Glucagon receptor blockage inhibits ?-cell dedifferentiation through FoxO1

Glucagon-secreting pancreatic a-cells play pivotal roles in the development of diabetes. Glucagon promotes insulin secretion from I3-cells. However, the long-term effect of glucagon on the function and phenotype of I3-cells had remained elusive. In this study, we found that long-term glucagon intervention or glucagon intervention with the presence of palmitic acid downregulated I3-cell-specific markers and inhibited insulin secretion in cultured I3-cells. These results suggested that glucagon induced I3-cell dedifferentiation under pathological conditions. Glucagon blockage by a glucagon receptor (GCGR) monoclonal antibody (mAb) attenuated glucagon-induced I3-cell dedifferentiation. In primary islets, GCGR mAb treatment upregulated I3-cell-specific markers and increased insulin content, suggesting that blockage of endogenous glucagon-GCGR signaling inhibited I3-cell dedifferentia-tion. 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 I3-cell dedifferentiation. In db/db mice and I3-cell lineage-tracing diabetic mice, GCGR mAb lowered glucose level, upregulated plasma insulin level, increased I3-cell area, and inhibited I3-cell dedifferentiation. In aged I3-cell-specific FoxO1 knockout mice (with the blood glucose level elevated as a dia-betic model), the glucose-lowering effect of GCGR mAb was attenuated and the plasma insulin level, I3-cell area, and I3-cell dedif-ferentiation were not affected by GCGR mAb. Our results proved that glucagon induced I3-cell dedifferentiation under pathological conditions, and the effect was partially mediated by FoxO1. Our study reveals a novel cross talk between a- and I3-cells and is helpful to understand the pathophysiology of diabetes and discover new targets for diabetes treatment.NEW & NOTEWORTHY Glucagon-secreting pancreatic a-cells can interact with I3-cells. However, the long-term effect of gluca-gon on the function and phenotype of I3-cells has remained elusive. Our new finding shows that long-term glucagon induces I3-cell dedifferentiation in cultured I3-cells. FoxO1 inhibitor mimicks whereas glucagon signaling blockage by GCGR mAb reverses the effect of glucagon. In type 2 diabetic mice, GCGR mAb increases I3-cell area, improves I3-cell function, and inhibits I3-cell de-differentiation, and the effect is partially mediated by FoxO1.