| First Author | Wei T | Year | 2023 |
| Journal | Diabetes | Volume | 72 |
| Issue | 5 | Pages | 599-610 |
| PubMed ID | 36826938 | Mgi Jnum | J:353344 |
| Mgi Id | MGI:7468563 | Doi | 10.2337/db22-0784 |
| Citation | Wei T, et al. (2023) Glucagon Acting at the GLP-1 Receptor Contributes to beta-Cell Regeneration Induced by Glucagon Receptor Antagonism in Diabetic Mice. Diabetes 72(5):599-610 |
| abstractText | Dysfunction of glucagon-secreting alpha-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 beta-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 beta-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 beta-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 beta-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 beta-cell specific marker expression, was reduced by a glucagon nAb, or by the GLP-1R antagonist Ex9, or by a pancreasspecific Glp1r knockout. These findings suggest that activation of GLP-1R by glucagon participates in beta-cell regeneration induced by GCGR antagonism in diabetic mice. |
