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

• Published in: Nature medicine Vol. 21; no. 5; pp. 506 - 511
• Main Authors: Duca, Frank A, Côté, Clémence D, Rasmussen, Brittany A, Zadeh-Tahmasebi, Melika, Rutter, Guy A, Filippi, Beatrice M, Lam, Tony K T
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.05.2015; Nature Publishing Group
• Subjects: 631/443/319/1642/137; AMP-Activated Protein Kinases - metabolism; Animals; Biomedicine; Blood Glucose - chemistry; Cancer Research; Diabetes Mellitus, Type 2 - blood; Dosage and administration; Drug therapy; Duodenum - drug effects; Gene Expression Regulation, Enzymologic; Glucagon-Like Peptide-1 Receptor; Glucose; Glucose - metabolism; Glucose Clamp Technique; Health aspects; HEK293 Cells; Humans; Infectious Diseases; Insulin; Insulin Resistance; Intestine, Small; letter; Liver; Liver - enzymology; Male; Metabolic Diseases; Metformin; Metformin - administration & dosage; Metformin - chemistry; Molecular Medicine; Neurosciences; Niacinamide - chemistry; Obesity; Obesity - metabolism; Protein kinases; Rats; Rats, Sprague-Dawley; Receptors, Glucagon - metabolism; Signal Transduction; Synthesis; Type 2 diabetes
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.3787

Two papers show that Ampk and Sirt1 respond to metformin and resveratrol, respectively, in the duodenum to initiate a gut-brain-liver axis that reduces hepatic glucose production, thus explaining the antidiabetic actions of these two class of drugs. 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 , 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 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.