AUTHOR=Barbosa Maria Andréa , Barbosa Claudiane Maria , Lima Taynara Carolina , Santos Robson Augusto Souza dos , Alzamora Andréia Carvalho 

TITLE=The Novel Angiotensin-(1–7) Analog, A-1317, Improves Insulin Resistance by Restoring Pancreatic β-Cell Functionality in Rats With Metabolic Syndrome

JOURNAL=Frontiers in Pharmacology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2020.01263

DOI=10.3389/fphar.2020.01263

ISSN=1663-9812

ABSTRACT=<p>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-<italic>β</italic>-cyclodextrin (HP<italic>β</italic>CD) or empty HP<italic>β</italic>CD (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 <italic>angiotensinogen</italic>, <italic>AT1R</italic>, <italic>ACE</italic> 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 <italic>β</italic> cell capacity by increasing HOMA-<italic>β</italic> and QUICKI, whereas Ang-(1–7) reduced HOMA-<italic>β</italic> and QUICKI. In addition, Ang-(1–7) increased <italic>Mas</italic> and <italic>AKT</italic> liver mRNA gene expression, while A-1317 increased both <italic>Mas</italic> and <italic>MRGD</italic> and <italic>AMPK</italic> 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 <italic>via</italic> MRGD <italic>via</italic> activation of AMPK and increasing <italic>β</italic> cell function.</p>