Dokument

Summary:
IL-1β induces a profound and long-lasting hypoglycemia in C57BL/6J mice (wild type, WT) and resets glucose homeostasis at central levels. Intracerebroventricular (i.c.v.) injection of IL-1 at a dose that has no effect when injected intraperitoneally (i.p.), induces hypoglycemia, even after a glucose load. Interestingly, IL-1 also increases corticosterone plasma levels, although this effect is of shorter duration than hypoglycemia. Myeloid-differentiation factor 88 (MyD88) is a central adaptor molecule involved in IL-1 signalling, but MyD88-independent IL-1-signalling pathways have also been described. The first part of this work investigated if IL-1β-induced hypoglycemia and the increase in glucocorticoid levels are MyD88-dependent by using two approaches: a) administration of IL-1β into MyD88 knockout (MyD88KO) mice; and b) pharmacological inhibition of MyD88 in WT mice prior to IL-1β injection. No changes in glucose and corticosterone blood levels were detected in MyD88KO mice after IL-1β injection as compared to WT mice. Administration of the MyD88 inhibitor to WT mice did not abolish the hypoglycaemic effect of IL-1. Since the inhibitor did not affect IL-1-induced IL-6 production either, it is possible that the concentration used was insufficient. However, a short-lasting hyperglycaemia was observed when the inhibitor was injected alone to WT mice. Particularly the results obtained in MyD88KO mice show that IL-1β-induced hypoglycemia and the increase in corticosterone concentrations depend on this adaptor molecule. The second part of this thesis studied cerebral energy metabolism during IL-1β-induced hypoglycemia, and compared it to the effects of a similar hypoglycemia induced by insulin, and to euglycaemic conditions. In vivo cerebral H1-magnetic resonance spectroscopy (MRS) was used for this purpose. It was found that, as opposite to insulin, the concentrations of lactate, creatine, and N-acetyl aspartate, in relation to those of choline, are increased during IL-1β-induced hypoglycemia. These results provide further evidence that IL-1β injected peripherally influences cerebral energy metabolism in parallel to a long-lasting and profound hypoglycemia. Besides its relevance for normal physiology, these results might beimportant during psychiatric diseases during which impairments of cerebral energymetabolism are observed, but also several immune-derived cytokines are involved.

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