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Urocortin 3 regulates glucose-stimulated insulin secretion and energy homeostasis.

Authors: Li, C  Chen, P  Vaughan, J  Lee, KF  Vale, W 
Citation: Li C, etal., Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):4206-11. Epub 2007 Feb 27.
Pubmed: (View Article at PubMed) PMID:17360501
DOI: Full-text: DOI:10.1073/pnas.0611641104

Urocortin 3 (Ucn 3), a member of the corticotropin-releasing factor (CRF) family of peptides, is strongly expressed in mammalian pancreatic beta cells and has been shown to stimulate insulin secretion. Here we report the investigation of the hypothesis that endogenous Ucn 3 regulates insulin secretion, particularly in the presence of nutrient excess. Secretion of Ucn 3-like immunoreactivity from cultured beta cells was stimulated by high glucose and insulin secretagogs such as GLP-1; furthermore, 5 pancreatic Ucn 3 mRNA levels in vivo were increased during the positive energy balance caused by high-fat diet and by the absence of leptin. Immunoneutralization of Ucn 3 or pharmacologic blockade of its receptor, the type 2 CRF receptor (CRFR2), attenuated high but not low glucose-induced insulin secretion from isolated islets in vitro. Cultured islets isolated from Ucn 3-null mice also secreted less insulin in response to high glucose concentrations. Consistently, peripheral injection of a selective CRFR2 antagonist before the administration of a glucose challenge significantly attenuated glucose-induced insulin secretion in vivo. Ucn 3-null mice were relatively protected from the hyperinsulinemia, hyperglycemia, glucose intolerance, hepatic steatosis, and hypertriglyceridemia induced by high-fat diet. Additionally, we found that aged Ucn 3-null mice maintained better glucose tolerance than age-matched wild-type littermates. These results suggest that endogenous Ucn 3 in the pancreas is induced under excessive caloric conditions and acts locally to augment insulin production, which in the long-term may contribute to reduced insulin sensitivity and harmful metabolic consequences.

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CRRD Object Information
CRRD ID: 2306172
Created: 2009-03-24
Species: All species
Last Modified: 2009-03-24
Status: ACTIVE



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