Serum alpha-hydroxybutyrate (alpha-HB) predicts elevated 1 h glucose levels and early-phase beta-cell dysfunction during OGTT

Objective: Serum alpha-hydroxybutyrate (alpha-HB) is elevated in insulin resistance and diabetes. We tested the hypothesis that the alpha-HB level predicts abnormal 1 h glucose levels and beta-cell dysfunction inferred from plasma insulin kinetics during a 75 g oral glucose tolerance test (OGTT). Research design and methods: This cross-sectional study included 217 patients at increased risk for diabetes. 75 g OGTTs were performed with multiple postload glucose and insulin measurements over a 30-120 min period. OGTT responses were analyzed by repeated measures analysis of variance (ANOVA). Multivariable logistic regression was used to predict 1 h glucose >= 155 mg/dL with alpha-HB added to traditional risk factors. Results: Mean +/- SD age was 51 +/- 15 years (44% male, 25% with impaired glucose tolerance). Fasting glucose and insulin levels, but not age or body mass index (BMI), were significantly higher in the second/third alpha-HB tertiles (> 3.9 mu g/mL) than in the first tertile. Patients in the second/third alpha-HB tertiles exhibited a higher glucose area under the receiver operating characteristics curve (AUC) and reduced initial slope of insulin response during OGTT. The AUC for predicting 1 h glucose >= 155 mg/dL was 0.82 for a base model that included age, gender, BMI, fasting glucose, glycated hemoglobin (HbA1c), and insulin, and increased to 0.86 with alpha-HB added (p=0.015), with a net reclassification index of 52% (p<0.0001). Conclusions: Fasting serum alpha-HB levels predicted elevated 1 h glucose during OGTT, potentially due to impaired insulin secretion kinetics. This association persisted even in patients with an otherwise normal insulin-glucose homeostasis. Measuring serum alpha-HB could thus provide a rapid, inexpensive screening tool for detecting early subclinical hyperglycemia, beta-cell dysfunction, and increased risk for diabetes.