In vitro and in vivo analysis of the mechanism of action of Tauroursodeoxycholic Acid (TUDCA) on the pancreatic alpha cell morphofunction and on the glucagon counter-regulatory response in a model of malnutrition associated with obesity.

• Grant number: 21/02734-8
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: February 01, 2022
• End date: February 28, 2025
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Everardo Magalhães Carneiro
• Grantee: Joel Alves da Silva Junior
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 18/26080-4 - Characterization of molecular and functional mechanisms involved in endocrine-metabolic, cardiovascular and neural dysfunctions induced by the restriction of amino acids in vitro and in vivo: possible therapeutic role of bile acid TUDCA, AP.TEM

Abstract

Malnutrition is still a public health issue that affects 462 million adult individuals across the globe. Intrauterine and postnatal nutritional deficiency triggers metabolic disorders in rodents and humans, leading to imbalance in glycemic control and energy homeostasis, predisposing to the development of obesity and type 2 Diabetes Mellitus (DM2) in adulthood. DM2 is characterized by impaired insulin action, secretion and degradation, in addition to hyperglucagonemia, which is a factor that also contributes to this disease and its progression. Thus, therapeutic strategies against obesity, glucose intolerance and DM2 should take into account both the action and the secretion of insulin and glucagon. Tauroursodeoxycholic Acid (TUDCA) has stood out as a therapeutic molecule in the treatment of obesity and DM2. In obesity models, treatment with TUDCA reduced adiposity and improved insulin action and secretion. In alpha cell culture and pancreatic islets, it reduced glucagon secretion. However, the therapeutic action of TUDCA on pancreatic alpha cell morpho function and glucagon action has not yet been evaluated in rodents with obesity associated with malnutrition. Therefore, in this project we will characterize the effects of TUDCA on alpha cell, and on islets isolated from mice subjected to amino acid restriction in association with fatty acids, with a focus on glucagon secretion. In addition, we will evaluate the effects of TUDCA on glucagon secretion and action, systemically, in mice fed a hypo protein diet in association with a high fat diet.