Endothelial extracellular vesicles: their possible function and clinical significance in diabetic vascular complications.

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

Diabetic microvascular disease in non-classical beds: the hidden impact beyond the retina, the kidney, and the peripheral nerves.

Diabetes microangiopathy, a hallmark complication of diabetes, is characterised by structural and functional abnormalities within the intricate network of microvessels beyond well-known and documented target organs, i.e., the retina, kidney, and peripheral nerves. Indeed, an intact microvascular bed is crucial for preserving each organ's specific functions and achieving physiological balance to meet their respective metabolic demands. Therefore, diabetes-related microvascular dysfunction leads to widespread multiorgan consequences in still-overlooked non-traditional target organs such as the brain, the lung, the bone tissue, the skin, the arterial wall, the heart, or the musculoskeletal system. All these organs are vulnerable to the physiopathological mechanisms that cause microvascular damage in diabetes (i.e., hyperglycaemia-induced oxidative stress, inflammation, and endothelial dysfunction) and collectively contribute to abnormalities in the microvessels' structure and function, compromising blood flow and tissue perfusion. However, the microcirculatory networks differ between organs due to variations in haemodynamic, vascular architecture, and affected cells, resulting in a spectrum of clinical presentations. The aim of this review is to focus on the multifaceted nature of microvascular impairment in diabetes through available evidence of specific consequences in often overlooked organs. A better understanding of diabetes microangiopathy in non-target organs provides a broader perspective on the systemic nature of the disease, underscoring the importance of recognising the comprehensive range of complications beyond the classic target sites.

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

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

Common mechanisms underlying diabetic vascular complications: focus on the interaction of metabolic disorders, immuno-inflammation, and endothelial dysfunction.

Diabetic vascular complications (DVCs), including macro- and micro- angiopathy, account for a high percentage of mortality in patients with diabetes mellitus (DM). Endothelial dysfunction is the initial and role step for the pathogenesis of DVCs. Hyperglycemia and lipid metabolism disorders contribute to endothelial dysfunction via direct injury of metabolism products, crosstalk between immunity and inflammation, as well as related interaction network. Although physiological and phenotypic differences support their specified changes in different targeted organs, there are still several common mechanisms underlying DVCs. Also, inhibitors of these common mechanisms may decrease the incidence of DVCs effectively. Thus, this review may provide new insights into the possible measures for the secondary prevention of DM. And we discussed the current limitations of those present preventive measures in DVCs research. Video Abstract.

Noncoding RNAs involved in DNA methylation and histone methylation, and acetylation in diabetic vascular complications.

Diabetes is a metabolic disorder and its incidence is still increasing. Diabetic vascular complications cause major diabetic mobility and include accelerated atherosclerosis, nephropathy, retinopathy, and neuropathy. Hyperglycemia contributes to the pathogenesis of diabetic vascular complications via numerous mechanisms including the induction of oxidative stress, inflammation, metabolic alterations, and abnormal proliferation of EC and angiogenesis. In the past decade, epigenetic modifications have attracted more attention as they participate in the progression of diabetic vascular complications despite controlled glucose levels and regulate gene expression without altering the genomic sequence. DNA methylation and histone methylation, and acetylation are vital epigenetic modifications and their underlying mechanisms in diabetic vascular complication are still urgently needed to be investigated. Non-coding RNAs (nc RNAs) such as micro RNAs (miRNAs), long non-coding RNA (lncRNAs), and circular RNAs (circ RNAs) were found to exert transcriptional regulation in diabetic vascular complication. Although nc RNAs are not considered as epigenetic components, they are involved in epigenetic modifications. In this review, we summarized the investigations of non-coding RNAs involved in DNA methylation and histone methylation and acetylation. Their cross-talks might offer novel insights into the pathology of diabetic vascular complications.

Thiamine pyrophosphate improved vascular complications of diabetes in rats with type 2 diabetes by reducing glycation, oxidative stress, and inflammation markers.

Background: Thiamine deficiency contributes to hyperglycemia and diabetes complications. Thus, in this study, the effect of thiamine pyrophosphate (TPP) on the in vivo and in vitro formation of glycation, oxidative stress, and inflammatory markers (the main contributors of vascular diabetes complications) was examined in type 2 diabetes rat model. Methods: Type 2 diabetes was induced in rats with a combination of streptozotocin and nicotinamide (55+200 mg/kg). Two groups of rats, healthy and diabetic, were treated with 0.1% TPP in drinking water daily for 3 months and the 2 others received water only. The glucose, insulin, early to end glycation products, the activity of glyoxalase system, lipid profile, LDL oxidation markers, inflammatory markers, creatinine in the serum, and proteinuria in the urine of all rats were determined. Moreover, albumin and LDL were incubated with glucose in the presence and absence of TPP, and the samples were investigated for glycation and oxidation products. Different variables in all 4 groups were compared with multiple analysis of variance (MANOVA-Tukey) test using SPSS version 16. Significance level was set at p<0.05. Results: TPP decreased the formation of diverse glycation and oxidation products in both in vivo (glycated LDL= 144.50±3.48 and oxidized LDL= 54.08±2.67 µmol/l) and in vitro (glycated LDL= 107.00±2.82 and oxidized LDL= 50.83±1.22 µmol/l). In addition, the vitamin reduced fasting blood sugar (9.23±0.29), insulin resistance (9.10±0.50), tumor necrosis factor-α (285.43±15.97), interleukin-6 (257.65±13.06), and improved the lipid profile, the activity of Glo system (Glo-I= 31.65±1.06 and Glo-II= 27.01±0.90 U/mL) and renal function in the diabetic rat (p<0.001). Conclusion: TPP decreased the major risk factors for diabetic complications and corrected the alternations of glucose and lipid metabolism in type 2 diabetic rats; thus, it is recommended for diabetes treatment.

Investigation of galectin-3 levels in diabetic foot ulcers.

OBJECTIVE: It has been shown that galectin-3 (Gal-3) promotes angiogenesis and new vessel formation. Serum Gal-3 is a risk factor for vascular complications in type 2 diabetes. The aim of this study is to compare Gal-3 levels with a range of biochemical parameters. METHOD: A prospective study consisted of individuals as a control group (group 1), patients diagnosed with type 2 diabetes without DFUs (group 2), and patients with type 2 diabetes with a DFU (group 3). Patient levels of endothelin-1 (ET-1), vascular endothelial growth factor-A (VEGF-A), nitric oxide (NO), and Gal-3 were measured. RESULTS: In total, 91 patients participated, (28 male, 63 female with a mean age of 55.83±6.35 years) Mean ET-1 (39.0±16.9), NO (17.6±7.6), VEGF-A (33.5±13.4) and Gal-3 (535.1±420.5) levels were significantly higher in group 3 compared with the other two groups (p<0.01). Furthermore, the Gal-3 level was positively and statistically significantly correlated with C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), ET-1 and NO levels in all groups. CONCLUSION: In our study, the level of Gal-3 was shown to be positively correlated with the VEGF-A level. Hence, Gal-3 can be considered as a defence mechanism against complications of diabetes, thus contributing to wound healing. Gal-3 may play a critical role in DFU formation and progression. Moreover, it could be suggested that Gal-3 may give an indication of prognosis, as it elevates VEGF-A levels and stimulates angiogenesis. Further studies are required to confirm the findings of this study.

Effect of crocetin on vascular smooth muscle cells migration induced by advanced glycosylation end products.

Crocetin is a major active constituent of Gardenia jasminoides J. Ellis, and can aid in the prevention of cardiovascular disease. The effect and possible mechanism of crocetin on the migration of vascular smooth muscle cells (VSMCs) induced by advanced glycosylation end products (AGEs) were investigated. VSMCs were pre-incubated with or without crocetin and exposed to AGEs subsequently. The invasion of the cells was investigated using a 24-well Cell Invasion Chamber. The anti-proliferative activity of crocetin was evaluated by MTT assay and VSMCs cell-cycle distribution was examined by flow cytometry. Cytokine TNF-α and IL-6 secreted by VSMCs and the amount of matrix metalloproteinase MMP-2 and MMP-9 in the culture supernatant were detected by ELISA. The expression level of RAGE (AGEs receptor), in cells was analyzed by western blot. The results demonstrated that AGEs increased about two-fold migration of VSMCs compared with control (OD=0.778±0.191 vs OD=0.413±0.214, P<0.01), and the proliferation increased by about 20% (OD=0.335±0.043 vs OD=0.281±0.037, P<0.01). Pre-treatment with crocetin (1.0µM) or RAGE antibody (10µg/ml) could inhibit the AGEs triggered migration of VSMCs obviously. Furthermore, both crocetin and RAGE antibody inhibited the increase of RAGE protein in VSMCs stimulated by AGEs. The levels of TNF-α and IL-6 decreased in the crocetin (1.0µM) pre-treated group compared to the AGEs (without pre-treated) group (37.60±3.08pg/ml vs 46.59±1.92pg/ml, 32.11±4.69pg/ml vs 49.99±8.84pg/ml, respectively). Crocetin (1.0µM) also reduced the value of MMP-2 and MMP-9 compared with the AGEs group (2.81±0.35ng/ml vs 6.40±0.85ng/ml, 2.69±0.25ng/ml vs 4.32±0.57ng/ml, respectively). In summary, crocetin inhibits the migration of VSMCs induced by AGEs through RAGE-dependent signaling pathway. And it is meaningful to diabetic vascular complications.

O-GlcNAcase overexpression reverses coronary endothelial cell dysfunction in type 1 diabetic mice.

Cardiovascular disease is the primary cause of morbidity and mortality in diabetes, and endothelial dysfunction is commonly seen in these patients. Increased O-linked N-acetylglucosamine (O-GlcNAc) protein modification is one of the central pathogenic features of diabetes. Modification of proteins by O-GlcNAc (O-GlcNAcylation) is regulated by two key enzymes: ß-N-acetylglucosaminidase [O-GlcNAcase (OGA)], which catalyzes the reduction of protein O-GlcNAcylation, and O-GlcNAc transferase (OGT), which induces O-GlcNAcylation. However, it is not known whether reducing O-GlcNAcylation can improve endothelial dysfunction in diabetes. To examine the effect of endothelium-specific OGA overexpression on protein O-GlcNAcylation and coronary endothelial function in diabetic mice, we generated tetracycline-inducible, endothelium-specific OGA transgenic mice, and induced OGA by doxycycline administration in streptozotocin-induced type 1 diabetic mice. OGA protein expression was significantly decreased in mouse coronary endothelial cells (MCECs) isolated from diabetic mice compared with control MCECs, whereas OGT protein level was markedly increased. The level of protein O-GlcNAcylation was increased in diabetic compared with control mice, and OGA overexpression significantly decreased the level of protein O-GlcNAcylation in MCECs from diabetic mice. Capillary density in the left ventricle and endothelium-dependent relaxation in coronary arteries were significantly decreased in diabetes, while OGA overexpression increased capillary density to the control level and restored endothelium-dependent relaxation without changing endothelium-independent relaxation. We found that connexin 40 could be the potential target of O-GlcNAcylation that regulates the endothelial functions in diabetes. These data suggest that OGA overexpression in endothelial cells improves endothelial function and may have a beneficial effect on coronary vascular complications in diabetes.

SGLT inhibitors attenuate NO-dependent vascular relaxation in the pulmonary artery but not in the coronary artery.

Inhibitors of sodium-glucose cotransporter (SGLT)2 are a new class of oral drugs for type 2 diabetic patients that reduce plasma glucose levels by inhibiting renal glucose reabsorption. There is increasing evidence showing the beneficial effect of SGLT2 inhibitors on glucose control; however, less information is available regarding the impact of SGLT2 inhibitors on cardiovascular outcomes. The present study was designed to determine whether SGLT inhibitors regulate vascular relaxation in mouse pulmonary and coronary arteries. Phlorizin (a nonspecific SGLT inhibitor) and canagliflozin (a SGLT2-specific inhibitor) relaxed pulmonary arteries in a dose-dependent manner, but they had little or no effect on coronary arteries. Pretreatment with phlorizin or canagliflozin significantly inhibited sodium nitroprusside (SNP; a nitric oxide donor)-induced vascular relaxation in pulmonary arteries but not in coronary arteries. Phlorizin had no effect on cGMP-dependent relaxation in pulmonary arteries. SNP induced membrane hyperpolarization in human pulmonary artery smooth muscle cells, and pretreatment of cells with phlorizin and canagliflozin attenuated SNP-induced membrane hyperpolarization by decreasing K(+) activities induced by SNP. Contrary to the result observed in ex vivo experiments with SGLT inhibitors, SNP-dependent relaxation in pulmonary arteries was not altered by chronic administration of canagliflozin. On the other hand, canagliflozin administration significantly enhanced SNP-dependent relaxation in coronary arteries in diabetic mice. These data suggest that SGLT inhibitors differentially regulate vascular relaxation depending on the type of arteries, duration of the treatment, and health condition, such as diabetes.

Evaluation of salivary glycopatterns based diagnostic models for prediction of diabetic vascular complications.

Diabetic vascular complications (DVC) are the main cause of death in diabetic patients. However, there is a lack of effective biomarkers or convenient methods for early diagnosis of DVC. In this study, the salivary glycopatterns from 130 of healthy volunteers (HV), 139 patients with type 2 diabetes mellitus (T2DM) and 167 patients with DVC were case-by-case analyzed by using lectin microarrays. Subsequently, diagnostic models were developed using logistic regression and machine learning algorithms based on the data of lectin microarrays in training set. The performance of diagnostic models was evaluated in an independent blind cohort. The results of lectin microarrays indicated that the glycopatterns identified by 16 lectins (e.g. BS-I, PWM and EEL) were significantly altered in DVC patients compared with patients with T2DM, which suggested the alterations in salivary glycopatterns could reflect onset of DVC. Notably, K-Nearest Neighbor (KNN) model exhibited better performance for distinguishing DVC (accuracy: 0.939) than other models in blind cohort. The integrated classifier, which combined three machine learning models, exhibited a higher overall accuracy (≥ 0.933) than other models in blind cohort. Our study provided a cost-effective and non-invasive method for auxiliary diagnosis DVC based on the combination of salivary glycopatterns and machine learning algorithms.

Network pharmacology, molecular docking, and in vitro experimental verification of the mechanism of Guanxining in treating diabetic atherosclerosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Guanxinning(GXN) tablet is a patented traditional Chinese medicine widely used to prevent and treat cardiovascular diseases. However, its potential mechanism and target in anti-diabetic atherosclerosis have not been clarified. AIM: The aim of this study was to investigate the underlying targets and mechanisms of action GXN in the treatment of diabetic atherosclerosis, employing a combination of network pharmacology, molecular docking, and in vitro experimental verification. METHODS: We predicted the core components and targets of GXN in the treatment of diabetic atherosclerosis through various databases, and made analysis and molecular docking. In vitro, we induced injury in human umbilical vein endothelial cells using glucose/palmitate and observed the effects of GXN on cellular damage high-glucose and high-fat conditions, subsequently elucidating its molecular mechanisms. RESULTS: A total of 14 active components and 157 targets of GXN were identified. Using the PPI network, we selected 9 core active components and 20 targets of GXN. GO functional analysis revealed that these targets were primarily associated with apoptosis signaling pathways in response to endoplasmic reticulum stress and reactive oxygen species responses. Molecular docking confirmed the strong binding affinities of the primary active components of GXN with ERN1, MAPK1 and BECN1. In vitro experiments demonstrated the ability of GXN to restore endothelial cell activity, enhance cell migration and inhibit sICAM secretion, and upregulate the expression of endoplasmic reticulum stress-related proteins (IRE1, XBP1) and autophagy-related proteins (Beclin1, LC3A, and LC3B), while simultaneously inhibiting endothelial cell apoptosis under high-glucose and high-fat conditions. CONCLUSIONS: Our findings suggest that GXN can potentially safeguard endothelial cells from the adverse effects of high-glucose and high-fat by modulating the interactions between endoplasmic reticulum stress and autophagy. Therefore, GXN is a promising candidate for the prevention and treatment of diabetic atherosclerosis.

Traditional Chinese medicine and its active substances reduce vascular injury in diabetes via regulating autophagic activity.

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

Aldose reductase inhibitory and antiglycation properties of phytoconstituents of Cichorium intybus: Potential therapeutic role in diabetic retinopathy.

Diabetic vascular complication including diabetic retinopathy is a major morbidity in Saudia Arabia. The polyol pathway aka aldose reductase (AR) pathway has gained significant association with diabetic retinopathy with regard to chronically enhanced glucose metabolism. Considerable research has been put forth to develop more effective therapeutic strategies to overcome the overwhelming challenges of vascular complications associated with diabetes. In this regard, constituents of Cichorium intybus can offer strong AR inhibitory potential because of their strong antidiabetic properties. Therefore, aim of this study was to investigate the AR inhibitory as well as antiglycation potential of C. intybus extract/compounds. The preliminary in vitro results showed that methanolic extract of C. intybus could significantly inhibit AR enzyme and advanced glycation end product formation. Eventually, based on previous studies and reviews, we selected one hundred fifteen C. intybus root constituents and screened them through Lipinski's rule of five and ADMET analysis. Later, after molecular docking analysis of eight compounds, five best were selected for molecular dynamics simulation to deduce their binding affinity with the AR enzyme. Finally, three out of five compounds were further tested in vitro for their AR inhibitory potential and antiglycation properties. Enzyme assay and kinetic studies showed that all the three tested compounds were having potent AR inhibitory properties, although to a lesser extent than ellagic acid and tolrestat. Similarly, kaempferol showed strong antiglycation property equivalent to ellagic acid, but greater than aminoguanidine. Intriguingly, significant reduction in sorbitol accumulation in RBCs by the tested compounds substantiated strong AR inhibition by these compounds. Moreover, decrease in sorbitol accumulation under high glucose environment also signifies the potential application of these compounds in diabetic retinopathy and other vascular complications. Thus, in sum, the in silico and in vitro studies combinedly showed that C. intybus root is a treasure for therapeutic compounds and can be explored further for drug development against diabetic retinopathy.

Endothelial progenitor cells as biomarkers of diabetes-related cardiovascular complications.

Diabetes mellitus (DM) constitutes a chronic metabolic disease characterized by elevated levels of blood glucose which can also lead to the so-called diabetic vascular complications (DVCs), responsible for most of the morbidity, hospitalizations and death registered in these patients. Currently, different approaches to prevent or reduce DM and its DVCs have focused on reducing blood sugar levels, cholesterol management or even changes in lifestyle habits. However, even the strictest glycaemic control strategies are not always sufficient to prevent the development of DVCs, which reflects the need to identify reliable biomarkers capable of predicting further vascular complications in diabetic patients. Endothelial progenitor cells (EPCs), widely known for their potential applications in cell therapy due to their regenerative properties, may be used as differential markers in DVCs, considering that the number and functionality of these cells are affected under the pathological environments related to DM. Besides, drugs commonly used with DM patients may influence the level or behaviour of EPCs as a pleiotropic effect that could finally be decisive in the prognosis of the disease. In the current review, we have analysed the relationship between diabetes and DVCs, focusing on the potential use of EPCs as biomarkers of diabetes progression towards the development of major vascular complications. Moreover, the effects of different drugs on the number and function of EPCs have been also addressed.

Ethnic disparities of vascular complications in pre-diabetes, undiagnosed diabetes, and newly diagnosed diabetes.

In the U.S., ethnic minorities with pre-diabetes, undiagnosed type 2 diabetes (T2D), and newly diagnosed T2D had a higher prevalence of microvascular complications than non-Hispanic Whites and exhibited distinct risk factors, whereas Whites had a higher rate of cardiovascular disease.

Nox4 as a novel therapeutic target for diabetic vascular complications.

Diabetic vascular complications can affect both microvascular and macrovascular. Diabetic microvascular complications, such as diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, and diabetic cardiomyopathy, are believed to be caused by oxidative stress. The Nox family of NADPH oxidases is a significant source of reactive oxygen species and plays a crucial role in regulating redox signaling, particularly in response to high glucose and diabetes mellitus. This review aims to provide an overview of the current knowledge about the role of Nox4 and its regulatory mechanisms in diabetic microangiopathies. Especially, the latest novel advances in the upregulation of Nox4 that aggravate various cell types within diabetic kidney disease will be highlighted. Interestingly, this review also presents the mechanisms by which Nox4 regulates diabetic microangiopathy from novel perspectives such as epigenetics. Besides, we emphasize Nox4 as a therapeutic target for treating microvascular complications of diabetes and summarize drugs, inhibitors, and dietary components targeting Nox4 as important therapeutic measures in preventing and treating diabetic microangiopathy. Additionally, this review also sums up the evidence related to Nox4 and diabetic macroangiopathy.

Correlation Between Blood Glucose Indexes Generated by the Flash Glucose Monitoring System and Diabetic Vascular Complications.

Objective: To discuss the relationship between time in range (TIR) which is deprived of the FGMS and the risk of diabetic vascular complications and to provide a theoretical foundation for the clinical application of TIR and other FGMS-deprived indexes. Methods: Patients with T2DM who wore the FGMS sensor continuously were enrolled. Relevant indexes such as TIR, time below range (TBR), time above range (TAR), a standard deviation of blood glucose (SDBG), coefficient of variation of blood glucose (CV), and mean amplitude of glycemic excursion (MAGE) generated by the FGMS were recorded, and the risk of diabetic vascular complications were followed up for one year. The TIR was measured by continuous glucose monitoring at baseline, and patients were grouped according to TIR every 20%. Finally, the Cox proportional hazards regression model was used to estimate the association of different levels of TIR with different rates of diabetic vascular complications. Results: TIR was negatively correlated with HbA1C, CV, SDBG, and amplitude of glycemic excursion (MV), wherein, the lower the TIR, the higher the HbA1C, CV, SDBG, and MV. TIR in the diabetic microvascular complication was significantly lower than that in the non-microvascular complication group, and the difference was statistically significant. TIR <40% was identified as a risk factor for DN, DPN, and DR according to the risk assessment. The mean TAR in the DN group was significantly higher than that in the non-DN group. TAR, CV, SD, MAGE, and HbA1C in the DR group were significantly higher than those in the non-DR group. TAR, ABG, CV, SD, MAGE, and HbA1C in the DPN group were significantly higher than those in the non-DPN group. Conclusion: The relationships between the TIR and the prevalence and risk of diabetic vascular complications and the HbA1C may be negative. Other CGM-deprived indexes such as CV and MV should be integrated into glycemic control and diabetes complication prediction.

Associations of Obesity Indices with Bone Mineral Densities and Risk of Osteoporosis Stratified Across Diabetic Vascular Disease in T2DM Patients.

Objective: To evaluate associations of obesity indices with bone mineral densities (BMD) and risk of osteoporosis in T2DM patients totally and stratified across presence of any diabetic cardiovascular complications. Methods: Cross-sectional analyses of baseline information on a cohort of 250 T2DM patients were conducted in Xiamen, China. Obesity indices included body weight, height, body mass index (BMI), waist and waist hip ratio (WHR). BMD was measured using dual-energy X-ray absorptiometry at three different sites, and osteoporosis was defined based on the minimum T-scores of BMD. Presence of any diabetic vascular complications was confirmed by checking their medical records histories. Results: Among the 250 T2DM patients, 50 (20.0%) were defined as osteoporosis. Multivariable linear regression and multivariable logistic regression analyses showed that igher obesity indices, including body weight, BMI and waist, but neither body height nor waist hip ratio, were positively associated with the minimum T-scores of BMD and had significantly decreased risk of osteoporosis. Stratified analyses across presence of any of diabetic vascular complications showed similar results for those with any of diabetic vascular complications, while no significant association between obesity indices and minimum T-scores of BMD was found for those without. Postmenopausal women (vs men) and ever drinking were significantly associated with increased risk of osteoporosis, and the adjusted odds ratios (95% CIs) were 5.165 (1.762-15.138, p = 0.003) and 3.789 (1.087-13.214, p = 0.037), respectively. None of metabolic profiles, including systolic and diastolic blood pressure, triglyceride, total cholesterol, high-density lipoprotein cholesterol, HbA1c and blood uric acid, was significantly associated with either minimum T-scores of BMD or risk of osteoporosis. Conclusion: Associations of obesity indices with either BMD or risk of osteoporosis in T2DM patients varied by presence of any diabetic vascular complication and should be not interpreted as causal without considering the often-unmeasured effect modification by health status.

Association of Time in Range with Endothelial Injury in Patients with Type 2 Diabetes Treated with Exenatide.

INTRODUCTION: We aimed to investigate whether treatment with exenatide could increase time in range (TIR) and decrease glycemic variability, and to evaluate the association between TIR and endothelial injury in patients with type 2 diabetes mellitus (T2DM). METHODS: Two-hundred patients with T2DM treated with exenatide for 16 weeks were included in this study. Seven-point fingerstick blood glucose was used to evaluate derived TIR and glycemic variability. The serum levels of soluble endothelial cell protein C receptor (sEPCR) and von Willebrand factor (vWF) were measured. Ninety-three patients having the data of endothelial injury markers were categorized as derived TIR > 70% or ≤ 70% after the treatment and the association between TIR and endothelial injury were evaluated. RESULTS: Treatment with exenatide for 16 weeks resulted in a significant reduction in fasting blood glucose, postprandial 2 h blood glucose, and glycated hemoglobin A1c (HbA1c) levels in patients with T2DM. Compared with baseline, derived TIR value was significantly increased [85.7 (57.1, 100.0) % vs. 42.9 (14.9, 71.4) %, P < 0.001], and the parameters of glycemic variability were remarkably decreased after the treatment. After the treatment, serum sEPCR level was significantly decreased from baseline in patients with TIR > 70% [74.5 (32.8, 122.5) ng/mL vs. 96.9 (48.5, 150.9) ng/mL, P = 0.006] but not in those with TIR ≤ 70%; serum vWF level was remarkably decreased in patients with TIR > 70% [from 1166.2 (848.1, 1335.5) mIU/mL to 907.4 (674.3, 1335.1) mIU/mL, P = 0.001] while this effect was modest in those with TIR ≤ 70%. CONCLUSIONS: Treatment with exenatide increases TIR and decreases glycemic variability in patients with T2DM. Moreover, the amelioration of endothelial injury is more pronounced in patients with TIR > 70% after the treatment. TRIAL REGISTRATION: ChiCTR-IPR-15006558 (registered, 27 May 2015).