The Funamental Study On Diabetes Prevention And Treatment By Natural Polyphenolic Insulin Sensitizers

Diabetes mellitus remains one of the world's most pressing public health concerns and diabetes prevention and treatment has attracted extensive attention.Insulin sensitizers are highly efficacious therapies for diabetes prevention and treatment.However,the clinical application of insulin sensitizers are still controversial,due to the side effects,including weight gain and increased risk of heart failure.Flavonoids and phenolic acids are the main polyphenols which widely exist in frequently consumed fruits and vegetables as well as in some medicinal plants and these compounds have a favorable safety profile.Therefore,it has great significance to discovery polyphenolic insulin sensitizers from natrual product and determine the effect and mechanism of these polyphenols on diabetes prevention and treatment.In view of the above problems,this paper make study on the follow aspects.Firstly,a series of extracts were screened with peroxisome proliferator activated receptor?(PPAR?)transcriptional activation and protein tyrosine phosphatase 1B(PTP1B)inhibitory activities.As a result,Oroxylum indicum seed extract(OISE)which has PPARy transcriptional activation activity was obtained.After separation,purification and structrual identification,chrysin and oroxin A were obtained as PPARy transcriptional activators.A Yunnan soil fungus extract showed strong PTP1B inhibitory activity.The PTP1B inhibitory experiments and docking experiments indicated that a series of varic acid analogues were the main active components of this extract and they show preliminary structure-activity relationships(SARs)gainst PTP1B.Different numbers of structral units might have great influence on PTP1B inhibition activity(three units>two units>one unit).The hydroxyl groups on C-2 and C-4 might be important for PTP1B inhibition activity.The long-chain substitution group on C-6 of the benzene ring might be unfavorable to the inhibition activity.The carboxylic group in C-6' have a slight influence on inhibition activity.Trivaric acid was the strongest PTP1B inhibitor of varic acid analogues,whose IC50 was 0.17?M.The kinetics studies indicated that trivaric acid was a reversible typical competitive inhibitor of PTPIB.Secondly,Sub-acute and acute oral toxicities of OISE were measured to evaluate the safety of OISE and to determine the maximal dosage.A prediabetic mouse model using high fat diet and streptozocin(STZ)was induced to evaluate the therapeutic effects of OISE and its main flavonoids on diabetes prevention with acarbose.The results indicated the relative risk reduction from prediabetes to diabetes(RRRD)of the combination of OISE and acarbose,the combination of baicalein and acarbose and oroxin A was 75%,83.3%and 66.7%,respectively.These three drugs could improve insulin resistance,reduce oxidant stress,prevent abnormal lipid and pathological changes of hepatic tissues.The mechanism of OISE and its main flavonoids on insulin sensitivity and diabetes prevention were investigated.Oroxin A could improve insulin sensitivity by increasing phosphorylation of insulin receptor substrate 1(IRS1),the abundance of glucose transporter-2(GLUT-2)and the glucose consumption via activating PPARy in vitro and in vivo.Baicalein could also improve insulin sensitivity by reducing the expression of suppressor of cytokine signaling 3(SOCS3),increasing the phosphorylation of IRS1 and protein kinase B(Aktl),reducing the phosphorylation of glycogen synthase kinase 3(GSK3?)and increasing the level of hepatic glycogen in vitro and in vivo.Insulin sensitization increment and anti-oxidation from chrysin,baicalein or oroxin A might be the main mechanisms of OISE and its main flavonoids on diabetes prevention with acarbose.Trivaric acid can significantly reduce postprandial hyperglycemia by both i.v and i.g single administration.A long-term experiment data indicated that trivaric acid could improve insulin resistance,leptin resistance and lipid metabolism by reducing fasting blood glucose,fasting blood insulin and fasting blood leptin.Mechanism studies indicated that trivaric acid could improve the insulin sensitivity by increasing the phosphorylation of IRS1,insulin receptor(IR)and Akt,the abundance of GLUT-2 and the glucose consumption via inhibiting PTP1B in vitro.In this study,the therapeutic effects and mechanisms of four compounds or combinations from natural product on diabetes prevention or treatment were ivestgated.These data provided the theoretic foundation for developing new drugs of natural sources for diabetes prevention and treatment.