Diabetic patients are highly susceptible to cardiovascular and renal diseases. As a newly updated comprehensive index for assessing cardiovascular health (CVH), Life's essential 8 (LE8) has the potential to serve as a practical tool for evaluating the risk of diabetic kidney disease (DKD). We are committed to exploring the relationship between LE8 and its subscales with DKD in diabetic patients, aiming to provide preliminary evidence for the formulation of clinical strategies.

A total of 3,715 NHANES participants were included in this study, representing 18.9 million non-institutionalized residents of the United States. The mean age of all subjects was 59.72 years, and the weighted prevalence of DKD among diabetic patients was 36.39%. After adjusting for potential confounding factors, it was found that compared to the low LE8 group, the risk of developing DKD was significantly lower in the moderate LE8 group (OR: 0.54, 95% CI: 0.43-0.66) and the high LE8 group (OR: 0.18, 95% CI: 0.08-0.42). A similar trend was observed across the subscales of the LE8 score. The results of the fully adjusted restricted cubic spline regression analysis revealed a linear relationship between LE8 and its subscales with DKD. The findings remained consistent in subgroup and sensitivity analyses, with no significant interactions observed between subgroups.

Higher scores on the LE8 and its subscales were associated with a lower risk of developing DKD. However, the long-term causal relationship between LE8 and DKD risk necessitates further validation and exploration through large-scale, rigorously designed prospective studies.

The risk of diabetic cardiovascular complications is closely linked to the length of hyperglycemia exposure. Mitophagy plays a significant role in vascular endothelial injury. However, the specific mechanisms by which mitophagy contributes to endothelial injury during sustained hyperglycemia remain unclear. In diabetic ApoE-/- mice and human umbilical vein endothelial cell (HUVEC) models, mitophagy is enhanced following short-term and long-term high-glucose exposure. Short-term high-glucose exposure promotes Parkin-mediated mitophagy and upregulates mitochondrial fission protein 1 (Fis1) expression, whereas long-term high-glucose exposure suppresses Parkin-mediated mitophagy and downregulates Fis1. With prolonged high-glucose exposure, Syntaxin 17 (STX17) translocates from the endoplasmic reticulum to the mitochondria, activating STX17-mediated mitophagy. Silencing STX17 alleviates mitochondrial degradation, decreases reactive oxygen species (ROS) levels, enhances endothelial nitric oxide synthase (eNOS) phosphorylation, and reduces apoptosis. Silencing Fis1 accelerates the switching to STX17-mediated mitophagy, worsening endothelial dysfunction, whereas Fis1 overexpression prevents this switching, reducing ROS and apoptosis and enhancing eNOS phosphorylation. In summary, these findings suggest that the switching from Parkin-mediated to STX17-mediated mitophagy drives vascular endothelial injury following long-term hyperglycemic exposure, providing valuable insights into therapeutic strategies for diabetic cardiovascular complications.

The endothelium plays a key role in vascular health, and its dysfunction is a major risk factor for cardiovascular diseases (CVD). Non-invasive neuromodulation techniques, such as NESA, aim to improve vascular tone and function by targeting the autonomic nervous system. However, evidence regarding their acute vascular effects is still limited.

A randomized controlled trial was conducted with 40 participants divided into NESA (n = 20) and placebo (n = 20) groups. Both groups underwent 20-min interventions. Sonographic assessments of the left CCA, including lumen diameter (LD), intima-media thickness (IMT), and peak systolic velocity (PSV), along with blood pressure (BP) and heart rate (HR), were performed before and immediately after the intervention.

Significant increases in LD and cross-sectional area (CSA) were observed in the NESA group compared to placebo (p < 0.001), alongside a decrease in IMT (p < 0.05). HR showed a significant reduction post-intervention in both groups, with a more pronounced effect in the NESA group (p = 0.001). No significant changes were found in BP or PSV.

The findings demonstrate that NESA neuromodulation induces immediate changes in vascular parameters, including increased LD and CSA and decreased IMT. These results highlight measurable acute vascular effects in healthy individuals following NESA intervention.

Insulin resistance and prostate cancer (PCa) association results remain controversial. However, few studies have compared the role of various non-insulin-based insulin resistance (NI-IR) indices and mean platelet volume (MPV) in PCa.

We conducted a cross-sectional study, the case group included 354 patients with PCa, and the control group included 1,498 non-PCa participants. We performed inverse probability weighting to reduce the impact of differences in baseline information between the case and control groups on results. Weighted logistic regression analysis for assessing the relationship between NI-IR indices and PCa risk. Fitting 4-point restricted cubic spline (RCS) plots to show the trend of NI-IR indices with PCa risk. The interaction between insulin resistance and platelet volume based on generalized additive model (GAM) to reveal the impact of the interaction between insulin resistance and cardiovascular risk on PCa. In the end, we performed three sensitivity analyses to verify the stability of results.

Weighted logistic regression analysis revealed that all NI-IR indices were associated with PCa. When NI-IR indices were evaluated as continuous variables, in the all variables adjusted model (model 3), the adjusted OR of ZJU index was 1.337 (95%CI: 1.296-1.379), the adjusted OR of TyG index was 5.300 (95%CI:4.208-6.675), the adjusted OR of TG/HDL-c was 1.431 (95%CI:1.335-1.534), and the adjusted OR of METS-IR was 1.129 (95%CI:1.110-1.149). When NI-IR indices were analyzed as categorical variables, also in model 3, using Q1 as reference, the adjusted OR of ZJU index in Q5 was 15.592 (95%CI:10.809-22.492), the adjusted OR of TyG index in Q5 was 7.306 (95%CI:5.182-10.301), the adjusted OR of TG/HDL-c in Q5 was 4.790 (95%CI:3.459-6.632), and the adjusted OR of METS-IR in Q5 was 9.844 (95%CI:6.862-14.121). RCS displayed that PCa risk tended to increase as the ZJU index, TyG index, TG/HDL-c, and METS-IR increased. The interaction test based on the GAM indicated that the value of the interaction between TG/HDL-c and MPV on the PCa risk was χ2 = 6.924(P = 0.009). With the increase in TG/HDL-c and the decrease in MPV, the PCa risk progressively increases. The sensitivity analysis further confirmed the robustness of the results.

NI-IR indices were associated with an increased PCa risk. The interaction between MPV and insulin resistance may further contribute to the PCa risk.

Vasculopathy is the most prevalent complication of diabetes. Endothelial damage, a primary contributor to hyperglycemic vascular complications, impacts macro- and micro-vasculatures, causing functional impairment of multiple organs. SETD7 was initially identified as a transcriptional activator based on its ability to methylate histone 3 lysine 4. However, its function in the context of diabetic endothelial dysfunction remains poorly understood. This study aims to elucidate the involvement and underlying mechanisms of SETD7 in diabetic endothelial dysfunction.

SETD7 knockout mice were generated to investigate the effects of SETD7 on Streptozotocin (STZ)-induced hyperglycemia and vascular endothelial injury. Endothelial-specific SETD7 interruption adeno-associated virus (AAV) system was utilized to investigate the effects of SETD7 on diabetic vascular endothelial injury in BKS-DB(Lepr) KO/KO (db/db) mice. In vitro manipulation of SETD7 activation or knockdown was conducted to assess its regulation on the lipid peroxidation, oxidative stress, and cell function of primary rat aortic endothelial cells (RAECs) under high glucose conditions.

Our study revealed that knockout and endothelial deficiency of SETD7 partially restored damaged vascular function and attenuated the inflammatory response caused by high glucose in both STZ-induced and db/db mice. Moreover, SETD7 activation aggravated oxidative stress injury and resulted in profound dysfunction through Glutathione Peroxidase 4 (GPX4)-mediated lipid peroxidation in RAECs. Mechanistically, SETD7 deficiency reduced p53 mono-methylation and blocked FBXO45 transcription, thereby inhibiting the protein degradation of GPX4 and subsequent lipid peroxidation as well as oxidative stress.

In summary, our study demonstrates that SETD7-p53-FBXO45-GPX4 is involved in high glucose-induced oxidative stress injury and exacerbated endothelial dysfunction, which offering great significance for mitigating hyperglycemia-induced endothelial damage.

It has been demonstrated that clusterin (CLU) is a protective protein involved in a variety of diseases and disorders. However, the role of CLU in diabetic atherosclerosis is not elucidative. The objective of this study is to investigate the role of CLU in diabetic atherosclerosis and the molecular mechanisms.

In in vivo experiments, Clu knockout and overexpressed murine models were used to investigate the role of Clu in diabetic atherosclerosis. Atherosclerotic plaque formation was determined by hematoxylin-eosin (H&E) staining and Oil Red O staining. F4/80 and CD68 levels were determined by immunohistochemical staining. Transmission electron microscopy was used to observe changes in cell pyroptosis morphology. NLRP3 and IL-1β levels were determined by Western blot and immunofluorescence staining. In in vitro experiments, TNF-α, IL-6, and IL-1β levels in THP-1 derived macrophages were determined by real-time qPCR and ELISA.

We found that Clu-overexpression reduced while Clu knockout promoted atherosclerotic plaque formation, macrophage infiltration and inflammatory factor expression in mouse aortic plaques. Consistently, CLU overexpression inhibits the production of TNF-α, IL-6, and IL-1β in THP-1 derived macrophages. Moreover, Clu inhibited the release of inflammatory factors and macrophage pyroptosis in diabetic atherosclerosis murine models.

Our study revealed that CLU could ameliorate diabetic atherosclerosis via suppressing inflammatory factors release and pyroptosis of macrophage. CLU may be a promising therapeutic target for diabetic atherosclerosis.

Small for gestational age (SGA), with increased risk of adult-onset cardiovascular diseases and metabolic syndromes, is known to associate with endothelial dysfunction, but the pathogenic mechanisms remain unclear. In this study, the pathological state of human umbilical vein endothelial cells (HUVECs) from SGA individuals was characterized by presenting increased angiogenesis, migration, proliferation, and wound healing ability relative to their normal counterparts. Genome-wide mapping of transcriptomes and open chromatins unveiled global gene expression alterations and chromatin remodeling in SGA-HUVECs. Specifically, we revealed increased chromatin accessibility at active enhancers, along with dysregulation of genes associated with angiogenesis, and further identified CD44 as the key gene driving HUVECs' dysfunction by regulating pro-angiogenic genes' expression and activating phosphorylated ERK1/2 and phosphorylated endothelial NOS expression in SGA. In SGA-HUVECs, CD44 was abnormally upregulated by 3 active enhancers that displayed increased chromatin accessibility and interacted with CD44 promoter. Subsequent motif analysis uncovered activating protein-1 (AP-1) as a crucial transcription factor regulating CD44 expression by binding to CD44 promoter and associated enhancers. Enhancers CRISPR interference and AP-1 inhibition restored CD44 expression and alleviated the hyperangiogenesis of SGA-HUVECs. Together, our study provides a foundational understanding of the epigenetic alterations driving pathological angiogenesis and offers potential therapeutic insights into addressing endothelial dysfunction in SGA.

Diabetic neuropathic pain (DNP) is one of the most prevalent complications of diabetes, characterized by a high global prevalence and a substantial affected population with limited effective therapeutic options. Although DNP is closely associated with hyperglycemia, an increasing body of research suggests that elevated blood glucose levels are not the sole inducers of DNP. The pathogenesis of DNP is intricate, involving the release of inflammatory mediators, alterations in synaptic plasticity, demyelination of nerve fibers, and ectopic impulse generation, yet the precise mechanisms remain to be elucidated. The spinal dorsal horn coordinates dynamic interactions between peripheral and central pain pathways, wherein dorsal horn neurons, microglia, and astrocytes synergize with Schwann cell-derived signals to process nociceptive information flow. Abnormally activated neurons can alter signal transduction by modifying the local microenvironment, compromising myelin integrity, and diminishing trophic support, leading to neuronal sensitization and an amplifying effect on peripheral pain signals, which in turn triggers neuropathic pain. Ion channels play a pivotal role in signal conduction, with the modulation of sodium, potassium, and calcium channels being particularly crucial for the regulation of pain signals. In light of the rising incidence of diabetes and the current scarcity of effective DNP treatments, a thorough investigation into the interactions between neurons and glial cells, especially the mechanisms of ion channel function in DNP, is imperative for identifying potential drug targets, developing novel therapeutic strategies, and thereby enhancing the prospects for DNP management.

Diabetes mellitus (DM) may lead to microvascular and macrovascular complications. Screening for these complications is crucial, and so non-invasive methods with high-dissemination potential are needed. Diabetic peripheral neuropathy (DPN) is particularly challenging to screen due to the lack of reliable clinical markers and endpoints. In this context, Raster Scan Optoacoustic Mesoscopy (RSOM) emerges as a highly promising technique that offers hybrid, non-invasive imaging of optical absorption using light-induced ultrasound waves within tissue without the use of contrast agents. RSOM provides high-resolution visualisation of micro-vasculature and other tissue structures along with functional information. The technique has already assessed microvasculature loss as a function of diabetes progression and used it to characterise DPN severity. RSOM has also shown that cutaneous vessels in the mesoscopic range (mean diameters of 30-40 µm) are most prominently affected by DM and that the mean number of cutaneous vessels was lower in subjects with DM than in healthy participants (p < 0.001 and p < 0.05, respectively). Although experience is still limited, we present an overview of the novel technique in relation to its potential for detecting early DM onset and development of microvascular complications.

3-O-Methyl-D-chiro-inositol (pinitol) has been reported to possess insulin-like effects and is known as one of the anti-diabetic agents for improving muscle and liver function. However, the beneficial effects of pinitol on human dermal microvascular endothelial cells (HDMECs) are not well understood. In this study, we investigated whether pinitol could protect HDMECs from damage induced by lipopolysaccharides (LPSs), which cause various cell defects. We observed that pinitol enhanced wound healing for LPS-damaged HDMECs. We found that pinitol significantly downregulated the LPS-induced upregulation of reactive oxygen species (ROS). Pinitol also significantly restored the mitochondrial membrane potential in these cells. Immunofluorescence analysis revealed that pinitol notably reduced the nuclear localization of NF-κB in LPS-damaged HDMECs. Furthermore, we demonstrated that pinitol decreased the phosphorylation levels of the MAPK family in LPS-damaged HDMECs. Interestingly, we observed that pinitol improved tube formation in LPS-damaged HDMECs. Taken together, we suggest that pinitol exerts several beneficial effects on LPS-damaged HDMECs and may be a promising therapeutic agent for improving vascular-related skin diseases.

Stromal interaction molecule 1 (STIM1), a key regulator of calcium signaling located in the endoplasmic reticulum, is crucial for platelet function. While elevated STIM1 expression is observed in platelets from diabetic patients, its role in diabetes-induced platelet hyperreactivity remains unclear. In this study, we found a positive correlation between STIM1 expression and agonist-induced platelet aggregation in platelets from patients with type 2 diabetes mellitus (T2DM). Platelets with high STIM1 expression exhibited enhanced aggregation, P-selectin release, integrin αIIbβ3 activation, spreading, and clot retraction compared to those with low STIM1 expression. Similar findings were observed in db/db mice. Furthermore, the store-operated calcium entry channel inhibitor CM4620 demonstrated superior antiplatelet and antithrombotic efficacy compared to aspirin in both db/db mice and patients with T2DM. Our results suggest that elevated STIM1 expression contributes to enhanced platelet reactivity in diabetes, and targeting STIM1 may offer a promising novel therapeutic approach for thrombosis prevention in this patient population.

Diabetic kidney disease (DKD) is the main cause of end-stage renal disease. Ketogenic diets (KD) is a high-fat, low-carbohydrate diet. KD produces ketone bodies to supplement energy in the case of insufficient glucose in the body. β-Hydroxybutyrate (BHB) is the main component of ketone bodies. BHB serves as "ancillary fuel" substituting (but also inducing) anti-oxidative, anti-inflammatory, and cardio-protective features by binding to several target proteins, including histone acylation modification, or G protein-coupled receptors (GPCRs). KD have been used to treat epilepsy, obesity, type-2 diabetes mellitus, polycystic ovary syndrome, cancers, and other diseases. According to recent research, KD and the induced BHB delay DKD progression by improving the metabolism of glucose and lipids, regulating autophagy, as well as alleviating inflammation, oxidative stress and fibrosis. However, due to some side-effects, the role and mechanism of action of KD and BHB in the prevention and treatment of DKD are controversial. This review focuses on recent progress in the research of KD and BHB in clinical and preclinical studies of DKD, and provides new perspectives for DKD treatment.

Adipose-derived stem cells (ADSCs) have been shown to accelerate diabetic wound healing by promoting neovascularization, though the underlying mechanisms are not fully understood. This study aims to explore whether ADSCs influence endothelial progenitor cells (EPCs) function to enhance diabetic wound healing.

Human adipose-derived stem cells (hADSCs) were isolated from patient adipose tissue and cultured under normal and high glucose (HG) conditions. RNA sequencing analyzed gene expression, while immunofluorescence validated findings in patient wound tissues. Mouse adipose-derived stem cells (ADSCs) from C57BL/6 mice were evaluated in vitro for their effects on EPCs under HG using EdU, Transwell, and tube formation assays. A diabetic mouse wound model was used to assess ADSCs therapeutic effects via digital imaging, histology, and immunofluorescence. Kruppel-like factor 5 (KLF5), identified via the JASPAR database, was confirmed by immunohistochemistry and immunofluorescence. KLF5 and C-X-C motif chemokine 12 (CXCL12) expression levels were measured by enzyme-linked immunosorbent assay (ELISA), western blot, and quantitative reverse transcription polymerase chain reaction (RT-qPCR), and their relationship was validated through dual-luciferase assays.

We constructed a neovascularization-related signature (NRS) comprising 75 genes on the basis of differentially expressed genes (DEGs) linked to neovascularization. GO and KEGG analyses revealed that the NRS is primarily involved in vasculature development and receptor-ligand activity. Seven hub genes (CD34, CXCL12, FGF7, FGF18, FGF1, TEK, KIT) were identified and validated. In a diabetic mouse model, CXCL12 knockdown in ADSCs reduced their ability of promoting wound healing and neovascularization. KLF5 expression was lower in patients with diabetic ulcers and diabetic mice wound tissues compared with normal tissues, while ADSCs treatment significantly increased KLF5 expression in diabetic mice wounds. Dual-luciferase reporter assays confirmed KLF5 as an upstream transcription factor of CXCL12. Additionally, knocking down KLF5 in ADSCs impaired their therapeutic effects on diabetic wound healing. In vitro, the addition of exogenous CXCL12 recombinant protein restored EPCs proliferation, migration, and vasculogenic capacity in a high glucose environment after KLF5 silencing in ADSCs.

Our findings underscore the pivotal role of KLF5 in enhancing CXCL12 transcription within ADSCs, thereby facilitating EPC-mediated neovascularization and improving diabetic wound healing. Additionally, KLF5 emerges as a promising therapeutic target for accelerating tissue repair in diabetic wounds.

Formononetin (FMN) is a common natural metabolite that can be extracted and isolated from some common botanical drugs. In recent years, FMN has garnered increasing attention due to its beneficial biological activities. In this paper, we systematically summarize the sources of FMN and provide a comprehensive review of its pharmacological activities and molecular mechanisms, co-administration, toxicity, derivatives, and drug delivery systems in the last 5 years. The study results found that FMN has a wide range of pharmacological activities in neurological disorders, organ damage and cancer, showing great potential for clinical application and broad prospects. Researchers are exploring various types of delivery systems, including nanoparticle carriers, ligand modifications and polymer microspheres. These advanced delivery systems can enhance the stability of FMN, prolong its release time in vivo, and improve targeting, thereby optimizing its therapeutic efficacy and reducing side effects, and greatly improving its bioavailability. In conclusion, FMN is a natural metabolite with considerable research value, and its diverse biological activities make it a promising candidate for drug development and medical research.

Hyperglycemia and poststroke immunosuppression can lead to a decline in immune function, resulting in an increased incidence of infectious events. The relationship between the glucose-to-lymphocyte ratio (GLR), a novel indicator, and stroke-associated pneumonia (SAP) remains unclear. The objective of this study is to investigate the early predictive value of the GLR in the context of SAP.

A retrospective analysis was conducted on acute stroke patients admitted to the Department of Neurology at the First Affiliated Hospital of Kunming Medical University from 2017 to 2021. The dataset included demographic information, vascular risk factors, and laboratory test results. Logistic regression analysis was used to assess the correlation between the GLR and the incidence of SAP. The GLR was converted into a categorical variable for trend testing, and compared the predictive efficiency of GLR through the receiver operating characteristic (ROC) curve and Bonferroni correction analysis.

This study included 711 patients with acute stroke according to a 1:2 case-control ratio, with 237 (33.3%) in the SAP group and 474 (66.7%) in the Non-SAP group. The baseline level of the GLR was significantly greater in the SAP group than in the Non-SAP group (p < 0.001). After correction using multifactorial logistic regression analysis, GLR (OR: 1.182, 95% CI: 1.090-1.281, p < 0.001) was identified as an independent risk factor for SAP. When GLR was converted into a categorical variable, the risk of SAP in group Q3 was 3.210 times greater than that in group Q1, and the trend test yielded p < 0.001. The analysis of the ROC curve revealed that the area under the curve (AUC) for the GLR was 0.737, with a sensitivity of 70.0% and specificity of 67.1% at a cutoff value of 4.110. The predictive efficacy of the GLR for SAP patients was superior to that of either blood glucose or lymphocyte counts alone (p < 0.0167).

An elevated GLR within 24 h of hospital admission following an acute stroke is an independent risk factor for SAP. The risk of SAP increases progressively with increasing GLR, suggesting that the GLR may have a certain early predictive value for the occurrence of SAP.

Hyperglycemia is a major contributor to endothelial dysfunction and blood vessel damage, leading to severe diabetic microvascular complications. Despite the growing body of research on the underlying mechanisms of endothelial cell (EC) dysfunction, the available drugs based on current knowledge fall short of effectively alleviating these complications. Therefore, our endeavor to explore novel insights into the cellular and molecular mechanisms of endothelial dysfunction is crucial for the field.

In this study, we performed a high-resolution imaging and time-lapse imaging analysis of the behavior of ECs in Tg(kdrl:ras-mCherry::fli1a:nGFP) zebrafish embryos upon high glucose treatment. Genetic manipulation and chemical biology approaches were utilized to analyze the underlying mechanism of high glucose-induced nuclei aggregation and aberrant migration of zebrafish ECs and cultured human ECs. Bioinformatical analysis of single-cell RNA-sequencing data and molecular biological techniques was performed to identify the target genes of foxo1a.

In this study, we observed that the high glucose treatment resulted in nuclei aggregation of ECs in zebrafish intersegmental vessels. Additionally, the aberrant migration of microvascular ECs in high glucose-treated embryos, which might be a cause of nuclei aggregation, was discovered. High glucose induced aggregation of vascular endothelial nuclei via foxo1a downregulation in zebrafish embryos. Then, we revealed that high glucose resulted in the downregulation of foxo1a expression and increased the expression of its direct downstream effector, klf2a, through which the aberrant migration and aggregation of vascular endothelial nuclei were caused.

High glucose treatment caused the nuclei of ECs to aggregate in vivo, which resembles the crowded nuclei of ECs in microaneurysms. High glucose suppresses foxo1a expression and increases the expression of its downstream effector, klf2a, thereby causing the aberrant migration and aggregation of vascular endothelial nuclei. Our findings provide a novel insight into the mechanism of microvascular complications in hyperglycemia.

The objective of this study was to examine the effects of empagliflozin on endothelium-dependent and endothelium-independent vasodilatation and systemic hemodynamic parameters and to assess the role of the nitric oxide (NO) system in patients with type 2 diabetes (T2DM).

In this double-blind, placebo-controlled cross over trial, patients with T2DM were treated with either empagliflozin 10 mg or matching placebo for 4 weeks. Following a 2-week washout, participants were crossed over to 4 weeks of the opposite treatment. Forearm blood flow (FBF) was measured after each treatment period using venous occlusion plethysmography. Acetylcholine and sodium nitroprusside (SNP) were infused into the brachial artery to assess endothelium-dependent and endothelium-independent vasodilatory function, respectively. Total peripheral resistance, 24-h blood pressure (BP) and biochemical markers of NO activity were measured as well.

Sixteen participants completed the trial. The mean age was 68 ± 8 years, and 69% were male. The SNP response increased by 21% (geometric mean ratio 1.21, 95% CI: 1.09; 1.33) during treatment with empagliflozin compared to placebo (p ≤ 0.001), but not during acetylcholine infusion (p = 0.290). Empagliflozin decreased 24-h systolic BP by 5 mmHg (95% CI: -9; -1 mmHg) (p = 0.015), diastolic BP by 2 mmHg (95% CI: -5; 0 mmHg) (p = 0.029) and systemic vascular resistance by 48 dyn×s/m5 (95% CI: -94; -1 dyn×s/m5) (p = 0.044). Furthermore, empagliflozin reduced plasma levels of nitrite and urinary levels of NOx.

Empagliflozin improves endothelium-independent vasodilation, reduces vascular resistance and lowers 24-h BP in patients with T2DM, whereas no change in endothelial-dependent vasodilation was observed.

EU Clinical Trials Register number: 2019-004303-12 (https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-004303-12/DK).

Understanding the dynamics of blood flow regulation in diabetic conditions is crucial for developing targeted interventions. This study aimed to investigate the impact of acute intraocular pressure (IOP) elevation on retinal and choroidal microvasculature in diabetic and control rats.

Male Sprague-Dawley rats were divided into two groups: diabetic and control. Acute IOP elevation was achieved through controlled perfusion pressure. Retinal and choroidal blood flow was measured using Swept-Source Optical Coherence Tomography Angiography (SS-OCT/OCTA).

At baseline IOP levels, there were no statistically significant differences in perfusion area (PA) between the two groups in all regions of the retina and choroid. During acute IOP elevation, both diabetic and control rats experienced a significant reduction in retinal and choroidal blood flow perfusion. Diabetic rats manifested significantly higher (P<0.05) alterations in PA across nearly all retinal regions compared to the control group, barring specific sub-regions of the outer ring. Concerning choroidal PA, the diabetic group exhibited a more pronounced alteration than the control group across the entire 6-mm region and certain sub-regions of the outer ring.

Our results demonstrate a clear association between diabetes and impaired choroidal vascular autoregulation during acute IOP elevation. The observed reduction in retinal and choroidal microvasculature in diabetic rats points towards a compromised ability to maintain blood flow homeostasis under stress conditions.

Cinnamic acid (CA) is a bioactive compound isolated from cinnamon. It has been demonstrated to ameliorate inflammation and metabolic diseases, which are associated with endothelial dysfunction. This study was aimed to study the potential protective effects of CA against diabetes-associated endothelial dysfunction and its underlying mechanisms.

High-fat diet (HFD) with 60 kcal% fat was used to induce obesity/diabetes in C57BL/6 mice for 12 weeks. These diet-induced obese (DIO) mice were orally administered with CA at 20 or 40 mg/kg/day, pioglitazone (PIO) at 20 mg/kg/day or same volume of vehicle during the last 4 weeks. Isolated mouse aortic segments and primary culture rat aortic endothelial cells (RAECs) were induced with high glucose (HG) to mimic hyperglycemia and co-treated with different concentrations of CA.

In DIO mice, four-week administration of CA, particularly at 40 mg/kg/day, diminished the body weights, blood pressure, fasting blood glucose and plasma lipid levels, and ameliorated endothelium-dependent relaxations (EDRs) and oxidative stress in aortas. The beneficial effects of CA were comparable to the positive control group, PIO. Western blotting results indicated that CA treatment upregulated the expression of peroxisome proliferator-activated receptor delta (PPARδ), and activated nuclear factor erythroid 2-related factor 2 (Nrf2)/ heme oxygenase-1 (HO-1) and AMP-activated protein kinase (AMPK)/ protein kinase B (Akt)/ endothelial nitric oxide synthase (eNOS) signaling pathways in mouse aortas in vivo and ex vivo. HG stimulation impaired EDRs in mouse aortas and inhibited nitric oxide (NO) production but elevated reactive oxygen species (ROS) levels in RAECs. CA reversed these impairments. Importantly, PPARδ antagonist GSK0660 abolished the vasoprotective effects of CA. Molecular docking analysis suggested a high likelihood of mutual binding between CA and PPARδ.

CA protects against endothelial dysfunction and oxidative stress in diabetes and obesity by targeting PPARδ through Nrf2/HO-1 and Akt/eNOS signaling pathways.

The impact of macrovascular and microvascular complications, the common vascular complications of type 2 diabetes, on long-term mortality has been well evaluated, but the impact of different complications of newly diagnosed type 2 diabetes (diagnosed within the past 2 years) on long-term mortality has not been reported. We aimed to investigate the relationship between all-cause mortality and vascular complications in U.S. adults (aged ≥ 20 years) with newly diagnosed type 2 diabetes.

We used data from the 1999-2018 National Health and Nutritional Examination Surveys (NHANES). Cox proportional hazard models was used to assess hazard ratios (HR) and 95% confidence intervals for all-cause mortality.

A total of 928 participants were enrolled in this study. At a mean follow-up of 10.8 years, 181 individuals died. In the fully adjusted model, the hazard ratio (HR) (95% confidence interval [CI]) of all-cause mortality for individuals with any single complication compared with those with newly diagnosed type 2 diabetes without complications was 2.24 (1.37, 3.69), and for individuals with two or more complications was 5.34 (3.01, 9.46).Co-existing Chronic kidney disease (CKD) and diabetic retinopathy (DR) at baseline were associated with the highest risk of death (HR 6.07[2.92-12.62]), followed by CKD and cardiovascular disease (CVD) (HR 4.98[2.79-8.89]) and CVD and DR (HR 4.58 [1.98-10.57]).

The presence of single and combined diabetes complications exerts a long-term synergistic adverse impact on overall mortality in newly diagnosed U.S. adults with type 2 diabetes, underscoring the importance of comprehensive complication screening to enhance risk stratification and treatment.

This review article explores the relationship between hyperglycemia during pregnancy and the visual development of offspring, specifically focusing on refractive error. The authors conducted a comprehensive search for relevant articles in various databases and assessed the methodological quality of the included studies. The findings consistently indicate that hyperglycemia during pregnancy can have a detrimental impact on the structural and functional aspects of visual development in offspring. The intrauterine hyperglycemic environment appears to negatively affect the retina and lens, leading to refractive errors. In conclusion, there is likely an association between hyperglycemia during pregnancy and the development of refractive errors in offspring.

The escalating prevalence of Type 2 Diabetes Mellitus (T2DM) overwhelms healthcare systems. Lifestyle interventions enhancing patient monitoring and adherence vary in efficacy, emphasizing the need to understand differential response across patient subgroups. This study aimed to segment patients with T2DM into distinct latent classes and identify characteristics associated with optimal 12-month glycated haemoglobin (HbA1c) reduction.

We prospectively recruited 1000 patients with T2DM from government-funded outpatient clinics in Singapore, aged ≥ 40-year-old with HbA1c ≥ 7.0 %. Exclusion criteria included insulin treatment and cognitive impairment. Latent class analysis was applied to 912 patients, using mHealth interventions, age, education, living arrangement, baseline HbA1c, step count, and motivation (Patient Activation Measure) as indicators. 12-Month HbA1c reduction was assessed with one-way ANOVA and pairwise T-test.

Within cohort, younger patients with higher education, physical activity, and baseline HbA1c exhibited the greatest HbA1c improvement (1.14 ± 1.79 %). Younger patients with lower education, despite high baseline HbA1c, exhibited a moderately lower HbA1c improvement (0.52 ± 1.41 %).

Individuals with higher baseline HbA1c, education, motivation, and activity levels experienced the most significant HbA1c reductions in response to lifestyle interventions. A tailored approach to these modifiable characteristics may help patients achieve substantial 12-month HbA1c reductions.

Vascular complications caused by diabetes mellitus contribute a major threat to increased disability and mortality of diabetic patients, which are characterized by damaged endothelial cells and angiogenesis. Human umbilical cord-derived mesenchymal stem cells (hucMSCs) have been demonstrated to alleviate endothelial cell damage and improve angiogenesis. However, these investigations overlooked the pivotal role of vasculogenesis. In this study, we utilized blood vessel organoids (BVOs) to investigate the impact of high glucose on vasculogenesis and subsequent angiogenesis. We found that BVOs in the vascular lineage induction stage were more sensitive to high glucose and more susceptible to affect endothelial cell differentiation and function. Moreover, hucMSCs can alleviate the high glucose-induced inhibition of endothelial cell differentiation and dysfunction through MAPK signaling pathway downregulation, with the MAPK activator dimethyl fumarate further illustrating the results. Thereby, we demonstrated that high glucose can lead to abnormal vasculogenesis and impact subsequent angiogenesis, and hucMSCs can alleviate this effect.

Glomerular endothelial cell (GENC) injury is a characteristic of early-stage diabetic nephropathy (DN), and the investigation of potential therapeutic targets for preventing GENC injury is of clinical importance.

To investigate the role of β-arrestin-2 in GENCs under DN conditions.

Eight-week-old C57BL/6J mice were intraperitoneally injected with streptozotocin to induce DN. GENCs were transfected with plasmids containing siRNA-β-arrestin-2, shRNA-activating transcription factor 6 (ATF6), pCDNA-β-arrestin-2, or pCDNA-ATF6. Additionally, adeno-associated virus (AAV) containing shRNA-β-arrestin-2 was administered via a tail vein injection in DN mice.

The upregulation of β-arrestin-2 was observed in patients with DN as well as in GENCs from DN mice. Knockdown of β-arrestin-2 reduced apoptosis in high glucose-treated GENCs, which was reversed by the overexpression of ATF6. Moreover, overexpression of β-arrestin-2 Led to the activation of endoplasmic reticulum (ER) stress and the apoptosis of GENCs which could be mitigated by silencing of ATF6. Furthermore, knockdown of β-arrestin-2 by the administration of AAV-shRNA-β-arrestin-2 alleviated renal injury in DN mice.

Knockdown of β-arrestin-2 prevents GENC apoptosis by inhibiting ATF6-mediated ER stress in vivo and in vitro. Consequently, β-arrestin-2 may represent a promising therapeutic target for the clinical management of patients with DN.

Diabetes mellitus is a chronic metabolic disease characterized by abnormally elevated blood glucose levels. Type II diabetes accounts for approximately 90% of all cases. Several drugs are available for hyperglycemia treatment. However, the current therapies for managing high blood glucose do not prevent or reverse the disease progression, which may result in complications and adverse effects, including diabetic neuropathy, retinopathy, and nephropathy. Hence, developing safer and more effective methods for lowering blood glucose levels is imperative. Transient receptor potential vanilloid-1 (TRPV1) is a significant member of the transient receptor potential family. It is present in numerous body tissues and organs and performs vital physiological functions.

This review aimed to develop new targeted TRPV1 hypoglycemic drugs by systematically summarizing the mechanism of action of the TRPV1-based signaling pathway in preventing and treating diabetes and its complications.

Literature searches were performed in the PubMed, Web of Science, Google Scholar, Medline, and Scopus databases for 10 years from 2013 to 2023. The search terms included "diabetes," "TRPV1," "diabetic complications," and "capsaicin."

TRPV1 is an essential potential target for treating diabetes mellitus and its complications. It reduces hepatic glucose production and food intake and promotes thermogenesis, metabolism, and insulin secretion. Activation of TRPV1 ameliorates diabetic nephropathy, retinopathy, myocardial infarction, vascular endothelial dysfunction, gastroparesis, and bladder dysfunction. Suppression of TRPV1 improves diabetes-related osteoporosis. However, the therapeutic effects of activating or suppressing TRPV1 may vary when treating diabetic neuropathy and periodontitis.

This review demonstrates that TRPV1 is a potential therapeutic target for diabetes and its complications. Additionally, it provides a theoretical basis for developing new hypoglycemic drugs that target TRPV1.

As the global incidence of diabetes rises and diagnoses among younger patients increase, transplant centers worldwide are encountering more organ donors with diabetes. This study examined 80 donors and 160 recipients, including 30 donors with diabetes (DD) and their 60 recipients (DDR). The control group comprised 50 non-diabetic donors (ND) and 100 recipients (NDR). We analyzed clinical, biochemical, and pathological data for both diabetic and control groups, using logistic regression to identify risk factors for delayed graft function (DGF) after kidney transplantation. Results showed that pre-procurement blood urea nitrogen levels were significantly higher in DD [18.20 ± 10.63 vs. 10.86 ± 6.92, p = 0.002] compared to ND. Renal pathological damage in DD was notably more severe, likely contributing to the higher DGF incidence in DDR compared to NDR. Although DDR had poorer renal function during the first three months post-transplant, both groups showed similar renal function thereafter. No significant differences were observed in 1-year or 3-year mortality rates or graft failure rates between DDR and NDR. Notably, according to the Renal Pathology Society (RPS) grading system, kidneys from diabetic donors with a grade > IIb are associated with significantly lower postoperative survival rates. Recipient gender [OR: 5.452 (1.330-22.353), p = 0.013] and pre-transplant PRA positivity [OR: 34.879 (7.698-158.030), p < 0.001] were identified as independent predictors of DGF in DDR. In conclusion, transplant centers may consider utilizing kidneys from diabetic donors, provided they are evaluated pathologically, without adversely impacting recipient survival and graft failure rates.

The pancreatic vasculature displays tissue-specific physiological and functional adaptations that support rapid insulin response by β-cells. However, the digestive enzymes have made it difficult to characterize pancreatic endothelial cells (ECs), resulting in the poor understanding of pancreatic EC specialization.

Available single-nuclei/single-cell RNA-sequencing data sets were mined to identify pancreatic EC-enriched signature genes and to develop an integrated atlas of human pancreatic ECs. We validated the findings using independent single-nuclei/single-cell RNA-sequencing data, bulk RNA-sequencing data of isolated ECs, spatial transcriptomics data, immunofluorescence, and RNAScope of selected markers. The NK2 homeobox 3 (NKX2-3) TF (transcription factor) was expressed in HUVECs via gene transfection, and the expression of pancreatic EC-enriched signature genes was assessed via RT-qPCR.

We defined a pancreatic EC-enriched gene signature conserved across species and developmental stages that included genes involved in ECM (extracellular matrix) composition (COL15A1 and COL4A1), permeability and barrier function (PLVAP, EHD4, CAVIN3, HSPG2, ROBO4, HEG1, and CLEC14A), and key signaling pathways (S1P [sphingosine-1-phosphate], TGF-β [transforming growth factor-β], RHO/RAC GTPase [guanosine triphosphatase], PI3K/AKT [phosphoinositide 3-kinase/protein kinase B], and PDGF [platelet-derived growth factor]). The integrated atlas revealed the vascular hierarchy within the pancreas. We identified and validated a specialized islet capillary subpopulation characterized by genes involved in permeability (PLVAP and EHD4), immune-modulation (FABP5, HLA-C, and B2M), ECM composition (SPARC and SPARCL1), IGF (insulin-like growth factor) signaling (IGFBP7), and membrane transport (SLCO2A1, SLC2A3, and CD320). Importantly, we identified NKX2-3 as a key TF enriched in pancreatic ECs. DNA-binding motif analysis found NKX2-3 motifs in ≈40% of the signature genes. Induction of NKX2-3 in HUVECs promoted the expression of the islet capillary EC-enriched genes PLVAP and SPARCL1.

We defined a validated transcriptomic signature of pancreatic ECs and uncovered their intratissue transcriptomic heterogeneity. We showed that NKX2-3 acts upstream of PLVAP and provided a single-cell online resource that can be further explored by the community: https://vasconcelos.shinyapps.io/pancreatic_endothelial/.

The treatment of diabetic wounds is impaired by the intricate nature of diabetes and its associated complications, necessitating novel strategies. The utilization of mesenchymal stem/stromal cells (MSCs) as a therapeutic modality for chronic and recalcitrant wounds in diabetic patients is an active area of investigation aimed at enhancing its therapeutic potential covering tissue regeneration. The threat posed to the patient and their environment by the presence of a diabetic foot ulcer (DFU) is so significant that any additional therapeutic approach that opens new pathways to halt the progression of local changes, which subsequently lead to a generalized inflammatory process, offers a chance to reduce the risk of amputation or even death. This article explores the potential of MSCs in diabetic foot ulcer treatment, examining their mechanisms of action, clinical application challenges, and future directions for research and therapy.

This study tested the hypothesis that administration of the KCa channel activator SKA-31 restores endothelium-dependent vasodilation in vivo in Type 2 Diabetic (T2D) rats.

Acute treatment of isolated resistance arteries from T2D rats and humans with SKA-31 significantly improved endothelium-dependent vasodilation. However, it is unknown whether these in situ actions translate to intact vascular beds in vivo.

Male Sprague Dawley (SD) and T2D Goto-Kakizaki (GK) rats (26-32 weeks of age) were injected intraperitoneally with either drug vehicle or 10 mg/kg SKA-31. Doppler ultrasound imaging was used to record reactive hyperemia/flow-mediated dilation (FMD) in the femoral artery following release of an occlusion cuff on the distal hind limb, along with diameter changes in the left main coronary artery in response to inhaled isoflurane (2 % → 5 %).

Vehicle treated SD rats exhibited a robust and reversible FMD response, the magnitude and time course of which did not differ in SD rats treated with SKA-31. In contrast, only a weak FMD response was observed in vehicle-treated T2D GK rats, whereas prior SKA-31 administration restored FMD to the level observed in control SD rats. Exposure of SD rats to 5 % isoflurane caused robust coronary artery dilation, which was not altered by prior treatment with SKA-31. In T2D GK rats, 5 % isoflurane inhalation alone did not increase coronary artery diameter, however, a strong vasodilatory response was observed following SKA-31 treatment. SKA-31 administration did not modify intrinsic heart rate responses in either protocol.

Enhancement of KCa channel activity in vivo restores endothelium-dependent vasodilation in T2D rats that exhibit peripheral endothelial dysfunction.

Endothelial dysfunction exacerbates hypertension and other vascular complications in diabetes mellitus (DM). Circulating microparticles (MPs) and extracellular vesicles released in patients with DM have emerged as novel regulators of endothelial dysfunction. The obstruction of mineralocorticoid receptors (MRs) is a potential therapeutic approach to reduce cardiovascular complications. Their impact on the obstruction of MRs on circulating MPs and endothelial dysfunction in DM remains unclear. DM was induced in mice through a single intravenous dose of streptozotocin (STZ; 200 mg/kg). Esaxerenone (ESAX; 3 mg/kg/day), a MR blocker was administered via diet for 8 weeks. In this study, the aortas of the DM group showed the endothelial dysfunction and the administration of ESAX ameliorated the endothelial-dependent responses. Moreover, ESAX influences the impaired endothelial-dependent responses of DM-derived MPs. Interestingly, MP levels increased in DM whereas decreased after ESAX administration. In the aorta, the DM-derived MPs increased the expression of intercellular adhesion molecule-1 (ICAM-1). ESAX inhibited the adhesion of DM-derived MPs. Moreover, the ICAM-1 inhibitor A205804 shows similar effects as ESAX. These results indicate that the release and adhesion properties of MPs can be partially obstructed by ESAX via the ICAM-1 signaling pathway, which clarifies the other functions beyond the anti-hypertensive effects of ESAX.

Diabetes mellitus is a metabolic disease with an escalating global prevalence. Despite the abundance and relative efficacies of current therapeutic approaches, they primarily focus on attaining the intended glycaemic targets, but patients ultimately still suffer from various diabetes-associated complications such as retinopathy, nephropathy, cardiomyopathy, and atherosclerosis. There is a need to explore innovative and effective diabetic treatment strategies that not only address the condition itself but also combat its complications. One promising option is the reproductive hormone relaxin, an endogenous ligand of the RXFP1 receptor. Relaxin is known to exert beneficial actions on the cardiovascular system through its vasoprotective, anti-inflammatory and anti-fibrotic effects. Nevertheless, the native relaxin peptide exhibits a short biological half-life, limiting its therapeutic potential. Recently, several relaxin mimetics and innovative delivery technologies have been developed to extend its biological half-life and efficacy. The current review provides a comprehensive landscape of the cardiovascular effects of relaxin, focusing on its potential therapeutic applications in managing complications associated with diabetes. The latest advancements in the development of relaxin mimetics and delivery methods for the treatment of cardiometabolic disorders are also discussed.

The pancreatic islet vasculature comprises microvascular endothelial cells surrounded by mural cells (pericytes). Both cell types support the islet by providing (1) a conduit for delivery and exchange of nutrients and hormones; (2) paracrine signals and extracellular matrix (ECM) components that support islet development, architecture, and endocrine function; and (3) a barrier against inflammation and immune cell infiltration. In type 2 diabetes, the islet vasculature becomes inflamed, showing loss of endothelial cells, detachment, and/or trans-differentiation of pericytes, vessel dilation, and excessive ECM deposition. While most work to date has focused either on endothelial cells or pericytes in isolation, it is very likely that the interaction between these cell types and disruption of that interaction in diabetes are critically important. In fact, dissociation of pericytes from endothelial cells is an early, key feature of microvascular disease in multiple tissues/disease states. Moreover, in beta-cell replacement therapy, co-transplantation with microvessels versus endothelial cells alone is substantially more effective in improving survival and function of the transplanted cells. Ongoing studies, including characterization of islet vascular cell signatures, will aid in the identification of new therapeutic targets aimed at improving islet function and benefiting people living with all forms of diabetes.

Background: Type 2 diabetes mellitus (T2DM) and its consequences are a serious global public health issue. By 2030, the number of people with type 2 diabetes is predicted to reach 439 million. The purpose of this study is to evaluate the plasma levels of glucose, HbA1c, insulin, and lipid profile in Sudanese T2DM patients. Methods: This case control study included 165 Sudanese patients with diabetic type 2 and a cardiovascular condition as cases and 165 diabetic type 2 volunteers without a cardiovascular disorder as controls. The concentrations of plasma glucose, HbA1c, and lipid profile were assessed using a Mindray BS-480 auto-chemistry analyzer, and insulin was analyzed using a Cobase 411 auto analyzer. The collected data were analyzed using statistical tools for social science computer programs (SPSS version 21). Results: According to the findings, (59.4%) of patients between the ages of (50-69). Females made up 50.9%. (38.2%) of patients had an illness duration of between (8-15 years). (41.8%) of individuals did not have hypertension. There was a substantial rise in BMI, FBG, HbA1c, HDL-C, and insulin among diabetics with cardiovascular disease compared to diabetics without cardiovascular disease (p-value = 0.001, 0.000, 0.018, and 0.000). Females had significantly higher blood TC, LDL-C, HDL-C, and BMI than males (p-values = 0.000, 0,001, and 0.000, respectively). There were significant positive correlation between FBS, HBA1c, insulin and duration of disease (r=0.155, p, value=0.005) (r=0.160, p, value=0.004)(r=0.103, p. value=0.061)respectively, while there were significant negative correlation between TC, TG,LDL-C, HDL-C and duration of disease (r=-0.152, p, value= 0.006)(r=-0.023, p, value=0.678)(r=-0.113, p, value= 0.040)(r=-0.145, p, value=0.008)respectively. Conclusion: When comparing diabetics with cardiovascular disease to diabetics without cardiovascular disease, there was a substantial rise in BMI, FBG, HbA1c, HDL-C, and insulin. FBS, HBA1c, insulin, and illness duration all had a strong positive connection.

To compare the acute response of moderate intensity continuous exercise (MICE) vs moderate intensity interval exercise (MIIE) on endothelial function, post-exercise hypotension (PEH), and glycemia in type 2 diabetes (T2DM) with hypertension.

Twelve T2DM (aged 52.8 ± 3.8 years old) patients with hypertension underwent a randomized cross-over study following isocaloric (200 kcal) protocols: (i) MICE: walk-jogging at 50% of VO2peak, (ii) MIIE session: walking - jogging (stimulus/recovery - 3:3 min each) at 60% of VO2peak followed by recovery at 40% of VO2peak, and (iii) control (CON): lying quietly in a supine position for 30 min. A generalized estimating equation was utilized to verify possible differences over time × session.

The %FMD (Baseline: 3.59 ± 1.58 vs. 30 min: 6.73 ± 4.34) and the absolute FMD changed after MIIE (Baseline: 0.16 ± 0.10 vs. 30 min: 0.17 ± 0.14). Only absolute FMD changed after MIIE (Baseline: 0.14 ± 0.07 vs. 30 min: 0.16 ± 0.07). Besides, MIIE at 30 min provides higher absolute FMD values when compared to baseline from MICE and baseline, 30 min, and 60 min from control. Regarding blood pressure, no PEH statistical main effect was found. Finally, the glycemia changed at baseline vs. 30 min and 60 min after MIIE (210.5 ± 9.4 vs. 127.6 ± 10.0 and 120 ± 8.9), MICE (219.5 ± 12.7 vs. 125.2 ± 12.0 and 118.2 ± 11.6), and control sessions (215.9 ± 11.8 vs. 187.4 ± 11.2 and 172.6 ± 11.3 mg/dL, p < 0.05). However, MIIE and MICE showed higher decreases compared to the control.

MIIE and MICE sessions are similar and effective exercise strategies to induce changes in endothelial function and glycemic responses in type-2 diabetics with hypertension.

Polymetabolic syndrome achieved pandemic proportions and dramatically influenced public health systems functioning worldwide. Chronic vascular complications are the major contributors to increased morbidity, disability, and mortality rates in diabetes patients. Nitric oxide (NO) is among the most important vascular bed function regulators. However, NO homeostasis is significantly deranged in pathological conditions. Additionally, different hormones directly or indirectly affect NO production and activity and subsequently act on vascular physiology. In this paper, we summarize the recent literature data related to the effects of insulin, estradiol, insulin-like growth factor-1, ghrelin, angiotensin II and irisin on the NO regulation in physiological and diabetes circumstances.

Since the discovery of nitric oxide (NO), a long journey has led us to the present, during which much knowledge has been gained about its pathway members and their roles in physiological and various pathophysiological conditions. Soluble guanylyl cyclase (sGC), the main NO receptor composed of the sGCα1 and sGCβ1 subunits, has been one of the central figures in this narrative. However, the sGCα1 and sGCβ1 subunits remained obscured by the focus on sGC's enzymatic activity for many years. In this review, we restore the significance of the sGCα1 and sGCβ1 subunits by compiling and analyzing available but previously overlooked information regarding their roles beyond enzymatic activity. We delve into the basics of sGC expression regulation, from its transcriptional regulation to its interaction with proteins, placing particular emphasis on evidence thus far demonstrating the actions of each sGC subunit in different tumor models. Exploring the roles of sGC subunits in cancer offers a valuable opportunity to enhance our understanding of tumor biology and discover new therapeutic avenues.