Abstract
BackgroundComplex etiology and pathogenesis of pathophysiological components of the cardio-metabolic syndrome have been demonstrated in humans and animal models.Methodology/Principal FindingsWe 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.ConclusionsOur 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.
Highlights
The combination of a decreased sensitivity to insulin of target tissues and compensatory hyperinsulinaemia predispose to the development of a collection of abnormalities including glucose intolerance, obesity, dyslipidemia and hypertension [1,2]
Our results emphasize the importance of rat congenic models for defining the impact of genetic variants in well-characterised quantitative trait loci (QTL) regions on in vivo pathophysiological features and cis-/trans- regulation of gene expression
Related quantitative trait loci (QTL) identified in crosses derived from different disease rat strains often cluster [6,7], suggesting that a proportion of genetic variants isolated in strains selectively bred for different pathologies are common and underlie shared pathophysiological mechanisms
Summary
The combination of a decreased sensitivity to insulin of target tissues (insulin resistance) and compensatory hyperinsulinaemia predispose to the development of a collection of abnormalities including glucose intolerance, obesity, dyslipidemia (increased plasma triglycerides and decreased HDL cholesterol) and hypertension [1,2]. Rat chromosome 1 (RNO1) which harbors QTLs for phenotypes relevant to the cardio-metabolic syndrome and renal failure [6,8,9,10,11,12,13,14] is a prime example of this situation The fact that both the spontaneously hypertensive rat (SHR) and the diabetic Goto Kakizaki (GK) rat carry a naturally occurring functional polymorphism in a gene encoding an inositol 5-phosphatase (SHIP2), illustrates the existence of common genetic and pathophysiological backgrounds in these strains which originate from a similar Wistar outbred stock [5]. Complex etiology and pathogenesis of pathophysiological components of the cardio-metabolic syndrome have been demonstrated in humans and animal models
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