Pro-α-cell-derived β-cells contribute to β-cell neogenesis induced by antagonistic glucagon receptor antibody in type 2 diabetic mice

被引：21

作者：

Cui, Xiaona ^{[1
,2
]}

Feng, Jin ^{[1
]}

Wei, Tianjiao ^{[1
,2
]}

Gu, Liangbiao ^{[1
,2
]}

Wang, Dandan ^{[1
]}

Lang, Shan ^{[1
]}

Yang, Kun ^{[1
,2
]}

Yang, Jin ^{[1
,2
]}

Yan, Hai ^{[3
,4
]}

Wei, Rui ^{[1
,2
]}

Hong, Tianpei ^{[1
,2
]}

机构：

[1] Peking Univ Third Hosp, Dept Endocrinol & Metab, Beijing 100191, Peoples R China

[2] Peking Univ Third Hosp, Clin Stem Cell Res Ctr, Beijing 100191, Peoples R China

[3] REMD Biotherapeut, Camarillo, CA 93012 USA

[4] Beijing Cosci REMD, Beijing 102206, Peoples R China

来源：

ISCIENCE | 2022年 / 25卷 / 07期

基金：

中国博士后科学基金; 中国国家自然科学基金;

关键词：

INSULIN-RESISTANCE; KNOCKOUT; GLUCOSE; PHARMACOLOGY; DYSFUNCTION; EXPRESSION; DIET;

D O I：

10.1016/j.isci.2022.104567

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The deficiency of pancreatic beta-cells is the key pathogenesis of diabetes, while glucagon-secreting alpha-cells are another player in the development of diabetes. Here, we aimed to investigate the effects of glucagon receptor (GCGR) antagonism on beta-cell neogenesis in type 2 diabetic (T2D) mice and explore the origins of the neogenic beta-cells. We showed that GCGR monoclonal antibody (mAb) elevated plasma insulin level and increased beta-cell mass in T2D mice. By using alpha-cell lineage-tracing (glucagon-cre-beta-gal) mice and inducible Ngn3(+) pancreatic endocrine progenitor lineage-tracing (Ngn3-CreERT2-tdTomato) mice, we found that GCGR mAb treatment promoted alpha-cell regression to progenitors, and induced Ngn3(+) progenitor reactivation and differentiation toward beta-cells. Besides, GCGR mAb upregulated the expression levels of beta-cell regeneration-associated genes and promoted insulin secretion in primary mouse islets, indicative of a direct effect on beta-cell identity. Our findings suggest that GCGR antagonism not only increases insulin secretion but also promotes pro-alpha-cell-derived beta-cell neogenesis in T2D mice.

引用

页数：18

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