Cardiovascular disease (CVD) is the leading cause of morbidity and mortality among patients with diabetes mellitus (DM). DM can lead to multiple cardiovascular complications, including coronary artery disease (CAD), cardiac hypertrophy, and heart failure (HF). HF represents one of the most common causes of death in patients with DM and results from DM-induced CAD and diabetic cardiomyopathy. Oxidative stress is closely associated with the pathogenesis of DM and results from overproduction of reactive oxygen species (ROS). ROS overproduction is associated with hyperglycemia and metabolic disorders, such as impaired antioxidant function in conjunction with impaired antioxidant activity. Long-term exposure to oxidative stress in DM induces chronic inflammation and fibrosis in a range of tissues, leading to formation and progression of disease states in these tissues. Indeed, markers for oxidative stress are overexpressed in patients with DM, suggesting that increased ROS may be primarily responsible for the development of diabetic complications. Therefore, an understanding of the pathophysiological mechanisms mediated by oxidative stress is crucial to the prevention and treatment of diabetes-induced CVD. The current review focuses on the relationship between diabetes-induced CVD and oxidative stress, while highlighting the latest insights into this relationship from findings on diabetic heart and vascular disease.
BackgroundType 2 diabetes mellitus (T2DM) greatly increases the risks of cardiovascular disease and heart failure. In particular, left ventricular diastolic dysfunction that develops from the early stages of T2DM is an important factor in the onset and exacerbation of heart failure. The effect of sodium-glucose cotransporter 2 inhibitors on left ventricular diastolic function has not been elucidated. We have performed the first prospective study on the effects of canagliflozin on left ventricular diastolic function in T2DM.MethodsThis study was performed to evaluate the effects of additional treatment with canagliflozin for 3 months on left ventricular diastolic function in patients with T2DM. A total of 38 patients with T2DM were consecutively recruited for this study. Left ventricular diastolic function was assessed by echocardiography. The primary study outcome was a change in the septal E/e′ as a parameter of left ventricular diastolic function.ResultsA total of 37 patients (25 males and 12 females) were included in the analysis. Mean age of participants was 64.2 ± 8.1 years (mean ± SD), mean duration of diabetes was 13.5 ± 8.1 years, and mean HbA1c was 7.9 ± 0.7%. Of the participants, 86.5% had hypertension, 100% had dyslipidemia, and 32.4% had cardiovascular disease. Canagliflozin significantly improved left ventricular diastolic function (septal E/e′ ratio 13.7 ± 3.5–12.1 ± 2.8, p = 0.001). Furthermore, among the various parameters that changed through the administration of canagliflozin, only changes in hemoglobin significantly correlated with changes in the septal E/e′ ratio (p = 0.002). In multiple regression analysis, changes in hemoglobin were also revealed to be an independent predictive factor for changes in the septal E/e′ ratio.ConclusionsThis study showed for the first time that canagliflozin could improve left ventricular diastolic function within 3 months in patients with T2DM. The benefit was especially apparent in patients with substantially improved hemoglobin values.Trial registration UMIN Clinical Trials Registry UMIN000028141Electronic supplementary materialThe online version of this article (10.1186/s12933-018-0717-9) contains supplementary material, which is available to authorized users.
To identify a novel target for the treatment of heart failure, we examined gene expression in the failing heart. Among the genes analyzed, Alox15 encoding the protein 12/15 lipoxygenase (LOX) was markedly up-regulated in heart failure. To determine whether increased expression of 12/15-LOX causes heart failure, we established transgenic mice that overexpressed 12/15-LOX in cardiomyocytes. Echocardiography showed that Alox15 transgenic mice developed systolic dysfunction. Cardiac fibrosis increased in Alox15 transgenic mice with advancing age and was associated with the infiltration of macrophages. Consistent with these observations, cardiac expression of monocyte chemoattractant protein 1 (MCP-1) was up-regulated in Alox15 transgenic mice compared with wild-type mice. Treatment with 12-hydroxy-eicosatetraenoic acid, a major metabolite of 12/15-LOX, increased MCP-1 expression in cardiac fibroblasts and endothelial cells but not in cardiomyocytes. Inhibition of MCP-1 reduced the infiltration of macrophages into the myocardium and prevented both systolic dysfunction and cardiac fibrosis in Alox15 transgenic mice. Likewise, disruption of 12/15-LOX significantly reduced cardiac MCP-1 expression and macrophage infiltration, thereby improving systolic dysfunction induced by chronic pressure overload. Our results suggest that cardiac 12/15-LOX is involved in the development of heart failure and that inhibition of 12/15-LOX could be a novel treatment for this condition.
Evaluation of OGTT Normal type: if both values belong to normal range Diabetic type a : if any of the two values falls into diabetic range Borderline type: neither normal nor diabetic types Even for normal type, if 1-h value is C180 mg/dL (10.0 mmol/L), the risk of progression to diabetes mellitus is greater than for \180 mg/dL (10.0 mmol/L) and should be treated as with borderline type (follow up observation, etc.). Fasting plasma glucose level of 100-109 mg/dL (5.5-6.0 mmol/L) is called ''high-normal'': within the range of normal fasting plasma glucose. Plasma glucose level after glucose load in OGTT is not included in casual plasma glucose levels a Casual plasma glucose C200 mg/dL (C11.1 mmol/L) and HbA1c C6.5 % are also regarded as to indicate diabetic type Evidence-based practice guideline 2013 153
Diabetes affects cardiac structure and function, and it has been suggested that diabetes leads to cardiomyopathy. Arachidonate 12/15-lipoxygenase (LOX) has been suggested to play an important role in atherogenesis and heart failure. However, the role of 12/15-LOX in diabetic cardiomyopathy has not been examined. In this study, we investigated the effects of cardiac 12/15-LOX on diabetic cardiomyopathy. We created streptozotocin (STZ)-induced diabetic mice and compared them with Alox15-deficient mice. Expression of 12/15-LOX and inflammatory cytokines such as tumor necrosis factor (TNF)-α and nuclear factor (NF)-κB were upregulated in STZ-induced diabetic hearts. Disruption of 12/15-LOX significantly improved STZ-induced cardiac dysfunction and fibrosis. Moreover, deletion of 12/15-LOX inhibited the increases of TNF-α and NF-κB as well as the production of STZ-induced reactive oxygen species in the heart. Administration of N-acetylcysteine in diabetic mice prevented STZ-induced cardiac fibrosis. Neonatal cultured cardiomyocytes exposed to high glucose conditions induced the expression of 12/15-LOX as well as TNF-α, NF-κB, and collagen markers. These increases were inhibited by treatment of the 12/15-LOX inhibitor. Our results suggest that cardiac 12/15-LOX–induced inflammation and oxidative stress are involved in the development of diabetic cardiomyopathy and that inhibition of 12/15-LOX could be a novel treatment for this condition.
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