CN103622992B - The purposes of hydrogen sulfide and its donor sodium hydrosulfide in treatment diabetes medicament is prepared - Google Patents
The purposes of hydrogen sulfide and its donor sodium hydrosulfide in treatment diabetes medicament is prepared Download PDFInfo
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- CN103622992B CN103622992B CN201210307009.8A CN201210307009A CN103622992B CN 103622992 B CN103622992 B CN 103622992B CN 201210307009 A CN201210307009 A CN 201210307009A CN 103622992 B CN103622992 B CN 103622992B
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Abstract
The invention belongs to medicine pharmacy field, the purposes of the pharmaceutical usage for being related to hydrogen sulfide and its donor sodium hydrosulfide new in pharmacy, more particularly to hydrogen sulfide and its donor sodium hydrosulfide in treatment diabetes medicament is prepared.The present invention is used for insulin sensitivity enhancing and experiment that is hypoglycemic to type ii diabetes and increasing insulin level using exogenous hydrogen sulfide and its donor sodium hydrosulfide NaHS, through skeletal muscle and the correlation test of fat cell and insulin resistance, the animal model of diabetes insulin resistance carries out insulin tolerance tests, glucose consumption is tested, animal model test and give NaHS intervention zooperies etc. that diabetes insulin is resisted, as a result show:NaHS can play a part of to promote glucose uptake in the presence of insulin, it is shown that the effect of enhancing insulin.Hydrogen sulfide of the invention and its donor sodium hydrosulfide can be used as insulin sensitizer and medicines that is hypoglycemic to type II diabetes and increasing insulin level.
Description
Technical field
The invention belongs to medicine pharmacy field, the pharmaceutical usage for being related to hydrogen sulfide and its donor sodium hydrosulfide new in pharmacy,
More particularly to the purposes of hydrogen sulfide and its donor sodium hydrosulfide in treatment diabetes medicament is prepared.Hydrogen sulfide of the invention and its
Donor sodium hydrosulfide can be used as insulin sensitizer and medicine that is hypoglycemic to type II diabetes and increasing insulin level.
Background technology
Prior art discloses hydrogen sulfide(H2S)It is the metabolite of cysteine in human body, its content in human body
Very low about 20~50 μm of ol/L, and manual control is difficult, document also reports H2S is a kind of the new of participation regulation and control cardiovascular activity
Type endogenous gas molecule, with the purposes for promoting angiocardiopathy angiogenesis.
Statistics report, at present, diabetes are 1-2% in the population of China incidence of disease, up to 12% in the elderly.According to the world
The diabetes diagnostic criterion of diabetologist committee modification, diagnosis standards of fasting plasma glucose is >=126mg/ml, the hair of diabetes
Sick rate is in ascendant trend, diabetes B year by year(Most of is senile diabetes)Patient dramatically increase, to the danger of human health
Evil also will be bigger.
At present, the clinical treatment to diabetes B is general to use diet combination hypoglycemic drug as basic skills.
Oral hypoglycemic thing mainly uses western medicine, but, practice display, angiocarpy and liver, kidney etc. of the Western medicine to diabetic
There is adverse side effect, and should not be used for multiple complications person.For many years, domestic and international endocrine, diabetologist,
Various methods and medicine of the person from all many-sided discussion treatment diabetes.People expect have safer, effective and have no side effect
New medicine comes out early.
The content of the invention
Purpose of the invention is to provide hydrogen sulfide(H2S)And its donor sodium hydrosulfide(NaHS)New use in pharmacy
On the way.More particularly to the purposes of hydrogen sulfide and its donor sodium hydrosulfide in treatment diabetes medicament is prepared.Hydrogen sulfide of the invention
And its donor sodium hydrosulfide can be used as insulin sensitizer and medicine that is hypoglycemic to type II diabetes and increasing insulin level.
The present invention is used for insulin sensitivity enhancing and to II type glycosuria using exogenous hydrogen sulfide and its donor sodium hydrosulfide NaHS
Disease experiment that is hypoglycemic and increasing insulin level, including:The correlation test of skeletal muscle and fat cell and insulin resistance,
The animal model of diabetes insulin resistance carries out insulin tolerance tests, glucose consumption experiment, diabetes insulin resistance
Animal model test and give NaHS and intervene zoopery etc., as a result show:The situation that NaHS can exist in insulin
Under play a part of to promote glucose uptake, point out NaHS to strengthen the effect of insulin, hydrogen sulfide and its donor sulphur are hydrogenated
Sodium can be used as insulin sensitizer;
By skeletal muscle and the correlation test of fat cell and insulin resistance, as a result, it was confirmed that NaHS is thin to cultivating
The metabolism of the skeletal muscle and fat cell glucose under insulin stimulating is dramatically increased in the range of the substantially nontoxic safe concentration of born of the same parents;
The animal model resisted by diabetes insulin carries out insulin tolerance tests, as a result shows the H of low dose2S
The insulin sensitivity of GK rats can be increased;
Confirmed by glucose consumption experimental result, NaHS shows in the range of the safe concentration substantially nontoxic to cultured cells
Write the metabolism of the skeletal muscle and fat cell glucose increased under insulin stimulating;Hydrogen sulfide is normal for fat cell and model
The glucose uptake of cell base state has facilitation, but does not have for the glucose uptake of Skeletal Muscle Cell base state
Influence;
The animal model test resisted by diabetes insulin, is as a result shown, hydrogen sulfide and its donor sodium hydrosulfide pair
Type II diabetes has hypoglycemic and insulin-sensitizing effect, can increase insulin level;
NaHS zooperies are given by chronic, is as a result shown, the chronic NaHS that gives can reduce ROS in GK rat kidney
The numbers of glomeruli of generation crescent lesion in GK rat kidney is expressed and can reduced, shows hydrogen sulfide and its hydrogenation of donor sulphur
Sodium has protective effect to the kidney injury that diabetes cause, i.e., the effect frozen with preventing and treating diabetogenous nephrosis popular name for, can be with
Reduce the oxidative stress of kidney.
The results show, hydrogen sulfide of the present invention and its donor sodium hydrosulfide NaHS can be used as insulin sensitivity enhancings
Agent, and by hypoglycemic and insulin-sensitizing effect, insulin level can be increased, as treatment type II diabetes medicine, institute
The hydrogen sulfide and its donor sodium hydrosulfide stated have protective effect to the kidney injury that diabetes cause, and can prevent and treat diabetes kidney
The effect that disease is frozen, can also reduce the oxidative stress of kidney.
H of the invention2The advantage of S and its donor NaHS has:
1st, hydrogen sulfide and its donor sodium hydrosulfide can be used as insulin sensitizers;
2nd, hydrogen sulfide and its donor sodium hydrosulfide have hypoglycemic and insulin-sensitizing effect, Ke Yizeng to type II diabetes
High insulin levels;
3rd, hydrogen sulfide and its donor sodium hydrosulfide have protective effect to the kidney injury that diabetes cause, i.e., with preventing and treating
The effect that diabetogenous nephrosis popular name for is frozen, can also reduce the oxidative stress of kidney.
Brief description of the drawings
The NaHS of Fig. 1 various concentrations(0-200μmol/L)Skeletal Muscle Cell is incubated after 24 hours, to insulin stimulating shape
The influence of glucose uptake under state.
The NaHS of Fig. 2 various concentrations(0-200μmol/L)Fat cell is incubated after 24 hours, to insulin stimulating state
The influence of lower glucose uptake.
The NaHS of Fig. 3 various concentrations(0-200μmol/L)The Skeletal Muscle Cell of incubation insulin resistance is right after 24 hours
The influence of glucose uptake under insulin stimulating state.
The NaHS of Fig. 4 various concentrations(0-200μmol/L)The fat cell of insulin resistance is incubated after 24 hours, to pancreas
The influence of glucose uptake under the element stimulation state of island.
Fig. 5 control groups and NaHS(50μmol/L)Low sugar(5.5mmol/L)It is incubated the Skeletal Muscle Cell 24 of insulin resistance
After hour, to insulin of different concentration(0-100nmol/L)The influence of glucose uptake under stimulation state.
Fig. 6 control groups and NaHS(50μmol/L)Low sugar(5.5mmol/L)The fat cell 24 for being incubated insulin resistance is small
Shi Hou, to insulin of different concentration(0-100nmol/L)The influence of glucose uptake under stimulation state.
Fig. 7 control groups and NaHS(50μmol/L)Sugar high(25mmol/L)It is incubated the Skeletal Muscle Cell 24 of insulin resistance
After hour, to insulin of different concentration(0-100nmol/L)The influence of glucose uptake under stimulation state.
Fig. 8 control groups and NaHS(50μmol/L)Sugar high(25mmol/L)The fat cell 24 for being incubated insulin resistance is small
Shi Hou, to insulin of different concentration(0-100nmol/L)The influence of glucose uptake under stimulation state.
After Fig. 9 intraperitoneal injection insulin(0.75U/kg), the time changing curve of GK rat blood sugars.
After Figure 10 intraperitoneal injection insulin(0.75U/kg), the time changing curve of Wistar rat blood sugars.
After Figure 11 intraperitoneal injection insulin(0.40U/kg), the time changing curve of Wistar rat blood sugars.
Figure 12 .NaHS be administered 10 weeks during GK rats and Wistar rat chronics fasting blood-glucose change.
Sugar tolerance is tested after Figure 13 .GK rat chronics are administered 8 weeks
Sugar tolerance is tested after Figure 14 .Wistar rat chronics are administered 8 weeks
Figure 15 .GK rat chronics be administered 8 weeks after insulin level
After 10 weeks, ROS expresses and occurs the glomerulus number of crescent lesion to Figure 16 chronic administrations in the kidney of GK rats
Amount.
Specific embodiment
The hydrogen sulfide of embodiment 1 and its donor sodium hydrosulfide are tested as insulin sensitizer
The NaHS of various concentrations(1-200μmol/L)After being incubated 24 hours, for normal Skeletal Muscle Cell base state
Under glucose uptake do not influence, have detected in the presence of insulin NaHS for Skeletal Muscle Cell glucose uptake
Either with or without effect, the NaHS of various concentrations is detected(0-200μmol/L)It is incubated glucose(5.5μmol/L)And insulin
(100nmol/L)After 24 hours, as a result the influence to glucose uptake under insulin stimulating state shows the Skeletal Muscle Cell of resistance
Show(As shown in Figure 1), NaHS dramatically increases in the concentration of 25,50 and 100 μm of ol/L3H- deoxyglucose Sugar intakes, NaHS promotees
Enter the optium concentration of glucose uptake for 100 μm of ol/L, 1 times is increased above compared with control group, be 2.06 ± 0.29(P <
0.01), 25 and 50 μm of NaHS of ol/L increase glucose uptake rate to 1.54 ± 0.08 and 1.72 ± 0.32 respectively;Result shows
NaHS can play a part of to promote glucose uptake in the presence of insulin, point out NaHS to strengthen insulin
Effect, i.e. insulin-sensitizing effect;
The NaHS of various concentrations, from(0-200 μm of ol/L) be incubated 24 hours after, for normal fat cell insulin pierce
The glucose uptake swashed under state does not influence, and points out NaHS to be worked for the glucose uptake of fat cell and may not passed through
Insulin;The NaHS of various concentrations, from(0-200μmol/L)After being incubated 24 hours, glucose uptake experiment is carried out, as a result shown
(As shown in Figure 2), hydrogen sulfide is obviously promoted work for the glucose uptake under normal fat cell insulin existence
With NaHS is dramatically increased in the concentration of 25,50 and 100 μm of ol/L3H- deoxyglucose Sugar intakes, it is different from Skeletal Muscle Cell,
It is 50 μm of ol/L that NaHS promotes the optium concentration of fat cell glucose uptake, is 1.54 times of control group;
Result shows that role of the adipose tissue in glucose transport is much smaller than skeletal muscle tissue, skeletal muscle tissue
Participate in the fat cell caused by 75%, the NaHS valid density of overall glucose intake3H- deoxyglucose Sugar intakes it is increased
Amplitude is much smaller than Skeletal Muscle Cell.
Insulin sensitivity is badly damaged in type II diabetes, and we observe in normal skeletal myoblast
Vulcanization Hydrogen Energy increases the glucose uptake in the presence of insulin, but the glucose uptake of base state is not influenceed.This knot
Really pointing out us may have certain insulin-sensitizing effect by hydrogen sulfide.
According to diabetes when Patients with Insulin Resistance body in generally existing hyperinsulinism or/and hyperglycaemia pathological characteristic,
Reported according to pertinent literature in the present embodiment, on the basis of normal culture Skeletal Muscle Cell, with high concentration insulin sugar high
Environmental induction culture Skeletal Muscle Cell, sets up the cell model of insulin resistance(IR models), and pass through3H- deoxyglucoses are taken the photograph
Take experiment to be identified, glucose of the hydrogen sulfide to the cell of insulin resistance under detection base state and insulin stimulating state
The effect of intake.
Including,
The cell model of insulin resistance is set up, with model group(IR)Glucose uptake amount as intake base value, each group
Respectively by comparison as respective glucose uptake rate, as a result show, NaHS is thin for IR model skeletal muscle after being incubated 24 hours
The basal glucose intake of born of the same parents is without influence, and this is consistent with the result of normal cell base state, and prompting NaHS works dependence
In the presence of insulin;
Further research insulin presence in the case of NaHS for the grape cell Sugar intake of IR models effect, as a result
It has been shown that,
In insulin stimulating(100nmol/L)In the case of, NaHS significantly increases in the concentration of 25,50 and 100 μm of ol/L
Plus IR model L6 cells3H- deoxyglucose Sugar intakes(As shown in Figure 3), wherein the NaHS of 50 and 100 μm of ol/L is thin for IR
The effect of born of the same parents is close, and the increase degree of the glucose uptake that NaHS valid density causes in IR model cells is significantly less than
Normal cell, the NaHS of 25,50 and 100 μm of ol/L increases glucose uptake to 1.61 ± 0.57,1.72 ± 0.53 Hes respectively
1.56 ± 0.36 times, illustrate that NaHS can play a part of to promote glucose uptake under pathological state;
The NaHS of various concentrations, after being incubated 24 hours from 0-200 μm of ol/L, for normal fat cell insulin stimulating
Glucose uptake under state does not influence, and compared with the control, glucose uptake rate has increase to 25 μm of NaHS of ol/L, points out
NaHS works for the glucose uptake of fat cell may not pass through insulin;
The NaHS of various concentrations, after being incubated 24 hours from 0-200 μm of ol/L, carries out glucose uptake experiment, hydrogen sulfide pair
Effect is obviously promoted in the glucose uptake under normal fat cell insulin existence, NaHS is in 25,50 and 100 μ
The concentration of mol/L is dramatically increased3H- deoxyglucose Sugar intakes, different from Skeletal Muscle Cell, NaHS promotes fat cell grape
The optium concentration of Sugar intake is 50 μm of ol/L, is 1.54 times of control group;
The NaHS of various concentrations, after being incubated 24 hours from 0-200 μm of ol/L, for IR model fat cell insulin stimulatings
Glucose uptake under state does not influence, and compared with the control, glucose uptake rate is increased slightly 50 μm of NaHS of ol/L;
Cell sets up the cell model of insulin resistance through sugar high hyperinsulinism combined induction culture, with model group(IR)'s
, used as intake base value, each group is respectively by comparison as respective glucose uptake rate for glucose uptake amount(As shown in Figure 4), NaHS
There is facilitation for the glucose uptake under the fat cell insulin stimulating of IR models after being incubated 24 hours, with normal fat
The result of fat cell is consistent, and it is 50 μm of ol/L that NaHS promotes the optium concentration of IR model fat cell glucose uptakes, is control
2.02 ± 0.86 times of group, the NaHS of 25 and 100 μm of ol/L increases to 1.75 ± 0.68 and 1.56 ± 0.44 times.
Hydrogen sulfide is have detected in the present embodiment to insulin of different concentration(0-100nmol/L)Glucose is taken the photograph under stimulation state
The influence for taking, as a result shows,
Control group and NaHS(50μmol/L)Treatment group low sugar(5.5mmol/L)It is incubated the Skeletal Muscle Cell of insulin resistance
(As shown in Figure 5)And fat cell(As shown in Figure 6)After 24 hours, when insulin concentration is 10 and 100nmol/L, NaHS treatment
Compared with the control, glucose uptake is significantly increased group, wherein without significant difference when 0,1 and 5nmol/L;
Control group and NaHS(50μmol/L)Treatment group sugar high(25mmol/L)It is incubated the Skeletal Muscle Cell of insulin resistance
(As shown in Figure 7)And fat cell(As shown in Figure 8)After 24 hours, when insulin concentration is 10 and 100nmol/L, NaHS treatment
Compared with the control, glucose uptake is significantly increased group, wherein without significant difference when 0,1 and 5nmol/L;
The correlation test of the skeletal muscle of embodiment 2 and fat cell and insulin resistance
Using wide variety of insulin resistance and diabetes cell in the prior art in the present embodiment:Wherein, skeletal muscle
Sarcoblast strain is Yaffe isolated from the primary culture of rat thigh flesh, can be melted under certain condition of culture
Conjunction forms the myotube and rhabdium of multinuclear;Fat cell strain derive from MEC, through clonal expansion into
It is pre-adipose cell lines, then mature fat cell is induced to differentiate into through specific differentiation agent;
1)The evaluation of cellular level insulin sensitivity
The glucose uptake of isotope marks is tested using cell, evaluates glucose uptake of the cell to insulin stimulating
And Utilization ability, so as to evaluate the sensitiveness of insulin, judge that insulin resistance whether there is;
Glucose consumption is tested:The amount of sugar consumption is calculated by determining the sugared concentration in 24 hours wild Oryza species for the treatment of, is commented
Sentence the ability of cellular uptake sugar, to reflect the glucose metabolism situation of cell, therefore, the present embodiment combination glucose consumption and Portugal
Influence of the result overall merit hydrogen sulfide of grape Sugar intake to Skeletal Muscle Cell and the insulin sensitivity of fat cell, wherein,
Including effect of the hydrogen sulfide to Skeletal Muscle Cell and the glucose uptake of fat cell under physiology and pathological state;
(1)Set up insulin resistance cell model
Insulin resistance cell model is set up with the method for sugar hyperinsulinism high, it is high in Patients with Insulin Resistance body to simulate
The pathology environment of blood sugar hyperinsulinemia, wherein, the fat cell and Skeletal Muscle Cell myotube of differentiation use high concentration pancreas islet
Element and high sugar induced culture 24h, then with3H- deoxyglucoses Sugar intake is verified;
Each effective ingredient is monitored in various concentrations to fat cell and Skeletal Muscle Cell vigor with mtt assay in experiment
Influence, as a result show, NaHS concentration be 10 to 200 μm of ol/L when cell viability is had no significant effect, concentration be more than 500 μ
Glucose consumption and glucose uptake experiment after having certain toxicity, the present embodiment to determine after mol/L to cell is used dense
It is 10 to 200 μm of ol/L to spend.
Glucose consumption experimental result confirms that NaHS significantly increases in the range of the safe concentration substantially nontoxic to cultured cells
Plus the metabolism of the skeletal muscle and fat cell glucose under insulin stimulating;
Normal and insulin resistant model cell3H- deoxyglucose Sugar intake result of the tests show, model cell grape
Sugar intake ability is decreased obviously under basis and insulin stimulating state compared with normal cell, and high concentration glucose is highly concentrated
Degree insulin can substantially suppress the intake of glucose;
Pharmaceutical intervention result shows, hydrogen sulfide glucose uptake normal for fat cell and model cell base state
There is facilitation, but do not influenceed for the glucose uptake of Skeletal Muscle Cell base state;In the presence of insulin, NaHS
The glucose uptake of fat cell and Skeletal Muscle Cell can be dramatically increased, and this to act on normal and insulin resistant model thin
All exist in born of the same parents;Result is pointed out, and hydrogen sulfide may be different to the mechanism of action of Skeletal Muscle Cell and fat cell.
The hypoglycemic and insulin-sensitizing effect of the hydrogen sulfide of embodiment 3 and its donor sodium hydrosulfide to type II diabetes
The animal model for selecting the GK rats at 2 monthly ages to be resisted as the present embodiment diabetes insulin;
Routine carries out insulin tolerance test, test result indicate that, in a certain amount of pancreas of the rats by intraperitoneal injection of chronic administration
60 minutes after the element of island, the ratio that the blood sugar of 30 μm of ol/kg groups of GK rats NaHS declines is significantly greater than control group(Such as Fig. 9 institutes
Show), the ratio that the blood sugar of 60 μm of ol/kg groups of Wistar rats NaHS declines is significantly greater than control group(As shown in Figure 10);Pancreas islet
Plain sensitivity experiments, using the insulin of low concentration(0.4U/kg)Hungry 4 hours Wistar rats, 60 μm of ol/kg groups of NaHS
Compare with control group and be decreased obviously(As shown in figure 11), as a result show, low dose of H2S can increase the insulin of GK rats
Sensitiveness;
Detect within 2,4,6 weeks the fasting blood-glucose content of GK diabetes rats respectively after NaHS administrations(As shown in figure 12), give
Medicine low dose NaHS after 4 weeks(30μmol/kg)Hypoglycemic effect is shown, there is significant difference compared with control group, show low
Concentration H2S can reduce the fasting blood-glucose of GK diabetes rats.
Carbohydrate tolerance test shows that each group GK rats blood sugar at each time point after glucose load is all remarkably higher than Wistar groups, explanation
The reduction of GK rats sugar tolerance(As shown in figure 13), in intraperitoneal injection glucose 30 minutes and 90 minutes, NaHS administration low dosages
The blood sugar concentration of the rat of group is significantly lower than control group;The blood glucose value ratio of 30 and 90 minutes NaHS, 30 μm of ol/kg groups after glucose load
Control group is significantly reduced, and illustrates that NaHS increases sugar tolerance;
The NaHS low dose groups in intraperitoneal injection glucose 30 minutes(30 and 60 μm of ol/kg)Have with control group blood glucose value
Significant difference(As shown in figure 14), 60 μm of ol/kg groups of NaHS and control group blood glucose value in intraperitoneal injection glucose 60 minutes
With significant difference, show H2S has an impact to Wistar rat diabetes glucose tolerances;
Low concentration NaHS(30μmol/kg/d)The insulin resistance of GK rats can be improved, fasting blood-glucose is reduced(FBG),
Increase glucose tolerance, and heavy dose NaHS(120μmol/kg/d)The insulin resistance of GK rats, fasting blood-glucose are then aggravated
Raise, as a result glucose tolerance reduction shows H2S has dual regulation to act on for internal insulin resistance.
The protective effect of the kidney injury that the hydrogen sulfide of embodiment 4 and its donor sodium hydrosulfide cause to diabetes
It is chronic according to a conventional method to give NaHS various concentrations(30th, 60 and 120 μm of ol/L)After 10 weeks, GK rat kidney is observed
The expression of interior ROS, as a result shows(As shown in Figure 16 A):ROS expression is big apparently higher than Wistar in GK rat control group kidneys
Mouse;GK rat medication groups compare with GK rat control groups, NaHS various concentrations(30th, 60 and 120 μm of ol/L)Can significantly reduce
The expression of ROS in kidney, and into certain concentration dependent(As shown in Figure 16 C4);
It is chronic to give NaHS various concentrations(30th, 60 and 120 μm of ol/L)After 10 weeks, Kidney sections are dyeed, as a result with PAS
It has been shown that, the extracellular matrix severe hyperplasia of GK rat controls group glomerulus compared with Wistar rats forms tuberous sclerosis, in same
Heart round shape is arranged, i.e. Kimmelstiel-Wilson tubercles(Kimmelstie l-Wilson nodule), give NaHS different
Concentration(30th, 60 and 120 μm of ol/L)After 10 weeks(As shown in Figure 16 B and D), the numbers of glomeruli of hyperplasia compares bright with GK control groups
It is aobvious to reduce, show it is chronic give NaHS and can reduce in GK rat kidney there is the numbers of glomeruli of crescent lesion, hydrogen sulfide and
Its donor sodium hydrosulfide has protective effect to the kidney injury that diabetes cause.
Claims (2)
1. the purposes of hydrogen sulfide and its donor sodium hydrosulfide in treatment type ii diabetes medicine is prepared, described hydrogen sulfide and its
Donor sodium hydrosulfide reduction and increases insulin level at type ii diabetes blood sugar, wherein, the concentration of NaHS for 25,50 or
100μmol/L。
2. the purposes as described in claim 1, it is characterised in that described medicine is used as insulin sensitizer.
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CN106176801B (en) * | 2015-05-06 | 2020-06-09 | 复旦大学 | Application of hydrogen sulfide in preparation of medicine for treating inflammatory anemia |
CN106539818A (en) * | 2015-09-20 | 2017-03-29 | 复旦大学 | Hydrogen sulfide and its donor sodium hydrosulfide are preparing the purposes promoted in hemopoietic medicine |
IT202000009700A1 (en) | 2020-05-04 | 2021-11-04 | Parthenogen Sagl | COMBINATION OF MICRONUTRIENTS TO STIMULATE THE ENDOGENOUS PRODUCTION OF HYDROGEN SULFIDE (H2S) |
CN113801841A (en) * | 2020-06-12 | 2021-12-17 | 温州医科大学 | Method for detecting insulin sensitivity of AdipoRon to mouse skeletal muscle cells |
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