Getting grip on glucocorticoid-induced metabolic derangements

PhD ceremony: Ms. A.J. Laskewitz, 16.15 uur, Aula Academiegebouw, Broerstraat 5, Groningen

Dissertation: Getting grip on glucocorticoid-induced metabolic derangements

Promotor(s): prof. F. Kuipers, prof. A.K. Groen

Faculty: Medical Sciences

Synthetic glucocorticoids, such as prednisolone, are potent anti-inflammatory agents which are widely prescribed for the treatment of chronic inflammatory diseases. Unfortunately, these drugs can elicit severe adverse effects, many of which resemble features of the metabolic syndrome such as hyperglycemia, insulin resistance and dyslipidemia. The work described in this thesis focused on the metabolic adverse effects of prednisolone treatment in mice and aimed to unravel the (molecular) mechanisms of these effects in appropriate mouse models using stable isotope methodologies.

A series of novel stable isotope methods to evaluate glucose metabolism in a fasted state were developed and applied in various groups of mice, all treated with vehicle or prednisolone. Surprisingly, in neither model a ‘classical insulin resistance’ could be detected, although the mice showed distinct metabolic derangements upon prednisolone treatment. In addition, a novel non-steroidal glucocorticoid receptor-selective compound was evaluated in these mouse models and was found to show less side effects. Finally, the origin of prednisolon-induced dyslipidemia was examined in mice with a dimerization-defective glucocorticoid receptor.

The in vivo studies described in this thesis provide in-depth analyses of the effects of glucocorticoids on glucose and lipid metabolism and on insulin sensitivity in mice and contribute to an improved understanding of glucocorticoid-induced side effects. They provide an important step in the recognition of the value of mouse models to evaluate glucocorticoid-related adverse effects.