alpha-hydroxybutyrate is an early biomarker of insulin resistance and glucose intolerance in a nondiabetic population.
BACKGROUND
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.


METHODS
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).


RESULTS
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.


CONCLUSIONS
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.
Gall
Walter E
WE
Metabolon, Inc., Research Triangle Park, North Carolina, United States of America. wgall@metabolon.com
Beebe
Kirk
K
Lawton
Kay A
KA
Adam
Klaus-Peter
KP
Mitchell
Matthew W
MW
Nakhle
Pamela J
PJ
Ryals
John A
JA
Milburn
Michael V
MV
Nannipieri
Monica
M
Camastra
Stefania
S
Natali
Andrea
A
Ferrannini
Ele
E
D000328:Adult; D015415:Biomarkers / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D003710:Demography; D003920:Diabetes Mellitus / Q000097:blood / Q000378:metabolism*; D005260:Female; D018149:Glucose Intolerance / Q000378:metabolism*; D006801:Humans; D006885:Hydroxybutyrates / Q000378:metabolism*; D007333:Insulin Resistance; D008297:Male; D055442:Metabolome; D008875:Middle Aged; D008954:Models, Biological; D011972:Receptor, Insulin / Q000378:metabolism
D015415:Biomarkers; D001786:Blood Glucose; D006885:Hydroxybutyrates; D011972:Receptor, Insulin; C031570:2-hydroxybutyric acid