The role of endogenous glucocorticoids in glucose metabolism and immune status of MIF-deficient mice

Ivana Nikolic, Milica Vujicic, Tamara Saksida, Timea Berki, Stanislava Stosic-Grujicic, Ivana Stojanovic

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12 Citations (Scopus)

Abstract

Macrophage migration inhibitory factor (MIF)-deficient mice develop glucose intolerance and hypergly-cemia, 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.

Original languageEnglish
Pages (from-to)498-506
Number of pages9
JournalEuropean Journal of Pharmacology
Volume714
Issue number1-3
DOIs
Publication statusPublished - Jan 1 2013

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Keywords

  • Diabetes
  • Glucocorticoids
  • Inflammation
  • Insulin
  • Macrophage migration inhibitory factor

ASJC Scopus subject areas

  • Pharmacology

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