Is it possible to counteract the mechanisms of pancreatic beta-cell stress in diabetes mellitus?

ANDREONE LUZ; ORELLANO, MIRANDA SOL; SETULA, CAROLINA; ARGAÑARAS, MILAGROS; PERONE, MARCELO JAVIER

Ebsdorfergrund

Workshop; 2nd European Psychoneuroimmunology Network (EPN) Autumn School; 2023

Introduction: Pancreatic β-cells are specialized to secrete insulin in response to circulating nutrients, mainlyglucose. Type 1 diabetes (T1D) is characterized by an immune-mediated progressive β-cell destruction. Due tothe high rate of insulin production and secretion under stimulated conditions, β-cells undergo physiologicendoplasmic reticulum (ER) stress. Severe and uncompensated ER stress in β-cells and subsequent insulinsecretory deficiency is induced by proinflammatory microenvironment before onset and during T1D. Moreover,hyperglycemia triggers excess production of mitochondrial reactive oxygen species (ROS) that overwhelm theanti-oxidative capacity of β-cells, leading to oxidative stress. The crosstalk between the ER and oxidative stressfurther contributes to β-cell dysfunction. We described that Compound A (CpdA), a selective glucocorticoidreceptor (GR/NR3C1) ligand that exerts inflammation-suppressive activity in vivo, is an efficient modulator ofeffector T and dendritic cells, but in a GR-independent manner. Here, we explore the protective effects of CpdAon proinflammatory cytokine-induced β-cell ER and oxidative stress.Methods: Rat insulinoma INS-1E cell line, murine and human pancreatic islets, and NOD mice were use as T1Dcellular and animal experimental models. Quantification of NO by Griess method; insulin by ELISA; cell death byHoechst and propidium iodide staining; cell viability by MTT test; mRNA by RT-qPCR (Sybr Green/Rox); proteinsby BCA, Western blot and immunofluorescence; insulin by ELISA; transcriptional activity by LUC-reporter plasmid.Results: We demonstrate that CpdA improves the unfolded protein response (UPR) by attenuating ER stress ofβ-cells exposed to an environment of proinflammatory cytokines (IL-1B+IFN-G; CYT). CpdA significantly reducedCYT-induced activation of NF-KB signaling pathway and NO secretion (p