Acta Diabetologica

, 46:217

Association between insulin secretion, insulin sensitivity and type 2 diabetes susceptibility variants identified in genome-wide association studies

  • Stephanie-May Ruchat
  • Cathy E. Elks
  • Ruth J. F. Loos
  • Marie-Claude Vohl
  • S. John Weisnagel
  • Tuomo Rankinen
  • Claude Bouchard
  • Louis Pérusse
Original Article

Abstract

Several single nucleotide polymorphisms (SNPs) for type 2 diabetes mellitus (T2DM) risk have been identified by genome wide association studies (GWAS). The objective of the present study was to investigate the impact of these SNPs on T2DM intermediate phenotypes in order to clarify the physiological mechanisms through which they exert their effects on disease etiology. We analysed 23 SNPs in 9 T2DM genes (CDKAL1, CDKN2B, HHEX/IDE, IGF2BP2, KCNJ11, SLC30A8, TCF2, TCF7L2 and WFS1) in a maximum of 712 men and women from the Quebec Family Study. The participants underwent a 75 g oral glucose tolerance test (OGTT) and were measured for glucose, insulin and C-peptide levels. Indices of insulin sensitivity and insulin secretion were derived from fasting and OGTT measurements. We confirmed the significant associations of variants in CDKAL1, CDKN2B, HHEX/IDE, KCNJ11 and TCF7L2 with insulin secretion and also found associations of some of these variants with insulin sensitivity and glucose tolerance. IGF2BP2 and SLC30A8 SNPs were not associated with insulin secretion but were with insulin sensitivity and glucose tolerance (0.002 ≤ P ≤ 0.02). To examine the joint effects of these variants and their contribution to T2DM endophenotypes variance, stepwise regression models were used and the model R2 was computed. The variance in the phenotypes explained by combinations of variants ranged from 2.0 to 8.5%. Diabetes-associated variants in CDKAL1, CDKN2B, HHEX/IDE, IGF2BP2, KCNJ11, SLC30A8 and TCF7L2 are associated with physiological alterations leading to T2DM, such as glucose intolerance, impaired insulin secretion or insulin resistance, supporting their role in the disease aetiology. These variants were found to account for 2.0–8.5% of the variance of T2DM-related traits.

Keywords

Glucose tolerance Insulin secretion Insulin sensitivity Diabetes-associated polymorphisms 

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Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Stephanie-May Ruchat
    • 1
    • 2
  • Cathy E. Elks
    • 3
  • Ruth J. F. Loos
    • 3
  • Marie-Claude Vohl
    • 2
  • S. John Weisnagel
    • 1
    • 2
  • Tuomo Rankinen
    • 4
  • Claude Bouchard
    • 4
  • Louis Pérusse
    • 1
    • 2
    • 5
  1. 1.Department of Preventive MedicineLaval UniversityQuebec CityCanada
  2. 2.Lipid Research Center CHUL Research CenterQuebec CityCanada
  3. 3.Medical Research Council Epidemiology UnitInstitute of Metabolic ScienceCambridgeUK
  4. 4.Human Genomics LaboratoryPennington Biomedical Research CenterBaton RougeUSA
  5. 5.Division of Kinesiology, Department of Social and Preventive Medicine, Faculty of MedicineLaval UniversityQuebec CityCanada

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