Let-7 underlies metformin-induced inhibition of hepatic glucose production

Metformin, the frontline antidiabetic drug, has gained increasing attention for the prevention and treatment of aging, cancer, and cardiovascular disease. Yet a clear mechanistic understanding of its action is still lacking, largely due to the suprapharmacological concentrations of metformin used in most studies. Here, we report an inhibition of glucose production by primary hepatocytes from dietary and genetic mouse models of type 2 diabetes (T2D) using metformin at clinically relevant concentrations. Mechanistically, metformin up-regulates microRNA let-7 that in turn down-regulates TET3, evoking a change in the ratio of hepatocyte nuclear factor 4 alpha (HNF4 alpha) isoforms and subsequent inhibition of key gluconeogenic genes. Importantly, this let-7-mediated mechanism is faithfully recapitulated in mice with T2D chronically treated with therapeutic doses of metformin. Furthermore, hepatic delivery of let-7 ameliorates hyperglycemia and improves glucose homeostasis in diabetic mice, whereas liver-specific inhibition of let-7 abrogates these beneficial effects of metformin. Moreover, let-7 overexpression decreases glucose production from primary hepatocytes from obese humans. Thus, we propose the reactivation of a let-7-dependent pathway that is pathologically repressed in the liver of diabetes as a major mechanism of metformin action and that liver-specific delivery of let-7 represents a potential therapeutic for T2D. Our findings are also pertinent to the development of therapeutic strategies for other chronic diseases.

Automated summary

This study investigates the mechanism of action of metformin, a frontline antidiabetic drug, in inhibiting glucose production in hepatocytes. The researchers found that metformin up-regulates microRNA let-7, which in turn down-regulates TET3, leading to a change in the ratio of hepatocyte nuclear factor 4 alpha (HNF4 alpha) isoforms and subsequent inhibition of gluconeogenic genes. They also demonstrated that let-7-mediated mechanism is faithfully recapitulated in mice with type 2 diabetes treated with therapeutic doses of metformin. The findings suggest that reactivation of the let-7-dependent pathway could be a major mechanism of metformin action and liver-specific delivery of let-7 may represent a potential therapeutic for type 2 diabetes.