Expression of glutamic acid decarboxylase (GAD) in the alpha, beta and delta cells of normal and diabetic pancreas: implications for the pathogenesis of type I diabetes.

One of the paradoxes of insulin-dependent diabetes mellitus is that the destruction of the pancreatic islets' endocrine cells is restricted to the insulin-producing beta cells, whereas the main autoantibodies, islet cell antibodies (ICA), are directed against all endocrine islet cells. GAD has recently been proposed as the main target of the humoral and cellular autoimmune attack to the islets, and since in rat pancreas this enzyme was expressed only in the beta cells, this provided an explanation for the cell specificity of the destructive process. The finding of GAD-positive cells in the islets of two diabetic patients, one of whom had completely lost the beta cells, led us to study in detail the distribution of GAD in normal human islet cells using a panel of GAD antisera and the double indirect immunofluorescence technique on cryostat sections, monolayer cultures and cytosmears. The results showed that GAD is present not only in the cytoplasm of beta cells but also in 69% of the alpha and 27% of the delta cells. GAD was not present, however, on the surface of the islet cells. These results suggest that the cellular distribution of GAD can not by itself explain the selectivity of beta cell destruction in insulin-dependent diabetes mellitus.