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Current Vascular Pharmacology 2021Having in mind that diabetes mellitus (DM) and obesity are some of the greatest health challenges of the modern era, diabetic cardiomyopathy (DCM) is becoming more and...
BACKGROUND
Having in mind that diabetes mellitus (DM) and obesity are some of the greatest health challenges of the modern era, diabetic cardiomyopathy (DCM) is becoming more and more recognized in clinical practice. Main Text: Initially, DM is asymptomatic, but it may progress to diastolic and then systolic left ventricular dysfunction, which results in congestive heart failure. A basic feature of this DM complication is the absence of hemodynamically significant stenosis of the coronary blood vessels. Clinical manifestations are the result of several metabolic disorders that are present during DM progression. The complexity of metabolic processes, along with numerous regulatory mechanisms, has been the subject of research that aims at discovering new diagnostic (e.g. myocardial strain with echocardiography and cardiac magnetic resonance) and treatment options. Adequate glycaemic control is not sufficient to prevent or reduce the progression of DCM. Contemporary hypoglycemic medications, such as sodium-glucose transport protein 2 inhibitors, significantly reduce the frequency of cardiovascular complications in patients with DM. Several studies have shown that, unlike the above-stated medications, thiazolidinediones and dipeptidyl peptidase-4 inhibitors are associated with deterioration of heart failure.
CONCLUSION
Imaging procedures, especially myocardial strain with echocardiography and cardiac magnetic resonance, are useful to identify the early signs of DCM. Research and studies regarding new treatment options are still "in progress".
Topics: Diabetic Cardiomyopathies; Echocardiography; Humans; Magnetic Resonance Imaging; Myocardium
PubMed: 33143612
DOI: 10.2174/1570161119999201102213214 -
Archives of Cardiovascular Diseases Nov 2020Besides coronary artery disease, which remains the main cause of heart failure in patients with diabetes, factors independent of coronary artery disease are involved in... (Review)
Review
Besides coronary artery disease, which remains the main cause of heart failure in patients with diabetes, factors independent of coronary artery disease are involved in the development of heart failure in the onset of what is called diabetic cardiomyopathy. Among them, hyperglycaemia - a hallmark of type 2 diabetes - has both acute and chronic deleterious effects on myocardial function, and clearly participates in the establishment of diabetic cardiomyopathy. In the present review, we summarize the cellular and tissular events that occur in a heart exposed to hyperglycaemia, and depict the complex molecular mechanisms proposed to be involved in glucotoxicity. Finally, from a more translational perspective, different therapeutic strategies targeting hyperglycaemia-mediated molecular mechanisms will be detailed.
Topics: Animals; Blood Glucose; Diabetes Mellitus; Diabetic Cardiomyopathies; Heart Failure; Humans; Hyperglycemia; Hypoglycemic Agents; Myocardium; Risk Factors; Signal Transduction
PubMed: 33189592
DOI: 10.1016/j.acvd.2020.06.006 -
Diabetes & Metabolism Jun 2020Type 2 diabetes (DT2) increases the risk of cardiovascular events and cardiac insufficiency. This insufficiency is mostly post-ischaemic in nature, but other aetiologies... (Review)
Review
Type 2 diabetes (DT2) increases the risk of cardiovascular events and cardiac insufficiency. This insufficiency is mostly post-ischaemic in nature, but other aetiologies are possible in this high-risk population. In patients with DT2, diabetic cardiomyopathy is a recognized cause of cardiac insufficiency secondary to chronic hyperglycaemia and myocardial lipotoxicity, which promotes cardiomyocyte hypertrophy (and, frequently, apoptosis of these cells), interstitial fibrosis and a decrease in myocardial contractile performance. Several studies have shown that diabetic cardiomyopathy is associated with modifications to the intestinal microbiota, and changes in the synthesis of bacterial metabolites and their diffusion into the host, some of which appear to have direct deleterious effects on cardiac contractility. These findings open up new perspectives for pathophysiological studies by establishing the presence of a 'microbiota-myocardium' axis and raising the possibility of innovative new treatments. Correction of intestinal dysbiosis in patients with cardiac insufficiency could, therefore, constitute an innovative therapeutic approach to cases of this disease with a poor prognosis.
Topics: Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Gastrointestinal Microbiome; Humans
PubMed: 31678397
DOI: 10.1016/j.diabet.2019.10.003 -
Trends in Molecular Medicine Jun 2021Diabetic cardiomyopathy is the leading cause of death among people with diabetes. Despite its severity and poor prognosis, there are currently no approved specific drugs... (Review)
Review
Diabetic cardiomyopathy is the leading cause of death among people with diabetes. Despite its severity and poor prognosis, there are currently no approved specific drugs to prevent or even treat diabetic cardiomyopathy. There is a need to understand the pathogenic mechanisms underlying the development of diabetic cardiomyopathy to design new therapeutic strategies. These mechanisms are complex and intricate and include metabolic dysregulation, inflammation, oxidative stress, fibrosis, and apoptosis. Sirtuins, a group of deacetylase enzymes, play an important role in all these processes and are, therefore, potential molecular targets for treating this disease. In this review, we discuss the role of sirtuins in the heart, focusing on their contribution to the pathogenesis of diabetic cardiomyopathy and how their modulation could be therapeutically useful.
Topics: Animals; Diabetes Mellitus; Diabetic Cardiomyopathies; Humans; Inflammation; Oxidative Stress; Signal Transduction; Sirtuins
PubMed: 33839024
DOI: 10.1016/j.molmed.2021.03.004 -
Pflugers Archiv : European Journal of... Jan 2022Diabetic cardiomyopathy is defined as the myocardial dysfunction that suffers patients with diabetes mellitus (DM) in the absence of hypertension and structural heart... (Review)
Review
Diabetic cardiomyopathy is defined as the myocardial dysfunction that suffers patients with diabetes mellitus (DM) in the absence of hypertension and structural heart diseases such as valvular or coronary artery dysfunctions. Since the impact of DM on cardiac function is rather silent and slow, early stages of diabetic cardiomyopathy, known as prediabetes, are poorly recognized, and, on many occasions, cardiac illness is diagnosed only after a severe degree of dysfunction was reached. Therefore, exploration and recognition of the initial pathophysiological mechanisms that lead to cardiac dysfunction in diabetic cardiomyopathy are of vital importance for an on-time diagnosis and treatment of the malady. Among the complex and intricate mechanisms involved in diabetic cardiomyopathy, Ca mishandling and mitochondrial dysfunction have been described as pivotal early processes. In the present review, we will focus on these two processes and the molecular pathway that relates these two alterations to the earlier stages and the development of diabetic cardiomyopathy.
Topics: Animals; Calcium; Cytosol; Diabetic Cardiomyopathies; Excitation Contraction Coupling; Humans; Mitochondria, Heart; Prediabetic State; Sarcoplasmic Reticulum
PubMed: 34978597
DOI: 10.1007/s00424-021-02650-y -
Journal of Cardiology Jan 2021Diabetic cardiomyopathy, clinically diagnosed as ventricular dysfunction in the absence of coronary atherosclerosis or hypertension in diabetic patients, is a cardiac... (Review)
Review
Diabetic cardiomyopathy, clinically diagnosed as ventricular dysfunction in the absence of coronary atherosclerosis or hypertension in diabetic patients, is a cardiac muscle-specific disease that increases the risk of heart failure and mortality. Its clinical course is characterized initially by diastolic dysfunction, later by systolic dysfunction, and eventually by clinical heart failure from an uncertain mechanism. Light microscopic features such as interstitial fibrosis, inflammation, and cardiomyocyte hypertrophy are observed in diabetic cardiomyopathy, but are common to failing hearts generally and are not specific to diabetic cardiomyopathy. Electron microscopic studies of biopsy samples from diabetic patients with heart failure have revealed that the essential mechanism underlying diabetic cardiomyopathy involves thickening of the capillary basement membrane, accumulation of lipid droplets, and glycogen as well as increased numbers of autophagic vacuoles within cardiomyocytes. Autophagy is a conserved mechanism that contributes to maintaining intracellular homeostasis by degrading long-lived proteins and damaged organelles and is observed more often in cardiomyocytes within failing hearts. Diabetes mellitus (DM) impairs cardiac metabolism and leads to dysregulation of energy substrates that contribute to cardiac autophagy. However, a "snapshot" showing greater numbers of autophagic vacuoles within cardiomyocytes may indicate that autophagy is activated into phagophore formation or is suppressed due to impairment of the lysosomal degradation step. Recent in vivo studies have shed light on the underlying molecular mechanism governing autophagy and its essential meaning in the diabetic heart. Autophagic responses to diabetic cardiomyopathy differ between diabetic types: they are enhanced in type 1 DM, but are suppressed in type 2 DM. This difference provides important insight into the pathophysiology of diabetic cardiomyopathy. Here, we review recent advances in our understanding of the pathophysiology of diabetic cardiomyopathy, paying particular attention to autophagy in the heart, and discuss the therapeutic potential of interventions modulating autophagy in diabetic cardiomyopathy.
Topics: Animals; Autophagy; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Heart Failure; Humans; Myocytes, Cardiac
PubMed: 32907780
DOI: 10.1016/j.jjcc.2020.05.009 -
Trends in Pharmacological Sciences Nov 2022Patients with diabetes have an increased risk of developing heart failure, preceded by (often asymptomatic) cardiac abnormalities, collectively called diabetic... (Review)
Review
Patients with diabetes have an increased risk of developing heart failure, preceded by (often asymptomatic) cardiac abnormalities, collectively called diabetic cardiomyopathy (DC). Diabetic heart failure lacks effective treatment, remaining an urgent, unmet clinical need. Although structural and functional characteristics of the diabetic human heart are well defined, clinical studies lack the ability to pinpoint the specific mechanisms responsible for DC. Preclinical animal models represent a vital component for understanding disease aetiology, which is essential for the discovery of new targeted treatments for diabetes-induced heart failure. In this review, we describe the current landscape of preclinical DC models (genetic, pharmacologically induced, and diet-induced models), highlighting their strengths and weaknesses and alignment to features of the human disease. Finally, we provide tools, resources, and recommendations to assist future preclinical translation addressing this knowledge gap.
Topics: Animals; Diabetes Mellitus; Diabetic Cardiomyopathies; Heart Failure; Humans
PubMed: 35779966
DOI: 10.1016/j.tips.2022.04.005 -
International Journal of Molecular... Nov 2023Ginsenoside Rg3 extracted from has therapeutic effects on diabetes and heart diseases. However, the underlying mechanism of ginsenoside Rg3 on diabetic cardiomyopathy...
Ginsenoside Rg3 extracted from has therapeutic effects on diabetes and heart diseases. However, the underlying mechanism of ginsenoside Rg3 on diabetic cardiomyopathy (DCM) remains unclear. 24-week-old diabetic db/db mice were treated with ginsenoside Rg3 for 12 weeks, then body weight, serum lipids, adiponectin levels, as well as cardiac function and pathological morphology, were measured. The targets of ginsenoside Rg3 and its regulation of the adiponectin pathway were also evaluated on 3T3-L1 or H9c2 cells. Ginsenoside Rg3 directly bound to PPAR-γ, improving adiponectin secretion and promoting adiponectin signaling. Significantly attenuated overweight, hyperglycemia, and hyperlipidemia, as well as alleviated lipid accumulation and dysfunction in adipose, liver, and heart tissues, were observed in the ginsenoside Rg3-treated group. Ginsenoside Rg3 could be a promising drug targeting PPAR-γ to treat diabetic cardiomyopathy.
Topics: Animals; Mice; Adiponectin; Diabetes Mellitus; Diabetic Cardiomyopathies; Ginsenosides; PPAR gamma; Signal Transduction
PubMed: 38069059
DOI: 10.3390/ijms242316736 -
Biology Direct Nov 2022Cardiac fibrosis is a leading cause of cardiac dysfunction in patients with diabetes. However, the underlying mechanisms of cardiac fibrosis remain unclear. This study...
BACKGROUND
Cardiac fibrosis is a leading cause of cardiac dysfunction in patients with diabetes. However, the underlying mechanisms of cardiac fibrosis remain unclear. This study aimed to investigate the role of the long non-coding RNA (LncRNA) Airn in the pathogenesis of cardiac fibrosis in diabetic cardiomyopathy (DCM) and its underlying mechanism.
METHODS
Diabetes mellitus (DM) was induced in mice by streptozotocin injection. An intramyocardial adeno-associated virus (AAV) was used to manipulate Airn expression. The functional significance and underlying mechanisms in DCM fibrosis were investigated both in vitro and in vivo.
RESULTS
Diabetic hearts showed a significant impairment in cardiac function, accompanied by obviously increased cardiac fibrosis. Interestingly, lncRNA Airn expression was significantly decreased in both diabetic hearts and high glucose (HG)-treated cardiac fibroblasts (CFs). AAV-mediated Airn reconstitution prevented cardiac fibrosis and the development of DCM, while Airn knockdown induced cardiac fibrosis phenotyping DCM. As in vitro, Airn reversed HG-induced fibroblast-myofibroblast transition, aberrant CFs proliferation and section of collagen I. In contrast, Airn knockdown mimicked a HG-induced CFs phenotype. Mechanistically, we identified that Airn exerts anti-fibrotic effects by directly binding to insulin-like growth factor 2 mRNA-binding protein 2 (IMP2) and further prevents its ubiquitination-dependent degradation. Moreover, we revealed that Airn/IMP2 protected p53 mRNA from degradation in m6A manner, leading to CF cell cycle arrest and reduced cardiac fibrosis. As a result, ablation of p53 blunted the inhibitory effects of Airn on fibroblast activation and cardiac fibrosis.
CONCLUSIONS
Our study demonstrated for the first time that Airn prevented the development of cardiac fibrosis in diabetic heart via IMP2-p53 axis in an m6A dependent manner. LncRNA Airn could be a promising therapeutic target for cardiac fibrosis in DCM.
Topics: Animals; Mice; Diabetes Mellitus; Diabetic Cardiomyopathies; Fibroblasts; Fibrosis; RNA, Long Noncoding; RNA, Messenger; Tumor Suppressor Protein p53; RNA-Binding Proteins
PubMed: 36384975
DOI: 10.1186/s13062-022-00346-6 -
Toxicology and Applied Pharmacology Oct 2023Oxidative stress and insulin resistance are two key mechanisms for the development of diabetic cardiomyopathy (DCM, cardiac remodeling and dysfunction). In this review,... (Review)
Review
Oxidative stress and insulin resistance are two key mechanisms for the development of diabetic cardiomyopathy (DCM, cardiac remodeling and dysfunction). In this review, we discussed how zinc and metallothionein (MT) protect the heart from type 1 or type 2 diabetes (T1D or T2D) through its anti-oxidative function and insulin-mediated PI3K/Akt signaling activation. Both T1D and T2D-induced DCM, shown by cardiac structural remodeling and dysfunction, in wild-type mice, but not in cardiomyocyte-specific overexpressing MT mice. In contrast, mice with global MT gene deletion were more susceptible to the development of DCM. When we used zinc to treat mice with either T1D or T2D, cardiac remodeling and dysfunction were significantly prevented along with increased cardiac MT expression. To support the role of zinc homeostasis in insulin signaling pathways, treatment of diabetic mice with zinc showed the preservation of phosphorylation levels of insulin-mediated glucose metabolism-related Akt2 and GSK-3β and even rescued cardiac pathogenesis induced by global deletion of Akt2 gene in a MT-dependent manner. These results suggest the protection by zinc from DCM is through both the induction of MT and sensitization of insulin signaling. Combined our own and other works, this review comprehensively summarized the roles of zinc homeostasis in the development and progression of DCM and its therapeutic implications. At the end, we provided pre-clinical and clinical evidence for the preventive and therapeutic potential of zinc supplementation through its anti-oxidative stress and sensitizing insulin signaling actions. Understanding the intricate connections between zinc and DCM provides insights for the future interventional approaches.
Topics: Mice; Animals; Diabetic Cardiomyopathies; Zinc; Insulin; Diabetes Mellitus, Type 2; Diabetes Mellitus, Type 1; Diabetes Mellitus, Experimental; Ventricular Remodeling; Glycogen Synthase Kinase 3 beta; Phosphatidylinositol 3-Kinases; Myocytes, Cardiac; Signal Transduction; Oxidative Stress
PubMed: 37739320
DOI: 10.1016/j.taap.2023.116694