OR34-08 Exploring genetic risk factors for β-cell deterioration in type 2 diabetes mellitus: Insights from longitudinal C-peptide analysis

Abstract Disclosure: S. Morita: None. Y. Shimajiri: None. T. Sanke: None. T. Matsuoka: None. Aim: Insulin secretion in type 2 diabetes mellitus deteriorates over time, but the factors influencing its degree remain unclear. This study aims to specifically identify genetic factors associated with this decline. Methods: A retrospective longitudinal study was conducted with 116 Japanese patients with type 2 diabetes mellitus without significant obesity or renal dysfunction, observed over 10.5 ± 4.7 years. The individual annual decline of fasting serum C-peptide (IAD) was calculated as the slope of the regression line derived from fasting CP value (y-axis) measured over the observation period (x-axis). 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 the previous cross-sectional studies. Results: The IAD was -1.513 [-2.635: -0.129] ×10-2 nmol/L/year across all of the subjects. 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). The association between IAD and the TT allele of KCNJ11 (rs5219) remained significant even after adjusting for clinical covariates. Additional analysis revealed additive effects of risk genotypes (CDKAL1, UBE2E2, HHEX, and KCNJ11) selected based on a lenient threshold of P-value (P <0.25), showing that IAD decreases significantly with an increasing number of risk genotypes, indicating a faster decline in insulin secretion. Conclusions: This study highlights the utility of IAD as a longitudinal indicator of insulin secretion decline and identifies KCNJ11 (rs5219) SNP as a significant genetic factor influencing β-cell deterioration in Japanese patients with type 2 diabetes mellitus. The additive effects of other risk SNPs also suggest a complex genetic landscape contributing to disease progression. Presentation: Monday, July 14, 2025