The inhibitory effect of recent type 2 diabetes risk loci on insulin secretion is modulated by insulin sensitivity.

CONTEXT/OBJECTIVE: Recently novel type 2 diabetes risk loci were identified and reported to associate with beta-cell dysfunction. We assessed whether the risk alleles in TCF7L2, CDKAL1, HHEX, SLC30A8, IGF2BP2, CDKN2A/2B, JAZF1, and WFS1 reduce insulin secretion in an additive manner and whether their impact is influenced by insulin sensitivity.

DESIGN/METHODS: We genotyped 1397 nondiabetic subjects for the aforementioned risk alleles and performed risk allele summation. Participants underwent an oral glucose tolerance test and in a subgroup also an iv glucose tolerance test with C-peptide and insulin measurements. In our cohort, only polymorphisms in SLC30A8, HHEX, TCF7L2, and CDKAL1 influenced insulin secretion. So we tested only these polymorphisms and, in a separate analysis, all above-mentioned polymorphisms.

RESULTS

We observed a 28% decline in insulin secretion with increment of risk alleles (P <or= 0.0018). Subjects with two to four risk alleles displayed a progressive decline in ss-cell function, which was not further enhanced in carriers of five to seven alleles. After stratification for insulin sensitivity, subjects with low insulin sensitivity revealed a significant decline in insulin secretion with increment of risk alleles (P = 0.0086), whereas this was not seen in subjects with high insulin sensitivity (P = 0.07). The additional study with eight risk alleles provided similar results.

CONCLUSIONS

The negative effects of the risk alleles on ss-cell function appear additive in subjects with low insulin sensitivity but not in subjects with high insulin sensitivity. Effective compensatory mechanisms may exist in subjects with high insulin sensitivity that limit the impact of these genes.