Pro-α-cell-derived β-cells contribute to β-cell neogenesis induced by antagonistic glucagon receptor antibody in type 2 diabetic mice.
Pro-α-cell-derived β-cells contribute to β-cell neogenesis induced by antagonistic glucagon receptor antibody in type 2 diabetic mice.
复制标题
前α细胞衍生的β细胞有助于2型糖尿病小鼠拮抗性胰高血糖素受体抗体诱导的β细胞新生
DOI：
10.1016/j.isci.2022.104567
复制
发表时间：
2022-07-15
期刊：
影响因子：
5.8
通讯作者：
Hong, Tianpei
中科院分区：
文献类型：
--
作者：
Cui, Xiaona;Feng, Jin;Wei, Tianjiao;Gu, Liangbiao;Wang, Dandan;Lang, Shan;Yang, Kun;Yang, Jin;Yan, Hai;Wei, Rui;Hong, Tianpei
胰腺β细胞的缺乏是糖尿病的关键发病机制，而胰高血糖素分泌α细胞是糖尿病发展的另一个参与者。本研究旨在探讨胰高血糖素受体（glucagon receptor，GCGR）拮抗剂对2型糖尿病（type 2 diabetes，T2 D）小鼠胰岛β细胞新生的影响，并探讨新生胰岛β细胞的来源。我们发现，GCGR单克隆抗体（mAb）提高了T2 D小鼠的血浆胰岛素水平和β细胞质量。通过使用α-细胞谱系示踪（glucagon-cre-β-gal）小鼠和诱导型Ngn 3+胰腺内分泌祖细胞谱系示踪（Ngn 3-CreERT 2-tdTomato）小鼠，我们发现GCGR mAb处理促进α-细胞退化为祖细胞，并诱导Ngn 3+祖细胞重新激活并向β-细胞分化。此外，GCGR mAb上调β细胞再生相关基因的表达水平，并促进原代小鼠胰岛中的胰岛素分泌，表明对β细胞特性的直接影响。我们的研究结果表明，GCGR拮抗作用不仅增加胰岛素分泌，而且促进T2 D小鼠中前α细胞衍生的β细胞新生。阻断α-细胞衍生的胰高血糖素促进2型糖尿病（T2 D）小鼠原位β细胞再生胰高血糖素受体（GCGR）mAb诱导α-细胞向β-细胞的转分化GCGR mAb促进α-细胞向胰腺内分泌祖细胞的退化GCGR mAb诱导Ngn 3+祖细胞再活化和向β-细胞的分化生理学;细胞生理学;内分泌学;细胞生物学
The deficiency of pancreatic β-cells is the key pathogenesis of diabetes, while glucagon-secreting α-cells are another player in the development of diabetes. Here, we aimed to investigate the effects of glucagon receptor (GCGR) antagonism on β-cell neogenesis in type 2 diabetic (T2D) mice and explore the origins of the neogenic β-cells. We showed that GCGR monoclonal antibody (mAb) elevated plasma insulin level and increased β-cell mass in T2D mice. By using α-cell lineage-tracing (glucagon-cre-β-gal) mice and inducible Ngn3+ pancreatic endocrine progenitor lineage-tracing (Ngn3-CreERT2-tdTomato) mice, we found that GCGR mAb treatment promoted α-cell regression to progenitors, and induced Ngn3+ progenitor reactivation and differentiation toward β-cells. Besides, GCGR mAb upregulated the expression levels of β-cell regeneration-associated genes and promoted insulin secretion in primary mouse islets, indicative of a direct effect on β-cell identity. Our findings suggest that GCGR antagonism not only increases insulin secretion but also promotes pro-α-cell-derived β-cell neogenesis in T2D mice. Blockage of α-cell-derived glucagon promotes β-cell regeneration in situ in type 2 diabetic (T2D) mice Glucagon receptor (GCGR) mAb induces the trans-differentiation of α-cells to β-cells GCGR mAb promotes α-cell regression to pancreatic endocrine progenitors GCGR mAb induces Ngn3+ progenitor reactivation and differentiation toward β-cells Physiology; Cellular physiology; Endocrinology; Cell biology
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DOI：
10.1111/j.1463-1326.2011.01447.x
发表时间：
2011-10
期刊：
Diabetes, obesity & metabolism
影响因子：
--
作者：
Vuguin PM;Charron MJ
通讯作者：
Charron MJ
影响因子：
7.7
作者：
Lee Y;Wang MY;Du XQ;Charron MJ;Unger RH
通讯作者：
Unger RH
影响因子：
29
作者：
van der Meulen T;Lee S;Noordeloos E;Donaldson CJ;Adams MW;Noguchi GM;Mawla AM;Huising MO
通讯作者：
Huising MO
影响因子：
105.7
作者：
Li, Yongze;Teng, Di;Shan, Zhongyan
通讯作者：
Shan, Zhongyan
DOI：
10.1073/pnas.1918314117
发表时间：
2020-05-19
影响因子：
11.1
作者：
Qadir, Mirza Muhammad Fahd;Alvarez-Cubela, Silvia;Dominguez-Bendala, Juan
通讯作者：
Dominguez-Bendala, Juan