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

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 inmany 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 associatedwith 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 caAktTg 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 caAktTg 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.