Diabetic Vascular Complications Research Articles

105-OR: Omega-3 Polyunsaturated Fatty Acids in the Treatment of Diabetic Peripheral Neuropathy—Is the Source Important?

Introduction: We have shown that omega-3 polyunsaturated fatty acids (PUFA) derived from fish oil (FO) was an effective treatment for diabetes vascular and neural complications. However, is FO the best source of omega-3 PUFA for treating diabetic peripheral neuropathy (DPN)? Methods: To address this question we used a rat model of type 2 diabetes and a late intervention protocol. After 10 weeks of hyperglycemia, diabetic rats were treated for 12 weeks via diet with omega-3 PUFA derived from a variety of sources including menhaden (fish) oil (MO), krill oil (KO), oils derived from algae that produce primarily eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) or combination of EPA and DHA, or commercial ethyl esters of EPA, DHA or combination of EPA and DHA. Primary endpoints were motor (MNCV) and sensory (SNCV) nerve conduction velocity, intraepidermal and cornea nerve fiber density, thermal and cornea sensitivity, and vascular reactivity of epineurial arterioles that provide circulation to the sciatic nerve. The omega-3 index, and serum fatty acid levels were also determined. Results: The dose of each omega-3 PUFA supplement was customized to create a healthy omega-3 index. Defined as the sum of EPA and DHA as a percentage of total fatty acids in red blood cells, range for healthy level 8 - 12%. Following 22 weeks of untreated diabetes neural and vascular endpoints were significantly impaired compared to control rats. Treatment with MO provided the greatest improvement for all neural endpoints followed by KO and algal oils or ethyl esters containing a combination of EPA and DHA. Algal oil or ethyl ester of EPA alone was the least effective. The greatest improvement in vascular reactivity of epineurial arterioles to acetylcholine was realized following treatment with MO with less benefit from the other omega-3 PUFA sources. Conclusion: These pre-clinical studies suggest that in a clinical trial for DPN the best outcome may be obtained by using FO as the source for omega-3 PUFA. Disclosure M.A.Yorek: Consultant; Novo Nordisk. Funding U.S. Department of Veterans Affairs (RX003826-01)

Role of mean platelet volume in patients with type 2 diabetes mellitus

In type 2 diabetes mellitus, increased platelet activity is crucial for the emergence of vascular complications. Mean platelet volume (MPV), an indicator of enhanced platelet activity, may be helpful in identifying the thromboembolic events that lead to these vascular complications. This study aims to assess MPV in Type 2 Diabetes patients and investigate the relationship between MPV and glycaemic and diabetic complications. : A comparative cross-sectional study was carried out on 266 subjects (133 diabetic patients and 133 nondiabetic controls) at B.P Koirala Institute of Health Sciences for a period of one year. MPV was analyzed in both the groups and the potential association of MPV with diabetic complications and glycaemic parameters was evaluated. Statistical analysis was carried out with Student t-test and Pearson Correlation Coefficient.: The results of the study showed that diabetics' MPV was considerably higher than that of non-diabetic controls (10.07 + 1.41 vs. 7.47 + 0.60 fl, P0.001) and that diabetic patients who had complications had significantly higher MPV than those who did not (10.61 + 1.35 vs. 9.37 + 1.15 fl, P0.001). Retinopathy (p=0.004), nephropathy (p=0.001), and Peripheral artery disease (p=0.03) were diabetes complications with significantly increased MPV. With regard to HbA1C, FBS levels, and the duration of diabetes, MPV demonstrated a statistically significant positive connection (p0.001 and positive r-value).: MPV is a cost-effective tool in the early detection of vascular complications in diabetes and hence proves to be a promising indicator in preventing vascular complications.

Dapagliflozin restores diabetes-associated decline in vasculogenic capacity of endothelial progenitor cells via activating AMPK-mediated inhibition of inflammation and oxidative stress

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) provide added vascular protection beyond glucose lowering to patients with type 2 diabetes mellitus (T2DM). Endothelial progenitor cells (EPCs) are an important endogenous repair mechanism for diabetic vascular complications. Yet, whether SGLT2i protect vessels in diabetic patients by improving the function of EPCs remains to be elucidated. Here we enrolled Sixty-three T2DM patients and 60 healthy participants and 15 of T2DM group took dapagliflozin for 3 months. Retinal capillary density (RCD) was examined before and after meditation. Moreover, vasculogenic capacity of EPCs cocultured with or without dapagliflozin in vitro and in vivo (hind limb ischemia model) were assessed. Mechanically, genes related to inflammation/oxidative stress, and the AMPK signaling of EPCs were determined. Our results found T2DM demonstrated a declined RCD and a decreased number of circulating EPCs compared with healthy controls. Compared with the EPCs from healthy individuals, vasculogenic capacity of T2DM EPCs was significantly impaired, which could be restored by dapagliflozin meditation or dapagliflozin coculture. Increased expression of inflammation correlative genes and decreased anti-oxidative stress related genes expression were found in EPCs form T2DM, which were accompanied with reduced phosphorylation level of AMPK. Dapagliflozin treatment activated AMPK signaling, decreased the level of inflammation and oxidative stress, and rescued vasculogenic capacity of EPCs from T2DM. Furthermore, AMPK inhibitor pretreatment diminished the enhancement vasculogenic capacity of diabetic EPCs from dapagliflozin treatment. This study demonstrates for the first time that dapagliflozin restores vasculogenic capacity of EPCs via activating AMPK-mediated inhibition of inflammation and oxidative stress in T2DM.

Profiling of Differentially Expressed MicroRNAs in Human Umbilical Vein Endothelial Cells Exposed to Hyperglycemia via RNA Sequencing.

Hyperglycemia is the hallmark of diabetes mellitus that results in oxidative stress, apoptosis, and diabetic vascular endothelial dysfunction. An increasing number of microRNAs (miRNAs) have been found to be involved in the pathogenesis of diabetic vascular complications. However, there is a limited number of studies that characterize the miRNA profile of endothelial cells exposed to hyperglycemia. Therefore, this study aims to analyze the miRNA profile of human umbilical-vein endothelial cells (HUVECs) exposed to hyperglycemia. HUVECs were divided into two groups: the control (treated with 5.5 mM glucose) and hyperglycemia (treated with 33.3 mM glucose) groups. RNA sequencing identified 17 differentially expressed miRNAs between the groups (p < 0.05). Of these, 4 miRNAs were upregulated, and 13 miRNAs were downregulated. Two of the most differentially expressed miRNAs (novel miR-1133 and miR-1225) were successfully validated with stem-loop qPCR. Collectively, the findings show that there is a differential expression pattern of miRNAs in HUVEC following exposure to hyperglycemia. These 17 differentially expressed miRNAs are involved in regulating cellular functions and pathways related to oxidative stress and apoptosis that may contribute to diabetic vascular endothelial dysfunction. The findings provide new clues on the role of miRNAs in the development of diabetic vascular endothelial dysfunction, which could be useful in future targeted therapy.

Down-regulation of WWP2 aggravates Type 2 diabetes mellitus-induced vascular endothelial injury through modulating ubiquitination and degradation of DDX3X

BackgroundEndothelial injury caused by Type 2 diabetes mellitus (T2DM) is considered as a mainstay in the pathophysiology of diabetic vascular complications (DVCs). However, the molecular mechanism of T2DM-induced endothelial injury remains largely unknown. Here, we found that endothelial WW domain-containing E3 ubiquitin protein ligase 2 (WWP2) act as a novel regulator for T2DM-induced vascular endothelial injury through modulating ubiquitination and degradation of DEAD-box helicase 3 X-linked (DDX3X).MethodsSingle-cell transcriptome analysis was used to evaluate WWP2 expression in vascular endothelial cells of T2DM patients and healthy controls. Endothelial-specific Wwp2 knockout mice were used to investigate the effect of WWP2 on T2DM-induced vascular endothelial injury. In vitro loss- and gain-of-function studies were performed to assess the function of WWP2 on cell proliferation and apoptosis of human umbilical vein endothelial cells. The substrate protein of WWP2 was verified using mass spectrometry, coimmunoprecipitation assays and immunofluorescence assays. The mechanism of WWP2 regulation on substrate protein was investigated by pulse-chase assay and ubiquitination assay.ResultsThe expression of WWP2 was significantly down-regulated in vascular endothelial cells during T2DM. Endothelial-specific Wwp2 knockout in mice significantly aggravated T2DM-induced vascular endothelial injury and vascular remodeling after endothelial injury. Our in vitro experiments showed that WWP2 protected against endothelial injury by promoting cell proliferation and inhibiting apoptosis in ECs. Mechanically, we found that WWP2 is down-regulated in high glucose and palmitic acid (HG/PA)-induced ECs due to c-Jun N-terminal kinase (JNK) activation, and uncovered that WWP2 suppresses HG/PA-induced endothelial injury by catalyzing K63-linked polyubiquitination of DDX3X and targeting it for proteasomal degradation.ConclusionOur studies revealed the key role of endothelial WWP2 and the fundamental importance of the JNK-WWP2-DDX3X regulatory axis in T2DM-induced vascular endothelial injury, suggesting that WWP2 may serve as a new therapeutic target for DVCs.

Restoration of coronary microvascular function by OGA overexpression in a high-fat diet with low-dose streptozotocin-induced type 2 diabetic mice.

Sustained hyperglycemia results in excess protein O-GlcNAcylation, leading to vascular complications in diabetes. This study aims to investigate the role of O-GlcNAcylation in the progression of coronary microvascular disease (CMD) in inducible type 2 diabetic (T2D) mice generated by a high-fat diet with a single injection of low-dose streptozotocin. Inducible T2D mice exhibited an increase in protein O-GlcNAcylation in cardiac endothelial cells (CECs) and decreases in coronary flow velocity reserve (CFVR, an indicator of coronary microvascular function) and capillary density accompanied by increased endothelial apoptosis in the heart. Endothelial-specific O-GlcNAcase (OGA) overexpression significantly lowered protein O-GlcNAcylation in CECs, increased CFVR and capillary density, and decreased endothelial apoptosis in T2D mice. OGA overexpression also improved cardiac contractility in T2D mice. OGA gene transduction augmented angiogenic capacity in high-glucose treated CECs. PCR array analysis revealed that seven out of 92 genes show significant differences among control, T2D, and T2D + OGA mice, and Sp1 might be a great target for future study, the level of which was significantly increased by OGA in T2D mice. Our data suggest that reducing protein O-GlcNAcylation in CECs has a beneficial effect on coronary microvascular function, and OGA is a promising therapeutic target for CMD in diabetic patients.

Overview of diabetes and its curative approach using medicinal plants: A narrative review

Diabetes mellitus is a long term, diverse metabolic illness with a complex pathophysiology. Hyperglycemia, which stems from anomalies in either insulin secretion or insulin action or both, is its defining feature. Metabolic dysfunctions involving proteins, carbohydrates, and fats originate from hyperglycemia, which can express itself in a variety of ways. The main cause of diabetes related morbidity and mortality is long term hyperglycemia, which frequently results in a variety of microvascular and macro vascular diabetic complications. The main biomarker for determining diabetes diagnosis is hyperglycemia. The increase in prevalence rate, high expense of treatment, common side effects of oral antidiabetic medications is a global health challenge. Therefore, medicinal plants could be a viable ways to maximize its utilization in both food and medicine for management of diabetes and its complications. This review discussed the classification of diabetes, its pathophysiology, approved drugs and several medicinal plants that are used to manage diabetes.

Brain and Cognition Signature Fingerprinting Vascular Health in Diabetic Individuals: An International Multi-Cohort Study

To evaluate the correlation between cognitive signatures and the risk of diabetic vascular complications and mortality, based on a multicountry prospective study. The participants comprised 27,773 diabetics from the UK Biobank (UKB) and 1307 diabetics from the Guangzhou Diabetic Eye Study (GDES) cohort. The exposures were brain volume and cognitive screening tests for UKB participants, whilst the global cognitive score (GCS) measuring orientation to time and attention, episodic memory, and visuospatial abilities were determined for GDES participants. The outcomes for the UKB group were mortality, as well as macrovascular (myocardial infarction [MI] and stroke), microvascular (end-stage renal disease [ESRD], and diabetic retinopathy [DR]) events. The outcomes for the GDES group were retinal and renal microvascular damage. In the UKB group, a 1-SD reduction in brain gray matter volume was associated with 34%-77% higher risks of incident MI, ESRD, and DR. The presence of impaired memory was associated with 18%-73% higher risk of mortality and ESRD; impaired reaction was associated with 1.2-1.7-fold higher risks of mortality, stroke, ESRD, and DR. In the GDES group, the lowest GCS tertile exhibited 1.4-2.2-fold higher risk of developing referable DR and a twofold faster decline in renal function and retinal capillary density compared with the highest tertile. Restricting data analysis to individuals aged less than 65 years produced consistent results. Cognitive decline significantly elevates the risk of diabetic vascular complications and is correlated with retinal and renal microcirculation damage. Cognitive screening tests are strongly recommended as routine tools for management of diabetes.

The Pillars for Renal Disease Treatment in Patients with Type 2 Diabetes.

The diabetes epidemic and the increasing number of patients with diabetic chronic vascular complications poses a significant challenge to health care providers. Diabetic kidney disease is a serious diabetes-mediated chronic vascular complication and represents a significant burden for both patients and society in general. Diabetic kidney disease not only represents the major cause of end stage renal disease but is also paralleled by an increase in cardiovascular morbidity and mortality. Any interventions to delay the development and progression of diabetic kidney disease are important to reduce the associated cardiovascular burden. In this review we will discuss five therapeutic tools for the prevention and treatment of diabetic kidney disease: drugs inhibiting the renin-angiotensin-aldosterone system, statins, the more recently recognized sodium-glucose co-transporter-2 inhibitors, glucagon-like peptide 1 agonists, and a novel non-steroidal selective mineralocorticoid receptor antagonist.

Deletion of Smooth Muscle O-GlcNAc Transferase Prevents Development of Atherosclerosis in Western Diet-Fed Hyperglycemic ApoE-/- Mice In Vivo.

Accumulating evidence highlights protein O-GlcNAcylation as a putative pathogenic contributor of diabetic vascular complications. We previously reported that elevated protein O-GlcNAcylation correlates with increased atherosclerotic lesion formation and VSMC proliferation in response to hyperglycemia. However, the role of O-GlcNAc transferase (OGT), regulator of O-GlcNAc signaling, in the evolution of diabetic atherosclerosis remains elusive. The goal of this study was to determine whether smooth muscle OGT (smOGT) plays a direct role in hyperglycemia-induced atherosclerotic lesion formation and SMC de-differentiation. Using tamoxifen-inducible Myh11-CreERT2 and Ogtfl/fl mice, we generated smOGTWT and smOGTKO mice, with and without ApoE-null backgrounds. Following STZ-induced hyperglycemia, smOGTWT and smOGTKO mice were kept on a standard laboratory diet for the study duration. In a parallel study, smOGTWTApoE-/- and smOGTKOApoE-/- were initiated on Western diet at 8-wks-age. Animals harvested at 14-16-wks-age were used for plasma and tissue collection. Loss of smOGT augmented SM contractile marker expression in aortic vessels of STZ-induced hyperglycemic smOGTKO mice. Consistently, smOGT deletion attenuated atherosclerotic lesion lipid burden (Oil red O), plaque area (H&E), leukocyte (CD45) and smooth muscle cell (ACTA2) abundance in Western diet-fed hyperglycemic smOGTKOApoE-/- mice. This was accompanied by increased SM contractile markers and reduced inflammatory and proliferative marker expression. Further, smOGT deletion attenuated YY1 and SRF expression (transcriptional regulators of SM contractile genes) in hyperglycemic smOGTKOApoE-/- and smOGTKO mice. These data uncover an athero-protective outcome of smOGT loss-of-function and suggest a direct regulatory role of OGT-mediated O-GlcNAcylation in VSMC de-differentiation in hyperglycemia.

Vaccinium as Potential Therapy for Diabetes and Microvascular Complications

Diabetes mellitus is one of the most critical global health concerns, with a fast-growing prevalence. The incidence of diabetic vascular complications is also rapidly increasing, exacerbating the burden on individuals with diabetes and the consumption of public medical resources. Despite the overall improvements in the prevention, diagnosis, and treatment of diabetic microvascular complications in recent years, safe and effective alternative or adjunctive therapies are urgently needed. The mechanisms underlying diabetic vascular complications are complex, with hyperglycemia-induced oxidative stress and inflammation being the leading causes. Therefore, glycemic control, antioxidation, and anti-inflammation are considered the main targets for the treatment of diabetes and its vascular comorbidities. Vaccinium L. (Ericaceae) is a genus of plants enriched with polyphenolic compounds in their leaves and fruits. Vaccinium and its extracts have demonstrated good bioactivity in reducing blood glucose, oxidative stress, and inflammation, making them excellent candidates for the management of diabetes and diabetic vascular complications. Here, we review recent preclinical and clinical studies on the potential effect of Vaccinium on ameliorating diabetes and diabetic complications, particularly diabetic kidney disease and diabetic retinopathy.

Bisphenol A instigates diminished sirtuin-1 mediated vascular complications in type 2 diabetes mellitus

Endocrine society has evidence that plastics can disrupt the endocrine system to cause severe diseases in humans and animals. However, plastics are still used in a variety of models for their applications. The overproduction of plastics simultaneously increases health hazards in human and animal living society. The pancreas is an endocrine system to produces insulin to maintain the glucose level in the blood when that insulin level resists or does not synthesize causing diabetes mellitus. It is one of the highest prevalence diseases occurred in worldwide. Sirtuin-1 is a protein involved in glucose homeostasis and it regulates insulin action. In the human body, hampered the level of insulin, sirtuin-1, and glucose cause diabetes and its vascular complications. Furthermore, many researchers evidenced that the endocrine disruptor of bisphenol A (BPA) causes diabetes mellitus and its vascular complications. Nevertheless, the biological pathway is unclear. This review discusses the linkage between the endocrine disruptor of BPA and diabetes and explores Sirtuin-1 mediated BPA-induced diabetic vascular complications.

Clinical Relevance of lncRNA and Mitochondrial Targeted Antioxidants as Therapeutic Options in Regulating Oxidative Stress and Mitochondrial Function in Vascular Complications of Diabetes.

Metabolic imbalances and persistent hyperglycemia are widely recognized as driving forces for augmented cytosolic and mitochondrial reactive oxygen species (ROS) in diabetes mellitus (DM), fostering the development of vascular complications such as diabetic nephropathy, diabetic cardiomyopathy, diabetic neuropathy, and diabetic retinopathy. Therefore, specific therapeutic approaches capable of modulating oxidative milieu may provide a preventative and/or therapeutic benefit against the development of cardiovascular complications in diabetes patients. Recent studies have demonstrated epigenetic alterations in circulating and tissue-specific long non-coding RNA (lncRNA) signatures in vascular complications of DM regulating mitochondrial function under oxidative stress. Intriguingly, over the past decade mitochondria-targeted antioxidants (MTAs) have emerged as a promising therapeutic option for managing oxidative stress-induced diseases. Here, we review the present status of lncRNA as a diagnostic biomarker and potential regulator of oxidative stress in vascular complications of DM. We also discuss the recent advances in using MTAs in different animal models and clinical trials. We summarize the prospects and challenges for the use of MTAs in treating vascular diseases and their application in translation medicine, which may be beneficial in MTA drug design development, and their application in translational medicine.

TO KNOW THE ASSOCIATION OF PLATELET ACTIVITY ON GLYCEMIC STATUS AND VASCULAR COMPLICATIONS IN DIABETES MELLITUS

Background: Diabetes mellitus is a global pandemic disease. Hyperglycemia contributes to greater platelet reactivity through direct effects and by promoting glycation of proteins. Mean platelet volume(MPV) and Mean platelet count(MPC) is an indicator of average size and activity of the platelets and is high in diabetes mellitus. Objectives: 1) To nd the association between MPC and MPVwith HBA1C in diabetic patients. 2) To nd the association of MPC and MPV with vascular complications in diabetic patients. Methodology: A retrospective study conducted in the Department of Pathology from January 2021 to June 2021. Data was collected from backbone stored in digital form. Sample size : 92 diabetic patients and are divided into 2 groups. 1) Group 1: HbA1c &lt;7. 2) Group 2: HbA1C ≥7. Platelet count, MPV, HbA1c values and vascular complications were analyzed. Results: Out of 92 diabetic patients 74 had vascular complications. MPC in group 1 and group 2 was found to be 231.727 and 312.346 respectively with signicant p value of 0.036 and mean difference of -80.6184. MPV in group 1 and group 2 was found to be 10.200 and 9.999 respectively which showed no signicant correlation with p value of 0.528 and mean difference of 0.2012. The MPC and MPV in diabetic patients with complications were 332.056 and 10.239 respectively showing no signicant correlation. Conclusion: MPC and MPV were found to be raised in group 2. MPC between the 2 groups showed statiscally signicant difference. However MPV does not show any signicance between the two groups. Though there was no signicant difference between Platelet count and vascular complication, MPVwas higher in patients with complications. Diabetic patients suffer mostly from vascular complications, therefore platelet count and HbA1c can be a useful prognostic marker of vascular complications in diabetics.

Angiotensin II Increases Oxidative Stress and Inflammation in Female, But Not Male, Endothelial Cells.

Women are at elevated risk for certain cardiovascular diseases, including pulmonary arterial hypertension, Alzheimer's disease, and vascular complications of diabetes. Angiotensin II (AngII), a circulating stress hormone, is elevated in cardiovascular disease; however, our knowledge of sex differences in the vascular effects of AngII are limited. We therefore analyzed sex differences in human endothelial cell response to AngII treatment. Male and female endothelial cells were treated with AngII for 24h and analyzed by RNA sequencing. We then used endothelial and mesenchymal markers, inflammation assays, and oxidative stress indicators to measure female and male endothelial cell functional changes in response to AngII. Our data show that female and male endothelial cells are transcriptomically distinct. Female endothelial cells treated with AngII had widespread gene expression changes related to inflammatory and oxidative stress pathways, while male endothelial cells had few gene expression changes. While both female and male endothelial cells maintained their endothelial phenotype with AngII treatment, female endothelial cells showed increased release of the inflammatory cytokine interleukin-6 and increased white blood cell adhesion following AngII treatment concurrent with a second inflammatory cytokine. Additionally, female endothelial cells had elevated reactive oxygen species production compared to male endothelial cells after AngII treatment, which may be partially due to nicotinamide adenine dinucleotide phosphate oxidase-2 (NOX2) escape from X-chromosome inactivation. These data suggest that endothelial cells have sexually dimorphic responses to AngII, which could contribute to increased prevalence of some cardiovascular diseases in women. The online version contains supplementary material available at 10.1007/s12195-023-00762-2.

Nebivolol Alleviates Vascular Endothelial Insulin Resistance by Inhibiting Endoplasmic Reticulum Stress.

Vascular endothelial insulin resistance (IR) is an important risk factor in the development of vascular complications in diabetes. Prolonged endoplasmic reticulum stress (ERS) contributes to the development and progression of endothelial IR. The current study assessed the effects and mechanism of nebivolol on vascular IR in Goto-Kakizaki (GK) rats and endothelial IR induced by high glucose (33.3 mmol/L) associated with high insulin (10-7 mol/L) in human aortic endothelial cells (HAECs). Rats were divided into Wistar, Wistar + Neb (Wistar rats treated with nebivolol, 10 mg/kg, ig), GK, and GK + Neb (GK rats treated with nebivolol, 10 mg/kg, ig). GK rats showed hyperglycemia, dyslipidemia, impaired glucose homeostasis, metabolic IR, reduced relaxation to insulin, and lower serum nitric oxide (NO) level. Treatment with nebivolol for 4 months ameliorated insulin's vasorelaxation and NO production, and relieved dyslipidemia in GK rats. Additionally, nebivolol increased glucose uptake and NO level in the endothelial IR group in vitro. Nebivolol increased aortic expressions of IRS-1/PI3K/Akt/eNOS relative proteins and GLUT4 and reduced expressions of ERS markers (ATF6, GRP78, and CHOP, p-JNK/JNK). Furthermore, both nebivolol and TUDCA (ERS inhibitor) alleviated the attenuated IRS-1PI3K/Akt/eNOS pathway and enhanced ERS in HAECs IR. Tunicamycin (ERS inducer) not only induced endothelial IR but also blocked nebivolol's alleviation on the IRS-1PI3K/Akt/eNOS pathway and ERS. Nebivolol ameliorated endothelial IR partially by inhibiting ERS and then regulating the IRS-1/PI3K/Akt/eNOS signal.

Relationship Between Cardio-metabolic Parameters in Diabetic Non-smokers, Current Smokers, and Quitters: A Systematic Review and Meta-analysis

Background: Smoking is associated with an increase in macrovascular and microvascular complications in people with diabetes. In addition to other concomitant vascular disturbances, it also appears to affect cardio-metric parameters. This may partly explain the acceleration of vascular complications in people with diabetes. This study aimed to investigate the relationship between smoking and its cessation in cardio-metric parameters in diabetes. Materials and Methods: Searches were conducted in Medline, Embase, and CINAHL. After screening 6866 studies, 14 observational studies with a total of 98978 participants with type 1 or type 2 diabetes were selected for the investigation. Results: Meta-analysis demonstrated that the mean difference of hemoglobin A1c (HBA1C) between non-smokers and smokers was 0.61% (95% confidence interval [CI] -0.88 to -0.33, P&lt;0.001). The difference in low-density lipoprotein cholesterol between non-smokers and smokers was 0.11 mmol/L (95% CI -20.21 to 0.01, P=0.04). The difference in high-density lipoprotein cholesterol between non-smokers and smokers was 0.12 mmol/L (95% CI 0.08-0.15, P&lt;0.001). However, there was no statistically significant difference in blood pressure (BP) between the two groups. The difference in HBA1C between quitters and continuing smokers was not statistically significant at 10.0.10% (95 CI -0.42 to 0.21, P=0.53). Conversely, the results revealed that over 10 years, HBA1C was comparable between non-smokers and quitters. Conclusion: Smoking in patients with diabetes was widespread and should be the target of smoking cessation campaigns. Smoking cessation does not lead to an increase in HBA1C in the long term and may reduce vascular complications in diabetes by its desirable effect on the lipid profile.

M6A reader IGF2BP1 accelerates apoptosis of high glucose-induced vascular endothelial cells in a m6A-HMGB1 dependent manner.

Emerging evidence indicates that N6-methyladenosine (m6A) plays a critical role in vascular biological characteristic. In diabetes mellitus pathophysiology, high glucose (HG)-induced vascular endothelial dysfunction is associated with diabetes vascular complications. Nevertheless, the underlying mechanism of high glucose (HG)-related m6A regulation on vascular endothelial cells is still unclear. Results indicated that m6A reader insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) was up-regulated in HG-treated human umbilical vascular endothelium cells (HUVECs) comparing to normal group. Functionally, results indicated that IGF2BP1 knockdown recovered the proliferation of HUVECs inhibited by HG-administration. Besides, IGF2BP1 knockdown reduced the apoptosis induced by HG-administration. Mechanistically, IGF2BP1 interacted with HMGB1 mRNA and stabilized its expression of m6A-modified RNA. Therefore, these findings provided compelling evidence demonstrating that m6A reader IGF2BP1 contributes to the proliferation and apoptosis of vascular endothelial cells in hyperglycaemia, serving as a target for development of diabetic angiopathy therapeutics.

Suramin Affects the Renal VEGF-A/VEGFR Axis in Short-Term Streptozotocin-Induced Diabetes

Diabetic nephropathy (DN) accounts for approximately 50% of end-stage renal diseases. Vascular endothelial growth factor A (VEGF-A) is thought to be a critical mediator of vascular dysfunction in DN, but its role is unclear. The lack of pharmacological tools to modify renal concentrations further hinders the understanding of its role in DN. In this study, rats were evaluated after 3 weeks of streptozotocin-induced diabetes and two suramin treatments (10 mg/kg, ip). Vascular endothelial growth factor A expression was evaluated by western blot of glomeruli and immunofluorescence of the renal cortex. RT-PCR for receptors Vegfr1 mRNA and Vegfr2 mRNA quantitation was performed. The soluble adhesive molecules (sICAM-1, sVCAM-1) in blood were measured by ELISA and the vasoreactivity of interlobar arteries to acetylcholine was evaluated using wire myography. Suramin administration reduced the expression and intraglomerular localisation of VEGF-A. Increased VEGFR-2 expression in diabetes was reduced by suramin to non-diabetic levels. Diabetes reduced the sVCAM-1 concentrations. Suramin in diabetes restored acetylcholine relaxation properties to non-diabetic levels. In conclusion, suramin affects the renal VEGF-A/VEGF receptors axis and has a beneficial impact on endothelium-dependent relaxation of renal arteries. Thus, suramin may be used as a pharmacological agent to investigate the potential role of VEGF-A in the pathogenesis of renal vascular complications in short-term diabetes.

Homoplantaginin attenuates high glucose-induced vascular endothelial cell apoptosis through promoting autophagy via the AMPK/TFEB pathway.

Vascular endothelial cell (VEC) injury is a key factor in the development of diabetic vascular complications. Homoplantaginin (Hom), one of the main flavonoids from Salvia plebeia R. Br. has been reported to protect VEC. However, its effects and mechanisms against diabetic vascular endothelium remain unclear. Here, the effect of Hom on VEC was assessed using high glucose (HG)-treated human umbilical vein endothelial cells and db/db mice. In vitro, Hom significantly inhibited apoptosis and promoted autophagosome formation and lysosomal function such as lysosomal membrane permeability and the expression of LAMP1 and cathepsin B. The antiapoptosis effect of Hom was reversed by autophagy inhibitor chloroquine phosphate or bafilomycin A1. Furthermore, Hom promoted gene expression and nuclear translocation of transcription factor EB (TFEB). TFEB gene knockdown attenuated the effect of Hom on upregulating lysosomal function and autophagy. Moreover, Hom activated adenosine monophosphate-dependent protein kinase (AMPK) and inhibited the phosphorylation of mTOR, p70S6K, and TFEB. These effects were attenuated by AMPK inhibitor Compound C. Molecular docking showed a good interaction between Hom and AMPK protein. Animal studies indicated that Hom effectively upregulated the protein expression of p-AMPK and TFEB, enhanced autophagy, reduced apoptosis, and alleviated vascular injury. These findings revealed that Hom ameliorated HG-mediated VEC apoptosis by enhancing autophagy via the AMPK/mTORC1/TFEB pathway.