Endocrine Pancreas Histology of Congenic BB-Rat Strains with Reduced Diabetes Incidence After Genetic Manipulation on Chromosomes 4, 6 and X

Abstract

Congenic BB.SHR rat strains were established by crossing of spontaneously diabetic BB/OK rats and diabetes-resistant SHR rats. Chromosomal regions on which the genes Iddm 4 (BB.6s), Iddm6 (BB.Xs) and Iddm 2 (BB.LL) are located were exchanged. As a result of genetic manipulation diabetes incidence was markedly reduced from 80% in BB/OK to 50% in BB.SHR (Chr. X), to 14% in BB.SHR (Chr. 6) and to 0% in BB.LL rats. Pancreata of these newly generated BB.SHR rats were investigated histologically. In newly diagnosed diabetic rats of congenic strains pancreatic insulin content (BB.6s: p < 0.05; BB.Xs p < 0.01) and relative volume of insulin-positive cells (BB.Xs: p < 0.001) were significantly higher than in BB/OK rats. The degree of insulitis was not different in 90-day-old and newly diagnosed diabetic animals. Surprisingly, in 30-day-old rats we observed an increase of the degree of insulitis with decreasing diabetes incidence. We suppose that by an earlier occurrence of the immunological beta-cell destruction, a part of the animals is able to develop a secondary diabetes resistance. The exchange of the BB-lymphopenia gene by that of SHR-rats prevented the development of hyperglycaemia without altering the auto-reactive immune response, which could be observed in all animals investigated.

Diabetes per se and metabolic state influence gene expression in tissue‐dependent manner of BB/OK rats

“…That means the autoimmune process starts before 10 days. In addition, infiltrating mononuclear cells like activated macrophages and T-cells can be detected in islets of Langerhans at an age of 30 days [11,12]. Alone, the obviously elevated Lepr gene expression in poorly compensated rats seems to be the result of the disturbed metabolism.…”

Introgression of F344 Rat Genomic DNA on BB Rat Chromosome 4 Generates Diabetes-Resistant Lymphopenic BB Rats

“…Genome-wide linkage analysis for the diabetes phenotype have identified additional loci after crossing different inbred BB rats with DA rats (Iddm3 on chromosome 18) (17), WF rats (Iddm4 and Iddm5 on chromosomes 4 and 13, respectively) (18,19), and SHR rats (Iddm6 on the X chromosome) (20). These genetic factors therefore seem to be dependent on the rat strain used in the cross, i.e., influenced by a differing genome background.…”

Alleles on Rat Chromosome 4 (D4Got41‐Fabp1/Tacr1) Regulate Subphenotypes of Obesity

“…The significantly higher AUC in BB/OK may be an indication that on this exchanged region of chromosome 4, there are alleles of BB/OK that negatively influence the glucose tolerance. This finding could be explained by the fact that all BB/OK rats remaining normoglycemic up to an age of 30 weeks are characterized by a decreased pancreatic insulin content and decreased islet‐ and insulin‐producing β‐cell volume compared with 30‐ and 50‐day‐old BB/OK rats (14,15). The significantly higher AUC of BB/OK rats compared with BB.4S and BB.4W is explainable by the reduction in number of β‐cells, which does not result in hyperglycemia but in glucose intolerance.…”