Insulin Mutation Screening in 1044 Patients with Diabetes: Mutations in the INS gene are a Common Cause of Neonatal Diabetes but a Rare Cause of Diabetes Diagnosed in Childhood or Adulthood

  1. Emma L. Edghill1,
  2. Sarah E. Flanagan1,
  3. Ann-Marie Patch1,
  4. Chris Boustred1,
  5. Andrew Parrish1,
  6. Beverley Shields1,
  7. Maggie H. Shepherd2,
  8. Khalid Hussain3,
  9. Ritika R. Kapoor3,
  10. Maciej Malecki4,
  11. Michael J. MacDonald5,
  12. Julie Støy6,
  13. Donald F. Steiner6,,7,
  14. Louis H. Philipson6,
  15. Graeme I. Bell the Neonatal Diabetes International Collaborative Group6,,8,
  16. Andrew T. Hattersley (andrew.hattersley{at} and
  17. Sian Ellard1
  1. From the 1Institute of Biomedical and Clinical Science, Peninsula Medical School, Barrack Road, Exeter, United Kingdom
  2. 2Institute of Health and Social Care, Peninsula Medical School, Exeter EX2 5DW, United Kingdom
  3. 3Departments of Endocrinology, Great Ormond Street Hospital for Children NHS Trust and the Institute of Child Health, University College London, United Kingdom
  4. 4Department of Metabolic Diseases, Jagiellonian University, Krakow, Poland
  5. 5Department of Pediatrics, University of Wisconsin Medical School, Madison, Wisconsin
  6. Departments of6Medicine
  7. 7Biochemistry and Molecular Biology and
  8. 8Human Genetics, The University of Chicago, Chicago, Illinois


    Objective: Insulin gene (INS) mutations have recently been described as a cause of permanent neonatal diabetes. We aimed to determine the prevalence, genetics and clinical phenotype of INS mutations in large cohorts of patients with neonatal diabetes and permanent diabetes diagnosed in infancy, childhood or adulthood.

    Research Design and Methods: The INS gene was sequenced in 285 patients with diabetes diagnosed before 2 years, 296 probands with MODY and 463 patients with young onset T2D (non-obese, diagnosed <45 years). None had a molecular genetic diagnosis of monogenic diabetes.

    Results: We identified heterozygous INS mutations in 33/141 probands diagnosed <6 months, 2/86 between 6-12 months and 0/58 between 12-24 months. Three known mutations (A24D, F48C and R89C) account for 46% of cases. There were six novel mutations: H29D, L35P, G84R, C96S, S101C and Y103C. INS mutation carriers were all insulin treated from diagnosis and were diagnosed later than KATP mutation carriers (11 vs 8 weeks, P<0.01). In 279 patients with permanent neonatal diabetes, the frequency of KCNJ11, ABCC8 and INS gene mutations was 31%% 10% and 12%, respectively. A heterozygous R6C mutation co-segregated with diabetes in a MODY family and is probably pathogenic, but the L68M substitution identified in a patient with young onset T2D may be a rare non-functional variant.

    Conclusions: We conclude that INS mutations are the second most common cause of permanent neonatal diabetes and a rare cause of MODY. Insulin gene mutation screening is recommended for all diabetic patients diagnosed before one year.


      • Received October 3, 2007.
      • Accepted December 14, 2007.