Metformin activates a duodenal Ampk–dependent pathway to lower hepatic glucose production in rats

FA Duca, CD Côté, BA Rasmussen… - Nature medicine, 2015 - nature.com
FA Duca, CD Côté, BA Rasmussen, M Zadeh-Tahmasebi, GA Rutter, BM Filippi, TKT Lam
Nature medicine, 2015nature.com
Metformin is a first-line therapeutic option for the treatment of type 2 diabetes, even though
its underlying mechanisms of action are relatively unclear,,,,,. Metformin lowers blood
glucose levels by inhibiting hepatic glucose production (HGP), an effect originally postulated
to be due to a hepatic AMP-activated protein kinase (AMPK)-dependent mechanism,.
However, studies have questioned the contribution of hepatic AMPK to the effects of
metformin on lowering hyperglycemia,,, and a gut–brain–liver axis that mediates intestinal …
Abstract
Metformin is a first-line therapeutic option for the treatment of type 2 diabetes, even though its underlying mechanisms of action are relatively unclear,,,,,. Metformin lowers blood glucose levels by inhibiting hepatic glucose production (HGP), an effect originally postulated to be due to a hepatic AMP-activated protein kinase (AMPK)-dependent mechanism,. However, studies have questioned the contribution of hepatic AMPK to the effects of metformin on lowering hyperglycemia,,, and a gut–brain–liver axis that mediates intestinal nutrient- and hormone-induced lowering of HGP has been identified. Thus, it is possible that metformin affects HGP through this inter-organ crosstalk. Here we show that intraduodenal infusion of metformin for 50 min activated duodenal mucosal Ampk and lowered HGP in a rat 3 d high fat diet (HFD)-induced model of insulin resistance. Inhibition of duodenal Ampk negated the HGP-lowering effect of intraduodenal metformin, and both duodenal glucagon-like peptide-1 receptor (Glp-1r)–protein kinase A (Pka) signaling and a neuronal-mediated gut–brain–liver pathway were required for metformin to lower HGP. Preabsorptive metformin also lowered HGP in rat models of 28 d HFD–induced obesity and insulin resistance and nicotinamide (NA)–streptozotocin (STZ)–HFD-induced type 2 diabetes. In an unclamped setting, inhibition of duodenal Ampk reduced the glucose-lowering effects of a bolus metformin treatment in rat models of diabetes. These findings show that, in rat models of both obesity and diabetes, metformin activates a previously unappreciated duodenal Ampk–dependent pathway to lower HGP and plasma glucose levels.
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