Interaction between redox state and calcium in the pathophysiology of type 1 and 2 diabetes mellitus

• Grant number: 24/17148-5
• Support Opportunities: Regular Research Grants
• Start date: May 01, 2025
• End date: April 30, 2028
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Eloisa Aparecida Vilas Boas
• Grantee: Eloisa Aparecida Vilas Boas
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Fernanda Ortis ; Leticia Prates Roma ; Patrícia Reckziegel
• Associated scholarship(s): 25/11333-8 - Impact of ROS production at different sites and times on mitochondrial Ca2+ dynamics in pancreatic beta cells, BP.MS

Abstract

In type 1 diabetes mellitus (T1D), there is an absolute insulin deficiency due to an autoimmune destruction of pancreatic beta cells. In type 2 diabetes mellitus (T2D), there is a progressive loss of insulin secretion, associated to various degrees of peripheral resistance to the hormone action. In both cases, the common outcome is chronic hyperglycemia and its associated complications. Two of the main intracellular signals involved in pancreatic beta cells pathophysiology are calcium (Ca2+) and reactive oxygen species (ROS); those are modulated by three essential intracellular microdomains: (i) mitochondria, (ii) NADPH oxidase (NOX) and (iii) the endoplasmic reticulum (ER). The intracellular activated pathways include: oxidative stress and mitochondrial dysfunction, oxidative stress via NOX, accumulation of misfolded proteins, ER Ca2+ depletion and ER stress. All of these events appear to be highly interconnected, impacting beta cells functionality under pathophysiological conditions. However, despite the knowledge of some of the main intracellular microdomains involved in ROS and Ca2+ dynamics, the causal and hierarchical relationships between them in response to stress remain uncertain. Therefore, we are still not able to propose pharmacological modulation strategies. Our previously published data show the temporal regulation of ROS production in different compartments (mitochondria vs. cytosol). Furthermore, from preliminary RNA-seq analyses, we know that the induction of mitochondrial ROS production in pancreatic beta cells acts mainly on the expression of ER-related genes (unpublished data), highlighting the interaction between ROS and Ca2+. Through already established national and international partnerships, we intend to initially implement and use in Brazil new and robust tools that allow us to evaluate ROS and Ca2+ in real time and with intracellular microdomain resolution. From there, we will evaluate the interaction between different intracellular microdomains (mitochondria, NOX and ER) to dissect the effects of ROS and Ca2+ on the functionality and survival of pancreatic beta cells in the context of DM1 and DM2. Thus, the aim is to contribute to the development of pharmacological modulation strategies for possible prevention of dysfunction and/or recovery of insulin-producing cells. (AU)