Research advances in drugs targeting endoplasmic reticulum stress for treatment of type 1 diabetes mellitus
ZHANG Ziyang1 WANG Li2 CHEN Chunlin1 ZHANG Mengjun1
1.Teaching and Research Section of Pharmaceutical Analysis, College of Pharmacy, Army Medical University, Chongqing 400038, China;
2.Teaching and Research Section of Immunology, Basic Medical College, Army Medical University, Chongqing 400038, China
Abstract：Type 1 diabetes mellitus (T1DM) is an organ-specific autoimmune disease. Currently, there is a lack of radical treatment for T1DM. Endoplasmic reticulum stress is an important pathological feature of the early onset of T1DM and an important factor promoting its occurrence and development. Pathological endoplasmic reticulum stress is a new target for the treatment of T1DM. Drugs targeting pathological endoplasmic reticulum stress are conducive to restoring the quantity and quality of pancreatic β cells, so as to treat T1DM. Accumulation of misfolded proteins in the endoplasmic reticulum in islet β cells induces endoplasmic reticulum stress, which in turn activates three classical pathways of excessive unfolded protein response: inositol-requiring enzyme 1, proteinkinase R-like endoplasmic reticulum kinase, and activating transcription factor-6 pathways. This article reviews the progress of drug research targeting these three pathways and folded or misfolded proteins for the treatment of T1DM.
[1] Roep BO，Thomaidou S，van Tienhoven R，et al. Type 1 diabetes mellitus as a disease of the beta-cell（do not blame the immune system？）[J]. Nat Rev Endocrinol，2021，17（3）：150-161.
[2] Catrina AM，Popa MA，V?觍caru AM，et al. Inflammatory status of the pancreas in NOD mice that do not develop overt diabetes [J]. Rom J Morphol Embryol，2021，62（1）：109-115.
[3] Richardson SJ，Pugliese A. 100 Years of insulin：pancreas pat- hology in type 1 diabetes：an evolving story [J]. J Endocrinol，2021，252（2）：R41-R57.
[4] Cao ZH，Wu Z，Hu C，et al. Endoplasmic reticulum stress and destruction of pancreatic β cells in type 1 diabetes [J]. Chin Med J（Engl），2020，133（1）：68-73.
[5] Sahin GS，Lee H，Engin F. An accomplice more than a mere victim：the impact of β-cell ER stress on type 1 diabetes pathogenesis [J]. Mol Metab，2021，54：101365.
[6] Zhang IX，Raghavan M，Satin LS. The endoplasmic reticulum and calcium homeostasis in pancreatic beta cells [J]. Endocrinology，2020，161（2）：bqz028.
[7] Rodrigues-Dos-Santos K，Roy G，Binns DD，et al. Small mol- ecule-mediated insulin hypersecretion induces transient ER stress response and loss of beta cell function [J]. Endocrinology，2022，163（7）：bqac081.
[8] Syed I，Rubin de Celis MF，Mohan JF，et al. PAHSAs attenuate immune responses and promote β cell survival in autoimmune diabetic mice [J]. J Clin Invest，2019，129（9）：3717- 3731.
[9] Vig S，Lambooij JM，Zaldumbide A，et al. Endoplasmic reticulum-mitochondria crosstalk and beta-cell destruction in type 1 diabetes [J]. Front Immunol，2021，12：669492.
[10] Piganelli JD，Mamula MJ，James EA. The role of beta cell stress and neo-epitopes in the immunopathology of type 1 diabetes [J]. Front Endocrinol（Lausanne），2020，11：624590.
[11] Bilekova S，Sachs S，Lickert H. Pharmacological targeting of endoplasmic reticulum stress in pancreatic beta cells [J]. Trends Pharmacol Sci，2021，42（2）：85-95.
[12] So JS. Erratum to：roles of endoplasmic reticulum stress in immune responses [J]. Mol Cells，2019，42（6）：501.
[13] Ghosh R，Colon-negron K，Papa FR. Endoplasmic reticulum stress，degeneration of pancreatic islet β-cells，and therapeutic modulation of the unfolded protein response in diabetes [J]. Mol Metab，2019，27S：S60-S68.
[14] Morita S，Villalta SA，Feldman HC，et al. Targeting ABL- IRE1α signaling spares ER-stressed pancreatic β cells to reverse autoimmune diabetes [J]. Cell Metab，2017，25（4）：883-897.
[15] Ghosh R，Wang L，Wang ES，et al. Allosteric inhibition of the IRE1alpha RNase preserves cell viability and function during endoplasmic reticulum stress [J]. Cell，2014，158（3）：534-548.
[16] Gitelman SE，Bundy BN，Ferrannini E，et al. Imatinib therapy for patients with recent-onset type 1 diabetes：a multicentre，randomised，double-blind，placebo-controlled，phase 2 trial [J]. Lancet Diabetes Endocrinol，2021，9（8）：502-514.
[17] Moreno JA，Halliday M，Molloy C，et al. Oral Treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion-infected mice [J]. Sci Transl Med，2013，5（206）：206ra138.
[18] Kim MJ，Min SH，Shin SY，et al. Attenuation of PERK enhances glucose-stimulated insulin secretion in islets [J]. J Endocrinol，2018，6（3）：125-136.
[19] Cnop M，Toivonen S，Igoillo-Esteve M，et al. Endoplasmic reticulum stress and eIF2α phosphorylation：The Achilles heel of pancreatic β cells [J]. Mol Metab，2017，6（9）：1024- 1039.
[20] Abdulkarim B，Hernangomez M，Igoillo-esteve M，et al. Guanabenz sensitizes pancreatic β cells to lipotoxic endoplasmic reticulum stress and apoptosis [J]. Endocrinology，2017，158（6）：1659-1670.
[21] Odisho T，Zhang L，Volchuk A. ATF6β regulates the Wfs1 gene and has a cell survival role in the ER stress response in pancreatic β-cells [J]. Exp Cell Res，2015，330（1）：111- 122.
[22] Paxman R，Plate L，Blackwood EA，et al. Pharmacologic ATF6 activating compounds are metabolically activated to selectively modify endoplasmic reticulum proteins [J]. Elife， 2018，7：e37168.
[23] Blackwood EA，Azizi K，Thuerauf DJ，et al. Pharmacologic ATF6 activation confers global protection in widespread disease models by reprograming cellular proteostasis [J]. Nat Commun，2019，10（1）：187.
[24] Kitazawa T，Yoshino Y，Suzuki S，et al. Lopinavir inhibits insulin signaling by promoting protein tyrosine phosphatase 1B expression [J]. Exp Ther Med，2014，8（3）：851-855.
[25] Martin GM，Min WS，Shyng SL. Pharmacological chaperones of ATP-sensitive potassium channels：Mechanistic insight from cryoEM structures [J]. Molecular and Cellular Endocrinology，2020，502：110667.
[26] 沈凌花，张英娴，杨威，等.三例KCNJ11基因R201突变致永久性新生儿糖尿病诊断与治疗分析[J].中国糖尿病杂志，2021，29（6）：401-404.
[27] Bronczek GA，Vettorazzi JF，Soares GM，et al. The bile acid TUDCA improves beta-cell mass and reduces insulin degradation in mice with early-stage of type-1 diabetes [J]. Front Physiol，2019，10：561.
[28] Kusaczuk M. Tauroursodeoxycholate-bile acid with chaperoning activity：molecular and cellular effects and therapeutic perspectives [J]. Cells，2019，8：1471.
[29] Lombardi A，Tomer Y. Interferon alpha impairs insulin production in human beta cells via endoplasmic reticulum stress [J]. J Autoimmun，2017，80：48-55.
[30] Liu YF，Powrie J，Arif S，et al. Immune and metabolic effects of antigen-specific immunotherapy using multiple β-cell peptides in type 1 diabetes [J]. Diabetes，2022，71（4）：722- 732.
[31] Zhang X，Dong Y，Liu D，et al. Antigen-specific immunotherapies in type 1 diabetes [J]. J Trace Elem Med Biol，2022， 73：127040.
[32] Kreiner FF，von Scholten BJ，Coppieters K，et al. Current state of antigen-specific immunotherapy for type 1 diabetes [J]. Curr Opin Endocrinol Diabetes Obes，2021，28（4）： 411-418.
[33] Bluestone JA，Buckner JH，Herold KC. Immunotherapy：Building a bridge to a cure for type 1 diabetes [J]. Science，2021，373（6554）：510-516.
[34] Brawerman G，Thompson PJ. Beta cell therapies for preventing type 1 diabetes：from bench to bedside [J]. Biomol- ecules，2020，10（12）：1681.
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