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The tyrphostin agent AG490 prevents and reverses type 1 diabetes in NOD mice.

Davoodi-Semiromi A, Wasserfall CH, Xia CQ, Cooper-DeHoff RM, Wabitsch M, Clare-Salzler M, Atkinson M - PLoS ONE (2012)

Bottom Line: However, the therapeutic effects of AG490 on the development of T1D are unknown.AG490 significantly inhibited the development of T1D (p = 0.02, p = 0.005; at two different time points).The use of such agents, given their extensive safety profiles, provides a strong foundation for their translation to humans with or at increased risk for the disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacotherapy & Translational Research, College of Pharmacy, University of Florida, Gainesville, Florida, United States of America. dsemiromi@cop.ufl.edu

ABSTRACT

Background: Recent studies in the NOD (non-obese diabetic) mouse model of type 1 diabetes (T1D) support the notion that tyrosine kinase inhibitors have the potential for modulating disease development. However, the therapeutic effects of AG490 on the development of T1D are unknown.

Materials and methods: Female NOD mice were treated with AG490 (i.p, 1 mg/mouse) or DMSO starting at either 4 or 8 week of age, for five consecutive week, then once per week for 5 additional week. Analyses for the development and/or reversal of diabetes, insulitis, adoptive transfer, and other mechanistic studies were performed.

Results: AG490 significantly inhibited the development of T1D (p = 0.02, p = 0.005; at two different time points). Monotherapy of newly diagnosed diabetic NOD mice with AG490 markedly resulted in disease remission in treated animals (n = 23) in comparision to the absolute inability (0%; 0/10, p = 0.003, Log-rank test) of DMSO and sustained eugluycemia was maintained for several months following drug withdrawal. Interestingly, adoptive transfer of splenocytes from AG490 treated NOD mice failed to transfer diabetes to recipient NOD.Scid mice. CD4 T-cells as well as bone marrow derived dendritic cells (BMDCs) from AG490 treated mice, showed higher expression of Foxp3 (p<0.004) and lower expression of co-stimulatory molecules, respectively. Screening of the mouse immune response gene arrary indicates that expression of costimulaotry molecule Ctla4 was upregulated in CD4+ T-cell in NOD mice treated with AG490, suggesting that AG490 is not a negative regulator of the immune system.

Conclusion: The use of such agents, given their extensive safety profiles, provides a strong foundation for their translation to humans with or at increased risk for the disease.

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Related in: MedlinePlus

AG490 induces remission of diabetes in NOD and in STZ-induced diabetic mice.Newly diagnosed and established diabetic NOD mice were treated with AG490 (i.p, 1 mg/mouse) without insulin supplement (A) (n = 23) or with DMSO (B) (n = 10). Blood glucose was measured by ACCU-CHECK 2–3 times weekly. Sustainable euglycemia was observed for several months after drug withdrawal while DMSO treated mice expired within 2–4 week after disease onset. The average blood glucose at the disease onset in the cured NOD mice was 314.43 mg/d (Max = 374; Min = 277 mg/dl) versus 384.58 mg/dl (Max = 478, Min = 335 mg/dl) in mice that AG490 failed to restore euglycemia (p<0.0014). An average blood glucose in cured NOD mice treated with AG490 was 169.82 mg/dl±23.21, n = 7 versus 555.13±63.79, n = 17 in uncured NOD mice (p = 1.15E-11). (C) Diabetes was induced by STZ injection in male BALB/c mice and one week after the last injection diabetic mice were treated with either AG490 or DMSO (D) (n = 5/group). The blood glucose level was significantly lower (p<0.004) in AG490 treated mice when compared with DMSO treated mice. [This figure is intended to be in color online and black and white in print.]
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pone-0036079-g002: AG490 induces remission of diabetes in NOD and in STZ-induced diabetic mice.Newly diagnosed and established diabetic NOD mice were treated with AG490 (i.p, 1 mg/mouse) without insulin supplement (A) (n = 23) or with DMSO (B) (n = 10). Blood glucose was measured by ACCU-CHECK 2–3 times weekly. Sustainable euglycemia was observed for several months after drug withdrawal while DMSO treated mice expired within 2–4 week after disease onset. The average blood glucose at the disease onset in the cured NOD mice was 314.43 mg/d (Max = 374; Min = 277 mg/dl) versus 384.58 mg/dl (Max = 478, Min = 335 mg/dl) in mice that AG490 failed to restore euglycemia (p<0.0014). An average blood glucose in cured NOD mice treated with AG490 was 169.82 mg/dl±23.21, n = 7 versus 555.13±63.79, n = 17 in uncured NOD mice (p = 1.15E-11). (C) Diabetes was induced by STZ injection in male BALB/c mice and one week after the last injection diabetic mice were treated with either AG490 or DMSO (D) (n = 5/group). The blood glucose level was significantly lower (p<0.004) in AG490 treated mice when compared with DMSO treated mice. [This figure is intended to be in color online and black and white in print.]

Mentions: We sought to investigate whether AG490 would reverse pathogenesis of T1D in newly diagnosed diabetic NOD mice. Newly dignosed and established diabetic NOD mice were treated with AG490 (i.p, 1 mg/mouse; no insulin was given to mice at any time) and control group was treated with vehicle and blood glucose was measured. Our data indicate that AG490 led significantly to remission of diabetic mice (p = 0.003, Log-rank test) while DMSO treated control mice led to remission of 0% (n = 10) (figure 2A & B). Once euglycemia was established (Table S1), treatment was ceased and normaglycemia lasts for several weeks and sustainable euglycemia was maintained after drug withdrawal in majority of the cured mice. These data suggest that NOD mice did not develop resistance to AG490 treatment and additionally suggests that AG490 has a durable effect on restoration of blood glucose metabolism/regulation. However, diabetic NOD mice treated with DMSO or left untreated expired within 2–4 weeks (figure 2B). Average of blood glucose in the cured NOD mice at the disease onset was 314.43 mg/dl (Max = 374; Min = 277 mg/dl) versus 384.58 mg/dl (Max = 478, Min = 335 mg/dl) (p<0.0014) in mice that AG490 failed to restore euglycemia while an average blood glucose in cure NOD mice was 169.82±23.21 mg/dl versus 555.13±63.79 (p = 1.15E-11) in uncured NOD mice. This data suggest that AG490 was more effective in diabetic mice with blood glucose level <314.43 mg/dl. A combination therapy, e.g AG490+ insulin, may improve efficacy of AG490 treatment in mice with blood glucose level >314.43 mg/dl.


The tyrphostin agent AG490 prevents and reverses type 1 diabetes in NOD mice.

Davoodi-Semiromi A, Wasserfall CH, Xia CQ, Cooper-DeHoff RM, Wabitsch M, Clare-Salzler M, Atkinson M - PLoS ONE (2012)

AG490 induces remission of diabetes in NOD and in STZ-induced diabetic mice.Newly diagnosed and established diabetic NOD mice were treated with AG490 (i.p, 1 mg/mouse) without insulin supplement (A) (n = 23) or with DMSO (B) (n = 10). Blood glucose was measured by ACCU-CHECK 2–3 times weekly. Sustainable euglycemia was observed for several months after drug withdrawal while DMSO treated mice expired within 2–4 week after disease onset. The average blood glucose at the disease onset in the cured NOD mice was 314.43 mg/d (Max = 374; Min = 277 mg/dl) versus 384.58 mg/dl (Max = 478, Min = 335 mg/dl) in mice that AG490 failed to restore euglycemia (p<0.0014). An average blood glucose in cured NOD mice treated with AG490 was 169.82 mg/dl±23.21, n = 7 versus 555.13±63.79, n = 17 in uncured NOD mice (p = 1.15E-11). (C) Diabetes was induced by STZ injection in male BALB/c mice and one week after the last injection diabetic mice were treated with either AG490 or DMSO (D) (n = 5/group). The blood glucose level was significantly lower (p<0.004) in AG490 treated mice when compared with DMSO treated mice. [This figure is intended to be in color online and black and white in print.]
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Related In: Results  -  Collection

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pone-0036079-g002: AG490 induces remission of diabetes in NOD and in STZ-induced diabetic mice.Newly diagnosed and established diabetic NOD mice were treated with AG490 (i.p, 1 mg/mouse) without insulin supplement (A) (n = 23) or with DMSO (B) (n = 10). Blood glucose was measured by ACCU-CHECK 2–3 times weekly. Sustainable euglycemia was observed for several months after drug withdrawal while DMSO treated mice expired within 2–4 week after disease onset. The average blood glucose at the disease onset in the cured NOD mice was 314.43 mg/d (Max = 374; Min = 277 mg/dl) versus 384.58 mg/dl (Max = 478, Min = 335 mg/dl) in mice that AG490 failed to restore euglycemia (p<0.0014). An average blood glucose in cured NOD mice treated with AG490 was 169.82 mg/dl±23.21, n = 7 versus 555.13±63.79, n = 17 in uncured NOD mice (p = 1.15E-11). (C) Diabetes was induced by STZ injection in male BALB/c mice and one week after the last injection diabetic mice were treated with either AG490 or DMSO (D) (n = 5/group). The blood glucose level was significantly lower (p<0.004) in AG490 treated mice when compared with DMSO treated mice. [This figure is intended to be in color online and black and white in print.]
Mentions: We sought to investigate whether AG490 would reverse pathogenesis of T1D in newly diagnosed diabetic NOD mice. Newly dignosed and established diabetic NOD mice were treated with AG490 (i.p, 1 mg/mouse; no insulin was given to mice at any time) and control group was treated with vehicle and blood glucose was measured. Our data indicate that AG490 led significantly to remission of diabetic mice (p = 0.003, Log-rank test) while DMSO treated control mice led to remission of 0% (n = 10) (figure 2A & B). Once euglycemia was established (Table S1), treatment was ceased and normaglycemia lasts for several weeks and sustainable euglycemia was maintained after drug withdrawal in majority of the cured mice. These data suggest that NOD mice did not develop resistance to AG490 treatment and additionally suggests that AG490 has a durable effect on restoration of blood glucose metabolism/regulation. However, diabetic NOD mice treated with DMSO or left untreated expired within 2–4 weeks (figure 2B). Average of blood glucose in the cured NOD mice at the disease onset was 314.43 mg/dl (Max = 374; Min = 277 mg/dl) versus 384.58 mg/dl (Max = 478, Min = 335 mg/dl) (p<0.0014) in mice that AG490 failed to restore euglycemia while an average blood glucose in cure NOD mice was 169.82±23.21 mg/dl versus 555.13±63.79 (p = 1.15E-11) in uncured NOD mice. This data suggest that AG490 was more effective in diabetic mice with blood glucose level <314.43 mg/dl. A combination therapy, e.g AG490+ insulin, may improve efficacy of AG490 treatment in mice with blood glucose level >314.43 mg/dl.

Bottom Line: However, the therapeutic effects of AG490 on the development of T1D are unknown.AG490 significantly inhibited the development of T1D (p = 0.02, p = 0.005; at two different time points).The use of such agents, given their extensive safety profiles, provides a strong foundation for their translation to humans with or at increased risk for the disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacotherapy & Translational Research, College of Pharmacy, University of Florida, Gainesville, Florida, United States of America. dsemiromi@cop.ufl.edu

ABSTRACT

Background: Recent studies in the NOD (non-obese diabetic) mouse model of type 1 diabetes (T1D) support the notion that tyrosine kinase inhibitors have the potential for modulating disease development. However, the therapeutic effects of AG490 on the development of T1D are unknown.

Materials and methods: Female NOD mice were treated with AG490 (i.p, 1 mg/mouse) or DMSO starting at either 4 or 8 week of age, for five consecutive week, then once per week for 5 additional week. Analyses for the development and/or reversal of diabetes, insulitis, adoptive transfer, and other mechanistic studies were performed.

Results: AG490 significantly inhibited the development of T1D (p = 0.02, p = 0.005; at two different time points). Monotherapy of newly diagnosed diabetic NOD mice with AG490 markedly resulted in disease remission in treated animals (n = 23) in comparision to the absolute inability (0%; 0/10, p = 0.003, Log-rank test) of DMSO and sustained eugluycemia was maintained for several months following drug withdrawal. Interestingly, adoptive transfer of splenocytes from AG490 treated NOD mice failed to transfer diabetes to recipient NOD.Scid mice. CD4 T-cells as well as bone marrow derived dendritic cells (BMDCs) from AG490 treated mice, showed higher expression of Foxp3 (p<0.004) and lower expression of co-stimulatory molecules, respectively. Screening of the mouse immune response gene arrary indicates that expression of costimulaotry molecule Ctla4 was upregulated in CD4+ T-cell in NOD mice treated with AG490, suggesting that AG490 is not a negative regulator of the immune system.

Conclusion: The use of such agents, given their extensive safety profiles, provides a strong foundation for their translation to humans with or at increased risk for the disease.

Show MeSH
Related in: MedlinePlus