TY - JOUR
T1 - Metabolic and genomic dissection of diabetes in the Cohen rat
AU - Yagil, Chana
AU - Barkalifa, Ronit
AU - Sapojnikov, Marina
AU - Wechsler, Alexander
AU - Ben-Dor, David
AU - Weksler-Zangen, Sarah
AU - Kaiser, Nurit
AU - Raz, Itamar
AU - Yagil, Yoram
PY - 2007/4/24
Y1 - 2007/4/24
N2 - 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.
AB - 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.
KW - Candidate genes
KW - Diet-induced
KW - Genetic susceptibility
UR - http://www.scopus.com/inward/record.url?scp=34247895434&partnerID=8YFLogxK
U2 - 10.1152/physiolgenomics.00210.2006
DO - 10.1152/physiolgenomics.00210.2006
M3 - Article
AN - SCOPUS:34247895434
SN - 1094-8341
VL - 29
SP - 181
EP - 192
JO - Physiological Genomics
JF - Physiological Genomics
IS - 2
ER -