TY - JOUR
T1 - E4orf1
T2 - A protein for enhancing glucose uptake despite impaired proximal insulin signaling
AU - Shastri, Anuradha A.
AU - Hegde, Vijay
AU - Peddibhotla, Swetha
AU - Feizy, Zahra
AU - Dhurandhar, Nikhil V.
N1 - Publisher Copyright:
Copyright: © 2018 Shastri et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2018/12
Y1 - 2018/12
N2 - Background Type 2 diabetes is often linked with impaired proximal insulin signaling. Hence, a therapeutic agent that enhances cellular glucose uptake without requiring proximal insulin signaling would be desirable for improving glycemic control. The E4orf1 peptide (E4) derived from human adenovirus 36 (Ad36) promotes cellular glucose uptake in vitro and in vivo, independent of insulin. E4 bypasses a part of insulin signaling to upregulate cellular glucose uptake. We tested the hypothesis that E4 requires the distal but not proximal insulin signaling to enhance cellular glucose disposal. Methods 3T3-L1 preadipocytes inducibly expressing E4 or a null vector (NV) were treated with inhibitor of insulin receptor (S961), inhibitor of insulin like growth factor-1receptor (IGF-1R) (Picropodophyllin, PPP), PPP+S961, or phosphatidyl inositol-3 kinase (PI3K) inhibitor (Wortmannin, WM). We used PPP and S961 to block the proximal insulin signaling, or WM to block the distal insulin signaling. Cells were exposed to 0 or 100nM insulin. Results As expected, when the proximal or distal insulin signaling was blocked in NV cells, insulin could not enhance pAKT protein abundance, Glut4 translocation, or glucose uptake. Whereas, E4 cells significantly increased pAKT abundance, Glut4 translocation and glucose uptake independent of the presence of insulin or proximal insulin signaling. Enhanced glucose disposal in E4 cells was completely abrogated when the distal insulin signaling was blocked. Conclusions E4 bypasses the proximal insulin signaling but uses the distal insulin signaling to activate pAkt and in turn Glut4 translocation to improve cellular glucose uptake. E4 offers a promising template to improve glycemic control when the proximal insulin signaling is impaired.
AB - Background Type 2 diabetes is often linked with impaired proximal insulin signaling. Hence, a therapeutic agent that enhances cellular glucose uptake without requiring proximal insulin signaling would be desirable for improving glycemic control. The E4orf1 peptide (E4) derived from human adenovirus 36 (Ad36) promotes cellular glucose uptake in vitro and in vivo, independent of insulin. E4 bypasses a part of insulin signaling to upregulate cellular glucose uptake. We tested the hypothesis that E4 requires the distal but not proximal insulin signaling to enhance cellular glucose disposal. Methods 3T3-L1 preadipocytes inducibly expressing E4 or a null vector (NV) were treated with inhibitor of insulin receptor (S961), inhibitor of insulin like growth factor-1receptor (IGF-1R) (Picropodophyllin, PPP), PPP+S961, or phosphatidyl inositol-3 kinase (PI3K) inhibitor (Wortmannin, WM). We used PPP and S961 to block the proximal insulin signaling, or WM to block the distal insulin signaling. Cells were exposed to 0 or 100nM insulin. Results As expected, when the proximal or distal insulin signaling was blocked in NV cells, insulin could not enhance pAKT protein abundance, Glut4 translocation, or glucose uptake. Whereas, E4 cells significantly increased pAKT abundance, Glut4 translocation and glucose uptake independent of the presence of insulin or proximal insulin signaling. Enhanced glucose disposal in E4 cells was completely abrogated when the distal insulin signaling was blocked. Conclusions E4 bypasses the proximal insulin signaling but uses the distal insulin signaling to activate pAkt and in turn Glut4 translocation to improve cellular glucose uptake. E4 offers a promising template to improve glycemic control when the proximal insulin signaling is impaired.
UR - http://www.scopus.com/inward/record.url?scp=85057994122&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0208427
DO - 10.1371/journal.pone.0208427
M3 - Article
C2 - 30521580
AN - SCOPUS:85057994122
SN - 1932-6203
VL - 13
JO - PloS one
JF - PloS one
IS - 12
M1 - e0208427
ER -