TY - JOUR

T1 - Genetic underpinnings of fasting and oral glucose-stimulated based insulin sensitivity indices

AU - Suleman, Sufyan

AU - Madsen, Anne L

AU - Ängquist, Lars H

AU - Schubert, Mikkel

AU - Linneberg, Allan

AU - Loos, Ruth J F

AU - Hansen, Torben

AU - Grarup, Niels

N1 - © The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.

PY - 2024

Y1 - 2024

N2 - 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 two 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=5,343), 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 (ρG) and phenotypic (ρP) pairwise correlations (ρG and ρP: 0.88 to 1) The OGTT0,120 indices displayed a wide range of pairwise correlations (ρG: 0.17-1.00 and ρP: 0.13-0.97). We identified statistically significant associations between IS indices and established T2D-associated variants. The PPARG rs11709077 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.

AB - 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 two 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=5,343), 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 (ρG) and phenotypic (ρP) pairwise correlations (ρG and ρP: 0.88 to 1) The OGTT0,120 indices displayed a wide range of pairwise correlations (ρG: 0.17-1.00 and ρP: 0.13-0.97). We identified statistically significant associations between IS indices and established T2D-associated variants. The PPARG rs11709077 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.

U2 - 10.1210/clinem/dgae275

DO - 10.1210/clinem/dgae275

M3 - Journal article

C2 - 38635292

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

SN - 0021-972X

ER -