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Experimental Diabetes Research
Volume 2012, Article ID 716404, 13 pages
http://dx.doi.org/10.1155/2012/716404
Review Article

The Role of Metformin in the Management of NAFLD

Endocrinology Unit, Department of Clinical and Experimental Medicine, University Magna Graecia of Catanzaro, Campus Universitario, Località Germaneto, Viale Europa, 88100 Catanzaro, Italy

Received 14 July 2011; Accepted 4 October 2011

Academic Editor: Konstantinos Kantartzis

Copyright © 2012 Angela Mazza et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. D. Festi, A. Colecchia, T. Sacco, M. Bondi, E. Roda, and G. Marchesini, “Hepatic steatosis in obese patients: clinical aspects and prognostic significance,” Obesity Reviews, vol. 5, no. 1, pp. 27–42, 2004. View at Publisher · View at Google Scholar · View at Scopus
  2. G. Marchesini, E. Bugianesi, G. Forlani et al., “Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome,” Hepatology, vol. 37, no. 4, pp. 917–923, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  3. P. Loria, A. Lonardo, S. Bellentani, C. P. Day, G. Marchesini, and N. Carulli, “Non-alcoholic fatty liver disease (NAFLD) and cardiovascular disease: an open question,” Nutrition, Metabolism and Cardiovascular Diseases, vol. 17, no. 9, pp. 684–698, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  4. N. M. W. de Alwis and C. P. Day, “Non-alcoholic fatty liver disease: the mist gradually clears,” Journal of Hepatology, vol. 48, supplement 1, pp. S104–S112, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  5. P. Socha, A. Horvath, P. Vajro, P. Dziechciarz, A. Dhawan, and H. Szajewska, “Pharmacological interventions for nonalcoholic fatty liver disease in adults and in children: a systematic review,” Journal of Pediatric Gastroenterology and Nutrition, vol. 48, no. 5, pp. 587–596, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  6. J. B. Schwimmer, O. Khorram, V. Chiu, and W. B. Schwimmer, “Abnormal aminotransferase activity in women with polycystic ovary syndrome,” Fertility and Sterility, vol. 83, no. 2, pp. 494–497, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  7. T. L. Setji, N. D. Holland, L. L. Sanders, K. C. Pereira, A. M. Diehl, and A. J. Brown, “Nonalcoholic steatohepatitis and nonalcoholic fatty liver disease in young women with polycystic ovary syndrome,” Journal of Clinical Endocrinology and Metabolism, vol. 91, no. 5, pp. 1741–1747, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  8. P. Angulo, “Medical progress: nonalcoholic fatty liver disease,” The New England Journal of Medicine, vol. 346, no. 16, pp. 1221–1231, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  9. C. P. Day and O. F. W. James, “Steatohepatitis: a tale of two 'Hits'?” Gastroenterology, vol. 114, no. 4, pp. 842–845, 1998. View at Publisher · View at Google Scholar · View at Scopus
  10. N. Matsuzawa, T. Takamura, S. Kurita et al., “Lipid-induced oxidative stress causes steatohepatitis in mice fed an atherogenic diet,” Hepatology, vol. 46, no. 5, pp. 1392–1403, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  11. C. L. Gentile and M. J. Pagliassotti, “The role of fatty acids in the development and progression of nonalcoholic fatty liver disease,” Journal of Nutritional Biochemistry, vol. 19, no. 9, pp. 567–576, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  12. N. Stefan and H.-U. Häring, “The metabolically benign and malignant fatty liver,” Diabetes, vol. 60, no. 8, pp. 2011–2017, 2011. View at Publisher · View at Google Scholar · View at PubMed
  13. P. Mofrad, M. J. Contos, M. Haque et al., “Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values,” Hepatology, vol. 37, no. 6, pp. 1286–1292, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  14. N. Stefan, K. Kantartzis, J. Machann et al., “Identification and characterization of metabolically benign obesity in humans,” Archives of Internal Medicine, vol. 168, no. 15, pp. 1609–1616, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  15. E. Fabbrini, F. Magkos, B. S. Mohammed et al., “Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 36, pp. 15430–15435, 2009. View at Publisher · View at Google Scholar · View at PubMed
  16. D. H. Akbar and A. H. Kawther, “Non-alcoholic fatty liver disease and metabolic syndrome: what we know and what we don't know,” Medical Science Monitor, vol. 12, no. 1, pp. RA23–RA26, 2006. View at Google Scholar · View at Scopus
  17. J. D. Browning, L. S. Szczepaniak, R. Dobbins et al., “Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity,” Hepatology, vol. 40, no. 6, pp. 1387–1395, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  18. A. Kotronen, J. Westerbacka, R. Bergholm, K. H. Pietilainen, and H. Yki-Jarvinen, “Liver fat in the metabolic syndrome,” The Journal of Clinical Endocrinology & Metabolism, vol. 92, pp. 3490–3497, 2007. View at Google Scholar
  19. A. Wieckowska, A. J. McCullough, and A. E. Feldstein, “Noninvasive diagnosis and monitoring of nonalcoholic steatohepatitis: present and future,” Hepatology, vol. 46, no. 2, pp. 582–589, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  20. M. Hamaguchi, T. Kojima, N. Takeda et al., “The metabolic syndrome as a predictor of nonalcoholic fatty liver disease,” Annals of Internal Medicine, vol. 143, no. 10, pp. 722–728, 2005. View at Google Scholar · View at Scopus
  21. M. Tobari, E. Hashimoto, S. Yatsuji, N. Torii, and K. Shiratori, “Imaging of nonalcoholic steatohepatitis: advantages and pitfalls of ultrasonography and computed tomography,” Internal Medicine, vol. 48, no. 10, pp. 739–746, 2009. View at Publisher · View at Google Scholar · View at Scopus
  22. S. Dasarathy, J. Dasarathy, A. Khiyami, R. Joseph, R. Lopez, and A. J. McCullough, “Validity of real time ultrasound in the diagnosis of hepatic steatosis: a prospective study,” Journal of Hepatology, vol. 51, no. 6, pp. 1061–1067, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  23. R. Vuppalanchi and N. Chalasani, “Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: selected practical issues in their evaluation and management,” Hepatology, vol. 49, no. 1, pp. 306–317, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  24. T. Yamauchi, J. Kamon, Y. Minokoshi et al., “Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase,” Nature Medicine, vol. 8, no. 11, pp. 1288–1295, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  25. E. A. Tsochatzis, G. V. Papatheodoridis, and A. J. Archimandritis, “Adipokines in nonalcoholic steatohepatitis: from pathogenesis to implications in diagnosis and therapy,” Mediators of Inflammation, vol. 2009, Article ID 831670, 8 pages, 2009. View at Publisher · View at Google Scholar · View at PubMed
  26. D. G. Tiniakos, M. B. Vos, and E. M. Brunt, “Nonalcoholic fatty liver disease: pathology and pathogenesis,” Annual Review of Pathology, vol. 5, pp. 145–171, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  27. M. Yoneda, K. Fujita, M. Inamori et al., “Transient elastography in patients with non-alcoholic fatty liver disease (NAFLD),” Gut, vol. 56, no. 9, pp. 1330–1331, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  28. P. Angulo, J. M. Hui, G. Marchesini et al., “The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD,” Hepatology, vol. 45, no. 4, pp. 846–854, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  29. V. Ratziu, P. Giral, F. Charlotte et al., “Liver fibrosis in overweight patients,” Gastroenterology, vol. 118, no. 6, pp. 1117–1123, 2000. View at Google Scholar · View at Scopus
  30. J. B. Dixon, P. S. Bhathal, and P. E. O'Brien, “Nonalcoholic fatty liver disease: predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese,” Gastroenterology, vol. 121, no. 1, pp. 91–100, 2001. View at Google Scholar · View at Scopus
  31. M. A. Huang, J. K. Greenson, C. Chao et al., “One-year intense nutritional counseling results in histological improvement in patients with nonalcoholic steatohepatitis: a pilot study,” American Journal of Gastroenterology, vol. 100, no. 5, pp. 1072–1081, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  32. M. Palmer and F. Schaffner, “Effect of weight reduction on hepatic abnormalities in overweight patients,” Gastroenterology, vol. 99, no. 5, pp. 1408–1413, 1990. View at Google Scholar · View at Scopus
  33. R. T. Wang, R. L. Koretz, and H. F. Yee Jr., “Is weight reduction an effective therapy for nonalcoholic fatty liver? A systematic review,” American Journal of Medicine, vol. 115, no. 7, pp. 554–559, 2003. View at Publisher · View at Google Scholar · View at Scopus
  34. A. Kadayifci, R. B. Merriman, and N. M. Bass, “Medical treatment of non-alcoholic steatohepatitis,” Clinics in Liver Disease, vol. 11, no. 1, pp. 119–140, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  35. G. A. Garinis, B. Fruci, A. Mazza et al., “Metformin versus dietary treatment in nonalcoholic hepatic steatosis: a randomized study,” International Journal of Obesity, vol. 34, no. 8, pp. 1255–1264, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  36. G. A. Marlatt, M. E. Larimer, P. D. Mail et al., “Journeys of the circle: a culturally congruent life skills intervention for adolescent Indian drinking,” Alcoholism, vol. 27, no. 8, pp. 1327–1329, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  37. M. Tiikkainen, A. M. Häkkinen, E. Korsheninnikova, T. Nyman, S. Mäkimattila, and H. Yki-Järvinen, “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, vol. 53, no. 8, pp. 2169–2176, 2004. View at Publisher · View at Google Scholar · View at Scopus
  38. V. Ratziu, P. Giral, S. Jacqueminet et al., “Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial,” Gastroenterology, vol. 135, no. 1, pp. 100–110, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  39. A. J. Sanyal, P. S. Mofrad, M. J. Contos et al., “A pilot study of vitamin E versus vitamin E and pioglitazone for the treatment of nonalcoholic steatohepatitis,” Clinical Gastroenterology and Hepatology, vol. 2, no. 12, pp. 1107–1115, 2004. View at Publisher · View at Google Scholar · View at Scopus
  40. R. Belfort, S. A. Harrison, K. Brown et al., “A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis,” The New England Journal of Medicine, vol. 355, no. 22, pp. 2297–2307, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  41. G. P. Aithal, J. A. Thomas, P. V. Kaye et al., “Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis,” Gastroenterology, vol. 135, no. 4, pp. 1176–1184, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  42. K. Promrat, D. E. Kleiner, H. M. Niemeier et al., “Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis,” Hepatology, vol. 51, no. 1, pp. 121–129, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  43. A. J. Sanyal, N. Chalasani, K. V. Kowdley et al., “Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis,” The New England Journal of Medicine, vol. 362, no. 18, pp. 1675–1685, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  44. C. L. Chaffer, D. M. Thomas, E. W. Thompson, and E. D. Williams, “PPARγ-independent induction of growth arrest and apoptosis in prostate and bladder carcinoma,” BMC Cancer, vol. 6, article 53, 2006. View at Publisher · View at Google Scholar · View at PubMed
  45. L. He, A. Sabet, S. Djedjos et al., “Metformin and insulin suppress hepatic gluconeogenesis through phosphorylation of CREB binding protein,” Cell, vol. 137, no. 4, pp. 635–646, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  46. M. Stumvoll, N. Nurjhan, G. Perriello, G. Dailey, and J. E. Gerich, “Metabolic effects of metformin in non-insulin-dependent diabetes mellitus,” The New England Journal of Medicine, vol. 333, no. 9, pp. 550–554, 1995. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  47. R. Loomba, G. Lutchman, D. E. Kleiner et al., “Clinical trial: pilot study of metformin for the treatment of non-alcoholic steatohepatitis,” Alimentary Pharmacology and Therapeutics, vol. 29, no. 2, pp. 172–182, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  48. M. Kohjima, N. Higuchi, M. Kato et al., “SREBP-1c, regulated by the insulin and AMPK signaling pathways, plays a role in nonalcoholic fatty liver disease,” International Journal of Molecular Medicine, vol. 21, no. 4, pp. 507–511, 2008. View at Google Scholar · View at Scopus
  49. P. Huypens, E. Quartier, D. Pipeleers, and M. Van De Casteele, “Metformin reduces adiponectin protein expression and release in 3T3-L1 adipocytes involving activation of AMP activated protein kinase,” European Journal of Pharmacology, vol. 518, no. 2-3, pp. 90–95, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  50. H. Z. Lin, S. Q. Yang, C. Chuckaree, F. Kuhajda, G. Ronnet, and A. M. Diehl, “Metformin reverses fatty liver disease in obese, leptin-deficient mice,” Nature Medicine, vol. 6, no. 9, pp. 998–1003, 2000. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  51. S. Zhang, X. Liu, W. J. Brickman et al., “Association of plasma leptin concentrations with adiposity measurements in rural Chinese adolescents,” Journal of Clinical Endocrinology and Metabolism, vol. 94, no. 9, pp. 3497–3504, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  52. G. Marchesini, M. Brizi, G. Bianchi, S. Tomassetti, M. Zoli, and N. Melchionda, “Metformin in non-alcoholic steatohepatitis,” Lancet, vol. 358, no. 9285, pp. 893–894, 2001. View at Publisher · View at Google Scholar · View at Scopus
  53. S. Nair, A. M. Diehl, M. Wiseman, G. H. Farr Jr., and R. P. Perrillo, “Metformin in the treatment of non-alcoholic steatohepatitis: a pilot open label trial,” Alimentary Pharmacology and Therapeutics, vol. 20, no. 1, pp. 23–28, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  54. A. Uygun, A. Kadayifci, A. T. Isik et al., “Metformin in the treatment of patients with non-alcoholic steatohepatitis,” Alimentary Pharmacology and Therapeutics, vol. 19, no. 5, pp. 537–544, 2004. View at Publisher · View at Google Scholar · View at Scopus
  55. E. Bugianesi, E. Gentilcore, R. Manini et al., “A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver disease,” American Journal of Gastroenterology, vol. 100, no. 5, pp. 1082–1090, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  56. A. Duseja, A. Das, R. K. Dhiman et al., “Metformin is effective in achieving biochemical response in patients with nonalcoholic fatty liver disease (NAFLD) not responding to lifestyle interventions,” Annals of Hepatology, vol. 6, no. 4, pp. 222–226, 2007. View at Google Scholar · View at Scopus
  57. C. P. M. S. de Oliveira, J. T. Stefano, E. R. F. De Siqueira et al., “Combination of N-acetylcysteine and metformin improves histological steatosis and fibrosis in patients with non-alcoholic steatohepatitis,” Hepatology Research, vol. 38, no. 2, pp. 159–165, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  58. R. Idilman, D. Mizrak, D. Corapcioglu et al., “Clinical trial: insulin-sensitizing agents may reduce consequences of insulin resistance in individuals with non-alcoholic steatohepatitis,” Alimentary Pharmacology and Therapeutics, vol. 28, no. 2, pp. 200–208, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  59. J. W. Haukeland, Z. Konopski, H. B. Eggesbø et al., “Metformin in patients with non-alcoholic fatty liver disease: a randomized, controlled trial,” Scandinavian Journal of Gastroenterology, vol. 44, no. 7, pp. 853–860, 2009. View at Publisher · View at Google Scholar · View at PubMed
  60. D. J. Janiec, E. R. Jacobson, A. Freeth, L. Spaulding, and H. Blaszyk, “Histologic variation of grade and stage of non-alcoholic fatty liver disease in liver biopsies,” Obesity Surgery, vol. 15, no. 4, pp. 497–501, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  61. Z. Omer, S. Cetinkalp, M. Akyildiz et al., “Efficacy of insulin-sensitizing agents in nonalcoholic fatty liver disease,” European Journal of Gastroenterology and Hepatology, vol. 22, no. 1, pp. 18–23, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  62. A. Nar and O. Gedik, “The effect of metformin on leptin in obese patients with type 2 diabetes mellitus and nonalcoholic fatty liver disease,” Acta Diabetologica, vol. 46, no. 2, pp. 113–118, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  63. J. B. Schwimmer, C. Behling, R. Newbury et al., “Histopathology of pediatric nonalcoholic fatty liver disease,” Hepatology, vol. 42, no. 3, pp. 641–649, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  64. K. J. Nadeau, L. B. Ehlers, P. S. Zeitler, and K. Love-Osborne, “Treatment of non-alcoholic fatty liver disease with metformin versus lifestyle intervention in insulin-resistant adolescents,” Pediatric Diabetes, vol. 10, no. 1, pp. 5–13, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  65. V. Nobili, M. Marcellini, R. Devito et al., “NAFLD in children: a prospective clinical-pathological study and effect of lifestyle advice,” Hepatology, vol. 44, no. 2, pp. 458–465, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  66. J. E. Lavine, J. B. Schwimmer, J. P. Molleston et al., “Treatment of nonalcoholic fatty liver disease in children: TONIC trial design,” Contemporary Clinical Trials, vol. 31, no. 1, pp. 62–70, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  67. D. Kirpichnikov, S. I. McFarlane, and J. R. Sowers, “Metformin: an update,” Annals of Internal Medicine, vol. 137, no. 1, pp. 25–33, 2002. View at Google Scholar · View at Scopus
  68. K. Landin, L. Tengborn, and U. Smith, “Treating insulin resistance inhypertension with metformin reduces both blood pressure and metabolic risk factors,” Journal of Internal Medicine, vol. 229, no. 2, pp. 181–187, 1991. View at Google Scholar · View at Scopus
  69. J. S. Petersen and G. F. DiBona, “Acute sympathoinhibitory actions of metformin in spontaneously hypertensive rats,” Hypertension, vol. 27, no. 3, pp. 619–625, 1996. View at Google Scholar · View at Scopus
  70. V. A. Morrow, F. Foufelle, J. M. C. Connell, J. R. Petrie, G. W. Gould, and I. P. Salt, “Direct activation of AMP-activated protein kinase stimulates nitric-oxide synthesis in human aortic endothelial cells,” Journal of Biological Chemistry, vol. 278, no. 34, pp. 31629–31639, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  71. E. Fabbrini, S. Sullivan, and S. Klein, “Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications,” Hepatology, vol. 51, no. 2, pp. 679–689, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  72. K. Johansen, “Efficacy of metformin in the treatment of NIDDM: meta-analysis,” Diabetes Care, vol. 22, no. 1, pp. 33–37, 1999. View at Publisher · View at Google Scholar · View at Scopus
  73. E. Haupt, B. Knick, T. Koschinsky, H. Liebermeister, J. Schneider, and H. Hirche, “Oral antidiabetic combination therapy with sulphonylureas and metformin,” Diabete et Metabolisme, vol. 17, no. 1, pp. 224–231, 1991. View at Google Scholar · View at Scopus
  74. R. Pasquali, A. Gambineri, D. Biscotti et al., “Effect of long-term treatment with metformin added to hypocaloric diet on body composition, fat distribution, and androgen and insulin levels in abdominally obese women with and without the polycystic ovary syndrome,” Journal of Clinical Endocrinology and Metabolism, vol. 85, no. 8, pp. 2767–2774, 2000. View at Publisher · View at Google Scholar · View at Scopus
  75. C. J. Glueck, P. Wang, R. Fontaine, T. Tracy, and L. Sieve-Smith, “Metformin-induced resumption of normal menses in 39 of 43 (91%) previously amenorrheic women with the polycystic ovary syndrome,” Metabolism: Clinical and Experimental, vol. 48, no. 4, pp. 511–519, 1999. View at Google Scholar · View at Scopus
  76. H. Yki-Järvinen, K. Nikkilä, and S. Mäkimattila, “Metformin prevents weight gain by reducing dietary intake during insulin therapy in patients with type 2 diabetes mellitus,” Drugs, vol. 58, supplement 1, pp. 53–54, 1999. View at Google Scholar
  77. J. R. Sowers, “Obesity and cardiovascular disease,” Clinical Chemistry, vol. 44, no. 8, pp. 1821–1825, 1998. View at Google Scholar · View at Scopus
  78. “Effects of withdrawal from metformin on the development of diabetes in the diabetes prevention program,” Diabetes Care, vol. 26, no. 4, pp. 977–980, 2003. View at Publisher · View at Google Scholar · View at Scopus
  79. S. I. McFarlane, M. Banerji, and J. R. Sowers, “Insulin resistance and cardiovascular disease,” Journal of Clinical Endocrinology and Metabolism, vol. 86, no. 2, pp. 713–718, 2001. View at Publisher · View at Google Scholar · View at Scopus
  80. I. J. Hickman, J. R. Jonsson, J. B. Prins et al., “Modest weight loss and physical activity in overweight patients with chronic liver disease results in sustained improvements in alanine aminotransferase, fasting insulin, and quality of life,” Gut, vol. 53, no. 3, pp. 413–419, 2004. View at Publisher · View at Google Scholar · View at Scopus
  81. D. E. Larson-Meyer, B. R. Newcomer, L. K. Heilbronn et al., “Effect of 6-month calorie restriction and exercise on serum and liver lipids and markers of liver function,” Obesity, vol. 16, no. 6, pp. 1355–1362, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  82. J. Krakoff, J. M. Clark, J. P. Crandall et al., “Effects of metformin and weight loss on serum alanine aminotransferase activity in the diabetes prevention program,” Obesity, vol. 18, no. 9, pp. 1762–1767, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  83. W. C. Knowler, E. Barrett-Connor, S. E. Fowler et al., “Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin,” The New England Journal of Medicine, vol. 346, no. 6, pp. 393–403, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  84. E. Diamanti-Kandarakis, “Polycystic ovarian syndrome: pathophysiology, molecular aspects and clinical implications,” Expert Reviews in Molecular Medicine, vol. 10, no. 3, pp. 1–21, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  85. Y. Gutierrez-Grobe, G. Ponciano-Rodríguez, M. H. Ramos, M. Uribe, and N. Méndez-Sánchez, “Prevalence of non alcoholic fatty liver disease in premenopausal, posmenopausal and polycystic ovary syndrome women. The role of estrogens,” Annals of Hepatology, vol. 9, no. 4, pp. 402–409, 2010. View at Google Scholar
  86. G. Chodick, A. D. Heymann, L. Rosenmann et al., “Diabetes and risk of incident cancer: a large population-based cohort study in Israel,” Cancer Causes and Control, vol. 21, no. 6, pp. 879–887, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  87. P. Vigneri, F. Frasca, L. Sciacca, L. Frittitta, and R. Vigneri, “Obesity and cancer,” Nutrition, Metabolism and Cardiovascular Diseases, vol. 16, no. 1, pp. 1–7, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  88. H. D. Strickler, J. Wylie-Rosett, T. Rohan et al., “The relation of type 2 diabetes and cancer,” Diabetes Technology and Therapeutics, vol. 3, no. 2, pp. 263–274, 2001. View at Publisher · View at Google Scholar · View at Scopus
  89. S. S. Coughlin, E. E. Calle, L. R. Teras, J. Petrelli, and M. J. Thun, “Diabetes mellitus as a predictor of cancer mortality in a large cohort of US adults,” American Journal of Epidemiology, vol. 159, no. 12, pp. 1160–1167, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  90. A. G. Renehan, M. Tyson, M. Egger, R. F. Heller, and M. Zwahlen, “Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies,” The Lancet, vol. 371, no. 9612, pp. 569–578, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  91. L. A. Cantrell, C. Zhou, A. Mendivil, K. M. Malloy, P. A. Gehrig, and V. L. Bae-Jump, “Metformin is a potent inhibitor of endometrial cancer cell proliferation-implications for a novel treatment strategy,” Gynecologic Oncology, vol. 116, no. 1, pp. 92–98, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  92. H. Vainio, R. Kaaks, and F. Bianchini, “Weight control and physical activity in cancer prevention: international evaluation of the evidence,” European Journal of Cancer Prevention, vol. 11, supplement 2, pp. S94–S100, 2002. View at Google Scholar · View at Scopus
  93. A. Belfiore and F. Frasca, “IGF and insulin receptor signaling in breast cancer,” Journal of Mammary Gland Biology and Neoplasia, vol. 13, no. 4, pp. 381–406, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  94. A. B. Siegel and A. X. Zhu, “Metabolic syndrome and hepatocellular carcinoma: two growing epidemics with a potential link,” Cancer, vol. 115, no. 24, pp. 5651–5661, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  95. G. Guzman, E. M. Brunt, L. M. Petrovic, G. Chejfec, T. J. Layden, and S. J. Cotler, “Does nonalcoholic fatty liver disease predispose patients to hepatocellular carcinoma in the absence of cirrhosis?” Archives of Pathology and Laboratory Medicine, vol. 132, no. 11, pp. 1761–1766, 2008. View at Publisher · View at Google Scholar · View at Scopus
  96. M. Zakikhani, R. Dowling, I. G. Fantus, N. Sonenberg, and M. Pollak, “Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells,” Cancer Research, vol. 66, no. 21, pp. 10269–10273, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  97. J. M. M. Evans, L. A. Donnelly, A. M. Emslie-Smith, D. R. Alessi, and A. D. Morris, “Metformin and reduced risk of cancer in diabetic patients,” British Medical Journal, vol. 330, no. 7503, pp. 1304–1305, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  98. S. L. Bowker, S. R. Majumdar, P. Veugelers, and J. A. Johnson, “Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin,” Diabetes Care, vol. 29, no. 2, pp. 254–258, 2006. View at Google Scholar · View at Scopus
  99. Y. Zhuang and W. K. Miskimins, “Cell cycle arrest in Metformin treated breast cancer cells involves activation of AMPK, downregulation of cyclin D1, and requires p27Kip1 or p21Cip1,” Journal of Molecular Signaling, vol. 3, article 18, 2008. View at Publisher · View at Google Scholar · View at PubMed
  100. V. Donadon, M. Balbi, M. Ghersetti et al., “Antidiabetic therapy and increased risk of hepatocellular carcinoma in chronic liver disease,” World Journal of Gastroenterology, vol. 15, no. 20, pp. 2506–2511, 2009. View at Publisher · View at Google Scholar · View at Scopus
  101. G. Verlato, G. Zoppini, E. Bonora, and M. Muggeo, “Mortality from site-specific malignancies in type 2 diabetic patients from Verona,” Diabetes Care, vol. 26, no. 4, pp. 1047–1051, 2003. View at Publisher · View at Google Scholar · View at Scopus
  102. B. Balkau, H. S. Kahn, D. Courbon, E. Eschwège, and P. Ducimetière, “Hyperinsulinemia predicts fatal liver cancer but is inversely associated with fatal cancer at some other sites: the Paris Prospective Study,” Diabetes Care, vol. 24, no. 5, pp. 843–849, 2001. View at Google Scholar
  103. J. K. J. Gaidos, B. E. Hillner, and A. J. Sanyal, “A decision analysis study of the value of a liver biopsy in nonalcoholic steatohepatitis,” Liver International, vol. 28, no. 5, pp. 650–658, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  104. X. Jin, Y. F. Ye, S. H. Chen, C. H. Yu, J. Liu, and Y. M. Li, “MicroRNA expression pattern in different stages of nonalcoholic fatty liver disease,” Digestive and Liver Disease, vol. 41, no. 4, pp. 289–297, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  105. O. Cheung, P. Puri, C. Eicken et al., “Nonalcoholic steatohepatitis is associated with altered hepatic MicroRNA expression,” Hepatology, vol. 48, no. 6, pp. 1810–1820, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  106. G. Musso, R. Gambino, and M. Cassader, “Emerging molecular targets for the treatment of nonalcoholic fatty liver disease,” Annual Review of Medicine, vol. 61, pp. 375–392, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  107. J. Krützfeldt, N. Rajewsky, R. Braich et al., “Silencing of microRNAs in vivo with ‘antagomirs’,” Nature, vol. 438, no. 7068, pp. 685–689, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  108. J. Elmén, M. Lindow, S. Schütz et al., “LNA-mediated microRNA silencing in non-human primates,” Nature, vol. 452, no. 7189, pp. 896–899, 2008. View at Publisher · View at Google Scholar · View at PubMed
  109. R. Bergeron, S. F. Previs, G. W. Cline et al., “Effect of 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside infusion on in vivo glucose and lipid metabolism in lean and obese zucker rats,” Diabetes, vol. 50, no. 5, pp. 1076–1082, 2001. View at Google Scholar · View at Scopus
  110. K. G. Park, A. K. Min, E. H. Koh et al., “Alpha-lipoic acid decreases hepatic lipogenesis through adenosine monophosphate-activated protein kinase (AMPK)-dependent and AMPK-independent pathways,” Hepatology, vol. 48, no. 5, pp. 1477–1486, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  111. J. R. Lewis and S. R. Mohanty, “Nonalcoholic fatty liver disease: a review and update,” Digestive Diseases and Sciences, vol. 55, no. 3, pp. 560–578, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  112. X. Ding, N. K. Saxena, S. Lin, N. Gupta, and F. A. Anania, “Exendin-4, a glucagon-like protein-1 (GLP-1) receptor agonist, reverses hepatic steatosis in ob/ob mice,” Hepatology, vol. 43, no. 1, pp. 173–181, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  113. M. E. Tushuizen, M. C. Bunck, P. J. Pouwels, J. H. T. van Waesberghe, M. Diamant, and R. J. Heine, “Incretin mimetics as a novel therapeutic option for hepatic steatosis,” Liver International, vol. 26, no. 8, pp. 1015–1017, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus