| First Author | Jung Y | Year | 2018 |
| Journal | Endocrinology | Volume | 159 |
| Issue | 2 | Pages | 869-882 |
| PubMed ID | 29220426 | Mgi Jnum | J:258318 |
| Mgi Id | MGI:6111467 | Doi | 10.1210/en.2017-00663 |
| Citation | Jung Y, et al. (2018) Isl1beta Overexpression With Key beta Cell Transcription Factors Enhances Glucose-Responsive Hepatic Insulin Production and Secretion. Endocrinology 159(2):869-882 |
| abstractText | Adenoviral gene transfer of key beta cell developmental regulators including Pdx1, Neurod1, and Mafa (PDA) has been reported to generate insulin-producing cells in the liver. However, PDA insulin secretion is transient and glucose unresponsive. Here, we report that an additional beta cell developmental regulator, insulin gene enhancer binding protein splicing variant (Isl1beta), improved insulin production and glucose-responsive secretion in PDA mice. Microarray gene expression analysis suggested that adenoviral PDA transfer required an additional element for mature beta cell generation, such as Isl1 and Elf3 in the liver. In vitro promoter analysis indicated that splicing variant Isl1, or Isl1beta, is an important factor for transcriptional activity of the insulin gene. In vivo bioluminescence monitoring using insulin promoter-luciferase transgenic mice verified that adenoviral PDA + Isl1beta transfer produced highly intense luminescence from the liver, which peaked at day 7 and persisted for more than 10 days. Using insulin promoter-GFP transgenic mice, we further confirmed that Isl1beta supplementation to PDA augmented insulin-producing cells in the liver, insulin production and secretion, and beta cellrelated genes. Finally, the PDA + Isl1beta combination ameliorated hyperglycemia in diabetic mice for 28 days and enhanced glucose tolerance and responsiveness. Thus, our results suggest that Isl1beta is a key additional transcriptional factor for advancing the generation of insulin-producing cells in the liver in combination with PDA. |
