title: GLP-1 analog liraglutide enhances proinsulin processing in pancreatic β-cells via a PKA-dependent pathway.
abstract: Hyperproinsulinemia has gained increasing attention in the development of type 2 diabetes. Clinical studies have demonstrated that glucagon-like peptide-1 (GLP-1)-based therapies significantly decrease plasma proinsulin/insulin ratio in patients with type 2 diabetes. However, the underlying mechanism remains unclear. Prohormone convertase (PC)-1/3 and PC2 are primarily responsible for processing proinsulin to insulin in pancreatic β-cells. We have recently reported that Pax6 mutation down-regulated PC1/3 and PC2 expression, resulting in defective proinsulin processing in Pax6 heterozygous mutant (Pax6(m/+)) mice. In this study, we investigated whether and how liraglutide, a novel GLP-1 analog, modulated proinsulin processing. Our results showed that liraglutide significantly up-regulated PC1/3 expression and decreased the proinsulin to insulin ratio in both Pax6(m/+) and db/db diabetic mice. In the cultured mouse pancreatic β-cell line, Min6, liraglutide stimulated PC1/3 and PC2 expression and lowered the proinsulin to insulin ratio in a dose- and time-dependent manner. Moreover, the beneficial effects of liraglutide on PC1/3 and PC2 expression and proinsulin processing were dependent on the GLP-1 receptor-mediated cAMP/protein kinase A signaling pathway. The same mechanism was recapitulated in isolated mouse islets. In conclusion, liraglutide enhanced PC1/3- and PC2-dependent proinsulin processing in pancreatic β-cells through the activation of the GLP-1 receptor/cAMP/protein kinase A signaling pathway. Our study provides a new mechanism for improvement of pancreatic β-cell function by the GLP-1-based therapy.
authors: Department of Endocrinology and Metabolism (L.W., Y.L., J.Y., H.Z., J.K., Q.T., L.Z., R.W., T.H.), Peking University Third Hospital, and Peking University Stem Cell Research Center (J.W., T.H.), Peking University Health Science Center, Beijing 100191, China.
authors: Liang
authors: L
authors: Wang
authors: Ye
authors: Y
authors: Liu
authors: Jin
authors: J
authors: Yang
authors: Hejun
authors: H
authors: Zhao
authors: Jing
authors: J
authors: Ke
authors: Qing
authors: Q
authors: Tian
authors: Lin
authors: L
authors: Zhang
authors: Jinhua
authors: J
authors: Wen
authors: Rui
authors: R
authors: Wei
authors: Tianpei
authors: T
authors: Hong
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives* / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D000069450:Liraglutide; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D011384:Proinsulin / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D011384:Proinsulin; D017868:Cyclic AMP-Dependent Protein Kinases