Chronic Prednisolone Treatment Reduces Hepatic Insulin Sensitivity while Perturbing the Fed-to-Fasting Transition in Mice

• Published in: Endocrinology (Philadelphia) 2010-05, Vol.151 (5), p.2171-2178
• Main Authors: Laskewitz, Anke J, van Dijk, Theo H, Bloks, Vincent W, Reijngoud, Dirk-Jan, van Lierop, Marie-José, Dokter, Wim H, Kuipers, Folkert, Groen, Albert K, Grefhorst, Aldo
• Format: Article
• Language: English
• Subjects: Algorithms; Animals; Blood; Blood glucose; Blood Glucose - metabolism; Eating - physiology; Energy metabolism; Energy Metabolism - drug effects; Fasting; Fasting - blood; Fasting - physiology; Fibroblast Growth Factors - genetics; Gene Expression - drug effects; Glucocorticoids; Glucocorticoids - pharmacology; Glucose; Glucose - metabolism; Glucose - pharmacokinetics; Glucose Clamp Technique; Growth factors; Hyperglycemia; Inflammatory diseases; Insulin; Insulin - blood; Insulin Resistance; Kinetics; Liver - drug effects; Liver - metabolism; Liver diseases; Male; Metabolism; Mice; Mice, Inbred C57BL; Phenotypes; Plasma; PPAR alpha - genetics; Prednisolone; Prednisolone - pharmacology; Sensitivity; Side effects; Tissue Distribution - drug effects
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2009-1374

Chronic glucocorticoid use for treatment of inflammatory diseases is accompanied by severe side effects in humans (e.g. hyperglycemia and insulin resistance). The present studies were conducted to characterize consequences of chronic treatment with the synthetic glucocorticoid prednisolone on insulin sensitivity and blood glucose kinetics in mice. Prednisolone treatment increased fasting blood glucose and plasma insulin concentrations, but this apparently reduced insulin sensitivity could not be confirmed in hyperinsulinemic euglycemic clamp studies. Therefore, a novel method to study whole body glucose kinetics was used. This method revealed that prednisolone-treated mice show an increased hepatic glucose production (HGP). The increased HGP was accompanied by elevated plasma insulin concentrations, indicating reduced insulin sensitivity of hepatic glucose metabolism in prednisolone-treated mice. Compared with vehicle, prednisolone-treated mice had lower blood glucose concentrations, higher plasma free fatty acids, and higher plasma fibroblast growth factor-21 concentrations in the fed condition, i.e. mimicking a fasting situation. Next, the effects of 24-h fasting on energy metabolism were studied. Compared with controls, fasted prednisolone-treated mice had higher blood glucose concentrations and lower plasma β-hydroxybutyrate concentrations. In conclusion, these results indicate that chronic prednisolone treatment reduces insulin sensitivity of HGP, induces a fasting-like phenotype in fed mice, and perturbs the fed-to-fasting transition. Chronic prednisolone treatment in mice reduces insulin sensitivity of hepatic glucose production, induces a fasting-like phenotype in fed mice, and perturbs the fed-to-fasting transition.