β-Cell autophagy in the pathogenesis of type 1 diabetes

Muralidharan, Charanya; Linnemann, Amelia K.

doi:10.1152/ajpendo.00151.2021

Cited by 29 publications

(28 citation statements)

References 58 publications

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“…The selective degradation of autophagy can stabilize the cellular state and prevent the occurrence of diseases ( Levine and Kroemer, 2019 ). The disruption of autophagy has an impact on the development of several diseases such as cancer ( Ferro et al, 2020 ), diabetes ( Muralidharan and Linnemann, 2021 ), cardiovascular diseases ( Bravo-San Pedro et al, 2017 ), neurological related diseases ( Bingol, 2018 ) and inflammatory diseases ( Yao et al, 2021 ) ( Figure 1 ).…”

Section: Autophagymentioning

confidence: 99%

Research progress on the relationship between autophagy and chronic complications of diabetes

Wang

Fei

et al. 2022

Front. Physiol.

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Diabetes is a common metabolic disease whose hyperglycemic state can induce diverse complications and even threaten human health and life security. Currently, the treatment of diabetes is restricted to drugs that regulate blood glucose and have certain accompanying side effects. Autophagy, a research hotspot, has been proven to be involved in the occurrence and progression of the chronic complications of diabetes. Autophagy, as an essential organismal defense mechanism, refers to the wrapping of cytoplasmic proteins, broken organelles or pathogens by vesicles, which are then degraded by lysosomes to maintain the stability of the intracellular environment. Here, we review the relevant aspects of autophagy and the molecular mechanisms of autophagy in diabetic chronic complications, and further analyze the impact of improving autophagy on diabetic chronic complications, which will contribute to a new direction for further prevention and treatment of diabetic chronic complications.

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Section: Autophagymentioning

confidence: 99%

Research progress on the relationship between autophagy and chronic complications of diabetes

Wang

Fei

et al. 2022

Front. Physiol.

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“…Crosstalk between the immune cells and the β cells, as well as endoplasmic reticulum (ER) stress and pro-apoptotic signaling are thought to play key roles in T1D pathogenesis [2][3][4]. Recently, dysfunctional autophagy caused by impaired lysosome function and leakage of lysosomal cathepsins was proposed as a contributory factor [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Cathepsin C Regulates Cytokine-Induced Apoptosis in β-Cell Model Systems

Fløyel

Frørup

Størling

et al. 2021

Genes

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Emerging evidence suggests that several of the lysosomal cathepsin proteases are genetically associated with type 1 diabetes (T1D) and participate in immune-mediated destruction of the pancreatic β cells. We previously reported that the T1D candidate gene cathepsin H is downregulated by pro-inflammatory cytokines in human pancreatic islets and regulates β-cell function, apoptosis, and disease progression in children with new-onset T1D. In the present study, the objective was to investigate the expression patterns of all 15 known cathepsins in β-cell model systems and examine their role in the regulation of cytokine-induced apoptosis. Real-time qPCR screening of the cathepsins in human islets, 1.1B4 and INS-1E β-cell models identified several cathepsins that were expressed and regulated by pro-inflammatory cytokines. Using small interfering RNAs to knock down (KD) the cytokine-regulated cathepsins, we identified an anti-apoptotic function of cathepsin C as KD increased cytokine-induced apoptosis. KD of cathepsin C correlated with increased phosphorylation of JNK and p38 mitogen-activated protein kinases, and elevated chemokine CXCL10/IP-10 expression. This study suggests that cathepsin C is a modulator of β-cell survival, and that immune modulation of cathepsin expression in islets may contribute to immune-mediated β-cell destruction in T1D.

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“…Growing body of evidence indicate association of defects in autophagy with insulin resistance, obesity and beta cell dysfunction in diabetes ( 77 , 78 ). This lysosomal degradation machinery includes macroautophagy, crinophagy and microautophagy which regulate cellular homeostasis by recycling damaged macromolecules and organelles for new protein synthesis and energy production ( 78 ). Dysfunctional autophagy in beta cells under oxidative stress conditions could result with accumulation of excess proteins and their toxic effects ( 71 ).…”

Section: Redox-related Mechanisms Involved In Beta Cell Death and Dys...mentioning

confidence: 99%

Oxidative stress-mediated beta cell death and dysfunction as a target for diabetes management

et al. 2022

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The biggest drawback of a current diabetes therapy is the treatment of the consequences not the cause of the disease. Regardless of the diabetes type, preservation and recovery of functional pancreatic beta cells stands as the biggest challenge in the treatment of diabetes. Free radicals and oxidative stress are among the major mediators of autoimmune destruction of beta cells in type 1 diabetes (T1D) or beta cell malfunction and death provoked by glucotoxicity and insulin resistance in type 2 diabetes (T2D). Additionally, oxidative stress reduces functionality of beta cells in T2D by stimulating their de-/trans-differentiation through the loss of transcription factors critical for beta cell development, maturity and regeneration. This review summarizes up to date clarified redox-related mechanisms involved in regulating beta cell identity and death, underlining similarities and differences between T1D and T2D. The protective effects of natural antioxidants on the oxidative stress-induced beta cell failure were also discussed. Considering that oxidative stress affects epigenetic regulatory mechanisms involved in the regulation of pancreatic beta cell survival and insulin secretion, this review highlighted huge potential of epigenetic therapy. Special attention was paid on application of the state-of-the-art CRISPR/Cas9 technology, based on targeted epigenome editing with the purpose of changing the differentiation state of different cell types, making them insulin-producing with ability to attenuate diabetes. Clarification of the above-mentioned mechanisms could provide better insight into diabetes etiology and pathogenesis, which would allow development of novel, potentially more efficient therapeutic strategies for the prevention or reversion of beta cell loss.

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β-Cell autophagy in the pathogenesis of type 1 diabetes

Cited by 29 publications

References 58 publications

Research progress on the relationship between autophagy and chronic complications of diabetes

Research progress on the relationship between autophagy and chronic complications of diabetes

Cathepsin C Regulates Cytokine-Induced Apoptosis in β-Cell Model Systems

Oxidative stress-mediated beta cell death and dysfunction as a target for diabetes management

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