Physiopathology of pancreatic β-cells
par- 26 novembre 2012
Responsable : Stéphane DALLE, DR2 INSERM
Pancreatic β-cells are the unique cells of the organism with the capacity to biosynthesize, store and secrete insulin in response to physiological needs. β-cells play a central role in the etiology of Diabetes. Preservation or restoration of a functional β-cell mass is essential. Our objectives, divided into basic research components and clinical investigation, are to examine the cellular and molecular mechanisms controlling function, survival and death of β-cells, to investigate how these go awry in the pathogenesis of diabetes, and how stress and environnement influence β-cell function and survival. A better understanding of the signaling pathways linked to G-protein coupled receptors (GPCRs) and tyrosine kinase receptors (TKRs) in β-cells is essential to identify new molecular targets to treat Diabetes with the aim to preserve or restore the β-cell functional mass. The specific aims of our project are :
To identify the cellular and molecular mechanisms involved in the synergism between signaling pathways engaged by GPCRs (PACAP and GLP-1 receptors, taken as drug targets for type 2 diabetes), TKRs (Insulin and IGF-1 receptors) and glucose in β-cells.
To investigate the effects and the mechanisms whereby prolonged exposure to elevated concentration of glucose (chronic hyperglycemia, a key feature of type 2 diabetes), inflammation, or high fat diet adversely affects β-cell function and survival.
To propose and to validate new therapeutic strategies aiming at preserving or restoring a functional β-cell mass in diabetic subjects.
Ravier MA., Daro D., Prates Roma L., Jonas JC., Cheng-Xue R., Schuit FC., Gilon P. Mechanisms of control of the free Ca2+ concentration in the endoplasmic reticulum of mouse pancreatic beta-cells : interplay with cell metabolism and [Ca2+]c, and role of SERCA2b and SERCA3. (2011) Diabetes, 60, 2533-2445
Dalle S., Ravier MA., Bertrand G. Emerging roles for β-arrestin 1 in the control of pancreatic β-cells function and mass : New therapeutic strategies and consequences for drug screening. (2011) Cell Signalling, 23, 522-528
Quoyer J., Longuet C., Broca C., Linck N., Costes S., Varin E., Bockaert J., Bertrand G., Dalle S. GLP-1 mediates antiapoptotic effect by phosphorylating Bad through a β-arrestin 1-mediated ERK1/2 activation in pancreatic β-cells. (2010) J Biol Chem, 285, 1989-2002
Costes S., Vandewalle B., Tourrel-Cuzin C., Broca C., Linck N., Bertrand G., Kerr-Conte J., Portha B., Pattou F., Bockaert J., Dalle S. Degradation of cAMP-Responsive Element-Binding protein by ubiquitin-proteasome pathway contributes toglucotoxicity in β-cells and human pancreatic islets. (2009) Diabetes, 58, 1105-1115
Broca C., Quoyer J., Costes S., Linck N., Varrault A., Deffayet PM., Bockaert J., Dalle S., Bertrand G. β-arrestin 1 is required for PAC1 receptor-mediated potentiation of long-lasting ERK1/2 activation by glucose in pancreatic β-cells. (2009) J Biol Chem, 284, 4332-4342