The novel Angiotensin-(1-7) analog, A-1317, improves insulin resistance by restoring pancreatic β-Cell functionality in rats with metabolic syndrome.
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2020
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Abstract
In previous studies we have shown that oral Ang-(1–7) has a beneficial therapeutic effect on cardiometabolic disturbances present in metabolic syndrome (MetS). Based on the fact that Ang-(1–7) acts through release of nitric oxide (NO), a new peptide, A-1317 was engineered adding the amino acid L-Arginine, the NO precursor, to the N-terminal portion of the Ang-(1– 7). Therefore, in a single molecule the substrate and the activator of NO are combined. In the present study, we evaluated the effect of A-1317 oral treatment on liver-glucose metabolism in MetS induced by high fat (HF) diet in rats. Rats were subjected to control (AIN-93M, CT) or HF diets for 15 weeks to induce MetS and treated with A-1317, Ang-(1–7) included into hydroxypropyl-b-cyclodextrin (HPbCD) or empty HPbCD (E), in the last 7 weeks. At the end of 15 weeks, hemodynamic, biometric, and biochemical parameters, redox process, and qRT-PCR gene expression of NO synthase and RAS components were evaluated in the liver. HF/E rats increased body mass gain, adiposity index, despite the reduction in food intake, increased plasma leptin, total cholesterol, triglycerides, ALT, fasting blood glucose, OGTT and insulin, HOMA-IR and MAP and HR. Furthermore, the MetS rats presented increased in liver angiotensinogen, AT1R, ACE mRNA gene expression and concentration of MDA and carbonylated protein. Both Ang-(1–7) and A-1317 oral treatment in MetS rats reverted most of these alterations. However, A-1317 was more efficient in reducing body mass gain, ALT, AST, total cholesterol, insulin, fasting blood glucose, ameliorating b cell capacity by increasing HOMA-b and QUICKI, whereas Ang-(1–7) reduced HOMA-b and QUICKI. In addition, Ang- (1–7) increased Mas and AKT liver mRNA gene expression, while A-1317 increased both Mas and MRGD and AMPK liver mRNA gene expression, suggesting a distinct pathway of action of Ang-(1–7) and A-1317 in MetS rats. Taken together, our data showed that treatment with A-1317 was able to ameliorate MetS disorders and suggested that this effect was mainly via MRGD via activation of AMPK and increasing b cell function.
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Keywords
Liver metabolism, Mas-related G protein-coupled receptor member D, Adenosine monophosphate activated protein kinase
Citation
BARBOSA, M. A. et al. The novel Angiotensin-(1-7) analog, A-1317, improves insulin resistance by restoring pancreatic β-Cell functionality in rats with metabolic syndrome. Frontiers in Pharmacology, v. 11, artigo 1263, ago. 2020. Disponível em: <https://www.frontiersin.org/articles/10.3389/fphar.2020.01263/full>. Acesso em: 10 jun. 2021.