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Åke Lernmark

Principal investigator

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Differential effects of leptin receptor mutation on male and female BBDR.Gimap5-/Gimap5- spontaneously diabetic rats

Author

  • Daniel H. Moralejo
  • Carl T. Hansen
  • Piper Treuting
  • Martin J Hessner
  • Jessica M. Fuller
  • Brian Van Yserloo
  • Richard Jensen
  • William Osborne
  • Anne E. Kwitek
  • Åke Lernmark

Summary, in English

Rodents homozygous for autosomal leptin receptor gene mutations not only become obese, insulin resistant, and hyperleptinemic but also develop a dysregulated immune system. Using marker-assisted breeding to introgress the Koletsky rat leptin receptor mutant (lepr-/lepr-), we developed a novel congenic BBDR.lepr-/lepr- rat line to study the development of obesity and type 2 diabetes (T2D) in the BioBreeding (BB) diabetesresistant (DR) rat. While heterozygous lepr (-/+) or homozygous (+/+) BBDR rats remained lean and metabolically normal, at 3 wk of age all BBDR.lepr-/lepr- rats were obese without hyperglycemia. Between 45 and 70 days of age, male but not female obese rats developed T2D. We had previously developed congenic BBDR. Gimap5-/Gimap5-rats, which carry an autosomal frameshift mutation in the Gimap5 gene linked to lymphopenia and spontaneous development of type 1 diabetes (T1D) without sex differences. Because the autoimmune-mediated destruction of pancreatic islet β-cells may be affected not only by obesity but also by the absence of leptin receptor signaling, we next generated BBDR.lepr-/lepr-,Gimap5-/Gimap5- double congenic rats carrying the mutation for Gimap5 and T1D as well as the Lepr mutation for obesity and T2D. The hyperleptinemia rescued end-stage islets in BBDR. lepr-/lepr-,Gimap5-/Gimap5- congenic rats and induced an increase in islet size in both sexes, while T1D development was delayed and reduced only in females. These results demonstrate that obesity and T2D induced by introgression of the Koletsky leptin receptor mutation in the BBDR rat result in islet expansion associated with protection from T1D in female but not male BBDR. lepr-/lepr-,Gimap5-/Gimap5- congenic rats. BBDR. lepr-/lepr-,Gimap5-/Gimap5- congenic rats should prove valuable to study interactions between lack of leptin receptor signaling, obesity, and sex-specific T2D and T1D.

Publishing year

2010

Language

English

Pages

9-20

Publication/Series

Physiological Genomics

Volume

41

Issue

1

Document type

Journal article

Publisher

American Physiological Society

Keywords

  • Diabetes
  • Islet inflammation
  • Lymphopenia
  • Obesity

Status

Published

ISBN/ISSN/Other

  • ISSN: 1094-8341