Vascular Complications Of Diabetes Mellitus Research Articles

The IRELAnD study—investigating the role of early low-dose aspirin in diabetes mellitus: a double-blinded, placebo-controlled, randomized trial

Although aspirin therapy is being increasingly advocated with the intention of risk modification for a wide range of pregnancy complications, women with prepregnancy diabetes mellitus are commonly excluded from clinical trials. The primary aim of this study was to examine the effect of aspirin therapy on a composite measure of adverse perinatal outcome in pregnancies complicated by pregestational diabetes mellitus. A double-blinded, placebo-controlled randomized trial was conducted at 6 university-affiliated perinatology centers. Women with type 1 diabetes mellitus or type 2 diabetes mellitus of at least 6 months' duration were randomly allocated to 150-mg daily aspirin or placebo from 11 to 14 weeks' gestation until 36 weeks. Established vascular complications of diabetes mellitus, including chronic hypertension or nephropathy, led to exclusion from the trial. The primary outcome was a composite measure of placental dysfunction (preeclampsia, fetal growth restriction, preterm birth <34 weeks' gestation, or perinatal mortality). The planned sample size was 566 participants to achieve a 35% reduction in the primary outcome, assuming 80% statistical power. Secondary end points included maternal and neonatal outcomes and determination of insulin requirements across gestation. Data were centrally managed using ClinInfo and analyzed using SAS 9.4. The 2 treatment groups were compared using t tests or chi-square tests, as required, and longitudinal data were compared using a repeated-measures analysis. From February 2020 to September 2022, 191 patients were deemed eligible, 134 of whom were enrolled (67 randomized to aspirin and 67 to placebo) with a retrospective power of 64%. A total of 101 (80%) women had type 1 diabetes mellitus and 25 (20%) had type 2 diabetes mellitus. Reaching the target sample size was limited by the impact of the COVID-19 pandemic. Baseline characteristics were similar between the aspirin and placebo groups. Treatment compliance was very high and similar between groups (97% for aspirin, 94% for placebo). The risk of the composite measure of placental dysfunction did not differ between groups (25% aspirin vs 21% placebo; P=.796). Women in the aspirin group had significantly lower insulin requirements throughout pregnancy compared with the placebo group. Insulin requirements in the aspirin group increased on average from 0.7 units/kg at baseline to 1.1 units/kg by 36 weeks' gestation (an average 83% within-patient increase), and increased from 0.7 units/kg to 1.3 units/kg (a 181% within-patient increase) in the placebo group, over the same gestational period (P=.002). Serial hemoglobin A1c levels were lower in the aspirin group than in the placebo group, although this trend did not reach statistical significance. In this multicenter, double-blinded, placebo-controlled randomized trial, aspirin did not reduce the risk of adverse perinatal outcome in pregnancies complicated by prepregnancy diabetes mellitus. Compared with the placebo group, aspirin-treated patients required significantly less insulin throughout pregnancy, indicating a beneficial effect of aspirin on glycemic control. Aspirin may exert a plausible placenta-mediated effect on pregestational diabetes mellitus that is not limited to its antithrombotic properties.

An Ayurvedic Management of Diabetic Retinopathy - A Case Report

Diabetic retinopathy (DR) is the most frequent micro vascular complication of Diabetes mellitus. It is an eye condition that can cause vision loss and blindness. Globally the prevalence of Diabetic retinopathy among diabetic patients is estimated to be 27.0% which leads to 0.4 million blindness in the world.[1] It affects blood vessels in the retina (the light-sensitive layer of tissue in the back of the eye). It commonly affects both eyes and can lead to vision loss if it left untreated. Currently available conventional treatments (Focal laser therapy, Anti-vascular growth factor drug) for DR have certain limitations, considering which options from alternative resources are being searched. Despite advances in science the treatment of DR is challenging. So, in this case Ayurveda treatment was done.

Relationship between elevated circulating thrombospondin-1 levels and vascular complications in diabetes mellitus.

Thrombospondin-1 (TSP-1) participates in a series of physiological and pathological processes by binding to various receptors regulating cell proliferation, adhesion and apoptosis. Elevated circulating TSP-1 is linked with diabetic vascular complications (DVC). This study aimed to determine the relationship between circulating TSP-1 levels and DVC. A comprehensive search of PubMed, Embase, Web of Science and CNKI databases was carried out. A meta-analysis was carried out to compare circulating TSP-1 levels between diabetes patients without vascular complications (DNVC), diabetes patients with DVC and non-diabetes patients. The correlation between TSP-1 and metabolic parameters was also analyzed. Subgroup analysis was carried out according to complication type, defined as diabetic retinopathy, diabetic nephropathy and diabetic cardiovascular disease (DCVD). A total of eight studies were included. Compared with non-diabetes patients, diabetic patients, including DNVC and DVC, had significantly higher circulating TSP-1 levels (standardized mean difference [SMD] 2.660, 95% CI 1.17-4.145, P = 0.000). DNVC had significantly higher circulating TSP-1 levels than non-diabetes patients (SMD 3.613, 95% CI 1.607-5.619, P = 0.000). DVC had significantly higher TSP-1 levels than DNVC (SMD 0.568, 95% CI 0.100-1.036, P = 0.017). TSP-1 was significantly positively correlated with fasting plasma glucose (overall Fisher's z = 0.696, 95% CI 0.559-0.833) and HbA1c (overall Fisher's z = 0.849, 95% CI 0.776-0.923). Elevated circulating TSP-1 levels are closely related to DVC, especially in diabetic nephropathy and diabetic cardiovascular disease. Circulating TSP-1 detection might be helpful in the timely diagnosis and treatment of DVC.

The relationship between cardiovascular pathology and impaired glucose metabolism with vitamin D deficiency (literature review and own data)

Background. Vitamin D plays a significant role in many processes in the human body, which diversifies the symptoms of its insufficiency, so it is not always possible to diagnose its deficiency in a timely manner. At the same time, according to a number of clinical studies, an inverse relationship has been proven between a reduced level of vitamin D and mortality from all causes and cardiovascular diseases, the course of diabetes mellitus (DM), hypertension, chronic kidney disease, atherosclerosis, coronary heart disease; and the mechanisms of the influence of vitamin D deficiency on various metabolic processes have been revealed. The development and progression of cardiovascular diseases and vascular complications of DM are currently the main causes of disability and mortality of patients. All this substantiates the need to control and monitor the vitamin D supply in patients with this comorbid pathology. Aim of the study is to investigate the presence and severity of vitamin D deficiency in patients with type 2 DM and the presence of concomitant cardiac pathology. Materials and methods. Main group included 31 patients (17 men and 14 women aged 51.51 ± 1.73 years, with duration of DM of 8.59 ± 1.70 years) who were treated in the endocrinology clinic from October 2022 to May 2023. The comparison group consisted of 27 patients with type 2 DM who stayed in this clinic in 2020–2021. Serum level of 25-hydroxycholecalciferol (25(OH)D) was studied using the enzyme-linked immunosorbent assay. The level of vitamin D less than 20–30 ng/ml was considered as its insufficiency, and the level below 20 ng/ml as deficiency. Statistical processing was carried out using Microsoft Excel and Statistica 6.0. Results. In the main group, cardiac pathology manifested itself by the presence of hypertension detected in all patients (stage I — 6 cases; stage II — 21 and stage IІI — 4); coronary heart disease and cardiosclerosis — in 7 patients; heart failure of the first or second degree — in all individuals. All patients in the main group were vitamin D deficient or insufficient: 15 had a deficiency (12.96 ± 1.06 ng/ml), and 16 had an insufficiency (23.68 ± 0.72 ng/ml). In contrast to the comparison group, patients from the main group had a significantly lower average level of vitamin D (18.49 ± 1.16 ng/ml vs 28.98 ± 1.02 ng/ml, p &lt; 0.001). Taking into account a decrease in the level of vitamin D supply of patients, including those with comorbid pathology examined in 2022–2023, which is obviously associated with a long stay in shelters and a stressful situation caused by the state of war, and its impact on the course of cardiovascular diseases and diabetes, it is necessary to pay more attention to the detection and timely appropriate correction of vitamin D deficiency. Conclusions. In patients with type 2 diabetes and comorbid cardiovascular pathology, there is a decrease in the level of vitamin D supply. During the war in Ukraine, there is a probable deepening of vitamin D deficiency. The negative impact of vitamin D deficiency on the course of diabetes and cardiovascular pathology justifies the need to monitor vitamin D supply in such patients.

Determinants of diabetic retinopathy in Ethiopia: A systematic review and meta-analysis.

Diabetic retinopathy (DR) is the primary retinal vascular complication of diabetes mellitus and a leading cause of visual impairment and blindness. It affects the global diabetic population. In Ethiopia, about one-fifth of diabetic patients were affected by DR, but there were inconsistent finding across studies about the determinants factors of DR. Therefore, we aimed to identify the risk factors for DR among diabetic patients. We have accessed previous studies through an electronic web-based search strategy using PubMed, Google (Scholar), the Web of Science, and the Cochrane Library with a combination of search terms. The quality of each included article was assessed using the Newcastle Ottawa Assessment Scale. All statistical analyses were carried out using Stata version 14 software. The odds ratios of risk factors were pooled using a fixed-effect meta-analysis model. Heterogeneity was assessed using the Cochrane Q statistics and I-Square (I2). Furthermore, publication bias was detected based on the graphic asymmetry test of the funnel plot and/or Egger's test (p< 0.05). The search strategy retrieved 1285 articles. After the removal of duplicate articles, 249 articles remained. Following further screening, about 18 articles were assessed for eligibility, of which three articles were excluded because of reporting without the outcome of interest, poor quality, and not full text. Finally, fifteen studies were reviewed for the final analysis. Co-morbid hypertension (HTN) (AOR 2.04, 95%CI: 1.07, 3.89), poor glycemic control (AOR = 4.36, 95%CI: 1.47, 12.90), and duration of diabetes illness (AOR = 3.83, 95%CI: 1.17, 12.55) were found to be confirmed associated factors of diabetic retinopathy. In this study, co-morbid HTN, poor glycemic control, and longer duration of diabetes illness were found to be the determinant factors of DR. Aggressive treatment of co-morbid HTN and blood glucose, and regular eye screening should be implemented to reduce the occurrence of DR. The review protocol was registered in the international prospective register of systematic reviews (PROSPERO) with registration number PROSPERO: CRD42023416724.

Frequency of Metabolic Syndrome and Lipid Profile Analysis among Patient with Type 2 Diabetes: A Single Center Study

Background: Diabetes mellitus is associated with various metabolic disorders, which leads to the progression of the disease and its complications. Dyslipidemia has been noted to play an integral role in the pathogenesis and progression of micro and macro vascular complications in diabetes mellitus (DM) patients. Lipid profile is the indicators of dyslipidemia. Aim of the Study: The aim of this study was to accumulate the frequency of metabolic syndrome and lipid profile among patient with type 2 diabetes. Methods: This hospital based descriptive type of observational study was conducted in the Department of Medicine, North Bengal Medical College and Hospital, Sirajgonj, Bangladesh during the period from January 2022 to December 2022. In total 97 diagnosed patients with type 2 diabetes mellitus were enrolled in this study as the study subjects. Proper written consents were taken from all the participants before data collection. All demographic as well as clinical data were recorded. Data were processed, analyzed and disseminated by using MS Excel and SPSS version 23.0 program as per necessity. Results: The highest number (37%) of our participants was from 41-50 years’ age group and the female participants were dominating in number. Majority of the patients (63%) were obese: ≥30. In this current study, the frequency of metabolic syndrome was found as 71%. The mean± SD total cholesterol, triglyceride, LDL cholesterol and HDL cholesterol of the respondents were found as 179.88±42.81, 179.88±42.81, 109.74±46.69 and 44.75±7.68 mg/dL respectively. Among the majority of our patients (72%) normal (≥40 mg/dL) HDL level was found. Conclusion: The higher frequency of metabolic syndrome among type 2 diabetes patients demands more attention from health professionals as well as the policy makers. There may not have any significant correlation of metabolic syndrome or type 2 diabetes with lipid profile but aged people may be prone to those diseases.

Downregulation of miR-210-3p Attenuates High Glucose-Induced Angiogenesis of Vascular Endothelial Cells via Targeting FGFRL1

Introduction: Vascular endothelial cell injury and angiogenesis induced by hyperglycemia are the main pathological basis of vascular complications in diabetes mellitus. Our study aimed to investigate the role and mechanism of miR-210-3p in high glucose (HG)-induced angiogenesis. Methods: Human umbilical vein endothelial cells (HUVECs) were treated with HG to mimic the pathological process of hyperglycemia. HUVECs were divided into the control group, HG group, HG+inhibitor-NC group, and HG+miR-210-3p inhibitor group. Proliferation and migration were tested by wound healing assay, tube formation, and Transwell assay. Quantitation real-time PCR and Western blots were performed to determine the expression of miR-210-3p and relative proteins, respectively. Results: The level of miR-210-3p significantly increased in HUVECs treated by HG. The knockdown of miR-210-3p attenuated the tube formation, proliferation, and migration of cultured HUVECs in vitro to inhibit angiogenesis by increasing the expression of fibroblast growth factor receptor-like 1 (FGFRL1) and then attenuating the phosphorylation of signal transducer and activator of transcription 3 (STAT3), extracellular regulated protein kinases, and protein kinase B (Akt). Conclusion: Our study revealed that miR-210-3p might be a promising target for treating diabetic-associated vascular injury.

PS-B09-9: ENOS-NO PATHWAY REGULATES INFLAMMASOME ACTIVATION IN DIABETIC MICE VIA MODULATION OF CEBP TRANSLOCATION

Background: Diabetic kidney disease (DKD) is one of the most common vascular complications of diabetes mellitus (DM). Endothelial dysfunction is also a common pathophysiologic mechanism of diabetic vascular complications. Nitric oxide (NO) produced in the endothelial cells by endothelial nitric oxide synthase (eNOS) is an important mediator for the maintenance of vascular homeostasis. In persons with diabetes, eNOS produces superoxide anion rather than nitric oxide, referred to as eNOS uncoupling which may contribute to endothelial dysfunction, albuminuria, and diabetic nephropathy. eNOS uncoupling can then lead to dysfunction of the eNOS-NO-pathway in diabetic glomeruli. To determine the mechanism of regulation of inflammasome activation by eNOS-NO pathway in DKD, we used eNOS deficient mice and eNOS-ASC double knockout mice. Methods: We used wild-type (WT) and eNOS-deficient mice (eNOSKO) to determine the role of the eNOS-NO pathway. Diabetes was induced by a single intraperitoneal injection of streptozocin. We then divided the mice into four groups: WT, WT/STZ, eNOSKO, and eNOS/STZ. Four weeks after the induction of DM, the mice were sacrificed, and their kidney tissues were harvested. Urinary albumin excretion was checked before the sacrifice, and glomerular damage was assessed by periodic acid-Schiff (PAS) staining. To determine the role of inflammasome on the development of glomerulopathy, we generated eNOS-ASC double knockout mice (eNOS-ASC-DKO). Also, to investigate inflammasome activation in glomeruli, the glomeruli were isolated from the kidney tissue by using Dynabeads. Results: Urinary albumin excretion was increased in WT/STZ compared with WT. These urinary albumin excretions were increased much more in eNOS/STZ than in WT/STZ, while the glomeruli were more damaged in eNOSKO/STZ than in WT/STZ. Urinary albumin excretion was lower in eNOS-ASC-DKO/STZ compared with eNOSKO/STZ, and the glomerular damage also was ameliorated in eNOS-ASC-DKO after treatment with STZ. S-Nitroso glutathione (GSNO) attenuated NLRP3 inflammasome activation after treatment with LPS-ATP. These results indicate that NO directly inhibits NLRP3-inflammasome activation. In addition, GSNO decreased the expression of inflammasome-related genes. To investigate the detailed the mechanism (epigenetic regulation), we performed Assay for Transposase-Accessible Chromatin-Sequencing (ATAC-seq) analysis. The binding region of the transcription factor CCAAT/ enhancer binding protein (C/EBP) β; was closed in the LPS+GSNO group significantly, compared with the LPS group. Conclusion: In eNOS-deficient mice, inflammasomes were activated, and glomerular injuries were exacerbated. However in eNOS-ASC-STZ mice, the glomerular damage were attenuated. Our data suggested that eNOS/NO signaling attenuates inflammasome activation via regulation of CEBP β;, leading to the suppressed development of DKD.

Pathophysiological correlation of arginase-1 in development of type 2 diabetes from obesity in adolescents

BackgroundThere is great interest to understand causal pathophysiological correlation between obesity and diabetes mellitus (DM). Vascular endothelial dysfunction is crucially involved in pathogenesis of vascular complications in DM. Recently, increased arginase expression and activity have been described as underlying mechanisms of endothelial dysfunction in DM and vascular inflammation in obesity. By limiting L-arginine bioavailability to endothelial nitric oxide synthase (NOS III), nitric oxide production is potentially impaired. MethodsWe investigated the impact of plasma from diabetic and obese adolescents on arginase and NOS III expression in cultured human endothelial cells (ECs). A total of 148 male adolescents participated in this study including 18 obese, 28 type 1-, 28 type 2-DM patients, and 74 age-matched healthy volunteers. ResultsA concurrent increase in arginase-1 (1.97-fold) and decrease in NOS III expression (1.45-fold) was observed in ECs exposed to type 2 diabetic plasma compared to control subjects. ECs incubated with type 1 DM plasma had a diminished NOS III level without impact on arginase-1 expression. Urea-assay featured an increased arginase activity in treated ECs with type 1- or 2-DM plasma. Despite increased pro-inflammatory cytokines and chemokines in obese plasma, arginase-1 expression/activity did not change in treated ECs. However, NOS III expression was significantly reduced. Pearson analysis revealed positive correlation between arginase-1, but not NOS III, expression with FBS in ECs treated with type 2-DM plasma. ConclusionsOur data demonstrate that increased arginase-1 expression/activity in ECs, as critical pathogenic factor is correlated with development of obesity-related type 2-DM and linked vascular disease.

Phytochemical profile, anti-glycation effect, and advanced glycation end-products protein cross-link breaking ability of Sclerocarya birrea stem-bark crude extracts

Introduction: Sclerocarya birrea stem-bark is widely used for the treatment of many medical conditions. Advanced glycation end-products (AGEs) are implicated in the pathogenesis of vascular complications of diabetes mellitus. The study, other than phytochemical composition, evaluated the anti-glycation and AGEs-protein cross-link breaking effects of S. birrea stem-bark extracts. Methods: Different S. birrea extracts and aminoguanidine (used as control) were incubated with bovine serum albumin (BSA) and glucose/fructose at 37oC for 40 days. Amounts of fluorescent AGEs (FAGEs) and immunogenic AGEs formed were determined. Anti-glycation activity percentage of each extract and aminoguanidine was calculated. Their AGEs-protein cross-link breaking abilities were also assessed. Standard techniques were employed for phytochemical screening. Volatile compounds were identified by means of gas chromatography mass spectrometry (GC-MS). Results: S. birrea stem-bark n-hexane extract was statistically more effective than aminoguanidine against the formation of total immunogenic AGEs (P&lt;0.05). For FAGEs, ethyl acetate, methanol, and water extracts exerted significantly higher anti-glycation effects than aminoguanidine (P&lt;0.001). Methanol extract exhibited the highest anti-glycation effect with an average IC50 value of 0.142 mg/mL against FAGEs. All extracts were effective in releasing BSA from the preformed collagen-AGEs-BSA cross-links. GC-MS enabled the identification of many biologically important compounds, including campesterol, stigmasterol, and 1-heptatricontanol. Conclusion: S. birrea stem-bark has a potential for usage in the management of complications in uncontrolled glucose metabolism.

Сomprehensive assessment of macro- and microcirculation parameters in patients with type 2 diabetes mellitus and subclinical stage of diabetic peripheral neuropathy during treatment with antihypoxic drug

The leading cause of systemic vascular complications in diabetes mellitus (DM) is partial damage to the vascular wall and hemorheological changes in the lumen of blood vessels against the background of chronic hyperglycemia. Vasoconstriction, edema, ischemia and tissue hypoxia develop as a result of these processes, which, in addition to increasing the risk of cardiovascular diseases, lead to impaired endoneural circulation. The use of a drug with an antihypoxant effect as a pathogenetic therapy in patients with type 2 diabetes mellitus (T2DM) and a subclinical stage of diabetic peripheral neuropathy (DPN1) makes it possible to slow down the progression of micro- and macrovascular complications, along with achieving sustainable compensation for diabetes.Aim. To assess the effect of a drug with antihypoxic effects (Actovegin®) on the parameters of macro- and microcirculation of the capillary bed, arterial stiffness and endothelial function in patients with T2DM and DPN1.Material and methods. A comparative study of macro- and microcirculation parameters, arterial stiffness and endothelial function in patients with T2DM and DPN1 before and after treatment with Actovegin® (group “A”, n = 20), and a group of patients with T2DM and DPN1 without Actovegin® treatment (group “B”, n = 20).Results. An improvement in the parameters of microcirculation was revealed: expansion of the arterial section of the capillaries during treatment with Actovegin®. In patients with reduced endothelial function during treatment with Actovegin®, there is a significant increase in its function, as well as a decrease in perivascular edema. Treatment with Actovegin® does not affect the indicators of central hemodynamics and indicators of arterial stiffness in patients with T2DM and DPN1.Conclusion. The results of the study clearly demonstrated that the use of a drug with an antihypoxic effect (Actovegin®) in patients with T2DM and DPN1 significantly improves the parameters of microcirculation, and, therefore, can be recommended as pathogenetic therapy at the earliest stages of diabetes development. Integral assessment of microcirculation parameters, as well as a new technology for determining the pulse wave velocity and endothelial function allows to identify patients in need of more intensive monitoring. Conducting this examination before the start of drug therapy can serve as a guideline in assessing the effectiveness of the treatment.

NADH-Cytochrome B5 reductase 2 suppresses retinal vascular dysfunction through regulation of vascular endothelial growth factor A in diabetic retinopathy

Diabetic retinopathy (DR) is a progressive vascular complication of diabetes mellitus (DM) and is related to retinal vascular abnormalities. NADH-Cytochrome B5 Reductase 2 (CBR2) has been implicated in angiogenesis, but the effect of CBR2 on angiogenesis and endothelial cell biological behavior in DR remains unclear. Here, we aimed to explore the effect of CBR2 on retinal vascular dysfunction under diabetic conditions. The histological analyses were performed to explore the effect of CBR2 on pathological change in streptozotocin (STZ)-induced diabetic rat retinas. The effect of CBR2 on endothelial cell function was explored by CCK-8, scratch wound, transwell, tube formation, and immunofluorescence assays in high glucose (HG)-stimulated human retinal microvascular endothelial cells (HRMECs). CBR2 expression was significantly downregulated in DM rat retinas and HG-stimulated HRMECs. Intravitreal injection of CBR2-expressing lentivirus under diabetic conditions reduced retinal angiogenesis, acellular capillary formation, and pericyte loss, along with decreased expression of hypoxia-inducible factor-1α (HIF-1α), cluster of differentiation 31 (CD31), and vascular endothelial growth factor A (VEGFA) in vivo. Moreover, CBR2 overexpression inhibited cell growth and tube formation and led to decreased expression of HIF-1α and VEGFA in HG-induced HRMECs. Interestingly, the repressive effects of CBR2 on cell proliferation, migration, and tube formation under HG conditions were strongly reversed when VEGFA was overexpressed. Overall, the key findings of our study suggested that CBR2 might alleviate retinal vascular dysfunction and abnormal endothelial proliferation during the process of DR by regulating VEGFA, providing a piece of potent evidence for DR therapy.

MG53 represses high glucose-induced inflammation and angiogenesis in human retinal endothelial cells by repressing the EGR1/STAT3 axis

Background Diabetic retinopathy (DR) is a vascular complication of diabetes mellitus that leads to visual injury and blindness. Both angiogenesis and inflammation play an important role in the pathogenesis of DR. Here we aimed to explore the mechanisms of mitsugumin 53 (MG53) in ameliorating the dysfunction induced by high glucose (HG) in humans retinal microvascular endothelial cells (HRECs). Methods HRECs were subjected to HG in the presence or absence of MG53 overexpression. The effect of MG53 on cell viability and inflammatory response in HG-treated HRECs was measured using the Cell Counting Kit-8 and ELISAs, respectively. Expression of MG53, EGR1, p-STAT3, FGF2, TGFB1, and Angiopoietin-1 in HG-treated HRECs was quantified by western blot or quantitative real-time polymerase chain reaction. Results HG significantly downregulated MG53 in HRECs, which reduced cell viability while inducing angiogenesis and inflammatory response. Upregulation of MG53 reversed these effects of HG. MG53 directly interacted with EGR1 and repressed its expression, which decreased phosphorylation of STAT3 and downregulated FGF2, TGFB1, and Angiopoietin-1. EGR1 up-regulation or STAT3 activation antagonized the protective effects of MG53. Conclusion MG53 alleviates HG-induced dysfunction in HRECs by repressing EGR1/STAT3 signaling. Thereby MG53 may have therapeutic potential in DR.

IDF21-0689 Prevalence of microvascular complications in type 2 diabetic patients with dyslipidemia

Background: The role of chronic hyperglycemia in the pathogenesis of vascular complications of diabetes mellitus has so far been well elucidated. However, there are other factors and comorbidities that may contribute in the development of mircovascular dysfunction and metabolic disorders. Aim: The purpose of our work is to study the correlation between dyslipidemia and microvascular disease in type 2 diabetic patients. Method: Our study is retrospective descriptive, involving 398 type 2 diabetic patients followed in our center from 2014 to 2021. Dyslipidemia was identified in 177 patients. Microvascular disease was studied in both groups: the 1st group (G1) with dyslipidemia (n = 177) and the 2nd group (G2) with a normal lipid profile (n = 221). Results: The mean age of our patients was 63±5.6 years with a sex ratio F/H of 2.2. Dyslipidemia was found in 44.5% of cases. Diabetic retinopathy was found in 29,5% of patients with dyslipidemia and 24% of patients with a normal lipid profile. The difference was statistically significant (p=0.03). Diabetic nephropathy and neuropathy were also more frequently observed in the first group in respectively 21% and 13% of the cases and the difference was statistically significant between the two groups (p=0.01, p=0.02). However, no difference was found between the two groups regarding age, sex and duration of diabetes. Diabetic retinopathy and nephropathy were found respectively in 16.6% and 20,8% of cases with hypercholesterolemia, 28,4% and 25% with hypertriglyceridemia, and in 34% and 33% of mixed dyslipidemia. However, diabetic neuropathy was seen only in 8% of patients with hypercholesterolemia, 14,7% of hypertriglyceridemia and 7% of mixed dyslipidemia. Discussion: Microvascular disease was strongly associated with lipid metabolism impairment in type 2 diabetic patients. Early diagnosis and optimal management of the different comorbidities may limit the incidence of these complications and avoid the consequences (blindness, end-stade renal failure, diabetic foot problems…).

SETD8 cooperates with MZF1 to participate in hyperglycemia-induced endothelial inflammation via elevation of WNT5A levels in diabetic nephropathy

ObjectiveDiabetic nephropathy (DN) is regarded as the main vascular complication of diabetes mellitus, directly affecting the outcome of diabetic patients. Inflammatory factors were reported to participate in the progress of DN. Wingless-type family member 5 (WNT5A), myeloid zinc finger 1 (MZF1), and lysine methyltransferase 8 (SETD8) have also been reported to elevate inflammatory factor levels and activate the nuclear factor kappa B (NF-κB) pathway to induce endothelial dysfunction. In the current study, it was assumed that MZF1 associates with SETD8 to regulate WNT5A transcription, thus resulting in hyperglycemia-induced glomerular endothelial inflammation in DN.MethodsThe present study recruited 25 diagnosed DN patients (type 2 diabetes) and 25 control participants (nondiabetic renal cancer patients with normal renal function, stage I–II) consecutively. Moreover, a DN rat and cellular model was constructed in the present study. Immunohistochemistry, Western blot, and quantitative polymerase chain reaction (qPCR) were implemented to determine protein and messenger RNA (mRNA) levels. Coimmunoprecipitation (CoIP) and immunofluorescence were implemented in human glomerular endothelial cells (HGECs). Chromatin immunoprecipitation assays and dual luciferase assays were implemented to determine transcriptional activity.ResultsThe results of this study indicated that levels of WNT5A expression, p65 phosphorylation (p-p65), and inflammatory factors were all elevated in DN patients and rats. In vitro, levels of p-p65 and inflammatory factors increased along with the increase of WNT5A expression in hyperglycemic HGECs. Moreover, high glucose increased MZF1 expression and decreased SETD8 expression. MZF1 and SETD8 inhibit each other under the stimulus of high glucose, but cooperate to regulate WNT5A expression, thus influencing p-p65 and endothelial inflammatory factors levels. Overexpression of MZF1 and silencing of SETD8 induced endothelial p-p65 and inflammatory factors levels, which can be reversed by si-WNT5A. Mechanistic research indicated that MZF1, SETD8, and its downstream target histone H4 lysine 20 methylation (H4K20me1) all occupied the WNT5A promoter region. sh-SETD8 expanded the enrichment of MZF1 on WNT5A promoter. Our in vivo study proved that SETD8 overexpression inhibited levels of WNT5A, p-p65 expression, and inflammatory factors in DN rats.ConclusionsMZF1 links with SETD8 to regulate WNT5A expression in HGECs, thus elevating levels of hyperglycemia-mediated inflammatory factors in glomerular endothelium of DN patients and rats.Trial registration ChiCTR, ChiCTR2000029425. 2020/1/31, http://www.chictr.org.cn/showproj.aspx?proj=48548

Plasma glycation adducts and various RAGE isoforms are intricately associated with oxidative stress and inflammatory markers in type 2 diabetes patients with vascular complications

BackgroundThe secondary vascular complications in diabetes mellitus (DM) are contributed by acute as well as inflammatory responses which get activated due to interaction between glycation adducts and respective receptors. AimThe present work was performed to understand the relationship between Advanced glycation end products (AGEs)-receptor for advanced glycation end products (RAGE) interaction with oxidative stress and inflammation in vascular complications. MethodsFor the present work we recruited 103 controls, 200 patients with type 2 DM, and 200 patients with Diabetic complications. Different Plasma glycation adducts (fructosamine, carbonyls, AGEs, β-amyloid content, free amino groups, and free thiol groups); RAGE isoforms, level of antioxidant such as glutathione, catalase activity, nitric oxide level, total antioxidant capacity, and superoxide dismutase activity, as well as oxidative markers, and expression of Nε-carboxymethyl-lysine (CML), different isoforms of RAGE, NF-κB, and inflammatory markers were analyzed. ResultsGlycation adducts were higher in DM patients and more elevated in nephropathy patients where free amino groups and thiol groups lowered as compared to controls. sRAGE levels and expression were increased mainly in nephropathy. CML expression was higher in nephropathy patients. The antioxidant profile indicates a reduced level of different antioxidants while increased lipid peroxidation and intracellular ROS generation in DM and much higher in nephropathy patients. Expression of membrane RAGE, NF-κB, and inflammatory markers showed a remarkably increased level in DM patients with nephropathy. ConclusionThis work provides the first evidence of four different RAGE isoforms in diabetes and in complications. The glycation via the activation of RAGE, oxidative stress, and resultant inflammation plays a crucial role in the development of diabetic complications.

Racial disparities in the screening and treatment of diabetic retinopathy

Diabetic retinopathy is a progressive disease and primary retinal vascular complication of diabetes mellitus, the third leading cause of blindness in the United States. Racial and ethnic minorities are more likely to suffer from diabetic retinopathy and diabetic macular edema, and typically undergo less screening. Lack of screening is due to a variety of factors, such as patient, provider, and institutional barriers. Due to the disparity in screening, minorities often present with more advanced stages of diabetic eye disease. As the minority population increases, the burden of treatment for these patients will also increase. It is imperative to understand the barriers and social determinants of health limiting visual outcomes in minority populations.Diabetic retinopathy and its complications are often preventable if detected and treated early. Advances in screening technology and intravitreal anti-VEGF injections have changed the landscape in preventing vision loss in diabetic patients.

A new detection model of microaneurysms based on improved FC-DenseNet

Diabetic retinopathy (DR) is a frequent vascular complication of diabetes mellitus and remains a leading cause of vision loss worldwide. Microaneurysm (MA) is usually the first symptom of DR that leads to blood leakage in the retina. Periodic detection of MAs will facilitate early detection of DR and reduction of vision injury. In this study, we proposed a novel model for the detection of MAs in fluorescein fundus angiography (FFA) images based on the improved FC-DenseNet, MAs-FC-DenseNet. FFA images were pre-processed by the Histogram Stretching and Gaussian Filtering algorithm to improve the quality of FFA images. Then, MA regions were detected by the improved FC-DenseNet. MAs-FC-DenseNet was compared against other FC-DenseNet models (FC-DenseNet56 and FC-DenseNet67) or the end-to-end models (DeeplabV3+ and PSPNet) to evaluate the detection performance of MAs. The result suggested that MAs-FC-DenseNet had higher values of evaluation metrics than other models, including pixel accuracy (PA), mean pixel accuracy (MPA), precision (Pre), recall (Re), F1-score (F1), and mean intersection over union (MIoU). Moreover, MA detection performance for MAs-FC-DenseNet was very close to the ground truth. Taken together, MAs-FC-DenseNet is a reliable model for rapid and accurate detection of MAs, which would be used for mass screening of DR patients.

Involvement of caveolae in hyperglycemia-induced changes in adiponectin and leptin expressions in vascular smooth muscle cells

Hyperglycemia exerts various harmful effects on the vasculature. Studies have shown an association between the levels of the adipokines leptin and adiponectin (APN) and vascular complications in diabetes mellitus. The aim of our study was to investigate the molecular mechanisms mediated by APN and leptin that are involved in hyperglycemia-induced vascular remodeling, especially at the level of oxidative stress and actin cytoskeleton dynamics. Rat aorta organ culture was used to investigate the effect of hyperglycemia on APN and leptin protein expression in vascular smooth muscle cells (VSMCs) using Western blot analysis and immunohistochemistry. Hyperglycemia lead to a significant increase in APN synthesis in VSMCs, mainly through caveolae, but this increase failed to provide vascular protection because of the decreased expression of APN receptors, especially AdipoR2, which was assessed by qPCR. In addition, hyperglycemia significantly upregulated leptin expression in VSMCs through caveolae and the RhoA/ROCK pathway. These variations lead to a marked increase in reactive oxygen species (ROS) production, detected by dihydroethidium (DHE) staining, and in NADPH oxidase type 4 (Nox4) expression. Moreover, Nox4 mediated the synthesis of APN in hyperglycemia in VSMCs. Finally, hyperglycemia activated the RhoA/ROCK pathway and subsequently induced the polymerization of globular actin (G-actin) into filamentous actin (F-actin), decreasing the G/F-actin ratio. Taken together, these data show that hyperglycemia increases oxidative stress and changes actin cytoskeleton dynamics in the aorta via caveolae, favoring vascular remodeling.

A Prospective Observational Study on Diabetic Induced Complications and their Prone towards Surgery

Background: This study was mainly aimed to find out the diabetic complications that had been lead to surgey. The Diabetes mellitus describes a metabolic disorder of multiple aetiology characterized by chronic hyperglycaemia with disturbances of carbohydrate,fat and protein metabolism resulting from defects in insulin secretion,insulin action, or both.The effects of diabetes mellitus include long-term damage,dysfunction and failure of various organs.&#x0D; Materials and Methods: A prospective observational study was conducted in the Santhiram college &amp; general hospital for 6 months (December 2020 – May 2021)to assess the macro vascular and micro vascular complications of diabetes mellitus and prone to surgery of diabetic complications by using case sheets, prescriptions in tertiary care teaching hospital.&#x0D; Results: A total of 150 patients are included in this study.In patients with diabetic complications we have observed: Diabetic ulcer with cellulitis in 19, gangrene in 19, peripheral vascular disease in 6, gangrene with cellulitis in 11,Non healing diabetes foot ulcer in 35, Coronary artery disease 24, diabetic retinopathy 25, MI in 11 patients.Among all complications, non healing diabetic foot was observed to be more when compared to other diabetic complications.In the study performed in diabetic induced complications of patients, debridement was performed in 30% patients, Amputation were performed in 13%, skin grating was performed in 13% patients, Angioplasty were performed in 23% patients and lasix surgery performed in 13% patients.&#x0D; Conclusion: In our study we conclude that out of 150 cases, male patients are more prone to diabetic complications than females.The patient counselling should involve in minimizing the incidence and prevalence of diabetes by conducting the continuing health education and other health programms.