1203-OR: V1bR Signaling Amplifies Alpha-Cell Glucagon Secretion and Coordinates Islet Paracrine Regulation of Glucose Homeostasis

Introduction and Objective: Although hyperglucagonemia contributes to excessive hepatic glucose output and hyperglycemia in diabetes, many mechanisms that regulate glucagon secretion remain poorly understood. The Gq-coupled vasopressin 1b receptor (V1bR) is highly expressed in α-cells and activated by vasopressin (AVP), which is elevated in patients with type 2 diabetes. The objective of this study was to determine how α-cell V1bR contributes to glucagon secretion and glucose homeostasis. Methods: We generated an α-cell-specific V1bR knockdown mouse model using CRISPRi (αV1bR-KD). Plasma glucose and glucagon were measured after intraperitoneal glucose or 2-deoxy-D-glucose (2DG) injection. Glucagon secretion was also assessed using perifusion assays. Islet Ca2+ and cAMP dynamics were evaluated with dyes or genetically encoded indicators. Results: αV1bR-KD mice show improved glucose tolerance compared with α-Cre controls, demonstrated by decreased area under the curve (AUC, -5110±1950, P<0.05). Additionally, blocking glycolysis with 2DG caused reduced plasma glucagon in αV1bR-KD mice (-37.26±11.98 pM/L, P<0.05). V1bR activation enhanced α-cell Ca2+ influx in a glucose-dependent manner (11.22±1.82 AUC, P<0.01), leading to increased glucagon secretion in α-Cre control islets, whereas no effect was observed in αV1bR-KD islets (-0.7±0.1 AUC, P<0.01). The glucose dependence of V1bR signaling was dependent on SST signaling and blocked by SSTR2 inhibitors. V1bR-mediated glucagon secretion also caused paracrine stimulation of β-cell cAMP (3.0±0.5 AUC, P<0.01) and β-cell Ca2+ oscillation frequency (0.09±0.02 per minute, P<0.05). Conclusion: α-cell V1bR amplifies glucagon secretion during hypoglycemia and enhances α- to β-cell paracrine signaling but reduces glucose tolerance. These findings suggest that alterations in circulating AVP during the pathogenesis of diabetes may contribute to hyperglucagonemia and hyperglycemia.