Effects of prednisolone on glucose kinetics after 21 days of treatment.

<p>(<b>A</b>) Blood glucose concentrations (<b>B</b>) MCR (<b>C</b>) EGP levels MCR (<b>D</b>) C-peptide concentrations (<b>E</b>) C-peptide HOMA-IR. Results represent means ± SD and are outlined for each experimental group (n = 12). * Significant difference p≤0.05, ** significant difference p≤0.01, *** significant difference p≤0.001, ^#significant difference (p≤0.05) when compared to the placebo-treated non-arthritic mice, NS  =  not significant.</p

Treatment parameters for both non-arthritic and arthritic mice treated with prednisolone for 21 days.

<p>Both non-arthritic and arthritic mice are treated with prednisolone (0, 1.5, 10 and 30 mg/kg/day) for 21 days. Each experimental group consists of 12 mice; in total 48 non-arthritic and 48 arthritic mice were included. Values represent means ± SD during the blood glucose kinetics test except BW, which is represented as means ± SD before the test.</p><p>* Significant difference (p≤0.05) when compared to the placebo-treated group of that same parameter.</p>#<p>Significant difference (p≤0.05) when compared to the placebo-treated non-arthritic mice.</p><p>Treatment parameters for both non-arthritic and arthritic mice treated with prednisolone for 21 days.</p

Treatment parameters for both non-arthritic and arthritic mice treated with placebo, prednisolone (10 mg/kg) or ORG 37663 (12 mg/kg) for 21 days.

<p>Both non-arthritic and arthritic mice are treated with placebo, prednisolone (10 mg/kg/day) or ORG 37663 (12 mg/kg/day) for 21 days. Each experimental group consists of 12 mice; in total 36 non-arthritic and 36 arthritic mice were included. Values represent means ± SD during the blood glucose kinetics test except BW, which is represented as means ± SD before the test.</p><p>* Significant difference (p≤0.05) when compared to the placebo-treated group of that same parameter.</p>#<p>Significant difference (p≤0.05) when compared to the placebo-treated non-arthritic mice.</p><p>Treatment parameters for both non-arthritic and arthritic mice treated with placebo, prednisolone (10 mg/kg) or ORG 37663 (12 mg/kg) for 21 days.</p

The formulas used to calculate the concentration <i>vs</i>. time curves and the kinetic parameters in a first order absorption process in an one-compartment model.

<p>C_t, D-[6,6-²H]-glucose concentration at time point t; M_t, fractional contribution of D-[6,6-²H]-glucose at time point t; [glc]_t, blood glucose concentration at time point t. C(0)^ab, initial concentration of D-[6,6-²H]-glucose determined by extrapolation of the absorption period; C(0)^el, initial concentration of D-[6,6-²H]-glucose determined by extrapolation of the elimination period; k^ab, absorption rate constant; k^el, absorption rate constant. D, dose D-[6,6-²H]-glucose administrated; BG, average blood glucose concentration during the test; Ra = EGP.</p><p>The formulas used to calculate the concentration <i>vs</i>. time curves and the kinetic parameters in a first order absorption process in an one-compartment model.</p

Effects of prednisolone on bodyweight, thymus weight and arthritis development after 21 days of treatment.

<p>(<b>A</b>) Bodyweight (<b>B</b>) thymus weight (<b>C</b>) AUC of the overall arthritis score (<b>D</b>) X-ray analysis to assess bone destruction. Results are represented as means ± SD for bodyweight and thymus weight and as mean ±SEM for AUC arthritis score and X-ray score and are outlined for each experimental group (n = 12). * Significant difference p≤0.05, ** significant difference p≤0.01, *** significant difference p≤0.001, NS  =  not significant.</p

Effects of ORG 37663 and prednisolone on glucose kinetics after 21 days of treatment.

<p>(<b>A</b>) Blood glucose concentrations (<b>B</b>) MCR (<b>C</b>) EGP levels (<b>D</b>) C-peptide concentrations (<b>E</b>) C-peptide HOMA-IR. Results represent means ± SD and are outlined for each experimental group (n = 12). * Significant difference p≤0.05, ** significant difference p≤0.01, *** significant difference p≤0.001, ^#significant difference (p≤0.05) when compared to the placebo-treated non-arthritic mice, NS  =  not significant.</p

Effects of ORG 37663 and prednisolone on bodyweight, thymus weight and arthritis development after 21 days of treatment.

<p>(<b>A</b>) Bodyweight (<b>B</b>) thymus weight (<b>C</b>) AUC of the overall arthritis score (<b>D</b>) X-ray analysis to assess bone destruction. Results are represented as means ± SD for bodyweight and thymus weight and as mean ±SEM for AUC arthritis score and X-ray score and are outlined for each experimental group (n = 12). * Significant difference p≤0.05, ** significant difference p≤0.01, *** significant difference p≤0.001, ^#significant difference (p≤0.05) when compared to the placebo-treated non-arthritic mice, NS  =  not significant.</p

Arthritis development.

<p>Arthritis development in mice subjected to blood glucose kinetics three times and in mice in which no experiments were performed. (<b>A</b>) AUC of the overall arthritis score, corrected for base line, after 21 days. (<b>B</b>) X-ray analysis to assess bone destruction. Results are presented as mean ± SEM (n = 20). No significant differences between the two groups was observed. NS  =  not significant.</p

Assessment of insulin sensitivity by the use of the insulin tolerance test (ITT).

<p>(<b>A</b>) AUC of the overall arthritis score, corrected for base line, after 21 days. (<b>B</b>) Blood glucose concentrations of non-arthritic and arthritic mice treated with prednisolone or vehicle. (<b>C</b>) Blood glucose values during the ITT of non-arthritic mice treated with prednisolone or vehicle. (<b>D</b>) ITT AUC values of non-arthritic mice treated with prednisolone or vehicle. (<b>E</b>) Blood glucose values during the ITT of arthritic mice treated with prednisolone or vehicle. (<b>F</b>) ITT AUC values of arthritic mice treated with prednisolone or vehicle.). * Significant difference p≤0.05, *** significant difference p≤0.001, NS  =  not significant.</p

Org 214007-0 does not effect rates of hepatic enzyme fluxes.

<p>Mass Isotopomer Distribution Analysis (MIDA), as described in detail in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0048385#s4" target="_blank">Materials and Methods</a>, was performed in mice treated p.o., once daily, for 7 days with either vehicle, prednisolone (10 mg/kg) or Org 214007-0 (1.5 mg/kg). These doses of each compound are equi-efficacious in suppression of CIA. Neither the glucose-6-phosphatase flux (A) nor the glycogen phosphorylase flux (B) were affected by treatment with prednisolone or Org 214007-0. The glucokinase flux rate (C) was not changed by Org 214007-0, but significantly differed from the effect by prednisolone (##: p = 0.01 <i>vs</i> prednisolone). The glycogen synthase flux rate (D) was significantly decreased by prednisolone (**: p = 0.005 <i>vs</i> vehicle), whereas Org 214007-0 had no significant effect on this flux, but differed significantly from prednisolone (##: p = 0.002 <i>vs</i> prednisolone). Neither Org 214007-0 nor prednisolone, at equi-efficacious dosages, effects the gluconeogenic flux (<i>de novo</i> synthesis of glucose-6-phophate) (E).</p