Originals

Diabetologia

, Volume 36, Issue 5, pp 414-422

First online:

A mutation (Trp1193→Leu1193) in the tyrosine kinase domain of the insulin receptor associated with type A syndrome of insulin resistance

  • M. IwanishiAffiliated withFirst Department of Medicine, Toyama Medical and Pharmaceutical University
  • , T. HarutaAffiliated withFirst Department of Medicine, Toyama Medical and Pharmaceutical University
  • , Y. TakataAffiliated withFirst Department of Medicine, Toyama Medical and Pharmaceutical University
  • , O. IshibashiAffiliated withFirst Department of Medicine, Toyama Medical and Pharmaceutical University
  • , T. SasaokaAffiliated withFirst Department of Medicine, Toyama Medical and Pharmaceutical University
  • , K. EgawaAffiliated withFirst Department of Medicine, Toyama Medical and Pharmaceutical University
  • , T. ImamuraAffiliated withFirst Department of Medicine, Toyama Medical and Pharmaceutical University
  • , K. NaitouAffiliated withDivision of Endocrinology and Metabolism, Nagoya Second Red Cross Hospital
  • , T. ItazuAffiliated withDivision of Endocrinology and Metabolism, Nagoya Second Red Cross Hospital
    • , M. KobayashiAffiliated withFirst Department of Medicine, Toyama Medical and Pharmaceutical University

Rent the article at a discount

Rent now

* Final gross prices may vary according to local VAT.

Get Access

Summary

We evaluated a 35-year-old diabetic male patient with type A insulin resistance, showing acanthosis nigricans. Insulin binding to the patient's Epstein-Barr-virus transformed lymphocytes was mildly reduced. The maximal insulin-stimulated autophosphorylation of the insulin receptor from the patient's transformed lymphocytes was decreased to 45% of that from the control subjects. On examination, the biological activities of insulin and insulin-like growth factor I in the patient's cultured fibroblasts, insulin sensitivity of amino isobutyric acid uptake and thymidine incorporation was decreased, but insulin-like growth factor I action was normal. The sequence analysis of amplified genomic DNA revealed that the patient was heterozygous for a mutation substituting Leu for Trp at codon 1193 in exon 20 of the insulin receptor gene. The patient's mother and sister were also heterozygous for a mutation in the insulin receptor gene that substituted Leu for Trp1193 in the Β subunit of the receptor. Therefore, the mutation causes insulin resistance in a dominant fashion. They were less hyperglycaemic and more hyperinsulinaemic than the proband after glucose loading. The mother had diabetes mellitus but did not show acanthosis nigricans, while the sister did not have diabetes and showed acanthosis nigricans. These results suggest that this mutation causes defective tyrosine kinase activity of the insulin receptor, which results in insulin resistance. Insulin action and phenotypic appearance may be mediated by different factors.

Key words

Insulin receptor mutation tyrosine kinase activity