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

Diabetologia. 2013 Jun;56(6):1282-90. doi: 10.1007/s00125-013-2880-6. Epub 2013 Mar 14.

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.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Blood Glucose / genetics
  • Cohort Studies
  • Delta-5 Fatty Acid Desaturase
  • Diabetes Mellitus, Type 2 / blood*
  • Diabetes Mellitus, Type 2 / diagnosis
  • Diabetes Mellitus, Type 2 / genetics*
  • Female
  • Genetic Variation
  • Glucose Clamp Technique
  • Glycated Hemoglobin / chemistry
  • Hispanic or Latino
  • Humans
  • Hyperglycemia / diagnosis
  • Insulin / metabolism*
  • Insulin Resistance / genetics
  • Linkage Disequilibrium
  • Male
  • Middle Aged
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Time Factors

Substances

  • Blood Glucose
  • Delta-5 Fatty Acid Desaturase
  • Glycated Hemoglobin A
  • Insulin
  • FADS1 protein, human