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This Article Full Text Full Text (PDF) All Versions of this Article: 294/1/E157    most recent 00615.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Bonaventura, M. M. Articles by Lux-Lantos, V. A. Search for Related Content PubMed PubMed Citation Articles by Bonaventura, M. M. Articles by Lux-Lantos, V. A.

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

¹Instituto de Biología y Medicina Experimental-Consejo Nacional de Investigaciones Científicas y Técnicas; ²Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina; ³Lawson Health Research Institute, St. Joseph's Health Care, London, Ontario, Canada; and ⁴Department of Biomedicine, University of Basel, Basel, Switzerland

Submitted 16 November 2006 ; accepted in final form 22 October 2007

GABA has been proposed to inhibit insulin secretion through GABA_B receptors (GABA_BRs) in pancreatic β-cells. We investigated whether GABA_BRs 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_BR (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_BR 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_BRs are involved in the regulation of glucose homeostasis in vivo and that the constitutive absence of GABA_BRs induces alterations in pancreatic histology, physiology, and insulin resistance.

-aminobutyric acid; insulin; glycemia; pancreas histology