CN112891540A - Application of OGT (one glass solution) as target in preparation of medicine for treating abnormal glucagon secretion in diabetes - Google Patents
Application of OGT (one glass solution) as target in preparation of medicine for treating abnormal glucagon secretion in diabetes Download PDFInfo
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- CN112891540A CN112891540A CN202110116263.9A CN202110116263A CN112891540A CN 112891540 A CN112891540 A CN 112891540A CN 202110116263 A CN202110116263 A CN 202110116263A CN 112891540 A CN112891540 A CN 112891540A
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/158—Expression markers
Abstract
The invention discloses application of OGT (one glass solution) as a target spot in preparation of a medicine for treating abnormal glucagon secretion in diabetes. The medicine is a medicine for inhibiting the expression of O-GlcNAc glycosyltransferase OGT, wherein the functional component can be at least one of shRNA, siRNA, dsRNA, miRNA, cDNA, antisense RNA/DNA, low molecular compound, peptide and antibody. According to the invention, the research finds that the O-GlcNAc glycosyltransferase OGT is knocked out or inhibited, the secretion amount of glucagon can be reduced, simultaneously, the withering of islet alpha cells can be promoted, the proliferation of the islet alpha cells can be inhibited, and the O-GlcNAc glycosyltransferase OGT can be used as a target point for treating diabetes.
Description
Technical Field
The invention belongs to the technical field of biology, and particularly relates to application of OGT (one glass solution) as a target spot in preparation of a medicine for treating abnormal glucagon secretion in diabetes.
Background
Diabetes Mellitus (DM) is an endocrine-metabolic disease characterized by hyperglycemia, and is a lifelong disease that affects the organs of the body. According to the estimation of the World Health Organization (WHO), the total number of diabetes patients worldwide exceeds 1.3 hundred million at present, and 3 hundred million will be broken through in 2025. In addition, the prevalence rate of diabetes in China is also increased from 0.9% to 11.6% in 30 years, which is as short as 1980 to 2010, and is the most frequent country in the world. By 2017, 1 of every 4 diabetics worldwide comes from china. Long-term hyperglycemia in the body leads to chronic damage and dysfunction of various tissue organs, such as the heart, kidneys, retina, nerves, etc., and thus diabetes has become a health problem facing countries all over the world. Currently, the global diabetes healthcare expenditure amounts to $ 6730 million, second only to the tumor rank second. About 460 million people die of diabetes every year, and on average 1 person is removed from diabetes every 7 seconds.
Diabetes is divided into type I diabetes and type II diabetes, wherein the latter accounts for 90% of the total diabetes, and blood sugar disorder is the main clinical characterization of diabetic patients. The blood sugar balance of the body is mainly determined by the co-regulation of two hormones: one is Glucagon (Glucagon) secreted by islet alpha cells with elevated blood glucose concentrations; the other is Insulin (Insulin) with reduced blood glucose concentration secreted by islet beta cells. Insulin acts mainly on liver, muscle and adipose tissue, and promotes the conversion of excess glucose into glycogen or fat for storage by increasing glycogen synthesis reaction and inhibiting gluconeogenesis. Conversely, when the body's blood glucose concentration decreases, glucagon increases the blood glucose concentration by activating the glycogenolytic and gluconeogenic effects in the liver, releasing glucose. Therefore, the blood sugar balance of the body is damaged due to secretion disorder of glucagon and insulin, and adverse reactions such as acute brain injury of the body can be caused by severe hypoglycemia; hyperglycemia is the most common clinical feature of diabetes. The research finds that the abnormal increase of glucagon secretion in the body of a diabetic patient causes hyperglycemia, and is closely related to the occurrence of diabetes. When the diabetes condition is controlled and the blood sugar is basically normal, the high secretion state of the glucagon can be inhibited and even can be recovered to the normal level. Therefore, the glucagon can be used as an auxiliary index for observing the curative effect of the diabetes. The blood sugar disorder of the diabetic is caused by insufficient or relative insufficient insulin secretion of islet beta cells and the functional disorder of islet alpha cells or excessive glucagon secretion, but compared with the extensive research on beta cells and insulin, the alpha cell function and glucagon secretion regulation mechanism are not completely clear, which may become one of the obstacles for treating the diabetes process, so that the research on the functional change of islet alpha cells and the specific glucagon secretion regulation mechanism under physiological and pathological levels has great research prospects and is concerned by scholars at home and abroad.
Oxygen-linked N-acetylglucosaminylation (O-GlcNAcylation, O-GlcNAc modification) is a novel post-translational modification of proteins, the substrate uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) is derived from extracellular glucose, free fatty acids, glycerol and the amino acid glutamine. On one hand, the intracellular O-GlcNAc level can be used as a receptor (sensor) of nutrient substances to regulate a cellular metabolic pathway under physiological conditions, and on the other hand, when the O-GlcNAc level is disordered, a series of pathological reactions such as diabetes, heart disease, cancer and the like can occur in the body, but no report about the production mechanism of the diabetes and the influence on the glucagon secretion amount of the O-GlcNAc glycosyltransferase OGT are found.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides an application of OGT as a target spot in preparing a medicine for treating abnormal glucagon secretion in diabetes, wherein the principle that OGT promotes glucagon secretion in a diabetes environment is as follows: the stimulation of high sugar for a long time can promote a large amount of protein glycosylation reactions in cells, mainly through: O-GlcNAc transferase OGT combined with PIP3 on cell membrane is phosphorylated and activated, glycosylating and modifying proteins of IRS1, PI3K, PDK1, Akt and the like in an IR channel, inhibiting phosphorylation, preventing the activation of the IR-PI3K channel, cutting off the inhibition effect of the IR channel on a calcium channel, promoting the intracellular release of calcium ions, and promoting pancreasGlucagon secretion; ② simultaneous OGT to Ca2+The/calmodulin kinase 2 and 4 glycosylation modification promotes the activation of calcium channel and further promotes the secretion of glucagon.
In order to achieve the purpose, the technical scheme adopted by the invention for solving the technical problems is as follows:
the application of O-GlcNAc glycosyltransferase OGT as target in preparing medicine for treating abnormal secretion of glucagon in diabetes.
Further, the drug is a drug that inhibits the expression of O-GlcNAc glycosyltransferase OGT.
Further, the component inhibiting the expression of the O-GlcNAc glycosyltransferase OGT in the drug is at least one of shRNA, siRNA, dsRNA, miRNA, cDNA, antisense RNA/DNA, low molecular compound, peptide and antibody.
Further, the medicament inhibits glucagon secretion from pancreatic islet alpha cells of the diabetic patient by inhibiting the expression of O-GlcNAc glycosyltransferase OGT.
The application of O-GlcNAc glycosyltransferase OGT as a marker in the preparation of a reagent for detecting diabetes and/or evaluating the curative effect.
A kit for diabetes detection and/or therapeutic effect evaluation, comprising a primer for detecting the amount of expression of O-GlcNAc glycosyltransferase OGT.
An application of an O-GlcNAc glycosyltransferase OGT inhibitor in preparing the medicines for treating the abnormal secretion of glucagon in diabetes is disclosed.
Further, the inhibitor can inhibit O-GlcNAc glycosyltransferase OGT expression.
The invention has the beneficial effects that:
by knocking out or inhibiting O-GlcNAc glycosyltransferase OGT, the secretion of glucagon can be reduced, simultaneously, the withering of islet alpha cells can be promoted, the proliferation of islet alpha cells can be inhibited, and the O-GlcNAc glycosyltransferase OGT can be used as a target point for treating diabetes.
Drawings
FIG. 1 shows the detection result of sh-OGT vector construction;
FIG. 2 shows the PCR detection results of OGT knockout mice;
FIG. 3 shows the results of the measurement of the effect of OGT knockout on the function of mouse pancreatic islet;
FIG. 4 shows the measurement result of the glucagon secretion amount after meal before OGT knockout mice.
Detailed Description
The following description of the embodiments of the present invention is provided to facilitate the understanding of the present invention by those skilled in the art, but it should be understood that the present invention is not limited to the scope of the embodiments, and it will be apparent to those skilled in the art that various changes may be made without departing from the spirit and scope of the invention as defined and defined in the appended claims, and all matters produced by the invention using the inventive concept are protected.
Example 1 construction of islet alpha cell OGT-specific knockout mouse model
1. Construction of adenovirus sh-OGT vector
(1) Three shRNA targets are designed aiming at the homologous region of the mouse Ogt gene, and the specific sequences are as follows:
shRNA-1:5’-GCAGCTTATCTTCGTGCCTTA-3’；(SEQ ID NO.1)
shRNA-2:5’-CCCATTTCTTTCAGCAGAAAT-3’；(SEQ ID NO.2)
shRNA-3:5’-GCTCTTAATATGCCCGTTATT-3’；(SEQ ID NO.3)
and designing corresponding primers aiming at each target point, wherein the sequences of the primers are as follows:
oligo-1F:CCGGGCAGCTTATCTTCGTGCCTTACTCGAGTAAGGCACGAA GATAAGCTGCTTTTTG；(SEQ ID NO.4)
oligo-1R:AATTCAAAAAGCAGCTTATCTTCGTGCCTTACTCGAGTAAGG CACGAAGATAAGCTGC；(SEQ ID NO.5)
oligo-2F:CCGGCCCATTTCTTTCAGCAGAAATCTCGAGATTTCTGCTGAA AGAAATGGGTTTTTG；(SEQ ID NO.6)
oligo-2R:AATTCAAAAACCCATTTCTTTCAGCAGAAATCTCGAGATTTCT GCTGAAAGAAATGGG；(SEQ ID NO.7)
oligo-3F:CCGGGCTCTTAATATGCCCGTTATTCTCGAGAATAACGGGCAT ATTAAGAGCTTTTTG；(SEQ ID NO.8)
oligo-3R:AATTCAAAAAGCTCTTAATATGCCCGTTATTCTCGAGAATAAC GGGCATATTAAGAGC。(SEQ ID NO.9)
(2) adenovirus vectors Adeno-FV010-OGT-shRNA-1, Adeno-FV010-OGT-shRNA-2 and Adeno-FV010-OGT-shRNA-3 are respectively constructed by the primer and shRNA target; and Adeno-FV010-EGFP-CON is used as a contrast.
2. Viral transfection
(1) The Gcg glucagon promoter with red fluorescent label is added into the adenovirus vector to transfect mouse islet alpha cells and isolate the cultured islet tissue mass, and the islet alpha cells can be specifically marked under a fluorescent microscope (see figure 1C, the right side of the figure is the islet alpha cells with fluorescence under the microscope).
(2) Transferring the constructed adenovirus vector into TC1-6, wherein the specific process comprises the following steps:
s1, planting the target cells in a pore plate 12-18 hours before infection;
s2, taking out the virus from a refrigerator at minus 80 ℃, putting the virus on ice or melting the virus at 4 ℃, and after the virus is completely melted, using a desktop centrifuge to centrifuge the virus at a low speed for 20 seconds (only the virus is completely suspended at the bottom of a centrifuge tube);
s3, infecting cells according to the MOI value of the virus as 100;
s4, adding the virus, slightly shaking in a cross direction to uniformly distribute the virus on the cell surface, and putting the cell surface back to the incubator for incubation;
s5, culturing for 8-12 hours, and observing the cell state;
s6, after the virus infects the cell 24H, replacing the culture medium;
s7, detecting the mRNA level of the OGT gene 48H-72 hours after the virus infects the cells, wherein the result is shown as A and B in figure 1, A is western blotting detection result, B is PCR detection result, and shOgt-1 in the figure represents the cells transfected by adenovirus vector Adeno-FV 010-OGT-shRNA-1; shOgt-2 represents cells transfected by adenovirus vector Adeno-FV 010-OGT-shRNA-2; shOgt-3 represents cells transfected with adenovirus vector Adeno-FV 010-OGT-shRNA-3.
As shown in a and B in fig. 1; the OGT expression level in the cells is obviously reduced, and the success of OGT gene knockout in islet alpha cells can be determined.
2. Construction of pancreatic alpha cell tissue-specific OGT knockout mice
C57BL/6 mouse is selected as a carrier, and an ES cell targeting technology is utilized to construct an islet cell tissue-specific OGT gene knockout mouse (Gcg)Cre-OGTloxp/loxp) The specific process is as follows:
ogt gene sequence number (NM-139144) is searched on NCBI, 22 exons are identified, two LoxP sites are inserted into two ends of No. 2 exon of Ogt gene by utilizing ES targeting technology based on DNA homologous recombination and embryonic stem cell microinjection and the like, and floxed mice are prepared. Exon 2 knockout resulted in loss of Ogt gene function in mice, and pancreatic specific recombinase Gcg-Cre mice were then selected for hybridization with OGT-floxed mice and verified by PCR, the results of which are shown in fig. 2.
As shown in fig. 2, two bands shown in the left region in the figure are both heterozygotes, the lowest band in the three bands in the right region is wild type, and the other two bands are homozygotes, which indicates that the OGT knockout mouse model is successfully constructed.
The OGT knockout mouse constructed by STZ induction is adopted to construct a type 1 diabetes mellitus mouse model, and relevant functionality detection is carried out on the mouse model in the embodiment 2.
Example 2 examination of the Effect of OGT knockdown on mouse islet function in the OGT-specific knockout mouse model constructed in example 1
1. Cell proliferation potency assay
The Cell Counting Kit-8(CCK8) reagent is adopted to detect the proliferation capacity of the islet alpha cells, and the specific detection process comprises the following steps: after cell adherent culture, shRNA-Ogt virus is added for transfection for 24 hours, PBS is added for cleaning, and the mixture is mixed with CCK8 reagent 10: the reaction solution was added at a ratio of 1 (100. mu.L per 96 wells). Incubating in an incubator at 37 ℃ for 30 minutes to 4 hours, and measuring the OD value at the wavelength of 450nm by using an enzyme-labeling instrument; the results are shown in FIG. 3A.
As shown in fig. 3A, the proliferative capacity of mouse cells was significantly reduced after OGT knockout compared to the control group.
2. Apoptosis detection
Detecting the apoptosis level change of the Ogt gene knocked-down alpha cells by using flow cytometry, which comprises the following specific processes: FITThe C Annexin V Apoptosis Detection Kit was purchased from eBioscience. Pancreatin digestion of cells in control group and shOgt group, centrifugation, addition of appropriate amount of 1 × binding buffer for resuspension, keeping the cell number at 1-5 × 106And/ml. mu.L of the cell suspension and 5ml of the centrifuge tube were mixed, and 5. mu.L of Annexin V reagent was added. Standing at room temperature for 10-15 min, centrifuging, taking 200 μ L of 1 × binding buffer to resuspend cells, adding 5 μ L of propadium Iodide stabilizing Solution, storing on ice and immediately detecting in a flow cytometer; the results are shown in FIG. 3B. As shown in fig. 3B, apoptosis of mouse islet α cells was accelerated following OGT knockout.
3. Study of OGT knockout on glucagon secretion and Ca release in islet tissue2+Influence of (2)
Separating islet cell clusters of a wild mouse and an OGT knockout mouse, transfecting the islet cell clusters of the two groups by using an adenovirus vector with an islet alpha cell specific marker, distinguishing alpha cells by using a red fluorescent probe, observing the change of the number of the alpha cells, and monitoring Ca in the alpha cells with different concentrations of glucose and under the stimulation of insulin in real time under an all-internal-angle microscope2+Dynamically changing in real time, collecting culture supernatant, and detecting the secretion of glucagon. Collecting each group of islet cell clusters, and detecting the change of the level of calmodulin kinase O-GlcNAc in the islet tissues by Western Blot; immunostaining detects changes in Glucagon expression in alpha cells. The results are shown in FIGS. 3C and D.
As shown in FIG. 3C, Ca was obtained after OGT knockout compared to the control group2+The release is obviously reduced, which indicates that OGT knockout can influence and regulate Ca2+A channel; fig. 3D shows that the amount of glucagon secretion is significantly reduced after knockout of OGT compared to the control group, indicating that the decrease in the amount of glucagon secretion in diabetic environments can be modulated by knockout or inhibition of OGT expression.
4. Detection of knockout mouse GcgCre-OGTloxp/loxp(OGT-alpha) and control mice OGT-loxp in the body secrete quantity of glucagon before meal (before) and after meal (after), and the specific process is as follows: the mice are fed with drinking water in normal diet, the mice are evacuated from the feed at 8 night before the experiment and the padding of the mice is replaced to prevent scattered food fragments in the padding, but the mice are fed with drinking water in normal dietDrinking water was not removed. The glucagon in the blood of the mice was measured at 8 am after 12 hours, i.e. the pre-meal value. After the pre-meal value was measured, the food was returned to the mouse cage, and after 2 hours, the glucagon value in the blood was measured again, which was the post-meal value, and the results are shown in fig. 4.
The glucagon secretion amount of the OGT knockout mouse is obviously lower than that of the control group before meal and also lower than that of the control group after meal, and the fact that the OGT gene knockout mouse can obviously reduce the glucagon secretion amount of the mouse body can be seen.
Sequence listing
<110> Binzhou medical college
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Claims (9)
- The application of O-GlcNAc glycosyltransferase OGT as target in preparing medicine for treating abnormal secretion of glucagon in diabetes.
- 2. The use according to claim 1, wherein the medicament is a medicament that inhibits the expression of O-GlcNAc glycosyltransferase, OGT.
- 3. The use according to claim 2, wherein the agent that inhibits the expression of the O-GlcNAc glycosyltransferase OGT is at least one of shRNA, siRNA, dsRNA, miRNA, cDNA, antisense RNA/DNA, low molecular weight compounds, peptides and antibodies.
- 4. The use of claim 1, wherein the medicament inhibits glucagon secretion from pancreatic islet alpha cells of a diabetic patient by inhibiting the expression of O-GlcNAc glycosyltransferase, OGT.
- Use of O-GlcNAc glycosyltransferase OGT as a marker in the preparation of a reagent for the detection and/or assessment of the efficacy of diabetes.
- 6. A kit for diabetes detection and/or efficacy evaluation, characterized by comprising a primer for detecting the amount of OGT expression of O-GlcNAc glycosyltransferase.
- 7. An application of an O-GlcNAc glycosyltransferase OGT inhibitor in preparing the medicines for treating the abnormal secretion of glucagon in diabetes is disclosed.
- 8. The use according to claim 7, wherein the inhibitor is capable of inhibiting the expression of O-GlcNAc glycosyltransferase OGT.
- 9. A medicament for the treatment of diabetes comprising the inhibitor of claim 7 or the medicament of claim 1.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113368249A (en) * | 2021-06-07 | 2021-09-10 | 中国人民解放军军事科学院军事医学研究院 | OGT inhibitor and application thereof |
| CN113368243A (en) * | 2021-06-07 | 2021-09-10 | 中国人民解放军军事科学院军事医学研究院 | Therapeutic target of medulloblastoma and application thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113368249A (en) * | 2021-06-07 | 2021-09-10 | 中国人民解放军军事科学院军事医学研究院 | OGT inhibitor and application thereof |
| CN113368243A (en) * | 2021-06-07 | 2021-09-10 | 中国人民解放军军事科学院军事医学研究院 | Therapeutic target of medulloblastoma and application thereof |
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