Coisogenic, NOD/ShiLtJ-Leprdb-5J/LtJ (NOD- Leprdb-5J) homozygous mice develop juvenile onset obesity and type II diabetes coupled with suppression of spontaneous type I diabetes in which the NOD/ShiLtJ (NOD/ShiLt) strain is known. RT-PCR confirms the expression of the leptin receptor long isoform (Rb) in the hypothalamus. NOD/ShiLt mice homozygous for this mutation are viable and retain some fertility although the stock is maintained by heterozygous matings. By five weeks of age, homozygous mice are hyperphagic, eating twice the amount of mouse chow as lean controls and develop hyperglycemia not requiring insulin therapy for long tem survival (39+ weeks of age). Lean littermate mice (wild-type or heterozygotes) develop spontaneous type 1 diabetes in an age dependent (post-adolescent) manner. In contrast, Leprdb-5J homozygotes of both sexes develop hyperglycemia within one to two weeks of weaning. This is a type II diabetes based upon chronically elevated insulin and leptin levels maintained over periods up to one year. Pancreatic histopathology in most individuals shows islet hypertrophy with beta cell hyperplasia that is not restricted by insulitis. Insulitis, when present, is primarily peri-vascular/periductular and not intra-islet. Approximately one third of mutants progress to an end-stage Type II diabetes with decreases in body weight and plasma insulin whereas two thirds maintain obese body weight (35-45g) in association with a beta cell hypertrophy/hyperplasia phenotype (Lee et all., 2005). Originally, mutant males were reported as more severely affected than females, but current unpublished results show the same multiplicity of phenotypes in females. Serum lipid levels were not significantly increased in any of the Leprdb-5J homozygous mutant mice, current studies are showing an unexplained variability in this phenotype. 
No significant pathology was originally observed in the liver or kidney (Lee et al., 2005). Splenic leukocytes from young, hyperglycemic mutants transferred into NOD.Rag1 recipients did not transfer type I diabetes over 13 weeks; whereas wild-type donor cells did. However, widespread insulitis was transferred by Leprdb-5J donors, indicating that their splenocytes contained a less-activated effector population at the time of transfer. Reciprocal bone marrow transfers confirmed that Leprdb-5J marrow contained diabetogenic stem cells; however, the slower diabetes generated by either wild-type or mutant marrow transferred into irradiated Leprdb-5J recipients indicated that the disturbed metabolic milieu produced by the obesity mutation was the major reason for suppressing the diabetogenic potential of marrow precursors (Lee et al., 2006). 
Leptin has been reported to accelerate T1D onset in juvenile NOD females (Matarese et al., 2002). The leptin-resistant NOD-Leprdb-5J mouse is useful for dissecting the interaction between the endocrine and immune system in type 1 diabetes-prone mice; understanding the trophic factors generated to produce robust proliferation of B-cells; and studying the involvement of leptin signaling in cueing the cytopathic function of autoimmune T-effector cells.

These mice carry a spontaneous new leptin receptor (LEPR)mutation, and homozygous mice develop juvenile onset obesity and type II diabetes coupled with suppression of spontaneous type I diabetes.

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