A commonality between type 1 and type 2 diabetes is the decline in functional β-cell mass. The transcription factor Nkx6.1 regulates β-cell development and is integral for proper β-cell function. We have previously demonstrated that Nkx6.1 depends on c-Fos mediated upregulation and the nuclear hormone receptors Nr4a1 and Nr4a3 to increase β-cell insulin secretion, survival, and replication. Here, we demonstrate that Nkx6.1 overexpression results in upregulation of the bZip transcription factor CEBPA and that CEBPA expression is independent of c-Fos regulation. In turn, CEBPA overexpression is sufficient to enhance INS-1 832/13 β-cell and primary rat islet proliferation. CEBPA overexpression also increases the survival of β-cells treated with thapsigargin. We demonstrate that increased survival in response to ER stress corresponds with changes in expression of various genes involved in the unfolded protein response, including decreased Ire1a expression. These data show that CEBPA is sufficient to enhance functional β-cell mass by increasing β-cell proliferation and modulating the unfolded protein response.
Keywords: CEBPA; ER Stress; Ire1a; Nkx6.1; Nr4a3; UPR; beta cell; cell death; cell proliferation.