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Altered Expression and Function of the Insulin Receptor in a Family with Lipoatrophic Diabetes^*

KRISTINA M. KRIAUCIUNAS, C. RONALD KAHN, DIRK MULLER-WIELAND, S. SETHU, K. REDDY and REBECCA TAUB

Research Division, Joslin Diabetes Center; the Department of Medicine, Brigham and Women’s Hospital; and the Department of Medicine, Harvard Medical School (K.M.K., C.R.K., D.M.-W., S.S.K.R.) Boston, Massachusetts 02215
The Howard Hughes Medical Institute and the Department of Human Genetics, University of Pennsylvania School of Medicine (R.T.) Philadelphia, Pennsylvania 19104

Address all correspondence and requests for reprints to: C. Ronald Kahn, M.D., Research Division, Joslin Diabetes Center, One Joslin Place, Boston, Massachusetts 02215.

To determine the role of genetic defects in the insulin receptor in the insulin resistance of lipoatrophic diabetes mellitus, we studied insulin binding, insulin receptor autophosphorylation, and insulin receptor mRNA levels and performed Southern blot analysis of genomic DNA in four siblings, all of whom have some degree of insulin resistance and three of whom have lipoatrophy. The insulin receptor concentration in Epstein-Barr virus-transformed lymphocytes was about 30% of normal in all three lipoatrophic siblings (LAI, LA2, and LA3) and was 55% of normal in the nonlipoatrophic sibling (LAS). Insulin receptor mRNA concentrations in the lymphocytes paralleled insulin binding and ranged from 15–67% of the mean normal level. Insulin binding to fibroblasts was also reduced about 50% in the lipoatrophic siblings. In addition, insulin binding to fibroblasts of LAS and LA2 exhibited a rightward shift of the competition curve, suggesting reduced receptor affinity [ED₅₀, 35 and 50 ng/mL (5845 and 8350 pmol/L); normal, 1–3 ng/mL (167–501 pmol/L)]. Receptor autophosphorylation determined using Triton X-100 extracts of the fibroblasts was decreased in LAI and LA3, but normal in LA2 and LAS.

Using restriction enzyme digests of genomic DNA and probes spanning the entire cDNA of the insulin receptor, no gross alterations in receptor gene structure were detected in any members of this family. In 2 of the lipoatrophic siblings (LAI and LA3) and in the sibling with insulin resistance but no lipoatrophy (LAS), a unique variant BamHI site was detected using a probe to the -subunit region. This site was not found in 200 normal or diabetic insulin receptor alleles. By use of probes 5' and 3' to the -subunit probe and by genomic cloning analysis, this variant BamHI site was localized to an intron in the insulin receptor gene downstream of exon 3 which encodes amino acids 191–296 of the -subunit of the receptor.

These data indicate the complex nature of familial lipoatrophic diabetes mellitus, with alterations in insulin receptor expression and/or function in both clinically affected and nonaffected siblings. Both the reduced insulin binding and reduced levels of insulin receptor mRNA in the lipoatrophic siblings suggest that an insulin receptor gene defect contributes to this syndrome. Several members of this family also carry a unique variant insulin receptor gene, which, however, could not be linked to a specific alteration in receptor expression or the presence of lipoatrophy. Thus, although an insulin receptor gene defect may occur in lipoatrophic diabetes, full clinical expression of the disease may require interactions with other genes regulating adipocyte mass.

^* This work was supported by NIH Grant DK-31036, Diabetes Endocrinology Research Center Grant DK-36836, and a Biomedical Research Award from Pfizer Pharmaceutical Co.

Supported by a fellowship from the Deutsche Forschungsgemeinshaft.

Supported by a Diabetes Canada Research Fellowship.

Received May 24, 1988.

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