Characterization of Viral Insulins Reveals White Adipose Tissue Specific Effects in Mice [preprint]
Authors
Chrudinová, MartinaMoreau, Francois
Noh, Hye Lim
Páníková, Terezie
Žáková, Lenka
Friedline, Randall H.
Valenzuela, Francisco A.
Kim, Jason K.
Jiracek, Jiri
Kahn, C. Ronald
Altindis, Emrah
UMass Chan Affiliations
Department of Medicine, Division of Endocrinology, Metabolism and DiabetesProgram in Molecular Medicine
Document Type
PreprintPublication Date
2020-08-22Keywords
Cell Biologyviral insulins
insulin
white adipose tissue
Cell Biology
Cellular and Molecular Physiology
Endocrinology
Endocrinology, Diabetes, and Metabolism
Hormones, Hormone Substitutes, and Hormone Antagonists
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Show full item recordAbstract
Members of the insulin/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). GIV and SGIV dcVILPs bind to both isoforms of human insulin receptor (IR-A, 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 in awake mice revealed that while insulin (0.015 nmol/kg/min) and GIV dcVILP (0.75nmol/kg/min) stimulated a comparable glucose uptake in heart, 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. Taken together, these 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 analogues that specifically target the tissues, and provide new insights into their potential role in disease.Source
bioRxiv 2020.08.21.261321; doi: https://doi.org/10.1101/2020.08.21.261321. Link to preprint on bioRxiv service.
DOI
10.1101/2020.08.21.261321Permanent Link to this Item
http://hdl.handle.net/20.500.14038/29549Related Resources
Now published in Molecular Metabolism doi: 10.1016/j.molmet.2020.101121 and also available in eScholarship@UMMS.
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The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It is made available under a CC-BY-NC-ND 4.0 International license.Distribution License
http://creativecommons.org/licenses/by-nc-nd/4.0/ae974a485f413a2113503eed53cd6c53
10.1101/2020.08.21.261321
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Except where otherwise noted, this item's license is described as The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It is made available under a CC-BY-NC-ND 4.0 International license.