Glp2r is required for postprandial glycemic control (1114.3)

Abstract

Glucagon‐like peptide 2 (GLP‐2) is secreted from enteroendocrine L cells and proposed as a key promoter of intestinal metabolic reprogramming and tissue regeneration, contributing to improving glucose homeostasis and insulin sensitivity after RYGB. Through the gut‐brain‐liver axis, GLP‐2 plays crucial roles in the control of food intake and hepatic glucose production. We showed in Cell Metab (2013) that GLP‐2 receptor (Glp2r) in POMC neurons is required for GLP‐2 to promote glucose homeostasis at the postabsorptive status. However, little is known about the physiological relevance of GLP‐2 in the glycemic control at the postprandial status when GLP‐2 is physiologically secreted. In this study, we first developed an innovative stable isotopic tracer approach to quantify non‐steady postprandial glucose kinetics in mice, which were assessed by the appearance rate of ingested glucose (Ra,ingested) after intragastric feeding U‐13C6‐D‐glucose‐enriched elementary diet; and the appearance rate of endogenous glucose (Ra,endogenous) by iv infusion of 6,6‐2H2‐D‐glucose. We then generated mice with Glp2r deletion in the intestinal epithelium by crossing Glp2r‐floxed mice with villin‐Cre mice. Finally, we show that Glp2r global KO mice display glucose intolerance after an oral GTT and postprandial hyperglycemia after the elementary meal as a result of increased hepatic production of endogenous glucose (Ra,endogenous, attributed to the increased rate of gluconeogenesis) and decreased splanchnic sequestration of ingested glucose (Ra,ingested), pointing to a physiological role of GLP‐2 in postprandial glycemic control. Moreover, villin‐Glp2r KO mice display postprandial glucose intolerance, suggesting that the gut epithelium is a key site for GLP‐2 action to promote postprandial glycemic control. We conclude that Glp2r activation is required for postprandial glycemic control and GLP‐2 secretion augmentation may contribute to improving postprandial hyperglycemia in diabetes.Grant Funding Source: Supported by the USDA CRIS 6250‐51000‐055