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

Abstract

Recently, we identified in normally type 1 diabetes–prone NOD/LtJ mice a spontaneous new leptin receptor (LEPR) mutation (designated Lepr^db-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-Lepr^db-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-Lepr^db-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-Lepr^db-5J/Lt by inhibiting activation of T-effector cells.