EFFECTS OF GABAB AGONISTS AND ANTAGONISTS ON GLYCEMIA REGULATION IN MICE

MM. BONAVENTURA; M. CRIVELLO; ML. FERREIRA; C. LIBERTUN; V. LUX-LANTOS

Boston, USA

Congreso; ENDO 93rd Annual Meeting & Expo; 2011

g-Aminobutyric acid (GABA) has been proposed to inhibit insulin secretion through GABAB receptors (GABABRs) in pancreatic b-cells. GABABR knock-out mice show disruptions in glucose homeostasis (1). In clinical practice GABAB agonists are used in the treatment of anxiety, dream disorders and neuropathic pain; antagonists improve cognitive performance. Little is found in the literature analyzing the effect of GABAB analogues on glucose homeostasis in vivo, so this was the aim of our studies. BALB/c mice were chronically or acutely injected with GABAB agonist baclofen (Bac: 5 and 7.5 mg/kg of body weight –bw-) and/or antagonist 2-hydroxisaclofen (2OH: 10 and 15 mg/kg bw). Blood glucose was measured by a One touch® Ultra™ glucose meter from tail blood, serum insulin and glucagon by ELISA and serum corticosterone by RIA. Pancreatic islets were isolated from mice and glucose-stimulated insulin secretion tests (GSIS) were evaluated by RIA, in presence or absence of GABAB analogs. Mice acutely treated with Bac presented glucose intolerance [glycemia (mg/dl) at 75 min: Bac, 187 ± 16 vs sal 122 ± 5, Two-way ANOVA for repeated measures (RM), p<0.05] and diminished insulin secretion (serum insulin: Bac vs sal, two way ANOVA-RM, interaction: ns, Treatment factor p<0.05) during a glucose tolerance test (GTT). 2OH improved GTTs (glycemia at 75 min: 2OH, 113 ± 5 vs sal 155 ± 10, Two-way ANOVA-PM, p<0.05) and reversed the effect of Bac (glycemia at 75 min: Bac, 200 ± 16 vs sal, 166 ± 11, p<0.05; 2OH-Bac, 176 ± 7 vs sal, 166 ± 11, ns. Two-way ANOVA-RM). Also a slight increase in insulin secretion was observed with 2OH. In chronically-treated animals both the agonist and the antagonist induced impaired GTTs (glycemia: Bac and 2OH vs sal, two way ANOVA-RM, interaction: ns, Treatment factor p<0.05); the antagonist, but not the agonist, also induced a decrease in insulin secretion (serum insulin: 2OH vs sal, two way ANOVA-RM, interaction: ns, Treatment factor p<0.05). No alteration in insulin tolerance tests, body weight or food intake was observed with treatments. Bac inhibited glucose-stimulated insulin secretion and 2OH reversed the effect of Bac, both without affecting basal levels. Results demonstrate that GABABRs are involved in the regulation of glucose homeostasis in vivo. Treatment with agonists or antagonists, given acutely or chronically, altered glucose homeostasis and insulin secretion alerting to the need to evaluate glucose metabolism during clinical practice.