Both major forms of diabetes are characterized by a decrease in functional β-cell mass. Type 1 diabetes is caused by autoimmune destruction of pancreatic β-cells, whereas type 2 diabetes involves the combined loss of glucose-stimulated insulin secretion (GSIS) and a decrease of β-cell mass by nonautoimmune mechanisms.  Finding mechanisms that will increase functional islet β-cell mass by enhancing islet β-cell proliferation, survival, and function is the major goal of my research group.

In collaboration with Dr. Christopher Newgard, the Director of the Duke Molecular Physiology Institute, we have demonstrated that two homeodomain transcription factors involved in islet β-cell development, Pdx-1 and Nkx6.1, are able to induce robust increases in islet-cell proliferation when overexpressed in adult rodent islets. Overexpression of Nkx6.1 stimulates mainly β-cell proliferation, whereas Pdx-1 stimulates both α-cell and β-cell proliferation (1,2). Combined overexpression of Pdx-1 and Nkx6.1 led to an additive effect on islet-cell proliferation suggesting that Pdx-1 and Nkx6.1 have discrete activating mechanisms (2). Consistent with this observation, we demonstrated that overexpression of Pdx-1 and Nkx6.1 activate different cell cycle control genes (2,3). Overexpression of Pdx-1 upregulates expression of cyclins D1 and D2 and inhibition of cyclin D activation using a cdk4 inhibitor blocks Pdx-1-stimulated proliferation completely, but does not affect Nkx6.1 stimulated islet cell proliferation. Further investigation of the Nkx6.1 pathway revealed that the Nkx6.1 proliferative response is dependent on upregulation of the orphan nuclear receptors Nr4a1 and Nr4a3. The Nr4a factors in turn activate expression of key positive cell cycle regulators (cyclin E1 and E2F) while also causing degradation of the cell cycle repressor protein, p21, via activation of elements of the anaphase promoting complex (3).

We also investigated the functional impact overexpression of these transcription factors has. Overexpression of Pdx-1 maintains glucose-stimulated insulin secretion (GSIS), while overexpression of Nkx6.1 actually enhances GSIS. This distinguishes these two transcription factors among the reagents that are capable of increasing β-cell proliferation. In most cases induction of β-cell proliferation causes a loss of function such as insulin content or GSIS. The potentiation of GSIS by Nkx6.1 is mediated by a prohormone, VGF, and one of its processed peptides, TLQP-21 (4). TLQP-21 has a second positive effect on β-cell   function in that it protects β-cells from apoptotic cell death (4). 

We continue to explore the mechanisms by which Pdx-1, Nkx6.1, and their target genes increase β-cell proliferation, enhance β-cell function, and protect against β-cell stressors with the goal of discovering target genes that can be developed for the treatment of diabetes.

We conducted a screen of small molecules that engage with the Nkx6.1 signaling pathway(s) and identified two compounds that replicate the effects of Nkx6.1 to enhance islet cell proliferation and GSIS (5).  Importantly these effects were observed in human as well as rodent islets.  Current studies are focused on understanding the mechanism(s) of action of these compounds, and on developing chemical variants of the index molecules with more attractive pharmacokinetic properties for in vivo studies.  

Integrated Islet distribution program

Attie Lab diabetes database  

www.betacell.org