Exenatide substantially improves proinsulin conversion and cell survival that augment Ins2+/Akita beta cell function

•Exenatide rapidly improves the proinsulin/insulin ratio of Ins2+/Akita beta-cell.•The 15 min improvement is calcium-independent.•The 120 min improvement is calcium/cAMP-dependent but PKA-independent.•Efficacy also on Ins2+/Akita beta-cell survival and Akita mouse's glucose tolerance.•GLP-1 mimetics show a potential in alleviating proinsulin misfolding consequences.

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.