Diabetologia

, Volume 35, Issue 5, pp 486–489

Insulin receptor and insulin-responsive glucose transporter (GLUT 4) mutations and polymorphisms in a welsh type 2 (non-insulin-dependent) diabetic population

  • S. O'Rahilly
  • A. Krook
  • R. Morgan
  • A. Reese
  • J. S. Flier
  • D. E. Moller
Rapid Communications

Summary

We have recently examined the exons encoding the insulin receptor tyrosine kinase domain and GLUT 4 in 30 subjects with Type 2 (non-insulin-dependent) diabetes mellitus using a molecular scanning approach. The variant sequences Val-Met985 and Lys-Glu1068 of the insulin receptor and Val-Ile383 of GLUT 4 were each separately found in three different diabetic subjects. In a study of a Welsh population, the GLUT 4383 variant was found in three of 160 diabetic and none of the 80 control subjects. In this study, the same group of Welsh Type 2 diabetic and control subjects was analysed using allele-specific oligonucleotide hybridisation, single nucleotide primer extension and allele-specific restriction digestion to ascertain the frequency of the two insulin receptor mutations. The Val-Met985 mutation was found in none of the 160 Welsh Caucasian Type 2 diabetic subjects and two of 80 control subjects. The Lys-Glu1068 mutation removes a Sty 1 site and digestion of amplified exon 18 with Sty 1 confirmed the presence of this mutation in the heterozygous state in the original subject. None of the Welsh diabetic or control subjects had the Glu1068 mutation. The discovery of a very common silent polymorphism at codon 130 of GLUT 4 allowed examination of the association of this locus with Type 2 diabetes using allele-specific oligonucleotide hybridisation in a subset of the Welsh subjects. The genotypic frequencies (homozygous wild-type and heterzygous polymorphic (poly) sequences) were not significantly different between diabetic and control subjects (Type 2 diabetic subjects: wild-type/wild-type 40%, wild-type/poly 46%, poly/poly 14%; Control subjects: wild-type/wild-type 37%0, wild-type/poly 45 %, poly/poly 18 %;p > 0.05). In conclusion, in a British Caucasian population the examined insulin receptor tyrosine kinase domain mutations are uncommon. Also the GLUT 4 locus does not appear to be strongly associated with Type 2 diabetes.

Key words

Genetics Type 2 (non-insulin-dependent) diabetes mellitus insulin receptor glucose transporters 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Taylor S, Kadowaki T, Kadowaki H, Accili D, Cama A, McKeon C (1990) Mutations in the insulin receptor gene in insulin-resistant patients. Diab Care 13: 257–279Google Scholar
  2. 2.
    Lekanne-Deprez RH, Potter van Loon BJ, van der Zon GCM et al. (1989) Individuals with only one allele for a functional insulin receptor have a tendency to hyperinsulinaemia but not to hyperglycaemia. Diabetologia 32: 740–744PubMedGoogle Scholar
  3. 3.
    Moller DE, Yokota A, Flier JS (1989) Normal insulin receptor cDNA sequence in Pima Indians with non-insulin dependent diabetes mellitus Diabetes 38: 1496–1500PubMedGoogle Scholar
  4. 4.
    O'Rahilly S, Choi WH, Patel P, Turner RC, Flier IS, Moller DE (1991) Detection of mutations in the insulin receptor gene in noninsulin-dependent diabetic patients by analysis of single-stranded conformation polymorphisms. Diabetes 40: 777–782PubMedGoogle Scholar
  5. 5.
    Choi WH, O'Rahilly S, Rees A, Morgan R, Flier JS, Moller DE (1991) Molecular scanning of the insulin responsive glucose transporter gene in patients with non-insulin-dependent diabetes. Diabetes 40: 1712–1718PubMedGoogle Scholar
  6. 6.
    Goldfine A, Magre J, Goldstein BJ, Krowlewski AJ, Kahn CR (1991) Denaturing gradient gel electrophoresis of glucose transporter and insulin receptor genes. Clin Res 39: 383 A (Abstract)Google Scholar
  7. 7.
    Kuppuswamy MN, Hoffmann JW, Kasper CK, Spitzer SG, Groce SL, Bajaj SP (1991) Single nucleotide primer extension to detect genetic diseases: experimental application to haemophilia B and cystic fibrosis genes. Proc Natl Acad Sci USA 88: 1143–1147PubMedGoogle Scholar
  8. 8.
    Shier P, Watt VM (1989) Primary structure of a putative receptor for a ligand of the insulin family. J Biol Chem 264: 14605–14608PubMedGoogle Scholar
  9. 9.
    Lillioja S, Mott DM, Zawadzki JK et al. (1987) In vivo insulin action is a familial characteristic in non-insulin dependent diabetic Pima Indians. Diabetes 36: 1329–1335PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1992

Authors and Affiliations

  • S. O'Rahilly
    • 1
  • A. Krook
    • 1
  • R. Morgan
    • 2
  • A. Reese
    • 2
  • J. S. Flier
    • 3
  • D. E. Moller
    • 3
  1. 1.Departments of Medicine and Clinical Biochemistry, University of CambridgeAddenbrooke's HospitalCambridgeUK
  2. 2.Department of MedicineUniversity Hospital of WalesCardiffUK
  3. 3.Department of MedicineBeth Israel HospitalBostonUSA

Personalised recommendations