Intermittent calorie restriction alters T cell subsets and metabolic markers in people with multiple sclerosis

Background: Intermittent fasting or calorie restriction (CR) diets provide anti-inflammatory and neuroprotective advantages in models of multiple sclerosis (MS); data in humans are sparse. Methods: We conducted a randomized-controlled feeding study of different CR diets in 36 people with MS over 8 weeks. Patients were randomized to receive either: a daily CR diet (22% reduction in calories, 7 days/week), an intermittent CR diet (75% reduction, 2 days/week; 100%, 5 days/week), or a weight-stable diet (100%, 7 days/week). Untargeted metabolomics was performed on plasma samples at weeks 0, 4 and 8 at Metabolon Inc (Durham, NC). Flow cytometry of cryopreserved peripheral blood mononuclear cells at weeks 0 and 8 were used to identify CD4+ and CD8+ T cell subsets including effector memory, central memory, and naïve cells. Results: 31 (86%) completed the trial. Over time, individuals randomized to intermittent CR had significant reductions in CD4+CM -4.87%; 95%CI: -8.59%, -1.15%; p=0.01), CD4+EM (-3.82%; 95%CI: -7.44, -0.21; p=0.04), and CD8+EM (-6.96%; 95%CI: -11.96, -1.97; p=0.006) with proportional increases in naïve subsets (CD4+Naïve: 5.81%; 95%CI: -0.01, 11.63%; p=0.05; CD8+Naïve: 10.11%; 95%CI: 3.30, 16.92%; p=0.006). No changes were observed for daily CR or weight-stable diets. Larger within-person changes in lysophospholipid and lysoplasmalogen metabolites in intermittent CR were associated with larger reductions in memory T cell subsets and larger increases in naïve T cell subsets. Conclusions: In people with MS, an intermittent CR diet was associated with reduction in memory T cell subsets. The observed changes may be mediated by changes in specific classes of lipid metabolites. Trial Registration: This study is registered on Clinicaltrials.gov with identifier NCT02647502. Funding: National MS Society, NIH, Johns Hopkins Catalyst Award

Breath biomarkers of insulin resistance in pre-diabetic Hispanic adolescents with obesity

Insulin resistance (IR) affects a quarter of the world’s adult population and is a major factor in the pathogenesis of cardio-metabolic disease. In this pilot study, we implemented a non-invasive breathomics approach, combined with random forest machine learning, to investigate metabolic markers from obese pre-diabetic Hispanic adolescents as indicators of abnormal metabolic regulation. Using the ReCIVA breathalyzer device for breath collection, we have identified a signature of 10 breath metabolites (breath-IR model), which correlates with Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) (R = 0.95, p < 0.001). A strong correlation was also observed between the breath-IR model and the blood glycemic profile (fasting insulin R = 0.91, p < 0.001 and fasting glucose R = 0.80, p < 0.001). Among tentatively identified metabolites, limonene, undecane, and 2,7-dimethyl-undecane, significantly cluster individuals based on HOMA-IR (p = 0.003, p = 0.002, and p < 0.001, respectively). Our breath-IR model differentiates between adolescents with and without IR with an AUC-ROC curve of 0.87, after cross-validation. Identification of a breath signature indicative of IR shows utility of exhaled breath metabolomics for assessing systemic metabolic dysregulation. A simple and non-invasive breath-based test has potential as a diagnostic tool for monitoring IR progression, allowing for earlier detection of IR and implementation of early interventions to prevent onset of type 2 diabetes mellitus.

Associations of circulating biomarkers with the presence and severity of coronary, carotid and femoral arterial atherosclerosis

Aim. To identify and characterize the associations of the presence and severity of atherosclerosis of various localization with the blood level of biochemical parameters, as well as to assess the potential of their use as markers of metabolic disorders with increased atherogenic potential.Material and methods. The study included 216 patients (men, 53%) aged 24-87 years (mean age, 61,5±10,73 years). All patients underwent coronary angiography, carotid (CA) and femoral arterial (FA) duplex ultrasound to assess the presence and severity of atherosclerosis. In blood serum/plasma, biochemical parameters were analyzed using standard methods.Results. Based on the analysis of circulating biomarker profile, diagnostic complexes have been established that allow assessing atherosclerosis of different localization. According to the data obtained, the determinants of coronary and CA atherosclerosis are endothelial dysfunction (concentration of nitric oxide metabolites <36,0 μmol/L) and an increased level of creatinine (≥73,0 μmol/L). The specific markers associated with severe atherosclerosis of coronary and FAs (but not CA) were low high-density lipoprotein cholesterol (≤1,0/1,2 μmol/L for male/ female, respectively) and an increased C-reactive protein level (≥1,0 mg/l). Severe peripheral atherosclerosis (CA and FA involvement) was associated with hyperglycemia (glucose ≥6,1 μmol/L), while severe FA atherosclerosis — with hyperinsulinemia (insulin ≥14,0 μU/ml).Conclusion. The analysis of associations of circulating biochemical parameters with atherosclerosis localization and severity revealed a number of metabolic markers associated with the increased atherogenic potential. It is possible to distinguish both universal parameters that are associated with atherosclerosis, regardless of its localization and/or severity, and specific biomarkers that characterize either the localization or the severity of atherosclerosis, or both.

Association between being metabolically healthy/unhealthy and metabolic syndrome in Iranian adults

Introduction The prevalence of metabolically healthy obesity (MHO) varies based on different criteria. We assessed the prevalence of MHO and metabolic unhealthiness based on body mass index (BMI) and their association with metabolic syndrome (MetS) in a nation-wide study. Methods Data were taken from the STEPs 2016 study, from 18,459 Iranians aged ≥25 years. Demographic, metabolic, and anthropometric data were collected. Subjects were stratified by BMI, metabolic unhealthiness, and having MetS. The latter was defined based on National Cholesterol Education Program Adult Treatment Panel III 2004 (NCEP ATP III), was then assessed. Results The prevalence of MHO and metabolic unhealthiness in obese subjects was 7.5% (about 3.6 million) and 18.3% (about 8.9 million), respectively. Most of the metabolic unhealthy individuals were female (53.5%) or urban residents (72.9%). Low physical activity was significantly and positively associated (Odds Ratio: 1.18, 95% CI: 1.04–1.35) with metabolic unhealthiness, while being a rural residence (0.83, 0.74–0.93), and having higher education (0.47, 0.39–0.58) significantly but negatively affected it. Dyslipidemia was the most frequent MetS component with a prevalence rate of 46.6% (42.1–51.1), 62.2% (60.8–63.6), 76.3% (75.1–77.5), and 83.4% (82.1–84.6) among underweight, normal weight, overweight and obese phenotypes, respectively. Conclusion BMI aside, an additional set of criteria such as metabolic markers should be taken into account to identify normal weight but metabolically unhealthy individuals. Given the highest prevalence of dyslipidemia among obese subjects, further interventions are required to raise public awareness, promote healthy lifestyles and establish lipid clinics.

Potential Novel Serum Metabolic Markers Associated With Progression of Prediabetes to Overt Diabetes in a Chinese Population

BackgroundIdentifying the metabolite profile of individuals with prediabetes who turned to type 2 diabetes (T2D) may give novel insights into early T2D interception. The purpose of this study was to identify metabolic markers that predict the development of T2D from prediabetes in a Chinese population.MethodsWe used an untargeted metabolomics approach to investigate the associations between serum metabolites and risk of prediabetes who turned to overt T2D (n=153, mean follow up 5 years) in a Chinese population (REACTION study). Results were compared with matched controls who had prediabetes at baseline [age: 56 ± 7 years old, body mass index (BMI): 24.2 ± 2.8 kg/m2] and at a 5-year follow-up [age: 61 ± 7 years old, BMI: 24.5 ± 3.1 kg/m2]. Confounding factors were adjusted and the associations between metabolites and diabetes risk were evaluated with multivariate logistic regression analysis. A 10-fold cross-validation random forest classification (RFC) model was used to select the optimal metabolites panels for predicting the development of diabetes, and to internally validate the discriminatory capability of the selected metabolites beyond conventional clinical risk factors.FindingsMetabolic alterations, including those associated with amino acid and lipid metabolism, were associated with an increased risk of prediabetes progressing to diabetes. The most important metabolites were inosine [odds ratio (OR) = 19.00; 95% confidence interval (CI): 4.23-85.37] and carvacrol (OR = 17.63; 95% CI: 4.98-62.34). Thirteen metabolites were found to improve T2D risk prediction beyond eight conventional T2D risk factors [area under the curve (AUC) was 0.98 for risk factors + metabolites vs 0.72 for risk factors, P &lt; 0.05].InterpretationsUse of the metabolites identified in this study may help determine patients with prediabetes who are at highest risk of progressing to diabetes.

Dental Pulp Stem Cell Heterogeneity: Finding Superior Quality “Needles” in a Dental Pulpal “Haystack” for Regenerative Medicine-Based Applications

Human dental pulp stem/stromal cells (hDPSCs) derived from the permanent secondary dentition are recognised to possess certain advantageous traits, which support their potential use as a viable source of mesenchymal stem/stromal cells (MSCs) for regenerative medicine-based applications. However, the well-established heterogeneous nature of hDPSC subpopulations, coupled with their limited numbers within dental pulp tissues, has impeded our understanding of hDPSC biology and the translation of sufficient quantities of these cells from laboratory research, through successful therapy development and clinical applications. This article reviews our current understanding of hDPSC biology and the evidence underpinning the molecular basis of their heterogeneity, which may be exploited to distinguish individual subpopulations with specific or superior characteristics for regenerative medicine applications. Pertinent unanswered questions which still remain, regarding the developmental origins, hierarchical organisation, and stem cell niche locations of hDPSC subpopulations and their roles in hDPSC heterogeneity and functions, will further be explored. Ultimately, a greater understanding of how key features, such as specific cell surface, senescence and other relevant genes, and protein and metabolic markers, delineate between hDPSC subpopulations with contrasting stemness, proliferative, multipotency, immunomodulatory, anti-inflammatory, and other relevant properties is required. Such knowledge advancements will undoubtedly lead to the development of novel screening, isolation, and purification strategies, permitting the routine and effective identification, enrichment, and expansion of more desirable hDPSC subpopulations for regenerative medicine-based applications. Furthermore, such innovative measures could lead to improved cell expansion, manufacture, and banking procedures, thereby supporting the translational development of hDPSC-based therapies in the future.

Effects of Vitamin E Supplementation to Metabolic Markers on Diet-Induced Obesity in Mice

Introduction: Obesity creates health problems by increasing the risks of chronic diseases such as type 2 diabetes and cardiovascular disorders. Obesity leads to insulin resistance, higher blood glucose and cholesterol levels. Adipose tissues synthesize adiponectin which acts as anti-inflammatory, antidiabetic, and anti-atherogenic agent. Meanwhile, vitamin E is an antioxidant that acts as an anti-inflammation. Aim: The purpose of this study was to analyze the effects of vitamin E supplementation to metabolic markers on diet-induced obesity in mice. Materials and methods: Twenty-four mice (Mus musculus, L) aged four weeks were divided into six groups which were fed different diets and given vitamin E in different dosages or methods. The period of treatment was 18 weeks. The mice body weights were measured every week; blood sugar and cholesterol levels were measured every six weeks, and the adiponectin level measurement was done at week 18. Results: A repeated measures ANOVA showed that body weight and cholesterol level within groups were not significantly different [F(15,&nbsp;54)=1.417, 0.173 and F(10,&nbsp;36)=1.391, 0.224 respectively]. The glucose levels were found to be significantly different [F(7.646,&nbsp;27.526)=2.625, 0.030]. There was no significant difference in the adiponectin levels. Conclusions: Vitamin E supplementation could not prevent the increase of body weight, the elevation of blood sugar and cholesterol levels, and also could not increase adiponectin level.

Food Consumption and Metabolic Risks in Young University Students

The purpose of this study was to analyze the association between components of the diet, metabolic risks, and the serum concentrations of adiponectin and interleukin-6 (IL-6). With prior informed consent, an analytical cross-sectional study was carried out with 72 students in their first year of university. The subjects had a mean age of 19.2 ± 1.0 years and body mass index of 23.38 ± 4.2, and they were mainly women (80.6%). Sociodemographic, anthropometric, and dietary data and metabolic risk factors were evaluated, and biochemical parameters and adipocytokines were also considered. The data were analyzed using means, ranges, and correlations, as well as principal components. In general, the protein, fat, and sodium intake were higher than the international dietary recommendations, and deficiencies in vitamins B5 and E, potassium, phosphorus, selenium, and zinc were observed. The most frequently observed metabolic risks were insulin resistance and hypoalphalipoproteinemia. IL-6 was positively correlated with lipid and protein intake. Adiponectin showed a positive correlation with high-density lipoprotein and a negative correlation with insulin, weight, and waist, while the adiponectin pattern was similar to that of vitamins E and A, which decreased with increasing intake of calories, macronutrients, and sodium. In general, a hypercaloric diet that was high in protein, fat, and sodium and deficient in vitamins, mainly fat-soluble, was associated with a lower concentration of adiponectin and a higher concentration of IL-6, which favor the presence of metabolic risks, including insulin resistance. Intervention studies are required to evaluate the dietary intake of metabolic markers in young people without comorbidities, which will lay the foundation for implementing prevention strategies.