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Current Problems in Cardiology Jan 2024Diabetes mellitus (DM) is considered by many the pandemic of the 21st century and is associated with multiple organ damages. Among these, cardiovascular complications... (Review)
Review
Diabetes mellitus (DM) is considered by many the pandemic of the 21st century and is associated with multiple organ damages. Among these, cardiovascular complications are responsible for an incredible burden of mortality and morbidity in Western Countries. The study of the pathological mechanisms responsible for the cardiovascular complications in DM patients is key for the development of new therapeutic strategies. The metabolic disorders caused by hyperglycemia, insulin resistance, and dyslipidemia, results in a cascade of pathomorphological changes favoring the atherosclerotic process and leading to myocardial remodeling. Parallel to this, oxidative stress, calcium overload, mitochondrial dysfunction, activation of protein kinase C signaling pathways, myocardial lipomatosis, and low-grade inflammation of the myocardium - are the main pathways responsible for the diabetic cardiomyopathy development. This review aims to appraise and discuss the pathogenetic mechanisms behind the diabetic cardiomyopathy development.
Topics: Humans; Diabetic Cardiomyopathies; Myocardium; Oxidative Stress; Signal Transduction; Diabetes Mellitus
PubMed: 37640176
DOI: 10.1016/j.cpcardiol.2023.102052 -
Cardiovascular Diabetology Oct 2023The PI3K/AKT pathway transduces the majority of the metabolic actions of insulin. In addition to cytosolic targets, insulin-stimulated phospho-AKT also translocates to...
BACKGROUND
The PI3K/AKT pathway transduces the majority of the metabolic actions of insulin. In addition to cytosolic targets, insulin-stimulated phospho-AKT also translocates to mitochondria in the myocardium. Mouse models of diabetes exhibit impaired mitochondrial AKT signaling but the implications of this on cardiac structure and function is unknown. We hypothesized that loss of mitochondrial AKT signaling is a critical step in cardiomyopathy and reduces cardiac oxidative phosphorylation.
METHODS
To focus our investigation on the pathophysiological consequences of this mitochondrial signaling pathway, we generated transgenic mouse models of cardiac-specific, mitochondria-targeting, dominant negative AKT1 (CAMDAKT) and constitutively active AKT1 expression (CAMCAKT). Myocardial structure and function were examined using echocardiography, histology, and biochemical assays. We further investigated the underlying effects of mitochondrial AKT1 on mitochondrial structure and function, its interaction with ATP synthase, and explored in vivo metabolism beyond the heart.
RESULTS
Upon induction of dominant negative mitochondrial AKT1, CAMDAKT mice developed cardiac fibrosis accompanied by left ventricular hypertrophy and dysfunction. Cardiac mitochondrial oxidative phosphorylation efficiency and ATP content were reduced, mitochondrial cristae structure was lost, and ATP synthase structure was compromised. Conversely, CAMCAKT mice were protected against development of diabetic cardiomyopathy when challenged with a high calorie diet. Activation of mitochondrial AKT1 protected cardiac function and increased fatty acid uptake in myocardium. In addition, total energy expenditure was increased in CAMCAKT mice, accompanied by reduced adiposity and reduced development of fatty liver.
CONCLUSION
CAMDAKT mice modeled the effects of impaired mitochondrial signaling which occurs in the diabetic myocardium. Disruption of this pathway is a key step in the development of cardiomyopathy. Activation of mitochondrial AKT1 in CAMCAKT had a protective role against diabetic cardiomyopathy as well as improved metabolism beyond the heart.
Topics: Animals; Mice; Adenosine Triphosphate; Diabetes Mellitus; Diabetic Cardiomyopathies; Energy Metabolism; Insulin; Mice, Transgenic; Mitochondria, Heart; Myocardium; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt
PubMed: 37891673
DOI: 10.1186/s12933-023-02020-1 -
International Journal of Molecular... Jun 2023Diabetic cardiomyopathy (DCM) is a cardiovascular disease which has been reported as a major cause of mortality worldwide for several years. Berberine (BBR) is a natural...
Diabetic cardiomyopathy (DCM) is a cardiovascular disease which has been reported as a major cause of mortality worldwide for several years. Berberine (BBR) is a natural compound extracted from a Chinese herb, with a clinically reported anti‑DCM effect; however, its molecular mechanisms have not yet been fully elucidated. The present study indicated that BBR markedly alleviated DCM by inhibiting IL‑1β secretion and the expression of gasdermin D (Gsdmd) at the post‑transcriptional level. Considering the importance of microRNAs (miRNAs/miRs) in the regulation of the post‑transcriptional process of specific genes, the ability of BBR to upregulate the expression levels of miR‑18a‑3p by activating its promoter (‑1,000/‑500) was examined. Notably, miR‑18a‑3p targeted Gsdmd and abated pyroptosis in high glucose‑treated H9C2 cells. Moreover, miR‑18a‑3p overexpression inhibited Gsdmd expression and improved biomarkers of cardiac function in a rat model of DCM. On the whole, the findings of the present study indicate that BBR alleviates DCM by inhibiting miR‑18a‑3p‑mediated Gsdmd activation; thus, BBR may be considered a potential therapeutic agent for the treatment of DCM.
Topics: Animals; Rats; Berberine; Diabetes Mellitus; Diabetic Cardiomyopathies; Inflammasomes; MicroRNAs; Pyroptosis
PubMed: 37114562
DOI: 10.3892/ijmm.2023.5252 -
International Journal of Molecular... Jul 2022Diabetic cardiomyopathy (DCM) is defined as the presence in diabetic patients of abnormal cardiac structure and performance (such as left ventricular hypertrophy,... (Review)
Review
Diabetic cardiomyopathy (DCM) is defined as the presence in diabetic patients of abnormal cardiac structure and performance (such as left ventricular hypertrophy, fibrosis, and arrhythmia) in the absence of other cardiac risk factors (such as hypertension or coronary artery disease). Although the pathogenesis of DCM remains unclear currently, mitochondrial structural and functional dysfunctions are recognised as a central player in the DCM development. In this review, we focus on the role of mitochondrial dynamics, biogenesis and mitophagy, Ca metabolism and bioenergetics in the DCM development and progression. Based on the crucial role of mitochondria in DCM, application of mitochondria-targeting therapies could be effective strategies to slow down the progression of the disease.
Topics: Diabetes Mellitus; Diabetic Cardiomyopathies; Heart; Humans; Mitochondria; Mitochondrial Dynamics; Mitophagy
PubMed: 35887211
DOI: 10.3390/ijms23147863 -
Oxidative Medicine and Cellular... 2022As a serious cardiovascular complication, diabetic cardiomyopathy (DCM) refers to diabetes-related changes in myocardial structure and function, which is obviously... (Review)
Review
As a serious cardiovascular complication, diabetic cardiomyopathy (DCM) refers to diabetes-related changes in myocardial structure and function, which is obviously different from those cardiomyopathy secondary to hypertension, coronary heart disease, and valvular disease. The clinical features of DCM are left ventricular hypertrophy, myocardial fibrosis, and impaired diastolic function. DCM will lead to cardiac dysfunction, eventually progress to cardiac arrhythmia, heart failure, and sudden cardiac death. At present, the pathogenesis of DCM is complex and not fully elucidated, and oxidative stress (OS), inflammatory response, glucolipid metabolism disorder, etc., are considered as the potential pathophysiological mechanisms. As a consequence, there is no specific and effective treatment for DCM. OS refers to the imbalance between reactive oxygen species (ROS) accumulation and scavenging, oxidation, and antioxidants in vivo, which is widely studied in DCM. Numerous studies have pointed out that regulating the OS signaling pathways and reducing the generation and accumulation of ROS are potential directions for the treatment of DCM. This review summarizes the major OS signaling pathways that are related to the pathogenesis of DCM, providing ideas about further research and therapy.
Topics: Diabetes Complications; Diabetic Cardiomyopathies; Humans; NF-kappa B; Oxidative Stress; Reactive Oxygen Species; Signal Transduction; Sirtuin 1
PubMed: 35103095
DOI: 10.1155/2022/5913374 -
Frontiers in Endocrinology 2021The global burden of diabetes mellitus and its complications are currently increasing. Diabetic cardiomyopathy (DCM) is the main cause of diabetes mellitus associated... (Review)
Review
The global burden of diabetes mellitus and its complications are currently increasing. Diabetic cardiomyopathy (DCM) is the main cause of diabetes mellitus associated morbidity and mortality; therefore, a comprehensive understanding of DCM development is required for more effective treatment. A disorder of epigenetic posttranscriptional modification of histones in chromatin has been reported to be associated with the pathology of DCM. Recent studies have implicated that histone deacetylases could regulate cardiovascular and metabolic diseases in cellular processes including cardiac fibrosis, hypertrophy, oxidative stress and inflammation. Therefore in this review, we summarized the roles of histone deacetylases in the pathogenesis of DCM, aiming to provide insights into exploring potential preventative and therapeutic strategies of DCM.
Topics: Diabetic Cardiomyopathies; Epigenesis, Genetic; Histone Deacetylases; Humans; Myocardium; Oxidative Stress
PubMed: 34367065
DOI: 10.3389/fendo.2021.679655 -
Biomedicine & Pharmacotherapy =... Jun 2024Diabetic cardiomyopathy (DCM) is a cardiac microvascular complication caused by metabolic disorders. It is characterized by myocardial remodeling and dysfunction. The... (Review)
Review
Diabetic cardiomyopathy (DCM) is a cardiac microvascular complication caused by metabolic disorders. It is characterized by myocardial remodeling and dysfunction. The pathogenesis of DCM is associated with abnormal cellular metabolism and organelle accumulation. Autophagy is thought to play a key role in the diabetic heart, and a growing body of research suggests that modulating autophagy may be a potential therapeutic strategy for DCM. Here, we have summarized the major signaling pathways involved in the regulation of autophagy in DCM, including Adenosine 5'-monophosphate-activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR), Forkhead box subfamily O proteins (FOXOs), Sirtuins (SIRTs), and PTEN-inducible kinase 1 (PINK1)/Parkin. Given the significant role of autophagy in DCM, we further identified natural products and chemical drugs as regulators of autophagy in the treatment of DCM. This review may help to better understand the autophagy mechanism of drugs for DCM and promote their clinical application.
Topics: Diabetic Cardiomyopathies; Humans; Autophagy; Animals; Signal Transduction
PubMed: 38776677
DOI: 10.1016/j.biopha.2024.116790 -
Life Sciences Nov 2023Diabetic Mellitus has been characterized as the most prevalent disease throughout the globe associated with the serious morbidity and mortality of vital organs.... (Review)
Review
Diabetic Mellitus has been characterized as the most prevalent disease throughout the globe associated with the serious morbidity and mortality of vital organs. Cardiomyopathy is the major leading complication of diabetes and within this, myocardial dysfunction or failure is the leading cause of the emergency hospital admission. The review is aimed to comprehend the perspectives associated with diabetes-induced cardiovascular complications. The data was collected from several electronic databases such as Google Scholar, Science Direct, ACS publication, PubMed, Springer, etc. using the keywords such as diabetes and its associated complication, the prevalence of diabetes, the anatomical and physiological mechanism of diabetes-induced cardiomyopathy, the molecular mechanism of diabetes-induced cardiomyopathy, oxidative stress, and inflammatory stress, etc. The collected scientific data was screened by different experts based on the inclusion and exclusion criteria of the study. This review findings revealed that diabetes is associated with inefficient substrate utilization, inability to increase glucose metabolism and advanced glycation end products within the diabetic heart resulting in mitochondrial uncoupling, glucotoxicity, lipotoxicity, and initially subclinical cardiac dysfunction and finally in overt heart failure. Furthermore, several factors such as hypertension, overexpression of renin angiotensin system, hypertrophic obesity, etc. have been seen as majorly associated with cardiomyopathy. The molecular examination showed biochemical disability and generation of the varieties of free radicals and inflammatory cytokines and becomes are the substantial causes of cardiomyopathy. This review provides a better understanding of the involved pathophysiology and offers an open platform for discussing and targeting therapy in alleviating diabetes-induced early heart failure or cardiomyopathy.
Topics: Humans; Diabetic Cardiomyopathies; Heart Failure; Oxidative Stress; Diabetes Mellitus
PubMed: 37714373
DOI: 10.1016/j.lfs.2023.122087 -
International Immunopharmacology Oct 2023Diabetic cardiomyopathy (DCM) is a prevalent cardiovascular complication of diabetes mellitus, characterized by high morbidity and mortality rates worldwide. However,... (Review)
Review
Diabetic cardiomyopathy (DCM) is a prevalent cardiovascular complication of diabetes mellitus, characterized by high morbidity and mortality rates worldwide. However, treatment options for DCM remain limited. For decades, a substantial body of evidence has suggested that the inflammatory response plays a pivotal role in the development and progression of DCM. Notably, DCM is closely associated with alterations in inflammatory cells, exerting direct effects on major resident cells such as cardiomyocytes, vascular endothelial cells, and fibroblasts. These cellular changes subsequently contribute to the development of DCM. This article comprehensively analyzes cellular, animal, and human studies to summarize the latest insights into the impact of inflammation on DCM. Furthermore, the potential therapeutic effects of current anti-inflammatory drugs in the management of DCM are also taken into consideration. The ultimate goal of this work is to consolidate the existing literature on the inflammatory processes underlying DCM, providing clinicians with the necessary knowledge and tools to adopt a more efficient and evidence-based approach to managing this condition.
Topics: Animals; Humans; Diabetic Cardiomyopathies; Endothelial Cells; Inflammation; Myocytes, Cardiac; Anti-Inflammatory Agents; Diabetes Mellitus
PubMed: 37586299
DOI: 10.1016/j.intimp.2023.110747 -
Diabetologia Sep 2019Heart failure (HF) is an important comorbidity in individuals with diabetes. Most commonly, the condition is secondary to ischaemia and hypertension. Diabetic... (Review)
Review
Heart failure (HF) is an important comorbidity in individuals with diabetes. Most commonly, the condition is secondary to ischaemia and hypertension. Diabetic cardiomyopathy is becoming increasingly recognised as a cause of HF and blood glucose control plays a pivotal role in the prevention and treatment of HF. Since the US Food and Drug Administration regulatory guidance in 2008, new glucose-lowering agents are evaluated routinely by cardiovascular outcome trials. These trials offer a wealth of knowledge and allow better understanding of the risks and benefits of contemporary diabetes medications. In this review, we will focus on the risks of HF with emerging glucose-lowering therapies and the safety of these medications in patients with established HF. We will summarise the guidance that is available for the treatment algorithm of diabetes in those with HF and highlight future areas of research.
Topics: Algorithms; Diabetes Mellitus; Diabetic Cardiomyopathies; Female; Heart Failure; Humans; Hypoglycemic Agents; Male
PubMed: 31342083
DOI: 10.1007/s00125-019-4958-2