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Novel leptin receptor mutation in NOD/LtJ mice suppresses type 1 diabetes progression: II. Immunologic analysis. Diabetes 2006 Jan;55(1):171-8



Pubmed ID




Scopus ID

2-s2.0-33644781754   28 Citations


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.

Author List

Lee CH, Chen YG, Chen J, Reifsnyder PC, Serreze DV, Clare-Salzler M, Rodriguez M, Wasserfall C, Atkinson MA, Leiter EH


Yi-Guang Chen PhD Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adoptive Transfer
Amino Acid Sequence
Blood Glucose
Concanavalin A
Diabetes Mellitus, Type 1
Disease Progression
Islets of Langerhans
Mice, Inbred NOD
Point Mutation
Radiation Chimera
Receptors, Cell Surface
Receptors, Leptin
T-Lymphocyte Subsets