Systematic evaluation of validated type 2 diabetes and glycaemic trait loci for association with insulin clearance

Abstract

Aims/hypothesis Insulin clearance is a highly heritable trait, for which few quantitative trait loci have been discovered. We sought to determine whether validated type 2 diabetes and/or glycaemic trait loci are associated with insulin clearance. Methods Hyperinsulinaemic–euglycaemic clamps were performed in two Hispanic-American family cohorts totalling 1329 participants in 329 families. The Metabochip was used to fine-map about 50 previously identified loci for type 2 diabetes, fasting glucose, fasting insulin, 2 h glucose or HbA1c. This resulted in 17,930 variants, which were tested for association with clamp-derived insulin clearance via meta-analysis of the two cohorts. Results In the meta-analysis, 38 variants located within seven loci demonstrated association with insulin clearance (p < 0.001). The top signals for each locus were rs10241087 (DGKB/TMEM195 [TMEM195 also known as AGMO]) (p = 4.4 × 10−5); chr1:217605433 (LYPLAL1) (p = 3.25 × 10−4); rs2380949 (GLIS3) (p = 3.4 × 10−4); rs55903902 (FADS1) (p = 5.6 × 10−4); rs849334 (JAZF1) (p = 6.4 × 10−4); rs35749 (IGF1) (p = 6.7 × 10−4); and rs9460557 (CDKAL1) (p = 6.8 × 10−4). Conclusions/interpretation While the majority of validated loci for type 2 diabetes and related traits do not appear to influence insulin clearance in Hispanics, several of these loci do show evidence of association with this trait. It is therefore possible that these loci could have pleiotropic effects on insulin secretion, insulin sensitivity and insulin clearance.

A Fasting Insulin–Raising Allele at IGF1 Locus Is Associated with Circulating Levels of IGF-1 and Insulin Sensitivity

“…It has been recently reported that another polymorphism near IGF1 (rs35749) is associated with insulin clearance [8]. We found that insulin clearance did not differ between carriers of the GG genotype and subjects carrying the A allele of the rs35767 polymorphism, thus excluding the possibility that raised fasting insulin levels observed in carriers of the GG genotype was mediated by variation in insulin clearance.…”

Zinc, insulin, and the liver: a ménage à trois

“…Although fasting insulin is used as a surrogate measure of insulin resistance, it has a stronger correlation with insulin clearance, which is highly heritable (19,20). Future human genetic studies will be important for determining whether genetic variation in SLC30A8 contributes to T2D entirely through its effect on insulin clearance and how much of the heritability of insulin clearance is due to SLC30A8.…”

Insulin Clearance Is Associated with Hepatic Lipase Activity and Lipid and Adiposity Traits in Mexican Americans

“…While follow-up studies suggested variation in this locus may affect insulin secretion [8, 9], an effect on insulin clearance remains possible. A Metabochip study found that seven loci previously associated with type 2 diabetes were associated with insulin clearance [10]. To date, the only published GWAS of insulin clearance identified a variant in the GNA15 gene that nearly met genome-wide significance [11].…”