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Oral administration of angiotensin-(1–7) ameliorates type 2 diabetes in rats

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Abstract

Diabetes mellitus type 2 (DM2) is a disease with increasing importance in modern societies and insufficient treatment options. Pharmacological stimulation of insulin signaling, which is blunted in DM2, is a promising approach to treat this disease. It has been shown that activation of the angiotensin (Ang)-(1–7)/Mas axis of the renin–angiotensin system leads to an improved glucose uptake. In this study, we intended to evaluate, whether this effect could be exploited therapeutically. We first confirmed that Ang-(1–7) improves insulin signaling and glucose uptake in vitro in cultured cardiomyocytes. We then evaluated the therapeutic effect of a newly developed hydro-xypropyl-β-cyclodextrin-based Ang-(1–7) nano-formulation in a novel transgenic rat model of inducible insulin resistance and DM2. The chronic administration of this compound prevented the marked elevation in blood glucose levels in these rats at a dose of 30 μg/kg, reversed the established hyperglycemic state at a dose of 100 μg/kg, and resulted in improved insulin sensitivity, reduced plasma insulin and decreased diabetic nephropathy. In conclusion, an oral Ang-(1–7) formulation reverses hyperglycemia and its consequences in an animal model of DM2 and represents a novel therapeutic option for the treatment of DM2 and other cardio-metabolic diseases.

Key message

  • A novel rat model with inducible diabetes can be used to evaluate new therapies.

  • Angiotensin-(1–7) is effective in an oral formulation packaged in cyclodextrine.

  • Angiotensin-(1–7) is a promising antidiabetic drug.

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Acknowledgments

The authors would like to thank Astrid Schiche for excellent assistance in the animal experiments.

Disclosure

The authors have no conflict of interest to disclose.

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Authors and Affiliations

  1. National Institute in Science and Technology NanoBioFar (INCT NanoBioFar) and Laboratory of Hypertension and Department of Physiology and Biophysics, Department of Pharmacology, Biological Sciences Institute (ICB), Federal University of Minas Gerais (UFMG), Av Antonio Carlos 6627-ICB, 31270-901, Belo Horizonte, MG, Brazil

    Sérgio H. S. Santos, Janaina F. Braga & Robson A. S. Santos

  2. Instituto de Química y Fisicoquímica Biológicas, Departamento de Química Biológica, Facultad de Farmacia y Bioquímica (IQUIFIB), Universidad de Buenos Aires, Junín 956, (1113), Buenos Aires, Argentina

    Jorge F. Giani, Valeria Burghi, Johanna G. Miquet & Fernando P. Dominici

  3. Max-Delbrück-Center for Molecular Medicine (MDC), Buch, 13125, Berlin, Germany

    Fatimunnisa Qadri, Mihail Todiras, Katarina Kotnik, Natalia Alenina & Michael Bader

Authors
  1. Sérgio H. S. Santos
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  2. Jorge F. Giani
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  3. Valeria Burghi
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  4. Johanna G. Miquet
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  5. Fatimunnisa Qadri
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  8. Katarina Kotnik
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  9. Natalia Alenina
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  10. Fernando P. Dominici
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  11. Robson A. S. Santos
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  12. Michael Bader
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Correspondence to Fernando P. Dominici, Robson A. S. Santos or Michael Bader.

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Santos, S.H.S., Giani, J.F., Burghi, V. et al. Oral administration of angiotensin-(1–7) ameliorates type 2 diabetes in rats. J Mol Med 92, 255–265 (2014). https://doi.org/10.1007/s00109-013-1087-0

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  • DOI: https://doi.org/10.1007/s00109-013-1087-0

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