Portal de Periódicos da CAPES

Novel Leptin Receptor Mutation in NOD/LtJ Mice Suppresses Type 1 Diabetes Progression

2006; American Diabetes Association; Volume: 55; Issue: 1 Linguagem: Inglês

10.2337/diabetes.55.01.06.db05-1129

1939-327X

Chul‐Ho Lee, Yi‐Guang Chen, Jing Chen, Peter C. Reifsnyder, David Serreze, Michael Clare‐Salzler, Michelle Rodriguez, Clive Wasserfall, Mark A. Atkinson, Edward H. Leiter,

Pancreatic function and diabetes

Recently, we identified in normally type 1 diabetes–prone NOD/LtJ mice a spontaneous new leptin receptor (LEPR) mutation (designated Leprdb-5J) producing juvenile obesity, hyperglycemia, hyperinsulinemia, and hyperleptinemia. This early type 2 diabetes syndrome suppressed intra-islet insulitis and permitted spontaneous diabetes remission. No significant differences in plasma corticosterone, splenic CD4+ or CD8+ T-cell percentages, or functions of CD3+ T-cells in vitro distinguished NOD wild-type from mutant mice. Yet splenocytes from hyperglycemic mutant donors failed to transfer type 1 diabetes into NOD.Rag1−/− recipients over a 13-week period, whereas wild-type donor cells did so. This correlated with significantly reduced (P < 0.01) frequencies of insulin and islet-specific glucose-6-phosphatase catalytic subunit–related protein–reactive CD8+ T-effector clonotypes in mutant mice. Intra-islet insulitis was also significantly suppressed in lethally irradiated NOD-Leprdb-5J/Lt recipients reconstituted with wild-type bone marrow (P < 0.001). In contrast, type 1 diabetes eventually developed when mutant marrow was transplanted into irradiated wild-type recipients. Mitogen-induced T-cell blastogenesis was significantly suppressed when splenic T-cells from both NOD/Lt and NOD-Leprdb-5J/Lt donors were incubated with irradiated mutant peritoneal exudate cells (P < 0.005). In conclusion, metabolic disturbances elicited by a type 2 diabetes syndrome (insulin and/or leptin resistance, but not hypercorticism) appear to suppress type 1 diabetes development in NOD-Leprdb-5J/Lt by inhibiting activation of T-effector cells.