Common variants of the novel type 2 diabetes genes, CDKAL1 and HHEX/IDE, are associated with decreased pancreatic β-cell function
- Laura Pascoe, BSc.Hons.,
- Andrea Tura, PhD,
- Sheila K. Patel, PhD,
- Ibrahim M. Ibrahim, MB.BS,
- Ele Ferrannini, PhD,
- The RISC Consortium,
- The UK Type 2 Diabetes Genetics Consortium,
- Eleftheria Zeggini, PhD,
- Michael N. Weedon, PhD,
- Andrea Mari, PhD,
- Andrew T. Hattersley, DM,
- Mark I. McCarthy, MD,
- Timothy M. Frayling, PhD and
- Mark Walker, MD (Mark.Walker{at}ncl.ac.uk)
- Diabetes Research Group, Newcastle University, Newcastle upon Tyne, UK
- CNR Institute of Biomedical Engineering, Padova, Italy
- Cardiovascular Research Group, Department of Medicine, University of Melbourne, Australia
- University of Pisa, School of Medicine, Pisa, Italy
- Membership of the RISC Consortium is listed on supporting on line text
- Membership of the UK Type 2 Diabetes Genetics Consortium is listed on supporting on line text
- Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, and Wellcome Trust Centre for Human Genetics University of Oxford, Oxford, UK
- Diabetes Genetics Group and Genetics of Complex traits, Peninsula Medical School, Exeter, UK
Abstract
Objective: type 2 diabetes is characterized by impaired pancreatic β-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 β-cell function and whole body insulin sensitivity.
Research Design and Methods: 1276 healthy subjects of European ancestry were studied at 19 centres. Indices of β-cell function (including 30min insulin response and glucose sensitivity) were derived from a 75g OGTT 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 centre.
Results: the CDKAL1 and HHEX/IDE diabetes associated alleles were both associated with decreased 30min insulin response (both, p=0.0002) and decreased pancreatic β-cell glucose sensitivity (p=9.86 X10-5 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: the CDKAL1 and HHEX/IDE diabetes associated alleles are associated with decreased pancreatic β-cell function, including decreased β-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 was associated with whole body insulin sensitivity.
Footnotes
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- Received May 9, 2007.
- Accepted August 24, 2007.
- Copyright © American Diabetes Association
