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

Abstract

Objective: Serum 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 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 α-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 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).

Conclusions: Fasting 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.

Keywords: Biomarkers; Insulin Resistance; Oral Glucose Tolerance Test; Pancreatice Insulin Secretion.

Figure 1

(A) Oral glucose tolerance test (OGTT) glucose and (C) natural logarithm of insulin responses over time with SEM bars comparing the first tertile to the second and third tertiles combined in routine clinical practice patients (N=217); *p value <0.05. The F-test for the α-hydroxybutyrate (AHB) group by time interaction is given above the panel. (B) OGTT glucose response area under the curve (AUC) above 50 mg/dL. (D) 30 min rise in log(insulin).

Figure 2

Receiver operating characteristic (ROC) curves for classifying patients having a 1 h glucose ≥155 mg/dL during oral glucose tolerance test. The area increased by 0.039 (95% CI 0.008 to 0.070, p=0.015) when α-hydroxybutyrate (AHB) was added to age, gender, body mass index, fasting glucose, log(fasting insulin), log(triglycerides), high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol in the logistic regression model.

Figure 3

Comparison of receiver operating characteristic (ROC) curves for predicting oral glucose tolerance test (OGTT) 1 h postload glucose ≥155 mg/dL in (A) patients with fasting glucose <100 mg/dL and glycated hemoglobin (HbA1c) <5.7% (N=137, with 33 events); the area increased by 0.10 (p=0.059), 0.09 (p=0.087), or 0.17 (p=0.0044) when using fasting glucose, log(HbA1c), or α-hydroxybutyrate (AHB) alone, respectively; or in (B) patients additionally with insulin ≤12 (U/mL, 2 h glucose <140 mg/dL, and a negative antiglutamic acid decarboxylase (anti-GAD) antibody (N=93, with 15 events). The area increased by 0.15 (p=0.016), 0.15 (p=0.038), or 0.24 (p=0.0007), respectively.