What question did this study set out to answer?

The study aims to explore the role of α-cell V1bR in glucagon secretion and its effects on glucose homeostasis.

June 8, 2026

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

Key Points

The study aims to explore the role of α-cell V1bR in glucagon secretion and its effects on glucose homeostasis.
Developed α-cell-specific V1bR knockdown mouse model using CRISPRi.
Measured plasma glucose and glucagon levels post glucose or 2DG injections.
Assessed glucagon secretion via perifusion assays and evaluated islet Ca2+ and cAMP dynamics.
αV1bR-KD mice displayed improved glucose tolerance with a decrease in AUC (-5110±1950, P<0.05).
Blocking glycolysis with 2DG led to reduced plasma glucagon in αV1bR-KD mice (-37.26±11.98 pM/L, P<0.05).
V1bR activation increased α-cell Ca2+ influx (11.22±1.82 AUC, P<0.01) and glucagon secretion in α-Cre controls, while αV1bR-KD islets showed no effect (-0.7±0.1 AUC, P<0.01).

Abstract

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, P0.05). Additionally, blocking glycolysis with 2DG caused reduced plasma glucagon in αV1bR-KD mice (-37.26±11.98 pM/L, P0.05). V1bR activation enhanced α-cell Ca2+ influx in a glucose-dependent manner (11.22±1.82 AUC, P0.01), leading to increased glucagon secretion in α-Cre control islets, whereas no effect was observed in αV1bR-KD islets (-0.7±0.1 AUC, P0.01). 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, P0.01) and β-cell Ca2+ oscillation frequency (0.09±0.02 per minute, P0.05). 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. Disclosure S. Gibson: None. P. Dadi: None. A. Lucerne: None. S. Peachee: None. D. Jacobson: None.

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