Insulin resistance contributes to the pathogenesis of several disease states including obesity and noninsulin-dependent diabetes mellitus (NIDDM). We have investigated the insulin receptor gene in patients with genetic forms of insulin resistance to gain insight into biochemical defects that give rise to disease. Five classes of mutations have been identified: 1. Impaired receptor biosynthesis, due to either decreased levels of insulin receptor mRNA and/or premature chain termination mutations. 2. Impaired transport of receptors to the plasma membrane, due to missense mutations in the extracellular domain of the receptor. 3. Decreased affinity of insulin binding. 4. Decreased activity of the insulin receptor tyrosine kinase. 5. Accelerated receptor degradation associated with resistance to the effect of acid pH to dissociate insulin from its receptor within the endosome. Studies are presently underway to estimate the prevalence of mutations in the insulin receptor gene in order to determine whether mutations in this gene contribute to the pathogenesis of the common form of noninsulin- dependent diabetes mellitus.
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