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Beyond Glucose: The Dual Assault of Oxidative and ER Stress in Diabetic Disorders

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Abstract

Diabetes mellitus, a prevalent global health concern, is characterized by hyperglycemia. However, recent research reveals a more intricate landscape where oxidative stress and endoplasmic reticulum (ER) stress orchestrate a dual assault, profoundly impacting diabetic disorders. This review elucidates the interplay between these two stress pathways and their collective consequences on diabetes. Oxidative stress emanates from mitochondria, where reactive oxygen species (ROS) production spirals out of control, leading to cellular damage. We explore ROS-mediated signaling pathways, which trigger β-cell dysfunction, insulin resistance, and endothelial dysfunction the quintessential features of diabetes. Simultaneously, ER stress unravels, unveiling how protein folding disturbances activate the unfolded protein response (UPR). We dissect the UPR's dual role, oscillating between cellular adaptation and apoptosis, significantly influencing pancreatic β-cells and peripheral insulin-sensitive tissues. Crucially, this review exposes the synergy between oxidative and ER stress pathways. ROS-induced UPR activation and ER stress-induced oxidative stress create a detrimental feedback loop, exacerbating diabetic complications. Moreover, we spotlight promising therapeutic strategies that target both stress pathways. Antioxidants, molecular chaperones, and novel pharmacological agents offer potential avenues for diabetes management. As the global diabetes burden escalates, comprehending the dual assault of oxidative and ER stress is paramount. This review not only unveils the intricate molecular mechanisms governing diabetic pathophysiology but also advocates a holistic therapeutic approach. By addressing both stress pathways concurrently, we may forge innovative solutions for diabetic disorders, ultimately alleviating the burden of this pervasive health issue.

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Acknowledgments

The authors gratefully acknowledge the Department of Pharmacology and Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSSAHER, Mysuru, Karnataka, India and appreciates the interdisciplinary collaboration with the Department of Chemistry, Indian Institute of Technology (IIT) Delhi, Hauz Khas Campus, New Delhi for their collaborative efforts that significantly enriched this for drafting this article.

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  1. Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysore, Karnataka, 570015, India

    Tamsheel Fatima Roohi, MD. Awaise Iqbal Baig, Seema Mehdi, Nabeel Kinattingal & K. L. Krishna

  2. Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysore, Karnataka, 570015, India

    Syed Faizan

  3. Department of Chemistry, Indian Institute of Technology (IIT) Delhi, Hauz Khas Campus, New Delhi, 110016, India

    Zahoor Ahmad Parray

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TFR: Conceptualization (lead); writing original draft (lead); formal analysis (lead); writing, review and editing (equal). SF: writing original draft (lead); review and editing (equal). ZAP: Conceptualization (supporting); review and editing (equal). MDAIB: Review and editing (equal). SM: Review and editing (equal). NK: Review and editing (equal). KLK: Conceptualization (supporting); Supervision; review and editing (equal). All authors have reviewed the manuscript.

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Roohi, T.F., Faizan, S., Parray, Z.A. et al. Beyond Glucose: The Dual Assault of Oxidative and ER Stress in Diabetic Disorders. High Blood Press Cardiovasc Prev 30, 513–531 (2023). https://doi.org/10.1007/s40292-023-00611-3

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