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Obesity and insulin resistance stiffen the vasculature, with females appearing to be more adversely affected. As augmented arterial stiffness is an independent predictor of cardiovascular disease (CVD), the increased predisposition of women with obesity and insulin resistance to arterial stiffening may explain their heightened risk for CVD. However, the cellular mechanisms by which females are more vulnerable to arterial stiffening associated with obesity and insulin resistance remain largely unknown. In this study, we provide evidence that female mice are more susceptible to Western diet–induced endothelial cell stiffening compared with age-matched males. Mechanistically, we show that the increased stiffening of the vascular intima in Western diet–fed female mice is accompanied by enhanced epithelial sodium channel (ENaC) activity in endothelial cells (EnNaC). Our data further indicate that: (i) estrogen signaling through estrogen receptor α (ERα) increases EnNaC activity to a larger extent in females compared with males, (ii) estrogen-induced activation of EnNaC is mediated by the serum/glucocorticoid inducible kinase 1 (SGK-1), and (iii) estrogen signaling stiffens endothelial cells when nitric oxide is lacking and this stiffening effect can be reduced with amiloride, an ENaC inhibitor. In aggregate, we demonstrate a sexual dimorphism in obesity-associated endothelial stiffening, whereby females are more vulnerable than males. In females, endothelial stiffening with obesity may be attributed to estrogen signaling through the ERα–SGK-1–EnNaC axis, thus establishing a putative therapeutic target for female obesity-related vascular stiffening.

Consumption of a Western Diet (WD) high in saturated fat and refined carbohydrates causes obesity and leads to insulin resistance and associated vascular stiffening in females earlier than males. This diet-induced obesity is characterized by enhanced activation of vascular mineralocorticoid receptors (MRs). Our recent work suggests that enhanced MR signaling in female mice prompts increased expression and translocation of the α-subunit of the epithelial sodium channel to the endothelial cell (EC) surface (EnNaC). However, the influence of EnNaC on endothelial function in the kidney remains unknown. Therefore, we hypothesized that WD feeding would induce kidney microvessel dysfunction and kidney injury through inflammatory pathways. Using a model of cell specific deletion of the α-subunit of EnNaC, female KO mice and littermate controls were fed a diet high in fat (46%) and fructose (17.5%) for 12 weeks. There were increases in indices of weight gain and fat mass in WD fed mice along with increased measures of central aortic stiffness, renal arteriolar remodeling, perivascular fibrosis and aortic and kidney endothelial stiffening in the absence of increases in blood pressure or proteinuria. The central aortic stiffness, renal arteriolar remodeling, perivascular fibrosis and aortic and kidney endothelial stiffening occurred in temporal relation to reductions in bioavailable nitric oxide. All of these abnormalities were attenuated in the EnNaC α-subunit knockout (endothelial stiffness, WD, 9.2 ± 0.65 kPA; WD-KO, 5.38 ± 0.75kPA). Our observations suggest, that central aortic and kidney vessel stiffening along with arterial wall remodeling occur in conjunction to renal injury.

Consumption of a diet high in fat and refined carbohydrates (Western diet [WD]) is associated with obesity and insulin resistance, both major risk factors for cardiovascular disease (CVD). In women, obesity and insulin resistance abrogate the protection against CVD likely afforded by estrogen signaling through estrogen receptor (ER)α. Indeed, WD in females results in increased vascular stiffness, which is independently associated with CVD. We tested the hypothesis that loss of ERα signaling in the endothelium exacerbates WD-induced vascular stiffening in female mice. We used a novel model of endothelial cell (EC)-specific ERα knockout (EC-ERαKO), obtained after sequential crossing of the ERα double floxed mice and VE-Cadherin Cre-recombinase mice. Ten-week-old females, EC-ERαKO and aged-matched genopairs were fed either a regular chow diet (control diet) or WD for 8 weeks. Vascular stiffness was measured in vivo by pulse wave velocity and ex vivo in aortic explants by atomic force microscopy. In addition, vascular reactivity was assessed in isolated aortic rings. Initial characterization of the model fed a control diet did not reveal changes in whole-body insulin sensitivity, aortic vasoreactivity, or vascular stiffness in the EC-ERαKO mice. Interestingly, ablation of ERα in ECs reduced WD-induced vascular stiffness and improved endothelial-dependent dilation. In the setting of a WD, endothelial ERα signaling contributes to vascular stiffening in females. The precise mechanisms underlying the detrimental effects of endothelial ERα in the setting of a WD remain to be elucidated.

PURPOSE OF THE REVIEW: In the present review, we will discuss the evidence and the mechanisms underlying the complex interplay between obesity, mineralocorticoid receptor activation, and cardiovascular dysfunction with special emphasis on the pathogenesis of cardiovascular disease (CVD) in obese and insulin-resistant females. RECENT FINDINGS: Since the initial isolation of aldosterone in 1953 and the cloning of the mineralocorticoid receptor (MR) decades later, our understanding has expanded tremendously regarding their involvement in the pathogenesis of CVD. Recent results from both pre-clinical and clinical studies support a close correlation between increase adiposity and enhanced aldosterone production (MR activation). SUMMARY: Importantly, insulin resistance and obese females are more prone to the deleterious cardiovascular effects of MR activation, and enhanced MR activation in females has emerged as an important causative event in the genesis of a more severe CVD in diabetic women. Different clinical trials have been completed examining the effect of MR blockade in subjects with CVD. Despite its important beneficial mortality impact, side effects are frequent and a newer MR antagonist, finerenone, with less risk of hyperkalemia is currently being tested in large clinical trials.

Novel therapies are needed for treating the increasing prevalence of hepatic steatosis in Western populations. In this regard, dipeptidyl peptidase-4 (DPP-4) inhibitors have recently been reported to attenuate the development of hepatic steatosis, but the potential mechanisms remain poorly defined. In the current study, 4-week-old C57Bl/6 mice were fed a high-fat/high-fructose Western diet (WD) or a WD containing the DPP-4 inhibitor, MK0626, for 16 weeks. The DPP-4 inhibitor prevented WD-induced hepatic steatosis and reduced hepatic insulin resistance by enhancing insulin suppression of hepatic glucose output. WD-induced accumulation of hepatic triacylglycerol (TAG) and diacylglycerol (DAG) content was significantly attenuated with DPP-4 inhibitor treatment. In addition, MK0626 significantly reduced mitochondrial incomplete palmitate oxidation and increased indices of pyruvate dehydrogenase activity, TCA cycle flux, and hepatic TAG secretion. Furthermore, DPP-4 inhibition rescued WD-induced decreases in hepatic PGC-1α and CPT-1 mRNA expression and hepatic Sirt1 protein content. Moreover, plasma uric acid levels in mice fed the WD were decreased after MK0626 treatment. These studies suggest that DPP-4 inhibition ameliorates hepatic steatosis and insulin resistance by suppressing hepatic TAG and DAG accumulation through enhanced mitochondrial carbohydrate utilization and hepatic TAG secretion/export with a concomitant reduction of uric acid production.

Therapies to prevent renal injury in obese hypertensive individuals are being actively sought due to the obesity epidemic arising from the Western diet (WD), which is high in fructose and fat. Recently, activation of the immune system and hyperuricemia, observed with high fructose intake, have been linked to the pathophysiology of hypertension and renal injury. Because dipeptidyl peptidase 4 (DPP4) is a driver of maladaptive T-cell/macrophage responses, renal-protective benefits of DPP4 inhibition in the WD-fed mice were examined. Mice fed a WD for 16 weeks were given the DPP4 inhibitor MK0626 in their diet beginning at 4 weeks of age. WD-fed mice were obese, hypertensive, and insulin-resistant and manifested proteinuria and increased plasma DPP4 activity and uric acid levels. WD-fed mice also had elevated kidney DPP4 activity and monocyte chemoattractant protein-1 and IL-12 levels and suppressed IL-10 levels in the kidney, suggesting macrophage-driven inflammation, glomerular and tubulointerstitial injury. WD-induced increases in DPP4 activation in the plasma and kidney and proteinuria in WD mice were abrogated by MK0626, although blood pressure and systemic insulin sensitivity were not improved. Contemporaneously, MK0626 reduced serum uric acid levels, renal oxidative stress, and IL-12 levels and increased IL-10 levels, suggesting that suppression of DPP4 activity leads to suppression of renal immune/inflammatory injury responses to a WD. Taken together, these results demonstrate that DPP4 inhibition prevents high-fructose/high-fat diet-induced glomerular and tubular injury independent of blood pressure/insulin sensitivity and offers a potentially novel therapy for diabetic and obesity-related kidney disease.

Nonalcoholic fatty liver disease (NAFLD), a common clinical disorder, is increasing largely due to increasing consumption of diets high in fructose and fat (1–3). Indeed, NAFLD has been reported to be present in up to 30% of the U.S. population (3), closely mirroring the prevalence of obesity. Its presence carries an increased risk for type 2 diabetes, end-stage liver disease, and cardiovascular disease (2). Obesity and type 2 diabetes are characterized by chronic low-grade inflammation in which maladaptive immune responses contribute to the development of resistance to the metabolic actions of insulin, thus generating a proinflammatory milieu that leads to steatosis and fibrosis of the liver (4). A critical event in the pathophysiology of tissue inflammation is the shift in the polarization status of macrophages from an anti-inflammatory (M2) to a proinflammatory (M1) phenotype of macrophages (5,6). M1 polarization of hepatic Kupffer cells (KCs) plays an important role in the genesis of hepatic steatosis and insulin resistance in response to chronic overnutrition (6). M1 polarization results in increased expression of proinflammatory mediators, such as CD11c, tumor necrosis factor α, interleukin (IL)-6, and inducible nitric oxide synthase (7). Conversely, the anti-inflammatory M2 phenotype secretes preferentially CD206, arginase1, and IL-10 (8). The role of macrophage M1/M2 polarization status in conditions of insulin resistance has been explored using myeloid-specific knockout …

Diabetic women are at greater risk of developing cardiovascular disease than diabetic men. Our group has shown that insulin resistant female mice are more prone to develop diastolic dysfunction than male mice when fed a high fat/high fructose (western diet - WD). T regulatory cells (Tregs) suppress inflammation and insulin resistance, and estrogen receptor alpha (ERα) signaling has been postulated to modulate their function. Consequently, using a novel rodent model lacking ERα in Treg cells (TregERαKO) we tested the hypothesis that in conditions of WD-feeding, abrogation of ERα signaling in Tregs in female mice results in worsened whole-body and cardiac-specific insulin sensitivity, as well as diastolic function. Female TregERαKO mice and ERαFloxed (ERα Fl2 ) littermate controls were fed a WD for 16 weeks. WD consisted of high fat (46%) and high carbohydrate as sucrose (17.5%) and high fructose corn syrup (17.5%). At the end of the intervention, rodents underwent hyperinsulinemic-euglycemic clamps (n=7-9 per group) and, in a separate cohort, cardiac MRI (n=4 per group). Although TregERα deletion did not significantly impact whole-body insulin sensitivity (glucose infusion rate at steady state: 20 ± 2 vs. 17 ± 2 mg/Kg/min, TregERαKO vs. ERαFl 2 respectively, p=0.22), cardiac glucose uptake was significantly lower in the TregERαKO cohort (214.0±7.5 vs.167.3±19.6 μmol/min/100g tissue, TregERαKO and ERαFl 2 respectively p2 respectively, p Conclusions: In female mice fed a WD, lack of ERα signaling in Tregs results in cardiac-specific insulin resistance. However, the decreased cardiac glucose uptake did not translate into deterioration of diastolic function. Further studies are needed to evaluate the differential effects of TregERα deletion on glucose uptake and diastolic function. Acknowledgments: We acknowledge Vanderbilt MMPC for performing the clamps. MMPC is supported in part by grant U24 DK059637.

The incidence of type 2 diabetes mellitus (DM2) has increased dramatically over the last several decades, largely driven by equally worrisome growing rates of obesity. Chronic diabetic complications are leading causes of morbidity and mortality worldwide. Key players in the pathophysiology of DM2 are insulin resistance and β cell dysfunction, which in turn is a result of both β cell functional abnormality as well as reduced β cell mass. The mechanisms implicated are multifactorial and include genetic and environmental factors related to obesity. Glucose homeostasis is critically dependent on a finely regulated balance between insulin sensitivity and output in the pancreas, and insulin resistance demands a corresponding rise in insulin output in order to maintain normal glycemia. However, this compensation is lost in individuals predisposed to DM2, resulting in overt hyperglycemia. Furthermore, insulin resistance related to excess adiposity is linked to several abnormalities which impact β cell function and viability. These include glucotoxicity, lipotoxicity, increased oxidative stress, and inflammation. In addition, insulin signaling in the β cell is essential to its own functionality and viability, and obesity-related abnormalities in insulin signaling are known to induce failure of insulin secretion and hyperglycemia. Insulin resistance in the β cell arises from defects in phosphorylation/activation of insulin receptor substrates (IRS) proteins, which result in impairment in glucose sensing, glucose stimulated insulin secretion, and also in increased loss of β cells. This review intends to provide an update on the main characteristics and mechanisms that link obesity and insulin resistance to β cell dysfunction in the pathogenesis of DM2.

Type 2 Diabetes Mellitus (T2DM) and hypertension (HTN) both increase cardiovascular disease (CVD) morbidity and mortality, and impose a tremendous burden on worldwide heath care systems in recent years. The mechanisms underlying the frequent coexistence of T2DM and HTN, two main components of the Cardiometabolic Syndrome (CMS), remain to be fully uncovered. Interestingly, both conditions are linked by chronic inflammatory processes and insulin resistance that are instigated by enhanced activation of the Renin Angiotensin Aldosterone System (RAAS). Inappropriate activation of the RAAS and insulin resistance with compensatory hyperinsulinemia trigger numerous pathophysiological pathways that ultimately result in endothelial dysfunction, inflammation, proliferation, and remodeling in cardiovascular and renal tissue. Blockade of RAAS has proven beneficial in the management of T2DM and HTN as well as associated CVD and chronic kidney diseases. This review focuses on current knowledge about the role of RAAS and insulin resistance and accompanying inflammation and oxidative stress in the pathophysiology that links DM and HTN.

The relationship between HTNand other components of the CMSis complex. However, there is growing evidence that enhanced activation of the RAAS is a key factor in the development of endothelial dysfunction and HTN. Insulin resistance is induced by activation of the RAAS and resulting increases in ROS. This insulin resistance occurs in cardiovascular tissue and in tissues traditionally considered as targets for the action of insulin, such as muscle and liver. Indeed, there is a mounting body of evidence that the resultant insulin resistance in cardiovascular tissue and kidneys contributes to the development of endothelial dysfunction, HTN, atherosclerosis, CKD, and CVD.77 RAAS-associated signaling by way of the AT1R and MR, triggers tissue activation of the NADPH oxidase enzymatic activation and increased production of ROS. Oxidative stress in cardiovascular tissue is derived from both NADPH oxidase and mitochondrial generation of ROS, and is central to the development of insulin resistance, endothelial dysfunction, HTN, and atherosclerosis. Pharmacologic blockade of the RAAS not only improves blood pressure, but alsohas a beneficial impact on inflammation, oxidative stress, insulin sensitivity, and glucose homeostasis. Several strategies are available for RAAS blockade, including ACE inhibitors, ARBs, and MR blockers, which have been proven in the clinical trials to result in improved CVD and CKD outcomes. New research in these areas will allow for a better understanding of the relationship between HTN, insulin resistance, and activation of the RAAS, which could result in newer alternatives for a more comprehensive management of HTN in the setting of the CMS..

Renin is the rate-limiting enzyme in renin-angiotensin system (RAS) activation. We sought to determine the impact of renin inhibition on whole-body insulin sensitivity and skeletal muscle RAS, oxidative stress, insulin signaling, and glucose transport in the transgenic TG(mRen2)27 rat (Ren2), which manifests increased tissue RAS activity, elevated serum aldosterone, hypertension, and insulin resistance. Young (aged 6–9 wk) Ren2 and age-matched Sprague Dawley control rats were treated with aliskiren [50 mg/kg · d, ip] or placebo for 21 d and administered an ip glucose tolerance test. Insulin metabolic signaling and 2-deoxyglucose uptake in soleus muscle were examined in relation to tissue renin-angiotensin-aldosterone system [angiotensin (Ang) II, mineralocorticoid receptor (MR), and Ang type I receptor (AT1R)] and measures of oxidative stress as well as structural changes evaluated by light and transmission electron microscopy. Ren2 rats demonstrated systemic insulin resistance with decreased skeletal muscle insulin metabolic signaling and glucose uptake. This was associated with increased Ang II, MR, AT1R, oxidative stress, and reduced tyrosine insulin receptor substrate-1 phosphorylation, protein kinase B/(Akt) phosphorylation and glucose transporter-4 immunostaining. The Ren2 also demonstrated perivascular fibrosis and mitochondrial remodeling. Renin inhibition improved systemic insulin sensitivity, insulin metabolic signaling, and glucose transport along with normalization of Ang II, AT1R, and MR levels, oxidative stress markers, fibrosis, and mitochondrial structural abnormalities. Our data suggest that renin inhibition improves systemic insulin sensitivity, skeletal muscle insulin metabolic signaling, and glucose transport in Ren2 rats. This is associated with reductions in skeletal muscle tissue Ang II, AT1R, and MR expression; oxidative stress; fibrosis; and mitochondrial abnormalities.

Type 2 Diabetes Mellitus confers an excess risk of cardiovascular disease. The mechanisms involved in the development of the disease are an active field of research, and prompt the development of newer and safer therapeutics with implications for cardiovascular disease. Currently there is increasing awareness of the role of platelet dysfunction, low-grade chronic inflammation and thrombogenesis in the pathophysiology of insulin resistance, T2DM, as well as type 1 diabetes mellitus and cardiovascular disease. This new evolving knowledge has allowed a better understanding of the role of aspirin, an old medication with proven beneficial effects on patients with established cardiovascular disease. The influence of salicylates on insulin resistance, glucose homeostasis, platelet function and inflammatory pathways, in particular related to the activation of the NF κB pathway, is a promising field of active research, and will help in the management of both diabetes mellitus and atherosclerotic-related cardiovascular disease.

Background/Aim: There is an emerging relationship between insulin resistance/hyperinsulinemia, oxidative stress, and glomerular injury manifesting as albuminuria. HMG-CoA reductase inhibitors (statins) have been shown to reduce oxidative stress in the vasculature as well as albuminuria in animal models and in human studies. The glomerular filtration barrier is emerging as a critical determinant of albumin filtration. We investigated the effects of insulin resistance and rosuvastatin or placebo on the glomerular filtration barrier. Method: Young Zucker obese and Zucker lean rats (6–7 weeks old) were treated with the HMG-CoA reductase inhibitor rosuvastatin (10 mg/kg/day) or placebo for 21 days. Results: In the Zucker obese rats, homeostasis model assessment-insulin resistance index, oxidative markers (NADPH oxidase activity, reactive oxygen species, and urine isoprostane formation), podocyte foot process effacement, and albuminuria were increased as compared with Zucker lean controls, independent of increases in systolic blood pressure. Albuminuria correlated with podocyte foot process effacement (r2 = 0.61) and insulin level (r2 = 0.69). Rosuvastatin treatment improved albuminuria, filtration barrier indices, and oxidative stress via copper/zinc superoxide dismutase. Conclusions: These data indicate that hyperinsulinemia together with insulin resistance is associated with podocyte injury and albuminuria independent of the systolic blood pressure. Further, rosuvastatin modulates filtration barrier injury and albuminuria and improves oxidative stress measures via copper/zinc superoxide dismutase.

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.

The incidence of obesity, cardiometabolic syndrome (CMS), and type 2 diabetes mellitus (DM2), as well as their devastating cardiovascular consequences, keep rising with increasing human and economical costs. For a long time, insulin resistance has been the main player in the pathogenesis and treatment of DM2, but every day more knowledge is gained about the central role of beta-cell failure, not only in the appearance of hyperglycemia but also in the failure of the pharmacological therapy. beta-Cell failure implies impairment of glucosestimulated insulin secretion and loss of beta-cell mass. Hyperglycemia, elevated circulating fatty acids, inadequate local activation of renin angiotensin system, and chronic low grade inflammation are conditions that coexist in the CMS and DM2 that turn out to be deleterious for the beta-cell functioning and existance. Excessive oxidative stress secondary to increased production of reactive oxygen species and decreased availability of antioxidants is a possible common converging point of the multiple noxious stimuli. Activation of the NADPH oxidase complex secondary to angiotensin II stimulation is of interest, as its pharmacological blockade has beneficial effects. New knowledge about the intimate mechanisms of oxidative-stress induced beta-cell failure will provide new therapeutic targets against CMS and DM2.

Background: Women with obesity, insulin resistance and type 2 diabetes mellitus (T2D) lose the cardiovascular disease protection normally afforded by female sex hormones, but the underlying mechanism(s) remain unknown. Increases in vascular stiffness occur with aging, but conditions of insulin resistance such as obesity and T2D are characterized by accelerated development of this phenomenon. Under physiological conditions, vascular estrogen signaling via estrogen receptor alpha (ERα) increases endothelial bioavailable nitric oxide which decreases stiffness. Nevertheless, in conditions of insulin resistance, the effects of ERα signaling may be deleterious. Methods: We used a novel rodent model lacking ERα in the endothelial cells (ECERαKO). The genomic region encompassing exon 3 of the ERα gene was flanked by loxP sites. ECERαKO mice were generated by crossing ERα doubled floxed mice with Cad-Cre+ mice (VE-Cadherin promoter driving expression of Cre-recombinase). Female ECERαKO mice and littermates were fed a high fructose/high sucrose (Western diet - WD) for 8 weeks. The WD diet consisted of 60% fat and 20% sucrose. At the end of the intervention period, mice underwent in vivo and ex vivo assessment of vascular stiffness. Results: The absence of EC ERα did not impact whole body insulin sensitivity (examined by HOMA-IR). Females lacking the endothelial specific ERα had less vascular stiffness when assessed in vivo via aortic pulse wave velocity than the littermates fed with a WD (3.43 ± 0.184 m/s vs. 4.080 ± 0.172 m/s, p Conclusion: Endothelial ERα does not protect females from vascular stiffness induced by a WD. Indeed, the present data suggest a predisposition toward protection of rodent lacking ERα in conditions of insulin resistance.

Obesity is a leading risk factor for the development of type 2 diabetes mellitus (DM2) and cardiovascular disease (CVD), however the underlying mechanisms still remain to be fully uncovered. It is now well accepted that dysfunctional adipose tissue in conditions of obesity is a critical source of inflammation that impacts the cardiovascular system and contributes to CVD. Although traditionally visceral adipose tissue has been linked to increased CVD risk, there is mounting interest in the role that fat accumulation around the vasculature plays in the pathogenesis of vascular dysfunction. Perivascular adipose tissue (PVAT) is in intimate contact with large, medium and small diameter arterial beds in several tissues, and has been shown to control vascular function as well as remodeling. PVAT does not merely mirror visceral adipose tissue changes seen in obesity, but has unique features that impact vascular biology. In lean individuals PVAT exerts vasodilatory and anti-inflammatory functions, however obesity results in PVAT inflammation, characterized by imbalance between pro- and anti-inflammatory cells as wells as adipokines. PVAT inflammation promotes insulin resistance in the vasculature, thus resulting in impaired insulin-mediated vasodilatory responses and vascular remodeling. In this review we address current knowledge about the mechanisms that link PVAT inflammation to insulin resistance and vascular dysfunction. Indeed, PVAT emerges as a novel type of adipose tissue that participates in the pathogenesis of CVD, independently to a large extent to visceral adipose tissue.

The epidemic of obesity experienced in both industrialized and nonindustrialized countries largely accounts for the increase in the prevalence of the cardiometabolic syndrome (CMS). Obesity and the CMS significantly increase the risk for cardiovascular disease (CVD) and chronic kidney disease (CKD). Multiple abnormalities that can lead to kidney injury have been identified in overweight and obese people, including insulin resistance, compensatory hyperinsulinemia, inappropriate activation of the renin-angiotensin-aldosterone system and increased oxidative stress, endoplasmic reticulum stress, coagulability, and impaired fibrinolysis. The combined effects of these conditions induce in the kidneys impaired pressure natriuresis, glomerular hypertension, endothelial dysfunction, and vasoconstriction, as well as matrix proliferation and expansion. Among the consequences are microalbuminuria, now known to be a surrogate of diffuse endothelial dysfunction as well as a predictor of CVD, and CKD. Diet and regular physical activity are the cornerstones of weight management, and they add to currently available pharmacologic agents and bariatric surgery. The understanding of the pathophysiology of obesity/CMS helps to explain the benefits of agents that improve insulin sensitivity, control inflammation, and block the renin-angiotensin-aldosterone system. The increasing prevalence of obesity and CMS contribute to the growing frequency of CKD and demands the development of multifactorial strategies directed at identifying people at risk, as well as preventing excessive weight gain and its deleterious consequences.

Chronic kidney disease (CKD) is increasingly recognized as a major risk factor for end-stage renal disease (ESRD), cardiovascular (CV) disease, and CV-related premature death. More than 8 million people in the United States have CKD; therefore, preventive stratiegies should be directed at identifying risk factors for this condition. There is growing evidence implicating the cardiometabolic syndrome, a clustering of CV risk factors that include obesity, insulin resistance, compensatory hyperinsulinemia, dysglycemia, atherogenic dyslipidemia, and hypertension. Factors mediating this relationship include increased glomerular filtration, increased vascular permeability, oxidative and endoplasmic reticulum stress, activation of the renin-angiotensin system, and inappropriate secretion of growth factors. The consequences are microalbuminuria, a marker of inflammation and endothelial dysfunction, renal vascular proliferation, extracellular matrix expansion, and CKD. Prevention of CKD should be directed at controlling all components of the cardiometabolic syndrome, with the ultimate goal of reducing the burden imposed by ESRD.

The regulation of blood glucose levels involves a finely tuned relationship between insulin sensitivity, hepatic glucose output, and production of insulin. The cardiometabolic syndrome includes in its definition criteria a disturbance of normal glucose tolerance and implies development of both insulin resistance and beta-cell dysfunction. There is now abundant evidence pointing toward a central role of dysregulation of the beta-cell function and mass in the development of impaired glucose tolerance. Mechanisms implicated in beta-cell dysfunction include genetic abnormalities, prenatal and early postnatal insults, and environmental events along with obesity, dyslipidemia-lipotoxicity, glucotoxicity, oxidative stress, chronic low-grade inflammation, amyloid deposition, and activation of the local renin-angiotensin system. Novel therapeutic characteristics of known medications such as metformin, thiazolidinediones, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and novel medications such as exendin-4 promise encouraging possibilities to battle against the cardiometabolic syndrome and the future development of cardiovascular disease.

Cardiovascular disease (CVD) and Type 2 diabetes mellitus (DM2), once conceived as different entities, share common origins and pathways. Increased activity of the renin-angiotensin-aldosterone-system, insulin resistance, chronic low-grade inflammation and oxidative stress collectively contribute to endothelial dysfunction and atherosclerosis, which manifest clinically as CVD. Nowadays, it is possible to identify and intervene in high-risk populations even before the clinical diagnosis of DM2. The control of dietary patterns and increased physical activity is completely feasible, as well as the management of hypertension and dyslipidaemia. Pharmacological interventions targeted at blocking renin-angiotensin-aldosterone-system and sensitising to insulin have a role in the prevention of DM2 and CVD, and are avidly explored worldwide. In the near future, ongoing trials should provide data that will allow us to better treat patients with the cardiometabolic syndrome and diabetes in order to reduce CVD morbidity and mortality.

Two-thirds of adults in the United States are overweight or obese, and another 26 million have type 2 diabetes. Decreased insulin sensitivity in cardiovascular tissue is an underlying abnormality in these individuals. Insulin metabolic signaling increases endothelial cell nitric oxide production. Impaired vascular insulin sensitivity is an early defect leading to impaired vascular relaxation. In overweight and obese persons, as well as in those with hypertension, systemic and vascular insulin resistance often occurs in conjunction with activation of the cardiovascular tissue renin–angiotensin–aldosterone system (RAAS). Activated angiotensin II type 1 receptor and mineralocorticoid receptor signaling promote the development of vascular insulin resistance and impaired endothelial nitric oxide–mediated relaxation. Research in this area has implicated excessive serine phosphorylation and proteasomal degradation of the docking protein insulin receptor substrate and enhanced signaling through hybrid insulin/insulin-like growth factor (IGF-1) receptor as important mechanisms underlying RAAS impediment of downstream vascular insulin metabolic signaling. This review will present recent evidence supporting the notion that RAAS signaling represents a potential pathway for the development of vascular insulin resistance and impaired endothelial-mediated vasodilation.

Obesity is a leading contributor to morbidity and mortality worldwide. Chronic overnutrition and lack of physical activity result in excess deposition of adipose tissue and insulin resistance, which plays a key role in the pathophysiology of type 2 diabetes mellitus (DM2) and associated cardiovascular disease (CVD). Dysfunctional adipose tissue in obese individuals is characterized by chronic low-grade inflammation that spreads to several tissues as well as systemically and is able to impact the cardiovascular system, resulting in both functional and anatomical abnormalities. Inflammation is characterized by abnormalities in both innate and adaptive immunity including adipose tissue infiltration by CD4+ T lymphocytes, pro-inflammatory (M1) macrophages, and increased production of adipokines. The renin-angiotensin-aldosterone system (RAAS) is inappropriately activated in adipose tissue and contributes to originating and perpetuating inflammation and excessive oxidative stress by increasing production of reactive oxygen species (ROS). In turn, ROS and pro-inflammatory adipokines cause resistance to the metabolic actions of insulin in several tissues including cardiovascular and adipose tissue. Insulin resistance in cardiovascular tissues is characterized by impaired vascular reactivity and abnormal cardiac contractility as well as hypertrophy, fibrosis, and remodeling, which ultimately result in CVD. In this context, weight loss through caloric restriction, regular physical activity, and surgery as well as pharmacologic RAAS blockade all play a key role in reducing obesity-related cardiovascular morbidity and mortality.

Angiotensin receptor (type 1) blockers (ARBs) can reduce both hypertension and insulin resistance induced by local and systemic activation of the renin-angiotensin-aldosterone system. The effectiveness of azilsartan medoxomil (AZIL-M), a novel imidazole-based ARB, to facilitate metabolic improvements in conditions of angiotensin II (Ang II)-associated insulin resistance is currently unknown. The aim of this study was to determine the impact of chronic AZIL-M treatment on glucose transport activity and key insulin signaling elements in red skeletal muscle of Ang II-treated rats. Male Sprague-Dawley rats were treated for 8 weeks with or without Ang II (200 ng/kg/min) combined with either vehicle or AZIL-M (1 mg/kg/day). Ang II induced significant (p < 0.05) increases in blood pressure, which were completely prevented by AZIL-M. Furthermore, Ang II reduced insulin-mediated glucose transport activity in incubated soleus muscle, and AZIL-M co-treatment increased this parameter. Moreover, AZIL-M treatment of Ang II-infused animals increased the absolute phosphorylation of insulin signaling molecules, including Akt [both Ser473 (81%) and Thr308 (23%)] and AS160 Thr642 (42%), in red gastrocnemius muscle frozen in situ. Absolute AMPKα (Thr172) phosphorylation increased (98%) by AZIL-M treatment, and relative Thr389 phosphorylation of p70 S6K1, a negative regulator of insulin signaling, decreased (51%) with AZIL-M treatment. These results indicate that ARB AZIL-M improves the in vitro insulin action on glucose transport in red soleus muscle and the functionality of the Akt/AS160 axis in red gastrocnemius muscle in situ in Ang II-induced insulin-resistant rats, with the latter modification possibly associated with enhanced AMPKα and suppressed p70 S6K1 activation.

Background/Aims: There are important sex-related differences in the prevalence of obesity, type 2 diabetes mellitus and cardiovascular disease. Indeed, premenopausal women have a lower prevalence of these conditions relative to age-matched men. Estrogen participates in the modulation of insulin sensitivity, energy balance, and body composition. In this paper, we investigated the impact of estrogen signaling through estrogen receptor α (ERα) on systemic insulin sensitivity and insulin signaling in skeletal muscle. Methods: In 14- and 30-week-old female ERα knockout (ERαKO) mice and age-matched controls, we assessed insulin sensitivity by a euglycemic-hyperinsulinemic clamp and intraperitoneal glucose tolerance testing. Blood pressure was evaluated by tail cuff and telemetry. We studied ex vivo insulin-stimulated glucose uptake in skeletal muscle tissue, as well as insulin metabolic signaling molecule phosphorylation by immunoblotting and oxidative stress by immunostaining for 3-nitrotyrosine. Results: Body weight was higher in ERαKO mice at 14 and 30 weeks of age. At 30 weeks, intraperitoneal glucose tolerance testing and clamp results demonstrated impaired systemic insulin sensitivity in ERαKO mice. Insulin-stimulated glucose uptake in soleus was lower in ERαKO mice at both ages. The insulin receptor substrate 1/phosphatidylinositol 3-kinase association and the activation of protein kinase B were decreased in ERαKO mice, whereas immunostaining for 3-nitrotyrosine was increased. Conclusions: Our data demonstrate a critical age-dependent role for estrogen signaling through ERα on whole-body insulin sensitivity and insulin metabolic signaling in skeletal muscle tissue. These findings have potential translational implications for the prevention and management of type 2 diabetes mellitus and cardiovascular disease in women, who are at increased risk for these conditions.

The incidence of type 2 diabetes mellitus (DM2) has increased dramatically over the last several decades, largely driven by equally worrisome growing rates of obesity. Chronic diabetic complications are leading causes of morbidity and mortality worldwide. Key players in the pathophysiology of DM2 are insulin resistance and β cell dysfunction, which in turn is a result of both β cell functional abnormality as well as reduced β cell mass. The mechanisms implicated are multifactorial and include genetic and environmental factors related to obesity. Glucose homeostasis is critically dependent on a finely regulated balance between insulin sensitivity and output in the pancreas, and insulin resistance demands a corresponding rise in insulin output in order to maintain normal glycemia. However, this compensation is lost in individuals predisposed to DM2, resulting in overt hyperglycemia. Furthermore, insulin resistance related to excess adiposity is linked to several abnormalities which impact β cell function and viability. These include glucotoxicity, lipotoxicity, increased oxidative stress, and inflammation. In addition, insulin signaling in the β cell is essential to its own functionality and viability, and obesity-related abnormalities in insulin signaling are known to induce failure of insulin secretion and hyperglycemia. Insulin resistance in the β cell arises from defects in phosphorylation/activation of insulin receptor substrates (IRS) proteins, which result in impairment in glucose sensing, glucose stimulated insulin secretion, and also in increased loss of β cells. This review intends to provide an update on the main characteristics and mechanisms that link obesity and insulin resistance to β cell dysfunction in the pathogenesis of DM2.

Obesity and HTN are on the rise in the world. HTN seems to be the most common obesity-related health problem and visceral obesity seems to be the major culprit. Unfortunately, only 31% of hypertensives are treated to goal. This translates into an increased incidence of CVD and related morbidity and mortality. Several mechanisms have been postulated as the causes of obesity-related HTN. Activation of the RAAS, SNS, insulin resistance, leptin, adiponectin, dysfunctional fat, FFA, resistin, 11 Beta dehydrogenase, renal structural and hemodynamic changes, and OSA are some of the abnormalities in obesity-related HTN. Many of these factors are interrelated. Treatment of obesity should begin with weight loss via lifestyle modifications, medications, or bariatric surgery. According to the mechanisms of obesity-related HTN, it seems that drugs that blockade the RAAS and target the SNS should be ideal for treatment. There is not much evidence in the literature that one drug is better than another in controlling obesity-related HTN. There have only been a few studies specifically targeting the obese hypertensive patient, but recent trials that emphasize the importance of BP control have enrolled both overweight and obese subjects. Until we have further studies with more in-depth information about the mechanisms of obesity-related HTN and what the targeted treatment should be, the most important factor necessary to control the obesity-related HTN pandemic and its CVD and CKD consequences is to prevent and treat obesity and to treat HTN to goal.

Hypertension is often associated with increased oxidative stress and systemic insulin resistance. Use of β-adrenergic receptor blockers in hypertension is limited because of potential negative influence on insulin sensitivity and glucose homeostasis. We sought to determine the impact of nebivolol, a selective vasodilatory β1-adrenergic blocker, on whole-body insulin sensitivity, skeletal muscle oxidative stress, insulin signaling, and glucose transport in the transgenic TG(mRen2)27 rat (Ren2). This rodent model manifests increased tissue renin angiotensin expression, excess oxidative stress, and whole-body insulin resistance. Young (age, 6-9 weeks) Ren2 and age-matched Sprague-Dawley control rats were treated with nebivolol 10 mg/(kg d) or placebo for 21 days. Basal measurements were obtained for glucose and insulin to calculate the homeostasis model assessment. In addition, insulin metabolic signaling, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, reactive oxygen species, and ultrastructural changes as evaluated by transmission electron microscopy were examined ex vivo in skeletal muscle tissue. The Ren2 rat demonstrated systemic insulin resistance as examined by the homeostasis model assessment, along with impaired insulin metabolic signaling in skeletal muscle. This was associated with increased oxidative stress and mitochondrial remodeling. Treatment with nebivolol was associated with improvement in insulin resistance and decreased NADPH oxidase activity/levels of reactive oxygen species in skeletal muscle tissue. Nebivolol treatment for 3 weeks reduces NADPH oxidase activity and improves systemic insulin resistance in concert with reduced oxidative stress in skeletal muscle in a young rodent model of hypertension, insulin resistance, and enhanced tissue RAS expression.

Obesity and insulin resistance-related proteinuria is associated with oxidative stress and impaired tissue bioavailable nitric oxide. Recent data suggest that nicotinamide adenine dinucleotide phosphate oxidase-mediated oxidative injury to the proximal tubule, like that seen in the glomerulus, contributes to proteinuria in insulin-resistant states. The vasodilator β-blocker nebivolol reduces nicotinamide adenine dinucleotide phosphate oxidase activity, increases bioavailable nitric oxide, and improves insulin sensitivity. To test the hypothesis that a treatment strategy that reduces oxidative stress and attenuates obesity-associated increases in glomerular and proximal tubule derived protein, we treated young Zucker obese (ZO) and age-matched Zucker lean male rats with nebivolol (10 mg · kg−1 · d−1) for 21 d. Compared with Zucker lean, ZO controls exhibited increased proteinuria and γ-glutamyl transpeptidase, reductions in systemic insulin sensitivity in association with increased renal renin, (pro)renin receptor, angiotensin II type 1 receptor, and mineralocorticoid receptor immunostaining, oxidative stress, and glomerular tubular structural abnormalities that were substantially improved with in vivo nebivolol treatment. Nebivolol treatment also led to improvements in glomerular podocyte foot-process effacement and improvement in podocyte-specific proteins (nephrin and synaptopodin) as well as proximal tubule-specific proteins (megalin and lysosomal-associated membrane protein-2) and proximal tubule ultrastructural remodeling in the ZO kidney. Our findings support the notion that obesity and insulin resistance lead to increased glomerulotubular oxidative stress and resultant glomerular and tubular sources of excess urine protein. Furthermore, the results of this study suggest the beneficial effect of nebivolol on proteinuria was derived from improvements in weight and insulin sensitivity and reductions in renal oxidative stress in a state of obesity and insulin resistance.

Hypertension and type 2 diabetes mellitus (T2DM) are powerful risk factors for cardiovascular disease (CVD) and chronic kidney disease (CKD), both of which are leading causes of morbidity and mortality worldwide. Research into the pathophysiology of CVD and CKD risk factors has identified salt sensitivity and insulin resistance as key elements underlying the relationship between hypertension and T2DM. Excess dietary salt and caloric intake, as commonly found in westernized diets, is linked not only to increased blood pressure, but also to defective insulin sensitivity and impaired glucose homeostasis. In this setting, activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system (RAAS), as well as increased signaling through the mineralocorticoid receptor (MR), result in increased production of reactive oxygen species and oxidative stress, which in turn contribute to insulin resistance and impaired vascular function. In addition, insulin resistance is not limited to classic insulin-sensitive tissues such as skeletal muscle, but it also affects the cardiovascular system, where it participates in the development of CVD and CKD. Current clinical knowledge points towards an impact of salt restriction, RAAS blockade, and MR antagonism on cardiovascular and renal protection, but also on improved insulin sensitivity and glucose homeostasis.

The recent epidemic of obesity has led to an increasing incidence of the cardiometabolic syndrome defined by the NCEP ATP III guidelines as a cluster of abdominal obesity, low HDL, high triglycerides, HTN, and impaired fasting glucose. Obesity predisposes the body to a state of inflammation, insulin resistance, and hyperinsulinemia, and individuals with the metabolic syndrome are at increased risk for developing CAD, stroke, PVD, CKD, and T2DM. There are various mechanisms by which these complications of the metabolic syndrome occur, and activation of systemic and local renin angiotensin aldosterone system (RAAS) and resultant oxidative stress in different organ systems is probably the most important one. Finally, based on recent trials, the approach toward management of the metabolic syndrome is usually multifactorial and multiagent and studies are still being performed to assess the efficacy of newer drugs.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in women in the USA. Women with diabetes are at a greater risk of CVD than men with diabetes. In this chapter we review the various mechanisms by which hyperglycemia potentiates this increased CVD risk, including coagulation abnormalities as well as endothelial dysfunction. Where applicable, sex-specific differences in these mechanisms are highlighted. Finally, the impact and burden of diabetes on CVD as well as screening for CVD in women are discussed.

The role of mineralocorticoids in the development of cardiovascular disease (CVD), cardiometabolic syndrome, type 2 diabetes mellitus, chronic kidney disease (CKD), and hypertension is a growing field of interest. Aldosterone, mainly through nongenomic actions that result in proliferation, fibrosis, inflammation, and tissue remodeling, has been linked to CVD and CKD. Increased circulating aldosterone is also associated with insulin resistance and impaired glucose homeostasis that contribute to the development of endothelial dysfunction, atherosclerosis, and kidney disease. Aldosterone-induced oxidative stress and inflammation play a key role in impairing insulin signaling. Mineralocorticoid receptor blockade restores insulin sensitivity, counterbalances the deleterious cardiovascular and renal effects of aldosterone, and emerges as an alternative to improve blockade of the renin-angiotensin-aldosterone system, which potentially could contribute to reduce the burden of CVD and CKD.

Renin-angiotensin-aldosterone system (RAAS) activation mediates increases in reactive oxygen species (ROS) and impaired insulin signaling. The transgenic Ren2 rat manifests increased tissue renin-angiotensin system activity, elevated serum aldosterone, hypertension, and insulin resistance. To explore the role of aldosterone in the pathogenesis of insulin resistance, we investigated the impact of in vivo treatment with a mineralocorticoid receptor (MR) antagonist on insulin sensitivity in Ren2 and aged-matched Sprague-Dawley (SD) control rats. Both groups (age 6–8 wk) were implanted with subcutaneous time-release pellets containing spironolactone (0.24 mg/day) or placebo over 21 days. Systolic blood pressure (SBP) and intraperitoneal glucose tolerance test were determined. Soleus muscle insulin receptor substrate-1 (IRS-1), tyrosine phosphorylated IRS-1, protein kinase B (Akt) phosphorylation, GLUT4 levels, and insulin-stimulated 2-deoxyglucose uptake were evaluated in relation to NADPH subunit expression/oxidase activity and ROS production (chemiluminescence and 4-hydroxy-2-nonenal immunostaining). Along with increased soleus muscle NADPH oxidase activity and ROS, there was systemic insulin resistance and reduced muscle IRS-1 tyrosine phosphorylation, Akt phosphorylation/activation, and GLUT4 expression in the Ren2 group (each P < 0.05). Despite not decreasing blood pressure, low-dose spironolactone treatment improved soleus muscle insulin signaling parameters and systemic insulin sensitivity in concert with reductions in NADPH oxidase subunit expression/activity and ROS production (each P < 0.05). Our findings suggest that aldosterone contributes to insulin resistance in the transgenic Ren2, in part, by increasing NADPH oxidase activity in skeletal muscle tissue.

Obesity, Type 2 Diabetes Mellitus (T2DM) and Cardiovascular Disease (CVD) are worldwide leading causes of morbidity and mortality. Once considered as separate metabolic and hemodynamic/cardiovascular entities respectively, it has become nowadays clear that the relationship between these conditions is not coincidental, and has common pathophysiological features that allows considering both obesity and T2DM as part of the cardiovascular diseases spectrum. Furthermore, from a clinical standpoint it is also clear that cardiovascular risk factors seldom are isolated findings, but frequently present as a clustering of different conditions, including abnormalities in blood pressure, body weight, glucose homeostasis and albuminuria. The tendency of CVD risk factors to cluster has been described in the medical literature since the decade of 1920s (Avogaro et al 1967). However, the concept of Cardiometabolic Syndrome (CMS) is still evolving, and makes reference to a group of cardiovascular /metabolic risk factors, including hypertension (HTN), dysglycemia, atherogenic dyslipidemia, albuminuria and obesity, which confer an excess high risk for CVD than its individual components. Several names have been given to the condition, including Syndrome X, Dysmetabolic Syndrome, Insulin Resistance Syndrome, Metabolic Syndrome and more recently Cardiometabolic Syndrome. In addition, numerous worldwide organizations have described the CMS and have used different definition criteria, which take into account the current epidemiologic, clinic and pathophysiological evidence available about the condition. These include the National Cholesterol Education

Acanthosis nigricans (AN) is so closely linked with insulin resistance (IR) that it has been called a clinical surrogate for laboratory-determined hyperinsulinemia.1 The presence of AN can therefore indicate patients with IR, allowing implementation of interventions that may prevent progression to type 2 diabetes mellitus.2 We report 30 patients who presented with elevated body mass index (BMI, calculated as weight in kilograms divided by height in meters squared) to correlate IR with different AN physical findings.

Hypertension and cardiovascular disease are leading causes of morbidity and mortality. Accumulating data demonstrate a relationship between hypertension and several vascular and metabolic abnormalities that are components of the cardiometabolic syndrome. The components of the cardiometabolic syndrome include insulin resistance/hyperinsulinemia, central obesity, dyslipidemia, hypertension, microalbuminuria, increased inflammation, and oxidative stress. There is growing evidence that tissue activation of the renin‐angiotensin‐aldosterone system participates in endothelial dysfunction, microalbuminuria, insulin resistance, and subsequent cardiovascular and chronic kidney disease. The notion that hypertension is a metabolic as well as a vascular disease opens a new paradigm for the treatment of this disorder.