Nutrient-Dependent Association of Cdk5 Regulatory Associated Protein 1-Like 1 Gene with Insulin Secretion

Objective: Since type 2diabetes (DM) is a life-style related disease, life-style should be considered, when association between genetic factors and DM are examined. However, most studies did not examine genetic associations with such consideration, as the case of Cdk5 regulatory associated protein 1-like 1 (CDKAL1) gene, whose reduced activity in β-cell was shown to reduce insulin secretion. Only a study examined association of CDKAL1 polymorphism and glucose tolerance in consideration with a life-style related factor (energy intake) with significant interaction between them. We here examined the association in consideration with the interaction between the gene polymorphism and various nutrient factors including Zn and Mg.

Research Design and Methods: Among participants of the population-based Iwaki study of Japanese held in 2014 to 2016, those with information of nutrient factors evaluated by a self-administered diet history questionnaire and CDKAL1 genotype (rs9465871: C/T) were included in the study (n=1656).

Results: Mean HbA1c levels in subjects with the CC genotype were significantly higher than those with the TT genotype (5.87±0.66 vs. 5.77±0.53, p<0.02). Stratification based on the amount of each nutrient intake showed association of the CC genotype with lower insulin secretion evaluated based on C-peptide (CPI) and higher prevalence of DM in the highest tertile alone of fat intake (CC vs. CT+TT: 1.15±0.36 vs. 1.27±0.55, p<0.01, 17.4% vs. 9.9%, p=0.02, respectively), and with lower insulin secretion and higher HbA1c levels in the higher half alone of Zn and Mg intake.

Conclusions: Association of CDKAL1 gene with DM seems to be dependent of nutrient intake such as fat, Mg, and Zn, which indicates interaction between CDKAL1 and nutrient factors on pathophysiology leading to DM.