Hypoglycemic effect of protopanaxadiol-type ginsenosides and compound K on Type 2 Diabetes mice induced by High-Fat Diet combining with Streptozotocin via suppression of hepatic gluconeogenesis
Graphical abstract
Protopanaxadiol-type ginsenosides (PDG) and compound K (CK) show hypoglycemic effect on Type 2 Diabetes mice induced by High-Fat Die/Streptozotocin.
CK inhibit glucose production via suppression of PEPCK and G6Pase expression in liver.
This is a new mechanism for CK action in the regulation of glucose metabolism.
Introduction
Type 2 diabetes is a complex, heterogenous, polygenic disease characterized mainly by insulin resistance and pancreatic β-cell dysfunction [1]. Impaired postprandial insulin secretion because of functional defects and the loss of surviving pancreatic β-cells leads to hyperglycemia and a subsequent decline in insulin sensitivity [2], [3]. Recently, more and more studies found that gluconeogenesis is a main cause of the elevated hepatic glucose production, contributing 50–60% of the released glucose [4]. Excessive hepatic glucose production via the gluconeogenesis pathway is partially responsible for the elevated glucose levels observed in patients with T2DM [5], [6]. The rate of gluconeogenesis is regulated by the activity of two rate-limiting gluconeogenic enzyme, Phosphoenolpyruvate carboxykinase (PEPCK) and Glucose-6-phosphatase (G6Pase) [7]. Inhibition of hepatic gluconeogenesis (suppression of PEPCK and G6Pase expression) contributes to glycemic control in the diabetic patients by insulin sensitizers [8]. Therefore, inhibitors of hepatic gluconeogenesis are potentially excellent targets in the treatment of T2DM.
Although several drugs are available for the treatment of diabetes, side effects and adverse reactions are of great concern. Recently, many researchers are seeking natural products or dietary interventions to prevent or treat T2DM. For thousands of years with medical practice, a great deal of valuable experience has been accumulated in the traditional Chinese medical system for diabetes therapy. To date, ginseng (Panax ginseng C.A Meyer) was considered as one of the most powerful complementary and alternative medicine for diabetes treatment [9], [10]. Generally, the pharmacological properties of ginseng are mainly attributed to ginsenosides which mainly classified into protopanaxadiol-type ginsenosides (PDG, e.g. ginsenosides Rb1, Rb2, Rc, Rd, Rg3 and Rh2) and protopanaxatriol-type ginsenosides (PTG, e.g., ginsenosides Reand Rg1) based on sapogenins with a dammarane skeleton [11]. During our previous investigation on anti-obesity activity of ginsenosides, PDG was found to significantly inhibit pancreatic lipase activity in vitro and decrease the plasma lipids in mice fed with a high-fat diet [12]. It is well known that PDG are metabolized by intestinal bacteria after oral administration to their final derivative 20-O-β-D-glucopyranosyl-20(S)-protopanaxadiol, also named compound K (the major form of PDG absorbed in the intestine) [13], [14]. Recently, CK have received increasing attention in view of various biological activities including anti-cancer [15], [16], anti-inflammation [17] and hepatoprotective effect [18]. The structure of CK is shown in Fig. 1.
Prior to this investigation, some researcher have also demonstrated the reduction of blood glucose and increase in insulin sensitivity in db/db mice [19], as well as reducing of HepG2 cellular triglyceride accumulation with CK treatment [20]. Up to now, however, little attention has been focus on the role of CK for treating type 2 diabetes, a more prevalent form of diabetes. Furthermore, given that CK inhibits hepatic gluconeogenesis, this possibility may represent a new mechanism for CK in the control of blood glucose. In summary, the primary objective of this paper was to carry out the hypoglycemic effect of CK and PDG on the HFD/STZ mice and to look into the mechanism of anti-diabetic activity. The data presented here suggest that CK exerts anti-diabetic effects partly via down-regulation of expression of PEPCK and G6Pase. To the best of our knowledge, this is the first report on CK ameliorates hyperglycemia via suppress hepatic gluconeogenesis.
Section snippets
Materials
STZ was purchased from Sigma Chemicals, insulin was purchased from Eli Lilly, Changchun, China; Glucose, total cholesterol (TC), triglyceride (TG) test kit were obtained from BHKT Clinical Reagent Co., Ltd, Beijing, China; Iodine [125I] Insulin Radioimmunoassay Kit was purchased from Tianjin Nine Tripods Medical & Bioengineering Co., Ltd, Tianjin, China; Other reagents were purchased from Beijing Chemical Factory, Beijing, China. Compound K used in this study was isolated and purified from P.
Enzymatic preparation of CK from PDG
Generally, CK is considered as the main pharmacologically active metabolites detected in blood after the oral administration of PDG. However, CK is not present in most natural ginseng plants. Hence, it is of great significance to convert major ginsenosides to CK. To date, enzymatic preparation is considered to be an effective way to produce CK, via the cleavage of sugar moieties at the C-3 and/or C-20 positions. The hydrolyzing ability of several glycolytic enzymes based on the glycosidic
Discussion
In the past decades, type 2 diabetes mellitus (T2DM) prevalence has been increasing rapidly and is now considered a worldwide epidemic [22]. Therefore, better treatments and novel prevention strategies for T2DM are urgently needed. To accomplish this goal, it is vital to establish an appropriate experimental animal model [23]. To date, some spontaneous and experimental diabetic animal models were available for study of type 2 diabetes, some of which possessed pathological features resembling
Acknowledgements
This work was supported Jilin Science & Technology Development Plan (20070728-2, 20096040 and 20100914).
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The first two authors contributed equally to this work and were considered co-first author.