CN110548025A - Application of atractylenolide II in preparation of medicine for improving insulin resistance and glycolipid metabolic disorder caused by obesity - Google Patents
Application of atractylenolide II in preparation of medicine for improving insulin resistance and glycolipid metabolic disorder caused by obesity Download PDFInfo
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- CN110548025A CN110548025A CN201910856099.8A CN201910856099A CN110548025A CN 110548025 A CN110548025 A CN 110548025A CN 201910856099 A CN201910856099 A CN 201910856099A CN 110548025 A CN110548025 A CN 110548025A
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- atractylenolide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
Abstract
The invention discloses application of atractylenolide II in preparing a medicament for improving insulin resistance and glycolipid metabolic disorder caused by obesity. After high fat feeding, the weight of the mice is increased, the respiratory entropy and the energy consumption are obviously reduced, which shows that fat mice are changed from sugar metabolism to fat metabolism, fat tissues are diseased, fat drops are increased, and meanwhile, the liver injury and the insulin resistance of the mice are proved by some index detections of plasma and liver. The invention discovers that after the treatment of the atractylenolide II, the weight and the glycolipid metabolism of obese mice are improved, the lipid drops in the liver are reduced, and the insulin resistance is recovered. Therefore, the atractylenolide II can effectively improve insulin resistance and glycolipid metabolic disorders caused by obesity.
Description
Technical Field
The invention belongs to the field of medicines, relates to new application of a known compound, and particularly relates to application of atractylenolide II in preparation of a medicine for improving insulin resistance and glycolipid metabolic disorder caused by obesity.
background
Obesity is caused by an excess of ingested energy, which significantly exceeds consumed energy, resulting in a disturbance in lipid metabolism that can reduce insulin sensitivity, causing insulin resistance. In the pathological process of obesity-induced insulin resistance, high expression of lipase (LPL) is found in liver of liver-specific insulin resistant lipid accumulation mice, and recent researches show that hepatic Diacylglycerol (DAGs) or ceramide (Ceramides) are the material basis for causing insulin resistance. In the pre-obese type II diabetes model, mainly liver tissue DAGs mediate insulin resistance due to lipid accumulation. Increased DAGs activate PKC epsilon, which is transferred to the cell membrane to directly act on IRS-1/2 and inhibit insulin-induced tyrosine phosphorylation, thereby reducing insulin-dependent PI3K activity, and PI3K inactivation causes reduction in protease 1(PDK1) dependent AKT2 activity. AKT2 inhibits glycogen synthesis in liver tissue by regulating glycogen synthase kinase-3 (GSK3) and Glycogen Synthase (GS) signal pathway as substrate; in addition, the AKT2 activity is reduced, FOXO1 phosphorylation is inhibited, FOXO1 nuclear translocation is promoted, downstream target genes of Pyruvate Carboxylase (PC), phosphoenolcarboxylase (PEPCK) and glucose-6-phosphatase (G6Pase) are promoted, and therefore gluconeogenesis of the liver is increased. In conclusion, obesity leads to the disturbance of body lipid metabolism, leads to the accumulation of DAGs in liver cells, and the activation of protein kinase PKC epsilon is a key link for causing liver insulin resistance.
Atractylodes macrocephala lactone II is extracted from dried rhizome of Atractylodes macrocephala Koidz of Compositae, and has effects of invigorating spleen, invigorating qi, eliminating dampness, promoting diuresis, arresting sweating, preventing miscarriage, resisting inflammation, resisting tumor and regulating gastrointestinal tract.
At present, the application of atractylenolide II in improving insulin resistance and glycolipid metabolic disorders caused by obesity is not available.
disclosure of Invention
the invention aims to provide the application of atractylenolide II in preparing a medicament for improving insulin resistance caused by obesity, and aims to provide the application of atractylenolide II in preparing a medicament for improving glycolipid metabolic disorder caused by obesity.
The above purpose of the invention is realized by the following technical scheme:
The medical application of atractylenolide II in preparing the medicine for improving insulin resistance caused by obesity.
Preferably, the medicament takes atractylenolide II as an active ingredient and also contains a pharmaceutically acceptable carrier, and is prepared into a pharmaceutically acceptable dosage form.
More preferably, the carrier is a solid, semi-solid or liquid.
More preferably, the dosage form is tablet, injection, capsule, oral liquid.
The medical application of atractylenolide II in preparing the medicine for improving glycolipid metabolic disorder caused by obesity.
Preferably, the medicament takes atractylenolide II as an active ingredient and also contains a pharmaceutically acceptable carrier, and is prepared into a pharmaceutically acceptable dosage form.
More preferably, the carrier is a solid, semi-solid or liquid.
More preferably, the dosage form is tablet, injection, capsule, oral liquid.
The medical application of atractylenolide II in preparing a medicine for improving liver injury caused by obesity.
Has the advantages that:
After high fat feeding, the weight of the mice is increased, the respiratory entropy and the energy consumption are obviously reduced, which shows that fat mice are changed from sugar metabolism to fat metabolism, fat tissues are diseased, fat drops are increased, and meanwhile, the liver injury and the insulin resistance of the mice are proved by some index detections of plasma and liver. The invention discovers that after the treatment of the atractylenolide II, the weight and the glycolipid metabolism of obese mice are improved, the lipid drops in the liver are reduced, and the insulin resistance is recovered. Therefore, the atractylenolide II can effectively improve insulin resistance caused by obesity and effectively improve glycolipid metabolic disorder caused by obesity.
Drawings
FIG. 1 shows the effect of atractylenolide II on body weight and food intake of mice;
FIG. 2 is a graph of the effect of atractylenolide II on respiratory entropy RQ, O 2 consumption, CO 2 output and energy expenditure EE in mice;
FIG. 3 shows the effect of atractylenolide II on body fat content in mice;
FIG. 4 is a graph of the effect of atractylenolide II on blood glucose in mice;
FIG. 5 is a graph of the effect of atractylenolide II on TC, LDL-c, ALT and AST in the blood of mice;
FIG. 6 shows the results of H & E liver staining and oil red O staining.
Detailed Description
The following detailed description of the present invention is provided in connection with the accompanying drawings and examples, but not intended to limit the scope of the invention.
Reagents and materials
C57BL/6J mice, 6-7 weeks old, male, SPF grade. Purchased from sbefu (beijing) biotechnology limited (license: SCXK (beijing) 2016-: the detection room of Beijing Witonglihua laboratory animal technology Limited company, animal experiment unit: university of chinese pharmacy, No.1103241911003587, laboratory use license number: SYXK (Su) 2016-.
Atractylenolide II (2-Atractylenolide) was purchased from medemns biotechnology limited, product number: a0373-3g, batch number: MUST-19030202, CAS NO: 73069-14-4, MF: C15H20O2, MW:232.32 Purity: 99.99% (HPLC).
metformin (Metformin Hydrochloride) was purchased from MedChemExpress, product number: HY-17471A/CS-1851, CAS NO: 1115-70-4, M.Wt: 165.62, Purity: 99.98 percent.
Mouse maintenance feed: synergistic organism, cargo number: 1010007.
High fat diet D12492 (20.0% carbohydrate, 60.0% fat, 20.0% protein).
Second, Experimental methods
C57BL/6J mice were adapted to feed for 1 week after purchase, and divided into 5 groups, 9 Control groups (Control), 9 model groups (HFD), 9 atractylenolide II low dose groups (HFD + AT II 30mg/kg), 9 atractylenolide II high dose groups (HFD + ATII 60mg/kg), and 7 metformin groups (HFD + Met 280mg/kg), and then the Control groups were given normal diet, and the model and administration groups were given high fat diet D12492. Meanwhile, the administration group is intragastrically administered, and the control group and the model group are intragastrically administered with the same volume of the menstruum. After 8 weeks of gavage, various indexes of the mice were tested.
Intragastric administration dosage: atractylodes macrocephala lactone II 30 mg/kg/day and 60 mg/kg/day, metformin 280 mg/kg/day, dissolved with 0.5% CMC-Na solution, and gavaged at a dosage of 0.1ml/10g C57 mouse body weight.
Third, detecting the index
1. Diet measurement of body weight
The body weight and food intake of the mice were measured once a week according to a conventional method, and the body weight and food intake of the mice in each group were compared.
2. Mouse basal metabolism monitoring
The change in body weight of mice is due to metabolic changes in vivo, and therefore basal metabolic differences among groups of mice were compared by measuring oxygen consumption, carbon dioxide output, respiratory entropy and energy expenditure of mice by a conventional metabolic cage test (after the last administration).
3. Body fat content detection
After the last dose, the fat distribution, body-to-fat ratio and fat-to-muscle ratio of each group of mice were examined by magnetic resonance imaging (Biospec 7T/20USR) according to conventional procedures.
4. Determination of oral glucose tolerance, insulin tolerance and pyruvate tolerance
4.1 determination of oral glucose tolerance or pyruvate tolerance
After 8 weeks of gavage, the mice were fasted and fed with water for 10-12 h. Each group was collected for 0h prior to the start of the experiment. The stomach of each group was perfused with 2g/kg glucose or sodium pyruvate. And (3) taking blood from the tail end, detecting blood sugar values of 0min, 15 min, 30 min, 60 min, 90 min and 120min by using a glucometer (ohm dragon), and calculating the area under the Oral glucose tolerance (OGTT) or (PTT).
4.2 insulin tolerance test
After 8 weeks of gavage, mice were fasted for 4 h. Each group was collected for 0h prior to the start of the experiment. Each group was administered with 0.5U/kg of insulin by intraperitoneal injection. Blood is taken from the tail end, blood glucose values of 0min, 15 min, 30 min, 60 min, 90 min and 120min are detected by a glucometer (ohm dragon), and the area under the line of insulin tolerance (ITT) is calculated.
5. Blood biochemical index detection
The contents of TC, LDL-c, ALT and AST in the blood of the mice were determined according to a conventional method.
6. tissue section
H & E and oil red O staining are carried out on mouse liver tissues according to a conventional method, H & E staining is carried out on adipose tissues, and liver pathological changes of mice in each group are compared.
7. Statistical analysis
All data are plotted as mean ± SD, homogeneity of variance is tested using One-way ANOVA with One-way analysis of variance, and analyzed using Student's-t test, with p <0.05 indicating significant differences.
Fourth, experimental results
1. Effect of Atractylodes macrocephala lactone II on mouse weight and food intake
The influence of atractylenolide II on the body weight and food intake of mice is shown in figure 1, and the body weight of the mice in the model group is obviously increased compared with that in the control group; compared with the model group, the weight of the atractylenolide II is obviously reduced in the low and high dose group, and the dosage dependence is shown. The food consumption of the mice fed with high fat has no obvious difference, and is obviously lower than that of the control group.
2. Effect of Atractylodes Macrocephala lactone II on metabolism in mice
FIG. 2 shows the effect of atractylenolide II on the respiratory entropy RQ, the consumption of O 2, the output of CO 2 and the energy consumption EE of mice, the respiratory entropy, i.e. the ratio of carbon dioxide output to oxygen consumption at the same time, RQ being 1 when carbohydrates are consumed and RQ being 0.7 when fat is consumed, the respiratory entropy is significantly reduced after high fat feeding, and the respiratory entropy is significantly adjusted back after administration of atractylenolide II, indicating that the mice recover from lipid metabolism to sugar metabolism and glycolipid metabolism is improved, the consumption of O 2 and the output of CO 2 are statistically determined to reduce the consumption of O 2, the output of CO 2 and the output of CO 2 in comparison with the consumption of O 2 respectively, the energy consumption is also consistent with the respiratory entropy change, the energy consumption of mice is reduced after high fat feeding, lipids are accumulated, the weight is increased, the energy consumption of mice is increased and the weight is relatively reduced after administration of atractylenolide II, therefore the metabolic cage test data indicate that the metabolic cage test data of atractylenolide II can improve the glycolipid metabolism disorder.
3. Effect of Atractylodes macrocephala lactone II on fat content of mouse body
The influence of atractylenolide II on body fat content of mice is shown in figure 3, and detection by using mouse magnetic resonance imaging (MRM) technology shows that the fat content of mice is increased after high-fat feeding, and the fat content is reduced after treatment with atractylenolide II, which indicates that atractylenolide II has lipid-lowering effect.
4. Effect of Atractylodes macrocephala lactone II on blood sugar of mice
The influence of atractylenolide II on the blood sugar of mice is shown in figure 4, oral glucose tolerance (OGTT), insulin tolerance (ITT) and pyruvic acid tolerance (PTT) of the mice are respectively measured, in a GTT experiment, 2g/kg of glucose solution is perfused into the stomach of the mice to cause the increase of the blood sugar of the mice, due to the existence of insulin, the blood sugar value can be recovered to the original level after a certain time, the insulin resistance is shown as the decrease of the capacity of the insulin for promoting the glucose uptake and utilization, and the time required for recovering to the original level after the blood sugar value is increased is long, namely the blood sugar reduction value is small in the same time. The blood sugar value of the model group is slowly reduced after being increased, and the blood sugar value of the obese mouse is quickly reduced after being treated by the atractylenolide II, which indicates that the insulin resistance of the mouse is improved to a certain extent. In an ITT experiment, the abdominal cavity of a mouse is injected with 0.5U/kg of insulin to promote the consumption of blood sugar in vivo, the blood sugar value of a model group is slowly reduced, and the blood sugar value of an obese mouse treated by the atractylenolide II is quickly reduced. In a PTT experiment, 2g/kg of sodium pyruvate is intragastrically administered to a mouse, pyruvic acid is a gluconeogenesis substrate, the gluconeogenesis ability of the mouse is evaluated, the blood sugar of the model group mouse is slowly reduced after being increased, and the blood sugar is rapidly reduced after being treated by atractylenolide II, which shows that the atractylenolide II enhances the sensitivity of insulin. The area under the curve of blood sugar values measured by statistics of GTT, ITT and PTT can also find that the model group is obviously increased and is reduced after administration, so that the GTT, ITT and PTT experiments prove that high fat fed mice cause insulin resistance and the bighead atractylodes rhizome lactone II can play a role in improving the insulin resistance after treatment.
5. effect of Atractylodes macrocephala lactone II on TC, LDL-c, ALT and AST in blood of mice
The effect of atractylenolide II on TC, LDL-c, ALT and AST in the blood of mice is shown in fig. 5, where TC, cholesterol, increased levels of TC in the serum of mice fed with high fat, and decreased levels of TC after treatment with atractylenolide II; LDL-c (low-density lipoprotein) is lipoprotein rich in cholesterol, the content of cholesterol in blood is increased, the content of LDL-c is also increased, the increased LDL-c is easy to induce diseases such as atherosclerosis, and the content of LDL-c is reduced after the treatment of atractylenolide II; ALT (glutamic pyruvic transaminase) is mainly present in liver, and the activity of the enzyme is increased when lesion occurs in tissues, AST (glutamic oxaloacetic transaminase) is similar to ALT, and ALT and AST are two markers for measuring liver injury. After the mice are induced by high fat, the ALT content and the AST content are both obviously increased, the content is reduced after the treatment of the atractylenolide II, the liver injury of the mice is improved, and the blood fat level is improved after the treatment of the atractylenolide II.
6. Effect of Atractylodes Macrocephala lactone II on mouse liver tissue
H & E and oil Red O staining results As shown in FIG. 6, the liver of the high fat-fed mice showed distinct lipid droplets, white vacuoles were visible in the H & E staining, distinct red lipid droplets were visible in the oil Red O staining, and the lipid droplets were significantly reduced after treatment with atractylenolide II. The white adipose tissues of epididymis are obviously increased in volume after high-fat feeding, slightly reduced after administration, and the brown adipose tissues are not obviously changed.
In conclusion, after high fat feeding, the weight of the mice is increased, the respiratory entropy and the energy consumption are obviously reduced, which indicates that fat mice are mainly changed from sugar metabolism to fat metabolism, fat tissue lesion and fat drop increase, and meanwhile, detection of some indexes of plasma and liver also proves liver injury and insulin resistance symptoms of the mice. Therefore, the atractylenolide II can effectively improve insulin resistance and glycolipid metabolic disorders caused by obesity.
The above-described embodiments are intended to be illustrative of the nature of the invention, but those skilled in the art will recognize that the scope of the invention is not limited to the specific embodiments.
Claims (9)
1. The medical application of atractylenolide II in preparing the medicine for improving insulin resistance caused by obesity.
2. Use according to claim 1, characterized in that: the medicament takes atractylenolide II as an active ingredient and also contains a pharmaceutically acceptable carrier, and is prepared into pharmaceutically acceptable dosage forms.
3. Use according to claim 2, characterized in that: the carrier is a solid, semi-solid, or liquid.
4. Use according to claim 2, characterized in that: the preparation forms are tablets, injections, capsules and oral liquid.
5. The medical application of atractylenolide II in preparing the medicine for improving glycolipid metabolic disorder caused by obesity.
6. Use according to claim 5, characterized in that: the medicament takes atractylenolide II as an active ingredient and also contains a pharmaceutically acceptable carrier, and is prepared into pharmaceutically acceptable dosage forms.
7. Use according to claim 6, characterized in that: the carrier is a solid, semi-solid, or liquid.
8. Use according to claim 6, characterized in that: the preparation forms are tablets, injections, capsules and oral liquid.
9. The medical application of atractylenolide II in preparing a medicine for improving liver injury caused by obesity.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112516152A (en) * | 2020-11-18 | 2021-03-19 | 广东药科大学 | Application of cirsium japonicum glycosides in preparing medicine for treating glycolipid metabolism and composition thereof |
| CN115282157A (en) * | 2022-01-10 | 2022-11-04 | 温州医科大学附属第一医院 | Application of diosmin in preparation of drug for improving glycolipid metabolic disorder |
-
2019
- 2019-09-11 CN CN201910856099.8A patent/CN110548025A/en active Pending
Non-Patent Citations (2)
| Title |
|---|
| CHAO, CHIEN-LIANG等: "Sesquiterpenes from Baizhu Stimulate Glucose Uptake by Activating AMPK and PI3K", 《THE AMERICAN JOURNAL OF CHINESE MEDICINE》 * |
| QI REN等: "Atractylenolide II-ameliorated hyperlipidemia in mice by regulating AMPK/PPAR/SREBP-1C signaling pathway", 《MATER. EXPRESS》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112516152A (en) * | 2020-11-18 | 2021-03-19 | 广东药科大学 | Application of cirsium japonicum glycosides in preparing medicine for treating glycolipid metabolism and composition thereof |
| CN115282157A (en) * | 2022-01-10 | 2022-11-04 | 温州医科大学附属第一医院 | Application of diosmin in preparation of drug for improving glycolipid metabolic disorder |
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