Glucagon-like peptide-2 receptor modulates islet adaptation to metabolic stress in the ob/ob mouse.

Abstract

BACKGROUND & AIMS:

Glucagon-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.

METHODS:

Body weight, islet function, glucose tolerance, and islet histology were studied in wild-type, high-fat fed, lean diabetic, Glp2r(-/-) and ob/ob:Glp2r(-/-) mice.

RESULTS:

GLP-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 alpha-cell mass, impaired intraperitoneal glucose tolerance and hyperglycemia, reduced beta-cell mass, and decreased islet proliferation in ob/ob:Glp2r(-/-) mice.

CONCLUSIONS:

Our 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.

• Authors: Jasmine Bahrami, Christine Longuet, Laurie L Baggio, Karen Li, Daniel J Drucker
• Journal: Gastroenterology (Gastroenterology) Vol. 139 Issue 3 Pg. 857-68 (Sep 2010) ISSN: 1528-0012 [Electronic] United States
• PMID: 20546737 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

Chemical References

• Blood Glucose
• Glucagon-Like Peptide 2
• Glucagon-Like Peptide-2 Receptor
• Insulin
• Receptors, Glucagon
• Glucagon

Topics

• Adaptation, Physiological
• Animals
• Blood Glucose (metabolism)
• Body Weight
• Cell Proliferation
• Diabetes Mellitus, Experimental (genetics, metabolism, pathology, physiopathology)
• Disease Models, Animal
• Glucagon (blood)
• Glucagon-Like Peptide 2 (metabolism)
• Glucagon-Like Peptide-2 Receptor
• Glucose Intolerance (metabolism, physiopathology)
• Glucose Tolerance Test
• Hypoglycemia (metabolism, physiopathology)
• Insulin (blood)
• Islets of Langerhans (metabolism, pathology, physiopathology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Obesity (genetics, metabolism, pathology, physiopathology)
• Receptors, Glucagon (deficiency, genetics, metabolism)
• Signal Transduction
• Stress, Physiological
• Time Factors