Prostaglandin E2 receptor, EP3, is induced in diabetic islets and negatively regulates glucose- and hormone-stimulated insulin secretion.
Prostaglandin E2 receptor, EP3, is induced in diabetic islets and negatively regulates glucose- and hormone-stimulated insulin secretion.
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作者：
Kimple ME;Keller MP;Rabaglia MR;Pasker RL;Neuman JC;Truchan NA;Brar HK;Attie AD
由于β细胞不能补偿外周胰岛素抵抗，遗传性肥胖导致小鼠患上严重的糖尿病。在分析BTBR胰岛基因表达模式时，我们观察到前列腺素E受体3(EP3)基因Pgter3在糖尿病时上调。前列腺素E2(PGE2)刺激EP3受体与Gi亚家族的G蛋白偶联，减少细胞内cAMP，钝化葡萄糖刺激的胰岛素分泌(GSIS)。与PGE2合成有关的几个基因也上调了。我们推测，通过EP3增加的信号可能与糖尿病的发展相一致，并导致β细胞功能障碍。我们证实，PGE2-to-EP3信号通路在确诊的糖尿病BTBR小鼠和人类身体供体的胰岛中是活跃的，EP3表达增加，PGE2产生增加，EP3激动剂和拮抗剂功能调节cAMP产生和GSIS。我们还分析了EP3受体激活对通过胰升糖素样肽(GLP)-1受体传递信号的影响。我们证明EP3激动剂拮抗GLP-1信号，降低GLP-1对cAMP产生和GSIS的最大作用。综上所述，我们的结果确定EP3是治疗T2D中β细胞功能障碍的新靶点。
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.
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影响因子：
4.8
作者：
Kimple, Michelle E.;Joseph, Jamie W.;Casey, Patrick J.
通讯作者：
Casey, Patrick J.
影响因子：
4.8
作者：
Maida, Adriano;Lovshin, Julie A.;Drucker, Daniel J.
通讯作者：
Drucker, Daniel J.
影响因子：
7.3
作者：
Aarab, L;Siaume-Perez, S;Chabardès, D
通讯作者：
Chabardès, D
DOI：
10.1152/ajprenal.00169.2012
发表时间：
2012-09-01
影响因子：
4.2
作者：
Flores, Daniel;Liu, Yu;Rohatgi, Rajeev
通讯作者：
Rohatgi, Rajeev
影响因子：
2.7
作者：
Belley, M;Gallant, M;Zamboni, RJ
通讯作者：
Zamboni, RJ