0000000000013477
AUTHOR
Francesca Iannantuoni
Does Metformin Modulate Endoplasmic Reticulum Stress and Autophagy in Type 2 Diabetic Peripheral Blood Mononuclear Cells?
Since type 2 diabetes (T2D) is associated with oxidative stress and metformin has been shown to exert a protective role against the said stress, we wondered whether metformin treatment might also modulate endoplasmic reticulum (ER) stress and autophagy in leukocytes of T2D patients. We studied 53 T2D patients (37 of whom had been treated with metformin 1700 mg for at least 1 year) and 30 healthy volunteers. Leukocytes from both groups of T2D patients exhibited increased protein levels of 78-kDa glucose-regulated protein (GRP78) with respect to controls, whereas activating transcription factor 6 (ATF6) was enhanced specifically in nonmetformin-treated T2D, and (s-xbp1) and phosphorylated euk…
Estudio de los mecanismos de estrés oxidativo, activación del inflamasoma NLRP3 y las interacciones leucocito-endotelio en la Diabetes: Efectos del papel de la Empagliflozina
La diabetes mellitus (DM) presenta un problema de salud pública a nivel mundial. La DM es un grupo de enfermedades metabólicas heterogéneas asociadas a alteraciones en el metabolismo glucídico, lipídico y proteico y inflamación sistémica crónica de bajo grado. Además, está caracterizada por un estado de hiperglucemia secundaria a un defecto absoluto o relativo en la secreción de insulina por parte de las células-β del páncreas. Tanto en la DM tipo 1 como en la DM de tipo 2 (DM1 y DM2) la hiperglucemia, la inflamación sistémica y el estrés oxidativo, son unos de los mayores factores predisponentes a la disfunción endotelial y a las enfermedades cardiovasculares. En los últimos años se han de…
Moderate weight loss attenuates chronic endoplasmic reticulum stress and mitochondrial dysfunction in human obesity
Abstract Objective In obese patients undergoing caloric restriction, there are several potential mechanisms involved in the improvement of metabolic outcomes. The present study further explores whether caloric restriction can modulate endoplasmic reticulum (ER) stress and mitochondrial function, as both are known to be mechanisms underlying inflammation and insulin resistance (IR) during obesity. Methods A total of 64 obese patients with BMI ≥35 kg/m2 underwent a dietary program consisting of 6 weeks of a very-low-calorie diet followed by 18 weeks of low-calorie diet. We evaluated changes in the metabolic and inflammatory markers -TNFα, hsCRP, complement component 3 (C3c), and retinol bindi…
Does Glycemic Control Modulate the Impairment of NLRP3 Inflammasome Activation in Type 2 Diabetes?
Since mitochondrial dysfunction is associated with NOD-like receptor family protein 3 (NLRP3) activation in type 2 diabetes (T2D), which can eventually lead to an impaired immune response, we set out to determine if glycemic control modulates the effects of T2D on the NLRP3 inflammasome. We have studied leukocytes from 61 diabetic patients [25 with glycated hemoglobin (HbA(1c)) 7% and 36 with HbA(1c) 8%] and 40 healthy controls. Total and mitochondrial reactive oxygen species (ROS) production was enhanced in T2D patients, and mitochondrial ROS was more pronounced in those with poor glycemic control. Levels of gene and protein expression of NLRP3 were decreased in both diabetic groups and mo…
Testosterone administration increases leukocyte-endothelium interactions and inflammation in transgender men
Objective To evaluate the effect of testosterone treatment on metabolic and inflammation parameters and leukocyte-endothelium interactions in transgender men (TGM). Design Prospective observational study. Setting University hospital. Patient(s) One hundred fifty-seven TGM. Intervention(s) Administration of testosterone undecanoate (1,000 mg, intramuscular) every 12 weeks. Main Outcome Measure(s) Endocrine parameters, adhesion molecules (vascular cell adhesion molecule-1, intercellular cell adhesion molecule-1, and E-selectin), proinflammatory cytokines interleukin-6, and tumor necrosis factor alpha were evaluated in serum before and after treatment using Luminex’s xMAP technology. In additi…
Characterization of Differentially Expressed Circulating miRNAs in Metabolically Healthy versus Unhealthy Obesity
Obese individuals without metabolic comorbidities are categorized as metabolically healthy obese (MHO). MicroRNAs (miRNAs) may be implicated in MHO. This cross-sectional study explores the link between circulating miRNAs and the main components of metabolic syndrome (MetS) in the context of obesity. We also examine oxidative stress biomarkers in MHO vs. metabolically unhealthy obesity (MUO). We analysed 3536 serum miRNAs in 20 middle-aged obese individuals: 10 MHO and 10 MUO. A total of 159 miRNAs were differentially expressed, of which, 72 miRNAs (45.2%) were higher and 87 miRNAs (54.7%) were lower in the MUO group. In addition, miRNAs related to insulin signalling and lipid metabolism pat…
Mitochondrial Alterations and Enhanced Human Leukocyte/Endothelial Cell Interactions in Type 1 Diabetes
Type 1 diabetes has been associated with oxidative stress. This study evaluates the rates of oxidative stress, mitochondrial function, leukocyte&ndash
Does Empagliflozin Modulate Leukocyte–Endothelium Interactions, Oxidative Stress, and Inflammation in Type 2 Diabetes?
Sodium-glucose co-transporter 2 inhibitors (iSGLT2) have been linked to cardiovascular risk reduction in patients with type 2 diabetes (T2D). However, their underlying molecular mechanisms remain unclear. This study aimed to evaluate the effects of empagliflozin, a novel potent and selective iSGLT-2, on anthropometric and endocrine parameters, leukocyte–endothelium interactions, adhesion molecules, ROS production, and NFkB-p65 transcription factor expression. According to standard clinical protocols, sixteen T2D patients receiving 10 mg/day of empagliflozin were followed-up for 24 weeks. Anthropometric and analytical measurements were performed at baseline, 12 weeks, and 24 weeks. Interacti…
Association between Proinflammatory Markers, Leukocyte–Endothelium Interactions, and Carotid Intima–Media Thickness in Type 2 Diabetes: Role of Glycemic Control
Glycated hemoglobin monitorization could be a tool for maintaining type 2 diabetes (T2D) under control and delaying the appearance of cardiovascular events. This cross-sectional study was designed to assess the role of glycemic control in modulating early-stage markers of cardiovascular complications. One hundred and eight healthy controls and 161 type 2 diabetic patients were recruited and distributed according to their glycemic control, setting the threshold at 6.5% (good control). Biochemical and anthropometrical parameters were registered during the initial visit, and peripheral blood was extracted to obtain polymorphonuclear cells and analyze inflammatory markers, adhesion molecules, l…
Relationship Between Oxidative Stress, ER Stress, and Inflammation in Type 2 Diabetes: The Battle Continues
Type 2 diabetes (T2D) is a metabolic disorder characterized by hyperglycemia and insulin resistance in which oxidative stress is thought to be a primary cause. Considering that mitochondria are the main source of ROS, we have set out to provide a general overview on how oxidative stress is generated and related to T2D. Enhanced generation of reactive oxygen species (ROS) and oxidative stress occurs in mitochondria as a consequence of an overload of glucose and oxidative phosphorylation. Endoplasmic reticulum (ER) stress plays an important role in oxidative stress, as it is also a source of ROS. The tight interconnection between both organelles through mitochondrial-associated membranes (MAM…
Systemic Oxidative Stress and Visceral Adipose Tissue Mediators of NLRP3 Inflammasome and Autophagy Are Reduced in Obese Type 2 Diabetic Patients Treated with Metformin.
Obesity is a low-grade inflammatory condition affecting a range of individuals, from metabolically healthy obese (MHO) subjects to type 2 diabetes (T2D) patients. Metformin has been shown to display anti-inflammatory properties, though the underlying molecular mechanisms are unclear. To study whether the effects of metformin are mediated by changes in the inflammasome complex and autophagy in visceral adipose tissue (VAT) of obese patients, a biopsy of VAT was obtained from a total of 68 obese patients undergoing gastric bypass surgery. The patients were clustered into two groups: MHO patients and T2D patients treated with metformin. Patients treated with metformin showed decreased levels o…
The Mitochondria-Targeted Antioxidant MitoQ Modulates Mitochondrial Function and Endoplasmic Reticulum Stress in Pancreatic β Cells Exposed to Hyperglycaemia.
Background/aims Mitochondria-targeted antioxidants such as mitoquinone (MitoQ) have demonstrated protective effects against oxidative damage in several diseases. The increase in reactive oxygen species (ROS) production during glucose metabolism in β cells can be exacerbated under hyperglycaemic conditions such as type 2 diabetes (T2D), thus contributing to β cell function impairment. In the present work, we aimed to evaluate the effect of MitoQ on insulin secretion, oxidative stress, endoplasmic reticulum (ER) stress and nuclear factor kappa B (NFκB) signalling in a pancreatic β cell line under normoglycaemic (NG, 11.1 mM glucose), hyperglycaemic (HG, 25 mM glucose) and lipidic (palmitic ac…
The Mitochondrial Antioxidant SS-31 Modulates Oxidative Stress, Endoplasmic Reticulum Stress, and Autophagy in Type 2 Diabetes
Mitochondrial dysfunction has been shown to play a central role in the pathophysiology of type 2 diabetes (T2D), and mitochondria-targeted agents such as SS-31 are emerging as a promising strategy for its treatment. We aimed to study the effects of SS-31 on leukocytes from T2D patients by evaluating oxidative stress, endoplasmic reticulum (ER) stress and autophagy. Sixty-one T2D patients and 53 controls were included. Anthropometric and analytical measurements were performed. We also assessed reactive oxygen species (ROS) production, calcium content, the expression of ER stress markers GRP78, CHOP, P-eIF2&alpha
Mechanisms of action of metformin in type 2 diabetes: Effects on mitochondria and leukocyte-endothelium interactions.
Type 2 diabetes (T2D) is a very prevalent, multisystemic, chronic metabolic disorder closely related to atherosclerosis and cardiovascular diseases. It is characterised by mitochondrial dysfunction and the presence of oxidative stress. Metformin is one of the safest and most effective anti-hyperglycaemic agents currently employed as first-line oral therapy for T2D. It has demonstrated additional beneficial effects, unrelated to its hypoglycaemic action, on weight loss and several diseases, such as cancer, cardiovascular disorders and metabolic diseases, including thyroid diseases. Despite the vast clinical experience gained over several decades of use, the mechanism of action of metformin i…
Relationship between PMN-endothelium interactions, ROS production and Beclin-1 in type 2 diabetes.
Type 2 diabetes is closely related to oxidative stress and cardiovascular diseases. In this study, we hypothesized that polymorphonuclear leukocytes (PMN)-endothelium interactions and autophagy are associated. We evaluated PMN-endothelial interactions, ROS production and autophagy parameters in 47 type 2 diabetic patients and 57 control subjects. PMNs from type 2 diabetic patients exhibited slower rolling velocity (p < 0.001), higher rolling flux (p < 0.001) and adhesion (p < 0.001) in parallel to higher levels of total (p < 0.05) and mitochondrial ROS (p < 0.05). When the protein expression of autophagy markers was analysed, an increase of Beclin-1 (p < 0.05), LC3I (p < 0.05), LC3II (p < 0…
The SGLT2 Inhibitor Empagliflozin Ameliorates the Inflammatory Profile in Type 2 Diabetic Patients and Promotes an Antioxidant Response in Leukocytes
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Mitochondrial DNA Haplogroup JT is Related to Impaired Glycaemic Control and Renal Function in Type 2 Diabetic Patients
The association between mitochondrial DNA (mtDNA) haplogroup and risk of type 2 diabetes (T2D) is undetermined and controversial. This study aims to evaluate the impact of the main mtDNA haplogroups on glycaemic control and renal function in a Spanish population of 303 T2D patients and 153 healthy controls. Anthropometrical and metabolic parameters were assessed and mtDNA haplogroup was determined in each individual. Distribution of the different haplogroups was similar in diabetic and healthy populations and, as expected, T2D patients showed poorer glycaemic control and renal function than controls. T2D patients belonging to the JT haplogroup (polymorphism m.4216T>
Downregulation of miR-31 in Diabetic Nephropathy and its Relationship with Inflammation
Background/Aims: There is a lack of reliable biological markers for the early diagnosis of diabetic nephropathy (DN) during type 2 diabetes. In this pilot study we aim to assess whether miR-31 levels are modulated by the presence of DN and whether the expression of this miRNA is related to leukocyte-endothelial interactions and inflammation. Methods: Thirty-one T2D patients were enrolled in this pilot study; 18 with no diabetic complications and 13 with diabetic nephropathy. 24 non-diabetic subjects and 13 T2D patients with retinopathy (absent of other complications) were included to test the specificity of miR-31. Following anthropometric and biochemical evaluation, serum miR-31 levels wer…
The mitochondrial antioxidant SS-31 increases SIRT1 levels and ameliorates inflammation, oxidative stress and leukocyte-endothelium interactions in type 2 diabetes
AbstractThere is growing focus on mitochondrial impairment and cardiovascular diseases (CVD) in type 2 diabetes (T2D), and the development of novel therapeutic strategies in this context. It is unknown whether mitochondrial-targeting antioxidants such as SS-31 protect sufficiently against oxidative damage in diabetes. We aimed to evaluate if SS-31 modulates SIRT1 levels and ameliorates leukocyte-endothelium interactions, oxidative stress and inflammation in T2D patients. Anthropometric and metabolic parameters were studied in 51 T2D patients and 57 controls. Production of mitochondrial reactive oxygen species (ROS), mitochondrial membrane potential, glutathione content, leukocyte-endotheliu…