EGR2 Targets Insulin Receptor Substrate 2 and Affects the Children's Type 1 Diabetes Progression In Vivo and In Vitro

Background: Early Growth Response 2 (EGR2) is a transcription factor implicated in inflammation and cell stress, yet its role in the pathogenesis of pediatric type 1 diabetes (T1D) remains largely unexplored. Moreover, the molecular mechanisms linking EGR2 to pancreatic β-cell dysfunction in T1D are unknown. This study aimed to elucidate the role of EGR2 in T1D progression and to explore the underlying molecular mechanisms. Methods: The expression profile of dataset GSE9006 was analyzed using R software to assess EGR2 expression in peripheral blood mononuclear cells (PBMCs) from children with T1D. Bioinformatic analyses were further complemented by experimental validation to confirm these findings. The effects of EGR2 on MIN6 cell function were examined using Cell counting kit-8 (CCK-8) assay, 5-Ethynyl-2′-deoxyuridine (EdU) proliferation assay, flow cytometry, glucose-stimulated insulin secretion, quantitative PCR (qPCR), and immunoblotting. The regulatory influence of EGR2 on insulin receptor substrate 2 (IRS2) transcription was examined using qPCR and immunoblotting. In vivo, apoptosis was assessed by immunoblot analysis and Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, pancreatic islet injury was evaluated using hematoxylin and eosin (H&E) staining, and blood glucose levels were measured with a glucose meter. Results: EGR2 is highly expressed in PBMC in children with T1D. In addition, EGR2 knockdown alleviated Cytomix-induced MIN6 cell dysfunction and inhibited IRS2 transcription. EGR2 knockdown ameliorated disturbances in STZ-induced blood glucose levels in mice, mitigated pancreatic islet injury in mice, and reduced apoptosis of mouse islet cells. Conclusion: EGR2 knockdown enhances IRS2 transcription and mitigates the pathological features of T1D both in vivo and in vitro, suggesting that EGR2 may serve as a key regulator in T1D progression.