C‐Fos increases functional β‐cell mass

Abstract

β‐cell mass is lost in both major forms of diabetes. Mature β‐cells have restricted proliferative capacity. Studies aimed at increasing β‐cell mass frequently have the unwanted side effects of decreased glucose stimulated insulin secretion (GSIS) or increased apoptotic rates. Understanding the molecular pathways that enhance β‐cell mass while maintaining or improving GSIS and the response to apoptotic stimuli could be used as a treatment for diabetes. Overexpression of the β‐cell transcription factor Nkx6.1 induces β‐cell proliferation, enhances GSIS and protects against apoptosis. Nkx6.1 induces expression of VGF, which is necessary for enhanced GSIS and apoptotic resistance. Nr4a1 and Nr4a3 are also induced in the Nkx6.1 molecular pathway, and are necessary for β‐cell proliferation. Microarray analysis of Nkx6.1 expressing primary rat islets demonstrates upregulation of c‐Fos at 24 and 48 hours after adenoviral transduction. We have shown that c‐Fos upregulates expression of VGF, Nr4a1 and Nr4a3. In addition c‐Fos is sufficient to induce β‐cell proliferation. Finally, preliminary data suggest that c‐Fos modulates GSIS and the β‐cell response to apoptotic insults. We present a model by which c‐Fos is necessary for Nkx6.1 mediated β‐cell proliferation, enhanced GSIS and protection from apoptosis by inducing expression of Nr4a1, Nr4a3 and VGF.