin resistance is a risk factor for esophageal varices in hepatitis C virus cirrhosis. Hepatology 2009; 49: 195-203.
79. Nagao Y, Kawasaki K, Sata M. Insulin resistance and lichen planus in patients with HCV-infectious liver diseases. J Gastroenterol Hepatol 2008; 23: 580-5.
80. Nagao Y, Sata M. High incidence of multiple primary carcinomas in HCV-infected patients with oral squamous cell carcinoma. Med Sci Monit 2009; 15: CR453-9.
81. Nagao Y, Kawaguchi T, Tanaka K, Kumashiro R, Sata M. Extrahepatic manifestations and insulin resistance in an HCV hyperendemic area. Int J Mol Med 2005; 16: 291-6.
82. Adami HO, Chow WH, Nyren O, et al. Excess risk of primary liver cancer in patients with diabetes mellitus. J Natl Cancer Inst 1996; 88: 1472-7.
83. Wideroff L, Gridley G, Mellemkjaer L, et al. Cancer incidence in a population-based cohort of patients hospitalized with diabetes mellitus in Denmark. J Natl Cancer Inst 1997; 89: 1360-5.
84. El-Serag HB, Tran T, Everhart JE. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology 2004; 126: 460-8.
85. Davila JA, Morgan RO, Shaib Y, Mcglynn KA, El-Serag HB. Diabetes increases the risk of hepatocellular carcinoma in the United States: a population based case control study. Gut 2005; 54: 533-9.
86. El-Serag HB, Richardson PA, Everhart JE. The role of diabetes in hepatocellular carcinoma: a case-control study among United States Veterans. Am J Gastroenterol 2001; 96: 2462-7.
87. La Vecchia C, Negri E, Decarli A, Franceschi S. Diabetes mellitus and the risk of primary liver cancer. Int J Cancer 1997; 73: 204-7.
88. Lagiou P, Kuper H, Stuver SO, Tzonou A, Trichopoulos D, Adami HO. Role of diabetes mellitus in the etiology of hepatocellular carcinoma. J Natl Cancer Inst 2000; 92: 1096-9.
89. 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: 710-5.
90. Chen CL, Yang HI, Yang WS, et al. Metabolic factors and risk of hepatocellular carcinoma by chronic hepatitis B/C infection: a follow- up study in Taiwan. Gastroenterology 2008; 135: 111-21.
91. Wang CS, Yao WJ, Chang TT, Wang ST, Chou P. The impact of type 2 diabetes on the development of hepatocellular carcinoma in different viral hepatitis statuses. Cancer Epidemiol Biomarkers Prev 2009; 18: 2054-60.
92. Ohata K, Hamasaki K, Toriyama K, et al. Hepatic steatosis is a risk factor for hepatocellular carcinoma in patients with chronic hepatitis C virus infection. Cancer 2003; 97: 3036-43.
93. Lai MS, Hsieh MS, Chiu YH, Chen TH. Type 2 diabetes and hepatocellular carcinoma: a cohort study in high prevalence area of hepatitis virus infection. Hepatology 2006; 43: 1295-302.
94. Henderson WA, Shankar R, Gill JM, et al. Hepatitis C progressing to hepatocellular carcinoma: the HCV dialysis patient in dilemma. J Viral Hepatitis 2010; 17(1): 59-64.
95. Koga M, Kasayama S, Kanehara H, Bando Y. CLD (chronic liver diseases)-HbA1C as a suitable indicator for estimation of mean plasma glucose in patients with chronic liver diseases. Diabetes Res Clin Pract 2008; 81: 258-62.
96. Donadon V, Balbi M, Valentia G, et al. Association between type 2 diabetes mellitus and hepatocellular carcinoma: role of insulin resistance and hyperinsulinemia. Hepatology 2009; 50: 1081A.
97. Cantley LC. The phosphoinositide 3-kinase pathway. Science 2002; 296: 1655-7.
98. Boulton TG, Nye SH, Robbins DJ, et al. ERKs: a family of proteinserine/ threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF. Cell 1991; 65: 663-75.
99. Saito K, Inoue S, Saito T, et al. Augmentation effect of postprandial hyperinsulinaemia on growth of human hepatocellular carcinoma. Gut 2002; 51: 100-4.
100. Bugianesi E, Marchesini G, Gentilcore E, et al. Fibrosis in genotype 3 chronic hepatitis C and nonalcoholic fatty liver disease: role of insulin resistance and hepatic steatosis. Hepatology 2006; 44: 1648-55.
101. Fartoux L, Poujol-Robert A, Guechot J, Wendum D, Poupon R, Serfaty L. Insulin resistance is a cause of steatosis and fibrosis progression in chronic hepatitis C. Gut 2005; 54: 1003-8.
102. Paradis V, Perlemuter G, Bonvoust F, et al. High glucose and hyperinsulinemia stimulate connective tissue growth factor expression: a potential mechanism involved in progression to fibrosis in nonalcoholic steatohepatitis. Hepatology 2001; 34: 738-44.
103. Alberti KG, Zimmet P, Shaw J. The metabolic syndrome--a new worldwide definition. Lancet 2005; 366: 1059-62.
104. Kelesidis T, Kelesidis I, Chou S, Mantzoros CS. Narrative review: the role of leptin in human physiology: emerging clinical applications. Ann Intern Med 2010; 152: 93-100.
105. Cua IH, Hui JM, Bandara P, et al. Insulin resistance and liver injury in hepatitis C is not associated with virus-specific changes in adipocytokines. Hepatology 2007; 46: 66-73.
106. Degoricija V, Zjacic-Rotkvic V, Marout J, Sefer S, Troskot B. Clinical and neurohumoral response to posture, physical exercise, and ascites treatment in Child-Pugh C liver cirrhosis: randomized prospective trial. Croat Med J 2003; 44: 178-86.
107. Kawaguchi T, Taniguchi E, Itou M, et al. Supplement improves nutrition and stresses caused by examination-associated fasting in patients with liver cirrhosis. Hepatol Res 2008; 38: 1178-85.
108. Owen OE, Trapp VE, Reichard GA, Jr., et al. Nature and quantity of fuels consumed in patients with alcoholic cirrhosis. J Clin Invest 1983; 72: 1821-32.
109. Kalaitzakis E, Bosaeus I, Ohman L, Bjornsson E. Altered postprandial glucose, insulin, leptin, and ghrelin in liver cirrhosis: correlations with energy intake and resting energy expenditure. Am J Clin Nutr 2007; 85: 808-15.
110. Nielsen MF, Caumo A, Aagaard NK, et al. Contribution of defects in glucose uptake to carbohydrate intolerance in liver cirrhosis: assessment during physiological glucose and insulin concentrations. Am J Physiol Gastrointest Liver Physiol 2005; 288: G1135-43.
111. Miwa Y, Shiraki M, Kato M, et al. Improvement of fuel metabolism by nocturnal energy supplementation in patients with liver cirrhosis. Hepatol Res 2000; 18: 184-9.
112. Muller MJ, Lautz HU, Plogmann B, Burger M, Korber J, Schmidt FW. Energy expenditure and substrate oxidation in patients with cirrhosis: the impact of cause, clinical staging and nutritional state. Hepatology 1992; 15: 782-94.
113. Nakaya Y, Harada N, Kakui S, et al. Severe catabolic state after prolonged fasting in cirrhotic patients: effect of oral branched-chain amino-acid-enriched nutrient mixture. J Gastroenterol 2002; 37: 531-6.
114. Tajika M, Kato M, Mohri H, et al. Prognostic value of energy metabolism in patients with viral liver cirrhosis. Nutrition 2002; 18: 229-34.
115. Aspen Board of Directors and the Clinical Guidelines Task Force. Guidelines for the use of parenteral and enteral nutrition in adult and pediatric patients. JPEN J Parenter Enteral Nutr 2002; 26: 1SA-138SA.
116. Aoyama K, Tsuchiya M, Mori K, et al. Effect of a late evening snack on outpatients with liver cirrhosis. Hepatol Res 2007; 37: 608-14.
117. Carty H. Scintigraphy in sports injuries: is it underutilized? Nucl Med Commun 1991; 12: 173-4.
118. Tsuchiya M, Sakaida I, Okamoto M, Okita K. The effect of a late evening snack in patients with liver cirrhosis. Hepatol Res 2005; 31: 95-103.
119. Utsugi T, Yoshida A, Kanda T, et al. Oral administration of branched chain amino acids improves virus-induced glucose intolerance in mice. Eur J Pharmacol 2000; 398: 409-14.
120. Marchesini G, Bianchi G, Merli M, et al. Nutritional supplementation with branched-chain amino acids in advanced cirrhosis: a double- blind, randomized trial. Gastroenterology 2003; 124: 1792-801.
121. Muto Y, Sato S, Watanabe A, et al. Effects of oral branched-chain amino acid granules on event-free survival in patients with liver cirrhosis. Clin Gastroenterol Hepatol 2005; 3: 705-13.
122. Muto Y, Sato S, Watanabe A, et al. Overweight and obesity increase the risk for liver cancer in patients with liver cirrhosis and long-term oral supplementation with branched-chain amino acid granules inhibits liver carcinogenesis in heavier patients with liver cirrhosis. Hepatol Res 2006; 35: 204-14.
123. Nishitani S, Takehana K, Fujitani S, Sonaka I. Branched-chain amino acids improve glucose metabolism in rats with liver cirrhosis. Am J Physiol Gastrointest Liver Physiol 2005; 288: G1292-300.
124. Morifuji M, Koga J, Kawanaka K, Higuchi M. Branched-chain amino acid-containing dipeptides, identified from whey protein hydrolysates, stimulate glucose uptake rate in L6 myotubes and isolated skeletal muscles. J Nutr Sci Vitaminol (Tokyo) 2009; 55: 81-6.
125. Ikehara O, Kawasaki N, Maezono K, Komatsu M, Konishi A. Acute and chronic treatment of L-isoleucine ameliorates glucose metabolism in glucose-intolerant and diabetic mice. Biol Pharm Bull 2008; 31: 469-72.
126. She P, Reid TM, Bronson SK, et al. Disruption of BCATm in mice leads to increased energy expenditure associated with the activation of a futile protein turnover cycle. Cell Metab 2007; 6: 181-94.
127. Kawaguchi T, Nagao Y, Matsuoka H, Ide T, Sata M. Branchedchain amino acid-enriched supplementation improves insulin resistance in patients with chronic liver disease. Int J Mol Med 2008; 22: 105-12.
128. Urata Y, Okita K, Korenaga K, Uchida K, Yamasaki T, Sakaida I. The effect of supplementation with branched-chain amino acids in patients with liver cirrhosis. Hepatol Res 2007; 37: 510-6.
129. Yoshiji H, Noguchi R, Kitade M, et al. Branched-chain amino acids suppress insulin-resistance-based hepatocarcinogenesis in obese diabetic rats. J Gastroenterol 2009; 44: 483-91.
130. Carrascosa M, Pascual F, Aresti S. Acarbose-induced acute severe hepatotoxicity. Lancet 1997; 349: 698-9.
131. Khattab M, Emad M, Abdelaleem A, et al. Pioglitazone improves virological response to peginterferon alpha-2b/ribavirin combination therapy in hepatitis C genotype 4 patients with insulin resistance. Liver Int 2010; 30(3): 447-54.
132. Al-Salman J, Arjomand H, Kemp DG, Mittal M. Hepatocellular injury in a patient receiving rosiglitazone. A case report. Ann Intern Med 2000; 132: 121-4.
133. Gouda HE, Khan A, Schwartz J, Cohen RI. Liver failure in a patient treated with long-term rosiglitazone therapy. Am J Med 2001; 111: 584-5.
134. Lenhard MJ, Funk WB. Failure to develop hepatic injury from rosiglitazone in a patient with a history of troglitazone-induced hepatitis. Diabetes Care 2001; 24: 168-9.
135. Hemkens LG, Grouven U, Bender R, et al. Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study. Diabetologia 2009; 52: 1732-44.
136. Yang YX, Hennessy S, Lewis JD. Insulin therapy and colorectal cancer risk among type 2 diabetes mellitus patients. Gastroenterology 2004; 127: 1044-50.
137. Li D, Yeung SC, Hassan MM, Konopleva M, Abbruzzese JL. Antidiabetic therapies affect risk of pancreatic cancer. Gastroenterology 2009; 137: 482-8.
138. Donadon V, Balbi M, Casarin P, Vario A, Alberti A. Association between hepatocellular carcinoma and type 2 diabetes mellitus in Italy: potential role of insulin. World J Gastroenterol 2008; 14: 5695-700.
139. Donadon V, Balbi M, Ghersetti M, et al. Antidiabetic therapy and increased risk of hepatocellular carcinoma in chronic liver disease. World J Gastroenterol 2009; 15: 2506-11.
140. Kawaguchi T, Taniguchi E, Morita Y, et al. Association of exogenous insulin or sulfonylurea treatment with an increased incidence of hepatoma in patients with HCV infection. Liver Int 2010; 30(3): 479-86.
141. Komura T, Mizukoshi E, Kita Y, et al. Impact of diabetes on recurrence of hepatocellular carcinoma after surgical treatment in patients with viral hepatitis. Am J Gastroenterol 2007; 102: 1939-46.
142. Godsland IF. Insulin resistance and hyperinsulinaemia in the development and progression of cancer. Clin Sci (Lond) 2009; 118: 315-32.
143. Sandow J. Growth effects of insulin and insulin analogues. Arch Physiol Biochem 2009; 115: 72-85.
144. Dong-Dong L, Xi-Ran Z, Xiang-Rong C. Expression and significance of new tumor suppressor gene PTEN in primary liver cancer. J Cell Mol Med 2003; 7: 67-71.
145. Wan XW, Jiang M, Cao HF, et al. The alteration of PTEN tumor suppressor expression and its association with the histopathological features of human primary hepatocellular carcinoma. J Cancer Res Clin Oncol 2003; 129: 100-6.
146. Wu SK, Wang BJ, Yang Y, Feng XH, Zhao XP, Yang DL. Expression of PTEN, PPM1A and P-Smad2 in hepatocellular carcinomas and adjacent liver tissues. World J Gastroenterol 2007; 13: 4554-9.
147. Tsochatzis EA, Manolakopoulos S, Papatheodoridis GV, Archimandritis AJ. Insulin resistance and metabolic syndrome in chronic liver diseases: old entities with new implications. Scand J Gastroenterol 2009; 44: 6-14.
148. Creutzfeldt W. The [pre-] history of the incretin concept. Regul Pept 2005; 128: 87-91.
149. Seltzer HS, Allen EW, Herron AL, Jr., Brennan MT. Insulin secretion in response to glycemic stimulus: relation of delayed initial release to carbohydrate intolerance in mild diabetes mellitus. J Clin Invest 1967; 46: 323-35.
150. Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology 2007; 132: 2131-57.
151. Drucker DJ. The biology of incretin hormones. Cell Metab 2006; 3: 153-65.
152. Holst JJ. Glucagon-like peptide-1: from extract to agent. The Claude Bernard Lecture, 2005. Diabetologia 2006; 49: 253-60.
153. Thorens B. Expression cloning of the pancreatic beta cell receptor for the gluco-incretin hormone glucagon-like peptide 1. Proc Natl Acad Sci USA 1992; 89: 8641-5.
154. Vilsboll T, Krarup T, Madsbad S, Holst JJ. Both GLP-1 and GIP are insulinotropic at basal and postprandial glucose levels and contribute nearly equally to the incretin effect of a meal in healthy subjects. Regul Pept 2003; 114: 115-21.
155. Nauck MA, Kleine N, Orskov C, Holst JJ, Willms B, Creutzfeldt W. Normalization of fasting hyperglycaemia by exogenous glucagon- like peptide 1 (7-36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia 1993; 36: 741-4.
156. Deacon CF, Pridal L, Klarskov L, Olesen M, Holst JJ. Glucagonlike peptide 1 undergoes differential tissue-specific metabolism in the anesthetized pig. Am J Physiol 1996; 271: E458-64.
157. Hansen L, Deacon CF, Orskov C, Holst JJ. Glucagon-like peptide-1-(7-36)amide is transformed to glucagon-like peptide-1-(9-36)amide by dipeptidyl peptidase IV in the capillaries supplying the L cells of the porcine intestine. Endocrinology 1999; 140: 5356-63.
158. Larsson H, Holst JJ, Ahren B. Glucagon-like peptide-1 reduces hepatic glucose production indirectly through insulin and glucagon in humans. Acta Physiol Scand 1997; 160: 413-22.
159. Mommsen TP, Andrews PC, Plisetskaya EM. Glucagon-like peptides activate hepatic gluconeogenesis. FEBS Lett 1987; 219: 227-32.
160. Redondo A, Trigo MV, Acitores A, Valverde I, Villanueva- Penacarrillo ML. Cell signalling of the GLP-1 action in rat liver. Mol Cell Endocrinol 2003; 204: 43-50.
161. Park S, Hong SM, Ahn IS. Exendin-4 and exercise improve hepatic glucose homeostasis by promoting insulin signaling in diabetic rats. Metabolism 2010; 59: 123-33.
162. Aviv V, Meivar-Levy I, Rachmut IH, Rubinek T, Mor E, Ferber S. Exendin-4 promotes liver cell proliferation and enhances the PDX-1-induced liver to pancreas transdifferentiation process. J Biol Chem 2009; 284: 33509-20.
163. Prigeon RL, Quddusi S, Paty B, D'alessio DA. Suppression of glucose production by GLP-1 independent of islet hormones: a novel extrapancreatic effect. Am J Physiol Endocrinol Metab 2003; 285: E701-7.
164. Harada T, Kim DW, Sagawa K, et al. Characterization of an established human hepatoma cell line constitutively expressing nonstructural proteins of hepatitis C virus by transfection of viral cDNA. J Gen Virol 1995; 76 (Pt 5): 1215-21.
165. Maes M, Bonaccorso S, Marino V, et al. Treatment with interferonalpha (IFN alpha) of hepatitis C patients induces lower serum dipeptidyl peptidase IV activity, which is related to IFN alphainduced depressive and anxiety symptoms and immune activation. Mol Psychiatry 2001; 6: 475-80.
166. Asselah T, Benhamou Y, Marcellin P. Protease and polymerase inhibitors for the treatment of hepatitis C. Liver Int 2009; 29 (Suppl 1): 57-67.
167. Harrison SA. Small molecule and novel treatments for chronic hepatitis C virus infection. Am J Gastroenterol 2007; 102: 2332-8.
168. Lange CM, Sarrazin C, Zeuzem S. Review article: HCV - STAT-C era of therapy. Aliment Pharmacol Ther 2010; [Epub ahead of print]
169. Moucari R, Marcellin P. Hepatitis C: The role of new interferons in the era of STAT-C. Nat Rev Gastroenterol Hepatol 2009; 6: 509-11.
170. Parfieniuk A, Jaroszewicz J, Flisiak R. Specifically targeted antiviral therapy for hepatitis C virus. World J Gastroenterol 2007; 13: 5673-81.
171. Pereira AA, Jacobson IM. New and experimental therapies for HCV. Nat Rev Gastroenterol Hepatol 2009; 6: 403-11.
172. Schinazi RF, Bassit L, Gavegnano C. HCV drug discovery aimed at viral eradication. J Viral Hepatitis 2010; 17: 77-90.
173. Berman K, Kwo PY. Boceprevir, an NS3 protease inhibitor of HCV. Clin Liver Dis 2009; 13: 429-39.
174. Flint M, Mullen S, Deatly AM, et al. Selection and characterization of hepatitis C virus replicons dually resistant to the polymerase and protease inhibitors HCV-796 and boceprevir (SCH 503034). Antimicrob Agents Chemother 2009; 53: 401-11.
175. Hezode C, Forestier N, Dusheiko G, et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med 2009; 360: 1839-50.
176. Hoofnagle JH. A step forward in therapy for hepatitis C. N Engl J Med 2009; 360: 1899-901.
177. Kao JH. Telaprevir for chronic HCV infection. N Engl J Med 2009; 361: 534-5.
178. Kronenberger B, Zeuzem S. Current and future treatment options for HCV. Ann Hepatol 2009; 8: 103-12.
179. Liu-Young G, Kozal MJ. Hepatitis C protease and polymerase inhibitors in development. AIDS Patient Care STDS 2008; 22: 449-57.
180. Mchutchison JG, Everson GT, Gordon SC, et al. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med 2009; 360: 1827-38.
181. Mchutchison JG, Manns MP, Muir AJ, et al. Telaprevir for previously treated chronic HCV infection. N Engl J Med 2010; 362: 1292-303.
182. Njoroge FG, Chen KX, Shih NY, Piwinski JJ. Challenges in modern drug discovery: a case study of boceprevir, an HCV protease inhibitor for the treatment of hepatitis C virus infection. Acc Chem Res 2008; 41: 50-9.
183. Van der Meer AJ, De Knegt RJ. Telaprevir for chronic HCV infection. N Engl J Med 2009; 361: 533-4; author reply 34-5.
184. Gentile I, Viola C, Borgia F, Castaldo G, Borgia G. Telaprevir: a promising protease inhibitor for the treatment of hepatitis C virus infection. Curr Med Chem 2009; 16: 1115-21.
185. Suzuki F, Akuta N, Suzuki Y, et al. Rapid loss of hepatitis C virus genotype 1b from serum in patients receiving a triple treatment with telaprevir (MP-424), pegylated interferon and ribavirin for 12 weeks. Hepatol Res 2009; 39: 1056-63.
186. Akuta N, Suzuki F, Hirakawa M, et al. Amino acid substitutions in the hepatitis C virus core region of genotype 1b affect very early viral dynamics during treatment with telaprevir, peginterferon, and ribavirin. J Med Virol 2010; 82: 575-82.
187. Kawaguchi T, Yamagishi SI, Itou M, et al. Pigment epitheliumderived factor inhibits lysosomal degradation of Bcl-xL and apoptosis in HepG2 cells. Am J Pathol 2010; 176(1): 168-76.
188. Veldt BJ, Chen W, Heathcote EJ, et al. Increased risk of hepatocellular carcinoma among patients with hepatitis C cirrhosis and diabetes mellitus. Hepatology 2008; 47: 1856-62.