@article{
author = "Vujičić, Milica and Senerovic, Lidija and Nikolić, Ivana and Saksida, Tamara and Stošić-Grujičić, Stanislava and Stojanović, Ivana D.",
year = "2014",
abstract = "Macrophage migration inhibitory factor (MIF) is a molecule with plethora
of functions such as regulation of immune response, hormone-like,
enzymatic and chaperone-like activity. Further, MIF is a major
participant in glucose homeostasis since it is an autocrine stimulator
of insulin secretion. MIF absence in male knockout mice (MW-MO) results
in development of glucose intolerance, while sensitivity to insulin is
fully preserved. Since our results confirm that beta cells from MIF-KO
mice express, produce and secrete insulin similarly to beta cells of
their wild type (WT) counterparts C57BL/6 mice, we hypothesize that
MIF-KO-derived insulin is less active. Indeed, insulin from MIF-KO
islets is unable to significantly induce glucose uptake into hepatocytes
and to efficiently promote insulin-triggered Akt phosphorylation
determined by immunoblot. However, MIF's tautomerase function is not
crucial for insulin biosynthesis since MIF inhibitors had no impact on
WT insulin activity. Importantly, MIF recognition by anti-MIF anti-body
(ELISA) after in vitro co-incubation with purified insulin was
significantly lower suggesting that insulin covers MIF immunodominant
epitope. In addition, MIF binds insulin within beta cell as confirmed by
co-immunoprecipitation. WT and MIF-KO-derived insulin exhibited
different cleavage patterns suggesting different protein conformations.
Finally, pre-incubation of recombinant MIF with insulin promotes
formation of insulin hexamers. These results imply that MIF probably
enables proper insulin folding what results in insulin full activity.
This newly discovered feature of the cytokine MIF could be potentially
important for commercially produced insulin, for increasing its
stability and/or bioavailability. (C) 2014 Elsevier Ltd. All rights
reserved.",
journal = "Cytokine",
title = "The critical role of macrophage migration inhibitory factor in insulin
activity",
number = "1",
volume = "69",
doi = "10.1016/j.cyto.2014.05.013",
pages = "39-46"
}
