Plasma copeptin and markers of arterial disorder in patients with type 2 diabetes, a cross-sectional study.

OBJECTIVES: There is currently limited understanding of the relationship between copeptin, the midregional portion of proadrenomedullin (MRproADM) and the midregional fragment of the N-terminal of proatrial natriuretic peptide (MRproANP), and arterial disorders. Toe brachial index (TBI) and aortic pulse wave velocity (aPWV) are established parameters for detecting arterial disorders. This study evaluated whether copeptin, MRproADM, and MRproANP were associated with TBI and aPWV in patients with type 2 diabetes with no history of cardiovascular disease (CVD). METHODS: In the CARDIPP study, a cross-sectional analysis of 519 patients with type 2 diabetes aged 55-65 years with no history of CVD at baseline, had complete data on copeptin, MRproADM, MRproANP, TBI, and aPWV was performed. Linear regression analysis was used to investigate the associations between conventional CVD risk factors, copeptin, MRproADM, MRproANP, TBI, and aPWV. RESULTS: Copeptin was associated with TBI (ß-0.0020, CI-0.0035- (-0.0005), p = 0.010) and aPWV (ß 0.023, CI 0.002-0.044, p = 0.035). These associations were independent of age, sex, diabetes duration, mean 24-hour ambulatory systolic blood pressure, glycated hemoglobin A1c, total cholesterol, estimated glomerular filtration rate, body mass index, and active smoking. CONCLUSIONS: Plasma copeptin may be a helpful surrogate for identifying individuals at higher risk for arterial disorders. TRIAL REGISTRATION:  ClinicalTrials.gov identifier NCT010497377.

Nocturnal hypoxemic burden and micro- and macrovascular disease in patients with type 2 diabetes.

BACKGROUND: Micro- and macrovascular diseases are common in patients with type 2 diabetes mellitus (T2D) and may be partly caused by nocturnal hypoxemia. The study aimed to characterize the composition of nocturnal hypoxemic burden and to assess its association with micro- and macrovascular disease in patients with T2D. METHODS: This cross-sectional analysis includes overnight oximetry from 1247 patients with T2D enrolled in the DIACORE (DIAbetes COhoRtE) study. Night-time spent below a peripheral oxygen saturation of 90% (T90) as well as T90 associated with non-specific drifts in oxygen saturation (T90non - specific), T90 associated with acute oxygen desaturation (T90desaturation) and desaturation depths were assessed. Binary logistic regression analyses adjusted for known risk factors (age, sex, smoking status, waist-hip ratio, duration of T2D, HbA1c, pulse pressure, low-density lipoprotein, use of statins, and use of renin-angiotensin-aldosterone system inhibitors) were used to assess the associations of such parameters of hypoxemic burden with chronic kidney disease (CKD) as a manifestation of microvascular disease and a composite of cardiovascular diseases (CVD) reflecting macrovascular disease. RESULTS: Patients with long T90 were significantly more often affected by CKD and CVD than patients with a lower hypoxemic burden (CKD 38% vs. 28%, p < 0.001; CVD 30% vs. 21%, p < 0.001). Continuous T90desaturation and desaturation depth were associated with CKD (adjusted OR 1.01 per unit, 95% CI [1.00; 1.01], p = 0.008 and OR 1.30, 95% CI [1.06; 1.61], p = 0.013, respectively) independently of other known risk factors for CKD. For CVD there was a thresholdeffect, and only severly and very severly increased T90non-specific was associated with CVD ([Q3;Q4] versus [Q1;Q2], adjusted OR 1.51, 95% CI [1.12; 2.05], p = 0.008) independently of other known risk factors for CVD. CONCLUSION: While hypoxemic burden due to oxygen desaturations and the magnitude of desaturation depth were significantly associated with CKD, only severe hypoxemic burden due to non-specific drifts was associated with CVD. Specific types of hypoxemic burden may be related to micro- and macrovascular disease.

Ion channel Piezo1 activation aggravates the endothelial dysfunction under a high glucose environment.

BACKGROUND: Vasculopathy is the most common complication of diabetes. Endothelial cells located in the innermost layer of blood vessels are constantly affected by blood flow or vascular components; thus, their mechanosensitivity plays an important role in mediating vascular regulation. Endothelial damage, one of the main causes of hyperglycemic vascular complications, has been extensively studied. However, the role of mechanosensitive signaling in hyperglycemic endothelial damage remains unclear. METHODS: Vascular endothelial-specific Piezo1 knockout mice were generated to investigate the effects of Piezo1 on Streptozotocin-induced hyperglycemia and vascular endothelial injury. In vitro activation or knockdown of Piezo1 was performed to evaluate the effects on the proliferation, migration, and tubular function of human umbilical vein endothelial cells in high glucose. Reactive oxygen species production, mitochondrial membrane potential alternations, and oxidative stress-related products were used to assess the extent of oxidative stress damage caused by Piezo1 activation. RESULTS: Our study found that in VECreERT2;Piezo1flox/flox mice with Piezo1 conditional knockout in vascular endothelial cells, Piezo1 deficiency alleviated streptozotocin-induced hyperglycemia with reduced apoptosis and abscission of thoracic aortic endothelial cells, and decreased the inflammatory response of aortic tissue caused by high glucose. Moreover, the knockout of Piezo1 showed a thinner thoracic aortic wall, reduced tunica media damage, and increased endothelial nitric oxide synthase expression in transgenic mice, indicating the relief of endothelial damage caused by hyperglycemia. We also showed that Piezo1 activation aggravated oxidative stress injury and resulted in severe dysfunction through the Ca2+-induced CaMKII-Nrf2 axis in human umbilical vein endothelial cells. In Piezo1 conditional knockout mice, Piezo1 deficiency partially restored superoxide dismutase activity and reduced malondialdehyde content in the thoracic aorta. Mechanistically, Piezo1 deficiency decreased CaMKII phosphorylation and restored the expression of Nrf2 and its downstream molecules HO-1 and NQO1. CONCLUSION: In summary, our study revealed that Piezo1 is involved in high glucose-induced oxidative stress injury and aggravated endothelial dysfunction, which have great significance for alleviating endothelial damage caused by hyperglycemia.

Endothelial dysfunction in vascular complications of diabetes: a comprehensive review of mechanisms and implications.

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

BAG3 promotes proliferation and migration of arterial smooth muscle cells by regulating STAT3 phosphorylation in diabetic vascular remodeling.

BACKGROUND: Diabetic vascular remodeling is the most important pathological basis of diabetic cardiovascular complications. The accumulation of advanced glycation end products (AGEs) caused by elevated blood glucose promotes the proliferation and migration of vascular smooth muscle cells (VSMCs), leading to arterial wall thickening and ultimately vascular remodeling. Therefore, the excessive proliferation and migration of VSMCs is considered as an important therapeutic target for vascular remodeling in diabetes mellitus. However, due to the lack of breakthrough in experiments, there is currently no effective treatment for the excessive proliferation and migration of VSMCs in diabetic patients. Bcl-2-associated athanogene 3 (BAG3) protein is a multifunctional protein highly expressed in skeletal muscle and myocardium. Previous research has confirmed that BAG3 can not only regulate cell survival and apoptosis, but also affect cell proliferation and migration. Since the excessive proliferation and migration of VSMCs is an important pathogenesis of vascular remodeling in diabetes, the role of BAG3 in the excessive proliferation and migration of VSMCs and its molecular mechanism deserve further investigation. METHODS: In this study, BAG3 gene was manipulated in smooth muscle to acquire SM22αCre; BAG3FL/FL mice and streptozotocin (STZ) was used to simulate diabetes. Expression of proteins and aortic thickness of mice were detected by immunofluorescence, ultrasound and hematoxylin-eosin (HE) staining. Using human aorta smooth muscle cell line (HASMC), cell viability was measured by CCK-8 and proliferation was measured by colony formation experiment. Migration was detected by transwell, scratch experiments and Phalloidin staining. Western Blot was used to detect protein expression and Co-Immunoprecipitation (Co-IP) was used to detect protein interaction. RESULTS: In diabetic vascular remodeling, AGEs could promote the interaction between BAG3 and signal transducer and activator of transcription 3 (STAT3), leading to the enhanced interaction between STAT3 and Janus kinase 2 (JAK2) and reduced interaction between STAT3 and extracellular signal-regulated kinase 1/2 (ERK1/2), resulting in accumulated p-STAT3(705) and reduced p-STAT3(727). Subsequently, the expression of matrix metallopeptidase 2 (MMP2) is upregulated, thus promoting the migration of VSMCs. CONCLUSIONS: BAG3 upregulates the expression of MMP2 by increasing p-STAT3(705) and decreasing p-STAT3(727) levels, thereby promoting vascular remodeling in diabetes. This provides a new orientation for the prevention and treatment of diabetic vascular remodeling.

Novel Angiogenesis Role of GLP-1(32-36) to Rescue Diabetic Ischemic Lower Limbs via GLP-1R-Dependent Glycolysis in Mice.

BACKGROUND: Restoring the capacity of endothelial progenitor cells (EPCs) to promote angiogenesis is the major therapeutic strategy of diabetic peripheral artery disease. The aim of this study was to investigate the effects of GLP-1 (glucagon-like peptide 1; 32-36)-an end product of GLP-1-on angiogenesis of EPCs and T1DM (type 1 diabetes) mice, as well as its interaction with the classical GLP-1R (GLP-1 receptor) pathway and its effect on mitochondrial metabolism. METHODS: In in vivo experiments, we conducted streptozocin-induced type 1 diabetic mice as a murine model of unilateral hind limb ischemia to examine the therapeutic potential of GLP-1(32-36) on angiogenesis. We also generated Glp1r-/- mice to detect whether GLP-1R is required for angiogenic function of GLP-1(32-36). In in vitro experiments, EPCs isolated from the mouse bone marrow and human umbilical cord blood samples were used to detect GLP-1(32-36)-mediated angiogenic capability under high glucose treatment. RESULTS: We demonstrated that GLP-1(32-36) did not affect insulin secretion but could significantly rescue angiogenic function and blood perfusion in ischemic limb of streptozocin-induced T1DM mice, a function similar to its parental GLP-1. We also found that GLP-1(32-36) promotes angiogenesis in EPCs exposed to high glucose. Specifically, GLP-1(32-36) has a causal role in improving fragile mitochondrial function and metabolism via the GLP-1R-mediated pathway. We further demonstrated that GLP-1(32-36) rescued diabetic ischemic lower limbs by activating the GLP-1R-dependent eNOS (endothelial NO synthase)/cGMP/PKG (protein kinase G) pathway. CONCLUSIONS: Our study provides a novel mechanism with which GLP-1(32-36) acts in modulating metabolic reprogramming toward glycolytic flux in partnership with GLP-1R for improved angiogenesis in high glucose-exposed EPCs and T1DM murine models. We propose that GLP-1(32-36) could be used as a monotherapy or add-on therapy with existing treatments for peripheral artery disease. REGISTRATION: URL: www.ebi.ac.uk/metabolights/; Unique identifier: MTBLS9543.

Artificial intelligence of arterial Doppler waveforms to predict major adverse outcomes among patients with diabetes mellitus.

OBJECTIVE: Patients with diabetes mellitus (DM) are at increased risk for peripheral artery disease (PAD) and its complications. Arterial calcification and non-compressibility may limit test interpretation in this population. Developing tools capable of identifying PAD and predicting major adverse cardiac event (MACE) and limb event (MALE) outcomes among patients with DM would be clinically useful. Deep neural network analysis of resting Doppler arterial waveforms was used to detect PAD among patients with DM and to identify those at greatest risk for major adverse outcome events. METHODS: Consecutive patients with DM undergoing lower limb arterial testing (April 1, 2015-December 30, 2020) were randomly allocated to training, validation, and testing subsets (60%, 20%, and 20%). Deep neural networks were trained on resting posterior tibial arterial Doppler waveforms to predict all-cause mortality, MACE, and MALE at 5 years using quartiles based on the distribution of the prediction score. RESULTS: Among 11,384 total patients, 4211 patients with DM met study criteria (mean age, 68.6 ± 11.9 years; 32.0% female). After allocating the training and validation subsets, the final test subset included 856 patients. During follow-up, there were 262 deaths, 319 MACE, and 99 MALE. Patients in the upper quartile of prediction based on deep neural network analysis of the posterior tibial artery waveform provided independent prediction of death (hazard ratio [HR], 3.58; 95% confidence interval [CI], 2.31-5.56), MACE (HR, 2.06; 95% CI, 1.49-2.91), and MALE (HR, 13.50; 95% CI, 5.83-31.27). CONCLUSIONS: An artificial intelligence enabled analysis of a resting Doppler arterial waveform permits identification of major adverse outcomes including all-cause mortality, MACE, and MALE among patients with DM.

What is the impact of microvascular complications of diabetes on severe COVID-19?

Evidence suggests severe coronavirus disease-19 (COVID-19) infection is characterised by pulmonary and systemic microvasculature dysfunction, specifically, acute endothelial injury, hypercoagulation and increased capillary permeability. Diabetes, which is also characterised by vascular injury in itself, confers an increased risk of adverse COVID-19 outcomes. It has been suggested that pre-existing endothelial dysfunction and microvascular disease in diabetes will exacerbate the vascular insults associated with COVID-19 and thus lead to increased severity of COVID-19 infection. In this article, we evaluate the current evidence exploring the impact of microvascular complications, in the form of diabetic retinopathy and nephropathy, in individuals with COVID-19 and diabetes. Future insights gained from exploring the microvascular injury patterns and clinical outcomes may come to influence care delivery algorithms for either of these conditions.

Management of hypertension and renin-angiotensin-aldosterone system blockade in adults with diabetic kidney disease: Association of British Clinical Diabetologists and the Renal Association UK guideline update 2021.

People with type 1 and type 2 diabetes are at risk of developing progressive chronic kidney disease (CKD) and end-stage kidney failure. Hypertension is a major, reversible risk factor in people with diabetes for development of albuminuria, impaired kidney function, end-stage kidney disease and cardiovascular disease. Blood pressure control has been shown to be beneficial in people with diabetes in slowing progression of kidney disease and reducing cardiovascular events. However, randomised controlled trial evidence differs in type 1 and type 2 diabetes and different stages of CKD in terms of target blood pressure. Activation of the renin-angiotensin-aldosterone system (RAAS) is an important mechanism for the development and progression of CKD and cardiovascular disease. Randomised trials demonstrate that RAAS blockade is effective in preventing/ slowing progression of CKD and reducing cardiovascular events in people with type 1 and type 2 diabetes, albeit differently according to the stage of CKD. Emerging therapy with sodium glucose cotransporter-2 (SGLT-2) inhibitors, non-steroidal selective mineralocorticoid antagonists and endothelin-A receptor antagonists have been shown in randomised trials to lower blood pressure and further reduce the risk of progression of CKD and cardiovascular disease in people with type 2 diabetes. This guideline reviews the current evidence and makes recommendations about blood pressure control and the use of RAAS-blocking agents in different stages of CKD in people with both type 1 and type 2 diabetes.

Progression of Diabetic Complications in Subgroups of People with Long Term Diabetes Type 1 According to Clinical Course.

AIMS: Prevention and prediction of microvascular complications are important aims of medical care in people with type 1 diabetes. Since the course of the disease is heterogenous, we tried to identify subgroups with specific risk profiles for microvascular complications. METHODS: Retrospective analysis of a cohort of 285 people (22637 consultations) with >10 years of type 1 diabetes. Persons were grouped into slow (<15 years), fast (>15 years) and non progressors according to the average onset of microvascular complications. Generalized estimating equations for binary outcomes were applied and pseudo coefficients of determination were calculated. RESULTS: Progression to microvascular disease was associated with age (OR: 1.034 [1.001-1.068]; p=0.04), diabetes duration (OR: 1.057 [1.021-1.094]; p=0.002), HbA1c (OR: 1.035 [1.011-1.060]; p=0.005), BMI (OR: 0.928 [0.866-0.994]; p=0.034) and the social strata index (OR: 0.910 [0.830-0.998]; p=0.046). Generalized estimating equations predicted 31.02% and exclusion of HbA1c marginally reduced the value to 28.88%. The proportion of patients with LADA was higher in fast than slow progressors [13 (26.5%) vs. 14 (11.9%); p=0.019]. A generalized estimating equation comparing slow to fast progressors revealed no significant markers. CONCLUSION: In our analysis, we were able to confirm known risk factors for microvascular disease in people with type 1 diabetes. Overall, prediction of individual risk was difficult, the effect of individual markers minor and we could not find differences regarding slow or fast progression. We therefore emphasis the need for additional markers to predict individual risk for microvascular disease.

Early ABI Testing May Decrease Risk of Amputation for Patients With Lower Extremity Ulcers.

BACKGROUND: Patients with lower extremity wounds from diabetes mellitus or peripheral artery disease (PAD) have a risk of amputation as high as 25%. In patients with arterial disease, revascularization decreases the risk of amputation. We aimed to determine if the early assessment of arterial perfusion correlates with the risk of amputation. METHODS: We retrospectively reviewed patients referred to the vascular clinic over 18 months with Rutherford Grade 5 and 6 chronic limb-threatening ischemia to determine if patients had a pulse exam done at the time the wound was identified and when ankle brachial index (ABI) testing to evaluate perfusion was performed. Kaplan Meier analysis was used to determine if the timing of ABI testing affected the time to revascularization, wound healing, and risk of amputation. RESULTS: Ninety-three patients with lower extremity wounds were identified. Of these, 59 patients (63%) did not have a pulse exam performed by their primary care provider when the wound was identified. Patients were classified by when they underwent ankle brachial index testing to assess arterial perfusion. Twenty-four had early ABI (<30 days) testing, with the remaining 69 patients having late ABI testing. Patients in the early ABI group were more likely to have a pulse exam done by their PCP than those in the late group, 12 (50%) vs. 22 (32%), P = 0.03. Early ABI patients had a quicker time to vascular referral (13 days vs. 91 days, P < 0.001). Early ABI patients also had quicker times to wound healing than those in the late group (117 days vs. 287 days, P < 0.001). Finally, patients that underwent early ABI were less likely to require amputation (Fig. 1), although this did not reach statistical significance (P = 0.07). CONCLUSIONS: Early ABI testing expedites specialty referral and time to revascularization. It can decrease the time to wound healing. Larger cohort studies are needed to determine the overall effect of early ABI testing to decrease amputation rates.

Assessment of Tissue Viability Following Amputation Surgery Using Near-Infrared Fluorescence Imaging With Indocyanine Green.

BACKGROUND: Patients with chronic limb threatening ischemia have a risk of undergoing a major amputation within 1 year of nearly 30% with a substantial risk of re-amputation since wound healing is often impaired. Quantitative assessment of regional tissue viability following amputation surgery can identify patients at risk for impaired wound healing. In quantification of regional tissue perfusion, near-infrared (NIR) fluorescence imaging using Indocyanine Green (ICG) seems promising. METHODS: This pilot study included adult patients undergoing lower extremity amputation surgery due to peripheral artery disease or diabetes mellitus. ICG NIR fluorescence imaging was performed within 5 days following amputation surgery using the Quest Spectrum PlatformⓇ. Following intravenous administration of ICG, the NIR fluorescence intensity of the amputation wound was recorded for 10 minutes. The NIR fluorescence intensity videos were analyzed and if a fluorescence deficit was observed, this region was marked as "low fluorescence." All other regions were marked as "normal fluorescence." RESULTS: Successful ICG NIR fluorescence imaging was performed in 10 patients undergoing a total of 15 amputations. No "low fluorescence" regions were observed in 11 out of 15 amputation wounds. In 10 out of these 11 amputations, no wound healing problems occurred during follow-up. Regions with "low fluorescence" were observed in 4 amputation wounds. Impaired wound healing corresponding to these regions was observed in all wounds and a re-amputation was necessary in 3 out of 4. When observing time-related parameters, regions with low fluorescence had a significantly longer time to maximum intensity (113 seconds vs. 32 seconds, P = 0.003) and a significantly lesser decline in outflow after five minutes (80.3% vs. 57.0%, P = 0.003). CONCLUSIONS: ICG NIR fluorescence imaging was able to predict postoperative skin necrosis in all four cases. Quantitative assessment of regional perfusion remains challenging due toinfluencing factors on the NIR fluorescence intensity signal, including camera angle, camera distance and ICG dosage. This was also observed in this study, contributing to a large variety in fluorescence intensity parameters among patients. To provide surgeons with reliable NIR fluorescence cut-off values for prediction of wound healing, prospective studies on the intra-operative use of this technique are required. The potential prediction of wound healing using ICG NIR fluorescence imaging will have a huge impact on patient mortality, morbidity as well as the burden of amputation surgery on health care.

Downregulation of Erythrocyte miR-210 Induces Endothelial Dysfunction in Type 2 Diabetes.

Red blood cells (RBC) act as mediators of vascular injury in type 2 diabetes mellitus (T2DM). miR-210 plays a protective role in cardiovascular homeostasis and is decreased in whole blood of T2DM mice. We hypothesized that downregulation of RBC miR-210 induces endothelial dysfunction in T2DM. RBC were coincubated with arteries and endothelial cells ex vivo and transfused in vivo to identify the role of miR-210 and its target protein tyrosine phosphatase 1B (PTP1B) in endothelial dysfunction. RBC from patients with T2DM and diabetic rodents induced endothelial dysfunction ex vivo and in vivo. miR-210 levels were lower in human RBC from patients with T2DM (T2DM RBC) than in RBC from healthy subjects. Transfection of miR-210 in human T2DM RBC rescued endothelial function, whereas miR-210 inhibition in healthy subjects RBC or RBC from miR-210 knockout mice impaired endothelial function. Human T2DM RBC decreased miR-210 expression in endothelial cells. miR-210 expression in carotid artery plaques was lower in T2DM patients than in patients without diabetes. Endothelial dysfunction induced by downregulated RBC miR-210 involved PTP1B and reactive oxygen species. miR-210 mimic attenuated endothelial dysfunction induced by RBC via downregulating vascular PTP1B and oxidative stress in diabetic mice in vivo. These data reveal that the downregulation of RBC miR-210 is a novel mechanism driving the development of endothelial dysfunction in T2DM.

PPARß down-regulation is involved in high glucose-induced endothelial injury via acceleration of nitrative stress.

Endothelial injury plays a vital role in vascular lesions from diabetes mellitus (DM). Therapeutic targets against endothelial damage may provide critical venues for the treatment of diabetic vascular diseases. Peroxisome proliferator-activated receptor ß (PPARß) is a crucial regulator in DM and its complications. However, the molecular signal mediating the roles of PPARß in DM-induced endothelial dysfunction is not fully understood. The impaired endothelium-dependent relaxation and destruction of the endothelium structures appeared in high glucose incubated rat aortic rings. A high glucose level significantly decreased the expression of PPARß and endothelial nitric oxide synthase (eNOS) at the mRNA and protein levels, and reduced the concentration of nitric oxide (NO), which occurred in parallel with an increase in the expression of inducible nitric oxide synthase (iNOS) and 3-nitrotyrosine. The effect of high glucose was inhibited by GW0742, a PPARß agonist. Both GSK0660 (PPARß antagonist) and NG-nitro-l-arginine-methyl ester (NOS inhibitor) could reverse the protective effects of GW0742. These results suggest that the activation of nitrative stress may, at least in part, mediate the down-regulation of PPARß in high glucose-impaired endothelial function in rat aorta. PPARß-nitrative stress may hold potential in treating vascular complications from DM.

Tissue sodium content correlates with hypertrophic vascular remodeling in type 2 diabetes.

BACKGROUND: Prospective studies describe a linkage between increased sodium intake and higher incidence of cardiovascular organ damage and end points. We analyzed whether tissue sodium content in the skin and muscles correlate with vascular hypertrophic remodeling, a risk factor for cardiovascular disease. METHODS: In patients with type 2 diabetes we assessed tissue sodium content and vascular structural parameters of the retinal arterioles. The structural parameters of retinal arterioles assessed by Scanning Laser Doppler Flowmetry were vessel (VD) and lumen diameter (LD), wall thickness (WT), wall-to-lumen ratio (WLR) and wall cross sectional area (WCSA). Tissue sodium content was measured with a 3.0 T clinical 23Sodium-Magnetic Resonance Imaging (23Na-MRI) system. RESULTS: In patients with type 2 diabetes (N = 52) we observed a significant correlation between muscle sodium content and VD (p = 0.005), WT (p = 0.003), WCSA (p = 0.002) and WLR (p = 0.013). With respect to skin sodium content a significant correlation has been found with VD (p = 0.042), WT (p = 0.023) and WCSA (p = 0.019). Further analysis demonstrated that tissue sodium content of skin and muscle is a significant determinant of hypertrophic vascular remodeling independent of age, gender, diuretic use and 24-hour ambulatory BP. CONCLUSION: With the 23Na-MRI technology we could demonstrate that high tissue sodium content is independently linked to hypertrophic vascular remodeling in type 2 diabetes. TRIAL REGISTRATION: Trial registration number: NCT02383238 Date of registration: March 9, 2015.

Roles and Mechanisms of Dipeptidyl Peptidase 4 Inhibitors in Vascular Aging.

Vascular aging is characterized by alterations in the constitutive properties and biological functions of the blood vessel wall. Endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) are indispensability elements in the inner layer and the medial layer of the blood vessel wall, respectively. Dipeptidyl peptidase-4 (DPP4) inhibitors, as a hypoglycemic agent, play a protective role in reversing vascular aging regardless of their effects in meliorating glycemic control in humans and animal models of type 2 diabetes mellitus (T2DM) through complex cellular mechanisms, including improving EC dysfunction, promoting EC proliferation and migration, alleviating EC senescence, obstructing EC apoptosis, suppressing the proliferation and migration of VSMCs, increasing circulating endothelial progenitor cell (EPC) levels, and preventing the infiltration of mononuclear macrophages. All of these showed that DPP4 inhibitors may exert a positive effect against vascular aging, thereby preventing vascular aging-related diseases. In the current review, we will summarize the cellular mechanism of DPP4 inhibitors regulating vascular aging; moreover, we also intend to compile the roles and the promising therapeutic application of DPP4 inhibitors in vascular aging-related diseases.

Diabetes in Patients With Heart Failure With Reduced Ejection Fraction During Hospitalization: A Retrospective Observational Study.

Background: Diabetes is prevalent worldwide including hospitalized patients with heart failure with reduced ejection fraction (HFrEF). This retrospective study investigated the association of diabetes with in-hospital adverse events in patients with HFrEF. Methods: We analyzed data from electronic medical records of patients hospitalized with HFrEF in West China Hospital of Sichuan University from January 1, 2011, to September 30, 2018. Propensity score matching balances the baseline characteristics between patients with and without diabetes. Logistic and Poisson regressions investigated the association of diabetes with risks of intubation, cardiogenic shock, acute kidney injury (AKI), intensive care unit (ICU) admission and death during hospitalization, and length of ICU and hospital stay in the matched cases. Results: Among 6,022 eligible patients (including 1,998 with diabetes), 1,930 patient pairs with and without diabetes were included by propensity score matching. Patients with diabetes had a significantly increased risk of intubation (odds ratio [OR], 2.69; 95% confidence interval [CI], 2.25-3.22; P<0.001), cardiogenic shock (OR, 2.01; 95% CI, 1.72-2.35; P<0.001), AKI at any stage (OR, 1.67; 95% CI, 1.44-1.94; P<0.001), ICU admission (OR, 1.89; 95% CI, 1.65-2.15; P<0.001), and death (OR, 4.25; 95% CI, 3.06-6.02; P<0.001) during hospitalization. Patients with diabetes had longer ICU (median difference, 1.47 days; 95% CI, 0.96-2.08; P<0.001) and hospital stay (2.20 days; 95% CI, 1.43-2.86; P<0.001) than those without diabetes. There were potential subgroup effects by age and by hypertension, and CKD status on the association of diabetes with risk of AKI at any stage; and subgroup effects by sex and CKD status on the association of diabetes with risk of intubation. The increase in length of hospital stay was larger in patients without hypertension than those with hypertension. Conclusions: Among patients with HFrEF, those with diabetes have a worse prognosis, including a higher risk of in-hospital intubation, cardiogenic shock, AKI, ICU admission and death during hospitalization, and longer ICU and hospital stay.

Contributions of Sodium-Hydrogen Exchanger 1 and Mitogen-Activated Protein Kinases to Enhanced Retinal Venular Constriction to Endothelin-1 in Diabetes.

Diabetes elevates endothelin-1 (ET-1) in the vitreous and enhances constriction of retinal venules to this peptide. However, mechanisms contributing to ET-1-induced constriction of retinal venules are incompletely understood. We examined roles of sodium-hydrogen exchanger 1 (NHE1), protein kinase C (PKC), mitogen-activated protein kinases (MAPKs), and extracellular calcium (Ca2+) in retinal venular constriction to ET-1 and the impact of diabetes on these signaling molecules. Retinal venules were isolated from control pigs and pigs with streptozocin-induced diabetes for in vitro studies. ET-1-induced vasoconstriction was abolished in the absence of extracellular Ca2+ and sensitive to c-Jun N-terminal kinase (JNK) inhibitor SP600125 but unaffected by extracellular signal-regulated kinase (ERK) inhibitor PD98059, p38 kinase inhibitor SB203580, or broad-spectrum PKC inhibitor Gö 6983. Diabetes (after 2 weeks) enhanced venular constriction to ET-1, which was insensitive to PD98059 and Gö 6983 but was prevented by NHE1 inhibitor cariporide, SB203580, and SP600125. In conclusion, extracellular Ca2+ entry and activation of JNK, independent of ERK and PKC, mediate constriction of retinal venules to ET-1. Diabetes activates p38 MAPK and NHE1, which cause enhanced venular constriction to ET-1. Treatments targeting these vascular molecules may lessen retinal complications in early diabetes.

Hypoglycaemic and Antioxidant Properties of Acrocomia aculeata (Jacq.) Lodd Ex Mart. Extract Are Associated with Better Vascular Function of Type 2 Diabetic Rats.

Oxidative stress is involved in the metabolic dysregulation of type 2 diabetes (DM2). Acrocomia aculeata (Aa) fruit pulp has been described for the treatment of several diseases, and recently we have proved that its leaves have phenolic compounds with a marked antioxidant effect. We aimed to assess whether they can improve metabolic, redox and vascular functions in DM2. Control Wistar (W-Ctrl) and non-obese type 2 diabetic Goto-Kakizaki (GK-Ctrl) rats were treated for 30 days with 200 mg.kg-1 aqueous extract of Aa (EA-Aa) (Wistar, W-EA-Aa/GK, GK-EA-Aa). EA-Aa was able to reduce fasting glycaemia and triglycerides of GK-EA-Aa by improving proteins related to glucose and lipid metabolism, such as GLUT-4, PPARγ, AMPK, and IR, when compared to GK-Ctrl. It also improved viability of 3T3-L1 pre-adipocytes exposed by H2O2. EA-Aa also increased the levels of catalase in the aorta and kidney, reduced oxidative stress and increased relaxation of the aorta in GK-treated rats in relation to GK-Ctrl, in addition to the protective effect against oxidative stress in HMVec-D cells. We proved the direct antioxidant potential of the chemical compounds of EA-Aa, the increase in antioxidant defences in a tissue-specific manner and hypoglycaemic properties, improving vascular function in type 2 diabetes. EA-Aa and its constituents may have a therapeutic potential for the treatment of DM2 complications.

Deteriorated regional calf microcirculation measured by contrast-free MRI in patients with diabetes mellitus and relation with physical activity.

OBJECTIVE: To evaluate regional calf muscle microcirculation in people with diabetes mellitus (DM) with and without foot ulcers, compared to healthy control people without DM, using contrast-free magnetic resonance imaging methods. METHODS: Three groups of subjects were recruited: non-DM controls, DM, and DM with foot ulcers (DM + ulcer), all with ankle brachial index (ABI) > 0.9. Skeletal muscle blood flow (SMBF) and oxygen extraction fraction (SMOEF) in calf muscle were measured at rest and during a 5-min isometric ankle plantarflexion exercise. Subjects completed the Yale physical activity survey. RESULTS: The exercise SMBF (ml/min/100 g) of the medial gastrocnemius muscle were progressively impaired: 63.7 ± 18.9 for controls, 42.9 ± 6.7 for DM, and 36.2 ± 6.2 for DM + ulcer, p < 0.001. Corresponding exercise SMOEF was the lowest in DM + ulcers (0.48 ± 0.09). Exercise SMBF in the soleus muscle was correlated moderately with the Yale physical activity survey (r = 0.39, p < 0.01). CONCLUSIONS: Contrast-free MR imaging identified progressively impaired regional microcirculation in medial gastrocnemius muscles of people with DM with and without foot ulcers. Exercise SMBF in the medial gastrocnemius muscle was the most sensitive index and was associated with HbA1c. Lower exercise SMBF in the soleus muscle was associated with lower Yale score.