RGD Reference Report - Differential effects of leptin receptor mutation on male and female BBDR Gimap5-/Gimap5- spontaneously diabetic rats. - Rat Genome Database

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

Authors: Moralejo, DH  Hansen, CT  Treuting, P  Hessner, MJ  Fuller, JM  Van Yserloo, B  Jensen, R  Osborne, W  Kwitek, AE  Lernmark, A 
Citation: Moralejo DH, etal., Physiol Genomics. 2010 Mar 3;41(1):9-20. Epub 2009 Dec 8.
RGD ID: 6893459
Pubmed: PMID:19996157   (View Abstract at PubMed)
PMCID: PMC2841494   (View Article at PubMed Central)
DOI: DOI:10.1152/physiolgenomics.00186.2009   (Journal Full-text)

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) diabetes-resistant (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 beta-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.

RGD Manual Disease Annotations    Click to see Annotation Detail View

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
BBDR.LA-(D5Rat98-D5Rat233)/RhwRathyperglycemia NOTIAGP  RGD 
BBDR.LA-(D5Rat98-D5Rat233), BBDP-(D4Mit6-D4Mit7)/RhwRatlymphopenia  IAGP compared to BBDR/RhwRGD 
BBDR.LA-(D5Rat98-D5Rat233), BBDP-(D4Mit6-D4Mit7)/RhwRatobesity  IAGP compared to BBDR/RhwRGD 
BBDR.LA-(D5Rat98-D5Rat233)/RhwRatobesity  IAGP compared to BBDR/RhwRGD 
BBDR.BBDP-(D4Mit6-D4Mit7)/1RhwRattype 1 diabetes mellitus susceptibilityIAGP compared to BBDR/RhwRGD 
BBDR.LA-(D5Rat98-D5Rat233), BBDP-(D4Mit6-D4Mit7)/RhwRattype 1 diabetes mellitus susceptibilityIAGP delayed and reduced in femalesRGD 
BBDR/RhwMcwiRattype 1 diabetes mellitus MODEL: spontaneousIAGP  RGD 
BBDR/RhwMcwiRattype 1 diabetes mellitus MODEL: treatmentIAGP  RGD 
BBDR.LA-(D5Rat98-D5Rat233)/RhwRattype 2 diabetes mellitus  IAGP only obese malesRGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
BBDR.BBDP-(D4Mit6-D4Mit7)/1RhwRatabnormal pancreatic islet morphology susceptibilityIAGP compared to BBDR/RhwRGD 
BBDR.LA-(D5Rat98-D5Rat233), BBDP-(D4Mit6-D4Mit7)/RhwRatabnormal pancreatic islet morphology  IAGP compared to BBDR/RhwRGD 
BBDR.LA-(D5Rat98-D5Rat233)/RhwRatabnormal pancreatic islet morphology  IAGP compared to BBDR/RhwRGD 
BBDR.LA-(D5Rat98-D5Rat233)/RhwRatdecreased lymphocyte cell number  IAGP compared to BBDR/RhwRGD 
BBDR.LA-(D5Rat98-D5Rat233)/RhwRatincreased body weight  IAGP compared to BBDR/RhwRGD 
BBDR.LA-(D5Rat98-D5Rat233), BBDP-(D4Mit6-D4Mit7)/RhwRatincreased circulating cholesterol level  IAGP in femalesRGD 
BBDR.LA-(D5Rat98-D5Rat233)/RhwRatincreased circulating cholesterol level  IAGP compared to BBDR/RhwRGD 
BBDR.LA-(D5Rat98-D5Rat233)/RhwRatincreased circulating glucose level  IAGP compared to BBDR/Rhw and in malesRGD 
BBDR.LA-(D5Rat98-D5Rat233), BBDP-(D4Mit6-D4Mit7)/RhwRatincreased circulating insulin level  IAGP  RGD 
BBDR.LA-(D5Rat98-D5Rat233)/RhwRatincreased circulating insulin level  IAGP compared to BBDR/Rhw and in femalesRGD 
BBDR.LA-(D5Rat98-D5Rat233), BBDP-(D4Mit6-D4Mit7)/RhwRatincreased circulating leptin level  IAGP  RGD 
BBDR.LA-(D5Rat98-D5Rat233)/RhwRatincreased circulating leptin level  IAGP compared to BBDR/RhwRGD 
BBDR.LA-(D5Rat98-D5Rat233)/RhwRatincreased gonadal fat pad weight  IAGP compared to BBDR/RhwRGD 
BBDR.LA-(D5Rat98-D5Rat233)/RhwRatincreased mesenteric fat pad weight  IAGP compared to BBDR/RhwRGD 
BBDR.LA-(D5Rat98-D5Rat233)/RhwRatincreased retroperitoneal fat pad weight  IAGP compared to BBDR/RhwRGD 
BBDR.BBDP-(D4Mit6-D4Mit7)/1RhwRatincreased susceptibility to autoimmune diabetes susceptibilityIAGP compared to BBDR/RhwRGD 
BBDR.LA-(D5Rat98-D5Rat233), BBDP-(D4Mit6-D4Mit7)/RhwRatincreased susceptibility to non-insulin-dependent diabetes  IAGP compared to BBDR/RhwRGD 
BBDR.LA-(D5Rat98-D5Rat233)/RhwRatincreased susceptibility to non-insulin-dependent diabetes  IAGP compared to BBDR/RhwRGD 
BBDR.LA-(D5Rat98-D5Rat233), BBDP-(D4Mit6-D4Mit7)/RhwRatobese  IAGP compared to BBDR/RhwRGD 
BBDR.LA-(D5Rat98-D5Rat233)/RhwRatobese  IAGP compared to BBDR/RhwRGD 
BBDR.BBDP-(D4Mit6-D4Mit7)/1RhwRatpancreas inflammation susceptibilityIAGP compared to BBDR/RhwRGD 
BBDR.LA-(D5Rat98-D5Rat233), BBDP-(D4Mit6-D4Mit7)/RhwRatpancreas inflammation  IAGP compared to BBDR/RhwRGD 
BBDR.LA-(D5Rat98-D5Rat233)/RhwRatpancreas inflammation  IAGP compared to BBDR/RhwRGD 
BBDR.LA-(D5Rat98-D5Rat233), BBDP-(D4Mit6-D4Mit7)/RhwRatpancreatic islet hyperplasia  IAGP compared to BBDR/RhwRGD 
BBDR.LA-(D5Rat98-D5Rat233)/RhwRatpancreatic islet hyperplasia  IAGP compared to BBDR/RhwRGD 
Objects referenced in this article
Strain LA/N-cp null Rattus norvegicus

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