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

Abstract

ObjectiveSerum α-hydroxybutyrate (α-HB) is elevated in insulin resistance and diabetes. We tested the hypothesis that the α-HB level predicts abnormal 1 h glucose levels and β-cell dysfunction inferred from plasma insulin kinetics during a 75 g oral glucose tolerance test (OGTT).Research design and methodsThis 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 α-HB added to traditional risk factors.ResultsMean±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 α-HB tertiles (>3.9 µg/mL) than in the first tertile. Patients in the second/third α-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 α-HB added (p=0.015), with a net reclassification index of 52% (p<0.0001).ConclusionsFasting serum α-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 α-HB could thus provide a rapid, inexpensive screening tool for detecting early subclinical hyperglycemia, β-cell dysfunction, and increased risk for diabetes.

α-Hydroxybutyric Acid Is a Selective Metabolite Biomarker of Impaired Glucose Tolerance

“…Our data replicate the finding with L-GPC and glycine (RISC only), whereas acetylcarnitine was not measured. A third study found a-HB to be a predictive biomarker of the 1-h plasma glucose value from the OGTT in a cohort of subjects at increased risk of diabetes (28). Finally, we recently reported that a-HB is correlated with 2hPG and is a predictive biomarker of IGT in RISC and DMVhi (15).…”

Interorgan Metabolic Crosstalk in Human Insulin Resistance

“…Circulating ␣HB negatively relates to whole body insulin sensitivity and distinguishes impaired glucose tolerance from impaired fasting glucose (79). Additionally, ␣HB predicts worsening of glucose tolerance in the prospective RISC and Botnia cohorts (118) and may relate to abnormal ␤-cell function in humans at risk for diabetes (409). Whether ␣HB also mediates distant metabolic effects remains unclear.…”

GC–MS based Gestational Diabetes Mellitus longitudinal study: Identification of 2-and 3-hydroxybutyrate as potential prognostic biomarkers

“…Metabolomics has the potential to determine set of metabolites that are predictive of both prediabetes and T2DM, even before onset of the disease [12]. Thus, the evidence of metabolomics benefitting T2DM, and also GDM patients, makes its clinical application inevitable.…”

“…Despite disparities in predictive biomarkers [11], metabolomics studies have the potential to determine sets of metabolites that are predictive of both prediabetes and T2DM, even before the onset of disease, thereby improving patients' health, as shown recently for T2DM [12]. In fact, an increasing number of studies have confirmed elevation of circulating branched-chain amino acids and 2-hydroxybutyrate before manifestation of T2DM.…”