@article{Duca:2015:10.1038/nm.3787,
author = {Duca, FA and Cote, CD and Rasmussen, BA and Zadeh-Tahmasebi, M and Rutter, GA and Filippi, BM and Lam, TKT},
doi = {10.1038/nm.3787},
journal = {Nature Medicine},
pages = {506--511},
title = {Metformin activates a duodenal Ampk-dependent pathway to lower hepatic glucose production in rats},
url = {http://dx.doi.org/10.1038/nm.3787},
volume = {21},
year = {2015}
}
TY - JOUR
AB - 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.
AU - Duca,FA
AU - Cote,CD
AU - Rasmussen,BA
AU - Zadeh-Tahmasebi,M
AU - Rutter,GA
AU - Filippi,BM
AU - Lam,TKT
DO - 10.1038/nm.3787
EP - 511
PY - 2015///
SN - 1078-8956
SP - 506
TI - Metformin activates a duodenal Ampk-dependent pathway to lower hepatic glucose production in rats
T2 - Nature Medicine
UR - http://dx.doi.org/10.1038/nm.3787
UR - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000354068800018&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR - https://www.nature.com/articles/nm.3787
VL - 21
ER -