Characterization of Viral Insulin-Like Peptides Reveals Unique White Adipose Tissue Specific Characteristics

The members of the insulin superfamily are well conserved across the evolution tree. We recently showed that four viruses in the Iridoviridae family possess genes that share high similarity with human insulin and IGF-1. By chemically synthesizing single chain (sc, IGF-1 like) forms of these viral insulin/IGF-1 like peptides (VILPs), we previously showed that sc VILPs have insulin/IGF properties in vitro and in vivo. However, characteristics of double chain (dc, insulin-like) VILPs remain unknown. In this study, we characterized dc forms of VILPs for Grouper iridovirus (GIV), Singapore grouper iridovirus (SGIV) and Lymphocystis disease virus-1 (LCDV-1). We showed that GIV and SGIV dcVILPs bind to both isoforms of human insulin receptor (IR-A, IR-B) and they bind to IGF-1R with a higher affinity than human insulin. These dcVILPs stimulate receptor phosphorylation and post-receptor signaling in vitro and in vivo. LCDV-1 dcVILP stimulated a weak response in in vitro signaling experiments, although we could not determine binding competition. Both GIV and SGIV dcVILPs stimulated glucose uptake in mice. In vivo infusion experiments in awake mice revealed that while insulin (2.5 mU/kg/min) and GIV dcVILP (125 mU/kg/min) stimulate a comparable glucose uptake in heart, skeletal muscle and brown adipose tissue, GIV dcVILP stimulates ~2 fold higher glucose uptake in white adipose tissue (WAT) compared to insulin. This is due to increased Akt phosphorylation and glucose transporter type 4 (GLUT4) expression compared to insulin specifically in WAT. Taken together, these results show that dc GIV and SGIV dcVILPs are active members of the insulin superfamily with unique characteristics. This observation evokes questions about their potential roles in human disease including diabetes and cancer. Elucidating the mechanism of tissue specificity for GIV dcVILP will help us to better understand insulin action and design new analogues that specifically target the tissues.