Search

As a progressive disease process, early diagnosis and ongoing monitoring and treatment of lower limb peripheral artery disease (PAD) is critical to reduce the risk of diabetes-related foot ulcer (DFU) development, non-healing of wounds, infection and amputation, in addition to cardiovascular complications. There are a variety of non-invasive tests available to diagnose PAD at the bedside, but there is no consensus as to the most diagnostically accurate of these bedside investigations or their reliability for use as a method of ongoing monitoring. Therefore, the aim of this systematic review was to first determine the diagnostic accuracy of non-invasive bedside tests for identifying PAD compared to an imaging reference test and second to determine the intra- and inter-rater reliability of non-invasive bedside tests in adults with diabetes. A database search of Medline and Embase was conducted from 1980 to 30 November 2022. Prospective and retrospective investigations of the diagnostic accuracy of bedside testing in people with diabetes using an imaging reference standard and reliability studies of bedside testing techniques conducted in people with diabetes were eligible. Included studies of diagnostic accuracy were required to report adequate data to calculate the positive likelihood ratio (PLR) and negative likelihood ratio (NLR) which were the primary endpoints. The quality appraisal was conducted using the Quality Assessment of Diagnostic Accuracy Studies and Quality Appraisal of Reliability quality appraisal tools. From a total of 8517 abstracts retrieved, 40 studies met the inclusion criteria for the diagnostic accuracy component of the review and seven studies met the inclusion criteria for the reliability component of the review. Most studies investigated the diagnostic accuracy of ankle -brachial index (ABI) (N = 38). In people with and without DFU, PLRs ranged from 1.69 to 19.9 and NLRs from 0.29 to 0.84 indicating an ABI 1.3, TBI of

Summary: Insulin resistance, defined as an impaired biological response to insulin stimulation in target tissues, arises most frequently in the presence of central obesity. Although obesity is generally associated with increased bone mass, recent data challenge this view and, if complicated by T2DM, obese patients are at high risk for fragility fractures. IR may play a key role in this increased fracture risk through effects on bone quality rather than bone quantity. Further understanding of the mechanisms and approaches to prevent osteoporotic fractures in IR-related diseases is needed. Clinical relevance: The dramatic increase in obesity and metabolic syndrome (MetS) over the last half-century has led to a worldwide epidemic of type 2 diabetes mellitus (T2DM) as well as in the incidence of insulin resistance (IR). IR is defined as an impaired biological response to insulin stimulation in target tissues and is primarily related to the liver, muscle, and adipose tissue. The most frequent underlying cause is central obesity, and it is known that excess abdominal adipose tissue secretes increased amounts of free fatty acids, which directly affects insulin signalling, reduces glucose uptake in muscle, and triggers excessive triglyceride synthesis and gluconeogenesis in the liver. When pancreatic β cells are unable to secrete the higher levels of insulin needed, T2DM, the main complication of IR, occurs. Observations: Although obesity is generally associated with increased bone mass, recent data challenge this view and highlight the multifaceted nature of the obesity-bone relationship. Patients with T2DM are at significant risk for well-known complications of diabetes, including retinopathy, nephropathy, macrovascular disease, and neuropathy, but it is clear that they are also at high risk for fragility fractures. Moreover, recent data provide strong evidence that IR may key role in the increased fracture risk observed in both obesity and T2DM. Conclusions: In this concise review article, the role of IR in increased risk of osteoporotic fractures in MetS, obesity, and T2DM is discussed and summarised, including consideration of the need for fracture risk assessment as a 'preventive measure', especially in patients with T2DM and chronic MetS with abdominal obesity. Personalised and targeted diagnostic and therapeutic approaches to prevent osteoporotic fractures in IR-related diseases are needed and could make significant contributions to health outcomes. [ABSTRACT FROM AUTHOR]

Background: Reduced red blood cell deformability (RBCD) is associated with diabetic vascular complications, but early pathophysiological RBC changes and predictive demographic and clinical factors in populations with diabetes are unclear. An understanding of early diabetes-specific RBC changes associated with impaired RBCD is essential in investigating mechanisms that predispose to diabetic vascular complications. Methods: We conducted an outpatient cross-sectional study of participants in a well-controlled diabetes cohort (N81) and nondiabetic controls (N78) at the National Institutes of Health. First, between-group differences in RBCD measures were assessed with shear stress-gradient ektacytometry. Differences in structural RBC parameters were assessed using osmotic gradient ektacytometry and NaCl osmotic fragility. Functional RBC changes were assessed using hemoglobin-oxygen dissociation: p50. Results: All shear-stress gradient RBCD measures were significantly altered in the diabetes cohort vs. nondiabetic controls, even after adjustment for confounding covariates (p < 0.001). Adjusted for diabetes-status and demographic factors, significant predictors of reduced RBCD included older age, Black race, male gender, hyperglycemia, and vascular complications (all p < 0.05). Reduced RBCD was also associated with aberrant osmotic-gradient parameters, with a left-shift on osmotic gradient profile indicative of dehydrated RBCs in diabetes. A structure-function relationship was observed with reduced RBCD associated with reduced osmotic fragility (P < 0.001) and increased hemoglobin-oxygen dissociation (P < 0.01). Conclusions: Findings suggest impaired RBCD incurs similar demographic and clinical risk factors as diabetic vascular disease, with early pathophysiological RBC changes indicative of disordered RBC hydration in diabetes. Findings provide strong evidence for disordered oxygen release as a functional consequence of reduced RBCD. Clinical trial number: NCT00071526. [ABSTRACT FROM AUTHOR]

Diabetic vascular complications attract increased attention due to their high morbidity, mortality and disability rate. Comprehensive and in-depth exploration of the etiology and pathogenesis of diabetic vascular complications is important for diagnosis and treatment. Endothelial extracellular vesicles (EVs) serve as potential intercellular communicators, transmitting biological information from the donor cell to the recipient cell, exerting both harmful and beneficial effects on vascular function. Endothelial EVs are new diagnostic and therapeutic targets and biomarkers in diabetic vascular complications. This review summarizes the biogenesis and release of endothelial EVs, as well as isolation and characterization methods, and discusses the role of endothelial EVs in the maintenance of vascular homeostasis along with their contributions to vascular dysfunction. Finally, the article illustrates the impact of endothelial EVs on the pathogenesis of diabetic vascular complications and evaluates their potential as therapeutic tools and diagnostic markers in diabetic vascular complications. [ABSTRACT FROM AUTHOR]

Background: By 2045, it is expected that 693 million individuals worldwide will have diabetes and with greater risk of morbidity, mortality, loss of vision, renal failure, and a decreased quality of life due to the devastating effects of macro- and microvascular complications. As such, clinical variables and glycemic control alone cannot predict the onset of vascular problems. An increasing body of research points to the importance of genetic predisposition in the onset of both diabetes and diabetic vascular complications. Objectives: Purpose of this article is to review these approaches and narrow down genetic findings for Diabetic Mellitus and its consequences, highlighting the gaps in the literature necessary to further genomic discovery. Material and methods: In the past, studies looking for genetic risk factors for diabetes complications relied on methods such as candidate gene studies, which were rife with false positives, and underpowered genome-wide association studies, which were constrained by small sample sizes. Results: The number of genetic findings for diabetes and diabetic complications has over doubled due to the discovery of novel genomics data, including bioinformatics and the aggregation of global cohort studies. Using genetic analysis to determine whether diabetes individuals are at the most risk for developing diabetic vascular complications (DVC) might lead to the development of more accurate early diagnostic biomarkers and the customization of care plans. Conclusions: A newer method that uses extensive evaluation of single nucleotide polymorphisms (SNP) in big datasets is Genome-Wide Association Studies (GWAS). [ABSTRACT FROM AUTHOR]

• MTHFR C677T polymorphism was associated with T2DM microangiopathy. • The study discovered that the MTHFR A1298C polymorphism is related to microangiopathy in T2DM. • Study findings aid early T2DM microangiopathy diagnosis and treatment. Extensive case-control association studies have been conducted over the past few decades to investigate the relationship between MTHFR polymorphism and type 2 diabetes mellitus (T2DM) microangiopathy. However, the strength of the evidence and clinical significance are unclear. Consequently, a meta-analysis was performed to examine the correlations between two prevalent MTHFR single nucleotide polymorphisms, MTHFR C677T and A1298C, and T2DM microangiopathy. Randomized controlled trials were systematically searched in PubMed, Cochrane, Embase, Web of Science, CNKI, VIP database, China Biology Medicine, and Wanfang until August 2023. A total of 42 studies were included. Random-effect models were utilized to estimate odds ratios (ORs) with 95% confidence intervals (CIs) to assess the association between MTHFR polymorphisms and T2DM microangiopathy susceptibility. T2DM microangiopathy was significantly associated with the MTHFR C677T polymorphism in the overall population (T vs C, OR = 1.43, 95% CI = 1.25-1.64; TT + CT vs CC: OR = 1.56, 95% CI = 1.30-1.88; TT vs CT + CC: OR = 1.66, 95% CI = 1.38-1.99; TT vs CC: OR = 2.03, 95% CI = 1.58-2.60). Additionally, the dominant model revealed that the MTHFR A1298C polymorphism was associated with T2DM microangiopathy (OR = 1.27, 95% CI: 1.09-1.47). This meta-analysis revealed that MTHFR may be involved in the pathogenesis of T2DM microangiopathy, providing a reference for early diagnosis and treatment of T2DM. Our meta-analysis of 42 studies found that C677T/A1298C polymorphism wes associated with T2DM microangiopathy. T2DM microangiopathy was significantly associated with the MTHFR C677T polymorphism in the overall population (Allele: T vs C, Dominant: TT + CT vs CC, Recessive: TT vs CT + CC, Homozygote: TT vs CC: P OR <.001). Additionally, the dominant model revealed that the MTHFR A1298C polymorphism was associated with T2DM microangiopathy (Dominant: CC + AC vs AA: P OR =.002). Abbreviations: RCTs, randomized controlled trials; T2DM, type 2 diabetes mellitus. [Display omitted] [ABSTRACT FROM AUTHOR]

Objective: This study aimed to comprehensively analyze the incidence of amputation in Chinese patients with diabetic foot ulcers (DFUs). Methods: The Preferred Reporting Items for a Systematic Review and Metaanalysis (PRISMA) guidelines were used. The CNKI, Wanfang Data, VIP, PubMed, Web of Science, and Embase databases were searched to collect relevant literature on the incidence of amputation in Chinese patients with DFUs. Two researchers independently screened the literature, extracted data, and evaluated the risk of bias. The data were systematically analyzed using Stata 17.0 software to determine the incidence of amputation in this patient population. Results: A total of 25 papers were included in the study, revealing an incidence of amputation in Chinese patientswithDFUs of 22.4% (95% confidence interval: 18.3-26.5%). The subgroup analysis revealed that a history of ulcers, Wagner grade >3, and diabetic peripheral vascular disease were the primary risk factors associated with a higher incidence of amputation in Chinese patients with DFUs (P<0.05). Among Chinese patients with DFUs, the amputation group and the nonamputation group showed significant differences in body mass index, duration of DFUs, total cholesterol, triglyceride, fasting blood glucose, white blood cell count, hemoglobin A1c, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, high-sensitivity C-reactive protein, and uric acid (P<0.05). Conclusion: The high incidence of amputation among Chinese patients with DFUs indicates that interventions should be implemented to prevent or minimize amputations. [ABSTRACT FROM AUTHOR]

Diabetic vascular disease is a major complication of diabetes mellitus (DM). Chemokine C-C motif ligand 7 (CCL7) attracts macrophages and monocytes, amplifying inflammatory processes in the vasculature. We hypothesized a causal role for CCL7 in diabetic vasculopathy. CCL7 concentrations were higher in the plasma of patients with type 2 DM, as well as in supernatants from their endothelial progenitor cells (EPCs). High-glucose stimulation increased the secretion of CCL7 from human dermal microvascular endothelial cells (HDMECs) through the c-Fos and c-Jun signaling pathways. CCL7 inhibition using knockdown or neutralization antibody treatment reversed the high glucose–induced impaired tube formation and migration abilities of EPCs, human aortic endothelial cells, human coronary artery endothelial cells, and HDMECs. Administration of recombinant human CCL7 protein impaired tube formation and migration abilities by down-regulating the AKT–endothelial nitric oxide synthase and AKT/nuclear factor erythroid 2–related factor 2/heme oxygenase–1/vascular endothelial growth factor/stromal cell–derived factor–1 pathways and by up-regulating ERK/phosphorylated p65/interleukin-1β/interleukin-6/tumor necrosis factor–α pathways through CC chemokine receptor 3 in endothelial cells. Ccl7 knockout in streptozotocin-treated mice showed improved neovasculogenesis in ischemic limbs and accelerated wound repair, with increased circulating EPCs and capillary density. CCL7 antibody treatment in db/db mice and high-fat diet–induced hyperglycemia mice showed improved neovasculogenesis in ischemic limbs and wound areas, accompanied by up-regulation of angiogenic proteins and down-regulation of inflammatory proteins. Endothelial cell–specific Ccl7-knockout mice showed ameliorated diabetic vasculopathy in streptozotocin-induced DM. This study highlights the potential of CCL7 as a therapeutic target for diabetic vasculopathy. Editor's summary: Diabetes can result in harmful vascular complications. It is not fully understood how inflammatory cells contribute to diabetic vasculopathy. Chang et al. showed that CCL7, an immune cell–recruiting factor, could be inhibited to improve vascular function in diabetes models. Inhibiting CCL7 in human cells promoted endothelial functions under high-glucose stress. In mouse models of diabetes including streptozotocin treatment, leptin receptor mutation, or high-fat diet feeding, CCL7 neutralization antibody treatment or genetic knockout improved blood flow recovery after experimental limb ischemia. Wound closure was also accelerated by CCL7 inhibition in each mouse model. Endothelial-specific CCL7 knockout had similar protective effects in streptozotocin-treated mice. These data suggest that CCL7 inhibition could be a therapeutic target for diabetic vasculopathy. —Brandon Berry [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effects of CT to improve HbA1C and ABI among the T2DM-associated PAD population. Methods: A randomized, single-blinded, two-arm trial was conducted at the Department of Rehabilitation Sciences of Dr. Ziauddin Hospital in Karachi between July to September 2023. A total of 80 T2DM-associated PAD patients were included and randomly divided into Experimental Group (n=40) and Control Group (n=40), using the sealed envelope method. Experimental group patients received Concurrent Training (CT), whereas Control Group patients underwent Aerobic Training (AT) for 12 weeks. Both groups received thirty-minute sessions three times a week that was progressed to 60 minutes over 12 weeks. HbA1C and ABI were measured at baseline and after 12 weeks. Results: Analysis revealed an average age of 46.75±3.59 and the duration of T2DM for developing PAD is 14.82±2.23 on average. Findings revealed that both training groups were significantly effective (p<0.000) at 95% CI in improving glycemic and vascular parameters after 12 weeks. Subsequently, findings showed that the CT group showed more significant improvement than AT group in improving HbA1C for glycemic control (p=0.002, CT: pre: 9.53±1.406, post: 7.81±0.81, AT: pre: 8.74±0.908, post: 8.15±0.83) and ABI for systemic blood flow (p=0.0001, CT: pre: 0.84±0.03, post: 0.94±0.03, AT: pre: 0.82±0.02, post: 0.86±0.02). Conclusion: CT showed a two-fold improvement in glycemic control and arterial blood flow than AT group, which represents that CT is an effective therapeutic approach for T2DM-associated Fontain’s stage IIa PAD rehabilitation. [ABSTRACT FROM AUTHOR]

Background: Diabetes mellitus (DM) increases the risk complications in addition to mortality. Quantifying the risk of complications using artificial intelligence could be a way to design comprehensive patient healthcare programs. Objective: Predicting the probability of macro and microvascular complications in patients with DM through Machine Learning. Methods: Retrospective cohort study. Based on an outpatient follow-up program for diabetic patients, 64,081 records and 287 variables were identified, with highly unbalanced data. Predictive models for chronic kidney disease (CKD), lower extremity amputation (LEA), coronary heart disease (CHD), and early mortality (MOR) were developed. An exhaustive computational method was conducted to find the best combination between machine learning (ML) algorithms and sampling method. Results: The best model was determined by assessing its performance through the heuristics obtained from a comprehensive analysis of the accuracy and F1 values for ML, sampling, and dataset. Regarding each complication, 99.9% accuracy was obtained for LEA, 94.3% for CHD, 97.4% for MOR, and 98.8% for CKD. F1 was assessed to identify false positives, with 84.5% for CKD, 63.6% for MOR, 46.2% for LEA, and 44.8% for CHD. Conclusions: This ML model can be applied to predict CHD, CKD, and MOR. The success of ML predictions lies in the clinical definition of initial variables and their simplification for obtaining variables based on which the algorithms can identify patients that are likely to develop a complication. For clinical application of this system, it is necessary to assess the cross performance of metrics, as found here (accuracy higher 95% and F1-Score higher than 80%). [ABSTRACT FROM AUTHOR]

ABSTRACT Erectile dysfunction is observed in about 50% of men. It has been found that diabetes mellitus increases its prevalence to 19-86.3%, necessitating attention to a therapeutic strategy. Among the available treatment methods, intracavernosal injections of mesenchymal stem cells have proven to be particularly effective. Objective The purpose of study is to assess and analyse the effectiveness of their use in the treatment of erectile dysfunction in patients with diabetes mellitus. Materials and Methods The literature search was conducted using systematic methods and analysis in databases such as Web of Science, Scopus, PubMed, Elsevier, and Springer, with 41 sources included for further review. Results The study highlights microangiopathic and neuropathic links as key factors in erectile dysfunction development in diabetic patients, stemming from endothelial dysfunction and conductivity disturbances. Mesenchymal stem cell therapy from bone marrow, adipose tissue, and umbilical cord mitigates pathogenic impact through regenerative and anti-apoptotic effects. Due to this, most studies indicate high efficacy of the treatment and rapid therapeutic action through intracavernosal administration. Some studies suggest an increase in the body’s receptor sensitivity to other drugs, such as sildenafil. Conclusion From the perspective of further research on this issue, standardising the preparation of stem cells and the treatment method using a large sample size is essential to introduce such a method as an extremely promising therapy for this delicate issue in men into practical medicine. The practical value of the study lies in the systematisation of information on different sources of mesenchymal stem cells for treating erectile dysfunction.

Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia, leading to various vascular complications. Accumulating evidence indicates that endothelial colony-forming cells (ECFCs) have attractive prospects for repairing and restoring blood vessels. Thus, ECFCs may be a novel therapeutic option for diabetic patients with vascular complications who require revascularization therapy. However, it has been reported that the function of ECFCs is impaired in DM, which poses challenges for the autologous transplantation of ECFCs. In this review, we summarize the molecular mechanisms that may be responsible for ECFC dysfunction and discuss potential strategies for improving the therapeutic efficacy of ECFCs derived from patients with DM. Finally, we discuss barriers to the use of ECFCs in human studies in light of the fact that there are no published reports using these cells in humans. [ABSTRACT FROM AUTHOR]

Objective: Retinal vascular endothelial cell (RVECs) injury is a major cause of morbidity and mortality among the patients with diabetes. RVECs dysfunction is the predominant pathological manifestation of vascular complication in diabetic retinopathy. N6-methyladenosine (m6A) serves as the most prevalent modification in eukaryotic mRNAs. However, the role of m6A RNA modification in RVECs dysfunction is still unclear. Methods: RT-qPCR analysis and western blot were conducted to detect the change of m6A RNA modification in diabetic retinopathy. CCK-8 assay, transwell experiment, wound healing assay, tube formation experiment, m6A-IP-qPCR were performed to determine the role of YTHDC1 in RVECs. Retinal trypsin digestion test and H&E staining were used to evaluate histopathological changes. Results: The levels of m6A RNA methylation were significantly up-regulated in HG-induced RVECs, which were caused by increased expression of YTHDC1. YTHDC1 regulated the viability, proliferation, migration and tube formation ability in vitro. YTHDC1 overexpression impaired RVECs function by repressing CDK6 expression, which was mediated by YTHDC1-dependent mRNA decay. Moreover, it showed sh-YTHDC1 inhibited CDK6 nuclear export. Sh-YTHDC1 promotes the mRNA degradation of CDK6 in the nucleus but does not affect the cytoplasmic CDK6 mRNA. In vivo experiments showed that overexpression of CDK6 reversed the protective effect of sh-YTHDC1 on STZ-induced retinal tissue damage. Conclusion: YTHDC1-mediated m6A methylation regulates diabetes-induced RVECs dysfunction. YTHDC1-CDK6 signaling axis could be therapeutically targeted for treating DR. [ABSTRACT FROM AUTHOR]

Aim: To investigate the association between cardiovascular health metrics defined by Life's Essential 8 (LE8) scores and vascular complications among individuals with type 2 diabetes (T2D). Materials and Methods: This prospective study included 11 033 participants with T2D, all devoid of macrovascular diseases (including cardiovascular and peripheral artery disease) and microvascular complications (e.g. diabetic retinopathy, neuropathy and nephropathy) at baseline from the UK Biobank. The LE8 score comprised eight metrics: smoking, body mass index, physical activity, non‐high‐density lipoprotein cholesterol, blood pressure, glycated haemoglobin, diet and sleep duration. Cox proportional hazards models were established to assess the associations of LE8 scores with incident macrovascular and microvascular complications. Results: During a median follow‐up of 12.1 years, we identified 1975 cases of incident macrovascular diseases and 1797 cases of incident microvascular complications. After adjusting for potential confounders, each 10‐point increase in the LE8 score was associated with an 18% lower risk of macrovascular diseases and a 15% lower risk of microvascular complications. Comparing individuals in the highest and lowest quartiles of LE8 scores revealed hazard ratios of 0.55 (95% confidence interval 0.47‐0.62) for incident macrovascular diseases, and 0.61 (95% confidence interval 0.53‐0.70) for incident microvascular complications. This association remained robust across a series of sensitivity analyses and nearly all subgroups. Conclusion: Higher LE8 scores were associated with a lower risk of incident macrovascular and microvascular complications among individuals with T2D. These findings underscore the significance of adopting fundamental strategies to maintain optimal cardiovascular health and curtail the risk of developing diabetic vascular complications. [ABSTRACT FROM AUTHOR]

Hyperglycemia is critical for initiation of diabetic vascular complications. We systemically addressed the role of hyperglycemia in the regulation of TLRs in primary human macrophages. Expression of TLRs (1–9) was examined in monocyte-derived M(NC), M(IFNγ), and M(IL4) differentiated in normoglycemic and hyperglycemic conditions. Hyperglycemia increased expression of TLR1 and TLR8 in M(NC), TLR2 and TLR6 in M(IFNγ), and TLR4 and TLR5 in M(IL4). The strongest effect of hyperglycemia in M(IL4) was the upregulation of the TLR4 gene and protein expression. Hyperglycemia amplified TLR4-mediated response of M(IL4) to lipopolysaccharide by significantly enhancing IL1β and modestly suppressing IL10 production. In M(IL4), hyperglycemia in combination with synthetic triacylated lipopeptide (TLR1/TLR2 ligand) amplified expression of TLR4 and production of IL1β. In summary, hyperglycemia enhanced the inflammatory potential of homeostatic, inflammatory, and healing macrophages by increasing specific profiles of TLRs. In combination with dyslipidemic ligands, hyperglycemia can stimulate a low-grade inflammatory program in healing macrophages supporting vascular diabetic complications. [ABSTRACT FROM AUTHOR]

Co-occurrence of anorexia nervosa (AN) and diabetes mellitus type 1 (T1DM) is an uncommon disease combination in clinical practice. Treatment of T1DM may affect outcomes in AN patients due to self-modification of insulin dosage. In the presented case 14-year-old patient diagnosed with both T1DM and AN has been modifying her insulin-dependent treatment to prevent gaining weight. Undercontrolled glucose levels resulted in early-stage diabetic vascular complications in the central nervous system found in MRI. Due to higher T1DM morbidity of eating disorders patients, adjustments and special control of insulin treatment and blood glucose levels as well as HbA1c should be maintained in the prevention of diabetic complications, especially in individuals with lower treatment compliance. As AN may lead to structural changes and a decrease in cognitive functions, increased supervision of AN patients with T1DM can lower the risk of cumulative negative effects on the brain. [ABSTRACT FROM AUTHOR]

Erectile dysfunction (ED) affects a significant proportion of men aged 40-70 and is caused by cavernous tissue dysfunction. Presently, the most common treatment for ED is phosphodiesterase 5 inhibitors; however, this is less effective in patients with severe vascular disease such as diabetic ED. Therefore, there is a need for development of new treatment, which requires a better understanding of the cavernous microenvironment and cell-cell communications under diabetic condition. Pericytes are vital in penile erection; however, their dysfunction due to diabetes remains unclear. In this study, we performed single-cell RNA sequencing to understand the cellular landscape of cavernous tissues and cell type-specific transcriptional changes in diabetic ED. We found a decreased expression of genes associated with collagen or extracellular matrix organization and angiogenesis in diabetic fibroblasts, chondrocytes, myofibroblasts, valve-related lymphatic endothelial cells, and pericytes. Moreover, the newly identified pericyte-specific marker, Limb Bud-Heart (Lbh), in mouse and human cavernous tissues, clearly distinguishing pericytes from smooth muscle cells. Cell-cell interaction analysis revealed that pericytes are involved in angiogenesis, adhesion, and migration by communicating with other cell types in the corpus cavernosum; however, these interactions were highly reduced under diabetic conditions. Lbh expression is low in diabetic pericytes, and overexpression of LBH prevents erectile function by regulating neurovascular regeneration. Furthermore, the LBH-interacting proteins (Crystallin Alpha B and Vimentin) were identified in mouse cavernous pericytes through LC-MS/MS analysis, indicating that their interactions were critical for maintaining pericyte function. Thus, our study reveals novel targets and insights into the pathogenesis of ED in patients with diabetes. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes exposes the body to a state of high blood sugar for a long time and causes varying degrees of hardening of the arteries, making it more prone to cardiovascular emergencies. Objective: The aim of the study was to explore the risk factors of early arterial stiffness in patients with type 2 diabetes mellitus (T2DM). Methods: A retrospective study was conducted on 316 T2DM patients without macroangiopathy in The First Hospital of Qinhuangdao. Early arterial stiffness was evaluated by brachial-ankle pulse wave velocity (baPWV). Results: Ninety patients (28.5%) had baPWV≥1800cm/s. baPWV showed positive correlation with systolic blood pressure (r=0.456, p<0.001), diastolic blood pressure (r=0.133, p=0.018), urine albumin-creatinine ratio (UACR) (r=0.232, p<0.001), neutrophil lymphocyte ratio (NLR) (r=0.185, p=0.001), and visceral fat area (r=0.139, p=0.014). In multiple linear regression analysis, systolic blood pressure (β=6.240, p<0.001), UACR (β=3.805, p=0.019), NLR (β=43.722, p=0.013), and visceral fat area (β=0.778, p=0.030) were significant independent predictors for baPWV. Conclusion: The decline of arterial elasticity was common in T2DM patients without macroangiopathy. Elevated blood pressure, microangiopathy, chronic inflammation, and visceral fat accumulation were the risk factors of early arterial stiffness in patients with T2DM. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) is a risk factor for male infertility, but the underlying molecular mechanisms remain unclear. Advanced glycation end products (AGEs) are pathogenic molecules for diabetic vascular complications. Here, we investigated the effects of the DNA aptamer raised against AGEs (AGE-Apt) on testicular and sperm abnormalities in a T2DM mouse model. KK-Ay (DM) and wild-type (non-DM) 4- and 7-week-old male mice were sacrificed to collect the testes and spermatozoa for immunofluorescence, RT-PCR, and histological analyses. DM and non-DM 7-week-old mice were subcutaneously infused with the AGE-Apt or control-aptamer for 6 weeks and were then sacrificed. Plasma glucose, testicular AGEs, and Rage gene expression in 4-week-old DM mice and plasma glucose, testicular AGEs, oxidative stress, and pro-inflammatory gene expressions in 7-week-old DM mice were higher than those in age-matched non-DM mice, the latter of which was associated with seminiferous tubular dilation. AGE-Apt did not affect glycemic parameters, but it inhibited seminiferous tubular dilation, reduced the number of testicular macrophages and apoptotic cells, and restored the decrease in sperm concentration, motility, and viability of 13-week-old DM mice. Our findings suggest that AGEs-Apt may improve sperm abnormality by suppressing AGE–RAGE-induced oxidative stress and inflammation in the testes of DM mice. [ABSTRACT FROM AUTHOR]

The occurrence and development of diabetic vascular diseases are closely linked to inflammation‐induced endothelial dysfunction. Puerarin (Pue), the primary component of Pueraria lobata, possesses potent anti‐inflammatory properties. However, its vasoprotective role remains elusive. Therefore, we investigated whether Pue can effectively protect against vascular damage induced by diabetes. In the study, Pue ameliorated lipopolysaccharide‐adenosine triphosphate (LPS‐ATP) or HG‐primed cytotoxicity and apoptosis, while inhibited reactive oxygen species (ROS)‐mediated NLR family pyrin domain containing 3 (NLRP3) inflammasome in HUVECs, as evidenced by significantly decreased ROS level, NOX4, Caspase‐1 activity and expression of NLRP3, GSDMD, cleaved caspase‐1, IL‐1β and IL‐18. Meanwhile, ROS inducer CoCI2 efficiently weakened the effects of Pue against LPS‐ATP‐primed pyroptosis. In addition, NLRP3 knockdown notably enhanced Pue's ability to suppress pyroptosis in LPS‐ATP‐primed HUVECs, whereas overexpression of NLRP3 reversed the inhibitory effects of Pue. Furthermore, Pue inhibited the expression of ROS and NLRP3 inflammasome‐associated proteins on the aorta in type 2 diabetes mellitus rats. Our findings indicated that Pue might ameliorate LPS‐ATP or HG‐primed damage in HUVECs by inactivating the ROS‐NLRP3 signalling pathway. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) is a metabolic disease that can be a significant cause of cardiovascular disease (CVD), leading to macrovascular and microvascular diseases. Many researchers around the world have investigated the effects of weight change on micro and macro CVD in patients with T2DM. This study aimed to investigate the effect of weight change (weight gain and loss) on microvascular and macrovascular complications in patients with T2DM. We searched PubMed, Scopus and Google Scholar from the database until January 2023. We screened the title, abstract, and full text of articles, and after quality assessment, we extracted data from interrelated ones into this systematic review. Reviewing the results of 11 cohort studies with 219,839 individuals (T2DM patients) showed that weight loss caused an increase in the mortality rate in diabetic patients, while weight gain after diabetes diagnosis increased the risk of CVD, chronic kidney disease (CKD), microvascular disease, stroke and mortality. It should be noted that severe body weight variability increases the mortality rate and the risk of microvascular disease. Unlike other studies, one study showed that more than 5% weight gain positively affected CVD and coronary heart disease in T2DM patients. Generally, weight change in patients with T2DM is an essential sign of cardiovascular complications. According to our findings, the risk of cardiovascular complications in patients with weight loss is seen to be higher than in patients with weight gain. In regular patients with body mass index (BMI), stable weight in a healthy range is reported to decrease the risk of CVD. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the advantages and problems in the diagnosis and treatment of diabetic foot (DF) patients by analyzing the results of a 5-year follow-up of the organ system based (TOSF) treatment model. Methods: A retrospective study was conducted in 229 patients with diabetic foot. Chi-square test and rank-sum test were used to analyze the effects of patients' general condition, behavioral and nutritional status, degree of infection (inflammatory markers), comorbidity, diabetic foot grade/classification, and revascularization on readmission rate, amputation rate, all-cause mortality, incidence of other complications, and wound healing time. Logistic regression was used to analyze the risk factors affecting the prognosis of diabetic foot. Kaplan-Meier survival curve was used to analyze the differences in amputation rate and mortality rate at each time point. Results: This study showed that nutritional status, degree of infection, and revascularization influenced readmission rates. General condition, behavior and nutritional status, degree of infection, Wagner grade and revascularization affect the amputation rate. General conditions, behavioral and nutritional status, degree of infection, comorbidities, classification and revascularization affect the mortality of patients. Age and white blood cell(WBC) count affected the incidence of other complications. Influence of infection degree and Wagner grade and revascularization in patients with wound healing time. Revascularization was an independent protective factor for readmission, amputation, and mortality.Elevated serum inflammatory markers are an independent risk factor for amputation. Hypoproteinemia is an independent risk factor for mortality. Conclusion: In the "TOSF" diagnosis and treatment pattern, diabetic foot patients have a good prognosis. Special attention should be paid to the screening and revascularization of lower extremity vascular disease in patients with diabetic foot. [ABSTRACT FROM AUTHOR]

Glycolytic overload promotes accumulation of the highly reactive dicarbonyl compounds, resulting in harmful conditions called dicarbonyl stress. Methylglyoxal (MG) is a highly reactive dicarbonyl species and its accumulation plays a crucial pathophysiological role in diabetes and its vascular complications. MG cytotoxicity is mediated by reactive oxygen species (ROS) generation, a key event underlying the intracellular signaling pathways leading to inflammation and apoptosis. The identification of compounds able to inhibit ROS signaling pathways and counteract the MG-induced toxicity is a crucial step for developing new therapeutic strategies in the treatment of diabetic vascular complications. In this study, the effect of genistein, a natural soybean isoflavone, has been evaluated on MG-induced cytotoxicity in human endothelial cells. Our results show that genistein is able to counteract the MG-induced apoptosis by restraining ROS production, thus inhibiting the MAPK signaling pathways and caspase-3 activation. These findings identify a beneficial role for genistein, providing new insights for its potential clinical applications in preserving endothelial function in diabetic vascular complications. [ABSTRACT FROM AUTHOR]

Diabetic vascular complications are prevalent and severe among diabetic patients, profoundly affecting both their quality of life and long-term prospects. These complications can be classified into macrovascular and microvascular complications. Under the impact of risk factors such as elevated blood glucose, blood pressure, and cholesterol lipids, the vascular endothelium undergoes endothelial dysfunction, characterized by increased inflammation and oxidative stress, decreased NO biosynthesis, endothelial-mesenchymal transition, senescence, and even cell death. These processes will ultimately lead to macrovascular and microvascular diseases, with macrovascular diseases mainly characterized by atherosclerosis (AS) and microvascular diseases mainly characterized by thickening of the basement membrane. It further indicates a primary contributor to the elevated morbidity and mortality observed in individuals with diabetes. In this review, we will delve into the intricate mechanisms that drive endothelial dysfunction during diabetes progression and its associated vascular complications. Furthermore, we will outline various pharmacotherapies targeting diabetic endothelial dysfunction in the hope of accelerating effective therapeutic drug discovery for early control of diabetes and its vascular complications. [ABSTRACT FROM AUTHOR]

Objective: To identify the risk factors based on clinical, echocardiographic and therapeutic parameters which predict the development of cardiac complications among patients with diabetes and acute myocardial infarction (AMI). Materials and methods: An observational, analytical, case-control study was conducted at Centro de Cardiología y Cirugía Cardiovascular de Santiago de Cuba, attached to Hospital Provincial Saturnino Lora, from 2019 to 2021. The sample consisted of 266 patients, chosen by simple random sampling 1:2. The study included demographic, clinical- echocardiographic and therapeutic variables. A multivariate analysis was performed with all the variables considered as risk factors; one-way analysis of variance and binary logistic regression were used. Results: The most frequent cardiac complications were atrial fibrillation and heart failure (approximately 12 %). A metabolic control analysis on admission yielded altered results (OR = 6.92; LI: 2.61; LS: 18.32; p = 0.001). The univariate analysis showed that ten factors increased the risk of complications, including the diagnosis of diabetes mellitus ≥ 10 years (OR = 2.50; LI: 1.14; LS: 5.45; p = 0.020). On the other hand, the multivariate analysis revealed six factors that predict the development of cardiac complications: age ≥ 60 years (OR = 5.624; CI = 1.607-19.686; p = 0.007), altered metabolic control on admission (OR = 5.245; CI = 1.491-18.447; p = 0.010), lack of use of thrombolytic therapy (OR = 5.74; CI = 1.46-22.586; p = 0.012), left ventricular ejection fraction (LVEF) ≤ 40 % (OR = 5.245; CI = 1.17-23.433; p = 0.030), left atrial pressure ≥ 15 mmHg (OR = 12.335; CI = 3.45-44.08; p = 0.001) and motility ≥ 1.5 points (OR = 4.702; CI = 1.258-17.575; p = 0.021). Conclusions: The study demonstrated the value of six risk factors of cardiac complications among patients with diabetes and AMI, where glycemic control on admission, decreased LVEF, increased left atrial pressure and no reperfusion therapy stand out. [ABSTRACT FROM AUTHOR]

Diabetes alters the function of ion channels responsible for regulating arterial smooth muscle membrane potential, resulting in vasoconstriction. Our prior research demonstrated an elevation of TMEM16A in diabetic arteries. Here, we explored the mechanisms involved in Transmembrane protein 16A (TMEM16A) gene expression. Our data indicate that a Snail-mediated repressor complex regulates arterial TMEM16A gene transcription. Snail expression was reduced in diabetic arteries while TMEM16A expression was upregulated. The TMEM16A promoter contained three canonical E-box sites. Electrophoretic mobility and super shift assays revealed that the −154 nt E-box was the binding site of the Snail repressor complex and binding of the repressor complex decreased in diabetic arteries. High glucose induced a biphasic contractile response in pressurized nondiabetic mouse hindlimb arteries incubated ex vivo. Hindlimb arteries incubated in high glucose also showed decreased phospho-protein kinase D1 and TMEM16A expression. In hindlimb arteries from nondiabetic mice, administration of a bolus dose of glucose activated protein kinase D1 signaling to induce Snail degradation. In both in vivo and ex vivo conditions, Snail expression exhibited an inverse relationship with the expression of protein kinase D1 and TMEM16A. In diabetic mouse arteries, phospho-protein kinase D1 increased while Akt2 and pGSK3β levels declined. These results indicate that in nondiabetic mice, high glucose triggers a transient deactivation of the Snail repressor complex to increase arterial TMEM16A expression independently of insulin signaling. Conversely, insulin resistance activates GSK3β signaling and enhances arterial TMEM16A channel expression. These data have uncovered the Snail-mediated regulation of arterial TMEM16A expression and its dysfunction during diabetes. NEW & NOTEWORTHY: The calcium-activated chloride channel, TMEM16A, is upregulated in the diabetic vasculature to cause increased vasoconstriction. In this paper, we have uncovered that the TMEM16A gene expression is controlled by a Snail-mediated repressor complex that uncouples with both insulin-dependent and -independent pathways to allow for upregulated arterial protein expression thereby causing vasoconstriction. The paper highlights the effect of short- and long-term glucose-induced dysfunction of an ion channel expression as a causative factor in diabetic vascular disease. [ABSTRACT FROM AUTHOR]

Vascular complications in Type 2 diabetes mellitus (T2DM) patients increase morbidity and mortality. In T2DM, angiogenesis is impaired and can be enhanced or reduced in different tissues ("angiogenic paradox"). The present study aimed to delineate differences between macrovascular and microvascular endothelial cells that might explain this paradox. In a monoculture system of human macrovascular (EaHy926) or microvascular (HMEC-1) endothelial cell lines and a monocytic cell line (U937), high glucose concentrations (25 mmole/L) increased the secretion of the pro-angiogenic factors CD147/EMMPRIN, VEGF, and MMP-9 from both endothelial cells, but not from monocytes. Co-cultures of EaHy926/HMEC-1 with U937 enhanced EMMPRIN and MMP-9 secretion, even in low glucose concentrations (5.5 mmole/L), while in high glucose HMEC-1 co-cultures enhanced all three factors. EMMPRIN mediated these effects, as the addition of anti-EMMPRIN antibody decreased VEGF and MMP-9 secretion, and inhibited the angiogenic potential assessed through the wound assay. Thus, the minor differences between the macrovascular and microvascular endothelial cells cannot explain the angiogenic paradox. Metformin, a widely used drug for the treatment of T2DM, inhibited EMMPRIN, VEGF, and MMP-9 secretion in high glucose concentration, and the AMPK inhibitor dorsomorphin enhanced it. Thus, AMPK regulates EMMPRIN, a key factor in diabetic angiogenesis, suggesting that targeting EMMPRIN may help in the treatment of diabetic vascular complications. [ABSTRACT FROM AUTHOR]

Due to its high prevalence, poor prognosis, and heavy burden on healthcare costs, diabetic vascular complications have become a significant public health issue. Currently, the molecular and pathophysiological mechanisms underlying diabetes-induced vascular complications remain incompletely understood. Autophagy, a highly conserved process of lysosomal degradation, maintains intracellular homeostasis and energy balance via removing protein aggregates, damaged organelles, and exogenous pathogens. Increasing evidence suggests that dysregulated autophagy may contribute to vascular abnormalities in various types of blood vessels, including both microvessels and large vessels, under diabetic conditions. Traditional Chinese medicine (TCM) possesses the characteristics of “multiple components, multiple targets and multiple pathways,” and its safety has been demonstrated, particularly with minimal toxicity in liver and kidney. Thus, TCM has gained increasing attention from researchers. Moreover, recent studies have indicated that Chinese herbal medicine and its active compounds can improve vascular damage in diabetes by regulating autophagy. Based on this background, this review summarizes the classification, occurrence process, and related molecular mechanisms of autophagy, with a focus on discussing the role of autophagy in diabetic vascular damage and the protective effects of TCM and its active compounds through the regulation of autophagy in diabetes. Moreover, we systematically elucidate the autophagic mechanisms by which TCM formulations, individual herbal extracts, and active compounds regulate diabetic vascular damage, thereby providing new candidate drugs for clinical treatment of vascular complications in diabetes. Therefore, further exploration of TCM and its active compounds with autophagy-regulating effects holds significant research value for achieving targeted therapeutic approaches for diabetic vascular complications. [ABSTRACT FROM AUTHOR]

Over the past decade, the prevalence of diabetes has increased significantly worldwide, leading to an increase in vascular complications of diabetes (VCD), such as diabetic cardiomyopathy (DCM), diabetic nephropathy (DN), and diabetic retinopathy (DR). Noncoding RNAs (ncRNAs), such as microRNAs (miRNAs), long Noncoding RNAs (lncRNAs), and circular RNAs (circRNAs), play a key role in cellular processes, including the pathophysiology of diabetes and VCD via pyroptosis. ncRNAs (e.g., miR‐17, lnc‐MEG3, and lnc‐KCNQ1OT1) can regulate pyroptosis in pancreatic β cells. Some ncRNAs are involved in VCD progression. For example, miR‐21, lnc‐KCNQ1OT1, lnc‐GAS5, and lnc‐MALAT1 were reported in DN and DCM, and lnc‐MIAT was identified in DCM and DR. Herein, this review aimed to summarize recent research findings related to ncRNAs‐mediated pyroptosis at the onset and progression of diabetes and VCD. Significance statement: Metabolic disease, such as diabetes, have seriously caused economic and social burden. The role of noncoding RNAs (ncRNAs) in diabetes and its vascular complications has been widely concerned. ncRNAs is a new discovery in the field of pyroptosis, which may provide a new idea for the regulation of VCD. There are many tandem parts in the regulation process of ncRNAs and pyroptosis. This paper summarized the involvement of ncRNAs including microRNAs, long Noncoding RNAs, and circular RNAs in mediating pyroptosis, an inflammatory form of programmed cell death, in diabetes and diabetic vascular complications. [ABSTRACT FROM AUTHOR]

Endothelial damage caused by persistent glucose and lipid metabolism disorders is the main reason of diabetic vascular diseases. Daidzein exerts positive effects on vascular dysfunction. Peroxisome proliferator-activated receptors (PPARs) regulate critically glucose and lipid metabolism. However, the interaction of daidzein to PPARs is still insufficiently explored. In this study, the cell proliferation was detected by EdU. The intrinsic activity and binding affinity of daidzein for human PPARs (hPPARs) were estimated by transactivation reporter gene test and HPLC-UV method, respectively. Daidzein significantly reversed high glucose (HG, at 30 mmol/l)-induced injury in HUVECs, which was inhibited by both PPARα and PPARγ antagonist, but no PPARβ antagonist. Daidzein selectively activated hPPARα and hPPARγ1, but weakly hPPARβ. Additionally, daidzein also bound to both hPPARα and hPPARγ1. The findings suggested that daidzein may be a PPARα and PPARγ dual-agonist. The amelioration of daidzein on HUVECs from hyperglycemia may be mediated by the activation of PPARα and PPARγ receptors. [ABSTRACT FROM AUTHOR]

Introduction: Herbal medicines are commonly used by many people with diabetes in addition to standard treatment. Plants contain numerous known and unknown compounds that may exacerbate or ameliorate diabetes complications. Therefore, it is crucial to be aware of the side effects of these herbs before prescribing them. This study aimed to investigate the effects of hydroalcoholic extracts of Securigera securidaca (HESS) seeds alone and in combination with glibenclamide on the angiogenic/anti-angiogenic balance in streptozotocin (STZ)-induced diabetic rats. Methods: Groups involved in this animal study included diabetic and healthy controls, three doses of HESS, glibenclamide, and combination therapy. Serum samples were collected and analyzed for a vascular endothelial growth factor (VEGF), fibroblast growth factor 21 (FGF21), fetal liver kinase 1 (FLK-1), soluble fms-like tyrosine kinase 1 (sFLT-1), and transforming growth factor -beta (TGF-β). Results: Induction of diabetes increased VEGF, FGF21, and TGF-β serum levels and decreased circulating FLK-1 and sFLT-1 factors. Herbal extract, except TGF-β, had little effect on the above blood levels even at the highest doses. Glibenclamide was more effective than the highest dose of HESS in improving the vascular complications of diabetes. Combination therapy with the highest dose of HESS partly enhanced the glibenclamide effects. Conclusion: Compared with glibenclamide as a standard chemical drug, HESS had no significant effects on the blood levels of the pro/anti-angiogenesis factor in diabetic rats. Glibenclamide attenuated the levels of the biomarkers and its effects were somewhat enhanced in combination with the highest dose of HESS. [ABSTRACT FROM AUTHOR]

ABSTRACT Objective To gather the available evidence in the literature on the prevalence and associated factors of diabetic retinopathy (DR) in Latin America. Methods This scoping review was developed according to the PRISMA-ScR. Prevalence data were summarized by weighted mean, considering the type of DM and country. For the analysis of associated factors, meta-analyses were performed with the most homogeneous studies, and the ORs and their 95%CIs were calculated. Results Forty-two articles published between 2004 and 2020 were included in this study. The mean prevalence of DR ranged from 15.0% in Costa Rica to 32.7% in Brazil. Conclusion This variation may be related to the diagnostic method, age of the studied population, duration of disease, glycemic control, or other associated factors such as the presence of diabetic nephropathy or hypertension. This review discloses an important burden of DR in Latin America and highlights the need for further in-country studies.

Background: Diabetes vascular complications are classified as either macrovascular (cardiovascular disease) or microvascular (nephropathy). These complications considerably raise the risk of morbidity and death. Irisin is a myokine that has been linked to metabolic disorders and cardiovascular disease. The purpose of this study was to look at the relationship between irisin and vascular complications among type 2 diabetic (T2DM) individuals. In this case–control study, the patients were put into four groups based on the occurrence of a diabetic cardiovascular complications and the presence of diabetic nephropathy into group 1: twenty T2DM cases without complications, group 2: twenty T2DM cases with diabetic nephropathy, group 3: twenty T2DM cases with cardiovascular complications, and group 4: thirty controls. History was taken, and clinical examination was done. Laboratory investigations (fasting blood glucose, 2-h postprandial blood glucose, HbA1C, cholesterol, triglycerides, HDL-C and LDL-C, serum urea and creatinine, albumin/creatinine ratio, eGFR, serum irisin) were analyzed. Results: Serum level of irisin was significantly lower in T2DM patients than in control. Also, irisin level was significantly lower in diabetic cases with vascular complications versus those without complications. Irisin level had a negative correlation to BMI and lipid profile in diabetic cases and had a positive correlation to eGFR in diabetic patients with cardiovascular complications. Conclusions: Irisin level was significantly lower in T2DM patients than control and in diabetic patients with vascular complications than patients without complications. So, irisin may have a role as a marker of vascular complications in T2DM. [ABSTRACT FROM AUTHOR]

Aims/Introduction: 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. Materials and Methods: 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). Results: 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). Conclusions: 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. [ABSTRACT FROM AUTHOR]

Copyright of Chinese Journal of Clinical Healthcare is the property of Chinese Journal of Clinical Healthcare and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Diabetes mellitus (DM) is a progressive disease that involves multiple organs due to increased blood glucose, and diabetic retinopathy (DR) is the main complication of DM in the eyes and causes irreversible vision loss. In the pathogenesis of diabetic vascular disease, oxidative stress caused by hyperglycemia plays an important role in Müller cell impairment. In recent years, AdipoRon, an adiponectin analog that demonstrated important physiological functions in obesity, diabetes, inflammation, and cardiovascular diseases, demonstrated cellular protection from apoptosis and reduced inflammatory damage through a receptor-dependent mechanism. Here, we investigated how AdipoRon reduced oxidative stress and apoptosis in Müller glia in a high glucose environment. Results: By binding to adiponectin receptor 1 on Müller glia, AdipoRon activated 5ʹ adenosine monophosphate-activated protein kinase (AMPK)/acetyl-CoA carboxylase phosphorylation downstream, thereby alleviating oxidative stress and eventual apoptosis of cells and tissues. Transcriptome sequencing revealed that AdipoRon promoted the synthesis and expression of early growth response factor 4 (EGR4) and inhibited the cellular protective effects of AdipoRon in a high-glucose environment by reducing the expression of EGR4. This indicated that AdipoRon played a protective role through the EGR4 and classical AMPK pathways. Conclusions: This provides a new target for the early treatment of DR. [ABSTRACT FROM AUTHOR]

Major contributors to morbidity and mortality in diabetic patients are diabetic vascular complications. The impairment of endothelial function seems to be a constant observation in people with diabetes. The objective of the current study was to investigate the impact of various treatment modalities on the endothelial biomarker in T2DM. This study involved 182 participants, divided into seven groups: 20 healthy subjects as a control, 35 newly diagnosed patients with diabetes without treatment, and 127 patients already on different antidiabetic medications for three months. Levels of cholesterol, triglycerides (TG), low-density lipoprotein (LDL), glycated hemoglobin (HbA1c), random blood sugar (RBS), oxidized nitric oxide (NOx), endoglin (ENG), intercellular adhesion molecule (ICAM-1), and glutathione (GSH) are measured for all participants compared with the healthy control. All the other groups significantly increased their lipid profile, HbA1c, RBS, and blood pressure, with a high significance observed in the untreated group. In contrast, a significant increase in NOx levels in the pioglitazone-treated group and ENG levels seems close to normal control, while a significant elevation of ICAM-1 and reduction in GSH levels. Although SGLT2 therapy caused a significant decrease in cholesterol and LDL, the level of ENG was significantly higher, and the level of GSH was considerably lower than in the other groups. In conclusion, the pioglitazone-treated group had the lowest HbA1c and blood pressure and was equivalent to the normal control group. The pioglitazone-treated group had the greatest amount of NOx, which prevents endothelial dysfunction, whereas the SGLT2 group had the lowest impact on these biomarkers. [ABSTRACT FROM AUTHOR]

Introduction: Walking pace is associated with various health‐related outcomes. The aim of this study was to investigate the association between self‐reported walking pace and the incidences of diabetic microvascular complications among participants with type 2 diabetes (T2D). Methods: Self‐reported walking pace was classified as brisk, average, or slow. The outcomes were the incidences of diabetic retinopathy, diabetic neuropathy, and diabetic nephropathy. COX proportional hazards models adjusted for sociodemographic, lifestyle, and health‐related factors were used to estimate hazard ratios (HRs) and 95% CIs. Results: A total of 14 518 participants with T2D in the UK Biobank (mean age 59.7 ± 7.0 years, 5028 [34.6%] women) were included. During a median follow‐up of 12.5 (interquartile range: 11.6–13.4) years, 2980 participants developed diabetic microvascular complications. After adjusting for confounding factors, and compared with brisk walkers, slow walkers had a multivariable‐adjusted HR of 1.98 (95% CI 1.58, 2.47) for composite diabetic microvascular complications, 1.54 (95% CI 1.11, 2.14) for diabetic retinopathy, 3.26 (95% CI 2.08, 5.11) for diabetic neuropathy, and 2.32 (95% CI 1.91, 2.82) for diabetic nephropathy. Average walking pace was associated with a higher risk for diabetic nephropathy (HR 1.51, 95 CI% 1.27–1.79) compared with brisk walking. Additionally, ≥1 diabetic microvascular complication occurred in 447 (14.7%) of participants with brisk walking pace, 1702 (19.5%) with average walking pace, and 831 (30.4%) with slow walking pace. Time from study recruitment to first diagnosis was shorter in participants who reported a slow walking pace, compared with brisk or average walkers. Among participants who had diabetic nephropathy as their first diagnosis, slow walking pace was associated with subsequent risk of a second diabetic microvascular complication (HR 3.88, 95 CI% 2.27–6.60). Conclusions: Self‐reported slow walking pace is associated with a higher risk of diabetic microvascular complications among participants with T2D in this population‐based cohort study. [ABSTRACT FROM AUTHOR]

Angiotensin II (Ang II), a key mediator of vascular diseases, is linked to methylglyoxal (MGO) formation, a by‐product of glucose metabolism implicated in vascular complications. The glyoxalase system, consisting of glyoxalase 1 (Glo1) and reduced glutathione (GSH), is responsible for detoxifying MGO. This study investigated the effect of Ang II on Glo1 activity and expression in vascular smooth muscle cells (VSMCs). Primary VSMCs were isolated from rat aortas and exposed to Ang II under standard or high glucose conditions. We examined Glo1 activity, expression, intracellular GSH, and methylglyoxal‐derived hydroimidazolone 1 (MG‐H1) levels. We also analyzed the expressions of nuclear factor‐κB (NF‐κB) p65 and nuclear factor erythroid 2‐related factor 2 (Nrf2) as potential regulators of Glo1 expression. The results demonstrated that Ang II reduced Glo1 activity, expression, and GSH levels while increasing MG‐H1 levels in VSMCs. Telmisartan and irbesartan, AT1R blockers, restored Glo1 activity, expression, and GSH levels and alleviated MG‐H1 levels. Treatment with AT1R blockers or inhibitors targeting signaling pathways involved in Ang II‐induced responses mitigated these effects. High glucose exacerbated the reduction in Glo1 activity and expression. In conclusion, this study provides evidence that Ang II reduces Glo1 activity and expression in VSMCs, which may contribute to developing vascular complications in diabetes. AT1R blockers and inhibitors targeting specific signaling pathways show potential in restoring Glo1 function and mitigating MGO‐associated damage. These findings highlight the complex interactions between RAS, MGO, and vascular diseases, highlighting potential therapeutic targets for diabetic vascular complications. Significance Statement: This study uncovers a crucial link between angiotensin II and vascular complications in diabetes. Angiotensin II was found to suppress an essential protective enzyme, glyoxalase 1, leading to increased levels of harmful methylglyoxal. Importantly, this effect was exacerbated by high glucose levels, resembling hyperglycemic conditions in diabetes. The research sheds light on the mechanisms behind diabetic vascular issues and highlights potential therapeutic strategies, such as angiotensin II receptor blockers and pathway‐specific inhibitors, to restore glyoxalase 1 function. These findings hold promise for future treatments aimed at reducing diabetic vascular complications. [ABSTRACT FROM AUTHOR]

Objectives: The activation of store-operated calcium entry (SOCE) channel and endoplasmic reticulum stress (ERS) induced by high glucose (HG) is recognized as a major cause of vascular endothelial dysfunction. This study aims to investigate the protective effect of homoplantaginin (Hom) on HG-induced endothelial dysfunction. Methods: HG-induced vascular endothelial dysfunction model in human umbilical vein endothelial cells (HUVECs) and rat-isolated thoracic aortas were established to observe the protective effect of Hom, further evaluated the mechanism of SOCE channel and ERS in the pathogenesis. Key findings: Hom increased the levels of nitric oxide (NO) and phospho-endothelial nitric oxide synthase (p-eNOS) in HUVECs and isolated rat thoracic aortas in a dose-dependent manner, restored acetylcholine-mediated endothelium-dependent vasodilation. Network pharmacology showed that the pathogenesis of diabetic vascular complications may involve calcium (Ca2+) signal pathway. Hom reduced Ca2+ concentration via blocking SOCE channel in HUVECs, and resisted ERS activation by down-regulating ERS-related proteins expression. Importantly, SKF96365 (SOCE inhibitor) intervention experiment showed that Hom inhibited ERS activation by blocking the SOCE channel, further increased the levels of NO and p-eNOS. Conclusion: Hom could alleviate HG-induced vascular endothelial dysfunction by inhibiting SOCE channel and ERS. This provided a potential pharmacological intervention strategy for the treatment of vascular endothelial dysfunction. Graphical Abstract [ABSTRACT FROM AUTHOR]

BackgroundPatients with lower extremity wounds from diabetes mellitus or peripheral artery disease (PAD) have a risk of amputation as high as 25%. In patients with arterial disease, revascularization decreases the risk of amputation. We aimed to determine if the early assessment of arterial perfusion correlates with the risk of amputation.MethodsWe retrospectively reviewed patients referred to the vascular clinic over 18 months with Rutherford Grade 5 and 6 chronic limb-threatening ischemia to determine if patients had a pulse exam done at the time the wound was identified and when ankle brachial index (ABI) testing to evaluate perfusion was performed. Kaplan Meier analysis was used to determine if the timing of ABI testing affected the time to revascularization, wound healing, and risk of amputation.ResultsNinety-three patients with lower extremity wounds were identified. Of these, 59 patients (63%) did not have a pulse exam performed by their primary care provider when the wound was identified. Patients were classified by when they underwent ankle brachial index testing to assess arterial perfusion. Twenty-four had early ABI (