ESTROGEN DEFICIENCY AND EXPERIMENTAL DIABETES MODEL: EFFECTS ON LIVER CHANGES AND ANNEXIN A1 EXPRESSION

• Grant number: 25/12500-5
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: August 01, 2025
• End date: July 31, 2026
• Field of knowledge: Biological Sciences - Morphology - Histology
• Principal Investigator: Cristiane Damas Gil
• Grantee: Suhailah Saleh Silva
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

Type 1 diabetes mellitus (DM1) is an autoimmune disease characterized by the destruction of pancreatic beta cells and consequent absolute insulin deficiency, leading to various metabolic and organic complications, including significant liver changes. Metabolic dysfunction-associated steatotic liver disease (MASLD) and glycogenic hepatopathy are conditions that are increasingly recognized in this context, associated with relative insulin resistance, glycemic fluctuations, and exogenous insulin administration. At the same time, estrogen depletion resulting from menopause aggravates metabolic and inflammatory outcomes, promoting liver changes and contributing to the development and progression of liver dysfunction in women with diabetes. Annexin A1 (AnxA1), a protein involved in inflammation resolution and metabolic regulation, has emerged as an important modulator of these changes, although its role in the hepatic pathophysiology of DM1, especially under the influence of estrogen deficiency, remains poorly understood. In this context, the overall objective of this project is to analyze the interaction between estrogen deficiency and streptozotocin (STZ) induced DM1 in the modulation of hepatic changes and AnxA1 expression in female mice. For this purpose, the animals will be divided into four experimental groups: SHAM (control), OVX (ovariectomized), DM (diabetes), and OVX+DM (ovariectomized and diabetic). Ovariectomy surgery will be performed in the first week; after three weeks, DM1 will be induced by intraperitoneal injections of STZ for five consecutive days. Body weight and blood glucose monitoring will be performed at weeks 4, 8, 12, and 16, when euthanasia will occur for liver collection and processing. Hepatic morphological changes, glycogen deposition and the expression pattern of AnxA1, glucose transporter GLUT2, and PI3K/AKT pathway will be characterized using histopathological, histochemical, immunohistochemical, and/or western blotting analyses. The results of this study are expected to broaden understanding of the pathophysiological mechanisms linking DM1 and estrogen deficiency to liver dysfunction, as well as contributing to the identification of potential therapeutic targets related to AnxA1, aiming to prevent or to mitigate liver complications associated with diabetes.