Mutations in the Insulin Gene can Cause MODY and Autoantibody-Negative Type 1 Diabetes

  1. Anders Molven1,,2,
  2. Monika Ringdal3,,4,
  3. Anita M. Nordbø3,,4,
  4. Helge Ræder5,
  5. Julie Støy6,
  6. Gregory M. Lipkind8,
  7. Donald F. Steiner6,,8,
  8. Louis H. Philipson6,
  9. Ines Bergmann9,
  10. Dagfinn Aarskog10,
  11. Dag E. Undlien11,,12,
  12. Geir Joner13,,14,
  13. Oddmund Søvik3,
  14. the Norwegian Childhood Diabetes Study Group,
  15. Graeme I. Bell6,,7 and
  16. Pål R. Njølstad (pal.njolstad{at},,5
  1. From the 1Gade Institute, University of Bergen, Norway
  2. the 2Department of Pathology, Haukeland University Hospital, Bergen, Norway
  3. the 3Department of Clinical Medicine, University of Bergen, Bergen, Norway
  4. the 4Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
  5. the 5Department of Pediatrics, Haukeland University Hospital, Bergen, Norway
  6. the Departments of 6Medicine
  7. 7Human Genetics and
  8. 8Biochemistry and Molecular Biology, The University of Chicago, Chicago, Illinois, USA
  9. 9Kristiansund Hospital, Kristiansund, Norway
  10. 10Buskerud Hospital, Drammen, Norway
  11. the 11Institute of Medical Genetics, Faculty Division, Ullevål University Hospital, University of Oslo, Oslo, Norway
  12. the 12Department of Medical Genetics, Ullevål University Hospital, Oslo, Norway
  13. the 13Department of Pediatrics, Ullevål University Hospital, Oslo, Norway; and
  14. the 14Faculty of Medicine, University of Oslo, Oslo, Norway


    Objective: Mutations in the insulin (INS) gene can cause neonatal diabetes. We hypothesized that mutations in INS could also cause MODY and autoantibody-negative type 1 diabetes.

    Research Design And Methods: We screened INS in 62 probands with MODY, 30 probands with suspected MODY, and 223 subjects from the Norwegian Childhood Diabetes Registry selected on the basis of auto-antibody negativity or family history of diabetes.

    Results: Among the MODY patients, we identified the INS mutation c.137G>A (R46Q) in a proband, his diabetic father and a paternal aunt. They were diagnosed with diabetes at 20, 18 and 17 years of age, respectively, and are treated with small doses of insulin or diet only. In type 1 diabetes patients, we found the INS mutation c.163C>T (R55C) in a girl who 10 years old presented with ketoacidosis and insulin-dependent, GAD and IA-2 antibody-negative diabetes. Her mother had a de novo R55C mutation and was diagnosed with ketoacidosis and insulin-dependent diabetes at 13 years of age. Both had residual β–cell function. The R46Q substitution changes an invariant arginine residue in position B22, which forms a hydrogen bond with the glutamate at A17 stabilizing the insulin molecule. The R55C substitution involves the first of the two arginine residues localized at the site of proteolytic processing between the B-chain and the C-peptide.

    Conclusions: Our findings extend the phenotype of INS mutation carriers and suggest that INS screening is warranted not only in neonatal diabetes, but also in MODY and in selected cases of type 1 diabetes.


      • Received October 14, 2007.
      • Accepted January 6, 2008.