The hypoglycemic effects of guava leaf (Psidium guajava L.) extract are associated with improving endothelial dysfunction in mice with diet-induced obesity

Highlights

• Guava leaves improves the vascular dysfunction in obese mice.

• Administration of guava leaf extract has a positive impact on metabolic functions in obese mice.

• The beneficial effects ascribed to guava leaf extract in obese mice can be due to its phenolic content.

Abstract

Obesity is associated with a low-grade inflammatory status that affects vascular function. Previous studies have reported the beneficial effects of Psidium guajava L. (guava) on diabetes. Here we evaluate the how guava leaf extract at the dose of 5 mg/kg, affects vascular dysfunction in obese mice fed a high-fat diet for 7 weeks. Extract intake did not alter weight over time, although it reduced glycemia and insulin resistance, improving the serum lipid profile in obese mice. Additionally, guava leaf extract reversed the endothelial dysfunction found in obese mice in terms of endothelium- and NO (nitric oxide)-dependent vasodilatation induced by acetylcholine in aortic rings. In conclusion, the beneficial effects of guava leaf extract in obese mice were associated with improved vascular functions altered by obesity, probably due to its phenolic content.

Introduction

Diabetes mellitus (DM), one of the most common metabolic disorders worldwide, is increasing. In 2013, 382 million adults worldwide had diabetes, and 592 million are projected to be affected by 2035 (Guariguata et al., 2013). DM is a leading cause of mortality, morbidity, and health-system costs in the world, mainly because of metabolic and cardiovascular complications (Creager, Lüscher, Cosentino, & Beckman, 2003). In addition, metabolic syndrome has different components, such as abdominal obesity, impaired glucose metabolism, dyslipidemia, and hypertension, which synergistically increase the risk of cardiovascular disease as well as diabetes, this being clearly involved in premature mortality. Pre-diabetes is considered an underlying etiology of metabolic syndrome, characterized by a combination of excess body fat and insulin resistance, and manifested by impaired fasting glucose and/or impaired glucose tolerance, thus resulting in hyperglycemia (Grundy, 2012). The primary target of hyperglycemia appears to be the endothelial cells, which may induce endothelial dysfunction and accelerated atherosclerosis. These processes are associated with the development of a vascular inflammatory response, with the involvement of several mediators, including reactive oxygen metabolites, chemokines, and pro-inflammatory cytokines, which are clearly responsible for the cardiovascular complications that are the leading cause of morbidity and mortality associated with diabetes (Herder, Dalmas, Böni-Schnetzler, & Donath, 2015).

Several epidemiological studies and dietary interventions in human subjects have shown that high phenolic intake from different sources, such as grape, tea, cocoa or extra virgin olive oil, may be associated with a reduced risk of cardiovascular disease (Deka and Vita, 2011, Estruch et al., 2013, Hooper et al., 2012, Tomé-Carneiro et al., 2013). Different biological actions attributed to these phenolic compounds would support their potential cardiovascular protective effects, including improved vasodilation (Perez et al., 2014), lower blood pressure (Jiménez, Duarte, & Perez-Vizcaino, 2012), reduced insulin resistance (Dragan, Andrica, Serban, & Timar, 2015), and stronger immune responses and antioxidant defense system (Katz, Doughty, & Ali, 2011).

Psidium guajava L. is a small tree native to Mexico that has been widely used in traditional medicine for the treatment of diverse diseases, including hypertension, inflammation, pain, and diabetes (Gutiérrez, Mitchell, & Solis, 2008). With respect to its anti-diabetic properties, the beneficial effects of different guava leaf extracts have been reported in experimental models of type I or type II diabetes (Deguchi and Miyazaki, 2010, Eidenberger et al., 2013, Guo et al., 2013, Khan et al., 2013, Mathur et al., 2015, Soman et al., 2010). All these studies have revealed their ability to detain the rise in postprandial blood glucose, to ameliorate hyperglycemia, hypertriglycemia, and hypercholesterolemia, as well as to improve both hyperinsulinemia and insulin resistance. However, little attention has been paid to the impact that guava leaf extract administration may have on endothelial dysfunction that occurs in a diabetic status. The aim of the present study was to evaluate the effects of a phenolic enriched extract of P. guajava L. leaf on endothelial dysfunction induced by a high-fat diet (HFD) in mice. Notably, the phenolic profile of Spanish guava leaves has recently been reported with an assessment of the concentration of different flavonoids. Among these, flavonols and flavan-3-ols were the major subclasses found in the Andalusian guava leaves (Díaz-de-Cerio et al., 2016a, Díaz-de-Cerio et al., 2016b), which can contribute to the potential beneficial effects that the guava leaf extract may exert in obese mice, given the biological properties attributed to flavonoids under diabetic conditions (Testa, Bonfigli, Genovese, De Nigris, & Ceriello, 2016).