INSULIN-MEDIATED PSEUDOACROMEGALY - CLINICAL AND BIOCHEMICAL-CHARACTERIZATION OF A SYNDROME OF SELECTIVE INSULIN-RESISTANCE

We have performed clinical, physiological, in vitro biochemical and ge netic studies of a patient with severe insulin resistance associated w ith the phenotype of ''pseudoacromegaly,'' defined as the presence of acromegaloid features in the absence of elevated levels of GH or insul in-like growth factor-I (IGF-I). Despite marked hyperinsulinemia, insu lin and IGF-I binding to circulating blood cells and cultured skin fib roblasts was normal. Insulin and IGF-1-stimulated autophosphorylation of their respective receptors in cultured skin fibroblasts was also no rmal. However, neither insulin nor IGF-I were able to stimulate 2-deox y D-glucose uptake by cultured skin fibroblasts. In contrast, the abil ity of insulin and IGF-I (or IGF-II) to stimulate amino acid uptake an d thymidine incorporation into DNA was not impaired. This unique disco rdant signaling defect through both insulin and IGF-I receptors appear ed not to be the consequence of altered expression or primary structur e of the insulin receptor or the GLUT-4 glucose transporter, as assess ed by several genetic and biochemical techniques. GLUT-4 expression in muscle was normal on Western blots, and SSCP screening of all 11 exon s of the gene for nucleotide variation revealed no variations from nor mal. DNA sequencing and SSCP screening of exons 2-22 of the insulin re ceptor gene revealed only one variation predicted to alter the amino a cid sequence (Val985-->Met). No functional differences between Met985 and wild-type human insulin receptors were evident in studies performe d with Chinese hamster ovary cell transfectants that overexpress eithe r receptor. This data combined with our previously published epidemiol ogical data concerning the frequency of the Met985 allele, indicate th at this variant insulin receptor is not responsible for the insulin re sistant glucose uptake or the clinical syndrome of pseudoacromegaly. W e conclude that: 1) The molecular lesion responsible for the selective biochemical defect in this individual appears to involve a signaling intermediate required for insulin and IGF-I regulation of glucose tran sport, and/or an effector mechanism operative in this process. 2) Cell s derived from this patient may be a valuable tool in the search for s uch molecular mechanisms. 3) The Met985 allele is a relatively common variant which has no demonstrable adverse consequences for insulin rec eptor function. 4) Pseudoacromegaly can be viewed as the expected resu lt of hyperinsulinemia driving the unopposed mitogenic and anabolic ac tions of insulin.