Metformin and metabolic diseases: a focus on hepatic aspects

Frontiers of Medicine

Volumn 9, Issue 2, 2015, Pages 173-186

  Zheng, Juan ^a,b   Woo, Shih Lung ^a   Hu, Xiang ^a,b   Botchlett, Rachel ^a   Chen, Lulu ^b   Huo, Yuqing ^c   Wu, Chaodong ^a  

^a TEXAS A AND M UNIVERSITY   (United States)

^b HUAZHONG UNIVERSITY OF SCIENCE AND TECHNOLOGY   (China)

^c PEKING UNIVERSITY   (China)

Author keywords

diabetes; hepatic steatosis; inflammatory response; insulin resistance; metformin

Indexed keywords

ANTIDIABETIC AGENT; METFORMIN;

DRUG EFFECTS; HUMAN; LIVER; METABOLIC DISEASES; PATHOPHYSIOLOGY;

HUMANS; HYPOGLYCEMIC AGENTS; LIVER; METABOLIC DISEASES; METFORMIN;

EID: 84974632986     PISSN: 20950217     EISSN: 20950225     Source Type: Journal    
DOI: 10.1007/s11684-015-0384-0     Document Type: Review

References (151)

1. Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, Peters AL, Tsapas A, Wender R, Matthews DR. Management of hyperglycaemia in type 2 diabetes: a patientcentered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2012; 55(6): 1577–1596
2. Mazza A, Fruci B, Garinis GA, Giuliano S, Malaguarnera R, Belfiore A. The role of metformin in the management of NAFLD. Exp Diabetes Res 2012; 2012: 716404
3. Cahova M, Drahota Z, Oliarnyk O, Cervinkova Z, Kucera O, Dankova H, Kazdova L. The effect of metformin on liver mitochondria and lipid metabolism in NAFLD. Diabetologia 2010; 53(Suppl 1): S304
4. Valsamakis G, Lois K, Kumar S, Mastorakos G. Metabolic and other effects of pioglitazone as an add-on therapy to metformin in the treatment of polycystic ovary syndrome (PCOS). Hormones (Athens) 2013; 12(3): 363–378
5. Chen S, Zhou J, Xi M, Jia Y, Wong Y, Zhao J, Ding L, Zhang J, Wen A. Pharmacogenetic variation and metformin response. Curr Drug Metab 2013; 14(10): 1070–1082
6. Nies AT, Koepsell H, Damme K, Schwab M. Organic cation transporters (OCTs, MATEs), in vitro and in vivo evidence for the importance in drug therapy. Handbook Exp Pharmacol 2011; 201(201): 105–167
7. Takane H, Shikata E, Otsubo K, Higuchi S, Ieiri I. Polymorphism in human organic cation transporters and metformin action. Pharmacogenomics 2008; 9(4): 415–422
8. Graham GG, Punt J, Arora M, Day RO, Doogue MP, Duong JK, Furlong TJ, Greenfield JR, Greenup LC, Kirkpatrick CM, Ray JE, Timmins P, Williams KM. Clinical pharmacokinetics of metformin. Clin Pharmacokinet 2011; 50(2): 81–98
9. Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 2001; 108(8): 1167–1174
10. Paneni F. 2013 ESC/EASD guidelines on the management of diabetes and cardiovascular disease: established knowledge and evidence gaps. Diab Vasc Dis Res 2014; 11(1): 5–10
11. Adler AI, Shaw EJ, Stokes T, Ruiz F, Guideline Development G. Newer agents for blood glucose control in type 2 diabetes: summary of NICE guidance. BMJ 2009; 338: b1668
12. Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, Zinman B; 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 2009; 32(1): 193–203
13. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998; 352(9131): 854–865
14. Calvert JW, Gundewar S, Jha S, Greer JJ, Bestermann WH, Tian R, Lefer DJ. Acute metformin therapy confers cardioprotection against myocardial infarction via AMPK-eNOS-mediated signaling. Diabetes 2008; 57(3): 696–705
15. Paiva M, Riksen NP, Davidson SM, Hausenloy DJ, Monteiro P, Gonçalves L, Providência L, Rongen GA, Smits P, Mocanu MM, Yellon DM. Metformin prevents myocardial reperfusion injury by activating the adenosine receptor. J Cardiovasc Pharmacol 2009; 53(5): 373–378
16. Rena G, Pearson ER, Sakamoto K. Molecular mechanism of action of metformin: old or new insights? Diabetologia 2013; 56(9): 1898–1906
17. Chu CA, Wiernsperger N, Muscato N, Knauf M, Neal DW, Cherrington AD. The acute effect of metformin on glucose production in the conscious dog is primarily attributable to inhibition of glycogenolysis. Metabolism 2000; 49(12): 1619–1626
18. Silva FMD, da Silva MHRA, Bracht A, Eller GJ, Constantin RP, Yamamoto NS. Effects of metformin on glucose metabolism of perfused rat livers. Mol Cell Biochem 2010; 340(1–2): 283–289
19. Heishi M, Ichihara J, Teramoto R, Itakura Y, Hayashi K, Ishikawa H, Gomi H, Sakai J, Kanaoka M, Taiji M, Kimura T. Global gene expression analysis in liver of obese diabetic db/db mice treated with metformin. Diabetologia 2006; 49(7): 1647–1655
20. He L, Sabet A, Djedjos S, Miller R, Sun X, Hussain MA, Radovick S, Wondisford FE. Metformin and insulin suppress hepatic gluconeogenesis through phosphorylation of CREB binding protein. Cell 2009; 137(4): 635–646
21. Da Silva D, Zancan P, Coelho WS, Gomez LS, Sola-Penna M. Metformin reverses hexokinase and 6-phosphofructo-1-kinase inhibition in skeletal muscle, liver and adipose tissues from streptozotocin-induced diabetic mouse. Arch Biochem Biophys 2010; 496(1): 53–60
22. Lage R, Diéguez C, Vidal-Puig A, López M. AMPK: a metabolic gauge regulating whole-body energy homeostasis. Trends Mol Med 2008; 14(12): 539–549
23. Shaw RJ, Lamia KA, Vasquez D, Koo SH, Bardeesy N, Depinho RA, Montminy M, Cantley LC. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 2005; 310(5754): 1642–1646
24. Foretz M, Hébrard S, Leclerc J, Zarrinpashneh E, Soty M, Mithieux G, Sakamoto K, Andreelli F, Viollet B. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest 2010; 120(7): 2355–2369
25. Hardie DG. Neither LKB1 nor AMPK are the direct targets of metformin. Gastroenterology 2006; 131(3): 973, author reply 974–975
26. Emami Riedmaier A, Fisel P, Nies AT, Schaeffeler E, Schwab M. Metformin and cancer: from the old medicine cabinet to pharmacological pitfalls and prospects. Trends Pharmacol Sci 2013; 34(2): 126–135
27. Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J 2000; 348(Pt 3): 607–614
28. Ebert BL, Firth JD, Ratcliffe PJ. Hypoxia and mitochondrial inhibitors regulate expression of glucose transporter-1 via distinct Cis-acting sequences. J Biol Chem 1995; 270(49): 29083–29089
29. Guigas B, Bertrand L, Taleux N, Foretz M, Wiernsperger N, Vertommen D, Andreelli F, Viollet B, Hue L. 5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside and metformin inhibit hepatic glucose phosphorylation by an AMP-activated protein kinaseindependent effect on glucokinase translocation. Diabetes 2006; 55(4): 865–874
30. Foretz M, Viollet B. Regulation of hepatic metabolism by AMPK. J Hepatol 2011; 54(4): 827–829
31. Luo Q, Hu D, Hu S, Yan M, Sun Z, Chen F. In vitro and in vivo anti-tumor effect of metformin as a novel therapeutic agent in human oral squamous cell carcinoma. BMC Cancer 2012; 12(1): 517
32. Zhang J, Gao Z, Yin J, Quon MJ, Ye J. S6K directly phosphorylates IRS-1 on Ser-270 to promote insulin resistance in response to TNF-α signaling through IKK2. J Biol Chem 2008; 283(51): 35375–35382
33. Ouyang J, Parakhia RA, Ochs RS. Metformin activates AMP kinase through inhibition of AMP deaminase. J Biol Chem 2011; 286(1): 1–11
34. Miller RA, Chu Q, Xie J, Foretz M, Viollet B, Birnbaum MJ. Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature 2013; 494(7436): 256–260
35. Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F. Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond) 2012; 122(6): 253–270
36. Pavlović D, Kocić R, Kocić G, Jevtović T, Radenković S, Mikić D, Stojanović M, Djordjević PB. Effect of four-week metformin treatment on plasma and erythrocyte antioxidative defense enzymes in newly diagnosed obese patients with type 2 diabetes. Diabetes Obes Metab 2000; 2(4): 251–256
37. Esteghamati A, Eskandari D, Mirmiranpour H, Noshad S, Mousavizadeh M, Hedayati M, Nakhjavani M. Effects of metformin on markers of oxidative stress and antioxidant reserve in patients with newly diagnosed type 2 diabetes: a randomized clinical trial. Clin Nutr 2013; 32(2): 179–185
38. Bonnefont-Rousselot D, Raji B, Walrand S, Gardès-Albert M, Jore D, Legrand A, Peynet J, Vasson MP. An intracellular modulation of free radical production could contribute to the beneficial effects of metformin towards oxidative stress. Metabolism 2003; 52(5): 586–589
39. 2 emission without affecting respiratory capacity in skeletal muscle of obese rats. Free Radic Biol Med 2010; 49(6): 1082–1087
40. Martin-Montalvo A, Mercken EM, Mitchell SJ, Palacios HH, Mote PL, Scheibye-Knudsen M, Gomes AP, Ward TM, Minor RK, Blouin MJ, Schwab M, Pollak M, Zhang Y, Yu Y, Becker KG, Bohr VA, Ingram DK, Sinclair DA, Wolf NS, Spindler SR, Bernier M, de Cabo R. Metformin improves healthspan and lifespan in mice. Nat Commun 2013; 4: 2192
41. Nelson LE, Valentine RJ, Cacicedo JM, Gauthier MS, Ido Y, Ruderman NB. A novel inverse relationship between metformintriggered AMPK-SIRT1 signaling and p53 protein abundance in high glucose-exposed HepG2 cells. Am J Physiol Cell Physiol 2012; 303(1): C4–C13
42. Um JH, Yang S, Yamazaki S, Kang H, Viollet B, Foretz M, Chung JH. Activation of 5′-AMP-activated kinase with diabetes drug metformin induces casein kinase Iepsilon (CKIepsilon)-dependent degradation of clock protein mPer2. J Biol Chem 2007; 282(29): 20794–20798
43. Barnea M, Haviv L, Gutman R, Chapnik N, Madar Z, Froy O. Metformin affects the circadian clock and metabolic rhythms in a tissue-specific manner. Biochim Biophys Acta 2012; 1822(11): 1796–1806
44. Caton PW, Kieswich J, Yaqoob MM, Holness MJ, Sugden MC. Metformin opposes impaired AMPK and SIRT1 function and deleterious changes in core clock protein expression in white adipose tissue of genetically-obese db/db mice. Diabetes Obes Metab 2011; 13(12): 1097–1104
45. Liu HY, Han J, Cao SY, Hong T, Zhuo D, Shi J, Liu Z, Cao W. Hepatic autophagy is suppressed in the presence of insulin resistance and hyperinsulinemia: inhibition of FoxO1-dependent expression of key autophagy genes by insulin. J Biol Chem 2009; 284(45): 31484–31492
46. Noh BK, Lee JK, Jun HJ, Lee JH, Jia Y, Hoang MH, Kim JW, Park KH, Lee SJ. Restoration of autophagy by puerarin in ethanoltreated hepatocytes via the activation of AMP-activated protein kinase. Biochem Biophys Res Commun 2011; 414(2): 361–366
47. Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, Charlton M, Sanyal AJ. The diagnosis and management of nonalcoholic 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 2012; 55(6): 2005–2023
48. Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology 2010; 52(5): 1836–1846
49. Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther 2011; 34(3): 274–285
50. Wattacheril J, Chalasani N. Nonalcoholic fatty liver disease (NAFLD): is it really a serious condition? Hepatology 2012; 56(4): 1580–1584
51. Day CP, James OF. Steatohepatitis: a tale of two “hits”? Gastroenterology 1998; 114(4): 842–845
52. Browning JD, Horton JD. Molecular mediators of hepatic steatosis and liver injury. J Clin Invest 2004; 114(2): 147–152
53. Fabbrini E, Mohammed BS, Magkos F, Korenblat KM, Patterson BW, Klein S. Alterations in adipose tissue and hepatic lipid kinetics in obese men and women with nonalcoholic fatty liver disease. Gastroenterology 2008; 134(2): 424–431
54. Park EJ, Lee JH, Yu GY, He G, Ali SR, Holzer RG, Osterreicher CH, Takahashi H, Karin M. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 2010; 140(2): 197–208
55. Marchesini G, Bugianesi E, Forlani G, Cerrelli F, Lenzi M, Manini R, Natale S, Vanni E, Villanova N, Melchionda N, Rizzetto M. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 2003; 37(4): 917–923
56. Woo SL, Xu H, Li H, Zhao Y, Hu X, Zhao J, Guo X, Guo T, Botchlett R, Qi T, Pei Y, Zheng J, Xu Y, An X, Chen L, Chen L, Li Q, Xiao X, Huo Y, Wu C. Metformin ameliorates hepatic steatosis and inflammation without altering adipose phenotype in dietinduced obesity. PLoS ONE 2014; 9(3): e91111
57. Kita Y, Takamura T, Misu H, Ota T, Kurita S, Takeshita Y, Uno M, Matsuzawa-Nagata N, Kato K, Ando H, Fujimura A, Hayashi K, Kimura T, Ni Y, Otoda T, Miyamoto K, Zen Y, Nakanuma Y, Kaneko S. Metformin prevents and reverses inflammation in a nondiabetic mouse model of nonalcoholic steatohepatitis. PLoS ONE 2012; 7(9): e43056
58. Carlson CA, Kim KH. Regulation of hepatic acetyl coenzyme A carboxylase by phosphorylation and dephosphorylation. J Biol Chem 1973; 248(1): 378–380
59. Beg ZH, Allmann DW, Gibson DM. Modulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity with cAMP and wth protein fractions of rat liver cytosol. Biochem Biophys Res Commun 1973; 54(4): 1362–1369
60. Hardie DG. AMP-activated protein kinase: a key regulator of energy balance with many roles in human disease. J Intern Med 2014; 276(6): 543–559
61. Stumvoll M, Häring HU, Matthaei S. Metformin. Endocr Res 2007; 32(1–2): 39–57
62. Lin HZ, Yang SQ, Chuckaree C, Kuhajda F, Ronnet G, Diehl AM. Metformin reverses fatty liver disease in obese, leptin-deficient mice. Nat Med 2000; 6(9): 998–1003
63. Zang M, Zuccollo A, Hou X, Nagata D, Walsh K, Herscovitz H, Brecher P, Ruderman NB, Cohen RA. AMP-activated protein kinase is required for the lipid-lowering effect of metformin in insulin-resistant human HepG2 cells. J Biol Chem 2004; 279(46): 47898–47905
64. Li Y, Xu S, Mihaylova MM, Zheng B, Hou X, Jiang B, Park O, Luo Z, Lefai E, Shyy JY, Gao B, Wierzbicki M, Verbeuren TJ, Shaw RJ, Cohen RA, Zang M. AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice. Cell Metab 2011; 13(4): 376–388
65. Jia L, Vianna CR, Fukuda M, Berglund ED, Liu C, Tao C, Sun K, Liu T, Harper MJ, Lee CE, Lee S, Scherer PE, Elmquist JK. Hepatocyte Toll-like receptor 4 regulates obesity-induced inflammation and insulin resistance. Nat Commun 2014; 5: 3878
66. Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L, Lee J, Shoelson SE. Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-κB. Nat Med 2005; 11(2): 183–190
67. Guo X, Li H, Xu H, Halim V, Zhang W, Wang H, Ong KT, Woo SL, Walzem RL, Mashek DG, Dong H, Lu F, Wei L, Huo Y, Wu C. Palmitoleate induces hepatic steatosis but suppresses liver inflammatory response in mice. PLoS ONE 2012; 7(6): e39286
68. Huo Y, Guo X, Li H, Xu H, Halim V, Zhang W, Wang H, Fan YY, Ong KT, Woo SL, Chapkin RS, Mashek DG, Chen Y, Dong H, Lu F, Wei L, Wu C. Targeted overexpression of inducible 6- phosphofructo-2-kinase in adipose tissue increases fat deposition but protects against diet-induced insulin resistance and inflammatory responses. J Biol Chem 2012; 287(25): 21492–21500
69. Deng ZB, Liu Y, Liu C, Xiang X, Wang J, Cheng Z, Shah SV, Zhang S, Zhang L, Zhuang X, Michalek S, Grizzle WE, Zhang HG. Immature myeloid cells induced by a high-fat diet contribute to liver inflammation. Hepatology 2009; 50(5): 1412–1420
70. Dong Z, Wei H, Sun R, Tian Z. The roles of innate immune cells in liver injury and regeneration. Cell Mol Immunol 2007; 4(4): 241–252
71. Su GL. Lipopolysaccharides in liver injury: molecular mechanisms of Kupffer cell activation. Am J Physiol Gastrointest Liver Physiol 2002; 283(2): G256–G265
72. Fan J, Zhong L, Wang G, et al. The role of Kupffer cells in nonalcoholic steatohepatitis of rats chronically fed with high-fat diet. Chin J Hepatol (Zhonghua Gan Zang Bing Za Zhi) 2001; 9(1): 16–18 (in Chinese)
73. Rivera CA, Adegboyega P, van Rooijen N, Tagalicud A, Allman M, Wallace M. Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis. J Hepatol 2007; 47(4): 571–579
74. Salminen A, Hyttinen JM, Kaarniranta K. AMP-activated protein kinase inhibits NF-κB signaling and inflammation: impact on healthspan and lifespan. J Mol Med (Berl) 2011; 89(7): 667–676
75. El-Mir MY, Nogueira V, Fontaine E, Avéret N, Rigoulet M, Leverve X. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem 2000; 275(1): 223–228
76. Marchesini G, Brizi M, Bianchi G, Tomassetti S, Zoli M, Melchionda N. Metformin in non-alcoholic steatohepatitis. Lancet 2001; 358(9285): 893–894
77. Nair S, Diehl AM, Wiseman M, Farr GH Jr, Perrillo RP. Metformin in the treatment of non-alcoholic steatohepatitis: a pilot open label trial. Aliment Pharmacol Ther 2004; 20(1): 23–28
78. Uygun A, Kadayifci A, Isik AT, Ozgurtas T, Deveci S, Tuzun A, Yesilova Z, Gulsen M, Dagalp K. Metformin in the treatment of patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2004; 19(5): 537–544
79. Loomba R, Lutchman G, Kleiner DE, Ricks M, Feld JJ, Borg BB, Modi A, Nagabhyru P, Sumner AE, Liang TJ, Hoofnagle JH. Clinical trial: pilot study of metformin for the treatment of nonalcoholic steatohepatitis. Aliment Pharmacol Ther 2009; 29(2): 172–182
80. Bugianesi E, Gentilcore E, Manini R, Natale S, Vanni E, Villanova N, David E, Rizzetto M, Marchesini G. A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver disease. Am J Gastroenterol 2005; 100(5): 1082–1090
81. Duseja A, Das A, Dhiman RK, Chawla YK, Thumburu KT, Bhadada S, Bhansali A. Metformin is effective in achieving biochemical response in patients with nonalcoholic fatty liver disease (NAFLD) not responding to lifestyle interventions. Ann Hepatol 2007; 6(4): 222–226
82. de Oliveira CP, Stefano JT, de Siqueira ER, et al. Combination of N-acetylcysteine and metformin improves histological steatosis and fibrosis in patients with non-alcoholic steatohepatitis. Hepatol Res 2008; 38(2): 159–165
83. Haukeland JW, Konopski Z, Eggesbø HB, von Volkmann HL, Raschpichler G, Bjøro K, Haaland T, Løberg EM, Birkeland K. Metformin in patients with non-alcoholic fatty liver disease: a randomized, controlled trial. Scand J Gastroenterol 2009; 44(7): 853–860
84. Garinis GA, Fruci B, Mazza A, De Siena M, Abenavoli S, Gulletta E, Ventura V, Greco M, Abenavoli L, Belfiore A. Metformin versus dietary treatment in nonalcoholic hepatic steatosis: a randomized study. Int J Obes (Lond) 2010; 34(8): 1255–1264
85. Shargorodsky M, Omelchenko E, Matas Z, Boaz M, Gavish D. Relation between augmentation index and adiponectin during oneyear metformin treatment for nonalcoholic steatohepatosis: effects beyond glucose lowering? Cardiovasc Diabetol 2012; 11(1): 61
86. Han Y, Shi JP, Ma AL, Xu Y, Ding XD, Fan JG. Randomized, vitamin E-controlled trial of bicyclol plus metformin in nonalcoholic fatty liver disease patients with impaired fasting glucose. Clin Drug Investig 2014; 34(1): 1–7
87. Li Y, Liu L, Wang B, Wang J, Chen D. Metformin in non-alcoholic fatty liver disease: a systematic review and meta-analysis. Biomedical reports 2013; 1(1): 57–64
88. Rakoski MO, Singal AG, Rogers MA, Conjeevaram H. Metaanalysis: insulin sensitizers for the treatment of non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2010; 32(10): 1211–1221
89. Musso G, Gambino R, Cassader M, Pagano G. A meta-analysis of randomized trials for the treatment of nonalcoholic fatty liver disease. Hepatology 2010; 52(1): 79–104
90. Musso G, Cassader M, Rosina F, Gambino R. Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of randomised trials. Diabetologia 2012; 55(4): 885–904
91. Kaul S, Bolger AF, Herrington D, Giugliano RP, Eckel RH. Thiazolidinedione drugs and cardiovascular risks: a science advisory from the American Heart Association and American College of Cardiology Foundation. Circulation 2010; 121(16): 1868–1877
92. Hofmann CA, Colca JR. New oral thiazolidinedione antidiabetic agents act as insulin sensitizers. Diabetes Care 1992; 15(8): 1075–1078
93. Masoudi FA, Wang Y, Inzucchi SE, Setaro JF, Havranek EP, Foody JM, Krumholz HM. Metformin and thiazolidinedione use in Medicare patients with heart failure. JAMA 2003; 290(1): 81–85
94. Sinha B, Ghosal S. Pioglitazone—do we really need it to manage type 2 diabetes? Diabetes Metab Syndr 2013; 7(1): 52–55
95. Buckingham RE, Hanna A. Thiazolidinedione insulin sensitizers and the heart: a tale of two organs? Diabetes Obes Metab 2008; 10(4): 312–328
96. Lebovitz HE. Differentiating members of the thiazolidinedione class: a focus on safety. Diabetes Metab Res Rev 2002; 18(S2 Suppl 2): S23–S29
97. Pouwels KB, van Grootheest K. The rosiglitazone decision process at FDA and EMA. What should we learn? Int J Risk Saf Med 2012; 24(2): 73–80
98. Sadikot SM, Ghosal S. India suspends pioglitazone: is it justified? Diabetes Metab Syndr 2014; 8(1): 53–56
99. Yau H, Rivera K, Lomonaco R, Cusi K. The future of thiazolidinedione therapy in the management of type 2 diabetes mellitus. Curr Diab Rep 2013; 13(3): 329–341
100. Kung J, Henry RR. Thiazolidinedione safety. Expert Opin Drug Saf 2012; 11(4): 565–579
101. Shaw RJ. Metformin trims fats to restore insulin sensitivity. Nat Med 2013; 19(12): 1570–1572
102. Diabetes Prevention Program Research Group. Long-term safety, tolerability, and weight loss associated with metformin in the Diabetes Prevention Program Outcomes Study. Diabetes Care 2012; 35(4): 731–737
103. Reitman ML, Schadt EE. Pharmacogenetics of metformin response: a step in the path toward personalized medicine. J Clin Invest 2007; 117(5): 1226–1229
104. Lautatzis ME, Goulis DG, Vrontakis M. Efficacy and safety of metformin during pregnancy in women with gestational diabetes mellitus or polycystic ovary syndrome: a systematic review. Metabolism 2013; 62(11): 1522–1534
105. Ekström N, Schiöler L, Svensson AM, Eeg-Olofsson K, Miao Jonasson J, Zethelius B, Cederholm J, Eliasson B, Gudbjörnsdottir S. Effectiveness and safety of metformin in 51 675 patients with type 2 diabetes and different levels of renal function: a cohort study from the Swedish National Diabetes Register. BMJ Open 2012; 2(4): e001076
106. Spinozzi S, Colliva C, Camborata C, Roberti M, Ianni C, Neri F, Calvarese C, Lisotti A, Mazzella G, Roda A. Berberine and its metabolites: relationship between physicochemical properties and plasma levels after administration to human subjects. J Nat Prod 2014; 77(4): 766–772
107. Liu Y, Zhang L, Song H, Ji G. Update on berberine in nonalcoholic Fatty liver disease. Evid Based Complement Alternat Med 2013; 2013: 308134
108. Affuso F, Mercurio V, Fazio V, Fazio S. Cardiovascular and metabolic effects of berberine. World J Cardiol 2010; 2(4): 71–77
109. Hu Y, Young AJ, Ehli EA, Nowotny D, Davies PS, Droke EA, Soundy TJ, Davies GE. Metformin and berberine prevent olanzapine-induced weight gain in rats. PLoS ONE 2014; 9(3): e93310
110. Chang W, Zhang M, Li J, Meng Z, Wei S, Du H, Chen L, Hatch GM. Berberine improves insulin resistance in cardiomyocytes via activation of 5∟-adenosine monophosphate-activated protein kinase. Metabolism 2013; 62(8): 1159–1167
111. Chen Y, Li Y, Wang Y, Wen Y, Sun C. Berberine improves freefatty-acid-induced insulin resistance in L6 myotubes through inhibiting peroxisome proliferator-activated receptor Γ and fatty acid transferase expressions. Metabolism 2009; 58(12): 1694–1702
112. Kong WJ, Zhang H, Song DQ, Xue R, Zhao W, Wei J, Wang YM, Shan N, Zhou ZX, Yang P, You XF, Li ZR, Si SY, Zhao LX, Pan HN, Jiang JD. Berberine reduces insulin resistance through protein kinase C-dependent up-regulation of insulin receptor expression. Metabolism 2009; 58(1): 109–119
113. Shan CY, Yang JH, Kong Y, Wang XY, Zheng MY, Xu YG, Wang Y, Ren HZ, Chang BC, Chen LM. Alteration of the intestinal barrier and GLP2 secretion in berberine-treated type 2 diabetic rats. J Endocrinol 2013; 218(3): 255–262
114. Li Z, Geng YN, Jiang JD, Kong WJ. Antioxidant and antiinflammatory activities of berberine in the treatment of diabetes mellitus. Evid Based Complement Alternat Med 2014; 2014: 289264
115. Zhang H, Wei J, Xue R, Wu JD, Zhao W, Wang ZZ, Wang SK, Zhou ZX, Song DQ, Wang YM, Pan HN, Kong WJ, Jiang JD. Berberine lowers blood glucose in type 2 diabetes mellitus patients through increasing insulin receptor expression. Metabolism 2010; 59(2): 285–292
116. Han J, Lin H, Huang W. Modulating gut microbiota as an antidiabetic mechanism of berberine. Med Sci Monit 2011; 17(7): RA164–RA167
117. Dong H, Wang N, Zhao L, Lu F. Berberine in the treatment of type 2 diabetes mellitus: a systemic review and meta-analysis. Evid Based Complement Alternat Med 2012; 2012: 591654
118. Tillhon M, Guamán Ortiz LM, Lombardi P, Scovassi AI. Berberine: new perspectives for old remedies. Biochem Pharmacol 2012; 84(10): 1260–1267
119. Xia X, Yan J, Shen Y, Tang K, Yin J, Zhang Y, Yang D, Liang H, Ye J, Weng J. Berberine improves glucose metabolism in diabetic rats by inhibition of hepatic gluconeogenesis. PLoS ONE 2011; 6(2): e16556
120. Yin J, Gao Z, Liu D, Liu Z, Ye J. Berberine improves glucose metabolism through induction of glycolysis. Am J Physiol Endocrinol Metab 2008; 294(1): E148–E156
121. Turner N, Li JY, Gosby A, To SW, Cheng Z, Miyoshi H, Taketo MM, Cooney GJ, Kraegen EW, James DE, Hu LH, Li J, Ye JM. Berberine and its more biologically available derivative, dihydroberberine, inhibit mitochondrial respiratory complex I: a mechanism for the action of berberine to activate AMP-activated protein kinase and improve insulin action. Diabetes 2008; 57(5): 1414–1418
122. Witters LA. The blooming of the French lilac. J Clin Invest 2001; 108(8): 1105–1107
123. Ma RC. Acarbose: an alternative to metformin for first-line treatment in type 2 diabetes? Lancet Diabetes Endocrinol 2014; 2(1): 6–7
124. Holman R. Metformin as first choice in oral diabetes treatment: the UKPDS experience. Journ Annu Diabetol Hotel Dieu 2007; 2007: 13–20
125. Prutsky G, Domecq JP, Tsapas A. Insulin secretagogues were associated with increased mortality compared with metformin in type 2 diabetes. Ann Intern Med 2012; 156(2): JC1–JC7
126. Vecchio S, Giampreti A, Petrolini VM, Lonati D, Protti A, Papa P, Rognoni C, Valli A, Rocchi L, Rolandi L, Manzo L, Locatelli CA. Metformin accumulation: lactic acidosis and high plasmatic metformin levels in a retrospective case series of 66 patients on chronic therapy. Clin Toxicol (Phila) 2014; 52(2): 129–135
127. Lin KD, Lin JD, Juang JH. Metformin-induced hemolysis with jaundice. N Engl J Med 1998; 339(25): 1860–1861
128. Babich MM, Pike I, Shiffman ML. Metformin-induced acute hepatitis. Am J Med 1998; 104(5): 490–492
129. Saadi T, Waterman M, Yassin H, Baruch Y. Metformin-induced mixed hepatocellular and cholestatic hepatic injury: case report and literature review. Int J Gen Med 2013; 6: 703–706
130. Miralles-Linares F, Puerta-Fernandez S, Bernal-Lopez MR, Tinahones FJ, Andrade RJ, Gomez-Huelgas R. Metformininduced hepatotoxicity. Diabetes Care 2012; 35(3): e21
131. Kutoh E. Possible metformin-induced hepatotoxicity. Am J Geriatr Pharmacother 2005; 3(4): 270–273
132. Aksay E, Yanturali S, Bayram B, Hocaoglu N, Kiyan S. A rare side effect of metformin: metformin-induced hepatotoxicity. Turk J Med Sci 2007; 37(3): 173–175
133. Holstein A, Egberts EH. Currently listed contraindications to the use of metformin — more harmful than beneficial? Deut Med Wochenschr 2006; 131(3): 105–110
134. Harris K, Smith L. Safety and efficacy of metformin in patients with type 2 diabetes mellitus and chronic hepatitis C. Ann Pharmacother 2013; 47(10): 1348–1352
135. Xun YH, Zhang YJ, Pan QC, Mao RC, Qin YL, Liu HY, Zhang YM, Yu YS, Tang ZH, Lu MJ, Zang GQ, Zhang JM. Metformin inhibits hepatitis B virus protein production and replication in human hepatoma cells. J Viral Hepat 2014; 21(8): 597–603
136. Donadon V, Balbi M, Mas MD, Casarin P, Zanette G. Metformin and reduced risk of hepatocellular carcinoma in diabetic patients with chronic liver disease. Liver Int 2010; 30(5): 750–758
137. Bhalla K, Hwang BJ, Dewi RE, Twaddel W, Goloubeva OG, Wong KK, Saxena NK, Biswal S, Girnun GD. Metformin prevents liver tumorigenesis by inhibiting pathways driving hepatic lipogenesis. Cancer Prev Res (Phila) 2012; 5(4): 544–552
138. DeCensi A, Puntoni M, Goodwin P, Cazzaniga M, Gennari A, Bonanni B, Gandini S. Metformin and cancer risk in diabetic patients: a systematic review and meta-analysis. Cancer Prev Res (Phila) 2010; 3(11): 1451–1461
139. Huang X, Wullschleger S, Shpiro N, McGuire VA, Sakamoto K, Woods YL, McBurnie W, Fleming S, Alessi DR. Important role of the LKB1-AMPK pathway in suppressing tumorigenesis in PTENdeficient mice. Biochem J 2008; 412(2): 211–221
140. Buzzai M, Jones RG, Amaravadi RK, Lum JJ, DeBerardinis RJ, Zhao F, Viollet B, Thompson CB. Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res 2007; 67(14): 6745–6752
141. Jalling O, Olsen C. The effects of metformin compared to the effects of phenformin on the lactate production and the metabolism of isolated parenchymal rat liver cell. Acta Pharmacol Toxicol (Copenh) 1984; 54(5): 327–332
142. Chang CT, Chen YC, Fang JT, Huang CC. Metformin-associated lactic acidosis: case reports and literature review. J Nephrol 2002; 15(4): 398–402
143. Rojas LB, Gomes MB. Metformin: an old but still the best treatment for type 2 diabetes. Diabetol Metab Syndr 2013; 5(1): 6
144. Cusi K, Consoli A, DeFronzo RA. Metabolic effects of metformin on glucose and lactate metabolism in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1996; 81(11): 4059–4067
145. Salpeter SR, Greyber E, Pasternak GA, Salpeter EE. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus: systematic review and meta-analysis. Arch Intern Med 2003; 163(21): 2594–2602
146. Kadayifci A. Nonalcoholic steatohepatitis: role of leptin in pathogenesis and benefits of metformin in treatment. Am J Gastroenterol 2003; 98(10): 2330
147. Salpeter SR, Greyber E, Pasternak GA, Salpeter EE. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev 2010; (4): CD002967
148. Brackett CC. Clarifying metformin’s role and risks in liver dysfunction. J Am Pharm Assoc (2003) 2010; 50(3): 407–410
149. Chitturi S, George J. Hepatotoxicity of commonly used drugs: nonsteroidal anti-inflammatory drugs, antihypertensives, antidiabetic agents, anticonvulsants, lipid-lowering agents, psychotropic drugs. Semin Liver Dis 2002; 22(2): 169–183
150. Edwards CMB, Barton MA, Snook J, David M, Mak VHF, Chowdhury TA. Metformin-associated lactic acidosis in a patient with liver disease. QJM 2003; 96(4): 315–316
151. Møller S, Hillingsø J, Christensen E, Henriksen JH. Arterial hypoxaemia in cirrhosis: fact or fiction?. Gut 1998; 42(6): 868–874