Plasma amino acid and metabolite signatures tracking diabetes progression in the UCD-T2DM rat model.
Elevations of plasma concentrations of branched-chain amino acids (BCAAs) are observed in human insulin resistance and type 2 diabetes mellitus (T2DM); however, there has been some controversy with respect to the passive or causative nature of the BCAA phenotype. Using untargeted metabolomics, plasma BCAA and other metabolites were assessed in lean control Sprague-Dawley rats (LC) and temporally during diabetes development in the UCD-T2DM rat model, i.e., prediabetic (PD) and 2 wk (D2W), 3 mo (D3M), and 6 mo (D6M) post-onset of diabetes. Plasma leucine, isoleucine, and valine concentrations were elevated only in D6M rats compared with D2W rats (by 28, 29, and 30%, respectively). This was in contrast to decreased plasma concentrations of several other amino acids in D3M and/or D6M relative to LC rats (Ala, Arg, Glu, Gln, Met, Ser, Thr, and Trp). BCAAs were positively correlated with fasting glucose and negatively correlated with plasma insulin, total body weight, total adipose tissue weight, and gastrocnemius muscle weight in the D3M and D6M groups. Multivariate analysis revealed that D3M and D6M UCD-T2DM rats had lower concentrations of amino acids, amino acid derivatives, 1,5-anhydroglucitol, and conduritol-β-opoxide and higher concentrations of uronic acids, pantothenic acids, aconitate, benzoic acid, lactate, and monopalmitin-2-glyceride relative to PD and D2W UCD-T2DM rats. The UCD-T2DM rat does not display elevated plasma BCAA concentrations until 6 mo post-onset of diabetes. With the acknowledgement that this is a rodent model of T2DM, the results indicate that elevated plasma BCAA concentrations are not necessary or sufficient to elicit an insulin resistance or T2DM onset.
Arkansas Children's Nutrition Center, Little Rock, Arkansas; Department of Pediatrics, University of Arkansas for Medical Science, Little Rock, Arkansas;
Brian D
BD
Piccolo
Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California; Department of Nutrition, University of California, Davis, California;
James L
JL
Graham
Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California; Department of Nutrition, University of California, Davis, California;
Kimber L
KL
Stanhope
West Coast Metabolomics Center, Genome Center, University of California, Davis, California; and King Abdulaziz University, Biochemistry Department, Jeddah, Saudi Arabia.
Oliver
O
Fiehn
Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California; Department of Nutrition, University of California, Davis, California;
Peter J
PJ
Havel
Arkansas Children's Nutrition Center, Little Rock, Arkansas; Department of Pediatrics, University of Arkansas for Medical Science, Little Rock, Arkansas; Department of Nutrition, University of California, Davis, California; SHAdams@uams.edu.
Sean H
SH
Adams
D000597:Amino Acids, Branched-Chain / Q000097:blood*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001798:Blood Proteins / Q000032:analysis; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000175:diagnosis*; D004195:Disease Models, Animal; D018450:Disease Progression; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index
D000597:Amino Acids, Branched-Chain; D015415:Biomarkers; D001798:Blood Proteins
University of California at Davis Type 2 Diabetes rat model; amino acids; branched-chain amino acids; branched-chain amino aicds; diabetes