Glucose-inhibition of glucagon secretion involves activation of GABAA-receptor chloride channels

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Abstract
THE endocrine part of the pancreas plays a central role in blood-glucose regulation. It is well established that an elevation of glucose concentration reduces secretion of the hyperglycaemia-associated hormone glucagon from pancreatic α2 cells. The mechanisms involved, however, remain unknown. Electrophysio-logical studies have demonstrated that α2 cells generate Ca2+-dependent action potentials. The frequency of these action poten-tials, which increases under conditions that stimulate glucagon release, is not affected by glucose or insulin1. The inhibitory neurotransmitter γ-aminobutyric acid (GABA) is present in the endocrine part of the pancreas at concentrations comparable to those encountered in the central nervous system2, and co-localizes with insulin in pancreatic β cells3. We now describe a mechanism whereby GABA, co-secreted with insulin from β cells, may mediate part of the inhibitory action of glucose on glucagon secretion by activating GABAA-receptor Cl− channels in α2 cells. These observations provide a model for feedback regulation of glucagon release, which may be of significance for the understanding of the hypersecretion of glucagon frequently associated with diabetes4.