Pancreatic Regenerating Gene Overexpression in the Nonobese Diabetic Mouse During Active Diabetogenesis

Abstract

The reg gene has previously been shown to be associated with regeneration of pancreatic islets. Strategies for influencing the replication and the growth of the (3-cell mass may be important for prevention and/or treatment of type I diabetes. In this study, we have examined the level of reg gene expression at various degrees of diabetogenesis in the pancreas of the NOD mouse (male, female, and cyclophosphamide-treated male) using both human reg cDNA as the probe and dot blot analysis. The expression of the reg gene was found to be significantly increased in female mice compared with male mice, and in both cases, the expression level was not influenced by age. Nondiabetic female mice have a significantly higher expression of the gene than diabetic female mice, and there was a positive correlation between the age of diabetes onset and the reg mRNA level. In addition, overexpression of the reg gene was found in male mice treated by cyclophosphamide, an agent known to be a potent inducer of diabetes in male NOD mice. None of these results were found in the diabetes-resistant control OF1 mice, in which pancreatic reg gene expression did not differ between female and male mice treated or untreated with cyclophosphamide. All of these data suggest that there is a strong correlation between reg gene expression in the pancreas of the NOD mouse and the likelihood of developing diabetes.

Pancreatitis-Associated Protein (HIP/PAP) Gene Expression Is Upregulated in NOD Mice Pancreas and Localized in Exocrine Tissue during Diabetes

“…This data is in keeping with the results of McKie et al [14]who demonstrated by Northern blot that the steady-state level of PAP mRNA in the normal mouse pancreas was virtually undetectable. However, we found significantly higher levels of PAP mRNAs in the NOD mouse pancreas but in contrast to that we previously found for reg genes [7, 8]there were no differences between diabetes-prone female mice and diabetes-resistant male mice, demonstrating that the increase of PAP mRNA levels in NOD mice was not specifically associated with a high risk of diabetes. These results suggest that the PAP gene expression in this strain is only correlated with the presence of insulitis, the main characteristic of the NOD mice which corresponds to lymphocyte infiltration.…”

“…We observed a pancreatic overexpression of the reg II gene (and to a lesser degree of the reg I gene) in female NOD mice which develop diabetes early in life, whereas NOD males, which are relatively protected, have a low mRNA level similar to the level found in a control mouse strain [7, 8]. The specificity of this overexpression in the diabetogenic process was reinforced by the fact that it was also observed in NOD male mice after treatment with cyclophosphamide, an immunosuppressive drug known to accelerate diabetes in this strain.…”

“…For hybridization with PAP, trypsinogen and amylase probes, the dilutions were from 5 to 0.156 µg, with the 28S cDNA probe the dilutions were from 50 to 1.56 ng. Hybridization was performed as previously described [7]. For each sample, the densitometrically scanned readings for HIP/PAP, trypsinogen or amylase were corrected to the 28S signal to eliminate possible differences in total RNA loading.…”

“…We have previously shown a specific significant overexpression of the two reg genes in the non-obese diabetic (NOD) mouse pancreas during active diabetogenesis [7, 8]. With regard to the high homology which exists between reg and PAP genes, it was important to investigate whether the overexpression of the reg genes observed in the NOD mouse pancreas during the active phase of diabetogenesis could represent a general phenomenon for other related reg genes, such as HIP/PAP.…”

The Relationship between Pentosidine and Hemodialysis- Related Connective Tissue Disorders

“…The intra- and inter-molecular crosslinks are believed to play a significant role in these changes in the extracellular matrix [8]. Pentosidine, a crosslink between arginine and lysine, is one of the AGEs [9].…”