详细记录  
题名:Prostaglandin E2 Receptor, EP3, Is Induced in Diabetic Islets and Negatively Regulates Glucose- and Hormone-Stimulated Insulin Secretion.
作者:KIMPLE ME; KELLER MP; RABAGLIA MR; PASKER RL; NEUMAN JC; TRUCHAN NA; BRAR HK; ATTIE AD;
来源:Diabetes. 2013 Jun;62(6):1904-12. doi: 10.2337/db12-0769. Epub 2013 Jan 24. [ IF= 8.29 ] ]
URL :10.2337/db12-0769
日期:20130702
摘要:BTBR mice develop severe diabetes in response to genetically induced obesity due
to a failure of the beta-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 beta-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
beta-cell dysfunction in T2D.

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