Liệu pháp kháng insulin trong các bệnh khác ngoài tiểu đường loại 2

Laura Pala1, Valeria Barbaro1,2, Ilaria Dicembrini2,3, Carlo Maria Rotella2
1Endocrine Unit, Department of Biomedical Experimental and Clinical Sciences, University of Florence, Careggi University Hospital, Florence, Italy
2Department of Biomedical Experimental and Clinical Sciences, Obesity Agency, University of Florence, Careggi University Hospital, Florence, Italy
3Department of Biomedical Experimental and Clinical Sciences, Diabetes Agency, University of Florence, Careggi University Hospital, Florence, Italy

Tóm tắt

Kháng insulin là một tình trạng lâm sàng được chia sẻ bởi nhiều bệnh ngoài tiểu đường loại 2 (T2DM) như béo phì, hội chứng buồng trứng đa nang (PCOS) và bệnh gan nhiễm mỡ không do rượu (NAFLD). Bằng chứng thực nghiệm được sản xuất qua nhiều năm cho thấy metformin có nhiều lợi ích trong điều trị các bệnh này. Metformin là thuốc điều trị hàng đầu cho bệnh nhân tiểu đường loại 2 thừa cân và béo phì, mang lại một phương pháp tiếp cận sinh lý bệnh chọn lọc thông qua tác động của nó lên sự kháng insulin. Hơn nữa, một số nghiên cứu đã xác lập tác động tích cực của metformin lên cân nặng cơ thể, không chỉ khi đánh giá chỉ số khối cơ thể (BMI), mà còn khi xem xét thành phần khối lượng cơ thể, thông qua việc giảm khối lượng mỡ. Ngoài ra, nó còn làm giảm kháng insulin, hyperinsulinemia, các thông số lipid, huyết áp động mạch và rối loạn chức năng nội mạch. Đặc biệt, một chế phẩm metformin giải phóng kéo dài (ER) mới hiện đã có mặt với các chế phẩm khác nhau ở các quốc gia khác nhau. Metformin ER truyền thuốc hoạt động qua các polymer hydrat hóa, mở rộng khả năng tiếp nhận chất lỏng an toàn, kéo dài thời gian di chuyển trong dạ dày và làm chậm quá trình hấp thụ thuốc trong ống tiêu hóa trên. Thêm vào đó, Metformin ER gây ra một sự giảm nhỏ nhưng có ý nghĩa thống kê trong BMI khi được thêm vào chương trình can thiệp lối sống ở thanh thiếu niên béo phì. Bởi vì những lợi ích được gợi ý trong điều trị kháng insulin ở nhiều tình trạng lâm sàng, ngoài tiểu đường loại 2, khả năng đưa ra nhiều chỉ định điều trị metformin đang trở thành hiện thực.

Từ khóa

#Metformin #kháng insulin #tiểu đường loại 2 #béo phì #hội chứng buồng trứng đa nang #bệnh gan nhiễm mỡ không do rượu #chỉ số khối cơ thể #điều trị.

Tài liệu tham khảo

Randle PJ, Garland PB, Hales CN, Newsholme EA (1963) The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1:785–789 Johnson AM, Olefsky JM (2013) The origins and drivers of insulin resistance. Cell 152:673–684 Myers MG Jr, Olson DP (2012) Central nervous system control of metabolism. Nature 491:357–363 Reaven GM (2005) The insulin resistance syndrome: definition and dietary approaches to treatment. Annu Rev Nutr 25:391–406 Guo S, Copps KD, Dong X, Park S, Cheng Z, Pocai A, Rossetti L, Sajan M, Farese RV, White MF (2009) The Irs1 branch of the insulin signaling cascade plays a dominant role in hepatic nutrient homeostasis. Mol Cell Biol 29:5070–5083 Bouche C, Lopez X, Fleischman A, Cypess AM, O’Shea S, Stefanovski D, Bergman RN, Rogatsky E, Stein DT, Kahn CR et al (2010) Insulin enhances glucose-stimulated insulin secretion in healthy humans. PNAS 107:4770–4775 Rhodes CJ, White MF, Leahy JL, Kahn SE (2013) Direct autocrine action of insulin on b-cells: does it make physiological sense? Diabetes 62:2157–2163 Bruning JC, Michael MD, Winnay JN, Hayashi T, Horsch D, Accili D, Goodyear LJ, Kahn CR (1998) A muscle-specific insulin receptor knockout exhibits features of the metabolic syndrome of NIDDM without altering glucose tolerance. Mol Cell 2:559–569 Qi Y, Xu Z, Zhu Q, Thomas C, Kumar R, Feng H, Dostal DE, White MF, Baker KM, Guo S (2013) Myocardial loss of IRS1 and IRS2 causes heart failure and Is controlled by p38a MAPK during insulin resistance. Diabetes 62:3887–3900 Muniyappa R, Iantorno M, Quon MJ (2008) An integrated view of insulin resistance and endothelial dysfunction. Endocrinol Metab Clin North Am 37:685–711 Ferron M, Wei J, Yoshizawa T, Del Fattore A, DePinho RA, Teti A, Ducy P, Karsenty G (2010) Insulin signaling in osteoblasts integrates bone remodeling and energy metabolism. Cell 142:296–308 Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R et al (2009) American Diabetes Association; European Association for Study of Diabetes. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 32(1):193–203 Diamanti-Kandarakis E, Christakou CD, Kandaraki E, Economou FN (2010) Metformin: an old medication of new fashion: evolving new molecular mechanisms and clinical implications in polycystic ovary syndrome. Eur J Endocrinol 162(2):193–212 Rotella CM, Monami M, Mannucci E (2006) Metformin beyond diabetes: new life for an old drug. Curr Diabetes Rev 2(3):307–315 Tankova T (2003) Current indications for metformin therapy. Rom J Intern Med 41(3):215–225 Muntoni S (2011) Insulin resistance: pathophysiology and rationale for treatment. Ann Nutr Metab 58(1):25–36 Kendall DL, Amin R, Clayton PE (2014) Metformin in the treatment of obese children and adolescents at risk of type 2 diabetes. Paediatr Drugs 16(1):13–20 Bouza C, López-Cuadrado T, Gutierrez-Torres LF, Amate J (2012) Efficacy and safety of metformin for treatment of overweight and obesity in adolescents: an updated systematic review and meta-analysis. Obes Facts 5(5):753–765 Matson KL, Fallon RM (2012) Treatment of obesity in children and adolescents. J Pediatr Pharmacol Ther 17(1):45–57 Park MH, Kinra S, Ward KJ, White B, Viner RM (2009) Metformin for obesity in children and adolescents: a systematic review. Diabetes Care 32(9):1743–1745 Rezvanian H, Hashemipour M, Kelishadi R, Tavakoli N, Poursafa P (2010) A randomized, triple masked, placebo-controlled clinical trial for controlling childhood obesity. World J Pediatr 6(4):317–322 Brufani C, Crinò A, Fintini D, Patera PI, Cappa M, Manco M (2013) Systematic review of metformin use in obese nondiabetic children and adolescents. Horm Res Paediatr 80(2):78–85 Kuller LH (2012) Metformin use among individuals at risk for type 2 diabetes. Curr Diab Rep 12(3):265–273 McDonagh MS, Selph S, Ozpinar A, Foley C (2014) Systematic review of the benefits and risks of metformin in treating obesity in children aged 18 years and younger. JAMA Pediatr 168(2):178–184 Wales J, Wright N, Clayton P, Hall C (2013) Metformin in obese children and adolescents: the MOCA trial. J Clin Endocrinol Metab 98(1):322–329 Tankova T, Dakovska L, Kirilov G, Koev D (2003) Metformin in the treatment of obesity in subjects with normal glucose tolerance. Rom J Intern Med 41(3):269–275 Evia-Viscarra ML, Rodea-Montero ER, Apolinar-Jiménez E, Muñoz-Noriega N, García-Morales LM, Leaños-Pérez C, Figueroa-Barrón M, Sánchez-Fierros D, Reyes-García JG (2012) The effects of metformin on inflammatory mediators in obese adolescents with insulin resistance: controlled randomized clinical trial. J Pediatr Endocrinol Metab 25(1–2):41–49 He H, Zhao Z, Chen J, Ni Y, Zhong J, Yan Z, Li Y, Liu D, Pletcher MJ, Zhu Z (2012) Metformin-based treatment for obesity-related hypertension: a randomized, double-blind, placebo-controlled trial. J Hypertens 30(7):1430–1439 LeBlanc E, O’Connor E, Whitlock EP, Patnode C, Kapka T (2011). Screening for and management of obesity and overweight in adults [Internet], Oct. Report. Agency for Healthcare Research and Quality (US), Rockville Miller JL, Linville TD, Dykens EM (2013) Effects of metformin in children and adolescents with Prader-Willi syndrome and early-onset morbid obesity: a pilot study. J Pediatr Endocrinol Metab 24:1–7 Rodríguez Y, Giri M, Feyen E, Christophe AB (2004) Effect of metformin vs. placebo treatment on serum fatty acids in non-diabetic obese insulin resistant individuals. Prostaglandins Leukot Essent Fatty Acids 71(6):391–397 Fernández-Galilea M, Pérez-Matute P, Prieto-Hontoria PL, Martinez JA, Moreno-Aliaga MJ (2012) Effects of lipoic acid on lipolysis in 3T3-L1 adipocytes. J Lipid Res 53:2296–2306 Weili Y, Nong L, Xiaojuan H, Yongdi H, Weiguo Z, Qian W, Fugang W, Chenchen W, Xiaohu Z, Ruiwei X, Kai Y, Xiuhua D, Xiaoling W (2013) Effect of oral ALA supplementation on oxidative stress and insulin sensitivity among overweight/obese adults: a double-blinded, randomized, controlled, cross-over intervention trial. Int J Cardiol 167(2):602–603 Adams J, Polson DW, Franks S (1986) Prevalence of polycystic ovaries in women with anovulation and idiopathic hirsutism. Br Med J (Clin Res Ed) 293:355–359 Michelmore KF, Balen AH, Dunger DB, Vessey MP (1999) Polycystic ovaries and associated clinical and biochemical features in young women. Clin Endocrinol (Oxf) 51:779–786 Pasquali R, Gambineri A, Pagotto U (2006) The impact of obesity on reproduction in women with polycystic ovary syndrome. BJOG 113(10):1148–1597 Legro RS, Driscoll D, Straus JF III, Fox J, Dunaif A (1998) Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome. Proc Natl Acad Sci USA 95:14956–14960 Amato P, Simpson JL (2004) The genetics of polycystic ovary syndrome. Best Pract Res Clin Obstet Gynaecol 18(5):707–718 Vink JM, Sadrzadeh S, Lambalk CB, Boomsma DI (2006) Heritability of polycystic ovary syndrome in a Dutch twin-family study. J Clin Endocrinol Metab 91(6):2100–2104 Diamanti-Kandarakis E, Papavassiliou AG (2006) Molecular mechanisms of insulin resistance in polycystic ovary syndrome. Trends Mol Med 12:324–332 Legro RS (1998) Polycystic ovary syndrome: current and future treatment paradigms. Am J Obstet Gynecol 179(Suppl):101–108 Burghen GA, Givens JR, Kitabchi AE (1980) Correlation with hyperandrogenism et hyperinsulinism in polycystic ovarian disease. J Clin Endocrinol Metab 50:113–116 Dunaif A, Segal KR, Shelley DR, Green G, Dobrjansky A, Licholai T (1992) Evidence for distinctive and intrinsic defects in insulin action in polycystic ovary syndrome. Diabetes 41:1257–1266 Dunaif A, Finegood DT (1996) Beta-cell dysfunction independent of obesity and glucose intolerance in the polycystic ovary syndrome. J Clin Endocrinol Metab 81:942–947 Laven JSE, Mulders AGMGJ, van Santbrink, EJP, Eijkemans, MJC, Fauser, BCJM (2005). PCOS: backgrounds, evidence and problems in diagnosing the syndrome. In: Slager E, Fauser B, van Geijn H, Brölmann H, Vervest H, editors. Gynaecology, obstetrics, and reproductive medicine in daily practice, Proceedings of the 15th congress of gynaecology, obstetrics and reproductive medicine. International congress series, vol 1279, pp 10–15 Robinson S, Kiddy D, Gelding SV, Willis D, Niththyananthan R et al (1993) The relationship of insulin insensitivity to menstrual pattern in women with hyperandrogenism and polycystic ovaries. Clin Endocrinol (Oxf) 39(3):351–355 Diamanti-Kandarakis E, Kouli C, Tsianateli T, Bergiele A (1998) Therapeutic effects of metformin on insulin-resistance and hyperandrogenism in polycystic ovary syndrome. Eur J Endocrinol 138:269–274 Nestler JE, Jakubowicz DJ (1996) Decrease in ovarian cytochrome P450c17 alpha activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. N Engl J Med 335:617–623 Attia GR, Rainey WE, Carr BR (2001) Metformin directly inhibits androgen production in human thecal cells. Fertil Steril 76:517–524 La Marca A, Morgante G, Palumbo M, Cianci A, Petraglia F, De Leo V (2002) Insulin-lowering treatment reduces aromatase activity in response to follicle-stimulating hormone in women with polycystic ovary syndrome. Fertil Steril 78:1234–1239 Tosca L, Solnais P, Ferre P, Foufelle F, Dupont J (2006) Metformin-induced stimulation of adenosine 5′ monophosphate-activated protein kinase (PRKA) impairs progesterone secretion in rat granulosa cells. Biol Reprod 75:342–351 Lord JM, Flight IH, Norman RJ (2003) Metformin in polycystic ovary syndrome: systematic review and meta-analysis. BMJ 327:951–953 Chang KI, Sharma ST, Nestler JE (2006) Is metformin a primary ovulatory agent in patients with polycystic ovary syndrome? Gynecol Endocrinol 22:595–604 Harborne L, Fleming R, Lyall H, Satar N, Norman J (2003) Metformin or antiandrogen in the treatment of hirsutism in polycystic ovary syndrome. J Clin Endocrinol Metab 88:4116–4123 Tang T, Lord JM, Norman RJ, Yasmin E, Balen AH (2010). Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligoamenorrhoea and subfertility. Cochrane Database Syst Rev;1:CD003053 Sharma ST, Wickham EP III, Nestler JE (2007) Changes in glucose tolerance with metformin treatment in polycystic ovary syndrome: a retrospective analysis. Endocr Pract 13:373–379 Norman RJ, Davies MJ, Lord J, Moran LJ (2002) The role of lifestyle modification in polycystic ovary syndrome. Trends Endocrinol Met 13:251–257 Fauser BC, Tarlatzis BC, Rebar RW, Legro RS, Balen AH, Lobo R, Carmina E, Chang J, Yildiz BO, Laven JS, Boivin J, Petraglia F, Wijeyeratne CN, Norman RJ, Dunaif A, Franks S, Wild RA, Dumesic D, Barnhart K (2012) Consensus on women’s health aspects of polycystic ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group. Fertil Steril 97(1):28–38 Saltiel AR (1990) Second messengers of insulin action. Diabetes Care 13:244–256 Nestler JE, Jakubowicz DJ, Reamer P, Gunn RD, Allan G (1999) Ovulatory and metabolic effects of D-chiro-inositol in the polycystic ovary syndrome. N Engl J Med 340:1314–1320 Genazzani AD, Lanzoni C, Ricchieri F, Jasonni VM (2008) Myo-inositol administration positively affects hyperinsulinemia and hormonal parameters in overweight patients with polycystic ovary syndrome. Gynecol Endocrinol 24:139–144 Fenkci V, Fenkci S, Yilmazer M, Serteser M (2003) Decreased total antioxidant status and increased oxidative stress in women with polycystic ovary syndrome may contribute to the risk of cardiovascular disease. Fertil Steril 80(1):123–127 Estrada DE, Ewart HS, Tsakiridis T et al (1996) Stimulation of glucose uptake by the natural coenzyme α-lipoic acid/thioctic acid. Participation of elements of the insulin signaling pathway. Diabetes 45:1798–1804 Masharani U, Gjerde C, Evans JL, Youngren JF, Goldfine ID (2010) Effects of controlled-release alpha lipoic acid in lean, nondiabetic patients with polycystic ovary syndrome. J Diabetes Sci Technol 4(2):359–364 Lee WJ, Song KH, Koh EH, Won JC, Kim HS, Park HS, Kim MS, Kim SW, Lee KU, Park JY (2005) Alpha-lipoic acid increases insulin sensitivity by activating AMPK in skeletal muscle. Biochem Biophys Res Commun 332(3):885–891 Olaywi M, Bhatia T, Anand S, Singhal S (2013) Novel anti-diabetic agents in non-alcoholic fatty liver disease: a mini-review. Hepatobiliary Pancreat Dis Int 12(6):584–588 Mazza A, Fruci B, Garinis GA, Giuliano S, Malaguarnera R, Belfiore A (2012) The role of metformin in the management of NAFLD. Exp Diabetes Res. 2012:716404 Gentile CL, Pagliassotti MJ (2008) The role of fatty acids in the development and progression of nonalcoholic fatty liver disease. J Nutr Biochem 19(9):567–576 Stefan N, Häring HU (2011) The metabolically benign and malignant fatty liver. Diabetes 60(8):2011–2017 Paredes AH, Torres DM, Harrison SA (2012) Nonalcoholic fatty liver disease. Clin Liver Dis 16(2):397–419 Fruci B, Giuliano S, Mazza A, Malaguarnera R, Belfiore A (2013) Nonalcoholic fatty liver: a possible new target for type 2 diabetes prevention and treatment. Int J Mol Sci 14(11):22933–22966 Kenny PR, Brady DE, Torres DM, Ragozzino L, Chalasani N, Harrison SA (2010) Exenatide in the treatment of diabetic patients with non-alcoholic steatohepatitis: a case series. Am J Gastroenterol 105(12):2707–2709 Kohjima M, Higuchi N, Kato M, Kotoh K, Yoshimoto T, Fujino T, Yada M, Yada R, Harada N, Enjoji M, Takayanagi R, Nakamuta M (2008) SREBP-1c, regulated by the insulin and AMPK signaling pathways, plays a role in nonalcoholic fatty liver disease. Int J Mol Med 21(4):507–511 Liu F, Wang C, Zhang L, Xu Y, Jang L, Gu Y, Cao X, Zhao X, Ye J, Li Q (2014) Metformin prevents hepatic steatosis by regulating the expression of adipose differentiation-related protein. Int J Mol Med 33(1):51–58 Marchesini G, Brizi M, Bianchi G, Tomassetti S, Zoli M, Melchionda N (2001) Metformin in non-alcoholic steatohepatitis. Lancet 358(9285):893–894 Uygun A, Kadayifci A, Isik AT, Ozgurtas T, Deveci S, Tuzun A, Yesilova Z, Gulsen M, Dagalp K (2004) Metformin in the treatment of patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther 19(5):537–544 Nair S, Diehl AM, Wiseman M, Farr GH Jr, Perrillo RP (2004) Metformin in the treatment of non-alcoholic steatohepatitis: a pilot open label trial. Aliment Pharmacol Ther 20(1):23–28 Bugianesi E, Gentilcore E, Manini R, Natale S, Vanni E, Villanova N, David E, Rizzetto M, Marchesini G (2005) A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver disease. Am J Gastroenterol 100(5):1082–1090 Janiec DJ, Jacobson ER, Freeth A, Spaulding L, Blaszyk H (2005) Histologic variation of grade and stage of non-alcoholic fatty liver disease in liver biopsies. Obes Surg 15(4):497–501 Duseja A, Das A, Dhiman RK, Chawla YK, Thumburu KT, Bhadada S, Bhansali A (2007) Metformin is effective in achieving biochemical response in patients with nonalcoholic fatty liver disease (NAFLD) not responding to lifestyle interventions. Ann Hepatol 6(4):222–226 De Oliveira CP, Stefano JT, De Siqueira ER, Silva LS, De Campos Mazo DF, Lima VM, Furuya CK, Mello ES, Souza FG, Rabello F, Santos TE, Nogueira MA, Caldwell SH, Alves VA, Carrilho FJ (2008) Combination of N-acetylcysteine and metformin improves histological steatosis and fibrosis in patients with non-alcoholic steatohepatitis. Hepatol Res 38(2):159–165 Idilman R, Mizrak D, Corapcioglu D, Bektas M, Doganay B, Sayki M, Coban S, Erden E, Soykan I, Emral R, Uysal AR, Ozden A (2008) Clinical trial: insulin-sensitizing agents may reduce consequences of insulin resistance in individuals with non-alcoholic steatohepatitis. Aliment Pharmacol Ther 28(2):200–208 Loomba R, Lutchman G, Kleiner DE, Ricks M, Feld JJ, Borg BB, Modi A, Nagabhyru P, Sumner AE, Liang TJ, Hoofnagle JH (2009) Clinical trial: pilot study of metformin for the treatment of non-alcoholic steatohepatitis. Aliment Pharmacol Ther 29(2):172–182 Garinis GA, Fruci B, Mazza A, De Siena M, Abenavoli S, Gulletta E, Ventura V, Greco M, Abenavoli L, Belfiore A (2010) Metformin versus dietary treatment in nonalcoholic hepatic steatosis: a randomized study. Int J Obes (Lond) 34(8):1255–1264 Haukeland JW, Konopski Z, Eggesbø HB, von Volkmann HL, Raschpichler G, Bjøro K, Haaland T, Løberg EM, Birkeland K (2009) Metformin in patients with non-alcoholic fatty liver disease: a randomized, controlled trial. Scand J Gastroenterol 44(7):853–860 Omer Z, Cetinkalp S, Akyildiz M, Yilmaz F, Batur Y, Yilmaz C, Akarca U (2010) Efficacy of insulin-sensitizing agents in nonalcoholic fatty liver disease. Eur J Gastroenterol Hepatol 22(1):18–23 Nar A, Gedik O (2009) The effect of metformin on leptin in obese patients with type 2 diabetes mellitus and nonalcoholic fatty liver disease. Acta Diabetol 46(2):113–118 Shields WW, Thompson KE, Grice GA, Harrison SA, Coyle WJ (2009) The effect of metformin and standard therapy versus standard therapy alone in nondiabetic patients with insulin resistance and nonalcoholic steatohepatitis (NASH): a pilot trial. Therap Adv Gastroenterol 2(3):157–163 Lavine JE, Schwimmer JB, Molleston JP, Scheimann AO, Murray KF, Abrams SH, Rosenthal P, Sanyal AJ, Robuck PR, Brunt EM, Unalp A, Tonascia J, Nonalcoholic Steatohepatitis Clinical Research Network Research Group (2010) Treatment of nonalcoholic fatty liver disease in children: TONIC trial design. Contemp Clin Trials 31(1):62–70 Younossi ZM, Reyes MJ, Mishra A, Mehta R, Henry L (2014) Systematic review with meta-analysis: non-alcoholic steatohepatitis—a case for personalised treatment based on pathogenic targets. Aliment Pharmacol Ther 39(1):3–14 Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, Charlton M, Sanyal AJ (2012) The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology 55(6):2005–2023 Boettcher E, Csako G, Pucino F, Wesley R, Loomba R (2012) Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther 35(1):66–75 Wang CH, Leung CH, Liu SC, Chung CH (2006) Safety and effectiveness of rosiglitazone in type 2 diabetes patients with nonalcoholic fatty liver disease. J Formos Med Assoc 105(9):743–752 Akyüz F, Demir K, Ozdil S, Aksoy N, Poturoğlu S, Ibrişim D, Kaymakoğlu S, Beşişik F, Boztaş G, Cakaloğlu Y, Mungan Z, Cevikbaş U, Okten A (2007) The effects of rosiglitazone, metformin, and diet with exercise in nonalcoholic fatty liver disease. Dig Dis Sci 52(9):2359–2367 Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, Balas B, Gastaldelli A, Tio F, Pulcini J, Berria R, Ma JZ, Dwivedi S, Havranek R, Fincke C, DeFronzo R, Bannayan GA, Schenker S, Cusi K (2006) A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 355(22):2297–2307 Aithal GP, Thomas JA, Kaye PV, Lawson A, Ryder SD, Spendlove I, Austin AS, Freeman JG, Morgan L, Webber J (2008) Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology 135(4):1176–1184 Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, Ferrell LD, Liu YC, Torbenson MS, Unalp-Arida A, Yeh M, McCullough AJ, Sanyal AJ, Nonalcoholic Steatohepatitis Clinical Research Network (2005) Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 41(6):1313–1321 Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, Neuschwander-Tetri BA, Lavine JE, Tonascia J, Unalp A, Van Natta M, Clark J, Brunt EM, Kleiner DE, Hoofnagle JH, Robuck PR, NASH CRN (2010) Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 362(18):1675–1685 Dohahue S, Marathe P, Guld T., Meeker J. (2002) The pharmacokinetics and pharmacodynamics of extended-release metformin tablets vs immediate-release metformin in subjects with Type 2 diabetes. Diabetes 51 (suppl. 2): A468 Pala L, Rotella CM (2014) The slower the better. JEI 37:497–498 Wilson DM, Abrams SH, Aye T, Lee PD, Lenders C, Lustig RH, Osganian SV, Feldman HA, Glaser Pediatric Research Network Obesity Study Group (2010) Metformin extended release treatment of adolescent obesity: a 48-week randomized, double-blind, placebo-controlled trial with 48-week follow-up. Arch Pediatr Adolesc Med. 164(2):116–123