Metformin activates duodenal AMPK and a neuronal network to lower glucose production

Metformin is a first-line therapeutic option for the treatment of hyperglycemia in type 2 diabetes, despite its underlying regulatory mechanisms remaining relatively unknown. Metformin lowers blood glucose levels by inhibiting hepatic glucose production (GP), originally postulated to be resultant from hepatic AMP-activated protein kinase (AMPK) activation. However, while studies have questioned the contribution of hepatic AMPK in metformin’s effect, a gut-brain-liver axis has recently been discovered to mediate intestinal nutrient- and hormonal-induced lowering of GP. Here we show that intraduodenal infusion of metformin for 50 min increases phosphorylation of duodenal AMPK and lowers GP in a model of 3 d high fat diet (HFD)-induced insulin resistance. Molecular and chemical inhibition of duodenal AMPK negates the GP-lowering effect of metformin, while a duodenal GLP-1R-PKA signaling pathway and a neuronal gut-brain-liver axis are demonstrated to be the downstream effectors. The ability of preabsorptive metformin to lower GP remains in both a 28 d HFD-induced obese and insulin resistant and a NA-STZ/HFD induced type 2 diabetic model. Finally, molecular inhibition of duodenal AMPK signaling reduces the overall acute glucose-lowering effect of a bolus treatment of metformin in diabetes. These findings unveil that metformin activates a previously unappreciated duodenal AMPK-dependent neuronal pathway to lower GP and plasma glucose levels in obesity and diabetes.