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

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