Genetic Underpinnings of Fasting and Oral Glucose-stimulated Based Insulin Sensitivity Indices

Context Insulin sensitivity (IS) is an important factor in type 2 diabetes (T2D) and can be estimated by many different indices.Objective We aimed to compare the genetic components underlying IS indices obtained from fasting and oral glucose-stimulated plasma glucose and serum insulin levels.Methods We computed 21 IS indices, classified as fasting, OGTT0,120, and OGTT0,30,120 indices, using fasting and oral glucose tolerance test (OGTT) data in 2 cohorts. We used data from a family cohort (n = 313) to estimate the heritability and the genetic and phenotypic correlations of IS indices. The population cohort, Inter99 (n = 5343), was used to test for associations between IS indices and 426 genetic variants known to be associated with T2D.Results Heritability estimates of IS indices ranged between 19% and 38%. Fasting and OGTT0,30,120 indices had high genetic (rho G) and phenotypic (rho P) pairwise correlations (rho G and rho P: 0.88 to 1) The OGTT0,120 indices displayed a wide range of pairwise correlations (rho G: 0.17-1.00 and rho P: 0.13-0.97). We identified statistically significant associations between IS indices and established T2D-associated variants. The PPARG rs11709077 variant was associated only with fasting indices and PIK3R rs4976033 only with OGTT0,30,120 indices. The variants in FAM63A/MINDY1, GCK, C2CD4A/B, and FTO loci were associated only with OGTT0,120 indices.Conclusion Even though the IS indices mostly share a common genetic background, notable differences emerged between OGTT0,120 indices. The fasting and OGTT-based indices have distinct associations with T2D risk variants. This work provides a basis for future large-scale genetic investigations into the differences between IS indices.