Metformin is a first-line therapeutic option for the treatment of type 2 diabetes, even though its underlying mechanisms of action are relatively unclear1,2,3,4,5,6. 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 mechanism5,6. However, studies have questioned the contribution of hepatic AMPK to the effects of metformin on lowering hyperglycemia1,3,4, and a gut–brain–liver axis that mediates intestinal nutrient- and hormone-induced lowering of HGP has been identified7. 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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The authors are grateful to E. Burdett for technical assistance. This work is supported by a research grant from the Canadian Institute of Health Research (MOP-82701 to T.T.K.L.). F.A.D. is a Banting Fellow. B.A.R. is supported by a Canadian Institute of Health Research Doctoral Vanier Canada scholarship. C.D.C. is supported by a Banting and Best Diabetes Centre graduate studentship. M.Z.-T. is supported by a Banting and Best Diabetes Centre graduate studentship. G.A.R. is supported by the Wellcome Trust Senior Investigator (WT098424AIA), the Medical Research Council Programme (MR/J0003042/1), the Diabetes UK Project Grant (11/0004210) and Royal Society Wolfson Research Merit awards. T.K.T.L. holds the John Kitson McIvor (1915–1942) Endowed Chair in Diabetes Research and the Canada Research Chair in Obesity at the Toronto General Research Institute and the University of Toronto.
The authors declare no competing financial interests.
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Duca, F., Côté, C., Rasmussen, B. et al. Metformin activates a duodenal Ampk–dependent pathway to lower hepatic glucose production in rats. Nat Med 21, 506–511 (2015). https://doi.org/10.1038/nm.3787
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