Glucagon receptor blockage inhibits Β-cell dedifferentiation through FoxO1.

Glucagon-secreting pancreatic a-cells play pivotal roles in the development of diabetes. Glucagon promotes insulin secretion from b-cells. However, the long-term effect of glucagon on the function and phenotype of &#914-cells had remained elusive. In this study, we found that long-term glucagon intervention or glucagon intervention with the presence of palmitic acid downregulated &#914-cell-specific markers and inhibited insulin secretion in cultured &#914-cells. These results suggested that glucagon induced &#914-cell dedifferentiation under pathological conditions. Glucagon blockage by a glucagon receptor (GCGR) monoclonal antibody (mAb) attenuated glucagon-induced &#914-cell dedifferentiation. In primary islets, GCGR mAb treatment upregulated &#914-cell-specific markers and increased insulin content, suggesting that blockage of endogenous glucagon-GCGR signaling inhibited &#914-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 &#914-cell dedifferentiation. In db/db mice and &#914-cell lineage-tracing diabetic mice, GCGR mAb lowered glucose level, upregulated plasma insulin level, increased &#914-cell area, and inhibited &#914-cell dedifferentiation. In aged &#914-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, &#914-cell area, and &#914-cell dedifferentiation were not affected by GCGR mAb. Our results proved that glucagon induced &#914-cell dedifferentiation under pathological conditions, and the effect was partially mediated by FoxO1. Our study reveals a novel cross talk between a- and &#914-cells and is helpful to understand the pathophysiology of diabetes and discover new targets for diabetes treatment. [ABSTRACT FROM AUTHOR]