Hongying An

Keywords metformin action mitochondrial respiration intestine epithelial cells lactate overproduction insulin sensitivity Research topic(s) CP: metabolism Introduction Metformin is the first-line anti-diabetic agent and is the second most prescribed drug in the USA.

Highlights • Clinically relevant metformin dose improves liver mitochondrial respiration in obesity • Pharmacological metformin increases mitochondrial respiration and fission • Supra-pharmacological metformin inhibits mitochondrial activity by ADP reduction • AMPK is required for metformin suppression of liver glucose production Summary Impaired mitochondrial respiratory activity contributes to the development of insulin resistance in type 2 diabetes.

A high-fat, western-style diet is an important predisposing factor for the onset of diabetes and obesity. Mice developed insulin resistance 2 weeks after consuming an HFD (60% calories from fat) along with increased glucose production (Fig. 1a–c and Supplementary Fig. 1a). Considering that acetyltransferase P300 and CBP are critical co-activators in the regulation of hepatic glucose production23, 24, we determined the protein levels of these co-activators in the liver of mice fed an HFD.