Incidence Of MetS Research Articles

385Prospective associations between serum homocysteine, folate, vitamin B12 and risk of metabolic syndrome

Abstract Background Both elevated homocysteine (Hcy) and metabolic syndrome (MetS) are associated with cardio-metabolic disease. However, the potential causality in the association between Hcy and MetS is unclear, and there is uncertainty about the importance of serum level of folate and vitamin B12 for MetS. The aim of this study was to determine the prospective associations between serum homocysteine, folate and vitamin B12, and incidence of MetS in a community-based cohort of Korean adults aged ≥ 40 years. Methods We measured serum Hcy, folate and vitamin B12 in 2,895 participants (1,187 men and 1,708 women) who did not have MetS. During follow-up (10,043 person-years), 471 MetS cases were newly diagnosed. Results Higher Hcy levels were positively associated with risk of MetS (adjusted incidence rate ratio, IRR 1.87; 95% CI, 1.07–3.25 for ≥15 compared with <10 μmol/L of Hcy in men; IRR 1.81; 95% CI, 1.06–3.08 for ≥10 compared with <5 μmol/L of Hcy in women). However, serum folate was not associated with MetS, and higher serum vitamin B12 levels were associated with a statistically significant protection of MetS in men only (IRR 0.61; 95% CI, 0.42–0.90; P for trend=0.0082 in the highest tertile). Conclusions Hcy levels were positively associated in men and women, and serum vitamin B12 was inversely associated with risk of MetS in men but not in women. Serum folate do not seem to be a protective marker for MetS. Key messages Our results extend previously reported associations of Hcy with MetS, and the absence of associations of folate with MetS.

Elevated serum fluoride levels in perimenopausal women are related to the components of metabolic syndrome.

Increased fluoride levels can lead to numerous complications, including skeletal effects, cardiotoxicity, endocrine dysfunction, neurotoxicity, hepatotoxicity and nephrotoxicity. The aim of this study was to analyze the relationship between serum fluoride levels and MetS or its individual components, and to assess the diagnostic usefulness of fluoride as a factor contributing to MetS. The study included a group of 475 women (mean age of 52.9 years), living in the West Pomeranian Voivodeship in Poland. The study involved data collection and biochemical analysis. Analysis of the relationship between the levels of fluoride and the presence of MetS or its components showed that the mean fluoride level was statistically significantly higher in patients with hypertriglyceridemia (dCohen = 0.39; 95% CI; confidence limits: 0.13, 0.63) and hypertension (dCohen = 0.25; 95% CI; confidence limits: 0.07, 0.44). Moreover, the mean fluoride level was significantly higher in women who met the diagnostic criteria for MetS than in the remaining subjects (dCohen = 0.40; 95% CI; confidence limits: 0.17, 0.64). Elevated serum fluoride levels may be associated with an increased incidence of MetS among perimenopasal women, although its diagnostic value as a marker of MetS is limited.

A Higher Intake of Energy at Dinner Is Associated with Incident Metabolic Syndrome: A Prospective Cohort Study in Older Adults.

A higher energy intake (EI) at night has been associated with a higher risk of obesity, while a higher EI at lunch may protect against weight gain. This study examined the association between EI throughout the day and incident metabolic syndrome (MetS) among older adults. A cohort of 607 individuals aged ≥ 60 free from MetS at baseline was followed from 2008–2010 until 2015. At baseline, habitual EI was assessed on six eating occasions: breakfast, mid-morning snack, lunch, afternoon snack, dinner, and snacking. MetS was defined according to the harmonized definition. Statistical analyses were performed with logistic regression and adjusted for the main confounders, including total EI, diet quality, and physical activity/sedentary behavior. During follow-up, 101 new MetS cases occurred. Compared to the lowest sex-specific quartile of EI at dinner, the OR (95% confidence interval) for incident MetS were: 1.71 (0.85–3.46) in the second, 1.70 (0.81–3.54) in the third, and 2.57 (1.14–5.79) in the fourth quartile (p-trend: 0.034). Elevated waist circumference and triglycerides were the MetS components that most contributed to this association. A higher EI at dinner was associated with a higher risk of MetS in older adults. Reducing EI at dinner might be a simple strategy to prevent MetS.

Does weight change modify the association between the consumption of sugar-sweetened beverages and 100% fruit juice and the risk of metabolic syndrome?

This study aimed to determine the prospective relationship between the consumption of sugar-sweetened beverages (SSBs) and 100% fruit juice and metabolic syndrome (MetS) and to investigate whether weight change can modify this association in a representative sample of the population of Tehran, Iran. In this 8.9-year follow-up study, the consumption of SSBs and 100% fruit juice by 1915 individuals, who participated in Tehran Lipid and Glucose Study (TLGS), was examined using a validated food frequency questionnaire. The MetS was defined according to the Joint Interim Statement. Participants were categorized as those who lost weight (≥-2%), those with weight stability (-1.9%-1.9%), and those who gained weight (≥2%). The Cox regression model was used to determine the relationship between the consumption of SSBs and 100% fruit juice and the risk of MetS and weight gain ≥2%. Also, the modifying effect of weight change including weight loss, weight stability and weight gain on the relationship between SSBs and 100% fruit juice consumption and the incidence of MetS was assessed. There was no significant association between the consumption of SSBs and the risk of MetS in the crude model; however, after adjustments for confounders, a significant positive association was found between the consumption of SSBs and the risk of MetS (HR: 1.33; 95% CI: 1.07-1.66). Also, no significant association was observed between the consumption of 100% fruit juice and the risk of MetS in the crude model. However, after adjustments for the potential confounders, 100% fruit juice was inversely associated with the MetS risk (HR: 0.78; 95% CI: 0.63-0.95). The consumption of SSBs and 100% fruit juice was positively associated with weight gain (≥2% during the follow-up). Nevertheless, after adjustments for lifestyle and dietary factors, there was no significant association between the consumption of SSBs and weight gain. On the other hand, the consumption of 100% fruit juice was positively associated with the increased risk of weight gain (HR: 1.41; 95% CI: 1.20-1.65). Among participants with weight loss, the first, second and third tertiles of 100% fruit juice reduced the risk of MetS by 29% (HR: 0.71; 95% CI: 0.51-0.99), 47% (HR: 0.53; 95% CI: 0.37-0.75) and 35% (HR: 0.65; 95% CI: 0.46-0.92), respectively. Although 100% fruit juice reduced the risk of MetS, its consumption must be limited due to its positive effect on weight gain. On the other hand, the consumption of 100% fruit juice reduced the risk of MetS, depending on the individual's weight change. Also, high consumption of SSBs was associated with the incidence of MetS.

Delayed heart rate recovery after exercise predicts development of metabolic syndrome: A retrospective cohort study.

ABSTRACTAims/IntroductionSeveral cross‐sectional studies have shown that delayed heart rate recovery (HRR) after exercise is associated with the development of metabolic syndrome (MetS). However, there has been a lack of comprehensively designed longitudinal studies. Therefore, our aim was to evaluate the longitudinal association of delayed HRR following a graded exercise treadmill test (GTX) with incident MetS.Materials and MethodsThis was a retrospective longitudinal cohort study of participants without MetS, diabetes, or cardiovascular diseases. The HRR was calculated as the peak heart rate minus the resting heart rate after a 1 min rest (HRR1), a 2 min rest (HRR2), and a 3 min rest (HRR3). Multivariate Cox proportional hazards analysis was performed to investigate the association between HRR and development of MetS.ResultsThere were 676 (31.2%) incident cases of MetS identified during the follow‐up period (9,683 person‐years). The only statistically significant relationship was between HRR3 and the development of MetS. The hazard ratios (HRs) (95% confidence interval [CI]) of incident MetS comparing the first and second tertiles to the third tertile of HRR3 were 1.492 (1.146–1.943) and 1.277 (1.004–1.624) with P = 0.003 after adjustment for multiple risk factors. As a continuous variable, the HR (95% CI) of incident MetS associated with each one‐beat decrease in HRR3 was 1.015 (1.005–1.026) with P = 0.004 after full adjustments. An HRR3 value ≤45 beats per minute (bpm) was associated with a higher risk of incident MetS compared with values >45 bpm, with an HR (95% CI) of 1.304 (1.061–1.602) and P = 0.001.ConclusionsThe slow phase of HRR, particularly HRR3, might be more sensitive at predicting the risk of MetS.

Urinary Metal Mixtures and Incident Metabolic Syndrome in Midlife Women: the Study of Women’s Health Across the Nation (SWAN)

BACKGROUND AND AIM: Exposure to metals may contribute to the development of metabolic syndrome (MetS); however, evidence from midlife women who are at greater risk of cardiometabolic disease is limited. We prospectively examined the associations of 15 urinary metal concentrations with incident MetS in the Study of Women’s Health Across the Nation Multi-Pollutant Study. METHODS: The sample included 947 White, Black, Chinese and Japanese women from 5 study sites in the United States, aged 45-56 years and free of MetS at baseline (1999-2000), followed through 2017. Urinary concentrations of 15 metals, including arsenic, barium, cadmium, cobalt, cesium, copper, mercury, manganese, molybdenum, nickel, lead, antimony, tin, thallium, and zinc, were quantified at baseline. Incident MetS was identified annually as the presence of at least 3 of the following 5 components: high blood pressure, impaired fasting glucose, abdominal obesity, high triglycerides, and low high-density lipoprotein cholesterol. RESULTS:After adjustment for potential confounders, the hazard ratios (HR) (95% confidence interval (CI)) for MetS associated with each doubling of urinary metal concentration was 1.14 (1.08, 1.23) for arsenic, 1.14 (1.01, 1.29) for cobalt, and 1.20 (1.06, 1.37) for zinc, in Cox proportional hazards models. Positive associations of urinary arsenic with high blood pressure and impaired fasting glucose, positive associations of urinary cobalt with high blood pressure and abdominal obesity, and positive associations of urinary zinc with high blood pressure, impaired fasting glucose, abdominal obesity, and high triglyceride were observed. In the quantile-based g-computation assessing the joint effect of metal mixtures, increasing urinary arsenic, cobalt, and zinc concentrations by one quartile was associated with a higher incidence of MetS (HR=1.73, 95% CI: 1.21, 2.48). CONCLUSIONS:Higher urinary arsenic, cobalt, and zinc concentrations were associated with an elevated incidence of MetS in midlife women. Future studies should confirm these findings and further investigate the underlying mechanisms. KEYWORDS: Metals, mixtures, metabolic syndrome, women, cohort study.

The effect of migration on the incidence of new-onset metabolic syndrome in migrants to Qatar

Background: There is substantial evidence that migration to Western countries is associated with an increased risk of metabolic syndrome (MetS). However, there is a paucity of data on the incidence of MetS in migrants from different countries coming to Qatar. As a result, an important health problem is overlooked, and prevention measures are absent. This study aimed to investigate the effects of migration on the incidence of MetS following 24 months of residency in the Middle East (ME) among a group of migrants employed at Hamad Medical Corporation (HMC). Methods: This is a prospective longitudinal observational study. Migrants aged 18–65 years who joined HMC from June to December 2017 were invited to consent and participate. Baseline screening for MetS was conducted. Parameters included glycated hemoglobin (HbA1c), triglycerides (TG), high-density lipoprotein-cholesterol (HDL-C), blood pressure (BP), and waist circumference (WC) measurement. Migrants with normal metabolic parameters at baseline were invited to be rescreened 24 months post-migration. The International Diabetes Federation (IDF) Consensus Worldwide Definition of MetS was employed to diagnose MetS. Inferential statistics were applied to compare results before and after migration. Throughout the study, migrants with metabolic abnormalities were referred to physicians for further management. Results: Of the 1,379 screened migrants, 472 consented to participate. Of those, only 205 migrants had normal metabolic parameters. The incidence of MetS within the group with normal parameters rose to 17% (n = 27) after 24 months of residing in Qatar. Eighty-one percent (n = 129) developed at least one element of MetS. Migrants receiving medications that potentially induce MetS were more likely to develop MetS (odds ratio OR [(AOR 6.3, p < 0.001); 95% [CI], 0.07-0.59. p = 0.003). Conclusion: The incidence of MetS amongst migrants increases following residency in Qatar however, it is lower than that estimated in many developed countries (3, 4).

Incidence and prediction nomogram for metabolic syndrome in a middle-aged Vietnamese population: a 5-year follow-up study.

We aimed to determine the incidence and prediction nomogram for new-onset metabolic syndrome (MetS) in a middle-aged Vietnamese population. A population-based prospective study was conducted in 1150 participants aged 40-64 years without MetS at baseline and followed-up for 5 years. Data on lifestyle factors, socioeconomic status, family diabetes history, and anthropometric measures were collected. MetS incidence was estimated in general population and subgroup of age, gender, and MetS components. A Cox proportional hazards regression was used to estimate hazard ratios (HRs) with 95% confidence intervals (CI) for MetS. A prediction nomogram was developed and checked for discrimination and calibration. During median follow-up of 5.14 years, the accumulate MetS incidence rate was 23.4% (95% CI: 22.2-24.7). The annual incidence rate (95% CI) was 52.9 (46.7-60.1) per 1000 person-years in general population and higher in women [56.6 (48.7-65.9)] than men [46.5 (36.9-59.3)]. The HRs (95% CI) for developing MetS were gender [females vs males: 2.04 (1.26-3.29)], advanced age [1.02 (1.01-1.04) per one year], waist circumference [1.08 (1.06-1.10) per one cm] and other obesity-related traits, and systolic blood pressure [1.02 (1.01-1.03) per one mmHg]. The prediction nomogram for MetS had a good discrimination (C-statistics = 0.742) and fit calibration (mean absolute error = 0.009) with a positive net benefit in the predicted probability thresholds between 0.13 and 0.70. The study is the first to indicate an alarmingly high incidence of MetS in a middle-aged population in Vietnam. The nomogram with simply applicable variables would be useful to qualify individual risk of developing MetS.

Metabolic syndrome incidence in an aging workforce: Occupational differences and the role of health behaviors

This study investigates whether the incidence of metabolic syndrome (MetS), and its components, differs by occupational group among older workers (45–65 years) and whether health behaviors (smoking, leisure-time physical activity, diet quality, and alcohol consumption) can explain these differences. A sample of older workers (N = 34,834) from the North of the Netherlands was investigated. We analyzed data from two comprehensive measurement waves of the Lifelines Cohort Study and Biobank. MetS components were determined by physical measurements, blood markers, medication use, and self-reports. Occupational group and health behaviors were assessed by questionnaires. The association between occupational groups and MetS incidence was examined using logistic regression analysis. Health behaviors were subsequently added to the model to examine whether they can explain differences in MetS incidence between occupational groups. Low skilled white-collar (OR: 1.24; 95 % CI: 1.12, 1.37) and low skilled blue-collar (OR: 1.37; 95 % CI: 1.18, 1.59) workers had a significantly higher MetS incidence risk than high skilled white-collar workers. Similar occupational differences were observed on MetS component level. Combinations of unhealthy behaviors were more prevalent among blue-collar workers. MetS incidence in older workers differs between occupational groups and health behaviors explain a substantial part of these differences. Health promotion tailored to occupational groups may be beneficial specifically among older low skilled blue-collar workers. Research into other factors that contribute to occupational differences is needed as well as studies spanning the entire working life course.

Serum uric acid is associated with incident metabolic syndrome independent of body shape index and body roundness index in healthy individuals

Background and aimsElevated serum uric acid (SUA) levels, body shape index (BSI) and body roundness index (BRI) were associated with incident metabolic syndrome (MetS). We aimed to investigate the relationship among the SUA level, BSI, and BRI on the incidence of MetS. Methods and resultsWe retrospectively included 6221 healthy individuals from annual health exams at our hospital between 2016/1/1 and 2016/12/31. We defined hyperuricemia as SUA levels greater than 7 mg/dl in men and 6 mg/dl in women and MetS according to the contemporary definition. The study cohort included 6221 healthy individuals with an overall incidence rate of MetS of 9.8%. Compared with the normouricemic group, the hyperuricemic group had a greater incidence of MetS (17.2% vs. 9.6%, P < 0.001). After full adjustment for confounders, the SUA level was significantly associated with incident MetS in addition to body mass index (BMI) (adjusted OR [aOR]: 1.161, 95% CI: 1.071–1.259, P < 0.001), BRI (aOR: 1.196, 95% CI: 1.104–1.296, P < 0.001), and BSI (aOR: 1.297, 95% CI: 1.200–1.403, P < 0.001). Regarding the anthropometric indices, BMI and BRI were independent predictors of incident MetS, but the BSI lost its significant association in multivariate logistic regression analyses. In sensitivity analyses, various thresholds of elevated SUA levels remained associated with incident MetS. ConclusionWe showed a dose-response effect of SUA on incident MetS independent of BMI, BRI and BSI in healthy individuals. Future studies can use SUA levels to stratify cardiometabolic risk in healthy individuals. Clinical trialsClinicalTrials.gov with the identification number NCT03473951.

Socioeconomic status and lifestyle factors modifies the association between snack foods intake and incidence of metabolic syndrome

BackgroundIntake of snack foods has been previously associated with an elevated risk of chronic disease; however, studies on snack foods and metabolic syndrome (MetS) while considering the modifying effect of socioeconomic status (SES) and lifestyle factors on this association are lacking. We aimed to investigate the association between snack foods intake and the MetS risk, and the mediatory effects of SES and lifestyle factors on the forenamed association among adults who participated in the Tehran Lipid and Glucose Study (2006–2018).MethodsThis is a prospective study of 1915 participants (male, 40.5%), aged 19–74 year who were free of MetS at baseline. Dietary intakes were gathered using a validated, semi-quantitative food frequency questionnaire at baseline (2006–2008), and with 3-year intervals afterwards. Alternative approach was used for snack foods from all available questionnaires during follow-up. Snack foods were divided into 4 categories, including total snacks, biscuits and cakes, candies and chocolate, and salty snacks. Total snack foods intake and its subgroup (serving/week) were modeled as tertiles. MetS was diagnosed according to the Joint Interim Statement criteria. Physical activity level (PAL) categorized as low/medium and high levels. Information regarding smoking (Smoker/Non-smoker), education (higher/lower education), and occupation (employed/non-employed) was gathered using questionnaire. The Cox regression was used, regarding interaction between snack foods, SES, and PAL on the MetS risk.ResultsA total of 591 incident MetS cases were diagnosed during 8.9 years of follow-up. The median total snack foods intake was 5.2 serving/week (IQR: 3.0–9.1). Total snack foods intake was positively associated with the MetS risk after adjusting for potential confounders (adjusted for age and gender, energy intake, total fiber intake, smoking status, PAL, education levels, family history of diabetes, family history of CVD events, and BMI). After adjustment for confounders, among snacks’ subgroups, candies and chocolate intake was positively associated with MetS risk. Moreover, among lower-educated and non-employed participants, candies and chocolate intake was positively associated with the MetS risk, by 38 and 43% respectively. Stratification based on PAL resulted a positive association between intake of total snack foods and candies and chocolates and risk of MetS among participants with low PAL.ConclusionSnack foods, especially candies and chocolate, increased the risk of MetS, among individuals with a low PAL.

Depressive symptoms and 5-year incident metabolic syndrome among older adults

Little is known regarding the association between depressive symptoms and metabolic syndrome (MetS) among older Chinese adults. This study aimed to examine the association of depressive symptoms with MetS and its components among Chinese elderly. Based on whether they showed depressive symptoms at baseline, 262 age-gender-matched participants from a community-based cohort study were included. The presence of depressive symptoms was measured using the nine-item Patient Health Questionnaire (PHQ-9). MetS was defined according to the Adult Treatment Panel III of the National Cholesterol Education Program. Linear regression and logistic regression analyses were performed to assess associations of depressive symptoms with MetS and its components. The incidence of MetS among the participants with depressive symptoms at baseline was 15.27% (20/131). The association of the presence of depressive symptoms with MetS was significant (odds ratio [OR] = 2.53, 95% confidence intervals [CI] = 1.07, 5.95). There was a negative association between depressive symptoms and hypertension (OR = 0.04, 95% CI = 0.002, 0.98). The change in mean arterial pressure varies approximately 1.03 mmHg with a 1-point change in PHQ-9 score. In this study, baseline depressive symptoms were associated with subsequent MetS. The presence of depressive symptoms was negatively associated with elevated mean arterial pressure.

The Homocysteine and Metabolic Syndrome: A Mendelian Randomization Study.

Homocysteine (Hcy) is well known to be increased in the metabolic syndrome (MetS) incidence. However, it remains unclear whether the relationship is causal or not. Recently, Mendelian Randomization (MR) has been popularly used to assess the causal influence. In this study, we adopted MR to investigate the causal influence of Hcy on MetS in adults using three independent cohorts. We considered one-sample MR and two-sample MR. We analyzed one-sample MR in 5902 individuals (2090 MetS cases and 3812 controls) from the KARE and two-sample MR from the HEXA (676 cases and 3017 controls) and CAVAS (1052 cases and 764 controls) datasets to evaluate whether genetically increased Hcy level influences the risk of MetS. In observation studies, the odds of MetS increased with higher Hcy concentrations (odds ratio (OR) 1.17, 95%CI 1.12–1.22, p < 0.01). One-sample MR was performed using two-stage least-squares regression, with an MTHFR C677T and weighted Hcy generic risk score as an instrument. Two-sample MR was performed with five genetic variants (rs12567136, rs1801133, rs2336377, rs1624230, and rs1836883) by GWAS data as the instrumental variables. For sensitivity analysis, weighted median and MR–Egger regression were used. Using one-sample MR, we found an increased risk of MetS (OR 2.07 per 1-SD Hcy increase). Two-sample MR supported that increased Hcy was significantly associated with increased MetS risk by using the inverse variance weighted (IVW) method (beta 0.723, SE 0.119, and p < 0.001), the weighted median regression method (beta 0.734, SE 0.097, and p < 0.001), and the MR–Egger method (beta 2.073, SE 0.843, and p = 0.014) in meta-analysis. The MR–Egger slope showed no evidence of pleiotropic effects (intercept −0.097, p = 0.107). In conclusion, this study represented the MR approach and elucidates the significant relationship between Hcy and the risk of MetS in the Korean population.

Air pollution and metabolic syndrome risk: Evidence from nine observational studies

Background and aimsGlobally, the number of metabolic syndrome (MetS) cases has increased substantially over time. However, the association between air pollution (AP) and MetS risk has been contradictory in observational studies. This is the first reported meta-analysis quantitatively exploring the aforementioned association. MethodsWe searched PubMed, Embase, and Web of Science database entries up to September 14, 2020, and searches were updated up to December 6, 2020 to identify eligible articles on the AP-MetS risk association. No language restriction was imposed. Random-effects models were applied to estimate summary and subgroup effect sizes with 95% confidence intervals (CIs). PROSPERO registration number: CRD42020210431. ResultsEight articles (nine studies) were eligible for the meta-analysis. Increased MetS prevalence was not found to be associated with particulate matter less than 1 μm (PM1), 2.5 μm (PM2.5), and 10 μm (PM10) in diameter or nitrogen dioxide (NO2), and the summary effect sizes were 1.33 (95% CI: 0.95–1.85), 1.34 (95% CI: 0.96–1.89), 1.18 (95% CI: 0.98–1.19), and 1.28 (95% CI: 0.89–1.82), respectively, based on cross-sectional studies. The summary results indicated no association between each 10 μg/m3 increase in PM2.5 and MetS incidence (effect size 2.78 [95% CI: 0.70–11.02]), based on cohort studies. Subgroup analysis demonstrated that MetS incidence in older men increased dramatically by 992% with each 10 μg/m3 increase in PM2.5. ConclusionsThe evidence presented here suggests that although exposure to PM1, PM2.5, PM10, or NO2 was not found to have a significant association with the occurrence of MetS, the statistical significance of the relationship between exposure to PM1, PM2.5, or PM10 and MetS prevalence was approximately borderline. More studies on AP-MetS risk association in low-/middle-income countries, as well as on the association between other air pollutants and MetS risk, are warranted. A sufficient number of high-quality studies is required to perform a meaningful meta-analysis of the relationship between air pollutants and MetS.

Plasma glycerophospholipid profile, erythrocyte n–3 PUFAs, and metabolic syndrome incidence: a prospective study in Chinese men and women

Animal studies have highlighted critical roles of glycerophospholipid (GP) metabolism in various metabolic syndrome (MetS)-related features such as dyslipidemia, obesity, and insulin resistance. However, human prospective studies of associations between circulating GPs and risks of MetS are scarce. We aimed to investigate whether GPs are associated with incidence of MetS in a well-established cohort. A total of 1243 community-dwelling Chinese aged 50-70 y without MetS at baseline and followed up for 6 y were included in current analyses. A total of 145 plasma GPs were quantified by high-throughput targeted lipidomics. MetS was defined using the updated National Cholesterol Education Program Adult Treatment Panel III criteria for Asian Americans. After 6 y, 429 participants developed MetS. Eleven GPs, especially those with long-chain polyunsaturated fatty acids (LCPUFAs) or very-long-chain polyunsaturated fatty acids (VLCPUFAs) at the sn-2 position, including 1 phosphatidylcholine (PC) [PC(18:0/22:6)], 9 phosphatidylethanolamines (PEs) [PE(16:0/22:6), PE(18:0/14:0), PE(18:0/18:1), PE(18:0/18:2), PE(18:0/20:3), PE(18:0/22:5), PE(18:0/22:6), PE(18:1/22:6), and PE(18:2/22:6)], and 1 phosphatidylserine (PS) [PS(18:0/18:0)], were positively associated with incident MetS (RRs: 1.16-1.30 per SD change; Bonferroni-corrected P<0.05). In network analysis, the strongest positive association for MetS incidence was evidenced in a module mainly composed of PEs containing C22:6 and PSs [RR: 1.21; 95% CI: 1.12, 1.31 per SD change; Bonferroni-corrected P<0.05]. This association was more pronounced in participants with lower erythrocyte total n-3 PUFA concentrations [Bonferroni-corrected Pinter(P value for the interaction)<0.05]. Elevated plasma concentrations of GPs, especially PEs with LCPUFAs or VLCPUFAs at the sn-2 position, are associated with higher risk of incident MetS. Future studies are merited to confirm our findings.

Abstract 2844: The role of oxidative phosphorylation (OXPHOS) in melanoma brain metastasis (MBM) formation and growth

Abstract Introduction: MBMs are a deadly complication of melanoma. We previously showed that OXPHOS is increased in MBMs, but the roles of OXPHOS in MBM formation and growth are unknown. Methods: To determine if OXPHOS predicts formation of MBMs, RNA-sequencing (RNAseq) was performed on primary melanomas from patients (pts) diagnosed with MBM (P_MBM; n=19) and from pts diagnosed with metastases (mets) solely to non-CNS sites within 3-18 months of initial diagnosis (P_ECM; n=16), as well as pts who did not develop any mets within 5 years (P_NoMet; n=19). To functionally test the role of OXPHOS in brain and lung met formation and maintenance, brain-tropic YUMM5.2-Br3 cells were treated in vitro with the direct OXPHOS inhibitor IACS-010759 (100 nM) or vehicle control for 12 hours, and then injected into the left ventricle (intracardiac; ICa) in C57BL/6 mice. Mice were randomized to in vivo treatment with vehicle or IACS-010759 (7.5 mg/kg daily) for 14 days. Mice were euthanized and ex vivo bioluminescence imaging (BLI) was performed to evaluate the extent of brain and lung mets. We also evaluated A375P and G361 human melanoma cell lines stably transfected with shRNAs targeting the OXPHOS mediator PGC1α (shPGC1α) or scrambled control (shScr). Cells were injected ICa, intracranially (ICr) or subcutaneously (SQ) in CD-1 nude mice. Lung and brain tissues were harvested for histological analysis of mets once mice became moribund. SQ tumors were measured twice weekly to assess tumor growth. Mice with ICr injection were monitored for survival and euthanized once moribund. Results: Pathway analysis of the primary tumors from pts demonstrated elevated KEGG OXPHOS gene set expression in P_MBM and P_ECM groups compared to P_NoMet (FDR q-val= 0.048 and &amp;lt;0.001, respectively), suggesting a role for OXPHOS in metastasis. However, there was no significant enrichment of OXPHOS genes in P_MBM vs. P_ECM (FDR q-val=0.516), indicating a lack of specific association with MBM risk. Treatment with IACS-010759 (in vitro and/or in vivo) in the YUMM5.2-Br3 model did not impact the incidence of lung or brain mets. However, in vivo treatment with IACS-010759 significantly decreased MBM (but not lung) tumor burden. PGC1α knockdown (shPGC1α) reduced OXPHOS in A375P and G361 compared to shScr, but less than IACS-010759 treatment. shPGC1α did not impact lung or brain met formation or burden following ICa injection of A375P and G361 cells. shPGC1α also did not inhibit tumor incidence with SQ or ICr injection, and there was no significant difference in SQ tumor growth. However, shPGC1α significantly prolonged survival of mice injected ICr with A375P (p=0.0003) and G361 (p=0.0097). Conclusions: OXPHOS was associated with increased risk of mets in pts, but not specifically MBMs. In mice, OXPHOS inhibition did not prevent MBM formation, but reduced the growth of established MBMs. Thus, OXPHOS is critical to MBM maintenance. Citation Format: Grant M. Fischer, Renato A. Guerrieri, Qianghua Hu, Fernando C. Carapeto, Aron Y. Joon, Vashisht Y. Gopal, Barbara Knighton, Wanleng Deng, Lauren E. Haydu, Jeffrey E. Gershenwald, Alexander J. Lazar, Michael T. Tetzlaff, Michael A. Davies. The role of oxidative phosphorylation (OXPHOS) in melanoma brain metastasis (MBM) formation and growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2844.

Abstract 660: Real-world prevalence of metastasis and overall survival (OS) in patients with advanced non-small cell lung cancer (aNSCLC) with KRAS G12C and with or without STK11 or KEAP1 mutations

Abstract Introduction: KRAS mt are common in lung cancer, with G12C mt being the most prevalent in pts with aNSCLC. This study assessed pts with KRAS G12C aNSCLC with or without STK11 or KEAP1 mt. Methods: Pts diagnosed with aNSCLC between Jan 2011 and Dec 2019 in the US-based de-identified Flatiron Health-Foundation Medicine clinico-genomic database were included. Cox proportional hazards models adjusted for baseline demographics and clinical characteristics were used to analyze the effect of mutational status on OS in pts receiving immunotherapy (CIT), chemotherapy (chemo) or both (CIT+chemo). Results: Of 2217 1L pts, 454 (20.5%), 344 (15.5%) and 163 (7.4%) had tumors with KRAS G12C, STK11 and KEAP1 mt, respectively. Of 1019 2L pts, 234 (23.0%), 191 (18.7%) and 88 (8.6%) had tumors with KRAS G12C, STK11 and KEAP1 mt, respectively. A higher proportion of pts with KRAS G12C were females, PD-L1+ and had nonsquamous histology vs KRAS wildtype (WT) pts. Pts with KRAS G12C tumors had a higher cumulative incidence of mets (31.5% vs 25.8%) and brain mets (26.1% vs 18.8%) vs WT pts (P&amp;lt;0.001). No statistically significant difference was seen in the association of KRAS status with OS when stratifying by treatment type. In KRAS WT pts, STK11 mt vs WT pts had shorter OS in 1L (6.1 vs 9.4 mo) and 2L (4.5 vs 7.6 mo; Table); a similar trend was seen for pts receiving 1L CIT+chemo. In KRAS G12C pts, KEAP1 mt vs WT pts had shorter OS in 1L (4.9 vs 13.4 mo) and 2L (1.8 vs 9.4 mo); similar differences were seen in pts receiving 1L CIT+chemo or chemo. Conclusions: In pts with aNSCLC and KRAS WT, STK11 mt was associated with significantly worse OS; KRAS G12C co-occurring with KEAP1 mt had a similar result. Pts with STK11/KEAP1 mt have poor prognosis and high unmet medical need. This analysis highlights the importance of evaluating genomic alterations in clinical practice to better understand the interplay between treatment and survival. Table. Effect of KRAS mutational status and co-occurring known and likely STK11 and/or KEAP1 mutations on OS in patients with aNSCLC receiving any type of 1L or 2L therapy1L*2L†nMedian, mo (95% CI)HR‡ (95% CI)nMedian, mo (95% CI)HR‡ (95% CI)KRAS G12CSTK11WT32412.0(9.6-16.0)1.30(0.97-1.75)1699.2(7.8-11.4)1.05(0.68-1.63)STK11mt1047.5 (5.1-10.9)545.5(2.5-15.7)KEAP1WT35413.4(10.6-16.2)2.98§(1.91-4.64)1829.4(8.1-13.1)4.02§(2.10-7.70)KEAP1mt304.9(3.1-7.8)141.8(1.5-10.2)KRAS WTSTK11WT14599.4(8.5-10.6)1.57§(1.31-1.87)8477.6(6.5-8.8)1.66§(1.31-2.11)STK11mt2406.1(5.2-7.8)1374.5(3.5-7.6)KEAP1WT14059.3(8.3-10.5)1.43§(1.15-1.78)8137.6(6.4-8.8)1.25(0.93-1.68)KEAP1mt1336.2(4.7-7.8)744.9(3.3-8.0)1L, first line; 2L, second line; aNSCLC, advanced non-small cell lung cancer; HR, hazard ratio; Mb, megabase; mt; mutation; OS, overall survival; PD-L1, programmed death-ligand 1; TMB, tumor mutational burden; WT, wildtype.*Adjusted by age, sex, race, cancer type (de novo or recurrent), histology PD-L1 status, any metastases, TMB (mutations per Mb: &amp;lt;10 and ≥10), histology and treatment type.†Adjusted by age, sex, race, cancer type (de novo or recurrent), histology, PD-L1 status, any metastases, TMB (mutations per Mb: &amp;lt;16 and ≥16), histology and treatment type in 1L and 2L.‡HR comparing WT vs STK11 mt+ or KEAP mt+.§P&amp;lt;0.001. Citation Format: Cristina Julian, Navdeep Pal, Anda Gershon, Maria Evangelista, Hans Purkey, Peter Lambert, Zhen Shi, Qing Zhang. Real-world prevalence of metastasis and overall survival (OS) in patients with advanced non-small cell lung cancer (aNSCLC) with KRAS G12C and with or without STK11 or KEAP1 mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 660.

Plasma Sphingolipid Profile in Association with Incident Metabolic Syndrome in a Chinese Population-Based Cohort Study.

Although bioactive sphingolipids have been shown to regulate cardiometabolic homeostasis and inflammatory signaling pathways in rodents, population-based longitudinal studies of relationships between sphingolipids and onset of metabolic syndrome (MetS) are sparse. We aimed to determine associations of circulating sphingolipids with inflammatory markers, adipokines, and incidence of MetS. Among 1242 Chinese people aged 50–70 years who completed the 6-year resurvey, 76 baseline plasma sphingolipids were quantified by high-throughput liquid chromatography-tandem mass spectrometry. There were 431 incident MetS cases at 6-year revisit. After multivariable adjustment including lifestyle characteristics and BMI, 21 sphingolipids mainly from ceramide and hydroxysphingomyelin subclasses were significantly associated with incident MetS. Meanwhile, the baseline ceramide score was positively associated (RRQ4 versus Q1 = 1.31; 95% CI 1.05, 1.63; ptrend = 0.010) and the hydroxysphingomyelin score was inversely associated (RRQ4 versus Q1 = 0.60; 95% CI 0.45, 0.79; ptrend < 0.001) with incident MetS. When further controlling for clinical lipids, both associations were attenuated but remained significant. Comparing extreme quartiles, RRs (95% CIs) of MetS risk were 1.34 (95% CI 1.06, 1.70; ptrend = 0.010) for ceramide score and 0.71 (95% CI 0.51, 0.97; ptrend = 0.018) for hydroxysphingomyelin score, respectively. Furthermore, a stronger association between ceramide score and incidence of MetS was evidenced in those having higher inflammation levels (RRQ4 versus Q1 1.57; 95% CI 1.16, 2.12; pinteraction = 0.004). Our data suggested that elevated ceramide concentrations were associated with a higher MetS risk, whereas raised hydroxysphingomyelin levels were associated with a lower MetS risk beyond traditional clinical lipids.

The efficacy and safety of Dendropanax morbifera leaf extract on the metabolic syndrome: a 12-week, placebo controlled, double blind, and randomized controlled trial.

BACKGROUND/OBJECTIVESThe extract from Dendropanax morbifera exhibited diverse therapeutic potentials. We aimed to evaluate the efficacy and safety of D. morbifera leaf extract for improving metabolic parameters in human.SUBJECTS/METHODSA 12-week, double blind, placebo-controlled and randomized trial included a total of 74 adults, and they were assigned to the placebo group (n = 38) or 700 mg/day of D. morbifera group (n = 36). The efficacy endpoints were changes in glycemic, lipid, obesity, and blood pressure (BP) parameters, in addition to the prevalence of metabolic syndrome (MetS) and the numbers of MetS components. Safety was assessed by monitoring adverse events (AEs).RESULTSAfter 12 weeks of treatment, the hemoglobin A1c (HbA1c) level significantly decreased in the D. morbifera group compared to that of the placebo group (difference: −0.13 ± 0.20% vs. 0.00 ± 0.28%, P = 0.031; % of change: −2.27 ± 3.63% vs. 0.10 ± 5.10%, P = 0.025). The homeostatic model assessment for insulin resistance level also decreased significantly from its baseline in the D. morbifera group. The systolic BP of D. morbifera group decreased significantly than that of placebo group (difference: −3.9 ± 9.8 mmHg vs. 3.3 ± 11.7 mmHg, P = 0.005; % of change: −2.8 ± 7.7% vs. 3.3 ± 10.2%, P = 0.005). However, the lipid parameters and body composition including body weight did not differ between the groups. The prevalence of MetS (36.8% vs. 13.9%, P = 0.022) and the incidence of MetS (10.5% vs. 13.9%, P = 0.027) at 12 weeks was significantly lower in the D. morbifera group than it was in the placebo group. No serious AEs occurred in either group.CONCLUSIONSSupplementation with D. morbifera extracts over a 12-week period improved metabolic parameters such as HbA1c and BP and reduced the prevalence of MetS.Trial RegistrationClinical Research Information Service Identifier: KCT0004672

Endothelial Progenitor Cells Dysfunctions and Cardiometabolic Disorders: From Mechanisms to Therapeutic Approaches

Metabolic syndrome (MetS) is a cluster of several disorders, such as hypertension, central obesity, dyslipidemia, hyperglycemia, insulin resistance and non-alcoholic fatty liver disease. Despite health policies based on the promotion of physical exercise, the reduction of calorie intake and the consumption of healthy food, there is still a global rise in the incidence and prevalence of MetS in the world. This phenomenon can partly be explained by the fact that adverse events in the perinatal period can increase the susceptibility to develop cardiometabolic diseases in adulthood. Individuals born after intrauterine growth restriction (IUGR) are particularly at risk of developing cardiovascular diseases (CVD) and metabolic disorders later in life. It has been shown that alterations in the structural and functional integrity of the endothelium can lead to the development of cardiometabolic diseases. The endothelial progenitor cells (EPCs) are circulating components of the endothelium playing a major role in vascular homeostasis. An association has been found between the maintenance of endothelial structure and function by EPCs and their ability to differentiate and repair damaged endothelial tissue. In this narrative review, we explore the alterations of EPCs observed in individuals with cardiometabolic disorders, describe some mechanisms related to such dysfunction and propose some therapeutical approaches to reverse the EPCs dysfunction.