Modulation by dietary fat and carbohydrate of IRS1 association with type 2 diabetes traits in two populations of different ancestries

Abstract

Objective: Insulin receptor substrate 1 (IRS1) is central to insulin signaling pathways. This study aimed to examine the association of IRS1 variants with insulin resistance (IR) and related phenotypes, as well as potential modification by diet.

Research design and methods: Two IRS1 variants (rs7578326 and rs2943641) identified by genome-wide association studies as related to type 2 diabetes were tested for their associations with IR and related traits and interaction with diet in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study (n = 820) and the Boston Puerto Rican Health Study (BPRHS) (n = 844).

Results: Meta-analysis indicated that rs7578326 G-allele carriers and rs2943641 T-allele carriers had a lower risk of IR, type 2 diabetes, and metabolic syndrome (MetS). Significant interactions on IR and MetS were found for these two variants and their haplotypes with diet. In GOLDN, rs7578326 G-allele carriers and rs2943641 T-allele carriers and their haplotype G-T carriers had a significantly lower risk of IR and MetS than noncarriers only when the dietary saturated fatty acid-to-carbohydrate ratio was low (≤ 0.24). In both GOLDN (P = 0.0008) and BPRHS (P = 0.011), rs7578326 G-allele carriers had a lower risk of MetS than noncarriers only when dietary monounsaturated fatty acids were lower than the median intake of each population.

Conclusions: IRS1 variants are associated with IR and related traits and are modulated by diet in two populations of different ancestries. These findings suggest that IRS1 variants have important functions in various metabolic disorders and that dietary factors could modify these associations.

Figure 1

Interaction of IRS1 variant with dietary MUFA on insulin resistance in the GOLDN and BPRHS populations. Dietary MUFA interacted significantly (P = 0.024) with IRS1 variant rs7578326 on insulin resistance in GOLDN and marginally significantly (P = 0.07) in BPRHS. In both populations, G-allele carriers of rs7578326 had significantly lower HOMA-IR than noncarriers only when dietary MUFA intake was low (≤median intake of each population), but not when MUFA intake was high. P values in GOLDN were adjusted for age, sex, waist circumference, study center, smoking status, alcohol drinking, type 2 diabetes, physical activity, and family relationships. P values in the BPRHS were adjusted for age, sex, waist circumference, smoking status, alcohol drinking, type 2 diabetes, physical activity, and population structure. Number inside the bar indicates the number of subjects in that group. Values are means ± SEM.