title: Metabolic and genomic dissection of diabetes in the Cohen rat.
abstract: We investigated the metabolic and genetic basis of diabetes in the Cohen Diabetic rat, a model of diet-induced diabetes, as a means to identify the molecular mechanisms involved. By altering individual components in the diabetogenic diet, we established that the dietary susceptibility that leads to the development of diabetes in this model is directly related to the high casein and low copper content in chow. The development of diabetes is accompanied by depletion of the acini from the exocrine pancreas and replacement with fat cells, while the appearance of the islets of Langerhans remains intact. With reversion back from diabetogenic to regular diet, the diabetic phenotype disappears but the histological changes in the exocrine pancreas prevail. Using positional cloning, we detected a major quantitative trait locus (QTL) on rat chromosome 4 with a chromosomal span of 4.9 cM, and two additional loci on chromosomes 7 and X. A screen for genes within that QTL in the rat and in the syntenic regions in mouse and man revealed only 23 candidate genes. Notable among these genes is Ica1, which has been causally associated with diabetes and bovine casein. We conclude that the development of diabetes in our model is dependent upon high casein and low copper in diet, that it is accompanied by histomorphological changes in the exocrine but not endocrine pancreas, that it is reversible, and that it is associated with a major QTL on chromosome 4 in which we detected Ica1, a high priority candidate gene.
authors.affiliation: Laboratory for Molecular Medicine and Israeli Rat Genome Center, Ben-Gurion University Barzilai Medical Center Campus, Ashkelon, Israel. chyagil@bgu.ac.il
authors.forename: Chana
authors.initials: C
authors.lastname: Yagil
authors.forename: Ronit
authors.initials: R
authors.lastname: Barkalifa
authors.forename: Marina
authors.initials: M
authors.lastname: Sapojnikov
authors.forename: Alexander
authors.initials: A
authors.lastname: Wechsler
authors.forename: David
authors.initials: D
authors.lastname: Ben-Dor
authors.forename: Sarah
authors.initials: S
authors.lastname: Weksler-Zangen
authors.forename: Nurit
authors.initials: N
authors.lastname: Kaiser
authors.forename: Itamar
authors.initials: I
authors.lastname: Raz
authors.forename: Yoram
authors.initials: Y
authors.lastname: Yagil
mesh_terms: D000704:Analysis of Variance; D000821:Animal Feed / Q000032:analysis*; D000818:Animals; D001324:Autoantigens / Q000235:genetics; D002364:Caseins / Q000032:analysis; D002874:Chromosome Mapping; D003300:Copper / Q000032:analysis; D003921:Diabetes Mellitus, Experimental / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D004032:Diet; D004195:Disease Models, Animal; D005820:Genetic Testing; D008126:Lod Score; D010179:Pancreas / Q000473:pathology*; D040641:Quantitative Trait Loci; D051381:Rats
chemical_list: D001324:Autoantigens; D002364:Caseins; C490185:Ica1 protein, rat; D003300:Copper