| Abstract: | This review discusses the hypothesis that mitochondrial dysfunction plays a role in the pathogenesis of the most common form of diabetes, type II diabetes mellitus. Mitochondrial mutations have been linked to the development of diabetes mellitus as part of several rare syndromes, accounting for approximately 1.5% of all cases of the disease (“classic” mitochondrial diabetes). The characteristics of classic mitochondrial diabetes are intermediate between those of type I and type II diabetes, more closely resembling the latter. By studying the biochemical, cellular, and physiologic consequences of mitochondrial DNA mutations that cause classic mitochondrial diabetes, we may also gain important insights into the pathogenesis of type II diabetes mellitus. Individuals with classic mitochondrial diabetes exhibit a variety of defects in mitochondrial electron transfer enzyme activities. Complex I and Complex IV activities in skeletal muscle are almost universally decreased in mitochondrial diabetics compared with control individuals. The major physiologic abnormality in classic mitochondrial diabetes is delayed and insufficient insulin secretion in response to a glucose load. Insulin resistance is less commonly observed in these patients. The link between mitochondrial function and insulin secretion is supported by cellular studies in which introduction of inhibitors of oxidative phosphorylation or depletion of mitochondrial DNA markedly impairs glucose mediated insulin secretion from pancreatic β‐cells. Evidence for mitochondrial dysfunction in the common form of type II diabetes includes excessive free radical levels in the plasma of diabetics, increased reactive oxygen species, and decreased ATP synthase activity in cybrids constructed from mitochondria of diabetic patients, and maternal inheritance of the disease. By using the occurrence of diabetes in rare mitochondrial syndromes as an example, evidence supporting a relationship between mitochondrial dysfunction and the common form of type II diabetes is discussed. Mitochondrial function may represent a novel area for the development of therapeutic and diagnostic strategies for type II diabetes mellitus. Drug Dev. Res. 46:67–79, 1999. © 1999 Wiley‐Liss, Inc. |
