Insufficient Glycemic Control Increases Nuclear Factor-κB Binding Activity in Peripheral Blood Mononuclear Cells Isolated From Patients With Type 1 Diabetes

Hofmann, M.; Schiekofer, Stephan; Kanitz, Michael; Klevesath, M. S.; Joswig, Martina; Lee, Vong; Morcos, Michael; Tritschler, Hans; Ziegler, Reinhard; Wahl, Peter; Bierhaus, Angelika; Nawroth, Peter P.

doi:10.2337/diacare.21.8.1310

Cited by 155 publications

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“…The increased expression of iNOS may explain the increase in plasma NO concentration in diabetic patients which was also observed in previous studies [26,27]. ALA decreased NO, probably because of its ability to reduce oxidative stress-mediated NF-κB activation and subsequently iNOS expression in diabetic patients [28][29][30].…”

Section: Discussionsupporting

confidence: 49%

“…ALA can scavenge intracellular free radicals and therefore down-regulate proinflammatory redox-sensitive signal transduction processes including NF-κB activation [28,29]. The decrease in TNF-α levels and TGF-β expression in patients who received ALA in our study can be explained by the ability of α-lipoic acid to suppress NF-κB activation.…”

Section: Discussionmentioning

confidence: 58%

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Alpha-Lipoic Acid Improves Subclinical Left Ventricular Dysfunction in Asymptomatic Patients with Type 1 Diabetes

Hegazy¹,

Tolba²,

Mostafa³

et al. 2013

Rev Diabet Stud

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■ Abstract BACKGROUND:Oxidative stress plays an important role in the development of diabetic cardiomyopathy. Alpha-lipoic acid (ALA) is a powerful antioxidant that may have a protective role in diabetic cardiac dysfunction. AIM: We investigated the possible beneficial effect of alpha-lipoic acid on diabetic left ventricular (LV) dysfunction in children and adolescents with asymptomatic type 1 diabetes (T1D). SUB-JECTS AND METHODS: Thirty T1D patients (aged 10-14) were randomized to receive insulin treatment (n = 15) or insulin plus alpha-lipoic acid 300 mg twice daily (n = 15) for four months. Age and sex matched healthy controls (n = 15) were also included. Patients were evaluated with conventional 2-dimensional echocardiographic examination (2D), pulsed tissue Doppler (PTD), and 2-dimensional longitudinal strain echocardiography (2DS) before and after therapy. Glutathione, malondialdhyde (MDA), nitric oxide (NO), tumor necrosis factor-alpha (TNF-alpha), Fas ligand (Fas-L), matrix metalloproteinase 2 (MMP-2), and troponin-I were determined and correlated to echocardiographic parameters. RESULTS: Diabetic patients had significantly lower levels of glutathione and significantly higher MDA, NO, TNF-alpha, Fas-L, MMP-2, and troponin-I levels than control subjects. The expression of transforming growth factor beta (TGF-beta) mRNA in peripheral blood mononuclear cells was also increased in diabetic patients. Significant correlations of mitral e'/a' ratio and left ventricular global peak systolic strain with glutathione, MDA, NO, TNF-alpha, and Fas-L were observed in diabetic patients. Alpha-lipoic acid significantly increased glutathione level and significantly decreased MDA, NO, TNF-alpha, Fas-L, MMP-2, troponin-I levels, and TGF-beta gene expression. Moreover, alphalipoic acid significantly increased mitral e'/a' ratio and left ventricular global peak systolic strain in diabetic patients. CONCLUSION: These findings suggest that alpha-lipoic acid may have a role in preventing the development of diabetic cardiomyopathy in type 1 diabetes.

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Section: Discussionsupporting

confidence: 49%

Section: Discussionmentioning

confidence: 58%

Alpha-Lipoic Acid Improves Subclinical Left Ventricular Dysfunction in Asymptomatic Patients with Type 1 Diabetes

Hegazy¹,

Tolba²,

Mostafa³

et al. 2013

Rev Diabet Stud

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“…A high glucose concentration is known to activate NF-κ B in vitro (Morrissey and Klahr 1997;Hofmann et al 1998;Rangan et al 1999;Yerneni et al 1999;Jones et al 2001). To our knowledge, this is first in vivo study to suggest a correlation between DN and NF-κ B activation.…”

Section: Discussionmentioning

confidence: 99%

“…Activation of NF-κ B during hyperglycemia has been reported in many cell types, such as human peripheral blood mononuclear cells (Hofmann et al 1998), porcine vascular smooth muscle cells (Yerneni et al 1999), rat kidney cortex (Morrissey and Klahr 1997;Rangan et al 1999) and human proximal tubular cells (Jones et al 2001). Activation in nuclei of these cells is induced by second messengers, because it is unlikely that glucose itself could interact with NF-κ B or its components.…”

mentioning

confidence: 99%

Nuclear Factor-.KAPPA.B Activation in Diabetic Rat Kidney: Evidence for Involvement of P-Selectin in Diabetic Nephropathy

Iwamoto

Mizuiri

Arita

et al. 2005

Tohoku J. Exp. Med.

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Activation of a transcription factor, nuclear factor-κ B (NF-κ B), is a key step in the pathogenesis of diabetic nephropathy. In this study, we investigated the role of P-selectin, a platelet-derived adhesion molecule, in diabetic nephropathy by examining the activation status of NF-κ B in the renal cortex of streptozotocin (STZ)-treated rats. The STZ treatment induced pathogenetic parameters such as increased creatinine clearance, increased blood glucose and massive albuminuria in a timedependent manner. Electrophoretic mobility shift assays (EMSAs) with a specific probe, representing the P-selectin gene promoter, revealed the activation status of NF-κ B in the STZ-treated rats, as judged by the time-dependent increase in the formation of the specific protein-DNA complexes. This increase was associated with the increased pathogenetic parameters. Supershift assays with specific antibodies revealed that p50, but not p52, p65, Rel B, or c-Rel, may be involved in the activation of NF-κ B, though the component primarily responsible for the increase could not be determined. Western blot analysis confirmed an increase in P-selectin in STZ-treated rats. Notably, treatment with ammonium pyrrolidinedithiocarbamate, an antioxidant and inhibitor of NF-κ B, inhibited the activation of NF-κ B in STZ-treated rats and decreased P-selectin in the renal cortical tissue. Our results indicate that expression of the P-selectin gene is induced through the activation of NF-κ B and that P-selectin may be involved in the pathogenesis of diabetic nephropathy. nuclear factor-κ B; P-selectin; diabetic nephropathy; rat; streptozotocin

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“…Activation of NFKB can also be triggered by high levels of FFA's and pro-inflammatory cytokines like TNFα. Upregulation of these pathways results in impaired insulin action and further oxidative stress-induced insulin resistance [26]. When patients with diabetes were treated with the antioxidant lipoic acid (LA), a significant suppression of NFKB activation was observed [27].…”

Section: The Mostly Targeted Genes and Pathways Arementioning

confidence: 99%

Therapeutic Targets of Type 2 Diabetes: an Overview

Banu

Bhowmick

2017

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As the prevalence of type 2 diabetes (T2D) is rapidly increasing, and effective strategies to manage and prevent this disease are urgently required, as per WHO statistics undertaken in 2012, the number of people suffering from T2D in India is expected to shoot up from 40.9 million in 2007 to 69.9 million by the year 2025. Even though, the symptoms of T2D are seen in the later stages of life, the onset of the disease occurs quite early and is referred to as lifestyle disorder. Insulin resistance and β cell dysfunction are the main causative factors along with mutations in the genes regulating glucose homeostasis and β cell development. A vicious circle of the causes and effects of hyperglycemia interlinked together forms the whole picture of T2D. Our review discusses the molecular targets of the current oral therapeutic drugs, which cuts down hyperglycemia. This review aims to provide better insights to comprehension of the disease, recent advances in molecular and cellular therapies. A comprehensive analysis of these novel targets identified over the years and various therapeutic leads which successfully completed their clinical trials are presented in this review. Few of these lead molecules operate as GLP-1 agonist, SGLT2 inhibitors, and DPP-IV inhibitors and are termed as next generation anti-diabetic drugs.

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Insufficient Glycemic Control Increases Nuclear Factor-κB Binding Activity in Peripheral Blood Mononuclear Cells Isolated From Patients With Type 1 Diabetes

Cited by 155 publications

References 0 publications

Alpha-Lipoic Acid Improves Subclinical Left Ventricular Dysfunction in Asymptomatic Patients with Type 1 Diabetes

Alpha-Lipoic Acid Improves Subclinical Left Ventricular Dysfunction in Asymptomatic Patients with Type 1 Diabetes

Nuclear Factor-.KAPPA.B Activation in Diabetic Rat Kidney: Evidence for Involvement of P-Selectin in Diabetic Nephropathy

Therapeutic Targets of Type 2 Diabetes: an Overview

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