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 intraislet 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 Ϫ/Ϫ 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 isletspecific 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 NODLepr 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 NODLepr db-5J /Lt by inhibiting activation of T-effector cells.

Is islet autoimmunity related to insulin sensitivity or body weight in children of parents with type 1 diabetes?

“…This last point is supported by data from other studies [6][7][8] that show a clear relationship between insulin resistance measured during IVGTT tests and the development of clinical diabetes if beta cell function is considered in the statistical model. The notion that obesity and insulin demand do not affect the presentation of autoimmunity is also supported by animal models in which severely obese mice that were genetically susceptible to type 1 diabetes rarely developed the disease [25,26]. Indeed, it appears that the obesity protected from the development of autoimmunity in these mice, although it is possible that the leptin receptor mutation introduced into the mice may have conferred protection independently from the obesity.…”

Leptin as an immunomodulator

“…Leptin accelerates the disease onset and progression by stimulating autoimmune destruction of b-cells and significantly increased IFN-c production in peripheral T-cells (Matarese et al, 2002b). A recent study has shown that a spontaneous mutation of the leptin receptor in normally type 1 diabetes-prone NOD mice suppresses T1D development in the NOD mice by inhibiting activation of T-effector cells, demonstrating the important role of leptin signaling in the disease pathogenesis (Lee et al, 2006). Finally, leptin appears to also play a role in chronic graft-versus-host disease (cGVHD) in patients who receive hematopoietic stem cell transplantation (Tauchmanova et al, 2004), in which increased serum leptin levels are associated with the development of cGVHD.…”

Defective Leptin/Leptin Receptor Signaling Improves Regulatory T Cell Immune Response and Protects Mice From Atherosclerosis

“…9 More recent studies clearly showed that lack or inhibition of leptin/leptin receptor pathway protects against the development of various immunoinflammatory diseases in experimental models, ranging from colitis 31 to encephalomyelitis 11,12 or diabetes. 32 Protection was associated, at least in some experiments, 12 with a shift of the cytokine profile toward increased Th2/Treg type, increased expression of Foxp3, and increased number of Treg cells in lymphoid organs of mice with defective leptin signaling. These studies were also consistent with clinical findings showing a switch from Th1 toward Th2/Treg cytokine profile in individuals with leptin or leptin receptor deficiency, 33,34 and an inverse relationship between leptin secretion and the number of Treg cells in patients with multiple sclerosis.…”