Therapeutic potential of GHRH and metformin on pancreatic beta cell function against endoplasmic reticulum stress and type 2 diabetes mellitus progress

• Grant number: 18/06363-1
• Support Opportunities: Regular Research Grants
• Start date: July 01, 2018
• End date: December 31, 2020
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Helena Cristina de Lima Barbosa
• Grantee: Helena Cristina de Lima Barbosa
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated researchers: Gabriela Moreira Soares

Abstract

Type 2 diabetes mellitus (DM2) is an endocrine disorder characterized by the abnormally high concentration of glucose in the blood. The progressive decline of beta cell function by endoplasmic reticulum (ER) stress may occur in response to exposure to excess free fatty acids or inflammatory cytokines during the progression of DM2, activating the UPR (unfolded protein response). In this project we propose the investigation of two drugs with possible potential to reverse the deleterious effect of ER stress. GHRH, a hormone produced mainly in the hypothalamus, has its expression and its receptor in peripheral tissues, among them the endocrine pancreas. The actions of GHRH on target cells culminate in the activation of cell survival, proliferation and differentiation pathways. Considering dysfunction and cell death in DM2 progression, such GHRH actions make it a potential target on beta cell. We propose to investigate the role of GHRH in the beta cell through the use of MR-409, a hormone agonist peptide, evaluating the modulation of the UPR components during the dysfunction induced by palmitate or proinflammatory cytokines. The other drug to be studied is metformin. One of our hypotheses is that modulation of AMPK activity through metformin could reduce the damaging impact of UPR on the beta cell via Pdx-1 modulation, an important transcription factor in beta cell. Thus, this project could contribute to the better understanding of possible effects of therapeutic targets directed to the pancreatic beta cell, aiming to prevent or reverse the damage caused by obesity and inflammation during the progression of DM2. (AU)

Scientific publications

(5)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

ZANGEROLAMO, LUCAS; VETTORAZZI, JEAN F.; ROSA, LUCAS R. O.; CARNEIRO, EVERARDO M.; BARBOSA, HELENA C. L.. The bile acid TUDCA and neurodegenerative disorders: An overview. Life Sciences, v. 272, MAY 1 2021. (13/07607-8, 18/06363-1, 15/23729-1, 18/20213-2, 15/12611-0)

ZANGEROLAMO, LUCAS; SOLON, CARINA; SOARES, GABRIELA M.; ENGEL, DAIANE F.; VELLOSO, LICIO A.; BOSCHERO, ANTONIO C.; CARNEIRO, EVERARDO M.; BARBOSA, HELENA CRISTINA L.. Energy homeostasis deregulation is attenuated by TUDCA treatment in streptozotocin-induced Alzheimer's disease mice model. SCIENTIFIC REPORTS, v. 11, n. 1, SEP 13 2021. (13/07607-8, 18/20213-2, 18/06363-1)

ROSA, LUCAS RODOLFO DE OLIVEIRA; VETTORAZZI, JEAN FRANCIESCO; ZANGEROLAMO, LUCAS; CARNEIRO, EVERARDO MAGALHAES; BARBOSA, HELENA CRISTINA DE LIMA. UDCA receptors and their role on pancreatic beta cell. PROGRESS IN BIOPHYSICS & MOLECULAR BIOLOGY, v. 167, p. 26-31, DEC 2021. (19/23951-7, 12/14993-9, 15/12611-0, 13/07607-8, 18/06363-1)

ZANGEROLAMO, LUCAS; VETTORAZZI, JEAN F.; SOLON, CARINA; BRONCZEK, GABRIELA A.; ENGEL, DAIANE F.; KURAUTI, MIRIAN A.; SOARES, GABRIELA M.; RODRIGUES, KARINA S.; VELLOSO, LICIO A.; BOSCHERO, ANTONIO C.; et al. The bile acid TUDCA improves glucose metabolism in streptozotocin-induced Alzheimer's disease mice model. Molecular and Cellular Endocrinology, v. 521, FEB 5 2021. (13/07607-8, 15/12611-0, 17/13410-3, 15/23729-1, 18/06363-1, 18/20213-2)

RODRIGUES-DOS-SANTOS, KARINA; SOARES, GABRIELA M.; GUIMARAES, DIMITRIUS S. P. S. F.; ARAUJO, THIAGO R.; VETTORAZZI, JEAN F.; ZANGEROLAMO, LUCAS; MARCONATO-JUNIOR, EMILIO; CAI, RENZHI; SHA, WEI; SCHALLY, V, ANDREW; et al. Effects of growth hormone-releasing hormone agonistic analog MR-409 on insulin-secreting cells under cyclopiazonic acid-induced endoplasmic reticulum stress. Molecular and Cellular Endocrinology, v. 535, SEP 15 2021. (15/12611-0, 18/00665-6, 18/06363-1)