The impact of genetic variation in the G6PC2 gene on insulin secretion depends on glycemia.
BACKGROUND
Single-nucleotide polymorphisms (SNPs) within the G6PC2 locus are associated with fasting glucose and insulin secretion. These SNPs are not associated with type 2 diabetes risk.


OBJECTIVE
Our objective was to investigate whether the impact of the SNP on variables of glucose-stimulated insulin secretion is influenced by glucose tolerance status.


METHODS
In this cross-sectional study, we genotyped 1505 healthy Caucasian subjects [normal glucose tolerance (NGT), 1098; impaired glucose tolerance (IGT)/impaired fasting glucose (IFG), 407] for SNP rs560887 within the G6PC2 locus. A subgroup of 326 subjects underwent an iv glucose tolerance test, and 512 participants took part in a hyperinsulinemic-euglycemic clamp. For replication, SNP rs560887 was genotyped in 457 subjects (NGT, 265; IGT, 192) from four independent German and Dutch studies who underwent a hyperglycemic clamp.


METHODS
Insulin secretion was evaluated.


RESULTS
Carriers of the major G-allele exhibited increased fasting glycemia (P<0.0001). Insulin sensitivity and secretion were not associated with the SNP (P≥0.06). Glucose tolerance status and genotype interacted on insulin secretion (P=0.036), such that in NGT subjects, the minor A-allele of rs560887 was associated with decreased insulinogenic index (P=0.044), which was not the case in subjects with IFG/IGT (P=1.0). During the iv glucose tolerance test, an association of A-allele carriers with decreased first-phase insulin secretion was also observed only in NGT subjects (P=0.0053). Likewise, in the hyperglycemic clamp group, the A-allele was associated with decreased first-phase insulin secretion only in the NGT group (P=0.022) but not in the IGT group.


CONCLUSIONS
The effects of hyperglycemia on insulin secretion override the more subtle effects of genetic variation in the G6PC2 locus on insulin secretion.
Heni
Martin
M
Department of Internal Medicine, Eberhard Karls University Tübingen, Otfried-Müller-Strasse 10, 72076 Tübingen, Germany.
Ketterer
Caroline
C
Hart
Leen M 't
LM
Ranta
Felicia
F
van Haeften
Timon W
TW
Eekhoff
Elisabeth M
EM
Dekker
Jacqueline M
JM
Boomsma
Dorret I
DI
Nijpels
Giel
G
Kramer
Mark H
MH
Diamant
Michaela
M
Simonis-Bik
Annemarie M
AM
Heine
Robert J
RJ
de Geus
Eco J
EJ
Schäfer
Silke A
SA
Machicao
Fausto
F
Ullrich
Susanne
S
Thamer
Claus
C
Stefan
Norbert
N
Staiger
Harald
H
Häring
Hans-Ulrich
HU
Fritsche
Andreas
A
D000328:Adult; D001786:Blood Glucose / Q000378:metabolism*; D002353:Carrier State; D003430:Cross-Sectional Studies; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D005215:Fasting; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D015309:Glucose Clamp Technique; D018149:Glucose Intolerance / Q000235:genetics; D005951:Glucose Tolerance Test; D005952:Glucose-6-Phosphatase / Q000235:genetics*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000502:physiology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
D001786:Blood Glucose; D007328:Insulin; D005952:Glucose-6-Phosphatase; C492194:G6PC2 protein, human