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

ABSTRACT: 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.

SUBMITTER: Cui X

PROVIDER: S-EPMC9249614 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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

Cui Xiaona X Feng Jin J Wei Tianjiao T Gu Liangbiao L Wang Dandan D Lang Shan S Yang Kun K Yang Jin J Yan Hai H Wei Rui R Hong Tianpei T

iScience 20220609 7

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 (<i>glucagon</ ...[more]

PMID: 35789836

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Project description:Glucose homeostasis is determined by a balance between insulin and glucagon, produced by beta and alpha cells of the pancreas respectively. The levels of circulating hormones is partly determined by the mass of these two endocrine cell types. However, in contrast to beta cells, the identity of the signals regulating alpha cell number is not known. Mice with a global deletion of the glucagon receptor (Gcgr-/-) and mice with ablation of prohormone convertase 2 (PC2), the enzyme involved in the conversion of proglucagon into mature glucagon, develop alpha cell hyperplasia. These observations and the fact that Gcgr-/- mice exhibit high levels of circulating glucagon-like peptide-1 (GLP-1) suggested that members of the glucagon family of peptides could be directly involved in the regulation of alpha cell number. In this study we sought to determine whether alpha cells express receptors for Glucagon (Gcgr) and/or the glucagon-like peptide-1 (GLP1r). We examined the expression of these receptors in islets of Gcgr-/-, PC2-/- mice and control littermates, in an alpha (alphaTC1/9) and in a beta (betaTC3) cell line. Gcgr was expressed exclusively by islet beta cells, but not by alpha cells, of the two lines of mice lacking glucagon signaling. Similarly, betaTC but not alphaTC cells, expressed Gcgr. The expression of GLP1r by alpha cells was determined by the genotype and age of the mice. In embryos, GLU+ cells of Gcgr+/+ mice cells express GLP1r during early development, but not in adults. In contrast, alpha cells of Gcgr-/- mice were GLP1r+ throughout life, reflecting the immature state of GLU+ cells when Gcgr is deleted. Unlike alpha cells, beta cells of all mice lines examined initiate GLP1r expression after birth. These results suggest that GLP-1 may affect the maturation of postnatal but not prenatal beta cells. In addition, they also suggest that the incretin could mediate alpha cell proliferation, inducing the development of alpha cell hyperplasia in Gcgr-/- mice.

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

Publications

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

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