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

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.

Discovery of a highly potent glucocorticoid for asthma treatment

“…To test this hypothesis, we measured the major side effects (growth inhibition, insulin resistance and bone loss) of VSGC12 at a low dose in mouse models. We chose DBA/1 mice to do the side effects study based on the fact that not only the glucocorticoid-induced insulin resistance can be easily developed in this strain [ 36 ], but also the glucocorticoid caused bone loss is readily to be generated in this strain [ 37 ]. Judging from the lung function AHR data, the most critical data for asthma, the minimal dose to maximally repress (maximal effective dose) lung inflammation was 0.25 mg kg –1 for VSGC12, and 1 mg kg –1 for FF ( Figure 4e ).…”

“…Although VSGC12 at 0.25 mg kg –1 still caused insulin resistance, the resistance was much less severe than for FF, and at 0.0625 mg kg –1 , VSGC12 no longer induced insulin resistance ( Figure 5b ). Since glucocorticoid-induced insulin resistance is generally associated with an increase of endogenous insulin [ 36 ], we determined the plasma insulin level of mice treated with various doses of VSGC12 and FF. Consistent with the insulin-tolerance test data, 1 mg kg –1 FF caused a dramatic increase of the endogenous insulin level, while 0.25 mg kg –1 VSGC12 caused a moderate increase, and 0.0625 mg kg –1 VSGC12 did not significantly increase the endogenous insulin level ( Figure 5c ).…”

Clinical Efficacy of Adjuvant Treatment of Primary Nephrotic Syndrome in Pediatric Patients with Chinese Medicine

“…Hormone-resistant, hormone-dependent, and frequently relapsing nephropathies require treatment with hormones in combination with immunosuppressive drugs (e.g., cyclosporine A, tacrolimus, cyclophosphamide, tacrolimus, and rituximab) [ 5 – 7 ]. Long-term use of glucocorticoids also leads to an increased risk of adverse effects (e.g., osteoporosis, growth disorders, infections, and obesity) [ 8 ], and side effects such as nephrotoxicity, hypertension, and diabetes may occur with calcineurin inhibitors [ 9 ].…”

The art of quantifying glucose metabolism

“…Although highly informative, procedures are labor-intensive and multiple tests in individual mice cannot be performed. Therefore, we developed and published (12,19,22,23) an alternative method for this purpose, apparently unnoticed by Wang and colleagues (26).…”

“…Importantly, we use bloodspot sampling from the tail-tip on filter paper to reduce blood loss (total amount~120 l/mouse). Several studies applying this method have been published (12,19,22), showing its applicability even in frail mice ( 22) in which surgery is not possible. This method allows for repeated measures in individual animals and hence contributes to the societal quest to reduce numbers of experimental animals in biomedical research.…”