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An Efficient Hypoglycemic Fraction Screened from the Fruiting Bodies of Ganoderma Lucidum (Fr.) Karst and Its Antihyperglycemic Mechanism in Vivo

Author: ZuoBaoSong
Tutor: ZhouPing
School: Fudan University
Course: Polymer Chemistry and Physics
Keywords: Ganoderma Lucidum polysaccharide diabetes type2diabetes metabolic disorders protein tyrosine phosphatase1B
CLC: R284
Type: PhD thesis
Year: 2012
Downloads: 57
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Abstract


Objectives:Ganoderma lucidum has traditionally been used for the treatment of endocrine-related diseases, metabolic disorders and diabetes. This work aimed to study the antihyperglycemic mechanism in vivo of a Ganoderma Lucidum extraction, FYGL, screened from the fruiting bodies of Ganoderma Lucidum (Fr.) Karst.Methods:PTP1B inhibitors were screened from the fruiting bodies of G. lucidum. The chemical components of the PTP1B inhibitor were characterized by the Infrared (IR) and Nuclear Magnetic Resonance (NMR) spectrum for the functional groups, anion-exchange chromatography for the monosaccharide contents, and the amino acid analyzer for the amino acid residues. The db/db mice and streptozotocin (STZ)-induced type2diabetic mellitus (T2DM) model mice and rats were treated with FYGL as well as metformin and rosiglitazone. The levels of plasma glucose and insulin were measured, and the expression and activity of the protein tyrosine phosphatase1B (PTP1B) and the tyrosine phosphorylation level of the insulin receptor (IR) β-subunit in the livers and skeletal muscles of the T2DM rats and db/db mice were analyzed by immunoprecipitation and Western blotting methods. In addition, the inhibity ability to a-glucosidase, a-amylase and free radical of FYGL was also investigated in vitro. At last, the levels of free fatty acid and serum lipid profile including triglyceride, total cholesterol, low density lipoprotein-cholesterol and high density lipoprotein-cholesterol were measured using commercial kits for those trailed rats.Results:A PTP1B activity inhibitor was screened from the fruiting bodies of G. lucidum. The inhibitor, named FYGL, has an efficient PTP1B inhibitory potency with IC50value of5.12±0.05μg/mL in a competitive inhibition kinetics mechanism. It was demonstrated that FYGL is a water soluble proteoglycan with protein to polysaccharide ratio of17:77, and a viscosity-average molecular weight of2.6×105.Treatment for the STZ-induced type2diabetes mice, rats and db/db mice with a dose of150,120and225mg/kg FYGL for4weeks,30days and4weeks significantly decreased the fasting plasma glucose level by40.7%(p<0.01),31.8%(p<0.01) and29.1%(p<0.01), respectively, compared to the diabetic control group without drug treatment. The decrease in the plasma glucose concentration for the FYGL treatment group is comparable with that for the250mg/kg metformin and3mg/kg rosiglitazone treatment group. The FYGL does lead to the dose-and time-dependent decrease in the fasting plasma glucose. FYGL could decrease the insulin insistant of T2DM rats and db/db mice and promote the insulin release of T2DM rats. During the toxicity trial, the toxicity of FYGL was preliminarily evaluated as LD50=6g/kg with95%confidence limits of4.8-7.4g/kg.FYGL decreased the PTP1B expression and activity in the skeletal muscles of T2DM rats, but not in the livers of T2DM rats, while decreased the PTP1B expression in the liver and skeletal muscles and decreased the PTP1B activity in the skeletal muscles of db/db mice, consequently, increased the tyrosine phosphorylation level of the IR β-subunit (p<0.05) in the skeletal muscles of T2DM rats and the tyrosine phosphorylation level of the IR p-subunit in the liver and skeletal muscles of db/db mice.In addition, FYGL can inhibite the activity of a-glucosidase, a-amylase and free radical in vitro, which suggesting that FYGL has the multiple target point function.At last, FYGL significantly decreased the levels of free fatty acid, triglyceride, total cholesterol and low density lipoprotein-cholesterol as well as increased the level of high density lipoprotein-cholesterol, which are the important plasma biochemistry indexes.Conclusions:FYGL decreases the plasma glucose level based on the mechanism of the inhibiting the PTP1B expression and activity, consequently, mediating the tyrosine phosphorylation level of the IR β-subunit; meanwhile it decrease the serum insulin insistant and maybe recover the pancreatic β-cells function. As those results, FYGL can also control the plasma biochemistry indexes relative to the type2diabetes with metabolic disorders. Therefore, FYGL is promising to be used as a drug candidate for the type2diabetes and their metabolic disorders.

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