Fasting proinsulin as a predictor of future glucose tolerance deterioration in Japanese adults

ABSTRACT Aims/Introduction Proinsulin is associated with β‐cell stress and has been linked to subsequent deterioration in glucose metabolism in Western populations, but its predictive value in Asian populations remains unclear. We investigated whether proinsulin is associated with future glucose tolerance deterioration in community‐dwelling Japanese adults. Materials and Methods Of 160 individuals who underwent a 75‐g oral glucose tolerance test (OGTT) in 2020–2021, 88 completed a follow‐up OGTT in 2024–2025. Fasting proinsulin concentrations were measured using stored baseline serum samples from 84 participants. Associations with glucose tolerance deterioration were examined using Firth's penalized logistic regression, and discriminatory performance was evaluated using receiver operating characteristic (ROC) analysis. Results During the 4‐year follow‐up, glucose tolerance deteriorated in 16 participants. Fasting proinsulin concentrations were higher in progressors than in non‐progressors (5.8 vs. 3.6 pmol/L; P = 0.009). Each 1‐standard deviation increase in fasting proinsulin was associated with glucose tolerance deterioration (odds ratio 2.11, 95% confidence interval 1.31–3.72; P = 0.002). In exploratory ROC analysis, the area under the curve was 0.710, and a cutoff of 5.1 pmol/L yielded 68.8% sensitivity and 83.8% specificity. Participants with elevated fasting proinsulin (≥ 5.1 pmol/L) and a low disposition index (≤ 1.27) had the highest odds of deterioration. Conclusions Fasting proinsulin may help identify Japanese adults at risk of future glucose tolerance deterioration, particularly when combined with indices of β‐cell compensation.