Variants of CDKAL1 and IGF2BP2 affect first-phase insulin secretion during hyperglycaemic clamps.
OBJECTIVE
Genome-wide association studies have recently identified novel type 2 diabetes susceptibility gene regions. We assessed the effects of six of these regions on insulin secretion as determined by a hyperglycaemic clamp.


METHODS
Variants of the HHEX/IDE, CDKAL1, SLC30A8, IGF2BP2 and CDKN2A/CDKN2B genes were genotyped in a cohort of 146 participants with NGT and 126 with IGT from the Netherlands and Germany, who all underwent a hyperglycaemic clamp at 10 mmol/l glucose.


RESULTS
Variants of CDKAL1 and IGF2BP2 were associated with reductions in first-phase insulin secretion (34% and 28%, respectively). The disposition index was also significantly reduced. For gene regions near HHEX/IDE, SLC30A8 and CDKN2A/CDKN2B we did not find significant associations with first-phase insulin secretion (7-18% difference between genotypes; all p > 0.3). None of the variants showed a significant effect on second-phase insulin secretion in our cohorts (2-8% difference between genotypes, all p > 0.3). Furthermore, the gene variants were not associated with the insulin sensitivity index.


CONCLUSIONS
Variants of CDKAL1 and IGF2BP2 attenuate the first phase of glucose-stimulated insulin secretion but show no effect on the second phase of insulin secretion. Our results, based on hyperglycaemic clamps, provide further insight into the pathogenic mechanism behind the association of these gene variants with type 2 diabetes.
Groenewoud
M J
MJ
Department of Molecular Cell Biology, Leiden University Medical Center (LUMC), P.O. Box 9600, 2300 RC, Leiden, the Netherlands.
Dekker
J M
JM
Fritsche
A
A
Reiling
E
E
Nijpels
G
G
Heine
R J
RJ
Maassen
J A
JA
Machicao
F
F
Schäfer
S A
SA
Häring
H U
HU
't Hart
L M
LM
van Haeften
T W
TW
D000328:Adult; D001774:Blood Chemical Analysis; D001786:Blood Glucose / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics*; D014644:Genetic Variation; D015309:Glucose Clamp Technique; D006801:Humans; D006943:Hyperglycemia / Q000097:blood / Q000235:genetics*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D008875:Middle Aged; D016601:RNA-Binding Proteins / Q000235:genetics*; D012359:tRNA Methyltransferases
D001786:Blood Glucose; C498779:IGF2BP2 protein, human; D007328:Insulin; D016601:RNA-Binding Proteins; D012359:tRNA Methyltransferases; D051360:Cyclin-Dependent Kinase 5; C525110:CDKAL1 protein, human