Impaired glucose uptake and metabolism in peripheral tissues combined with increased glucose production by the liver [hepatic glucose production (HPG)] contributes to the hyperglycemia of type 2 diabetes. Normally, food triggers a gut-brain-liver axis to suppress HGP: The intestine releases signals, such as glucagon-like peptide 1 (GLP-1), that activate the vagal afferent nerves, stimulating glutamatergic activity in the brain, which in turn signals through vagal efferent nerves to the liver to suppress HGP (see Smith and Steinberg). Two papers report that metformin and resveratrol act within the duodenum to stimulate this gut-brain-liver axis and reduce HGP, thereby improving glucose metabolism in several rodent models of type 2 diabetes. Côté et al. confirmed the presence of the resveratrol target Sirt1, an NAD+-dependent deacetylase, in the duodenum. Intraduodenal infusion of resveratrol reduced HPG in rats fed a high-fat diet (HFD) compared with that of rats fed a normal diet, a response that was abolished by duodenal knockdown of Sirt1 or coinfusion of an inhibitor of Sirt1 or compound C, an inhibitor of AMP-activated protein kinase (AMPK). HFD rats had reduced abundance of Sirt1 transcripts and protein, which was normalized by intraduodenal infusion of resveratrol. Using the same experimental paradigm of intraduodenal infusion, Duca et al. showed that metformin, which stimulates AMPK activity, also suppressed HPG in HFD rats, an effect that was blocked by adenoviral-mediated introduction of dominant-negative AMPK into the duodenum or coinfusion of compound C. Coinfusion of an inhibitor of the GLP-1 receptor, a receptor that stimulates protein kinase A (PKA) signaling in vagal afferent nerves, or resection of the hepatic vagal efferent nerve blocked the reduction in HGP induced by intraduodenal infusion of metformin. Suppression of HPG by intraduodenal infusion of metformin or resveratrol was also blocked by coinfusion of a PKA inhibitor or intracranial infusion of a glutamate receptor antagonist. Preabsorptive action of resveratrol and metformin also occurred in two different rat models of type 2 diabetes, confirming the importance of this gut-brain-liver axis in the effects of these two compounds in improving glucose metabolism in a chronic pathological condition.
C. D. Côté, B. A. Rasmussen, F. A. Duca, M. Zadeh-Tahmasebi, J. A. Baur, M. Daljeet, D. M. Breen, B. M Filippi, T. K. T. Lam, Resveratrol activates duodenal Sirt1 to reverse insulin resistance in rats through a neuronal network. Nat. Med. 21, 498–505 (2015). [PubMed]
F. A. Duca, C. D. Côté, B. A. Rasmussen, M. Zadeh-Tahmasebi, G. A. Rutter, B. M. Filippi, T. K. T. Lam, Metformin activates a duodenal Ampk–dependent pathway to lower hepatic glucose production in rats. Nat. Med. 21, 506–511 (2015). [PubMed]
B. K. Smith, G. R. Steinberg, Duodenal energy sensing regulates hepatic glucose output. Nat. Med. 21, 428–429 (2015). [PubMed]