Cardiovascular Complications In Diabetic Patients Research Articles

Elevated glucose levels increase vascular calcification risk by disrupting extracellular pyrophosphate metabolism

BackgroundVascular calcification is a major contributor to cardiovascular disease, especially diabetes, where it exacerbates morbidity and mortality. Although pyrophosphate is a recognized natural inhibitor of vascular calcification, there have been no prior studies examining its specific deficiency in diabetic conditions. This study is the first to analyze the direct link between elevated glucose levels and disruptions in extracellular pyrophosphate metabolism.MethodsRat aortic smooth muscle cells, streptozotocin (STZ)-induced diabetic rats, and diabetic human aortic smooth muscle cells were used to assess the effects of elevated glucose levels on pyrophosphate metabolism and vascular calcification. The techniques used include extracellular pyrophosphate metabolism assays, thin-layer chromatography, phosphate-induced calcification assays, BrdU incorporation for DNA synthesis, aortic smooth muscle cell viability and proliferation assays, and quantitative PCR for enzyme expression analysis. Additionally, extracellular pyrophosphate metabolism was examined through the use of radiolabeled isotopes to track ATP and pyrophosphate transformations.ResultsElevated glucose led to a significant reduction in extracellular pyrophosphate across all diabetic models. This metabolic disruption was marked by notable downregulation of both the expression and activity of ectonucleotide pyrophosphatase/phosphodiesterase 1, a key enzyme that converts ATP to pyrophosphate. We also observed an upregulation of ectonucleoside triphosphate diphosphohydrolase 1, which preferentially hydrolyzes ATP to inorganic phosphate rather than pyrophosphate. Moreover, tissue-nonspecific alkaline phosphatase activity was markedly elevated across all diabetic models. This shift in enzyme activity significantly reduced the pyrophosphate/phosphate ratio. In addition, we noted a marked downregulation of matrix Gla protein, another inhibitor of vascular calcification. The impaired pyrophosphate metabolism was further corroborated by calcification experiments across all three diabetic models, which demonstrated an increased propensity for vascular calcification.ConclusionsThis study demonstrated that diabetes-induced high glucose disrupts extracellular pyrophosphate metabolism, compromising its protective role against vascular calcification. These findings identify pyrophosphate deficiency as a potential mechanism in diabetic vascular calcification, highlighting a new therapeutic target. Strategies aimed at restoring or enhancing pyrophosphate levels may offer significant potential in mitigating cardiovascular complications in diabetic patients, meriting further investigation.Graphical abstract

Association Between the Triglyceride-Glucose Index and Serum Uric Acid to High-Density Lipoprotein (HDL) Cholesterol Ratio in Type 2 Diabetes Mellitus in Gabes City, Tunisia.

Background Type 2 diabetes mellitus (T2DM) is a significant risk factor for cardiovascular diseases (CVD). The triglyceride-glucoseindex (TyGi) is a novel biomarker for insulin resistance, strongly linked to CVD. Elevated serum uric acid levels and the uric acid to high-density lipoproteincholesterol ratio (UHR) are emerging as markers of metabolic syndrome and cardiovascular risk in T2DM. This study aimed to explore the association between the TyGiand UHR in T2DM patients. Objectives The aim of this study is to compare metabolic parameters in T2DM patients and assess the association between the TyGiand serum UHR. Methodology A cross-sectional case-control study was conducted at the University Hospital of Gabes, Gabes City, Tunisia with 50 T2DM patients and 50 gender-matched healthy controls. Inclusion criteria included adults aged 30-75 years with a confirmed diagnosis of T2DM on stable medication for at least three months. Exclusion criteria included other types of diabetes, significant liver or kidney disease, recent cardiovascular events, endocrine disorders, and substance abuse. Metabolic and biochemical parameters, including fasting blood sugar, postprandial blood sugar, glycosylated hemoglobin, lipid profile, and renal function, were measured. The TyGiand serum UHR were calculated and analyzed for correlations. Results T2DM patients exhibited significantly higher fasting blood sugar, postprandial blood sugar, glycosylated hemoglobin, TyGi, and serum UHR compared to controls, indicating impaired glycemic control and adverse lipid profiles. The UHR showed a positive correlation with a strong negative correlation with HDL and a positive correlation with uric acid levels. The linear regression analysis indicated a weak positive trend between the TyGi and serum UHR, although not statistically significant. Conclusion This study underscores the importance of the TyGiand serum UHRas biomarkers for evaluating metabolic and cardiovascular risk in T2DM. Further research is needed to explore their combined utility in clinical practice for early detection and management of cardiovascular complications in diabetic patients.

Correlations between distal sensorimotor polyneuropathy and cardiovascular complications in diabetic patients in the North-Eastern region of Hungary.

Distal sensorimotor polyneuropathy (DSPN) is the earliest detectable and the most frequent microvascular complication in diabetes mellitus. Several studies have previously demonstrated correlations between cardiovascular risk factors in diabetic patients and independent risk factors for diabetic neuropathy. Our objective was to retrospectively analyze data from diabetic patients in the North-East region of Hungary who underwent neuropathy screening at the Diabetic Neuropathy Center, University of Debrecen, between 2017 and 2021. We aimed to investigate the correlations between cardiovascular risk factors and microvascular complications among patients with DSPN. The median age of the patients was 67 years, 59,6% were female, and 91,1% had type 2 diabetes. The prevalence of DSPN among the study subjects was 71.7%. A significantly longer duration of diabetes (p<0.01) was noted in patients with DSPN. Those with DSPN demonstrated a significantly higher HbA1c level (p<0.001) and a greater frequency of insulin use (p = 0.001). We observed a significantly elevated albumin/creatinine ratio (p<0.001) and a significantly lower eGFR (p<0.001) in patients with DSPN. Diabetic retinopathy exhibited a significantly higher prevalence in patients with DSPN (p<0.001). A higher prevalence of myocardial infarction (p<0.05), ischemic heart disease (p<0.001), peripheral arterial disease (p<0.05) and a history of atherosclerosis (p<0.05) was observed in patients with DSPN. In a multivariate logistic regression analysis, the following factors were independently associated with the presence of DSPN: higher HbA1c (OR:2.58, 95% CI:1.89-3.52, p<0.001), age (OR:1.03, 95% CI:1.01-1.05, p = 0.006), albumin/creatinine ratio above 3 mg/mmol (OR:1.23, 95% CI:1.06-1.45, p = 0.008), retinopathy (OR:6.06, 95% CI:1.33-27.53, p = 0.02), and composite cardiovascular endpoint (OR:1.95, 95% CI:1.19-3.19, p = 0.008). Our study revealed that age, elevated HbA1c levels, significant albuminuria, retinopathy, and cardiovascular complications may increase the risk of DSPN. Further investigation of these associations is necessary to understand the impact of patient characteristics during the treatment of diabetic neuropathy.

Mineralocorticoid receptor overactivation in diabetes mellitus: role of O-GlcNAc modification.

Hypertension is a significant risk factor for microangiopathy and cardiovascular complications in diabetic patients. The efficacy of mineralocorticoid receptor (MR) antagonists in impeding the advancement of diabetic nephropathy, along with the reduction in active renin concentration observed in diabetic retinopathy, strongly implies the involvement of MR overactivation in diabetic complications. This review provides a comprehensive review of various mechanisms proposed for MR overactivation in diabetes mellitus. In particular, it focuses on post-translational MR modifications, including O-linkedN-acetylglucosamine modification and phosphorylation, which have been implicated in MR protein stabilization and overactivation under conditions of high glucose. Given the role of MR overactivation in hyperglycemia, it emerges as a promising therapeutic target for preventing diabetic complications. Post-translational modifications (PTMs), such as O-GlcNAcylation and phosphorylation, are related to MR overactivation in diabetes and metabolic syndrome. Aldosterone binding promotes the proteasomal degradation of MR. Under conditions of high glucose, O-GlcNAcylation, and PKCβ-mediated MR phosphorylation are increased. Salt loading and oxidative stress also increase MR phosphorylation through the EGER/ERK pathway. PTMs inhibit ubiquitin attachment to the MR and interfere with the receptor's aldosterone-induced proteasomal degradation. Consequently, they increase the sensitivity of the MR to aldosterone and exacerbate aldosterone-associated complications.

Impact of Sex and Gender Differences on Cardiovascular Risk Factors and Cardiovascular Complications in Diabetic Patients in Benha City, Egypt: A Hospital-Based Cross-Sectional Study

Impact of Sex and Gender Differences on Cardiovascular Risk Factors and Cardiovascular Complications in Diabetic Patients in Benha City, Egypt: A Hospital-Based Cross-Sectional Study

Cardiovascular profile of patients with type 2 Diabetes

The diabetic patient is a subject at high cardiovascular risk. Accurate determination of cardiovascular risk requires reliable tools to implement preventive measures. Can risk equations, and in particular the SCORE (Systematic Coronary Risk Evaluation) equation, still be of interest in assessing the risk of the type 2 diabetic patient in the face of new methods such as the coronary calcium score? The objective of the work is to determine the cardiovascular profile of type 2 diabetic patients through Score. Material and methods: Observational and descriptive study involving 176 type 2 diabetic patients conducted during the month of April 2021. All of them benefited from a clinical examination, a metabolic, degenerative and cardiovascular risk calculation according to the Score. Results: The average age is 58.7 years with extremes of 28 to 85 years. A female predominance was noted (74.4%) with a sex ratio of 0.3. The average duration of diabetes evolution is 8.84 years with extremes ranging from 1 month to 44 years. 57.1% of patients were on oral treatment, versus 36.3% on insulin and 6.5% on diabetic diet only. Glycemic imbalance exists in more than 62% (estimated by HbA1c). The other associated risk factors found are: hypertension (56%), obesity and overweight (82.1%), smoking (12%) and sedentary lifestyle (60.7%), dyslipidemia was found in 66 patients (56.5%); 89.6% of women were menopausal. Microangiopathic complications are noted in 60.7% of cases: nephropathy (38.2%), retinopathy (33.3%), neuropathy (59.8%). Macroangiopathic complications affect 23.2%. In our population, 67.3% have a very high cardiovascular risk (&gt; 10%) according to the SCORE. Conclusion: Type 2 diabetic patients are already at high cardiovascular risk. The seriousness of cardiovascular complications in diabetic patients reflects the importance of assessing their cardiovascular risk and of comprehensive management integrating the various risk factors. The Score remains an important and simple tool for estimating cardiovascular risk in patients with type 2 diabetes.

Bach1 modulates AKT3 transcription to participate in hyperglycaemia-mediated EndMT in vascular endothelial cells.

Hyperglycaemia-mediated endothelial-to-mesenchymal transition (EndMT) is involved in the occurrence and progression of cardiovascular complications in diabetic patients. Previous studies reported that AKT serine/threonine kinase 3 (AKT3) and Bric-a-brac/Tramtrack/Broad (BTB) and cap'n'collar (CNC) homology 1 (bach1) participates in endothelial injury and epithelial-to-mesenchymal transition. In the present study, we proposed that bach1 regulates AKT3 transcription, thus involved in hyperglycaemia-mediated EndMT in vascular endothelium. Our results indicated that hyperglycaemia/high glucose increased AKT3 expression and induced EndMT in aorta of diabetic rats and hyperglycaemic human umbilical vein endothelial cells (HUVECs). Moreover, inhibition of AKT3 expression reversed high glucose-mediated EndMT in HUVECs. Further, hyperglycaemia/high glucose augmented bach1 expression in aorta of diabetic rats and hyperglycaemic HUVECs. Furthermore, si-bach1 countered high glucose-induced AKT3 expression and EndMT in HUVECs. In addition, the effect of bach1 overexpression is similar to that of high glucose treatment, which was reversed by si-AKT3. ChIP assays found bach1 enriched in the promoter region of AKT3. Bach1 overexpression augmented AKT3 promoter activity, which lost after specific binding site mutation. Bach1 was involved in hyperglycaemia-induced EndMT via modulation of AKT3 transcription.

Circadian rhythm of plasminogen activator inhibitor-1 and cardiovascular complications in type 2 diabetes.

Cardiovascular complications are a common death cause in type 2 diabetes patients, as they are often combined. Plasminogen-activator Inhibitor 1 (PAI-1) participates in the development and progression of cardiovascular complications in diabetes. Insulin resistance increases PAI-1 production, and high PAI-1 levels lead to an environment conducive to thrombosis and earlier and more severe vascular disease. Current evidence also suggests that PAI-1 has a rhythmic profile of circadian fluctuations and acrophase in the morning within a single day, which might explain the high morning incidence of cardiovascular events. Thus, PAI-1 is a possible drug target. Although several PAI-1 inhibitors have been developed, none have yet been allowed for clinical use. Research on rhythm has also led to the concept of "chronotherapy", a rhythm-based drug regimen expected to improve the treatment of cardiovascular complications in diabetic patients. Herein, we searched several databases and reviewed relevant articles to describe the circadian rhythm characteristics and endogenous molecular mechanisms of PAI-1, its relationship with insulin resistance, the causes of cardiovascular complications caused by PAI-1, and the current development of PAI-1 inhibitors. We also summarized the possibility of using the circadian rhythm of PAI-1 to treat cardiovascular complications in diabetic patients.

Efficacy of acupuncture on cardiovascular complications in patients with diabetes mellitus in Korea: A nationwide retrospective cohort

ObjectiveThe main aim of this study is to investigate whether acupuncture could be an effective complementary treatment for reducing the risk of macrovascular complications in diabetic patients currently taking antidiabetic medications using a nationwide population-based database. MethodsWe conducted a retrospective cohort study to assess the efficacy of acupuncture on cardiovascular complications in diabetic patients using data from patients between 40 and 79 years of age, newly diagnosed with diabetes between 2003 and 2006, found in the National Health Insurance Service-National Sample Cohort (NHIS-NSC) in Korea. From the data, we identified 21,232 diabetic patients who were taking antidiabetic medication between 2003 and 2006. The selected patients were divided into two groups—those who received acupuncture at least three times and those who received no acupuncture (non-acupuncture) in the year following their diagnosis of diabetes. After 1:1 propensity score matching (PSM), each group had 3350 patients, and the observation ceased at the occurrence of a major adverse cardiovascular event (MACE), which was defined as either myocardial infarction, stroke, or death due to cardiovascular cause. ResultsAfter PSM, the acupuncture group had a lower incidence of MACE (hazard ratio [HR]: 0.87; 95% confidence interval [CI]: 0.81–0.94; P = 0.0003) and all-cause mortality (HR: 0.77; 95% CI: 0.70–0.84; P < 0.0001) than the non-acupuncture group; the HRs for stroke-related mortality (HR: 0.75; 95% CI: 0.56–1.00; P = 0.0485), ischemic heart disease mortality (HR: 0.53; 95% CI: 0.34–0.84; P = 0.006) and circulatory system disease mortality (HR: 0.67; 95% CI: 0.55–0.82; P < 0.0001) were lower in the acupuncture group than in the non-acupuncture group in the secondary analysis. ConclusionOur results indicate that diabetic patients receiving acupuncture treatment might have a lower risk of MACE, all-cause mortality and cardiovascular mortality. This population-based retrospective study suggests beneficial effects of acupuncture in preventing macrovascular complications associated with diabetes. These findings call for further prospective cohort or experimental studies on acupuncture treatment for cardiovascular complications of diabetes.Please cite this article as: Jung H, Won T, Kim GY, Jang J, Yeo S, Lim S. Efficacy of acupuncture on cardiovascular complications in patients with diabetes mellitus in Korea: A nationwide retrospective cohort. J Integr Med. 2023; 21(2): 176–183.

Retracted: High Inflammatory Factor Levels Increase Cardiovascular Complications in Diabetic Patients Undergoing Coronary Artery Bypass Grafting.

[This retracts the article DOI: 10.1155/2022/7151414.].

Retinal artery occlusion as indicator of stroke in diabetes

Abstract Background Diabetes is associated with multiple complications in organs throughout the body, including an increased risk cardiovascular disease (1). Furthermore, an association between retinal artery occlusion and diabetes have been described as well (1,2). Early predictors of complications associated with diabetes would be useful for a better prognosis of the disease. Purpose Based on data from the Danish registries, the aim of this study was to investigate whether RAO is a predictor of stroke in diabetic patients. Methods We included 992 diabetic patients with incident RAO from the Danish National Patient Register with incident RAO between 1st of January 2000 and 31st of December 2018. Each of these cases were matched on age at index, sex, and time since diabetes diagnosis with 5 random diabetes patients with no subsequent diagnosis of RAO. Survival analyses were used to estimate and contrast the risk of stroke in diabetic RAO patients compared to diabetic patients with no prior diagnosis of RAO. The included analyses were all performed at 1 and 5-year follow-up. Results At 1-year follow-up, the incidence rate of stroke in diabetic RAO patients was 10.0 per 100 person years (PY) (95% CI: 8.13–12.10). The incidence for the controls at this time point was much lower at 1.82 per 100 PY (95% CI: 1.47–2.25). After 5-years of follow-up a large difference persisted, where the cumulative incidence was 19.3% (95% CI: 16.5–22.2%) for the RAO patients compared to 7.4% (95% CI: 6.5–8.2%) for the controls. The hazard rate ratio for stroke was 5.48 (95% CI: 4.06–7.39) after 1-year follow-up and 3.17 (95% CI: 2.60–3.86) after 5-year follow-up. The results support the use of RAO as a predictor of stroke in diabetic patients. Cardiovascular diseases contribute substantially to the morbidity and mortality in diabetic patients (3,4), underlining the need for especially a predictor of cardiovascular complications in these patients. To our knowledge, the predictive usage of RAO for cardiovascular complications in diabetic patients have not been investigated previously. Small occlusions, which could indicate systemic atherosclerosis, may not always be symptomatic. Therefore, the condition may not be diagnosed before more severe events occur. Conversely, RAO usually cause visual impairments, making RAO suitable as a potential predictor of subsequent cardiovascular events. The incidence rates of stroke suggest that diabetic RAO patients should be especially monitored the first year after their RAO diagnosis, but the monitoring would be beneficial even 5 years after the RAO diagnosis to continuously evaluate risk factors and instigate early intensified treatment. Conclusion The data of this study identified a substantial larger risk of stroke in diabetic RAO patients than diabetic patients with no RAO diagnosis, indicating RAO could be a predictor of stroke in diabetic patients. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): The Obel Family Foundation

Identification of key genes and mechanisms of epicardial adipose tissue in patients with diabetes through bioinformatic analysis.

BackgroundIn recent years, peri-organ fat has emerged as a diagnostic and therapeutic target in metabolic diseases, including diabetes mellitus. Here, we performed a comprehensive analysis of epicardial adipose tissue (EAT) transcriptome expression differences between diabetic and non-diabetic participants and explored the possible mechanisms using various bioinformatic tools.MethodsRNA-seq datasets GSE108971 and GSE179455 for EAT between diabetic and non-diabetic patients were obtained from the public functional genomics database Gene Expression Omnibus (GEO). The differentially expressed genes (DEGs) were identified using the R package DESeq2, then Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were analyzed. Next, a PPI (protein–protein interaction) network was constructed, and hub genes were mined using STRING and Cytoscape. Additionally, CIBERSORT was used to analyze the immune cell infiltration, and key transcription factors were predicted based on ChEA3.ResultsBy comparing EAT samples between diabetic and non-diabetic patients, a total of 238 DEGs were identified, including 161 upregulated genes and 77 downregulated genes. A total of 10 genes (IL-1β, CD274, PDCD1, ITGAX, PRDM1, LAG3, TNFRSF18, CCL20, IL1RN, and SPP1) were selected as hub genes. GO and KEGG analysis showed that DEGs were mainly enriched in the inflammatory response and cytokine activity. Immune cell infiltration analysis indicated that macrophage M2 and T cells CD4 memory resting accounted for the largest proportion of these immune cells. CSRNP1, RELB, NFKB2, SNAI1, and FOSB were detected as potential transcription factors.ConclusionComprehensive bioinformatic analysis was used to compare the difference in EAT between diabetic and non-diabetic patients. Several hub genes, transcription factors, and immune cell infiltration were identified. Diabetic EAT is significantly different in the inflammatory response and cytokine activity. These findings may provide new targets for the diagnosis and treatment of diabetes, as well as reduce potential cardiovascular complications in diabetic patients through EAT modification.

High Inflammatory Factor Levels Increase Cardiovascular Complications in Diabetic Patients Undergoing Coronary Artery Bypass Grafting.

Objective To investigate the association between inflammation and clinical outcomes of coronary artery bypass grafting (CABG) in diabetic patients. Methods A total of 300 diabetic patients with coronary heart disease who underwent CABG were selected. Patients were divided into a group with cardiovascular events (32 in the MACCE group) and a group without cardiovascular events (268 in the non-MACCE group) according to whether cardiovascular events occurred within 30 days. The differences in clinical parameters; serum levels of TNF-α, IL-6, IL-18, IL-1β, and CRP; factors associated with the occurrence of MACCE; and risk factors affecting the midterm all-cause mortality of patients were compared between the two groups. Results The serum levels of TNF-α, IL-6, IL-18, and CRP in the MACCE group were significantly higher than those in the non-MACCE group (p < 0.05). Gender, smoking, hyperlipidemia, duration of diabetes, and levels of TNF-α, IL-6, IL-18, and CRP were closely related to the occurrence of MACCE. The Kaplan-Meier survival analysis evaluation results showed that the levels of IL-6 and CRP significantly affected the midterm all-cause mortality rate (p < 0.05). Multivariate Cox regression analysis showed that the advanced age, hypertension, hyperlipidemia, long duration of diabetes, elevated serum IL-6, and CRP levels could be used as risk factors for midterm all-cause mortality. Conclusions Inflammation levels in diabetic patients are associated with complications and midterm all-cause mortality in patients undergoing coronary artery bypass grafting.

Metabonomic Characteristics of Myocardial Diastolic Dysfunction in Type 2 Diabetic Cardiomyopathy Patients.

Diabetic cardiomyopathy (DCM) is one of the most essential cardiovascular complications in diabetic patients associated with glucose and lipid metabolism disorder, fibrosis, oxidative stress, and inflammation in cardiomyocytes. Despite increasing research on the molecular pathogenesis of DCM, it is still unclear whether metabolic pathways and alterations are probably involved in the development of DCM. This study aims to characterize the metabolites of DCM and to identify the relationship between metabolites and their biological processes or biological states through untargeted metabolic profiling. UPLC-MS/MS was applied to profile plasma metabolites from 78 patients with diabetes (39 diabetes with DCM and 39 diabetes without DCM as controls). A total of 2,806 biochemical were detected. Compared to those of DM patients, 78 differential metabolites in the positive-ion mode were identified in DCM patients, including 33 up-regulated and 45 down-regulated metabolites; however, there were only six differential metabolites identified in the negative mode including four up-regulated and two down-regulated metabolites. Alterations of several serum metabolites, including lipids and lipid-like molecules, organic acids and derivatives, organic oxygen compounds, benzenoids, phenylpropanoids and polyketides, and organoheterocyclic compounds, were associated with the development of DCM. KEGG enrichment analysis showed that there were three signaling pathways (metabolic pathways, porphyrin, chlorophyll metabolism, and lysine degradation) that were changed in both negative- and positive-ion modes. Our results demonstrated that differential metabolites and lipids have specific effects on DCM. These results expanded our understanding of the metabolic characteristics of DCM and may provide a clue in the future investigation of reducing the incidence of DCM. Furthermore, the metabolites identified here may provide clues for clinical management and the development of effective drugs.

Abstract 11333: Muscle Specific MicroRNA-499-5p Impairs Angiogenesis in Ischemic Hindlimb of Diabetic Micehindlimb of Diabetic Mice

Introduction: Limb ischemia is one of the most prevalent cardiovascular complications in diabetic patients. The underlying mechanisms remain incompletely understood. Previously, we have reported that microvascular endothelial cells (MVECs) play an important role in angiogenesis. Recent study demonstrated that skeletal muscle cells (SKMCs) regulate angiogenesis process via paracrine signals; level of miR-499, a muscle specific miR, was enhanced in diabetic hearts/cardiomyocytes and overexpression of miR-499 impaired MVEC function. We observed that level of miR-499-5p, but not -3p, was increased in skeletal muscle cells (SKMCs), MVECs and SKMC-derived extracellular vehicles (SKMC-EVs) in db/db mice. Hypothesis: SKMC-EVs-derived miR-499-5p impairs MVEC function in diabetes. Methods: MVECs and SKMCs, and SKMC-EVs were isolated from 8-10-week male db/+ and db/db mice. Ischemic hind limb (IHL) surgery was conducted in 8-10-week male wildtype C57BL/6J, diabetic db/db and non-diabetic db/+ mice. Results: Level of miR-499-5p was increased in SKMCs and MVECs from db/db mice. Overexpression of miR-499-5p impaired tube formation and migratory activity of MVECs. Intramuscular injection of anti-miR-499-5p lentivirus ameliorated blood perfusion and capillary density in IHL of db/db mice. Mechanistically, miR-499-5p level was increased in diabetic SKMC-EVs. Inhibition of EV formation/section by GW4869 ameliorated diabetic SKMCs-enhanced miR-499-5p level in MVECs. Local injection of diabetic SKMC-EVs impaired blood perfusion and capillary density in C57BL/6J mice. Moreover, diabetic SKMC-EVs-impaired tube formation and migratory activity of MVECs was ameliorated by silencing of miR-499-5p in the diabetic SKMCs ameliorated. Level of sex-determining region Y-box 6 (SOX6), the most attractive gene targeted by miR-499-5p, was decreased in MVECs of db/db mice. Finally, silencing of SOX6 impaired tube formation, migration and pro-angiogenic factor secretion from MVECs. Conclusions: miR-499-5p impairs angiogenic property of MVECs in diabetic mice via SKMC-EV/miR-499-5p/SOX6/proangiogenic factors cascades. miR-499-5p and SOX6 may be novel targets for prevention/therapeutics of ischemic limb injury in diabetic patients.

Study of QT interval prolongation in asymptomatic type-2 diabetes mellitus patients with and without microalbuninuria

QT interval abnormalities are the best predictors of cardiovascular deaths. Microalbuminuria is an independent marker for cardiovascular disease in diabetes mellitus. Hence QT interval abnormalities in diabetics with or without microalbuminuria were evaluated in this study. To study QT interval abnormalities in asymptomatic type 2 diabetic patients with or without microalbuminuria. : Open label controlled study with 214 subjects of either sex. Group A healthy subjects (n=100), group B asymptomatic, type 2 diabetics with no clinical evidence of cardiac disease. Group B subdivided into B with microalbuminuria (n=62), Bwithout microalbuminuria (n=52). Corrected QT interval (QTC), microalbuminuria, and blood pressure were measured for all subjects. QTC was calculated by using Bazzet's formula. QTC more than 440msec was considered prolonged. QTC was within normal range in diabetic patients(415+25msec). Highly significant (p&amp;#60;0.0001) prolongation was observed in diabetics, compared to healthy subjects. Both B(p&amp;#60;0.0001) and B(p&amp;#60;0.001) groups showed a significant increase in QTC than in healthy subjects. Among Band Bgroups QTC was not statistically significant. Prolongation of QTC is indicative of CAN. CAN is often under-recognised and undiagnosed cardiac complication.QTC was more in asymptomatic type 2 diabetics irrespective of microalbuminuria compared to healthy individuals, though values were within normal range. This denotes high risk for future cardiovascular complications in diabetic patients.

Insulin Resistance and Contrainsular Response in Type 2 Diabetes Mellitus Patients with Acute Coronary Syndrome

BACKGROUND: The number of patients with diabetes mellitus (DM) is progressively increasing all over the world. Over the past three decades, the global burden of diabetes has increased from 30 million in 1985 to 382 million in 2015, and current trends indicate that the prevalence of diabetes grows progressively. The phenomenon of insulin resistance established in the majority of type 2 DM (T2DM) patients. T2DM is associated with β-cell deficiency, α-cell resistance to insulin, and reduced effects of incretin. However, the role of insulin and glucagon in the process of cardiovascular complications in diabetic patients is a matter of debate.&#x0D; AIM: Our study aims to estimate insulin resistance and the contrainsular response in patients with T2DM and acute coronary syndrome (ACS).&#x0D; METHODS: The 104 T2DM patients aged 18–70 years participated in the observational study carried out in the Karaganda regional cardiosurgery hospital and ambulatory. The first group included 37 patients hospitalized for ACS in the first 24 h of admission. The second group included 67 patients without ACS. Determination of insulin resistance and contrainsular response was provided using a multiplex immunological assay with XMap technology on Bioplex 3D.&#x0D; RESULTS: During the research, we have discovered a decreased level of glucagon and increased homeostasis model assessment of insulin resistance (HOMA-IR) in patients with T2DM diabetes and ACS. Evaluation of traditional correlation interactions of HOMA-IR and indicators of carbohydrate metabolism showed a positive correlation with fasting plasma glucose in both study groups (Group 1: R = 0.47, p = 0.003; Group 2: R = 0.41, p = 0.024). Glucagon-like peptide (GLP)-1 has a weak positive correlation with HOMA-IR only in the first group (R = 0.32, p = 0.006). Increased insulin resistance was associated with high GLP-1 levels and low glucagon. The logistic regression model established that an increased HOMA-IR index rises the chance of ACS by 10.6% (OR = 1.106 [95% CI 1.105–1.206], p = 0,021). The logistic regression model, reflecting the relation between glucagon and ACS, shows that increased glucagon reduces the ACS odds (OR = 0.989 [95% CI 0.979–0.999], p = 0.026). The adjusted regression model showed no significant influence of early presented factors on the probability of ACS.&#x0D; CONCLUSION: There is a trend toward elevated HOMA-IR insulin resistance index and decreased level of glucagon in diabetic patients with ACS.

Sphingolipid metabolism in type 2 diabetes and associated cardiovascular complications

Sphingolipid metabolism is dysregulated in type 2 diabetes mellitus (T2DM); however, the focus of previous studies was mostly limited to ceramide (Cer), and only few studies have investigated other metabolites, including sphingosine-1 phosphate (So1P). The present study aimed to examine the involvement of 8 major sphingolipid metabolites, including Cer, glucosyl ceramide (GluCer), lactosyl ceramide (LacCer), sphingomyelin (SM), sphinganine (Sa), So1P, sphingosine (So) and sphinganine-1-phosphate (Sa1P), during the progression of T2DM, and to evaluate the ability of serum sphingolipids to predict cases of diabetes with an elevated risk of cardiovascular complications. Blood samples were obtained from 245 participants who were divided into 3 groups: Healthy controls, pre-diabetes (pre-DM) and diagnosed diabetes. The 8 major sphingolipid metabolites were measured by high-performance liquid chromatography-tandem mass spectrometry and blood parameters were determined by routine laboratory assays for all subjects. Among the sphingolipid metabolites, So1P was associated with sex and lean mass index, but not with the body mass index. So1P was highest in healthy controls and gradually decreased when the disease proceeded to pre-DM and T2DM. GluCer, SM, Sa and So decreased in pre-DM and rose again in T2DM, graphically exhibiting a 'U' shape change during the progression of diabetes. So1P and Sa were identified to be significantly associated with cardiovascular complications by multivariate logistic regression analysis. Receiver operating characteristic curve analysis also suggested that So1P and Sa were able to indicate cardiovascular complications in diabetic patients. Pre-DM and diabetes were significantly associated with decreased So1P, SM, Sa and So, compared with the healthy controls. So1P was correlated with the progression of T2DM, and was a predictor of an elevated risk of cardiovascular complications among T2DM patients, along with Sa. The present study was registered with ClinicalTrials.gov (no. NCT02826759; April 2016).

The effects of Momordica balsamina methanolic extract on haematological function in streptozotocin-induced diabetic rats: Effects on selected markers

BackgroundChronic hyperglycaemia-induced haematological changes increase the risk of cardiovascular complications in diabetic patients. The administration of insulin injection as a bolus is accompanied with increased blood viscosity, which is not recommended for patients with congestive heart failure. Momordica balsamina methanolic extract (MB) has previously been shown to possess anti-hyperglycaemic and renal dysfunction ameliorative effects; however, the haematological effects of MB have not been shown. The current study therefore, investigated the short-term effects MB on selected haematological parameters in streptozotocin (STZ)-induced diabetic rats. MethodsBriefly, the air-dried Momordica balsamina leaves were sequentially extracted with methanol to yield a methanolic extract. STZ-induced diabetic rats were divided into untreated and treated groups with insulin (170 μg kg−1 s.c.) and metformin (500 mg kg−1 p.o.) MB (250 mg kg−1 p.o.). MB was administered twice daily for the 5-week experimental period. Blood glucose concentration was monitored weekly. Animals were sacrificed terminally. Blood and kidneys were collected for haematological and biochemical analysis respectively. ResultsTreatment with MB significantly decreased blood glucose concentration and improved erythropoietin secretion, thus significantly increasing red blood cell production in treated diabetic animals by comparison to untreated animals. MB also significantly improved haemoglobin concentrations and moderately increased erythrocyte indices specifically, mean corpuscular volume (MCV), mean corpuscular haemoglobin concentration (MCHC) and mean corpuscular haemoglobin (MCH) to no significance by comparison to untreated diabetic animals. MB treatment decreased the oxidative stress evoked by the induction of diabetes while improving the antioxidant status of treated animals by comparison to untreated animals respectively. ConclusionsAdministration of Momordica balsamina methanolic extract protects against some injurious haematological changes induced by hyperglycaemia, which may reduce the risks of cardiovascular complications.

Abstract 039: Adherence to a Healthy Lifestyle in Relation to Cardiovascular Disease Incidence and Mortality Among Adults With Type 2 Diabetes

Objective: To examine the associations of individual and combined low-risk lifestyle practices, including non-smoking, engaging in moderate to vigorous intensity physical activity (≥150 min/week), drinking alcohol in moderation (5-15 g/day for women and 5-30 g/day for men), and eating a high quality diet (top two fifths of Alternative Healthy Eating Index), with the risk of subsequent cardiovascular events among adults with incident diabetes. Methods: The prospective study included 11,527 participants with diabetes diagnosed during follow-up (8,970 women from the Nurses’ Health Study and 2,557 men from the Health Professionals Follow-Up Study), who were free of cardiovascular disease (CVD) and cancer at the time of diabetes diagnosis. Diet and lifestyle factors after diabetes diagnosis were repeatedly assessed every 2-4 years. Multivariable Cox regression models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of total CVD, coronary heart disease (CHD), and stroke incidence, and CVD mortality. Results: There were 2,311 incident CVD cases (including 498 stroke cases) and 858 CVD deaths during an average of 13.3 years of follow-up. After multivariate adjustment including medication use, the individual low-risk lifestyle factors after diabetes diagnosis were each significantly associated with a lower risk of CVD incidence and mortality. The multivariate-adjusted HR (95% CI) for participants with three or more low-risk lifestyle factors compared with zero was 0.48 (0.40-0.59) for total CVD incidence, 0.53 (0.42-0.66) for CHD incidence, 0.33 (0.21-0.51) for stroke incidence, and 0.32 (0.22-0.47) for CVD mortality (all P trend&lt;0.001). The population-attributable-risk for poor adherence to low-risk lifestyle was 42.6% (26.7%-55.1%) for CVD mortality. In addition, greater improvements in lifestyle factors from pre- to post-diabetes diagnosis were also significantly associated with a lower risk of CVD incidence and mortality. For per one number increment in low-risk lifestyle factors, there was a 16% reduced risk of incident total CVD, a 12% reduced risk of CHD, a 21% reduced risk of stroke, and a 30% reduced risk of CVD mortality (all P &lt;0.001). Similar results were observed when analyses were stratified by diabetes duration, sex/cohort, body mass index at diabetes diagnosis, smoking status, and lifestyle factors before diabetes diagnosis. Conclusions: Greater adherence to an overall healthy lifestyle is associated with a substantially lower risk of CVD incidence and mortality among adults with type 2 diabetes. These findings further support the tremendous benefits of adopting a healthy lifestyle in reducing the subsequent burden of cardiovascular complications in diabetic patients.