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

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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 α-cell mass, impaired intraperitoneal glucose tolerance and hyperglycemia, reduced β-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. © 2010 by the AGA Institute.

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Bahrami, J., Longuet, C., Baggio, L. L., Li, K., & Drucker, D. J. (2010). Glucagon-like peptide-2 receptor modulates islet adaptation to metabolic stress in the ob/ob mouse. Gastroenterology, 139(3), 857–868. https://doi.org/10.1053/j.gastro.2010.05.006

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