Effects of GABAB agonists and antagonists on glycemia regulation in mice

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

Boston

Congreso; The Endocrine Society's 93st Annual Meeting; 2011

Endocrine Society

g-Aminobutyric acid (GABA) is found in high concentrations in the pancreas and the enzymes of synthesis and degradation of GABA are also expressed in islet ß cells. Although a complete GABA system had been characterized in the endocrine pancreas, its role in the regulation of pancreatic physiology has remained somewhat elusive. GABA has been proposed to inhibit insulin secretion through GABAB receptors (GABABRs) in pancreatic b-cells. Also, GABA released from b-cells inhibits glucagon release from a-cells, through GABAAR. In clinical practice GABAB agonists are used in the treatment of anxiety, dream disorders and neuropathic pain, and antagonists improve cognitive performance; despite of this, little is found in the literature analyzing the effect of GABAB analogues on glucose homeostasis in vivo. Previous results from our group show that GABABR knock-out mice present disruptions in glucose homeostasis and insulin sensitivity (Bonaventura y col., AJP-EM 298,E157-67:2008). Based on this evidence, the aim of our studies is to evaluate the effects of GABAB agonists and/or antagonists in chronic and acute treatments on glycemia regulation in vivo. DISCUSION: Mice acutely treated with Bac presented glucose intolerance and diminished insulin secretion during a GTT. 2OH improved GTTs and reversed the effect of Bac. Also a slight increase in insulin secretion was observed with 2OH. In chronically-treated animals both the agonist and the antagonist induced impaired GTTs. The antagonist, but not the agonist, also induced a decrease in insulin secretion in a IST. No alteration in insulin tolerance tests, body weight or food intake was observed. In isolated islets in culture Bac inhibited glucose-stimulated insulin secretion and 2OH reversed the effect of Bac, both without affecting basal levels. Basal hormonal secretion was not altered by chronic treatments. CONCLUSION 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.