Major impact of vitamin D3 deficiency and supplementation on left ventricular torsional mechanics during dobutamine stress in uncomplicated type 2 diabetes.

BACKGROUND AND AIMS: Hypovitaminosis D is associated with the risk of diabetic complications. Its role in diabetic-related cardiac abnormalities remain poorly understood. We aimed therefore to evaluate the effect of vitamin D deficiency and supplementation on early left ventricular (LV) dysfunction in vitamin D deficient patients with uncomplicated T2D. METHODS AND RESULTS: Sixty-three consecutive T2D patients who had a diagnosis of vitamin D3 were prospectively recruited and allocated into 2 groups (25(OH)D < 20 ng/mL: VDD, >20 ng/mL VDND). Twenty-eight of them with 25(OH)D < 20 ng/mL benefited from a 3-month supplementation. At baseline and follow-up, after conventional echocardiography including evaluation of epicardial adipose tissue (EAT), both LV longitudinal (LS) and circumferential (CS) strains and rotation/twist mechanics were evaluated at rest and during dobutamine (DOB) stress. After treatment, T2D patients successfully normalized their 25(OH)D levels. The strongest associations between vitamin D deficiency and supplementation with LV myocardial function were noticed for torsional mechanics indexes under DOB. EAT correlated significantly (p < 0.01) with baseline 25(OH)D and was reduced after supplementation. Significant correlations were obtained between these 2 parameters with twist or apical rotation at baseline (p < 0.01) and between their delta changes at follow-up (p < 0.01) under DOB. Significant improvements in LS and CS (p < 0.05) under DOB were also underlined at follow-up, with major enhancements noticed in the apical region (p < 0.01) of the LV. CONCLUSIONS: This study provides the first evidences of the potential of vitamin D supplementation as an efficient prophylactic strategy to alleviate the progression of myocardial dysfunction in asymptomatic patients with uncomplicated T2D. CLINICALTRIALS: NCT03437421.

Vitamin D3 Supplementation Alleviates Left Ventricular Dysfunction in a Mouse Model of Diet-Induced Type 2 Diabetes: Potential Involvement of Cardiac Lipotoxicity Modulation.

PURPOSE: To evaluate the effectiveness of vitamin D3 supplementation, in secondary prevention, on cardiac remodeling and function, as well as lipid profile, in a mouse model of diet-induced type 2 diabetes. METHODS: Mice were fed a high fat and sucrose diet for 10 weeks. Afterward, diet was maintained for 15 more weeks and two groups were formed, with and without cholecalciferol supplementation. A control group was fed with normal chow. Glucose homeostasis and cardiac function were assessed at baseline and at the 10th and 24th weeks. Animals were killed at the 10th and 25th weeks for plasma and cardiac sample analysis. Cardiac lipid profile was characterized by LC-MS/MS. RESULTS: After 10 weeks of diet, mice exhibited pre-diabetes, mild left ventricle hypertrophy, and impaired longitudinal strain, but preserved myocardial circumferential as well as global diastolic and systolic cardiac function. After 15 more weeks of diet, animals presented with well-established type 2 diabetes, pathological cardiac hypertrophy, and impaired regional myocardial function. Cholecalciferol supplementation had no effect on glucose homeostasis but improved cardiac remodeling and regional myocardial function. After 25 weeks, non-supplemented mice exhibited increased myocardial levels of ceramides and diacylglycerol, both of which were normalized by vitamin D3 supplementation. CONCLUSION: This work brought to light the beneficial effects of cholecalciferol supplementation, in secondary prevention, on cardiac remodeling and function in a mouse model of diet-induced type 2 diabetes. Those cardioprotective effects may be, at least in part, attributed to the modulation of myocardial levels of lipotoxic species by vitamin D.

Combined Beneficial Effect of Voluntary Physical Exercise and Vitamin D Supplementation in Diet-induced Obese C57BL/6J Mice.

PURPOSE: Physical exercise (PE) combined with nutritional approaches has beneficial effects that are widely advocated to improve metabolic health. Here we used voluntary PE together with vitamin D (VD) supplementation, which has already shown beneficial effects in primary and tertiary prevention in obese mice models, to study their combined additive effects on body weight management, glucose homeostasis, metabolic inflammation, and liver steatosis as key markers of metabolic health. METHODS: Ten-week-old male C57BL/6J mice were fed a high-fat/sucrose (HFS) diet for 10 wk, then assigned to a 15-wk intervention period with PE, VD supplementation, or both PE and VD supplementation. Morphological, histological, and molecular phenotype data were characterized. RESULTS: The HFS-induced increases in body mass, adiposity, and adipocyte hypertrophy were improved by PE but not by VD supplementation. The HFS-induced inflammation (highlighted by chemokines mRNA levels) in inguinal adipose tissue was decreased by PE and/or VD supplementation. Furthermore, the intervention combining PE and VD showed additive effects on restoring insulin sensitivity and improving hepatic steatosis, as demonstrated through a normalization of size and number of hepatic lipid droplets and triglyceride content and a significant molecular-level decrease in the expression of genes coding for key enzymes in hepatic de novo lipogenesis. CONCLUSIONS: Taken together, our data show beneficial effects of combining PE and VD supplementation on obesity-associated comorbidities such as insulin resistance and hepatic disease in mice. This combined exercise-nutritional support strategy could prove valuable in obesity management programs.

Vitamin D Supplementation Improves Adipose Tissue Inflammation and Reduces Hepatic Steatosis in Obese C57BL/6J Mice.

The beneficial effect of vitamin D (VD) supplementation on body weight gain limitation and inflammation has been highlighted in primary prevention mice models, but the long-term effect of VD supplementation in tertiary prevention has never been reported in obesity models. The curative effect of VD supplementation on obesity and associated disorders was evaluated in high-fat- and high-sucrose (HFS)-fed mice. Morphological, histological, and molecular phenotype were characterized. The increased body mass and adiposity caused by HFS diet as well as fat cell hypertrophy and glucose homeostasis were not improved by VD supplementation. However, VD supplementation led to a decrease of HFS-induced inflammation in inguinal adipose tissue, characterized by a decreased expression of chemokine mRNA levels. Moreover, a protective effect of VD on HFS-induced hepatic steatosis was highlighted by a decrease of lipid droplets and a reduction of triglyceride accumulation in the liver. This result was associated with a significant decrease of gene expression coding for key enzymes involved in hepatic de novo lipogenesis and fatty acid oxidation. Altogether, our results show that VD supplementation could be of interest to blunt the adipose tissue inflammation and hepatic steatosis and could represent an interesting nutritional strategy to fight obesity-associated comorbidities.

Stress management in obesity during a thermal spa residential programme (ObesiStress): protocol for a randomised controlled trial study.

INTRODUCTION: Stress and obesity are two public health issues. The relationship between obesity and stress is biological through the actions of stress on the major hormones that regulate appetite (leptin and ghrelin). Many spa resorts in France specialise in the treatment of obesity, but no thermal spa currently proposes a specific programme to manage stress in obesity. The ObesiStress protocol has been designed to offer a new residential stress management programme. This thermal spa treatment of obesity implements stress management strategies as suggested by international recommendations. METHODS AND ANALYSIS: 140 overweight or obese participants with a Body Mass Index of >25 kg/m2 and aged over 18 years will be recruited. Participants will be randomised into two groups: a control group of usual practice (restrictive diet, physical activity and thermal spa treatment) and an intervention group with stress management in addition to the usual practice. In the present protocol, parameters will be measured on five occasions (at inclusion, at the beginning of the spa (day 0), at the end of the spa (day 21), and at 6 and 12 months). The study will assess the participants' heart rate variability, cardiac remodelling and function, electrodermal activity, blood markers, anthropometric profile, body composition, psychology and quality of life via the use of questionnaires and bone parameters. ETHICS AND DISSEMINATION: The ObesiStress protocol complies with the ethics guidelines for Clinical Research and has been approved by the ethics committee (CPP Sud-Est VI, Clermont-Ferrand - ANSM: 2016-A01774-47). This study aimed to highlight the efficacy of a 21-day thermal spa residential programme of stress management in obesity through objective measurements of well-being and cardiovascular morbidity. Results will be disseminated during several research conferences and articles published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03578757.

Involvement of bilitranslocase and beta-glucuronidase in the vascular protection by hydroxytyrosol and its glucuronide metabolites in oxidative stress conditions.

Olive oil vascular benefits have been attributed to hydroxytyrosol (HT). However, HT biological actions are still debated because it is extensively metabolized into glucuronides (GCs). The aim of this study was to test HT and GC vasculoprotective effects and the underlying mechanisms using aorta rings from 8-week-old male Wistar rats. In the absence of oxidative stress, incubation with 100 µM HT or GC for 5 min did not exert any vasorelaxing effect and did not influence the vascular function. Conversely, in condition of oxidative stress [upon incubation with 500 µM tert-butylhydroperoxide (t-BHP) for 30 min], preincubation with HT or GC improved acetylcholine-induced vasorelaxation compared with untreated samples (no t-BHP). This protective effect was lost for GC, but not for HT, when a washing step (15 min) was introduced between preincubation with HT or GC and t-BHP addition, suggesting that only HT enters the cells. In agreement, bilitranslocase inhibition with 100 µM phenylmethanesulfonyl fluoride for 20 min reduced significantly HT, but not GC, effect on the vascular function upon stress induction. Moreover, GC protective effect (improvement of endothelium-dependent relaxation in response to acetylcholine) in oxidative stress conditions was reduced by preincubation of aorta rings with 300 µM D-saccharolactone to inhibit ß-glucuronidase, which can deconjugate polyphenols. Finally, only HT was detected by high-pressure liquid chromatography in aorta rings incubated with GC and t-BHP. These results suggest that, in conditions of oxidative stress, GC can be deconjugated into HT that is transported through the cell membrane by bilitranslocase to protect vascular function.

Long-term cost reduction of routine medications following a residential programme combining physical activity and nutrition in the treatment of type 2 diabetes: a prospective cohort study.

OBJECTIVES: To demonstrate that lifestyle modifications will reduce the cost of routine medications in individuals with type 2 diabetes (T2D), through a mechanism involving glycaemic control. DESIGN: A within-trial cost-medication analysis with a 1-year time horizon. SETTING: Controlled environment within the spa resort of Chatel-Guyon, France. PARTICIPANTS: Twenty-nine participants (aged 50-70 years) with T2D. INTERVENTIONS: A 1-year follow-up intervention, beginning with a 3-week residential programme combining high exercise volume (15-20 hours/week), restrictive diet (-500 kcal/day) and education. Participants continued their routine medication, independently managed by their general practitioner. MAIN OUTCOME MEASURES: Number of medications, number of pills, cost of medications and health-related outcomes. RESULTS: Twenty-six participants completed the 1-year intervention. At 1 year, 14 patients out of 26 (54%) stopped/decreased their medications whereas only 5 (19%) increased or introduced new drugs (χ2=6.3, p=0.02). The number of pills per day decreased by 1.3±0.3 at 12 months (p<0.001). The annual cost of medications for T2D were lower at 1 year (€135.1±43.9) versus baseline (€212.6±35.8) (p=0.03). The regression coefficients on costs of routine medication were 0.507 (95% CI 0.056 to 0.959, p=0.027) for HbA1c and 0.156 (95% CI -0.010 to 0.322, p=0.06) for blood glucose levels. Diabetics patients with HbA1c >6.5% in the highest (last) quartile doubled their routine medication costs (66% vs 33%, p=0.037). CONCLUSIONS: Individuals with T2D reduced routine medication costs following a long-term lifestyle intervention that started with a 3-week residential programme. Combining high exercise volume, restrictive diet and education effectively supported the health of T2D. The main factor explaining reduced medication costs was better glycaemic control, independent of weight changes. Despite limitations precluding generalisability, cost-effective results of reduced medication should contribute to the evidence base required to promote lifestyle interventions for individuals with T2D. TRIAL REGISTRATION NUMBER: NCT00917917; Post-results.

Acute administration of l-arginine restores nitric oxide-mediated relaxation in isolated pulmonary arteries from pulmonary hypertensive exercise trained rats.

Hypoxia-induced pulmonary hypertension is associated with an impairment of nitric oxide-mediated vasorelaxation in the pulmonary circulation that is not prevented by exercise training. The present study was designed to test the hypothesis that a decrease in l-arginine bioavailability could be involved in this blunted response to exercise training. Male Wistar rats were randomly assigned to 4 groups: normotensive sedentary, normotensive trained, pulmonary hypertensive sedentary, pulmonary hypertensive trained. Pulmonary hypertension was induced by chronic exposure to hypobaric hypoxia (PIO(2) approximately 90 mmHg). Endothelium-dependent vasorelaxation to acetylcholine (10(-8)-10(-4) M) with or without l-arginine (10(-3) M) and/or nitro-l-arginine methyl ester (5.10(-6) M) was assessed on isolated pulmonary arterial rings. Maximal relaxation to acetylcholine was impaired in both pulmonary hypertensive groups. Acute l-arginine supplementation improved acetylcholine-induced vasorelaxation in the pulmonary hypertensive trained rats (P<0.01), to the level obtained in the normotensive sedentary ones, but not in the pulmonary hypertensive sedentary rats. This improvement was abolished when nitro-l-arginine methyl ester was added to the organ bath and was accounted for by an increase in eNOS protein content. These results confirm that the potential beneficial effect of exercise on nitric oxide-mediated pulmonary artery vasorelaxation is partly blunted by deleterious effects of hypoxia on l-arginine bioavailability. Further studies are needed to evaluate the benefit of the combination of exercise training and l-arginine supplementation for the treatment of pulmonary hypertension.