Enhanced beta cell proliferation in mice overexpressing a constitutively active form of Akt and one allele of p21Cip.
OBJECTIVE
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 p2(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
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.
Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, Brehm Center for Diabetes Research, University of Michigan Medical Center, Ann Arbor, MI 48109-0678, USA.
M
M
Blandino-Rosano
E U
EU
Alejandro
A
A
Sathyamurthy
J O
JO
Scheys
B
B
Gregg
A Y
AY
Chen
L
L
Rachdi
A
A
Weiss
D J
DJ
Barker
A P
AP
Gould
L
L
Elghazi
E
E
Bernal-Mizrachi
D000818:Animals; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000235:genetics*; D005215:Fasting / Q000378:metabolism; D005951:Glucose Tolerance Test; D006946:Hyperinsulinism / Q000378:metabolism; D007003:Hypoglycemia / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055550:Protein Stability; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
D050759:Cyclin-Dependent Kinase Inhibitor p21; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt