Evaluation of Fasting State-/Oral Glucose Tolerance Test-Derived Measures of Insulin Release for the Detection of Genetically Impaired β-Cell Function

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. METHODOLOGY/PRINCIPAL FINDINGS 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/SIGNIFICANCE 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)).