Interactions between molecular pathways in the loss of functional beta-cell mass during the development of type 1 diabetes mellitus

• Grant number: 25/02351-2
• Support Opportunities: Regular Research Grants
• Start date: May 01, 2026
• End date: April 30, 2029
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Fernanda Ortis
• Grantee: Fernanda Ortis
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• City of the host institution: São Paulo
• Associated researchers: Eloisa Aparecida Vilas Boas ; Fernando Rodrigues de Moraes Abdulkader ; Gustavo Jorge dos Santos ; Sandra Mara Ferreira

Abstract

Diabetes mellitus (DM) is a group of metabolic diseases characterized by chronic hyperglycemia that frequently leads to decrease in the quality of life, presenting a significant increase in the number of cases in the last years. Although there are different types of DM, differing by its etiology, beta cell mass loss is a crucial phenomenon for its development. Thus, a better understanding of pathways that lead to b-cell dysfunction and death is very important to help the design for more efficient therapies for its prevention. Our group studies the molecular mechanisms involved in b-cell dysfunction and death induced by a pro-inflammatory environment, a model for DM1, studding the importance of Endoplasmic Reticulum (RE) and oxidative stress in b-cell destruction. We also observed that the HNF-4a transcription factor, involved in Maturity Onset Diabetes in the Young (MODY)1, has an important function in ER homeostasis and differentiated phenotype maintenance of the b-cell. We also showed that in ¿-cells HNF-4a is modulated by cytokines and seems to modulate NF-kB activation, which has specific characteristic in b cell that confers it a pro-apoptotic effect and is responsible for ER stress activation. We have also studied the role of NADPH oxidases, an important family of ROS producers' transmembrane enzymes, in the b-cell physiopathology. These enzymes are modulated by cytokines and contribute to b-cell oxidative stress. In addition, in other models NADPH oxidases can modulate cytokine-induced NF-kB activation. Here we propose to study the crosstalk between these different pathways, that are important for b-cell destiny after cytokine exposure, evaluating: a) role of HNF-4a in the ER homeostasis and differentiated b-cell phenotype maintenance; b) interaction between cytokine-induced activation of HNF-4a and NF-kB, and its role in ER stress activation and expression of genes involved in b-cell demise; c) if NADPH oxidase activation is involved in modulation of cytokine-induced NF-kB activation and consequent ER stress induction; d) which is the role of specific cytokine-induced NADPH oxidase in b-cell function and death. This study has the potential to produce new information about the crosstalk between these pathways, bringing light to key mechanisms involved with b-cell function mass loss in the DM. (AU)