GABAB receptors and glucose homeostasis:: evaluation in GABAB receptor knockout mice

GABA has been proposed to inhibit insulin secretion through GABA(B) receptors (GABA(B)Rs) in pancreatic beta-cells. We investigated whether GABA(B)Rs participated in the regulation of glucose homeostasis in vivo. The animals used in this study were adult male and female BALB/C mice, mice deficient in the GABA(B1) subunit of the GABA(B)R (GABA(B)(-/-)), and wild types (WT). Blood glucose was measured under fasting/fed conditions and in glucose tolerance tests (GTTs) with a Lifescan Glucose meter, and serum insulin was measured by ELISA. Pancreatic insulin content and islet insulin were released by RIA. Western blots for the GABA(B1) subunit in islet membranes and immunohistochemistry for insulin and GABA(B1) were performed in both genotypes. BALB/C mice preinjected with Baclofen (GABA(B)R agonist, 7.5 mg/kg ip) presented impaired GTTs and decreased insulin secretion compared with saline-preinjected controls. GABA(B)(-/-) mice showed fasting and fed glucose levels similar to WT. GABA(B)(-/-)mice showed improved GTTs at moderate glucose overloads (2 g/kg). Baclofen pretreatment did not modify GTTs in GABA(B)(-/-)mice, whereas it impaired normal glycemia reinstatement in WT. Baclofen inhibited glucose-stimulated insulin secretion in WT isolated islets but was without effect in GABA(B)(-/-)islets. In GABA(B)(-/-)males, pancreatic insulin content was increased, basal and glucose-stimulated insulin secretion were augmented, and impaired insulin tolerance test and increased homeostatic model assessment of insulin resistance index were determined. Immunohistochemistry for insulin demonstrated an increase of very large islets in GABA(B)(-/-)males. Results demonstrate that GABA(B)Rs are involved in the regulation of glucose homeostasis in vivo and that the constitutive absence of GABA(B)Rs induces alterations in pancreatic histology, physiology, and insulin resistance.