Advances in Knowledge of Candidate Genes Acting at the Beta-Cell Level in the Pathogenesis of T1DM

Pang, Haipeng; Luo, Shuoming; Huang, Gan; Xia, Ying; Xie, Zhiguo; Zhou, Zhiguang

doi:10.3389/fendo.2020.00119

Cited by 32 publications

(31 citation statements)

References 110 publications

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“…Currently, the combination of susceptible genes and islet autoantibodies is the most useful biomarker to predict T1DM risk (63). Previous studies have identified more than 50 candidate loci; a minority of genes (HLA) have large effects, but a majority of these genes have small effects (2). HLA genes confer the greatest risk for the development of T1DM, and the HLA-DR (DR3/4) and HLA-DQ (DQ8) genotypes are mostly used to predict the risk of developing islet autoimmunity (64,65).…”

Section: Exosomes As Novel Biomarkers Of T1dmmentioning

confidence: 99%

“…Type 1 diabetes mellitus (T1DM) is an autoimmune disorder characterized by beta-cell dysfunction and death caused by autoreactive T cells, an absolute lack of insulin, and elevated blood glucose levels (1)(2)(3). Persistent hyperglycemia leads to the development of life-threatening diabetesassociated complications such as blindness, stroke, kidney diseases, and heart diseases, thus decreasing the quality of life of patients and imposing a considerable economic burden on society and individuals.…”

Section: Introductionmentioning

confidence: 99%

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Emerging Roles of Exosomes in T1DM

et al. 2020

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Type 1 diabetes mellitus (T1DM) is a complex autoimmune disorder that mainly affects children and adolescents. The elevated blood glucose level of patients with T1DM results from absolute insulin deficiency and leads to hyperglycemia and the development of life-threatening diabetic complications. Although great efforts have been made to elucidate the pathogenesis of this disease, the precise underlying mechanisms are still obscure. Emerging evidence indicates that small extracellular vesicles, namely, exosomes, take part in intercellular communication and regulate interorgan crosstalk. More importantly, many findings suggest that exosomes and their cargo are associated with the development of T1DM. Therefore, a deeper understanding of exosomes is beneficial for further elucidating the pathogenic process of T1DM. Exosomes are promising biomarkers for evaluating the risk of developingty T1DM, monitoring the disease state and predicting related complications because their number and composition can reflect the status of their parent cells. Additionally, since exosomes are natural carriers of functional proteins, RNA and DNA, they can be used as therapeutic tools to deliver these molecules and drugs. In this review, we briefly introduce the current understanding of exosomes. Next, we focus on the relationship between exosomes and T1DM from three perspectives, i.e., the pathogenic role of exosomes in T1DM, exosomes as novel biomarkers of T1DM and exosomes as therapeutic tools for T1DM.

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Section: Exosomes As Novel Biomarkers Of T1dmmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Emerging Roles of Exosomes in T1DM

et al. 2020

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“…IL-1β induces the migration of proinflammatory cells into pancreatic islets, mediates cytokine-induced beta-cell apoptosis, exerts direct cytotoxic effects on beta-cells, and may function as inflammatory signal in the early stage of T1DM (102,104,105). IL-1β levels are increased in both patients with a new T1DM diagnosis and patients with chronic T1DM compared with healthy controls, and after treatment, IL-1β levels are decreased in patients who have been newly diagnosed with T1DM (106)(107)(108).…”

Section: The Nlpr3 Inflammasome and T1dmmentioning

confidence: 99%

The NLRP3 Inflammasome and Its Role in T1DM

Sun

Pang

et al. 2020

Front. Immunol.

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The NLRP3 (nucleotide-binding and oligomerization domain-like receptor family pyrin domain-containing 3) inflammasome is a protein complex expressed in cells. It detects danger signals and induces the production of active caspase-1 and the maturation and release of IL (interleukin)-33, IL-18, IL-1β and other cytokines. T1DM (type 1 diabetes mellitus) is defined as a chronic autoimmune disorder characterized by the autoreactive T cell-mediated elimination of insulin-positive pancreatic beta-cells. Although the exact underlying mechanisms are obscure, researchers have proposed that both environmental and genetic factors are involved in the pathogenesis of T1DM. Furthermore, immune responses, including innate and adaptive immunity, play an important role in this process. Recently, the NLRP3 inflammasome, a critical component of innate immunity, was reported to be associated with T1DM. Here, we review the assembly and function of the NLRP3 inflammasome. In addition, the activation and regulatory mechanisms that enhance or attenuate NLRP3 inflammasome activation are discussed. Finally, we focus on the relationship between the NLRP3 inflammasome and T1DM, as well as its potential value for clinical use.

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“…In addition, the sensitive mice showed more substantial islet mass reduction and islet degeneration, as well as more extensive inflammatory infiltration in the pancreatic islets compared with those in the tolerant mice ( Figure 1 ). It is well recognized that both genetic and environmental factors are responsible for the development and progression of T1DM [ 2 , 6 ]. Thus, these results indicated that one or more potential target(s) might be involved in the delayed progression of T1DM among the tolerant mice through the protection of pancreatic β -cell function.…”

Section: Discussionmentioning

confidence: 99%

“…It is widely accepted that both genetic and environmental factors are responsible for the pathogenesis and progression of T1DM [ 6 ]. However, the particular causes and precise pathogenic mechanisms of this disease are not completely understood.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of the Keap1/Nrf2 Signaling Pathway Significantly Promotes the Progression of Type 1 Diabetes Mellitus

Lou

Kong

et al. 2021

Oxidative Medicine and Cellular Longevity

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Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by insulin deficiency due to pancreatic β-cell damage and leads to hyperglycemia. The precise molecular mechanisms of the etiology of T1DM are not completely understood. Oxidative stress and the antioxidant status of pancreatic β-cells play a vital role in the pathogenesis and progression of T1DM. The Keap1/Nrf2 signaling pathway plays a critical role in cellular resistance to oxidative stress. This study is aimed at investigating the role of the Keap1/Nrf2 signaling pathway in the progression of T1DM. An alloxan- (ALX-) stimulated T1DM animal model in wild-type (WT) and Nrf2 knockout (Nrf2-/-) C57BL/6J mice and a mouse pancreatic β-cell line (MIN6) were established. Compared with the tolerant (ALX exposure, nondiabetic) WT mice, the sensitive (ALX exposure, diabetic) WT mice exhibited higher blood glucose levels and lower plasma insulin levels. The Keap1/Nrf2 signaling pathway was significantly inhibited in the sensitive WT mice, which was reflected by overexpression of Keap1 and low expression of Nrf2, accompanied by a marked decrease in the expression of the antioxidative enzymes. Compared with WT mice, the Nrf2-/- mice had an increased incidence of T1DM and exhibited more severe pancreatic β-cell damage. The results of in vitro experiments showed that ALX significantly inhibited the viability and proliferation and promoted the apoptosis of MIN6 cells. ALX also markedly increased intracellular ROS production and caused DNA damage in MIN6 cells. In addition, the Keap1/Nrf2 signaling pathway was significantly inhibited in the damaged MIN6 cells. Moreover, Nrf2 silencing by transfection with Nrf2 siRNA markedly exacerbated ALX-induced MIN6 cell injury. Conclusively, this study demonstrates that inhibition of the Keap1/Nrf2 signaling pathway could significantly promote the incidence of T1DM. This study indicates that activation of Keap1/Nrf2 signaling in pancreatic β-cells may be a useful pharmacological strategy for the clinical prevention and treatment of T1DM.

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Advances in Knowledge of Candidate Genes Acting at the Beta-Cell Level in the Pathogenesis of T1DM

Cited by 32 publications

References 110 publications

Emerging Roles of Exosomes in T1DM

Emerging Roles of Exosomes in T1DM

The NLRP3 Inflammasome and Its Role in T1DM

Inhibition of the Keap1/Nrf2 Signaling Pathway Significantly Promotes the Progression of Type 1 Diabetes Mellitus

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