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

• Published in: PloS one Vol. 5; no. 5; p. e10883
• Main Authors: Gall, Walter E., Beebe, Kirk, Lawton, Kay A., Adam, Klaus-Peter, Mitchell, Matthew W., Nakhle, Pamela J., Ryals, John A., Milburn, Michael V., Nannipieri, Monica, Camastra, Stefania, Natali, Andrea, Ferrannini, Ele
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 28.05.2010; Public Library of Science (PLoS)
• Subjects: Adult; Amino acids; Biochemistry; Bioindicators; Biomarkers; Biomarkers - metabolism; Biosynthesis; Biotechnology; Blood glucose; Blood Glucose - metabolism; Body mass; Cardiovascular disease; Cardiovascular diseases; Chromatography; Correlation analysis; Demography; Diabetes; Diabetes and Endocrinology; Diabetes and Endocrinology/Obesity; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus - blood; Diabetes Mellitus - metabolism; Diagnostic systems; Dilution; Disease control; Fatty acids; Female; Glucose; Glucose Intolerance - metabolism; Glucose tolerance; Health risks; Humans; Hydroxybutyrates - metabolism; Identification methods; Insulin; Insulin Resistance; Intermediates; Internal medicine; Intolerance; Lipid peroxidation; Male; Mass spectrometry; Mass spectroscopy; Medicine; Metabolism; Metabolites; Metabolome; Middle Aged; Models, Biological; Organic acids; Oxidation; Oxidative stress; Pathogenesis; Population (statistical); Public Health and Epidemiology/Preventive Medicine; Receptor, Insulin - metabolism; Resistance factors; Risk factors; Rodents; Scientific imaging; Sensitivity; Sensitivity analysis; Statistical analysis; North Carolina; United States > US; Italy
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0010883

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.