CN103478071A - Method for establishing diabetes-inducing model - Google Patents
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Abstract
The invention is suitable for the field of medicine and provides a method for establishing a diabetes-inducing model. The method comprises the following steps of feeding male monkeys with high-fat feed, wherein the male monkeys account for 5/6 of the total quantity of experimental animals, and are 7-20 years old, and the high-fat feed comprises the following main components: 18 percent of protein, 60 percent of saccharides and 22 percent of fat; feeding male monkeys with standard feed, wherein the male monkeys account for 1/6 of the total quantity of the experimental animals, and are 4-10 years old, and the standard feed comprises the following main components: 18 percent of protein, 69 percent of saccharides and 3 percent of fat. According to the method for establishing the diabetes-inducing model provided by the invention, by establishing the model for inducing diabetes by long-term diet, the problems that the long-term slow process of human diabetes development cannot be really simulated very well by drug modeling, and the whole organism is changed by the fact that the long-term slow process cannot be really simulated very well can be solved, and the scientificity is stronger.
Description
Technical field
The invention belongs to medical domain, relate in particular to a kind of method for building up of inducing diabetes model.
Background technology
At present, the animal that the research institute of diabetes adopts mostly is large and small mouse, and modeling method has the methods such as spontaneous and chemical induction.Diabetes study adopts rodent models more at present, but rodent and the mankind's affiliation is far away, and the life-span is short, therefore, is not suitable for the research of diabetes mechanism and complication thereof.In the non-human primate animal, it is report spontaneous, that diabetes model that Streptozotocin (streptozotocin, STZ) compound is induced, gene mutation or other approach obtain all has 1 type and diabetes B animal model.In the animal model of all kinds, blood sugar rule, the pathological characters of observing in non-human primate model and the Clinical symptoms of observing in human diabetic patient are the most similar.
In prior art, at streptozotocin, induce in zoic model with hyperglycemia, select animal, mouse commonly used or rat, also can select rabbit, dog and monkey etc., the STZ aqueous solution of preparation variable concentrations or single concentration, adopt vein or lumbar injection mode single or multiple repeat administration.Whether detect Cheng Mo after time through different disposal.Before injection STZ, different time after administration (general 2-6 month, 1 year was arranged) carries out blood-sugar level measuring, glucose tolerance experiment and serum insulin or the C peptide detects respectively, and frequency all has difference, and the body weight change of observed and recorded animal and clinical symptoms.
Induce in zoic model with hyperglycemia at streptozotocin, have following problem:
(1) STZ adopted is at different animals, and even, with in report, inducing the needed dosage of diabetes to be not quite similar, high dose STZ can not cause the modeling animal dead, and low dosage STZ is difficult to into mould, or turns out cloudy soon after Cheng Mo.In addition, STZ injection system (abdominal cavity, intravenous injection) etc. also has certain influence to modeling.Therefore, while adopting STZ to make diabetes animal model, must select applicable dosage and injection system, reduce on the one hand the toxic and side effect of STZ; Improve on the other hand the stability that STZ becomes mould.Be difficult to grasp, shortcoming is outstanding.
(2) the long-term slowly process that the pancreas islet caused by medicine STZ damages really good simulating human diabetes development reaches the whole body body variation caused thus, and therefore the science for correlative study is still not enough.
(3) the non-human primate diabetes that the STZ of report induces at present are type 1 diabetes, have no the report of inducing diabetes B, and the multiplex heterograft acceptor of making pancreatic cell, seldom for new drug evaluation.
(4) also not long on the time of non-human primate diabetes modeling, have pending more long-term research with the stability of determining model and the time inversion of phases.
In addition, in food-induced non-human primates diabetes model, Wagner etc. give the food that 45 machins feed Hi CHO and low cholesterol [18% albumen, 22% fat, 60% carbohydrate (fructose content reaches 20%)].Although it is normal that the fasting blood sugar of most of machin keeps, sugar tolerance detects to be found, its blood sugar concentration and the insulin content difference in individuality is very large.10 monkey fasting blood-glucose concentration and the insulin content of 8 monkeys of those tool hyperinsulinisms (HyperinSul inemic, HI) or impaired glucose tolerance (impaired glucose tolerant, IGT) raise significantly.5 monkeys (HI+IGT) that simultaneously have hyperglycaemia and an impaired glucose tolerance occur fat, and weight ratio control group monkey is many 40%, and this group monkey Of-thin element concentration is also high.Other monkeys of feeding with normal diet are compared, all above-mentioned monkey tool highs fat of blood and low HDL C, and wherein the value of HI+IGT group monkey is the highest.After 1 year, 3 in 10 IGT monkeys 1 and 5 HI+IGT monkeys are developed into diabetes.
In food-induced non-human primates diabetes model, there is following problems:
(1) animal of using is machin, and this monkey is tropical monkey, domestic Guangxi, Guangdong, Hainan San Sheng of mainly concentrating on, and the impact of climate environment, resources supplIes is very large.So be badly in need of the diabetes model animal of setting up other subspecies.
(2) time of prior art modeling, in 1 year, can't be observed development process and the variation of model well.
(3) not enough, stable model needs the more stable detection index of different time sections to support to the frequency of dynamic monitoring.
(4) such non-human primates diabetes model have not been reported at home.
Summary of the invention
The embodiment of the present invention provides a kind of method for building up of inducing diabetes model, is intended to solve in the modeling of prior art medicine toxic and side effect strong, the problem of poor stability.
The embodiment of the present invention is achieved in that a kind of method for building up of inducing diabetes model, and described method comprises:
5/6 male monkey of laboratory animal total amount, age 7-20 year, the monkey high lipid food of searching for food, Main Ingredients and Appearance is 18% protein, 60% carbohydrate, 22% fat; 1/6 male monkey of laboratory animal total amount, age 4-10 year, feeding monkey standard feed, Main Ingredients and Appearance is 18% protein, 69% carbohydrate, 3% fat.
The embodiment of the present invention adopts long-term meals to induce the model foundation of diabetes can solve the problem that is reached the whole body body variation caused thus by the medicine modeling for a long time slow process that really good simulating human diabetes develop, and science is stronger.
Embodiment
In order to make purpose of the present invention, technical scheme and advantage clearer, below in conjunction with embodiment, the present invention is further elaborated.Should be appreciated that specific embodiment described herein, only in order to explain the present invention, is not intended to limit the present invention.
The embodiment of the present invention adopts long-term meals to induce the model foundation of diabetes can solve the problem that is reached the whole body body variation caused thus by the medicine modeling for a long time slow process that really good simulating human diabetes develop, and science is stronger.
In embodiments of the present invention, laboratory animal is 60 Rhesus Monkey rivers West Asia kind (M.m.Iasiotis), regular grade, and age 4-20 year, body weight 5-18kg, provided the quality certification number: 22 with macaque provenance base by country (Sichuan) experiment.Before the feeding high lipid food, all animal fasting blood-glucoses (FPG)≤5mmol/l.Before test, quarantine qualified, content comprises health check-up, 2 bacillus subtuberculosis tests, parasite, salmonella, congratulate Salmonella and B virus checking.In stainless steel monkey cage, raise, 4/cage, receptacle temperature and humidity: 19-26 ℃ (66-79 °F) and 50 ± 20%; Rate of ventilation: 10 times/h, guarantee the periodicity of illumination of 12 (day)/12 (night) h.
In embodiments of the present invention, the test monitoring cycle is 2 years, freely absorbs experimental monkey groups feed 250g morning every day, selects afternoon 4 and gives 1 apple or equivalent vegetables.50 male monkeys, age 7-20 year, the monkey high lipid food of searching for food (feed formula in detail is slightly temporary transient, need to provide again), Main Ingredients and Appearance is 18% protein, 60% carbohydrate, 22% fat; 10 male monkeys, age 4-10 year, feeding monkey standard feed, Main Ingredients and Appearance is 18% protein, 69% carbohydrate, 3% fat.
In embodiments of the present invention, drinking water is running water, through the automatic water-drinking mouth, freely absorbs.Water sample need be analyzed element, heavy metal, organic matter and the chlorohydrocarbon content of soluble solids total amount, hardness, peculiar microorganism content, selection.Outcome record is in archives.Animal welfare meets " the Nat i onal Inst i tutes of Health Guide for the Care and Use of Laboratory Animal " requirement, all examination and the agreements with the committee of use through the center animal welfare of all experimental programs.
In embodiments of the present invention, the instrument adopted is automatic clinical chemistry analyzer (SYNCHRON CX4PRO), Shimadzu CL-8000 automatic clinical chemistry analyzer, spectrophotometer, full-automatic high-pressure autoclave (HVE-50, Hirayama), Sigma1-15 generic centrifuge (Sigma company), micropipettor (10 μ L, 200 μ L, 1000 μ L), vortex oscillator, thermostat water bath, low temperature refrigerator (Haier's electrical equipment), 725 type ultralow temperature refrigerator-freezers (Themo Forms company), the large animal balance of plum Teller-Tuo benefit XK3123 (METTLER TOLEDO) etc.
In embodiments of the present invention, details are as follows to induce the method for building up of diabetes model:
(1) body weight and body mass index (BMI) check
In embodiments of the present invention, 2 year experimental period,, 60 animals are observed general status and food consumption situation every day; Before high lipid food is induced, measure per month the long variation of body weight and body after inducing.Calculate BMI with body weight divided by long square of body.In this test, adopt the fat classification of people to diagnose monkey: partially thin (BMI≤18.5), normal range (NR) (BMI:18.5-25), partially fat (BMI:25-30), fat (BMI >=30).
(2) fasting blood-glucose (FPG), fasting plasma insulin (FPI) and glycosylated hemoglobin inspection
In embodiments of the present invention, 60 animals are induced first 1 time in high lipid food, February, March after inducing, May, July, October, November, December, 15 months, 16 months, 18 months, 19 months, 20 months, 22 months, 24 months, 16 hours hind leg femoral vein bloods after fasting, analyzed fasting blood-glucose and fasting plasma insulin level; Induce and within 24 months, detect HbAlc in high lipid food.
In embodiments of the present invention, fasting blood-glucose (FPG) detects and adopts Beckman Kuerle automatic clinical chemistry analyzer (SYNCHRON CX4PRO) to measure blood sugar, measures with not anti-freezing of blood, and assay method is the peroxidase end-point method.
In embodiments of the present invention, fasting plasma insulin (FPI) detects and adopts the double antibodies sandwich enzyme linked immunosorbent assay.
1. provide article for oneself: microplate reader shifts to an earlier date preheating, micropipet and suction nozzle, EP pipe, distilled water and filter paper.
2. sample treatment: whole blood sample centrifugal 20 minutes of 1000 * g after room temperature is placed 2 hours, get supernatant, 10 times of distilled water dilutings are to be measured.
3. operating procedure:
A.96 orifice plate is established respectively blank well, gauge orifice and testing sample hole, adds respectively 100 μ l sample diluting liquids, standard items and testing sample, adds 37 ℃ of incubations of overlay film 2 hours;
B. supernatant discarded, dry, and every hole adds detects liquid A working solution 100 μ l, adds 37 ℃ of incubations of overlay film 1 hour;
C. supernatant discarded, wash plate 3 times, soaks 1-2 minute at every turn, and about every hole 400 μ l dry;
D. every hole adds detection liquid B working solution 100 μ l, adds 37 ℃ of incubations of overlay film 1 hour;
E. supernatant discarded, dry, and washes plate 5 times, with step c;
F. every hole adds substrate solution 90 μ l, adds 37 ℃ of lucifuge colour developing 15-30 minute of overlay film, and when there is obvious gradient blueness in the front 3-4 hole of gauge orifice, rear 3-4 hole gradient can stop when not obvious;
G. every hole adds stop bath 50 μ l, and now blueness is transformed into yellow, reaction terminating at once;
H. use immediately the OD value of microplate reader in each hole of 450nm wavelength measurement.
4. computational methods: make seven point diagrams after getting standard items OD value deduction blank well OD value, the concentration of standard items of take is ordinate (logarithmic coordinates), and the OD value is abscissa (logarithmic coordinates) use curve expert1.3 drawing standard curve; Calculate the regression equation of calibration curve with the concentration of standard items and OD value, by sample OD value substitution equation, calculation sample concentration, then be multiplied by extension rate and obtain the sample actual concentrations.
In embodiments of the present invention, during glycosylated hemoglobin (HbAlc) detects, adopt Shimadzu CL-8000full self-biochemical to measure, measure with blood liquaemin anti-freezing.
(3) intravenous glucose injection resistance test
In embodiments of the present invention, high lipid food is induced latter 24 months, and 60 animals carry out intravenous glucose injection resistance test (IVGTT) diagnosis impaired glucose tolerance (IGT).Take 50% D-glucose with every kg body weight 0.5ml, make final dose reach every kg body weight 0.25g glucose.First at baseline values, detect blood sugar level, then on an empty stomach after 16 hours intravenous glucose injection measured respectively blood sugar level at 1,5,10,15,20 and 60 minute.Calculate glucose clearance (K with following formula
g): K
g=ln (5 minutes blood sugar levels)-ln (20 minutes blood sugar levels)/15 minute 100%.
In embodiments of the present invention, adopt IVGTT analysis of experiments insulin secretion susceptibility after the meal.High lipid food is induced latter 24 months, selects 6 FPG normal, 2 in IFG or IGT stage and 1 the overt diabetes stage monkey carry out.Detection time point is: first at baseline values, detect insulin level, then on an empty stomach after 16 hours intravenous glucose injection (mode is the same) measured respectively insulin at 1,3,5,7,10,15,30,45 and 60 minute.Plasma insulin (FPI) detects and adopts the double antibodies sandwich enzyme linked immunosorbent assay.
In embodiments of the present invention, provided the beverage containing 0.33g/ml glucose to monkey before within 16 hours, closing to an end on an empty stomach.Quantities of beverage is calculated supply with the monkey body weight, and monkey was only drunk 90% amount calculation success of the test up within 20 minutes, took altogether glucose amount and was approximately every kg body weight 2g, and the actual consumption amount needs as calculated.Withdraw beverage after 2 hours, gather 2 hours insulin of blood test and blood sugar level.
In embodiments of the present invention, adopt american diabetes association (ADA) and WHO2006 diabetes diagnosis standard, concrete diagnostic criteria is:
A. typical diabetic symptom (diuresis, drink and inexplicable Body weight loss) more, random plasma glucose >=11.1mmol/L or fasting blood-glucose (FPG) >=7.0mmol/L, be diabetes;
B. fasting blood-glucose (FPG)<6.11mmol/L and 2h-plasma glucose (2hPG)<7.77mmol/L, for normally;
C. 2h-plasma glucose (2hPG)>7.77mmol/L, but<be impaired glucose tolerance (IGT) during 11.1mmol/L;
D. fasting blood-glucose (FPG) >=6.11mmol/L, but<be the fasting blood-glucose damage during 6.99mmo/L.
In embodiments of the present invention, all data all adopt means standard deviation to show.The data of normal distribution are through the multiple comparing check of Tukey-Kramer, and difference adopts one-way analysis of variance (ANOVA) to be assessed.Difference between each group of normal distribution data adopts the Kruskal-Wallis non-parametric test.All data analyses all adopt NCSS2000 software (NCSS, Kaysvil l e, UT), and all analysis P values are less than 0.05 and all think the difference not statistically significant.
(4) interpretation of result
Embodiment of the present invention result is: 50 monkeys search for food containing 22% fatty feed 24 months, and 8 develop into overt diabetes, and 26 monkeys show as impaired glucose tolerance or IFG, and 16 monkeys show as sky, and to take blood sugar level normal; 10 feedings were containing the monkey standard feed of 3% fat 24 months, and it is normal that sky takes blood sugar level.West Asia, rhesus macaque river kind impaired glucose tolerance and diabetes B morbidity commitment feature show as obesity, the FPI compensatory increases, GLPP removing speed (KGluc5-20) significantly reduces, insulin secretion susceptibility descends after the meal, First-phase insulin secretion reduces, and within second o'clock, the phase insulin secretion postpones; HbAlc increases along with blood sugar level and rises; That chronic hyperglycemia monkey in late period shows as is thin and weak, diuresis is drunk more, and fasting blood-glucose can be greater than 10mmol/l, and the HbAlc level can reach 8.9%, FPI and significantly reduce, and half an hour, insulin secretion reduced rapidly after increasing after the meal.HbAlc has the excessive risk possibility that develops into diabetes B between 4.5-5%.
The embodiment of the present invention adopts long-term (2 term) meals to induce the model of diabetes to set up, meeting the long-term slowly process of human diabetes development and the whole body body caused thus changes, and safer stable after Cheng Mo, carry out correlative study and there is stronger science.West Asia, the macaque river kind of selecting extensively distributes in western Sichuan, and it is pure to have strain, and build miniaturization characteristics, can be towards the international and domestic animal model that provides.
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (7)
1. a method for building up of inducing diabetes model, is characterized in that, described method comprises:
5/6 male monkey of laboratory animal total amount, age 7-20 year, the monkey high lipid food of searching for food, Main Ingredients and Appearance is 18% protein, 60% carbohydrate, 22% fat; 1/6 male monkey of laboratory animal total amount, age 4-10 year, feeding monkey standard feed, Main Ingredients and Appearance is 18% protein, 69% carbohydrate, 3% fat.
2. the method for claim 1, is characterized in that, described method also comprises:
The test monitoring cycle is 2 years, freely absorbs experimental monkey groups feed 250g morning every day, selects afternoon 4 and gives 1 apple or equivalent vegetables.
3. method as claimed in claim 2, is characterized in that, described method also comprises:
2 year experimental period,, all laboratory animal are observed general status and food consumption situation every day, and induce forward and backward measure per month body weight and the long variation of body in high lipid food.
4. method as claimed in claim 3, is characterized in that, described method also comprises:
All laboratory animal are induced first 1 time in high lipid food, February, March after inducing, May, July, October, November, December, 15 months, 16 months, 18 months, 19 months, 20 months, 22 months, 24 months 16 hours hind leg femoral vein bloods after fasting, analyze fasting blood-glucose and fasting plasma insulin level, and induce and within 24 months, detect glycosylated hemoglobin in high lipid food.
5. method as claimed in claim 4, is characterized in that, described method also comprises:
High lipid food is induced latter 24 months, and all laboratory animal carry out intravenous glucose injection resistance test diagnosis impaired glucose tolerance.
6. method as claimed in claim 5, is characterized in that, described method also comprises:
Adopt american diabetes association and WH02006 diabetes diagnosis standard.
7. method as described as claim 1-6, is characterized in that, described laboratory animal is selected the macaque river West Asia kind of country's experiment with macaque provenance base.
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| CN106615710A (en) * | 2016-12-23 | 2017-05-10 | 广东省生物资源应用研究所 | High glucose and high fat semi-liquid diet for inducing type II diabetes quadrumana model and induction method thereof |
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| CN111557273A (en) * | 2020-07-02 | 2020-08-21 | 贵州中医药大学 | Method for inducing type 2 diabetes animal model by low temperature and diet rhythm regulation |
| CN113711994A (en) * | 2021-09-29 | 2021-11-30 | 湖北天勤生物技术研究院有限公司 | Method for establishing cynomolgus monkey type 2 diabetes mellitus model and application thereof |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105210981A (en) * | 2015-09-15 | 2016-01-06 | 中国科学院生物物理研究所 | Set up method and the application thereof of the ferret model that can be applicable to human diseases research |
| CN106212858A (en) * | 2016-07-15 | 2016-12-14 | 广州市饲料研究所 | A kind of high lipid food and animal model of diabetes mellitus type II |
| CN106615710A (en) * | 2016-12-23 | 2017-05-10 | 广东省生物资源应用研究所 | High glucose and high fat semi-liquid diet for inducing type II diabetes quadrumana model and induction method thereof |
| JP2019088220A (en) * | 2017-11-14 | 2019-06-13 | 日本ペットフード株式会社 | Health degree measurement method of companion animal, program for measuring health degree of companion animal using computer, and health degree measuring apparatus of companion animal |
| CN111557273A (en) * | 2020-07-02 | 2020-08-21 | 贵州中医药大学 | Method for inducing type 2 diabetes animal model by low temperature and diet rhythm regulation |
| CN111557273B (en) * | 2020-07-02 | 2022-02-08 | 贵州中医药大学 | Method for inducing type 2 diabetes animal model by low temperature and diet rhythm regulation and application thereof in diabetes treatment |
| CN113711994A (en) * | 2021-09-29 | 2021-11-30 | 湖北天勤生物技术研究院有限公司 | Method for establishing cynomolgus monkey type 2 diabetes mellitus model and application thereof |
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