Diabetic cardiomyopathy is characterised in its early stages by diastolic relaxation abnormalities and later by clinical heart failure in the absence of dyslipidaemia, hypertension and coronary ...artery disease. Insulin resistance, hyperinsulinaemia and hyperglycaemia are each independent risk factors for the development of diabetic cardiomyopathy. The pathophysiological factors in diabetes that drive the development of cardiomyopathy include systemic metabolic disorders, inappropriate activation of the renin–angiotensin–aldosterone system, subcellular component abnormalities, oxidative stress, inflammation and dysfunctional immune modulation. These abnormalities collectively promote cardiac tissue interstitial fibrosis, cardiac stiffness/diastolic dysfunction and, later, systolic dysfunction, precipitating the syndrome of clinical heart failure. Recent evidence has revealed that dysregulation of coronary endothelial cells and exosomes also contributes to the pathology behind diabetic cardiomyopathy. Herein, we review the relationships among insulin resistance/hyperinsulinaemia, hyperglycaemia and the development of cardiac dysfunction. We summarise the current understanding of the pathophysiological mechanisms in diabetic cardiomyopathy and explore potential preventative and therapeutic strategies.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Insulin resistance, type 2 diabetes mellitus and associated hyperinsulinaemia can promote the development of a specific form of cardiomyopathy that is independent of coronary artery disease and ...hypertension. Termed diabetic cardiomyopathy, this form of cardiomyopathy is a major cause of morbidity and mortality in developed nations, and the prevalence of this condition is rising in parallel with increases in the incidence of obesity and type 2 diabetes mellitus. Of note, female patients seem to be particularly susceptible to the development of this complication of metabolic disease. The diabetic cardiomyopathy observed in insulin- resistant or hyperinsulinaemic states is characterized by impaired myocardial insulin signalling, mitochondrial dysfunction, endoplasmic reticulum stress, impaired calcium homeostasis, abnormal coronary microcirculation, activation of the sympathetic nervous system, activation of the renin-angiotensin-aldosterone system and maladaptive immune responses. These pathophysiological changes result in oxidative stress, fibrosis, hypertrophy, cardiac diastolic dysfunction and eventually systolic heart failure. This Review highlights a surge in diabetic cardiomyopathy research, summarizes current understanding of the molecular mechanisms underpinning this condition and explores potential preventive and therapeutic strategies.
Abstract Insulin resistance is a hallmark of obesity, the cardiorenal metabolic syndrome and type 2 diabetes mellitus (T2DM). The progression of insulin resistance increases the risk for ...cardiovascular disease (CVD). The significance of insulin resistance is underscored by the alarming rise in the prevalence of obesity and its associated comorbidities in the Unites States and worldwide over the last 40–50 years. The incidence of obesity is also on the rise in adolescents. Furthermore, premenopausal women have lower CVD risk compared to men, but this protection is lost in the setting of obesity and insulin resistance. Although systemic and cardiovascular insulin resistance is associated with impaired insulin metabolic signaling and cardiovascular dysfunction, the mechanisms underlying insulin resistance and cardiovascular dysfunction remain poorly understood. Recent studies show that insulin resistance in obesity and diabetes is linked to a metabolic inflammatory response, a state of systemic and tissue specific chronic low grade inflammation. Evidence is also emerging that there is polarization of macrophages and lymphocytes towards a pro-inflammatory phenotype that contributes to progression of insulin resistance in obesity, cardiorenal metabolic syndrome and diabetes. In this review, we provide new insights into factors, such as, the renin–angiotensin–aldosterone system, sympathetic activation and incretin modulators (e.g., DPP-4) and immune responses that mediate this inflammatory state in obesity and other conditions characterized by insulin resistance.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Obesity is an emerging pandemic driven by consumption of a diet rich in fat and highly refined carbohydrates (a Western diet) and a sedentary lifestyle in both children and adults. There is mounting ...evidence that arterial stiffness in obesity is an independent and strong predictor of cardiovascular disease (CVD), cognitive functional decline, and chronic kidney disease. Cardiovascular stiffness is a precursor to atherosclerosis, systolic hypertension, cardiac diastolic dysfunction, and impairment of coronary and cerebral flow. Moreover, premenopausal women lose the CVD protection normally afforded to them in the setting of obesity, insulin resistance, and diabetes, and this loss of CVD protection is inextricably linked to an increased propensity for arterial stiffness. Stiffness of endothelial and vascular smooth muscle cells, extracellular matrix remodeling, perivascular adipose tissue inflammation, and immune cell dysfunction contribute to the development of arterial stiffness in obesity. Enhanced endothelial cortical stiffness decreases endothelial generation of nitric oxide, and increased oxidative stress promotes destruction of nitric oxide. Our research over the past 5 years has underscored an important role of increased aldosterone and vascular mineralocorticoid receptor activation in driving development of cardiovascular stiffness, especially in females consuming a Western diet. In this review the cellular mechanisms of obesity-associated arterial stiffness are highlighted.
Aldosterone is a steroid hormone that regulates blood pressure and cardiovascular function by acting on renal and vascular mineralocorticoid receptors (MRs) to promote sodium retention and modulate ...endothelial function. Indeed, MRs are expressed in endothelial cells, vascular smooth muscle cells, adipocytes, immune cells, skeletal muscle cells, and cardiomyocytes. Excessive aldosterone and associated MR activation impair insulin secretion, insulin metabolic signaling to promote development of diabetes, and the related cardiometabolic syndrome. These adverse effects of aldosterone are mediated, in part, via increased inflammation, oxidative stress, dyslipidemia, and ectopic fat deposition. Therefore, inhibition of MR activation may have a beneficial effect in prevention of impaired insulin metabolic signaling, type 2 diabetes, and cardiometabolic disorders. This review highlights findings from the recent surge in research regarding MR-related cardiometabolic disorders as well as our contemporary understanding of the detrimental effects of excess MR activation on insulin metabolic signaling.
Vascular dysfunction and impaired endothelial mediated relaxation are powerful underlying abnormalities in the pathogenesis of hypertension, coronary heart disease, and stroke. Obesity, type 2 ...diabetes mellitus, and other metabolic abnormalities are associated with activation of mineralocorticoid receptor (MRs) in the vasculature and adipose tissue. While MR signaling is involved in the normal physiological differentiation and maturation of adipocyte, enhanced activation of MRs also contributes to increase oxidative stress, release of pro-inflammatory adipokines, and dysregulation of adipocyte autophagy. This, in turn, increases the maladaptive expansion of subcutaneous, visceral and perivascular adipose tissue, resulting in systemic and cardiovascular (CV) insulin resistance and increased CV stiffness and impaired vascular and cardiac relaxation. This review summarizes the normal role of MR activation in adipose tissues and explores the mechanisms by which excessive MR activation mediates adipose tissue inflammation and vascular dysfunction. Potential preventative and therapeutic strategies directed in the prevention of MR activation and CV disease are also discussed.
Clinical and basic studies have documented that both hyperglycemia and insulin-resistance/hyperinsulinemia not only constitute metabolic disorders contributing to cardiometabolic syndrome, but also ...predispose to diabetic vasculopathy, which refers to diabetes-mellitus-induced microvascular and macrovascular complications, including retinopathy, neuropathy, atherosclerosis, coronary artery disease, hypertension, and peripheral artery disease. The underlying molecular and cellular mechanisms include inappropriate activation of the renin angiotensin-aldosterone system, mitochondrial dysfunction, excessive oxidative stress, inflammation, dyslipidemia, and thrombosis. These abnormalities collectively promote metabolic disorders and further promote diabetic vasculopathy. Recent evidence has revealed that endothelial progenitor cell dysfunction, gut dysbiosis, and the abnormal release of extracellular vesicles and their carried microRNAs also contribute to the development and progression of diabetic vasculopathy. Therefore, clinical control and treatment of diabetes mellitus, as well as the development of novel therapeutic strategies are crucial in preventing cardiometabolic syndrome and related diabetic vasculopathy. The present review focuses on the relationship between insulin resistance and diabetes mellitus in diabetic vasculopathy and related cardiovascular disease, highlighting epidemiology and clinical characteristics, pathophysiology, and molecular mechanisms, as well as management strategies.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Enhanced activation of the endothelial mineralocorticoid receptor contributes to the development of arterial stiffness, which is an independent predictor of cardiovascular disease. Previously, we ...showed that enhanced endothelium mineralocorticoid receptor signaling in female mice prompts expression and translocation of the α-subunit of the epithelial sodium channel to the endothelial cell (EC) surface (EnNaC) inducing vascular fibrosis and stiffness. Further, amiloride, an epithelial sodium channel antagonist, inhibits vascular fibrosis, remodeling, and stiffness induced by feeding a Western diet high in saturated fat and refined carbohydrates. However, how this occurs remains unknown. Thereby, we hypothesized that endothelial cell–specific EnNaC activation is necessary for aldosterone-mediated endothelium stiffness. To address this notion, EnNaC α-subunit knockout (EnNaC) and wild-type littermate female mice were administrated aldosterone (250 µg/kg per day) via osmotic minipumps for 3 weeks beginning at 25 to 28 weeks of age. In isolated mouse endothelial cells, inward sodium currents were significantly reduced in amiloride controls, as well as in EnNaC. Likewise, aldosterone-induced endothelium stiffness was increased and endothelium-dependent relaxation less in EnNaC versus wild-type. Further, EnNaC mice exhibited attenuated responses to aldosterone infusion, including aortic endoplasmic reticulum stress, endothelium nitric oxide synthase activation, endothelium permeability, expression of proinflammatory cytokines, oxidative stress, and aortic collagen 1 deposition, supporting the notion that αEnNaC subunit activation contributes to these vascular responses.
Overnutrition, mTOR signaling, and cardiovascular diseases Jia, Guanghong; Aroor, Annayya R; Martinez-Lemus, Luis A ...
American journal of physiology. Regulatory, integrative and comparative physiology,
11/2014, Volume:
307, Issue:
10
Journal Article
Peer reviewed
Open access
The prevalence of obesity and associated medical disorders has increased dramatically in the United States and throughout much of the world in the past decade. Obesity, induced by excess intake of ...carbohydrates and fats, is a major cause of Type 2 diabetes, hypertension, and the cardiorenal metabolic syndrome. There is emerging evidence that excessive nutrient intake promotes signaling through the mammalian target of rapamycin (mTOR), which, in turn, may lead to alterations of cellular metabolic signaling leading to insulin resistance and obesity-related diseases, such as diabetes, cardiovascular and kidney disease, as well as cancer. While the pivotal role of mTOR signaling in regulating metabolic stress, autophagy, and adaptive immune responses has received increasing attention, there remain many gaps in our knowledge regarding this important nutrient sensor. For example, the precise cellular signaling mechanisms linking excessive nutrient intake and enhanced mTOR signaling with increased cardiovascular and kidney disease, as well as cancer, are not well understood. In this review, we focus on the effects that the interaction between excess intake of nutrients and enhanced mTOR signaling have on the promotion of obesity-associated diseases and potential therapeutic strategies involving targeting mTOR signaling.
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