Isl1β over-expression with key β cell transcription factors enhances glucose-responsive hepatic insulin production and secretion.
Endocrinology. 2017 Dec 06;:
Authors: Jung Y, Zhou R, Kato T, Usui JK, Muratani M, Oishi H, Heck MMS, Takahashi S
Abstract
Adenoviral gene transfer of key β cell developmental regulators including Pdx1, Neurod1 and Mafa (PDA) has been reported to generate insulin-producing cells in liver. However, PDA insulin secretion is transient and glucose unresponsive. Here, we report that an additional β cell developmental regulator, insulin gene enhancer binding protein splicing variant (Isl1β), improved insulin production and glucose-responsive secretion in PDA mouse. Microarray gene expression analysis suggested that adenoviral PDA transfer required an additional element for mature β cell generation, such as Isl1 and Elf3 in liver. In vitro promoter analysis indicated that splicing variant Isl1, Isl1β, is an important factor for transcriptional activity of insulin gene. In vivo bioluminescence monitoring using insulin promoter-luciferase transgenic (MIP-Luc-VU) mice verified that adenoviral PDA-Isl1β 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 (MIP-GFP) mice, we further confirmed that Isl1β supplementation to PDA augmented insulin-producing cells in liver, insulin production and secretion, and β cell related genes. Finally, PDA-Isl1β combination ameliorated hyperglycemia in diabetic mice for 28 days and enhanced glucose tolerance and responsiveness. Thus, our results suggest that Isl1β is a key additional transcriptional factor for advancing the generation of insulin producing cells in liver in combination with PDA.
PMID: 29220426 [PubMed - as supplied by publisher]
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