title: Metformin activates a duodenal Ampk-dependent pathway to lower hepatic glucose production in rats.
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.
authors: Toronto General Research Institute and Department of Medicine, University Health Network, Toronto, Ontario, Canada.
authors: Frank A
authors: FA
authors: Duca
authors: 1] Toronto General Research Institute and Department of Medicine, University Health Network, Toronto, Ontario, Canada. [2] Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors: Clémence D
authors: CD
authors: Côté
authors: 1] Toronto General Research Institute and Department of Medicine, University Health Network, Toronto, Ontario, Canada. [2] Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors: Brittany A
authors: BA
authors: Rasmussen
authors: 1] Toronto General Research Institute and Department of Medicine, University Health Network, Toronto, Ontario, Canada. [2] Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors: Melika
authors: M
authors: Zadeh-Tahmasebi
authors: Section of Cell Biology, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College of London, Imperial Centre for Translational and Experimental Medicine, Hammersmith Hospital, London, UK.
authors: Guy A
authors: GA
authors: Rutter
authors: Toronto General Research Institute and Department of Medicine, University Health Network, Toronto, Ontario, Canada.
authors: Beatrice M
authors: BM
authors: Filippi
authors: 1] Toronto General Research Institute and Department of Medicine, University Health Network, Toronto, Ontario, Canada. [2] Department of Physiology, University of Toronto, Toronto, Ontario, Canada. [3] Department of Medicine, University of Toronto, Toronto, Ontario, Canada. [4] Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada.
authors: Tony K T
authors: TK
authors: Lam
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000737:chemistry; D003924:Diabetes Mellitus, Type 2 / Q000097:blood; D004386:Duodenum / Q000187:drug effects*; D015971:Gene Expression Regulation, Enzymologic; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique; D057809:HEK293 Cells; D006801:Humans; D007328:Insulin; D007333:Insulin Resistance; D008099:Liver / Q000201:enzymology*; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000737:chemistry*; D009536:Niacinamide / Q000737:chemistry; D009765:Obesity / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018027:Receptors, Glucagon / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D001786:Blood Glucose; C000593833:GLP1R protein, human; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D018027:Receptors, Glucagon; D009536:Niacinamide; D008687:Metformin; D055372:AMP-Activated Protein Kinases; D005947:Glucose