CN117700489A - Application of adipose-derived stem cells in medicine for treating diabetes - Google Patents
Application of adipose-derived stem cells in medicine for treating diabetes Download PDFInfo
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- CN117700489A CN117700489A CN202311751789.XA CN202311751789A CN117700489A CN 117700489 A CN117700489 A CN 117700489A CN 202311751789 A CN202311751789 A CN 202311751789A CN 117700489 A CN117700489 A CN 117700489A
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Landscapes
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
The invention relates to application of adipose-derived stem cells in a medicament for treating diabetes. The adipose-derived mesenchymal stem cells are separated and prepared, can well inhibit the blood glucose value of a hyperglycemic mouse, and can cooperatively reduce the blood glucose value after being used together with the hypoglycemic peptide obtained by separation and identification, and meanwhile, the adipose-derived mesenchymal stem cells can effectively increase the number of beta cells in pancreatic islets, and have good application prospects.
Description
Technical Field
The application relates to the field of biological treatment, in particular to application of adipose-derived stem cells in a medicament for treating diabetes.
Background
Mesenchymal Stem Cells (MSCs) are adult stem cells with self-renewal and multidirectional differentiation potential, are widely available, can be isolated from various tissues such as bone marrow, fat, umbilical cord and the like, have low immunogenicity, can secrete a large amount of active factors and participate in the immune regulation of organisms, and play a therapeutic role in various disease models, such as diabetes, myocardial infarction and acute kidney injury. Although bone marrow derived MSCs have been shown to exert hypoglycemic and insulin resistance ameliorating effects in type 2 diabetes, bone marrow harvesting can be painful, even requiring general anesthesia or intraspinal anesthesia, and the number of cells obtained is limited, which is unacceptable to patients and somewhat limiting clinical applications. Mesenchymal Stem Cells (MSCs) are adult stem cells with self-renewal and multidirectional differentiation potential, and have wide sources, so that the MSCs with fat sources have the advantages of convenience in acquisition, abundant sources and the like, and become another option for treating type 2 diabetes.
Adipose derived MSCs can improve beta cell function, whether it is type 1 diabetes or type 2 diabetes, and the dysfunction of human beta cells, which leads to insufficient insulin secretion, is an important cause of morbidity. MSCs can migrate specifically to damaged islets or promote proliferation of beta cells within damaged islets by secreting cytokines, inhibiting beta cell apoptosis after implantation into the body. MSCs can also differentiate directly into insulin secreting cells (IPCs) or promote differentiation of ductal cells, islet progenitor cells, into IPCs by increasing the absolute number of insulin secreting cells in the body, i.e. increasing insulin secretion, to ameliorate diabetic conditions. MSCs cannot differentiate directly into beta cells but can promote differentiation of islet progenitor cells into beta cells, and further studies have found that MSCs function by up-regulating the AKT pathway. MSCs from diabetics are subjected to in-vitro differentiation test and in-vivo transplantation test respectively, and MSCs are only slightly (about 3%) differentiated into insulin-secreting cells in vitro, but hyperglycemia symptoms can be improved in a short period after MSCs are transplanted into diabetes model mice, and further research shows that the number of MSCs differentiated into insulin-secreting cells in vivo is greatly increased and can reach about 18%, which is possibly related to microenvironment in model mice. The results of inducing diabetic model mice with STZ and High Fat Diet (HFD) and then transplanting MSCs at early stage (7 d) and late stage (21 d), respectively, indicate that both can improve hyperglycemia, but early transplanted group MSCs can promote beta cell function, but late stage cannot, and further studies find that MSCs cannot promote beta cell proliferation, but rather act by inhibiting beta cell apoptosis. It was found that MSCs can ameliorate type 2 diabetes caused by chronic hyperglycemia by up-regulating the level of beta cell autophagy, and further studies have found that transforming growth factor beta (TGF- β) secreted by MSCs plays an important role in this process. The conclusions drawn by the different researchers in the above study are not exactly the same, but it is clear that MSCs can improve diabetic conditions by increasing the absolute number of beta cells by affecting several pathways through different pathways. MSCs can ameliorate insulin resistance in peripheral target tissues insulin resistance is an important aspect in the pathogenesis of type 2 diabetes, and the mechanism specifically responsible for insulin resistance is the decreased expression of glucose transporter 4 (GLUT 4) in insulin target tissues such as muscle, fat, liver cells, and the disturbed phosphorylation of IRS-1 and AKT affecting insulin signal transduction. After MSCs were transplanted to STZ and HFD-induced diabetic model mice, both early and late in diabetes, insulin resistance was improved by up-regulating GLUT4 expression in insulin target tissues, affecting GLUT4 displacement, and up-regulating IRS-1 and AKT phosphorylation, thereby improving hyperglycemia symptoms. Insulin resistance is closely related to adipose tissue macrophages, and after MSCs are transplanted into a model mouse of type 2 diabetes induced by a high-fat diet and STZ, diabetes symptoms and insulin resistance are obviously improved, and further research shows that the MSCs mainly improve insulin resistance by secreting IL-6 to convert M1 type macrophages (pro-inflammatory type) into M2 type macrophages (anti-inflammatory type).
However, at present, MSCs have many advantages in treating diabetes, but there are still disadvantages. The curative effect of the single mesenchymal stem cell therapy needs to be further improved, and diabetics often need to be treated by combining 2 or 3 oral hypoglycemic drugs or insulin with other oral hypoglycemic drugs. Therefore, stem cell therapy requires research for use in combination with other drugs to enhance therapeutic effects. Recently, the direction of diabetes treatment has shifted to active peptides in natural active substances, with some success. However, the available polypeptides without patent barriers are not enough, and further development and use are needed.
Disclosure of Invention
The invention overcomes the defects of the prior art and provides a novel method for treating diabetes.
The method comprises administering adipose mesenchymal stem cells for lowering blood glucose value.
Further, the invention provides a pharmaceutical composition for treating diabetes, wherein the composition contains adipose-derived mesenchymal stem cells.
"adipose-derived stem cells" refers to multipotent stromal cells or stem cells derived from adipose tissue and capable of self-renewal. "fat" refers to any adipose tissue. Adipose tissue may be brown or white adipose tissue that originates subcutaneously from omentum/viscera, breast, gonads or other adipose tissue sites. Preferably, the fat is subcutaneous white adipose tissue. Such cells may comprise primary cell cultures or immortalized cell lines. Adipose tissue may be from any organism having adipose tissue. Preferably, the adipose tissue is mammalian, most preferably, the adipose tissue is human, and particularly preferably is adipose tissue (i.e., autologous tissue) derived from the subject to be treated or a clone of the subject.
Furthermore, the invention provides a hypoglycemic peptide, which is named as K2-T3 and has a sequence shown as DKHPFMVFFPCP.
In particular, the hypoglycemic peptide of the present invention may also be modified or replaced, but still retain the activity of the hypoglycemic peptide.
Further, the amino acid sequence of the polypeptide has 1 or more (preferably no more than 5, 4, 3, 2, 1) amino acid changes (preferably amino acid substitutions, more preferably amino acid conservative substitutions) compared to the amino acid sequence of the polypeptide.
Further, the pharmaceutical composition of the present invention comprises a hypoglycemic peptide and adipose mesenchymal stem cells.
Further, the pharmaceutical compositions of the present invention may also comprise suitable pharmaceutical excipients, such as pharmaceutically acceptable carriers, pharmaceutically acceptable excipients, including buffers, as known in the art.
As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, isotonic and absorption delaying agents, and the like that are physiologically compatible. Pharmaceutically acceptable carriers suitable for use in the present invention may be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. When the pharmaceutical composition is administered intravenously, water is a preferred carrier. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.
Physiologically acceptableIs typically an aqueous pH buffered solution. Examples of physiologically acceptable carriers include, but are not limited to, saline, solvents, dispersion media, cell culture media, aqueous buffers, such as phosphate, citrate, and other organic acids; antioxidants, including ascorbic acid; a low molecular weight (less than about 10 residues) polypeptide; proteins, such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions, such as sodium; and/or nonionic surfactants, e.g. TWEEN TM Polyethylene glycol (PEG).
Suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
The composition may also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
The compositions of the present invention may be in a variety of forms. These include, for example, liquid, semi-solid, and solid dosage forms, such as liquid solutions (e.g., injectable solutions and infusible solutions), dispersions or suspensions, liposomal agents, and suppositories. The preferred form depends on the intended mode of administration and the therapeutic use. A common preferred composition is in the form of an injectable solution or an infusible solution. The preferred mode of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular) injection. In a preferred embodiment, the polypeptide and stem cells are administered by intravenous infusion or injection. In another preferred embodiment, the polypeptide and stem cells are administered by intramuscular, intraperitoneal or subcutaneous injection.
In some embodiments, the invention provides methods for treating or preventing a diabetes-related disorder in a subject comprising administering to the subject a composition comprising the stem cells, thereby treating or preventing a hyperglycemia-related disease in the subject.
In some embodiments, the composition comprises as at least 10 6 Stem cells, e.g. at least 5X 10 6 ，10 7 ，5×10 8 ，5×10 9 And (3) stem cells. In some embodiments, administration is by injection or surgical grafting.
The therapeutic compositions of the present invention are administered in a manner compatible with the dosage formulation and in a therapeutically effective amount. The amount administered will depend on, for example, the subject and the weakness to be treated, the ability of the subject's organs, the cells and immune system in which the therapeutic composition is to be contained, and the nature of the cell or tissue therapy, etc. The therapeutic composition to be administered depends on the discretion of the practitioner and is specific to each individual. However, a suitable dosage of the therapeutic compositions of the present invention may be about 1-10 x10 per treatment site per day 6 Adipose stem cells/individual treated individual, preferably about 0.10-5×10 6 . Each treatment site per day, and depends on the route of administration and the size of the treatment site. Suitable amines for initial administration and subsequent administration are also variable, but may include initial administration followed by repeated administration by subsequent injections or at one or more intervals as desired or indicated (e.g., hours, days, weeks, months, or years).
In some embodiments, the stem cells are autologous or autologous.
Diabetes mellitus can be divided into two clinical syndromes: type 1 and type 2 diabetes. As used herein, "type 1", "type I" and "Insulin Dependent Diabetes Mellitus (IDDM)" are used interchangeably. Type 1 diabetes is a chronic autoimmune disease characterized by a massive loss of beta cells in the islets of langerhans, thereby producing insulin. As these cells gradually break down, the amount of secreted insulin decreases, eventually leading to hyperglycemia (abnormally high levels of glucose in the blood), when the amount of secreted insulin falls below normal blood glucose levels (normal blood glucose levels). Type 2 diabetes (also referred to herein as "type II" and "non-insulin dependent diabetes mellitus (NIDDM)") is a complex disease characterized by defects in glucose and lipid metabolism. In general, there are perturbations in many metabolic parameters, including fasting plasma glucose levels, increased levels of free fatty acids and triglycerides, and decreased HDL/LDL ratios. In this population, the insulin resistance phase characterized by type II diabetes is earlier than the late phase of insulin decline, which is considered to be particularly detrimental to tissue and organ function. One application of autologous ADSC therapy is that ADSC may modulate insulin resistance, thereby improving glucose utilization by tissues, and thus reducing hyperglycemia and its systemic adverse effects.
The polypeptide and stem cell group and the application of the invention can be used for treating type I diabetes by increasing the quantity of beta cells in pancreas islet, and can competitively inhibit various alpha-glucosidases in small intestine, so that the speed of decomposing starch into glucose is slowed down, thereby slowing down the absorption of glucose in intestinal tract, reducing postprandial hyperglycemia and further realizing the treatment of type II diabetes.
Advantageous effects
The adipose-derived mesenchymal stem cells are separated and prepared, can well inhibit the blood glucose value of a hyperglycemic mouse, and can cooperatively reduce the blood glucose value after being used together with the hypoglycemic peptide obtained by separation and identification, and meanwhile, the adipose-derived mesenchymal stem cells can effectively increase the number of beta cells in pancreatic islets, and have good application prospects.
Drawings
FIG. 1 is a graph showing the results of identification of antioxidant properties of K2-T3 polypeptides
FIG. 2 is a graph showing the results of blood glucose levels in each treatment group
FIG. 3 is a graph showing the results of the number of beta cells in each group
Detailed Description
Those skilled in the art can, with the benefit of this disclosure, suitably modify the process parameters to achieve this. It is expressly noted that all such similar substitutions and modifications will be apparent to those skilled in the art, and are deemed to be included in the present invention. While the methods and applications of this invention have been described in terms of preferred embodiments, it will be apparent to those skilled in the relevant art that variations and modifications can be made in the methods and applications described herein, and in the practice and application of the techniques of this invention, without departing from the spirit or scope of the invention. The methods, apparatus, materials, and so forth in the following examples, unless otherwise indicated, are all conventional in the art and are commercially available.
EXAMPLE 1 screening identification of Momordica Charantia anti-glycopeptides
Fresh balsam pear is ground into slurry, centrifuged at 4000r/min, supernatant is taken, papain (80 ten thousand U/g) and alkaline protease (20 ten thousand U/g) are purchased from Soy Bao company and are subjected to enzymolysis for 2 hours simultaneously, and after the reaction is finished, the enzyme is deactivated in boiling water bath for 10 min. Selecting a polypeptide with a filter membrane aperture of 3Kda and a molecular weight cutoff of less than 3Kda for ultrafiltration.
The zymolyte enters a SephadexG-15 gel column, and is separated into K1, K2, K3 and K44 components according to the molecular weight difference after water elution. The sample can remove part of impurities through gel chromatography. The main 4 components are collected in test tubes, concentrated by rotary evaporation, dried and subjected to an alpha-glucosidase activity experiment to determine the inhibition activity, and the components with large inhibition activity are subjected to the next separation analysis.
Alpha-glucosidase activity assay: an appropriate amount of α -glucosidase was weighed and dissolved in PBS solution (0.1 mol/L, pH=6.8) to prepare 0.2U/mL enzyme solution. An appropriate amount of sample was taken and configured as a concentration gradient of 0.1,0.5,1,1.5,2,2.5mg/mL of sample solution. In the experimental process, an enzyme-labeled instrument and a 96-well plate are used, and the sample addition is divided into 3 groups, namely: control, sample background. The respective components were treated as follows. Control group: 70 mu L of PBS, 20 mu L of 15mmolpNPG, uniformly mixing, reacting for 10min at 37 ℃, adding 20 mu L of alpha-glucosidase, uniformly mixing, reacting for 20min at 37 ℃, and stopping the reaction by 150 mu LNa2CO 3; sample group: 50. Mu.L of PBS, 20. Mu.L of sample, 20. Mu.L of 15mmolpNPG, mixing, reacting for 10min at 37 ℃, adding 20. Mu.L of alpha-glucosidase, mixing, reacting for 20min at 37 ℃, and stopping the reaction by 150. Mu.LNa 2CO 3; sample background group: 70. Mu.L of PBS, 20. Mu.L of sample, 20. Mu.L of 15mmo/LpNPG, and the mixture was then mixed, reacted at 37℃for 30 minutes, and the reaction was stopped at 150. Mu.LNa 2CO 3. The sample group is sample solution with concentration gradient and positive control acarbose. The absorbance was measured immediately after the loading reaction at 405 nm. IC50 values were calculated from enzyme activity inhibition versus concentration curve. Inhibition (%) = [ a control- (a sample-a sample background) ]/a control x 100%. Wherein, the sample A, the sample background A and the reference A are the absorbance values of the sample group, the sample background group and the reference group at 405nm respectively. The results are shown in Table 1.
Table 1 alpha-glucosidase inhibitory Activity of samples
| Group of | IC50(mg/mL) |
| Bitter gourd zymolyte | 2.11±0.28 |
| K1 | 1.03±0.17** |
| K2 | 0.08±0.01** |
| K3 | 0.79±0.08** |
| K4 | 0.67±0.14** |
| Acarbose candy | Less than 0.001 × |
Note that: p <0.01 is a very significant difference compared to the bitter gourd hydrolysate.
Wherein, the inhibition effect of the component K2 is significantly stronger than that of the other components (p < 0.05), but is significantly lower than that of positive control acarbose (less than 0.001 mg/mL) (p < 0.01). K2 was collected, concentrated to dryness by rotary evaporation and further studied.
The K2 component is subjected to sequence analysis by utilizing a liquid chromatography-mass spectrometry Nano-LC-MS/MS technology by using an Shimadzu LC-2030 type high performance liquid chromatograph to obtain 3 polypeptides which are respectively named as K2-T1, K2-T2 and K2-T3, and the sequences are EHIAKGGWFTD, HVRDFAFYKFSDP, DKHPFMVFFPCP. After solid-phase synthesis of the three polypeptides, the alpha-glucosidase activity was measured. The results are shown in Table 2.
TABLE 2 alpha-glucosidase inhibitory Activity of samples
| Group of | IC50(mg/mL) |
| K2-T1 | 0.024±0.005 |
| K2-T2 | 0.013±0.002 |
| K2-T3 | 0.007±0.001 |
| Acarbose candy | Less than 0.001 |
As can be seen from the results in Table 2, the K2-T3 polypeptide has a good alpha-glucosidase inhibitory activity. Since alpha-glucosidase inhibitors are a class to delay intestinal carbohydrate absorption to achieve treatment of diabetes. The mechanism of action is that various alpha-glucosidases in the small intestine are competitively inhibited, so that the speed of decomposing starch into glucose is reduced, the absorption of glucose in the intestinal tract is slowed down, and postprandial hyperglycemia is reduced. Alpha-glucosidase inhibitors do not stimulate insulin secretion by beta cells, but can reduce postprandial insulin levels, suggesting that insulin sensitivity may be increased. The K2-T3 peptide was selected for subsequent experiments.
EXAMPLE 2 identification of antioxidant Properties of K2-T3 Polypeptides
To further explore the properties of the polypeptides, the ABTS method was used to evaluate the total antioxidant capacity of the polypeptides. The mechanism for measuring the antioxidant capacity by the ABTS method is that the ABTS generates green ABTS+ under the action of certain oxidants, when the antioxidants exist, the colored substances are inhibited, the colors become light, the light absorption value at 734nm becomes weak, and the total antioxidant capacity can be calculated by calculating the reduced absorption value. The merck ABTS kit is used for measurement, the sample is added according to the requirement of the kit, and the absorption is measured by an enzyme-labeled instrument. The concentration of the solution is selected to be 0.1mg/mL, PBS solution is dissolved, ABTS working mother liquor is diluted 40 times, absorption is 0.64 at 734nm, the dilution is used for experiments in the range of the requirement of the kit (0.70-0.75), and enzymolysis products and Vc are used as controls. The results are shown in FIG. 1.
As can be seen from FIG. 1, under the same concentration, the K2-T3 polypeptide has better antioxidation capability than the zymolyte, the antioxidation capability reaches 83%, and the K2-T3 polypeptide has better antioxidation characteristic. The antioxidant activity of the polypeptide is closely related to the amino acid sequence composition, molecular weight and hydrophobicity, and the K2-T3 polypeptide is rich in Asp, glu, arg, his, tyr, met, leu, ala, pro or Val, so that the polypeptide has antioxidant activity.
Example 3 isolation and preparation of fat Stem cells
Taking 25ml of superficial fat after abdominal liposuction, flushing 3 times by PBS containing penicillin-streptomycin double antibody, and removing fascia and red blood cells visible to naked eyes; adding 0.075% type I collagenase in an equal volume, and digesting for 50min at 37 ℃ and 150 rpm; adding an equal volume of DMEM/F12 medium containing 10% fetal bovine serum, stopping digestion, centrifuging at 12000rpm for 15min, and removing upper layer oil and middle layer clear liquid; adding 5mL of erythrocyte lysate to resuspend, standing for 5min at room temperature, centrifuging at 1000rpm for 5min, and removing supernatant; with bovine serum containing 15% of fetusesRe-suspending the low-sugar DMEM culture medium, filtering the culture medium by a 70um cell screen, and transferring the culture medium into a culture dish for primary culture; changing the culture medium every 2-3 days; observing under an inverted phase contrast microscope, and discarding the old culture medium when the cells are fused and grown to 85%; washing with PBS for 2-3 times, adding 1mL of 0.25% trypsin, standing at room temperature for 1min, observing under a microscope, and tapping the side wall of the culture dish when the cell part begins to fall off; when the cells were mostly shed, digestion was stopped by adding an equal volume of DMEM/F12 medium containing 10% fbs; centrifuging at 1000rpm for 5min, discarding supernatant, and retaining precipitate; resuspension with low-sugar DMEM medium containing 15% fetal calf serum, and passaging according to the ratio of 1:2; the 3 rd generation cells were washed 3 times with PBS, digested with 0.25% trypsin, and prepared into 1X 10 by adding 700uLPBS 6 Cell suspension of/L; respectively adding the prepared cell suspension into a centrifuge tube, wherein each centrifuge tube is 100uL, and sequentially adding 5uL of PE-anti-humanCD29, FITC-anti-humanCD34, 488-anti-humanCD44, PE-anti-humanCD45, PE-anti-humanCD90, 488-anti-humanCD105 and PBS into the centrifuge tube; incubating for 30min at room temperature in dark place, centrifuging at 1000rpm for 5min, and removing supernatant; resuspension with 200uLPBS, centrifugation at 1000rpm for 5min, and removal of supernatant; the wash was repeated 2 times and 200uL resuspended and waiting for loading. The data were analyzed by flowjosoftwre7.6.1 and showed positive expression of CD29, CD44, CD90, CD105, with positive rates of: 99.8%, 91.4%, 97.2%, 89.8%, and CD34 and CD45 were expressed negatively with the following negative rates: 98.5% and 94.7% of the total mesenchymal stem cells, which are obtained by separation, are regulated to 10% in concentration 8 The sample was kept at one/mL.
EXAMPLE 4 mice treatment diabetes experiments
Streptozotocin (STZ, 25 mg/kg) was intraperitoneally administered to SD rats after 8 weeks of High Fat Diet (HFD) feeding to induce type 2 diabetic rats. Continuously taking tail venous blood 3d after STZ injection, and monitoring blood sugar by adopting a blood sugar meter, wherein the blood sugar value is more than or equal to 16.7mmol/L, and the modeling is successful.
Type 2 diabetic rats were randomly divided into a diabetes group (T2 DM, n=10), a adipose stem cell-treated group (n=10) and a adipose stem cell-combined K2-T3 polypeptide-treated group (n=10), a K2-T3 polypeptide control group (n=10), and an acarbose positive control group (n=10). 10 rats were also normally raised in the same period as the control group.
After 7d of STZ injection, 5X 10 6 The stem cells were suspended in 1ml of PBS and injected into the adipose-derived stem cell-treated group and the adipose-derived stem cell-treated group in combination with K2-T3 polypeptide via the tail vein, and the diabetes group was infused with an equal amount of PBS. K2-T3 polypeptide adopts gastric lavage (100 mg/(kg.d)), acarbose adopts gastric lavage (100 mg/(kg.d)), and the administration is carried out 1 time a day for 10d; blood glucose was monitored before and after 10d of dosing. The results are shown in FIG. 2.
As can be seen from fig. 2, after stem cell infusion, blood glucose was significantly reduced (P < 0.01) in either the stem cell treated group or the stem cell combined polypeptide group compared to the model group. The K2-T3 polypeptide has better blood sugar reducing effect by singly treating, the blood sugar value is only 7.9, and after the stem cells are combined with the polypeptide for treatment, the blood sugar value is reduced to only 5.8, which is basically similar to that of a normal mouse, and better synergistic treatment effect is shown.
After the experiment is finished, the rat is anesthetized and the chest is opened, pancreatic tissues are taken and placed in 30% sucrose for dehydration overnight, and then the pancreatic tissues are embedded in an embedding medium at-80 ℃ for standby. Pancreatic tissue was serially sectioned at 7 μm. Tissue sections were incubated with 0.5% Triton-X100 for 15min at room temperature, washed 3 times with PBS and blocked with serum at room temperature for 30min. After the end of the blocking, the instrin and Glucagon primary antibodies were added and incubated overnight at 4 ℃. PBS washes away cells which are not combined with primary antibody, then fluorescent secondary antibody is added for incubation for 2 hours at room temperature, nuclear dye is added for incubation for 10 minutes, and finally 50% glycerol is used for sealing. And (5) observing and collecting images under a laser confocal microscope. The beta cells in 40-50 islets were manually counted for each group and averaged.
From the results of fig. 3, it is shown that the number of β cells in islets of diabetes mellitus group is significantly reduced (P < 0.01) compared with that of normal group, the number of β cells in stem cell group and stem cell combined polypeptide group and polypeptide group itself is significantly increased (P < 0.01) compared with that of diabetes mellitus group, the polypeptide group and acarbose group maintain the substantially similar number of β cells, and the number of β cells is significantly increased compared with that of polypeptide group alone after the polypeptide group is combined with fat stem cells, thus showing excellent synergistic effect.
Although the embodiments of the present invention have been described above with reference to the accompanying drawings, the present invention is not limited to the above-described specific embodiments and application fields, and the above-described specific embodiments are merely illustrative, and not restrictive. Those skilled in the art, having the benefit of this disclosure, may effect numerous forms of the invention without departing from the scope of the invention as claimed.
Claims (6)
1. A hypoglycemic peptide having activity of inhibiting alpha-glucosidase activity while increasing beta cell number in pancreatic islets, the hypoglycemic peptide having an amino acid sequence as set forth in SEQ ID NO: 1.
2. A pharmaceutical composition for treating diabetes comprising the glycopeptide of claim 1 and a pharmaceutically acceptable carrier.
3. A pharmaceutical composition for treating diabetes, characterized by comprising the hypoglycemic peptide according to claim 1 and adipose-derived mesenchymal stem cells.
4. Use of a hypoglycemic peptide and adipose mesenchymal stem cells according to claim 1 for preparing a pharmaceutical composition for treating diabetes.
5. The use according to claim 4, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier.
6. The use according to claim 5, wherein the carrier comprises an excipient.
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