Abstract
BackgroundMetabolic syndrome (MS) is a construct used to separate “healthy” from “unhealthy” obese patients, and is a major risk factor for type 2 diabetes (T2D) and cardiovascular disease. There is controversy over whether obese “metabolically well” persons have a higher morbidity and mortality than lean counterparts, suggesting that MS criteria do not completely describe physiologic risk factors or consequences of obesity. We hypothesized that metabolomic analysis of plasma would distinguish obese individuals with and without MS and T2D along a spectrum of obesity-associated metabolic derangements, supporting metabolomic analysis as a tool for a more detailed assessment of metabolic wellness than currently used MS criteria.MethodsFasting plasma samples from 90 adults were assigned to groups based on BMI and ATP III criteria for MS: (1) lean metabolically well (LMW; n = 24); (2) obese metabolically well (OBMW; n = 26); (3) obese metabolically unwell (OBMUW; n = 20); and (4) obese metabolically unwell with T2D (OBDM; n = 20). Forty-one amino acids/dipeptides, 33 acylcarnitines and 21 ratios were measured. Obesity and T2D effects were analyzed by Wilcoxon rank-sum tests comparing obese nondiabetics vs LMW, and OBDM vs nondiabetics, respectively. Metabolic unwellness was analyzed by Jonckheere-Terpstra trend tests, assuming worsening health from LMW → OBMW → OBMUW. To adjust for multiple comparisons, statistical significance was set at p < 0.005. K-means cluster analysis of aggregated amino acid and acylcarnitine data was also performed.ResultsAnalytes and ratios significantly increasing in obesity, T2D, and with worsening health include: branched-chain amino acids (BCAAs), cystine, alpha-aminoadipic acid, phenylalanine, leucine + lysine, and short-chain acylcarnitines/total carnitines. Tyrosine, alanine and propionylcarnitine increase with obesity and metabolic unwellness. Asparagine and the tryptophan/large neutral amino acid ratio decrease with T2D and metabolic unwellness. Malonylcarnitine decreases in obesity and 3-OHbutyrylcarnitine increases in T2D; neither correlates with unwellness. Cluster analysis did not separate subjects into discreet groups based on metabolic wellness.DiscussionLevels of 15 species and metabolite ratios trend significantly with worsening metabolic health; some are newly recognized. BCAAs, aromatic amino acids, lysine, and its metabolite, alpha-aminoadipate, increase with worsening health. The lysine pathway is distinct from BCAA metabolism, indicating that biochemical derangements associated with MS involve pathways besides those affected by BCAAs. Even those considered “obese, metabolically well” had metabolite levels which significantly trended towards those found in obese diabetics. Overall, this analysis yields a more granular view of metabolic wellness than the sole use of cardiometabolic MS parameters. This, in turn, suggests the possible utility of plasma metabolomic analysis for research and public health applications.
Highlights
Obesity, a major risk factor for cardiovascular disease, type 2 diabetes (T2D), and allcause mortality, has dramatically increased in population prevalence over the past several decades (Ogden, Carroll & Flegal, 2003; The GBD 2015 Obesity Collaborators, 2017)
The lysine pathway is distinct from branched-chain amino acids (BCAAs) metabolism, indicating that biochemical derangements associated with Metabolic syndrome (MS) involve pathways besides those affected by BCAAs
Obesity was regarded as BMI >30 kg/m2 and metabolic wellness was determined by Adult Treatment Panel III (ATP III) criteria as described in the Methods section, ‘Determination of metabolic wellness’
Summary
A major risk factor for cardiovascular disease, type 2 diabetes (T2D), and allcause mortality, has dramatically increased in population prevalence over the past several decades (Ogden, Carroll & Flegal, 2003; The GBD 2015 Obesity Collaborators, 2017). To group these factors into standardized criteria, four main definitions of metabolic syndrome (MS) have been formulated: the original World Health Organization (WHO) definition of 1998; criteria of the European Group for the study of Insulin Resistance (EGIR); criteria of the National Cholesterol Education Program Adult Treatment Panel (NCEP ATP) III; and criteria of the International Diabetes Foundation (IDF) (Alberti & Zimmet, 1998; Balkau & Charles, 1999; Zimmet et al, 2005; Grundy et al, 2005) These criteria differ, but most include increased body mass index, hyperglycemia, hypertension, and dyslipidemia to describe an individual’s degree of progression toward cardiovascular disease and/or T2D. Cluster analysis did not separate subjects into discreet groups based on metabolic wellness
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