Liraglutide and glucolipotoxicity: a study in INS-1E cells to understand the mechanisms of pancreatic function preservation.

• Grant number: 25/21870-0
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: December 01, 2025
• End date: November 30, 2026
• Field of knowledge: Biological Sciences - Physiology - General Physiology
• Principal Investigator: Aparecida Emiko Hirata
• Grantee: João Victor de Figueiredo Bani
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

Type 2 diabetes mellitus (T2DM) is one of the leading chronic diseases today, with agrowing prevalence worldwide, particularly associated with obesity. It is estimated that about80% of patients with T2DM are overweight, highlighting the strong link between the twoconditions. The accumulation of adipose tissue, especially visceral fat, is a critical risk factorfor the development of the disease, as it promotes insulin resistance through mechanisms thatinclude low-grade chronic inflammation, lipotoxicity, and alterations in energy metabolism.A critical point in the pathophysiology of T2DM is the progressive deterioration ofpancreatic ¿-cell function, which becomes unable to secrete sufficient insulin to compensatefor peripheral resistance. One of the main factors underlying this cellular failure is oxidativestress, which occurs due to an imbalance between the production of reactive oxygen species(ROS) and the body's antioxidant defenses. In an environment of chronic hyperglycemia andhigh concentrations of fatty acids, ¿-cells-which naturally have low antioxidantcapacity-become highly vulnerable to glucotoxicity and lipotoxicity. This detrimentalscenario leads to mitochondrial dysfunction, endoplasmic reticulum stress, and the activationof apoptotic pathways, ultimately resulting in the loss of functional ¿-cell mass.In this context, new strategies that not only control glycemia but also protectpancreatic cells from damage are of great importance. GLP-1 analogs, such as liraglutide,emerge as a promising option due to their multiple benefits. These molecules activate GLP-1receptors on ¿-cells and promote insulin secretion in a glucose-dependent manner. Studieshave shown that GLP-1 analogs can reduce apoptosis, stimulate cell proliferation, modulateoxidative stress, and attenuate endoplasmic reticulum stress, thereby helping to preserve¿-cell viability and secretory function.Thus, investigating the effects of GLP-1 analogs under conditions that mimic theenvironment of diabetes and obesity is a highly relevant scientific strategy. This knowledgenot only expands the understanding of the cellular mechanisms underlying pancreatic failurebut can also lead to the development of more effective therapies capable of preservingpancreatic function and delaying the progression of type 2 diabetes