Investigação dos efeitos de extratos de Terminalia glabrescens e Terminalia phaeocarpa (combretaceae) em modelo de diabetes tipo 2 e na síndrome metabólica induzida por dieta hiperlipídica

Abstract

Type 2 diabetes mellitus (T2DM), obesity and metabolic syndrome (MTS) have become a public health problem throughout the western world. The currently available therapeutic arsenal is still ineffective to significantly reduce the morbidities associated with these diseases. Species of the genus Terminalia are used in Asia for the treatment of diabetes and obesity, while in Brazil there are no reports of the use of plants of this genus in the treatment of these diseases. Recent phytochemical studies suggest that Asian and Brazilian species have a similar chemical profile. For this reason, in the present project we decided to investigate the antidiabetic and antiobesity activities of the leaves of Terminalia phaeocarpa and Terminalia glabrescens. In this study, in vitro assays were performed for α-glucosidase, α-amylase and lipase activity; and in vivo for oral starch tolerance (OStTT) and sucrose (OSuTT) test. Crude ethanolic extracts and respective fractions of the two Terminalia were also evaluated in male Swiss mice with T2DM induced by the association of fructose / nicotinamide / streptozotocin treated for 4 weeks. The most active Terminalia was tested in a MTS model induced by the association of high fat diet and fructose. In these mice, serum parameters such as glucose, insulin, triglycerides, total cholesterol, glycated hemoglobin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkalin phosphatase (ALP), creatinine and uric acid were evaluated. In addition, systolic blood pressure (SBP), lipid peroxidation and hepatic activity of glycogen phosphorylase (GP), phosphoenol-pyruvatocarboxykinase (PEPCK) protein tyrosine phosphatase 1-B (PTP1-B), were also measured. Glucose, uric acid and creatinine were measured in the urine. In vitro tests showed that extracts and fractions of T. phaeocarpa and T. glabrescens inhibit activity of the enzymes tested in a concentration-dependent manner, while in vivo only T. phaeocarpa extract and fractions significantly reduced plasma glucose in OStTT. In T2DM mice, only crude extract (CE) and ethyl acetate fraction (EAF) of T. phaeocarpa induced a consistent reduction in glycemia, triglycerides, total cholesterol, ALT, AST, ALP, lipid peroxidation and liver PTP1-B activity. In MTS mice, treatment with EAF of T. phaeocarpa significantly reduced body mass gain, serum glucose levels, triglycerides, cholesterol, total, uric acid, total protein, insulin, ALT, AST, PAS and endothelial dysfunction in mesenteric arteries, while insulin sensitivity, total hemoglobin and ALP levels increased. These results allow us to conclude that the Terminalia phaeocarpa plant is more promising than Terminalia glabrescens for the treatment of metabolic disorders. T. phaeocarpa exhibits antidiabetic activity by a mechanism dependent on inhibition of glucose absorption in the gastrointestinal tract, by inhibition of neoglycogenesis through fat breakdown and increased insulin sensitivity via inhibition of PTP1-B enzyme. Additionally, the present results also allow us to conclude that T. phaeocarpa treatment improves metabolic profile and cardiovascular changes associated with hyperlipidic diet-induced MTS.