Document Detail


Prostaglandin E2 receptor, EP3, is induced in diabetic islets and negatively regulates glucose- and hormone-stimulated insulin secretion.
MedLine Citation:
PMID:  23349487     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BTBR mice develop severe diabetes in response to genetically induced obesity due to a failure of the β-cells to compensate for peripheral insulin resistance. In analyzing BTBR islet gene expression patterns, we observed that Pgter3, the gene for the prostaglandin E receptor 3 (EP3), was upregulated with diabetes. The EP3 receptor is stimulated by prostaglandin E2 (PGE2) and couples to G-proteins of the Gi subfamily to decrease intracellular cAMP, blunting glucose-stimulated insulin secretion (GSIS). Also upregulated were several genes involved in the synthesis of PGE2. We hypothesized that increased signaling through EP3 might be coincident with the development of diabetes and contribute to β-cell dysfunction. We confirmed that the PGE2-to-EP3 signaling pathway was active in islets from confirmed diabetic BTBR mice and human cadaveric donors, with increased EP3 expression, PGE2 production, and function of EP3 agonists and antagonists to modulate cAMP production and GSIS. We also analyzed the impact of EP3 receptor activation on signaling through the glucagon-like peptide (GLP)-1 receptor. We demonstrated that EP3 agonists antagonize GLP-1 signaling, decreasing the maximal effect that GLP-1 can elicit on cAMP production and GSIS. Taken together, our results identify EP3 as a new therapeutic target for β-cell dysfunction in T2D.
Authors:
Michelle E Kimple; Mark P Keller; Mary R Rabaglia; Renee L Pasker; Joshua C Neuman; Nathan A Truchan; Harpreet K Brar; Alan D Attie
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-01-24
Journal Detail:
Title:  Diabetes     Volume:  62     ISSN:  1939-327X     ISO Abbreviation:  Diabetes     Publication Date:  2013 Jun 
Date Detail:
Created Date:  2013-05-24     Completed Date:  2013-08-02     Revised Date:  2013-10-30    
Medline Journal Info:
Nlm Unique ID:  0372763     Medline TA:  Diabetes     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1904-12     Citation Subset:  AIM; IM    
Affiliation:
Department of Medicine, University of Wisconsin, Madison, Madison, Wisconsin, USA. mkimple@medicine.wisc.edu
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MeSH Terms
Descriptor/Qualifier:
Animals
Dinoprostone / metabolism
Female
Glucose / pharmacology*
Humans
Insulin / metabolism,  secretion*
Insulin-Secreting Cells / drug effects,  metabolism
Islets of Langerhans / drug effects*,  metabolism*
Mice
Receptors, Glucagon / genetics,  metabolism
Receptors, Prostaglandin E, EP3 Subtype / agonists,  antagonists & inhibitors,  metabolism*
Grant Support
ID/Acronym/Agency:
DK066369/DK/NIDDK NIH HHS; DK080845/DK/NIDDK NIH HHS; DK58037/DK/NIDDK NIH HHS; R01 DK058037/DK/NIDDK NIH HHS; R01 DK066369/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Insulin; 0/Ptger3 protein, mouse; 0/Receptors, Glucagon; 0/Receptors, Prostaglandin E, EP3 Subtype; 0/glucagon-like peptide-1 receptor; 363-24-6/Dinoprostone; 50-99-7/Glucose

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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