Glucose kinetics in the collagen-induced arthritis model: an all-in-one model to assess both efficacy and metabolic side effects of glucocorticoids.

Erik J M Toonen,Ellen A J Bastiaanssen,Cindy Van Doorn,Aldo Grefhorst,Albert K Groen,Monique A J Van Der Vleuten,Anke J Laskewitz,Aycha Bleeker,Marije I Koenders,Wim H A Dokter,Marie-Jose C Van Lierop,Theo H Van Dijk,Annelies E Schouten,Dov B Ballak

doi:10.1371/journal.pone.0098684

Abstract

Prednisolone and other glucocorticoids (GCs) are potent anti-inflammatory drugs, but chronic use is hampered by metabolic side effects. Therefore, there is an urgent medical need for improved GCs that are as effective as classical GCs but have a better safety profile. A well-established model to assess anti-inflammatory efficacy is the chronic collagen-induced arthritis (CIA) model in mice, a model with features resembling rheumatoid arthritis. Models to quantify undesired effects of glucocorticoids on glucose kinetics are less well-established. Recently, we have described a model to quantify basal blood glucose kinetics using stably-labeled glucose. In the present study, we have integrated this blood glucose kinetic model in the CIA model to enable quantification of both efficacy and adverse effects in one animal model. Arthritis scores were decreased after treatment with prednisolone, confirming the anti-inflammatory properties of GCs. Both inflammation and prednisolone induced insulin resistance as insulin secretion was strongly increased whereas blood glucose concentrations and hepatic glucose production were only slightly decreased. This insulin resistance did not directly resulted in hyperglycemia, indicating a highly adaptive compensatory mechanism in these mice. In conclusion, this ‘all-in-one’ model allows for studying effects of (novel) GC compounds on the development of arthritis and glucose kinetics in a single animal. This integrative model provides a valuable tool for investigating (drug-induced) metabolic dysregulation in an inflammatory setting.

Highlights

Prednisolone and other glucocorticoids (GCs) are very potent immunosuppressive and anti-inflammatory compounds that are among the top 10 most prescribed drugs [1]
Very effective in reducing inflammation, prolonged treatment at medium or high dose of GCs is hampered by a wide range of metabolic side effects such as derangements of glucose metabolism, induction of insulin-resistance, beta-cell dysfunction, hyperlipidemia, fat redistribution and central obesity that are all strongly associated with elevated risk for cardiovascular disease and type 2 Diabetes mellitus in humans [3,4,5]
The mechanisms of action underlying these metabolic side effects are largely unknown. Seen this wide range of GC-induced side effects, there is a high medical need for improved anti-inflammatory drugs that are as effective as classical GCs but show less metabolic side effects

Summary

Introduction

Prednisolone and other glucocorticoids (GCs) are very potent immunosuppressive and anti-inflammatory compounds that are among the top 10 most prescribed drugs [1]. The mechanisms of action underlying these metabolic side effects are largely unknown. Seen this wide range of GC-induced side effects, there is a high medical need for improved anti-inflammatory drugs that are as effective as classical GCs but show less metabolic side effects. This type of experimental compounds are often referred to as selective GR modulators (SGRMs) [4]. Given the complexity of glucocorticoid actions, the use of animal models is required to investigate these mechanisms and several animal models have been applied to study the efficacy and/or

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