title: Branched-Chain Amino Acids and Insulin Metabolism: The Insulin Resistance Atherosclerosis Study (IRAS).
abstract: Recent studies using untargeted metabolomics approaches have suggested that plasma branched-chain amino acids (BCAAs) are associated with incident diabetes. However, little is known about the role of plasma BCAAs in metabolic abnormalities underlying diabetes and whether these relationships are consistent across ethnic populations at high risk for diabetes. We investigated the associations of BCAAs with insulin sensitivity (SI), acute insulin response (AIR), and metabolic clearance of insulin (MCRI) in a multiethnic cohort.
  
  
  
  In 685 participants without diabetes of the Insulin Resistance Atherosclerosis Study (IRAS) (290 Caucasians, 165 African Americans, and 230 Hispanics), we measured plasma BCAAs (sum of valine, leucine, and isoleucine) by mass spectrometry and SI, AIR, and MCRI by frequently sampled intravenous glucose tolerance tests.
  
  
  
  Elevated plasma BCAAs were inversely associated with SI and MCRI and positively associated with fasting insulin in regression models adjusted for potential confounders (β = -0.0012 [95% CI -0.0018, -0.00059], P < 0.001 for SI; β = -0.0013 [95% CI -0.0018, -0.00082], P < 0.001 for MCRI; and β = 0.0015 [95% CI 0.0008, 0.0023], P < 0.001 for fasting insulin). The association of BCAA with SI was significantly modified by ethnicity, with the association only being significant in Caucasians and Hispanics. Elevated plasma BCAAs were associated with incident diabetes in Caucasians and Hispanics (multivariable-adjusted odds ratio per 1-SD increase in plasma BCAAs: 1.67 [95% CI 1.21, 2.29], P = 0.002) but not in African Americans. Plasma BCAAs were not associated with SI-adjusted AIR.
  
  
  
  Plasma BCAAs are associated with incident diabetes and underlying metabolic abnormalities, although the associations were generally stronger in Caucasians and Hispanics.
authors.affiliation: Department of Nutritional Sciences, University of Toronto, Toronto, ON, Canada.
authors.forename: C Christine
authors.initials: CC
authors.lastname: Lee
authors.affiliation: Lipomics Technologies, Inc., a division of Metabolon, Inc., West Sacramento, CA.
authors.forename: Steve M
authors.initials: SM
authors.lastname: Watkins
authors.affiliation: Division of Clinical Epidemiology, University of Texas Health Science Center, San Antonio, TX.
authors.forename: Carlos
authors.initials: C
authors.lastname: Lorenzo
authors.affiliation: Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Lynne E
authors.initials: LE
authors.lastname: Wagenknecht
authors.affiliation: School of Public Health, Georgia State University, Atlanta, GA.
authors.forename: Dora
authors.initials: D
authors.lastname: Il'yasova
authors.affiliation: Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, Torrance, CA.
authors.forename: Yii-Der I
authors.initials: YD
authors.lastname: Chen
authors.affiliation: Retired, San Antonio, TX.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Haffner
authors.affiliation: Department of Nutritional Sciences, University of Toronto, Toronto, ON, Canada Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, Toronto, ON, Canada anthony.hanley@utoronto.ca.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Hanley
mesh_terms: D001741:Black or African American; D000597:Amino Acids, Branched-Chain / Q000097:blood*; D050197:Atherosclerosis / Q000097:blood*; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000378:metabolism*; D005260:Female; D005500:Follow-Up Studies; D005951:Glucose Tolerance Test; D006630:Hispanic or Latino; D006801:Humans; D015994:Incidence; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D007333:Insulin Resistance; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D044465:White People
chemical_list: D000597:Amino Acids, Branched-Chain; D007328:Insulin