Skeletal muscle insulin resistance: role of inflammatory cytokines and reactive oxygen species

The cardiometabolic syndrome (CMS), with its increased risk for cardiovascular disease (CVD), nonalcoholic fatty liver disease (NAFLD), and chronic kidney disease (CKD), has become a growing worldwide health problem. Insulin resistance is a key factor for the development of the CMS and is strongly related to obesity, hyperlipidemia, hypertension, type 2 diabetes mellitus (T2DM), CKD, and NAFLD. Insulin resistance in skeletal muscle is particularly important since it is normally responsible for more than 75% of all insulin-mediated glucose disposal. However, the molecular mechanisms responsible for skeletal muscle insulin resistance remain poorly defined. Accumulating evidence indicates that low-grade chronic inflammation and oxidative stress play fundamental roles in the development of insulin resistance, and inflammatory cytokines likely contribute to the link between inflammation, oxidative stress, and skeletal muscle insulin resistance. Understanding the mechanisms by which skeletal muscle tissue develops resistance to insulin will provide attractive targets for interventions, which may ultimately curb this serious problem. This review is focused on the effects of inflammatory cytokines and oxidative stress on insulin signaling in skeletal muscle and consequent development of insulin resistance.     

Impact of different ectopic fat depots on cardiovascular and metabolic diseases

A growing body of evidence is pointing out the pathophysiological role of fat accumulation in different organs. Ectopic fat depots within heart, liver, skeletal muscle, kidney, and pancreas as well as around blood vessels might be more associated to cardiometabolic risk than classical variables, such as body mass index. Among different mechanisms, lipid metabolism appears to be particularly influenced by ectopic fat depots. Indeed, intracellular accumulation of nonesterified fatty acids, and triglycerides promotes endoplasmic reticulum stress, mitochondrial uncoupling, oxidative stress, and altered membrane composition/function, finally promoting inflammatory response and cell death. The dysfunctional adipose tissue was shown to induce both local and systemic effects, with relevant clinical consequences. Epicardial fat and myocardial steatosis have been associated with the development of atrial fibrillation and ventricular dysfunction. Similarly perivascular adipose tissue appears to trigger atherosclerosis and hypertension. Nonalcoholic fatty liver disease has been recognized both as the hepatic manifestation of metabolic syndrome and as a cardiovascular (CV) risk factor. Importantly, the renal sinus fat emerged as a potential player in kidney dysfunction. Finally, both skeletal muscle and pancreatic fat depots have been indicated as potential endocrine modulators of insulin resistance. Considering the global rise in the prevalence of obesity, the understanding of mechanisms underlying ectopic fat accumulation represents an urgent need, with potential clinical implications for CV risk stratification. Here, we attempt to update the current knowledge of the different ectopic fat depots, focusing on underlying mechanisms and potential clinical implications.     

Central role of the adipocyte in the insulin-sensitising and cardiovascular risk modifying actions of the thiazolidinediones

Insulin resistance is a key metabolic defect in type 2 diabetes that is exacerbated by obesity, especially if the excess adiposity is located intra-abdominally/centrally. Insulin resistance underpins many metabolic abnormalities-collectively known as the insulin resistance syndrome-that accelerate the development of cardiovascular disease. Thiazolidinedione anti-diabetic agents improve glycaemic control by activating the nuclear receptor peroxisome proliferator activated receptor-gamma (PPARgamma). This receptor is highly expressed in adipose tissues. In insulin resistant fat depots, thiazolidinediones increase pre-adipocyte differentiation and oppose the actions of pro-inflammatory cytokines such as tumour necrosis factor-alpha. The metabolic consequences are enhanced insulin signalling, resulting in increased glucose uptake and lipid storage coupled with reduced release of free fatty acids (FFA) into the circulation. Metabolic effects of PPARgamma activation are depot specific-in people with type 2 diabetes central fat mass is reduced and subcutaneous depots are increased. Thiazolidinediones increase insulin sensitivity in liver and skeletal muscle as well as in fat, but they do not express high levels of PPARgamma, suggesting that improvement in insulin action is indirect. Reduced FFA availability from adipose tissues to liver and skeletal muscle is a pivotal component of the insulin-sensitising mechanism in these latter two tissues. Adipocytes secrete multiple proteins that may both regulate insulin signalling and impact on abnormalities of the insulin resistance syndrome--this may explain the link between central obesity and cardiovascular disease. Of these proteins, low plasma adiponectin is associated with insulin resistance and atherosclerosis--thiazolidinediones increase adipocyte adiponectin production. Like FFA, adiponectin is probably an important signalling molecule regulating insulin sensitivity in muscle and liver. Adipocyte production of plasminogen activator inhibitor-1 (PAI-1), an inhibitor of fibrinolysis, and angiotensin II secretion are partially corrected by PPARgamma activation. The favourable modification of adipocyte-derived cardiovascular risk factors by thiazolidinediones suggests that these agents may reduce cardiovascular disease as well as provide durable glycaemic control in type 2 diabetes.     

Muscle Carnosine Is Associated with Cardiometabolic Risk Factors in Humans

BackgroundCarnosine is a naturally present dipeptide abundant in skeletal muscle and an over-the counter food additive. Animal data suggest a role of carnosine supplementation in the prevention and treatment of obesity, insulin resistance, type 2 diabetes and cardiovascular disease but only limited human data exists.ConclusionOur data shows that higher carnosine content in human skeletal muscle is positively associated with insulin resistance and fasting metabolic preference for glucose. Moreover, it is negatively associated with HDL-cholesterol and basal energy expenditure. Intervention studies targeting insulin resistance, metabolic and cardiovascular disease risk factors are necessary to evaluate its putative role in the prevention and management of type 2 diabetes and cardiovascular disease.     

Novel aspects of adipocyte-induced skeletal muscle insulin resistance

Insulin resistance in skeletal muscle is an early event in the development of diabetes with obesity being one of the major contributing factors. Conditioned medium (CM) from differentiated human adipocytes impairs insulin signalling in human skeletal muscle cells. Recent data on adipocyte-induced insulin resistance in skeletal muscle cells describes underlying mechanisms of this process. Skeletal muscle insulin resistance involves multiple pathways and irreversible changes in the expression level of critical proteins. Furthermore, the reversibility of insulin resistance could be demonstrated. Several strategies to combat insulin resistance have been developed. One recent approach to treat obesity and the metabolic syndrome is the use of endocannabinoid receptor antagonists such as rimonabant. These compounds might also reduce insulin resistance in type 2 diabetes with effects on adipose tissue and liver and possibly skeletal muscle.     

Metabolic syndrome in mice induced by expressing a transcriptional activator in adipose tissue

Metabolic syndrome is a combination of medical disorders that increases the risk of developing cardiovascular disease and diabetes. Constitutive overexpression of 11β-HSD1 in adipose tissue in mice leads to metabolic syndrome. In the process of generating transgenic mice overexpressing 11β-HSD1 in an inducible manner, we found a metabolic syndrome phenotype in control, transgenic mice, expressing the reverse tetracycline-transactivator (rtTA) in adipose tissue. The control mice exhibited all four sequelae of metabolic syndrome (visceral obesity, insulin resistance, dyslipidemia, and hypertension), a pro-inflammatory state and marked hepatic steatosis. Gene expression profiling of the adipose tissue, muscle and liver of these mice revealed changes in expression of genes involved in lipid metabolism, insulin resistance, and inflammation. Transient transfection of rtTA, but not tTS, into 3T3-L1 cells resulted in lipid accumulation. We conclude that expression of rtTA in adipose tissue causes metabolic syndrome in mice.     

Bio-informatics analysis of a gene co-expression module in adipose tissue containing the diet-responsive gene <Emphasis Type="Italic">Nnat</Emphasis>

Background  

Obesity causes insulin resistance in target tissues - skeletal muscle, adipose tissue, liver and the brain. Insulin resistance predisposes to type-2 diabetes (T2D) and cardiovascular disease (CVD). Adipose tissue inflammation is an essential characteristic of obesity and insulin resistance. Neuronatin (Nnat) expression has been found to be altered in a number of conditions related to inflammatory or metabolic disturbance, but its physiological roles and regulatory mechanisms in adipose tissue, brain, pancreatic islets and other tissues are not understood.     

Metabolic syndrome in rheumatic diseases: epidemiology,pathophysiology, and clinical implications

Subjects with metabolic syndrome–a constellation of cardiovascular risk factors of which central obesity and insulin resistance are the most characteristic–are at increased risk for developing diabetes mellitus and cardiovascular disease. In these subjects, abdominal adipose tissue is a source of inflammatory cytokines such as tumor necrosis factor-alpha, known to promote insulin resistance. The presence of inflammatory cytokines together with the well-documented increased risk for cardiovascular diseases in patients with inflammatory arthritides and systemic lupus erythematosus has prompted studies to examine the prevalence of the metabolic syndrome in an effort to identify subjects at risk in addition to that conferred by traditional cardiovascular risk factors. These studies have documented a high prevalence of metabolic syndrome which correlates with disease activity and markers of atherosclerosis. The correlation of inflammatory disease activity with metabolic syndrome provides additional evidence for a link between inflammation and metabolic disturbances/vascular morbidity.     

Cardiac Health in Women With Metabolic Syndrome: Clinical Aspects and Pathophysiology

Although the classical cardiovascular risk factors (e.g., smoking and hypertension) are becoming more effectively managed, a continuous increase of the so‐called “cardiometabolic risk” is noted. Starting from this century, the nomenclature “metabolic syndrome” has become more popular to identify a cluster of disorders including obesity, dyslipidemia, hypertension, and insulin resistance. It is a primary risk factor for diabetes and cardiovascular disease in both genders. Interestingly, the metabolic diseases display a distinct gender disparity with an apparent “female advantage” in the premenopausal women compared with age‐matched men. However, women usually lose such “sex protection” following menopause or affliction of metabolic syndrome especially insulin resistance. A controversy exists in the medical literature concerning whether metabolic syndrome is a real syndrome or simply a cluster of risk factors. Several scenarios are speculated to contribute to the gender dimorphism in the cardiovascular sequelae in patients with metabolic syndrome including sex hormones, intrinsic organ function, and the risk factor profile (e.g., hypertension, dyslipidemia, obesity, sedentary lifestyle, and atherogenic diet). With the alarming rise of obesity prevalence, heart problems in metabolic syndrome continue to rise with a distinct gender dimorphism. Although female hearts seem to better tolerate the stress insults compared with the male counterparts, the female sex hormones such as estrogen can interact with certain risk factors to precipitate myopathic changes in the hearts. This synthetic review of recent literature suggests a role of gender disparity in myopathic factors and risk attributable to each metabolic component in the different prevalence of metabolic syndrome.     

Effect of Metabolic Syndrome on Mitsugumin 53 Expression and Function

Metabolic syndrome is a cluster of risk factors, such as obesity, insulin resistance, and hyperlipidemia that increases the individual’s likelihood of developing cardiovascular diseases. Patients inflicted with metabolic disorders also suffer from tissue repair defect. Mitsugumin 53 (MG53) is a protein essential to cellular membrane repair. It facilitates the nucleation of intracellular vesicles to sites of membrane disruption to create repair patches, contributing to the regenerative capacity of skeletal and cardiac muscle tissues upon injury. Since individuals suffering from metabolic syndrome possess tissue regeneration deficiency and MG53 plays a crucial role in restoring membrane integrity, we studied MG53 activity in mice models exhibiting metabolic disorders induced by a 6 month high-fat diet (HFD) feeding. Western blotting showed that MG53 expression is not altered within the skeletal and cardiac muscles of mice with metabolic syndrome. Rather, we found that MG53 levels in blood circulation were actually reduced. This data directly contradicts findings presented by Song et. al that indict MG53 as a causative factor for metabolic syndrome (Nature 494, 375-379). The diminished MG53 serum level observed may contribute to the inadequate tissue repair aptitude exhibited by diabetic patients. Furthermore, immunohistochemical analyses reveal that skeletal muscle fibers of mice with metabolic disorders experience localization of subcellular MG53 around mitochondria. This clustering may represent an adaptive response to oxidative stress resulting from HFD feeding and may implicate MG53 as a guardian to protect damaged mitochondria. Therapeutic approaches that elevate MG53 expression in serum circulation may be a novel method to treat the degenerative tissue repair function of diabetic patients.     

Drug-induced lipotoxicity: Lipodystrophy associated with HIV-1 infection and antiretroviral treatment

A subset of HIV-1-infected patients undergoing antiretroviral treatment develops a lipodystrophy syndrome. It is characterized by loss of peripheral subcutaneous adipose tissue (face, limbs, buttocks), visceral fat accumulation, and, in some cases, lipomatosis, especially in the dorsocervical area. In addition, these patients show metabolic alterations reminiscent of the metabolic syndrome, particularly dyslipidemia and insulin resistance. These alterations lead to enhanced cardiovascular risk in patients and favor the development of diabetes. Although a complex combination of HIV-1 infection and drug treatment-related events triggers the syndrome, lipotoxicity appears to contribute to the development of the syndrome. Active lipolysis in subcutaneous fat, combined with impaired fat storage capacity in the subcutaneous depot, drive ectopic deposition of lipids, either in the visceral depot or in nonadipose sites. Both hepatic steatosis and increased lipid content in skeletal muscle take place and surely contribute to systemic metabolic alterations, especially insulin resistance. Pancreatic function may also be affected by the exposure to high levels of fatty acids; together with direct effects of antiretroviral drugs, this may contribute to impaired insulin release and a prodiabetic state in the patients. Addressing lipotoxicity as a pathogenic actor in the lipodystrophy syndrome should be considered in strategies for treating and/or preventing the morphological alterations and systemic metabolic disturbances associated with lipodystrophy.     

The influence of resistance training on patients with metabolic syndrome--significance of changes in muscle fiber size and muscle fiber distribution

People who are afflicted with "metabolic syndrome" exhibit multiple coronary disease risk factors such as insulin resistance, hypertension, hyperlipidemia, or obesity. Twenty-six volunteers (13 women and 13 men) with such disease risk factors (56 ± 5 years) participated in a 14-week resistance training program. Given the fact that resistance training may improve cardiometabolic parameters, the fasting total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides, insulin, glucose value, homeostatic model assessment (HOMA) index, and blood pressure and body mass index (BMI) were measured before and after the training intervention. In addition, muscle biopsies from the vastus lateralis muscle of 11 of the men and 5 of the women were analyzed to determine whether changes in the muscle morphology influence the cardiometabolic parameters. Resistance training resulted in a significant increase in fasting HDL for the entire group (from 44.35 ± 9.43 to 48.57 ± 10.96 mg·dl(-1), p = 0.016). No other blood parameter changed significantly. No change was observed in the HOMA index, blood pressure, or BMI. The muscle fiber type distribution did not change, but a significant hypertrophy of muscle fibers was evident (an increase of the ellipse minor axis of 67.3 ± 16.6 to 72.1 ± 12.3 μm, p = 0.004). Moderate intensity resistance training, as was performed in our study, induces hypertrophic impulses but does not seem to have a clear positive influence on cardiometabolic risk factors. However, 2 sessions of moderate intensity resistance training per week can enhance the fasting HDL cholesterol in middle-aged subjects.     

Glucocorticoids produce whole body insulin resistance with changes in cardiac metabolism

Insulin resistance is viewed as an insufficiency in insulin action, with glucocorticoids being recognized to play a key role in its pathogenesis. With insulin resistance, metabolism in multiple organ systems such as skeletal muscle, liver, and adipose tissue is altered. These metabolic alterations are widely believed to be important factors in the morbidity and mortality of cardiovascular disease. More importantly, clinical and experimental studies have established that metabolic abnormalities in the heart per se also play a crucial role in the development of heart failure. Following glucocorticoids, glucose utilization is compromised in the heart. This attenuated glucose metabolism is associated with altered fatty acid supply, composition, and utilization. In the heart, elevated fatty acid use has been implicated in a number of metabolic, morphological, and mechanical changes and, more recently, in "lipotoxicity". In the present article, we review the action of glucocorticoids, their role in insulin resistance, and their influence in modulating peripheral and cardiac metabolism and heart disease.     

Diabetes and apoptosis: lipotoxicity

Obesity is an established risk factor in the pathogenesis of insulin resistance, type 2 diabetes mellitus and cardiovascular disease; all components that are part of the metabolic syndrome. Traditionally, insulin resistance has been defined in a glucocentric perspective. However, elevated systemic levels of fatty acids are now considered significant contributors towards the pathophysiological aspects associated with the syndrome. An overaccumulation of unoxidized long-chain fatty acids can saturate the storage capacity of adipose tissue, resulting in a lipid ‘spill over’ to non-adipose tissues, such as the liver, muscle, heart, and pancreatic-islets. Under these circumstances, such ectopic lipid deposition can have deleterious effects. The excess lipids are driven into alternative non-oxidative pathways, which result in the formation of reactive lipid moieties that promote metabolically relevant cellular dysfunction (lipotoxicity) and programmed cell-death (lipoapoptosis). Here, we focus on how both of these processes affect metabolically significant cell-types and highlight how lipotoxicity and sequential lipoapoptosis are as major mediators of insulin resistance, diabetes and cardiovascular disease.     

Immunity as a link between obesity and insulin resistance

Obesity is a major public health problem in the United States and worldwide. Further, obesity is causally linked to the pathogenesis of insulin resistance, metabolic syndrome and type-2 diabetes (T2D). A chronic low-grade inflammation occurring in adipose tissue is at least in part responsible for the obesity-induced insulin resistance. This adipose tissue inflammation is characterized by changes in immune cell populations giving rise to altered adipo/cytokine profiles, which in turn induces skeletal muscle and hepatic insulin resistance. Detailed molecular mechanisms of insulin resistance, adipose tissue inflammation and the implications of these findings on therapeutic strategies are discussed in this review.     

Muscle lipid metabolism in the metabolic syndrome

PURPOSE OF REVIEW: The metabolic syndrome has been emphasized as affecting an important subset of individuals at high risk for cardiovascular disease leading the National Cholesterol Educational Program Adult Treatment Panel III in highlighting awareness of insulin-resistance syndrome. Insulin resistance is thought to be an underlying feature of the metabolic syndrome and in the last few years efforts have been performed to assess the effects of ectopic fat accumulation on whole-body glucose metabolism and on the pathogenesis of insulin resistance. RECENT FINDINGS: Abnormality of fatty acid metabolism and ectopic fat accumulation within skeletal muscle has been measured using the traditional biopsy technique but this field of investigation has been exploited considerably more recently thanks to the use of non-invasive H-magnetic resonance spectroscopy. Initial data supported the hypothesis that a strong causal relationship between increased intra-myocellular lipid (IMCL) content and whole-body insulin resistance might exist. Indeed, experimental evidence is still controversial especially when the modulation of the IMCL content is induced by physical exercise and nutritional interventions. SUMMARY: It has been suggested recently that the flux of muscular fatty acids as a source of oxidative energy may play a pivotal role into the development of the abnormalities of muscle and whole-body energy metabolism, potentially as the basis of the pathogenesis of obesity, the metabolic syndrome and type 2 diabetes.     

Potential utility of telmisartan, an angiotensin II type 1 receptor blocker with peroxisome proliferator-activated receptor-gamma (PPAR-gamma)-modulating activity for the treatment of cardiometabolic disorders

The metabolic syndrome is strongly associated with insulin resistance and consists of a constellation of factors such as hypertension and hyperlipidemia that raise the risk for cardiovascular diseases and diabetes mellitus. There is widespread agreement that the renin-angiotensin system (RAS) plays a pivotal role in the pathogenesis of insulin resistance and cardiovascular disease in diabetes. Indeed, large clinical trials have demonstrated substantial benefit of the blockade of this system for cardiovascular end-organ protection. Thus the blockade of the RAS may be a promising strategy for the treatment of the patients with the metabolic syndrome. Although several types of angiotensin II type 1 (AT(1)) receptor blockers (ARBs) are commercially available for the treatment of patients with hypertension, we have recently found that telmisartan (Micardis) could have the strongest binding affinity to AT(1) receptor. Further, telmisartan is reported to act as a partial agonist of peroxisome proliferator-activated receptor-gamma (PPAR-gamma). These observations suggest that, due to its unique PPAR-gamma-modulating activity, telmisartan may be one of the most promising sartans for the treatment of cardiometabolic disorders. In this paper, we reviewed the potential utility of telmisartan in insulin resistance and vascular complications in diabetes.     

Mitochondria and endoplasmic reticulum: Targets for a better insulin sensitivity in skeletal muscle?

Obesity and its associated metabolic disorders represent a major health burden, with economic and social consequences. Although adapted lifestyle and bariatric surgery are effective in reducing body weight, obesity prevalence is still rising. Obese individuals often become insulin-resistant. Obesity impacts on insulin responsive organs, such as the liver, adipose tissue and skeletal muscle, and increases the risk of cardiovascular diseases, type 2 diabetes and cancer. In this review, we discuss the effects of obesity and insulin resistance on skeletal muscle, an important organ for the control of postprandial glucose. The roles of mitochondria and the endoplasmic reticulum in insulin signaling are highlighted and potential innovative research and treatment perspectives are proposed.