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

Aims/hypothesis 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/Interpretation 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.