Oxidative stress and insulin action: is there a relationship? G. Paolisso, D. Giugliano. Department of Geriatric Medicine and Metabolic Diseases, Second. resistance to the action of insulin.7 Insulin resistance is an important component of .. The Possible Link Between Oxidative Stress and. Inflammation in Insulin. Anthropometric parameters, IR, and oxidative stress were analyzed before and Also, it was observed that concurrent training, depending on the frequency, . relationship between oxidative stress and insulin action [36–38].Signal Transduction Pathways
On the other hand, in conditions such as obesity, MetS, and T2DM, chronic inflammation induces changes in metabolic function and alters homoeostatic set points, which exacerbate the disease. For instance, the link between the metabolic disturbances, such as high lipid profile and development of atherosclerosis, was first demonstrated in and classified as a catastrophic disease [ 16 ]. However, the relationship between obesity and T2DM was only illustrated in vivo twenty years later, in [ 17 ].
Oxidative stress and insulin action: is there a relationship?
In normal conditions, binding of insulin to the IR induces the production of triacylglycerols from diet-derived fatty acids and glucose-derived glycerol 3-phosphate. Therefore, insulin promotes a simultaneous uptake of lipids and glucose into adipose tissue in vivo.
Any impairment of these interactions will lead to a surplus of circulating glucose and fatty acids, which is predominantly observed in T2DM. Conversely, in periods of fasting, starvation, and strenuous exercise, adipose tissue will release nonesterified fatty acids NEFAs and glycerol into the vasculature, under the action of various lipases to replenish the plasma nutrient levels and spare glucose for brain function in these conditions. The adipose tissue is also able to synthesise and releases adipokines into the circulation, including leptin and adiponectin.
Leptin was demonstrated to modulate satiety and energy balance, an effect dependent on neuroendocrine signalling in the hypothalamus [ 19 ]. Similarly, adiponectin was shown to promote insulin sensitivity, and mice with adiponectin-deficiency are highly insulin resistant [ 20 ]. In addition, elevated basal adiponectin levels may be associated with a reduced risk of T2DM [ 21 ]. Therefore, adipokines are considered to modulate insulin sensitivity in the key insulin target organs, including liver and skeletal muscle.
However, in chronic expansion of adipose tissue, low-grade inflammation occurs with consequent infiltration of immune cells that can lead to a reduction in adipokine secretion, subsequently resulting in systemic insulin resistance. The Role of Unresolved Inflammation in Extrapancreatic Periphery Macrophage accumulation in obese adipose tissue is common, and here they secrete proinflammatory cytokines that modulate adipose tissue glucose and lipid metabolism [ 20 ].
Consequently, these effects would encourage increased plasma lipid levels, against the backdrop of reduced lipid disposal by adipose tissue, which perpetuates lipotoxicity in the T2DM condition. Increasing plasma concentrations of NEFA and ceramide are important in connecting nutrient metabolism with inflammation.
A follow-up study demonstrated that both glucose and minimally modified low density lipoprotein mmLDLboth of which are elevated in T2DM [ 25 ], were required for full IAPP-mediated activation of NLRP3 inflammasomes in bone marrow-derived macrophages. Furthermore, Toll-Like Receptor-4 TLR4 downstream pathways were found to be critical for transducing these signals [ 24 ].
The Central Role of Infiltrating Macrophages The activation status of infiltrating macrophages is important in the progression of metabolic diseases. Two different polarisation states, M1 proinflammatory and M2 anti-inflammatoryhave been characterised so far.
Conversely, the M2 anti-inflammatory phenotype has significantly reduced proinflammatory characteristics, and these cells release high levels of anti-inflammatory cytokines, for instance, IL Interestingly, ingestion of a diet high in lipid content was shown to polarise Kupffer cells of the liver towards the M1 phenotype [ 26 ].
These cells are resident macrophages of the liver and this polarisation was associated with the pathogenesis of obesity-induced insulin resistance and fatty liver disease [ 26 ]. However, there is a heterogeneous population of immune cells in the liver, but Kupffer cells, in particular, are believed to facilitate both insulin resistance and hepatic steatosis and steatohepatitis, which are associated with increased c-Jun N-terminal protein kinase JNK1 activation and consequent lowering of heat shock protein HSP pathways, which are anti-inflammatory [ 27 ].
Interestingly, chemical removal of these cells can improve insulin sensitivity during consumption of a high-fat diet. Therefore, the delicate balance and adaptability of macrophages between M1 and M2 phenotypes are important to liver metabolism. Consequently, maintenance of the M2 phenotype over M1 phenotype is desirable in the liver and key for appropriate glucose and lipid production along with subsequent release. Taken together, these data suggested that the high nutrient milieu observed in T2DM may activate circulating macrophages that could possibly lead to chronic low-grade inflammation, which is a hallmark of obesity and T2DM.
Moreover, interactions of macrophages and production of proinflammatory cytokines can negatively affect metabolic processes in tissues that are physiological targets for insulin.
These inflammatory exchanges may lead to hyperglycaemia and dyslipidaemia, which are important characteristics indicative of obesity, T2DM, and MetS. Impaired Insulin-Signalling Pathways Insulin resistance does play a key role in the pathogenesis and progression of chronic metabolic diseases that are proinflammatory in nature, such as obesity, T2DM, brain dysfunction, and heart disease [ 28 ].
Insulin resistance is an important health issue since it flourishes silently much before the onset of such metabolic manifestations [ 1529 ]. Insulin resistance refers to impaired or failed intracellular transduction of the insulin-mediated signalling cascade in sensitive tissues, especially the liver, skeletal muscle, and adipose tissue.
This leads to an impaired disposal of blood glucose along with an elevated hepatic glucose output, both combining to result in elevated plasma glucose. However, insulin sensitivity can be improved using pharmacological drugs, control of diet, and regular exercise [ 30 ].
To investigate the mechanisms leading to insulin resistance, one must first understand insulin signalling in the context of normal insulin-mediated interactions that are observed in nondiabetic models.
Insulin elicits its anabolic effects via association with the transmembrane IR, present in target tissues. These key membrane-bound receptors are present in cells that store surplus carbohydrate in the form of glycogen liver and muscle or as triacylglycerol adipose tissue. The interaction with insulin induces autophosphorylation of the receptor at tyrosine residues Tyr, Tyr, and Tyr [ 31 ], and this initiates the recruitment and phosphorylation of the intracellular adapter proteins IRS.
This conversion activates 3-phosphoinositide-dependent protein kinase 1 PDK1 that subsequently recruits and phosphorylates protein kinase B pAkt at the plasma membrane.
Downstream of these interactions, pAkt has over substrates that regulate many cellular processes including cell proliferation, differentiation, endocytosis, survival, and glucose homeostasis [ 35 ]. Three isoforms of Akt exist, and Akt2 is recognised as the most abundant in insulin sensitive tissues.
Interestingly, when Akt2 was deleted in knockout mice, increased insulin resistance was observed illustrating the important physiological role played by Akt2 in mediating glucose homeostasis [ 36 ]. Mechanistically, Akt is an important regulator of translocation of GLUT4 vesicles to the plasma membrane, which is critical for the intracellular uptake of free glucose in insulin sensitive tissues [ 3738 ].
Appropriate insulin signalling may be interrupted because of either genetic alterations or physical changes to any of the aforementioned signalling nodes, and this may manifest as insulin resistance.
Mutations and serine hyperphosphorylation of IRS proteins are especially associated with development of insulin resistance, as they are thought to decrease the interaction of IRS with PI3K reviewed by [ 39 ]. Previously, homozygous disruption of IRS1 transcription led to mild insulin resistance [ 40 ], while IRS2-knockout mice exhibited severe insulin resistance [ 41 ].
Furthermore, in T2DM patients, many precise amino acid substitutions in IRS1 proteins are believed to alter protein function, but some of these substitutions have been controversial.
For example, researchers have reported that GlyArg is a common polymorphism in T2DM patients [ 4243 ], but others have failed to observe similar findings in other T2DM populations [ 44 ]. In addition, hyperphosphorylation of serine at residues Ser, Ser, Ser, and Ser in IRS1 was suggested to be responsible for increased insulin resistance in animal models [ 39 ].
However, it is not entirely known which specific serine residues or combination thereof require hyperphosphorylation to elicit the insulin-resistant phenotype, as excessive phosphorylation at Ser and Ser has been demonstrated in muscle samples from patients with metabolic syndrome, but not at Ser, Ser, or Ser as reported by others [ 45 ].
Taken together, these data demonstrate the complexity of the role played by IRS proteins, but also their importance in modulating insulin resistance. Insulin resistance and the role of inflammation. Overnutrition leads to high levels of lipids and glucose and overtime development of obesity and metabolic syndrome MetSultimately causing chronic low-grade inflammation.
High lipids can also promote inflammation through generation of ceramide, and high glucose increases overall oxidative stress. PI3K lipid kinases are composed of two polypeptide subunits, one p catalytic subunit and a p85, p65, or p55 regulatory subunit, and these proteins are classified according to the combination of both domains. Importantly, a balance between the active heterodimer and the individually expressed inactive regulatory domains exists in the cytosol. This system allows for tight regulation and appropriate activation of the PI3K-Akt pathway, where the regulatory domains compete for IRS binding sites with the active heterodimer [ 39 ].
However, it was suggested that excessive expression of individual regulatory domains e. Conversely, in mice with the genetic deletion of p85 in the liver, improved hepatic and peripheral insulin sensitivity was shown [ 47 ], which eloquently demonstrates the impact of dysfunctional PI3K-signalling on insulin resistance.
Alternatively, decreased IR expression or desensitisation to the insulin ligand may occur and may be involved in the insulin resistant phenotype. Importantly, under normal conditions these signalling pathways are regulated by a negative-feedback mechanism to control IR sensitivity [ 49 ]. Hyperinsulinaemia is a key pathological characteristic of insulin resistance but it is not clear whether this is a cause or a consequence of insulin resistance.
Chronically elevated insulin levels can reduce IR expression in the liver [ 5051 ] and primary adipocytes [ 49 ] and in the kidney [ 52 ], and it is a possible mechanism that exasperates development of insulin resistance. In addition, it was suggested that decreased IR expression in the kidney of insulin resistant rats increased sodium reabsorption in the proximal tubule [ 52 ], and this salt retention promoted hypertension, which is closely associated with cardiovascular disease, obesity, diabetes, and insulin resistance.
Hyperglycaemia Negatively Impacts Insulin-Responsive Tissues Interestingly, in skeletal muscle excessively increased carbohydrate levels can also decrease insulin association with the IR and cause decreased IR expression [ 53 ].
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Supporting experiments that mimicked the milieu of T2DM showed that high glucose and high insulin in combination reduced insulin binding to the IR in adipocytes [ 54 ]. These ex vivo treatments also decreased the expression of IRS1 and IRS2, further demonstrating inhibition of insulin signal transduction, while these treatments also impacted negatively Akt sensitivity. This latter work revealed the effects of high glucose and insulin on inducing postreceptor defects. However, the precise molecular processes by which elevated carbohydrates promote insulin resistance are not fully understood but are believed to involve modifications of postreceptor molecules such as IRS, PI3K, and Akt.
In adipocyte and muscle cell lines, it was observed that hydrogen peroxide H2O2 reduced insulin signalling and consequently glucose transport [ 38 ] Figure 1. Thus, it is not a coincidence that, in obesity and T2DM patients, proinflammatory cytokines and plasma nutrients are chronically elevated, compared to healthy and lean subjects [ 2957 ].
When these processes are coupled with elevated oxidative stress, a proinflammatory environment is maintained, which leads to the unresolved inflammation and chronic activation of proinflammatory signalling pathways activation e.
As a consequence, the progression of the disease occurs along with time several yearsand immune cell recruitment occurs in insulin target tissues, such as liver and adipose tissue, but also in tissues not directly associated with insulin action, including the islet [ 5 ].
Both groups had reduced body weight and body mass indexbut only CT1 showed lower body fat percentage and increased basal metabolic rate.
Oxidative Medicine and Cellular Longevity
On the other hand, both training protocols reduced the GPx activity. It can be concluded that both types of concurrent training could be an alternative for lowering body weight and BMI. Also, it was observed that concurrent training, depending on the frequency, can contribute to reducing body fat, oxidative damage protein oxidationand IR but can induce oxidative damage to lipids.
More studies are needed to elucidate the mechanisms involved. Introduction Sedentary lifestyle contributes to an increase in the incidence of obesity in most countries [ 1 ]. Obesity is defined as a chronic and multifactorial disease, which is associated with high mortality, especially in industrialized areas [ 1 ]. This disease is associated with many comorbidities, such as cardiovascular complications, hypertension, atherosclerosis, chronic inflammation, dyslipidemia, insulin resistance IRdiabetes mellitus DMand other metabolic disorders [ 12 ].
Furthermore, studies show that obesity can cause increased reactive species production and a depletion of antioxidant defenses, leading to oxidative stress. This condition induces oxidative damage to proteins, lipids, and DNA [ 34 ]. Oxidative stress can be reduced by physical exercise with adequate frequency and intensity, which can provide adaptive changes to the regulation of antioxidant defenses, resulting in less oxidative cell damage [ 5 — 7 ].
The benefits of regular physical exercise are well documented [ 5 ]. However, there are few studies that approach the benefits of concurrent training aerobic plus strength in the obese population.
Data demonstrate that this training can help to lose weight and body fat and to gain lean body mass [ 78 ]. However, it is still unclear how concurrent training modulates parameters of IR and oxidative stress in obese individuals. Thus, this study aimed to evaluate anthropometric parameters, IR, and oxidative stress in obese individuals subjected to concurrent training of moderate intensity but differing in frequency.
Materials and Methods 2. Experimental Approach to the Problem Concurrent training consisted in aerobic exercise combined with strength exercises. The training was divided into two groups: Each training session was divided into five minutes of initial warm-up, 30 minutes of walking, 30 minutes of strength exercises, and five minutes of stretching.
CT1 was performed five days per week and CT2 three days per week. These different training frequencies were used to check for changes of oxidative profile and insulin resistance in obese sedentary individuals. Schedule of concurrent training. Thus, this study consisted of 25 individuals, 18 women and 7 men. The CT1 group was composed of 8 women and 4 men with age of years and height of cm.
The CT2 group was composed of 10 women and 3 men, with age of years and height of cm. Procedures Before the beginning of the training period, all individuals had a cardiorespiratory test, which consisted of a progressive test until exhaustion on a treadmill ATL Inbramed Millennium, Porto Alegre, Brazil with an ergospirometer V, Medgraphics, St. The test was conducted according to the modified Bruce protocol [ 9 ]. The Borg scale was used to monitor the intensity of the test, so that the intensity could be reproduced during physical training.
To determine the intensity of exercise and follow a progressive linear intensity, the highest mean oxygen uptake during 30 seconds was expressed as the peak oxygen uptake because a plateau was invariably not observed during the test, although other criteria for given in the literature i. The 1RM test was performed for lower body by squat exercise and for upper body by supine exercise with free weights before starting the training period.
Strength training was based on the method of alternating segments with the following exercises: The abdominal and plantar flexion exercises were performed with no load and fixed in 15 repetitions.
Moreover, before and after the training period, samples of venous blood were collected 10 mL without anticoagulant, after an overnight fast of 8 hours. To evaluate the oxidative profile of the participants, lipid peroxidation was determined by the thiobarbituric acid reactive substances TBARS method described by Wills [ 12 ]. Protein carbonyl levels were measured to determine protein oxidation as described by Reznick and Packer [ 13 ].
Total sulfhydryl groups were assayed by the technique described by Aksenov and Markesbery [ 14 ]. We also determined the activities of the antioxidant enzymes catalase CAT [ 15 ], superoxide dismutase SOD [ 16 ], and glutathione peroxidase GPx [ 17 ]. Statistical Analysis All variables were tested for normality of distribution by the Shapiro-Wilk test. All statistical tests were two-tailed and performed using a significance level of. Results It was observed that both training protocols were able to reduce body weight and BMI Table 2.
But only CT1 showed significantly decreased body fat percentage and increased free fat mass and BMR after the training period. Regarding the circumference measurements, hip circumference was decreased in CT1, and abdomen and hip circumferences were decreased in CT2 Table 2. Anthropometric parameters of obese individuals before and after concurrent training with different frequencies.