Effects of the bile acid tauroursodeoxycholic (TUDCA) in glycemic homeostasis: insulin and glucagon

Author(s)

Jean Franciesco Vettorazzi

• Document type: Doctoral Thesis
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia
• Defense date: 2017-08-18

Examining board members

Everardo Magalhães Carneiro; Sandra Lucinei Balbo; Maria Lúcia Bonfleur; Licio Augusto Velloso; Bruno Geloneze Neto

• Advisor: Ivan Quesada Moll; Everardo Magalhães Carneiro; Rosane Aparecida Ribeiro

Abstract

Obesity and type 2 diabetes mellitus (DM2) have been growing considerably worldwide, mainly due to changes in lifestyle and consumption of hypercaloric diets. DM2 is characterized by a failure in insulin secretion and signaling, besides elevation in glucagon levels, culminating in hyperglycemia and the development of cardiac, renal, visual complications, etc. Several strategies that modulate the secretion and action of insulin / glucagon have been studied in the treatment of DM2 and obesity, among which we highlight the bile acids. Bile acids are cholesterol-derived compounds that help in the digestive process and are now recognized as endocrine signals that regulate energy, glycemic and lipid metabolism. Taurine-conjugated bile acid (TUDCA) exhibits chemical chaperone activity, leading to the reduction of reticulum stress in several cell types, including pancreatic beta cells. However, the role of TUDCA in the maintenance of glycemic homeostasis has not been explored. In this study, using C57BL6 mice submitted or not the high fat diet, we sought to investigate the effects of TUDCA on insulin secretion and degradation, as well as on glucagon secretion. Exposure of pancreatic islets to TUDCA potentiates glucose-stimulated insulin secretion, an effect not accompanied by electrophysiological changes but dependent on intracellular increase in cAMP. In mice treated with a high fat diet supplemented with TUDCA for 15 days, we observed an improvement in glucose tolerance and insulin sensitivity, accompanied by increased hepatic expression of IDE and insulin degradation. Finally, exposure of pancreatic islets, as well as the linea alpha-TC1-9, reduces glucagon secretion stimulated by glucose, an effect accompanied by reduction in intracellular calcium oscillations and opening of KATP channels. Therefore, we conclude that TUDCA leads to increased glucose-stimulated insulin secretion and regulates insulin clearance through increased hepatic expression of IDE. In addition, TUDCA contributes to the maintenance of glycemic homeostasis through reduction in glucagon secretion stimulated by glucose, proving to be a possible tool in the treatment of obesity and DM2 (AU)

• FAPESP's process: 13/01318-4 - Characterization of tauroursodesoxicolic (TUDCA) action on the pancreatic endocrine function and action in tissue glucagon target ob / ob mice
• Grantee: Jean Franciesco Vettorazzi
• Support Opportunities: Scholarships in Brazil - Doctorate