α-Hydroxybutyrate Association With Incident Type 2 Diabetes Over 10 Years Across Different Glycemic States

To investigate the association between baseline plasma α-hydroxybutyrate (α-HB), an organic acid derived from aminoacid catabolism and glutathione anabolism, and the 10-year incidence of Type 2 diabetes (T2DM).

This prospective study analysed 1349 participants from the Swedish PAROKRANK study. At baseline, participants without known diabetes underwent a standardised 2-h oral glucose tolerance test and were categorised into four groups: normoglycemia, impaired fasting glucose, impaired glucose tolerance and T2DM. Incident T2DM was identified over a 9.95-year median follow-up via national registries. Plasma α-HB concentrations were quantified using an enzymatic test kit (XpressGT). Risk of incident T2DM was analysed using uni- and multi-variate Cox regression models. Model performance was further assessed using the category-less Net Reclassification Improvement (NRI).

α-HB levels showed a stepwise elevation across the spectrum of dysglycemia at baseline. During follow-up, 134 (11%) individuals developed T2DM. Each unit increase in log-transformed α-HB was associated with a nearly twofold increase in the risk of developing T2DM (HR 1.99; 95% CI 1.32-3.01) in the univariate analysis, which remained significant after adjustment for relevant clinical variables including BMI and fasting Hba1c (HR 1.78; 95% CI 1.19-2.67). The addition of α-HB to a clinical model yielded a significant NRI improvement (0.23; p = 0.01).

Plasma α-HB is a robust, independent risk marker of incident T2DM over a decade, which identifies long-term metabolic risk not fully captured by glycaemic status alone. Its reliance on a single fasting measurement may offer a practical tool for refining early risk stratification.