Glucagon-Like Peptide-2 Receptor Modulates Islet Adaptation to Metabolic Stress in the ob/ob Mouse

Background & AimsGlucagon-like peptide-2 (GLP-2) is a gut hormone that increases gut growth, reduces mucosal cell death, and augments mesenteric blood flow and nutrient absorption. Exogenous GLP-2(1-33) also stimulates glucagon secretion and enhances gut barrier function with implications for susceptibility to systemic inflammation and subsequent metabolic dysregulation. We examined the importance of GLP-2 receptor (GLP-2R) signaling for glucose homeostasis in multiple models of metabolic stress, diabetes, and obesity.MethodsBody weight, islet function, glucose tolerance, and islet histology were studied in wild-type, high-fat fed, lean diabetic, Glp2r−/− and ob/ob:Glp2r−/− mice.ResultsGLP-2 did not stimulate glucagon secretion from isolated pancreatic islets in vitro, and exogenous GLP-2 had no effect on the glucagon response to insulin-induced hypoglycemia in vivo. Glp2r−/− mice exhibit no change in glycemia, and plasma glucagon levels were similar in Glp2r−/− and Glp2r+/+ mice after hypoglycemia or after oral or intraperitoneal glucose challenge. Moreover, glucose homeostasis was comparable in Glp2r−/− and Glp2r+/+ mice fed a high-fat diet for 5 months or after induction of streptozotocin-induced diabetes. In contrast, loss of the GLP-2R leads to increased glucagon secretion and α-cell mass, impaired intraperitoneal glucose tolerance and hyperglycemia, reduced β-cell mass, and decreased islet proliferation in ob/ob:Glp2r−/− mice.ConclusionsOur results show that, although the GLP-2R is not critical for the stimulation or suppression of glucagon secretion or glucose homeostasis in normal or lean diabetic mice, elimination of GLP-2R signaling in obese mice impairs the normal islet adaptive response required to maintain glucose homeostasis.