Abstract 344: Endothelin-1 Overexpression Exaggerates Diabetes-induced Endothelial Dysfunction

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Noureddine IDRIS KHODJA ◽  
Muhammad Oneeb Rehman Mian ◽  
Tlili Barhoumi ◽  
Sofiane Ouerd ◽  
Jordan Gornitsky ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Endothelial Dysfunction ◽  
Vascular Complications ◽  
Fold Increase ◽  
Wild Type ◽  
No Donor ◽  
Meclofenamic Acid ◽  
Fibronectin Expression ◽  
Endothelium Dependent Relaxation

Objective: Vascular disease associated with endothelial dysfunction is a major cause of morbidity in patients with type-1 diabetes. Endothelin (ET)-1 plays a role in diabetes-induced vascular complications, since ET-1 type A receptor blockade reduces diabetes-induced vascular injury. However, whether ET-1 contributes to diabetes-induced endothelial dysfunction remains unproven. We hypothesized that vascular ET-1 overexpression will exaggerate diabetes-induced endothelial dysfunction. Methods: Diabetes was induced by streptozotocin treatment (STZ, 55 mg/kg/day, ip) for 5 days in 6-week-old male wild-type (WT) mice and in mice overexpressing ET-1 restricted to the endothelium (eET-1). Mice were studied 14 weeks later. Blood was collected to determine glucose. Mesenteric artery reactivity and remodeling were evaluated using pressurized myography and aortic fibronectin expression by immnunofluorescence. Results: STZ-induced diabetes was confirmed by a 3-fold increase in glycemia in WT and eET-1 ( P <0.001). Diabetes impaired endothelium-dependent relaxation (EDR) reponses to acetylcholine in WT (60.9±6.4% vs 83.9±3.4%, P <0.05) and eET-1 (48.6±5.1% vs 81.5±5.2%, P <0.001). EDR impairment was exaggerated in eET-1 compared to WT ( P <0.05). Meclofenamic acid, an inhibitor of cyclooxygenase, increased EDR in eET-1 compared to WT (78.4±9.4% vs 66.7±3.2%, P <0.01), which was not observed in diabetic mice. L-NAME, an inhibitor of nitric oxide (NO) synthase, completely blocked EDR in WT, eET-1 and diabetic WT, but not in diabetic eET-1 (4.1±1.6%, 6.4±5.7%, 2.2±4.6% and 26.6±4.6%, P <0.05). Apamin plus Tram34, inhibitors of endothelium-dependent hyperpolarization inhibited EDR in the four groups. Endothelium-independent relaxation to sodium nitroprusside, a NO donor, was similar in the four groups. Diabetes reduced media/lumen in WT (2.7±0.3 vs 3.6±0.3, P <0.05) and eET-1 (2.9±0.2 vs 3.8±0.3, P <0.05). Diabetes decreased aortic fibronectin expression in WT (94.0±11.0 vs. 151.9±21.8 RFU/μm 2 , P <0.05) and eET-1 (66.3±8.7 vs. 146.6±20.7 RFU/μm 2 , P <0.05). Conclusion: ET-1 contributes to alterations in several pathways mediating endothelium-dependent relaxation in type-1 diabetes, leading to exaggerated endothelial dysfunction.

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

2015 ◽  
Vol 309 (9) ◽  
pp. C593-C599 ◽  
Author(s):  
Ayako Makino ◽  
Anzhi Dai ◽  
Ying Han ◽  
Katia D. Youssef ◽  
Weihua Wang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Protein Modification ◽  
Control Level ◽  
Vascular Complications ◽  
Capillary Density ◽  
Diabetic Mice ◽  
Endothelium Dependent Relaxation

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: β- 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.

Abstract P225: Nox1 or Nox4 Deletion Prevents Type-1 Diabetes-induced Endothelial Dysfunction

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Sofiane Ouerd ◽  
Noureddine Idris-Khodja ◽  
Michelle Trindade ◽  
Suellen C Coelho ◽  
Mario F Neves ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Endothelial Dysfunction ◽  
Vascular Injury ◽  
Vascular Remodeling ◽  
Vascular Complications ◽  
Macrovascular Disease ◽  
Mesenteric Arteries ◽  
Small Arteries ◽  
Increased Risk

Objective: The prognosis of type-1 diabetes is in part related to the increased risk of vascular complications such as atherosclerosis. Overproduction of reactive oxygen species by NADPH oxidase (NOX) is believed to play an important role in diabetes-related vascular injury. NOX1 may play a role in the macrovascular disease, whereas NOX4 may have protective actions. Nevertheless, their role in diabetic vascular injury is less well understood. We hypothesized that deletion of Nox1 would prevent diabetes-induced endothelial dysfunction and vascular remodeling of small arteries whereas Nox4 would exaggerate vascular injury in atherosclerosis-prone apolipoprotein knockout ( Apoe -/- ) mice. Methods: Diabetes was induced by streptozotocin IP injections (STZ, 55 mg/kg/day) for 5 days in 6-week-old male Apoe -/- mice, Apoe -/- mice deficient in Nox1 ( Apoe -/- / Nox1 y/- ) and Nox4 ( Apoe -/- / Nox4 -/- ). Mice were studied 14 weeks later. Endothelial function and vascular remodeling were assessed in mesenteric arteries (MA) using pressurized myography. Results: Apoe -/- mice presented a maximal endothelium-dependent vasodilatory response (E max ) to acetylcholine of 48±8%, which was further decreased by diabetes to 20±6%. In contrast, endothelium-dependent relaxations to acetylcholine were 1.5-fold higher in diabetic Apoe -/- / Nox1 y/- and Apoe -/- / Nox4 -/- mice compared to non-diabetic Apoe -/- mice (E max : 72±9 and 70±7 vs 48±8%). Diabetes decreased MA stiffness in Apoe -/- mice, as indicated by a rightward displacement of the stress-strain curves (strain at 140 mm Hg: 1.02±0.04 vs 0.75±0.04), which was blunted by Nox1 or Nox4 knockout (strain at 140 mm Hg: 0.77±0.02 and 0.81±0.02). MA media/lumen was unaltered by diabetes. Knockout of Nox4 but not Nox1 increased MA media/lumen 1.4-fold in diabetic Apoe -/- mice (4.1±0.4 and 3.5±0.2 vs 2.9±0.2%). Conclusions: These results suggest that NOX1 and NOX4 play a pathophysiological role in diabetes-induced endothelial dysfunction and contribute to potentially maladaptive changes in vascular stiffness. NOX4 seems to have dual actions on the vasculature, as it is also protective against vascular remodeling of small arteries in type 1 diabetes.

scholarly journals A review of risk factors associated with insulin omission for weight loss in type 1 diabetes

2021 ◽  
pp. 135910452110261
Author(s):  
Rebecca Hall ◽  
Leanna Keeble ◽  
Sandra-Ilona Sünram-Lea ◽  
Michelle To
Keyword(s):  
Risk Factors ◽  
Weight Loss ◽  
Type 1 Diabetes ◽  
Body Dissatisfaction ◽  
Vascular Complications ◽  
Anxiety And Depression ◽  
Weight Concerns ◽  
Complications And Mortality ◽  
Insulin Omission

Research suggests that as many as 60% of people with type 1 diabetes (T1D) admit to misusing insulin. Insulin omission (IO) for the purpose of weight loss, often referred to as diabulimia, is a behaviour becoming increasingly recognised, not least since prolonged engagement can lead to serious vascular complications and mortality. Several risk factors appear to be relevant to the development of IO, most notably gender, anxiety and depression and increased weight concerns and body dissatisfaction. Evidence suggests that women, especially young girls, are more likely to omit insulin as a method of weight loss compared to men. Mental health conditions such as anxiety and depression are increasingly prevalent in people with T1D compared to their peers, and appear to contribute to the risk of IO. Increased weight concerns and body dissatisfaction are further prominent risk factors, especially given increases in weight which often occur following diagnosis and the monitoring of weight by diabetes teams. This review presents evidence examining these risk factors which increase the likelihood of a person with T1D engaging in IO and highlights the complications associated with prolongment of the behaviour. Further research looking at the comorbidities of these risk factors, alongside other factors, would provide greater insight into understanding IO in people with T1D.

scholarly journals Sphingosine-1-phosphate inhibits high glucose-mediated ERK1/2 action in endothelium through induction of MAP kinase phosphatase-3

2009 ◽  
Vol 296 (2) ◽  
pp. C339-C345 ◽  
Author(s):  
Angela M. Whetzel ◽  
David T. Bolick ◽  
Catherine C. Hedrick
Keyword(s):  
Endothelial Cells ◽  
Type 1 Diabetes ◽  
Vascular Complications ◽  
Nod Mice ◽  
Endothelial Activation ◽  
Adhesion Assay ◽  
Monocyte Adhesion ◽  
Map Kinase Phosphatase ◽  
Sphingosine 1 Phosphate

Endothelial activation is a key early event in vascular complications of Type 1 diabetes. The nonobese diabetic (NOD) mouse is a well-characterized model of Type 1 diabetes. We previously reported that Type 1 diabetic NOD mice have increased endothelial activation, with increased production of monocyte chemoattractant protein (MCP)-1 and IL-6, and a 30% increase of surface VCAM-1 expression leading to a fourfold increase in monocyte adhesion to the endothelium. Sphingosine-1-phosphate (S1P) prevents monocyte:endothelial interactions in these diabetic NOD mice. Incubation of diabetic NOD endothelial cells (EC) with S1P (100 nmol/l) reduced ERK1/2 phosphorylation by 90%, with no significant changes in total ERK1/2 protein. In the current study, we investigated the mechanism of S1P action on ERK1/2 to reduce activation of diabetic endothelium. S1P caused a significant threefold increase in mitogen-activated kinase phosphatase-3 (MKP-3) expression in EC. MKP-3 selectively regulates ERK1/2 activity through dephosphorylation. Incubation of diabetic NOD EC with S1P and the S1P1-selective agonist SEW2871 significantly increased expression of MKP-3 and reduced ERK1/2 phosphorylation, while incubation with the S1P1/S1P3 antagonist VPC23019 decreased the expression of MKP-3, both results supporting a role for S1P1 in MKP-3 regulation. To mimic the S1P-mediated induction of MKP-3 diabetic NOD EC, we overexpressed MKP-3 in human aortic endothelial cells (HAEC) cultured in elevated glucose (25 mmol/l). Overexpression of MKP-3 in glucose-cultured HAEC decreased ERK1/2 phosphorylation and resulted in decreased monocyte:endothelial interactions in a static monocyte adhesion assay. Finally, we used small interfering RNA to MKP-3 and observed increased monocyte adhesion. Moreover, S1P was unable to inhibit monocyte adhesion in the absence of MKP-3. Thus, one mechanism for the anti-inflammatory action of S1P in diabetic EC is inhibition of ERK1/2 phosphorylation through induction of MKP-3 expression via the S1P-S1P1 receptor axis.

scholarly journals YKL-40, a Marker of Inflammation and Endothelial Dysfunction, Is Elevated in Patients With Type 1 Diabetes and Increases With Levels of Albuminuria

Diabetes Care ◽  
2008 ◽  
Vol 32 (2) ◽  
pp. 323-328 ◽  
Author(s):  
C. N. Rathcke ◽  
F. Persson ◽  
L. Tarnow ◽  
P. Rossing ◽  
H. Vestergaard
Keyword(s):  
Type 1 Diabetes ◽  
Endothelial Dysfunction

scholarly journals CCAAT/enhancer binding protein β-deficiency enhances type 1 diabetic bone phenotype by increasing marrow adiposity and bone resorption

2011 ◽  
Vol 300 (5) ◽  
pp. R1250-R1260 ◽  
Author(s):  
Katherine J. Motyl ◽  
Michelle Raetz ◽  
Srinivasan Arjun Tekalur ◽  
Richard C. Schwartz ◽  
Laura R. McCabe
Keyword(s):  
Bone Marrow ◽  
Type 1 Diabetes ◽  
Bone Resorption ◽  
Bone Loss ◽  
Wild Type ◽  
Bone Stiffness ◽  
Bone Phenotype ◽  
Enhancer Binding Protein ◽  
Marrow Adiposity

Bone loss in type 1 diabetes is accompanied by increased marrow fat, which could directly reduce osteoblast activity or result from altered bone marrow mesenchymal cell lineage selection (adipocyte vs. osteoblast). CCAAT/enhancer binding protein beta (C/EBPβ) is an important regulator of both adipocyte and osteoblast differentiation. C/EBPβ-null mice have delayed bone formation and defective lipid accumulation in brown adipose tissue. To examine the balance of C/EBPβ functions in the diabetic context, we induced type 1 diabetes in C/EBPβ-null (knockout, KO) mice. We found that C/EBPβ deficiency actually enhanced the diabetic bone phenotype. While KO mice had reduced peripheral fat mass compared with wild-type mice, they had 5-fold more marrow adipocytes than diabetic wild-type mice. The enhanced marrow adiposity may be attributed to compensation by C/EBPδ, peroxisome proliferator-activated receptor-γ2, and C/EBPα. Concurrently, we observed reduced bone density. Relative to genotype controls, trabecular bone volume fraction loss was escalated in diabetic KO mice (−48%) compared with changes in diabetic wild-type mice (−22%). Despite greater bone loss, osteoblast markers were not further suppressed in diabetic KO mice. Instead, osteoclast markers were increased in the KO diabetic mice. Thus, C/EBPβ deficiency increases diabetes-induced bone marrow (not peripheral) adipose depot mass, and promotes additional bone loss through stimulating bone resorption. C/EBPβ-deficiency also reduced bone stiffness and diabetes exacerbated this (two-way ANOVA P < 0.02). We conclude that C/EBPβ alone is not responsible for the bone vs. fat phenotype switch observed in T1 diabetes and that suppression of CEBPβ levels may further bone loss and decrease bone stiffness by increasing bone resorption.

scholarly journals Molecular disorders of erythrocyte and platelet membranes in vascular complications of type 1 diabetes mellitus

2006 ◽  
Vol 5 (4) ◽  
pp. 33-41
Author(s):  
Ye. B. Kravets ◽  
N. V. Ryazantseva ◽  
N. M. Yakovleva ◽  
V. N. Butusova ◽  
O. M. Choudakova ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
Type 1 Diabetes Mellitus ◽  
Vascular Complications ◽  
Platelet Membranes

scholarly journals The profile of plasma non-esterified fatty acids in children with different terms of type 1 diabetes mellitus

2016 ◽  
Vol 62 (2) ◽  
pp. 206-211 ◽  
Author(s):  
V.A. Akmurzina ◽  
E.E. Petryairina ◽  
S.V. Saveliev ◽  
A.A. Selishcheva
Keyword(s):  
Diabetes Mellitus ◽  
Fatty Acids ◽  
Type 1 Diabetes ◽  
Type 1 Diabetes Mellitus ◽  
Plasma Lipids ◽  
Solid Phase ◽  
Fold Increase ◽  
Healthy Children ◽  
Esterified Fatty Acids

Composition and quantitative content of non-esterified fatty acids (NEFA) were investigated in plasma samples of healthy children (12) and children with type 1 diabetes mellitus (DM1) (31) by gas chromatography (GC) after preliminary NEFA solid-phase extraction from plasma lipids. There was a significant (p<0.001) 1.6-fold increase in the total level of NEFA regardless of the disease duration. In the group of DM1 children with the disease period less than 1 year there was an increase in the arachidonic acid (20:4) content (30%) and the oleic acid trans-isomer (18:1) content (82%), and also a decrease in the docosahexaenoic acid (22:6 n3) content (26% ) and the docosapentaenoic acids (22:5 n-6) content (60%). In the group of DM1 children with prolonged course of this disease the altered NEFA levels returned to the normal level

Abstract 5826: MicroSPECT-CT Imaging Demonstrates Impairment of Matrix Metalloproteinases Activation in Ischemic Peripheral Angiogenesis in Type-1 Diabetes Associated with Glycation

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Lawrence W Dobrucki ◽  
Donna Dione ◽  
Leszek Kalinowski ◽  
Albert J Sinusas
Keyword(s):  
Type 1 Diabetes ◽  
Matrix Metalloproteinases ◽  
Advanced Glycation Endproducts ◽  
Fold Increase ◽  
Ct Imaging ◽  
Invasive Approach ◽  
Glycation Endproducts ◽  
Glucose Levels ◽  
Fasting Glycemia

We previously demonstrated an impairment of ischemic peripheral angiogenesis (IPA) in a murine model of hindlimb ischemia using a radiolabeled RGD peptide targeted at alpha-v integrin in type-1 diabetes mellitus (DM) in association with advanced glycation endproducts (AGE). Glycation of the extracellular matrix (ECM) in DM inhibits ECM degradation by matrix metalloproteinases (MMPs), and impairs IPA. We hypothesized that targeted microSPECT-CT imaging of MMP activation with 99m Tc-labeled peptidomimetic (RP805; Lantheus, USA) would demonstrate impaired MMP activation during IPA in DM in association with AGE accumulation. Right femoral artery was surgically ligated on C57BL/6 male non-DM mice (n= 12) and DM mice (n= 17) 4–6 wks after STZ treatment (40 mg/kg i.p. for 5 days). DM mice demonstrated glycosuria and fasting glycemia (>200 mg/dL). RP805 (1.6± 0.5mCi) was injected and microSPECT-CT imaging performed 60 min later in mice 1 week (non-DM: n= 5; DM: n= 9) and 2 weeks (non-DM: n= 7; DM: n= 8) post-ligation. Blood was collected in additional non-DM (n= 4) and DM (n= 4) mice for measurement of HbA1c, an index of AGE accumulation. MicroSPECT-CT images were analyzed for RP805 activity within hindlimb distal to ligation, and ischemic-to-nonischemic (I/N) activity ratios calculated. DM mice demonstrated ~3-fold increase in glucose levels, and ~2.7-fold increase in AGE. Quantitative RP805 imaging demonstrated an impairment of MMP activation (~47%, P< 0.05) in DM at 1 week post-ligation, which normalized at 2 weeks. RP805 microSPECT-CT imaging provides a novel non-invasive approach for evaluation of impaired MMP activation during IPA in DM, and was associated with AGE accumulation.

scholarly journals Sexual Dysfunction in Young Women with Type 1 Diabetes

2020 ◽  
Vol 17 (12) ◽  
pp. 4468
Author(s):  
Edyta Cichocka ◽  
Michał Jagusiewicz ◽  
Janusz Gumprecht
Keyword(s):  
Type 1 Diabetes ◽  
Urinary Tract ◽  
Sexual Function ◽  
Urinary Tract Infections ◽  
Vascular Complications ◽  
Chronic Complications ◽  
Patients With Diabetes ◽  
The Mean ◽  
Tract Infections

Introduction: Sexual dysfunctions (SD) are chronic complications that can develop due to vascular complications or autonomic neuropathy. Additionally, such complications can be of hormonal, infectious or psychogenic etiology. Objectives: The aim of study was to assess the sexual function and acceptance of the chronic disease in young sexually active women with type 1 diabetes (T1DM). Materials and methods: A total of 169 female patients with T1DM completed two standardized questionnaires, the Female Sexual Function Index (FSFI) and the Acceptance of Illness Scale (AIS). Other medical data were collected from medical history. Results: The mean FSFI score was 27.96 ± 5.00, and the mean AIS score was 29.67 ± 8.28. The score < 26 points in FSFI was obtained by 28.7% of patients. Analysis of correlation between the FSFI and the AIS showed that the higher the score on the FSFI, the higher the score on the AIS. Patients who underwent regular physical activity (55%) had a significantly higher acceptance of the disease (p = 0.0026) and reported painful intercourse significantly less frequently (p = 0.01). The value of HbA1c in the study group was 7.31 ± 1.25%. Patients with poorer glycemic control (HbA1c > 8%) obtained significantly lower scores on the FSFI (p = 0.03), whereas no differences were found on the AIS. Diabetes-related complications were observed in 25.5% of patients. The presence of chronic complications did not affect the results of the FSFI or the AIS. Patients with diabetes and hypertension had poorer functioning in the sexual sphere and had significantly lower scores on the FSFI. Past or present history of depression was reported by 36% of patients and also negatively affected acceptance of diabetes (p = 0.0015). Patients who reported recurrent urinary tract infections (17%) achieved significantly lower scores on the FSFI (p = 0.03) and showed that sex-related pain was significantly more prevalent (p = 0.02). In the case of the statement related to the embarrassment of people around the patient due to diabetes, patients with lower scores complained of SD significantly more often (p = 0.0033). Past deliveries, the type of labor, the use of contraceptives or the number of sexual partners had no influence on the overall assessment in both scales. However, in terms of desire, women who had delivered obtained higher scores (p = 0.0021). Conclusion: SD in women with T1DM may result from diabetes-related complications, hormonal disorders or recurrent genital or urinary tract infections. However, they usually have a psychological basis due to the lack of acceptance of the problems related to the treatment of diabetes.

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