GABA is an inhibitory neurotransmitter synthesized and secreted by β-cells that is reported to modulate glucagon, somatostatin (SST) , and insulin secretion. However, the direction of the effect of GABA, whether stimulatory or inhibitory, on insulin secretion is controversial. Our results from human islets show that GABA is inhibitory to insulin secretion under glucose-stimulating conditions. Further, islets from conditional knockout mice lacking the GABA-synthesizing enzymes GAD65 and GAD67 oversecrete insulin during glucose stimulation, consistent with GABA being inhibitory. However, the inhibitory effect of GABA is somewhat paradoxical as ligation of GABA-A receptor Cl channels are expected to depolarize the β-cell that should contribute to stimulating insulin secretion. It is also unclear if GABA signaling in β-cells is strictly autocrine or if the observed inhibition is mediated through an indirect effect of inducing SST secretion which, in turn, inhibits β-cells. Here, we improve understanding of GABA’s effect on insulin secretion by transiently applying 100 μM of GABA to human islets during perifusion with low (3 mM) and high glucose (16.7 mM) . GABA stimulated both insulin and SST in low glucose but inhibited insulin and SST when applied in high glucose. Thus, the modulation of GABA presents both stimulatory and inhibitory effects on β- and δ-cells depending on glucose concentration. In addition, the effect of GABA on β-cells appears to be direct and independent of SST signaling because SST and insulin secretion both change in the same direction with applied GABA. These results suggest the hypothesis that β-cell GABA-A receptors convey stimulatory responses to GABA under low glucose, but that G-protein coupled GABA-B receptors mediate inhibitory GABA signaling under high glucose. This mechanism would provide a consensus model that reconciles decades of seemingly antithetical studies where GABA is either inhibitory or stimulatory.
S.Ferreira: None. D.W.Hagan: None. E.Phelps: Research Support; Immunocore, Ltd.
National Institutes of Health (R01DK124267)