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Diabetes mellitus (DM) is a heterogeneous disease, with diverse clinical phenotypes, all with hyperglycemia. Historically, four factors have been used to identify this diversity: the age at onset, the severity of the disease, that is, the degree of loss of beta cell function and insulin resistance, and the presence of circulating autoantibodies. Currently, the parameters used to classify the different types of DM make it difficult to diagnose and treat patients. The different clinical manifestations require an accurate diagnosis to achieve an effective therapeutic approach through the use of immunogenetics and clinical biochemistry. This practical guide aims to accurately classify the often uncertain clinical presentations within the two main types of diabetes.

Introduction: The development of the autoimmune process during type 1 diabetes (DM1) contributes to insulitis; in this context, both β-cell stress and subsequent insulin secretory deficiency precede clinical signs of disease. Hyperglycemia triggers excess production of mitochondrial reactive oxygen species (ROS) that overwhelm the anti-oxidative capacity of β-cells, leading to oxidative stress. Islet inflammatory microenvironment during the autoimmune attack contributes to the activation of oxidative and endoplasmic reticulum (ER) stress resulting in β-cell dysfunction and death. The transcription factor Nrf2 regulates the expression of cytoprotective genes in response to oxidative stress, its induction is crucial for the normal β-cell physiology. We reported that Compound A (CpdA), a dissociative glucocorticoid receptor-ligand, is an effective modulator of key immune cells involved in insulitis, T and dendritic cells. In addition, we observed that CpdA ameliorates cytokine (IL-1b+IFN-g; CYT)-induced ER stress in β-cells and that in vivo CpdA administration leads to a significant delay of disease onset in an accelerated murine model of DM1. The development of new agents, with anti-inflammatory and immunomodulatory action and protective potential directed against dysfunctional signaling of β-cells is of clinical interest in diabetes. Objectives: The aim of this study was to explore the effect of CpdA on Nrf2 signaling pathway and CYT-induced oxidative stress in β-cells. Materials & Methods: A rat insulinoma cell line (INS-1E) was used as experimental model. CpdA chemical formula: 2-(4-acetoxyphenyl)-2-chloro-N-methylethylammonium chloride. A reporter plasmid (ARE-LUC) was used for the evaluation of Nrf2 transcriptional activity (luminometry); RTqPCR (Sybr Green) for analysis of mRNA expression; WB for protein expression analysis; a DCFDA based commercial kit to evaluate ROS (fluorometry); MTT assay for cell viability analysis and ELISA for insulin.