title: Baclofen, a gamma-aminobutyric acid-b receptor agonist, delays diabetes onset in the non-obese diabetic mouse.
abstract: Glutamic acid decarboxylase (GAD) is the enzyme responsible for the synthesis of gamma-aminobutyric acid (GABA). GAD has been identified as a 64-kDa antigen expressed in pancreatic beta-cells, to which autoantibodies are generated prior to the onset of type 1 (insulin-dependent) diabetes mellitus. GAD may therefore be an initiating factor in beta-cell destruction. We administered baclofen, a GABA-B receptor agonist, to non-obese diabetic (NOD) mice in an attempt to down-regulate GAD expression and thereby reduce the incidence of diabetes. Twenty-four female NOD mice were given baclofen in their drinking water at a final dose of 50 mg/kg body weight daily from weaning to 30 weeks of age. Twenty-four sex- and litter-matched mice were used as controls. At 30 weeks there was no difference in the incidence of diabetes in the treated group compared with the controls. However, there was a significant delay in the onset of diabetes in the treated group (P < 0.001, parallelism test). The degree of insulitis and the GAD activity in the pancreas per mg of protein were unchanged by baclofen treatment with respect to controls. These results suggest that baclofen may be effective in delaying diabetes onset in NOD mice by stimulating GABA activity, as this neurotransmitter, localised in the islets, may modulate insulin secretion and the antigen expression associated with it.
authors.affiliation: Department of Diabetes and Metabolism, St. Bartholomew's Hospital, London, UK.
authors.forename: P E
authors.initials: PE
authors.lastname: Beales
authors.forename: M
authors.initials: M
authors.lastname: Hawa
authors.forename: A J
authors.initials: AJ
authors.lastname: Williams
authors.forename: M C
authors.initials: MC
authors.lastname: Albertini
authors.forename: A
authors.initials: A
authors.lastname: Giorgini
authors.forename: P
authors.initials: P
authors.lastname: Pozzilli
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D001418:Baclofen / Q000494:pharmacology*; D003922:Diabetes Mellitus, Type 1 / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D058788:GABA-B Receptor Antagonists; D005968:Glutamate Decarboxylase / Q000378:metabolism; D007515:Islets of Langerhans / Q000473:pathology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D012469:Salivary Glands / Q000201:enzymology
chemical_list: D058788:GABA-B Receptor Antagonists; D005968:Glutamate Decarboxylase; D001418:Baclofen