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Review
, 2012, 716404

The Role of Metformin in the Management of NAFLD

Affiliations
Review

The Role of Metformin in the Management of NAFLD

Angela Mazza et al. Exp Diabetes Res.

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disorder worldwide. Its prevalence ranges 10-24% in the general population, reaching 60-95% and 28-55% in obese and diabetic patients, respectively. Although the etiology of NAFLD is still unclear, several lines of evidences have indicated a pathogenetic role of insulin resistance in this disorder. This concept has stimulated several clinical studies where antidiabetic drugs, such as insulin sensitizers including metformin, have been evaluated in insulin-resistant, NAFLD patients. These studies indicate that metformin might be of benefit in the treatment of NAFLD, also in nondiabetic patients, when associated to hypocaloric diet and weight control. However, the heterogeneity of these studies still prevents us from reaching firm conclusions about treatment guidelines. Moreover, metformin could have beneficial tissue-specific effects in NAFLD patients irrespective of its effects as insulin sensitizer.

Figures

Figure 1
Figure 1
Metformin action in peripheral tissues. Metabolic effects of metformin are mainly mediated through the activation of adenosine monophosphate-activated protein kinase (AMPK), a master regulator of glucose and lipid metabolism. In skeletal muscle, metformin increases glucose uptake by enhancing the atypical protein kinase C (PKC) ι/λ-dependent glucose transporter (GLUT4) translocation to the cell membrane, while, in liver, metformin-dependent activation of PKC ι/λ reduces gluconeogenic enzyme gene expression through the dissociation of the CREB-CBP-TORC2 complex via CREB binding protein phosphorylation. In liver, muscle, and adipose tissues, AMPK decreases cholesterol and fatty acid synthesis and increases fatty acid oxidation by inhibiting the enzymes acetyl-CoA carboxylase (ACC), 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase and fatty acid synthase (FAS) and activating the malonyl-CoA carboxylase (M-CoA). Moreover, it downregulates the sterol regulatory element-binding protein-1c (SREBP-1c), which is a transcription factor for lipogenetic genes. In adipose tissue, metformin inhibits lipolysis through attenuation of PKA and ERK1/2 signaling. It may also impact on the endocrine function of adipose tissue, through modulation of adipokines synthesis or secretion, probably in an AMPK-dependent manner. Adiponectin also activates AMPK, thereby, enhancing metformin action.
Figure 2
Figure 2
Schematic representation of NAFDL diagnosis and management. No consensus is available for the use of insulin sensitizers (metformin and pioglitazone), although studies have generally shown beneficial effects. The US Food and Drug Administration (FDA) has recently released a note to inform that the use of pioglitazone for more than one year may be associated with an increased risk of bladder cancer. In France the use of pioglitazone has been suspended while in Germany it is recommended not to start pioglitazone in new patients. Scanty data are available with regard to the efficacy of statins and hepatoprotective agents. Liver ultrasonography, the most practicable method for NAFLD detection is actually used to monitor response to treatment although not yet validated. Liver function tests may be useful despite a poor sensibility for NAFLD diagnosis and disease monitoring. Metabolic parameters still represent viable indexes of response to therapy.

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