The SHBG genotype rs1799941 is associated with insulin secretion and carotid atherosclerosis, independently of insulin sensitivity, in a healthy European population

Abstract

Background and aims: Studies applying the Mendelian randomization approach suggest that sex hormone-binding globulin (SHBG) may be involved in the pathogenesis of type 2 diabetes. The SHBG A allele at rs1799941 is associated with an increase in plasma SHBG concentration and a reduced risk of type 2 diabetes. However, the underlying mechanisms remain poorly identified. The aim of our study was to explore whether this SHBG variant is associated with insulin secretion and early atherosclerosis after taking into account the degree of insulin sensitivity, in a cohort with a detailed phenotypic characterisation of glucose metabolism and assessment of carotid intimamedia thickness (IMT). Materials and methods: We studied 1097 healthy individuals from the RISC study (Relationship between Insulin Sensitivity and Cardiovascular disease) for whom the SHBG genotype was available. All participants had a euglycemic- hyperinsulinemic clamp and an OGTT with determination of various indices of insulin secretion and an ultra sound recording of the carotid arteries, with a centralised evaluation of IMT. Results: Clamp-assessed insulin sensitivity (M/I value) did not differ according to the SHBG rs1799941 genotype. The insulinogenic index [(Insulin30 min-Insulin0 min)/(Glucose30 min-Glucose0 min)], which represents early phase insulin secretion, was significantly higher in those who carried the SHBG A allele at rs1799941 [111.4 ± 168.8 for A/G or A/A (n=437) vs 82.6 ± 192.5 pmol/mmol for GG genotype (n=594), p=0.001)]. The disposition index (insulinogenic index x M/I value), which estimates early insulin secretion after taking into account for insulin sensitivity, was also significantly increased in the presence of the A allele (15.3 ± 25.2 for A/G or A/A vs 10.3 ± 41.4 l2/ mmol2 for the GG genotype, p=0.001). The association between the A allele and increased insulin secretion, as assessed with various indices, persisted after adjustment for age, sex, recruitment centre, waist, physical activity, smoking (p=0.008 for the disposition index). These associations were not modified after adjustment for insulin sensitivity (M/I value). In addition, carotid IMT was lower in those who carried the A allele (1.92 ± 0.3 for A/G or A/A vs 1.86 ± 0.3 mm for GG genotype, p=0.001).The A allele was associated with a reduced risk of having an increased intima media thickness (IMT), highest vs lower three quartiles (OR: 0.70; 95% CI: 0.53-0.93, p=0.01), independently of conventional risk factors including LDL-c, glycaemia and blood pressure. Conclusion: In a healthy population, the SHBG variant rs1799941 was associated with enhanced β-cell function and a reduced risk of carotid atherosclerosis, independently of insulin sensitivity. The impact of this SHBG variant on cardiovascular outcomes needs to be further studied in diabetic patients.