GABAB receptors and glucose homeostasis: evaluation in GABAB receptor knock-out mice

BONAVENTURA MM; CATALANO, P. N; CHAMSON-REIG, ASTRID; EDITH ARANY; DAVID HILL; BETTLER B; LIBERTUN C; LUX-LANTOS, V

AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM

The Society of Physiology

Lugar: Bethesda MD; Año: 2008 vol. 294 p. 157 - 167

0193-1849

GABA has been proposed to inhibit insulin secretion through GABAB receptors(GABABRs) in pancreatic β-cells. We investigated whether GABABRs participated inthe regulation of glucose homeostasis in vivo.Animals: adult, male and female, BALB/C mice; mice deficient in the GABAB1 subunitof the GABABR (GABAB(-/-)) and wild-types (WT). Blood glucose was measured underfasting/fed conditions and in glucose tolerance tests (GTTs) with a Lifescan Glucosemeter, serum insulin was measured by Elisa. Pancreatic insulin content and islet insulinrelease by RIA. Western blots for the GABAB1 subunit in islet membranes andimmunohistochemistry for insulin and GABAB1 were performed in both genotypes.BALB/C mice pre-injected with Baclofen (GABABR agonist, 7.5 mg/kg ip) presentedimpaired 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). Baclofenpretreatment did not modify GTTs in GABAB(-/-) mice while impairing normal glycemiareinstatement in wild-types. Baclofen inhibited glucose-stimulated insulin secretion inwild-type isolated islets but was without effect in GABAB(-/-) islets. In GABAB(-/-) males:pancreatic insulin content was increased, basal and glucose-stimulated insulin secretionwas augmented, impaired insulin tolerance test and increased homeostatic modelassessment of insulin resistance index were determined. Immunohistochemistry forinsulin demonstrated an increase of very large islets in GABAB(-/-) males.Results demonstrate that GABABRs are involved in the regulation of glucosehomeostasis in vivo, and that the constitutive absence of GABABRs induces alterationsin pancreatic histology, physiology as well as insulin resistance.