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.

Three Interacting Genomic Loci Incorporating Two Novel Mutations Underlie the Evolution of Diet-induced Diabetes

“…We studied the metabolic phenotype of F2 and parental strains over 4 months, using as surrogate blood glucose level (BGL) during an oral glucose tolerance test (OGTT). We performed the OGTT as previously described (1,2) in the same animals repeatedly at 1, 2.5 and 4 months after initiation of DD. We calculated the area under the curve (AUC) of BGL during the OGTT and used AUC as a quantitative measure reflecting the diabetic status.…”

“…major dietary culprits that we have identified as contributing to the development of the disease (2). Thereafter, diabetes in this model evolves into its chronic phase over the subsequent months, as long as the animals continue to be fed with DD (3,2).…”

“…Thereafter, diabetes in this model evolves into its chronic phase over the subsequent months, as long as the animals continue to be fed with DD (3,2).…”

“…We have previously focused our studies on the pathophysiology of diabetes during the induction phase of diabetes after the first 4 weeks of exposure to DD (3,2). In the current study, we adopted an integrative genomic approach to investigate the evolution of diabetes during its different phases, from its initiation into its chronic phase.…”

Development of Improved Animal Models for the Study of Diabetes

“…Routine histopathological investigation reveals intact pancreas islets and replacement of exocrine acini with adipose tissue. Degeneration of exocrine pancreas remains intact when diabetogenic diet is replaced with a regular one [149]. CD rats develop early hyperinsulinemia and insulin resistance, followed by the exhaustion of β-cells and hypoinsulinemia.…”