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学科主题: 临床医学
题名:
GLP-1 Analog Liraglutide Enhances Proinsulin Processing in Pancreatic beta-Cells via a PKA-Dependent Pathway
作者: Wang, Liang1; Liu, Ye1; Yang, Jin1; Zhao, Hejun1; Ke, Jing1; Tian, Qing1; Zhang, Lin1; Wen, Jinhua2; Wei, Rui1; Hong, Tianpei1,2
刊名: ENDOCRINOLOGY
发表日期: 2014-10-01
DOI: 10.1210/en.2014-1218
卷: 155, 期:10, 页:3817-3828
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Endocrinology & Metabolism
研究领域[WOS]: Endocrinology & Metabolism
关键词[WOS]: GLUCAGON-LIKE PEPTIDE-1 ; TYPE-2 DIABETES-MELLITUS ; DISPROPORTIONATELY ELEVATED PROINSULIN ; PEPTIDASE-4 INHIBITOR SITAGLIPTIN ; STIMULATED INSULIN-SECRETION ; PROTEIN-KINASE-A ; GLUCOSE-TOLERANCE ; GLYCEMIC CONTROL ; TRANSLATIONAL CONTROL ; CHINESE POPULATION
英文摘要:

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 beta-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 beta-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 beta-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 beta-cell function by the GLP-1-based therapy.

语种: 英语
所属项目编号: 2012CB517502 ; 81070701 ; 81000315 ; 81270858 ; 20100001110083 ; 20120001120069 ; 20120001120063 ; 20120001120076
项目资助者: Chinese National 973 Program ; National Natural Sciences Foundation of China ; Specialized Research Fund for the Doctoral Program of Higher Education
WOS记录号: WOS:000342345000011
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/66222
Appears in Collections:北京大学第三临床医学院_期刊论文

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作者单位: 1.Peking Univ, Dept Endocrinol & Metab, Hosp 3, Beijing 100191, Peoples R China
2.Peking Univ, Stem Cell Res Ctr, Hlth Sci Ctr, Beijing 100191, Peoples R China

Recommended Citation:
Wang, Liang,Liu, Ye,Yang, Jin,et al. GLP-1 Analog Liraglutide Enhances Proinsulin Processing in Pancreatic beta-Cells via a PKA-Dependent Pathway[J]. ENDOCRINOLOGY,2014,155(10):3817-3828.
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