Diabetes Coronary Artery Disease Research Articles

Plasma from type 1 diabetes patients promotes pro-atherogenic cholesterol transport in human macrophages.

Hyperglycemia, one of the major risk factors for atherosclerosis, leads to the accumulation of advanced glycation end products (AGEs), contributing to cardiovascular complications. Such accumulation may accelerate the progression of vascular disease in patients with diabetes. Reverse cholesterol transport (RCT) protein, ATP-binding membrane cassette transporters A1 and G1 (ABCA1 and ABCG1) and cholesterol 27-hydroxylase facilitate cholesterol removal from macrophages. AGE inhibits RCT by reducing the expression of ABCA1 and ABCG1. This study aimed to evaluate whether plasma from poorly controlled adolescents with type 1 diabetes (T1D) disrupts cholesterol homeostasis in human monocytes/macrophages. Twenty healthy controls (HCs) and 20 patients with type 1 diabetes mellitus (T1DM), 10-19 years old, were enrolled. Naïve THP-1 macrophages were exposed to plasma from each HC and patient with T1D. Following incubation, mRNA for cholesterol efflux (ABCA1, ABCG1, and 27-hydroxylase) and cholesterol uptake (CD36, ScR-A1, lectin oxidized low-density lipoprotein (LOX)-1, and CXCL16) were isolated. Foam cell formation was quantified to confirm the pro-atherogenic effects of T1D plasma on macrophages. Results showed that T1D plasma had an elevated level of N-(carboxymethyl)-lysine-modified proteins and upregulated CXCL16 and, to a lesser degree, ScR-A1. This change in gene expression in the presence of T1D plasma is associated with increased lipid accumulation and foam cell formation by THP-1 macrophages. In our study, these cells' uptake of an AGE product occurred mainly through the SR-A1 and CXCL16 receptors, leading to increased intracellular oxidized low-density lipoprotein. We conclude that AGEs may contribute to accelerated atherosclerosis in diabetes through effects on both forward and reverse cholesterol movement.

The GDF15 3′ UTR Polymorphism rs1054564 Is Associated with Diabetes and Subclinical Atherosclerosis

Growth differentiation factor 15 (GDF15) is a stress-response cytokine related to a wide variety of metabolic diseases. However, the impact of GDF15-specific genetic variants on the abovementioned conditions is poorly known. The aim of this study was to assess the impact of selected GDF15 single-nucleotide polymorphisms (SNPs) on metabolic disturbances and subclinical atherosclerosis. A cross-sectional study involving 153 participants of a metabolic patient-based cohort was performed. Three selected SNPs (rs888663, rs1054564 and rs1059369) in a locus on chromosome 19 including the GDF15 gene were genotyped by Polymerase Chain Reaction (PCR), and its relationship with the serum GDF15 levels, health status and clinical variables were analyzed. Of the three SNPs analyzed, only rs1054564 showed different distributions between the healthy volunteers and patients suffering lipid alterations and associated disorders. Accordingly, just the rs1054564 variant carriers showed a significant increase in GDF15 serum levels compared to the wild-type carriers. The group of variant carriers showed a higher frequency of individuals with diabetes, compared to the wild-type carrier group, without showing differences in other metabolic conditions. Additionally, the frequency of individuals with atherosclerotic carotid plaque was higher in the rs1054564 variant carriers than in the wild-type carriers. Logistic regression models identified that the presence of the rs1054564 variant carriers increase the likelihood for both diabetes and carotid plaque independently of confounding factors. Overall, the findings of this study identify the rs1054564 variant as a potential indicator for the likelihood of diabetes and subclinical atherosclerosis.

Blockade of foam cell formation by an AP-1 inhibitor attenuates atherosclerosis in diabetes

Abstract Background Atherosclerosis is a major contributor to cardiovascular disease (CVD) related premature deaths in people with diabetes. Residual increased risk of CVD remains even after treatment of standard risk factors including hyperglycaemia. Therefore, there is an unmet clinical need of novel therapies that can directly target the intrinsic pathobiology of atherosclerotic plaque development. Macrophage associated pro-atherosclerotic processes including impaired cholesterol efflux resulting in foam cell formation are important therapeutic targets in atherosclerosis. Expression of genes linked to impaired cholesterol efflux can be regulated by multiple factors including transcription factors (TFs) such as activator protein 1 (AP-1) complex. Although, previous studies have implicated the role of foam cells in atherosclerosis, the role of AP-1 TF complex in foam cell formation in diabetes induced atherosclerosis is not known. Methods Diabetes was induced with streptozotocin (STZ) in atheroprone Apoe-/- mice and 10 weeks later aortae were subjected to single cell RNA sequencing (scRNA-seq) analysis using 10X Genomics platform. In vitro model mimicking diabetes-induced foam cell formation was established in human monocytes THP-1 derived macrophages using high glucose (25mM) and ox-LDL ± a small molecular inhibitor of AP-1, T-5224. AP-1 activity, gene expression and foam cell formation were assessed with activity assay, RT PCR and Oil Red O staining respectively in this setting. Complementary in vitro AP-1 knockdown experiments using shRNA were also performed. Furthermore, preclinical intervention studies were also performed where Apoe-/- mice made diabetic with STZ were treated 5-weeks post diabetes with T-5224 (30 mg/kg body weight daily for 5 weeks). Results scRNA-seq analysis identified a well-defined cluster of foam cells within macrophages with a diabetes specific proatherogenic transcriptomic profile. Differential gene expression analysis showed increased expression of AP-1 members cFos, Atf3, Atf4 and Junb exclusively in foam cell cluster in diabetes (cut off = FDR<0.05, Log2FC -2/2). Comparison with the ENCODE dataset for AP-1 target genes using Harmonizome version 3 showed that indeed multiple differentially expressed genes in diabetes were targets of AP-1. AP-1 members were also upregulated in the THP-1-based in vitro model of high glucose induced foam cell formation. THP-1 derived foam cells showed increased AP-1 activity and lipid uptake. Interestingly, AP-1 inhibition by T-5224 attenuated foam cell formation. AP-1 knockdown experiments validated experimental findings of AP-1 inhibition studies in THP-1 derived macrophages. Importantly, T-5224 treatment blocked foam cell formation resulting in reduced atherosclerosis in diabetic Apoe-/- mice in our intervention study design. Conclusion This study identified the AP-1 inhibition with T-5224 as a potential treatment for the diabetes induced foam cell formation and associated atherosclerosis.

Blockade of endothelial to mesenchymal transition (EndMT) by an inhibitor of histone methyltransferase EZH2 attenuates atherosclerosis in diabetes

Abstract Background Atherosclerosis is a major contributor to cardiovascular disease (CVD) related deaths in individuals with diabetes. Persistent endothelial cell activation caused by factors such as hyperglycaemia induces endothelial to mesenchymal transition (EndMT), which promotes both initiation as well as progression of atherosclerosis. Gene expression changes that occur during EndMT, are regulated by multiple factors including epigenetic modifiers such as the histone methyltransferase EZH2 (Enhancer of zest homolog 2). Recent studies have implicated the role of EndMT in cardiovascular complications of diabetes including atherosclerosis. However, the role of EZH2 in induction of EndMT in diabetes associated atherosclerosis is not known. Methods Aortae of atheroprone diabetic Apoe-/- mice were subjected to single cell RNA sequencing (scRNA-seq) analysis using 10X Genomics platform. In vitro model mimicking diabetes-induced EndMT was established in human aortic endothelial cells (HAECs) using high glucose (25mM) and TNF-α containing media for 72 hrs ± a small molecule inhibitor of EZH2, GSK126. RNA and Chromatin Immunoprecipitation (ChIP) sequencing was performed to identify EZH2-mediated epigenomic and corresponding transcriptomic changes in this setting. Complementary in vitro EZH2 knockdown experiments using shRNA were also performed. Moreover, Apoe-/- mice made diabetic with streptozotocin, were treated with GSK126 (50 mg/kg BW daily for 5 weeks) in an intervention study design. Aortic sections from treated and control mice were subjected to immunofluorescent staining specific for the EndMT pathway. Results scRNA-seq analysis identified an EndMT+ve endothelial cell sub-population with a diabetes specific proatherogenic transcriptomic profile. Comparison with the ENCODE dataset for EZH2 target genes using Harmonizome showed that indeed multiple repressed genes in diabetes were targets of EZH2. Methyltransferase activity of EZH2 was elevated in in vitro settings of EndMT. Interestingly, EZH2 inhibition by GSK126 attenuated EndMT. Gene expression analysis showed that GSK126 treatment rescued 76 of 242 differentially expressed genes in HAECs exposed to EndMT conditions. Several differentially expressed genes including COL1A2, MMP2, NOS3, COL4A1, and TGFB2 (FDR <0.05, Log2 fold change (2x)) were targets of EZH2 validating integrated analysis of our scRNA-seq with the ENCODE dataset. EZH2 knockdown experiments validated experimental findings of EZH2 inhibition studies using GSK126 in HAECs. Importantly, GSK126 treatment blocked EndMT resulting in reduced atherosclerosis in diabetic Apoe-/- mice in intervention studies. Conclusion This study showed that the inhibition of EZH2 with GSK126 is a potential vasculoprotective treatment for the diabetes induced EndMT and associated atherosclerosis.

Body mass index and clinical outcomes in patients with diabetes and stable coronary artery disease in THEMIS

Abstract Background Physiologic changes due to extremes of body weight may affect the efficacy and tolerability of antiplatelet treatment. However, it remains unclear whether the risks and benefits of intensified antiplatelet therapy among patients with diabetes and stable coronary artery disease (CAD) are affected by body mass index (BMI). Purpose To assess the relationship between baseline BMI and major adverse cardiovascular (CV) events, and to determine if the effects of ticagrelor vs. placebo varied across the BMI spectrum, in patients with diabetes and stable CAD. Methods THEMIS was a randomized, controlled trial of 19,220 individuals aged ≥50 years with type 2 diabetes and stable CAD, randomly allocated to ticagrelor or placebo on top of aspirin. Patients with a prior myocardial infarction (MI) or stroke, or already on dual antiplatelet therapy, were excluded. The primary efficacy outcome was a composite of CV death, MI, or stroke. The primary safety outcome was TIMI major bleeding. We examined prognostic implications of BMI using 1) restricted cubic splines for the overall trends with outcomes; 2) Cox regression models with predefined BMI intervals (<25 kg/m2, 25-29.9 kg/m2, and ≥30 kg/m2) adjusted for demographic, clinical, and laboratory variables; and 3) Cox regression models for the effects of ticagrelor vs. placebo on outcomes across the spectrum of BMI values (test for interaction). A two-sided P-value <0.01 was considered statistically significant to control the overall chance of type I errors. Results BMI was available in 19,202 (99.9%) participants, with a median of 29 kg/m2 (interquartile range: 26-33). A total of 3352 (17.5%) individuals had a BMI <25 kg/m2, 7644 (39.8%) had a BMI 25-29.9 kg/m2, and 8206 (42.7%) had a BMI ≥30 kg/m2. Median follow-up was 39.9 months (range 0-57), with 1554 primary efficacy events and 306 primary safety events occurring over the course of the study. BMI was not associated with the primary efficacy or safety outcome, or with their individual components. However, BMI was significantly associated with hospitalization for heart failure (HHF) (BMI <25 kg/m2: reference; hazard ratio [HR] for BMI 25-29.9 kg/m2: 1.07, 95% confidence interval [CI], 0.82 to 1.40; HR for BMI ≥30 kg/m2: 1.41, 95% CI, 1.07 to 1.84) and with the composite of HHF or CV death (comparable estimates) after multivariable adjustment (Figure). BMI was also significantly, positively associated with serious adverse events (BMI <25 kg/m2: reference; HR for BMI 25-29.9 kg/m2: 0.99, 95% CI, 0.93 to 1.06; HR for BMI ≥30 kg/m2: 1.20, 95% CI, 1.12 to 1.29). BMI did not modify the risks and benefits of ticagrelor vs. placebo. Conclusions BMI was independently associated with the risk of HHF and the composite of HHF or CV death, but not with other efficacy or safety outcomes, in patients with stable CAD and type 2 diabetes. Ticagrelor was of similar benefit on the primary efficacy outcome vs. placebo across the full range of BMI.

Angioprotein-like 3 and atheroma progression in statin-treated type 2 diabetic patients with coronary artery disease: the pre-specified analysis from the OPTIMAL randomized controlled trial

Abstract Introduction Despite guideline-recommended control of LDL-C with a statin, type 2 diabetic patients more likely cause cardiovascular events. This indicates the need to identify additional therapeutic targets in those patients. Angioprotein-like 3 (ANGPTL3) is an inhibitor of lipoprotein and endothelial lipase, which increases the levels of LDL-C and other atherogenic lipoproteins. These properties suggest ANGPTL3 as a potential driver associated with diabetic atherosclerosis. The OPTIMAL randomized controlled trial (jRCT1052180152) compared the efficacy of continuous glucose monitoring-guided versus HbA1c-guided glycemic control on coronary atherosclerosis in statin-treated type 2 diabetic patients by using serial intravascular ultrasound (IVUS) imaging. This pre-specified analysis of the OPTIMAL study was designed to evaluate whether ANGPTL3 affects progression of coronary atheroma in statin-treated type 2 diabetic patients. Purpose To elucidate the association of serial change in ANGPTL3 with the degree of atheroma progression in statin-treated type 2 diabetic patients. Methods 59 patients (59 lesions) with serial ANGPTL3 levels at baseline and week 48 were included into the current analysis. Clinical demographics and IVUS-derived measure were compared in patients with and without any increase in ANGPTL3. Results All of study subjects received a statin, and over 60% of them were treated with high-intensity statin. Under these lipid-lowering therapies, any increase in ANGPTL3 levels at week 48 was observed in 52.5% of study participants. Patients with any increase in ANGPTL3 were more likely to have a history of hypertension (90.0% vs. 64.3%, p=0.02), whereas there was no significant difference in on-treatment LDL-C levels between the two groups (1.8 ± 0.4 vs. 1.6 ± 0.6 mmol/L, p=0.25) (Table). On IVUS imaging analysis, baseline percent atheroma volume (PAV) did not differ in those with and without any increase in ANGPTL3. However, patients with any increase in ANGPTL3 presented a greater progression of PAV (0.08 ± 0.28 vs. -0.74 ± 0.29, p=0.04). There was a trend toward a lower frequency of PAV regression in those exhibiting any increase in ANGPTL3 (48.4% vs. 57.1%), but this comparison did not meet statistical significance (p=0.50) (Figure). Multivariate analysis adjusting clinical characteristics demonstrated that any increase in ANGPTL3 level was not independently associated with PAV progression (β=0.16, 95%CI=-0.01 – 0.18, p=0.27). Conclusion Over 50% of statin-treated type 2 diabetic patients with coronary atherosclerosis showed any increase in ANGPTL3 levels at week 48. Serial IVUS imaging revealed that patients with any increase in ANGPTL3 more likely presented a greater atheroma progression. However, this relationship did not exist after adjusting clinical characteristics. Our findings suggest that ANGPTL3 may not be a pivotal driver associated with atheroma progression in statin-treated type 2 diabetic patients.

Integrated multi-omics predictive analysis of atherosclerosis: a sub-study from the Mineralocorticoid Receptor Antagonism in Diabetic Atherosclerosis (MAGMA) trial

Abstract Background/Introduction Mineralocorticoid receptor (MR) antagonists (MRA) are beneficial in cardiorenal outcomes in randomized controlled trials but the mechanisms are unclear. MAGMA was an NHLBI sponsored randomized, double-blind, placebo controlled, 12-month trial comparing Spironolactone (n = 37) vs. placebo (n = 42) in Type 2 diabetics with CKD stages 3-4 on maximal renin-angiotensin system (RAS) blockade and a prior atherosclerotic event and/or left ventricular (LV) hypertrophy. The primary outcome of percent (%) change in total aortic wall volume (TWV) at 12 months, measured by magnetic resonance imaging (MRI), was significantly reduced by Spironolactone. Purpose/Originality The purpose of this analysis was to understand mechanistic pathways of MRAs using a multi-omics approach that could help tease out molecular mechanisms of benefit. Revealing for the first time which of these integrated pathways are predictive of the primary outcome will help design treatments for targeted interventions. Methods Plasma and peripheral blood mononuclear cells from patients randomized to Spironolactone or placebo at baseline and 3-months were measured for aptamer-based proteomic biomarkers (7,596 proteins) and 10-X platform-based single-cell RNA-sequencing (scRNAseq), respectively. Pre-selected candidate predictors were used as inputs of a predictive model of changes of TWV. We fit a Mixed-Multivariate Random Forest (RF) model, a variation of the RF supervised tree-based machine learning method to take the experimental design into account in the regression formulation. The two sources of "omics predictors" were integrated into a supervised multi-omics model to jointly explain the outcome using an extension of Sparse Generalized Canonical Correlation Analysis (SGCCA). Integrated multiome functional analyses with graphical visualizations were carried out by statistical enrichment analysis using Over Representation Analysis (ORA) and Gene Set Enrichment Analysis (GSEA) against databases of gene ontologies, biological pathways, putative regulatory motifs, proteins, or disease annotations. Results The plasma proteome in response to Spironolactone revealed downregulation of MR targets including fibrosis, immune activation/inflammation, leukocyte activation, proliferation and pathways involved in cytokine stimulation. scRNAseq pathways revealed negative regulation of cytokines production such as IL-2 and redistribution of multiple cell types. Predictors of plaque progression involved cytokine-receptor, complement-coagulation, cell adhesion and axonal guidance targets. Multiome integrated functional analyses results of predictive pathways will be presented. Conclusions The changes in plasma proteomic profile with Spironolactone were consistent with the phenotype of reduced atherosclerosis and downregulation of multiple inflammatory, immune response and profibrotic pathways.

Endothelial KLF11 is a novel protector against diabetic atherosclerosis

BackgroundAtherosclerotic cardiovascular diseases remain the leading cause of mortality in diabetic patients, with endothelial cell (EC) dysfunction serving as the initiating step of atherosclerosis, which is exacerbated in diabetes. Krüppel-like factor 11 (KLF11), known for its missense mutations leading to the development of diabetes in humans, has also been identified as a novel protector of vascular homeostasis. However, its role in diabetic atherosclerosis remains unexplored.MethodsDiabetic atherosclerosis was induced in both EC-specific KLF11 transgenic and knockout mice in the Ldlr−/− background by feeding a diabetogenic diet with cholesterol (DDC). Single-cell RNA sequencing (scRNA-seq) was utilized to profile EC dysfunction in diabetic atherosclerosis. Additionally, gain- and loss-of-function experiments were conducted to investigate the role of KLF11 in hyperglycemia-induced endothelial cell dysfunction.ResultsWe found that endothelial KLF11 deficiency significantly accelerates atherogenesis under diabetic conditions, whereas KLF11 overexpression remarkably inhibits it. scRNA-seq profiling demonstrates that loss of KLF11 increases endothelial-to-mesenchymal transition (EndMT) during atherogenesis under diabetic conditions. Utilizing gain- and loss-of-function approaches, our in vitro study reveals that KLF11 significantly inhibits EC inflammatory activation and TXNIP-induced EC oxidative stress, as well as Notch1/Snail-mediated EndMT under high glucose exposure.ConclusionOur study demonstrates that endothelial KLF11 is an endogenous protective factor against diabetic atherosclerosis. These findings indicate that manipulating KLF11 could be a promising approach for developing novel therapies for diabetes-related cardiovascular complications.

Topical Anti-ulcerogenic Effect of the Beta-adrenergic Blockers on Diabetic Foot Ulcers: Recent Advances and Future Prospectives.

Patients with diabetes suffer from major complications like Diabetic Retinopathy, Diabetic Coronary Artery Disease, and Diabetic Foot ulcers (DFUs). Diabetes complications are a group of ailments whose recovery time is especially delayed, irrespective of the underlying reason. The longer duration of wound healing enhances the probability of problems like sepsis and amputation. The delayed healing makes it more critical for research focus. By understanding the molecular pathogenesis of diabetic wounds, it is quite easy to target the molecules involved in the healing of wounds. Recent research on beta-adrenergic blocking drugs has revealed that these classes of drugs possess therapeutic potential in the healing of DFUs. However, because the order of events in defective healing is adequately defined, it is possible to recognize moieties that are currently in the market that are recognized to aim at one or several identified molecular processes. The aim of this study was to explore some molecules with different therapeutic categories that have demonstrated favorable effects in improving diabetic wound healing, also called the repurposing of drugs. Various databases like PubMed/Medline, Google Scholar and Web of Science (WoS) of all English language articles were searched, and relevant information was collected regarding the role of beta-adrenergic blockers in diabetic wounds or diabetic foot ulcers (DFUs) using the relevant keywords for the literature review. The potential beta-blocking agents and their mechanism of action in diabetic foot ulcers were studied, and it was found that these drugs have a profound effect on diabetic foot ulcer healing as per reported literatures. There is a need to move forward from preclinical studies to clinical studies to analyze clinical findings to determine the effectiveness and safety of some beta-antagonists in diabetic foot ulcer treatment.

Role of lymphocyte-to-monocyte ratio as a predictive marker for diabetic coronary artery disease: A cross-sectional study.

The lymphocyte to monocyte ratio (LMR) is considered a marker of systemic inflammation in cardiovascular disease and acts as predictor of mortality in coronary artery disease. To investigate the predictive role of LMR in diabetic coronary artery disease patients. This cross-sectional study was conducted at tertiary care super-specialty hospital at New Delhi, India. A total of 200 angiography-proven coronary artery disease (CAD) patients were enrolled and grouped into two categories: Group I [CAD patients with type 2 diabetes mellitus (T2DM) and glycated hemoglobin (HbA1c) levels ≥ 6.5%], and Group II (CAD patients without T2DM and HbA1c levels < 6.5%). Serum lipoproteins, HbA1c, and complete blood count of enrolled patients were analyzed using fully automatic analyzers. The logistic regression analysis showed an odds ratio of 1.48 (95%CI: 1.28-1.72, P < 0.05) for diabetic coronary artery disease patients (Group I) in unadjusted model. After adjusting for age, gender, diet, smoking, and hypertension history, the odds ratio increased to 1.49 (95%CI: 1.29-1.74, P < 0.01) in close association with LMR. Further adjustment for high cholesterol and triglycerides yielded the same odds ratio of 1.49 (95%CI: 1.27-1.75, P < 0.01). Receiver operating characteristic curve analysis revealed 74% sensitivity, 64% specificity, and 0.74 area under the curve (95%CI: 0.67-0.80, P < 0.001), suggesting moderate predictive accuracy for diabetic CAD patients. LMR showed positive association with diabetic coronary artery disease, with moderate predictive accuracy. These findings have implications for improving CAD management in diabetics, necessitating further research and targeted interventions.

Thiamine Deficiency and its Implications on Microvascular Complications of Diabetes Mellitus

Thiamine is the first vitamin discovered and belongs to Vit B family. The main effect seen with thiamine deficiency is Beri-Beri, Wernicke’s encephalopathy, Wernicke-Korsak off syndrome and are considered as a serious condition but often can be reversed. The deficient status of thiamine can also cause varied affects and can overlap with other conditions to exacerbate its potent effects. It is seen that thiamine is necessary for the metabolism of glucose in the form of cofactors, deficiency of which leads to accumulation of toxic glucose metabolites leading to formation of free radicals and oxidative stress. Glucose is not only important for the formation of energy but its improper metabolism proves to have deleterious effects in the body. In this review, an attempt is made to correlate microvascular complications of diabetes with thiamine deficiency and can be discerned that oxidative stress is one of the important factors for the progress of microvascular complications, as well as diabetic ketoacidosis, atherosclerosis and cardiovascular damage in patients with diabetes mellitus and these can be prevented or maintained by optimizing thiamine levels in the body.

Preparation and characterization of BSA-loaded liraglutide and platelet fragment nanoparticle delivery system for the treatment of diabetic atherosclerosis

BackgroundDiabetic atherosclerosis is one of the main causes of morbidity and mortality worldwide, but its therapeutic options are limited. Liraglutide (LIR), a synthetic analog of GLP-1 approved as an anti-obesity drug by the FDA, has been reported as a promising drug for diabetic atherosclerosis. However, the main problem with LIR is its use that requires regular parenteral injections, which necessitates the improvement of drug delivery for increased efficiency and minimization of injection numbers.ResultsThe objective of our present study was to prepare and characterize nanoparticles (BSA@LIR-PMF) for targeted drug delivery using LIR-encapsulated platelet membrane fragments (PMF) coated bovine serum albumin (BSA). We used various methods to characterize the prepared nanoparticles and evaluated their efficiency on diabetes-induced atherosclerosis in vitro and in vivo. The results showed that the nanoparticles were spherical and had good stability and uniform size with intact membrane protein structure. The loading and encapsulation rates (LR and ER) of BSA@LIR-PMF were respectively 7.96% and 85.56%, while the cumulative release rate was around 77.06% after 24 h. Besides, we also examined the impact of BSA@LIR-PMF on the proliferation, migration, phagocytosis, reactive oxygen species (ROS) levels, oxidative phosphorylation, glycolysis, lactate and ATP levels, and lipid deposition in the aortas. The results indicated that BSA@LIR-PMF could effectively inhibit ox-LDL-stimulated abnormal cell proliferation and migration, reduce the level of ROS and lactate concentration, and enhance the level of ATP, thereby improving oxidative phosphorylation in ox-LDL-treated cells.ConclusionBSA@LIR-PMF significantly inhibited diabetes-induced atherosclerosis. It was anticipated that the BSA@LIR-PMF nanoparticles might be used for treating diabetes-associated cardiovascular complications.

Macrophages regulate plaque progression in diabetic Apoe−/− mice dependent on Pi4p/Nlrp3 signaling pathway

Background and aimsAtherosclerotic cardiovascular disease complicated by diabetes mellitus (DM) is the leading cause of death in diabetic patients, and it is strongly associated with macrophages and inflammasomes. It has been found that activation of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome is closely associated with phosphatidylinositol 4-phosphate (PI4P) on the trans-Golgi. However, how PI4P and NLRP3 regulate macrophage function and its role in diabetic atherosclerotic plaques is unclear. MethodsThe expression of Pi4p and Nlrp3-inflammasome-related proteins in atherosclerosis in apolipoprotein E-deficient (Apoe−/−) and Apoe−/− DM mice was investigated. Then, Pi4p levels were affected by shRNA-Pi4kb or cDNA-Sac1 plasmid to investigate the effects of changes in Pi4p-related metabolic enzymes on macrophage function. Finally, genetically modified macrophages were injected into diabetic Apoe−/− mice to explore the effects on atherosclerosis. ResultsDM promoted plaque progression in atherosclerotic mice and increased expression of Pi4p and Nlrp3 in plaques. In addition, impaired macrophage function induced by high glucose was reversed by transfected shRNA-Pi4kb or cDNA-Sac1 plasmid. Furthermore, decreased levels of Pi4p reduced plaque area in diabetic Apoe−/− mice. ConclusionsOur data suggests that Pi4p/Nlrp3 in macrophages play an important role in the exacerbation of atherosclerosis in diabetic mice. Pi4p-related metabolizing enzymes (PI4KB and SAC1) may be a potential therapeutic strategy for diabetic atherosclerosis, and macrophage therapy is also a potential treatment.

Functions of Adipocytokines and Link with Primary Glomerulonephritis

Abstract Adipocytokines are substances with endocrine functions produced by adipose tissue, playing crucial roles in regulating metabolic functions and inflammatory processes. Dysregulation of fatty tissue's endocrine functions and dysregulation of the production of adipocytokines such as adiponectin, leptin, fibroblast-stimulating factor, and others can lead to a low-grade systemic inflammation and an insulin resistance in patients. These conditions contribute to the pathophysiology of type 2 diabetes mellitus, atherosclerosis, arterial hypertension, metabolic syndrome, and other disorders. Conversely, these metabolic disorders exert feedback-regulatory effects on adipocytokines and their functions. Glomerulonephritis encompasses a group of immune-mediated diseases characterized by inflammation of the glomeruli. Diagnosis can involve examining urine sediment, detecting autoantibodies, and identifying immune complexes in the blood. However, a kidney biopsy is required for definitive confirmation of glomerulonephritis and is considered the gold standard and a necessity in diagnosis. Affecting the level of adipocytokines could be one of the new strategies for the pharmacological treatment of many diseases. Given a better understanding of their functions and molecular targets, adipocytokines may herald the emergence of new diagnostic approaches (1, 2). Monitoring the level of adipocytokines could contribute to a better patient management and thus become an auxiliary tool for predicting and diagnosing diseases.

The impact of lipoprotein(a) level on cardiac pathologies in diabetes: a cardiac CT study.

We aimed to explore the imaging profile of coronary atherosclerosis, perivascular inflammation, myocardial perfusion, and interstitial fibrosis in diabetes stratified by lipoprotein(a) [Lp(a)] levels. In this prospective study, we enrolled diabetic patients who had undergone computed tomography (CT) angiography, stress CT-myocardial perfusion imaging, and late iodine enhancement in 20 months. Then, we categorized them into elevated and normal groups based on an Lp(a) cutoff level of 30 mg/dL. All imaging data, including coronary atherosclerosis parameters, pericoronary adipose tissue (PCAT) density, stress myocardial blood flow (MBF), and extracellular volume (ECV), were collected for further analysis. In total, 207 participants (mean age: 59.1 ± 12.0 years, 111 males) were included in this study. Patients with elevated Lp(a) level had more pronounced percent atheroma volume (2.55% (1.01-9.01%) versus 1.30% (0-4.95%), p = 0.010), and demonstrated a higher incidence of positive remodeling, spotty calcification, and high-risk plaque (HRP) than those with normal Lp(a) levels (75.6% versus 54.8%, p = 0.015; 26.8% versus 9.6%, p = 0.003; 51.2% versus 30.1%, p = 0.011, respectively). Results of the multivariate analysis revealed that after adjusting for all clinical characteristics, elevated Lp(a) levels were an independent parameter associated with HRP (odds ratio = 2.608; 95% confidence interval: 1.254-5.423, p = 0.010). However, no significant difference was found between the two groups in terms of PCAT density, stress MBF, and ECV. Elevated Lp(a) levels are associated with extensive coronary atherosclerosis and HRP development. However, they are not related to perivascular inflammation, decreased myocardial perfusion, and interstitial fibrosis in diabetes. Elevated lipoprotein(a) levels are associated with extensive coronary atherosclerosis and a high incidence of HRPs. However, they are not related to perivascular inflammation, decreased myocardial perfusion, and interstitial fibrosis in diabetes. Diabetes is a known risk factor that accelerates cardiovascular disease progression. Diabetics with elevated lipoprotein(a) (Lp(a)) levels had a higher percent atheroma volume and positive remodeling, spotty calcification, and HRPs. Patients with diabetes should be screened for elevated Lp(a) using CCTA for comprehensive evaluation of atherosclerotic characteristics.

Unlocking Healing Potential: A Case Study on the Management of Diabetic Foot Ulcer

Diabetes stands as one of the most prevalent diseases globally, and diabetic patients are at risk of developing foot ulcers as a microvascular complication. These ulcers stem from diabetic neuropathy or atherosclerosis, leading to ischemia or breakdown of glucose-laden tissue, resulting in inflammation and ulceration. If left untreated, these ulcers can become infected, spreading to the underlying tissues. In Ayurveda, such ulcers are termed as Madhumehajanya Vrana. Sushruta Acharya outlined Anushastra Karma for managing Vrana, which includes Ksharakarma (application of alkalis) and Jalukavacharana (leech therapy). Kshara functions by actions like Chhedana, Bhedana, Lekhana and Ropana. Jalukavacharana possesses anti-inflammatory properties, promotes fresh blood supply by removing vitiated Dosha from the blood, and fosters wound healing by forming healthy granulation tissue. A 65-year-old female patient presented with a non-healing wound on the plantar aspect of her left foot below the greater toe since 8 months, associated with foul-smelling pus discharge for 6 months. She had a known history of diabetes mellitus since 10 years. The ulcer measured 4cm x 3cm x 2.5cm, GRBS was 380mg/dl with HbA1c of 12%. Patient was treated with Ksharataila infiltration, application of Tilwaka pratisaraneeya kshara followed by Lekhana of callosity present over the edges of the ulcer, and Jalukavacharana therapy for four sessions with seven days interval, in addition to internal medications. Glycemic control was achieved by Inj. Insulin Mixtard 30/70 30 units in morning and 15units at night.

The Role of Activator Protein-1 Complex in Diabetes-Associated Atherosclerosis: Insights From Single-Cell RNA Sequencing.

Despite advances in the treatment of atherosclerotic cardiovascular disease, it remains the leading cause of death in patients with diabetes. Even when risk factors are mitigated, the disease progresses, and thus newer targets need to be identified that directly inhibit the underlying pathobiology of atherosclerosis in diabetes. A single cell sequencing approach was utilised to distinguish the proatherogenic transcriptional profile in aortic cells in diabetes using a streptozotocin induced-diabetic Apoe-/- mouse model. Human carotid endarterectomy specimens from individuals with and without diabetes were also evaluated via immunohistochemical analysis. Further mechanistic studies were performed in human aortic endothelial cells and human THP-1 derived macrophages. We then performed a preclinical study using an AP-1 inhibitor in a diabetic Apoe-/- mouse model. Single cell RNA sequencing analysis identified the AP-1 complex as a novel target in diabetes-associated atherosclerosis. AP-1 levels were elevated in carotid endarterectomy specimens from diabetic when compared to non-diabetic individuals. AP-1 was validated as a mechanosensitive transcription factor via immunofluorescence staining for regional heterogeneity of endothelial cells of the aortic region exposed to turbulent blood flow and by performing microfluidics experiments in HAECs. AP-1 inhibition with T-5224 blunted endothelial cell activation as assessed by a monocyte adhesion assay and expression of genes relevant to endothelial function. Furthermore, AP-1 inhibition attenuated foam cell formation. Critically, treatment with T-5224 attenuated atherosclerosis development in diabetic Apoe-/- mice. This study has identified the AP-1 complex as a novel target, inhibition of which treats the underlying pathobiology of atherosclerosis in diabetes.

Discovering hidden patterns: Association rules for cardiovascular diseases in type 2 diabetes mellitus.

It is increasingly common to find patients affected by a combination of type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD), and studies are able to correlate their relationships with available biological and clinical evidence. The aim of the current study was to apply association rule mining (ARM) to discover whether there are consistent patterns of clinical features relevant to these diseases. ARM leverages clinical and laboratory data to the meaningful patterns for diabetic CAD by harnessing the power help of data-driven algorithms to optimise the decision-making in patient care. To reinforce the evidence of the T2DM-CAD interplay and demonstrate the ability of ARM to provide new insights into multivariate pattern discovery. This cross-sectional study was conducted at the Department of Biochemistry in a specialized tertiary care centre in Delhi, involving a total of 300 consented subjects categorized into three groups: CAD with diabetes, CAD without diabetes, and healthy controls, with 100 subjects in each group. The participants were enrolled from the Cardiology IPD & OPD for the sample collection. The study employed ARM technique to extract the meaningful patterns and relationships from the clinical data with its original value. The clinical dataset comprised 35 attributes from enrolled subjects. The analysis produced rules with a maximum branching factor of 4 and a rule length of 5, necessitating a 1% probability increase for enhancement. Prominent patterns emerged, highlighting strong links between health indicators and diabetes likelihood, particularly elevated HbA1C and random blood sugar levels. The ARM technique identified individuals with a random blood sugar level > 175 and HbA1C > 6.6 are likely in the "CAD-with-diabetes" group, offering valuable insights into health indicators and influencing factors on disease outcomes. The application of this method holds promise for healthcare practitioners to offer valuable insights for enhancing patient treatment targeting specific subtypes of CAD with diabetes. Implying artificial intelligence techniques with medical data, we have shown the potential for personalized healthcare and the development of user-friendly applications aimed at improving cardiovascular health outcomes for this high-risk population to optimise the decision-making in patient care.

Association between cardiometabolic index and hepatic steatosis and liver fibrosis: a population-based study.

The cardiometabolic index (CMI) is a new type of obesity index that is based on a combination of lipid levels and abdominal obesity indicators. It is closely correlated with the occurrence of diabetes mellitus, atherosclerosis, hypertension, and other diseases, thus playing an important role in the screening of metabolic diseases. This is coupled with hepatic steatosis and fibrosis which are characterized by excessive liver fat deposition. The aim of this study was to investigate the possible association between CMI and hepatic steatosis and liver fibrosis. A cross-sectional investigation was conducted using the 2017-2020 National Health and Nutrition Examination Survey (NHANES) dataset to probe the relationship between CMI and hepatic steatosis and liver fibrosis, while multiple linear regression models were used to test the linear association between CMI and controlled attenuation parameter (CAP) and liver stiffness measurement (LSM). Smooth-fit curves and threshold effects analysis were used to describe the nonlinear relationships. Subgroup analyses were performed according to gender, age, body mass index (BMI), hypertension, diabetes, cardiovascular disease, and smoking status. A total of 3084 adults aged 18-80 years were included in this analysis, and after controlling for a variety of variables, there was a significant positive correlation between CMI and CAP [20.38 (16.27,24.49)]. When subgroups were analyzed, this positive correlation was found to be stronger in the female population than in the male (P for interaction = 0.0303). Furthermore, the association between CMI and CAP was nonlinear. Using multiple regression analysis, it was shown that the linear relationship between CMI and liver fibrosis was not significant [-0.09 (-0.47,0.29)]. The findings suggest that elevated CMI levels are associated with hepatic steatosis, but that CMI is not linked to liver fibrosis. Larger prospective investigations are needed to confirm our findings.

Nrf2 Signaling Pathway as a Key to Treatment for Diabetic Dyslipidemia and Atherosclerosis.

Diabetes mellitus (DM) is a chronic endocrine disorder that affects more than 20 million people in the United States. DM-related complications affect multiple organ systems and are a significant cause of morbidity and mortality among people with DM. Of the numerous acute and chronic complications, atherosclerosis due to diabetic dyslipidemia is a condition that can lead to many life-threatening diseases, such as stroke, coronary artery disease, and myocardial infarction. The nuclear erythroid 2-related factor 2 (Nrf2) signaling pathway is an emerging antioxidative pathway and a promising target for the treatment of DM and its complications. This review aims to explore the Nrf2 pathway's role in combating diabetic dyslipidemia. We will explore risk factors for diabetic dyslipidemia at a cellular level and aim to elucidate how the Nrf2 pathway becomes a potential therapeutic target for DM-related atherosclerosis.