Akt Induces β-Cell Proliferation by Regulating Cyclin D1, Cyclin D2, and p21 Levels and Cyclin-Dependent Kinase-4 Activity

Abstract

Proliferation is the major component for maintenance of ␤-cell mass in adult animals. Activation of phosphoinositide 3-kinase/Akt-kinase pathway is a critical regulator of ␤-cell mass. Pancreatic ␤-cell overexpression of constitutively active Akt in mice (caAkt Tg ) resulted in marked expansion of ␤-cell mass by increase in ␤-cell proliferation and size. The current studies provide new insights into the molecular mechanisms involved in ␤-cell proliferation by Akt. Proliferation of ␤-cells in caAkt Tg was associated with increased cyclin D1, cyclin D2, and p21 levels and cyclindependent kinase-4 (cdk4) activity. To determine the role of cdk4 in ␤-cell proliferation induced by Akt, we generated caAkt Tg mice that were homozygous, heterozygous, or nullizygous for cdk4. The results of these studies showed that deletion of one cdk4 allele significantly reduced ␤-cell expansion in caAkt Tg mice by decreased proliferation. CaAktTg mice deficient in cdk4 developed ␤-cell failure and diabetes. These experiments suggest that Akt induces ␤-cell proliferation in a cdk4-dependent manner by regulation of cyclin D1, cyclin D2, and p21 levels. These data also indicate that alteration in levels of these cell cycle components could affect the maintenance of ␤-cell mass in basal states and the adaptation of ␤-cells to pathological states resulting in diabetes. Diabetes 55:318 -325, 2006 T he defects that result in diabetes are diverse, but pancreatic ␤-cell failure is a major component of this disease (1,2). Pancreatic ␤-cell mass results from a dynamic balance of neogenesis, proliferation, cell size, and apoptosis (3). Recent data using cell lineage tracing experiments suggest that replication is a major component involved in maintenance of ␤-cell mass in adult animals (4). The molecular mechanisms involved in regulation of ␤-cell mass are unknown. Several lines of evidence suggest that activation of phosphoinositide 3-kinase (PI 3-kinase) signaling pathway plays critical roles in regulation of ␤-cell mass and function (5-10).One of the major targets of PI 3-kinase is the serinethreonine kinase Akt, the cellular homolog of the viral oncogene v-Akt (11). Akt is a convergent point of several growth signals induced by growth factors, insulin, and gut incretins. Transgenic mice overexpressing a constitutively active form of Akt in islet ␤-cells (caAkt Tg ) have provided further evidence for the role of this kinase in islet physiology (12,13). These mice exhibit striking increases in ␤-cell mass, proliferation, neogenesis, and cell size. Akt regulates cell cycle progression by alterations in levels and subcellular distribution of components of the cell cycle machinery (14). The molecules and the mechanisms involved in the regulation of cell cycle by growth signals mediated by Akt in pancreatic ␤-cells are ill defined.Insight into the mechanisms involved in the regulation of cell cycle in ␤-cells have been provided by experiments in cyclin-dependent kinase-4 (cdk4)-deficient mice. These mice exhibited growth retardation and diabetes du...

Early loss of mammalian target of rapamycin complex 1 (mTORC1) signalling and reduction in cell size during dominant-negative suppression of hepatic nuclear factor 1-α (HNF1A) function in INS-1 insulinoma cells

“…Overexpression of a constitutively active form of Akt1 has been shown to be associated with an increased S6K activity [43]. It has also been shown that targeted overexpression of constitutively active Akt1 in transgenic mice induced a striking increase in beta cell mass caused by an increase in both beta cell number and size [44]. However, our study demonstrated different dephosphorylation kinetics in response to DN-HNF1A expression, suggesting that AKT1 inactivation may not be the primary mechanism of mTORC1 and S6K1 inactivation in this model.…”

Regulation of Pancreatic β-Cell Regeneration in the Normoglycemic 60% Partial-Pancreatectomy Mouse

“…Studies of mice with altered gene expression suggest that the insulin signaling pathway via Akt/FoxO1/PDX1 regulates ␤-cell proliferation (7,12,14 -16). In turn, the ␤-cell proliferative response is associated with increased levels of cell cycle proteins, including cyclin D1, cyclin D2, p21, and cdk4 activity mediated by Akt (4,5,36,37). Thus, whereas FoxO1 haplodeficiency restored Pdx1 expression and ␤-cell proliferation in IRS2 Ϫ/Ϫ and Pdk1 Ϫ/Ϫ mice (12,15), PDX1 haplodeficiency abrogated ␤-cell compensatory response in insulin-resistant Insr ϩ/Ϫ…”

The Akt/FoxO1/p27 pathway mediates the proliferative action of liraglutide in β cells

“…One of the major targets of PI-3K, the serine threonine kinase Akt, was found to play a central role in β-cell growth and survival (21,22). An in vivo study revealed that overexpression of constitutively active Akt in mice pancreatic β cells resulted in marked expansion of β-cell mass by increasing the β-cell proliferation and size (23). A previous study found that Akt also played a critical role in the proliferative action of GLP-1 (7-36 amide) in pancreatic β cells (12).…”