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RasGAP-derived fragment N increases the resistance of beta cells towards apoptosis in NOD mice and delays the progression from mild to overt diabetes.
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.
Animals, Apoptosis/drug effects, Autoimmunity/drug effects, Cell Line, Tumor, Diabetes Mellitus/immunology, Diabetes Mellitus/metabolism, Diabetes Mellitus, Type 1/immunology, Diabetes Mellitus, Type 1/metabolism, Disease Progression, Female, Gene Expression Regulation, Insulin-Secreting Cells/drug effects, Insulin-Secreting Cells/metabolism, Mice, Mice, Inbred NOD, Peptide Fragments/metabolism, Peptide Fragments/pharmacology, Rats, Signal Transduction/drug effects, Time Factors, ras GTPase-Activating Proteins/chemistry
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