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

Abstract

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 beta-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.

Glucose Kinetics in the Collagen-Induced Arthritis Model: An All-in-One Model to Assess Both Efficacy and Metabolic Side Effects of Glucocorticoids

“…Regarding GC-induced insulin resistance in mice, many conflicting results have been reported [27], [31]–[38]. Also the results described in this paper show discrepancies in results when compared to previously reported studies.…”

“…Also the results described in this paper show discrepancies in results when compared to previously reported studies. For instance, we report a minimal decrease in glucose levels after treatment with prednisolone whereas other studies reported an increase of glucose levels after treatment with glucocorticoids [27], [31]–[34]. One reason explaining (at least partly) these differences in results is that different strains of mice were used.…”

“…However, seen from the perspective of laboratory animal welfare, performing such clamp studies within an inflammatory mouse model such as the CIA model is impossible. Measuring glucose kinetics by modeling the wash-out of ip injected D-[6,6- 2 H 2 ]-glucose is performed under fasted conditions whereas the HIEC utilizes steady-state insulin concentrations that are supraphysiological [13], [27], [28]. Thus, the wash-out of ip-injected glucose presumably reflects a more physiological relevant situation.…”

Lactose maldigestion during methotrexate-induced gastrointestinal mucositis in a rat model

“…The calculations for blood glucose kinetics were described recently by Van Dijk (34) and Laskewitz (18). In short, a single-pool, first-order kinetic model was assumed for this test.…”

Thiobenzothiazole-modified Hydrocortisones Display Anti-inflammatory Activity with Reduced Impact on Islet β-Cell Function

“…Excess GCs in circulation, such as occurs during Cushing disease or chronic GC therapy, promote both visceral fat deposition and hepatic insulin resistance (45,46). An increase in hepatic insulin resistance contributes to hyperglycemia in mouse models and in human subjects (47,48). Therefore, we examined expression of the Pck1 (Pepck) gene, one of the rate-controlling enzymes of hepatic glucose production, which is known to be regulated by glucocorticoids (49,50).…”