title: The impact of genetic variation in the G6PC2 gene on insulin secretion depends on glycemia.
abstract: 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.
authors.affiliation: Department of Internal Medicine, Eberhard Karls University Tübingen, Otfried-Müller-Strasse 10, 72076 Tübingen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Heni
authors.forename: Caroline
authors.initials: C
authors.lastname: Ketterer
authors.forename: Leen M 't
authors.initials: LM
authors.lastname: Hart
authors.forename: Felicia
authors.initials: F
authors.lastname: Ranta
authors.forename: Timon W
authors.initials: TW
authors.lastname: van Haeften
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: Eekhoff
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Dekker
authors.forename: Dorret I
authors.initials: DI
authors.lastname: Boomsma
authors.forename: Giel
authors.initials: G
authors.lastname: Nijpels
authors.forename: Mark H
authors.initials: MH
authors.lastname: Kramer
authors.forename: Michaela
authors.initials: M
authors.lastname: Diamant
authors.forename: Annemarie M
authors.initials: AM
authors.lastname: Simonis-Bik
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Heine
authors.forename: Eco J
authors.initials: EJ
authors.lastname: de Geus
authors.forename: Silke A
authors.initials: SA
authors.lastname: Schäfer
authors.forename: Fausto
authors.initials: F
authors.lastname: Machicao
authors.forename: Susanne
authors.initials: S
authors.lastname: Ullrich
authors.forename: Claus
authors.initials: C
authors.lastname: Thamer
authors.forename: Norbert
authors.initials: N
authors.lastname: Stefan
authors.forename: Harald
authors.initials: H
authors.lastname: Staiger
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Häring
authors.forename: Andreas
authors.initials: A
authors.lastname: Fritsche
mesh_terms: 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
chemical_list: D001786:Blood Glucose; D007328:Insulin; D005952:Glucose-6-Phosphatase; C492194:G6PC2 protein, human