REGULATION OF GAD EXPRESSION IN RAT PANCREATIC-ISLETS AND BRAIN BY GAMMA-VINYL-GABA AND GLUCOSE

Glutamic acid decarboxylase (GAD) is an important autoantigen in insul in-dependent diabetes mellitus (IDDM), but little is known about its r egulation and function in islet cells. We investigated the effects of the GABA-transaminase inhibitor gamma-vinyl-GABA (GVG) on GAD expressi on in rat islets and brain in vitro and in vivo. In islets incubated i n high glucose culture medium there was an increase in GAD activity, G AD65 and GAD67 protein levels compared to low-glucose conditions; howe ver, even in high glucose, GVG still significantly suppressed GAD acti vity and GAD67 expression. Our observations suggest that glucose and G VG act on GAD in islets through different mechanisms. Quantitative imm unohistochemistry of pancreatic sections from rats treated with GVG in vivo using novel monoclonal antibodies specific for GAD65 and GAD67, showed a decrease in GAD67 expression (p < 0.005) relative to untreate d rats. The effects of GVG on rat pancreatic islets were very similar to these observed in brain of rats treated with GVG in vivo. In homoge nates of cerebral tissue from GVG treated rats containing both membran e-bound and soluble protein GAD67 levels were significantly decreased while GAD65 levels were not significantly changed compared to untreate d rats. In contrast, in homogenates of cerebral tissues containing onl y soluble cytosolic protein, GVG-treatment was also significantly foun d to decrease GAD65 levels. Taken together these results suggest that GVG potentially could be of use to decrease GAD expression in islet ce lls and consequently to deviate/inhibit the autoimmune response agains t the beta cells seen in IDDM.