PATHOGENESIS OF DIABETES MELLITUS

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Insulin resistance, a highly prevalent state affecting approximately 50% of the population, is responsible for a number of pathophysiologic conditions including type II diabetes. The major site of insulin resistance as determined by conventional methods is muscle. The role of three factors likely to influence muscle insulin sensitivity will be explored--intrinsic muscle fiber profile (type I, IIa, and IIb), muscle membrane fluidity and its determinants (e.g., phospholipid fatty acid composition) and insulin-induced augmentation of muscle blood flow. The possibility that inherent muscle fiber profile may play a role in insulin resistance and altered basal energy expenditure will be examined. Insulin sensitivity and energy expenditure will be determined in subjects from the upper and lower quintiles for muscle fiber composition (lower quintile = decreased type I; increased IIb fibers). Studies are designed to determine whether muscle fiber profile changes observed in insulin resistance are primary or secondary, and which fiber type composition is more susceptible to inducible insulin resistance. Additionally these studies will explore how environmental factors (diet and exercise) affecting membrane fluidity and muscle phospholipid fatty acid composition interest with the inherent muscle profile to produce changes in insulin sensitivity. Monozygotic twins concordant and discordant for Type II diabetes will be used to probe the interaction between genetic and environmental factors in influencing muscle characteristics putatively important in determining insulin sensitivity. Finally the hypothesis will be examined that increased FFA of obesity and insulin resistant states may blunt the normal hemodynamic response to insulin by suppression of centrally-mediated adrenergic responses, thereby contributing to insulin resistance of muscle.