GABAergic regulation of pancreatic islet cells: Physiology and antidiabetic effects

Abstract

Diabetes occurs when pancreatic β‐cell death exceeds β‐cell growth, which leads to loss of β‐cell mass. An effective therapy must have two actions: promotion of β‐cell replication and suppression of β‐cell death. Previous studies have established an important role for γ‐aminobutyric acid (GABA) in islet‐cell hormone homeostasis, as well as the maintenance of the β‐cell mass. GABA exerts paracrine actions on α cells in suppressing glucagon secretion, and it has autocrine actions on β cells that increase insulin secretion. Multiple studies have shown that GABA increases the mitotic rate of β cells. In mice, following β‐cell depletion with streptozotocin, GABA therapy can restore the β‐cell mass. Enhanced β‐cell replication appears to depend on growth and survival pathways involving Akt activation. Some studies have also suggested that it induces transdifferentiation of α cells into β cells, but this has been disputed and requires further investigation. In addition to proliferative effects, GABA protects β cells against injury and markedly reduces their apoptosis under a variety of conditions. The antiapoptotic effects depend at least in part on the enhancement of sirtuin‐1 and Klotho activity, which both inhibit activation of the NF‐κB inflammatory pathway. Importantly, in xenotransplanted human islets, GABA therapy stimulates β‐cell replication and insulin secretion. Thus, the intraislet GABAergic system is a target for the amelioration of diabetes therapy, including β‐cell survival and regeneration. GABA (or GABAergic drugs) can be combined with other antidiabetic drugs for greater effect.

Harnessing the Endogenous Plasticity of Pancreatic Islets: A Feasible Regenerative Medicine Therapy for Diabetes?

“…In the islet, GABA is synthesized and released by β-cells and is likely involved in tuning the islet responses to glucose [73]. In vivo, GABA treatment of mouse models of diabetes improves glucose homeostasis by stimulating β-cell proliferation and decreasing apoptosis [74]. Consistent with these results, long-term treatment of wild-type mice causes islet hypertrophy mainly due to the increase in β-cell numbers [75].…”

Homotaurine Treatment Enhances CD4+ and CD8+ Regulatory T Cell Responses and Synergizes with Low-Dose Anti-CD3 to Enhance Diabetes Remission in Type 1 Diabetic Mice

“…The few residual b-cells in the islets of mice that had been severely diabetic make this model ill-suited for studies of GABA-R agonist's ability to induce b-cell replication because these agonists increase the frequency of replicative b-cells by only about 2-3-fold over the baseline level of ,1% in adult mice [reviewed in (68)]. However, we, and other groups, have observed GABA-enhanced b-cell replication in newly diabetic mice, which generally have a larger residual b-cell mass (11,26,69).…”

Propofol inhibits stromatoxin-1-sensitive voltage-dependent K+channels in pancreatic β-cells and enhances insulin secretion

“…It exerts this effect through potentiation of the inhibitory neurotransmitter γ -aminobutyric acid (GABA) at the GABA A receptor (GABA A R) (Korol et al, 2018; Sebel & Lowdon, 1989). β-cell-specific high-affinity GABA A R subtypes and physiologically relevant GABA concentrations together modulate insulin secretion in human pancreatic islets (Dong et al, 2006; Untereiner et al, 2019; Wang et al, 2019). Several studies indicate the involvement of GABA in human islet-cell hormone homeostasis, as well as the maintenance of the β-cell mass.…”