Oral administration of angiotensin-(1–7) ameliorates type 2 diabetes in rats
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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.
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.
KeywordsDiabetes RNA interference Angiotensin-(1–7) Antidiabetic
The authors would like to thank Astrid Schiche for excellent assistance in the animal experiments.
The authors have no conflict of interest to disclose.
- 17.Fraga da Silva RA, Pinheiro SVB, Goncalves ACC, Alenina N, Bader M, Santos RA (2008) The NO-mediated antithrombotic effect of angiotensin-(1–7) is abolished in mas-knockout mice. Mol Med 14:28–35Google Scholar
- 22.Giani JF, Mayer MA, Munoz MC, Silberman EA, Hocht C, Taira CA, Gironacci MM, Turyn D, Dominici FP (2009) Chronic infusion of angiotensin-(1–7) improves insulin resistance and hypertension induced by a high-fructose diet in rats. Am J Physiol Endocrinol Metab 296:E262–E271PubMedCrossRefGoogle Scholar
- 27.Lula I, Denadai AL, Resende JM, de Sousa FB, de Lima GF, Pilo-Veloso D, Heine T, Duarte HA, Santos RA, Sinisterra RD (2007) Study of angiotensin-(1–7) vasoactive peptide and its beta-cyclodextrin inclusion complexes: complete sequence-specific NMR assignments and structural studies. Peptides 28:2199–2210PubMedCrossRefGoogle Scholar
- 49.Andreozzi F, Laratta E, Sciacqua A, Perticone F, Sesti G (2004) Angiotensin II impairs the insulin signaling pathway promoting production of nitric oxide by inducing phosphorylation of insulin receptor substrate-1 on Ser312 and Ser616 in human umbilical vein endothelial cells. Circ Res 94:1211–1218PubMedCrossRefGoogle Scholar