Endoplasmic reticulum stress in diabetes mellitus: a comprehensive review of emerging insights and recent progress

Background/aim:
Endoplasmic reticulum stress (ERS), caused by excessive buildup of misfolded proteins in the ER lumen, has emerged as a major contributor to diabetes mellitus (type-1 and type-2; T1DM and T2DM), leading to β-cell dysfunction, insulin resistance, and related comorbidities. In this review, we aim to characterize the signal transduction pathways in normal versus diseased conditions and their impact on the development of insulin-dependent and insulin-independent diabetes.

Methods:
Evidence on ERS and diabetes were searched in MEDLINE and Google scholar databases using search strings that incorporated synonyms of ERS, diabetes, β-cell dysfunction and insulin resistance and their impact in disease progression. Our search was guided by the pertinent keywords as mentioned in the “keywords” section, that encompassed past twenty-five years of body of literature in this field as evident from Urano et al. 2000 till Sue et al. 2025.

Results/conclusion:
Our results and conclusion are the distillation of past two and half decades of scientific research dedicated towards understanding the biology of ERS dependent diabetes. The ERS-induced Unfolded Protein Response (UPR), comprising of three signaling cascades, is pivotal in either protecting against or contributing to the pathophysiology of T1DM and T2DM. Clinically, ERS manifests as insulin resistance, heightened inflammation, and β-cell destruction. Consequently, ERS effectors and proteins involved in the UPR pathways have become attractive targets for pharmacological investigation. We also review some of the protein biomarkers of ERS dependent diabetes and relevant in vivo/ex vivo models used in clinical versus preclinical settings, as well as the latest state-of-the-art targeted molecular and cellular therapies that are currently being tried for the diabetic patients.