GLP-1 analog liraglutide enhances proinsulin processing in pancreatic β-cells via a PKA-dependent pathway.
GLP-1 analog liraglutide enhances proinsulin processing in pancreatic β-cells via a PKA-dependent pathway.
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DOI：
10.1210/en.2014-1218
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发表时间：
2014-07
期刊：
影响因子：
4.8
通讯作者：
Liang Wang;Ye Liu;Jin Yang;Hejun Zhao;Jing Ke;Qing Tian;Lin Zhang;J. Wen;Rui Wei;T. Hong
中科院分区：
文献类型：
--
作者：
Liang Wang;Ye Liu;Jin Yang;Hejun Zhao;Jing Ke;Qing Tian;Lin Zhang;J. Wen;Rui Wei;T. Hong
高胰岛素原血症在 2 型糖尿病的发生过程中受到越来越多的关注。临床研究表明，基于胰高血糖素样肽 1 (GLP-1) 的疗法可显着降低 2 型糖尿病患者的血浆胰岛素原/胰岛素比率。然而，其根本机制仍不清楚。激素原转化酶 (PC)-1/3 和 PC2 主要负责在胰腺 β 细胞中将胰岛素原加工成胰岛素。我们最近报道 Pax6 突变下调 PC1/3 和 PC2 表达，导致 Pax6 杂合突变体 (Pax6(m/+)) 小鼠胰岛素原加工缺陷。在这项研究中，我们研究了利拉鲁肽（一种新型 GLP-1 类似物）是否以及如何调节胰岛素原加工。我们的结果表明，在 Pax6(m/+) 和 db/db 糖尿病小鼠中，利拉鲁肽显着上调 PC1/3 表达并降低胰岛素原与胰岛素的比率。在培养的小鼠胰腺 β 细胞系 Min6 中，利拉鲁肽刺激 PC1/3 和 PC2 表达，并以剂量和时间依赖性方式降低胰岛素原与胰岛素的比率。此外，利拉鲁肽对 PC1/3 和 PC2 表达以及胰岛素原加工的有益作用依赖于 GLP-1 受体介导的 cAMP/蛋白激酶 A 信号通路。在分离的小鼠胰岛中重现了相同的机制。总之，利拉鲁肽通过激活 GLP-1 受体/cAMP/蛋白激酶 A 信号通路增强胰腺 β 细胞中 PC1/3 和 PC2 依赖性胰岛素原加工。我们的研究提供了一种通过基于 GLP-1 的疗法改善胰腺 β 细胞功能的新机制。
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.