Abstract 516: Altered Autophagy Contributes to Endothelial Dysfunction in Human Diabetes Mellitus

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Jessica L Fetterman ◽  
Nir Flint ◽  
Monica Holbrook ◽  
Erika A Linder ◽  
Brittany D Berk ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Vascular Function ◽  
Experimental Models ◽  
Diabetic Patients ◽  
Autophagic Flux ◽  
Compensatory Response ◽  
Patients With Diabetes ◽  
Lc3 Puncta

Diabetes is associated with increased oxidative stress and decreased nitric oxide (NO) bioactivity in the vasculature. Autophagy is a critical multistep pathway that eliminates oxidatively damaged proteins and organelles from the cell. Emerging evidence implicates impaired autophagy in a variety of non-vascular tissues that contributes to the pathogenesis of diabetes in experimental models. We hypothesized that impaired autophagy contributes to endothelial dysfunction associated with type 2 diabetes mellitus in humans. We measured vascular function and markers of autophagy in freshly isolated endothelial cells from patients with diabetes (n=41) and non-diabetic controls (n=41). Diabetes was associated with endothelial dysfunction characterized by lower brachial artery flow-mediated dilation. Endothelial cells from diabetic patients displayed no differences in LC3 puncta compared to those from controls but had higher levels of endothelial p62 (p=0.004), a protein that accumulates with reduced autophagic flux. In endothelial cells from controls, the autophagy inhibitor bafilomycin impaired eNOS activation, confirming that intact autophagy is necessary for NO signaling. Global activation of autophagy with spermidine reversed endothelial dysfunction in cultured endothelial cells exposed to high glucose (p=0.007). In regard to mechanism of impairment, the autophagy initiator rapamycin failed to improve eNOS activation in endothelial cells from diabetics. Further, expression of beclin-1, a key contributor to autophagosome formation, was similar in diabetics and controls, arguing against impaired initiation of autophagy. In endothelial cells from diabetics, blocking the terminal step of autophagy with bafilomycin led to a further accumulation of p62 (P=0.01), suggesting intact but insufficient levels of autophagy. Lamp2a, which facilitates the merger of autophagosomes and lysosomes, was higher in diabetic cells, possibly reflecting a compensatory response to reduced flux. Collectively, these findings provide evidence for inadequate autophagic flux in endothelial cells from diabetic patients that contributes to endothelial dysfunction and may be a target for therapy of diabetic vascular disease.

Abstract 12185: Restoration of Autophagy in Endothelial Cells From Patients With Diabetes Improves Nitric Oxide Signaling

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Jessica L Fetterman ◽  
Nir Flint ◽  
Monica Holbrook ◽  
Erika A Linder ◽  
Brittany D Berk ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Vascular Function ◽  
Diabetic Patients ◽  
Autophagic Flux ◽  
Compensatory Response ◽  
Nitric Oxide Signaling ◽  
Patients With Diabetes ◽  
No Signaling

Diabetes is associated with oxidative stress and decreased nitric oxide bioactivity in the vasculature. Autophagy is a critical multistep pathway that eliminates damaged proteins and organelles from the cell. Emerging evidence suggests impaired autophagy in non-vascular tissues contributes to the pathogenesis of diabetes. We hypothesized that impaired autophagy contributes to endothelial dysfunction associated with diabetes in humans. We measured vascular function and autophagy markers in freshly isolated endothelial cells (ECs) from patients with diabetes and non-diabetic controls. Diabetes was associated with endothelial dysfunction characterized by lower brachial artery flow-mediated dilation and impaired activation of eNOS by insulin in ECs. ECs from diabetic patients had higher levels of p62 (Figure), a protein that accumulates with reduced autophagic flux. Measures of autophagy initiation including rapamycin stimulation, beclin 1 levels, and LC3 puncta were not different. Global activation of autophagy with spermidine reversed endothelial dysfunction in freshly isolated ECs from diabetic patients (Figure). In ECs from controls, inhibiting autophagy with bafilomycin impaired eNOS activation confirming that intact autophagy promotes NO signaling. Evidence from cultured endothelial cells in high glucose conditions suggested that lysosomal function is intact as measured by lysosomal number and acidification. Blocking the terminal step of autophagy with bafilomycin in ECs from diabetics led to a further accumulation of p62, suggesting intact but insufficient levels of autophagy. Lamp2a, which facilitates the merger of autophagosomes and lysosomes, was higher in diabetic cells, possibly reflecting a compensatory response to reduced flux. These findings provide evidence for inadequate autophagic flux in ECs from diabetic patients that contributes to impaired NO signaling and may be a target for therapy of diabetic vascular disease.

Deficient Autophagy Contributes to the Development of Diabetic Retinopathy

2020 ◽  
Author(s):  
Jacqueline M. Lopes de Faria ◽  
Marcella Neves Dátilo
Keyword(s):  
Diabetes Mellitus ◽  
Endothelial Cells ◽  
Diabetic Retinopathy ◽  
Cell Survival ◽  
Nutrient Recycling ◽  
Degradation Process ◽  
Microvascular Endothelial Cells ◽  
Diabetic Patients ◽  
Autophagic Flux ◽  
Retinal Glial Cell

Autophagy is a self-degradation process essential to maintain intracellular homeostasis and cell survival, controlling elimination of pathogens, damage to organelles, and nutrient recycling to generate energy. Alterations in autophagic flux have been reported in the mechanisms of several diseases such as neurodegenerative diseases, cancer, diabetes mellitus, and its associated complications. Diabetic retinopathy (DR) is a microvascular complication of diabetes, affecting nearly 30% of diabetic patients. Several pathways are triggered and repressed in the development of DR, and autophagy showed to be relevant in the pathogenesis of this devastating complication. In this chapter, autophagy’s involvement in the development and progression of DR will be discussed, mainly in retinal pigmented epithelial cells and retinal microvascular endothelial cells, as well as in Müller cells—the more prominent retinal glial cell.

Abstract 18673: JNK Inhibition Restores Endothelial Function in Type 2 Diabetes Mellitus

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Rosa Breton-Romero ◽  
Bihua Feng ◽  
Monika Holbrook ◽  
Melissa G Farb ◽  
Jessica L Fetterman ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Endothelial Cells ◽  
Cardiovascular Diseases ◽  
Endothelial Dysfunction ◽  
Diabetic Patients ◽  
Jnk Activation

Introduction: Diabetes mellitus type 2 is an increasingly public health problem and it is a major cause in the development of cardiovascular diseases. Endothelial dysfunction is a key mechanism that contributes to the pathogenesis of cardiovascular diseases and is a well-known feature of clinical diabetes. Prior studies have demonstrated an impaired nitric oxide bioavailability and a reduced endothelium-dependent vasodilation under diabetic conditions and in animal models, JNK activity has been widely described to be involved in systemic insulin resistance. Hypothesis: Our study aimed to evaluate the involvement of JNK in endothelial dysfunction, studying its potential role in altered eNOS activation and NO synthesis in diabetic patients. Methods: We measured endothelial function and JNK activity in freshly isolated endothelial cells from diabetic patients (n=38) and nondiabetic controls (n=40). Results: ECs from diabetic patients displayed impaired eNOS activation and reduced NO release after insulin and A23187 stimulation, consistent with the presence of endothelial dysfunction. JNK activation was higher in diabetic (**P=0.003), and was associated with lower flow-mediated dilation (r=-0.53, *P=0.02). In endothelial cells from diabetic patients, treatment with JNK chemical inhibitor (SP600125) restored eNOS activation and insulin response (***P<0.001). Nitric oxide bioactivity after A23187 stimuli with diabetes was also recovered in endothelial cells from patients with diabetes. Conclusions: In summary, our data suggest that JNK activation contributes to vascular insulin resistance and endothelial dysfunction in patients with type 2 diabetes and may represent a target in novel therapeutic opportunities.

Intramuscular Nerve and Neuromuscular Junction Alteration In Extraocular Muscles of Diabetic Mice

1985 ◽  
Vol 43 ◽  
pp. 682-683
Author(s):  
Bruce R. Pachter
Keyword(s):  
Diabetes Mellitus ◽  
Peripheral Nerves ◽  
Sudden Onset ◽  
Extraocular Muscles ◽  
Diabetic Patients ◽  
Oculomotor Palsy ◽  
Third Nerve Palsy ◽  
Patients With Diabetes ◽  
Intramuscular Nerve ◽  
Oculomotor Nerves

Diabetes mellitus is one of the commonest causes of neuropathy. Diabetic neuropathy is a heterogeneous group of neuropathic disorders to which patients with diabetes mellitus are susceptible; more than one kind of neuropathy can frequently occur in the same individual. Abnormalities are also known to occur in nearly every anatomic subdivision of the eye in diabetic patients. Oculomotor palsy appears to be common in diabetes mellitus for their occurrence in isolation to suggest diabetes. Nerves to the external ocular muscles are most commonly affected, particularly the oculomotor or third cranial nerve. The third nerve palsy of diabetes is characteristic, being of sudden onset, accompanied by orbital and retro-orbital pain, often associated with complete involvement of the external ocular muscles innervated by the nerve. While the human and experimental animal literature is replete with studies on the peripheral nerves in diabetes mellitus, there is but a paucity of reported studies dealing with the oculomotor nerves and their associated extraocular muscles (EOMs).

scholarly journals A preliminary study on diabetes self-management education and glycemic control among patients with diabetes mellitus

2019 ◽  
Vol 9 (9) ◽  
pp. 98 ◽  
Author(s):  
Kisokanth G. ◽  
Indrakumar J. ◽  
Prathapan S. ◽  
Joseph J. ◽  
Ilankoon I.M.P.S.
Keyword(s):  
Diabetes Mellitus ◽  
Glycemic Control ◽  
Management Education ◽  
Self Management ◽  
Rank Test ◽  
Diabetic Patients ◽  
Effective Measure ◽  
Before And After ◽  
Patients With Diabetes ◽  
Preliminary Study

This study was aimed to assess the effectiveness of diabetes self-management education (DSME) in the improvement of glycemic control among patients with type 2 Diabetes Mellitus (T2DM) in Batticaloa District, Sri Lanka. The study was a prospective interventional study and conducted as a preliminary study at medical clinic, Base hospital, Kaluwanchikudy, Batticaloa. Thirty patients with T2DM were included based on inclusion and exclusion criteria. A structured individual diabetes self-management education for 10 hours (one hour per week) was delivered to diabetic patients by the trained Nurse Health Educator. Glycosylate hemoglobin (HbA1c) was assessed as a main outcome measure and Fasting Blood Sugar (FBS), Body Mass Index (BMI) of each patient were also measured and recorded before and after the intervention. The respondent rate was 96.7% (n = 29). Majority of them were females (n = 25, 86.2%). A Wilcoxon signed rank test showed that DSME had a statistically significant reduction in HbA1c [8.60 (IQR 2.60) vs. 7.40 (IQR 2.10), p = .000] and FBS level [159.00 (IQR 77.50) vs. 134.00 (IQR 40.50), p = .002] at 3 months of intervention. The mean BMI at baseline was higher compared to 3 months of intervention [24.88 (SD ± 3.06) vs. 24.19 (SD ± 2.79)] which was statistically significant (p = .000). Majority of participants (n = 22, 75.9%) had improved their HbA1c level by ≥ 0.5% in 3 months. The diabetes self-management education is an effective measure in improving glycemic control and other clinical parameters among patients with T2DM. Thus, DSME needs to be implemented among clinic patients with T2DM for the better outcome and the preventions of complications.

scholarly journals When Uncontrolled Diabetes Mellitus and Severe COVID-19 Converge: The Perfect Storm for Mucormycosis

2021 ◽  
Vol 7 (4) ◽  
pp. 298
Author(s):  
Teny M. John ◽  
Ceena N. Jacob ◽  
Dimitrios P. Kontoyiannis
Keyword(s):  
Diabetes Mellitus ◽  
Risk Factors ◽  
Clinical Features ◽  
The Other ◽  
Diabetic Patients ◽  
Epidemiological Factors ◽  
Uncontrolled Diabetes ◽  
Diagnostic Certainty ◽  
Patients With Diabetes ◽  
Perfect Storm

Mucormycosis (MCR) has been increasingly described in patients with coronavirus disease 2019 (COVID-19) but the epidemiological factors, presentation, diagnostic certainty, and outcome of such patients are not well described. We review the published COVID-19-associated mucormycosis (CAMCR) cases (total 41) to identify risk factors, clinical features, and outcomes. CAMCR was typically seen in patients with diabetes mellitus (DM) (94%) especially the ones with poorly controlled DM (67%) and severe or critical COVID-19 (95%). Its presentation was typical of MCR seen in diabetic patients (mostly rhino-orbital and rhino-orbital-cerebral presentation). In sharp contrast to reported COVID-associated aspergillosis (CAPA) cases, nearly all CAMCR infections were proven (93%). Treating physicians should have a high suspicion for CAMCR in patients with uncontrolled diabetes mellitus and severe COVID-19 presenting with rhino-orbital or rhino-cerebral syndromes. CAMR is the convergence of two storms, one of DM and the other of COVID-19.

scholarly journals Crocodile blood supplementation protects vascular function in diabetic mice

2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Chui Yiu Bamboo Chook ◽  
Francis M. Chen ◽  
Gary Tse ◽  
Fung Ping Leung ◽  
Wing Tak Wong
Keyword(s):  
Endothelial Cells ◽  
Vascular Function ◽  
Quantitative Polymerase Chain Reaction ◽  
Functional Study ◽  
Diabetic Patients ◽  
Diabetic Mice ◽  
Gene Expressions ◽  
Inflammatory State ◽  
Crocodile Blood

Abstract Cardiovascular disease is a major cause of mortality in diabetic patients due to the heightened oxidative stress and pro-inflammatory state in vascular tissues. Effective approaches targeting cardiovascular health for diabetic patients are urgently needed. Crocodile blood, an emerging dietary supplement, was suggested to have anti-oxidative and anti-inflammatory effects in vitro, which have yet to be proven in animal models. This study thereby aimed to evaluate whether crocodile blood can protect vascular function in diabetic mice against oxidation and inflammation. Diabetic db/db mice and their counterparts db/m+ mice were treated daily with crocodile blood soluble fraction (CBSF) or vehicle via oral gavage for 4 weeks before their aortae were harvested for endothelium-dependent relaxation (EDR) quantification using wire myograph, which is a well-established functional study for vascular function indication. Organ culture experiments culturing mouse aortae from C57BL/6 J mice with or without IL-1β and CBSF were done to evaluate the direct effect of CBSF on endothelial function. Reactive oxygen species (ROS) levels in mouse aortae were assessed by dihydroethidium (DHE) staining with inflammatory markers in endothelial cells quantified by quantitative polymerase chain reaction (qPCR). CBSF significantly improved deteriorated EDR in db/db diabetic mice through both diet supplementation and direct culture, with suppression of ROS level in mouse aortae. CBSF also maintained EDR and reduced ROS levels in mouse aortae against the presence of pro-inflammatory IL-1β. Under the pro-inflammatory state induced by IL-1β, gene expressions of inflammatory cytokines were downregulated, while the protective transcripts UCP2 and SIRT6 were upregulated in endothelial cells. Our study suggests a novel beneficial effect of crocodile blood on vascular function in diabetic mice and that supplementation of diet with crocodile blood may act as a complementary approach to protect against vascular diseases through anti-oxidation and anti-inflammation in diabetic patients. Graphical abstract

scholarly journals Diabetes Mellitus—A Risk Factor for Unfavourable Outcome in COVID-19 Patients—The Experience of an Infectious Diseases Regional Hospital

Healthcare ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 788
Author(s):  
Egidia Miftode ◽  
Larisa Miftode ◽  
Ioana Coman ◽  
Cristian Prepeliuc ◽  
Maria Obreja ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Inflammatory Responses ◽  
Scientific Data ◽  
Risk Category ◽  
Diabetic Patients ◽  
Direct Effects ◽  
Unfavourable Outcome ◽  
Strong Connection ◽  
Risk Of Death ◽  
Patients With Diabetes

Early research into the implications concerning the evolution of the infection caused by the new coronavirus in people with glucose metabolism dysfunction, in this case diabetics, shows that severe forms of the disease predominate in this risk category. Moreover, it seems that even in patients with normal glycaemic status, COVID-19 may predispose to the development of hyperglycaemia which modulates immune mechanisms and inflammatory responses, with direct effects on morbidity and mortality. Thus, taking into account these scientific data, as well as the increased frequency of diabetes in the general population, we aimed to assess the risk of an unfavourable outcome of diabetic patients, which is in a strong connection with the presence and severity of pulmonary disease such as interstitial pneumonia/bronchopneumonia, as well as the effectiveness of Tocilizumab administration. The results of our study indicate a three-fold higher risk of death in patients with diabetes and COVID-19 (RR = 3.03; IC95%: 2.37–3.86; p = 0.001),compared to nondiabetic patients, and the risk of developing severe forms of acute respiratory failure was 1.5 times higher in the first studied category. In conclusion, we can say that the diabetic diagnosed with SARS-CoV-2 infection is more predisposed to immunological and organic dysfunctions that may ultimately result in death, and treatment with monoclonal anti-IL-6 antibodies was more effective in diabetic patients than non-diabetics (p < 0.05). The effectiveness of Tocilizumab was significant in both studied groups, but diabetic patients responded better to this therapy compared to non-diabetes-mellitus (DM) ones (76.7% vs. 35% p = 0.001).

scholarly journals Screening Strategy of Pancreatic Cancer in Patients with Diabetes Mellitus

Diagnostics ◽  
2020 ◽  
Vol 10 (8) ◽  
pp. 572
Author(s):  
Suguru Mizuno ◽  
Yousuke Nakai ◽  
Kazunaga Ishigaki ◽  
Kei Saito ◽  
Hiroki Oyama ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Pancreatic Cancer ◽  
Epidemiological Studies ◽  
Screening Strategy ◽  
Diabetic Patients ◽  
Reverse Causality ◽  
Pilot Studies ◽  
Patients With Diabetes ◽  
High Risk Populations ◽  
New Onset

The incidence of pancreatic cancer (PCa) is increasing worldwide and has become one of the leading causes of cancer-related death. Screening for high risk populations is fundamental to overcome this intractable malignancy. Diabetes mellitus (DM) is classically known as a risk factor for PCa. Recently the reverse causality is in the spotlight, that is to say, DM is considered to be a manifestation of PCa. Numbers of epidemiological studies clarified that new-onset DM (≤2-year duration) was predominant in PCa patients and the relative risk for PCa inversely correlated with duration of DM. Among patients with new-onset DM, elder onset, weight loss, and rapid exacerbation of glycemic control were reported to be promising risk factors and signs, and the model was developed by combining these factors. Several pilot studies disclosed the possible utility of biomarkers to discriminate PCa-associated DM from type 2 DM. However, there is no reliable biomarkers to be used in the practice. We previously reported the application of a multivariate index for PCa based on the profile of plasma free amino acids (PFAAs) among diabetic patients. We are further investigating on the PFAA profile of PCa-associated DM, and it can be useful for developing the novel biomarker in the near future.

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