Combined risk allele score of eight type 2 diabetes genes is associated with reduced first-phase glucose-stimulated insulin secretion during hyperglycemic clamps.
OBJECTIVE
At least 20 type 2 diabetes loci have now been identified, and several of these are associated with altered beta-cell function. In this study, we have investigated the combined effects of eight known beta-cell loci on insulin secretion stimulated by three different secretagogues during hyperglycemic clamps.


METHODS
A total of 447 subjects originating from four independent studies in the Netherlands and Germany (256 with normal glucose tolerance [NGT]/191 with impaired glucose tolerance [IGT]) underwent a hyperglycemic clamp. A subset had an extended clamp with additional glucagon-like peptide (GLP)-1 and arginine (n = 224). We next genotyped single nucleotide polymorphisms in TCF7L2, KCNJ11, CDKAL1, IGF2BP2, HHEX/IDE, CDKN2A/B, SLC30A8, and MTNR1B and calculated a risk allele score by risk allele counting.


RESULTS
The risk allele score was associated with lower first-phase glucose-stimulated insulin secretion (GSIS) (P = 7.1 x 10(-6)). The effect size was equal in subjects with NGT and IGT. We also noted an inverse correlation with the disposition index (P = 1.6 x 10(-3)). When we stratified the study population according to the number of risk alleles into three groups, those with a medium- or high-risk allele score had 9 and 23% lower first-phase GSIS. Second-phase GSIS, insulin sensitivity index and GLP-1, or arginine-stimulated insulin release were not significantly different.


CONCLUSIONS
A combined risk allele score for eight known beta-cell genes is associated with the rapid first-phase GSIS and the disposition index. The slower second-phase GSIS, GLP-1, and arginine-stimulated insulin secretion are not associated, suggesting that especially processes involved in rapid granule recruitment and exocytosis are affected in the majority of risk loci.
't Hart
Leen M
LM
Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands. l.m.t_hart@lumc.nl
Simonis-Bik
Annemarie M
AM
Nijpels
Giel
G
van Haeften
Timon W
TW
Schäfer
Silke A
SA
Houwing-Duistermaat
Jeanine J
JJ
Boomsma
Dorret I
DI
Groenewoud
Marlous J
MJ
Reiling
Erwin
E
van Hove
Els C
EC
Diamant
Michaela
M
Kramer
Mark H H
MH
Heine
Robert J
RJ
Maassen
J Antonie
JA
Kirchhoff
Kerstin
K
Machicao
Fausto
F
Häring
Hans-Ulrich
HU
Slagboom
P Eline
PE
Willemsen
Gonneke
G
Eekhoff
Elisabeth M
EM
de Geus
Eco J
EJ
Dekker
Jacqueline M
JM
Fritsche
Andreas
A
D000328:Adult; D000368:Aged; D000483:Alleles; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D005838:Genotype; D005858:Germany / Q000453:epidemiology; D005947:Glucose / Q000494:pharmacology*; D015309:Glucose Clamp Technique; D018149:Glucose Intolerance / Q000453:epidemiology / Q000235:genetics; D006801:Humans; D006943:Hyperglycemia / Q000097:blood / Q000139:chemically induced; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D008297:Male; D008875:Middle Aged; D009426:Netherlands / Q000453:epidemiology; D020641:Polymorphism, Single Nucleotide; D012016:Reference Values; D018570:Risk Assessment; D012307:Risk Factors
D007328:Insulin; D005947:Glucose