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Common Variants of the Novel Type 2 Diabetes Genes CDKAL1 and HHEX/IDE Are Associated With Decreased Pancreatic ß-Cell Function

¹ Diabetes Research Group, Newcastle University, Newcastle upon Tyne, U.K
² CNR Institute of Biomedical Engineering, Padova, Italy
³ Cardiovascular Research Group, Department of Medicine, University of Melbourne, Melbourne, Australia
⁴ University of Pisa, School of Medicine, Pisa, Italy
⁵ Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, and the Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K
⁶ Diabetes Genetics Group and Genetics of Complex Traits, Peninsula Medical School, Exeter, U.K

Address correspondence and reprint requests to Prof. Mark Walker, School of Clinical Medical Sciences, 4th Floor William Leech Bldg., The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, U.K. E-mail: mark.walker{at}ncl.ac.uk

Abbreviations: GWA, genome-wide association; OGTT, oral glucose tolerance test; RISC, Relationship between Insulin Sensitivity and Cardiovascular Disease; SNP, single nucleotide polymorphism

OBJECTIVE— Type 2 diabetes is characterized by impaired pancreatic ß-cell function and decreased insulin sensitivity. Genome-wide association studies have identified common, novel type 2 diabetes susceptibility loci within the FTO, CDKAL1, CDKN2A/CDKN2B, IGF2BP2, HHEX/IDE, and SLC30A8 gene regions. Our objective was to explore the relationships between the diabetes-associated alleles and measures of ß-cell function and whole-body insulin sensitivity.

RESEARCH DESIGN AND METHODS— A total of 1,276 healthy subjects of European ancestry were studied at 19 centers. Indexes of ß-cell function (including 30-min insulin response and glucose sensitivity) were derived from a 75-g oral glucose tolerance test, and whole-body insulin sensitivity (M/I) was assessed by hyperinsulinemic-euglycemic clamp. Genotype/phenotype relationships were studied by linear trend analysis correcting for age, sex, and recruitment center.

RESULTS— CDKAL1 and HHEX/IDE diabetes-associated alleles were both associated with decreased 30-min insulin response (both P = 0.0002) and decreased pancreatic ß-cell glucose sensitivity (P = 9.86 x 10^–5 and 0.009, respectively), and these relationships remained after correction for M/I. The FTO susceptibility allele showed a weak but consistent association with increased adiposity, which in turn was linked to a decrease in M/I. However, none of the other novel diabetes susceptibility alleles were associated with insulin sensitivity.

CONCLUSIONS— CDKAL1 and HHEX/IDE diabetes-associated alleles are associated with decreased pancreatic ß-cell function, including decreased ß-cell glucose sensitivity that relates insulin secretion to plasma glucose concentration. We confirmed the association between the FTO allele and increased adiposity, but none of the other novel susceptibility alleles were associated with whole-body insulin sensitivity.

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