Impact Of Type 2 Diabetes Susceptibility Loci On Variation In Physiologic Glycaemic Traits In Non-Diabetic Individuals

Objective - Type 2 diabetes (T2D) is characterized by beta-cell dysfunction and insulin resistance. We aimed to uncover the mechanistic basis of genetic associations with T2D by exploring the effects of T2D risk alleles on intermediate metabolic phenotypes in non-diabetic individuals. Research Design and Methods - We studied 37 T2D-associated genetic variants for their effects on indices of insulin processing, secretion and sensitivity gathered from basal fasting and dynamic (derived from oral glucose tolerance test; OGTT) measures. Sample sizes ranged from 13,912 to 58,614 for basal and 10,239 to 13,158 for dynamic tests. In addition, 4,169 individuals contributed data on intravenous (IV) measures of insulin sensitivity. An additive genetic model with adjustment for sex, age and body mass index was applied to cohort analyses followed by fixed effects inverse variance meta-analyses. Results - Cluster analysis grouped T2D loci into five major groups. Variants near PPARG, KLF14, IRS1 and GCKR were characterized by primary effects on insulin resistance with compensatory improvements in beta-cell function. Risk alleles at ARAP1 demonstrated a pronounced impact on insulin processing. Variants near MTNR1B and GCK displayed elevation in fasting glucose and a reduction in insulin processing and secretion (insulinogenic index). TCF7L2, SLC30A8 and HHEX/IDE risk alleles combined defects in insulin processing and secretion. Despite large sample sizes, we detected no clear-cut associations with basal or dynamic measures for the remaining loci. Meta-analyses of the three highly correlated IV assessments were broadly consistent with the results of OGTT-based indices and basal measures of insulin resistance, and the T2D-risk allele was associated with reduced insulin sensitivity at IRS1 (p=7x10-4) and at ADCY5 (p=0.006). Conclusions - Our findings indicate that T2D susceptibility variants exert their effects on glucose homeostasis through a variety of mechanisms.