GLP‐2 receptor is required for glucose homeostasis and energy balance

Abstract

Glucagon‐like peptides (GLP‐1/2) are co‐secreted from enteroendocrine L cells and preproglucagon neurons, and proposed as key promoters of glucose homeostasis and insulin sensitivity after gastric bypass surgery. GLP‐2 receptor (GLP‐2R) activation stimulates intestinal growth and absorption, while decreasing gut motility to inhibit food intake. However, it is unknown if GLP‐2 plays a physiological role in the long‐term control of energy balance and glucose homeostasis. To determine the physiological relevance of GLP‐2R in glycemic control and body adiposity, we generated Glp2r knockout (KO) mice. First, we validated that Glp2r mRNA and protein were not expressed in the KO gut and brain, and GLP‐2‐stimulated cell proliferation was negated in the KO gut. In comparison with wide‐type (WT) littermates, Glp2r KO mice displayed higher (+38%) fat body mass and lower lean body mass. The KO mice had higher food intake during refeeding while basal energy expenditure was not altered. Moreover, the KO mice displayed higher levels of fasting glucose and slower removal of postprandial glucose. After ip glucose challenge, the KO mice showed glucose intolerance. Using 6,6‐2H2‐glucose and 2H2O tracers, we quantified that the KO mice had higher basal hepatic glucose production (5.44 ± 0.20 vs 7.02 ± 0.26 mmol/kg/h, respectively, for the WT and KO mice), while they had lower glucose infusion rate (GIR) during hyperinsulinemic euglycemic clamp. Furthermore, iv infusion of GLP‐2 (500 pmol/kg/h) increased the GIR by +33% in the WT mice, but not in the KO mice. GLP‐2‐mediated improvement in insulin sensitivity was largely attributed to enhancing glucose disappearance rate during insulin stimulation. Our data indicate that Glp2r deficiency displays fasting hyperglycemia, glucose intolerance, and insulin resistance, pointing to a novel physiological role of GLP‐2R in glucose homeostasis and insulin sensitivity. In addition, Glp2r deficiency displays hyperphagic obesity, revealing a long‐term effect of GLP‐2R in energy balance.