Metabolomic analysis of obesity, metabolic syndrome, and type 2 diabetes: amino acid and acylcarnitine levels change along a spectrum of metabolic wellness

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.

One Anastomosis Gastric Bypass Reconstitutes the Appropriate Profile of Serum Amino Acids in Patients with Morbid Obesity

“…The decreased ADMA after OAGB ( Table 2) suggests that this surgical procedure can lead to decreased cardiovascular risk in patients. Some authors [9,12,14] observed elevated levels of lysine in patients before BS compared to levels in LCs; however, we observed lower levels of lysine in obese subjects and its impact on the biotin metabolism (7.55E06, impact 0.00; Table S2) and lysine metabolism (p < 0.0001, impact 0.10; Table S2) pathways ( Figure 3A). After OAGB, the levels of lysine were even lower than before in our patients.…”

“…It also plays a role in anemia, has an impact on the uptake of iron, and increases ferritin in blood [50]. Lysine is also a precursor of α-aminoadipic acid (AAD) formed during lysine degradation [12]. It seems that in our group of patients, catabolism of lysine is elevated; however, we did not investigate the AAD levels.…”

“…The changes in glutamine and glutamate concentrations will be discussed in the next section. Branched chain amino acids (BCAAs), including leucine, isoleucine, and valine, are associated with insulin resistance and type 2 diabetes mellitus [6,8,9,12,13,32]. Many authors emphasized the association of BCAAs with obesity [6,[8][9][10][11]13].…”

A Non-Targeted Capillary Electrophoresis-Mass Spectrometry Strategy to Study Metabolic Differences in an In Vitro Model of High-Glucose Induced Changes in Human Proximal Tubular HK-2 Cells

“…It is tempting to speculate that the increased levels of cysteine in high glucose extracellular fluid are due to the well-known oxidative stress induced by high glucose in proximal tubular cells [17], which leads to a disulfide bond by the oxidation of two molecules of cysteine and the consequent formation of cystine. This dipeptide can inhibit tyrosine aminotransferase activity and can lead to an increased plasma tyrosine level [52,53]. This is exactly what we have observed in our study.…”

Diet Alters Serum Metabolomic Profiling in the Mouse Model of Chronic Chagas Cardiomyopathy

“…Methionine sulfoxide is an indicator of oxidative stress. Increased kynurenine and alpha-AAA are associated with increased immune functions and metabolic dysfunctions, respectively [24]. The serum levels of serotonin significantly increased and the levels of creatinine and dopamine significantly decreased in infected RD mice compared to uninfected RD mice (Figure 4(b)), whereas the levels of sarcosine and putrescine significantly increased and serotonin significantly decreased in infected HFD mice compared to uninfected HFD mice (Figure 4(b)).…”