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Therapeutic approach for type 1 diabetes mellitus using the novel immunomodulator FTY720 (fingolimod) in combination with once-daily injection of insulin glargine in non-obese diabetic mice.

Tsuji T, Inoue M, Yoshida Y, Fujita T, Kaino Y, Kohno T - J Diabetes Investig (2012)

Bottom Line: Treatment was initiated at the time of onset of DM and continued for 70 days or until death.Therapeutic administration of FTY720 in combination with insulin glargine to NOD mice with hyperglycemia further improved survival (P < 0.05) compared with either FTY720 or insulin glargine alone (i.e. 85% of FTY720 + insulin glargine-treated mice survived to the end of the observation period).The efficacy of FTY720 in combination with insulin glargine was confirmed by histochemical, immunohistochemical and endocrinologic observations.   Combination therapy with FTY720 plus insulin glargine is a promising candidate for the treatment of DM and may allow for a reduction in the frequency of insulin self-injections. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00160.x, 2011).

View Article: PubMed Central - PubMed

Affiliation: Department of Pathological Biochemistry, Faculty of Pharmaceutical Sciences, Setsunan University, Osaka.

ABSTRACT

Unlabelled: Aims/Introduction:  The therapeutic effectiveness against type 1 diabetes mellitus (DM) of the novel immunomodulator FTY720 (fingolimod), alone and in combination with insulin glargine, was examined in the non-obese diabetic (NOD) mouse model.

Materials and methods:   Female NOD mice that had developed DM spontaneously were divided into four groups: (i) an FTY720 (0.1 mg/kg, p.o., twice weekly)-treated group; (ii) an insulin glargine (1.0 IU, s.c., once daily)-treated group; (iii) a combination FTY720 + insulin glargine (0.1-1.0 IU, s.c., once daily)-treated group; and (iv) a placebo (vehicle)-treated group. Treatment was initiated at the time of onset of DM and continued for 70 days or until death. The therapeutic efficacy of FTY720, insulin glargine and FTY720 + insulin glargine was evaluated by measuring the ratio of insulin-positive β-cells/total islet area, the extent of islet inflammation (insulitis score), blood glucose levels, and serum C-peptide levels.

Results:   Therapeutic administration of FTY720 to NOD mice with hyperglycemia (i.e. overt DM) significantly prolonged survival (P < 0.05 vs placebo). In the placebo group, all mice died within 63 days on the onset of DM; in contrast, 45% of FTY720-treated mice survived during the observation period (up to 70 days after the onset of DM). Therapeutic administration of FTY720 in combination with insulin glargine to NOD mice with hyperglycemia further improved survival (P < 0.05) compared with either FTY720 or insulin glargine alone (i.e. 85% of FTY720 + insulin glargine-treated mice survived to the end of the observation period). The efficacy of FTY720 in combination with insulin glargine was confirmed by histochemical, immunohistochemical and endocrinologic observations.

Conclusions:   Combination therapy with FTY720 plus insulin glargine is a promising candidate for the treatment of DM and may allow for a reduction in the frequency of insulin self-injections. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00160.x, 2011).

No MeSH data available.


Related in: MedlinePlus

 Effect of FTY720 alone or in combination with insulin glargine on survival rates of NOD mice with overt type 1 diabetes mellitus (DM). Female NOD mice with hyperglycemia (i.e. with overt DM) were treated with: 0.1 mg/kg, p.o., FTY720 twice a week (n = 11; ○); 1.0 IU, s.c., insulin glargine once daily, (n = 13; □); 0.1 mg/kg, p.o., FTY720 twice a week plus insulin glargine (for dosing, refer to Materials and Methods; n = 13; •); or vehicle (n = 11; △). Survival was monitored for 70 days after start of treatment. The significance of differences in survival was evaluated using the log rank test.
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f1:  Effect of FTY720 alone or in combination with insulin glargine on survival rates of NOD mice with overt type 1 diabetes mellitus (DM). Female NOD mice with hyperglycemia (i.e. with overt DM) were treated with: 0.1 mg/kg, p.o., FTY720 twice a week (n = 11; ○); 1.0 IU, s.c., insulin glargine once daily, (n = 13; □); 0.1 mg/kg, p.o., FTY720 twice a week plus insulin glargine (for dosing, refer to Materials and Methods; n = 13; •); or vehicle (n = 11; △). Survival was monitored for 70 days after start of treatment. The significance of differences in survival was evaluated using the log rank test.

Mentions: The NOD mice that had developed DM spontaneously were divided into an FTY720‐treated group (n = 11) and a placebo‐treated group (n = 11). The two groups were matched for blood glucose levels at the beginning of treatment (419 ± 98 and 434 ± 126 mg/dL in the FTY720‐ and placebo‐treated groups, respectively). Survival curves in the two groups are shown in Figure 1. In the placebo group, all mice died within 63 days after the start of treatment, whereas five mice (45%) in the FTY720 group survived throughout the observation period (up to 70 days after the beginning of treatment). There was a significant difference in survival rate between the two groups (P < 0.05, log rank test).


Therapeutic approach for type 1 diabetes mellitus using the novel immunomodulator FTY720 (fingolimod) in combination with once-daily injection of insulin glargine in non-obese diabetic mice.

Tsuji T, Inoue M, Yoshida Y, Fujita T, Kaino Y, Kohno T - J Diabetes Investig (2012)

 Effect of FTY720 alone or in combination with insulin glargine on survival rates of NOD mice with overt type 1 diabetes mellitus (DM). Female NOD mice with hyperglycemia (i.e. with overt DM) were treated with: 0.1 mg/kg, p.o., FTY720 twice a week (n = 11; ○); 1.0 IU, s.c., insulin glargine once daily, (n = 13; □); 0.1 mg/kg, p.o., FTY720 twice a week plus insulin glargine (for dosing, refer to Materials and Methods; n = 13; •); or vehicle (n = 11; △). Survival was monitored for 70 days after start of treatment. The significance of differences in survival was evaluated using the log rank test.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4020730&req=5

f1:  Effect of FTY720 alone or in combination with insulin glargine on survival rates of NOD mice with overt type 1 diabetes mellitus (DM). Female NOD mice with hyperglycemia (i.e. with overt DM) were treated with: 0.1 mg/kg, p.o., FTY720 twice a week (n = 11; ○); 1.0 IU, s.c., insulin glargine once daily, (n = 13; □); 0.1 mg/kg, p.o., FTY720 twice a week plus insulin glargine (for dosing, refer to Materials and Methods; n = 13; •); or vehicle (n = 11; △). Survival was monitored for 70 days after start of treatment. The significance of differences in survival was evaluated using the log rank test.
Mentions: The NOD mice that had developed DM spontaneously were divided into an FTY720‐treated group (n = 11) and a placebo‐treated group (n = 11). The two groups were matched for blood glucose levels at the beginning of treatment (419 ± 98 and 434 ± 126 mg/dL in the FTY720‐ and placebo‐treated groups, respectively). Survival curves in the two groups are shown in Figure 1. In the placebo group, all mice died within 63 days after the start of treatment, whereas five mice (45%) in the FTY720 group survived throughout the observation period (up to 70 days after the beginning of treatment). There was a significant difference in survival rate between the two groups (P < 0.05, log rank test).

Bottom Line: Treatment was initiated at the time of onset of DM and continued for 70 days or until death.Therapeutic administration of FTY720 in combination with insulin glargine to NOD mice with hyperglycemia further improved survival (P < 0.05) compared with either FTY720 or insulin glargine alone (i.e. 85% of FTY720 + insulin glargine-treated mice survived to the end of the observation period).The efficacy of FTY720 in combination with insulin glargine was confirmed by histochemical, immunohistochemical and endocrinologic observations.   Combination therapy with FTY720 plus insulin glargine is a promising candidate for the treatment of DM and may allow for a reduction in the frequency of insulin self-injections. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00160.x, 2011).

View Article: PubMed Central - PubMed

Affiliation: Department of Pathological Biochemistry, Faculty of Pharmaceutical Sciences, Setsunan University, Osaka.

ABSTRACT

Unlabelled: Aims/Introduction:  The therapeutic effectiveness against type 1 diabetes mellitus (DM) of the novel immunomodulator FTY720 (fingolimod), alone and in combination with insulin glargine, was examined in the non-obese diabetic (NOD) mouse model.

Materials and methods:   Female NOD mice that had developed DM spontaneously were divided into four groups: (i) an FTY720 (0.1 mg/kg, p.o., twice weekly)-treated group; (ii) an insulin glargine (1.0 IU, s.c., once daily)-treated group; (iii) a combination FTY720 + insulin glargine (0.1-1.0 IU, s.c., once daily)-treated group; and (iv) a placebo (vehicle)-treated group. Treatment was initiated at the time of onset of DM and continued for 70 days or until death. The therapeutic efficacy of FTY720, insulin glargine and FTY720 + insulin glargine was evaluated by measuring the ratio of insulin-positive β-cells/total islet area, the extent of islet inflammation (insulitis score), blood glucose levels, and serum C-peptide levels.

Results:   Therapeutic administration of FTY720 to NOD mice with hyperglycemia (i.e. overt DM) significantly prolonged survival (P < 0.05 vs placebo). In the placebo group, all mice died within 63 days on the onset of DM; in contrast, 45% of FTY720-treated mice survived during the observation period (up to 70 days after the onset of DM). Therapeutic administration of FTY720 in combination with insulin glargine to NOD mice with hyperglycemia further improved survival (P < 0.05) compared with either FTY720 or insulin glargine alone (i.e. 85% of FTY720 + insulin glargine-treated mice survived to the end of the observation period). The efficacy of FTY720 in combination with insulin glargine was confirmed by histochemical, immunohistochemical and endocrinologic observations.

Conclusions:   Combination therapy with FTY720 plus insulin glargine is a promising candidate for the treatment of DM and may allow for a reduction in the frequency of insulin self-injections. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00160.x, 2011).

No MeSH data available.


Related in: MedlinePlus