Metformin reverses fatty liver disease in obese, leptin-deficient mice

Lin, Hui-Kuan; Yang, Shi Qi; Chuckaree, Christine; Kuhajda, Francis P.; Ronnet, Gabriele; Diehl, Anna Mae

doi:10.1038/79697

Cited by 625 publications

(473 citation statements)

References 42 publications

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“…89 It has been shown that metformin reverses fatty liver disease in obese, leptin-deficient mice. 90 In 20 patients with NASH, 4 months of metformin treatment led to a reduction in serum transaminase (which were normalized in 50% of cases) and liver volume compared with no changes in non-compliant patients. 91 Clearly, a randomized controlled trial is urgently required to confirm these results.…”

Section: Drugs Improving Insulin Sensitivitymentioning

confidence: 97%

Obesity and liver disease

Scheen

Luyckx

2002

Best Practice & Research Clinical Endocrinology & Metab

119

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Non-alcoholic steatohepatitis (NASH) is a disease of emerging identity and importance. It is frequently associated with obesity, especially visceral fat, and is intimately related to fatty liver and markers of the insulin resistance syndrome. Both the prevalence and the severity of liver steatosis are related to body mass index, waist circumference, hyperinsulinaemia, hypertriglyceridaemia and impaired glucose tolerance or type 2 diabetes. The identification of obese patients who may progress from steatosis to NASH and from NASH to fibrosis/cirrhosis is an important clinical challenge. Substantial weight loss is accompanied by a marked attenuation of insulin resistance and related metabolic syndrome and, concomitantly, by a remarkable regression of liver steatosis in most patients, although increased inflammation may be detected in some subjects. Thus, NASH may be considered as another disease of affluence, as is the insulin resistance syndrome, and perhaps being part of it, especially in obese patients.

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Section: Drugs Improving Insulin Sensitivitymentioning

confidence: 97%

Obesity and liver disease

Scheen

Luyckx

2002

Best Practice & Research Clinical Endocrinology & Metab

119

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“…Metformin reduces fatty acid oxidation and stimulates aerobic metabolism and lactate production in preadipocytes. 4 In Ob/Ob mice, it increased relative expenditure of energy associated with decreased expression of uncoupling protein 2 (UCP-2) in hepatic tissue 5 resulting in reduced steatosis, aminotransferases, and hepatic tumor necrosis factor alpha (TNF-a) expression and improvement in IS. Metformin appears to be safe, with a single case report of acute hepatitis in a diabetic patient and no cases of lactic acidosis in NASH.…”

Section: Mode Of Actionmentioning

confidence: 99%

Therapeutic trials in nonalcoholic steatohepatitis: Insulin sensitizers and related methodological issues

2010

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Insulin sensitizers are attractive candidate therapies for nonalcoholic steatohepatitis mainly because of the strong association between this disease and insulin resistance. This review provides a critical overview of the mechanisms of action, clinical trial results, and safety issues of metformin and glitazones in nonalcoholic steatohepatitis. It also highlights methodological challenges for trial design and proposes endpoints for future proof of principle, registrational, and postmarketing trials. (HEPATOLOGY 2010;52:2206-2215 N onalcoholic steatohepatitis (NASH) is emerging as the next big therapeutic challenge in hepatology. 1 Currently the top cause of newly identified chronic liver diseases, NASH has potential for fibrosis, cirrhosis decompensation, and hepatocellular carcinoma. Not all individuals with metabolic risk factors will experience these adverse outcomes and identifying those at risk is critical. Prognostic markers for progression have mostly been derived from histological studies. Compared to steatosis alone or to steatosis and minimal inflammation, the coexistence of inflammation, cell injury (ballooning), and steatosis, a pathological aggregate labeled steatohepatitis, is associated with a significant increase in overall mortality and in liver-related mortality. The degree of inflammation is the best predictor of fibrosis progression, 2 a widely accepted surrogate for hard endpoints such as cirrhosis, endstage liver disease, and possibly hepatocellular carcinoma.Insulin resistance (IR) is consistently found in patients with NASH in both cross-sectional and longitudinal studies. Moreover, there is a stepwise increase in the severity of IR and its phenotypic complications (clustered as elements of the metabolic syndrome) between normal liver, isolated steatosis, and steatohepatitis that has prompted speculation that IR might contribute to liver damage. Logically, most therapeutic trials focused on insulin sensitizers (IS) as candidate therapies.The aim of this report is to critically review the results of trials of metformin and glitazones for NASH. We highlight methodological challenges for trial design and propose endpoints for future proof of principle, registrational, and postmarketing trials.

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“…The biguanide, metformin, reduces hyperinsulinemia and improves hepatic insulin resistance. 79 It is beneficial in animal models of NASH, 79 but initial open-label studies in humans suggested only transient improvements in serum liver enzymes. 80 In two recent small randomized trials of non-diabetic patients with NAFLD, metformin treatment significantly improved serum aminotransferases compared to treatment with calorie and lipid restricted diets, 81 or vitamin E, 82 but in only one study did metformin significantly decrease liver fat, necro-inflammation and fibrosis.…”

Section: Diagnosing Fatty Livermentioning

confidence: 99%