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Effect of exercise training on the endoplasmatic reticulum stress, inflammation and apoptotic pathways in pancreatic ² cells

Grant number: 14/17105-2
Support Opportunities:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): January 01, 2015
Effective date (End): December 31, 2015
Field of knowledge:Biological Sciences - Physiology - Physiology of Organs and Systems
Principal Investigator:Antonio Carlos Boschiero
Grantee:Flavia Maria Moura de Paula
Supervisor: Decio L. Eizirik
Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Research place: Université Libre de Bruxelles (ULB), Belgium  
Associated to the scholarship:13/03365-0 - Effect of the exercise training on the nitric oxide production in pancreatic islets of trained mice exposed to streptozotocin and inflammatory cytokines: cross talk between skeletal muscle and endocrine pancreas, BP.PD


Diabetes Mellitus affects more than 380 million individuals worldwide. The two main forms of diabetes are type 1 diabetes (T1D), which is caused by an autoimmune assault against pancreatic ² cells with loss of ² cell function and mass, and type 2 diabetes (T2D), usually associated with obesity, insulin resistance in peripheral tissues and a deficient insulin secretion by ² cells. Exercise is an important tool to improve glycemic control in T1D and T2D patients, but the mechanisms by which exercise contribute to restore ² cell function and mass remain to be characterized. Unpublished data obtained during my ongoing post-doctoral project at the UNICAMP showed that exercise prevents ² cell death in a model of T1D. In the present follow up project we aim to investigate the molecular mechanisms involved in this beneficial effect of exercise in ² cell, and to determine whether this protective effect of exercise also occurs in the presence of palmitate, a stress signal relevant for T2D development. We will focus on the activation of the endoplasmic reticulum (ER) stress-unfolded protein response (UPR) pathway, induction of insulitis and regulation of apoptosis. For this, we will incubate rodent MIN6 and INS-1E ² cell lines, FACS-purified rat ² cells and the human ² cell line EndoC-²H1 with inflammatory cytokines, palmitate and/or ER stressors in the presence or absence of serum from control or trained mice. After this, we will measure proteins related to the UPR-ER stress pathway (ATF6-BiP; PERK-ATF4-CHOP; IRE1-XBP1) and the mitochondrial pathway of apoptosis (DP5, PUMA, Bim). In addition, possible pathways involved in the protection against apoptosis will be analyzed, with focus on JunB-AKT. Moreover, we will also investigate the effect of exercise on the induction of inflammatory signals by ² cells, measuring the expression and release of inflammatory mediators by these cells during their exposure to inflammatory cytokines and/or palmitate. Studies on the molecular mechanisms by which exercise inhibits insulitis and ² cell death raise the possibility of identifying novel molecules able to improve ² cell function and survival in early diabetes. (AU)

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