Journal of Clinical Endocrinology & Metabolism, Vol 76, 1533-1541, Copyright © 1993 by Endocrine Society

ARTICLES

Insulin-mediated pseudoacromegaly: clinical and biochemical characterization of a syndrome of selective insulin resistance

JS Flier, DE Moller, AC Moses, S O'Rahilly, RL Chaiken, F Grigorescu, D Elahi, BB Kahn, JE Weinreb and R Eastman
Charles A. Dana Research Institute, Boston, Massachusetts.

We have performed clinical, physiological, in vitro biochemical and genetic studies of a patient with severe insulin resistance associated with the phenotype of "pseudoacromegaly," defined as the presence of acromegaloid features in the absence of elevated levels of GH or insulin-like growth factor-I (IGF-I). Despite marked hyperinsulinemia, insulin and IGF-I binding to circulating blood cells and cultured skin fibroblasts was normal. Insulin and IGF-I-stimulated autophosphorylation of their respective receptors in cultured skin fibroblasts was also normal. However, neither insulin nor IGF-I were able to stimulate 2-deoxy D-glucose uptake by cultured skin fibroblasts. In contrast, the ability of insulin and IGF-I (or IGF-II) to stimulate amino acid uptake and thymidine incorporation into DNA was not impaired. This unique discordant signaling defect through both insulin and IGF-I receptors appeared not to be the consequence of altered expression or primary structure of the insulin receptor or the GLUT-4 glucose transporter, as assessed by several genetic and biochemical techniques. GLUT-4 expression in muscle was normal on Western blots, and SSCP screening of all 11 exons of the gene for nucleotide variation revealed no variations from normal. DNA sequencing and SSCP screening of exons 2-22 of the insulin receptor gene revealed only one variation predicted to alter the amino acid sequence (Val985-- >Met). No functional differences between Met985 and wild-type human insulin receptors were evident in studies performed with Chinese hamster ovary cell transfectants that overexpress either receptor. This data combined with our previously published epidemiological data concerning the frequency of the Met985 allele, indicate that this variant insulin receptor is not responsible for the insulin resistant glucose uptake or the clinical syndrome of pseudoacromegaly. We 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 transport, and/or an effector mechanism operative in this process. 2) Cells derived from this patient may be a valuable tool in the search for such molecular mechanisms. 3) The Met985 allele is a relatively common variant which has no demonstrable adverse consequences for insulin receptor function. 4) Pseudoacromegaly can be viewed as the expected result of hyperinsulinemia driving the unopposed mitogenic and anabolic actions of insulin.

This article has been cited by other articles:

				S Srinivasan, M J Waters, J E Rowland, R C Baxter, and C F Verge Hyperinsulinism and overgrowth without obesity Arch. Dis. Child., April 1, 2003; 88(4): 332 - 334. [Abstract] [Full Text] [PDF]

				G. Pandini, F. Frasca, R. Mineo, L. Sciacca, R. Vigneri, and A. Belfiore Insulin/Insulin-like Growth Factor I Hybrid Receptors Have Different Biological Characteristics Depending on the Insulin Receptor Isoform Involved J. Biol. Chem., October 11, 2002; 277(42): 39684 - 39695. [Abstract] [Full Text] [PDF]

				R. Azziz Polycystic Ovary Syndrome, Insulin Resistance, and Molecular Defects of Insulin Signaling J. Clin. Endocrinol. Metab., September 1, 2002; 87(9): 4085 - 4087. [Full Text] [PDF]

				C. A Stratakis, M. L Turner, A. Lafferty, J. R Toro, S. Hill, J. M Meck, and J. Blancato A syndrome of overgrowth and acromegaloidism with normal growth hormone secretion is associated with chromosome 11 pericentric inversion J. Med. Genet., May 1, 2001; 38(5): 338 - 343. [Full Text]

				C.-B. Book and A. Dunaif Selective Insulin Resistance in the Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., September 1, 1999; 84(9): 3110 - 3116. [Abstract] [Full Text]

				L. Poretsky, N. A. Cataldo, Z. Rosenwaks, and L. C. Giudice The Insulin-Related Ovarian Regulatory System in Health and Disease Endocr. Rev., August 1, 1999; 20(4): 535 - 582. [Abstract] [Full Text] [PDF]

				G. A. Kaltsas, J. J. Mukherjee, P. J. Jenkins, M. A. Satta, N. Islam, J. P. Monson, G. M. Besser, and A. B. Grossman Menstrual Irregularity in Women with Acromegaly J. Clin. Endocrinol. Metab., August 1, 1999; 84(8): 2731 - 2735. [Abstract] [Full Text]

				P. H. Wang, A. Almahfouz, F. Giorgino, K. C. McCowen, and R. J. Smith In Vivo Insulin Signaling in the Myocardium of Streptozotocin-Diabetic Rats: Opposite Effects of Diabetes on Insulin Stimulation of Glycogen Synthase and c-Fos Endocrinology, March 1, 1999; 140(3): 1141 - 1150. [Abstract] [Full Text]

				N. A. Tritos and C. S. Mantzoros Syndromes of Severe Insulin Resistance J. Clin. Endocrinol. Metab., September 1, 1998; 83(9): 3025 - 3030. [Full Text]

				Y. Fukunaga, J. Minamikawa, D. Inoue, H. Koshiyama, and I. Fujisawa Pseudoacromegaly and Hyperinsulinemia: A Possibility of Premature Atherosclerosis? J. Clin. Endocrinol. Metab., October 1, 1997; 82(10): 3515a - 3516. [Full Text]