An energetic tale of AMPK-independent effects of metformin

Abstract

Metformin has become a mainstay in the modest therapeutic armamentarium for the treatment of the insulin resistance of type 2 diabetes mellitus. Although metformin functions primarily by reducing hepatic glucose output, the molecular mechanism mediating this effect had remained elusive until recently. Metformin impairs ATP production, activating the conserved sensor of nutritional stress AMP-activated protein kinase (AMPK), thus providing a plausible and generally accepted model for suppression of gluconeogenic gene expression and glucose output. In this issue of the JCI, Foretz et al. refute this hypothesis by showing that AMPK is dispensable for the effects of metformin on hepatic glucose output in primary hepatocytes; rather, their data suggest that the antidiabetic effects of metformin in the liver are mediated directly by reducing energy charge.

Figure 1. Regulation of hepatic glycolytic/gluconeogenic pathways.

Metformin inhibits mitochondrial complex I and increases the AMP/ATP ratio, which leads to the activation of the energy-sensing kinase AMPK. Foretz et al. (12) show that activation of AMPK is dispensable for metformin-induced reduction in hepatic glucose output. While multiple regulatory points exist for direct AMP- and ATP-mediated effects on glycolysis and gluconeogenesis, the mechanism of energy charge regulation of gluconeogenic gene expression described by Foretz et al. is currently unknown. PEP, phosphoenolpyruvate.