Benjamin Bitner, Jason Ray, Kyle Kener, and Brent Wright, Brigham Young University
Life Sciences
β-cell mass is lost in both major forms of diabetes. Mature β-cell 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. Without functional β-cells, the body is unable to reduce elevated blood glucose, which results in hyperglycemia induced maladies. Enhanaced GSIS 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. 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. Finally, preliminary data suggest that c-Fos modulates GSIS as demonstrated in INS-1 β-cell line, stable INS-1 knockdown cells transduced with lenti-sh-c-Fos and in primary islets. We present a model by which c-Fos is necessary for Nkx6.1 mediated enhanced GSIS by inducing expression of VGF.