The vascular system remodels throughout life to ensure adequate perfusion of tissues as they grow, regress, or change metabolic activity. Angiogenesis, the sprouting of new blood vessels to expand the capillary network, versus regression, in which endothelial cells die or migrate away to remove unneeded capillaries, controls capillary density. In addition, upstream arteries adjust their diameters to optimize blood flow to downstream vascular beds, which is controlled primarily by vascular endothelial cells sensing fluid shear stress (FSS) from blood flow. Changes in capillary density and small artery tone lead to changes in the resistance of the vascular bed, which leads to changes in flow through the arteries that feed these small vessels. The resultant decreases or increases in FSS through these vessels then stimulate their inward or outward remodeling, respectively. This review summarizes our knowledge of endothelial FSS-dependent vascular remodeling, offering insights into potential therapeutic interventions. We first provide a historical overview, then discuss the concept of set point and mechanisms of low-FSS-mediated and high-FSS-mediated inward and outward remodeling. We then cover in vivo animal models, molecular mechanisms, and clinical implications. Understanding the mechanisms underlying physiological endothelial FSS-mediated vascular remodeling and their failure due to mutations or chronic inflammatory and metabolic stresses may lead to new therapeutic strategies to prevent or treat vascular diseases.

Diabetes mellitus is a metabolic disorder, characterized by elevated blood sugar levels (hyperglycemia) and insulin dysregulation. This disease is associated with morbidity and mortality, including significant potential vascular complications. High levels of hyperglycemia lead to not only elevated levels of reactive oxygen species but also advanced glycation end products, which are detrimental to the vascular endothelium and reduce protective compounds such as nitric oxide and prostacyclin. This damage contributes to the development of both macrovascular and microvascular complications. The present investigation explores the pathophysiological mechanisms of diabetic vascular complications and evaluates current management strategies, including lifestyle modifications, pharmacological treatments, and emerging therapies. The review underscores the importance of ongoing progress in diabetes management and patient education to lead to optimal patient-health outcomes and quality of life for individuals with diabetes mellitus.

Some cereal proteins and their digestive peptides exhibit the potential to regulate blood glucose levels, which is important for the management of diabetes and its complications. Proteins in common grains, such as wheat and buckwheat, and in legumes, such as kidney beans and soybeans, contain proteinaceous α-amylase inhibitors (α-AIs) that inhibit the breakdown of starch into reducing sugars, thereby mitigating postprandial glucose spikes. Indigestible cereal proteins function similarly to dietary fibers by adsorbing glucose and facilitating its excretion and stabilizing blood glucose levels. Moreover, peptides derived from these proteins can suppress glucose transporter expression in the intestine, thereby reducing glucose absorption. They also promote insulin secretion by inhibiting dipeptidyl peptidase-IV (DPP-IV), an enzyme that breaks down incretin hormones. Collectively, these properties highlight the potential of cereal proteins and peptides in functional foods for blood glucose management.

Diabetes is a well-established risk factor for stroke. Understanding the pathophysiology of this connection is crucial to implementing appropriate prevention strategies. Lately, there has been a paradigm shift in the care of individuals with diabetes toward the use of glucose-lowering medications with potential cardiovascular, cerebrovascular or cardiorenal benefits. The aim of this article is to provide a critical analysis of the role of diabetes in cerebrovascular disease and current evidence and recommendations for the use of glucose-lowering medication with particular focus on the sodium glucose cotransporter-2 inhibitor (SGLT2i) class.

Intensive glycemic control in individuals with diabetes reduces the risk of microvascular complications, but there is less clear evidence for decreasing risk of macrovascular events (e.g., stroke). A multifaceted management of diabetes addressing healthy lifestyle practices, glycemic control, and optimization of other cardiovascular risk factors is highly recommended. SGLT2i are the latest class of antihyperglycemic agents available for diabetes management. Canagliflozin and empagliflozin are associated with reduction in major adverse cardiovascular events (MACE). Dapagliflozin did not reduce the rate of MACE but is associated with reduction in heart-failure related death and hospitalization and has the potential to decrease dementia risk. Ertugliflozin decreases rates of hospitalization related to heart failure however it was non-inferior to placebo in reducing MACE. There is increasing evidence that the use of SGLT2i may reduce the risk of stroke, particularly hemorrhagic stroke, in individuals with type 2 diabetes and a high risk of cardiovascular events, and that SGLT2i may also be beneficial for brain health by decreasing risk of cognitive decline and dementia. Antihyperglycemic therapy should be tailored to patients' circumstances. SGLT2i treatment should be considered in patients with type 2 diabetes and established or high-risk cardiovascular disease, heart failure, or chronic kidney disease, to reduce the overall cerebro-cardiovascular and renal risks.

Red blood cells (RBCs) induce endothelial dysfunction in type 2 diabetes (T2D), but the mechanism by which RBCs communicate with the endothelium is unknown. This study tested the hypothesis that extracellular vesicles (EVs) secreted by RBCs act as mediators of endothelial dysfunction in T2D. Despite a lower production of EVs derived from RBCs of T2D patients (T2D RBC-EVs), their uptake by endothelial cells was greater than that of EVs derived from RBCs of healthy individuals (H RBC-EVs). T2D RBC-EVs impaired endothelium-dependent relaxation, and this effect was attenuated following inhibition of arginase in EVs. Inhibition of vascular arginase or oxidative stress also attenuated endothelial dysfunction induced by T2D RBC-EVs. Arginase-1 was detected in RBC-derived EVs, and arginase-1 and oxidative stress were increased in endothelial cells following coincubation with T2D RBC-EVs. T2D RBC-EVs also increased arginase-1 protein in endothelial cells following mRNA silencing and in the endothelium of aortas from endothelial cell arginase-1-knockout mice. It is concluded that T2D-RBCs induce endothelial dysfunction through increased uptake of EVs that transfer arginase-1 from RBCs to the endothelium to induce oxidative stress and endothelial dysfunction. These results shed important light on the mechanism underlying endothelial dysfunction mediated by RBCs in T2D.

Endothelial dysfunction remains a cornerstone of diabetic vascular complications. RBCs emerge as pivotal players in endothelial dysfunction, yet the underlying mechanisms remain elusive. In this issue of the JCI, Collado et al. show that the detrimental action of RBCs on the endothelium is mediated by extracellular vesicles (EVs). EVs derived from RBCs (RBC-EVs) of patients with diabetes were taken up by the endothelium and were able to impair endothelium-dependent relaxation via an EV-mediated transfer of the prooxidant enzyme arginase-1 (Arg1) from RBCs to endothelial cells. These findings reveal events implicated in vascular oxidative stress and set the stage for personalized approaches preventing RBC-EVs' uptake by the endothelium.

This study aims to evaluate the feasibility of family-specific polygenic risk prediction in reducing the risk of type 2 diabetes (T2D) in the offspring from an infertile couple with a family history of early-onset T2D.

We innovatively established a family-specific polygenic risk prediction model for this T2D family and the embryo with the lowest risk of T2D were selected for implantation.

Initially, whole exome sequencing analysis in the family failed to identify monogenic-level pathogenic or likely pathogenic variants responsible for T2D. Thus, preimplantation genetic testing for monogenic disease (PGT-M) may be not applicable. Subsequently, we innovatively developed a family-specific polygenic-level T2D risk prediction model including 114 T2D risk SNPs and weighted by the genotype-phenotype correlation of asymptomatic individuals and T2D patients in the pedigree. Using this model, the euploid embryo P_5977_1C exhibited the lowest T2D risk and was selected for implantation. The newborn displayed the same lowest T2D polygenic risk and normal growth and development after a 16-month follow-up.

Our study provided preliminary evidence for the feasibility of developing a more accurate polygenic risk prediction model using pedigree information and its application in embryo selection.

Oxidative stress is a key driving factor for the progression of vascular disease in diabetes, and is closely related to endothelial dysfunction. The exact mechanism by which glucagon-like peptide-1 (GLP-1) directly protects vascular endothelium by reducing oxidative stress is not yet fully understood. In this study, we investigated the protective effect of GLP-1 on endothelial cells exposed to palmitic acid (PA)/high glucose-induced oxidative stress and further explored the potential mechanisms involved in microRNA-139-5p (miR-139-5p) regulation. We found that miR-139-5p expression was exhibited significantly elevated in HUVECs that were exposed to PA/high glucose or H2O2, which were reversed by glutathione. Interestingly, this expression was significantly attenuated after GLP-1 pretreatment, with reduced reactive oxygen species (ROS), increased GSH/GSSG ratio and amelioration of cell dysfunction. Overexpression of miR-139-5p resulted in increased ROS and apoptosis, decreased GSH/GSSG ratio, damaged migration and proliferation of HUVECs, while inhibition of miR-139-5p significantly restored PA-induced HUVECs impairments. Further investigation revealed that miR-139-5p directly targets superoxide dismutase 1 (SOD1)/glutamate-cysteine ligase catalytic (GCLc) subunit. The upregulation of miR-139-5p abrogated the protective effects of GLP-1 on cells exposed to PA, and GLP-1-induced downregulation of miR-139-5p was counteracted by the GLP-1 receptor antagonist exendin(9-39). These findings demonstrated that GLP-1 ameliorates oxidative stress-induced endothelial dysfunction, at least in part, by suppressing miR-139-5p, which targets SOD1 and GCLc. This provides further evidence for the vascular protective effects of GLP-1 intervention in diabetes.

Stress hyperglycemia ratio (SHR) is recognized as a reliable indicator of acute hyperglycemia during stress. Patients undergoing coronary artery bypass grafting (CABG) are at high risk of stress hyperglycemia, but little attention has been paid to this population. This study is the first to investigate the association between SHR and both short-term and long-term prognosis in CABG patients, with a further exploration of the impact of SHR across different glucose metabolic states.

A total of 18,307 patients undergoing isolated CABG were consecutively enrolled and categorized into three groups based on SHR tertiles. The perioperative outcome was defined as a composite of in-hospital death, myocardial infarction, cerebrovascular accident, and reoperation during hospitalization. The long-term outcome was major adverse cardiovascular and cerebrovascular events (MACCEs). Restricted cubic spline and logistic regression linked SHR to perioperative risks. Kaplan-Meier and Cox regression analyses were used to determine the relationship with long-term prognosis. Subgroup analyses were further conducted based on different glucose metabolic states.

A U-shaped association was observed between SHR and perioperative outcome in the overall population (P for nonlinear < 0.001). As SHR increased, the risk of perioperative events initially decreased (OR per SD: 0.87, 95% CI 0.79-0.97, P = 0.013) and then elevated (OR per SD: 1.16, 95% CI 1.04-1.28, P =  0.004), with an inflection point at 0.79. A similar U-shaped pattern was identified in patients with normal glucose regulation. Among those with prediabetes, the association was J-shaped, while in patients with diabetes, the association became nonsignificant when SHR exceeded 0.76. Adding SHR to the existing risk model improved the predictive performance for perioperative outcomes in the overall population (AUC: 0.720 → 0.752, P < 0.001; NRI: 0.036, P =  0.003; IDI: 0.015, P < 0.001). For long-term outcomes, the risk of events was monotonically elevated with increasing SHR, regardless of glucose metabolic status. The third tertile showed a 10.7% greater risk of MACCEs (HR: 1.107, 95% CI 1.023-1.231, P =  0.024).

SHR was significantly associated with prognosis in CABG patients, demonstrating a non-linear U-shaped relationship with short-term outcomes and a linear positive association with long-term outcomes. The in-hospital risk associated with SHR was attenuated in patients with diabetes.

WHAT IS CURRENTLY KNOWN ABOUT THIS TOPIC?: Stress hyperglycemia is common during the perioperative period in CABG patients and is linked to adverse short- and long-term outcomes. The stress hyperglycemia ratio (SHR) is a novel metric that accounts for baseline glycemia to better reflect acute stress-induced hyperglycemia. However, SHR has not been studied in the CABG population. WHAT IS THE KEY RESEARCH QUESTION?: This study is the first to investigate the association between SHR and both short-term and long-term prognosis in patients undergoing CABG, while further exploring its impact across different glucose metabolic states, categorized as normal glucose regulation, prediabetes, and diabetes. WHAT IS NEW?: In CABG patients, SHR shows a U-shaped relationship with perioperative events and a linear positive association with long-term outcomes, both of which are modulated by glucose metabolic status. HOW MIGHT THIS STUDYINFLUENCE CLINICAL PRACTICE?: Findings support the incorporation of SHR for risk stratification and personalized glucose management in CABG patients, ultimately improving both in-hospital and long-term prognosis.

Cardiovascular disease (CVD) remains a major global health challenge, particularly affected by glucose metabolism status. However, the relationship between estimated glucose disposal rate (eGDR) and future CVD risk across different glucose metabolism status remains unclear.

We analyzed data from the China Health and Retirement Longitudinal Study (2011-2020) of participants aged ≥ 45 years. The eGDR was calculated using waist circumference, hypertension status, and HbA1c levels. CVD events (stroke or cardiac events) were the outcome. Participants were categorized by glucose metabolism status (normoglycemia, prediabetes, diabetes). Cox proportional hazards models and restricted cubic splines were used to assess associations and potential non-linear relationships.

Among 7,828 participants (52.84% male, mean age 59.01 ± 9.21 years) followed for an average of 8.29 years, 1,944 participants (24.83%) developed CVD. Higher eGDR was inversely associated with CVD risk across all glucose metabolism states. Below the inflection points (11.77, 11.15, and 11.56 mg/kg/min for normoglycemia, prediabetes, and diabetes, respectively), each 1-unit increase in eGDR reduced CVD risk by 14% (HR = 0.86, 95%CI: 0.83-0.89), 10% (HR = 0.90, 95%CI: 0.86-0.93), and 14% (HR = 0.86, 95%CI: 0.81-0.91), respectively.

The eGDR demonstrates a potentially non-linear inverse association with future CVD risk across different glucose metabolism states.

Stress hyperglycemia ratio (SHR), which adjusts blood glucose levels using glycated hemoglobin to eliminate the influence of chronic hyperglycemia, has been demonstrated to have superior predictive value than absolute hyperglycemia. However, its predictive value for sepsis-associated acute kidney injury (SA-AKI) remains unclear. This study aimed to investigate the relationship between the SHR and the risk of developing SA-AKI.

Data were extracted from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Restricted cubic splines (RCS) were employed to depict the relationship between SHR and the likelihood of SA-AKI, determining an optimal cut-off value. Based on this threshold, patients were categorized into two groups. Logistic regression was utilized to evaluate SHR's predictive value for SA-AKI, with adjustments for confounding variables. Propensity score matching (PSM) was applied to balance baseline characteristics. Subgroup and sensitivity analyses were conducted.

A total of 2,249 patients were included. The RCS curve indicated a non-linear positive association between SHR and the likelihood of SA-AKI (P for non-linearity < 0.001), with an optimal cut-off at 1.55. Accordingly, patients were divided into SHR ≤ 1.55 and SHR > 1.55 subgroups, comprising 1,131 and 1,118 individuals, respectively. A higher incidence of SA-AKI was observed in the SHR > 1.55 group (38.64% vs. 27.23%, P < 0.001). This association persisted after baseline adjustment through PSM. Logistic regression analysis confirmed that SHR > 1.55 was linked to increased odds of SA-AKI in both unadjusted (OR: 1.68, P < 0.001) and adjusted models (OR: 1.73, P < 0.001), with SHR ≤ 1.55 serving as the reference. In subgroup analysis, all subgroups consistently demonstrated a significant association between SHR > 1.55 and elevated odds of SA-AKI (all OR > 1). Sensitivity analysis validated that SHR > 1.55 remained significantly correlated with SA-AKI occurrence in the survival subgroup (OR: 1.46, P < 0.001) and the non-CKD subgroup (OR: 1.69, P < 0.001).

The findings indicate a non-linear positive relationship between SHR and the likelihood of SA-AKI in patients with sepsis, suggesting that SHR could be a potential predictor for SA-AKI.

Peripheral arterial disease is a blockage or narrowing of arteries transporting blood from the heart to the legs and feet. Type 2 diabetes mellitus is the second most common risk factor for peripheral arterial disease. This condition is associated with patient mortality and morbidity. However, there is limited evidence on the time to develop peripheral arterial disease, its incidence, and its predictors in the Amhara region, Ethiopia.

To assess the incidence and predictors of peripheral arterial disease among adult type 2 diabetes mellitus patients at Felege Hiwot Comprehensive Specialized Hospital, Northwest Ethiopia, 2023.

A retrospective follow-up study was conducted using data from 552 type 2 diabetes mellitus patients, selected by simple random sampling from January 2006 to December 2021. Data from patient charts and follow-up forms were extracted using a standardized tool, entered into Epi-Data version 3.1, and analyzed in STATA version 14. Kaplan-Meier curves, life table, and Cox regression model were used to assess survival times, survival probabilities, and identify independent predictors of peripheral arterial disease, respectively.

The final analysis included 552 records. The median time for peripheral arterial disease was 13.5 years (95% CI: 11, 14.5). Being female (Adjusted Hazard Ratio (AHR) =  2.18, 95% CI: 1.36, 3.51), age above 65 years (AHR =  1.66, 95% CI: 1.06, 2.61), and fasting blood sugar of over 140 mg/dl (AHR =  3.34, 95% CI: 1.62, 6.90) were predictors for time to peripheral arterial disease in type 2 diabetes mellitus patients. We observed an incidence rate of 29 cases of peripheral arterial disease per 1000 person-years of observation (95% CI: 24-36).

Most peripheral arterial disease occurs after 10 years of diagnosis of type 2 diabetes mellitus. The incidence rate of peripheral arterial disease was high. Female sex, older age, and elevated baseline fasting blood sugar predicted the time until peripheral arterial disease developed. Therefore, clinicians and other stakeholders shall emphasize those types of type 2 diabetes mellitus patients who are female, older age, and with raised fasting blood sugar.

Identifying micro- and macrovascular damage through microalbuminuria and arterial stiffness is essential for preventing renal and cardiovascular complications in patients with type 2 diabetes mellitus (T2D). The primary goal of this research is to investigate the association of the phase angle (PA), triglyceride‒glucose (TyG) index, and homeostasis model assessment for insulin resistance (HOMA-IR) with microalbuminuria and arterial stiffness in patients with T2D.

In this retrospective cross-sectional study, 938 participants with T2D were enrolled. The PA was calculated from bioelectrical impedance analysis. Logistic regression was used to analyze the association of PA, the TyG index and HOMA-IR with microalbuminuria (urinary albumin-to-creatinine ratio [UACR] > 30 mg/g using overnight urine) and increased arterial stiffness (brachial-ankle pulse wave velocity [baPWV] > 1400 cm/s), respectively. Potential nonlinear relationships between PA, the TyG index, and the prevalence of microalbuminuria and increased arterial stiffness were assessed via restricted cubic splines (RCS). Subgroup analysis evaluated the robustness of the association.

PA was inversely correlated with the UACR (r = -0.29, P < 0.001) and baPWV (r = -0.37, P < 0.001). Confounder-adjusted analyses revealed that the highest tertile of PA was significantly associated with lower prevalences of both microalbuminuria and increased arterial stiffness than the lowest tertile, with ORs of 0.305 and 0.467 and P trends < 0.001 and 0.017, respectively. Conversely, the highest TyG tertile was associated with increased prevalences of microalbuminuria and increased arterial stiffness, with ORs of 1.727 and 1.625, respectively, but the P trends were not statistically significant. There were no significant associations between HOMA-IR and microalbuminuria and increased arterial stiffness. RCS analysis further confirmed a significant linear relationship between PA and both vascular complications. Subgroup analyses consistently demonstrated the association between PA and microalbuminuria across all subgroups stratified by sex, age, BMI, HbA1c, and duration of diabetes (all P < 0.01).

Compared with the TyG index and HOMA-IR, PA is independently and more strongly associated with microalbuminuria and increased arterial stiffness in patients with T2D.

In vitromodeling of vascular diseases provides a useful platform for drug screening and mechanistic studies, by recapitulating the essential structures and physiological characteristics of the native tissue. Bioprinting is an emerging technique that offers high-resolution 3D capabilities, which have recently been employed in the modeling of various tissues and associated diseases. Blood vessels are composed of multiple layers of distinct cell types, and experience different mechanical conditions depending on the vessel type. The intimal layer, in particular, is directly exposed to such hemodynamic conditions inducing shear stress, which in turn influence vascular physiology. 3D bioprinting techniques have addressed the structural limitations of the previous vascular models, by incorporating supporting cells such as smooth muscle cells, geometrical properties such as dilation, curvature, or branching, or mechanical stimulation such as shear stress and pulsatile pressure. This paper presents a review of the physiology of blood vessels along with the pathophysiology of the target diseases including atherosclerosis, thrombosis, aneurysms, and tumor angiogenesis. Additionally, it discusses recent advances in fabricatingin vitro3D vascular disease models utilizing bioprinting techniques, while addressing the current challenges and future perspectives for the potential clinical translation into therapeutic interventions.

A comprehensive assessment of combined modifiable risk factors with common complications of type 2 diabetes (T2D) is lacking, and the potential role of proteomics remains unclear. Here, we examine the associations of cardiovascular health (CVH) score and degree of risk factor control with common diabetic complications using data from the UK Biobank (n = 14,102). Furthermore, we explore the mediation effects of plasma proteomics in a subset with proteomic data (n = 1287). Over median follow-ups of 12.4-13.4 years, higher CVH score and higher degree of risk factor control are associated with lower risks of 30 and 22 of 45 adverse outcomes among individuals with T2D, respectively. Mediation analyses reveal that mortality and multiple vascular diseases share common mediators, such as uromodulin and pro-adrenomedullin. These findings highlight the importance of risk factors modification in reducing disease burden among people with T2D and facilitate the understanding of mediation effects of plasma proteins underlying these associations.

Background: Insulin resistance (IR) is a condition that precedes the onset of type 2 diabetes mellitus (T2DM), which is regarded as an established risk factor for atherosclerosis (AS). Considering that the same metabolic changes as those caused by IR are evidenced to promote the development of AS, we investigated whether IR estimated by the homeostasis model assessment of IR (HOMA-IR) could predict the occurrence of preclinical AS. Methods: The study participants were divided into two groups based on the presence of IR diagnosed during the baseline hospitalization and defined as a HOMA-IR value equal to or higher than 2.5. After a follow-up period of at least four years, a total of 79 (n = 79) were prospectively assessed in terms of the presence of preclinical AS, determined by either an abnormally low ankle-brachial index (ABI) (ABI < 0.9) or an increased carotid intima media thickness (CIMT) (CIMT > 1 mm). Results: Using the multivariate logistic regression analysis, it was demonstrated that the HOMA-IR was associated with an abnormally low ABI (odds ratio: 1.609, 95% confidence interval (CI): [1.041-2.487], p = 0.032). The Cox regression model revealed that the HOMA-IR was a predictor of both an abnormal ABI (hazard ratio: 1.435, CI: [1.076-1.913], p = 0.014) and increased CIMT (hazard ratio: 1.419, CI: [1.033-1.948], p = 0.031), independently of age, sex, dyslipidemia, smoking, triglycerides (TG), low-density lipoproteins (LDL), high-density lipoproteins (HDL), and total cholesterol levels. Conclusions: IR, as estimated by the HOMA-IR, may be considered as a predictor of preclinical AS, independently of cardiovascular risk factors.

Obesity and type 2 diabetes (T2D) increase cardiovascular risk, largely due to altered metabolic state. An early consequence of T2D/obesity is the loss of endothelial function and impaired nitric oxide (NO) signaling. In blood vessels, endothelial nitric oxide synthase (eNOS) synthesizes NO to maintain vessel homeostasis. The biological actions of NO are compromised by superoxide that is generated by NADPH oxidases (NOXs). Herein we investigated how altered metabolism affects superoxide/NO balance in obesity. We found that eNOS expression and NO bioavailability are significantly decreased in endothelial cells (ECs) from T2D patients and animal models of obesity. In parallel, PFKFB3, a key glycolytic regulatory enzyme, is significantly increased in ECs of obese animals. EC overexpression of wild-type and a cytosol-restricted mutant PFKFB3 decreased NO production due to increased eNOS-T495 phosphorylation. PFKFB3 also blunted Akt-S473 phosphorylation, reducing stimulus-dependent phosphorylation of S1177 and the activation of eNOS. Furthermore, PFKFB3 enhanced the activities of NOX1 and NOX5, which are major contributors to endothelial dysfunction. Prolonged exposure of ECs to high glucose or TNFα, which are hallmarks of T2D, leads to increased PFKFB3 expression. These results demonstrate a novel functional relationship between endothelial metabolism, ROS, and NO balance that may contribute to endothelial dysfunction in obesity.

During development, endothelial cells (ECs) undergo an extraordinary specialization by which generic capillary microcirculatory networks spanning from arteries to veins transform into patterned organotypic zonated blood vessels. These capillary ECs become specialized to support the cellular and metabolic demands of each specific organ, including supplying tissue-specific angiocrine factors that orchestrate organ development, maintenance of organ-specific functions and regeneration of injured adult organs. Here, we illustrate the mechanisms by which microenvironmental signals emanating from non-vascular niche cells induce generic ECs to acquire specific inter-organ and intra-organ functional attributes. We describe how perivascular, parenchymal and immune cells dictate vascular heterogeneity and capillary zonation, and how this system is maintained through tissue-specific signalling activated by vasculogenic and angiogenic factors and deposition of matrix components. We also discuss how perturbation of organotypic vascular niche cues lead to erasure of EC signatures, contributing to the pathogenesis of disease processes. We also describe approaches that use reconstitution of tissue-specific signatures of ECs to promote regeneration of damaged organs.

Insulin resistance (IR) plays a pivotal role in the interplay between metabolic disorders and heart failure with preserved ejection fraction (HFpEF). Various non-insulin-based indices emerge as reliable surrogate markers for assessing IR, including the triglyceride-glucose (TyG) index, the TyG index with body mass index (TyG-BMI), atherogenic index of plasma (AIP), and the metabolic score for insulin resistance (METS-IR). However, the ability of different IR indices to predict outcome in HFpEF patients has not been extensively explored.

Patients having HFpEF were recruited from January 2012 and December 2023. The outcome was defined as major adverse cardiovascular event (MACE), encompassing all-cause mortality and rehospitalization for heart failure. The potential linear relationship was visualized by the restricted cubic spline (RCS) curve. Both univariable and multivariable Cox proportional hazards models were employed to examine the association between the IR indexes and MACE. Furthermore, to assess the incremental prognostic value of the TyG index, we conducted comprehensive analyses using area under the curve (AUC), the continuous net reclassification index (cNRI), and the integrated discrimination index (IDI).

A total of 8693 patients met the inclusion criteria and were included in the final analysis. The mean age of the patients was 70.59 ± 10.6 years, with 5045 (58.04%) being male. The Kaplan-Meier survival analysis revealed that higher degree of the four IR indexes was associated with higher risk of MACE (all log-rank P < 0.05). When treated as a continuous variable, the TyG index showed a significant association with MACE (HR 2.1, 95% CI 1.98-2.23, P < 0.001 in model 1; HR 1.81, 95% CI 1.73-1.9, P < 0.001 in model 2; HR 1.68, 95% CI 1.6-1.76, P < 0.001 in model 3). When categorized into quartiles, the highest quartile of the TyG index (Q4) was significantly associated with MACE (HR 2.48, 95% CI 2.24-2.76, P < 0.001 in model 3). Similar significant associations were found between TyG-BMI, AIP, METS-IR, and MACE. The TyG index was found to enhance the risk stratification capability of the MAGGIC score (AUC from 0.601 to 0.666). When compared to other IR indicators, the TyG index exhibited superior discrimination and reclassification abilities in predicting MACE. Additionally, the TyG-BMI index revealed a U-shaped correlation with MACE, indicating that both an elevated and a lower TyG-BMI index were associated with an increased risk.

All four IR indices are independently associated with MACE in patients with HFpEF. Notably, these IR indices significantly enhance the predictive accuracy of the MAGGIC score, a widely used risk assessment tool in HFpEF. Among these indices, the TyG index demonstrated the highest discriminatory and reclassification abilities, providing the greatest incremental value in predicting MACE and exhibiting significant superiority compared to the other indices. These findings highlight the importance of assessing IR indices, particularly the TyG index, in the risk assessment and management strategies for HFpEF patients. However, it should be noted that our findings need to be validated in diverse populations to ensure their applicability and generalizability.

Atherosclerosis is a disease of large and medium arteries that can lead to life-threatening cardiovascular and cerebrovascular consequences, such as myocardial infarction and stroke. Moreover, atherosclerosis is a major contributor to cardiovascular-related mortality in individuals with diabetes mellitus. Diabetes aggravates the pathobiological mechanisms that underlie the development of atherosclerosis. Currently available anti-atherosclerotic drugs or strategies solely focus on optimal control of systemic risk factors, including hyperglycaemia and dyslipidaemia, but do not adequately target the diabetes-exacerbated mechanisms of atherosclerotic cardiovascular disease, highlighting the need for targeted, mechanism-based therapies. This Review focuses on emerging pathological mechanisms and related novel therapeutic targets in atherosclerotic cardiovascular disease in patients with diabetes.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder that significantly increases the risk of cardiovascular disease, which is the leading cause of morbidity and mortality among diabetic patients. A central pathophysiological mechanism linking T2DM to cardiovascular complications is oxidative stress, defined as an imbalance between reactive oxygen species (ROS) production and the body's antioxidant defenses. Hyperglycemia in T2DM promotes oxidative stress through various pathways, including the formation of advanced glycation end products, the activation of protein kinase C, mitochondrial dysfunction, and the polyol pathway. These processes enhance ROS generation, leading to endothelial dysfunction, vascular inflammation, and the exacerbation of cardiovascular damage. Additionally, oxidative stress disrupts nitric oxide signaling, impairing vasodilation and promoting vasoconstriction, which contributes to vascular complications. This review explores the molecular mechanisms by which oxidative stress contributes to the pathogenesis of cardiovascular disease in T2DM. It also examines the potential of lifestyle modifications, such as dietary changes and physical activity, in reducing oxidative stress and mitigating cardiovascular risks in this high-risk population. Understanding these mechanisms is critical for developing targeted therapeutic strategies to improve cardiovascular outcomes in diabetic patients.

Cardiovascular complications claim the lives of up to 70% of patients with diabetes mellitus (DM). The mechanisms increasing cardiovascular risk in DM remain to be fully understood and successfully addressed. Nonetheless, there is increasing evidence in the scientific literature of the participation of platelets in the cardiovascular complications of DM. Multiple reports describe the hyperactivity of platelets in DM and their participation in inflammatory responses. The understanding of the mechanisms underlying the contribution of platelets to cardiovascular pathologies in DM will help the development of targeted therapeutic strategies able to reduce cardiovascular risk in these patients. In this literature review, we summarise our current understanding of the molecular mechanisms leading to the contribution of platelets to cardiovascular risk in DM. Both platelet haemostatic activity leading to thrombus formation and their participation to inflammatory processes are stimulated by the biochemical conditions associated with DM. We also present evidence on how DM affect the efficacy of existing therapeutic treatments for thrombosis and, by converse, how antidiabetic drugs may affect platelet function and the haemostasis/thrombosis balance. Taken together, the growing evidence of the different and unexpected roles of platelets in the progression of DM provides a strong rationale for the design of cardiovascular drugs targeting specifically platelets, their pro-inflammatory activity and their activation mechanisms in this disease. Overall, this article provides an important up-to-date overview of the pathophysiological alterations of platelets in DM, which need to be taken into account for the effective management of cardiovascular health in this disease.

In patients with ischemic heart disease, coronary microvascular dysfunction is associated with cardiovascular risk factors and poor prognosis; however, data from healthy individuals are scarce.

The purpose of this study was to assess the impact of cardiovascular risk factors and subclinical atherosclerosis on coronary microvascular function in middle-aged asymptomatic individuals.

Myocardial perfusion was measured at rest and under stress using cardiac magnetic resonance in 453 individuals and used to generate myocardial blood flow (MBF) maps and calculate myocardial perfusion reserve (MPR). Subclinical atherosclerosis was assessed using 3-dimensional vascular ultrasound of the carotid and femoral arteries and coronary artery calcium scoring at baseline and at 3-year follow-up.

Median participant age was 52.6 years (range: 48.9-55.8 years), and 84.5% were male. After adjusting for age and sex, rest MBF was directly associated with the number of the metabolic syndrome components present (elevated waist circumference, systolic and diastolic blood pressure, fasting glucose, and triglycerides and low high-density lipoprotein cholesterol), insulin resistance (homeostatic model assessment for insulin resistance), and presence of diabetes. MPR was reduced in the presence of several metabolic syndrome components, elevated homeostatic model assessment for insulin resistance, and diabetes. Stress MBF was inversely associated with coronary artery calcium presence and with global plaque burden. Higher stress MBF and MPR were associated with less atherosclerosis progression (increase in plaque volume) at 3 years.

In asymptomatic middle-aged individuals free of known cardiovascular disease, the presence of cardiometabolic risk factors and systemic (poly-vascular) subclinical atherosclerosis are associated with impaired coronary microvascular function. Better coronary microvascular function reduces atherosclerosis progression at follow-up. (Progression of Early Subclinical Atherosclerosis [PESA]; NCT01410318).

Diabetes is a major risk factor for cardiovascular disease. However, the exact mechanism by which diabetes contributes to vascular damage is not fully understood. The aim of this study was to investigate the role of SUMO-1 mediated SERCA2a SUMOylation in the development of atherosclerotic vascular injury associated with diabetes mellitus. ApoE-/- mice were treated with streptozotocin (STZ) injection combined with high-fat feeding to simulate diabetic atherosclerosis and vascular injury. Human aortic vascular smooth muscle cells (HAVSMCs) were treated with high glucose (HG, 33.3 mM) and palmitic acid (PA, 200 µM) for 24 h to mimic a model of diabetes-induced vascular injury in vitro. Aortic vascular function, phenotypic conversion, migration, proliferation, intracellular Ca2+ concentration, the levels of small ubiquitin-like modifier type 1 (SUMO1), SERCA2a and SUMOylated SERCA2a were detected. Diabetes-induced atherosclerotic mice presented obvious atherosclerotic plaques and vascular injury, companied by significantly lower levels of SUMO1 and SERCA2a in aorta. HG and PA treatment in HAVSMCs reduced the expressions of SUMO1, SERCA2a and SUMOylated SERCA2a, facilitated the HAVSMCs phenotypic transformation, proliferation and migration, attenuated the Ca2+ transport, and increased the resting intracellular Ca2+ concentration. We also confirmed that SUMO1 directly bound to SERCA2a in HAVSMCs. Overexpression of SUMO1 restored the function and phenotypic contractile ability of HAVSMCs by upregulating SERCA2a SUMOylation, thereby alleviating HG and PA-induced vascular injury. These observations suggest an essential role of SUMO1 to protect diabetes-induced atherosclerosis and aortic vascular injury by the regulation of SERCA2a-SUMOylation and calcium homeostasis.

Several previous studies indicated that melatonin supplementation may positively affect glycemic control in patients with diabetes. However, research on the influence of melatonin supplementation on glycemic parameters remains inconclusive. Therefore, this study aimed to assess the impacts of melatonin supplementation on glycemic parameters in type 2 diabetes by conducting a meta-analysis.

PubMed/Medline, Scopus, and Web of Science were comprehensively searched until July 2024 to find eligible randomized clinical trials (RCTs). The overall effect sizes were estimated by using the randomeffect model and presented as weighted mean differences (WMD) with a 95% confidence interval (CI). Furthermore, the heterogeneity among the included trials was assessed by performing the Cochran Q test and interpreted based on the I² statistic.

Of the 1361 papers, eight eligible RCTs were included in this meta-analysis. Our findings indicated that melatonin supplementation significantly decreased fasting blood glucose (WMD = -12.65 mg/dl; 95% CI: -20.38, -4.92; P = 0.001), insulin (WMD = -2.30 μU/ml; 95% CI: -3.20, -1.40; P < 0.001), hemoglobin A1c (WMD = -0.79 %; 95% CI: -1.28, -0.29; P = 0.002), and HOMA-IR (WMD, -0.83; 95% CI: -1.59 to - 0.07; P = 0.03).

According to the results of the current meta-analysis, persons with type 2 diabetes who supplement with melatonin had improved glycemic control. It looks that supplementing with melatonin at a dose exceeding 6 mg daily for over a period of 12 weeks may be more successful than other forms of intervention. Nevertheless, further research with larger sample sizes is necessary to draw definitive conclusions.

 Multidisciplinary care with vascular surgery and plastic surgery is essential for lower extremity free flap (LEFF) success in the chronic wound population with diabetes and peripheral vascular disease. There is a lack of understanding on performing targeted direct endovascular reperfusion on a vessel that will be used as the flap recipient. Our study compares outcomes of patients who received targeted revascularization (TR) to the recipient vessel for LEFF anastomosis versus nontargeted revascularization (NR) of arterial recipients prior to LEFF.

 LEFF patients who underwent preoperative endovascular revascularization (ER) from July 2011 to January 2023 were reviewed. Location of ER, demographics, perioperative details, and outcomes were collected. TR was performed on the same vessel as the flap recipient and NR was located on a different vessel than the flap recipient.

 A total of 55 LEFF patients were identified. Overall, 50.91% (n = 28) received TR and 49.1% (n = 27) received NR. Average age was 60.3 ± 10.9 years and average Charlson Comorbidity Index was 5.3 ± 1.9. On preoperative angiogram, the TR group had significantly lower rates of ER above the knee (3.6 vs. 33.3%, p < 0.001). Immediate flap success rate was 98.2%, with no differences between groups (p = 1.000). No significant differences were found in rates of any postoperative flap complications (p = 0.898), takeback (p = 0.352), partial flap necrosis (p = 0.648), or dehiscence (p = 0.729). Both TR and NR groups had similar rates of a postoperative angiogram (42.9 vs. 48.2%, p = 0.694) and reintervention (35.7 vs. 40.7% p = 0.701). Amputation rates were similar between TR and NR (17.9 vs. 14.8%, p = 1.000).

 Close follow-up with vascular and plastic surgery is required for patients who undergo ER prior to LEFF, as nearly half of our cohort required additional endovascular procedures. Overall, we observed no significant differences in complication rates for the TR and NR groups, informing revascularization strategies for free tissue transfer in a highly comorbid chronic wound population.

Hyperglycaemia during gestational diabetes (GD) predisposes women and their offspring to later cardiometabolic disease. The hyperglycaemia-mediated epigenetic changes remain to be elucidated. Methyltransferase MLL1-induced trimethylation of histone 3 at lysine 4 (H3K4me3) activates inflammatory and oxidative phenotype. This epigenetic mark in GD women and its transmission to the offspring were investigated.

Peripheral blood mononuclear cells (PBMC) were collected from GD and control (C) women and also from adolescents born to women of both groups. Endothelial human umbilical vein endothelial cells (HUVEC) and cord blood mononuclear cells (CBMC) were from umbilical cords. The NF-κBp65 and NOX4 expressions were investigated by reverse transcription quantitative polymerase chain reaction and immunofluorescence (IF). MLL1 and H3K4me3 were investigated by immunoblotting and IF. H3K4me3 on NF-κBp65 and NOX4 promoters was studied by chromatin immunoprecipitation. Superoxide anion generation was measured by electron spin resonance spectroscopy. Plasma cytokines were measured by enzyme-linked immunosorbent assay. To investigate the role of MLL1, HUVEC were exposed to inhibitor MM102 or siRNA transfection.

PBMC, CBMC, and HUVEC showed an increase of NF-κBp65, IL-6, ICAM-1, MCP-1, and VCAM-1 mRNAs. These findings were associated with H3K4me3 enrichment in the promoter of NF-κBp65. Elevated H3K4me3 and cytokine levels were observed in GD adolescents. MLL1 drives H3K4me3 not only on NF-kB p65, but also on NOX4 promoter. Inhibition of MLL1 blunted NF-κBp65 and NOX4 by modulating inflammatory and oxidative phenotype.

Such proof-of-concept study shows persistence of MLL1-dependent H3K4me3 in offspring born to GD women, suggesting an epigenetic-driven transmission of maternal phenotype. These findings may pave the way for pharmacological reprogramming of adverse histone modifications to mitigate abnormal phenotypes underlying early ASCVD.

Type 2 diabetes mellitus (T2DM) is marked by insulin resistance, low grade chronic inflammation, and endothelial dysfunction. Vitamin K2, especially menaquinone-7 (MK-7), might delay T2DM progression and alleviate its consequences. Hence, this study evaluated the effects of MK-7 on serum and urine markers of diabetes in an animal model of T2DM.

Hetero- (fa/+, control) and homozygous (fa/fa, diabetic) male Zucker diabetic fatty (ZDF) rats were supplemented or not with MK-7 for 12 weeks. After euthanasia, vitamin K1, menaquinone-4 and MK-7 serum concentrations were analyzed via reversed phase high pressure liquid chromatography. Glucose (serum), fructosamine (serum) and creatinine (serum and urine) levels were assessed photometrically, serum cystatin C and urinary total protein were turbidimetrically determined. Serum transforming growth factor beta 1 (TGF-β1) and procollagen type III N-terminal peptide (PIIINP) were quantified with enzyme-linked immunosorbent assay. Urinary marker proteins were analyzed via sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Nephropathy was assessed histologically.

Supplementation led to significantly elevated MK-7 serum levels and a significant reduction of PIIINP serum levels in both hetero- and homozygous ZDF rats. Additionally, not statistically significant reductions of TGF-β1 serum levels, proteinuria as well as the nephropathy score were observed. In vivo body mass, serum fructosamine, glucose, cystatin C and creatinine levels were unaffected.

MK-7 reduced serum markers of fibrosis, histological features of nephropathy and urinary protein excretion, but failed to affect serum markers of T2DM. The therapeutic potential of MK-7 in T2DM and its mode of action should be further investigated in more detail.

Studies evaluating the cardiovascular safety of pioglitazone show inconsistent results and ischemic heart disease (IHD) risks associated with different anti-diabetic drugs added to metformin uncontrolled type 2 diabetes mellitus (T2DM) are not assessed. This study aimed to evaluate IHD risk associated with pioglitazone and/or insulin added to patients with metformin uncontrolled T2DM.

Data were extracted from the National Health Insurance Research Database of Taiwan. A total of 19,952 patients with T2DM uncontrolled on metformin received pioglitazone and/or insulin added to metformin were included.

Compared to those who never received pioglitazone and/or insulin, patients receiving both insulin and pioglitazone had higher cumulative risk of IHD (adjusted HR [aHR] = 1.911, 95 % confidence interval [CI]: 1.506-2.351), pioglitazone alone (aHR = 1.446, 95 % CI: 1.111-1.775), and insulin alone (aHR = 1.351, 95 % CI: 1.1052-1.684) (all, p < 0.05). Patients who received both pioglitazone and insulin had a higher cumulative risk of IHD than those who received insulin or pioglitazone as well as a similar result in the cumulative defined daily dose (cDDD) of the drugs.

Administering pioglitazone plus insulin to patients with T2DM uncontrolled on metformin may increase the risk of IHD, suggesting that other second-line anti-diabetes drugs may be a better choice for patients with T2DM uncontrolled on metformin.

Omentin-1 (oment-1) is a type of adipokines that is mainly expressed in visceral fat tissue. Based on accumulating evidence, oment-1 is closely related to diabetes and its complications. However, so far data about oment-1 and diabetes is fragmented. In this review, we focus on the role of oment-1 on diabetes, including its possible signalling pathways, the correlation of circulating omens-1 levels with diabetes and its complications.

The web of PubMed was searched for articles of relevant studies published until February, 2023.

Oment-1 might exert its effects by inhibiting the NF-κB pathway and activating the Akt and AMPK-dependent pathways. The level of circulating oment-1 is negatively correlated with the occurrence of type 2 diabetes and some complications, including diabetic vascular disease, cardiomyopathy, and retinopathy, which can be affected by anti-diabetic therapies. Oment-1 could be a promising marker for screening and targeted therapy for diabetes and its complications; however, more studies are still needed.

The impact of intensive hypertension criteria on multimorbidity prevalence and patterns remains understudied. We investigated the prevalence and patterns of multimorbidity using both the current (140/90 mmHg) and intensive (130/80 mmHg) hypertension criteria within a multi-ethnic Chinese population.

Data were obtained from the baseline survey of the Regional Ethnic Cohort Study in Northwest China, conducted from June 2018 to May 2019, which enrolled adults aged 35-74 years from five provinces. A total of 114,299 participants were included in this study. Multimorbidity was defined as the presence of at least two chronic diseases or conditions from a list of 26, ascertained through self-report and physical examination. Agglomerative hierarchical cluster analysis was employed to identify multimorbidity patterns. A hypertension-related multimorbidity pattern was identified and further analyzed. The prevalence of multimorbidity and hypertension-related pattern were analyzed in different subgroups, and subgroup cluster analyses were conducted stratified by sex, age, and ethnicity.

Applying the intensive 130/80 mmHg hypertension criteria resulted in an increase in multimorbidity prevalence from 17.6% (20,128 participants) to 21.7% (24,805 participants) compared to the 140/90 mmHg criteria. Four distinct multimorbidity patterns were consistently identified: cardiometabolic, digestive-bone-kidney, respiratory, and mental-cancer. Hypertension consistently clustered within the cardiometabolic pattern alongside diabetes, acute myocardial infarction, angina, and stroke/TIA, with relatively stable proportions observed even under the 130/80 mmHg threshold.

The revision of hypertension criteria significantly expands the population identified as having multimorbidity, without altering the identified multimorbidity patterns. Hypertension commonly co-occurs within the cardiometabolic cluster. These findings highlight the need for improved treatment and management strategies specifically targeting cardiometabolic multimorbidity.

This study aimed to investigate the impact of hepatic steatosis on cardiometabolic outcomes in young adults with prediabetes.

A nationwide cohort study was conducted with 896,585 young adults under 40 years old without diabetes or previous history of cardiovascular disease. Hepatic steatosis was identified using a fatty liver index of ≥ 60. The outcomes of this study were incident diabetes (DM) and composite major adverse cardiovascular events (MACE), including myocardial infarction, stroke, or cardiovascular death.

During a median follow-up of 11.8 years, 27,437 (3.1%) incident DM cases and 6,584 (0.7%) MACE cases were recorded. Young adults with prediabetes had a significantly higher risk of incident DM (hazard ratio [HR]: 2.81; 95% confidence interval [CI]: 2.74-2.88; P-value: <0.001) and composite MACE risk (HR: 1.10; 95% CI: 1.03-1.17; P-value: 0.003) compared to individuals with normoglycemia, after adjusting for relevant covariates. Stratification based on hepatic steatosis showed that the combination of prediabetes and hepatic steatosis posed the highest risk for these outcomes, after adjusting for relevant covariates. For incident DM, the HRs (95% CI; P-value) were: 3.15 (3.05-3.26; <0.001) for prediabetes without hepatic steatosis, 2.89 (2.78-3.01; <0.001) for normoglycemia with hepatic steatosis, and 6.60 (6.33-6.87; <0.001) for prediabetes with hepatic steatosis. For composite MACE, the HRs (95% CI; P-value) were 1.05 (0.97-1.13; 0.235) for prediabetes without hepatic steatosis, 1.39 (1.27-1.51; <0.001) for normoglycemia with hepatic steatosis, and 1.60 (1.44-1.78; <0.001) for prediabetes with hepatic steatosis.

Prediabetes and hepatic steatosis additively increased the risk of cardiometabolic outcomes in young adults. These findings hold significance for physicians as they provide insights into assessing high-risk individuals among young adults with prediabetes.

Glucagon-like peptide 1 (GLP-1) receptor agonists are frequently used to treat type 2 diabetes and obesity. Despite the development of several drugs for neuropathic pain management, their poor efficacy, tolerance, addiction potential, and side effects limit their usage. Teneligliptin, a DPP-4 inhibitor, has been shown to reduce spinal astrocyte activation and neuropathic pain caused by partial sciatic nerve transection. Additionally, we showed its capacity to improve the analgesic effects of morphine and reduce analgesic tolerance. Recent studies indicate that GLP-1 synthesized in the brain activates GLP-1 receptor signaling pathways, essential for neuroprotection and anti-inflammatory effects. Multiple in vitro and in vivo studies using preclinical models of neurodegenerative disorders have shown the anti-inflammatory properties associated with glucagon-like peptide-1 receptor (GLP-1R) activation. This study aimed to investigate the mechanism of antinociception and the effects of the GLP-1 agonist semaglutide (SEMA) on diabetic neuropathic pain in diabetic rats.

Male Wistar rats, each weighing between 300 and 350 g, were categorized into four groups: one non-diabetic sham group and three diabetic groups. The diabetic group received a single intraperitoneal injection of streptozotocin (STZ) at a dosage of 60 mg/kg to induce diabetic neuropathy. After 4 weeks of STZ injection, one diabetic group was given saline (vehicle), and the other two were treated with either 1× SEMA (1.44 mg/kg, orally) or 2× SEMA (2.88 mg/kg, orally). Following a 4-week course of oral drug treatment, behavioral, biochemical, and immunohistochemical analyses were carried out. The mechanical allodynia, thermal hyperalgesia, blood glucose, advanced glycation end products (AGEs), plasma HbA1C, and spinal inflammatory markers were evaluated.

SEMA treatment significantly reduced both allodynia and hyperalgesia in the diabetic group. SEMA therapy had a limited impact on body weight restoration and blood glucose reduction. In diabetic rats, SEMA lowered the amounts of pro-inflammatory cytokines in the spinal cord and dorsal horn. It also lowered the activation of microglia and astrocytes in the dorsal horn. SEMA significantly reduced HbA1c and AGE levels in diabetic rats compared to the sham control group.

These results indicate SEMA's neuroprotective benefits against diabetic neuropathic pain, most likely by reducing inflammation and oxidative stress by inhibiting astrocyte and microglial activity. Our findings suggest that we can repurpose GLP-1 agonists as potent anti-hyperalgesic and anti-inflammatory drugs to treat neuropathic pain without serious side effects.

Comprehensive evaluation of lower-extremity varicose veins (VVs) in patients with diabetes is crucial for treatment strategizing. The study aims to assess the feasibility of using ferumoxytol-enhanced MR venography (FE-MRV) for lower-extremity venous mapping and the detection of VVs in patients with diabetes.

As part of a phase II clinical trial of a generic brand of ferumoxytol, documented patients with diabetes were enrolled and underwent FE-MRV on a 3-Τ MRI system. Two observers assessed FE-MRV images for image quality, signal intensity ratio (SIR), perforator (PV) diameter, and luminal signal uniformity in deep-to-superficial venous networks with the assessment of intra- and inter-rater reliability. FE-MRV was used to detect lower-extremity VVs.

Eleven patients underwent FE-MRV without adverse events. The average image quality, as scored by the two observers who assessed 275 venous segments, was 3.4 ± 0.6. Two observers strongly agreed on image quality (κ = 0.90) and SIR measurements (interclass correlation coefficient [ICC]: 0.72) and had good agreement on PV diameter (ICC: 0.64). FE-MRV revealed uniform luminal signals in deep and saphenous venous networks (0.13 ± 0.05 vs 0.08 ± 0.03). Below-knee segments exhibited a significantly higher heterogeneity index than above-knee (p = 0.039) segments. Superficial VVs were observed in 55% (12/22) of legs in 64% (7/11) of patients. Calf muscle VVs were present in 64% (14/22) of legs in 9 patients.

FE-MRV safely and robustly mapped entire lower-extremity venous networks, enabling the detection and pre-treatment evaluation of both superficial, and deep VVs in patients with diabetes.

Ferumoxytol-enhanced magnetic resonance venography offers a "one-stop" imaging strategy for the detection and pre-operative evaluation of both superficial and deep VVs in diabetic patients.

Diabetic patients with VVs are at a higher risk of ulcer-related complications. FE-MRV allowed rapid and comprehensive visualization of the lower-limb venous networks and abdominopelvic veins in diabetic patients. This technique allowed for the detection of superficial and deep VVs in diabetic patients before the development of severe peripheral artery disease.

The poor healing characteristics of diabetic foot ulcers are partially attributed to diabetes-induced pro-inflammatory wounds. Our previous study reported that both miR-146a-5p and miR-200b-3p decrease endothelial inflammation in human aortic endothelial cells and db/db diabetic mice. Although miR-146a-5p has been reported to improve diabetic wound healing, the role of miR-200b-3p is not clear. This study compared the roles of these miRNAs in diabetic wound healing. Two 8-mm full-thickness wounds were created in 12-week-old male db/db mice on the left and right back. After surgery, 100 ng miR-146a-5p, miR-200b-3p, or miR-negative control (NC) was injected in each wound. Full-thickness skin samples were harvested from mice at the 14th day for real-time polymerase chain reaction and immunohistochemistry analyses. At the 14th day, the miR-200b-3p group showed better wound healing and greater granulation tissue thickness than the miR-146a-5p group. The miR-200b-3p group showed a significant decrease of IL-6 and IL-1β gene expression and a significant increase of Col3α1 gene expression compared to those in the miR-NC group. The miR-200b-3p group had the lowest gene expression of TGF-β1, followed by the miR-146a-5p and miR-NC groups. Our findings suggest that the miR-200b-3p group had better healing characteristics than the other two groups. Immunohistochemical staining revealed that CD68 immunoreactivity was significantly decreased in both the miR-146a-5p and miR-200b-3p groups compared with that in the miR-NC group. In addition, CD31 immunoreactivity was significantly higher in the miR-200b-3p group than in the miR-146a-5p group. In conclusion, these results suggest that miR-200b-3p is more effective than miR-146a-5p in promoting diabetic wound healing through its anti-inflammatory and pro-angiogenic effects.