Type 1 Diabetes (T1D) is known to develop over time when autoimmune processes attack and destroy beta cells thereby reducing the capacity to secrete adequate amounts of insulin. The relatively gradual progression of the disease offers an opportunity for therapeutic intervention to slow or prevent destruction of beta cells before the disease has reached symptomatic stages. Systematic development of drugs will be greatly accelerated with identification of steps that mediate the progression of the disease. An intrinsic hallmark of T1D is the appearance of several autoantibodies directed against islet cell antigens, including insulin and the 65kDa isoform of glutamate decarboxylase (GAD65). We recently revealed pathogenic effects of autoantibodies on isolated rat islets (that like human islets do express GAD65). The paradigm-shifting results of our now published study demonstrated the ability of GAD65mAb to

i. penetrate and accumulate in beta cells,

ii. localize to various and distinct subcellular structures and

iii. affect insulin secretory function.

Accordingly, our overall goal is to establish that our exciting in vitro results showing an impact of GAD65 autoantibodies (GAD65Ab) on intracellular processes in pancreatic beta cells support a mechanism for mediating Type 1 Diabetes (T1D). As a first step, we will endeavor to show the presence and effects of GAD65Ab in human islets and in particular in human islets from patients with T1D. Therefore we are requesting pancreatic slides to search for the presence of antibodies in GAD-positive vs. control patients.