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Role of the adherens and gap junctions for the endocrine pancreas function of mice in the onset of type 2 prediabetes

Abstract

In a tissue, cells are attached and interact among them through plasma membrane specializations termed intercellular junctions. These structures are involved in important cell functions such as recognition, communication, adhesion, and cell differentiation. The structure and function of cell junctions may be regulated by in vitro and in vivo conditions, and it is remarkable their role in many pathological conditions. The different endocrine cell types found in pancreatic islets are connected by tight junctions, gap junctions, adherens junctions and desmossomes. Among them, the gap junction (GJ) has been the best studied junction which has a crucial role to maintain the adequate functioning of pancreatic beta cells. Many studies revealed that the connexin (Cx) subtype expressed by pancreatic beta cell is the Cx36. We recently demonstrated that the cell coupling mediated by Cx36 channels is crucial for the functional maturation of rat pancreatic beta cells observed after birth. Moreover, a decreased Cx36 channel-dependent cell coupling was found in mice fed a high fat diet for 60 days (a model of pathogenesis of type 2 diabetes). However, the relevance of cell adhesion for the insulin secretion and the biochemical characterization of the adherens junction components in pancreatic islets are still matter of investigation. The aim of this project is to investigate the role of the cell-cell contacts mediated by the gap and the adherens junctions and their structural proteins (E- cadherin, N- cadherin, alpha-catenin and beta-catenin (associated to the adherens junction) and Cx36 (for the gap junction) for the dysfunction of pancreatic beta cells during the initial steps of pathogenesis of type 2 diabetes (type 2 prediabetes state). To address this issue, C57BL/6 mice will be fed a high fat diet (21% fat) for a short period of time (30 days). The control group it will be fed a regular chow diet (4.5% fat). To validate the model, we will follow the weight gain of the animals, and evaluate some other parameters such as: fasting blood glucose, plasma insulin levels, the intraperitoneal glucose tolerance test and insulin tolerance test. The assessment of pancreatic endocrine function it will be performed by the static and dynamic insulin secretion. The cellular distribution and expression of some gap- and adherens-junction associated proteins such as Cx36, E-cadherin, N-cadherin, alpha-catenin and beta-catenin will be evaluated by immunohistochemistry and Western blot analyzes. For the evaluation of the functioning of gap junction channels, we will analyze the fluorescence recovery after photobleaching (FRAP) in pancreatic islets for both groups exposed to carboxyfluorescein or rhodamine123. Additionally, we will investigate the modulation of the F-actin cytoskeleton in isolated islets from control and HF-fed mice exposed to basal and stimulatory glucose concentrations (2.8 or 16.7 mM of glucose). The development of this project can contribute to give new insights for the role of intercellular junctions for the beta cell dysfunction which occurs during the pathogenesis of type 2 diabetes. (AU)

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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)
VENTURA, PRISCILLA D. S.; CARVALHO, CAROLINA P. F.; BARROS, NILANA M. T.; MARTINS-SILVA, LEONARDO; DANTAS, EDILSON O.; MARTINEZ, CAROLINA; MELO, POLLYANA M. S.; PESQUERO, JOAO B.; CARMONA, ADRIANA K.; NAGAOKA, MARCIA R.; GAZARINI, MARCOS L. Malaria infection promotes a selective expression of kinin receptors in murine liver. Malaria Journal, v. 18, JUN 24 2019. Web of Science Citations: 0.

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