title: Association between insulin secretion, insulin sensitivity and type 2 diabetes susceptibility variants identified in genome-wide association studies.
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 <or= P <or= 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 R (2) 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.
authors.affiliation: Department of Preventive Medicine, Laval University, Quebec City, QC, Canada.
authors.forename: Stephanie-May
authors.initials: SM
authors.lastname: Ruchat
authors.forename: Cathy E
authors.initials: CE
authors.lastname: Elks
authors.forename: Ruth J F
authors.initials: RJ
authors.lastname: Loos
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Vohl
authors.forename: S John
authors.initials: SJ
authors.lastname: Weisnagel
authors.forename: Tuomo
authors.initials: T
authors.lastname: Rankinen
authors.forename: Claude
authors.initials: C
authors.lastname: Bouchard
authors.forename: Louis
authors.initials: L
authors.lastname: Pérusse
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011792:Quebec / Q000453:epidemiology; D012307:Risk Factors
chemical_list: D001786:Blood Glucose; D007328:Insulin