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Glucagon Acting at the GLP-1 Receptor Contributes to β-Cell Regeneration Induced by Glucagon Receptor Antagonism in Diabetic Mice

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Version 2 2023-03-13, 20:02
Version 1 2023-02-24, 16:14
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posted on 2023-03-13, 20:02 authored by Tianjiao Wei, Xiaona Cui, Yafei Jiang, Kangli Wang, Dandan Wang, Fei Li, Xiafang Lin, Liangbiao Gu, Kun Yang, Jin Yang, Tianpei Hong, Rui Wei

Dysfunction of glucagon-secreting α-cells participates in the progression of diabetes, and glucagon receptor (GCGR) antagonism is regarded as a novel strategy for diabetes therapy. GCGR antagonism upregulates glucagon and glucagon-like peptide-1 (GLP-1) secretion, and notably promotes β-cell regeneration in diabetic mice. Here, we aimed to clarify the role of GLP-1 receptor (GLP-1R) activated by glucagon and/or GLP-1 in the GCGR antagonism-induced β-cell regeneration. We showed that in db/db mice and type 1 diabetic wild-type or Flox/cre mice, GCGR monoclonal antibody (mAb) improved glucose control, upregulated plasma insulin level, and increased β-cell area. Notably, blockage of systemic or pancreatic GLP-1R signaling by exendin 9-39 (Ex9) or Glp1r knockout diminished the above effects of GCGR mAb. Furthermore, glucagon neutralizing antibody (nAb), which prevents activation of GLP-1R by glucagon, also attenuated the GCGR mAb-induced insulinotropic effect and β-cell regeneration. In cultured primary mouse islets isolated from normal mice and db/db mice, GCGR mAb action to increase insulin release, and to upregulate β-cell specific marker expression, was reduced by a glucagon nAb, or by the GLP-1R antagonist Ex9, or by a pancreas-specific Glp1r knockout. These findings suggest that activation of GLP-1R by glucagon participates in β-cell regeneration induced by GCGR antagonism in diabetic mice.

Funding

This work was supported by research grants 81830022 (T.H.), 81970671 (R.W.), 82270843 (R.W.), 82170875 (T.H.) and 82271611 (K.Y.) from the National Natural Science Foundation of China. This work was also supported by Peking University Medicine Fund of Fostering Young Scholars’ Scientific & Technological Innovation and Talent Project of Clinical Key Project of Peking University Third Hospital (R.W.). The funding agencies were not involved in the design of the study; the collection, analysis, and interpretation of data; writing the report; and did not impose any restrictions regarding the publication of the report.

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