Carrie Draney and Amanda Hobson, Brigham Young University
Decreased β-cell mass is a hallmark of type 1 and type 2 diabetes. The use of islet transplantation as a diabetes therapy is hampered by the relative paucity of transplant ready islets. Greater understanding of the proliferative pathways controlling islet proliferation may be harnessed to increase functional β-cell mass through transplantation or by enhanced growth of endogenous β-cells. We have shown that the β-cell transcription factor Nkx6.1 induces β-cell proliferation by upregulating the orphan nuclear hormone receptors Nr4a1 and Nr4a3. Using expression analysis to elucidate the Nkx6.1 independent mechanism by which Nr4a1 and Nr4a3 induce β-cell proliferation, we demonstrated that cyclin-dependent kinase 5 regulatory subunit 1 (Cdk5r1) is upregulated by Nr4a1 and Nr4a3 and not Nkx6.1. Adenovirus mediated overexpression of Cdk5r1 is sufficient to induce proliferation in primary rat islets. The observed proliferation is primarily in β-cells. Glucose stimulated insulin secretion is maintained with Cdk5r1 overexpression. The Cdk5 inhibitor, roscovitine, blocks islet proliferation, suggesting that Nr4a mediated β-cell proliferation is a kinase dependent event. Overexpression of Cdk5r1 results in pRb phosphorylation, which is inhibited by roscovitine treatment. These data demonstrate that activation of the Cdk5 complex is sufficient to induce β-cell proliferation while maintaining glucose stimulated insulin secretion.