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ARS Home » Pacific West Area » Davis, California » Western Human Nutrition Research Center » Obesity and Metabolism Research » Research » Publications at this Location » Publication #257735
Title: Plasma metabolomic profiles reflective of glucose homeostasis in non-diabetic and Type 2 diabetic obese African-American women

Author
item FIEHN, OLIVER - University Of California
item GARVEY, W. TIMOTHY - University Of Alabama
item Newman, John
item LOK, KERRY - University Of Alabama
item HOPPEL, CHARLES - Case Western Reserve University (CWRU)
item Adams, Sean

Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/31/2010
Publication Date: 12/10/2010
Citation: Fiehn, O., Garvey, W., Newman, J.W., Lok, K.H., Hoppel, C.L., Adams, S.H. 2010. Plasma Metabolomic Profiles Reflective of Glucose Homeostasis in Non-Diabetic and Type 2 Diabetic Obese African-American Women. PLoS One. Vol.5(12): e15234.

Interpretive Summary: Insulin resistance progressing to type 2 diabetes mellitus (T2DM) is marked by a broad perturbation of macronutrient intermediary metabolism. Understanding the biochemical networks that underlie metabolic homeostasis and how they associate with insulin action will help unravel diabetes etiology and should foster discovery of new biomarkers of disease risk and severity. We examined differences in plasma levels of >350 metabolites in fasted obese T2DM vs. obese non-diabetic African-American women, and utilized principal components analysis (PCA) to identify 53 metabolite components, many unique, contributing to a PC score strongly correlated with fasting HbA1c over a broad range of the latter (r=0.74; p<0.0001). In addition to many unidentified metabolites, specific metabolites that were increased significantly in T2DM subjects included certain amino acids (i.e., leucine/2-ketoisocaproate, valine, cystine, histidine), 2-hydroxybutanoate (2-HB), long-chain fatty acids, and carbohydrate derivatives. Leucine and valine concentrations significantly correlated with total acylcarnitine levels across the study cohort (and rising with increasing HbA1c). This appears to reflect a close link between abnormalities in glucose homeostasis, amino acid catabolism, and inefficiency of fuel combustion in the tricarboxylic acid (TCA) cycle. One proposed mechanism for the latter is “anaplerotic stress” concomitant with reduced amino acid-derived carbon flux to TCA cycle intermediates coupled to perturbation in cataplerosis (TCA intermediate loss).

Technical Abstract: Insulin resistance progressing to type 2 diabetes mellitus (T2DM) is marked by a broad perturbation of macronutrient intermediary metabolism. Understanding the biochemical networks that underlie metabolic homeostasis and how they associate with insulin action will help unravel diabetes etiology and should foster discovery of new biomarkers of disease risk and severity. We examined differences in plasma levels of >350 metabolites in fasted obese T2DM vs. obese non-diabetic African-American women, and utilized principal components analysis (PCA) to identify 53 metabolite components, many unique, contributing to a PC score strongly correlated with fasting HbA1c over a broad range of the latter (r=0.74; p<0.0001). In addition to many unidentified metabolites, specific metabolites that were increased significantly in T2DM subjects included certain amino acids (i.e., leucine/2-ketoisocaproate, valine, cystine, histidine), 2-hydroxybutanoate (2-HB), long-chain fatty acids, and carbohydrate derivatives. Leucine and valine concentrations significantly correlated with total acylcarnitine levels across the study cohort (and rising with increasing HbA1c). This appears to reflect a close link between abnormalities in glucose homeostasis, amino acid catabolism, and inefficiency of fuel combustion in the tricarboxylic acid (TCA) cycle. One proposed mechanism for the latter is “anaplerotic stress” concomitant with reduced amino acid-derived carbon flux to TCA cycle intermediates coupled to perturbation in cataplerosis (TCA intermediate loss).