The present proposal contains significant innovations from the progress report. The PI has made an interesting preliminary observation, namely that the generation of oxygen reactive species (ROS) is increased in diabetic patients. While this observation in itself is not novel (for example, Kitahara et al., Diabetes 29: 251, 1980; Hiramatsu et al., Diabetes 37:832, 1988), the PI made the novel observation that this finding can be explained by a decreased ATP generating capacity in the mitochondria. Based on the hypothesis that a mutation of mitochondrial DNA could account for this defect, the PI has identified a novel allele of mitochondrial DNA carrying a mutant haplotype of the ATP synthase 8 subunit. Next, he has shown that white blood cells from NIDDM patients show increased heteroplasmy for this mutant allele. Consistent with this observation, the PI has shown that ATP synthase activity in mitochondria of NIDDM patients is decreased. The PI espouses the view that impaired mitochondrial function may play a role in the pathogenesis of NIDDM, by impairing insulin secretion. Studies of mitochondrial function are proposed using the technique of mitochondria depletion followed by repopulation with mutant mitochondria from NIDDM patients. A clinical correlation with parameter such as insulin resistance, insulin secretion, hepatic glucose production will also be assessed.
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