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

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 GABA^A-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.