| First Author | Wang K | Year | 2023 |
| Journal | Am J Physiol Endocrinol Metab | Volume | 324 |
| Issue | 1 | Pages | E97-E113 |
| PubMed ID | 36383639 | Mgi Jnum | J:335236 |
| Mgi Id | MGI:7467551 | Doi | 10.1152/ajpendo.00101.2022 |
| Citation | Wang K, et al. (2023) Glucagon receptor blockage inhibits beta-cell dedifferentiation through FoxO1. Am J Physiol Endocrinol Metab 324(1):E97-E113 |
| abstractText | Glucagon-secreting pancreatic alpha-cells play pivotal roles in the development of diabetes. Glucagon promotes insulin secretion from beta-cells. However, the long-term effect of glucagon on the function and phenotype of beta-cells had remained elusive. In this study, we found that long-term glucagon intervention or glucagon intervention with the presence of palmitic acid downregulated beta-cell-specific markers and inhibited insulin secretion in cultured beta-cells. These results suggested that glucagon induced beta-cell dedifferentiation under pathological conditions. Glucagon blockage by a glucagon receptor (GCGR) monoclonal antibody (mAb) attenuated glucagon-induced beta-cell dedifferentiation. In primary islets, GCGR mAb treatment upregulated beta-cell-specific markers and increased insulin content, suggesting that blockage of endogenous glucagon-GCGR signaling inhibited beta-cell dedifferentiation. To investigate the possible mechanism, we found that glucagon decreased FoxO1 expression. FoxO1 inhibitor mimicked the effect of glucagon, whereas FoxO1 overexpression reversed the glucagon-induced beta-cell dedifferentiation. In db/db mice and beta-cell lineage-tracing diabetic mice, GCGR mAb lowered glucose level, upregulated plasma insulin level, increased beta-cell area, and inhibited beta-cell dedifferentiation. In aged beta-cell-specific FoxO1 knockout mice (with the blood glucose level elevated as a diabetic model), the glucose-lowering effect of GCGR mAb was attenuated and the plasma insulin level, beta-cell area, and beta-cell dedifferentiation were not affected by GCGR mAb. Our results proved that glucagon induced beta-cell dedifferentiation under pathological conditions, and the effect was partially mediated by FoxO1. Our study reveals a novel cross talk between alpha- and beta-cells and is helpful to understand the pathophysiology of diabetes and discover new targets for diabetes treatment.NEW & NOTEWORTHY Glucagon-secreting pancreatic alpha-cells can interact with beta-cells. However, the long-term effect of glucagon on the function and phenotype of beta-cells has remained elusive. Our new finding shows that long-term glucagon induces beta-cell dedifferentiation in cultured beta-cells. FoxO1 inhibitor mimicks whereas glucagon signaling blockage by GCGR mAb reverses the effect of glucagon. In type 2 diabetic mice, GCGR mAb increases beta-cell area, improves beta-cell function, and inhibits beta-cell dedifferentiation, and the effect is partially mediated by FoxO1. |
