Bioassay-guided Isolation of the Antidiabetic Active Principle from Salvia miltiorrhiza and its Stimulatory Effects on Glucose Uptake Using 3T3-L1 Adipocytes

Type 2 diabetes mellitus is a chronic metabolic disorder characterized by impaired insulin secretion and insulin sensitivity, which poses an imminent threat to become a worldwide epidemic according to world health organization [1-3]. Type 2 diabetes mellitus is associated with severe complications such as hypertension, dyslipidemia, microvascular and macrovascular cardiovascular diseases [4-6]. Insulin plays a regulatory role in this disease by stimulating the uptake of blood glucose into peripheral tissues through glucose transporters and the promotion of lipid biosynthesis in adipocytes [7]. Insulin resistance causes decrease in peripheral glucose disposal resulting in increased levels of blood glucose [7]. Some of the currently available antidiabetic drugs improve blood glucose levels by increasing the glucose uptake in peripheral tissues. However such drugs are associated with adverse side effects, which limit their use in diabetic patients. Therefore it is highly desirable to discover antidiabetic agents that improve blood glucose levels with minimal side effects. Salviamiltiorrhiza(Labiatae),danshen, is an annual sage mainly found inchinaand neighboring countries. The dried root and its preparations are currently being used inchinato treat patients with cardiovascular and cerebrovascular complications [8]. Many compounds have been isolated from Salviamiltiorrhizaroots, which could be classified as lipid soluble tanshinones and water-soluble phenolic acid compounds [9]. Among phenolic acids, salvianolic acid B is a major component of S.miltiorrhizaand extensive pharmacological studies have been reported for this compound. Salvianolic acid B inhibited the amyloid formation of human islet amyloid polypeptide and protects pancreatic beta cells against cytotoxicity [10]. Many authors have studied the effect of salvianolic acid B on different organ systems in animals as well as in humans. Salvianolic acid B showed beneficial and protective effect to brain from ischemia-reperfusion injury in animal studies [11]. In addition, salvianolic acid B has been shown to inhibit platelet aggregation [12] as well as cause oxidative modification of low-density lipoprotein (LDL) thereby, resulting into decreased uptake of LDL by cultured macrophages [13]. Furthermore, salvianolic acid B has been shown to stimulate the nitric oxide production of the endothelial cell [14] and inhibition of angiotensin IIinduced hyperplasia [15]. It significantly inhibited the activity of stressactivated protein (SAP) kinase [16]. Magnesium salt of salvianolic acid B has been shown to possess potent hepatoprotective activity and shows an improved effect on uremic symptoms [17,18]. An in vitro study also revealed that salvianolic acid B is an excellent scavenger for free radicals, both cation radicals and anion radicals [19]. It has been reported that salvianolic acid B has potent inhibitory effects on lipid or biomembrane peroxidation in a superoxide anion generating system [20,21]