Heredity of type 2 diabetes confers increased susceptibility to oxidative stress and inflammation

Introduction and objectiveHeredity of type 2 diabetes mellitus (T2DM) is associated with greater risk for developing T2DM. Thus, individuals who have a first-degree relative with T2DM (FDRT) provide a natural model to study factors of susceptibility towards development of T2DM, which are poorly understood. Emerging key players in T2DM pathophysiology such as adverse oxidative stress and inflammatory responses could be among possible mechanisms that predispose FDRTs to develop T2DM. Here, we aimed to examine the role of oxidative stress and inflammatory responses as mediators of this excess risk by studying dynamic postprandial responses in FDRTs.Research design and methodsIn this open-label case-control study, we recruited normoglycemic men with (n=9) or without (n=9) a family history of T2DM. We assessed plasma glucose, insulin, lipid profile, cytokines and F2-isoprostanes, expression levels of oxidative and inflammatory genes/proteins in circulating mononuclear cells (MNC), myotubes and adipocytes at baseline (fasting state), and after consumption of a carbohydrate-rich liquid meal or insulin stimulation.ResultsPostprandial glucose and insulin responses were not different between groups. Expression of oxidant transcription factor NRF2 protein (p<0.05 for myotubes) and gene (pgroup=0.002, ptime×group=0.016), along with its target genes TXNRD1 (pgroup=0.004, ptime×group=0.007), GPX3 (pgroup=0.011, ptime×group=0.019) and SOD-1 (pgroup=0.046 and ptime×group=0.191) was upregulated in FDRT-derived MNC after meal ingestion or insulin stimulation. Synergistically, expression of target genes of inflammatory transcription factor nuclear factor kappa B such as tumor necrosis factor alpha (pgroup=0.001, ptime×group=0.007) was greater in FDRT-derived MNC than in non-FDRT-derived MNC after meal ingestion or insulin stimulation.ConclusionsOur findings shed light on how heredity of T2DM confers increased susceptibility to oxidative stress and inflammation. This could provide early insights into the underlying mechanisms and future risk of FDRTs for developing T2DM and its associated complications.

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DBC1, p300, HDAC3, and Siah1 coordinately regulate ELL stability and function for expression of its target genes

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1912375117 ◽

2020 ◽

Vol 117 (12) ◽

pp. 6509-6520 ◽

Cited By ~ 1

Author(s):

Subham Basu ◽

Mahesh Barad ◽

Dipika Yadav ◽

Arijit Nandy ◽

Bidisha Mukherjee ◽

...

Keyword(s):

Type 2 Diabetes ◽

Rna Polymerase Ii ◽

Target Genes ◽

Mononuclear Cells ◽

Elongation Factor ◽

Diabetes Patient ◽

Elongation Complex ◽

Peripheral Blood Mononuclear ◽

And Function

Among all of the Super Elongation Complex (SEC) components, ELL1 (also known as ELL) is the only bona fide elongation factor that directly stimulates transcription elongation by RNA polymerase II. However, the mechanism(s) of functional regulation of ELL1 (referred to as ELL hereafter), through its stabilization, is completely unknown. Here, we report a function of human DBC1 in regulating ELL stability involving HDAC3, p300, and Siah1. Mechanistically, we show that p300-mediated site-specific acetylation increases, whereas HDAC3-mediated deacetylation decreases, ELL stability through polyubiquitylation by the E3 ubiquitin ligase Siah1. DBC1 competes with HDAC3 for the same binding sites on ELL and thus increases its acetylation and stability. Knockdown of DBC1 reduces ELL levels and expression of a significant number of genes, including those involved in glucose metabolism. Consistently, Type 2 diabetes patient-derived peripheral blood mononuclear cells show reduced expression of DBC1 and ELL and associated key target genes required for glucose homeostasis. Thus, we describe a pathway of regulating stability and functions of key elongation factor ELL for expression of diverse sets of genes, including ones that are linked to Type 2 diabetes pathogenesis.

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Research Status of Differentially Expressed Noncoding RNAs in Type 2 Diabetes Patients

BioMed Research International ◽

10.1155/2020/3816056 ◽

2020 ◽

Vol 2020 ◽

pp. 1-18

Author(s):

Rou Shi ◽

Yingjian Chen ◽

Yuanjun Liao ◽

Rang Li ◽

Chunwen Lin ◽

...

Keyword(s):

Type 2 Diabetes ◽

Signaling Pathways ◽

Insulin Signaling ◽

Target Genes ◽

Mononuclear Cells ◽

Noncoding Rnas ◽

Vascular Complications ◽

Differentially Expressed ◽

Circular Rnas

Aims. Noncoding RNAs (ncRNAs) play an important role in the occurrence and development of type 2 diabetes mellitus (T2DM). This paper summarized the current evidences of the involvement microRNAs, long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs) in the differential expressions and their interaction with each other in T2DM. Methods. The differentially expressed miRNAs, lncRNAs, and circRNAs in the blood circulation (plasma, serum, whole blood, and peripheral blood mononuclear cells) of patients with T2DM were found in PubMed, GCBI, and other databases. The interactions between ncRNAs were predicted based on the MiRWalk and the DIANA Tools databases. The indirect and direct target genes of lncRNAs and circRNAs were predicted based on the starBase V2.0, DIANA Tools, and LncRNA-Target databases. Then, GO and KEGG analysis on all miRNA, lncRNA, and circRNA target genes was performed using the mirPath and Cluster Profile software package in R language. The lncRNA–miRNA and circRNA–miRNA interaction diagram was constructed with Cytoscape. The aim of this investigation was to construct a mechanism diagram of lncRNA involved in the regulation of target genes on insulin signaling pathways and AGE–RAGE signaling pathways of diabetic complications. Results. A total of 317 RNAs, 283 miRNAs, and 20 lncRNAs and circRNAs were found in the circulation of T2DM. Dysregulated microRNAs and lncRNAs were found to be involved in signals related to metabolic disturbances, insulin signaling, and AGE–RAGE signaling in T2DM. In addition, lncRNAs participate in the regulation of key genes in the insulin signaling and AGE–RAGE signaling pathways through microRNAs, which leads to insulin resistance and diabetic vascular complications. Conclusion. Noncoding RNAs participate in the occurrence and development of type 2 diabetes and lead to its vascular complications by regulating different signaling pathways.

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Scutellarin alleviates type 2 diabetes (HFD/low dose STZ)- induced cardiac injury through modulation of oxidative stress, inflammation, apoptosis and fibrosis in mice

10.21203/rs.3.rs-410402/v1 ◽

2021 ◽

Author(s):

Yan Huo ◽

Abudureheman Mijiti ◽

Ruonan Cai ◽

Zhaohua Gao ◽

Maierpu Aini ◽

...

Keyword(s):

Oxidative Stress ◽

Type 2 Diabetes ◽

Body Weight ◽

Inflammatory Responses ◽

Cardiac Injury ◽

Health Concern ◽

Apoptosis Pathway ◽

Mitochondrial Apoptosis Pathway ◽

Inflammatory Status

Abstract Background: Diabetes is a serious global health concern which severely affected public health as well as socio-economic growth worldwide. Scutellarin (SCU), a bioactive flavonol is known for its efficacious action against a range of ailments including cardiovascular problems. The present study conducted to find out possible protective effect and its associated mechanisms of SCU on experimental type 2 diabetes-induced cardiac injury.Methods: Type 2 diabetes was induced by treating animals with high fat diet for 4 weeks and a single intraperitoneal dose (35 mg/kg body weight) of streptozotocin and diabetic animals received SCU (10 or 20 mg/kg/day) for 6 weeks.Results: SCU attenuated type 2 diabetes-induced hyperglycemia, body weight loss, hyperlipidemia, cardiac functional damage with histo-pathological alterations and fibrosis. SCU treatment to type 2 diabetic mice exacerbated oxidative stress, inflammatory status and apoptosis in heart. Furthermore, the underlying mechanisms for such mitigation of oxidative stress, inflammation and apoptosis in heart involved modulation of Nrf2/Keap1 pathway, TLR4/MyD88/NF-κB mediated inflammatory pathway and intrinsic (mitochondrial) apoptosis pathway, respectively.Conclusions: The current findings suggest that SCU is effective in protecting type 2 diabetes-induced cardiac injury by attenuating oxidative stress and inflammatory responses and apoptosis and it is also worth considering the efficacious potential of SCU to treat diabetic cardiomyopathy patients.

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The Effects of Crocin Supplementation on Metabolic Parameters, Oxidative Stress, AMP- Activated Protein Kinase and Inflammation-promoting Genes Expression in Peripheral Blood Mononuclear Cells in Patients With Type 2 Diabetes

Case Medical Research ◽

10.31525/ct1-nct04163757 ◽

2019 ◽

Author(s):

Keyword(s):

Oxidative Stress ◽

Type 2 Diabetes ◽

Protein Kinase ◽

Peripheral Blood Mononuclear Cells ◽

Mononuclear Cells ◽

Peripheral Blood Mononuclear ◽

Genes Expression ◽

Blood Mononuclear Cells ◽

Amp Activated Protein Kinase

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Effects of Oral Liposomal Glutathione in Altering the Immune Responses Against Mycobacterium tuberculosis and the Mycobacterium bovis BCG Strain in Individuals With Type 2 Diabetes

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.657775 ◽

2021 ◽

Vol 11 ◽

Author(s):

Kimberly To ◽

Ruoqiong Cao ◽

Aram Yegiazaryan ◽

James Owens ◽

Timothy Nguyen ◽

...

Keyword(s):

Oxidative Stress ◽

Type 2 Diabetes ◽

Mononuclear Cells ◽

World Health ◽

Therapeutic Effects ◽

Peripheral Blood Mononuclear ◽

Middle Income ◽

Health Organization

The World Health Organization (WHO) has identified type 2 diabetes (T2DM) as a neglected, important, and re-emerging risk factor for tuberculosis (TB), especially in low and middle-income countries where TB is endemic. In this clinical trial study, oral liposomal glutathione supplementation (L-GSH) or placebo was given to individuals with T2DM to investigate the therapeutic effects of L-GSH supplementation. We report that L-GSH supplementation for 3 months in people with T2DM was able to reduce the levels of oxidative stress in all blood components and prevent depletion of glutathione (GSH) in this population known to be GSH deficient. Additionally, L-GSH supplementation significantly reduced the burden of intracellular mycobacteria within in vitro granulomas generated from peripheral blood mononuclear cells (PBMCs) of T2DM subjects. L-GSH supplementation also increased the levels of Th1-associated cytokines, IFN-γ, TNF-α, and IL-2 and decreased levels of IL-6 and IL-10. In conclusion our studies indicate that oral L-GSH supplementation in individuals with T2DM for three months was able to maintain the levels of GSH, reduce oxidative stress, and diminish mycobacterial burden within in vitro generated granulomas of diabetics. L-GSH supplementation for 3 months in diabetics was also able to modulate the levels of various cytokines.

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Scutellarin alleviates type 2 diabetes (HFD/low dose STZ)-induced cardiac injury through modulation of oxidative stress, inflammation, apoptosis and fibrosis in mice

Human & Experimental Toxicology ◽

10.1177/09603271211045948 ◽

2021 ◽

pp. 096032712110459

Author(s):

Yan Huo ◽

Abudureheman Mijiti ◽

Ruonan Cai ◽

Zhaohua Gao ◽

Maierpu Aini ◽

...

Keyword(s):

Oxidative Stress ◽

Type 2 Diabetes ◽

Inflammatory Responses ◽

Cardiac Injury ◽

Health Concern ◽

Bodyweight Loss ◽

Apoptosis Pathway ◽

Mitochondrial Apoptosis Pathway ◽

Inflammatory Status

Background Diabetes is a serious global health concern which severely affected public health as well as socio-economic growth worldwide. Scutellarin (SCU), a bioactive flavonoid, is known for its efficacious action against a range of ailments including cardiovascular problems. The present study was conducted to find out possible protective effect and its associated mechanisms of SCU on experimental type 2 diabetes-induced cardiac injury. Methods Type 2 diabetes was induced by treating animals with high fat diet for 4 weeks and a single intraperitoneal dose (35 mg/kg body weight) of streptozotocin and diabetic animals received SCU (10 or 20 mg/kg/day) for 6 weeks. Results Scutellarin attenuated type 2 diabetes-induced hyperglycemia, bodyweight loss, hyperlipidaemia, cardiac functional damage with histopathological alterations and fibrosis. Scutellarin treatment to type 2 diabetic mice ameliorated oxidative stress, inflammatory status and apoptosis in heart. Furthermore, the underlying mechanisms for such mitigation of oxidative stress, inflammation and apoptosis in heart involved modulation of Nrf2/Keap1 pathway, TLR4/MyD88/NF-κB mediated inflammatory pathway and intrinsic (mitochondrial) apoptosis pathway, respectively. Conclusions The current findings suggest that SCU is effective in protecting type 2 diabetes-induced cardiac injury by attenuating oxidative stress and inflammatory responses and apoptosis, and it is also worth considering the efficacious potential of SCU to treat diabetic cardiomyopathy patients.

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