Diabetic Macrovascular Disease Research Articles

#1626 The role of sodium-glucose cotransporter 2 inhibitors in diabetic nephropathy and non diabetic renal disease in diabetes mellitus type 2 patients

Abstract Background and Aims Diabetes Mellitus type 2 (DM2) leads to chronic kidney disease in a 30-40% of diabetic patients and it is the major cause of end stage renal disease (ESRD). The clinical course of diabetic kidney disease is very heterogeneous and there is a lack of agreement between clinical parameters and renal histology. Besides, lesions of non-diabetic kidney disease (NDRD) can coexist with lesions of diabetic nephropathy (DN) in two-thirds of kidney biopsies in patients with diabetes. There is not a specific treatment against diabetic kidney disease, treatment based in the blockade of renin-angiotensin-aldosterone system has demonstrated a delay of kidney function decline but the diabetic kidney disease is still the main cause of renal replacement by dialysis. Recently, a new class of oral glucose -lowering drugs, sodium-glucose cotransporter 2 (SGLT2) inhibitors, have shown beneficial effects into cardiovascular protection and chronic kidney disease in diabetic patients but it is not clear the beneficial effect in DN. The aim of this study is to evaluate the role of SGLT2 inhibitors in diabetic patients with DN biopsy-confirmed and compare with a group of diabetic patients with NDRD (DN and superimposed non diabetic renal disease lesions, NDRD). Method This is a retrospective study with DM2 patients and kidney biopsy performed. Patient demographic characteristics were recorded and diagnosis of Hypertension, duration of DM2, presence or absence of diabetic retinopathy (DR), macrovascular disease and treatment with renin–angiotensin– aldosterone system blockers (RAASB), oral hypoglycaemic agents, insulin, and aldosterone antagonists. Histological lesions were recorded according to the pathologic classification of DN. Renal function was based on estimated filtration rate CKD-EPI (eGFR mil/min/m2), the urine albumin-creatinine ratio (UACR mg/gr) and the 24 h proteinuria (g/24 h). Diabetic patients were classified according to the kidney biopsies in DN and NDRD. The follow up was assessed at the time of sodium-glucose cotransporter 2 (SGLT2) inhibitors started, 6, 12 and 24 months. Results A total of 64 DM2 patients with kidney biopsy were included in the study. Basal characteristics are summarized in Table 1. DN was diagnosed in 47% and NDRD in 53% of DM2 patients. DM2 patients with NDRD were older (64 ± 10 vs 70 ± 10, p = 0.017), and with more macrovascular disease than patients with DN, 6 (20%) vs 15 (44%), p = 0.04. Instead, DM2 patients with DN showed higher uACR levels than NDRD (2355 ± 2540 vs 706 ± 730, p = 0.02). A 40% of DM2 patients with DN were classified in nodular sclerosis class III of glomerular classification of DN. Interstitial fibrosis and tubular atrophy score were higher in DN versus NDRD patients, (interstitial fibrosis 12 (40%) vs 3 (9%), p = 0.006, tubular atrophy 10 (33%) vs 3 (9%), p = 0.02, Table 2. At the end of follow up, 20% of DM2 patients developed ESRD. According SGLT2 inhibitors treatment, a higher proportion of ESRD and death were observed in DM2 patients without SGLT2 inhibitors than patients with SGLT2 inhibitors, ESRD 11 (39%) vs 2 (6%), p = 0.001, death 9 (32%) vs 4 (11%), p = 0.03. Serum creatinine levels were lower in DM2 patients with SGLT2 inhibitors (118 ± 63.7 vs 203 ± 80.7, p = 0.001), but no differences was observed in uACR between groups. A significant reduction in serum creatinine levels with better eGFR were observed in both groups (DN and NDRD) under SGLT2 inhibitors comparing to group without SGLT2 inhibitors, serum creatinine levels 124 ± 78 vs 236 ± 83, p = 0.008, 107 ± 40 vs 201 ± 110, p = 0.02, and eGFR mil/min/m2 60.9 ± 27.5 vs 25.1 ± 7.2, p = 0.004, 62.6 ± 21.2 vs 33.7 ± 16.2, p = 0.005, Table 3. Conclusion A higher proportion of DM2 showed NDRD lesions in kidney biopsy. Treatment with SGLT2 inhibitors reduced progression of chronic renal disease in DN and NDRD DM2 patients. A reduced progression to ESRD and death were also observed in NDRD DM2 patients with SGLT2 treatment.

Risk factors for carotid plaque formation in type 2 diabetes mellitus

ObjectPatients with type 2 diabetes mellitus (T2DM) are at higher risk of developing atherosclerosis. Previous studies have analyzed the factors associated with diabetic macrovascular disease, although whether these factors are applicable to T2DM patients with carotid atherosclerosis remains unclear. Therefore, the aim of this study was to investigate the risk factors for the formation of carotid atherosclerotic plaque in hospitalized T2DM patients and to provide a theoretical basis for early prevention and treatment of carotid atherosclerosis in these patients.MethodsA total of 949 patients with T2DM were included in the study. Carotid ultrasound identified 531 patients with carotid atherosclerotic plaque. The waist-to-hip ratio (WHR), blood glucose, liver and kidney function, blood lipid profile, islet function, and other indicators were measured at the same time to identify the risk factors and predictive significance of T2DM carotid plaque.ResultsThe proportions of men, diabetes nephropathy (DN) and hypertension in T2DM patients with carotid plaque are higher than those without carotid plaque(P < 0.05). Age, duration of diabetes, WHR, Postprandial glucose (PPG), lipoprotein (a) [Lip (a)], carcinoembryonic antigen(CEA) and estimated glomerular filtration rate (eGFR) in T2DM patients with carotid plaque were higher than those without plaque (P < 0.05). Age, WHR, duration of diabetes, hypertension, males, and Lip (a) were independent risk factors for T2DM patients with carotid plaque. Age, WHR, duration of diabetes, and Lip (a) had a higher AUC to predict T2DM with carotid artery plaque (AUC: 0.750, 0.640, 0.678, 0.552 respectively; P all < 0.001). After constructing the logit (P) value of the above risk factors, the area under the ROC curve was 0.816 (0.789–0.842, P < 0.001).ConclusionAge, WHR, duration of diabetes, hypertension, males, and Lip (a) levels are the main risk factors for the formation of carotid plaque in T2DM patients. Combining the above risk factors provides a better prediction of carotid plaque formation in T2DM.

Polymorphisms -374 T/A and -429 T/C of the Receptor for Advanced Glycation End-Products (RAGE) and Serum Levels of RAGE (sRAGE) Are Not Associated with Metabolic Syndrome.

RAGE is a multi-ligand transmembrane glycoprotein that promotes biological signals associated with inflammatory responses and degenerative diseases. sRAGE is a soluble variant, proposed as an inhibitor of RAGE activity. -374 T/A and -429 T/C polymorphisms of the advanced glycation end products receptor AGER gene are associated with the development of some diseases, such as type of cancer, cardiovascular disease, and micro and macrovascular disease in diabetes among others but their role in metabolic syndrome (MS) is still unknown. We studied 80 healthy men without MS, and 80 men with MS according to the harmonized criteria. -374 T/A and -429 T/C polymorphisms were genotyped by RT-PCR, and sRAGE was measured by ELISA. Allelic and genotypic frequencies did not differ between Non-MS and MS groups (-374 T/A p = 0.48, p = 0.57 and -429 T/C p = 0.36, p = 0.59). Significant differences were found in fasting glucose levels and diastolic blood pressure among the genotypes of the -374 T/A polymorphism in the Non-MS group (p < 0.01 and p = 0.008). Glucose levels were different between -429 T/C genotypes in the MS group (p = 0.02). sRAGE levels were similar in both groups, but in the Non-MS group showed a significant difference between individuals with only 1 or 2 components of the metabolic syndrome (p = 0.047). However, no associations of any SNP with MS were found (recessive model p = 0.48, dominant model p = 0.82 for -374 T/A; recessive model p = 0.48, dominant model p = 0.42 for -429 T/C). -374 T/A and -429 T/C polymorphisms are not associated with MS in Mexican population and have no influence on serum sRAGE levels.

Association Between Autism Spectrum Disorders and Cardiometabolic Diseases

Although the increased risk of obesity among individuals with autism has been well established, evidence on the association between autism, cardiometabolic disorders, and obesity remains inconclusive. To examine the association between autism spectrum disorders and cardiometabolic diseases in a systematic review and meta-analysis. PubMed, Scopus, Web of Science, ProQuest, Embase, and Ovid databases were searched from inception through July 31, 2022, without restrictions on date of publication or language. Observational or baseline data of interventional studies reporting the prevalence of cardiometabolic risk factors (ie, diabetes, hypertension, dyslipidemia, atherosclerotic macrovascular disease) among children and/or adults with autism and matched with participants without autism were included. Screening, data extraction, and quality assessment were performed independently by at least 2 researchers. DerSimonian-Laird random-effects meta-analyses were performed using the meta package in R. Relative risks (RRs) of diabetes, hypertension, dyslipidemia, and atherosclerotic macrovascular disease among individuals with autism were the primary outcomes. Secondary outcomes included the RR of type 1 and type 2 diabetes, heart disease, stroke, and peripheral vascular disease. A total of 34 studies were evaluated and included 276 173 participants with autism and 7 733 306 participants without autism (mean [range] age, 31.2 [3.8-72.8] years; pooled proportion [range] of female individuals, 47% [0-66%]). Autism was associated with greater risks of developing diabetes overall (RR, 1.57; 95% CI, 1.23-2.01; 20 studies), type 1 diabetes (RR, 1.64; 95% CI, 1.06-2.54; 6 studies), and type 2 diabetes (RR, 2.47; 95% CI, 1.30-4.70; 3 studies). Autism was also associated with increased risks of dyslipidemia (RR, 1.69; 95% CI, 1.20-2.40; 7 studies) and heart disease (RR, 1.46; 95% CI, 1.42-1.50; 3 studies). Yet, there was no significantly associated increased risk of hypertension and stroke with autism (RR, 1.22; 95% CI, 0.98-1.52; 12 studies; and RR, 1.19; 95% CI, 0.63-2.24; 4 studies, respectively). Meta-regression analyses revealed that children with autism were at a greater associated risk of developing diabetes and hypertension compared with adults. High between-study heterogeneity was a concern for several meta-analyses. Results suggest that the associated increased risk of cardiometabolic diseases should prompt clinicians to vigilantly monitor individuals with autism for potential contributors, signs of cardiometabolic disease, and their complications.

The ABC (HbA1c, blood pressure and LDL-cholesterol) of diabetes and oxidative stress: knowing the links

Introduction and Aim: Large body of evidence suggests that oxidative stress has a crucial role to play in diabetes and its related complications. In the present research we have tried to determine potential risk factors for oxidative stress in type 2 diabetes by conducting a cross-sectional study. Materials and Methods: We studied 238 patients with or without complications of diabetes, aged 40-75 years. Blood samples were analysed for fasting plasma glucose, glycated haemoglobin, malondialdehyde, total cholesterol, triglyceride, LDL-cholesterol and HDL-cholesterol. Each patient’s waist circumference, BMI, blood pressure was measured. Results: Participants mean age was 57.5 ± 8.9 years. Logistic regression analysis identified glycated haemoglobin (95% CI: 1.02-1.92; p=0.04), hypertension (95% CI: 0.99-4.08; p=0.05) and LDL-cholesterol (95% CI: 1.12-5.87; p=0.03) as independent risk factors for oxidative stress. Other contributors were age and presence of complications like nephropathy, retinopathy, peripheral neuropathy and macrovascular disease in diabetes. Conclusion: Our data demonstrate that ‘ABCs of diabetes’ namely HbA1c, blood pressure and LDL-cholesterol are independent risk factors for oxidative stress. Oxidative stress aggravates with age and presence of complications. It appears important to achieve a good ABC goal to bring down oxidative stress in diabetes.

Fu Fang Zhen Zhu Tiao Zhi Capsules Protect against Myocardial Ischemia by Inhibiting Cardiomyocyte Pyroptosis

Fu Fang Zhen Zhu Tiao Zhi (FTZ) is a traditional Chinese herbal prescription widely used to treat dyslipidemia, metabolic diseases, and diabetic coronary disorders. Cardiomyocyte death and loss of regenerative ability cause cardiac dysfunction and heart failure. FTZ can effectively treat diabetic cardiomyopathy and macrovascular diseases; however, the mechanism behind the phenomenon is still unclear. Here, we determined the mechanism of action of FTZ in treating myocardial infarction. Male C57BL/6 mice were treated with 2.4 or 1.2 g/kg FTZ, or administered saline by oral gavage daily for four weeks, and a 24-hour ligation was administered to the artery. Echocardiography was used to evaluate cardiac function. Hematoxylin and eosin and Evans blue/triphenyltetrazolium chloride staining were carried out by staining the cardiac tissue, used to evaluate cardiac function and infarct size. Using western blotting and reverse transcriptase-polymerase chain reaction, we determined the relative levels of NOD-like receptor protein (NLRP) 3, ASC, cleaved caspase-l (C-Caspase-1), GSDMD, and GSDMD-N. TUNEL, immunohistochemical, and immunofluorescence staining were used to determine cell death and NLRP3 expression. An enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of interleukin (IL)-1β and IL-18. FTZ reduced ischemia-induced cardiomyocyte cell death in vivo and H2O2-induced cell death in vitro by maintaining cardiac architecture and restoring cardiac function. FTZ decreased the NLRP3 expression and inhibited pyroptosis-correlated genes, including NLRP3, ASC, GSDMD, C-Caspase-1, and GSDMD-N. NLRP3 overexpression impaired the efficacy of FTZ by inducing pyroptosis. FTZ could preserve cardiac function resulting from ischemic insult by inhibiting pyroptosis, which was partially reversed by NLRP3 overexpression, indicating that NLRP3 could be a potential target of FTZ in treating myocardial infarction.

3,4‑Dihydroxyacetophenone attenuates oxidative stress‑induced damage to HUVECs via regulation of the Nrf2/HO‑1 pathway.

It has been reported that oxidative stress plays a prominent role in diabetic macrovascular diseases. 3,4-Dihydroxyacetophenone (3,4-DHAP) has been found to have a variety of biological activities. However, few studies have assessed the antioxidant capacity of 3,4-DHAP and the underlying mechanisms. Thus, the aim of the present study was to explore the effects of 3,4-DHAP on oxidative stress in human umbilical vein endothelial cells (HUVECs). HUVECs were pre-treated with 3,4-DHAP and then exposed to high glucose conditions. Cell viability and cytotoxicity were measured using an MTT assay. Reactive oxygen species (ROS) levels were measured using an inverted fluorescence microscope and a fluorescent enzyme labeling instrument. Protein expression levels of nuclear factor E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), microtubule-associated protein 1A/1B-light chain 3 (LC3) and poly ADP-ribose polymerase-1 (PARP-1) were measured using western blotting, and mRNA expression of Nrf2 and HO-1 were measured through reverse transcription-quantitative PCR (RT-qPCR). Nrf2 nuclear translocation was evaluated using immunofluorescence analysis and autophagosomes were observed using transmission electron microscope (TEM). The results of the present study demonstrated that compared with the control group, cell viability of the high glucose group was reduced and cell cytotoxicity of the high glucose group was increased. ROS production in the high glucose group was clearly enhanced. In addition, high glucose upregulated Nrf2 and HO-1 protein and mRNA expression levels. Nuclear translocation of Nrf2 in the high glucose group was also increased. The formation of autophagosomes in the high glucose group was also higher than that in the control group. Furthermore, LC3-II/LC3-I and PARP-1 protein expression levels were increased after treatment with high glucose. However, compared to the high glucose group, 3,4-DHAP (10 µmol/l) significantly enhanced cell viability. 3,4-DHAP markedly decreased the production of ROS, increased Nrf2 and HO-1 protein and mRNA expression levels, and promoted nuclear translocation of Nrf2 in HUVECs. In addition, 3,4-DHAP promoted the formation of autophagosomes, and notably increased the protein expression levels of LC3-II/LC3-I and PARP-1. Moreover, it was determined that compared to the 3,4-DHAP group, treatment with 3,4-DHAP and ML385 enhanced cell viability, and decreased ROS production, Nrf2 and HO-1 protein and mRNA expression levels, nuclear translocation of Nrf2, and LC3-II/LC3-I and PARP-1 protein expression levels. Collectively, the results of the present study showed that 3,4-DHAP protected HUVECs against oxidative stress via regulation of the Nrf2/HO-1 pathway, by increasing autophagy and promoting DNA damage repair.

The Charcot Foot: An Emerging Public Health Problem for African Diabetes Patients.

Background: Although the awareness, diagnosis, management of the complications associated with diabetes have improved in African countries over the past decade, surveillance activities in Tanzania and anecdotal reports from other African countries have suggested an increased prevalence of Charcot Neuroarthropathy (CN) over the past few years. Aim: To characterize the epidemiology and the clinical burden of CN in a large diabetes population in Tanzania, and to evaluate outcomes of persons with the condition. Methods: This was a prospective analytic cohort study conducted between January 2013 through December 2015. Following informed consent, patients were followed at the outpatient clinic. Detailed clinical assessments and documented presence of diabetic peripheral neuropathy (DPN), macrovascular disease and microvascular disease were recorded. Education and counseling were part of the follow-up program. Results: 3271 ulcerations were presented at the clinic during the 3-year study period. 571 (18%) met the case definition for CN; all patients had Type 2 diabetes. The prevalence for each of the years 2013, 2014, and 2015 was 19/1192 (1.6%), 209/1044 (20%), and 343/1035 (34%), respectively; the increases in the slope of the trendline was statistically significant (P < .001). Conclusion: The prevalence of CN is increasing in the Tanzanian diabetes patient population, and is strongly associated with neuropathy. CN can lead to severe deformity, disability, and amputation. Due to the risk of limb amputation, patients with diabetes must seek immediate care if signs or symptoms appear and avoid delay in seeking medical attention. Early diagnosis of CN by caregivers is extremely important for successful outcomes.

Characterization of cholesterol efflux capacity in diabetic and non-diabetic patients with coronary artery disease: comparison between acute coronary syndrome and stable coronary artery disease

Abstract Introduction Type 2 diabetic patients more likely exhibit a lower high-density lipoprotein (HDL) level. Given a greater glycation and oxidative stress in diabetic subjects, these atherogenic characteristics could cause dysfunctional HDL including a reduced cholesterol efflux capacity (CEC), which may account for an increased risk of diabetic macrovascular disease including acute coronary syndrome (ACS). However, it remains to be fully elucidated characteristics of HDL-mediated CEC in type 2 diabetic patients, in association with clinical presentation of coronary artery disease (CAD). Purpose To characterize CEC in CAD subjects with type 2 diabetes mellitus. Methods The current study prospectively analyzed 87 statin-naive patients with CAD. CEC was measured by using the collected apolipoprotein B-depleted serum. Liquid scintillation counting (Perkin-Elmer Analytical Sciences, MA, US) was used to quantify the efflux of radioactive cholesterol from J774 cells. Clinical characteristics and CEC were compared in diabetic and non-diabetic subjects. Results The averaged HbA1c in diabetic patients was 6.7±1.2, and 66.7% of them achieved HbA1c &amp;lt;7.0%. Diabetic subjects more likely exhibited a history of hypertension and dyslipidemia, and multi-vessel disease (Table). Moreover, a lower CEC level was observed in diabetic patients, accompanied by a lower HDL-C and apolipoprotein A-I levels with a higher level of triglyceride (Table). HDL-C (r=0.62, p-value&amp;lt;0.01) and Apolipoprotein A-I (r=0.70, p-value &amp;lt;0.01) were associated with CEC, whereas there was no significant difference in CEC between subjects with HbA1c &amp;lt;7.0% vs. ≥7.0% (0.74±0.07 vs. 0.78±0.08, p=0.22). On multivariate analysis, type 2 diabetes mellitus was an independent contributor to CEC &amp;lt;0.79 (median) (HR=2.75, 95% CI: 1.11–6.82, p=0.03). Interestingly in particular, CEC was substantially lower in diabetic patients with ACS compared to those with stable CAD (Figure). By contrast, clinical presentation of CAD did not affect CEC in non-diabetic subjects (Figure). Conclusions A lower CEC level was observed in subjects with type 2 diabetes mellitus. In particular, this HDL functionality was profoundly diminished in those presenting ACS. Our findings suggest functionality of HDL as a potential therapeutic target in diabetic patients experiencing ACS. Funding Acknowledgement Type of funding sources: None. Table 1Figure 1

Relationship Between Diabetic Retinopathy Stages and Risk of Major Lower-Extremity Arterial Disease in Patients With Type 2 Diabetes.

We evaluated the association between diabetic retinopathy stages and lower-extremity arterial disease (LEAD), its prognostic value, and the influence of potential contributors to this relationship in a prospective cohort of patients with type 2 diabetes. Diabetic retinopathy was staged at baseline as absent, nonproliferative, or proliferative. A Cox regression model was fitted in order to compute the hazard ratio (HR) (95% CI) for major LEAD (lower-limb amputation or revascularization) during follow-up by baseline retinopathy stages. The retinopathy-LEAD association was assessed in subgroups by age, sex, diabetes duration, HbA1c, systolic blood pressure, diabetic kidney disease, smoking, and macrovascular disease at baseline. The performance of retinopathy in stratifying LEAD risk was assessed by using the C statistic, integrated discrimination improvement (IDI), and net reclassification improvement (NRI). Among 1,320 participants without a history of LEAD at baseline, 94 (7.1%) developed a major LEAD during a 7.1-year median follow-up (incidence rate 9.6 per 1,000 person-years [95% CI 7.8-11.7]). The LEAD incidence rate (per 1,000 person-years) increased as retinopathy worsened: it was 5.5 (95% CI 3.9-7.8) in participants in whom retinopathy was absent, 14.6 (11.1-19.3) in those with nonproliferative retinopathy, and 20.1 (11.1-36.3) in those with proliferative retinopathy. Nonproliferative retinopathy (adjusted HR 2.31 [95% CI 1.43-3.81], P = 0.0006) and proliferative retinopathy (3.14 [1.40-6.15], P = 0.007) remained associated with major LEAD. No heterogeneity was observed across subgroups. Retinopathy enhanced the C statistic (+0.023 [95% CI 0.003-0.044], P = 0.02), IDI (0.209 [0.130-0.321], P < 0.001), and NRI (0.562 [0.382-0.799], P < 0.001) values for risk of LEAD, beyond traditional risk factors. An independent dose-response relationship was identified between diabetic retinopathy stages and major LEAD. Retinopathy yielded incremental prognostic information for stratifying risk of LEAD, suggesting its usefulness as a predictor of LEAD.

Healthcare Costs of Diabetes and Microvascular and Macrovascular Disease in Individuals with Incident Type 2 Diabetes Mellitus: A Ten-Year Longitudinal Study.

ObjectiveThe objective of this study was to estimate the incremental long-term costs associated with T2DM attributable to vascular diseases.Research Design and MethodsThis retrospective cohort study identified newly diagnosed (incident) T2DM patients in 2007 (baseline to 01/01/2006) using the HealthCore Integrated Research Database, a repository of nationally representative claims data. Incident T2DM patients were 1:1 exact matched on age, gender and other factors of interest to non-DM patients, and followed until the earlier of 8 follow-up years or death. Patients with documented vascular disease diagnosis were identified during the study period. All-cause and T2DM/vascular disease-related annual healthcare costs were examined for each follow-up year.ResultsThe study included 13,883 individuals with T2DM and matched non-DM controls. Among individuals with T2DM, 11,792 (85%) had vascular disease versus 9251 (66.6%) non-T2DM between 01/01/2006 and 12/31/2015. Among T2DM patients, mean all-cause annual costs were greater than in non-T2DM patients ($13,806 vs $7,243, baseline, $21,745 vs $8,524, post-index year 1, $12,756-$14,793 vs $8,349-$9,940 years 2–8, p< 0.001), respectively. A similar trend was observed for T2DM/vascular disease-related costs (p< 0. 001). T2DM/vascular disease-related costs were largest during post-index year 1, accounting for the majority of all-cause cost difference between T2DM patients and matched non-DM controls. Incident T2DM individuals without vascular disease at any time had significantly lower costs compared to non-DM controls (p< 0. 001) between years 2–8 of follow-up.ConclusionVascular disease increased the cost burden for individuals with T2DM. The cost impact of diabetes and vascular disease was highest in the year after diagnosis, and persisted for at least seven additional years, while the cost of T2DM patients without vascular disease trended lower than for matched non-DM patients. These data highlight potential costs that could be offset by earlier and more effective detection and management of T2DM aimed at reducing vascular disease burden.

Mechanism of Danzhi Jiangtang Capsules in treatment of diabetic macrovascular disease in GK rats based on correlation between microRNAs and inflammatory factors

This study was aimed to investigate the mechanism of Danzhi Jiangtang Capsules( DJC) in the treatment of diabetic macrovascular disease in Goto-Kakizaki( GK) rats. The diabetic macrovascular disease rat model was induced by feeding high-fat and high-sugar combined with endothelial nitric oxide synthase( NOS) inhibitor N-nitro-L-arginine methyl ester( L-NAME)( 0. 1 g·L-1·d-1). According to the random array table,the model rats were randomly divided into the model group,DJC groups( 1 260,630,320 mg·kg-1),atorvastatin group( 105 mg·kg-1) and metformin group( 10 mg·kg-1),with 12 rats in each group. The rats received gavage administration for 8 weeks. Twelve Wistar rats were selected as the normal control group. The changes of body weight,water intake,blood glucose,plasma total cholesterol( TC),triglyceride( TG),high density lipoprotein( HDL-C),low density lipoprotein( LDL-C),interleukin( IL-1β),IL-6,tumor necrosis factor( TNF-α),nitric oxide( NO),endothelin( ET-1) were observed in these rats. Aortic tissue was taken and the pathological changes were observed by HE staining. RT-PCR was used to detect the mRNA levels of IL-1β,IL-6,and TNF-α in rat aorta. RT-PCR of the stem loop was used to detect the levels of miRNA-126,miRNA-155,miRNA-146 a,and miRNA-21 in rat plasma and aortic tissue. The canonical correlation between miRNAs and inflammatory factors was then analyzed. The results showed that DJC increased the rat body weight,lowered water intake,reduced the random blood glucose,reversed the rat aorta tissue damage,reduced serum TC,TG,LDL-C,ET-1,IL-1β,IL-6,TNF-α,as well as miRNA-155,miRNA-146 a and miRNA-21 levels in serum,elevated plasma HDL-C,NO content,reduced the aorta mRNA of IL-1β,IL-6,TNF-α,and the miRNA-155,miRNA-146 a and miRNA-21,elevated miRNA-126 expression in aorta. Aortic miRNA-126,miRNA-155,miRNA-146 a and miRNA-21 expression levels were typically correlated with the expression of inflammatory factors,among which miRNA-126 was negatively correlated,miRNA-155,miRNA-146 a and miRNA-21 were positively correlated with the factors. These results suggested that DJC had therapeutic effects on diabetic macrovascular diseases,and the mechanism of action may be related to the regulation of miRNA-126,miRNA-155,miRNA-146 a and miRNA-21 levels,as well as the reduction of inflammatory factors and vascular inflammatory response.

The efficacy of glycemic control with continuous glucose monitoring on atheroma progression: rationale and design of the Observation of Coronary Atheroma Progression under Continuous Glucose Monitoring Guidance in Patients with Type 2 Diabetes Mellitus (OPTIMAL).

Patients with type 2 diabetes mellitus (T2DM) are high-risk subjects who more frequently have micro- and macrovascular diseases including coronary artery disease (CAD). Since impaired glycemic homeostasis directly influences the formation and propagation of atherosclerotic plaques, optimal management of glycemic status is required for the prevention of diabetic atherosclerosis. Continuous glucose monitoring (CGM) provides not only average glucose level but also the degree of glucose fluctuation and hypoglycemia. Given the association of glycemic variability with diabetic macrovascular diseases, CGM-based glycemic management could favorably modulate glycemic fluctuation, thereby potentially modifying atheroma burden in T2DM subjects. To test this hypothesis, the Observation of Coronary Atheroma Progression under Continuous Glucose Monitoring Guidance in Patients with Type 2 Diabetes Mellitus (OPTIMAL) study has been designed (Japan Registry of Clinical Trials: jRCT1052180152, University Hospital Medical Information Network Clinical Trial Registry UMIN000036721). The OPTIMAL is a single-center, randomized trial to evaluate the efficacy of CGM-based glycemic control on atheroma progression in T2DM patients with CAD by using serial intravascular ultrasound (IVUS) and near-infrared spectroscopy (NIRS) imaging. A total of 90 eligible subjects will be randomized 1:1 into two groups to receive either CGM-based glycemic control or HbA1c-baded glycemic management. Coronary angiography and NIRS/IVUS imaging is repeated at the end of the assigned treatment period. The primary endpoint is the normalized absolute change in total atheroma volume (TAV) from baseline to 12 months. The secondary endpoints include (I) the absolute change in percent atheroma volume, (II) the percent change in lipid core burden index, (III) the change in coefficient variance measured by CGM, (IV) the change in atherogenic markers (high-density lipoprotein functionality, proprotein convertase subxilisin/kexin type 9 and fatty-acid binding proteins), and (V) the frequency of hypoglycemia. Safety will also be evaluated. The collaboration of CGM use with serial NIRS/IVUS imaging will enable to compare atheroma progression rate under CGM-based glycemic management and HbA1c-based approach.

Research progress on the relationship between complement system and diabetic microangiopathy

Diabetic microangiopathy is an vital reason of disabling and death in patients with diabetes. Long-term hyperglycemia and insulin resistance in type 2 diabetes mellitus can be involved in the formation of microangiopathy by aggravating mitochondrial damage, inflammation, and protein kinase C/glycosylation end product pathways. Besides, in recent years, several studies have shown that the activation of complement system plays an important role in the progression of diabetic vascular disease (including diabetic microvascular and macrovascular disease). This review is about to discuss the role and mechanism of the complement system in the development of diabetes and its microandioathy. Key words: Complement activation; Diabetic angiopathies; Diabetes mellitus, type 2; Review

Locally delivered GLP-1 analogues liraglutide and exenatide enhance microvascular perfusion in individuals with and without type 2 diabetes

Aims/hypothesisGlucagon-like peptide-1 (GLP-1) analogues reduce the risk of macrovascular disease in diabetes; however, little is known about their microvascular effects. This research examined the microvascular actions of the GLP-1 analogues liraglutide and exenatide in individuals with and without type 2 diabetes (study 1). It also explored the involvement of the GLP-1 receptor (study 2) and the nitric oxide pathway in mediating the microvascular effects of the analogues.MethodsTrial design: Studies 1 and 2 had a randomised, controlled, double-blind study design. Study 1 participants, intervention and methods: three participant groups were recruited: individuals with well-controlled type 2 diabetes, and obese and lean individuals without diabetes (21 participants per group). Liraglutide (0.06 mg), exenatide (0.5 μg) and saline (154 mmol/l NaCl; 0.9%) control were microinjected into separate sites in the dermis (forearm) in a randomised order, blinded to operator and participant. Skin microvascular perfusion was assessed by laser Doppler perfusion imaging. Outcomes were stabilised response (mean skin perfusion between 7.5 and 10 min post microinjection) and total response (AUC, normalised for baseline perfusion). Perfusion response to GLP-1 analogues was compared with saline within each group as well as between groups. Study 2 participants, intervention and methods: in healthy individuals (N = 16), liraglutide (0.06 mg) and saline microinjected sites were pretreated with saline or the GLP-1 receptor blocker, exendin-(9,39), in a randomised order, blinded to participant and operator. Outcomes were as above (stabilised response and total perfusion response). Perfusion response to liraglutide was compared between the saline and the exendin-(9,39) pretreated sites. In vitro study: the effects of liraglutide and exenatide on nitrate levels and endothelial nitric oxide synthase phosphorylation (activation) were examined using human microvascular endothelial cells.ResultsStudy 1 results: both analogues increased skin perfusion (stabilised response and total response) in all groups (n = 21 per group, p < 0.001), with the microvascular responses similar across groups (p ≥ 0.389). Study 2 results: liraglutide response (stabilised response and total response) was not influenced by pretreatment with exendin-(9,39) (70 nmol/l) (N = 15, one dataset excluded) (p ≥ 0.609). Liraglutide and exenatide increased nitrate production and endothelial nitric oxide synthase (eNOS) phosphorylation (p ≤ 0.020).Conclusions/interpretationLiraglutide and exenatide increased skin microvascular perfusion in individuals with and without well-controlled diabetes, potentially mediated, at least in part, by NO.Trial registrationClinicalTrials.gov NCT01677104.FundingThis work was supported by Diabetes UK (grant numbers: 09/0003955 and 12/0004600 [RW and JM Collins Legacy, Funded Studentship]).

Inhibition of P53/miR-34a improves diabetic endothelial dysfunction via activation of SIRT1.

Endothelial dysfunction contributes to diabetic macrovascular complications, resulting in high mortality. Recent findings demonstrate a pathogenic role of P53 in endothelial dysfunction, encouraging the investigation of the effect of P53 inhibition on diabetic endothelial dysfunction. Thus, high glucose (HG)‐treated endothelial cells (ECs) were subjected to pifithrin‐α (PFT‐α)—a specific inhibitor of P53, or P53‐small interfering RNA (siRNA), both of which attenuated the HG‐induced endothelial inflammation and oxidative stress. Moreover, inhibition of P53 by PFT‐α or P53‐siRNA prohibited P53 acetylation, decreased microRNA‐34a (miR‐34a) level, leading to a dramatic increase in sirtuin 1 (SIRT1) protein level. Interestingly, the miR‐34a inhibitor (miR‐34a‐I) and PFT‐α increased SIRT1 protein level and alleviated the HG‐induced endothelial inflammation and oxidative stress to a similar extent; however, these effects of PFT‐α were completely abrogated by the miR‐34a mimic. In addition, SIRT1 inhibition by EX‐527 or Sirt1‐siRNA completely abolished miR‐34a‐I's protection against HG‐induced endothelial inflammation and oxidative stress. Furthermore, in the aortas of streptozotocin‐induced diabetic mice, both PFT‐α and miR‐34a‐I rescued the inflammation, oxidative stress and endothelial dysfunction caused by hyperglycaemia. Hence, the present study has uncovered a P53/miR‐34a/SIRT1 pathway that leads to endothelial dysfunction, suggesting that P53/miR‐34a inhibition could be a viable strategy in the management of diabetic macrovascular diseases.

Selenoprotein S protects against high glucose-induced vascular endothelial apoptosis through the PKCβII/JNK/Bcl-2 pathway.

Vascular endothelial apoptosis is closely associated with the pathogenesis and progression of diabetic macrovascular diseases. Selenoprotein S (SelS) participates in the protection of vascular endothelial and smooth muscle cells from oxidative and endoplasmic reticulum stress-induced injury. However, whether SelS can protect vascular endothelium from high glucose (HG)-induced apoptosis and the underlying mechanism remains unclear. The present study preliminarily analyzed aortic endothelial apoptosis and SelS expression in diabetic rats in vivo and the effects of HG on human umbilical vein endothelial cell (HUVEC) apoptosis and SelS expression in vitro. Subsequently, SelS expression was up- or downregulated in HUVECs using the pcDNA3.1-SelS recombinant plasmid and SelS-specific small interfering RNAs, and the effects of high/low SelS expression on HG-induced HUVEC apoptosis and a possible molecular mechanism were analyzed. As expected, HG induced vascular endothelial apoptosis and upregulated endothelial SelS expression in vivo and in vitro. SelS overexpression in HUVECs suppressed HG-induced increase in apoptosis and cleaved caspase3 level, accompanied by reduced protein kinase CβII (PKCβII), c-JUN N-terminal kinase (JNK), and B-cell lymphoma/leukemia-2 (Bcl-2) phosphorylation. In contrast, inhibiting SelS expression in HUVECs further aggravated HG-induced increase in apoptosis and cleaved caspase3 level, which was accompanied by increased PKCβII, JNK, and Bcl-2 phosphorylation. Pretreatment with PKC activators blocked the protective effects of SelS and increased the apoptosis and cleaved caspase3 level in HUVECs. In summary, SelS protects vascular endothelium from HG-induced apoptosis, and this was achieved through the inhibition of PKCβII/JNK/Bcl-2 pathway to eventually inhibit caspase3 activation. SelS may be a promising target for the prevention and treatment of diabetic macrovascular complications.

The association of diabetic microvascular and macrovascular disease with cutaneous circulation in patients with type 2 diabetes mellitus

AimsTo study the impact of diabetic neuropathy, both peripheral sensorimotor (DPN) and cardiac autonomic neuropathy (CAN), on transcutaneous oxygen tension (TcPO2) in patients with type 2 diabetes mellitus (T2DM). MethodsA total of 163 participants were recruited; 100 with T2DM and 63 healthy individuals. Peripheral arterial disease (PAD) was defined as ankle-brachial index (ABI) values ≤0.90. Diagnosis of DPN was based on neuropathy symptom score and neuropathy disability score (NDS), while diagnosis of CAN on the battery of the cardiovascular autonomic function tests. TcPO2 was measured using a TCM30 system. ResultsPatients with T2DM had lower TcPO2 levels when compared with healthy individuals. Among the diabetic cohort, those who had either PAD, DPN or CAN had significantly lower TcPO2 values than participants without these complications. Multivariate linear regression analysis, after controlling for diabetes duration, diastolic blood pressure, HbA1c, albumin to creatinine ratio and CAN score, demonstrated that TcPO2 levels were significantly and independently associated with current smoking (p = 0.013), ABI (p = 0.003), and NDS (p = 0.013). ConclusionPresence of DPN is independently associated with impaired cutaneous perfusion. Low TcPO2 in subjects with DPN may contribute to delay in healing of diabetic foot ulcers, irrespectively of PAD.

Association of the genetic variant rs2000999 with haptoglobin and diabetic macrovascular diseases in Chinese patients with type 2 diabetes

AimsThe common copy number variant (CNV) in the haptoglobin (Hp) gene may influence the susceptibility to diabetic macrovascular diseases. We aimed to investigate the relationship of the genetic variant rs2000999, located in the haptoglobin-related protein (HPR) gene, with serum Hp levels and diabetic macrovascular diseases in Chinese type 2 diabetes patients. MethodsThe Hp CNV and rs2000999 were genotyped in a group of 5457 Chinese patients with type 2 diabetes. Associations of rs2000999 with the common Hp CNV, susceptibility to diabetic macrovascular diseases and related metabolic traits were analysed. Furthermore, 886 patients were selected to detect serum Hp levels and to evaluate the correlation between rs2000999 and serum Hp levels. ResultsThe genetic variant rs2000999 was not associated with diabetic macrovascular diseases (P = 0.6109), while subjects carrying the A allele had higher levels of low-density lipoprotein cholesterol (P = 0.0578) and a smaller inter-adventitial diameter of the common carotid artery (P = 0.0266). Additionally, rs2000999 exhibited strong association with serum Hp levels (P = 2.03 × 10−21). ConclusionsThe genetic variant rs2000999 was not associated with diabetic macrovascular diseases but showed an association with metabolic traits and serum Hp levels in Chinese patients with type 2 diabetes.

Proteome profiling in the aorta and kidney of type 1 diabetic rats.

Diabetes is associated with a number of metabolic and cardiovascular risk factors that contribute to a high rate of microvascular and macrovascular complications. The risk factors and mechanisms that contribute to the development of micro- and macrovascular disease in diabetes are not fully explained. In this study, we employed mass spectrometric analysis using tandem LC-MS/MS to generate a proteomic profile of protein abundance and post-translational modifications (PTM) in the aorta and kidney of diabetic rats. In addition, systems biology analyses were employed to identify key protein markers that can provide insights into molecular pathways and processes that are differentially regulated in the aorta and kidney of type 1 diabetic rats. Our results indicated that 188 (111 downregulated and 77 upregulated) proteins were significantly identified in the aorta of diabetic rats compared to normal controls. A total of 223 (109 downregulated and 114 upregulated) proteins were significantly identified in the kidney of diabetic rats compared to normal controls. When the protein profiles from the kidney and aorta of diabetic and control rats were analyzed by principal component analysis, a distinct separation of the groups was observed. In addition, diabetes resulted in a significant increase in PTM (oxidation, phosphorylation, and acetylation) of proteins in the kidney and aorta and this effect was partially reversed by insulin treatment. Ingenuity pathway analysis performed on the list of differentially expressed proteins depicted mitochondrial dysfunction, oxidative phosphorylation and acute phase response signaling to be among the altered canonical pathways by diabetes in both tissues. The findings of the present study provide a global proteomics view of markers that highlight the mechanisms and putative processes that modulate renal and vascular injury in diabetes.