Type 2 diabetes risk allele near CENTD2 is associated with decreased glucose-stimulated insulin release.
OBJECTIVE
By combining multiple genome-wide association (GWA) studies and comprehensive replication efforts, 12 novel type 2 diabetes associated loci have recently been discovered. Here we evaluate the effect of lead variants of these loci on estimates of insulin release and insulin resistance derived from an oral glucose tolerance test.


METHODS
We examined 12 lead variants in or near HMGA2, CENTD2 (also known as ARAP1), KLF14, PRC1, TP53INP1, ZBED3, ZFAND6, CHCHD9, DUSP9, KCNQ1, BCL11A and HNF1A in 5,722 middle-aged people from the population-based Inter99 sample.


RESULTS
Carriers of the major diabetogenic allele of rs1552224 in CENTD2 had increased 30-min plasma glucose values (2.0%, p = 2 × 10(-5)) as well as 4.2% reduced insulin release 30 min after an oral glucose load (p = 0.001). Risk allele carriers also had decreased BIGTT-acute insulin release (AIR), which is a surrogate measure of insulin release where sex, BMI, plasma glucose and serum insulin are integrated (5.3%, p = 8 × 10(-7)). In addition, a decreased corrected insulin response (CIR; 9.9%, p = 3 × 10(-8)) was observed. For rs5945326 near DUSP9 on the X-chromosome we stratified according to sex. Male carriers of the risk allele showed nominally decreased BIGTT-AIR (2.6%, p = 0.01). No associations with intermediate metabolic traits were found in women. For the remaining ten lead variants no consistent associations were demonstrated.


CONCLUSIONS
Of the lead variants from 12 novel type 2 diabetes associated loci, CENTD2 significantly associated with increased plasma glucose values and decreased glucose-stimulated insulin release, suggesting that the diabetogenic effect of this locus is mediated through an impaired pancreatic beta cell function.
Marie Krogh Center for Metabolic Research, Section of Metabolic Genetics, Faculty of Health Sciences, University of Copenhagen, Universitetsparken 1, 2100 Copenhagen, Denmark. trine.nielsen@sund.ku.dk
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T
Nielsen
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T
Sparsø
N
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Grarup
T
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Jørgensen
C
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Pisinger
D R
DR
Witte
T
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Hansen
O
O
Pedersen
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000328:Adult; D000483:Alleles; D002352:Carrier Proteins / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology* / Q000235:genetics* / Q000378:metabolism; D054637:Dual-Specificity Phosphatases / Q000235:genetics; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D005947:Glucose / Q000494:pharmacology*; D005951:Glucose Tolerance Test; D025743:HMGA2 Protein / Q000235:genetics; D006360:Heat-Shock Proteins / Q000235:genetics; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D051657:KCNQ1 Potassium Channel / Q000235:genetics; D051741:Kruppel-Like Transcription Factors; D008297:Male; D008875:Middle Aged; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000235:genetics; D017720:Molecular Epidemiology / Q000379:methods; D009687:Nuclear Proteins / Q000235:genetics; D012097:Repressor Proteins; D051703:Sp Transcription Factors / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
C446513:ARAP1 protein, human; D048868:Adaptor Proteins, Signal Transducing; C486563:BCL11A protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D020690:GTPase-Activating Proteins; D025743:HMGA2 Protein; C496487:HNF1A protein, human; D006360:Heat-Shock Proteins; D051538:Hepatocyte Nuclear Factor 1-alpha; D007328:Insulin; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; C417549:KLF14 protein, human; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; C116662:PRC1 protein, human; D012097:Repressor Proteins; D051703:Sp Transcription Factors; C429767:TP53INP1 protein, human; D014157:Transcription Factors; C540253:ZBED3 protein, human; C417945:ZFAND6 protein, human; D054639:Mitogen-Activated Protein Kinase Phosphatases; C104821:DUSP9 protein, human; D054637:Dual-Specificity Phosphatases; D005947:Glucose
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