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.
