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

ANDREONE, LUZ; ORELLANO, MIRANDA SOLA; SÉTULA, CAROLINA; ARGAÑARÁS, MILAGROS; PERONE, MARCELO JAVIER

Hesse, Alemania

Congreso; 2nd European Psychoneuroimmunology Network (EPN) Autumn School: The skin-brain axis and the breaking of barriers; 2023

European Psychoneuroimmunology Network (EPN) Autumn School

Andreone, Luz a,b; Orellano, Miranda Sol a,b; Sétula, Carolina a,b; Argañarás, Milagros a; Perone, Marcelo Javier a,b (1) Is it possible to counteract the mechanisms of pancreatic β-cell stress in diabetesmellitus?a) Laboratory of Immuno-Endocrinology, Diabetes and Metabolism, Instituto de Investigaciones en Medicina Traslacional (IIMT), CONICET-Universidad Austral, Pilar, Argentina b) Facultad de Ciencias Biomédicas, Universidad Austral, Pilar, ArgentinaIntroduction: Pancreatic β-cells are specialized to secrete insulin in response to circulating nutrients, mainly glucose. Type 1 diabetes (T1D) is characterized by an immune-mediated progressive β-cell destruction. Due to the high rate of insulin production and secretion under stimulated conditions, β-cells undergo physiologic endoplasmic reticulum (ER) stress. Severe and uncompensated ER stress in β-cells and subsequent insulin secretory deficiency is induced by proinflammatory microenvironment before onset and during T1D. Moreover, hyperglycemia triggers excess production of mitochondrial reactive oxygen species (ROS) that overwhelm the anti-oxidative capacity of β-cells, leading to oxidative stress. The crosstalk between the ER and oxidative stress further contributes to β-cell dysfunction. We described that Compound A (CpdA), a selective glucocorticoid receptor (GR/NR3C1) ligand that exerts inflammation-suppressive activity in vivo, is an efficient modulator of effector T and dendritic cells, but in a GR-independent manner. Here, we explore the protective effects of CpdA on 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 T1D cellular and animal experimental models. Quantification of NO by Griess method; insulin by ELISA; cell death by Hoechst and propidium iodide staining; cell viability by MTT test; mRNA by RT-qPCR (Sybr Green/Rox); proteins by 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 of β-cells exposed to an environment of proinflammatory cytokines (IL-1b+IFN-y; CYT). CpdA significantly reduced CYT-induced activation of NF-kB signaling pathway and NO secretion (p