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

Aim 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). Materials and Methods 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). Results 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). Conclusions 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.