title: Pathophysiological, genetic and gene expression features of a novel rodent model of the cardio-metabolic syndrome.
abstract: BACKGROUND
  Complex etiology and pathogenesis of pathophysiological components of the cardio-metabolic syndrome have been demonstrated in humans and animal models.
  
  
  RESULTS
  We have generated extensive physiological, genetic and genome-wide gene expression profiles in a congenic strain of the spontaneously diabetic Goto-Kakizaki (GK) rat containing a large region (110 cM, 170 Mb) of rat chromosome 1 (RNO1), which covers diabetes and obesity quantitative trait loci (QTL), introgressed onto the genetic background of the normoglycaemic Brown Norway (BN) strain. This novel disease model, which by the length of the congenic region closely mirrors the situation of a chromosome substitution strain, exhibits a wide range of abnormalities directly relevant to components of the cardio-metabolic syndrome and diabetes complications, including hyperglycaemia, hyperinsulinaemia, enhanced insulin secretion both in vivo and in vitro, insulin resistance, hypertriglyceridemia and altered pancreatic and renal histological structures. Gene transcription data in kidney, liver, skeletal muscle and white adipose tissue indicate that a disproportionately high number (43-83%) of genes differentially expressed between congenic and BN rats map to the GK genomic interval targeted in the congenic strain, which represents less than 5% of the total length of the rat genome. Genotype analysis of single nucleotide polymorphisms (SNPs) in strains genetically related to the GK highlights clusters of conserved and strain-specific variants in RNO1 that can assist the identification of naturally occurring variants isolated in diabetic and hypertensive strains when different phenotype selection procedures were applied.
  
  
  CONCLUSIONS
  Our results emphasize the importance of rat congenic models for defining the impact of genetic variants in well-characterised QTL regions on in vivo pathophysiological features and cis-/trans- regulation of gene expression. The congenic strain reported here provides a novel and sustainable model for investigating the pathogenesis and genetic basis of risks factors for the cardio-metabolic syndrome.
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Wallis
authors.forename: Stephan C
authors.initials: SC
authors.lastname: Collins
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Kaisaki
authors.forename: Karène
authors.initials: K
authors.lastname: Argoud
authors.forename: Steven P
authors.initials: SP
authors.lastname: Wilder
authors.forename: Karin J
authors.initials: KJ
authors.lastname: Wallace
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Ria
authors.forename: Alain
authors.initials: A
authors.lastname: Ktorza
authors.forename: Patrik
authors.initials: P
authors.lastname: Rorsman
authors.forename: Marie-Thérèse
authors.initials: MT
authors.lastname: Bihoreau
authors.forename: Dominique
authors.initials: D
authors.lastname: Gauguier
mesh_terms: D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001481:Basal Metabolism; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure; D001835:Body Weight; D002874:Chromosome Mapping; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D004195:Disease Models, Animal; D005947:Glucose / Q000494:pharmacology; D006943:Hyperglycemia / Q000235:genetics*; D006946:Hyperinsulinism / Q000235:genetics*; D007328:Insulin / Q000097:blood / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D008055:Lipids / Q000097:blood; D009765:Obesity / Q000235:genetics*; D040641:Quantitative Trait Loci; D051381:Rats; D011919:Rats, Inbred Strains / Q000235:genetics
chemical_list: D001786:Blood Glucose; D007328:Insulin; D008055:Lipids; D001120:Arginine; D005947:Glucose