The Aqueous Extract of Gynura divaricata (L.) DC. Improves Glucose and Lipid Metabolism and Ameliorates Type 2 Diabetes Mellitus

Abstract

Type 2 diabetes mellitus (T2DM) is a chronic disease characterized by hyperglycemia and dyslipidemia caused by impaired insulin secretion and resistance of the peripheral tissues. A major pathogenesis of T2DM is obesity-associated insulin resistance. Gynura divaricata (L.) DC. (GD) is a natural plant and has been reported to have numerous health-promoting effects on both animals and humans. In this study, we aimed to elucidate the regulatory mechanism of GD improving glucose and lipid metabolism in an obesity animal model induced by high-fat and high-sugar diet in combination with low dose of streptozocin and an insulin-resistant HepG2 cell model induced by dexamethasone. The study showed that the water extract of GD (GD extract A) could significantly reduce fasting serum glucose, reverse dyslipidemia and pancreatic damage, and regulate the body weight of mice. We also found that GD extract A had low toxicity in vivo and in vitro. Furthermore, GD extract A may increase glucose consumption in insulin-resistant HepG2 cells, markedly inhibit NF-κB activation, and decrease the impairment in signaling molecules of insulin pathway, such as IRS-1, AKT, and GLUT1. Overall, the results indicate that GD extract A is a promising candidate for the prevention and treatment of T2DM.

Figure 1

The effect of GD on glucose metabolism in Dex-induced insulin-resistant HepG2 cells. HepG2 cells were incubated with or without 500 nM Dex for 24 hours and in 1 nM insulin with or without the drugs (pioglitazone or different extracts of GD) for another 24 hours (a). HepG2 cells were incubated with or without 500 nM Dex for 24 hours and in 1 nM insulin with or without the drugs (pioglitazone or different concentrations of extract A) for another 24 hours (b). ^#P < 0.05, ^##P < 0.01, and ^###P < 0.001 versus control group; ^∗P < 0.05 and ^∗∗∗P < 0.001 versus IR-Model group.

Figure 2

The effects of GD extract A on mice. The body weight was recorded every day (a). The blood glucose of mice after treatment with GD extract A at 100 mg/kg/day, pioglitazone at 0.03 g/kg/day, or saline (control mice) for 2 consecutive weeks (b) or 4 consecutive weeks (c). The data of GTT was collected at 0, 30, 60, and 120 min after the injection of glucose (d). ^##P < 0.01 and ^###P < 0.001 versus control group; ^∗P < 0.05 and ^∗∗P < 0.01 versus Model group. The arrow refers to the time point of the drug.

Figure 3

Blood biochemical indexes (cholesterol, triglyceride, LDL-C, HDL-C, insulin, and GLP-1) of diabetic mice. Blood samples were collected from the orbital sinus, and cholesterol (a), triglyceride (b), LDL-C (c), HDL-C (d), insulin (e), and GLP-1 (f) levels were measured following administration of GD extract A at 100 mg/kg/day, pioglitazone at 0.03 g/kg/day, or saline (control and model mice) for 4 consecutive weeks in high-fat-diet-treated mice. ^#P < 0.05, ^##P < 0.01, and ^###P < 0.001 versua control group; ^∗P < 0.05, ^∗∗P < 0.01, and ^∗∗∗P < 0.001 versus Model group.

Figure 4

Histopathological changes in the experimental groups. Light microscopic study of pancreatic islets (a1)–(a4), kidney (b1)–(b4), and liver (c1)–(c4) from different experimental groups: control: (a1), (b1), and (c1); model: (a2), (b2), and (c2); pioglitazone: (a3), (b3), and (c3); GD extract A: (a4), (b4), and (c4).

Figure 5

Effect of GD extract A and pioglitazone on insulin signaling pathways. NF-κB transcription activity with or without TNF-α (10 ng/ml) and GD extract A (10 mg/ml) in 293T cells was detected by luciferase reporter assays (a). HepG2 cells were incubated with or without 100 nM Dex for 24 hours and in 1 nM insulin with or without the drugs (pioglitazone or GD extract A) for another 24 hours. Cells lysates were separated by SDS-PAGE and subjected to Western blot analysis with IRS-1 (b), anti-phosphorylation AKT antibody (Ser473) (c), and GLUT1 antibody (d). ^##P < 0.01 versus control group; ^∗∗P < 0.01 and ^∗∗∗P < 0.001 versus IR-Model group.

Figure 6

Cytotoxicity of GD extract A. Cytotoxicity of GD extract A on (a) HEK-293 and (b) NIH-3T3 cells. Standard error bars represent three independent experiments, and each experiment was performed in triplicate.

Figure 7

Schematic summary of mechanism of action of GD extract A.