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- Title
In vivo proliferation of differentiated pancreatic islet beta cells in transgenic mice expressing mutated cyclin-dependent kinase 4.
- Authors
Hino, S.; Yamaoka, T.; Yamashita, Y.; Yamada, T.; Hata, J.; Itakura, M.
- Abstract
Aims/hypothesis. It has previously been hypothesised that highly differentiated endocrine cells do not proliferate or regenerate. However, recent studies have revealed that cyclin-dependent kinase 4 (CDK4) is necessary for the proliferation of pancreatic islet beta cells. The aim of this study was to determine whether activation of CDK4 can potentially he used as a radical treatment !br diabetes without malignant transformation. Methods. We generated transgenic mice expressing mutant CDK4 under the control of the insulin promoter to examine the effect of activated CDK4 over- expression in the postnatal development of pancreatic islets. Results. In the transgenic mice, total CDK4 protein ex- pression was increased by up to 5-foId, with a concomitant increase in CDK4 activity indicated by the detection of phosphorylated Rh protein in pancreatic islets. Histopathologically, many cells tested positive for proliferating cell nuclear antigen, and pancreatic islets displayed hyperplasia due to the extreme proliferation of beta cells containing a large number of insulin granules. Pancreatic islet alpha, delta and PP cells did not increase. Over an I 8-month observation period, the transgenic mice did not develop insulinoma. Levels of expression of GLUT1 and c-myc were comparable to those in the littermates of the transgenic mice. GLUT2 expression was identified in the pancreatic islets of transgenic mice. No significant differences in telomerase activities were detected between transgenic mice and their littermates. Transgenic mice were superior to their littennates in terms of glucose tolerance and insulin secretion in response to the intraperitoneal injection of glucose, and hypoglycaemia was not observed. Conclusions/interpretation. Activated CDK4 stimulates postnatal pancreatic beta cell proliferation, during which the highly differentiated phenotypes of pancreatic islet beta cells are preserved without malignant transformation.
- Subjects
ISLANDS of Langerhans; PANCREATIC beta cells; CELL proliferation; TRANSGENIC mice; CYCLIN-dependent kinases; GENE expression
- Publication
Diabetologia, 2004, Vol 47, Issue 10, p1819
- ISSN
0012-186X
- Publication type
Article
- DOI
10.1007/s00125-004-1522-4