期刊
MOLECULAR AND CELLULAR ENDOCRINOLOGY
卷 439, 期 C, 页码 297-307出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.mce.2016.09.015
关键词
Exenatide; Proinsulin maturation imperfections; Proinsulin conversion; Insulin secretion; Beta cell survival
资金
- Ohio State University
- Natural Science Foundation of China [81270861, 81370920]
- Natural Science Foundation of Jiangsu Province China [20131110]
- Jiangsu Province Six Talents Peak [2013WSN-023]
Proinsulin folding imperfections cause extensive beta-cell defects known in diabetes. Here, we investigated whether exenatide can alleviate such defects in proinsulin conversion, beta-cell survival, and insulin secretion, in the Ins(2+/Akita) beta-cells that have a spontaneous mutation (Cys 96 Tyr) in the insulin 2 gene caused dominant negative misfolding problem. 15 or 120 min exenatide administration substantially improves glucose-stimulated insulin secretion, marked in the secreted insulin levels and proinsulin/insulin ratio. This improvement is mainly due to enhanced conversion of proinsulin to insulin, having nothing to do with the prohormone convertase PC1 /3 and PC2 levels. The 15 min improvement is calcium-independent. The 120 min improvement is linked to calcium and/or CAMP dependent mechanisms. This efficacy is validated during longer treatment and in Akita islets. Exenatide improves Ins(2+/Akita) beta-cell survival and Akita mouse's glucose tolerance. The results suggest a potential of incretin mimetics in alleviating defective proinsulin conversion and other proinsulin misfolding consequences. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
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