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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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Diverging metabolic effects of 2 energy-restricted diets differing in nutrient quality: a 12-week randomized controlled trial in subjects with abdominal obesity.
Schutte, S, Esser, D, Siebelink, E, Michielsen, CJR, Daanje, M, Matualatupauw, JC, Boshuizen, HC, Mensink, M, Afman, LA
The American journal of clinical nutrition. 2022;116(1):132-150
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Energy restriction (ER) diets are considered an effective strategy for managing obesity and preventing or reducing the risk of associated comorbidities. However, there are very few previous studies comparing the quality of energy restriction diets and their effect on maximising the health benefits. Therefore, this 12-week, parallel-designed, randomised controlled trial compared the effects of a 25% high-quality ER diet with a 25% low-quality ER diet and a habitual diet on cardiometabolic risk factors of 110 participants with abdominal obesity. Both ER diets were nutritionally balanced. The high-quality ER diet had added Monounsaturated fatty acids (MUFAs), Omega-3 Polyunsaturated fatty acids (n-3 PUFAs), fibre, and plant protein and had less fructose in it. The low-quality ER diet contained Saturated fatty acids (SFAs) and monosaccharides such as fructose. At the end of the 12-week trial, participants on the 25% high-quality diet showed more promising results in weight loss, reduction in cholesterol and triglycerides, and adipose tissue gene expression of energy metabolism pathways compared to the 25% low-quality ER diet. Insulin-sensitive participants with abdominal obesity on a 25% high-quality diet lost more weight compared to the rest of the participants. Further robust studies are required to evaluate the findings due to the limitations of this study. However, healthcare professionals can use the results of this study to understand the beneficial effects of an ER diet when it is enriched with specific nutrients.
Abstract
BACKGROUND Despite the established relation between energy restriction (ER) and metabolic health, the most beneficial nutrient composition of a weight-loss diet is still a subject of debate. OBJECTIVES The aim of the study was to examine the additional effects of nutrient quality on top of ER. METHODS A parallel-designed, 12-week 25% ER dietary intervention study was conducted (clinicaltrials.gov: NCT02194504). Participants aged 40-70 years with abdominal obesity were randomized over 3 groups: a 25% ER high-nutrient-quality diet (n = 40); a 25% ER low-nutrient-quality diet (n = 40); or a habitual diet (n = 30). Both ER diets were nutritionally adequate, and the high-nutrient-quality ER diet was enriched in MUFAs, n-3 PUFAs, fiber, and plant protein and reduced in fructose. Before and after the intervention, intrahepatic lipids, body fat distribution, fasting and postprandial responses to a mixed-meal shake challenge test of cardiometabolic risk factors, lipoproteins, vascular measurements, and adipose tissue transcriptome were assessed. RESULTS The high-nutrient-quality ER diet (-8.4 ± 3.2) induced 2.1 kg more weight loss (P = 0.007) than the low-nutrient-quality ER diet (-6.3 ± 3.9), reduced fasting serum total cholesterol (P = 0.014) and plasma triglycerides (P < 0.001), promoted an antiatherogenic lipoprotein profile, and induced a more pronounced decrease in adipose tissue gene expression of energy metabolism pathways than the low-quality ER diet. Explorative analyses showed that the difference in weight loss between the two ER diets was specifically present in insulin-sensitive subjects (HOMA-IR ≤ 2.5), in whom the high-nutrient-quality diet induced 3.9 kg more weight loss than the low-nutrient-quality diet. CONCLUSIONS A high-nutrient-quality 25% ER diet is more beneficial for cardiometabolic health than a low-nutrient-quality 25% ER diet. Overweight, insulin-sensitive subjects may benefit more from a high- than a low-nutrient-quality ER diet with respect to weight loss, due to potential attenuation of glucose-induced lipid synthesis in adipose tissue.
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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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A whole-grain diet reduces peripheral insulin resistance and improves glucose kinetics in obese adults: A randomized-controlled trial.
Malin, SK, Kullman, EL, Scelsi, AR, Haus, JM, Filion, J, Pagadala, MR, Godin, JP, Kochhar, S, Ross, AB, Kirwan, JP
Metabolism: clinical and experimental. 2018;82:111-117
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Literature shows that dietary whole-grain intake is associated with a lower incidence of type 2 diabetes. The aim of the study was to investigate the association between a whole-grain diet and insulin resistance and glucose use in individuals at risk for type 2 diabetes. The study was a randomized, double-blind, controlled crossover trial involving fourteen middle-aged, obese adults at risk for diabetes. Randomisation was carried out prior to metabolic testing. Results indicate that whole-grain intake as part of a mixed-meal diet significantly improved post-prandial (after a meal) glucose metabolism in middle-aged obese adults. Furthermore, both whole-grain and refined-grain interventions induced about 3–6% weight and fat loss. Authors conclude that whole-grain intake effectively promotes glycaemic control by improving insulin action.
Abstract
BACKGROUND Whole-grain intake is associated with lower risk of type 2 diabetes but the mechanisms are unclear. PURPOSE We tested the hypothesis that a WG diet reduces insulin resistance and improves glucose use in individuals at risk for type 2 diabetes compared with an isocaloric-matched refined-grain diet. METHODS A double-blind, randomized, controlled, crossover trial of 14 moderately obese adults (Age, 38 ± 2 y; BMI, 34.0 ± 1.1 kg/m2). Insulin resistance and glucose metabolism was assessed using an oral glucose tolerance test combined with isotopic tracers of [6,6-2H2]-glucose and [U-13C]-glucose, and indirect calorimetry. Peripheral and hepatic insulin resistance was assessed as 1/(rate of disposal/insulin), and endogenous glucose rates of appearance (Ra) iAUC60-240 × insulin iAUC60-240, respectively. Both diets met ADA nutritional guidelines and contained either whole-grain (50 g per 1000 kcal) or equivalent refined-grain. All food was provided for 8 wk. with an 8-10 wk. washout period between diets. RESULTS Post-prandial glucose tolerance, peripheral insulin sensitivity, and metabolic flexibility (insulin-stimulated - fasting carbohydrate oxidation) improvements were greater after whole-grain compared to the refined-grain diet (P < 0.05). Compared to baseline, body fat (~2 kg) and hepatic Ra insulin resistance was reduced by both diets, while fasting glucose and exogenous glucose-meal were unchanged after both interventions. Changes in peripheral insulin resistance and metabolic flexibility correlated with improved glucose tolerance (P < 0.05). CONCLUSION Whole-grains reduced diabetes risk and the mechanisms appear to work through reduced post-prandial blood glucose and peripheral insulin resistance that were statistically linked to enhanced metabolic flexibility.
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The Effect of a Diet Moderately High in Protein and Fiber on Insulin Sensitivity Measured Using the Dynamic Insulin Sensitivity and Secretion Test (DISST).
Te Morenga, L, Docherty, P, Williams, S, Mann, J
Nutrients. 2017;9(12)
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The protein, fat and carbohydrate composition of diets can modify heart function abnormalities associated with insulin resistance (when cells in the muscles, fat, and liver do not respond well to insulin and cannot easily take up glucose from the blood) and therefore reduce the risk of diabetes. The aim of the study was to examine the effect of a reduced carbohydrate diet that was high in both protein and dietary fibre on insulin sensitivity and insulin secretion in overweight and obese women at risk of diabetes, independent of weight loss. The study is a randomised control trial which recruited 89 women at risk of diabetes. The participants were randomly assigned to either a standard diet or a relatively high protein and fibre diet group for a period of 10 weeks. Results indicate that a modest increase in consumption of dietary protein and fibre, without emphasis on energy reduction, improved several cardiometabolic risk factors in overweight women. There were modest reductions in body mass, total body fat and central body fat, without loss of lean mass and improvements in total serum and low-density lipoprotein cholesterol levels. Authors conclude that the heart function benefits achieved with moderate increases to fibre and protein, support the use of this dietary approach for overweight individuals at risk of diabetes.
Abstract
Evidence shows that weight loss improves insulin sensitivity but few studies have examined the effect of macronutrient composition independently of weight loss on direct measures of insulin sensitivity. We randomised 89 overweight or obese women to either a standard diet (StdD), that was intended to be low in fat and relatively high in carbohydrate (n = 42) or to a relatively high protein (up to 30% of energy), relatively high fibre (>30 g/day) diet (HPHFib) (n = 47) for 10 weeks. Advice regarding strict adherence to energy intake goals was not given. Insulin sensitivity and secretion was assessed by a novel method-the Dynamic Insulin Sensitivity and Secretion Test (DISST). Although there were significant improvements in body composition and most cardiometabolic risk factors on HPHFib, insulin sensitivity was reduced by 19.3% (95% CI: 31.8%, 4.5%; p = 0.013) in comparison with StdD. We conclude that the reduction in insulin sensitivity after a diet relatively high in both protein and fibre, despite cardiometabolic improvements, suggests insulin sensitivity may reflect metabolic adaptations to dietary composition for maintenance of glucose homeostasis, rather than impaired metabolism.
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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 .