Variants of CDKAL1 and IGF2BP2 affect first-phase insulin secretion during hyperglycaemic clamps

Abstract

Aims/hypothesis Genome-wide association studies have recently identified novel type 2 diabetes susceptibility gene regions. We assessed the effects of six of these regions on insulin secretion as determined by a hyperglycaemic clamp. Methods Variants of the HHEX/IDE, CDKAL1, SLC30A8, IGF2BP2 and CDKN2A/CDKN2B genes were genotyped in a cohort of 146 participants with NGT and 126 with IGT from the Netherlands and Germany, who all underwent a hyperglycaemic clamp at 10 mmol/l glucose. Results Variants of CDKAL1 and IGF2BP2 were associated with reductions in first-phase insulin secretion (34% and 28%, respectively). The disposition index was also significantly reduced. For gene regions near HHEX/IDE, SLC30A8 and CDKN2A/CDKN2B we did not find significant associations with first-phase insulin secretion (7-18% difference between genotypes; all p>0.3). None of the variants showed a significant effect on second-phase insulin secretion in our cohorts (2-8% difference between genotypes, all p>0.3). Furthermore, the gene variants were not associated with the insulin sensitivity index. Conclusions Variants of CDKAL1 and IGF2BP2 attenuate the first phase of glucose-stimulated insulin secretion but show no effect on the second phase of insulin secretion. Our results, based on hyperglycaemic clamps, provide further insight into the pathogenic mechanism behind the association of these gene variants with type 2 diabetes.

Genetic influences on the insulin response of the beta cell to different secretagogues

“…Most notably, all previous studies that used a hyperglycaemic clamp procedure comparable to the one used here confirm the independence of genetic effects on insulin secretion and insulin sensitivity. For instance, the risk variants of CDKAL1, IGF2BP2 [36], TCF7L2 [37] or WFS1 [38] clearly impaired glucose-or GLP-1-induced insulin secretion, but did not impact on insulin sensitivity. It has often been suggested that beta cell dysfunction is uncovered only when insulin resistance creates a strongly increased insulin demand.…”

Pharmacogenetics for T2DM and Anti-Diabetic Drugs

“…Patients with the GT+TT genotypes of rs4402960 also showed a better repaglinide therapeutic effect on PINS compared with individuals with the GG genotype. Replication of this research has indicated that IGF2BP2 variants were more likely to be associated with reduced -cell function [80,84]. IGF2BP2 was shown to affect insulin secretion in a previous study.…”

“…T2DM patients with different IGF2BP2 genotypes showed various levels of insulin secretion. It has been demonstrated that variants in IGF2BP2 gene affect first-phase insulin secretion and the disposition index detected by hyperglycemic clamps [80]. Interactions between genetic variation in IGF2BP2 and T2DM maybe exerted through this IGF2 pathway and through the insulin pathway.…”

“…The IGF2BP2 gene variant (rs4402960) was associated with insulin sensitivity, FPG, glucose AUC, and FPG [81]. SNP rs4402960 was also associated with reductions in first-phase insulin secretion and in the disposition index, which reflected the failing adaptive capacity of pancreatic -cells [80] resulting in hyperglycemia including FPG and PPG. SNP rs4402960 has also been shown to be associated with the disposition index in Hispanic Americans [82], HOMA-in non-diabetic Japanese individuals and lower acute insulin release and tolerance [64].…”

Functional loss of Cdkal1, a novel tRNA modification enzyme, causes the development of type 2 diabetes [Review]

“…These results suggest that variants in cdkal1 influence the risk of T2D from impaired insulin secretion and the Cdkal1 protein may be involved in the regulation of insulin secretion. In contrast, the gene variants are not associated with insulin sensitivity or obesity [9,12]. The association of the variants of cdkal1 with T2D is observed across different ethnic its Cdk5 activity through interaction with p35 and p39 [16].…”