Submitted on November 16, 2006
Accepted on October 22, 2007
GABAB RECEPTORS AND GLUCOSE HOMEOSTASIS: EVALUATION IN GABAB RECEPTOR KNOCK-OUT MICE
Maria Marta Bonaventura1, Paolo N Catalano1, Astrid Chamson-Reig2, Edith Arany3, David J. Hill3, Bernhard Bettler4, Flavia E Saravia5, Carlos Libertun6, and Victoria A Lux-Lantos7*
1 Neuroendocrinology Laboratory, Instituto de Biologia y Medicina Experimental, Buenos Aires, Argentina
2 Lawson Health Research Institute, St. Joseph's Health Care, London, Canada
3 London, Canada; Lawson Health Research Institute, St. Joseph's Health Care, London, Canada
4 Pharmazentrum/Biozentrum, University of Basel, Basel, Switzerland
5 IBYME, Laboratorio de Bioquimica Neuroendocrina, Capital Federal, Argentina
6 Neuroendocrinology Laboratory, IBYME, Buenos Aires, Argentina
7 Buenos Aires, Argentina; Neuroendocrinology Laboratory, IBYME, Buenos Aires, Argentina
* To whom correspondence should be addressed. E-mail: vlux{at}dna.uba.ar.
GABA has been proposed to inhibit insulin secretion through GABAB receptors (GABABRs) in pancreatic 
-cells. We investigated whether GABABRs participated in the regulation of glucose homeostasis in vivo.
Animals: adult, male and female, BALB/C mice; mice deficient in the GABAB1 subunit of the GABABR (GABAB(-/-)) and wild-types (WT). Blood glucose was measured under fasting/fed conditions and in glucose tolerance tests (GTTs) with a Lifescan Glucose meter, serum insulin was measured by Elisa. Pancreatic insulin content and islet insulin release by RIA. Western blots for the GABAB1 subunit in islet membranes and immunohistochemistry for insulin and GABAB1were performed in both genotypes.
BALB/C mice pre-injected with Baclofen (GABABR agonist, 7.5 mg/kg ip) presented impaired GTTs and decreased insulin secretion compared to saline-preinjected controls. GABAB(-/-) mice showed fasting and fed glucose levels similar to wild-types. GABAB(-/-) mice showed improved GTTs at moderate glucose overloads (2g/kg). Baclofen pretreatment did not modify GTTs in GABAB(-/-) mice while impairing normal glycemia reinstatement in wild-types. Baclofen inhibited glucose-stimulated insulin secretion in wild-type isolated islets but was without effect in GABAB(-/-) islets. In GABAB(-/-) males: pancreatic insulin content was increased, basal and glucose-stimulated insulin secretion was augmented, 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 GABAB(-/-) males.
Results demonstrate that GABABRs are involved in the regulation of glucose homeostasis in vivo, and that the constitutive absence of GABABRs induces alterations in pancreatic histology, physiology as well as insulin resistance.
