The critical role of macrophage migration inhibitory factor in insulin activity
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2014
Authors
Vujicić, MilicaŠenerović, Lidija
Nikolić, Ivana
Saksida, Tamara
Stošić-Grujičić, Stanislava
Stojanović, Ivana
Article (Published version)
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Show full item recordAbstract
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. Importantl...y, 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.
Keywords:
Macrophage migration inhibitory factor / Insulin / Insulin synthesis / Insulin activitySource:
Cytokine, 2014, 69, 1, 39-46Publisher:
- Academic Press Ltd- Elsevier Science Ltd, London
Funding / projects:
- Molecular mechanisms of physiological and pharmacological control of inflammation and cancer (RS-MESTD-Basic Research (BR or ON)-173013)
- Microbial diversity study and characterization of beneficial environmental microorganisms (RS-MESTD-Basic Research (BR or ON)-173048)
DOI: 10.1016/j.cyto.2014.05.013
ISSN: 1043-4666
PubMed: 25022960
WoS: 000340316700007
Scopus: 2-s2.0-84901770846
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Institut za molekularnu genetiku i genetičko inženjerstvoTY - JOUR AU - Vujicić, Milica AU - Šenerović, Lidija AU - Nikolić, Ivana AU - Saksida, Tamara AU - Stošić-Grujičić, Stanislava AU - Stojanović, Ivana PY - 2014 UR - https://imagine.imgge.bg.ac.rs/handle/123456789/717 AB - 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. PB - Academic Press Ltd- Elsevier Science Ltd, London T2 - Cytokine T1 - The critical role of macrophage migration inhibitory factor in insulin activity EP - 46 IS - 1 SP - 39 VL - 69 DO - 10.1016/j.cyto.2014.05.013 ER -
@article{ author = "Vujicić, Milica and Šenerović, Lidija and Nikolić, Ivana and Saksida, Tamara and Stošić-Grujičić, Stanislava and Stojanović, Ivana", 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.", publisher = "Academic Press Ltd- Elsevier Science Ltd, London", journal = "Cytokine", title = "The critical role of macrophage migration inhibitory factor in insulin activity", pages = "46-39", number = "1", volume = "69", doi = "10.1016/j.cyto.2014.05.013" }
Vujicić, M., Šenerović, L., Nikolić, I., Saksida, T., Stošić-Grujičić, S.,& Stojanović, I.. (2014). The critical role of macrophage migration inhibitory factor in insulin activity. in Cytokine Academic Press Ltd- Elsevier Science Ltd, London., 69(1), 39-46. https://doi.org/10.1016/j.cyto.2014.05.013
Vujicić M, Šenerović L, Nikolić I, Saksida T, Stošić-Grujičić S, Stojanović I. The critical role of macrophage migration inhibitory factor in insulin activity. in Cytokine. 2014;69(1):39-46. doi:10.1016/j.cyto.2014.05.013 .
Vujicić, Milica, Šenerović, Lidija, Nikolić, Ivana, Saksida, Tamara, Stošić-Grujičić, Stanislava, Stojanović, Ivana, "The critical role of macrophage migration inhibitory factor in insulin activity" in Cytokine, 69, no. 1 (2014):39-46, https://doi.org/10.1016/j.cyto.2014.05.013 . .