Improved Performance of Dynamic Measures of Insulin Response Over Surrogate Indices to Identify Genetic Contributors of Type 2 Diabetes: The GUARDIAN Consortium

Type 2 diabetes (T2D) is a heterogeneous disorder with contributions from peripheral insulin resistance and β-cell dysfunction. For minimization of phenotypic heterogeneity, quantitative intermediate phenotypes characterizing basal glucose homeostasis (insulin resistance and HOMA of insulin resistance [HOMA(IR)] and of β-cell function [HOMA(B)]) have shown promise in relatively large samples. We investigated the utility of dynamic measures of glucose homeostasis (insulin sensitivity [S(I)] and acute insulin response [AIR(g)]) evaluating T2D-susceptibility variants (n = 57) in Hispanic Americans from the GUARDIAN Consortium (n = 2,560). Basal and dynamic measures were genetically correlated (HOMA(B)-AIR(g): ρ(G) = 0.28–0.73; HOMA(IR)-S(I): ρ(G) = −0.73 to −0.83) with increased heritability for the dynamic measure AIR(g). Significant association of variants with dynamic measures (P < 8.77 × 10(−4)) was observed. A pattern of superior performance of AIR(g) was observed for well-established loci including MTNR1B (P = 9.46 × 10(−12)), KCNQ1 (P = 1.35 × 10(−4)), and TCF7L2 (P = 5.10 × 10(−4)) with study-wise statistical significance. Notably, significant association of MTNR1B with AIR(g) (P < 1.38 × 10(−9)) was observed in a population one-fourteenth the size of the initial discovery cohort. These observations suggest that basal and dynamic measures provide different views and levels of sensitivity to discrete elements of glucose homeostasis. Although more costly to obtain, dynamic measures yield significant results that could be considered physiologically “closer” to causal pathways and provide insight into the discrete mechanisms of action.