Exercise in the Metabolic Syndrome

Diabetes, 2012

Fat accumulation in skeletal muscle combined with low mitochondrial oxidative capacity is associated with insulin resistance (IR). Endurance-trained athletes, characterized by a high oxidative capacity, have elevated intramyocellular lipids, yet are highly insulin sensitive. We tested the hypothesis that a high oxidative capacity could attenuate lipid-induced IR. Nine endurance-trained (age = 23.4 6 0.9 years; BMI = 21.2 6 0.6 kg/m 2 ) and 10 untrained subjects (age = 21.9 6 0.9 years; BMI = 22.8 6 0.6 kg/m 2 ) were included and underwent a clamp with either infusion of glycerol or intralipid. Muscle biopsies were taken to perform high-resolution respirometry and protein phosphorylation/expression. Trained subjects had ;32% higher mitochondrial capacity and ;22% higher insulin sensitivity (P , 0.05 for both). Lipid infusion reduced insulin-stimulated glucose uptake by 63% in untrained subjects (P , 0.05), whereas this effect was blunted in trained subjects (29%, P , 0.05). In untrained subjects, lipid infusion reduced oxidative and nonoxidative glucose disposal (NOGD), whereas trained subjects were completely protected against lipid-induced reduction in NOGD, supported by dephosphorylation of glycogen synthase. We conclude that chronic exercise training attenuates lipid-induced IR and specifically attenuates the lipid-induced reduction in NOGD. Signaling data support the notion that high glucose uptake in trained subjects is maintained by shuttling glucose toward storage as glycogen. Diabetes 61: [2472][2473][2474][2475][2476][2477][2478] 2012 F at accumulation in skeletal muscle strongly associates with the development of muscle insulin resistance (IR), the main risk factor in the development of type 2 diabetes (T2D). Indeed, elevated intramyocellular triglycerides (IMTGs) are associated with obesity and T2D (1-6). However, the question of why triglycerides accumulate in skeletal muscle has not been answered yet. In recent years, mitochondrial dysfunction has received large attention as a putative candidate underlying IMTG accumulation and thereby the development of IR. Several studies showed compromised in vivo and ex vivo mitochondrial function as a contributor to the development of IR and T2D (7-11). Studies have indicated that intrinsic mitochondrial function (i.e., respiratory capacity per mitochondria) (10-12) as well as mitochondrial content is reduced in T2D and in first-degree relatives. However, whether mitochondrial function and content are important in the prevention of lipid-induced muscular fat accumulation and IR has not been firmly established.

2012

The metabolic syndrome (MS) recognized as a major cause of type 2 diabetes and cardiovascular diseases, has become one of the major public health challenges worldwide. The pathogenesis of the metabolic syndrome is multiple and still poorly understood. No single factor has yet been identified as an underlying causal factor. There is a growing belief, however, that obesity, specially visceral obesity, may play an important role in the development of the syndrome. Visceral adiposity seems to be an independent predictor of insulin sensitivity, impaired glucose tolerance, dyslipidaemia and elevated blood pressure. An increasing number of studies confirm that oxidative stress, chronic inflammation and angiogenesis all play important roles in the pathogenesis of MS. Chronic hyperglycemia causes oxidative stress in tissues prone to complications in patients with diabetes. Oxidative stress occurs in a cellular system when the production of free radical moieties exceeds the antioxidant capacity of that system. If cellular antioxidants do not remove free radicals, radicals attack and damage proteins, lipids, and nucleic acids. The oxidized or nitrosylated products of free radical attack have decreased biological activity, leading to loss of energy metabolism, cell signaling, transport, and other major functions. These altered products are also targeted for proteosome degradation, further decreasing cellular function. Accumulation of such injury ultimately leads a cell to die through necrotic or apoptotic mechanisms.In conclusion, a puzzle of many pieces of evidence suggests that free radical overgeneration may be considered the key in the generation of insulin resistance, diabetes, and cardiovascular disease.

International Journal of Molecular Sciences

Metabolic syndrome is a cluster of conditions associated with the risk of diabetes mellitus type 2 and cardiovascular diseases (CVDs). Metabolic syndrome is closely related to obesity. Increased adiposity promotes inflammation and oxidative stress, which are precursors of various complications involving metabolic syndrome components, namely insulin resistance, hypertension, and hyperlipidemia. An increasing number of studies confirm the importance of oxidative stress and chronic inflammation in the etiology of metabolic syndrome. However, few studies have reviewed the mechanisms underlying the role of oxidative stress in contributing to metabolic syndrome. In this review, we highlight mechanisms by which reactive oxygen species (ROS) increase mitochondrial dysfunction, protein damage, lipid peroxidation, and impair antioxidant function in metabolic syndrome. Biomarkers of oxidative stress can be used in disease diagnosis and evaluation of severity.

Current Opinion in Physiology, 2019

Exercise is a powerful means to maintain health, prevent disease, and even act as medicine for a wide range of noncommunicable diseases. The key effects by which exercise benefits our metabolic health include (i) events that occur during exercise and in the hours to days following exercise, and (ii) the adaptations that occur following long-term repeated exercise training. Here, we provide a contemporary overview of recent significant advances in our knowledge of exercise as medicine in metabolic disease with a focus on muscle glucose metabolism.

Current diabetes reports, 2017

Oxidative stress describes an imbalance between production and degradation of reactive oxygen species (ROS), which can damage macromolecules. However, ROS may also serve as signaling molecules activating cellular pathways involved in cell proliferation and adaptation. This review describes alterations in metabolic diseases including obesity, insulin resistance, and/or diabetes mellitus as well as responses to acute and chronic physical exercise. Chronic upregulation of oxidative stress associates with the development of insulin resistance and type 2 diabetes (T2D). While single bouts of exercise can transiently induce oxidative stress, chronic exercise promotes favorable oxidative adaptations with improvements in muscle mitochondrial biogenesis and glucose uptake. Although impaired antioxidant defense fails to scavenge ROS in metabolic diseases, chronic exercising can restore this abnormality. The different metabolic effects are likely due to variability of reactive species and disc...

Clinical Science, 2009

It is now widely accepted that hypertension and endothelial dysfunction are associated with an insulin-resistant state and thus with the development of T2DM (Type 2 diabetes mellitus). Insulin signalling is impaired in target cells and tissues, indicating that common molecular signals are involved. The free radical NO ᭹ regulates cell metabolism, insulin signalling and secretion, vascular tone, neurotransmission and immune system function. NO ᭹ synthesis is essential for vasodilation, the maintenance of blood pressure and glucose uptake and, thus, if levels of NO ᭹ are decreased, insulin resistance and hypertension will result. Decreased blood levels of insulin, increased AngII (angiotensin II), hyperhomocysteinaemia, increased ADMA (asymmetric ω-N G ,N G -dimethylarginine) and low plasma L-arginine are all conditions likely to decrease NO ᭹ production and which are associated with diabetes and cardiovascular disease. We suggest in the present article that the widely reported beneficial effects of exercise in the improvement of metabolic and cardiovascular health are mediated by enhancing the flux of muscle-and kidney-derived amino acids to pancreatic and vascular endothelial cells aiding the intracellular production of NO ᭹ , therefore resulting in normalization of insulin secretion, vascular tone and insulin sensitivity. Exercise may also have an impact on AngII and ADMA signalling and the production of pro-and anti-inflammatory cytokines in muscle, so reducing the progression and development of vascular disease and diabetes. NO ᭹ synthesis will be increased during exercise in the vascular endothelial cells so promoting blood flow. We suggest that exercise may promote improvements in health due to positive metabolic and cytokine-mediated effects.

Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy

Background: Aerobic exercise can greatly assist in reducing collateral effects of metabolic syndrome (MetS). Moreover, aerobic exercise is associated with sympathetic activation and adaptive responses to sustain muscle engagement, changes in the release of Orexin A, a pleiotropic neuropeptide. Aim: The aim of this study was to analyze the beneficial effects of aerobic exercise without dietary changes, in a cohort of MetS subjects, focusing on the role of sympathetic and orexinergic activity. Several blood parameters linked to MetS ROS production, heart rate, galvanic skin response, d-ROM test, and Orexin A serum levels were evaluated in ten males with MetS (BMI 30-34.9) before and after a period of 6 months of aerobic exercise compared to ten healthy subjects. Methods: Ten male subjects (aged 54 ± 4.16) with MetS (MetS group) and ten healthy males (aged 49.7 ± 2.79, Healthy group) were told about the study protocol and possible risks, signed the informed consent, and voluntarily participated in the study. Several blood parameters were evaluated in the two tested groups and were re-evaluated in the MetS group after 6 months of training (MetS6M group). The training protocol consisted of more than 30 min/day of walking (average speed of 4.5 km/h) and 3 days/week of aerobic activities (jogging under heart rate control-120-140 bpm for 45 min). Results: The results showed that exercise induced a significant increase in GSR and plasma Orexin A but no significant increase in d-ROM values. Significant decreases in the serum ALT enzyme, triglycerides, and total cholesterol were found, while the HDL levels were significantly higher. Finally, a significant reduction of BMI and resting HR were reported. Conclusion: The results of this study confirm that physical activity is associated with sympathetic activation, having a pivotal role against adverse effects linked to MetS. Moreover, this study demonstrates that, in patients with MetS, Orexin A is involved in hormonal adaptations to exercise.

Journal of Human Sport and Exercise - 2020 - Spring Conferences of Sports Science, 2020

Obesity is a long-term multifactorial chronic disease, characterized by energy imbalance, due to an excess of caloric intake compared to energy expenditure and deregulation of other metabolic parameters, as, altered lipid profile, increased insulin resistance and chronic pro-inflammatory state. A healthy lifestyle, characterized by hypocaloric diet and physical activity, is important to reduce a chronic inflammation, oxidative stress and metabolic disorders typical of obesity. It is well known that the chronic inflammation state and oxidative stress are responsible for the aging and development of many diseases, such as cancer. In the light of these evidences, the aim of this study is to analyse body composition, metabolic profile and oxidative stress levels in obese patients subjected to a physical activity program before and after weight loss. We analysed the glycaemic and lipid profile, body composition such as visceral adipose tissue (VAT), fat mass (FM), and the dROMs serum levels via the Fenton's reaction. We found that in obese patients before physical activity intervention there are higher levels in dROMs serum levels, altered glycaemic and lipid profile and body composition compared to obese patients after physical activity intervention. In conclusion, the physical activity has numerous beneficial effects in obesity, modulating not only metabolic profile but also inflammatory and oxidative stress response.

Sports Medicine, 2013

Background Numerous meta-analyses have investigated the effect of exercise in different populations and for single cardiovascular risk factors, but none have specifically focused on the metabolic syndrome (MetS) patients and the concomitant effect of exercise on all associated cardiovascular risk factors. Objective The aim of this article was to perform a systematic review with a meta-analysis of randomized and clinical controlled trials (RCTs, CTs) investigating the effect of exercise on cardiovascular risk factors in patients with the MetS. Methods RCTs and CTs C4 weeks investigating the effect of exercise in healthy adults with the MetS and published in a peer-reviewed journal up to November 2011 were included. Primary outcome measures were changes in waist circumference (WC), systolic and diastolic blood pressure, high-density lipoprotein cholesterol (HDL-C), triglycerides and fasting plasma glucose. Peak oxygen uptake ( _ VO 2peak ) was a secondary outcome. Random and fixed-effect models were used for analyses and data are reported as means and 95% confidence intervals (CIs). Results Seven trials were included, involving nine study groups and 206 participants (128 in exercise group and 78 in control group). Significant mean reductions in WC -3.4 (95% CI -4.9, -1.8) cm, blood pressure -7.1 (95% CI -9.03, -5.2)/-5.2 (95% CI -6.2, -4.1) mmHg and a significant mean increase in HDL-C ?0.06 (95% CI ?0.03, ?0.09) mmol/L were observed after dynamic endurance training. Mean plasma glucose levels -0.31 (95% CI -0.64, 0.01; p = 0.06) mmol/L and triglycerides -0.05 (95% CI -0.20, 0.09; p = 0.47) mmol/L remained statistically unaltered. In addition, a significant mean improvement in _ VO 2peak of ?5.9 (95% CI ?3.03, ?8.7) mL/kg/min or 19.3% was found. Conclusions Our results suggest that dynamic endurance training has a favourable effect on most of the cardiovascular risk factors associated with the MetS. However, in the search for training programmes that optimally improve total cardiovascular risk, further research is warranted, including studies on the effects of resistance training and combined resistance and endurance training. N. Pattyn and V. A. Cornelissen are joint first authors. N. Pattyn (&) Á V. A. Cornelissen Á S. R. T. Eshghi Á L. Vanhees

Sports Medicine - Open, 2015

Obesity-related oxidative stress, the imbalance between pro-oxidants and antioxidants (e.g., nitric oxide), has been linked to metabolic and cardiovascular disease, including endothelial dysfunction and atherosclerosis. Reactive oxygen species (ROS) are essential for physiological functions including gene expression, cellular growth, infection defense, and modulating endothelial function. However, elevated ROS and/or diminished antioxidant capacity leading to oxidative stress can lead to dysfunction. Physical activity also results in an acute state of oxidative stress. However, it is likely that chronic physical activity provides a stimulus for favorable oxidative adaptations and enhanced physiological performance and physical health, although distinct responses between aerobic and anaerobic activities warrant further investigation. Studies support the benefits of dietary modification as well as exercise interventions in alleviating oxidative stress susceptibility. Since obese individuals tend to demonstrate elevated markers of oxidative stress, the implications for this population are significant. Therefore, in this review our aim is to discuss (i) the role of oxidative stress and inflammation as associated with obesity-related diseases, (ii) the potential concerns and benefits of exercise-mediated oxidative stress, and (iii) the advantageous role of dietary modification, including acute or chronic caloric restriction and vitamin D supplementation.

Diabetes Care, 2013

OBJECTIVEdSystemic oxidative stress is associated with insulin resistance and obesity. We tested the hypothesis that systemic oxidative stress is linked to lower aerobic capacity and skeletal muscle dysfunction in metabolic syndrome (MetS).

Nutrition & Diabetes, 2013

BACKGROUND: Obesity is associated with low-grade systemic inflammation, in part because of secretion of proinflammatory cytokines, resulting into peripheral insulin resistance (IR). Increased oxidative stress is proposed to link adiposity and chronic inflammation. The effects of endurance exercise in modulating these outcomes in insulin-resistant obese adults remain unclear. We investigated the effect of endurance exercise on markers of oxidative damage (4-hydroxy-2-nonenal (4-HNE), protein carbonyls (PCs)) and antioxidant enzymes (superoxide dismutase (SOD), catalase) in skeletal muscle; urinary markers of oxidative stress (8-hydroxy-2-deoxyguanosine (8-OHdG), 8-isoprostane); and plasma cytokines (C-reactive protein (CRP), interleukin-6 (IL-6), leptin, adiponectin). METHODS: Age-and fitness-matched sedentary obese and lean men (n ¼ 9 per group) underwent 3 months of moderate-intensity endurance cycling training with a vastus lateralis biopsy, 24-h urine sample and venous blood samples taken before and after the intervention. RESULTS: Obese subjects had increased levels of oxidative damage: 4-HNE ( þ 37%; Pp0.03) and PC ( þ 63%; Pp0.02); evidence of increased adaptive response to oxidative stress because of elevated levels of copper/zinc SOD (Cu/ZnSOD) protein content ( þ 84%; Pp0.01); increased markers of inflammation: CRP ( þ 737%; Pp0.0001) and IL-6 ( þ 85%; Pp0.03), and these correlated with increased markers of obesity; and increased leptin ( þ 262%; Pp0.0001) with lower adiponectin ( À 27%; Pp0.01) levels vs lean controls. Training reduced 4-HNE ( À 10%; Pp0.04), PC ( À 21%; Pp0.05), 8-isoprostane ( À 26%; Pp0.02) and leptin levels ( À 33%; Pp0.01); had a tendency to decrease IL-6 levels ( À 21%; P ¼ 0.07) and IR ( À 17%; P ¼ 0.10); and increased manganese SOD (MnSOD) levels ( þ 47%; Pp0.01). CONCLUSION: Endurance exercise reduced skeletal muscle-specific and systemic oxidative damage while improving IR and cytokine profile associated with obesity, independent of weight loss. Hence, exercise is a useful therapeutic modality to reduce risk factors associated with the pathogenesis of IR in obesity.

International Journal of Cardiology, 2012

Antioxidants

Excess epicardial adiposity, within a state of obesity and metabolic syndrome, is emerging as an important risk factor for the development of cardiovascular diseases (CVDs). Accordingly, increased epicardial fat thickness (EFT) implicates the exacerbation of pathological mechanisms involving oxidative stress and inflammation within the heart, which may accelerate the development of CVDs. This explains increased interest in targeting EFT reduction to attenuate the detrimental effects of oxidative stress and inflammation within the setting of metabolic syndrome. Here, we critically discuss clinical and preclinical evidence on the impact of physical exercise on EFT in correlation with reduced CVD risk within a setting of metabolic disease. This review also brings a unique perspective on the implications of oxidative stress and inflammation as major pathological consequences that link increased EFT to accelerated CVD risk in conditions of metabolic disease.

Experimental Diabetes Research, 2012

Diabetes is a chronic metabolic disease which is characterized by absolute or relative deficiencies in insulin secretion and/or insulin action. The key roles of oxidative stress and inflammation in the progression of vascular complications of this disease are well recognized. Accumulating epidemiologic evidence confirms that physical inactivity is an independent risk factor for insulin resistance and type II diabetes. This paper briefly reviews the pathophysiological pathways associated with oxidative stress and inflammation in diabetes mellitus and then discusses the impact of exercise on these systems. In this regard, we discuss exercise induced activation of cellular antioxidant systems through "nuclear factor erythroid 2-related factor." We also discuss anti-inflammatory myokines, which are produced and released by contracting muscle fibers. Antiapoptotic, anti-inflammatory and chaperon effects of exercise-induced heat shock proteins are also reviewed.