Common variants of the novel type 2 diabetes genes CDKAL1 and HHEX/IDE are associated with decreased pancreatic beta-cell function.
OBJECTIVE
Type 2 diabetes is characterized by impaired pancreatic beta-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 beta-cell function and whole-body insulin sensitivity.


METHODS
A total of 1,276 healthy subjects of European ancestry were studied at 19 centers. Indexes of beta-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 beta-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 beta-cell function, including decreased beta-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.
Pascoe
Laura
L
Diabetes Research Group, Newcastle University, Newcastle upon Tyne, UK.
Tura
Andrea
A
Patel
Sheila K
SK
Ibrahim
Ibrahim M
IM
Ferrannini
Ele
E
Zeggini
Eleftheria
E
Weedon
Michael N
MN
Mari
Andrea
A
Hattersley
Andrew T
AT
McCarthy
Mark I
MI
Frayling
Timothy M
TM
Walker
Mark
M
D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000503:physiopathology*; D005060:Europe; D014644:Genetic Variation; D005947:Glucose / Q000502:physiology; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007328:Insulin / Q000502:physiology; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000502:physiology*; D012016:Reference Values; D014157:Transcription Factors / Q000235:genetics*; D044465:White People; D012359:tRNA Methyltransferases