scholarly journals Hyperglycemia-Induced Metabolic Reprogramming Mediates a Proatherogenic Phenotype in Healthy Human Monocytes

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A321-A321
Author(s):  
Anabel Lourdes Castro-Grattoni ◽  
Jisu Oh ◽  
Rong Mei Zhang ◽  
Adriana Dusso ◽  
Amy Elizabeth Riek ◽  
...  
Keyword(s):  
Mitochondrial Respiration ◽  
Oxidized Ldl ◽  
Glycemic Variability ◽  
Metabolic Reprogramming ◽  
Human Monocytes ◽  
Cytokine Release ◽  
Healthy Human ◽  
Acute Hyperglycemia ◽  
Patients With Diabetes ◽  
Ldl Uptake

Abstract Introduction: Poor glycemic control is considered an important contributor to cardiovascular disease in patients with diabetes. Episodic hyperglycemia as a surrogate for glycemic variability promotes monocyte adhesion and increases the prevalence of proinflammatory monocytes within atherosclerotic plaques of patients with diabetes. We previously found that acute hyperglycemia-induced a pro-inflammatory phenotype and promoted the development of foamy monocytes by increasing total cholesterol deposition, cholesterol ester, and free cholesterol content by enhancing oxidized LDL uptake. However, the mechanism by which acute hyperglycemia induces monocyte cholesterol deposition and inflammation remains unknown. Methods: Monocytes isolated from healthy individuals (age range 20–40; n=5) were cultured in low (5mM) or high (16.7mM) glucose conditions with or without a glycolysis inhibitor (2-deoxyglucose, 2DG, 5 mM) or an endoplasmic reticulum stress inhibitor (4-phenylbutyric acid, PBA; 20mM) for 6 hrs. After treatment, cytokine release, oxidized LDL uptake, and metabolic assays using Seahorse Technology were performed. Results: Healthy human monocytes exposed under high glucose conditions showed a pro-atherosclerotic phenotype with higher levels of the pro-inflammatory cytokines, TNFα(median of differences 6.34 pg/ml, p=0.002) and IL1β(12.04 pg/ml, p=0.003), and increased oxidized LDL uptake (5062ug Dil-Ox LDL/mg, p=0.001). Furthermore, hyperglycemia resulted in higher levels of glycolysis (basal glycolysis 12.94 pmol/min, p=0.01; basal proton efflux rate 15.5 pmol/min, p=0.03) and mitochondrial respiration (percentage of respiratory capacity 16pmol/min p=0.04), suggesting a significant alteration in the metabolic programming of these monocytes. Treatment with 2-DG or PBA attenuated the pro-atherosclerotic phenotype induced by hyperglycemia, promoting a reduction of cytokine release, a reduction of oxidized LDL uptake, and near normalization of the glycolic rate and mitochondrial respiration, stabilizing cellular bioenergetics. Conclusions: Altogether, our results suggest that monocyte ER stress in response to acute hyperglycemia promotes a hypermetabolic state characterized by a proinflammatory and proatherogenic monocyte phenotype. Therefore, acute hyperglycemia is a potential mechanism promoting atherosclerosis in patients with type 2 diabetes.

scholarly journals Glycated Hemoglobin (HbA1c) as a Biomarker for Diabetic Foot Peripheral Neuropathy

Diseases ◽  
2021 ◽  
Vol 9 (1) ◽  
pp. 16
Author(s):  
Giulia Casadei ◽  
Marta Filippini ◽  
Lorenzo Brognara
Keyword(s):  
Diabetes Mellitus ◽  
Peripheral Neuropathy ◽  
Diabetic Foot ◽  
Glycated Hemoglobin ◽  
Chronic Inflammatory Demyelinating Polyneuropathy ◽  
Glycemic Variability ◽  
Future Research ◽  
Patients With Diabetes ◽  
Axonal Dysfunction ◽  
Biomarker Research

Background: Diabetic peripheral neuropathy (DPN) is known to predict foot ulceration, lower-extremity amputation and mortality. Patients with diabetes mellitus have a predisposition toward developing chronic inflammatory demyelinating polyneuropathy, and this may also facilitate the formation of diabetic foot and cutaneous impairment, which are considered one of the most serious impairments of diabetes mellitus, with a prevalence of 4–10% in this population. Biomarkers research provides opportunities for the early diagnosis of these complications for specific treatments useful to prevent amputation and, therefore, physical inability and mental disturbance. The recent literature has suggested that glycemic levels may be a novel factor in the pathogenesis of diabetic foot complications and is an important mediator of axonal dysfunction. The aim of this systematic literary review is to determine whether hemoglobin A1c (HbA1c) is a positive predictor for diabetic foot peripheral neuropathy and its complications, such as foot cutaneous impairments. There is a lack of consensus regarding the effect of glycemic variability on diabetic foot peripheral neuropathy, unlike other complications such as retinopathy, nephropathy or micro/macrovascular pathology. Methods: Relevant articles were searched in the Medline database using PubMed and Scopus and relevant keywords. The primary search terms used were “glycated hemoglobin” OR “HbA1c” AND “diabetic neuropathies” AND “Foot”. Results: A number of articles (336) were initially identified while searching the scientific literature regarding this topic, and 32 articles were selected and included in this review. Conclusions: This review highlights the role of HbA1c in diabetic foot peripheral neuropathy. Biomarkers play an important role in the decision-making process, and HbA1c levels are extensively used for diabetic foot clinical outcomes and settings, but biomarker research in diabetic foot peripheral neuropathy is in its infancy and will require careful attention to a number of factors and associations, since the consequences of DPN also include neurological alterations. HbA1c is an accurate and easy-to-administer test and can be an effective biomarker in establishing the diagnosis of diabetes, but future research should focus on standardizing the HbA1c level and selecting which DPN value and its correlated complications, such as foot cutaneous impairments, are the most informative.

scholarly journals Glycemic variability and cardiovascular disease in patients with type 2 diabetes

2021 ◽  
Vol 9 (1) ◽  
pp. e002032
Author(s):  
Marcela Martinez ◽  
Jimena Santamarina ◽  
Adrian Pavesi ◽  
Carla Musso ◽  
Guillermo E Umpierrez
Keyword(s):  
Type 2 Diabetes ◽  
Blood Glucose ◽  
Glycated Hemoglobin ◽  
Glucose Monitoring ◽  
Glycemic Variability ◽  
Cardiovascular Complications ◽  
Glucose Levels ◽  
Increased Risk ◽  
Patients With Diabetes

Glycated hemoglobin is currently the gold standard for assessment of long-term glycemic control and response to medical treatment in patients with diabetes. Glycated hemoglobin, however, does not address fluctuations in blood glucose. Glycemic variability (GV) refers to fluctuations in blood glucose levels. Recent clinical data indicate that GV is associated with increased risk of hypoglycemia, microvascular and macrovascular complications, and mortality in patients with diabetes, independently of glycated hemoglobin level. The use of continuous glucose monitoring devices has markedly improved the assessment of GV in clinical practice and facilitated the assessment of GV as well as hypoglycemia and hyperglycemia events in patients with diabetes. We review current concepts on the definition and assessment of GV and its association with cardiovascular complications in patients with type 2 diabetes.

scholarly journals Ureaplasma urealyticum Modulates Endotoxin-Induced Cytokine Release by Human Monocytes Derived from Preterm and Term Newborns and Adults

2001 ◽  
Vol 69 (6) ◽  
pp. 3906-3915 ◽  
Author(s):  
Winston M. Manimtim ◽  
Jeffrey D. Hasday ◽  
Lisa Hester ◽  
Karen D. Fairchild ◽  
Judith C. Lovchik ◽  
...  
Keyword(s):  
Proinflammatory Cytokines ◽  
Ureaplasma Urealyticum ◽  
Human Monocytes ◽  
Cytokine Release ◽  
Proinflammatory Response ◽  
Pediatr Infect ◽  
High Inoculum ◽  
Tnf Α ◽  
Adult Cells

ABSTRACT We previously observed that Ureaplasma urealyticumrespiratory tract colonization in infants with a birth weight of ≤1,250 g was associated with increases in the tracheal aspirate proinflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin-8 (IL-8) relative to the counterregulatory cytokine IL-6 during the first week of life (A. M. Patterson, V. Taciak, J. Lovchik, R. E. Fox, A. B. Campbell, and R. M. Viscardi, Pediatr. Infect. Dis. J. 17:321–328, 1998). We hypothesized thatU. urealyticum alters the host immune response in the presence of a coinflammatory stimulus (e.g., bacterial infection or hyperoxia) by shifting the balance of cytokine expression towards the proinflammatory cytokines. To test this hypothesis, we compared the release of TNF-α, IL-8, IL-6, and IL-10 in vitro by unstimulated andU. urealyticum (with or without lipopolysaccharide [LPS])-stimulated human monocytes from adult peripheral blood and from term and preterm cord blood. U. urealyticum alone and in combination with LPS induced concentration- and development-dependent changes in cytokine release. In vitro inoculation with low-inoculum U. urealyticum (103color-changing units [CCU]) (i) partially blocked the LPS-stimulated IL-6 release by all cells and reduced LPS-stimulated IL-10 release by preterm cells, (ii) stimulated TNF-α and IL-8 release by preterm cells, and (iii) augmented LPS-stimulated TNF-α release in all cells. In preterm cells, high-inoculum U. urealyticum(106 CCU) (i) stimulated TNF-α and IL-8, but not IL-6 or IL-10, release and (ii) augmented LPS-stimulated TNF-α and IL-8 release. High-inoculum U. urealyticum (i) stimulated release of all four cytokines in term cells and IL-8 release in adult cells and (ii) augmented LPS-induced TNF-α, IL-10, and IL-8 release in term cells but did not significantly affect LPS-induced cytokine release in adult cells. We speculate that U. urealyticum enhances the proinflammatory response to a second infection by blocking expression of counterregulatory cytokines (IL-6 and IL-10), predisposing the preterm infant to prolonged and dysregulated inflammation, lung injury, and impaired clearance of secondary infections.

Metabolic reprogramming of mitochondrial respiration in metastatic cancer

2018 ◽  
Vol 37 (4) ◽  
pp. 643-653 ◽  
Author(s):  
P. M. Herst ◽  
C. Grasso ◽  
Michael V. Berridge
Keyword(s):  
Mitochondrial Respiration ◽  
Metastatic Cancer ◽  
Metabolic Reprogramming

scholarly journals The reciprocal relationship between adiponectin and LOX-1 in the regulation of endothelial dysfunction in ApoE knockout mice

2010 ◽  
Vol 299 (3) ◽  
pp. H605-H612 ◽  
Author(s):  
Xiuping Chen ◽  
Hanrui Zhang ◽  
Steve McAfee ◽  
Cuihua Zhang
Keyword(s):  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Sodium Nitroprusside ◽  
Oxidized Ldl ◽  
Reciprocal Relationship ◽  
Reciprocal Regulation ◽  
Tnf Α ◽  
Ldl Uptake ◽  
Apoe Ko Mice ◽  
Apoe Ko

We hypothesized that the reciprocal association between adiponectin and lectin-like oxidized LDL (ox-LDL) receptor (LOX)-1 contributes to the regulation of aortic endothelial dysfunction in atherosclerosis. To test this hypothesis, endothelium-dependent (ACh) and endothelium-independent (sodium nitroprusside) vasorelaxation of isolated aortic rings from control mice, apolipoprotein E (ApoE) knockout (KO) mice, and ApoE KO mice treated with either adiponectin (15 μg·day−1·mouse−1 sc for 8 days) or neutralizing antibody to LOX-1 (anti-LOX-1, 16 μg/ml, 0.1 ml/mouse ip for 7 days) were examined. Although vasorelaxation to sodium nitroprusside was not different between control and ApoE KO mice, relaxation to ACh was impaired in ApoE KO mice. Adiponectin and anti-LOX-1 restored nitric oxide-mediated endothelium-dependent vasorelaxation in ApoE KO mice. Aortic ROS formation and ox-LDL uptake were increased in ApoE KO mice. Both adiponectin and anti-LOX-1 treatment reduced ROS production and aortic ox-LDL uptake. In mouse coronary artery endothelial cells, TNF-α incubation increased endothelial LOX-1 expression. Adiponectin reduced TNF-α-induced LOX-1 expression. Consistently, in ApoE KO mice, adiponectin treatment reversed elevated LOX-1 expression in aortas. Immunofluorescence staining showed that adiponectin was mainly colocalized with endothelial cells. Although adiponectin expression was lower in ApoE KO versus control mice, anti-LOX-1 increased aortic adiponectin expression, suggesting a reciprocal regulation between adiponectin and LOX-1. Moreover, both adiponectin and anti-LOX-1 reduced NF-κB expression in ApoE KO mice. Thus, adiponectin and LOX-1 may converge on NF-κB signaling to regulate their function. In conclusion, our results indicate that the reciprocal regulation between adiponectin and LOX-1 amplifies oxidative stress and ox-LDL uptake, leading to endothelial dysfunction in atherosclerosis.

Dietary Ellagic Acid Attenuates Oxidized LDL Uptake and Stimulates Cholesterol Efflux in Murine Macrophages

SciVee ◽  
2011 ◽  
Author(s):  
Seon young Han ◽  
Eun sook Lee ◽  
Jung-lye Kim ◽  
Sin-hye Park ◽  
Ju hyun Gong ◽  
...  
Keyword(s):  
Ellagic Acid ◽  
Cholesterol Efflux ◽  
Oxidized Ldl ◽  
Murine Macrophages ◽  
Ldl Uptake

scholarly journals Metabolic Plasticity Is an Essential Requirement of Acquired Tyrosine Kinase Inhibitor Resistance in Chronic Myeloid Leukemia

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3443
Author(s):  
Miriam G. Contreras Mostazo ◽  
Nina Kurrle ◽  
Marta Casado ◽  
Dominik Fuhrmann ◽  
Islam Alshamleh ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Mitochondrial Respiration ◽  
Myeloid Leukemia ◽  
Chemotherapeutic Agents ◽  
Response To Therapy ◽  
Metabolic Reprogramming ◽  
Metabolic Inhibitors ◽  
Metabolic Plasticity ◽  
Tki Resistance

Tyrosine kinase inhibitors (TKIs) are currently the standard chemotherapeutic agents for the treatment of chronic myeloid leukemia (CML). However, due to TKI resistance acquisition in CML patients, identification of new vulnerabilities is urgently required for a sustained response to therapy. In this study, we have investigated metabolic reprogramming induced by TKIs independent of BCR-ABL1 alterations. Proteomics and metabolomics profiling of imatinib-resistant CML cells (ImaR) was performed. KU812 ImaR cells enhanced pentose phosphate pathway, glycogen synthesis, serine-glycine-one-carbon metabolism, proline synthesis and mitochondrial respiration compared with their respective syngeneic parental counterparts. Moreover, the fact that only 36% of the main carbon sources were utilized for mitochondrial respiration pointed to glycerol-phosphate shuttle as mainly contributors to mitochondrial respiration. In conclusion, CML cells that acquire TKIs resistance present a severe metabolic reprogramming associated with an increase in metabolic plasticity needed to overcome TKI-induced cell death. Moreover, this study unveils that KU812 Parental and ImaR cells viability can be targeted with metabolic inhibitors paving the way to propose novel and promising therapeutic opportunities to overcome TKI resistance in CML.

Effect of hyperglycemia on triggering of transient lower esophageal sphincter relaxations

2004 ◽  
Vol 286 (5) ◽  
pp. G797-G803 ◽  
Author(s):  
Qing Zhang ◽  
Michael Horowitz ◽  
Rachael Rigda ◽  
Christopher Rayner ◽  
Andrew Worynski ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Lower Esophageal Sphincter ◽  
Blood Glucose Concentration ◽  
Gastric Wall ◽  
Gastric Distension ◽  
Healthy Human ◽  
Patients With Diabetes ◽  
Esophageal Sphincter ◽  
Volume Controlled ◽  
Pressure Controlled

Acute changes in blood glucose concentration have major effects on gastrointestinal motor function. Patients with diabetes mellitus have an increased prevalence of gastroesophageal reflux. Transient lower esophageal sphincter (LES) relaxation (TLESR) is the most common sphincter mechanism underlying reflux. The aim of this study was to investigate the effect of acute hyperglycemia on triggering TLESRs evoked by gastric distension in healthy volunteers. TLESRs were stimulated by pressure-controlled and volume-controlled (500 ml) gastric distension using an electronic barostat and performed on separate days. On each day, esophageal manometry was performed in the sitting position during gastric distension for 1 h under euglycemia (5 mM), and either marked hyperglycemia (15 mM) or physiological hyperglycemia (8 mM) in randomized order was maintained by a glucose clamp. Marked hyperglycemia doubled the rate of TLESRs in response to both pressure-controlled [5 (3–10.5, median or interquartile range) to 10 (9.5–14.5) per hour, P < 0.02] and volume-controlled [4 (2.5–7.5) to 10.5 (7–12.5) per hour, P < 0.02] gastric distension but had no effect on basal LES pressure. Physiological hyperglycemia had no effect on the triggering of TLESRs or basal LES pressure. In healthy human subjects, marked hyperglycemia increases the rate of TLESRs. Increase in the rate of TLESRs is independent of proximal gastric wall tension. Mechanisms underlying the effect remain to be determined. Hyperglycemia may be an important factor contributing to the increased esophageal acid exposure in patients with diabetes mellitus.

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