title: Insulin secretion and sensitivity in the prediction of type 1 diabetes in children with advanced β-cell autoimmunity.
abstract: OBJECTIVE
  Reduced early insulin response has been shown to predict type 1 diabetes (T1D) in first-degree relatives of diabetic patients, while its role, as well as that of insulin resistance, has remained poorly defined in young children representing the general population. The predictive values of these markers and their relation to other risk factors of T1D were assessed in children with advanced β-cell autoimmunity, i.e. persistent positivity for two or more autoantibodies.
  
  
  METHODS
  Intravenous glucose tolerance tests (IVGTTs) were carried out in 218 children with HLA-DQB1-conferred disease susceptibility and advanced β-cell autoimmunity. Baseline, metabolic and growth data were compared between children progressing to diabetes and those remaining unaffected. Hazard ratios for the disease predictors and the progression rate of T1D were assessed.
  
  
  RESULTS
  Children developing T1D were younger at seroconversion, progressed more rapidly to advanced β-cell autoimmunity and had lower first-phase insulin response (FPIR) and homeostasis model assessment index for insulin resistance (HOMA-IR) than those remaining non-diabetic. The levels of HOMA-IR/FPIR, islet cell antibodies, insulin autoantibodies (IAA) and islet antigen 2 antibodies (IA-2A) were higher in progressors. BMI SDS, FPIR, age at IVGTT and levels of IAA and IA-2A were predictive markers for T1D.
  
  
  CONCLUSIONS
  Young age, higher BMI SDS, reduced FPIR and higher levels of IAA and IA-2A predicted T1D in young children with HLA-DQB1-conferred disease susceptibility and advanced β-cell autoimmunity. Disease risk estimates were successfully stratified by the assessment of metabolic status and BMI. The role of insulin resistance as an accelerator of the disease process was minor.
authors.affiliation: Children's Hospital, University of Helsinki and Helsinki University Central Hospital, PO Box 22, FI-00014 Helsinki, Finland.
authors.forename: Heli T
authors.initials: HT
authors.lastname: Siljander
authors.forename: Robert
authors.initials: R
authors.lastname: Hermann
authors.forename: Anne
authors.initials: A
authors.lastname: Hekkala
authors.forename: Jyrki
authors.initials: J
authors.lastname: Lähde
authors.forename: Laura
authors.initials: L
authors.lastname: Tanner
authors.forename: Päivi
authors.initials: P
authors.lastname: Keskinen
authors.forename: Jorma
authors.initials: J
authors.lastname: Ilonen
authors.forename: Olli
authors.initials: O
authors.lastname: Simell
authors.forename: Riitta
authors.initials: R
authors.lastname: Veijola
authors.forename: Mikael
authors.initials: M
authors.lastname: Knip
mesh_terms: D000293:Adolescent; D001323:Autoantibodies / Q000097:blood; D015551:Autoimmunity / Q000502:physiology*; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology* / Q000235:genetics / Q000276:immunology*; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D005951:Glucose Tolerance Test; D059866:HLA-DQ beta-Chains / Q000235:genetics; D006801:Humans; D007223:Infant; D007328:Insulin / Q000276:immunology / Q000378:metabolism*; D007330:Insulin Antibodies / Q000097:blood; D007333:Insulin Resistance / Q000276:immunology*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000276:immunology / Q000378:metabolism*; D008297:Male; D011236:Prediabetic State / Q000453:epidemiology / Q000235:genetics / Q000276:immunology; D011237:Predictive Value of Tests; D012307:Risk Factors
chemical_list: D001323:Autoantibodies; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D007328:Insulin; D007330:Insulin Antibodies