The risk allele load accelerates the age-dependent decline in beta cell function

Abstract

Aims/hypothesis: Among the novel type 2 diabetes risk loci identified by genome-wide association studies, TCF7L2, HHEX, SLC30A8 and CDKAL1 appear to affect beta cell function. In the present study we examined the effect of these genes' risk alleles on the age-dependent decline in insulin secretion. Methods: The SNPs rs7903146 (TCF7L2), rs7754840(CDKAL1), rs7923837 (HHEX) and rs13266634 (SLC30A8) were genotyped in 1,412 non-diabetic patients, who were subsequently grouped according to their number of risk alleles. All participants underwent an OGTT. Insulin secretion was assessed by validated indices and proinsulin conversion by calculating AUCproinsulin/AUCinsulin. Results: The number of risk alleles revealed a Gaussian distribution, with most participants carrying four risk alleles. Stratification into groups with low (LAL, up to three alleles), median (MAL, four alleles) and high (HAL, five to eight alleles) allele load resulted in MAL and HAL participants displaying significantly lower insulin secretion and proinsulin conversion than LAL participants (p∈ ∈0.0014 and p∈=∈0.0185, respectively). In the overall cohort, age was negatively associated with insulin secretion and proinsulin conversion (both p∈