ABSTRACT
Address correspondence to: Simeon I.Taylor, M.D., Ph.D. National Institutes of Health Building 10, Room 9S-213 10 Center Drive Bethesda, MD 20892 Tel. # (301)496-4658 EAX: (301)402-0573 e-mail: Simeon_Taylor@nih.gov
INTRODUCTION
The insulin receptor is a transmembrane glycoprotein that mediates the first step in insulin action (Figure 1) (1, 2). When insulin binds to the extracellular domain of the receptor, this stimulates the intrinsic tyrosine kinase activity of the intracellular domain. Activation of the receptor tyrosine kinase triggers multiple signaling pathways that mediate insulin action. Because of the essential role of the insulin receptor in insulin action, genetic defects in insulin receptor function can cause insulin resistance. Most of the reported mutations have been identified in patients with relatively uncommon variants of diabetes mellitus associated with extreme insulin resistance (e.g., leprechaunism, type A insulin resistance, and the Rabson-Mendenhall syndrome) (1, 2). All three syndromes have two clinical features in common: hyperandrogenism and acanthosis nigricans (1-3). In addition, each distinct syndrome is defined by the presence of specific clinical features. The clinical severity of the syndromes seems to be related to severity of the impairment in receptor function: 1. Type A insulin resistance. This is the mildest of the three syndromes, defined by insulin resistance, acanthosis nigricans, and hyperandrogenism in the absence of obesity or lipoatrophy (4). While most patients with type A insulin resistance are heterozygotes with a mutation in only one allele of the insulin receptor gene (5-8), some patients have two mutant alleles (9, 10). Patients with two mutant alleles usually develop fasting hyperglycemia during childhood or adolescence (4, 11), heterozygotes may manifest either insulin resistance or impaired glucose tolerance in the absence of overt diabetes. 2. Rabson-Mendenhall syndrome. In addition to insulin resistance, acanthosis nigricans, hyperandrogenism, the definition of the Rabson-Mendenhall syndrome included short stature, abnormalities of teeth and nails, and pineal hyperplasia (12). From the clinical point of view, this syndrome is intermediate in severity between type A insulin resistance and leprechaunism. Patients with the Rabson-Mendenhall syndrome have been reported to have mutations in both alleles of the insulin receptor gene (10, 13).
