Abstract:
: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 Ins2+/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 Ins2+/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.
journal_name
Mol Cell Endocrinoljournal_title
Molecular and cellular endocrinologyauthors
Tang W,Yuan Q,Xu B,Osei K,Wang Jdoi
10.1016/j.mce.2016.09.015subject
Has Abstractpub_date
2017-01-05 00:00:00pages
297-307eissn
0303-7207issn
1872-8057pii
S0303-7207(16)30380-Xjournal_volume
439pub_type
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