CN106420697B

CN106420697B - A kind of polymethoxyflavone, composition and its preparation are used to prevent or treat the purposes of diabetes

Info

Publication number: CN106420697B
Application number: CN201610827938.XA
Authority: CN
Inventors: 郑国栋; 刘鄂湖; 韦敏燕
Original assignee: Guangzhou Medical University
Current assignee: Guangzhou Medical University
Priority date: 2016-09-18
Filing date: 2016-09-18
Publication date: 2019-03-15
Anticipated expiration: 2036-09-18
Also published as: CN106420697A

Abstract

The invention discloses the purposes that a kind of polymethoxyflavone, composition and its preparation are used to prevent or treat diabetes, this is for preventing or treating the active constituent of the drug of diabetes to include polymethoxyflavone, polymethoxyflavone is 3,5,6,7,8,3', 4'- Heptamethoxyflavone, further include pharmaceutically acceptable carrier or excipient, pharmaceutically acceptable dosage form is made.The invention demonstrates that 3,5,6,7,8,3', the fasting blood sugar level that 4'- Heptamethoxyflavone can be effectively improved the diabetes model of high fat diet induction increases, and improves the type-2 diabetes mellitus for being reduced to main feature with impaired glucose tolerance and insulin sensitivity, can be used for treating and preventing diabetes.

Description

A kind of polymethoxyflavone, composition and its preparation are for preventing or treating diabetes Purposes

Technical field

The invention belongs to field of medicaments, are related to the new application of natural products, and in particular to a kind of polymethoxyflavone, combination Object and its preparation are used to prevent or treat the purposes of diabetes.

Background technique

Diabetes are a kind of since defect of insulin secretion (type-1 diabetes mellitus) or insulin resistance (type-2 diabetes mellitus) are with height The incretion metabolism disease that blood glucose is characterized has become the third-largest harm human health for being only second to cardiovascular disease and cancer Disease.2015, the report of International Diabetes Federation (IDF) publication claims the whole world, and there are about 4.15 hundred million adults with glycosuria Disease, it is contemplated that it is dead due to diabetes that there are about 5 million peoples.Treatment type-2 diabetes mellitus mainly uses diet, kinesiatrics, sulfonylurea at present Class, meglitinide, biguanides, thiazolidinediones, alpha-glucosaccharase inhibitor, insulin etc., but due to diabetes pathology, For etiological study so far there are no substantive breakthrough, cardiovascular pathological changes, kidney are continuously emerged while taking Western medicine for a long time in patient The complication such as popular name for change, neuropathy.Therefore the newtype drug for researching and developing effectively treatment diabetes has important clinical meaning.

Polymethoxyflavone (PolymethoxylatedFlavones, PMFs) is that one kind contains multiple methoxyl groups, low pole Property, the flavones ingredient for having strong bioactivity with planar structure, are 3 in phenyl chromone structure, 4,5,6,7, It is connected with 4 or 4 or more methoxyl groups at the positions such as 8,2', 3', 4', 5', 6', is mainly derived from Rutaceae Citrus, is present in In the medicinal materials such as dried orange peel, green peel, Exocarpium Citri Rubrum, fingered citron, the dried immature fruit of citron orange.3,5,6,7,8,3', 4'- Heptamethoxyflavone (HMF) are exactly wherein one Kind, molecular formula C₂₂H₂₄O₉, relative molecular mass 432.43, No. CAS is 1178-24-1, and chemical structure is as follows:

Summary of the invention

The object of the present invention is to provide a kind of polymethoxyflavone, composition and its preparations for preventing or treating diabetes Purposes, the polymethoxyflavone be 3,5,6,7,8,3', 4'- Heptamethoxyflavone (HMF).

Above-mentioned purpose is achieved by the following technical solution:

It is a kind of for preventing or treating the drug of diabetes, active constituent includes polymethoxyflavone.

Preferably, the polymethoxyflavone is 3,5,6,7,8,3', 4'- Heptamethoxyflavone.

Preferably, the active constituent further includes Radix Polygalae mouth mountain ketone, is the combination of polymethoxyflavone and Radix Polygalae mouth mountain ketone Object.

It is a kind of for preventing or treat the pharmaceutical preparation of diabetes, including above-mentioned active constituent, further including pharmaceutically can be with The carrier or excipient of receiving, are made pharmaceutically acceptable dosage form.

Preferably, the pharmaceutically acceptable carrier or excipient include one or more solids, semisolid or liquid Body auxiliary material.

Preferably, the pharmaceutically acceptable dosage form includes tablet, dispersible tablet, capsule, soft capsule, micro-capsule Agent, granule, injection, powder-injection, freeze drying powder injection, micropill preparation, pill, syrup, powder, extract, soft extract, mouth Take liquid preparation.

Beneficial effects of the present invention:

The invention demonstrates that 3,5,6,7,8,3', 4'- Heptamethoxyflavone can be effectively improved the glycosuria of high fat diet induction The fasting blood sugar level of disease model increases, and improves the II type sugar that main feature is reduced to impaired glucose tolerance and insulin sensitivity Urine disease, can be used for treating and preventing diabetes.

Detailed description of the invention

Fig. 1 is fasting blood sugar level；

Fig. 2 is blood glucose level curve after insulin injection；

Fig. 3 is blood glucose level quantitative analysis results (area under the curve AUC) after insulin injection；

Fig. 4 is blood glucose level curve after oral glucose；

Fig. 5 is blood glucose level quantitative analysis results (area under the curve AUC) after oral glucose.

Specific embodiment

Technical solution of the present invention is specifically introduced with reference to the accompanying drawings and examples.

Experimental method:

1, the foundation of animal model

C57BL/6 male mice 60, weight 18-20g are taken, 6 week old.Mouse adapts to random grouping after a week are as follows: normal Feed group (Normal chow diet, NCD), high fat diet group (High fat diet, HFD), 3,5,6,7,8,3', 4'- seven Methoxy flavone low dose group (HMF-L) and 3,5,6,7,8,3', 4'- Heptamethoxyflavone high dose group (HMF-H), except normal Other outer groups of feed group are all made of high fat diet.HFD feed formula are as follows: 1.25% cholesterol, 20% lard, 5% sucrose, 0.5% cholic acid, vitamin are adjusted to normal level.Modeling starts to be administered, and experimental period is 6 weeks, and NCD and HFD give same volume 0.5%CMC-Na solution.

2, dosage and administration mode: in HFD Induction experiments, mouse is carried out using the administration mode of stomach-filling.Modeling is opened Beginning administration, NCD and HFD give the 0.5%CMC-Na solution of same volume, are administered six weeks altogether.HMF-L group dosage is 25mg/ G/d, HMF-H group dosage are 50mg/g/d.HMF is with 0.5CMC-Na solution allocation at suspension.

3, blood sugar detection: at corresponding time point, Mouse Tail-tip blood sampling, using Omron and Omron blood sugar test paper into Row blood-sugar level measuring.

Experimental result:

It is one of diabetes diagnostic criterion as defined in World Health Organization that fasting blood sugar level, which is higher than 7.0mM, as shown in Figure 1, making High in fat group of blood glucose is up to 8.55mM after mould, illustrates Glycemia Decline success, HMF-L group and HMF-H group after administration, blood glucose difference 7.12 and 6.99mM are down to, there is statistical discrepancy (P < 0.05) compared with HFD.Insulin resistance is the main of type-2 diabetes mellitus Feature, i.e. impaired glucose tolerance, insulin sensitivity reduces, in order to further confirm that HMF to diabetes improvement result, is carried out respectively Insulin tolerance (Insulin tolerance test, ITT) and oral glucose tolerance (Oral glucose tolerance Test, OGTT), and area under its corresponding curve line (Area under the curve, AUC) is measured.

After being administered 4 weeks, insulin resistant measurement is carried out, after mouse fasting 6h, gives mouse peritoneal insulin injection 0.75IU/kg is injected intraperitoneally 0,30,60,90,120,150min, tail point blood sampling measurement mouse blood sugar, and calculates below ITT line Product.Insulin tolerance test is the experiment for reflecting body to insulin sensitivity, and type-2 diabetes mellitus is mainly characterized by insulin It resists, insulin sensitivity is reduced, i.e., blood glucose is higher than normal body in injection same insulin same time, as shown in Fig. 2, HFD group blood glucose decrease speed obviously slows down after giving identical insulin, in 30,60,90,120,150min fasting blood sugar level It is significantly higher than normal group, apparent insulin resistance occurs after prompting HFD modeling, effectively reversed this different after HMF administration It often occurs as AUC is the results show that the reverse effect of HMF-H is significant (P < 0.05).The above result shows that HMF can effectively be treated with pancreas Resist the type-2 diabetes mellitus being characterized in island.Further to confirm this as a result, we are calculated using GraphPad Prism software Area (AUC) is used for quantitative analysis under response curve line, as shown in figure 3, the AUC of HFD group ITT is about increased to NCD's after modeling Twice, insulin sensitivity significantly reduces after modeling, and HMF-H is significantly reduced compared to HFD group, and has statistical difference (P < 0.05), illustrate to significantly improve the sensibility of pancreas islet after administration is intervened.

After being administered 5 weeks, glucose tolerance measurement is carried out.Carbohydrate tolerance test is a kind of oral glucose load test, to Body is understood to the blood sugar regulation ability after feeding glucose, is the goldstandard of diagnosis diabetes generally acknowledged at present.It is resistance to by sugar Amount test, is conducive to the early detection of abnormal carbohydrate metabolism.It is clear when blood glucose increases but diabetes diagnostic criterion has not yet been reached Whether suffer from diabetes, antidiastole can be carried out using OGTT.Under normal circumstances, body has a set of mechanism for maintaining blood glucose, mouth Glucose is taken, restores normal after the of short duration raising of blood glucose rapidly, i.e. normal glucose tolerance, area under corresponding oral glucose tolerance curve line Smaller, the Use barriers of diabetic's sugar, blood glucose increases rapidly after oral glucose, and blood glucose decrease speed is slower, i.e., sugared resistance to Area is larger under the corresponding line of amount decline, impaired glucose tolerance in the experiment.As shown in figure 4, the mouse for giving overnight fasting is identical After the glucose of equivalent, HFD group fasting blood sugar level is above normal group in 15,30,60,90,120min, goes out after showing modeling Apparent sugar tolerance decline is showed, HMF-L and HMF-H intervention have effectively reversed this as a result, in order to better illustrate this Phenomenon, we are measured area (AUC) under its corresponding curve line, the results show that compared with NCD group, the AUC of HFD group It increases 64%, HMF-L and HMF-H group and has reversed this raising (Fig. 5) with dose-effect dependence, illustrate that HMF effectively changes Impaired glucose tolerance has been apt to it, that is, the main feature pancreas islet for improving type-2 diabetes mellitus is resisted.

In Fig. 1-Fig. 5, the meaning of symbology are as follows: compared with NCD, * P < 0.05, * * P < 0.01, * * * P < 0.001； Compared with HFD, there was no significant difference by n.s., * P < 0.05, * * P < 0.01, * * * P < 0.001.

In conclusion the fasting blood sugar level that HMF can be effectively improved the diabetes model of high fat diet induction increases, change The kind type-2 diabetes mellitus that main feature is reduced to impaired glucose tolerance and insulin sensitivity.

It has also been found that, Radix Polygalae mouth mountain ketone can be enhanced HMF and prevent and treat diabetes effect, according to above-mentioned experiment side in experiment Method using a half-value dose in HMF low dose group HMF and Radix Polygalae mouth mountain ketone (dosage be HMF dosage 0.1 times) group Closing to use can just make blood sugar recovery to the level of NCD group, and ITT area under the curve AUC is that 370, OGTT area under the curve is 810, there was no significant difference (P > 0.05) with NCD group.When individually giving the Radix Polygalae mouth mountain ketone of above-mentioned dosage, blood glucose and HFD group There was no significant difference (P > 0.05), ITT and OGTT area under the curve AUC is respectively 750,1290.

The effect of above-described embodiment, which is only that, illustrates essentiality content of the invention, but guarantor of the invention is not limited with this Protect range.Those skilled in the art should understand that can modify to technical solution of the present invention or equally replace It changes, without departing from the essence and protection scope of technical solution of the present invention.

Claims

1. a kind of application of agent for amelioration of insulin resistance in the drug of preparation prevention and treatment diabetes, it is characterised in that: the pancreas islet Element is resisted improver and is made of 3,5,6,7,8,3', 4'- Heptamethoxyflavone and Radix Polygalae mouth mountain ketone, and 3, and 5,6, The weight ratio of 7,8,3', 4'- Heptamethoxyflavone and Radix Polygalae mouth mountain ketone is 10:1.

2. a kind of for preventing and treating the pharmaceutical preparation of diabetes, it is characterised in that: change including insulin resistance described in claim 1 Kind agent further includes pharmaceutically acceptable carrier or excipient, pharmaceutically acceptable dosage form is made.

3. pharmaceutical preparation according to claim 2, it is characterised in that: the pharmaceutically acceptable carrier or excipient Including one or more solids, semisolid or Auxiliary Liquid Material.