Decreased β-cell mass is a hallmark of type 1 and type 2 diabetes. Islet transplantation as a method of diabetes therapy is hampered by the paucity of transplant ready islets. Understanding the pathways controlling islet proliferation may be used to increase functional β-cell mass through transplantation or by enhanced growth of endogenous β-cells. We have shown that the transcription factor Nkx6.1 induces β-cell proliferation by upregulating the orphan nuclear hormone receptors Nr4a1 and Nr4a3. Using expression analysis to define Nkx6.1-independent mechanisms 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 but not by Nkx6.1. Overexpression of Cdk5r1 is sufficient to induce primary rat β-cell proliferation while maintaining glucose stimulated insulin secretion. Overexpression of Cdk5r1 in β-cells confers protection against apoptosis induced by etoposide and thapsigargin, but not camptothecin. The Cdk5 kinase complex inhibitor roscovitine blocks islet proliferation, suggesting that Cdk5r1 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 kinase complex is sufficient to induce β-cell proliferation while maintaining glucose stimulated insulin secretion.

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The number of people affected by diabetes is continually rising, affecting over 400 million people worldwide. The insulin secreting pancreatic beta cells are essential to control proper glucose absorption and storage in insulin sensitive peripheral tissue. Both Type 1 and Type 2 diabetes are characterized by decreased functional beta cell mass and, consequently, decreased insulin production. One potential intervention is the use of beta cell transplantation from cadaveric donors. A major impediment to greater application of this treatment is the scarcity of transplant ready beta cells. Increasing the amount of functional beta cells will lead to increased insulin production and better management or a possible treatment strategy for the disease. Various genes have been defined that can induce beta cell replication. A major caveat of these findings, however, is that these factors induce replication in young beta cells and not aged beta cells. Given that the majority of beta cells that will be used for transplant will come from aged donors, it is imperative to understand why aged beta cells are refractory to these proliferative mechanisms. We aimed to determine why aged beta cells do not replicate as well as young beta cells. We hypothesized that one reason for why aged beta cells are refractory to genes that induce proliferation is greater expression of cell cycle inhibitors. The cell cycle is tightly regulated by cyclin‐dependent kinases. Cells also produce proteins known as cyclin‐dependent kinase inhibitors(CDKI's), which bind to cyclin dependent kinases, effectively shutting down cell proliferation. Here we demonstrate the expression of the INK4 and Cip/Kip family of CDKI's by mRNA, protein and histological expression in 5 week old and 5 month old primary rat beta cells. These results begin to define the functional changes that result in the inability of aged beta cells to replicate.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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