Progression to type 1 diabetes in islet cell antibody-positive relatives in the European Nicotinamide Diabetes Intervention Trial: the role of additional immune, genetic and metabolic markers of risk

Diabetologia. 2006 May;49(5):881-90. doi: 10.1007/s00125-006-0160-4. Epub 2006 Mar 3.


Aims/hypothesis: To examine the role of additional immune, genetic and metabolic risk markers in determining risk of diabetes in islet cell antibody (ICA)-positive individuals with a family history of type 1 diabetes recruited into the European Nicotinamide Diabetes Intervention Trial.

Methods: Five hundred and forty-nine first-degree relatives with confirmed ICA levels > or =20 Juvenile Diabetes Foundation units (mean age 15.9 years; interquartile range 10.4-33.7 years) were recruited from 20 countries. OGTTs and IVGTTs were performed at baseline, antibodies to glutamate decarboxylase (GADA), protein tyrosine phosphatase (IA-2A) and insulin (IAA) were determined by RIA, and HLA class II genotyping was performed by PCR of sequence-specific oligonucleotides.

Results: One hundred and fifty-nine participants developed diabetes within 5 years. Univariate analysis showed that the cumulative risk of development of diabetes within 5 years varied according to age, relationship to the proband, positivity for IAA, IA-2A and GADA, number and combination of islet antibodies, HLA class II genotype, baseline glucose tolerance, and first-phase insulin secretion, but not gender or incidence of childhood type 1 diabetes in the background population. Children aged < or =10 years had a 59% risk of diabetes within 5 years, compared with 11% in those > or =25 years (p<0.0001). Using multivariate analysis, independent determinants were age, first-phase insulin response, baseline glucose tolerance and number of additional antibody markers, but not antibody type or genotype. Individuals <25 years with two or more additional antibodies at baseline had a 62% risk of diabetes within 5 years and these combined criteria identified 81% of the cases in the whole cohort.

Conclusions/interpretation: We suggest that screening and recruitment for future intervention trials should be limited to family members aged <25 years, and should be based on islet autoantibodies alone.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Age of Onset
  • Autoantibodies / blood*
  • Biomarkers / blood
  • Child
  • Child, Preschool
  • Diabetes Mellitus, Type 1 / epidemiology
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / immunology*
  • Disease Progression
  • Europe / epidemiology
  • Female
  • Genotype
  • HLA-D Antigens / genetics*
  • Humans
  • Insulin / blood
  • Male
  • Middle Aged
  • Risk Assessment


  • Autoantibodies
  • Biomarkers
  • HLA-D Antigens
  • Insulin
  • islet cell antibody