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01-05-2012 | Article

Enhanced beta cell proliferation in mice overexpressing a constitutively active form of Akt and one allele of p21 ^Cip

Authors: M. Blandino-Rosano, E. U. Alejandro, A. Sathyamurthy, J. O. Scheys, B. Gregg, A. Y. Chen, L. Rachdi, A. Weiss, D. J. Barker, A. P. Gould, L. Elghazi, E. Bernal-Mizrachi

Published in: Diabetologia | Issue 5/2012

Abstract

Aims/hypothesis

The ability of pancreatic beta cells to proliferate is critical both for normal tissue maintenance and in conditions where there is an increased demand for insulin. Protein kinase B (Akt) plays a major role in promoting proliferation in many cell types, including the insulin-producing beta cells. We have previously reported that mice overexpressing a constitutively active form of Akt (caAkt ^Tg) show enhanced beta cell proliferation that is associated with increased protein levels of cyclin D1, cyclin D2 and cyclin-dependent kinase inhibitor 1A (p21^Cip). In the present study, we sought to assess the mechanisms responsible for augmented p21^Cip levels in caAkt ^Tg mice and test the role of p21^Cip in the proliferative responses induced by activation of Akt signalling.

Methods

To gain a greater understanding of the relationship between Akt and p21^Cip, we evaluated the mechanisms involved in the modulation of p21^Cip by Akt and the in vivo role of reduced p21^Cip in proliferative responses induced by Akt.

Results

Our experiments showed that Akt signalling regulates p21 ^Cip transcription and protein stability. caAkt ^Tg /p21 ^Cip+/− mice exhibited fasting and fed hypoglycaemia as well as hyperinsulinaemia when compared with caAkt ^Tg mice. Glucose tolerance tests revealed improved glucose tolerance in caAkt ^Tg /p21 ^Cip+/− mice compared with caAkt ^Tg. These changes resulted from increased proliferation, survival and beta cell mass in caAkt ^Tg /p21 ^Cip+/− compared with caAkt ^Tg mice.

Conclusions/interpretation

Our data indicate that increased p21^Cip levels in caAkt ^Tg mice act as a compensatory brake, protecting beta cells from unrestrained proliferation. These studies imply that p21^Cip could play important roles in the adaptive responses of beta cells to proliferate in conditions such as in insulin resistance.

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Title: Enhanced beta cell proliferation in mice overexpressing a constitutively active form of Akt and one allele of p21 Cip
Authors: M. Blandino-Rosano
E. U. Alejandro
A. Sathyamurthy
J. O. Scheys
B. Gregg
A. Y. Chen
L. Rachdi
A. Weiss
D. J. Barker
A. P. Gould
L. Elghazi
E. Bernal-Mizrachi
Publication date: 01-05-2012
Publisher: Springer-Verlag
Published in: Diabetologia / Issue 5/2012
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-012-2465-9

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