Enhanced p22phox expression impairs vascular function through p38 and ERK1/2 MAP kinase-dependent mechanisms in type 2 diabetic mice

Type 2 diabetes is associated with vascular complication. We hypothesized that increased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit p22 phox expression impairs vascular endothelium-dependent relaxation (EDR) in type 2 diabetes. Type 2 diabetic ( db − /db −) and control ( db − /db +) mice were treated with reactive oxygen species (ROS) scavenger, polyethylene glycol superoxide dismutase (1,000 U/kg daily ip), or small interfering RNA p22 phox (p22 phox-lentivirus-small interfering RNA, 100 μg iv, 2 times/wk) for 1 mo. EDR was impaired in microvascular bed (coronary arteriole and femoral and mesenteric resistance arteries) from diabetic mice compared with control. Interestingly, ROS scavenger and p22 phox downregulation did not affect blood glucose level or body weight but significantly improved EDR. Mitogen-activated protein kinases (ERK1/2 and p38) phosphorylation and NADPH oxidase activity were increased in arteries from diabetic mice and were reduced after ROS scavenger or p22 phox downregulation in db − /db − mice. The present study showed that enhanced p22 phox expression causes vascular dysfunction through ERK1/2 and p38-mitogen-activated protein kinase-dependent mechanisms in male type 2 diabetic mice. Therefore, p22 phox could be an important target to improve vascular function in diabetes.

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An anxiolytic drug buspirone ameliorates hyperglycemia and endothelial dysfunction in type 2 diabetic rat model

Turkish Journal of Biochemistry ◽

10.1515/tjb-2019-0224 ◽

2020 ◽

Vol 45 (4) ◽

pp. 397-404

Author(s):

Tugba Gurpinar Çavuşoğlu ◽

Ertan Darıverenli ◽

Kamil Vural ◽

Nuran Ekerbicer ◽

Cevval Ulman ◽

...

Keyword(s):

Type 2 Diabetes ◽

Blood Glucose ◽

Endothelial Dysfunction ◽

Vascular Function ◽

Fasting Blood Glucose ◽

Diabetic Rats ◽

Diabetic Rat ◽

Insulin Levels ◽

Type 2 Diabetic

AbstractObjectivesType 2 diabetes is a common metabolic disease and anxiety disorders are very common among diabetics. Buspirone is used in the treatment of anxiety, also having blood glucose-lowering effects. The aim of the study was to investigate the effects of buspirone on the glucose and lipid metabolism as well as vascular function in type 2 diabetic rats.MethodsA type 2-diabetic model was induced through a high-fat diet for eight weeks followed by the administration of low-dose streptozotocin (35 mg/kg, intraperitoneal) in rats. Buspirone was given at two different doses (1.5 mg/kg/d and 5 mg/kg/d) and combined with metformin (300 mg/kg/d). The fasting glucose and insulin levels, lipid profile were analyzed, and vascular response measured from the thoracic aorta was also evaluated.ResultsBoth doses of buspirone caused a significant improvement in fasting blood glucose levels. In particular, the buspirone treatment, combined with metformin, improved endothelial dysfunction and was found to be correlated with decreased nitrate/nitrite levels.ConclusionsBuspirone may be effective in the treatment of type 2 diabetes, either alone or in combination with other treatments, particularly in terms of endothelial dysfunction, inflammation and impaired blood glucose, and insulin levels.

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MiR-27b augments bone marrow progenitor cell survival via suppressing the mitochondrial apoptotic pathway in Type 2 diabetes

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00073.2017 ◽

2017 ◽

Vol 313 (4) ◽

pp. E391-E401 ◽

Cited By ~ 9

Author(s):

Hainan Li ◽

Jenny Liu ◽

Yihan Wang ◽

Zhiyao Fu ◽

Maik Hüttemann ◽

...

Keyword(s):

Type 2 Diabetes ◽

Bone Marrow ◽

Cell Therapy ◽

Progenitor Cell ◽

Diabetic Mice ◽

Tissue Repair And Regeneration ◽

Autologous Cell ◽

Autologous Cell Therapy ◽

Type 2 Diabetic

Bone marrow-derived progenitor cells (BMPCs) are potential candidates for autologous cell therapy in tissue repair and regeneration because of their high angiogenic potential. However, increased progenitor cell apoptosis in diabetes directly limits their success in the clinic. MicroRNAs are endogenous noncoding RNAs that regulate gene expression at the posttranscriptional level, but their roles in BMPC-mediated angiogenesis are incompletely understood. In the present study, we tested the hypothesis that the proangiogenic miR-27b inhibits BMPC apoptosis in Type 2 diabetes. Bone marrow-derived EPCs from adult male Type 2 diabetic db/db mice and their normal littermates db/+ mice were used. MiR-27b expression (real-time PCR) in EPCs was decreased after 24 h of exposure to methylglyoxal (MGO) or oxidized low-density lipoprotein but not high glucose, advanced glycation end products, the reactive oxygen species generator LY83583, or H2O2. The increase in BMPC apoptosis in the diabetic mice was rescued following transfection with a miR-27b mimic, and the increased apoptosis induced by MGO was also rescued by the miR-27b mimic. p53 protein expression and the Bax/Bcl-2 ratio in EPCs (Western blot analyses) were significantly higher in db/db mice, both of which were suppressed by miR-27b. Furthermore, mitochondrial respiration, as measured by oxygen consumption rate, was enhanced by miR-27b in diabetic BMPCs, with concomitant decrease of mitochondrial Bax/Bcl-2 ratio. The 3′ UTR binding assays revealed that both Bax, and its activator RUNX1, were direct targets of miR-27b, suggesting that miR-27b inhibits Bax expression in both direct and indirect manners. miR-27b prevents EPC apoptosis in Type 2 diabetic mice, at least in part, by suppressing p53 and the Bax/Bcl-2 ratio. These findings may provide a mechanistic basis for rescuing BMPC dysfunction in diabetes for successful autologous cell therapy.

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Decreased glycolytic and tricarboxylic acid cycle intermediates coincide with peripheral nervous system oxidative stress in a murine model of type 2 diabetes

Journal of Endocrinology ◽

10.1530/joe-12-0356 ◽

2012 ◽

Vol 216 (1) ◽

pp. 1-11 ◽

Cited By ~ 46

Author(s):

Lucy M Hinder ◽

Anuradha Vivekanandan-Giri ◽

Lisa L McLean ◽

Subramaniam Pennathur ◽

Eva L Feldman

Keyword(s):

Oxidative Stress ◽

Type 2 Diabetes ◽

Sciatic Nerve ◽

Peripheral Nerves ◽

Sural Nerve ◽

Tca Cycle ◽

Tricarboxylic Acid ◽

Diabetic Mice ◽

Type 2 Diabetic

Diabetic neuropathy (DN) is the most common complication of diabetes and is characterized by distal-to-proximal loss of peripheral nerve axons. The idea of tissue-specific pathological alterations in energy metabolism in diabetic complications-prone tissues is emerging. Altered nerve metabolism in type 1 diabetes models is observed; however, therapeutic strategies based on these models offer limited efficacy to type 2 diabetic patients with DN. Therefore, understanding how peripheral nerves metabolically adapt to the unique type 2 diabetic environment is critical to develop disease-modifying treatments. In the current study, we utilized targeted liquid chromatography–tandem mass spectrometry (LC/MS/MS) to characterize the glycolytic and tricarboxylic acid (TCA) cycle metabolomes in sural nerve, sciatic nerve, and dorsal root ganglia (DRG) from male type 2 diabetic mice (BKS.Cg-m+/+Leprdb;db/db) and controls (db/+). We report depletion of glycolytic intermediates in diabetic sural nerve and sciatic nerve (glucose-6-phosphate, fructose-6-phosphate, fructose-1,6-bisphosphate (sural nerve only), 3-phosphoglycerate, 2-phosphoglycerate, phosphoenolpyruvate, and lactate), with no significant changes in DRG. Citrate and isocitrate TCA cycle intermediates were decreased in sural nerve, sciatic nerve, and DRG from diabetic mice. Utilizing LC/electrospray ionization/MS/MS and HPLC methods, we also observed increased protein and lipid oxidation (nitrotyrosine; hydroxyoctadecadienoic acids) indb/dbtissue, with a proximal-to-distal increase in oxidative stress, with associated decreased aconitase enzyme activity. We propose a preliminary model, whereby the greater change in metabolomic profile, increase in oxidative stress, and decrease in TCA cycle enzyme activity may cause distal peripheral nerves to rely on truncated TCA cycle metabolism in the type 2 diabetes environment.

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The Efficacy of Red Ginseng in Type 1 and Type 2 Diabetes in Animals

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2013/593181 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7 ◽

Cited By ~ 19

Author(s):

Bin Na Hong ◽

Min Gun Ji ◽

Tong Ho Kang

Keyword(s):

Type 2 Diabetes ◽

Signal Intensity ◽

Diabetic Mice ◽

Red Ginseng ◽

Korean Red Ginseng ◽

Diabetes In Animals ◽

Brainstem Response ◽

Type 2 Diabetic

Diabetes mellitus (DM) is one of the most modern chronic metabolic diseases in the world. Moreover, DM is one of the major causes of modern neurological diseases. In the present study, the therapeutic actions of Korean red ginseng were evaluated in type 1 and type 2 diabetic mouse models using auditory electrophysiological measurement. The comprehensive results from auditory brainstem response (ABR), auditory middle latency response (AMLR), and transient evoked otoacoustic emission (TEOAE) demonstrate auditory functional damage caused by type 1 or 2 DM. Korean red ginseng improved the hearing threshold shift, delayed latencies and signal intensity decrease in type 2 diabetic mice. Type 1 diabetic mice showed a partial improvement in decreasing amplitude and signal intensity, not significantly. We suggest that the Korean red ginseng has a more potent efficacy in hearing loss in insulin resistance type 2 diabetes than in type 1 diabetes.

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ID: 1080 Adipose-derived stem cells alleviate glucose tolerance in type 2 diabetic mouse

Biomedical Research and Therapy ◽

10.15419/bmrat.v4is.354 ◽

2017 ◽

Vol 4 (S) ◽

pp. 166

Author(s):

Anh Nguyen Tu Bui ◽

Cong Le Thanh Nguyen ◽

Anh Thi Minh Nguyen ◽

Nhat Chau Truong ◽

Ngoc Kim Phan ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Stem Cells ◽

Blood Glucose ◽

Glucose Tolerance ◽

Adipose Derived Stem Cells ◽

Diabetic Mice ◽

Human Ascs ◽

Type 2 Diabetic

Background: Type 2 diabetes (T2D) is the most common form of diabetes and accounts for 90-95% of all existing diabetic cases. The main etiologies of T2D include insulin resistance in target tissues, insufficient secretion of insulin and subsequent decline of pancreatic β-cell function. Recently, many studies have suggested that adipose – derived stem cells (ASCs) were potential to alleviate insulin resistance and hyperglycemia and promote the islets repair. In this study, ASCs were hypothesized that they could have ameliorative effects on type 2 diabetic mice. Methods: Type 2 diabetic mice were induced by a combination of high-fat diet and injection of STZ 100 mg/kg and NA 120 mg/kg. Thereafter, two doses of 106 human ASCs were transplanted 2 week interval into each mouse via the tail vein. The mice were monitored health condition, rate of mortaity, body weight, consumption of food and water, blood glucose level, serum insulin level and histological structure of pancreatic islets. Results: Our results indicated that the ASC-treated mice expressed improved condition in comparision with non-treated diabetic mice. The consumption of food and water as well as the blood glucose level decreased. Simultaneously, ASC transplantation improved the impaired glucose tolerance and insulin tolerance in T2D mice. Besides, the total cholesterol have significantly decreased. Conclusion: it is suggested that human ASCs infusion is safe and effective for type 2 diabetes mellitus in mice regarding the improved glucose metabolism and insulin resistance.

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Adiponectin Ameliorates Lung Ischemia-Reperfusion Injury Through SIRT1-Pink1 Signaling-Mediated Mitophagy in Type 2 Diabetic Rats

10.21203/rs.3.rs-707226/v1 ◽

2021 ◽

Author(s):

Tao Jiang ◽

Tianhua Liu ◽

Xijin Deng ◽

Wengang Ding ◽

Ziyong Yue ◽

...

Keyword(s):

Oxidative Stress ◽

Lung Transplantation ◽

Protective Effect ◽

Mitochondrial Dysfunction ◽

Small Interfering Rna ◽

Ischemia Reperfusion ◽

Diabetic Rats ◽

Interfering Rna ◽

Type 2 Diabetic

Abstract BackgroundDiabetes mellitus (DM) is a key contributing factor to the poor survival in lung transplantation recipients. Mitochondrial dysfunction is recognized as a critical mediator in the pathogenesis of diabetic lung ischemia-reperfusion (IR) injury. The protective effects of adiponectin have been demonstrated in our previously study, but the underlying mechanism remained unclear. Here we demonstrated an important role of mitophagy in the protective effect of adiponectin during diabetic lung IR injury.Methods High-fat diet-fed streptozotocin-induced type 2 diabetic rats as recipients were exposed to adiponectin with or without administration of the SIRT1 inhibitor EX527 following lung transplantation. To unravel the mechanisms underlying the action of adiponectin, rat pulmonary microvascular endothelial cells were transfected with SIRT1 small-interfering RNA or Pink1 small-interfering RNA and then subjected to in vitro diabetic lung IR injury.ResultsMitophagy was impaired in the diabetic lung subjected to IR injury, accompanied by increased oxidative stress, inflammation, apoptosis, and mitochondrial dysfunction. Adiponectin induced mitophagy and attenuated subsequent diabetic lung IR injury by improving lung functional recovery, suppressing oxidative damage, diminishing inflammation, decreasing cell apoptosis, and preserving mitochondrial function. However, both inhibitors of mitophagy and knockdown of Pink1 suppressed mitophagy, and reduced the protective action of adiponectin. Furthermore, we demonstrated that APN affected Pink1 stabilization via the SIRT1 signaling pathway, and knockdown of SIRT1 suppressed Pink1 expression and compromised the protective effect of adiponectin.ConclusionThese data demonstrated that adiponectin attenuated reperfusion-induced oxidative stress, inflammation, apoptosis and mitochondrial dysfunction via activation of SIRT1-Pink1 signaling-mediated mitophagy in diabetic lung IR injury.

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Lipotoxicity dysregulates the immunoproteasome in podocytes and kidneys in type 2 diabetes

AJP Renal Physiology ◽

10.1152/ajprenal.00509.2020 ◽

2021 ◽

Vol 320 (4) ◽

pp. F548-F558

Author(s):

Hyun Soon Lee ◽

Ji Yeon Suh ◽

Byeong-Choel Kang ◽

Eugene Lee

Keyword(s):

Type 2 Diabetes ◽

Diabetic Nephropathy ◽

Fish Oil ◽

Olive Oil ◽

Renal Cortex ◽

Diabetic Mice ◽

Podocyte Injury ◽

Type 2 Diabetic

In podocytes, PA rapidly induced immunoproteasome expression but ultimately decreased it, while OA and EPA restored the decreased immunoproteasome levels. In the renal cortex of type 2 diabetic mice, immunoproteasome expression was significantly decreased, whereas feeding of OA-rich olive oil or EPA-rich fish oil diets protected them against the reduced immunoproteasome expression and progression of diabetic nephropathy. Thus, lipotoxicity-induced podocyte injury with impaired immunoproteasome expression may be related to the pathogenesis of diabetic nephropathy.

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The plasma 5′-AMP acts as a potential upstream regulator of hyperglycemia in type 2 diabetic mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00424.2011 ◽

2012 ◽

Vol 302 (3) ◽

pp. E325-E333 ◽

Cited By ~ 11

Author(s):

Ying Zhang ◽

Zhongqiu Wang ◽

Yue Zhao ◽

Ming Zhao ◽

Shiming Wang ◽

...

Keyword(s):

Type 2 Diabetes ◽

Blood Glucose ◽

Adenosine Monophosphate ◽

Plasma Free Fatty Acid ◽

Hepatic Glycogen ◽

Diabetic Mice ◽

Wild Type ◽

Upstream Regulator ◽

Type 2 Diabetic

Increased plasma free fatty acid (FFA) level is a hallmark of type 2 diabetes. However, the underlying molecular basis for FFA-caused hyperglycemia remains unclear. Here we identified plasma 5′-adenosine monophosphate (pAMP) markedly elevated in the plasma of type 2 diabetic mice. High levels of FFAs induced damage in vein endothelial cells and contributed to an increase in pAMP. Administration of synthetic 5′-AMP caused hyperglycemia and impaired insulin action in lean wild-type mice. 5′-AMP elevated blood glucose in mice deficient in adenosine receptors with equal efficiency as wild-type mice. The function of pAMP was initiated by the elevation of cellular adenosine levels, directly stimulating G-6-Pase enzyme activity, attenuating insulin-dependent GLUT4 translocation in skeletal muscle, and displaying a rapid and steep increase in blood glucose and a decrease in hepatic glycogen level. It was followed by an increase in the gene expression of hepatic Foxo1 and its targeting gene Pepck and G6Pase, which was similar to diabetic phenotype in db/db mice. Our results suggest that pAMP is a potential upstream regulator of hyperglycemia in type 2 diabetes.

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