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Acute Effects of Dietary Nitrate on Central Pressure and Endothelial Function in Hypertensive Patients: A Randomized, Placebo-Controlled Crossover Study.
Mattos, S, Cunha, MR, Marques, BC, D El-Rei, J, Baião, DDS, Paschoalin, VMF, Oigman, W, Neves, MF, Medeiros, F
Arquivos brasileiros de cardiologia. 2023;120(1):e20220209
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Eating habits influence several mechanisms involved with cardiovascular risk factors. The inorganic nitrate (NO3‾) content in root vegetables can provide a physiological substrate for the reduction to nitrite (NO2‾), nitric oxide and other metabolic products. The aim of this study was to evaluate the acute effects of dietary NO3‾ intake on blood pressure (BP) and endothelial function in treated hypertensive patients. This study was a randomised, crossover, placebo-controlled study which enrolled thirty-seven hypertensive patients aged between 40 and 70 years, of both genders, in regular use of antihypertensive drugs. Each participant was randomised to the crossover interventions; beetroot juice (BRJ) [rich in inorganic NO3‾] or water. Results show that after a single intake of inorganic NO3‾ there was an attenuation in the peripheral and central BP levels, reduction of ejection duration [the period in the cardiac cycle when the semilunar valves are open and blood is being ejected from the ventricles into the arterial system], increase in subendocardial viability ratio [an arterial stiffness parameter correlated with coronary flow reserve] and improvement of vascular function associated with elevated serum NO3‾ and NO2‾. Authors conclude that the intake of BRJ resulted in acute benefits on vascular parameters in hypertensive individuals, leading to greater subendocardial viability, higher performance in myocardial contraction and improvement in endothelial function.
Abstract
BACKGROUND The diet's inorganic nitrate (NO3-) may provide a physiological substrate for reducing nitrate (NO2-) to NO independent of the endothelium. Studies suggest that inorganic NO3- has beneficial effects on cardiovascular health. OBJECTIVE This study evaluated the acute effects of 500 mL nitrate-rich beetroot juice (BRJ; containing 11.5mmol NO3-) on blood pressure and endothelial function in treated hypertensive patients. METHODS A randomized, placebo-controlled, crossover study was conducted in treated hypertensive patients (n=37; women=62%) who underwent clinical and nutritional evaluation and assessment of central hemodynamic parameters and microvascular reactivity. The significance level was p<0.05. RESULTS The mean age was 59±7 years, and mean systolic and diastolic blood pressures were 142±10/83±9mmHg. There was a significant increase in the subendocardial viability ratio (SEVR; 149±25 vs. 165±30%, p<0.001) and reduction in ejection duration (ED; 37±4 vs. 34±4%, p<0.001) in the beetroot phase but no significant SEVR difference in the control phase. The % increase in perfusion (155 vs. 159 %, p=0.042) was significantly increased in the beetroot phase, which was not observed in the control phase. In the beetroot phase, the change in SEVR showed a significant correlation with the change in the area under the curve of post-occlusive reactive hyperemia (AUC-PORH) (r=0.45, p=0.012). The change in ED showed a significant correlation with the post-intervention perfusion peak (r=-0.37, p=0.031) and AUC-PORH (r=-0.36, p=0.046). CONCLUSIONS The acute ingestion of BRJ by hypertensive patients resulted in an improvement of endothelial function, which was associated with higher subendocardial viability and performance in myocardial contraction. FUNDAMENTO O nitrato inorgânico (NO3–) da dieta pode fornecer substrato fisiológico para reduzir o nitrito (NO2–) a óxido nítrico (NO) independente do endotélio. Estudos sugerem que o NO3– inorgânico tem efeitos benéficos na saúde cardiovascular. OBJETIVOS Este estudo avaliou os efeitos agudos de 500 mL de suco de beterraba rico em nitrato (SB; contendo 11,5mmol NO3–) na pressão arterial e na função endotelial em pacientes hipertensos tratados. MÉTODOS Estudo cruzado, randomizado, controlado por placebo foi realizado em pacientes hipertensos tratados (n=37; mulheres=62%) que foram submetidos à avaliação clínica e nutricional, avaliação dos parâmetros hemodinâmicos centrais e reatividade microvascular. O nível de significância foi p<0,05. RESULTADOS A média de idade foi 59±7 anos e das pressões sistólica e diastólica foi de 142±10/83±9 mmHg. Houve aumento significativo na taxa de viabilidade subendocárdica (RVSE; 149±25 vs. 165±30%, p<0,001) e redução na duração da ejeção (DE; 37±4 vs. 34±4%, p<0,001) na fase beterraba, mas nenhuma diferença significativa de RVSE na fase controle. O % de aumento na perfusão (155 vs. 159%, p=0,042) cresceu significativamente na fase beterraba, o que não foi observado na fase controle. Na fase beterraba, a alteração da RVSE apresentou correlação significativa com a alteração da área sob a curva de hiperemia reativa pós-oclusiva (ASC-HRPO) (r=0,45, p=0,012). A mudança na DE mostrou uma correlação significativa com pico de perfusão pós-intervenção (r=-0,37, p=0,031) e ASC-HRPO (r=-0,36, p=0,046). CONCLUSÃO: A ingestão aguda de SB por pacientes hipertensos resultou em melhora da função endotelial, que foi associada à maior viabilidade subendocárdica e desempenho na contração miocárdica. BACKGROUND The diet’s inorganic nitrate (NO3–) may provide a physiological substrate for reducing nitrate (NO2–) to NO independent of the endothelium. Studies suggest that inorganic NO3–has beneficial effects on cardiovascular health. OBJECTIVE This study evaluated the acute effects of 500 mL nitrate-rich beetroot juice (BRJ; containing 11.5mmol NO3–) on blood pressure and endothelial function in treated hypertensive patients. METHODS A randomized, placebo-controlled, crossover study was conducted in treated hypertensive patients (n=37; women=62%) who underwent clinical and nutritional evaluation and assessment of central hemodynamic parameters and microvascular reactivity. The significance level was p<0.05. RESULTS The mean age was 59±7 years, and mean systolic and diastolic blood pressures were 142±10/83±9mmHg. There was a significant increase in the subendocardial viability ratio (SEVR; 149±25 vs. 165±30%, p<0.001) and reduction in ejection duration (ED; 37±4 vs. 34±4%, p<0.001) in the beetroot phase but no significant SEVR difference in the control phase. The % increase in perfusion (155 vs. 159 %, p=0.042) was significantly increased in the beetroot phase, which was not observed in the control phase. In the beetroot phase, the change in SEVR showed a significant correlation with the change in the area under the curve of post-occlusive reactive hyperemia (AUC-PORH) (r=0.45, p=0.012). The change in ED showed a significant correlation with the post-intervention perfusion peak (r=-0.37, p=0.031) and AUC-PORH (r=-0.36, p=0.046). CONCLUSIONS The acute ingestion of BRJ by hypertensive patients resulted in an improvement of endothelial function, which was associated with higher subendocardial viability and performance in myocardial contraction.
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Oxidative Stress and Inflammation Are Associated With Age-Related Endothelial Dysfunction in Men With Low Testosterone.
Babcock, MC, DuBose, LE, Witten, TL, Stauffer, BL, Hildreth, KL, Schwartz, RS, Kohrt, WM, Moreau, KL
The Journal of clinical endocrinology and metabolism. 2022;107(2):e500-e514
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Serum testosterone declines gradually with age at a rate of ~1% per year after the third decade. Vascular aging, featuring endothelial dysfunction mediated by oxidative stress and inflammation, is a major risk factor for the development of age-associated cardiovascular disease (CVD). The aim of this study was to examine the effects of low testosterone on cardiovascular aging in men. This study is a cross-sectional study which recruited 58 healthy men of all races/ethnic backgrounds aged 50-75 years (middle-aged/older) and 18-40 years (young). Results show that middle-aged/older men with lower testosterone have evidence of “accelerated” vascular aging, as indicated by a greater age-associated endothelial dysfunction of large arteries compared with their age-matched peers. The greater macrovascular endothelial dysfunction in middle-aged/older men with chronically low testosterone was independent of CVD risk factors or symptoms of androgen deficiency. Furthermore, increased systemic oxidative stress and inflammation are mechanistically linked to the greater age-associated endothelial dysfunction in middle-aged/older men with lower testosterone. Authors conclude that normal physiological levels of testosterone may be beneficial to cardiovascular health by attenuating the age-related decline in endothelial function.
Abstract
CONTEXT Vascular aging, including endothelial dysfunction secondary to oxidative stress and inflammation, increases the risk for age-associated cardiovascular disease (CVD). Low testosterone in middle-aged/older men is associated with increased CVD risk. OBJECTIVE We hypothesized that low testosterone contributes to age-associated endothelial dysfunction, related in part to greater oxidative stress and inflammation. METHODS This cross-sectional study included 58 healthy, nonsmoking men categorized as young (N = 20; age 29 ± 4 years; testosterone 500 ± 58 ng/dL), middle-aged/older with higher testosterone (N = 20; age 60 ± 6 years; testosterone 512 ± 115 ng/dL), and middle-aged/older lower testosterone (N = 18; age 59 ± 8 years; testosterone 269 ± 48 ng/dL). Brachial artery flow-mediated dilation (FMDBA) was measured during acute infusion of saline (control) and vitamin C (antioxidant). Markers of oxidative stress (total antioxidant status and oxidized low-density lipoprotein cholesterol), inflammation (interleukin [IL]-6 and C-reactive protein [CRP]), and androgen deficiency symptoms were also examined. RESULTS During saline, FMDBA was reduced in middle-aged/older compared with young, regardless of testosterone status (P < 0.001). FMDBA was reduced in middle-aged/older lower testosterone (3.7% ± 2.0%) compared with middle-aged/older higher testosterone (5.7% ± 2.2%; P = 0.021), independent of symptoms. Vitamin C increased FMDBA (to 5.3% ± 1.6%; P = 0.022) in middle-aged/older lower testosterone but had no effect in young (P = 0.992) or middle-aged/older higher testosterone (P = 0.250). FMDBA correlated with serum testosterone (r = 0.45; P < 0.001), IL-6 (r = -0.41; P = 0.002), and CRP (r = -0.28; P = 0.041). CONCLUSION Healthy middle-aged/older men with low testosterone appear to have greater age-associated endothelial dysfunction, related in part to greater oxidative stress and inflammation. These data suggest that low testosterone concentrations may contribute to accelerated vascular aging in men.
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Essential Hypertension and Oxidative Stress: Novel Future Perspectives.
Franco, C, Sciatti, E, Favero, G, Bonomini, F, Vizzardi, E, Rezzani, R
International journal of molecular sciences. 2022;23(22)
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High blood pressure is one of the main risk factors for cardiovascular disease and a significant contributor to the development of strokes, heart attacks, and heart and kidney failure leading to early disability and reduced life expectancy. Essential or primary hypotension makes up 95% of high blood pressure cases, which is abnormally elevated blood pressure that is not a result of any other medical condition. Essential hypertension arises from various factors such as diet, lifestyle, environmental and genetic influences. Despite many available medications, not all patients attain well-managed blood pressure levels. Unmanaged high blood pressure can, over time, lead to narrowing and stiffening of the blood vessels and ultimately to structural and functional changes in the blood tissues. In part, this is mediated by oxidative stress, changes in antioxidant capacity and chronic low-grade inflammation, which damage the blood vessels' endothelial tissue and result in vascular stiffness. Melatonin is one of the most potent antioxidants found in nature and has been studied in short-term trials for its blood pressure lowering, antioxidant and vascular protective effects. This small open-label randomised study sought to get a better understanding of the long-term use of melatonin. Initially, the study assessed endothelial tissue damage, oxidative status and vascular stiffness in patients with high blood pressure. Subsequently, some of the participants received a low-dose melatonin supplement (1 mg/day) for one year, whilst being monitored for clinical and structural vascular changes. The study included 23 patients and 14 in the final analysis. After one year, the results showed a significant improvement in arterial stiffness in the melatonin group (11) and an improvement in endothelial tissue function, though the latter was not at statistically significant levels. Improvement in arterial stiffness seemed to be linked to a reduction in total antioxidant capacity (TAC). These findings suggest that melatonin can contribute to restoring oxidative balance in blood plasma, which reflects improved arterial stiffness. The study also demonstrated that besides being a well-tolerated intervention, melatonin also has clinical benefits even when administered at lower doses than normal.
Abstract
Among cardiovascular diseases, hypertension is one of the main risk factors predisposing to fatal complications. Oxidative stress and chronic inflammation have been identified as potentially responsible for the development of endothelial damage and vascular stiffness, two of the primum movens of hypertension and cardiovascular diseases. Based on these data, we conducted an open-label randomized study, first, to evaluate the endothelial damage and vascular stiffness in hypertense patients; second, to test the effect of supplementation with a physiological antioxidant (melatonin 1 mg/day for 1 year) in patients with essential hypertension vs. hypertensive controls. Twenty-three patients of either gender were enrolled and randomized 1:1 in two groups (control and supplemented group). The plasmatic total antioxidant capacity (as a marker of oxidative stress), blood pressure, arterial stiffness, and peripheral endothelial function were evaluated at the beginning of the study and after 1 year in both groups. Our results showed that arterial stiffness improved significantly (p = 0.022) in supplemented patients. The endothelial function increased too, even if not significantly (p = 0.688), after 1 year of melatonin administration. Moreover, the supplemented group showed a significative reduction in TAC levels (p = 0.041) correlated with the improvement of arterial stiffness. These data suggest that melatonin may play an important role in reducing the serum levels of TAC and, consequently, in improving arterial stiffness.
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A clinically meaningful metric of immune age derived from high-dimensional longitudinal monitoring.
Alpert, A, Pickman, Y, Leipold, M, Rosenberg-Hasson, Y, Ji, X, Gaujoux, R, Rabani, H, Starosvetsky, E, Kveler, K, Schaffert, S, et al
Nature medicine. 2019;25(3):487-495
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The human immune system changes with age, ultimately leading to a clinically evident, profound deterioration resulting in high morbidity and mortality rates attributed to infectious and chronic diseases. The aim of this study was to assess at high resolution the dynamics of older adults’ immune systems. The study uses multiple ‘omics’ technologies in a cohort of 135 adults (63 young adults and 72 older adults) of different ages who were sampled longitudinally over the course of 9 years to comprehensively capture population- and individual-level changes in the immune system over time. Results indicate that immune-cell frequencies changed at substantially different rates; some cell subsets show no directionality of change yet differ between young and old individuals, whereas other cell subsets continued changing (either increasing or decreasing) throughout the course of the study. Authors postulate that an individual’s immune age is a function of life history, namely environmental exposure coupled with genetic background. Thus, immune modulators may one day be identified that affect the position of an individual’s immune system along the immunological landscape.
Abstract
Immune responses generally decline with age. However, the dynamics of this process at the individual level have not been characterized, hindering quantification of an individual's immune age. Here, we use multiple 'omics' technologies to capture population- and individual-level changes in the human immune system of 135 healthy adult individuals of different ages sampled longitudinally over a nine-year period. We observed high inter-individual variability in the rates of change of cellular frequencies that was dictated by their baseline values, allowing identification of steady-state levels toward which a cell subset converged and the ordered convergence of multiple cell subsets toward an older adult homeostasis. These data form a high-dimensional trajectory of immune aging (IMM-AGE) that describes a person's immune status better than chronological age. We show that the IMM-AGE score predicted all-cause mortality beyond well-established risk factors in the Framingham Heart Study, establishing its potential use in clinics for identification of patients at risk.
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Effects of Dietary Protein and Fat Content on Intrahepatocellular and Intramyocellular Lipids during a 6-Day Hypercaloric, High Sucrose Diet: A Randomized Controlled Trial in Normal Weight Healthy Subjects.
Surowska, A, Jegatheesan, P, Campos, V, Marques, AS, Egli, L, Cros, J, Rosset, R, Lecoultre, V, Kreis, R, Boesch, C, et al
Nutrients. 2019;11(1)
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High sugar diets can lead to increased fat accumulation in the liver and skeletal muscles, as intrahepatocellular lipid (IHCL) and intramyocellular lipid (IMCL) respectively. Elevation in these lipid concentrations is associated with an increased risk of various chronic diseases. The aim of this randomised crossover trial was to assess whether the consequences of a high sugar diet differed according to the protein and fat composition in 12 healthy adults. At the beginning of each trial period, participants consumed a 3-day weight maintenance diet followed by a 6-day high calorie, high sugar diet consisting of either low protein-high fat or high protein-low fat with a 4-8 week washout period. IHCL and IMCL concentrations, energy expenditure and blood metabolites were monitored after each weight maintenance diet and after each 6-day intervention diet period. This study found that both diets led to increased lipid concentrations, most notably the in liver cells. Lipid increases induced by the high protein-low fat diet were significantly lower than those induced by the low protein-high fat diet. Based on these results, the authors conclude that when overfed on a high sugar diet, high protein-low fat markedly reduces the amount of fat accumulation in liver and muscle cells and suggest that either dietary protein may have a protective effect of sugar and fat may have an additive adverse effect.
Abstract
Sucrose overfeeding increases intrahepatocellular (IHCL) and intramyocellular (IMCL) lipid concentrations in healthy subjects. We hypothesized that these effects would be modulated by diet protein/fat content. Twelve healthy men and women were studied on two occasions in a randomized, cross-over trial. On each occasion, they received a 3-day 12% protein weight maintenance diet (WM) followed by a 6-day hypercaloric high sucrose diet (150% energy requirements). On one occasion the hypercaloric diet contained 5% protein and 25% fat (low protein-high fat, LP-HF), on the other occasion it contained 20% protein and 10% fat (high protein-low fat, HP-LF). IHCL and IMCL concentrations (magnetic resonance spectroscopy) and energy expenditure (indirect calorimetry) were measured after WM, and again after HP-LF/LP-HF. IHCL increased from 25.0 ± 3.6 after WM to 147.1 ± 26.9 mmol/kg wet weight (ww) after LP-HF and from 30.3 ± 7.7 to 57.8 ± 14.8 after HP-LF (two-way ANOVA with interaction: p < 0.001 overfeeding x protein/fat content). IMCL increased from 7.1 ± 0.6 to 8.8 ± 0.7 mmol/kg ww after LP-HF and from 6.2 ± 0.6 to 6.9 ± 0.6 after HP-LF, (p < 0.002). These results indicate that liver and muscle fat deposition is enhanced when sucrose overfeeding is associated with a low protein, high fat diet compared to a high protein, low fat diet.
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Carbohydrate restriction with postmeal walking effectively mitigates postprandial hyperglycemia and improves endothelial function in type 2 diabetes.
Francois, ME, Myette-Cote, E, Bammert, TD, Durrer, C, Neudorf, H, DeSouza, CA, Little, JP
American journal of physiology. Heart and circulatory physiology. 2018;314(1):H105-H113
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Prevention of cardiovascular disease in individuals with type 2 diabetes (T2D) is a major treatment goal. Within this, diet and exercise remain the cornerstone lifestyle therapies. The aim of this study was to examine the effects of 4 days of a low-carbohydrate diet, with or without daily post-meal walking, on vascular health in individuals with T2D. The study recruited sixteen individuals with physician-diagnosed T2D to complete 3 short-term controlled intervention periods in a randomised crossover design. Results indicate that attenuating postprandial hyperglycaemia (a very high rise in blood sugar following a meal) by restricting carbohydrates and post-meal walking can improve vascular health in individuals with T2D. Authors conclude that carbohydrate restriction and post-meal exercise may represent an effective strategy to mitigate the negative effects of postprandial hyperglycaemia and reduce cardiovascular disease risk in individuals with T2D.
Abstract
Postprandial hyperglycemia has deleterious effects on endothelial function. Restricting carbohydrate intake and postmeal walking have each been shown to reduce postprandial hyperglycemia, but their combination and subsequent effects on endothelial function have not been investigated. Here, we sought to examine the effect of blunting postprandial hyperglycemia by following a low-carbohydrate diet, with or without postmeal walking exercise, on markers of vascular health in type 2 diabetes (T2D). In a randomized crossover design, individuals with T2D ( n = 11) completed three 4-day controlled diet interventions consisting of 1) low-carbohydrate diet alone (LC), 2) low-carbohydrate diet with 15-min postmeal walks (LC + Ex), and 3) low-fat control diet (CON). Fasting blood samples and brachial artery flow-mediated dilation (%FMD) were measured before and after each intervention. Total circulating microparticles (MPs), endothelial MPs, platelet MPs, monocyte-platelet aggregates, and adhesion molecules were assessed as biomarkers of vascular health. There was a significant condition × time interaction for %FMD ( P = 0.01), with post hoc tests revealing improved %FMD after LC + Ex (+0.8 ± 1.0%, P = 0.02), with no change after LC or CON. Endothelial MPs were significantly reduced with the LC diet by ~45% (from 99 ± 60 to 44 ± 31 MPs/μl, P = 0.02), with no change after LC + Ex or CON (interaction: P = 0.04). Total MPs were lower (main effect time: P = 0.02), whereas monocyte-platelet aggregates were higher (main effect time: P < 0.01) after all interventions. Plasma adhesion molecules and C-reactive protein were unaltered. Attenuating postprandial hyperglycemic excursions using a low-carbohydrate diet combined with postmeal walking appears to be an effective strategy to improve endothelial function in individuals with T2D. NEW & NOTEWORTHY Carbohydrate restriction and postmeal walking lower postprandial hyperglycemia in individuals with type 2 diabetes. Here, we show that the combination significantly improved endothelial function and that carbohydrate restriction alone reduced circulating endothelial microparticles in individuals with type 2 diabetes. Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/low-carb-diet-and-exercise-improve-endothelial-health/ .
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Vitamin D supplementation for the prevention of type 2 diabetes in overweight adults: study protocol for a randomized controlled trial.
de Courten, B, Mousa, A, Naderpoor, N, Teede, H, de Courten, MP, Scragg, R
Trials. 2015;16:335
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With the rising rates of vitamin D deficiency, identifying cost-effective, preventative strategies are imperative. Vitamin D plays a well-known role in bone mineralisation, however its protective role against chronic diseases is not very well understood. The aim of this trial is to investigate whether vitamin D supplementation will increase insulin sensitivity and secretion, as well as to determine whether vitamin D deficiency underlies the inflammatory properties associated with obesity. 50 overweight adults between 18 and 60 years old were recruited and assigned to receive either 4,000 IU vitamin D daily or identical placebo capsules for 16 weeks. This study elucidates the potential role vitamin D supplementation could have on preventing diabetes and its associated co-morbidities. It also provides comprehensive insight into the potential mechanisms of action. The authors conclude that this trial can corroborate existing knowledge while expanding the understanding on the role of vitamin D in the inflammatory response and subsequent development of disease.
Abstract
BACKGROUND Despite Australia's sunny climate, low vitamin D levels are increasingly prevalent. Sun exposure is limited by long working hours, an increase in time spent indoors, and sun protection practices, and there is limited dietary vitamin D fortification. While the importance of vitamin D for bone mineralization is well known, its role as a protective agent against chronic diseases, such as type 2 diabetes and cardiovascular disease, is less understood. Observational and limited intervention studies suggest that vitamin D might improve insulin sensitivity and secretion, mainly via its anti-inflammatory properties, thereby decreasing the risk of development and progression of type 2 diabetes. The primary aim of this trial is to investigate whether improved plasma concentrations of 25-hydroxyvitamin D (25(OH)D), obtained through vitamin D supplementation, will increase insulin sensitivity and insulin secretion. A secondary aim is to determine whether these relationships are mediated by a reduction in underlying subclinical inflammation associated with obesity. METHODS/DESIGN Fifty overweight but otherwise healthy nondiabetic adults between 18 and 60 years old, with low vitamin D levels (25(OH)D < 50 nmol/l), will be randomly assigned to intervention or placebo. At baseline, participants will undergo a medical review and anthropometric measurements, including dual X-ray absorptiometry, an intravenous glucose tolerance test, muscle and fat biopsies, a hyperinsulinemic euglycemic clamp, and questionnaires assessing diet, physical activity, sun exposure, back and knee pain, and depression. The intervention group will receive a first dose of 100,000 IU followed by 4,000 IU vitamin D (cholecalciferol) daily, while the placebo group will receive apparently identical capsules, both for a period of 16 weeks. All measurements will be repeated at follow-up, with the primary outcome measure expressed as a change from baseline in insulin sensitivity and secretion for the intervention group compared with the placebo group. Secondary outcome measures will compare changes in anthropometry, cardiovascular risk factors, and inflammatory markers. DISCUSSION The trial will provide much needed clinical evidence on the impact of vitamin D supplementation on insulin resistance and secretion and its underlying mechanisms, which are relevant for the prevention and management of type 2 diabetes. TRIAL REGISTRATION Clinicaltrials.gov ID: NCT02112721 .