Endothelial Function in Patients with Multiple Sclerosis: The Role of GLP-1 Agonists, Lipoprotein Subfractions, and Redox Balance.

INTRODUCTION: Epidemiological studies have suggested an increased vascular risk in patients with multiple sclerosis (MS). There is increasing evidence of the beneficial effects of GLP-1 agonists (GLP-1a) in preventing vascular complications and slowing the progression of neurodegeneration. Our objective was to explore the changes in the endothelial function of MS patients after 12 months of GLP-1a therapy. We also explored the role of lipoprotein subfractions and the antioxidant capacity of plasma. METHODS: MS patients were enrolled in a prospective, unicentric study. GLP-1a (dulaglutide) was administered to 13 patients. The control population consisted of 12 subjects. Endothelial function was determined by peripheral arterial tonometry and expressed as reperfusion hyperemia index (RHI). Trolox equivalent antioxidant capacity (TEAC) was used to assess the total antioxidant capacity of the plasma. The levels of lipoprotein subfractions were evaluated. RESULTS: The GLP-1a group did not have a significant change in their RHIs after 12 months (2.1 ± 0.6 vs. 2.1 ± 0.7; p = 0.807). However, a significant increase in their TEACs was observed (4.1 ± 1.4 vs. 5.2 ± 0.5 mmol/L, p = 0.010). On the contrary, the subjects in the control group had a significant worsening of their RHIs (2.1 ± 0.5 vs. 1.8 ± 0.6; p = 0.030), without significant changes in their TEACs. Except for a significant decrease in very-low-density lipoprotein (VLDL) (30.8 ± 10.2 vs. 22.6 ± 8.3 mg/dL, p = 0.043), no other significant changes in the variables were observed in the control group. VLDL levels (beta = -0.637, p = 0.001), the use of GLP-1a therapy (beta = 0.560, p = 0.003), and small LDL (beta = 0.339, p = 0.043) were the only significant variables in the model that predicted the follow-up RHI. CONCLUSION: Our results suggest that the application of additional GLP-1a therapy may have atheroprotective and antioxidant effects in MS patients with high MS activity and thus may prospectively mitigate their vascular risk. However, the lipoprotein profile may also play an important role in the atherogenic risk of MS subjects.

Nutritional interventions for patients with alkaptonuria: A minireview.

Alkaptonuria (AKU, OMIM, No. 203500) is a rare, slow-progressing, irreversible, multisystemic disease resulting from a deficiency of the homogentisate 1,2-dioxygenase enzyme, which leads to the accumulation of homogentisic acid (HGA) and subsequent deposition as pigment in connective tissues called ochronosis. As a result, severe arthropathy of large joints and spondyloarthropathy with frequent fractures, ligament ruptures, and osteoporosis develops in AKU patients. Since 2020, the first-time treatment with nitisinone has become available in the European Union. Nitisinone significantly reduces HGA production and arrests ochronosis in AKU patients. However, blocking of the tyrosine metabolic pathway by the drug leads to tyrosine plasma and tissue concentrations increase. The nitisinone-induced hypertyrosinemia can lead to the development of corneal keratopathy, and once it develops, the treatment needs to be interrupted. A decrease in overall protein intake reduces the risk of the keratopathy during nitisinone-induced hypertyrosinemia in AKU patients. The low-protein diet is not only poorly tolerated by patients, but over longer periods, leads to a severe muscle loss and weight gain due to increased energy intake from carbohydrates and fats. Therefore, the development of novel nutritional approaches is required to prevent the adverse events due to nitisinone-induced hypertyrosinemia and the negative impact on skeletal muscle metabolism in AKU patients.

Effect of High-intensity Training and Probiotics on Gut Microbiota Diversity in Competitive Swimmers: Randomized Controlled Trial.

BACKGROUND: Physical exercise has favorable effects on the structure of gut microbiota and metabolite production in sedentary subjects. However, little is known whether adjustments in an athletic program impact overall changes of gut microbiome in high-level athletes. We therefore characterized fecal microbiota and serum metabolites in response to a 7-week, high-intensity training program and consumption of probiotic Bryndza cheese. METHODS: Fecal and blood samples and training logs were collected from young competitive male (n = 17) and female (n = 7) swimmers. Fecal microbiota were categorized using specific primers targeting the V1-V3 region of 16S rDNA, and serum metabolites were characterized by NMR-spectroscopic analysis and by multivariate statistical analysis, Spearman rank correlations, and Random Forest models. RESULTS: We found higher α-diversity, represented by the Shannon index value (HITB-pre 5.9 [± 0.4]; HITB-post 6.4 [± 0.4], p = 0.007), (HIT-pre 5.5 [± 0.6]; HIT-post 5.9 [± 0.6], p = 0.015), after the end of the training program in both groups independently of Bryndza cheese consumption. However, Lactococcus spp. increased in both groups, with a higher effect in the Bryndza cheese consumers (HITB-pre 0.0021 [± 0.0055]; HITB-post 0.0268 [± 0.0542], p = 0.008), (HIT-pre 0.0014 [± 0.0036]; HIT-post 0.0068 [± 0.0095], p = 0.046). Concomitant with the increase of high-intensity exercise and the resulting increase of anaerobic metabolism proportion, pyruvate (p[HITB] = 0.003; p[HIT] = 0.000) and lactate (p[HITB] = 0.000; p[HIT] = 0.030) increased, whereas acetate (p[HITB] = 0.000; p[HIT] = 0.002) and butyrate (p[HITB] = 0.091; p[HIT] = 0.019) significantly decreased. CONCLUSIONS: Together, these data demonstrate a significant effect of high-intensity training (HIT) on both gut microbiota composition and serum energy metabolites. Thus, the combination of intensive athletic training with the use of natural probiotics is beneficial because of the increase in the relative abundance of lactic acid bacteria.

Cardiac autonomic function in patients with early multiple sclerosis.

PURPOSE: Cardiac autonomic dysfunction has been reported in patients with long-standing multiple sclerosis (MS); however, data in early disease are limited. The present study was aimed at evaluating cardiac autonomic function in patients with early MS in the context of white matter metabolic status, which could potentially affect functions of the autonomic brain centers. METHODS: Cardiac sympathetic and baroreflex cardiovagal responses to the Valsalva maneuver, orthostatic test, and the Stroop test were evaluated in 16 early, treatment-naïve patients with relapsing-remitting MS, and in 14 healthy participants. Proton magnetic resonance spectroscopic imaging (MRSI) of the brain was performed in eight of these MS patients and in eight controls. RESULTS: Valsalva maneuver outcomes were comparable between patients and controls. At baseline, norepinephrine levels were lower (p = 0.027) in MS patients compared to controls. The patients had higher heart rate (p = 0.034) and lower stroke volume (p = 0.008), but similar blood pressure, cardiac output and norepinephrine increments from baseline to 2 min of the orthostatic test compared to controls. MS patients and controls did not differ in responses to the Stroop test. MRSI showed lower total N-acetylaspartate/total creatine (p = 0.038) and higher myo-inositol/total creatine (p = 0.013) in MS lesions compared to non-lesional white matter. CONCLUSION: Our results show normal cardiac sympathetic and baroreflex cardiovagal function in MS patients with relapsing-remitting MS with lesions at the post-acute/early resolving stage. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov under the Identifier: NCT03052595 and complies with the STROBE checklist for cohort, case-control, and cross-sectional studies.

Lipoprotein profiling in early multiple sclerosis patients: effect of chronic inflammation?

BACKGROUND: Inflammatory cytokines contribute to proatherogenic changes in lipid metabolism by reduction of HDL-cholesterol (HDL-C) levels, impairment of its antiinflammatory and antioxidant functions. Therefore, the protective actions of HDL-C can be limited in chronic inflammatory diseases such as multiple sclerosis (MS). The aim of this study was to assess the association between lipoprotein subfractions and inflammatory status in early stages of multiple sclerosis. METHODS: Polyacrylamide gel electrophoresis Lipoprint© System was used for lipoprotein profile analysis in 19 newly diagnosed MS patients, and in matched 19 healthy controls. Serum levels of interleukin (IL) 1ß, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 (p70), IL-13, IL-17, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor, interferon-γ and TNF-α were measured by multiplex bead assay. RESULTS: Concentrations of the measured cytokines and lipoprotein subclasses were comparable between MS patients and controls. Male, but not female MS patients had significantly higher total HDL-C and small HDL-C subfraction than healthy controls. Large HDL-C negatively correlated with all measured cytokines except IL-17 in MS but not in controls. Intermediate HDL-C subfractions correlated positively with all measured cytokines except G-CSF in MS females but not in MS males or controls. CONCLUSION: Our results of higher HDL-C and mainly its small HDL-C subfraction suggest that male MS patients are at higher risk of atherosclerosis and the subtle dyslipidemia is present in early stages of the disease. The correlations between specific HDL-C subfractions and the inflammatory cytokines demonstrate mutual links between systemic inflammation and lipid metabolism in MS. TRIAL REGISTRATION: ClinicalTrials.gov, Identifier: NCT03052595 Registered on Feb 14, 2017.

Effect of 8-weeks intensive lifestyle intervention on LDL and HDL subfractions.

OBJECTIVE: Atherogenic dyslipidemia is a cardinal feature of obesity and the metabolic syndrome, which increases the risk of cardiovascular diseases. Many interventional studies, describing the influence of weight loss on cardiometabolic risks, are bariatric surgery studies. The aim of our study was to analyze the effect of intensive lifestyle changes on LDL- and HDL-cholesterol subfractions and cardiometabolic risk factors in obese subjects. METHODS: A group of 41 patients with obesity (11M/30F; 44.1±12.4 years; BMI 30.2±6.3kg/m2) participated in an 8-week weight loss interventional program (NCT02325804), consisting of caloric intake reduced by 30% and physical activity (150min/week). Insulin sensitivity was evaluated according to the homeostasis model assessment of insulin resistance (HOMA-IR) and physical fitness was measured using bicycle ergometry. Lipid subfractions were measured using the Lipoprint system (Quantimetrix Corp., CA, USA). RESULTS: After the intervention, body weight was reduced by 5.4±4.5kg, as well as body fat mass and waist circumference. Physical fitness improved, systolic and diastolic blood pressure as well as heart rate decreased after the intervention. Insulin sensitivity improved after the intervention. Total, LDL, HDL cholesterol, as well as triglycerides decreased after the intervention. Regarding the lipoprotein subfractions, LDL2 and small HDL subfractions decreased, while others have not changed. CONCLUSION: Eight weeks of diet and physical activity intervention led to weight and fat mass loss and induced improvement of insulin sensitivity, as well as atheroprotective changes of lipid profile. However, the weight loss associated changes in cholesterol subfractions as cardiovascular risk biomarkers deserve further studies.

PCSK9 inhibitors and diabetes mellitus.

Proproteinconvertase subtilisin kexin 9 (PCSK9) is a key regulator of low-density lipoprotein receptor (LDLR) expression. Anti-PCSK9 monoclonal antibody (MAb) therapy reduces LDL-cholesterol (LDL-C) by ~60 % and reduces also the risk of major adverse cardiovascular events. Mendelian randomisation studies showed that patients carrying loss-of-function PCSK9 genetic variants display lower LDL-C and have an increased risk of developing type 2 diabetes (T2DM). Randomized controlled trials with anti-PCSK9 MAbs however showed no effect on the risk. A possible explanation of the discrepancy is that the deficiency of locally but not circulating PCSK9 is responsible for increased LDLR expression in pancreatic islets, which results in cholesterol accumulation and B-cell dysfunction. Thus PCSK9 lowering therapy with MAb targeting mainly circulating PCSK9 might have a limited impact on LDLR expression in pancreatic cells and on the risk of T2DM. Long-term clinical trials are however needed to confirm it. Key words: diabetes mellitus - LDL receptor - PCSK9.

LDL and HDL lipoprotein subfractions in multiple sclerosis patients with decreased insulin sensitivity.

OBJECTIVES: Increased metabolic and cardiovascular morbidity has been reported in multiple sclerosis (MS) patients. Previously, we have found decreased insulin sensitivity and hyperinsulinemia in a group of newly diagnosed MS patients. We hypothesize that these features may be associated with an altered lipid profile and low, intermediate, or high density lipoprotein (LDL, IDL, HDL) subclasses accelerating atherosclerosis and thus contributing to the cardiovascular risk increase in these patients. SUBJECTS AND METHODS: In a group of 19 newly diagnosed untreated MS patients with previously found hyperinsulinemia and insulin resistance and a matched group of 19 healthy controls, the lipoprotein subclasses profile was determined. Polyacrylamide gel electrophoresis was used to separate and measure the LDL (large LDL and small dense LDL), HDL (large, intermediate and small), and IDL (A, B and C) subclasses with the Lipoprint© System (Quantimetrix Corporation, Redondo Beach, CA, USA). RESULTS: No difference was found either in the conventional lipid or lipoprotein subclasses profile between the MS patients and healthy controls. We found an inverse association between the level of IDL-B with fasting insulin (r=-0.504, p=0.032), the insulin resistance estimated by homeo-static model assessment - insulin resistance (HOMA-IR) (r=-0.498, p=0.035), insulin response expressed as area under the curve (AUC; r=-0.519, p=0.027), and area above the baseline (AAB; r=-0.476, p=0.045) and positive association with insulin sensitivity estimated by insulin sensitivity index (ISI) Matsuda (r=0.470, 0.048) in MS patients, but not in healthy controls suggesting the first signs in lipoprotein subclasses profile change. CONCLUSIONS: Our data indicate that changes in lipoprotein profile and subclasses are preceded by insulin resistance and hyperinsulinemia in patients with newly diagnosed MS.