While diets rich in fruit and vegetables can decrease the risk for
type 2 diabetes (T2D), diets rich in fat and
carbohydrates can increase it. The flavanol-3-ol (-)-
epicatechin (EC) can improve
insulin sensitivity both in humans and animal models of T2D.
NADPH oxidases and oxidative stress can contribute to the development of
insulin resistance. This study investigated the capacity of EC and EC metabolites (ECM) to downregulate
NADPH oxidases and oxidative stress, and its association to an improvement of
insulin sensitivity. This was studied in in vivo (high fat-fed mice) and in vitro (HepG2 cells) conditions of hepatic
lipid overload. EC decreased NOX3/NOX4 liver expression and mitigated oxidative stress in high fat-fed mice. In HepG2 cells, incubation with
palmitate increased: i)
lipid deposition, ii) NOX3/NOX4 expression, iii)
NADPH oxidase activity, and iv) oxidative stress; promoting v) the activation of redox-sensitive
kinases (JNK and IKK), and vi) impaired
insulin responses. Physiological concentrations of EC and ECM, and
NADPH oxidase inhibitors (
apocynin,
VAS2870) prevented all those deleterious effects of
palmitate. The obtained results points to
NADPH oxidases as an important target in the capacity of EC to improve
insulin sensitivity in conditions of liver
lipid overload, as those associated with Western-style diets.