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Diabetes 54:2525-2532, 2005
© 2005 by the American Diabetes Association, Inc.

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

I. Pathophysiological Analysis

Chul-Ho Lee1,2, Peter C. Reifsnyder2, Jürgen K. Naggert2, Clive Wasserfall3, Mark A. Atkinson3, Jing Chen2, and Edward H. Leiter2

1 Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea
2 The Jackson Laboratory, Bar Harbor, Maine
3 Department of Pathology, University of Florida, Gainesville, Florida

A spontaneous single-base mutation in the leptin receptor of type 1 diabetes–prone NOD/LtJ mice (designated as Leprdb-5J) produced a glycine640valine transversion in the extracellular domain. All mutant mice became obese and hyperinsulinemic at weaning, with 70–80% developing early-onset hyperglycemia. However, these obese diabetic mice continued to gain weight without insulin therapy. Spontaneous diabetes remission was observed in all obese females and a subset of obese males. Insulitis was largely limited to islet perimeters, with intraislet insulitis infrequently observed. In 17 obese males (age 39 weeks), we observed phenotypic heterogeneity, including full remission from hyperglycemia (24%), intermediate hyperglycemia with elevated body weight (41%), and severe hyperglycemia and weight loss (35%). The remitting normoglycemic and intermediate hyperglycemic phenotypes were associated with extensive ß-cell hyperplasia. Unlike the extensive intraislet insulitis present in diabetic lean NOD/Lt mice, the severe obese diabetic phenotype was associated with islet atrophy without extensive intraislet insulitis. These results indicated that the manipulation of the leptin/leptin receptor axis may provide a novel means of downregulating autoimmunity in type 1 diabetes and confirmed a role for leptin as a mediator in the development of this disease in NOD mice.

Address correspondence and reprint requests to Edward H. Leiter, PhD, The Jackson Laboratory, 600 Main St., Bar Harbor, ME 04609. E-mail: ehl{at}jax.org

Abbreviations: IFN-{gamma}, {gamma}-interferon; IL, interleukin; Rb, leptin receptor long isoform


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C.-H. Lee, Y.-G. Chen, J. Chen, P. C. Reifsnyder, D. V. Serreze, M. Clare-Salzler, M. Rodriguez, C. Wasserfall, M. A. Atkinson, and E. H. Leiter
Novel Leptin Receptor Mutation in NOD/LtJ Mice Suppresses Type 1 Diabetes Progression: II. Immunologic Analysis
Diabetes, January 1, 2006; 55(1): 171 - 178.
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Copyright © 2005 by the American Diabetes Association.