CN103394089A - Application of DPP-IV inhibitor in type 2 diabetes - Google Patents
Application of DPP-IV inhibitor in type 2 diabetes Download PDFInfo
- Publication number
- CN103394089A CN103394089A CN2013102544091A CN201310254409A CN103394089A CN 103394089 A CN103394089 A CN 103394089A CN 2013102544091 A CN2013102544091 A CN 2013102544091A CN 201310254409 A CN201310254409 A CN 201310254409A CN 103394089 A CN103394089 A CN 103394089A
- Authority
- CN
- China
- Prior art keywords
- dpp
- inhibitor
- secretion
- diabetes
- glucose
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Abstract
Relating to the field of medical technologies, the invention in particular relates to application of a DPP-IV inhibitor in type 2 diabetes. The DPP-IV inhibitor is beta phenylethylamine or cyanopyrrolidine. The dosage of the DPP-IV inhibitor is 5-100mg every time, the drug-delivery way is oral administration. In the invention, under intravenous glucose stimulation and combined oral glucose stimulation conditions, the influences of two DPP-IV inhibitors on two-phase insulin secretion functions are compared. By detection, the cyanopyrrolidine DPP-IV inhibitor can remarkably increase the first-phase and second-phase insulin secretion and C peptide secretion, while the beta phenylethylamine DPP-IV inhibitor can obviously increase the first-phase insulin secretion and C peptide secretion. The two DPP-IV inhibitors both can inhibit the secretion of glucagon and increase the concentration of active GLP-1. The invention provides test data for better application of the DPP-IV inhibitor in type 2 diabetes.
Description
Technical field
The present invention relates to a kind of medical technical field, the particularly application of a kind of DPP-IV inhibitor in type 2 diabetes mellitus.
Background technology
Type 2 diabetes mellitus has become global health problem, and it is one of the three large killers of 21 century harm humans health, is only second to cardiovascular diseases and tumor.If patient's poor blood glucose control, can produce multiple chronic complicating diseases on arteriosclerosis and microangiopathies basis, as diabetic cardiovascular and cerebrovascular disease, diabetic nephropathy, diabetic retinopathy and neuropathy etc., very harmful, mortality rate is high, has a strong impact on quality of life.How to control blood glucose, complication, improving long-term prognosis is the main target for the treatment of diabetes.Because the present means for the treatment of diabetes still have larger limitation, hyperglycemia how effectively to control diabetes is still a significant challenge to modern medicine with the risk of the complication that reduces diabetes.Therefore, people are constantly exploring the new way for the treatment of diabetes always.
Since the perspective diabetes study of Britain (UKPDS) confirmation metformin in 1998 can reduce the incidence rate and case fatality rate of type 2 diabetes mellitus complication, metformin, due to its stable curative effect, was used as a line and recommends medicine.But because type 2 diabetes mellitus has the persistence progress, the patient need to, by initial change dietetic life mode and single oral drug therapy of planting, upgrade to the multi-medicament therapeutic alliance and just can reach the purpose of controlling blood glucose usually gradually.The upgrading of glucose-lowering treatment has the selection of many two wires combination.In general, sulfonylurea drugs is classical Drugs Promoting Insulin Secretion,, existing more than 50 years of clinical practice, all is used as for a long time the first-selection of type 2 diabetes mellitus Second line Drug.The nearly 2,000 ten thousand type 2 diabetes mellitus patients in the whole world apply sulfonylureas drugs for diabetes at present.The combined effect mechanism of Sulphonylurea is to stimulate the beta Cell of islet uelralante, strengthens the sensitivity of peripheral tissues's Insulin receptor INSR to insulin, reduces the decomposition of liver glycogen in human body, promotes the synthetic of liver glycogen, thereby reduces fasting glucose; The DPP-IV inhibitor is the novel hypoglycemic medicine of a class based on secretin's effect, the alternative DPP-IV activity that suppresses.Stop the active GLP-1 cracking of endogenous, increase the plasma concentration of GLP-1, thereby by the receptors bind with beta Cell of islet surface performance promote insulin secretion and synthetic, suppress the glicentin secretion, promote Beta cell proliferation and apoptosis inhibit, minimizing food intake, delay the physiological action such as gastric emptying, thereby regulate glycaemic homeostasis and energy metabolism.Therefore, be directed to the situation that different type 2 diabetes mellitus journeys and secretion are got involved, select with a definite target in view medicine and drug combination, just can reach desirable therapeutic effect.
, for the DPP-IV inhibitor, be mainly to stimulate insulin secretion by secretin's effect, so therefore its insulin secretion accelerating ability may be underestimated.OGTT can assess the insulin secretion under glucose load, but, because its accuracy is poor, can't distinguish secretion phase.
Summary of the invention
The purpose of this invention is to provide the application of a kind of DPP-IV inhibitor in type 2 diabetes mellitus.
Described DPP-IV inhibitor is β phenethylamine class or cyanopyrrole alkanes.
Described β phenethylamine class DPP-IV inhibitor is sitagliptin, and described cyanopyrrole alkanes DPP-IV inhibitor is BMS-477118.
The single-dose amount of described DPP-IV inhibitor is 5-100mg, and administering mode is oral, and one day once oral.
The DPP-IV t cell surface antigen cD26 that is otherwise known as, be a kind of serine protease of cell surface, and wide expression is Various Tissues in body, and part is present in blood circulation with soluble form.Be cell surface antigen or the circulation in soluble DPP-IV all have enzymatic activity, its main active function is that the 2nd aminoacid of identification N-terminal is the oligopeptide of proline (Pro) or alanine (Ala) and shears its N-terminal the first two aminoacid, and intestinal insulinotropic hormone GLP-1 and gastric inhibitory polypeptide GIP thus degrade.Such as sulfonylurea drugs is compared, GLP-1 is based on actual glucose concentration for the short effect of secreting of insulin with other traditional Insulin secretagogues, and this has also reduced the patient hypoglycemic risk occurs.In the type 2 diabetes mellitus patient, exogenous supplementary GLP-1 can increase insulin secretion, thereby reduces empty stomach and post-prandial glycemia.In addition, GLP-1 also has the short effect of secreting of a series of extra non-insulins,, such as suppressing the glicentin secretion, slows down gastric emptying, delays passing through and absorbing of carbohydrate, even by acting on hypothalamic feeding center appetite-suppressing.These effects all are conducive to type 2 diabetes mellitus patient glycemic control.In addition, GLP-1 can also promote the propagation of β cell, reduces apoptosis, plays the effect of protection β cell, is of value to long-term control and the long-term prognosis of diabetes.
, because the biological half-life of GLP-1 in circulation is very short, namely by the DPP-IV deactivation and by kidney, discharge very soon after synthetic the GLP-1 of half inactivation that just is degraded while not leaving local capillary bed after synthetic.Therefore, use the DPP-IV inhibitor can suppress the activity of DPP-IV, stop the rapid degraded of GLP-1 and stablize its endogenic biological activity after the meal, thereby bringing into play corresponding therapeutical effect.Therefore, in order to assess the impact of secretin's effect for insulin one phase and two-phase secretion and glicentin secretion, and the release of endogenous secretin is for the enlarge-effect of the biphase secretion of insulin.We stimulate the sugared euglycemic clamp of height to combine with oral glucoses, after first high sugar stage that vein sugar stimulates finishes, by regulating infusion rate, blood glucose is reduced to fasting blood glucose level, thereby islet cells is had a rest, and insulin again synthesizes and stores.Give at this moment oral glucose, pass through afterwards to regulate infusion rate and keep positive glucose level, the synthetic and storage again of assurance insulin is not subjected to the impact of blood glucose fluctuation.After 40 minutes, the impact that is oral glucose reaches maximization, and give again intravenous glucose this moment stimulates, and blood glucose is risen to rapidly the high sugar level identical with first stage, can stimulate so the abundant secretion of the first phase of insulin, well show biphase secretion pattern.
Beneficial effect of the present invention is:
1, the present invention is by under the stimulation of vein sugar and Combined with Oral sugar stimulation state, compared the impact on biphase insulin secretion function of β phenethylamine class and cyanopyrrole alkanes DPP-IV inhibitor, by detecting, cyanopyrrole alkanes DPP-IV inhibitor can significantly raise and one reach mutually the secretion of two-phase insulin secretion, C peptide, and β phenethylamine class DPP-IV inhibitor can obviously raise a phase insulin secretion, the secretion of C peptide; Two kinds of DPP-IV inhibitor all can significantly suppress the secretion of glicentin, effectively increase the concentration of active GLP-1.
2, the present invention is that the DPP-IV inhibitor is the application in type 2 diabetes mellitus better, and test data and theoretical foundation are provided.
Therefore 3, β phenethylamine class and cyanopyrrole alkanes DPP-IV inhibitor, the insulin secretion while mainly improving blood sugar increasing, can be used in conjunction with the medicine of different mechanisms such as euglycemic agent or metformin, can treat better type 2 diabetes mellitus.
Description of drawings
Fig. 1 is the insulin secretion area under curve comparison diagram under the effect of DPP-IV inhibitor.
Fig. 2 is that the C peptide secretion area under curve under the effect of DPP-IV inhibitor compares.
Fig. 3 is the glicentin secretion area under curve comparison diagram under the effect of DPP-IV inhibitor.
Fig. 4 be under the effect of DPP-IV inhibitor active GLP-1 secretion area under curve comparison diagram.
The specific embodiment
Below in conjunction with embodiment, the invention will be further described:
Testing required instrument and equipment is: thermostat (Shanghai leap medical apparatus and instruments factory produces), intravenous glucose infusion pump (BBRAUN perfusor compact), blood-sugar detecting instrument (Biosen5130, Neckar Heal thcare.Co.Ltd.Magdeburg, Germany), desk centrifuge (Eppendorf).
The test medication:
(1) sitagliptin (β phenethylamine class DPP-IV inhibitor)
Oral: the 100mg/ sheet, every day each a slice, morning, 7:00 took.
(2) BMS-477118 (cyanopyrrole alkanes DPP-IV inhibitor)
Oral: the 5mg/ sheet, every day each a slice, morning, 7:00 took.
Embodiment
1, research worker: enter to organize health volunteer's 20 examples, all from the volunteer of Ruijin Hospital clinic test center storehouse.
(1) age: 20-30 year; Sex: male.
(2)19<BMI<25kg/M2。
In (3) 3 months, weight fluctuations is no more than 5%.
(4) signature informed consent, and good compliance is arranged.
2, method of testing:
(1), test is prepared:
The experimenter of whole test phase should take in greater than 150g carbohydrate every day, and keeps the quantity of motion that equates.Each reception test rose in front 3 days, and the experimenter should avoid drug administration, stops tobacco and wine, and sufficient sleep, avoid excited, avoids violent physical demands.
Experimenter's fasting after test 8 o'clock evenings of the previous day, took medicine in test 7:00am on day same day after empty stomach 10-12 hour, the flat sleeping tranquillization two hours of taking medicine.The same day, 9:00am started to carry out vein dual oral hyperglycemic clamps.(the blank group is not accepted administration, from the flat sleeping tranquillization of 7:00am, starts to test to 9:00am in two hours.)
The venous detaining needle of heparinization is placed in a side arm central vein or cephalic vein, and arm is positioned in 50-60 ℃ of thermostat, make skin temperature keep stable, in order to blood drawing.Opposite side arm central vein or cephalic vein are open, in order to the glucose of instillation 20%.
(2), test process:
The first stage of test is vein sugar stimulation period: measure the current blood glucose value of experimenter at 9:00am, calculate 50% glucose intravenous injection amount=(target blood glucose value (mmol/L)-current blood glucose value (mmol/L) * body weight (kg) * 70/2).Give intravenous injection 50% glucose stimulate make blood glucose rise to fast this value of 12mmol/L(for for the normal person), adjusting venoclysis 20% glucose speed makes glucostasis at 12mmol/L.In originally 10 minutes, adopted venous blood every 2 minutes and survey the vein blood glucose of arterial revascularization.Adjust the droping rate of 20% glucose according to blood sugar level, keep blood glucose in above-mentioned level, the neuroendocrine response of avoiding hypoglycemia to cause.Adopted simultaneously venous blood every 2 minutes in order to surveying insulin and C peptide, front 10 minutes total secretion values are defined as one and secrete mutually index.Surveyed vein blood glucose to 90 minutes every 5 minutes after 10 minutes, adopted venous blood every 10 minutes and survey insulin and C peptide, total secretion value of 10 to 90 minutes is defined as two-phase secretion index.Before on-test, the 10th minute, adopted respectively venous blood survey glucagon on the 90th minute, active GLP-1 concentration, calculate total glicentin and the gross activity GLP-1 secretion value of 0 to 90 minute.
The second stage of test is the positive sugar stage: taking after blood sample to reduce glucose infusion speed on the 90th minute, to make blood glucose be reduced to 6mmol/L following (for the normal subjects, as far as possible near fasting glucose), surveyed vein blood glucose in every 5 minutes, give oral glucose 75g when blood glucose value during less than 6mmol/L, regulate venoclysis 20% glucose speed glucostasis was kept 40 minutes less than 6mmol/L.
The phase III of test is combined with intravenous oral glucose stimulation period: again according to current blood glucose value, calculate the 50% glucose intravenous injection amount that needs, giving vein 50% glucose stimulates that to make blood glucose rise to fast this value of 12mmol/L(be for the normal person).Regulating venoclysis 20% glucose speed makes glucostasis at 12mmol/L.In originally 10 minutes, adopted venous blood every 2 minutes and survey the vein blood glucose of arterial revascularization.Adjust the droping rate of 20% glucose according to blood sugar level, keep blood glucose in above-mentioned level, the neuroendocrine response of avoiding hypoglycemia to cause.Adopted simultaneously venous blood every 2 minutes in order to surveying insulin and C peptide,, front 10 minutes total secretion values are defined as one and secrete mutually index.Surveyed vein blood glucose to 90 minutes every 5 minutes after 10 minutes, adopted venous blood every 10 minutes and survey insulin and C peptide, total secretion value value of 10 to 90 minutes is defined as two-phase secretion index.Before on-test, the 10th minute, adopted respectively venous blood survey glucagon on the 90th minute, active GLP-1 concentration, calculate total glicentin and the gross activity GLP-1 secretion value of 0 to 90 minute.
2, test result:
(2), insulin result contrast
BMS-477118 can significantly raise and one reach mutually the two-phase insulin secretion, the sitagliptin phase insulin secretion that can obviously raise, specifically as shown in Figure 1.
(3), C peptide result contrast
BMS-477118 can obviously raise one mutually and the secretion of the C peptide of two-phase, and can obviously the raise C peptide of a phase of sitagliptin is secreted, specifically as shown in Figure 2.
(4) result contrast
BMS-477118 and sitagliptin all can significantly suppress the secretion of glicentin, specifically as shown in Figure 3.
(5) active GLP-1 result contrast
BMS-477118 and sitagliptin all can effectively increase the concentration of active GLP-1, specifically as shown in Figure 4.
Claims (3)
1. the application of DPP-IV inhibitor in type 2 diabetes mellitus.
2. application claimed in claim 1 is characterized in that: described DPP-IV inhibitor is β phenethylamine class or cyanopyrrole alkanes.
3. the described application of claim 1 or 2 is characterized in that: the dosage of described DPP-IV inhibitor is 5-100mg/ time, and administering mode is oral.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2013102544091A CN103394089A (en) | 2013-06-24 | 2013-06-24 | Application of DPP-IV inhibitor in type 2 diabetes |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2013102544091A CN103394089A (en) | 2013-06-24 | 2013-06-24 | Application of DPP-IV inhibitor in type 2 diabetes |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103394089A true CN103394089A (en) | 2013-11-20 |
Family
ID=49557935
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2013102544091A Pending CN103394089A (en) | 2013-06-24 | 2013-06-24 | Application of DPP-IV inhibitor in type 2 diabetes |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103394089A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103793594A (en) * | 2013-12-30 | 2014-05-14 | 上海交通大学医学院附属瑞金医院 | Method for constructing related intestinal canal-pancreatic islet regulation axis function evaluation model and application of model |
-
2013
- 2013-06-24 CN CN2013102544091A patent/CN103394089A/en active Pending
Non-Patent Citations (2)
| Title |
|---|
| 占美等: "沙格列汀治疗糖尿病安全性的系统评价", 《中国医院药学杂志》 * |
| 胡杰等: "西格列汀治疗2 型糖尿病的临床研究进展", 《医药导报》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103793594A (en) * | 2013-12-30 | 2014-05-14 | 上海交通大学医学院附属瑞金医院 | Method for constructing related intestinal canal-pancreatic islet regulation axis function evaluation model and application of model |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US11179323B2 (en) | Extended release of neuregulin for treating heart failure | |
| Sands et al. | Sotagliflozin, a dual SGLT1 and SGLT2 inhibitor, as adjunct therapy to insulin in type 1 diabetes | |
| Farrokhi et al. | Glycemic control in non-diabetic critically ill patients | |
| Fajans et al. | Benzothiadiazine suppression of insulin release from normal and abnormal islet tissue in man. | |
| Oiknine et al. | A critical appraisal of the role of insulin analogues in the management of diabetes mellitus | |
| Smolensky et al. | Biological rhythms, drug delivery, and chronotherapeutics | |
| CN101014360A (en) | Antidiabetic oral insulin-biguanide combination | |
| Gorgojo-Martinez et al. | Real-world effectiveness and safety of dapagliflozin therapy added to a GLP1 receptor agonist in patients with type 2 diabetes | |
| Prasathkumar et al. | Evaluation of hypoglycemic therapeutics and nutritional supplementation for type 2 diabetes mellitus management: an insight on molecular approaches | |
| CN103793594A (en) | Method for constructing related intestinal canal-pancreatic islet regulation axis function evaluation model and application of model | |
| CN103394089A (en) | Application of DPP-IV inhibitor in type 2 diabetes | |
| McFarlane | Antidiabetic medications and weight gain: implications for the practicing physician | |
| Kadhe et al. | Advances in drug delivery of oral hypoglycemic agents | |
| Mefford et al. | Improved diabetes control and pancreatic function in a type 2 diabetic after omeprazole administration | |
| Roy | Administration of once-daily canagliflozin to a non-diabetic patient in addition to standard aerobic exercise: a case report | |
| Yacoub | Impact of improving postprandial glycemic control with intensifying insulin therapy in type 2 diabetes | |
| Baby et al. | Prescribing pattern of antidiabetic drugs for type 2 diabetic in tertiary care teaching hospital | |
| CN104784192A (en) | Application of clam meat oligosaccharide in preparation of hypoglycemic drugs and preparation method of clam meat oligosaccharide | |
| CN109395065A (en) | A kind of polypeptide is used to prepare the purposes of slimming medicine | |
| Heikinheimo | Severe prolonged hypoglycemia following tolbutamide and carbutamide treatment | |
| Mustafayeva et al. | Clinical case of type 2 diabetes remission | |
| Wood et al. | The patient with endocrine disease | |
| Lansang et al. | Insulin glargine: A basal insulin for the management of diabetes | |
| Siddig et al. | Analytical Comparison of Continuous Subcutaneous Insulin Infusion and Multiple Daily Injections in Children and Adolescents with Type I Diabetes Mellitus | |
| Hompesch et al. | Glycemic exposure is affected favorably by inhaled human insulin (Exubera) as compared with subcutaneous insulin glargine (Lantus) in patients with type 2 diabetes |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20131120 |