In vivo proliferation of differentiated pancreatic islet beta cells in transgenic mice expressing mutated cyclin-dependent kinase 4.
OBJECTIVE
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 be used as a radical treatment for 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 overexpression in the postnatal development of pancreatic islets.


RESULTS
In the transgenic mice, total CDK4 protein expression was increased by up to 5-fold, with a concomitant increase in CDK4 activity indicated by the detection of phosphorylated Rb 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 18-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 littermates in terms of glucose tolerance and insulin secretion in response to the intraperitoneal injection of glucose, and hypoglycaemia was not observed.


CONCLUSIONS
Activated CDK4 stimulates postnatal pancreatic beta cell proliferation, during which the highly differentiated phenotypes of pancreatic islet beta cells are preserved without malignant transformation.
Division of Genetic Information, Institute for Genome Research, The University of Tokushima, Tokushima, Japan.
S
S
Hino
T
T
Yamaoka
Y
Y
Yamashita
T
T
Yamada
J
J
Hata
M
M
Itakura
D000818:Animals; D002454:Cell Differentiation; D002455:Cell Division; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D051272:Glucose Transporter Type 1; D051273:Glucose Transporter Type 2; D006801:Humans; D007515:Islets of Langerhans / Q000166:cytology* / Q000502:physiology*; D007700:Kinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D016296:Mutagenesis; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D012016:Reference Values
D051272:Glucose Transporter Type 1; D051273:Glucose Transporter Type 2; D009004:Monosaccharide Transport Proteins; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; C495677:SLC2A1 protein, human; C495678:Slc2a1 protein, mouse; C495900:CDK4 protein, human; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases