title: Insulin resistance and progression to type 1 diabetes in the European Nicotinamide Diabetes Intervention Trial (ENDIT).
abstract: OBJECTIVE
  Insulin resistance can modulate progression to type 1 diabetes in individuals with ongoing islet autoimmunity. We wanted to see whether measures of insulin resistance improved risk assessment in islet cell antibody (ICA)-positive relatives when added to other immune and metabolic markers.
  
  
  METHODS
  The retrospective cohort analysis included 213 family members participating in the European Nicotinamide Diabetes Intervention Trial. All were aged <25 years, with at least one islet antibody in addition to ICA >or=20 Juvenile Diabetes Foundation units. Median length of follow-up was 4.21 years, and 105 individuals developed diabetes. Oral and intravenous glucose tolerance tests were performed at baseline; antibodies to GAD, IA-2, and insulin were determined by radioimmunoassay; and insulin resistance was estimated by homeostasis model assessment. Risk was assessed by Cox regression analysis
  
  
  RESULTS
  The overall cumulative risk of diabetes within 5 years was 54.1% (95% CI 46.0-62.3). Multivariate analysis confirmed that baseline first-phase insulin response (FPIR) quartile (P < 0.0001), number of additional antibody markers (P < 0.0001), and 120-min glucose in the oral glucose tolerance test (P < 0.0001) were independent determinants of risk of progression, whereas addition of homeostasis model assessment of insulin resistance (HOMA2-IR) achieved only borderline significance (P = 0.06). HOMA2-IR was an independent determinant in participants with loss of FPIR (P = 0.025) but not in those with preserved FPIR (P = 0.3).
  
  
  CONCLUSIONS
  These data suggest that insulin resistance accelerates progression to type 1 diabetes in antibody-positive relatives in whom insulin secretion is markedly reduced but does not affect progression when insulin secretion is relatively well preserved.
authors.affiliation: Clinical Science at North Bristol, University of Bristol, UK. polly.bingley@bristol.ac.uk
authors.forename: Polly J
authors.initials: PJ
authors.lastname: Bingley
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Mahon
authors.forename: Edwin A M
authors.initials: EA
authors.lastname: Gale
mesh_terms: D000293:Adolescent; D015551:Autoimmunity; D002648:Child; D015331:Cohort Studies; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000453:epidemiology* / Q000276:immunology; D018450:Disease Progression; D005060:Europe / Q000453:epidemiology; D005190:Family; D005260:Female; D005951:Glucose Tolerance Test; D006801:Humans; D007333:Insulin Resistance; D008297:Male; D009536:Niacinamide / Q000627:therapeutic use; D011627:Puberty; D012189:Retrospective Studies; D012307:Risk Factors
chemical_list: D009536:Niacinamide