Of mice and men: Is there a future for metformin in the treatment of hepatic steatosis?

Abstract

Funding information LH is a BHF Senior Research Fellow in BasicScience. There is no project grant funding associated with this review.Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver diseases, of which the first stage is steatosis. It is one of the most common liver diseases in developed countries and there is a clear association between type 2 diabetes (T2DM) and NAFLD. It is estimated that 70% of people with T2DM have NAFLD and yet there is currently no licensed pharmacological agent to treat it. Whilst lifestyle modification may ameliorate liver fat, it is often difficult to achieve or sustain; thus, there is great interest in pharmacological treatments for NAFLD. Metformin is the first-line medication in the management of T2DM and evidence from animal and human studies has suggested that it may be useful in reducing liver fat via inhibition of lipogenesis and increased fatty acid oxidation. Findings from the majority of studies undertaken in rodent models clearly suggest that metformin may be a powerful therapeutic agent specifically to reduce liver fat accumulation; data from human studies are less convincing. In the present review we discuss the evidence for the specific effects of metformin treatment on liver fat accumulation in animal and human studies, as well as the underlying proposed mechanisms, to try and understand and reconcile the difference in findings between rodent and human work in this area. K E Y W O R D Santi-diabetic drug, fatty, drug mechanism, glucose metabolism, insulin resistance, liver

The regulation of hepatic fatty acid synthesis and partitioning: the effect of nutritional state

“…As individuals with T2DM typically have IHTAG accumulation, several studies have investigated the therapeutic effects of pharmacological agents and their effect on IHTAG content 157 . Briefly, these studies report that insulin-sensitising agents, including metformin and sulphonylureas, do not seem to decrease IHTAG content in humans, in contrast to the effects of metformin on reducing IHTAG levels in rodents 158 . Thiazolidinediones, which are selective ligands of the PPARs (of which there are α, β/δ and γ forms), seems to decrease IHTAG content 157 .…”

l-Carnitine counteracts in vitro fructose-induced hepatic steatosis through targeting oxidative stress markers

“…Furthermore, based on the closed correlation between excessive fructose intake, insulin resistance, and NAFLD, several studies indicated that metformin, an AMPK activator, might have therapeutic potential on liver steatosis [30]. Moreover, data obtained by increasing number of works suggest how SGLT2 inhibitors are an attractive option for NAFLD pharmacologic management [31].…”

Rationale and design of a randomised controlled trial testing the effect of personalised diet in individuals with pre-diabetes or type 2 diabetes mellitus treated with metformin

“…Metformin primarily targets the liver, inhibiting lipogenesis and increasing fatty acid oxidation; therefore, a beneficial effect on liver lipid and fibrosis with metformin has been assumed. 33 However, comprehensive meta-analyses of randomised clinical trials concluded that reduction in both steatosis and fibrosis with metformin were underwhelming. 34 35 Liver fibroscan measure is repeated after 6 months of treatment.…”