Pro-α-cell-derived β-cells contribute to β-cell neogenesis induced by antagonistic glucagon receptor antibody in type 2 diabetic mice
Xiaona Cui,
Jin Feng,
Tianjiao Wei,
Liangbiao Gu,
Dandan Wang,
Shan Lang,
Kun Yang,
Jin Yang,
Hai Yan,
Rui Wei,
Tianpei Hong
Affiliations
Xiaona Cui
Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing 100191, China; Clinical Stem Cell Research Center, Peking University Third Hospital, Beijing 100191, China
Jin Feng
Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing 100191, China
Tianjiao Wei
Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing 100191, China; Clinical Stem Cell Research Center, Peking University Third Hospital, Beijing 100191, China
Liangbiao Gu
Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing 100191, China; Clinical Stem Cell Research Center, Peking University Third Hospital, Beijing 100191, China
Dandan Wang
Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing 100191, China
Shan Lang
Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing 100191, China
Kun Yang
Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing 100191, China; Clinical Stem Cell Research Center, Peking University Third Hospital, Beijing 100191, China
Jin Yang
Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing 100191, China; Clinical Stem Cell Research Center, Peking University Third Hospital, Beijing 100191, China
Hai Yan
REMD Biotherapeutics, Camarillo, CA 93012, USA; Beijing Cosci-REMD, Beijing 102206, China
Rui Wei
Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing 100191, China; Clinical Stem Cell Research Center, Peking University Third Hospital, Beijing 100191, China; Corresponding author
Tianpei Hong
Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing 100191, China; Clinical Stem Cell Research Center, Peking University Third Hospital, Beijing 100191, China; Corresponding author
Summary: 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.
