Mitochondrial stress causes increased succination of proteins in adipocytes in response to glucotoxicity

2012 ◽  
Vol 445 (2) ◽  
pp. 247-254 ◽  
Author(s):  
Norma Frizzell ◽  
Sonia A. Thomas ◽  
James A. Carson ◽  
John W. Baynes
Keyword(s):  
High Glucose ◽  
Addition Reaction ◽  
Tricarboxylic Acid Cycle ◽  
Michael Addition Reaction ◽  
3T3 Cells ◽  
Mitochondrial Stress ◽  
High Glucose Medium ◽  
Transport Chain ◽  
Type 2 Diabetic

2SC [S-(2-succino)-cysteine] is a chemical modification formed by a Michael addition reaction of fumarate with cysteine residues in proteins. Formation of 2SC, termed ‘succination’ of proteins, increases in adipocytes grown in high-glucose medium and in adipose tissues of Type 2 diabetic mice. However, the metabolic mechanisms leading to increased fumarate and succination of protein in the adipocyte are unknown. Treatment of 3T3 cells with high glucose (30 mM compared with 5 mM) caused a significant increase in cellular ATP/ADP, NADH/NAD+ and Δψm (mitochondrial membrane potential). There was also a significant increase in the cellular fumarate concentration and succination of proteins, which may be attributed to the increase in NADH/NAD+ and subsequent inhibition of tricarboxylic acid cycle NAD+-dependent dehydrogenases. Chemical uncouplers, which dissipated Δψm and reduced the NADH/NAD+ ratio, also decreased the fumarate concentration and protein succination. High glucose plus metformin, an inhibitor of complex I in the electron transport chain, caused an increase in fumarate and succination of protein. Thus excess fuel supply (glucotoxicity) appears to create a pseudohypoxic environment (high NADH/NAD+ without hypoxia), which drives the increase in succination of protein. We propose that increased succination of proteins is an early marker of glucotoxicity and mitochondrial stress in adipose tissue in diabetes.

scholarly journals CD36 regulates β cell differentiation and influences type 2 diabetic sepsis

2021 ◽  
Author(s):  
Huogen Liu ◽  
Ling Gu ◽  
Yundi Shi ◽  
Hailin Shu ◽  
Fengming Huang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Differentiation ◽  
High Glucose ◽  
Cell Apoptosis ◽  
Cell Clone ◽  
Quantitative Polymerase Chain Reaction ◽  
Control Group ◽  
Β Cell ◽  
Type 2 Diabetic

Abstract Background This study aimed to investigate the diagnostic function of CD36 in type 2 diabetic (T2DM) sepsis complications (T2DSC) and its effect on β-cell differentiation. Methods First, Age - and sex-matched T2DM patients, T2DSC patients and healthy people (50 cases each) were included. Quantitative polymerase chain reaction was used to measure CD36, FOXO1, PDX1, MAFA, insulin, SOX9, Neurog3 and NANOG expression in blood samples. Second, cultured human β-cell line EndoC-βH1 and the interference and overexpression of CD36. Cell clone, apoptosis, inflammatory cytokine, oxidative stress and β-cell differentiation related proteins were also analysed. Third, examined the role of CD36 in high glucose, LPS-induced β-cell. Results CD36 mRNA, and endocrine progenitor β-cell biomarkers SOX9, Neurog3 and NANOG were significantly increased in T2DM than control group, whereas the β-cell maturation biomarkers FOXO1, PDX1, MAFA and insulin were significantly decreased. Compared with the T2DM group, CD36 and FOXO1 were significantly increased in T2DSC, but PDX1, insulin, MAFA, SOX9, Neurog3 and NANOG were significantly decreased. The receiver operating characteristic curve revealed that CD36 was useful for distinguishing T2MD and T2DSC from the control group. Furthermore, CD36 overexpression increased β-cell apoptosis and the secretion of IL-1β, IL-8 TNF-α, malondialdehyde and reactive oxygen species. CD36 induced cell defferentiation. Lastly, CD36 knockdown could inhibit the high glucose and LPS-induced cell apoptosis, inflammatory, oxidative stress and cell defferentiation. Conclusion Significant increase in CD36 can be used as a biomarker for T2MD and T2DSC. CD36 promotes T2MD or T2DSC development by inducing β-cell inflammatory and oxidative stress and defferentiation.

scholarly journals PTPN2 improves implant osseointegration in T2DM via inducing the dephosphorylation of ERK

2019 ◽  
Vol 244 (16) ◽  
pp. 1493-1503 ◽  
Author(s):  
Ya-Nan Wang ◽  
Tingting Jia ◽  
Jiajia Zhang ◽  
Jing Lan ◽  
Dongjiao Zhang ◽  
...  
Keyword(s):  
Osteogenic Differentiation ◽  
High Glucose ◽  
Histological Evaluation ◽  
Glucose Medium ◽  
Alizarin Red ◽  
Positive Effects ◽  
Pull Out ◽  
High Glucose Medium ◽  
Novel Target

Type 2 diabetes mellitus (T2DM) is considered to compromise implant osseointegration. Protein tyrosine phosphatase non-receptor type 2 (PTPN2) regulates glucose metabolism, systemic inflammation, and bone regeneration. This study aimed to investigate the role of PTPN2 in implant osseointegration in T2DM and explore the potential mechanisms. Streptozotocin-induced diabetic rats received implant surgery, with or without local overexpression of PTPN2 for three months, and implant osseointegration was examined by histological evaluation, micro-CT analysis, pull-out test, and scanning electron microscope. Rat bone marrow stem cells (RBMSCs) were isolated and exposed to high glucose, and osteogenic differentiation was evaluated by alizarin red staining, ALP assay, and Western blot analysis. Overexpression of PTPN2 could improve impaired implant osseointegration in T2DM rats and promote osteogenic differentiation of RBMSCs in high glucose. In addition, p-ERK level in RBMSCs was increased in high glucose and decreased after PTPN2 overexpression. These results suggest that PTPN2 promotes implant osseointegration in T2DM rats and enhances osteogenesis of RBMSCs in high glucose medium via inducing the dephosphorylation of ERK. PTPN2 may be a novel target for the therapy of impaired implant osseointegration in T2DM patients. Impact statement Using both in vivo and in vitro approaches, we made important findings that PTPN2 promoted implant osseointegration in T2DM rats and enhanced osteogenesis of RBMSCs in high glucose medium. The positive effects of PTPN2 on osteogenesis are related to the dephosphorylation of ERK and the inhibition of MAPK/ERK pathway. PTPN2 may be a novel target for the therapy of impaired implant osseointegration in T2DM patients.

scholarly journals Restoring redox balance enhances contractility in heart trabeculae from type 2 diabetic rats exposed to high glucose

2015 ◽  
Vol 308 (4) ◽  
pp. H291-H302 ◽  
Author(s):  
Niraj M. Bhatt ◽  
Miguel A. Aon ◽  
Carlo G. Tocchetti ◽  
Xiaoxu Shen ◽  
Swati Dey ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
High Glucose ◽  
Negative Impact ◽  
Antioxidant Activities ◽  
Contractile Function ◽  
Heart Function ◽  
Redox Balance ◽  
The Impact ◽  
Type 2 Diabetic

Hearts from type 2 diabetic (T2DM) subjects are chronically subjected to hyperglycemia and hyperlipidemia, both thought to contribute to oxidizing conditions and contractile dysfunction. How redox alterations and contractility interrelate, ultimately diminishing T2DM heart function, remains poorly understood. Herein we tested whether the fatty acid palmitate (Palm), in addition to its energetic contribution, rescues function by improving redox [glutathione (GSH), NAD(P)H, less oxidative stress] in T2DM rat heart trabeculae subjected to high glucose. Using cardiac trabeculae from Zucker Diabetic Fatty (ZDF) rats, we assessed the impact of low glucose (EG) and high glucose (HG), in absence or presence of Palm or insulin, on force development, energetics, and redox responses. We found that in EG ZDF and lean trabeculae displayed similar contractile work, yield of contractile work (Ycw), representing the ratio of force time integral over rate of O2 consumption. Conversely, HG had a negative impact on Ycw, whereas Palm, but not insulin, completely prevented contractile loss. This effect was associated with higher GSH, less oxidative stress, and augmented matrix GSH/thioredoxin (Trx) in ZDF mitochondria. Restoration of myocardial redox with GSH ethyl ester also rescued ZDF contractile function in HG, independently from Palm. These results support the idea that maintained redox balance, via increased GSH and Trx antioxidant activities to resist oxidative stress, is an essential protective response of the diabetic heart to keep contractile function.

scholarly journals High glucose and hyperglycemic sera from type 2 diabetic patients impair DC differentiation by inducing ROS and activating Wnt/β-catenin and p38 MAPK

2016 ◽  
Vol 1862 (4) ◽  
pp. 805-813 ◽  
Author(s):  
Maria Saveria Gilardini Montani ◽  
Marisa Granato ◽  
Laura Cuomo ◽  
Sandro Valia ◽  
Livia Di Renzo ◽  
...  
Keyword(s):  
P38 Mapk ◽  
High Glucose ◽  
Diabetic Patients ◽  
Type 2 Diabetic Patients ◽  
Type 2 Diabetic

SO021EFFECTS OF SODIUM-GLUCOSE COTRANSPORTER 2 INHIBITOR, CANAGLIFLOZIN ON GLOMERULAR HYPERFILTRATION AND OXIDATIVE STRESS IN MICE WITH TYPE 2 DIABETES

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Megumi Kondo ◽  
KENGO KIDOKORO ◽  
Yoshihisa Wada ◽  
Atsuyuki Tokuyama ◽  
Hiroyuki Kadoya ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Type 2 Diabetes ◽  
Kidney Disease ◽  
High Glucose ◽  
Glomerular Hyperfiltration ◽  
No Production ◽  
Sodium Glucose Cotransporter ◽  
Type 2 Diabetic ◽  
Urinary Space

Abstract Background and Aims In most developed countries, diabetic kidney disease (DKD) is the most common cause of chronic kidney disease, which can lead to end-stage renal disease. In recent clinical trials, sodium–glucose cotransporter 2 inhibitors (SGLT2is) slowed the progression of kidney disease as compared with a placebo in patients with type 2 diabetes. One of the main mechanisms of the renoprotective effects of SCLT2is in DKD is considered the ability of these inhibitors to improve glomerular hyperfiltration. We previously demonstrated that the adenosine/adenosine A1 receptor pathway played a pivotal role in the tubuloglomerular feedback(TGF) system in a type 1 diabetic model, Akita mice (Circulation, 2019). We also reported that increased oxidative stress was involved in the pathogenesis of diabetic vascular complications. Uncoupling of endothelial nitric oxide (NO) synthase (eNOS) via oxidation of tetrahydrobiopterin (BH4), a cofactor required for NO production, played a major role in generation of oxidative stress (AJPRP, 2005; JASN, 2013). In the present study, we explored the renal protective effects of SGLT2 inhibition, with a focus on glomerular hemodynamics and glomerular oxidative stress. Method This study used type 2 diabetic db/db mice and db/m+ mice as a control (male, 8wk old). We developed a novel method to measure the glomerular filtration rate of single nephrons (SNGFRs) in mice using multiphoton laser microscopy. In the first experiment, we measured the SNGFRs in 12 wk-old db/db and db/m+ mice to confirm glomerular hyperfiltration. Next, we evaluated the SNGFRs change before and after the administration of a single dose of canagliflozin (CANA) (10 mg/kg). The SNGFRs, glomerular permeability of macromolecules, glomerular reactive oxygen species (ROS) and NO production, and tetrahydrobiopterin (BH4) level in serum and kidney were evaluated after the CANA treatment for 8 wk. Finally, human glomerular endothelial cells (hGECs) were exposed to normal glucose (5 mmol/L), high glucose (30 mmol/L of D-glucose), or a hyperosmotic control (5 mmol/L of D-glucose plus 25 mmol/L of L-glucose) in the presence or absence of CANA (10 μmol/L). Results The CANA treatment ameliorated glomerular hyperfiltration in the db/db mice. In the db/db mice, glomerulus ROS production increased, and NO production decreased as compared with the levels in the control mice. CANA improved the imbalance between ROS and NO production. The serum and kidney concentrations of BH4 declined in the non-treated db/db mice, whereas the CANA treatment preserved the BH4 level. Leakage of 70-kD FITC-labeled albumin into the urinary space was observed in the db/db mice. The CANA treatment reduced the amount of FITC-labeled albumin in the urinary space of the db/db mice. The CANA treatment also alleviated vascular endothelial damage in glomeruli. BH4 levels decreased in the hGECs exposed to high glucose. CANA did not improved BH4 level in the hGECs exposed to high glucose. Conclusion SGLT2i ameliorated glomerular hyperfiltration, preserving BH4 levels and improving the glomerular ROS/NO imbalance in type 2 diabetic mice.

Anti-diabetic effects of shubat in type 2 diabetic rats induced by combination of high-glucose-fat diet and low-dose streptozotocin

2015 ◽  
Vol 169 ◽  
pp. 269-274 ◽  
Author(s):  
Tabusi Manaer ◽  
Lan Yu ◽  
Yi Zhang ◽  
Xue-Jun Xiao ◽  
Xin-Hua Nabi
Keyword(s):  
High Glucose ◽  
Low Dose ◽  
Diabetic Rats ◽  
Type 2 Diabetic

scholarly journals Bioenergetic Analysis of Single Pancreatic β-Cells Indicates an Impaired Metabolic Signature in Type 2 Diabetic Subjects

Endocrinology ◽  
2015 ◽  
Vol 156 (10) ◽  
pp. 3496-3503 ◽  
Author(s):  
Akos A. Gerencser
Keyword(s):  
Insulin Secretion ◽  
Membrane Potential ◽  
Energy Metabolism ◽  
Tricarboxylic Acid Cycle ◽  
Atp Synthesis ◽  
Tricarboxylic Acid ◽  
Β Cells ◽  
Acid Cycle ◽  
Type 2 Diabetic

Impaired activation of mitochondrial energy metabolism by glucose has been demonstrated in type 2 diabetic β-cells. The cause of this dysfunction is unknown. The aim of this study was to identify segments of energy metabolism with normal or with altered function in human type 2 diabetes mellitus. The mitochondrial membrane potential (ΔψM), and its response to glucose, is the main driver of mitochondrial ATP synthesis and is hence a central mediator of glucose-induced insulin secretion, but its quantitative determination in β-cells from human donors has not been attempted, due to limitations in assay technology. Here, novel fluorescence microscopic assays are exploited to quantify ΔψM and its response to glucose and other secretagogues in β-cells of dispersed pancreatic islet cells from 4 normal and 3 type 2 diabetic organ donors. Mitochondrial volume densities and the magnitude of ΔψM in low glucose were not consistently altered in diabetic β-cells. However, ΔψM was consistently less responsive to elevation of glucose concentration, whereas the decreased response was not observed with metabolizable secretagogue mixtures that feed directly into the tricarboxylic acid cycle. Single-cell analysis of the heterogeneous responses to metabolizable secretagogues indicated no dysfunction in relaying ΔψM hyperpolarization to plasma membrane potential depolarization in diabetic β-cells. ΔψM of diabetic β-cells was distinctly responsive to acute inhibition of ATP synthesis during glucose stimulation. It is concluded that the mechanistic deficit in glucose-induced insulin secretion and mitochondrial hyperpolarization of diabetic human β-cells is located upstream of the tricarboxylic acid cycle and manifests in dampening the control of ΔψM by glucose metabolism.

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