title: Metabolomic profile associated with insulin resistance and conversion to diabetes in the Insulin Resistance Atherosclerosis Study.
abstract: BACKGROUND
  Metabolomic profiling of amino acids and acylcarnitines has revealed consistent patterns associated with metabolic disease.
  
  
  OBJECTIVE
  This study used metabolomic profiling to identify analytes associated with insulin sensitivity (SI) and conversion to type 2 diabetes (T2D).
  
  
  METHODS
  A multiethnic cohort from the Insulin Resistance Atherosclerosis Study.
  
  
  METHODS
  Community-based.
  
  
  METHODS
  A total of 196 subjects (European American, Hispanic, and African American) were selected to represent extremes of the SI distribution and conversion to T2D between baseline and followup exams.
  
  
  RESULTS
  Mass spectrometry-based profiling of 69 metabolites. Subjects participated in a frequently sampled i.v. glucose tolerance test to measure SI and acute insulin response. T2D status was determined by a 2-hour oral glucose tolerance test.
  
  
  RESULTS
  Logistic regression analysis from 72 high and 75 low SI subjects revealed significantly decreased glycine and increased valine, leucine, phenylalanine, and combined glutamine and glutamate (P = .0079-7.7 × 10(-6)) in insulin-resistant subjects. Ethnic-stratified results were strongest in European Americans. Comparing amino acid profiles between subjects that converted to T2D (76 converters; 70 nonconverters) yielded a similar pattern of associations: decreased glycine and increased valine, leucine, and combined glutamine and glutamate (P = .016-.00010). Importantly, β-cell function as a covariate revealed a similar pattern of association.
  
  
  CONCLUSIONS
  A distinct pattern of differences in amino acids were observed when comparing subjects with high and low levels of SI. This pattern was associated with conversion to T2D, remaining significant when accounting for β-cell function, emphasizing a link between this metabolic profile and insulin resistance. These results demonstrate a consistent metabolic signature associated with insulin resistance and conversion to T2D, providing potential insight into underlying mechanisms of disease pathogenesis.
authors.affiliation: Department of Biochemistry (N.D.P., P.A.A., D.W.B.), Center for Genomics and Personalized Medicine Research (N.D.P., P.A.A., D.W.B.), and Center for Diabetes Research (N.D.P., P.A.A., D.W.B.), Wake Forest School of Medicine, Winston Salem, North Carolina 27157; Sarah W. Stedman Nutrition and Metabolism Center (R.D.S., C.B.N.), Duke University School of Medicine, Durham, North Carolina 27710; Department of Biostatistical Sciences (A.A.) and Department of Epidemiology & Prevention (L.E.W.), Wake Forest School of Medicine, Winston Salem, North Carolina 27157; and Department of Physiology and Biophysics (R.N.B.), Keck School of Medicine, University of Southern California, Los Angeles, California 90033.
authors.forename: Nicholette D
authors.initials: ND
authors.lastname: Palmer
authors.forename: Robert D
authors.initials: RD
authors.lastname: Stevens
authors.forename: Peter A
authors.initials: PA
authors.lastname: Antinozzi
authors.forename: Andrea
authors.initials: A
authors.lastname: Anderson
authors.forename: Richard N
authors.initials: RN
authors.lastname: Bergman
authors.forename: Lynne E
authors.initials: LE
authors.lastname: Wagenknecht
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Newgard
authors.forename: Donald W
authors.initials: DW
authors.lastname: Bowden
mesh_terms: D000328:Adult; D001741:Black or African American; D000368:Aged; D050197:Atherosclerosis / Q000208:ethnology / Q000378:metabolism; D044383:Black People; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000208:ethnology / Q000378:metabolism*; D005260:Female; D006630:Hispanic or Latino; D006801:Humans; D007333:Insulin Resistance / Q000208:ethnology; D008297:Male; D055442:Metabolome; D055432:Metabolomics; D008875:Middle Aged; D011236:Prediabetic State / Q000208:ethnology / Q000378:metabolism*; D044465:White People