Enhanced beta cell proliferation in mice overexpressing a constitutively active form of Akt and one allele of p21Cip

• Published in: Diabetologia 2012-05, Vol.55 (5), p.1380-1389
• Main Authors: Blandino-Rosano, M., Alejandro, E. U., Sathyamurthy, A., Scheys, J. O., Gregg, B., Chen, A. Y., Rachdi, L., Weiss, A., Barker, D. J., Gould, A. P., Elghazi, L., Bernal-Mizrachi, E.
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p21 - biosynthesis; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fasting - metabolism; Glucose Tolerance Test; Human Physiology; Hyperinsulinism - metabolism; Hypoglycemia - metabolism; Insulin-Secreting Cells - metabolism; Internal Medicine; Male; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Mice; Mice, Inbred C57BL; Mice, Transgenic; Protein Stability; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction - genetics; Signal Transduction - physiology
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-012-2465-9

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.