Insulin-sparing and fungible effects of E4orf1 combined with an adipocyte-targeting sequence in mouse models of type 1 and type 2 diabetes

Obesity impairs glycemic control and causes insulin resistance and type 2 diabetes. Adenovirus 36 (Ad36) infection can increase the uptake of excess glucose from blood into adipocytes by increasing GLUT4 translocation through the Ras–Akt signaling pathway, which bypasses PI3K–Akt-mediated insulin re...

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Veröffentlicht in:International Journal of Obesity 2017-10, Vol.41 (10), p.1601-1605
Hauptverfasser: Yoon, I-S, Park, S, Kim, R-H, Ko, H L, Nam, J-H
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Sprache:eng
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Zusammenfassung:Obesity impairs glycemic control and causes insulin resistance and type 2 diabetes. Adenovirus 36 (Ad36) infection can increase the uptake of excess glucose from blood into adipocytes by increasing GLUT4 translocation through the Ras–Akt signaling pathway, which bypasses PI3K–Akt-mediated insulin receptor signaling. E4orf1 , a viral gene expressed early during Ad36 infection, is responsible for this insulin-sparing effect and may be an alternative target for improving insulin resistance. To deliver the gene to adipocytes only, we connected the adipocyte-targeting sequence ( ATS ) to the 5′ end of E4orf1 ( ATS–E4orf1 ). In vitro transfection of ATS–E4orf1 into preadipocytes activated factors for GLUT4 translocation and adipogenesis to the same extent as did Hemagglutinin ( HA)-E4orf1 transfection as positive reference. Moreover, the Transwell migration assay also showed that ATS–E4orf1 secreted by liver cells activated Akt in preadipocytes. We used a hydrodynamic gene delivery technique to deliver ATS–E4orf1 into high-fat diet-fed and streptozotocin-injected mice (disease models of type 2 and type 1 diabetes, respectively). ATS–E4orf1 improved the ability to eliminate excess glucose from the blood and ameliorated liver function in both disease models. These findings suggest that ATS–E4orf1 has insulin-sparing and fungible effects in type 2 and 1 diabetes independent of the presence of insulin.
ISSN:0307-0565
1476-5497
DOI:10.1038/ijo.2017.142