Location: Arkansas Children's Nutrition CenterTitle: Plasma amino acid and metabolite signatures tracking diabetes progression in the UCD-T2DM rat model
|PICCOLO, BRIAN - Arkansas Children'S Nutrition Research Center (ACNC)|
|GRAHAM, JAMES - University Arkansas For Medical Sciences (UAMS)|
|STANHOPE, KIMBERLY - University Of California|
|FIEHN, OLIVER - University Of California|
|HAVEL, PETER - University Of California|
Submitted to: American Journal of Physiology - Endocrinology and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/15/2016
Publication Date: 6/1/2016
Citation: Piccolo, B., Graham, J., Stanhope, K., Fiehn, O., Havel, P., Adams, S.H. 2016. Plasma amino acid and metabolite signatures tracking diabetes progression in the UCD-T2DM rat model. American Journal of Physiology - Endocrinology and Metabolism. 310(11):958-969. doi: 10.1152/ajpendo.00052.2016.
Interpretive Summary: Elevations of blood concentrations of a specific type of amino acids, termed 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 a technology that allows for characterizing hundreds of metabolites in blood (metabolomics), blood plasma BCAA and other metabolites were assessed in an animal model that mimics development of T2DM over time. This system enabled the measurement of BCAA and other factors through time of development of the disease phenotype (weeks), which is difficult to address in human studies that can take years to complete. Through our studies with a specific rat model we learned that BCAAs were positively correlated with fasting blood sugar and negatively correlated with the glucose-regulating hormone insulin, total body weight, total adipose tissue weight, and gastrocnemius muscle weight in certain groups. These studies provide key new evidence that increases in BCAA are not necessary or sufficient to trigger diabetes, and in fact the blood concentration of BCAA occurred well after diabetes onset as metabolism deteriorated body-wide. The results are important to public health messaging about the health effects of BCAA-rich foods.
Technical Abstract: 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., pre-diabetic (PD), 2-weeks (D2W), 3-months (D3M) and 6-months (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, 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 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-beta-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 months post-onset of diabetes. With the acknowledgement that this is a rodent model of T2DM, that the results indicate that elevated plasma BCAA concentrations are not necessary or sufficient to elicit an insulin resistance or T2DM onset.