MECHNISMS OF PANCREATIC BETA CELL DEATH BY Ca^<2+>/CALMODULIN; USING TRANSGENIC MICE

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We investigated the mechanisms of the pancreatic beta cell death at the onset of diabetes mellitus using transgenic mice overexpressing calmodulin in a beta cell specific manner. We found the transgenic mice experienced the beta cell death in as early stage of the onset, which was worsened by the anti-diabetic sulphonylurea tolbutamide. This means that Ca^<2+> influx by tolbutamide via closure of the ATP-sensitive K^+-channel may cause the beta cell death. Ca^<2+>, the central second messenger for insulin secretion, may possess a toxic effect on the beta-cell life as an inducer of apoptosis. We also found L-NAME, an inhibitor of nitric oxide synthase (NOS), retarded the onset of hyperglycemia in the transgenic mice. Isoform-specific immunostaining of pancreata demonstrated neural NOS might participate in the beta cell apoptosis. Prevention of hyperglycemia in the mouse model occurred partially, suggesting other mechanisms are involved. Because glucose-induced this transgenic mouse is a model to investigate beta cell exhaustion under diabetic conditions.