Insulin protects islets from apoptosis via Pdx1 and specific changes in the human islet proteome

被引:164
作者
Johnson, James D. [1 ]
Bernal-Mizrachi, Ernesto
Alejandro, Emilyn U.
Han, Zhiqiang
Kalynyak, Tatyana B.
Li, Hong
Beith, Jennifer L.
Gross, Julia
Warnock, Garth L.
Townsend, R. Reid
Permutt, M. Alan
Polonsky, Kenneth S.
机构
[1] Univ British Columbia, Dept Cellular & Physiol Sci, Diabet Res Grp, Vancouver, BC V6T 1Z3, Canada
[2] Univ British Columbia, Dept Surg, Vancouver, BC V6T 1Z3, Canada
[3] Washington Univ, Sch Med, Dept Internal Med, St Louis, MO 63110 USA
关键词
diabetes; pancreatic beta-cells; programmed cell death; autocrine insulin feedback signaling; maturity onset diabetes of the young;
D O I
10.1073/pnas.0604208103
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Insulin is both a hormone regulating energy metabolism and a growth factor. We and others have shown that physiological doses of insulin initiate complex signals in primary human and mouse beta-cells, but the functional significance of insulin's effects on this cell type remains unclear. in the present study, the role of insulin in beta-cell apoptosis was examined. Exogenous insulin completely prevented apoptosis induced by serum withdrawal when given at picomolar or low nanomolar concentrations but not at higher concentrations, indicating that physiological concentrations of insulin are antiapoptotic and that insulin signaling is self-limiting in islets. Insulin treatment was associated with the nuclear localization of Pdx1 and the prosurvival effects of insulin were largely absent in islets 50% deficient in Pdx1, providing direct evidence that Pdx1 is a signaling target of insulin. Physiological levels of insulin did not increase Akt phosphorylation, and the protective effects of insulin were only partially altered in islets lacking 80% of normal Akt activity, suggesting the presence of additional insulin-regulated antiapoptotic pathways. Proteomic analysis of insulin-treated human islets revealed significant changes in multiple proteins. Bridge-1, a Pdx1-binding partner and regulator of, beta-cell survival, was increased significantly at low insulin doses. Together, these data suggest that insulin can act as a master regulator of islet survival by regulating Pdx1.
引用
收藏
页码:19575 / 19580
页数:6
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