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ENDO 2006 GABAB receptors in the regulation of glucose homeostasis: evaluation in the GABAB receptor knock-out mouse María M Bonaventura1*, Paolo N Catalano1,2, Flavia Saravia1,2, Bernhard Bettler3, Carlos Libertun1,2 and Victoria A Lux-Lantos1. 1Neuroendocrinology laboratory, Instituto de Biología y Medicina Experimental, Buenos Aires, Argentina, C1428ADN; 2Department of Physiology, Unversidad de Buenos Aires, Buenos Aires, Argentina and 3Department of Clinical-Biological Sciences, Institute of Physiology, University of Basel, Basel, Switzerland. GABA is found at high concentrations in the insular pancreas together with its synthetic and degrading enzymes, transporter proteins and receptors. GABAB receptors (GABABRs) are present in cells, while GABAARs are located mainly in cells. Although a complete GABA system is present in the endocrine pancreas, its role has remained controversial. Recently, it was demonstrated that GABA inhibits insulin secretion through GABABRs in MIN6 cells and in rat islets [1, 2]. Here our aim was to assess the role of GABABRs in the regulation of glucose homeostasis in vivo in: a) adult, male BALB/c mice treated with saline (SAL) or Baclofen (BACL, a GABABR agonist) and b) adult, male mice deficient in the GABAB1 subunit of the GABABR, which show a constitutive loss of GABAB responses (GABABKO) [3] and their wild-type (WT) controls. Blood glucose (GLUC) was measured with a Lifescan Glucose meter, serum insulin (INS) by a mouse insulin Elisa kit (Chrystalchem, Chicago, IL) and pancreatic insulin content by RIA. Pretreatment with BACL (7.5 mg/kg, 30 min before glucose injection) significantly impaired the blood glucose tolerance test (GTT) after a glucose load (2 g/kg, ip) (2-way ANOVA: interaction: p<0.01). GLUC returned to basal levels after 75 min in controls while remaining increased in BACL-injected mice, p<0.01. The INS response to ip glucose (3 g/kg) was significantly reduced by BACL pretreatment (p<0.01). Neither non-fasting nor fasting GLUC levels differed between WT and GABABKO mice. The GTT was significantly improved in GABABKO animals (2-way ANOVA: interaction: ns, genotype: p<0.001). Basal INS was slightly increased in GABABKO mice, though not reaching significance (p<0.07). After ip glucose injection, INS secretion was increased in GABABKO mice (Twoway ANOVA: interaction: ns, genotype: p<0.01). Pancreatic INS content was also augmented in GABABKO mice [INS (ng/mg tissue): WT: 9.81.9 (10) vs KO: 22.74.1 (12), p<0.01].We conclude that the activation of GABAB receptors by an agonist induces a significant inhibition of insulin secretion, with impairment in glucose tolerance. In the GABABKO mouse an increase in pancreatic insulin content is observed concomitant with an improved glucose tolerance test and increased insulin secretion upon stimulation. The results suggest that pancreatic GABA through its GABAB receptors is involved in the regulation of glucose homeostasis in vivo. The GABABKO mouse is an interesting model to study this hypothesis. References: 1 Brice NL, Varadi A, Aschcroft SJH, Molnar E: Metabobropic glutamate and GABAB receptors contribute to the modulation of glucose-stimulated insulin secretion in pancreatic beta cells. Diabetologia 2002;45:242-252. 2 Braun M, Wendt A, Buschard K, Salehi A, Sewing S, Gromada J, Rorsman P: GABAB receptor activation inhibits exocytosis in rat pancreatic {beta}-cells by G-protein-dependent activation of calcineurin. J Physiol 2004;559:397-409. 3 Schuler V, Luscher C, Blanchet C, Klix N, Sansig G, Klebs K, Schmutz M, Heid J, Gentry C, Urban L, Fox A, Spooren W, Jaton AL, Vigouret J, Pozza M, Kelly PH, Mosbacher J, Froestl W, Kaslin E, Korn R, Bischoff S, Kaupmann K, van der Putten H, Bettler B: Epilepsy, hyperalgesia, impaired memory, and loss of pre- and postsynaptic GABA(B) responses in mice lacking GABA(B(1)). Neuron 2001;31:47-58. Sources of Support: Supported by CONICET, ANPCYT, UBA, and Fundación de Ciencias Exactas y Naturales, Argentina