title: The role of endogenous glucocorticoids in glucose metabolism and immune status of MIF-deficient mice.
abstract: Macrophage migration inhibitory factor (MIF)-deficient mice develop glucose intolerance and hyperglycemia, but remain entirely responsive to exogenous insulin in adult age. Furthermore, as a consequence of MIF deficiency, the immune response in these mice is predominantly anti-inflammatory. Since MIF is a natural counter-regulator of glucocorticoid action, and it is known that excessive concentration of glucocorticoids contribute both to beta cell dysfunction and immunosuppression, we hypothesized that MIF absence enables elevation of glucocorticoids which in turn caused the observed condition. Our results confirm that MIF-knockout (MIF-KO) mice possess higher levels of circulating corticosterone, but lower expression of glucocorticoid receptor in pancreatic islets, liver and adipose tissue to the one observed in wild type (WT) mice. A significant up-regulation of glucocorticoid receptor expression was however noticed in MIF-deficient lymph node cells. The inhibition of glucocorticoid receptor by RU486 improved tolerance to glucose in MIF-KO mice and restored euglycemia. Although RU486 treatment did not alter the level of glucose receptor GLUT2, it enhanced insulin secretion and up-regulated insulin-triggered Akt phosphorylation within hepatic tissue. Finally, inhibition of glucocorticoid receptor changed anti-inflammatory phenotype of MIF-KO lymphocytes toward a physiological profile. Our results indicate that deregulated glucocorticoid secretion and glucocorticoid receptor expression in the absence of MIF possibly contributes to the development of glucose intolerance and immunosuppression in MIF-KO mice. However, since MIF-KO mice respond normally to insulin and their beta cell function is within physiological range, additional cause for glucose intolerance could be sought in the possible malfunction of their insulin.
authors.affiliation: Department of Immunology, Institute for Biological Research Sinisa Stankovic, University of Belgrade, Bulevar despota Stefana 142, 11108 Belgrade, Serbia.
authors.forename: Ivana
authors.initials: I
authors.lastname: Nikolic
authors.forename: Milica
authors.initials: M
authors.lastname: Vujicic
authors.forename: Tamara
authors.initials: T
authors.lastname: Saksida
authors.forename: Timea
authors.initials: T
authors.lastname: Berki
authors.forename: Stanislava
authors.initials: S
authors.lastname: Stosic-Grujicic
authors.forename: Ivana
authors.initials: I
authors.lastname: Stojanovic
mesh_terms: D000818:Animals; D003345:Corticosterone / Q000378:metabolism; D055786:Gene Knockout Techniques; D005938:Glucocorticoids / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D018149:Glucose Intolerance / Q000276:immunology / Q000378:metabolism; D007109:Immunity / Q000187:drug effects; D008263:Macrophage Migration-Inhibitory Factors / Q000172:deficiency* / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015735:Mifepristone / Q000494:pharmacology; D011965:Receptors, Glucocorticoid / Q000378:metabolism
chemical_list: D005938:Glucocorticoids; D008263:Macrophage Migration-Inhibitory Factors; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D005947:Glucose; D003345:Corticosterone
keywords: Diabetes; Glucocorticoids; Inflammation; Insulin; Macrophage migration inhibitory factor