Beta cell secreted GABA sets appropriate insulin secretion by modulating islet calcium oscillations

Abstract

Objectives: Gamma-aminobutyric acid (GABA) is produced in pancreatic beta cells and is implicated in modulating islet function, yet its precise physiological role remains uncertain. This study aimed to determine the function of endogenous beta cell-derived GABA on insulin secretion and islet calcium dynamics by developing a conditional beta cell-specific knockout of GABA-synthesizing enzymes (GAD65 and GAD67).

Methods: Conditional knockout mice (Gad^βKO) lacking both GAD65 and GAD67 specifically in pancreatic beta cells were generated. Glucose-stimulated insulin secretion was measured in isolated islets and in vivo and islet Ca²⁺ oscillations were recorded using calcium imaging. The effects of GABA and its receptor agonists/antagonists were tested under various glucose conditions. Additional analyses were performed in high-fat diet-fed mice and human islets from donors with and without type 2 diabetes (T2D).

Results: Gad^βKO islets were devoid of GABA and showed excessive insulin secretion in response to glucose without anatomical changes in islet composition. These islets had defective Ca²⁺ oscillations, with prolonged active phases and reduced amplitudes. GABA application suppressed Ca²⁺ oscillations, an effect mediated by GABA_A and GABA_B receptors. High-fat diet-fed and T2D human islets were unresponsive to GABA and exhibited impaired Ca²⁺ oscillations.

Conclusions: This is the first study using a beta cell-specific GAD65/GAD67 knockout model. Endogenous beta cell-derived GABA is critical for modulating insulin secretion by maintaining proper Ca²⁺ oscillation dynamics. GABA signaling likely operates as a delayed negative feedback mechanism that reinforces oscillatory homeostasis in islets. The loss of GABA responsiveness, as seen in metabolic stress or T2D, may contribute to islet dysfunction. This work establishes GABA as a key regulator of islet rhythm and glucose responsiveness.

Keywords: Calcium oscillations; GABA; GABA receptor; Insulin secretion; Pancreatic islet; Type 2 diabetes.