Cardiovascular diseases (CVDs) remain a significant public health burden, characterized by escalating morbidity and mortality rates and demanding novel therapeutic approaches. Cold shock protein Y-box binding protein 1 (YB-1), a highly conserved RNA/DNA-binding protein, has emerged as a pivotal regulator in various pathophysiological processes, including CVDs. YB-1 exerts pleiotropic functions by modulating gene transcription, pre-mRNA splicing, mRNA translation, and stability. The expression and function of YB-1 are intricately regulated by its subcellular localization, post-translational modifications, upstream regulatory signals. YB-1 plays a multifaceted role in CVDs, influencing inflammation, oxidative stress, cell proliferation, apoptosis, phenotypic switching of smooth muscle cells, and mitochondrial dysfunction. However, the regulation of YB-1 expression and function in CVDs is complex and context-dependent, exhibiting divergent effects even in the same disease across different cell types or at disease stages. This review comprehensively explores the structure, regulation, and functional significance of YB-1 in CVDs. We delve into the transcriptional and translational control mechanisms of YB-1, as well as its post-translational modifications. Furthermore, we elucidate the upstream signaling pathways that influence YB-1 expression, with a particular emphasis on non-coding RNAs and specific upstream molecules. Finally, we systematically examine the role of YB-1 in CVDs, summarizing its expression patterns, regulatory mechanisms, and therapeutic potential as a promising target for novel therapeutic interventions. By providing a comprehensive overview of YB-1's involvement in CVDs, this review aims to stimulate further research and facilitate the development of targeted therapies to improve cardiovascular health.

Cardiovascular complications are the primary cause of mortality and disability among diabetic patients. Lonicerin, a major bioactive compound in Lonicera japonica Thunb., has unclear effects and mechanisms on diabetic vascular injury.

The research aims to investigate the therapeutic effects of lonicerin on diabetic vascular injury and elucidate its underlying molecular mechanisms.

Streptozotocin (STZ)-induced mice and high glucose-treated human aortic endothelial cells (HAECs) were employed as animal and cellular models of diabetes. Endothelial-to-mesenchymal transition (EndMT) was validated by examining EndMT-related markers and endothelial/mesenchymal functions. RNA sequencing was used to identify potential mechanisms through which lonicerin alleviates EndMT. The relationship between lonicerin and its targets was investigated using RNAi, plasmid overexpression, western blot, qRT-PCR, immunofluorescence, flow cytometry, and calcineurin activity assays.

Lonicerin dose-dependently alleviates diabetes-induced vascular injury (intimal damage, inflammation, calcification, and fibrosis) and EndMT. Lonicerin produces anti-EndMT effect by inhibiting cytoplasmic Ca²⁺ levels. Further analysis reveals that adrenoceptor alpha 1D (ADRA1D) and R-spondin 3 (RSPO3) are targets of lonicerin. Lonicerin reduces high glucose-induced upregulation of ADRA1D and RSPO3, leading to decreased cytoplasmic Ca²⁺ levels. This reduction inhibits calcineurin activity, promotes nuclear factor of activated T cells 1 (NFAT1) phosphorylation, and prevents its nuclear translocation, ultimately exerting an anti-EndMT effect. EC-specific overexpression of ADRA1D or RSPO3 negates the inhibitory effects of lonicerin on EndMT and its therapeutic impact on diabetic vascular injury.

Lonicerin targets ADRA1D and RSPO3 to ameliorate diabetes-induced vascular injury through the Ca2+/Calcineurin/NFAT1-dependent anti-EndMT pathway. Thus, this study provides the first evidence that lonicerin is a potential novel therapeutic agent for diabetic vasculopathy.

Diabetic cardiomyopathy (DCM) is a common complication of type 2 diabetes mellitus (T2DM). The effects of methylophiopogonanone A (MO-A), a natural homoisoflavonoid with anti-inflammatory effects, on DCM and its underlying mechanisms were investigated in this study.

The T2DM mouse model was induced by intraperitoneal injection of 30 mg/kg streptozotocin for 7 consecutive days and fed with a high-fat diet for 12 weeks. T2DM mice received MO-A (2.5, 5, or 10 mg/kg) treatment for two weeks. Cardiac function, hypertrophy, fibrosis, and inflammation were evaluated. The binding energy between MO-A and JNK1 was analyzed using molecular docking. The underlying mechanism was further investigated in high glucose (HG)-induced H9C2 cells. The cytotoxic effects, cardiomyocyte hypertrophy, fibrosis, inflammation, and relevant signaling proteins were assessed.

MO-A treatment alleviated cardiac function and histopathological changes in DCM mice. Moreover, MO-A treatment significantly decreased COLI, TGF-β1, MYH7, and ANP expression levels in DCM mice. Furthermore, TNF-α, IL-6, and IL-1β expression levels were notably downregulated after treatment with MO-A in DCM mice. Similar results were also observed in vitro. Mechanistically, MO-A targets JNK1 and downregulates its phosphorylation levels in DCM mice. The protective properties of MO-A were reversed by JNK1 overexpression in HG-induced H9C2 cells.

Our results revealed that MO-A could alleviate cardiac function, hypertrophy, fibrosis, and inflammation in DCM via inhibiting JNK1 signaling.

The fatty acid (FA) transporter CD36 (FA translocase/cluster of differentiation 36) is the gatekeeper of cardiac FA metabolism. Preferential localisation of CD36 to the sarcolemma is one of the initiating cellular responses in the development of muscle insulin resistance and in the type 2 diabetic heart. Post-translational S-acylation controls protein trafficking, and in this study we hypothesised that increased CD36 S-acylation may underpin the preferential sarcolemmal localisation of CD36, driving metabolic and contractile dysfunction in diabetes.

Type 2 diabetes was induced in the rat using high fat diet and a low dose of streptozotocin. Forkhead box O1 (FoxO1) transcriptional regulation of zDHHC4 (zinc finger DHHC-type palmitoyltransferase 4) and subsequent S-acylation of CD36 was assessed using chromatin immunoprecipitation (ChIP) sequencing, ChIP-quantitative polymerase chain reaction, luciferase assays, siRNA (small interfering RNA) and shRNA silencing.

Type 2 diabetes increased cardiac CD36 S-acylation, CD36 sarcolemmal localisation, FA oxidation rates and triglyceride storage in the diabetic heart. CD36 S-acylation was increased in diabetic rats, db/db mice, diabetic pigs and insulin-resistant human iPSC-derived cardiomyocytes, demonstrating conservation between species. The enzyme responsible for S-acylating CD36, zDHHC4, was transcriptionally upregulated in the diabetic heart, and genetic silencing of zDHHC4 decreased CD36 S-acylation. We identified that zDHHC4 expression is under the regulation of the transcription factor FoxO1. Diabetic mice with cardiomyocyte-specific FoxO1 deletion had decreased cardiac zDHHC4 expression and decreased CD36 S-acylation, which was further confirmed using diabetic mice treated with the FoxO1 inhibitor AS1842856. Pharmacological inhibition of zDHHC enzymes in diabetic hearts decreased CD36 S-acylation, sarcolemmal CD36 content, FA oxidation rates and triglyceride storage, culminating in improved cardiac function in diabetes. Conversely, inhibiting the de-acylating enzymes in control hearts increased CD36 S-acylation, sarcolemmal CD36 content and FA metabolic rates in control hearts, recapitulating the metabolic phenotype seen in diabetic hearts.

Activation of the FoxO1-zDHHC4-CD36 S-acylation axis drives metabolic and contractile dysfunction in the type 2 diabetic heart.

Patients with diabetes are at an increased risk of diabetic cardiomyopathy (DCM) and acute myocardial infarction (AMI). Protecting the heart against AMI is more challenging in DCM than in nondiabetic hearts. We investigated whether intravenous (i.v.) atorvastatin administration during AMI exerts cardioprotection in DCM as seen in nondiabetic hearts. Sprague-Dawley rats were divided into streptozotocin-induced DCM and normoglycemic control groups. Our model of DCM rats exhibited interstitial fibrosis and cardiac dysfunction at 5 weeks. At this time point, all animals underwent AMI induction (coronary ligation for 45 min), receiving i.v. atorvastatin or vehicle during ischemia. Animals were reperfused and sacrificed 24 h later for myocardial infarct size analysis and cardiac tissue sampling. Echocardiography was performed. DCM vehicle rats had larger infarcts than normoglycemic vehicle-treated animals at a comparable area-at-risk. Intravenous atorvastatin reduced infarct size and preserved systolic function in both groups. Compared with vehicle animals, i.v. atorvastatin inhibited RhoA membrane translocation, induced AMPK phosphorylation, prevented apoptosis execution, and improved cardiac remodelling in the infarcted heart of both groups, whereas innate immune cell infiltration was further reduced in i.v. atorvastatin-treated DCM animals. The proven cardioprotective effectiveness of this i.v. statin formulation in the presence of DCM warrants its further development into a clinically therapeutic option.

Diabetic cardiomyopathy (DCM) significantly increases the risk of acute myocardial infarction and attenuates or abolishes the cardioprotective effects of several therapeutic approaches. Whether intravenous atorvastatin administration during ongoing acute myocardial infarction retains its cardioprotective potential in the presence of DCM was investigated. Intravenous atorvastatin during ischemia reduces infarct size and preserves cardiac function in DCM rats. The efficacy of this intravenous statin formulation in DCM supports its development as a viable therapeutic option for clinical use.

Individuals with diabetes have an elevated risk of heart disease, and there is a significant clinical need for evidence-based treatments. Heart disease in diabetes manifests as a distinct cardiopathology, with cardiac structural and functional remodeling underlying increased susceptibility to cardiac dysfunction and arrhythmias. An understanding of the mechanisms associated with cardiac vulnerability in diabetes is incomplete, but recent studies have advanced new insights into the roles of metabolic disturbances, gene dysregulation and epicardial adipose influence. This perspective article highlights these three promising new developments in proposed mechanisms, and discusses exciting advances in cardiac-targeting for potential treatment of diabetic heart disease.

Among the multitude of pressing global health concerns, diabetes mellitus stands out as a significant issue. An alarming consequence of this condition is diabetic cardiomyopathy (DCM), which represents a critical contributor to mortality in individuals with diabetes. Recently, research has unveiled the pivotal role that pyroptosis plays in the progression of myocardial fibrosis associated with DCM. An epimedial flavonoid monomer, Icariin (ICA), primarily sourced from Epimedium genus plants, has shown a safeguarding influence on cardiac health through various means, encompassing anti-inflammatory actions and its capacity against oxidative stress. Our research endeavor focuses on elucidating the beneficial impacts alongside the underlying physiological processes triggered by ICA within the context of DCM. An animal model representative of DCM was developed through intraperitoneal administration of streptozotocin (STZ). In parallel, in vitro experiments utilized H9C2 cardiomyocytes to mimic hyperglycemic environments relevant to disease states. In vivo experiments found that ICA improved cardiac function, alleviated myocardial fibrosis, and reduced NLRP3-mediated pyroptosis in heart tissue of DCM mice. Under in vitro settings characterized by elevated glucose concentrations, there was a notable elevation in both NLRP3 pyroptosis-associated proteins and oxidative stress markers within the heart muscle cells. ICA treatment attenuated pyroptosis and oxidative stress caused by high glucose in cardiomyocytes. Further studies revealed that when treated with an AMPK inhibitor, the shielding benefits conferred by ICA on cardiomyocytes were negated, suggesting that the regulatory effects of ICA on cardiomyocyte pyroptosis may be achieved through the AMPK-NLRP3 pathway. In conclusion, ICA exerts protective effects in DCM by inhibiting cardiomyocyte pyroptosis, alleviating myocardial fibrosis, and improving cardiac function via the AMPK-NLRP3 pathway.

Over the past few decades, the rising burden of metabolic disease, including type 2 diabetes, prediabetes, obesity, and metabolic dysfunction-associated steatotic liver disease, has corresponded with fundamental shifts in the landscape of heart failure (HF) epidemiology, including the rising prevalence of HF with preserved ejection fraction. It has become increasingly important to understand the role of extracardiac contributors and interorgan communication in the pathophysiology and phenotypic heterogeneity of HF. Whereas traditional epidemiological strategies have separately examined individual contributions of specific comorbidities to HF risk, these approaches may not capture the shared mechanisms and more complex, bidirectional relationships between cardiac and noncardiac comorbidities. In this review, we highlight the cardiac, kidney, liver, and metabolism multiorgan interactions and pathways that complicate HF development and progression and propose research strategies to further understand HF in the context of multiple organ disease. This includes evolving epidemiological approaches such as multiomics and machine learning which may better capture common underlying mechanisms and interorgan crosstalk. We review existing preclinical models of HF and how they have enhanced our understanding of the role of multiorgan disease in the development of HF subtypes. We suggest recommendations as to how clinical practice across multiple specialties should screen for and manage multiorgan involvement in HF. Finally, recognizing the advent of novel combinatorial therapeutic agents that may have multiple indications across the cardiac-kidney-liver metabolism continuum, we review the current clinical trials landscape. We specifically highlight a pressing need for the design of more inclusive trials that examine the contributions of multimorbidity and incorporate multiorgan end points, which we propose may lead to outcomes that are evermore clinically relevant today.

STRA13, a basic helix-loop-helix protein superfamily member, is a CLOCK gene. Previous studies have reported the role of STRA13 in regulating blood pressure. However, the role of STRA13 in diabetic cardiomyopathy (DCM) has not been fully elucidated. In this study, STRA13 full knockout mice were subjected to a high-fat diet (HFD) to induce DCM. We found that STRA13 was upregulated in both heart tissue and cardiomyocytes undergoing metabolic disorders. STRA13 knockout ameliorated HFD-induced cardiac dysfunction, fibrosis, mitochondrial dysfunction and cell apoptosis. STRA13 deficiency also protected against HFD-induced glucose and lipid metabolism disorders. STRA13 overexpression in mice worsened HFD-induced cardiac dysfunction, fibrosis, and injury. STRA13 overexpression in cardiomyocytes worsened high glucose-induced cell injury, mitochondrial dysfunction and oxidative stress. STRA13 silencing in cardiomyocytes protected against the high glucose (HG)-induced alterations described above. Moreover, STRA13 was found to downregulate retinoid X receptor alpha (RXRα), resulting in reduced expression of uncoupling protein 1 (UCP-1). Co-IP confirmed that STRA13 interacted with RXRα. A luciferase assay confirmed that RXRα regulated the transcription of UCP-1. Silencing of STRA13 did not protect cardiomyocytes from HG-induced injury caused by RXRα or UCP-1 knockdown. Cardiac overexpression of UCP-1 also blunted the deteriorating effects of STRA13. However, STRA13 inhibited RXRα nuclear expression, which hampered the protective effects of RXRα overexpression in vivo. Taken together, our findings demonstrate that STRA13 exacerbates diabetic cardiomyopathy by impairing mitochondrial function through the disruption of RXRα-UCP-1 signaling. Therefore, targeting the STRA13-RXRα-UCP-1 axis may represent a promising therapeutic strategy for mitigating mitochondrial dysfunction and cardiac injury in the context of DCM.

Diabetes is the most prevalent metabolic disorder worldwide, imposing a significant economic burden on society. Prediabetes has not received as much attention as diabetes, and among its complications, osteoporosis has been relatively under-researched compared to cardiovascular disease. Recent studies have identified nine indices related to glucose and lipid metabolism that may enhance osteoporosis risk assessment in diabetic and prediabetic individuals. The research examined the osteoporosis risk prediction potential of these indices and developed a nomogram to enhance predictive performance.

2,735 prediabetic and diabetic subjects were derived from National Health and Nutrition Examination Survey (NHANES) dataset collected between 2011 and 2020, then randomly assigned to development and validation cohorts in 7:3. The predictive capacity of glucolipid metabolism-related indices for osteoporosis risk was evaluated using receiver operating characteristic (ROC) curve analysis. The least absolute shrinkage and selection operator (LASSO) and multivariate logistic regression were used to identify predictors for constructing the risk model, which was visualized using a nomogram. The model's performance was further validated.

All the glucolipid metabolism-related indices showed predictive ability, and the best-performing index was metabolic score for insulin resistance (METS-IR). Multivariate logistic regression identified 5 predictors [Triglyceride-glucose index (TyG), age, METS-IR, TyG-waist circumference, and TyG-body mass index] with good predictive performance. These predictors were selected to establish the nomogram. ROC curve, calibration plot, as well as decision curve analysis (DCA) collectively demonstrated fairly good predictive ability of the nomogram.

Glucolipid metabolism-related indices are the predictors of osteoporosis risk. This newly developed nomogram based on glucolipid metabolism indices demonstrates optimal predictive accuracy for assessing combined osteoporosis risk in individuals with prediabetes and diabetes.

The protective effect of cruciferae-derived sulforaphane (SFN) on diabetic cardiomyopathy (DCM) has garnered increasing attention. However, no studies have specifically explored its mechanistic involvement in cardiac substrate metabolism and mitochondrial function. To address this gap, Type 2 diabetes mellitus (T2DM) db/db mice were orally gavaged with vehicle or 10 mg/kg body weight SFN every other day for 16 weeks, with vehicle-treated wild-type mice as controls. SFN intervention (SFN-I) alleviated hyperglycemia, dyslipidemia, HOMA-IR, serum MDA levels, and liver inflammation. Furthermore, SFN-I improved the lipotoxicity-related phenotype of T2DM cardiomyopathy, manifested as attenuation of diastolic dysfunction, cardiac injury, fibrosis, lipid accumulation and peroxidation, ROS generation, and decreased mitochondrial complex I and II activities and ATP content, despite having no effect on ceramide abnormalities. Protein expression data revealed that the model mice exhibited upregulated cardiac CD36, H-FABP, FATP4, CPT1B, PPARα, and PDK4 but downregulated GLUT4, with unchanged MPC1 and MPC2. Notably, SFN-I significantly attenuated the increase in CD36, H-FABP, CPT1B, and PPARα. These results suggest that chronic oral SFN-I protects against DCM by mitigating overall metabolic dysregulation and inhibiting cardiolipotoxicity. The latter might involve controlling cardiac fatty acid metabolism and improving mitochondrial function, rather than promoting glucose metabolism.

Exercise improves functional outcomes in patients with diabetic cardiomyopathy (DiaCM). The molecular mechanism underlying cardiac benefits of exercise in DiaCM remains incompletely understood. N6-methyladenosine (m6A) is the most common form of messenger RNA modification in eukaryotes and has been implicated in cardiac development and disease. However, the role of m6A in DiaCM and in the mitigating effects of exercise on this disease are unclear.

Cardiomyocyte-specific N6-adenosine-methyltransferase-like 3 (METTL3, an m6A methyltransferase) knockout mice and their wild-type littermates were subjected to either chow diet or high-fat diet feeding and injection of streptozotocin to induce DiaCM, followed by an 8-week exercise training and assessment of cardiac function. Some of the mice were injected with adeno-associated viral vector encoding METTL3 to overexpress METTL3 in cardiomyocytes. Cardiac METTL3 expressions were assessed in patients with nonischemic primary dilated cardiomyopathies without or with diabetes. Potential METTL3 downstream effector YBX1 (Y-box binding protein 1) was identified through RNA sequencing. The functional role of YBX1 was examined through adeno-associated viral vector overexpression or knockdown in cardiomyocytes in DiaCM mice.

We showed that cardiac METTL3 protein expression and m6A level were downregulated in patient with dilated cardiomyopathy and further downregulated in patients with dilated cardiomyopathy and diabetes. Consistently, cardiac METTL3 and m6A were downregulated in mouse with DiaCM, whereas they were upregulated by exercise. Cardiomyocyte-specific METTL3 knockout eliminated the cardiac benefits of exercise on DiaCM. Conversely, cardiomyocyte-specific METTL3 overexpression improved systolic and diastolic function in 2 DiaCM mouse models. We demonstrated that exercise enhanced cardiac METTL3 expression in DiaCM through signal transducer and activator of transcription 3. Moreover, METTL3 attenuated DiaCM through m6A-depdendent YBX1 upregulation and the subsequent activation of Nrf2. Cardiomyocyte-specific YBX1 overexpression promoted Nrf2 activation and attenuated oxidative stress, resulting in an improvement in cardiac function in DiaCM. In contrast, cardiomyocyte-specific YBX1 gene knockdown abolished the effect of METTL3 on cardiac improvement in mice with DiaCM. Further, pharmacological activation of METTL3 using a small molecule attenuated cardiac dysfunction in DiaCM.

These studies reveal an essential role of METTL3 in the cardiac benefits of exercise and identify METTL3 and YBX1 as promising therapeutic targets for treating DiaCM.

The production of ketones, referred to as ketogenesis, plays an essential role in maintaining energy homeostasis during prolonged fasting/starvation, which primarily stems from its ability to serve as a fuel source to support neuronal ATP production, thereby limiting muscle wasting. Over the years, the field has come to appreciate that ketones are much more than just a fuel source supporting neuronal metabolism, as many other oxidative organs, such as the heart and skeletal muscle, are capable of metabolizing ketones. Furthermore, ketones appear to be an important fuel source for exercising muscle. Beyond supporting ATP production, it is also becoming widely recognized that ketones are powerful signalling molecules, as they serve as ligands for G-protein coupled receptors and can even modify gene expression via regulating DNA post-translational modifications. As they play a key role in supporting whole-body physiology, it is not surprising that perturbations in ketone metabolism can contribute to various pathologies, particularly in relation to cardiometabolic diseases. Some of the strongest evidence supporting the aforementioned statement is seen for both heart failure and type 2 diabetes. Accordingly, we will review herein the multifaceted roles of ketones in supporting whole-body physiology, while interrogating the evidence to suggest whether modifying ketone metabolism may have a therapeutic role in the management of heart failure and type 2 diabetes.

Background: Although endothelial mesenchymal transition (EndMT) has been characterized as a basic process in embryogenesis, EndMT is the mechanism that accelerates the development of cardiovascular diseases, including heart failure, aging, and complications of diabetes or hypertension as well. Endothelial cells lose their distinct markers and take on a mesenchymal phenotype during EndMT, expressing distinct products. Methods: In this study, type 1 Diabetes mellitus (T1DM) was induced in rats with streptozotocin (STZ) by intraperitoneal injection at a 60 mg/kg dose. Diabetic rats were randomly divided into two groups, namely, control and diabetic rats, for 4 weeks. Heart, aorta, and plasma samples were collected at the end of 4 weeks. Sequentially, biochemical parameters, cytokines, reactive oxygen species (ROS), protein expression of EndMT markers (Chemokine C-X-C motif ligand-1 (CXCL-1), vimentin, citrullinated histone H3 (H3Cit), α-smooth muscle actin (α-SMA), and transforming growth factor beta (TGF-β) and versican), components of the extracellular matrix (matrix metalloproteinase 2 (MMP-2), tissue inhibitor of metalloproteinase-1(TIMP-1), and discoidin domain tyrosine kinase receptor 2 (DDR-2)) were detected by ELISA or Western blot, respectively. Results: Cytokines and ROS were increased in diabetic hearts, which induced partial EndMT. Among EndMT markers, histone citrullination, α-SMA, and CXCL-1 were increased; vimentin was decreased in DM. The endothelial marker endothelin-1 was significantly higher in the aortas of DM rats. Interestingly, TGF-β showed a significant decrease in the diabetic heart, plasma, and aorta. Additionally, MMP-2/TIMP-1 levels also decreased in DM. Conclusions: To sum up, the identification of molecules and regulatory pathways involved in EndMT provided novel therapeutic approaches for cardiac pathophysiological conditions.

Cardiomyopathies comprise a heterogeneous group of cardiac disorders characterized by structural and functional abnormalities in the absence of significant coronary artery disease, hypertension, valvular disease, or congenital defects. Major subtypes include hypertrophic, dilated, arrhythmogenic, and stress-induced cardiomyopathies. Oxidative stress (OS), resulting from an imbalance between reactive oxygen species (ROS) production and antioxidant defenses, has emerged as a key contributor to the pathogenesis of these conditions. ROS-mediated injury drives inflammation, protease activation, mitochondrial dysfunction, and cardiomyocyte damage, thereby promoting cardiac remodeling and functional decline. Although numerous studies implicate OS in cardiomyopathy progression, the precise molecular mechanisms remain incompletely defined. This review provides an updated synthesis of current findings on OS-related signaling pathways across cardiomyopathy subtypes, emphasizing emerging therapeutic targets within redox-regulatory networks. A deeper understanding of these mechanisms may guide the development of targeted antioxidant strategies to improve clinical outcomes in affected patients.

Diabetes leads to a more rapid development of diabetic cardiomyopathy (dbCM) and progression to heart failure in women than in men. Combination of high-fat diet (HFD) and freshly injected streptozotocin (STZ) has been widely used for diabetes induction; however, emerging data show that anomer-equilibrated STZ produces an early-onset and robust diabetes model. We designed a novel protocol using a combination of multiple doses of anomer-equilibrated STZ injections and HFD to develop a stable murine diabetes model featuring dbCM analogous to that in humans. Furthermore, we examined the effect of biological sex on the evolution of cardiometabolic dysfunction in diabetes. Our study included six experimental protocols (8 weeks) in male and female C57BL/6J mice (N = 109): fresh STZ + HFD, anomer-equilibrated STZ + HFD, HFD, fresh STZ, anomer-equilibrated STZ, and control diet + vehicle. Animals were characterized by extensive phenotyping in vivo and ex vivo. Anomer-equilibrated STZ + HFD led to induction of stable experimental murine diabetes characterized by impaired glucose homeostasis, cardiometabolic dysfunction, and altered metabolome of liver, skeletal muscle, kidney, and plasma. dbCM was more severe in female mice, including systolic dysfunction and reduced cardiac energy reserve. This study establishes a novel robust model of inducible murine diabetes and emphasizes the impact of biological sex on diabetes progression and severity.

In diabetes mellitus, dysregulated glucose and lipid metabolism lead to diabetic cardiomyopathy (DCM) by imparting pathological myocardial remodeling and cellular injury. Accelerated glycation, oxidative stress, and activated inflammatory pathways culminate in cardiac fibrosis and hypertrophy in DCM. The regulatory effects of l-Arginine (L-Arg) have been elucidated in the pathological changes of DCM, including myocardial fibrosis, hypertrophy, and apoptosis, by inhibiting glycation and oxidative stress-induced inflammation. Disturbed L-Arg metabolism and decreased intracellular L-Arg pool are correlated with the progression of DCM; therefore, L-Arg supplementation has been prescribed for various cardiovascular dysfunctions. This review expands the therapeutic potential of L-Arg supplementation in DCM by elucidating its molecular mechanism of action and exploring potential clinical outcomes.

The 4-dimensional automated left atrial quantification (4D Auto LAQ) technology for the left atrium was recently available. We aimed to evaluate LA function using 4D Auto LAQ in patients with type 2 diabetes mellitus (T2DM) and investigate its value in predicting left ventricular remodeling (LVR).

A total of 106 T2DM patients (56 with left ventricular [LV] remodeling and 50 with normal geometry) and 46 age- and sex-matched controls were enrolled. LA total emptying fraction (LATEF), LA active emptying fraction (LAAEF), LA passive emptying fraction (LAPEF), and strain parameters, including LA reservoir longitudinal/circumferential strain (LASr/LASr-c), LA conduit longitudinal/circumferential strain (LAScd/LAScd-c), and LA contraction longitudinal/circumferential strain (LASct/LASct-c), were assessed with 4D Auto LAQ.

Compared to controls, LASr, LAScd, and LAPEF significantly decreased in both groups of T2DM patients (p < 0.001). T2DM patients with LVR had significantly lower LASr and LAScd than those with normal geometry (p < 0.001). LATEF was also reduced in T2DM patients with LVR compared to the control group (p < 0.05). Among the 4D-LAQ parameters, only LASr (odds ratio [OR]: 0.860, p = 0.016) was associated with LV remodeling (LVR) in multivariate analysis. Receiver operating characteristic (ROC) curves identified a LASr value of ≤22.5% as the optimal cutoff point to predict LVR in the T2DM cohort (sensitivity, 86.0%; specificity, 64.3%; area under the curve [AUC], 0.770; p < 0.001). In addition, LASr was found to be negatively correlated with both LV mass index (LVMI) and relative wall thickness (RWT) but positively correlated with the absolute value of the LV global longitudinal strain (LVGLS).

Impairment of LA reservoir and conduit functions can be observed in patients with T2DM, particularly in those with LVR. LASr may serve as a predictor of LVR in patients with T2DM.

Excessive activation of the canonical Wnt/β-catenin pathway contributes to the development of diabetic cardiomyopathy (DCM). Transcription factor 7-like 2 (TCF7L2) is the main β-catenin partner of the TCF family in adult human hearts. Carbonic anhydrase 2 (CA2) is implicated in various hypertrophic cardiomyopathy. In this study, we aimed to investigate the role of the Wnt/β-catenin/TCF7L2 signaling and CA2 in the development of DCM. Streptozotocin (STZ)/high-fat diet (HFD)-induced diabetic mice and high glucose-stimulated neonatal rat cardiomyocytes (NRCMs) were used as in-vivo and in-vitro models of Type 2 diabetes (T2DM), respectively. Histopathological changes in the mouse myocardium were assessed with hematoxylin-eosin (HE) or Masson's trichrome staining. Cardiac function was evaluated with echocardiography. TCF7L2, β-catenin, and CA2 expression was determined with RT-qPCR, western blotting, and immunohistochemistry. Immunoprecipitation (IP) was used to evaluate the formation of the β-catenin/TCF7L2 bipartite. The regulatory relationship between the β-catenin/TCF7L2 bipartite and CA2 was investigated with chromatin immunoprecipitation (ChIP) and a luciferase reporter assay. Compared with the control mice, the T2DM mice exhibited increased myocardial β-catenin and TCF7L2 expression that was concentrated in the nucleus. Treatment of diabetic mice with the β-catenin/TCF7L2 bipartite inhibitor iCRT14 prevented myocardial remodeling and improved cardiac dysfunction. iCRT14 also prevented high glucose-induced hypertrophy in NRCMs, while the β-catenin stabilizer SKL2001 worsened hypertrophy. IP experiments confirmed the formation of the β-catenin/TCF7L2 bipartite in the control and T2DM mouse cardiomyocytes. Moreover, based on the results of RNA-sequencing analysis, CA2 was upregulated in T2DM cardiomyocytes in vitro and in vivo. TCF7L2 overexpression upregulated CA2, while iCRT14 treatment or TCF7L2 knockdown downregulated CA2. CA2 knockdown ameliorated NRCM hypertrophy induced by high glucose and SKL2001. The ChIP experiments revealed an increased interaction between β-catenin/TCF7L2 and the transcription initiation region of CA2 in the heart tissue of T2DM mice. The luciferase reporter assay confirmed that CA2 is directly regulated by the β-catenin/TCF7L2 bipartite. The results indicate that the canonical Wnt/β-catenin pathway upregulates CA2 via TCF7L2 to promote DCM. This research sheds new light on the pathogenesis of DCM and presents new potential therapeutic targets for this disease.

Patients with diabetes are at an increased risk for developing diabetic cardiomyopathy and other cardiovascular complications. Alterations in cardiac energy metabolism in patients with diabetes, including an increase in mitochondrial fatty acid oxidation and a decrease in glucose oxidation, are important contributing factors to this increase in cardiovascular disease. A switch from glucose oxidation to fatty acid oxidation not only decreases cardiac efficiency due to increased oxygen consumption but it can also increase reactive oxygen species production, increase lipotoxicity, and redirect glucose into other metabolic pathways that, combined, can lead to heart dysfunction. Currently, there is a lack of therapeutics available to treat diabetes-induced heart failure that specifically target cardiac energy metabolism. However, it is becoming apparent that part of the benefit of existing agents such as GLP-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors may be related to their effects on cardiac energy metabolism. In addition, direct approaches aimed at inhibiting cardiac fatty acid oxidation or increasing glucose oxidation hold future promise as potential therapeutic approaches to treat diabetes-induced cardiovascular disease.

The global prevalence of obesity is skyrocketing at an alarming rate, with recent data estimating that one-in-eight people are now living with the disease. Obesity is a chronic metabolic disorder that shares underlying pathophysiology with other metabolically-linked diseases such as type 2 diabetes mellitus, cardiovascular disease and diabetic cardiomyopathy. There is a distinct correlation between type 2 diabetes status and the likelihood of heart failure. Of note, there is an apparent sexual dimorphism, with women disproportionately affected with respect to the degree of severity of the cardiac phenotype of diabetic cardiomyopathy that results from diabetes. The current pharmacotherapies available for the attenuation of hyperglycaemia in type 2 diabetes are not always effective, and have varying degrees of efficacy in the setting of heart failure. Insulin can worsen heart failure prognosis whereas metformin, sodium-glucose cotransporter 2 inhibitors (SGLT2i) and more recently, glucagon-like peptide-1 receptor agonists (GLP-1RAs), have demonstrated cardioprotection with their administration. This review will highlight the advancement of incretin therapies for individuals with diabetes and heart failure and explore newly-reported evidence of the clinical usefulness of GLP-1R agonists in this distinct phenotype of heart failure.

Type 2 diabetes mellitus (T2DM) has led to a considerable increase in morbidity and mortality worldwide. Current treatments control blood glucose but cannot reverse the disease, making it important to identify biomarkers that predict T2DM onset and progression. This study explores heme oxygenase 1(HMOX1) as a novel biomarker for T2DM through bioinformatics and experimental validation. Core differentially expressed genes (DEGs) were identified using the Gene Expression Omnibus database, with Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Gene Set Enrichment Analysis analyses revealing notable pathways, including Toll-like receptor signaling and cytokine receptor interactions. A Nomogram model and receiver operating characteristic curves demonstrated strong diagnostic effectiveness for these core DEGs. The CIBERSORT algorithm assessed the relation between core DEGs and immune cell infiltration, showing substantial associations with several immune cell types, particularly highlighting HMOX1's correlation with eight immune cells (p < 0.05). In a mouse model, db/db mice displayed typical diabetic characteristics and lower serum HMOX1 levels compared to db/m controls (p < 0.01). Histological analysis confirmed liver damage and decreased expression of NFE2L2 and HMOX1 in diabetic mice tissues (p < 0.05). HMOX1 is identified as a promising biomarker for T2DM, with its downregulation confirmed through bioinformatics and experimental methods.

The direct cardiac effects of urotensin II (UII) in normal and diabetic subjects remain controversial. The alteration and functional significance of cardiac UII/UII receptor (UT) in diabetes are still unclear. We assessed the hypothesis that in diabetes, the cardiomyocyte UII/UT system is increased. This augmentation is proposed to exacerbate the dysfunctional [Ca2+]i regulation, enhance inhibitions of left ventricle (LV) and myocyte contraction and relaxation, leading to worsening cardiac dysfunction. We compared LV myocyte UII and UT expression, LV and myocyte contractile, [Ca2+]i transient ([Ca2+]iT) and calcium current (ICa,L) responses to UII stimulation in male Sprague-Dawley rats (12/group) with streptozotocin-induced diabetes mellitus and controls. We found that UII and UT protein levels were significantly greater in diabetic myocytes than in control myocytes. Compared with control rats, UII (400 pmol/kg, i.p.) administration produced greater decreases in LV contractility of EES (diabetes mellitus: 32% vs C: 13%) and MSW with significantly increased LV time constant relaxation in diabetes. In response to UII (10-5 M) superfusion, diabetic myocytes had much greater decreases in the velocity of shortening and relengthening accompanied by significantly larger decreases in the peak systolic [Ca2+]iT and ICa,L (29% vs 15%). These responses were abolished by pretreatment of diabetic myocytes with urantide, pertussis toxin, or dibutyryl-cAMP, respectively. We conclude that UII has direct negative inotropic and lusitropic cardiac effects in both normal and diabetic rats. In diabetes, cardiac UII/UT is upregulated, enhancing UII-caused negative modulation on cardiac function and [Ca2+]i regulation. This may contribute to the progression of cardiac dysfunction in diabetes and diabetic cardiomyopathy. SIGNIFICANCE STATEMENT: Urotensin II (UII) has direct negative inotropic and lusitropic cardiac effects in both normal and diabetic rats. Compared with normal rats, cardiac UII/UII receptors (UT) were upregulated in diabetic rats, resulting in significantly greater decreases in [Ca2+]iT and ICa,L and increased inhibitions of left ventricle and myocyte contraction and relaxation. These effects are coupled with UT and mediated by Gi proteins. These data provide new insights and evidence that upregulation of cardiomyocyte UII/UT may promote the progressive cardiac dysfunction in diabetes and diabetic cardiomyopathy.

Type 2 diabetes mellitus (T2DM) is a prevalent chronic condition often associated with low-grade inflammation. Previous studies have indicated that the monocyte-to-high-density lipoprotein cholesterol ratio (MHR) may serve as a novel inflammatory biomarker with potential predictive value for various metabolic diseases. This study aims to investigate the association between the MHR and the prevalence of T2DM in a general population, using data from the National Health and Nutrition Examination Survey (NHANES).

We conducted a cross-sectional study analyzing data from five NHANES cycles spanning 2007-2016. We excluded individuals aged under 20 years, those with missing data on monocytes, HDL-C, diabetes status, or other key covariates, and extreme MHR outliers. Statistical analyses were performed using SPSS 26.0, EmpowerStats 4.1, Stata 16, and DecisionLinnc1.0. We employed weighted logistic regression models, subgroup analyses, restricted cubic splines (RCS), and threshold analyses were used to assess the MHR-T2DM association.

A total of 10,066 participants met the inclusion criteria, of whom 1,792 were diagnosed with T2DM. The MHR levels in the T2DM group were significantly higher than those in the non-T2DM group. After adjusting for potential confounders, elevated MHR levels were significantly associated with an increased prevalence of T2DM (p < 0.001, OR = 2.80, 95% CI: 1.823-4.287). Subgroup analyses revealed a significant interaction between MHR and T2DM with respect to gender (P for interaction < 0.05), with a stronger association in women. No significant interactions were observed for age, race, education level, poverty income ratio (PIR), body mass index (BMI), smoking status, physical activity, alcohol consumption, or hypertension (P for interaction > 0.05). RCS analysis indicated a significant nonlinear relationship between MHR and T2DM, with a threshold point for MHR identified at 0.51. Above this threshold, the risk of T2DM increased significantly.

Our findings suggest that elevated MHR levels, particularly above the threshold of 0.51, are significantly associated with an increased prevalence of T2DM. The gender-specific interaction further highlights that women may be more susceptible to the impact of elevated MHR on T2DM risk. These findings suggest MHR as a potential biomarker for early T2DM screening and highlight gender-specific risk factors.

Impaired exercise capacity influences obesity and diabetes disease progression and vice versa. The primary objective of this prospective, observational, real-world study was to characterize exercise capacity in patients with obesity or type II diabetes mellitus and healthy controls by cardiac capacity (cardiac output (CO), cardiac power output (CPO)) and peripheral muscle capacity (peak power output (Pmax) and arterio-venous oxygen difference (avDO2)). The effects of an exercise and lifestyle intervention on these cardiac and peripheral muscular markers in obese and diabetic patient groups were additionally evaluated.

At a university sports medicine outpatient clinic, 24 obese (OB) and 38 diabetes mellitus type II (DM) patients and 20 healthy controls (HE) were investigated in a cross-sectional analysis. OB and DM were reexamined after a standard of care exercise intervention. Parameters were assessed at rest and during a cardiopulmonary exercise test (CPET). Blood pressure, impedance cardiography, and respiratory gas analysis were continuously recorded during CPET.

At Pmax, CO and CPO were lower in DM compared to obese (CO 16.26 l/min vs. 18.13 l/min, p < 0.04; CPO 5.67 W vs. 4.81 W, p < 0.01). HE did not differ in CO (18.19 l/min)) or CPO (5.27 W) from OB and DM. Maximum CPO in OB and DM was based on higher stroke volume and blood pressure, while HE had higher heart rates. Pmax was higher (p < 0.01) in HE (268 W) compared to OB (108 W) and DM (89 W), mainly caused by a higher (p < 0.01) avDO2 (HE 18.22 ml/dl, OB 10.45 ml/dl, DM 9.65 ml/dl). Exercise intervention improved Pmax in both groups of patients (+ 16 W in OB, + 12 W in DM), which was attributed to increased avDO2, but not to cardiac parameters.

Obese patients had higher cardiac power outputs and were primarily limited by muscular performance, while diabetic patients showed both muscular and cardiac limitations. Healthy subjects had comparable cardiac power outputs with significantly lower pressure-volume loads. Resistance training improved the alteration of our patient groups in exercise capacity. Future research is needed to interpret our findings regarding clinical endpoints, such as mortality and hospitalization.

The study was retrograde registered in the German Clinical Trial Register (DRKS00032545, 24.08.2023).

Cardio-inflammatory immune related adverse events (irAEs) while receiving immune checkpoint inhibitor (ICI) therapy are particularly consequential due to their associations with poorer treatment outcomes. Evaluation of predictive factors of these serious irAEs with a time dependent approach allows better understanding of patients most at risk.

To identify different elements of patient data that are significant predictors of early and late-onset or delayed cardio-inflammatory irAEs through various predictive modeling strategies.

A cohort of patients receiving ICI therapy from January 1, 2010 to May 1, 2022 was identified from TriNetX meeting inclusion/exclusion criteria. Patient data collected included occurrence of early and later cardio-inflammatory irAEs, patient survival time, patient demographic information, ICI therapies, comorbidities, and medication histories. Predictive and statistical modeling approaches identified unique risk factors for early and later developing cardio-inflammatory irAEs.

A cohort of 66,068 patients on ICI therapy were identified in the TriNetX platform; 193 (0.30%) experienced early cardio-inflammatory irAEs and 175 (0.26%) experienced later cardio-inflammatory irAEs. Significant predictors for early irAEs included: anti-PD-1 therapy at index, combination ICI therapy at index, and history of peripheral vascular disease. Significant predictors for later irAEs included: a history of myocarditis and/or pericarditis, cerebrovascular disease, and history of non-steroidal anti-inflammatory medication use.

Cardio-inflammatory irAEs can be divided into clinically meaningful categories of early and late based on time since initiation of ICI therapy. Considering distinct risk factors for early-onset and late-onset events may allow for more effective patient monitoring and risk assessment.

Diabetic cardiomyopathy (DCM) is a complex metabolic disorder resulting from chronic hyperglycemia and lipid toxicity, which leads to cardiac dysfunction, fibrosis, inflammation, and mitochondrial impairment. Traditional two-dimensional (2D) cell cultures and animal models have limitations in replicating human cardiac physiology and pathophysiology. In this study, we successfully developed a three-dimensional (3D) model of DCM using cardiac organoids generated from human induced pluripotent stem cells (hiPSCs). These organoids were treated with varying concentrations of glucose and sodium palmitate to mimic the high-glucose and high-lipid environment associated with diabetes. At lower concentrations, glucose and sodium palmitate enhanced cell viability, while higher concentrations induced significant cardiotoxic effects, including apoptosis, oxidative stress, and mitochondrial dysfunction. The cardiac organoids also exhibited increased expression of cardiac injury markers, fibrosis-related genes, and inflammatory cytokines under high-glucose and high-lipid conditions. Treatment with metformin, a widely used antidiabetic drug, mitigated these adverse effects, indicating the model's potential for drug testing and evaluation. Our findings demonstrate that this human-derived 3D cardiac organoid model provides a more physiologically relevant platform for studying DCM and can effectively complement traditional models. This model holds promise for advancing the understanding of diabetic heart disease and for assessing the efficacy of potential therapeutic interventions.

Diabetic cardiomyopathy (DCM) is a common and fatal cardiac complication caused by diabetes, with its pathogenesis involving various forms of cell death and mitochondrial dysfunction, particularly ferroptosis and mitochondrial injury. Recent studies have indicated that ferroptosis and mitochondrial damage play crucial roles in the onset and progression of DCM, though their precise regulatory mechanisms remain unclear. Of particular interest is the interaction between ferroptosis and mitochondrial damage, as well as their synergistic effects, which are not fully understood. This review summarizes the roles of ferroptosis and mitochondrial injury in the progression of DCM and explores the molecular mechanisms involved, with an emphasis on the interplay between these two processes. Additionally, the article offers an overview of targeted drugs shown to be effective in cellular experiments, animal models, and clinical trials, analyzing their mechanisms of action and potential side effects. The goal is to provide insights for future drug development and clinical applications. Moreover, the review explores the challenges and prospects of multi-target combination therapies and personalized medicine interventions in clinical practice to offer strategic guidance for the comprehensive prevention and management of DCM.

Recent investigations into the mechanisms underlying inflammation have highlighted the pivotal role of immune cells in regulating cardiac pathophysiology. Notably, these immune cells modulate cardiac processes through alternations in intracellular metabolism, including glycolysis and oxidative phosphorylation, whereas the extracellular metabolic environment is changed during cardiovascular disease, influencing function of immune cells. This dynamic interaction between immune cells and their metabolic environment has given rise to the novel concept of "immune metabolism". Consequently, both the extracellular and intracellular metabolic environment modulate the equilibrium between anti- and pro-inflammatory responses. This regulatory mechanism subsequently influences the processes of myocardial ischemia, cardiac fibrosis, and cardiac remodeling, ultimately leading to a series of cardiovascular events. This review examines how local microenvironmental and systemic environmental changes induce metabolic reprogramming in immune cells and explores the subsequent effects of aberrant activation or polarization of immune cells in the progression of cardiovascular disease. Finally, we discuss potential therapeutic strategies targeting metabolism to counteract abnormal immune activation.

Introduction: Cardiovascular diseases (CVDs) are a growing problem with increasing global prevalence and the most common cause of mortality worldwide. Knowledge about the disease and risk factors reduces exposure to modifiable risk factors and, as a result, contributes to prevention. As diabetes is a prevalent disease and there is limited research about CVD risk factors in Ethiopia, we conducted a study to assess this knowledge. Methods: A cross-sectional study was conducted on diabetes mellitus patients on follow-up at Tikur Anbessa Specialized Hospital from April 11 to May 16, 2021. The participants were selected using a consecutive sampling method. Knowledge was measured using a heart disease fact questionnaire, and a score of less than 70% was defined as suboptimal. Data were analyzed using SPSS Version 26.0. Associations between dependent and independent variables were identified based on AOR, with 95% CI and a p value less than or equal to 0.05. Result: A total of 404 patients with a mean age of 52.03 ± 14.39 participated in the study, and more than half, 217 (53.7%), of patients were females. About half of the patients (52%) had good knowledge of CVD risk factors. In multivariable logistic regression, urban residency (AOR, 3.335; 95% CI [1.134-9.809]), higher educational level (AOR, 4.016; 95% CI [1.78-9.061]), being employed (AOR, 1.942; 95% CI [1.058-3.566]), and hearing information about CVD risk factors (AOR, 2.492; 95% CI [1.573-3.949]) are associated with knowledge of CVD risk factors. Conclusion: This study revealed that almost half of diabetes mellitus patients had suboptimal knowledge about CVD risk factors. Urban residence, higher education level, employment, and information about CVD risk factors are positively associated with good knowledge of CVD risk factors. Health education is needed to improve their knowledge.

Diabetic cardiomyopathy (DCM), a cardiac complication of diabetes, is the main cause of the high prevalence of heart failure and associated mortality in diabetic patients. Oxidative stress and lipid metabolism disorder-induced myocardial cell damage are part of the pathogenesis of DCM. In this study, we investigated the effects of alpha-mangostin (A-MG), a natural antioxidant extracted from mangosteen peel, on in vitro and in vivo DCM models.

H9C2 rat cardiomyocytes were treated with high glucose (HG) and palmitic acid (PA) for 24 h to establish an in vitro DCM cell model. Cell viability and cytotoxicity were evaluated after treatment with varying concentrations of A-MG (0.3, 1, 3, 9, or 27 μM) using Cell Counting Kit-8 (CCK8) and lactate dehydrogenase (LDH) assays. Flow cytometry assessment was used to detect apoptosis. Molecular mechanisms were investigated through transcriptome analysis, quantitative PCR (RT-qPCR), and Western blotting. Type 2 diabetic (T2D) mice, induced by feeding a high-fat diet (HFD) combined with low-dose streptozotocin (STZ), received either vehicle, low-dose A-MG (100 mg/kg/d), or high-dose A-MG (200 mg/kg/d) for 6 weeks. Cardiac function was assessed by echocardiography. H&E and Masson's staining were used to evaluate cardiac tissue structure and fibrosis, and Western blotting was used to evaluate myocardial protein expression.

In HG/F-induced H9C2 cells, A-MG (1 and 3 μM) significantly increased cell viability (p < 0.01) and reduced LDH release (p < 0.05). A-MG (3 μM) attenuated lipid accumulation (p < 0.05), normalized mitochondrial membrane potential (p < 0.01), and inhibited reactive oxygen species (ROS) generation (p < 0.05), malondialdehyde (MDA) production (p < 0.01), and apoptosis (p < 0.05). A-MG also inhibited the nuclear translocation of Forkhead box class O1 (FOXO1) (p < 0.05); reduced the expression of CD36 (p < 0.05), PPARα (p < 0.01), and CPT1β (p < 0.05) proteins; enhanced superoxide dismutase (SOD) activity (p < 0.05); and upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) (p < 0.01), HO-1 (p < 0.05), and SOD2 (p < 0.05) protein expression levels. Further investigation in HG/F-induced H9C2 cells indicated that A-MG inhibits the uptake of fatty acids (FAs) by regulating the AKT/FOXO1/CD36 signaling pathway, reduces excessive β-oxidation of FAs mediated by PPARα/CPT1β through the inhibition of FOXO1 nuclear translocation, and stimulates the AKT/Nrf2/HO-1 signaling pathway to increase the cellular antioxidant capacity. In diabetic mice, low-dose A-MG treatment increased anti-oxidative stress capacity, decreased myocardial lipid accumulation, reduced fibrosis and cardiomyocyte apoptosis, and improved left ventricular contractile function.

Using both in vitro and in vivo DCM models, our study demonstrates that A-MG reduces lipid accumulation and excessive mitochondrial β-oxidation while enhancing antioxidant capacity. These results suggest that A-MG may be a novel therapeutic option for DCM.

Diabetic neuropathic pain (DNP) is one of the most prevalent complications of diabetes, characterized by a high global prevalence and a substantial affected population with limited effective therapeutic options. Although DNP is closely associated with hyperglycemia, an increasing body of research suggests that elevated blood glucose levels are not the sole inducers of DNP. The pathogenesis of DNP is intricate, involving the release of inflammatory mediators, alterations in synaptic plasticity, demyelination of nerve fibers, and ectopic impulse generation, yet the precise mechanisms remain to be elucidated. The spinal dorsal horn coordinates dynamic interactions between peripheral and central pain pathways, wherein dorsal horn neurons, microglia, and astrocytes synergize with Schwann cell-derived signals to process nociceptive information flow. Abnormally activated neurons can alter signal transduction by modifying the local microenvironment, compromising myelin integrity, and diminishing trophic support, leading to neuronal sensitization and an amplifying effect on peripheral pain signals, which in turn triggers neuropathic pain. Ion channels play a pivotal role in signal conduction, with the modulation of sodium, potassium, and calcium channels being particularly crucial for the regulation of pain signals. In light of the rising incidence of diabetes and the current scarcity of effective DNP treatments, a thorough investigation into the interactions between neurons and glial cells, especially the mechanisms of ion channel function in DNP, is imperative for identifying potential drug targets, developing novel therapeutic strategies, and thereby enhancing the prospects for DNP management.

Diabetic cardiomyopathy is a notable microvascular complication of diabetes, characterized primarily by myocardial fibrosis and functional abnormalities. Long-term hyperglycemia induces excessive activation and recruitment of immune cells and triggers the cascade of inflammatory responses, resulting in systemic and local cardiac inflammation. Emerging evidence highlights the significant roles of immunology in modulating the pathology of diabetic cardiomyopathy. As the primary effectors of inflammatory reactions, immune cells are consistently present in cardiac tissue and can be recruited under pathological hyperglycemia circumstances. A disproportionate favor to proinflammatory types of immune cells and the increased proinflammatory cytokine levels mediate fibroblast proliferation, phenotypic transformation, and collagen synthesis and ultimately rise to cardiac fibrosis and hypertrophy. Meanwhile, the severity of cardiac fibrosis is also strongly associated with the diverse phenotypes and phenotypic alterations of the immune cells, including macrophages, dendritic cells, mast cells, neutrophils, and natural killer cells in innate immunity and CD4+ T lymphocytes, CD8+ T lymphocytes, and B lymphocytes in adaptive immunity. In this review, we synthesized the current analysis of the critical role played by the immune system and its components in the progression of diabetic cardiomyopathy. Finally, we highlight preclinical and clinical immune targeting strategies and translational implications.

Cardiac lipotoxicity, characterized by excessive lipid accumulation in the cardiac tissue, is a critical contributor to the pathogenesis of diabetic heart. Recent research has highlighted the key mechanisms underlying lipotoxicity, including mitochondrial dysfunction, endoplasmic reticulum stress, inflammation, and cell apoptosis, which ultimately impair the cardiac function. Various therapeutic interventions have been developed to target these pathways, mitigate lipotoxicity, and improve cardiovascular outcomes in diabetic patients. Given the global escalation in the prevalence of diabetes and the urgent demand for effective therapeutic approaches, this review focuses on how targeting cardiac lipotoxicity may be a promising avenue for treating diabetes.

Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality worldwide, posing significant challenges to healthcare systems. Despite advances in medical interventions, the molecular mechanisms underlying CVDs are not yet fully understood. For decades, protein-coding genes have been the focus of CVD research. However, recent advances in genomics have highlighted the importance of long non-coding RNAs (lncRNAs) in cardiovascular health and disease. Changes in lncRNA expression specific to tissues may result from various internal or external factors, leading to tissue damage, organ dysfunction, and disease. In this review, we provide a comprehensive discussion of the regulatory mechanisms underlying lncRNAs and their roles in the pathogenesis and progression of CVDs, such as coronary heart disease, atherosclerosis, heart failure, arrhythmias, cardiomyopathies, and diabetic cardiomyopathy, to explore their potential as therapeutic targets and diagnostic biomarkers.

The nonenergy - producing functions of metabolism are attracting increasing attention, as metabolic changes are involved in discrete pathways modulating enzyme activity and gene expression. Substantial evidence suggests that myocardial metabolic remodeling occurring during diabetic cardiomyopathy, heart failure, and cardiac pathological stress (e.g., myocardial ischemia, pressure overload) contributes to the progression of pathology. Within the rewired metabolic network, metabolic intermediates and end-products can directly alter protein function and/or regulate epigenetic modifications by providing acyl groups for posttranslational modifications, thereby affecting the overall cardiac stress response and providing a direct link between cellular metabolism and cardiac pathology. This review provides a comprehensive overview of the functional diversity and mechanistic roles of several types of metabolite-mediated histone and nonhistone acylation, namely O-GlcNAcylation, lactylation, crotonylation, β-hydroxybutyrylation, and succinylation, as well as fatty acid-mediated modifications, in regulating physiological processes and contributing to the progression of heart disease. Furthermore, it explores the potential of these modifications as therapeutic targets for disease intervention.