Abstract-Insulin resistance is characteristic of obesity, type 2 diabetes, and components of the cardiometabolic syndrome, including hypertension and dyslipidemia, that collectively contribute to a substantial risk for cardiovascular disease. Metabolic actions of insulin in classic insulin target tissues (eg, skeletal muscle, fat, and liver), as well as actions in nonclassic targets (eg, cardiovascular tissue), help to explain why insulin resistance and metabolic dysregulation are central in the pathogenesis of the cardiometabolic syndrome and cardiovascular disease. Glucose and lipid metabolism are largely dependent on mitochondria to generate energy in cells. Thereby, when nutrient oxidation is inefficient, the ratio of ATP production/oxygen consumption is low, leading to an increased production of superoxide anions. Reactive oxygen species formation may have maladaptive consequences that increase the rate of mutagenesis and stimulate proinflammatory processes. In addition to reactive oxygen species formation, genetic factors, aging, and reduced mitochondrial biogenesis all contribute to mitochondrial dysfunction. These factors also contribute to insulin resistance in classic and nonclassic insulin target tissues. Insulin resistance emanating from mitochondrial dysfunction may contribute to metabolic and cardiovascular abnormalities and subsequent increases in cardiovascular disease. Furthermore, interventions that improve mitochondrial function also improve insulin resistance. Collectively, these observations suggest that mitochondrial dysfunction may be a central cause of insulin resistance and associated complications. In this review, we discuss mechanisms of mitochondrial dysfunction related to the pathophysiology of insulin resistance in classic insulin-responsive tissue, as well as cardiovascular tissue. (Circ Res. 2008;102:401-414.)Key Words: mitochondrial dysfunction Ⅲ insulin resistance Ⅲ cardiovascular disease T here are at least 47 million people in the United States who have the cardiometabolic syndrome, a precursor to diabetes and subsequent cardiovascular complications. 1 Furthermore, the development of insulin resistance, the cardinal feature of the cardiometabolic syndrome, is associated with increased tissue renin-angiotensin system activity and increasingly appears to be a nexus between components of the syndrome. 2,3 The metabolic actions of insulin maintain glucose homeostasis by promoting glucose uptake in skeletal muscle and suppressing glucose production in the liver. Insulin resistance is typically defined as decreased sensitivity to these metabolic actions of insulin. Insulin-resistant individuals are at higher risk of developing type 2 diabetes mellitus (T2DM) and cardiovascular disease compared with Original received October 12, 2007; revision received December 17, 2007; accepted January 9, 2008 Figure 2). 5-7 Furthermore, we and others have shown that blockade of the AT 1 R reduces oxidative stress and mitochondrial structure and functional abnormalities in rodent models of excessi...
Nonalcoholic fatty liver disease (NAFLD) includes hepatic steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. NAFLD is the most common liver disorder in the United States and worldwide. Due to the rapid rise of the metabolic syndrome, the prevalence of NAFLD has recently dramatically increased and will continue to increase. NAFLD has also the potential to progress to hepatocellular carcinoma (HCC) or liver failure. NAFLD is strongly linked to caloric overconsumption, physical inactivity, insulin resistance and genetic factors. Although significant progress in understanding the pathogenesis of NAFLD has been achieved in years, the primary metabolic abnormalities leading to lipid accumulation within hepatocytes has remained poorly understood. Mitochondria are critical metabolic organelles serving as "cellular power plants". Accumulating evidence indicate that hepatic mitochondrial dysfunction is crucial to the pathogenesis of NAFLD. This review is focused on the significant role of mitochondria in the development of NAFLD.
Sedentary lifestyle and poor dietary choices are leading to a weight gain epidemic in westernized countries, subsequently increasing the risk for developing the metabolic syndrome and nonalcoholic fatty liver disease (NAFLD). NAFLD is estimated to affect approximate 30% of the general US population and is considered the hepatic manifestation of the metabolic syndrome. Re c e n t f i n d i n g s l i n k i n g t h e c o m p o n e n t s o f t h e metabolic syndrome with NAFLD and the progression to nonalcoholic steatohepatitis (NASH) will be reviewed; in particular, the role of visceral adipose tissue, insulin resistance, and adipocytokines in the exacerbation of these condi tions. While no therapy has been proven effective for treating NAFLD/NASH, common recommendations will be discussed.
JR. Renin-angiotensin-aldosterone system and oxidative stress in cardiovascular insulin resistance. Am J Physiol Heart Circ Physiol 293: H2009 -H2023, 2007. First published June 22, 2007; doi:10.1152/ajpheart.00522.2007.-Hypertension commonly occurs in conjunction with insulin resistance and other components of the cardiometabolic syndrome. Insulin resistance plays a significant role in the relationship between hypertension, Type 2 diabetes mellitus, chronic kidney disease, and cardiovascular disease. There is accumulating evidence that insulin resistance occurs in cardiovascular and renal tissue as well as in classical metabolic tissues (i.e., skeletal muscle, liver, and adipose tissue). Activation of the renin-angiotensin-aldosterone system and subsequent elevations in angiotensin II and aldosterone, as seen in cardiometabolic syndrome, contribute to altered insulin/ IGF-1 signaling pathways and reactive oxygen species formation to induce endothelial dysfunction and cardiovascular disease. This review examines currently understood mechanisms underlying the development of resistance to the metabolic actions of insulin in cardiovascular as well as skeletal muscle tissue.HYPERTENSION is present in ϳ30% of the adult United States population and often occurs in conjunction with insulin resistance and other components of the cardiometabolic syndrome (CMS) (29,115,163,186,190). According to recent data, up to 70 million Americans have insulin resistance, which plays a significant role in the relationship between hypertension, Type 2 diabetes mellitus, chronic kidney disease (CKD), and cardiovascular (CV) disease (CVD) (69). There is accumulating evidence that insulin resistance occurs in CV and renal tissue as well as in classical metabolic tissues (i.e., skeletal muscle, liver, and adipose tissue) (125,186,190). This review focuses on currently accepted mechanisms underlying the development of resistance to the metabolic actions of insulin in CV tissue (see Figs. 1 and 2) as well as skeletal muscle tissues (27,190) (see Fig. 3). Normal Actions of Insulin in CV TissueBoth insulin and IGF-1 receptors exist in CV tissue (186). Upon binding to specific receptors, they activate a number of downstream signaling systems that result in vasorelaxation (125, 188 -191) and myocardial glucose uptake and alteration of cardiac energy homeostasis (125,186,190). Activation of the insulin receptor (IR) and IGF-1 receptor, ligand-activated transmembrane receptors with tyrosine kinase activity, phosphorylates intracellular substrates including IR substrate (IRS) family members and Shc, which, in turn, serve as docking proteins for downstream signaling molecules (27,125). IRS phosphorylation of tyrosine moieties results in the engagement of Src homology 2 (SH2) domain-binding motifs for SH2 domain signaling molecules, including phosphatidyl 3-kinase (PI3K) and Grb-2. When SH2 domains of the p85 regulatory subunit bind to tyrosine-phosphorylated motifs on IRS-1, this activates the preassociated p110 catalytic subunit to generate phosph...
The renin-angiotensin system (RAS) and reactive oxygen species (ROS) have been implicated in the development of insulin resistance and its related complications. There is also evidence that angiotensin II (Ang II)-induced generation of ROS contributes to the development of insulin resistance in skeletal muscle, although the precise mechanisms remain unknown. In the present study, we found that Ang II markedly enhanced NADPH oxidase activity and consequent ROS generation in L6 myotubes. These effects were blocked by the angiotensin II type 1 receptor blocker losartan, and by the NADPH oxidase inhibitor apocynin. Ang II also promoted the translocation of NADPH oxidase cytosolic subunits p47 phox and p67 phox to the plasma membrane within 15 min. Furthermore, Ang II abolished insulin-induced tyrosine phosphorylation of insulin receptor substrate 1 (IRS1), activation of protein kinase B (Akt), and glucose transporter-4 (GLUT4) translocation to the plasma membrane, which was reversed by pretreating myotubes with losartan or apocynin. Finally, small interfering RNA (siRNA)-specific gene silencing targeted specifically against p47 phox (p47siRNA), in both L6 and primary myotubes, reduced the cognate protein expression, decreased NADPH oxidase activity, restored Ang II-impaired IRS1 and Akt activation as well as GLUT4 translocation by insulin. These results suggest a pivotal role for NADPH oxidase activation and ROS generation in Ang II-induced inhibition of insulin signaling in skeletal muscle cells.Insulin resistance and hypertension often coexist and frequently progress to diabetes and cardiovascular disease (1, 2). A reduced response by target tissues to insulin (3) is the hallmark of the metabolic syndrome (1-5), which is defined by a cluster of abnormalities including impaired glucose tolerance, hypertension, abdominal obesity, and dyslipidemia (6). Insulin signaling is a complex process involving multiple pathways and phosphorylation events. Phosphorylation of protein kinase B (Akt) is a key step leading to the translocation of glucose transporter 4 (GLUT4) 2 from intracellular compartments to the plasma membrane. GLUT4 helps mediate the increase in glucose uptake in skeletal muscle and adipose tissues in the presence of insulin (7,8). Skeletal muscle insulin receptor signaling is defective in metabolic syndrome and type 2 diabetes mellitus (T2DM) both in experimental models and humans (1-6;9). Many factors have been reported to induce insulin resistance in vitro and in vivo, including angiotensin II (Ang II), tumor necrosis factor (TNF)-␣, interleukin 6 (IL-6), and free fatty acids (10 -13).Ang II is an important physiological regulator of blood pressure, cardiac function, and salt and fluid homeostasis. Its hypertensive, growth, and remodeling effects are mediated through the Ang II receptor 1 (AT 1 R) (1, 5, 11). In addition, Ang II appears to be antagonistic to insulin action and contributes to insulin resistance. Several prospective clinical studies have shown that treating hypertensive patients with angiote...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.