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, 9, e2

Ficus deltoidea Extract Down-Regulates Protein Tyrosine Phosphatase 1B Expression in a Rat Model of Type 2 Diabetes Mellitus: A New Insight Into Its Antidiabetic Mechanism

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Ficus deltoidea Extract Down-Regulates Protein Tyrosine Phosphatase 1B Expression in a Rat Model of Type 2 Diabetes Mellitus: A New Insight Into Its Antidiabetic Mechanism

Rehab F Abdel-Rahman et al. J Nutr Sci.

Abstract

Ficus deltoidea var. deltoidea Jack (FD) is a well-known plant used in Malay folklore medicine to lower blood glucose in diabetic patients. For further research of the antihyperglycemic mechanisms, the protein tyrosine phosphatase 1B (PTP1B)-inhibitory effect of FD was analysed both in vitro and in vivo. To optimise a method for FD extraction, water, 50, 70, 80, 90 and 95 % ethanol extracts were prepared and determined for their total phenolic and triterpene contents, and PTP1B-inhibition capacity. Among the tested extracts, 70 % ethanol FD extract showed a significant PTP1B inhibition (92·0 % inhibition at 200 µg/ml) and high phenolic and triterpene contents. A bioassay-guided fractionation of the 70 % ethanol extract led to the isolation of a new triterpene (3β,11β-dihydroxyolean-12-en-23-oic acid; F3) along with six known compounds. In vivo, 4 weeks' administration of 70 % ethanol FD extract (125, 250 and 500 mg/kg/d) to streptozotocin-nicotinamide-induced type 2 diabetic rats reversed the abnormal changes of blood glucose, insulin, total Hb, GLUT2, lipid profile, and oxidative stress in liver and pancreas. Moreover, FD reduced the mRNA expression of the key gluconeogenic enzymes (phosphoenolpyruvate carboxykinase and glucose 6-phosphatase) and restored insulin receptor and GLUT2 encoding gene (Slc2a2) expression. In addition, FD significantly down-regulated the hepatic PTP1B gene expression. These results revealed that FD could potentially improve insulin sensitivity, suppress hepatic glucose output and enhance glucose uptake in type 2 diabetes mellitus through down-regulation of PTP1B. Together, our findings give scientific evidence for the traditional use of FD as an antidiabetic agent.

Keywords: CAT, catalase; Dihydroxyolean-12-en-23-oic acid; FBG, fasting blood glucose; FD, Ficus deltoidea var. deltoidea Jack; Ficus deltoidea; G6Pase, glucose 6-phosphatase; GPx, glutathione peroxidase; GSH, reduced glutathione; Glucose 6-phosphatase; Glucose transporter-2; MDA, malondialdehyde; MET, metformin; NA, nicotinamide; PEPCK, phosphoenolpyruvate carboxykinase; PTP, protein tyrosine phosphatase; Phosphoenolpyruvate carboxykinase; Protein tyrosine phosphatase 1B; SOD, superoxide dismutase; STZ, streptozotocin; Slc2a2, GLUT2 gene; T2DM, type 2 diabetes mellitus.

Figures

Fig. 1.
Fig. 1.
(A) Structures of the isolated compounds F1–F7. (B) Heteronuclear multiple bond correlations for F3.
Fig. 2.
Fig. 2.
Protein tyrosine phosphatase 1B-inhibitory effects of extracts (A) and fractions (B). EtOH, ethanol; MeOH, methanol.
Fig. 3.
Fig. 3.
Hepatic (A) and pancreatic (B) GLUT2 concentrations. Values are means, with standard deviations represented by vertical bars. a,b Mean values with unlike letters were significantly different (P ≤0.05). MET, metformin; FD 125, Ficus deltoidei 125 mg/kg body weight; FD 250, F. deltoidei 250 mg/kg body weight; FD 500, F. deltoidei 500 mg/kg body weight.
Fig. 4.
Fig. 4.
Histopathology of the pancreas of the control group (A), diabetic group (B), group treated with Ficus deltoidei at 125 mg/kg body weight (C), group treated with F. deltoidei at 250 mg/kg body weight (D), group treated with F. deltoidei at 500 mg/kg body weight (E) and the metformin-treated group (F).
Fig. 5.
Fig. 5.
Morphometric analysis of the pancreatic islets. (A) Lesion score, β-cell/total islet area (B), α-cell/total islet area (C) and δ-cell/total islet area (D). Values are means, with standard deviations represented by vertical bars. * Mean value was statistically significantly different from that of the normal control group (P ≤ 0·05). † Mean value was statistically significantly different from that of the diabetic control group (P ≤ 0·05). FD 125 mg/kg, Ficus deltoidei 125 mg/kg body weight; FD 250 mg/kg, F. deltoidei 250 mg/kg body weight; FD 500 mg/kg, F. deltoidei 500 mg/kg body weight; p.duct, pancreatic duct; MNC, mononuclear cells.
Fig. 6.
Fig. 6.
Immunohistochemical analysis of insulin protein expression and islet morphology in the control group (A), diabetic group (B), group treated with Ficus deltoidei at 125 mg/kg body weight (C), group treated with F. deltoidei at 250 mg/kg body weight (D), group treated with F. deltoidei at 500 mg/kg body weight (E) and the metformin-treated group (F).
Fig. 7.
Fig. 7.
Immunohistochemical analysis of glucagon protein expression and islet morphology in the control group (A), diabetic group (B), group treated with Ficus deltoidei at 125 mg/kg body weight (C), group treated with F. deltoidei at 250 mg/kg body weight (D), group treated with F. deltoidei at 500 mg/kg body weight (E) and the metformin-treated group (F).
Fig. 8.
Fig. 8.
Immunohistochemical analysis of somatostatin protein expression and islet morphology in the control group (A), diabetic group (B), group treated with Ficus deltoidei at 125 mg/kg body weight (C), group treated with F. deltoidei at 250 mg/kg body weight (D), group treated with F. deltoidei at 500 mg/kg body weight (E) and the metformin-treated group (F).
Fig. 9.
Fig. 9.
Effects of Ficus deltoidea on glucose uptake and metabolism-related gene expression. Relative quantification (RQ) of mRNA expression of protein tyrosine phosphatase 1B (A), phosphoenolpyruvate carboxykinase (PEPCK) (B), glucose 6-phosphatase (G6Pase) (C), GLUT2 gene (Slc2a2) (D) and insulin receptor (INR) (E). Values are means, with standard deviations represented by vertical bars. a,b,c Mean values with unlike letters were significantly different (P ≤0.05). Group I, control group; group II, diabetic group; group III, group treated with F. deltoidei at 125 mg/kg body weight; group IV, group treated with F. deltoidei at 250 mg/kg body weight; group V, group treated with F. deltoidei at 500 mg/kg body weight; group VI, metformin-treated group.

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