Abstract
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 (mAbs) derived from a patient with prediabetes and demonstrated that a GAD65mAb penetrated and accumulated in β-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 ∼40% after 3 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 γ-aminobutyric acid 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 intraperitoneal (i.p.) injection of glucose were observed in rats after i.p. 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. ARTICLE HIGHLIGHTS: This study was undertaken to further investigate the ability of a monoclonal autoantibody to GAD65 from a patient with pre-type 1 diabetes to be deleterious to islet function. The study was designed to further characterize the effects, understand the mechanism mediating the effects, and demonstrate that the effects were operational in vivo. The effects of the GAD65 monoclonal antibody reduced ATP, γ-aminobutyric acid secretion, and insulin secretion with a similar time course and concentration dependency, which appeared to be mediated by effects on mitochondrial energetics and were similar in vivo in rats as in vitro. These findings raise the possibility that autoantibodies could play a pathogenic role in the development of type 1 diabetes.