Type I diabetes (IDDM) is an autoimmune disease characterized by the destruction of the insulin-producing b-cells of the islet. Programmed cell death (apoptosis) is recognized as the major mechanism, which participates in the destruction of pancreatic b-cells. On the opposite, type II diabetes (NIDDM) is a non-autoimmune disease characterized by insulin resistance and inadequate insulin secretion; several observations support also a possible role for apoptosis in type II diabetes.
It seems that apoptosis is a common feature of both type I and II diabetes and recent reviews have addressed different aspects of b-cell apoptosis in both forms of diabetes. If b-cell intracellular signalling events are more or less well characterized in type I diabetes, very little is know about the mechanism of apoptosis in type II diabetes.
We hypothesize that glucose and fatty acids can induce apoptosis in b-cell through the activation of the JNK pathway and that both nutrients can synergize with cytokines to amplify the b-cell death.
To this end we propose in these studies to characterize the molecular signalling pathway of glucose and/or fatty acid induced b-cell death; we propose the following experiments:
Investigate the potential interaction of glucose and/or fatty acids with the JNK signalling pathway. Investigate whether glucose and/or fatty acid potentate IL-1b-induced JNK activity in bINS cell lines and rat islets.
Investigate the role of PPARg in fatty acid induced apoptosis.
Characterize the interaction of PPARg/JNK using c-permeable peptide inhibitors.
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Die Gebert Rüf Stiftung bietet im Sinne eines Pilotprojektes einem hochqualifizierten, an einer ausländischen Forschungsstätten weilenden Nachwuchswissenschaftler ein Rückkehrstipendium an. Dieses soll Ihm den Wiedereinstieg an einer schweizerischen Forschungsstätte ermöglichen. Umgekehrt bringt er sein gesamtes neu erworbendes Know How mit in die Schweiz.
During these first six months, the most important effort was put to investigate the potential interaction of glucose and/or fatty acids with the JNK signalling pathway. Indeed, exposure of Insulin-secreting INS cells to high glucose concentration (20mM) induced JNK activation and apoptosis. INS can be protected from this glucose-induced apoptosis by JNKI, a peptidic inhibitor of JNK. Detailed analysis of the molecular mechanisms leading from glucose to apoptose are in progress.
In the same time, the group of Marc Donath in Zurich proposed a new pathway responsible for “glucotoxicity” in human islets, in wich IL-1b secretion by islets is followed by NF-kB activation. In collaboration with this group, we evaluate whether secreted IL-1b induce JNK activation.
Analysis of results concerning the fatty acids-induced apoptosis of b-cell, was a little surprising. We were not able to reproduce previous results of apoptosis. We will focus our research more on the interaction of PPARg with JNK pathway. We have preliminary results showing that the scaffold protein IB1 increase JNK activation of PPARg.
K. Maedler, C. Bielmann, N. Allamna-Pillet, C. Bonny, M. Donath and R. Roduit “Leptin and glucose induce b-cell apoptosis through activation of c-Jun N-terminal kinases (SAPK/JNK)” in preparation. 2004.
R. Roduit, S. Habinowski, J. Morin, E. Joli, Witters L. A. and Prentki M. “Characterization of the role of AMP-activated kinase in the glucose down regulation of Peroxisome Proliferator-Activated Receptor a.” In preparation.
S. Abdelli, J. Ansite, R. Roduit, T. Borsello, I. Matsumoto, T. Sawada, N. Allaman-Pillet, H. Henry, J.S. Beckmann, B.J. Hering & C. Bonny. ”Intracellular Stress Signalling Pathways Activated During Human Islet Preparation And Following Cytokine Attack.” Submitted Diabetes. 2004.
N. Allaman-Pillet, R. Roduit, A Oberson., J. Ruiz, and DF. Schorderet and C. Bonny “Circadian regulation of islet genes involved in insulin production and secretion.” Submitted to Molecular and Cellular Endocrinology 2004.
R. Roduit, S. Gremlich-Irrausch, R. Burcellin, M-L. Peyot, B. Desvergnes, L. Michaelic, C. Nolan, B. Thorens, M. Prentki and W. Wahli “PPARa, Lipid Partitioning and Glucose Stimulated Insulin Secretion.A Study in PPARa-Deficient Mice” Submitted to Endocrinology 2004.
Allaman-Pillet N., Størling J., Oberson A, Roduit R., Negri S., Sauser C. Beckmann J.S., Nicod P., Schorderet D.F., Mandrup-Poulsen T., Bonny C. “Calcium- and proteasome-dependent degradation of the JNK scaffold protein islet-brain 1.” J. Biol. Chem. 278: 48720-48726, 2003.
Roduit R.*, Nolan C.*, Alarcón C., Kelpe C., Przybykowski E., Morin J., Massé F., Massie B., Ruderman N., Rhodes C.J. Poitout V., and Prentki M. “Overexpressing malonyl-CoA decarboxylase in the cytosol alters lipid partitioning and glucose-induced insulin secretion in pancreatic b-cells.” Diabetes, 2004.
Revue de presse
Dernière mise à jour de cette présentation du projet 11.02.2020