Therapeutic opportunities for pancreatic β-cell ER stress in diabetes mellitus

Yong, Jing; Johnson, James D.; Arvan, Peter; Han, Jaeseok; Kaufman, Randal J.

doi:10.1038/s41574-021-00510-4

Cited by 146 publications

(112 citation statements)

References 162 publications

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“…Excessive ER stress activates inflammatory responses (Fritz et al, 2011;Yong et al, 2021). During ER stress, IRE1α recruits TRAF2 (TNF receptor-associated factor 2) to the ER membrane to initiate inflammatory responses via the NF-κB pathway (Urano et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

MFG-E8 Maintains Cellular Homeostasis by Suppressing Endoplasmic Reticulum Stress in Pancreatic Exocrine Acinar Cells

Ren

Liu

Zhang

et al. 2022

Front. Cell Dev. Biol.

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Excessive endoplasmic reticulum (ER) stress contributes significantly to the pathogenesis of exocrine acinar damage in acute pancreatitis. Our previous study found that milk fat globule EGF factor 8 (MFG-E8), a lipophilic glycoprotein, alleviates acinar cell damage during AP via binding to αvβ3/5 integrins. Ligand-dependent integrin-FAK activation of STAT3 was reported to be of great importance for maintaining cellular homeostasis. However, MFG-E8’s role in ER stress in pancreatic exocrine acinar cells has not been evaluated. To study this, thapsigargin, brefeldin A, tunicamycin and cerulein + LPS were used to induce ER stress in rat pancreatic acinar cells in vitro. L-arginine- and cerulein + LPS-induced acute pancreatitis in mice were used to study ER stress in vivo. The results showed that MFG-E8 dose-dependently inhibited ER stress under both in vitro and in vivo conditions. MFG-E8 knockout mice suffered more severe ER stress and greater inflammatory response after L-arginine administration. Mechanistically, MFG-E8 increased phosphorylation of FAK and STAT3 in cerulein + LPS-treated pancreatic acinar cells. The presence of specific inhibitors of αvβ3/5 integrin, FAK or STAT3 abolished MFG-E8’s effect on cerulein + LPS-induced ER stress in pancreatic acinar cells. In conclusion, MFG-E8 maintains cellular homeostasis by alleviating ER stress in pancreatic exocrine acinar cells.

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Section: Discussionmentioning

confidence: 99%

MFG-E8 Maintains Cellular Homeostasis by Suppressing Endoplasmic Reticulum Stress in Pancreatic Exocrine Acinar Cells

Ren

Liu

Zhang

et al. 2022

Front. Cell Dev. Biol.

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“…The accumulation of proinsulin within the ER could stem from activation of the ER stress response, which has been suggested to contribute to the development of β-cell dysfunction in T2D (Yong et al, 2021). While expansion of ER membranes has been demonstrated in both human and rodent T2D β-cells (Alarcon et al, 2016; Boland et al, 2017; Marchetti et al, 2007; Masini et al, 2012); dilation of the ER lumen, which is a key hallmark of proteotoxic stress, is not commonly observed.…”

Section: Resultsmentioning

confidence: 99%

“…Numerous studies have demonstrated that induction of ER stress can perturb β-cell function and may contribute to the development of β-cell dysfunction in T2D (Yong et al, 2021). Loss of critical ER stress response sensors, such as PERK and Ire1α, can sensitize β-cells to nutrient stresses and/or directly impair β-cell function leading to the development of diabetes (Delépine et al, 2000, p. 2; Harding et al, 2001; Hassler et al, 2015; Xu et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…While these studies demonstrate that perturbations in ER functions and proinsulin folding can compromise β-cell health and insulin production, direct evidence for ER stress as a causative feature in the development of T2D is less clear (Alarcon et al, 2016; Marchetti et al, 2007). Increased PERK and Ire1α activity have been described in pre-diabetic β-cells (Engin et al, 2014; Lipson et al, 2006; Yong et al, 2021), yet diminished, rather than increased, expression of ATF6 and XBP-1(s) occur in β-cells from humans with long-standing T2D (Engin et al, 2014). Moreover, human β-cells are known to cycle between varying levels of UPR protein expression (Xin et al, 2018), which may represent the natural β-cell adaptation to changes in nutrient load.…”

Section: Discussionmentioning

confidence: 99%

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Nutrient metabolism regulates insulin granule formation in the pancreatic islet β-cell via ER redox homeostasis

Rohli

Boyer

Bearrows

et al. 2021

Preprint

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Defects in the β-cells secretion system are well-described in Type 2 diabetes (T2D), including reduced insulin storage and impaired proinsulin processing; however, the cellular mechanisms underlying these secretory defects and the contribution of chronic hyperglycemia to this process remain poorly understood. In this study, we provide evidence that oxidative protein folding in the endoplasmic reticulum (ER) is perturbed in models of β-cell dysfunction, leading to delays in proinsulin trafficking and insulin granule formation. Using an in situ fluorescent pulse-chase labeling strategy and APEX2-based proximity labeling, we demonstrate that enriched interactions of proinsulin with ER oxidoreductases coincides with a delay in proinsulin ER export. Furthermore, our data show that proinsulin ER export can be regulated by metabolically-derived NADPH and reducing equivalent (glutathione) availability. Together, these data highlight an emerging role for nutrient metabolism and mitochondrial dysfunction in the maladaptive remodeling of the β-cells secretory pathway during the decline of β-cell function in T2D.

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“…This abnormal accumulation of unfolded proteins is termed ER stress [47,48]. ER stress is involved in the onset of various diseases including neurodegenerative disorders and diabetes [49,50]. Long-term inhibition of ERAD may enhance ER stress, leading to the pathogenesis of ER stress-related diseases.…”

Section: Degradation Of Mutant Ids By the Er-associated Degradation (Erad) Systemmentioning

confidence: 99%

Loss of Function of Mutant IDS Due to Endoplasmic Reticulum-Associated Degradation: New Therapeutic Opportunities for Mucopolysaccharidosis Type II

Matsuhisa

Imaizumi

2021

IJMS

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Mucopolysaccharidosis type II (MPS II) results from the dysfunction of a lysosomal enzyme, iduronate-2-sulfatase (IDS). Dysfunction of IDS triggers the lysosomal accumulation of its substrates, glycosaminoglycans, leading to mental retardation and systemic symptoms including skeletal deformities and valvular heart disease. Most patients with severe types of MPS II die before the age of 20. The administration of recombinant IDS and transplantation of hematopoietic stem cells are performed as therapies for MPS II. However, these therapies either cannot improve functions of the central nervous system or cause severe side effects, respectively. To date, 729 pathogenetic variants in the IDS gene have been reported. Most of these potentially cause misfolding of the encoded IDS protein. The misfolded IDS mutants accumulate in the endoplasmic reticulum (ER), followed by degradation via ER-associated degradation (ERAD). Inhibition of the ERAD pathway or refolding of IDS mutants by a molecular chaperone enables recovery of the lysosomal localization and enzyme activity of IDS mutants. In this review, we explain the IDS structure and mechanism of activation, and current findings about the mechanism of degradation-dependent loss of function caused by pathogenetic IDS mutation. We also provide a potential therapeutic approach for MPS II based on this loss-of-function mechanism.

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Therapeutic opportunities for pancreatic β-cell ER stress in diabetes mellitus

Cited by 146 publications

References 162 publications

MFG-E8 Maintains Cellular Homeostasis by Suppressing Endoplasmic Reticulum Stress in Pancreatic Exocrine Acinar Cells

MFG-E8 Maintains Cellular Homeostasis by Suppressing Endoplasmic Reticulum Stress in Pancreatic Exocrine Acinar Cells

Nutrient metabolism regulates insulin granule formation in the pancreatic islet β-cell via ER redox homeostasis

Loss of Function of Mutant IDS Due to Endoplasmic Reticulum-Associated Degradation: New Therapeutic Opportunities for Mucopolysaccharidosis Type II

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