Isl1β Overexpression With Key β Cell Transcription Factors Enhances Glucose-Responsive Hepatic Insulin Production and Secretion
Autor: | Satoru Takahashi, Margarete M. S. Heck, Jeffrey K Usui, Hisashi Oishi, Yunshin Jung, Ruyi Zhou, Toshiki Kato, Masafumi Muratani |
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Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Male medicine.medical_specialty Maf Transcription Factors Large Transgene medicine.medical_treatment education LIM-Homeodomain Proteins Mice Transgenic 03 medical and health sciences Mice Endocrinology Downregulation and upregulation Enhancer binding Internal medicine Insulin-Secreting Cells Insulin Secretion medicine Basic Helix-Loop-Helix Transcription Factors Animals Insulin Regulation of gene expression Homeodomain Proteins Mice Inbred ICR Chemistry Cell biology Up-Regulation 030104 developmental biology Glucose Gene Expression Regulation Liver Hyperglycemia NEUROD1 ISL1 Trans-Activators PDX1 Female Transcription Factors |
Zdroj: | Endocrinology. 159(2) |
ISSN: | 1945-7170 |
Popis: | Adenoviral gene transfer of key β 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 β cell developmental regulator, insulin gene enhancer binding protein splicing variant (Isl1β), 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 β cell generation, such as Isl1 and Elf3 in the liver. In vitro promoter analysis indicated that splicing variant Isl1, or Isl1β, 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 + 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 mice, we further confirmed that Isl1β supplementation to PDA augmented insulin-producing cells in the liver, insulin production and secretion, and β cell‒related genes. Finally, the 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 the liver in combination with PDA. |
Databáze: | OpenAIRE |
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