title: The common SLC30A8 Arg325Trp variant is associated with reduced first-phase insulin release in 846 non-diabetic offspring of type 2 diabetes patients--the EUGENE2 study.
abstract: OBJECTIVE
  A recent genome-wide association study identified the SLC30A8 rs13266634 polymorphism encoding an Arg325Trp polymorphism in the zinc transporter protein member 8 (ZnT-8) to be associated with type 2 diabetes. Here, we investigate whether the polymorphism is related to altered insulin release in response to intravenous and oral glucose loads in non-diabetic offspring of type 2 diabetic patients.
  
  
  METHODS
  We genotyped SLC30A8 rs13266634 in 846 non-diabetic offspring of type 2 diabetic patients from five different white populations: Danish (n = 271), Finnish (n = 217), German (n = 149), Italian (n = 109) and Swedish (n = 100). Participants were subjected to both IVGTTs and OGTTs, and measurements of insulin sensitivity.
  
  
  RESULTS
  Homozygous carriers of the major type 2 diabetes C risk-allele showed a 19% decrease in first-phase insulin release (0-10 min) measured during the IVGTT (CC 3,624 +/- 3,197; CT 3,763 +/- 2,674; TT 4,478 +/- 3,032 pmol l(-1) min(-1), mean +/- SD; p = 0.007). We found no significant genotype effect on insulin release measured during the OGTT or on estimates of insulin sensitivity.
  
  
  CONCLUSIONS
  Of European non-diabetic offspring of type 2 diabetes patients, 46% are homozygous carriers of the Arg325Trp polymorphism in ZnT-8, which is known to associate with type 2 diabetes. These diabetes-prone offspring are characterised by a 19% decrease in first-phase insulin release following an intravenous glucose load, suggesting a role for this variant in the pathogenesis of pancreatic beta cell dysfunction.
authors.affiliation: Steno Diabetes Center, Niels Steensens Vej 1, NLC2.12, DK-2820, Gentofte, Copenhagen, Denmark. tweb@steno.dk
authors.forename: T W
authors.initials: TW
authors.lastname: Boesgaard
authors.forename: J
authors.initials: J
authors.lastname: Zilinskaite
authors.forename: M
authors.initials: M
authors.lastname: Vänttinen
authors.forename: M
authors.initials: M
authors.lastname: Laakso
authors.forename: P-A
authors.initials: PA
authors.lastname: Jansson
authors.forename: A
authors.initials: A
authors.lastname: Hammarstedt
authors.forename: U
authors.initials: U
authors.lastname: Smith
authors.forename: N
authors.initials: N
authors.lastname: Stefan
authors.forename: A
authors.initials: A
authors.lastname: Fritsche
authors.forename: H
authors.initials: H
authors.lastname: Häring
authors.forename: M
authors.initials: M
authors.lastname: Hribal
authors.forename: G
authors.initials: G
authors.lastname: Sesti
authors.forename: D P
authors.initials: DP
authors.lastname: Zobel
authors.forename: O
authors.initials: O
authors.lastname: Pedersen
authors.forename: T
authors.initials: T
authors.lastname: Hansen
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D002353:Carrier State; D027682:Cation Transport Proteins / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D005838:Genotype; D006720:Homozygote; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D008297:Male; D008875:Middle Aged; D009679:Nuclear Family; D012016:Reference Values; D000075703:Zinc Transporter 8
chemical_list: D027682:Cation Transport Proteins; D007328:Insulin; C492522:SLC30A8 protein, human; D000075703:Zinc Transporter 8