RasGAP-derived fragment N increases the resistance of beta cells towards apoptosis in NOD mice and delays the progression from mild to overt diabetes
| Autor: | Hadi Khalil, Nieves Peltzer, Christian Widmann, Jiang-Yan Yang, Evrim Jaccard, Natasa Bulat, Gilles Dubuis |
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| Rok vydání: | 2011 |
| Předmět: |
Time Factors
Mouse medicine.medical_treatment Apoptosis Autoimmunity Nod Mice 0302 clinical medicine Endocrinology Mice Inbred NOD Insulin-Secreting Cells Molecular Cell Biology NOD mice 0303 health sciences education.field_of_study Multidisciplinary Cell Death Animal Models ras GTPase-Activating Proteins 030220 oncology & carcinogenesis Disease Progression Medicine Female Beta cell Signal Transduction Research Article Cell type medicine.medical_specialty Science Transgene Population Biology 03 medical and health sciences Model Organisms Internal medicine Cell Line Tumor medicine Diabetes Mellitus Animals education 030304 developmental biology Diabetic Endocrinology Type 1 diabetes Insulin Diabetes Mellitus Type 1 Diabetes Mellitus Type 2 medicine.disease Peptide Fragments Rats Diabetes Mellitus Type 1 Gene Expression Regulation Apoptosis/drug effects Autoimmunity/drug effects Diabetes Mellitus/immunology Diabetes Mellitus/metabolism Diabetes Mellitus Type 1/immunology Diabetes Mellitus Type 1/metabolism Insulin-Secreting Cells/drug effects Insulin-Secreting Cells/metabolism Peptide Fragments/metabolism Peptide Fragments/pharmacology Signal Transduction/drug effects ras GTPase-Activating Proteins/chemistry |
| Zdroj: | PLOS ONE PLoS One, vol. 6, no. 7, pp. e22609 PLoS ONE PLoS ONE, Vol 6, Iss 7, p e22609 (2011) |
| Popis: | The caspase-3-generated RasGAP N-terminal fragment (fragment N) inhibits apoptosis in a Ras-PI3K-Akt-dependent manner. Fragment N protects various cell types, including insulin-secreting cells, against different types of stresses. Whether fragment N exerts a protective role during the development of type 1 diabetes is however not known. Non-obese diabetic (NOD) mice represent a well-known model for spontaneous development of type 1 diabetes that shares similarities with the diseases encountered in humans. To assess the role of fragment N in type 1 diabetes development, a transgene encoding fragment N under the control of the rat insulin promoter (RIP) was back-crossed into the NOD background creating the NOD-RIPN strain. Despite a mosaic expression of fragment N in the beta cell population of NOD-RIPN mice, islets isolated from these mice were more resistant to apoptosis than control NOD islets. Islet lymphocytic infiltration and occurrence of a mild increase in glycemia developed with the same kinetics in both strains. However, the period of time separating the mild increase in glycemia and overt diabetes was significantly longer in NOD-RIPN mice compared to the control NOD mice. There was also a significant decrease in the number of apoptotic beta cells in situ at 16 weeks of age in the NOD-RIPN mice. Fragment N exerts therefore a protective effect on beta cells within the pro-diabetogenic NOD background and this prevents a fast progression from mild to overt diabetes. |
| Databáze: | OpenAIRE |
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