Journal
NATURE MEDICINE
Volume 21, Issue 5, Pages 506-U130Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.3787
Keywords
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Funding
- Canadian Institute of Health Research [MOP-82701]
- Canadian Institute of Health Research Doctoral Vanier Canada scholarship
- Banting and Best Diabetes Centre graduate studentship
- Wellcome Trust [WT098424AIA]
- Medical Research Council [MR/J0003042/1]
- Diabetes UK [11/0004210]
- Royal Society
- MRC [MR/K001981/1] Funding Source: UKRI
- Medical Research Council [MR/K001981/1] Funding Source: researchfish
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Metformin is a first-line therapeutic option for the treatment of type 2 diabetes, even though its underlying mechanisms of action are relatively unclear(1-6). 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 mechanism(5,6). However, studies have questioned the contribution of hepatic AMPK to the effects of metformin on lowering hyperglycemia(1,3,4), and a gut-brain-liver axis that mediates intestinal nutrient-and hormone-induced lowering of HGP has been identified(7). 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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