Exploring genetic risk factors for β-cell deterioration in type 2 diabetes mellitus: Insights from longitudinal C-peptide analysis

Abstract

Aims

Insulin secretion in type 2 diabetes mellitus deteriorates over time, but the factors influencing the degree of deteriorates remain unclear. This study aims to specifically identify genetic factors associated with this decline.

Methods

Fasting serum C-peptide was observed over 10.5 ± 4.7 years in 116 Japanese patients with type 2 diabetes mellitus without significant obesity or renal dysfunction. The individual annual decline of fasting serum C-peptide (IAD) was calculated using regression analysis. We evaluated the IAD in patients with or without susceptible allele of candidate single nucleotide polymorphisms (SNPs) in genes (KCNQ1, TCF7L2, CDKN2A/B, CDKAL1, UBE2E2, HHEX, and KCNJ11), which linked to insulin secretion in previous cross-sectional studies.

Results

The IAD was −1.513 [-2.635: −0.129] × 10⁻² nmol/L/year. Among the candidate SNPs, only KCNJ11 (rs5219) showed a significant difference in IAD between the patients with homozygous susceptibility allele TT (−2.583 [-3.285: −0.893] × 10⁻² nmol/L/year, N = 20) and those with TC/CC (−1.367 [-2.273: −0.767] × 10⁻² nmol/L/year, N = 96) (P = 0.035).

Conclusions

Using IAD calculated by fasting serum C-peptide over 10 years, KCNJ11 (rs5219) was identified as a genetic factor that was associated with the decline in insulin secretion in Japanese patients with type 2 diabetes mellitus.