Deleterious Effects of a GAD65 Monoclonal Autoantibody on Islet Function

An intrinsic hallmark of Type 1 Diabetes is the correlation between appearance of autoantibodies directed against islet cell autoantigens with subsequent development of the disease. We recently studied effects of human monoclonal autoantibodies (mAb) derived from a pre-diabetic patient and demonstrated that a GAD65mAb penetrated and accumulated in beta cells and significantly reduced the insulin secretion rate (ISR). Accordingly, in the current study we performed more detailed analyses of the effects of this GAD65mAb on rat and human islets. ISR was suppressed by about 40% after three days of exposure. Mechanisms mediating the effects were found to involve inhibition of mitochondrial generation of ATP, which decreased in parallel with that of ISR. As expected, the GAD65mAb inhibited GABA secretion. The effects of GAD65mAb were observed in rat and human islets, but not in mouse islets, which do not express GAD65. GAD65mAb also reduced insulin secretion in vivo where decreased insulin levels after IP injection of glucose were observed in rats after IP injection of GAD65mAb. Thus, it appears that an islet cell autoantibody against GAD65 can directly impact and impair secretory function in islets in vitro and in vivo through a mechanism that involves inhibition of mitochondrial energetics.