Gαz negatively regulates insulin secretion and glucose clearance
Gαz negatively regulates insulin secretion and glucose clearance
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DOI：
10.1074/jbc.m706481200
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发表时间：
2008-02-22
影响因子：
4.8
通讯作者：
Casey, Patrick J.
中科院分区：
文献类型：
--
作者：
Kimple, Michelle E.;Joseph, Jamie W.;Casey, Patrick J.
关于异源三聚体G蛋白G（z）的α亚基（G alpha（z））的体内功能知之甚少。最近，随着发现G α（z）的活化抑制胰岛素瘤细胞系中葡萄糖刺激的胰岛素分泌，出现了一种潜在功能的线索（Kimple，M. E、尼克松，A. B.，凯利，P。贝利角L.，扬，K。H、Fields，T.一、和凯西，P. J.（2005）生物化学杂志280，31708-31713）。为了在体内扩展该研究，利用G α（z）敲除小鼠模型来确定G α（z）功能是否在抑制胰岛素分泌中起作用。在G α（z）-null和野生型小鼠之间，在胰岛的大体形态或胰岛DNA、蛋白质或胰岛素含量方面没有发现差异。通过胰岛素耐量试验测量，G α（z）-null小鼠和野生型对照小鼠的胰岛素敏感性也没有差异。然而，与野生型对照组相比，G α（z）基因敲除小鼠在腹膜内和口服葡萄糖激发后确实显示出血浆胰岛素浓度增加和葡萄糖清除率相应增加。在G alpha（z）-null小鼠中观察到的血浆胰岛素增加最有可能是胰岛素分泌增强的直接结果，因为从G alpha（z）-null小鼠分离的胰岛显示出比野生型小鼠显著更高的葡萄糖刺激的胰岛素分泌。最后，在G α（z）-无效胰岛中观察到的胰岛素分泌增加似乎是由于腺苷酸环化酶的紧张性抑制的缓解，因为在不存在外源性刺激的情况下，G α（z）-无效胰岛中cAMP产生显著增加。这些发现表明，G alpha（z）可能是旨在改善2型糖尿病β细胞功能障碍的治疗方法的潜在新靶点。
Relatively little is known about the in vivo functions of the alpha subunit of the heterotrimeric G protein G(z) (G alpha(z)). Clues to one potential function recently emerged with the finding that activation of G alpha(z) inhibits glucose-stimulated insulin secretion in an insulinoma cell line (Kimple, M. E., Nixon, A. B., Kelly, P., Bailey, C. L., Young, K. H., Fields, T. A., and Casey, P. J. ( 2005) J. Biol. Chem. 280, 31708-31713). To extend this study in vivo, a G alpha(z) knock-out mouse model was utilized to determine whether G alpha(z) function plays a role in the inhibition of insulin secretion. No differences were discovered in the gross morphology of the pancreatic islets or in the islet DNA, protein, or insulin content between G alpha(z)-null and wild-type mice. There was also no difference between the insulin sensitivity of G alpha(z)-null mice and wildtype controls, as measured by insulin tolerance tests. G alpha(z)-null mice did, however, display increased plasma insulin concentrations and a corresponding increase in glucose clearance following intraperitoneal and oral glucose challenge as compared with wild-type controls. The increased plasma insulin observed in G alpha(z)-null mice is most likely a direct result of enhanced insulin secretion, since pancreatic islets isolated from G alpha(z)-null mice exhibited significantly higher glucose-stimulated insulin secretion than those of wild-type mice. Finally, the increased insulin secretion observed in G alpha(z)-null islets appears to be due to the relief of a tonic inhibition of adenylyl cyclase, as cAMP production was significantly increased in G alpha(z)-null islets in the absence of exogenous stimulation. These findings indicate that G alpha(z) may be a potential new target for therapeutics aimed at ameliorating beta-cell dysfunction in Type 2 diabetes.