Common genetic variants highlight the role of insulin resistance and body fat distribution in type 2 diabetes, independent of obesity

Abstract

We aimed to validate genetic variants as instruments for insulin resistance and secretion, to characterize their association with intermediate phenotypes, and to investigate their role in type 2 diabetes (T2D) risk among normal-weight, overweight, and obese individuals. We investigated the association of genetic scores with euglycemic-hyperinsulinemic clamp- and oral glucose tolerance test-based measures of insulin resistance and secretion and a range of metabolic measures in up to 18,565 individuals. We also studied their association with T2D risk among normal-weight, overweight, and obese individuals in up to 8,124 incident T2D cases. The insulin resistance score was associated with lower insulin sensitivity measured by M/I value (β in SDs per allele [95% CI], -0.03 [-0.04, -0.01]; P = 0.004). This score was associated with lower BMI (-0.01 [-0.01, -0.0]; P = 0.02) and gluteofemoral fat mass (-0.03 [-0.05, -0.02; P = 1.4 × 10(-6)) and with higher alanine transaminase (0.02 [0.01, 0.03]; P = 0.002) and γ-glutamyl transferase (0.02 [0.01, 0.03]; P = 0.001). While the secretion score had a stronger association with T2D in leaner individuals (Pinteraction = 0.001), we saw no difference in the association of the insulin resistance score with T2D among BMI or waist strata (Pinteraction > 0.31). While insulin resistance is often considered secondary to obesity, the association of the insulin resistance score with lower BMI and adiposity and with incident T2D even among individuals of normal weight highlights the role of insulin resistance and ectopic fat distribution in T2D, independently of body size.

Figure 1

a-b: Association of the insulin resistance and secretion risk scores with a range of standardised outcomes. Effect sizes are expressed per-risk allele. All models were adjusted for age, sex and BMI, other than anthropometric traits, which were adjusted only for age and sex.

Figure 1

a-b: Association of the insulin resistance and secretion risk scores with a range of standardised outcomes. Effect sizes are expressed per-risk allele. All models were adjusted for age, sex and BMI, other than anthropometric traits, which were adjusted only for age and sex.

Figure 2

Association of the insulin resistance score on standardised anthropometric traits in the Fenland study. Effect sizes are expressed per-risk allele. All models were adjusted for age and sex.

Figure 3

Association of the risk scores with type 2 diabetes in the EPIC-InterAct study. Associations are shown overall and by strata of BMI and waist circumference at baseline. BMI strata were defined by WHO BMI cutoffs and waist circumference strata were defined by sex-specific tertiles (low: M<94cm, F<78.5cm; med: M>94-103cm, F>78.5-90cm; high: M>103cm, F>90cm).