Metformin Lowers Fasting Hyperglycemia by Increasing Glucose Clearance in People with Moderately Controlled Type 2 Diabetes

Metformin is the most frequently prescribed antidiabetic drug worldwide; however, the mechanism by which it lowers blood glucose remains incompletely understood. The objective of this study was to examine the effects of metformin on whole-body and specifically on hepatic glucose and energy metabolism in type 2 diabetes. This open repeated-measures pilot study examined this question using Positional Isotopomer NMR Tracer Analysis (PINTA) to assess rates of endogenous glucose production (VEGP), hepatic pyruvate carboxylase flux (VPC), and citrate synthase (VCS) flux in 16 men with moderately controlled type 2 diabetes (T2D; BMI 30 ± 3 kg/m2, HbA1c 8.4 ± 1.4%) undergoing two examination days with (M+; 1 g twice daily) and without metformin (M−) treatment. Hepatic ATP and glycogen concentrations were quantified by 31P/13C magnetic resonance spectroscopy. M+ reduced fasting glycemia by 18%, which could mostly be attributed to a 24% increase in rates of whole-body glucose clearance. Surprisingly, these changes were accompanied by a 58% increase in VPC and a 34% increase in VCS, due to a 26% increase in plasma glucagon concentrations. The increase in VPC was offset by reductions in the contributions of glycerol conversion to glucose resulting in no change in VEGP. Metformin decreased hepatic ATP content by 16% and increased plasma GDF-15 concentrations, but did not alter rates of net hepatic glycogenolysis. Metformin treatment in male individuals of European ancestry with moderately controlled T2D decreases blood glucose concentrations by increasing rates of whole-body glucose clearance. Metformin further inhibits glycerol-derived gluconeogenesis, which is consistent with complex IV, not complex I, being the molecular target of metformin action. ClinicalTrials.gov ( https://clinicaltrials.gov/ ): NCT04088851. Metformin is the most frequently prescribed antidiabetic drug worldwide; however, the mechanism by which it lowers blood glucose remains incompletely understood. Former studies suggested that, in people with type 2 diabetes, the main mechanism of action of metformin is lowering of liver glucose production. However, recent studies including ours now provide evidence that this effect is only present in uncontrolled diabetes. In people with moderately to well controlled diabetes or without diabetes, metformin does not reduce liver glucose production but predominantly acts via stimulating glucose utilization by the body. Our results now explain these contradictory findings by (1) identifying complex IV of the respiratory chain as the key to the regulation of liver glucose production, and (2) suggesting that the magnitude of metformin effects on the liver may depend on the severity of adipose tissue dysfunction with excessive release of lipids into the blood entering the liver.