The Role of HMGB1 in the Pathogenesis of Type 2 Diabetes

Wang, Yanan; Zhong, Jixin; Zhang, Xiangzhi; Liu, Ziwei; Yang, Yuan; Gong, Quan; Ren, Boxu

doi:10.1155/2016/2543268

Cited by 84 publications

(67 citation statements)

References 142 publications

(137 reference statements)

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“…Others have also suggested that HMGB1 may be involved in impaired insulin signaling [6]. Thus, we investigated whether Box A and glycyrrhizin could inhibit the high glucose-induced loss of insulin receptor activation.…”

Section: Resultsmentioning

confidence: 97%

Inhibition of HMGB1 protects the retina from ischemia-reperfusion, as well as reduces insulin resistance proteins

2017

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The role of inflammation in diabetic retinal amage is well accepted. While a number of cytokines and inflammatory mediators are responsible for these changes, upstream regulators are less well studied. Additionally, the role for these upstream mediators in retinal health is unclear. In this study, we hypothesized that inhibition of high mobility group box 1 (HMGB1) could restore normal insulin signaling in retinal endothelial cells (REC) grown in high glucose, as well as protect the retina against ischemia/reperfusion (I/R)-induced retinal damage. REC were grown in normal (5mM) or high glucose (25mM) and treated with Box A or glycyrrhizin, two different HMGB1 inhibitors. Western blotting was done for HMGB1, toll-like receptor 4 (TLR4), insulin receptor, insulin receptor substrate-1 (IRS-1), and Akt. ELISA analyses were done for tumor necrosis factor alpha (TNFα) and cleaved caspase 3. In addition, C57/B6 mice were treated with glycyrrhizin, both before and after ocular I/R. Two days following I/R, retinal sections were processed for neuronal changes, while vascular damage was measured at 10 days post-I/R. Results demonstrate that both Box A and glycyrrhizin reduced HMGB1, TLR4, and TNFα levels in REC grown in high glucose. This led to reduced cleavage of caspase 3 and IRS-1Ser307 phosphorylation, and increased insulin receptor and Akt phosphorylation. Glycyrrhizin treatment significantly reduced loss of retinal thickness and degenerate capillary numbers in mice exposed to I/R. Taken together, these results suggest that inhibition of HMGB1 can reduce retinal insulin resistance, as well as protect the retina against I/R-induced damage.

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Section: Resultsmentioning

confidence: 97%

Inhibition of HMGB1 protects the retina from ischemia-reperfusion, as well as reduces insulin resistance proteins

2017

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“…It is a known mediator of NLRP3 inflammasome-induced damage to endothelial cells and promotes oxidative stress by inhibiting the antioxidant thioredoxin [16,17]. High mobility group box 1 (HMGB1) protein can be characterized as an alarmin that signals the need for initiation of the inflammatory response, thereby contributing to chronic inflammation and endothelial dysfunction [18]. Interleukins 1beta (IL-1b) and 18 (IL-18) are proinflammatory cytokines [19] produced by NLRP3 that play a critical role in the pathogenesis of numerous inflammatory diseases.…”

Section: Introductionmentioning

confidence: 99%

Cilostazol ameliorates high free fatty acid (FFA)-induced activation of NLRP3 inflammasome in human vascular endothelial cells

Wang

Huang

et al. 2019

Artificial Cells, Nanomedicine, and Biotechnology

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Cardiovascular disease is recognized as a leading cause of death worldwide, but the risk of death is 2-3 times higher for individuals with diabetes. NLRP3 inflammasome activation is a leading pathway of vascular damage, and new treatment methods are needed to reduce NLRP3 inflammasome expression, along with a detailed understanding of how those treatments work. In a series of assays on human vascular endothelial cells that were exposed to high concentrations of free fatty acids (FFA) to induce a diabetes-like environment, we found a significant impact of cilostazol, a vasodilator widely used to treat blood flow problems and well-tolerated medication. To our knowledge, this study is the first to demonstrate the effects of cilostazol in primary human aortic endothelial cells. We found that cilostazol significantly reduced NLRP3 inflammasome activation, as well as the activity of other related and harmful factors, including oxidative stress, expression of NADPH oxidase 4 (NOX-4), thioredoxin-interacting protein (TxNIP), high mobility group box 1 (HMGB-1), interleukin 1b (IL-1b) and IL-18. Cilostazol also protected the functionality of sirtuin 1 (SIRT1), which serves to restrict NLRP3 inflammasome activity, when exposure to FFAs would have otherwise impaired its function. Thus, it appears that cilostazol's mechanism of action in reducing NLRP3 inflammasome activation is an indirect one; it protects SIRT1, which then allows SIRT1 to perform its regulatory job. Cilostazol has potential as an already-available, well-tolerated preventive medication that may alleviate some of the adverse vascular effects of living with diabetes. The findings of the present study lay the groundwork for further research on the potential of cilostazol as a safe and effective treatment against diabetic endothelial dysfunction and vacular disease.

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“…Additionally, Pdk4-knockout mice presented an improved metabolic phenotype and were protected against diet-induced IR in their skeletal muscle [35]. Another IR-related gene Hmgb1, is an important mediator during diabetes onset and progression [59]. Increasing evidence also indicated its importance in inflammation, which led to the skeletal muscle dysfunction [60].…”

Section: Discussionmentioning

confidence: 99%

RNA-sequencing analysis reveals the potential contribution of lncRNAs in palmitic acid-induced insulin resistance of skeletal muscle cells

Han

You

et al. 2020

Bioscience Reports

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Insulin resistance (IR) has been considered as the common pathological basis and developmental driving force for most metabolic diseases. Long noncoding RNAs (lncRNAs) have emerged as pivotal regulators in modulation of glucose and lipid metabolism. However, the comprehensive profile of lncRNAs in skeletal muscle cells under the insulin resistant status and the possible biological effects of them were not fully studied. In this research, using C2C12 myotubes as cell models in vitro, deep RNA-sequencing was performed to profile lncRNAs and mRNAs between palmitic acid-induced IR C2C12 myotubes and control ones. The results revealed that a total of 144 lncRNAs including 70 up-regulated and 74 down-regulated (|fold change| > 2, q < 0.05) were significantly differentially expressed in palmitic acid-induced insulin resistant cells. In addition, functional annotation analysis based on the Gene Ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) databases revealed that the target genes of the differentially expressed lncRNAs were significantly enriched in fatty acid oxidation, lipid oxidation, PPAR signaling pathway, and insulin signaling pathway. Moreover, Via qPCR, most of selected lncRNAs in myotubes and db/db mice skeletal muscle showed the consistent expression trends with RNA-sequencing. Co-expression analysis also explicated the key lncRNA-mRNA interactions and pointed out a potential regulatory network of candidate lncRNA ENSMUST00000160839. In conclusion, the present study extended the skeletal muscle lncRNA database and provided novel potential regulators for future genetic and molecular studies on insulin resistance, which is helpful for prevention and treatment of the related metabolic diseases. sensitivity and whole-body metabolism. For example, perturbed heterogeneous nuclear ribonucleoprotein A1-induced turbulences in glucose homeostasis in the skeletal muscle could accelerate systemic IR under both basal and high-fat induced conditions [7]. Conversely, activating mTOR signaling, improved insulin sensitivity in the skeletal muscle, which could enhance whole-body metabolism via weight loss and an increased fatty acid oxidation capacity in the adipose tissue and liver [8,9]. Studies have shown that among the widely recognized mechanisms underlying IR in the skeletal muscle, quite a few studies displayed that accumulation of 'toxic' lipid metabolites was considered as an important contributor to IR in skeletal muscle [10][11][12][13][14]. Lipid-induced IR has been associated with different cellular events in skeletal muscle cells, including impaired insulin signaling transduction of IRS1-PI3K [15], activation of inflammatory and pro-inflammatory cytokines [16], abnormally accumulation of ceramides [17], and mitochondrial dysfunction [18]. Therefore, the factors or the mechanisms underlying IR in the skeletal muscle, which are induced by lipid overload, must be explored.Long noncoding RNAs (lncRNAs), transcribed by RNA polymerase II, is a kind of RNA molecules with lengths of more than 200 nucleot...

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The Role of HMGB1 in the Pathogenesis of Type 2 Diabetes

Cited by 84 publications

References 142 publications

Inhibition of HMGB1 protects the retina from ischemia-reperfusion, as well as reduces insulin resistance proteins

Inhibition of HMGB1 protects the retina from ischemia-reperfusion, as well as reduces insulin resistance proteins

Cilostazol ameliorates high free fatty acid (FFA)-induced activation of NLRP3 inflammasome in human vascular endothelial cells

RNA-sequencing analysis reveals the potential contribution of lncRNAs in palmitic acid-induced insulin resistance of skeletal muscle cells

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