title: Evaluation of fasting state-/oral glucose tolerance test-derived measures of insulin release for the detection of genetically impaired β-cell function.
abstract: BACKGROUND
  To date, fasting state- and different oral glucose tolerance test (OGTT)-derived measures are used to estimate insulin release with reasonable effort in large human cohorts required, e.g., for genetic studies. Here, we evaluated twelve common (or recently introduced) fasting state-/OGTT-derived indices for their suitability to detect genetically determined β-cell dysfunction.
  
  
  RESULTS
  A cohort of 1364 White European individuals at increased risk for type 2 diabetes was characterized by OGTT with glucose, insulin, and C-peptide measurements and genotyped for single nucleotide polymorphisms (SNPs) known to affect glucose- and incretin-stimulated insulin secretion. One fasting state- and eleven OGTT-derived indices were calculated and statistically evaluated. After adjustment for confounding variables, all tested SNPs were significantly associated with at least two insulin secretion measures (p≤0.05). The indices were ranked according to their associations' statistical power, and the ranks an index obtained for its associations with all the tested SNPs (or a subset) were summed up resulting in a final ranking. This approach revealed area under the curve (AUC)(Insulin(0-30))/AUC(Glucose(0-30)) as the best-ranked index to detect SNP-dependent differences in insulin release. Moreover, AUC(Insulin(0-30))/AUC(Glucose(0-30)), corrected insulin response (CIR), AUC(C-Peptide(0-30))/AUC(Glucose(0-30)), AUC(C-Peptide(0-120))/AUC(Glucose(0-120)), two different formulas for the incremental insulin response from 0-30 min, i.e., the insulinogenic indices (IGI)(2) and IGI(1), and insulin 30 min were significantly higher-ranked than homeostasis model assessment of β-cell function (HOMA-B; p<0.05). AUC(C-Peptide(0-120))/AUC(Glucose(0-120)) was best-ranked for the detection of SNPs involved in incretin-stimulated insulin secretion. In all analyses, HOMA-β displayed the highest rank sums and, thus, scored last.
  
  
  CONCLUSIONS
  With AUC(Insulin(0-30))/AUC(Glucose(0-30),) CIR, AUC(C-Peptide(0-30))/AUC(Glucose(0-30)), AUC(C-Peptide(0-120))/AUC(Glucose(0-120)), IGI(2), IGI(1), and insulin 30 min, dynamic measures of insulin secretion based on early insulin and C-peptide responses to oral glucose represent measures which are more appropriate to assess genetically determined β-cell dysfunction than fasting measures, i.e., HOMA-B. Genes predominantly influencing the incretin axis may possibly be best detected by AUC(C-Peptide(0-120))/AUC(Glucose(0-120)).
authors.affiliation: Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, Department of Internal Medicine, University Hospital Tübingen and Eberhard Karls University Tübingen, Tübingen, Germany.
authors.forename: Silke A
authors.initials: SA
authors.lastname: Herzberg-Schäfer
authors.forename: Harald
authors.initials: H
authors.lastname: Staiger
authors.forename: Martin
authors.initials: M
authors.lastname: Heni
authors.forename: Caroline
authors.initials: C
authors.lastname: Ketterer
authors.forename: Martina
authors.initials: M
authors.lastname: Guthoff
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Kantartzis
authors.forename: Fausto
authors.initials: F
authors.lastname: Machicao
authors.forename: Norbert
authors.initials: N
authors.lastname: Stefan
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Häring
authors.forename: Andreas
authors.initials: A
authors.lastname: Fritsche
mesh_terms: D000328:Adult; D019540:Area Under Curve; D001786:Blood Glucose / Q000378:metabolism; D002096:C-Peptide / Q000378:metabolism; D015331:Cohort Studies; D005215:Fasting; D005260:Female; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012044:Regression Analysis; D012306:Risk
chemical_list: D001786:Blood Glucose; D002096:C-Peptide; D007328:Insulin