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Characterization of viral insulins reveals white adipose tissue-specific effects
in mice.
Authors Chrudinová M, Moreau F, Noh HL, Páníková T, Žáková L, Friedline RH, Valenzuela
FA, Kim JK, Jirácek J, Kahn CR, Altindis E
Submitted By Submitted Externally on 2/22/2021
Status Published
Journal Molecular metabolism
Year 2021
Date Published 2/1/2021
Volume : Pages 44 : 101121
PubMed Reference 33220491
Abstract Members of the insulin/insulin-like growth factor (IGF) superfamily are well
conserved across the evolutionary tree. We recently showed that four viruses in
the Iridoviridae family possess genes that encode proteins highly homologous to
human insulin/IGF-1. Using chemically synthesized single-chain (sc), i.e.,
IGF-1-like, forms of the viral insulin/IGF-1-like peptides (VILPs), we
previously showed that they can stimulate human receptors. Because these
peptides possess potential cleavage sites to form double chain (dc), i.e., more
insulin-like, VILPs, in this study, we have characterized dc forms of VILPs for
Grouper iridovirus (GIV), Singapore grouper iridovirus (SGIV) and Lymphocystis
disease virus-1 (LCDV-1) for the first time., The dcVILPs were chemically
synthesized. Using murine fibroblast cell lines overexpressing insulin receptor
(IR-A or IR-B) or IGF1R, we first determined the binding affinity of dcVILPs to
the receptors and characterized post-receptor signaling. Further, we used
C57BL/6J mice to study the effect of dcVILPs on lowering blood glucose. We
designed a 3-h dcVILP in vivo infusion experiment to determine the glucose
uptake in different tissues., GIV and SGIV dcVILPs bind to both isoforms of
human insulin receptor (IR-A and IR-B) and to the IGF1R, and for the latter,
show higher affinity than human insulin. These dcVILPs stimulate IR and IGF1R
phosphorylation and post-receptor signaling in vitro and in vivo. Both GIV and
SGIV dcVILPs stimulate glucose uptake in mice. In vivo infusion experiments
revealed that while insulin (0.015 nmol/kg/min) and GIV dcVILP
(0.75 nmol/kg/min) stimulated a comparable glucose uptake in heart and skeletal
muscle and brown adipose tissue, GIV dcVILP stimulated 2-fold higher glucose
uptake in white adipose tissue (WAT) compared to insulin. This was associated
with increased Akt phosphorylation and glucose transporter type 4 (GLUT4) gene
expression compared to insulin in WAT., Our results show that GIV and SGIV
dcVILPs are active members of the insulin superfamily with unique
characteristics. Elucidating the mechanism of tissue specificity for GIV dcVILP
will help us to better understand insulin action, design new analogs that
specifically target the tissues and provide new insights into their potential
role in disease.


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