Action of PPAR gamma (Peroxisome Proliferator Activated Receptor gamma) and AMPK (AMP-activated protein kinase) on the expression of IDE (Insulin Degrading Enzyme) in pancreatic beta cells

• Grant number: 18/24368-0
• Support type: Scholarships in Brazil - Doctorate
• Effective date (Start): April 01, 2019
• Effective date (End): March 31, 2022
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal researcher: Antonio Carlos Boschiero
• Grantee: Carine Marmentini
• Home Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 15/12611-0 - Molecular mechanisms involved in pancreatic beta cell disfunction and dead in diabetes mellitus: strategies for the inhibition of these processes and restoration of the insular mass, AP.TEM

Abstract

The aggregation of amylin or IAPP (Islet Amyloid Polypeptide) in insoluble polymeric protein fibers (or pancreatic amyloid) is among the factors leading to loss of pancreatic beta cell mass observed in Diabetes Mellitus type 2 (DM2). The IDE (Insulin Degrading Enzyme) is the main enzyme responsible for the degradation of IAPP and studies have shown that the expression of the IDE can be modulated by PPAR gamma (Peroxisome Proliferator Activated Receptor gamma) and AMPK (AMP-Activated Protein Kinase) in neural, hepatic and muscular cells. However, the effect of PPAR gamma and AMPK on the expression of IDE in pancreatic beta cells has not been explored. Thus, we will investigate the role of PPAR gamma and AMPK on the expression of IDE using its agonists, rosiglitazone and metformin, respectively. For this, pancreatic beta cells of the INS-1E line will be distributed in the following groups: Control (CTL), group incubated with medium containing the drug solvents; Rosiglitazone (RGZ) or Metformin (MET), group incubated with medium containing the drugs; RGZ + ML345 and MET + ML345, groups incubated with medium containing the drugs and ML345, a potent inhibitor of IDE. It will be analyzed the gene and protein expression of IDE, degradation of IAPP, pancreatic amyloid formation, insulin secretion and cell death. Finally, we will evaluate the reproducibility of the results in beta cell line (EndoC-betaH1) and islet of humans. With this project, we hope to reveal new mechanisms of action from drugs already used in the treatment of DM2, against the toxicity of pancreatic amyloid and to instigate investigations of new treatments for DM2, aiming to improve the functioning of the IDE in pancreatic beta cells. (AU)

Scientific publications

(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)

MARMENTINI, CARINE; BRANCO, RENATO C. S.; BOSCHERO, ANTONIO C.; KURAUTI, MIRIAN A. Islet amyloid toxicity: From genesis to counteracting mechanisms. Journal of Cellular Physiology, OCT 2021. Web of Science Citations: 0.

MARMENTINI, CARINE; SOARES, GABRIELA M.; BRONCZEK, GABRIELA A.; PIOVAN, SILVANO; MAREZE-COSTA, CECILIA E.; CARNEIRO, EVERARDO M.; BOSCHERO, ANTONIO C.; KURAUTI, MIRIAN A. Aging Reduces Insulin Clearance in Mice. FRONTIERS IN ENDOCRINOLOGY, v. 12, MAY 12 2021. Web of Science Citations: 0.