α-Hydroxybutyrate Is an Early Biomarker of Insulin Resistance and Glucose Intolerance in a Nondiabetic Population

• DOI: 10.1371/journal.pone.0010883
• Publication Date: 2010-05-28T20:49:15Z
• Authors: Walter E. Gall; Kirk Beebe; Kay A. Lawton; Klaus-Peter Adam; Matthew W. Mitchell; Pamela J. Nakhle; John A. Ryals; Michael V. Milburn; Monica Nannipieri; Stefania Camastra; Andrea Natali; Ele Ferrannini
• Keywords: Adult; Blood Glucose; Male; 0301 basic medicine; 2. Zero hunger; Science; Q; R; Hydroxybutyrates; Middle Aged; Models, Biological; Receptor, Insulin; 3. Good health; 03 medical and health sciences; Glucose Intolerance; Diabetes Mellitus; Metabolome; Medicine; Humans; Female; Insulin Resistance; Biomarkers; Research Article; Demography

Insulin resistance is a risk factor for type 2 diabetes and cardiovascular disease progression. Current diagnostic tests, such as glycemic indicators, have limitations in the early detection of insulin resistant individuals. We searched for novel biomarkers identifying these at-risk subjects.Using mass spectrometry, non-targeted biochemical profiling was conducted in a cohort of 399 nondiabetic subjects representing a broad spectrum of insulin sensitivity and glucose tolerance (based on the hyperinsulinemic euglycemic clamp and oral glucose tolerance testing, respectively).Random forest statistical analysis selected alpha-hydroxybutyrate (alpha-HB) as the top-ranked biochemical for separating insulin resistant (lower third of the clamp-derived M(FFM) = 33 [12] micromol x min(-1) x kg(FFM) (-1), median [interquartile range], n = 140) from insulin sensitive subjects (M(FFM) = 66 [23] micromol x min(-1) x kg(FFM) (-1)) with a 76% accuracy. By targeted isotope dilution assay, plasma alpha-HB concentrations were reciprocally related to M(FFM); and by partition analysis, an alpha-HB value of 5 microg/ml was found to best separate insulin resistant from insulin sensitive subjects. alpha-HB also separated subjects with normal glucose tolerance from those with impaired fasting glycemia or impaired glucose tolerance independently of, and in an additive fashion to, insulin resistance. These associations were also independent of sex, age and BMI. Other metabolites from this global analysis that significantly correlated to insulin sensitivity included certain organic acid, amino acid, lysophospholipid, acylcarnitine and fatty acid species. Several metabolites are intermediates related to alpha-HB metabolism and biosynthesis.alpha-hydroxybutyrate is an early marker for both insulin resistance and impaired glucose regulation. The underlying biochemical mechanisms may involve increased lipid oxidation and oxidative stress.