The genetic variation in the IDE (insulin degrading enzyme) gene is associated with impaired insulin metabolism and increased risk of type 2 diabetes

Aims: Evidence for linkage of type 2 diabetes to a region on chromosome 10q23-q25 has been provided in several populations. Among genes in this region is IDE encoding insulin degrading enzyme which serve as a major enzyme responsible for insulin proteolysis. IDE knockout mice show a diabetic phenotype with hyperinsulinemia. Thus, the aim of the present study was to examine the genetic associations between IDE SNPs, insulin metabolism and the risk for T2DM in the Metabolic Syndrome Berlin-Potsdam (MESYBEPO) and European Prospective Investigation into Cancer and Nutrition-Potsdam (EPIC-Potsdam) study populations.

Methods: 12 SNPs from IDE gene were selected and genotyped in the MESYBEPO cohort (n=1023 (men=32.6%); subjects with T2DM=235, IGT+IFG=312, NGT=475). The IDE variant (94214145T>C, rs1887922) was additionally genotyped in a nested case-cohort population of incident diabetics of the EPIC-Potsdam cohort (n=801 cases; n=2248 controls).

Results: We compared genotype frequencies in subjects with T2DM with those with NGT and found an association for rs1887922 (odds ratio 1.58 [95% CI: 1.03–2.2]; p=0.036) in MESYBEPO. Adjusting for the effect of age strengthened the association (dominant model: odds ratio 1.85; p=0.009). In nondiabetic women, the risk genotype was associated with a reduction in insulin clearance derived from oral glucose tolerance tests (p=0.043). In the prospective EPIC-Potsdam population the same marker was associated with increased risk of T2DM in the additive inheritance model (RR 1.31 [95% CI: 1.11–1.55]; p=0.0015).

Conclusions: IDE gene marker rs 1887922 is associated with the risk for T2DM in two German populations. In NGT women, the risk genotype is associated with decreased insulin clearance. Furthermore, this study provides novel evidence that disturbances in the insulin degradation may play a role in the development of T2DM.