title: Exenatide substantially improves proinsulin conversion and cell survival that augment Ins2+/Akitabeta cell function.
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+/Akitabeta-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+/Akitabeta-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.
authors.affiliation: Department of Endocrinology, Jiangsu Province Geriatric Institute Islet Cell Senescence and Function Research Laboratory, Jiangsu Province Official Hospital, 65 Jiangsu Road, Nanjing 210024, China. Electronic address: drtangwei@aliyun.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Tang
authors.affiliation: Department of Endocrinology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Qingxin
authors.initials: Q
authors.lastname: Yuan
authors.affiliation: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 211166, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Xu
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Kwame
authors.initials: K
authors.lastname: Osei
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA; Division of Endocrinology, Jiangsu Province Hospital on Integration of Chinese and Western Medicine, Nanjing University of Chinese and Western Medicine, Nanjing, Jiangsu 210028, China. Electronic address: jiewn@yahoo.com.
authors.forename: Jie
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002118:Calcium / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D000077270:Exenatide; D005947:Glucose / Q000494:pharmacology; D005951:Glucose Tolerance Test; D006706:Homeostasis / Q000187:drug effects; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology*; D011384:Proinsulin / Q000378:metabolism*; D045664:Proprotein Convertase 1 / Q000378:metabolism; D013997:Time Factors; D014688:Venoms / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D010455:Peptides; D014688:Venoms; D011384:Proinsulin; D000077270:Exenatide; D000242:Cyclic AMP; D045664:Proprotein Convertase 1; D005947:Glucose; D002118:Calcium
keywords: Beta cell survival; Exenatide; Insulin secretion; Proinsulin conversion; Proinsulin maturation imperfections