Abstract 15716: Non-Targeted Metabolomic Profiling Identifies Novel Markers of Insulin Resistance

Background: Targeted metabolomic profiling has identified metabolite classes associated with insulin resistance (IR) and incident metabolic disease, including branched-chain (BCAAs) and aromatic amino acids (AAAs). Emerging non-targeted profiling methods, which facilitate screening of many-fold more metabolites, hold great promise for the identification of additional disease biomarkers and pathways. We developed a non-targeted workflow to determine differentially regulated metabolites in two groups that differed by the homeostatic model assessment of IR (HOMA-IR). Methods: We analyzed fasting plasma from subjects with IR (HOMA-IR ≥ 2.6) (mean age = 67 ± 1.49; BMI = 28 ± 0.63; HOMA-IR = 7.94 ± 1.67) and normal subjects (HOMA-IR ≤ 1.85) (mean age = 68 ± 2.42; BMI = 26 ± 0.86; HOMA-IR = 1.13 ± 0.08), using HILIC chromatography coupled to an Agilent™ 6550 iFunnel Q-TOF mass spectrometer operated in positive ion mode. Batch recursive metabolite feature extraction was performed using MH Profinder software followed by differential metabolite analysis and identification using MPP software. Results: We identified 56 differentially abundant compounds [p < 0.05; unpaired t-test with Benjamini-Hochberg FDR (B-H FDR) correction] in a derivation cohort (n=15 IR; n=15 control) and validated 28 of these compounds in a similarly sized independent cohort (p <0.05, BH-FDR corrected). As expected, we confirmed compounds known to be associated with IR, including the BCAA valine (p=2.9E-3), the AAA tryptophan (p=1.01E-2), and a hexanoylcarnitine (p=4.8E-2). In addition, we made putative identifications of novel compounds that were significantly elevated in IR subjects in both cohorts, including aminooctanoic acid (+41%, p=3.68E-3), methylhistidine (+92%, p=4.78E-3), and methylinosine (+51%, p=3.29E-2). Novel compounds that were significantly decreased in IR subjects included isovalerylglycine (-48%, p=2.03E-2). Conclusions: We have developed a non-targeted metabolite profiling platform and detected novel compounds associated with IR. Future work includes unambiguous identification and quantification of these metabolites using isotope-labeled standards, as well as evaluation of these markers in large, heterogeneous clinical populations.

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Metabolomic profiling identifies complex lipid species associated with response to weight loss interventions

10.1101/2020.10.05.326025 ◽

2020 ◽

Author(s):

Nathan A. Bihlmeyer ◽

Lydia Coulter Kwee ◽

Clary B. Clish ◽

Amy Anderson Deik ◽

Robert E. Gerszten ◽

...

Keyword(s):

Insulin Resistance ◽

Weight Loss ◽

Metabolic Pathways ◽

Model Assessment ◽

Metabolomic Profiling ◽

Lipid Species ◽

Complex Lipid ◽

Homeostatic Model Assessment ◽

Homeostatic Model ◽

Weight Loss Interventions

AbstractObesity is an epidemic internationally. While weight loss interventions are efficacious, they are compounded by heterogeneity with regards to clinically relevant metabolic responses. Thus, we sought to identify metabolic pathways and biomarkers that distinguish individuals with obesity who would most benefit from a given type of intervention. Liquid chromatography mass spectrometry-based profiling was used to measure 765 metabolites in baseline plasma from three different weight loss studies: WLM (behavioral intervention, N=443), STRRIDE-PD (exercise trial, N=163), and CBD (surgical cohort, N=125). The primary outcome was percent change in insulin resistance (as measured by the Homeostatic Model Assessment of Insulin Resistance [%ΔHOMA-IR]) over the intervention. Overall, 92 individual metabolites were associated with %ΔHOMA-IR after adjustment for multiple comparisons. Concordantly, the most significant metabolites were triacylglycerols (TAGs; p=2.3e-5) and diacylglycerols (DAGs; p=1.6e-4), with higher TAG and DAG levels associated with a greater improvement in HOMA-IR. In tests of heterogeneity, 50 metabolites changed differently between weight loss interventions; we found amino acids, peptides, and their analogues to be most significant (4.7e-3) in this category. Our results highlight novel metabolic pathways associated with heterogeneity in response to weight loss interventions, and related biomarkers which could be used in future studies of personalized approaches to weight loss interventions.

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Sarcopenic obesity and amino acids: Concord Health and Ageing in Men Project

The Journals of Gerontology Series A ◽

10.1093/gerona/glab076 ◽

2021 ◽

Author(s):

David G Le Couteur ◽

David J Handelsman ◽

Fiona Stanaway ◽

Louise M Waite ◽

Fiona M Blyth ◽

...

Keyword(s):

Insulin Resistance ◽

Amino Acids ◽

Amino Acid ◽

Branched Chain Amino Acids ◽

Obese Group ◽

Sarcopenic Obesity ◽

Model Assessment ◽

Homeostatic Model Assessment ◽

Branched Chain ◽

Amino Acid Concentrations

Abstract Although characteristic changes in amino acid concentrations occur in obesity and sarcopenia, amino acids concentrations have not been reported in sarcopenic obesity. We studied n=831 men aged 75 years and older from the five-year follow-up of the Concord Health and Ageing in Men Project (CHAMP). Sarcopenia was defined using the Foundation of the National Institutes of Health (FNIH) criteria and obesity was defined as >30% fat mass. There were 31 men (3.7%) who had sarcopenic obesity. Branched chain amino acids were elevated in the obese (but not sarcopenic) group (n=348) but reduced in both the sarcopenic (but not obese) (n=44) and the sarcopenic obese groups. Apart from this, most of the amino acid concentrations were between those for the obese and the sarcopenic groups. Yet despite low concentrations of branched chain amino acids, the sarcopenic obese group had indications of insulin resistance and diabetes mellitus (fasting glucose and insulin concentrations, homeostatic model assessment (HOMA-IR) and percentage of participants taking diabetes medications) that were similar to the obese group. In summary, sarcopenic obese subjects did not have a unique amino acid signature. In obesity, elevated branched chain amino acids are not a prerequisite for insulin resistance and diabetes if obesity is associated with sarcopenia.

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Metabolomic profiling identifies complex lipid species and amino acid analogues associated with response to weight loss interventions

PLoS ONE ◽

10.1371/journal.pone.0240764 ◽

2021 ◽

Vol 16 (5) ◽

pp. e0240764

Author(s):

Nathan A. Bihlmeyer ◽

Lydia Coulter Kwee ◽

Clary B. Clish ◽

Amy Anderson Deik ◽

Robert E. Gerszten ◽

...

Keyword(s):

Insulin Resistance ◽

Weight Loss ◽

Exercise Intervention ◽

Model Assessment ◽

Metabolomic Profiling ◽

Lipid Species ◽

Homeostatic Model Assessment ◽

Amino Acid Analogues ◽

Metabolic Biomarkers ◽

Weight Loss Interventions

Obesity is an epidemic internationally. While weight loss interventions are efficacious, they are compounded by heterogeneity with regards to clinically relevant metabolic responses. Thus, we sought to identify metabolic biomarkers that are associated with beneficial metabolic changes to weight loss and which distinguish individuals with obesity who would most benefit from a given type of intervention. Liquid chromatography mass spectrometry-based profiling was used to measure 765 metabolites in baseline plasma from three different weight loss studies: WLM (behavioral intervention, N = 443), STRRIDE-PD (exercise intervention, N = 163), and CBD (surgical cohort, N = 125). The primary outcome was percent change in insulin resistance (as measured by the Homeostatic Model Assessment of Insulin Resistance [%ΔHOMA-IR]) over the intervention. Overall, 92 individual metabolites were associated with %ΔHOMA-IR after adjustment for multiple comparisons. Concordantly, the most significant metabolites were triacylglycerols (TAGs; p = 2.3e-5) and diacylglycerols (DAGs; p = 1.6e-4), with higher baseline TAG and DAG levels associated with a greater improvement in insulin resistance with weight loss. In tests of heterogeneity, 50 metabolites changed differently between weight loss interventions; we found amino acids, peptides, and their analogues to be most significant (4.7e-3) in this category. Our results highlight novel metabolic pathways associated with heterogeneity in response to weight loss interventions, and related biomarkers which could be used in future studies of personalized approaches to weight loss interventions.

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Association of Serum Levels of Zinc, Copper, and Iron with Risk of Metabolic Syndrome

Nutrients ◽

10.3390/nu13020548 ◽

2021 ◽

Vol 13 (2) ◽

pp. 548

Author(s):

Chia-Wen Lu ◽

Yi-Chen Lee ◽

Chia-Sheng Kuo ◽

Chien-Hsieh Chiang ◽

Hao-Hsiang Chang ◽

...

Keyword(s):

Insulin Resistance ◽

Metabolic Syndrome ◽

Linear Models ◽

Serum Zinc ◽

Serum Levels ◽

Least Square ◽

Model Assessment ◽

Serum Concentrations ◽

Metabolic Factors ◽

Homeostatic Model Assessment

The association between serum concentrations of zinc, copper, or iron and the risk of metabolic syndrome are inconclusive. Therefore, we conduct a case-control study to explore the relationship between serum levels of zinc, copper, or iron and metabolic syndrome as well as each metabolic factor and insulin resistance. We enrolled 1165 adults, aged ≥ 40 (65.8 ± 10) years in a hospital-based population to compare the serum levels of zinc, copper, and iron between subjects with and without metabolic syndrome by using multivariate logistic regression analyses. The least square means were computed by general linear models to compare serum concentrations of zinc, copper, and iron in relation to the number of metabolic factors. The mean serum concentrations of zinc, copper, and iron were 941.91 ± 333.63 μg/L, 1043.45 ± 306.36 μg/L, and 1246.83 ± 538.13 μg/L, respectively. The odds ratios (ORs) of metabolic syndrome for the highest versus the lowest quartile were 5.83 (95% CI: 3.35–10.12; p for trend < 0.001) for zinc, 2.02 (95% CI: 1.25–3.25; p for trend: 0.013) for copper, and 2.11 (95% CI: 1.24–3.62; p for trend: 0.021) for iron after adjusting for age, sex, personal habits, body mass index, and homeostatic model assessment insulin resistance. Additionally, the serum zinc, copper, and iron concentrations increased as the number of metabolic factors rose (p for trend < 0.001). This was the first study to clearly demonstrate that higher serum levels of zinc, copper, and iron were associated with the risk of metabolic syndrome and the number of metabolic factors independent of BMI and insulin resistance.

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Metabolic syndrome and insulin resistance in pre-pubertal children with psoriasis

European Journal of Pediatrics ◽

10.1007/s00431-020-03924-w ◽

2021 ◽

Author(s):

Francesca Caroppo ◽

Alfonso Galderisi ◽

Laura Ventura ◽

Anna Belloni Fortina

Keyword(s):

Metabolic Disease ◽

Insulin Resistance ◽

Metabolic Syndrome ◽

Model Assessment ◽

Limited Data ◽

Single Center ◽

Increased Risk ◽

High Prevalence ◽

Homeostatic Model Assessment ◽

Homeostatic Model

AbstractPsoriasis in adults is associated with an increased risk of metabolic disease. Various cardiometabolic comorbidities have been reported in childhood psoriasis, but only a few studies have analyzed the prevalence of metabolic syndrome. We performed a single-center prospective study investigating the prevalence of metabolic syndrome and insulin resistance in children with psoriasis. The prevalence of metabolic syndrome was evaluated in 60 pre-pubertal children with psoriasis (age: 3–10 years), accordingly to recently established criteria for the diagnosis of metabolic syndrome in children. Insulin resistance was considered altered when the homeostatic model assessment (HOMA-IR) for insulin resistance was ≥ 90th sex- and age-specific percentile and HOMA 2-IR was > 1.8. Eighteen (30%) children with psoriasis were found to have metabolic syndrome. Sixteen (27%) children were found to have insulin resistance.Conclusion: Our data underline the importance of assessing metabolic syndrome not only in adults and adolescents but also in young children with psoriasis. What is Known:• Psoriasis in adults is strongly associated with metabolic disease and insulin resistance.• Very limited data are available on the prevalence of metabolic syndrome and insulin resistance in pre-pubertal children with psoriasis. What is New:• This study reports that in pre-pubertal children with psoriasis, there is a high prevalence of metabolic syndrome and insulin resistance.• In children with psoriasis metabolic syndrome risk factors should be assessed.

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P1279INSULIN RESISTANCE IN HEMODIALYSIS PATIENS

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p1279 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Pavel Filinyuk ◽

Aleksander Rumyantsev

Keyword(s):

Insulin Resistance ◽

Systemic Inflammation ◽

Clinical Manifestations ◽

Biological Response ◽

Fold Increase ◽

Atherogenic Dyslipidemia ◽

Model Assessment ◽

Peripheral Tissues ◽

Reactive Protein ◽

Homeostatic Model Assessment

Abstract Background and Aims insulin resistance (IR) is a decrease in the biological response of sensitive tissues to insulin. IR is known as an adverse risk factor in cardiovascular disease, which largely determines the prognosis of patients receiving hemodialysis (HD). But this issue is not well understood. For the screening of IR, special indices have been developed that characterize the sensitivity of tissues to insulin. The aim of the study was to compare the methods of screening for IR in patients receiving HD in relation to the markers of systemic inflammation and atherogenic dyslipidemia (AtD). Method 124 patients receiving HD for 75.4 ± 44.5 months were examined including 66 men and 58 women aged 57.6 ± 13.6 years. For IR screening, the Homeostatic Model Assessment-1 and 2 indices (HOMA-1 and HOMA-2), the Quantitative Insulin Sensitivity Check Index (QUICKI) and triglycerides / glucose (Tri/G) were used. Patients were examined in accordance with the recommendations of KDIGO. Data analysis was carried out using “STATISTICA 10.0”. Results fasting insulin levels were elevated in 19% of patients. But, the calculated indices were consistent with the idea that IR is much more common. So, the IR index in the HOMA -1 model was increased in 47%, in the HOMA -2 model - in 33%, in the QUICKI model - in 36%, the TriH indicator - in 91%. The sensitivity of peripheral tissues in the HOMA-1 and HOMA-2 models was equally reduced by 35-40%. The results of the correlation analysis between indicators of IR and plasma concentration of C-reactive protein and lipid profile are presented in table 1. Informativeness of IR indicators depending on the presence of obesity is presented in table 2 We were also interested in whether insulin resistance affects the development of clinical manifestations of atherosclerosis, cardiac arrhythmias, and heart failure. An analysis of this relationship did not reveal. Only the IR index in the HOMA-1 model with a value of more than 2.7 units was associated with a 4.5-fold increase in the risk of developing clinical manifestations of atherosclerotic lesions (χ2 = 4.582 p = 0.032). Statistically significant it was only in men. Given our data, perhaps IR is one of the reasons for the higher morbidity and mortality of men at HD. Conclusion a comparison of IR models allows us to distinguish HOMA-2 as the most accurate index. The highest correlation with systemic inflammation and AtD was in the HOMA-1 and HOMA-2 indices.

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The Relationship between Insulin Resistance and the Cardiovascular Biomarker Growth Differentiation Factor-15 in Obese Patients

Clinical Chemistry ◽

10.1373/clinchem.2010.153726 ◽

2011 ◽

Vol 57 (2) ◽

pp. 309-316 ◽

Cited By ~ 73

Author(s):

Greisa Vila ◽

Michaela Riedl ◽

Christian Anderwald ◽

Michael Resl ◽

Ammon Handisurya ◽

...

Keyword(s):

Insulin Resistance ◽

Gastric Bypass ◽

Insulin Sensitivity ◽

Oral Glucose ◽

Model Assessment ◽

Obese Patients ◽

Growth Differentiation Factor 15 ◽

Homeostatic Model Assessment ◽

Homeostatic Model ◽

The Relationship

BACKGROUND Growth differentiation factor-15 (GDF-15) is a stress-responsive cytokine linked to obesity comorbidities such as cardiovascular disease, inflammation, and cancer. GDF-15 also has adipokine properties and recently emerged as a prognostic biomarker for cardiovascular events. METHODS We evaluated the relationship of plasma GDF-15 concentrations with parameters of obesity, inflammation, and glucose and lipid metabolism in a cohort of 118 morbidly obese patients [mean (SD) age 37.2 (12) years, 89 females, 29 males] and 30 age- and sex-matched healthy lean individuals. All study participants underwent a 75-g oral glucose tolerance test; 28 patients were studied before and 1 year after Roux-en-Y gastric bypass surgery. RESULTS Obese individuals displayed increased plasma GDF-15 concentrations (P < 0.001), with highest concentrations observed in patients with type 2 diabetes. GDF-15 was positively correlated with age, waist-to-height ratio, mean arterial blood pressure, triglycerides, creatinine, glucose, insulin, C-peptide, hemoglobin A1c, and homeostatic model assessment insulin resistance index and negatively correlated with oral glucose insulin sensitivity. Age, homeostatic model assessment index, oral glucose insulin sensitivity, and creatinine were independent predictors of GDF-15 concentrations. Roux-en-Y gastric bypass led to a significant reduction in weight, leptin, insulin, and insulin resistance, but further increased GDF-15 concentrations (P < 0.001). CONCLUSIONS The associations between circulating GDF-15 concentrations and age, insulin resistance, and creatinine might account for the additional cardiovascular predictive information of GDF-15 compared to traditional risk factors. Nevertheless, GDF-15 changes following bariatric surgery suggest an indirect relationship between GDF-15 and insulin resistance. The clinical utility of GDF-15 as a biomarker might be limited until the pathways directly controlling GDF-15 concentrations are better understood.

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