The dual inhibitor Sacubitril-valsartan ameliorate high-fat high-fructose-induced metabolic disorders in rats superiorly compared to valsartan only.

This article investigates the metabolic effects of Sacubitril-valsartan (SAC-VAL), a dual neprilysin (NEP) inhibitor and angiotensin II receptor 1 (AT1R) blocker approved for heart failure treatment, in comparison to valsartan (VAL) alone in a rat model of type 2 diabetes mellitus induced by a high-fat (60%) and high-fructose (10%) diet. The study found that SAC-VAL significantly reduced food intake, body weight, and epididymal white adipose tissue weight, and normalized plasma insulin and glycated hemoglobin (HbA1c) levels, effects not observed with VAL alone. Both SAC-VAL and VAL improved glucose tolerance, insulin sensitivity, pyruvate tolerance (a marker of hepatic gluconeogenesis), and hepatic Akt phosphorylation, with SAC-VAL showing superior benefits on insulin secretion and glycemic control. Histopathological analysis revealed that both treatments attenuated hepatic steatosis and adipose tissue inflammation, but only SAC-VAL reduced adipose tissue weight. These findings suggest that SAC-VAL’s metabolic benefits in this model may be mediated primarily through NEP inhibition in addition to AT1R antagonism, indicating potential therapeutic advantages over VAL alone for metabolic disorders associated with hypercaloric diets.