CN114668845A - Application of liver Sirt5 protein in preparation of products for inhibiting gluconeogenesis and improving sugar tolerance - Google Patents
Application of liver Sirt5 protein in preparation of products for inhibiting gluconeogenesis and improving sugar tolerance Download PDFInfo
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Abstract
The invention discloses application of liver Sirt5 protein in preparing a product for inhibiting gluconeogenesis and improving sugar tolerance. Experiments prove that compared with a C57BL/6 mouse, the C57BL/6 mouse with the liver specifically over-expressing the SIRT5 protein has the advantages of obviously improved sugar tolerance, obviously improved pyruvic acid tolerance and obviously reduced liver glucose generation. Therefore, the liver SIRT5 protein can inhibit gluconeogenesis and improve sugar tolerance, and further prevent and/or treat diabetes. The invention has important application value.
Description
Technical Field
The invention belongs to the field of biomedicine, and particularly relates to application of liver Sirt5 protein in preparation of a product for inhibiting gluconeogenesis and improving glucose tolerance.
Background
Diabetes mellitus is a chronic metabolic disease caused by the disorder of carbohydrates and fats in the body under the regulation of related hormones, and is a disease condition which is manifested by hunger and abnormal hyperglycemia after meals in early stage. Diabetes mellitus is divided into two types, namely type 1 and type 2 according to pathogenesis, wherein the type 1 diabetes mellitus is diabetes mellitus which is caused by the fact that an autoimmune system destroys islet cells to cause insulin secretion defect, and the type 2 diabetes mellitus is caused by the fact that a series of peripheral tissues (such as muscles, fat, liver and the like) are reduced in sensitivity to insulin, namely insulin resistance, and the capacity of insulin cells to secrete insulin complexly at a later stage is damaged; more than 90% of patients are type 2 diabetes. Normal blood glucose levels in humans are regulated and maintained by insulin secreted by islet beta cells and glucagon secreted by islet alpha cells. Under starvation, islet alpha cells act on the adjacent liver to promote hepatic gluconeogenesis and glycogenolysis by secreting glucagon, which should acutely increase blood glucose levels. Excessive hepatic glucose output, whether type 1 or type 2, is a significant cause of fasting hyperglycemia and postprandial hyperglycemia, wherein the postprandial and hungry hyperglycemia symptoms occur in type 2 diabetic patients due to impaired hepatic gluconeogenesis inhibition by insulin caused by insulin resistance and relative reduction in insulin secretion.
The intake of a high-fat diet is generally considered to be one of the main causes of obesity and type 2 diabetes. High fat diets first induce obesity, and intracellular excess lipid metabolism intermediates Diacylglycerol (DAG) and Ceramide (Ceramide) may inhibit the insulin signaling pathway, cause insulin resistance, and progress to type 2 diabetes. One of the major sites of glucose metabolism is the liver, which plays an important role in glucose metabolism, and the blood glucose concentration is a common consequence of peripheral blood glucose utilization and liver production. In liver tissue, several hormones play a key role in the regulation of sugar metabolism, including insulin, glucagon, growth hormone, cortisol and catecholamines, and sugar metabolism mainly includes glycolysis, glucose oxidation, pentose phosphate, glycogen synthesis and decomposition. Under starvation, glucagon acts on the adjacent liver to promote hepatic gluconeogenesis and glycogenolysis, raising blood glucose levels. One of the important pathological causes of type 2 diabetes is that a large amount of free fatty acids generated by lipid metabolism disorder caused by insulin resistance of early muscle and adipose tissues weaken the sensitivity of other peripheral organs to insulin (insulin resistance), and obviously show that the lipid metabolism disorder has weakened inhibitory action on gluconeogenesis in liver, so that the gluconeogenesis process of the liver is strengthened, the gluconeogenesis process is continuously activated in the liver, and the excessive hepatic glucose output is an important reason of fasting hyperglycemia and postprandial hyperglycemia of type 2 diabetes patients. In the occurrence of type 2 diabetes hyperglycemia, the liver plays a key role, and factors such as hepatic glycogenolysis increase, hepatic gluconeogenesis enhancement, hepatic glycogen synthesis weakening and the like are mutually overlapped, and the factors and the reduction of glucose uptake capacity of surrounding tissues jointly form a mechanism for the occurrence of type 2 diabetes hyperglycemia, so that hepatic gluconeogenesis becomes a research hotspot for treating hyperglycemia. Hepatic gluconeogenesis plays an important role in diabetes and if left uncontrolled, will gradually develop various complications.
Disclosure of Invention
The object of the present invention is to prevent and/or treat diabetes.
The invention firstly protects the application of the liver SIRT5 protein in the preparation of products for improving the sugar tolerance; the application is realized by over-expressing SIRT5 protein in liver.
The invention also protects the application of the liver SIRT5 gene in the preparation of products for improving the sugar tolerance; the application is realized by over-expressing SIRT5 gene in liver.
In any of the above uses, the improvement in glucose tolerance may be manifested by an increase in the ability of the body to regulate blood glucose concentration.
The invention also protects the application of the liver SIRT5 protein in preparing a product for inhibiting gluconeogenesis; the application is realized by over-expressing SIRT5 protein in liver.
The invention also protects the application of the liver SIRT5 gene in the preparation of products for inhibiting gluconeogenesis; the application is realized by over-expressing SIRT5 gene in liver.
In any of the above uses, the inhibition of gluconeogenesis may be manifested as a decrease in hepatic glucose production or a decrease in blood glucose.
In any of the above uses, the inhibition of gluconeogenesis may be manifested as an increase in pyruvate tolerance.
Pyruvic acid is a gluconeogenic raw material. When the animal is in a hungry state, the higher the blood sugar, the stronger the gluconeogenic function is, the same dose of pyruvic acid is given. The pyruvic acid tolerance experiment is the current gold standard for studying gluconeogenesis.
The invention also protects the application of the liver SIRT5 protein in the preparation of products for preventing and/or treating diabetes; the application is realized by over-expressing SIRT5 protein in liver.
The invention also protects the application of the liver SIRT5 gene in the preparation of products for preventing and/or treating diabetes; the application is realized by over-expressing SIRT5 gene in liver.
In any of the above applications, the diabetes may be type 2 diabetes.
The Gene ID of any one of the SIRT5 proteins is 68346.
The GeneBank number of any one of the SIRT5 genes is NC-000079.7.
Experiments prove that compared with a C57BL/6 mouse, the C57BL/6 mouse (Liver SIRT5 OE mouse) with Liver specifically over-expressing SIRT5 protein has the advantages of obviously improving the regulation capability of blood sugar concentration (namely obviously improving the sugar tolerance), obviously reducing the hepatic glucose generation, obviously reducing the blood sugar and improving the pyruvic acid tolerance. Therefore, the liver SIRT5 protein can improve the glucose tolerance and inhibit gluconeogenesis, and further prevent and/or treat diabetes. The invention has important application value.
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FIG. 1 shows the results of blood glucose measurements in C57BL/6 mouse model with impaired glucose tolerance and C57BL/6 mouse model with control animals.
FIG. 2 shows the change of hepatic SIRT5 expression level and lysine malonyl modification in C57BL/6 mouse model with impaired glucose tolerance and C57BL/6 mouse model with control animal.
FIG. 3 shows the glucose tolerance changes of mouse model with abnormal glucose tolerance and mouse model with control animal.
FIG. 4 is a graph of the change in glucose/pyruvate tolerance after 12 weeks of high fat diet feeding of Liver SIRT5 OE and WT mice.
FIG. 5 shows the results of immunofluorescence and gluconeogenesis experiments on hepatocytes after 12 weeks of high fat diet feeding of Liver SIRT5 OE and WT mice.
Detailed Description
The present invention is described in further detail below with reference to specific embodiments, which are given for the purpose of illustration only and are not intended to limit the scope of the invention. The examples provided below serve as a guide for further modifications by a person skilled in the art and do not constitute a limitation of the invention in any way.
The experimental procedures in the following examples, unless otherwise indicated, are conventional and are carried out according to the techniques or conditions described in the literature in the field or according to the instructions of the products. Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
The C57BL/6 mouse specifically overexpressing the SIRT5 protein in the liver is a C57BL/6 mouse knocked in under the Sirt5 condition, is specifically obtained by a Biocytogen company (Beijing, China) by applying a CRISPR/Cas9 technology, and is described in the following documents: du, y.et al. sirt5 deacylates peptides-related proteins and peptides in ob/ob micro. ebiomedicine36, 347-: 10.1016/j.ebiom.2018.09.037(2018). C57BL/6 mice with liver specifically overexpressing SIRT5 protein are disclosed in Chinese patent application No. 202110175793.0. Hereinafter, C57BL/6 mice that Liver specifically overexpress SIRT5 protein are referred to as Liver SIRT5 OE mice.
High fat Diets are available from Research Diets under the catalog number D12492. A high fat diet consists of 60% fat, 20% protein and 20% carbohydrate.
The common diet is a product of Liaoning Changsheng Bio-Corp, and the catalog number of the product is CS-103. The normal diet consists of 18% fat, 24% protein and 58% carbohydrate.
Example 1 preparation of mouse model with impaired glucose tolerance
1. Method for preparing mouse model with abnormal glucose tolerance
An animal model of obesity-induced impaired glucose tolerance in mice was prepared by reference to the method in the literature (Yudong Ji, Zhenlong Luo, et al, hepatocyte-derived exosomes from early on set animal microorganism hormone sensitive gene miR-3075.Nat Metab.2021Sep; 3 (9): 1163-1174.doi:10.1038/s 42255-021-00444-1.). The method comprises the following specific steps:
(1) mice of 4 weeks of age and 15-20g in weight were fed with high fat diet and normal diet for 8 weeks, respectively.
(2) After the step (1) is finished, injecting glucose into the abdominal cavity after fasting for 6 hours, wherein the injection dose is 1g of glucose/kg of body weight; and collecting tail vein blood at 0min, 15min, 30min, 45min, 60min, 90min and 120min after glucose injection.
(3) And (3) after the step (2) is finished, respectively taking tail vein blood, and detecting the blood sugar by adopting a Roche glucometer. If the blood sugar of the mice fed with the high-fat diet is obviously improved compared with the mice fed with the ordinary diet, the mice fed with the high-fat diet are the animal models with the abnormal glucose tolerance of the mice; the mice fed by the ordinary diet are the mouse control animal models.
The result shows that the animal model with the abnormal glucose tolerance of the mice can be prepared by feeding the high-fat diet for 8 weeks, and the animal model with the abnormal glucose tolerance of the mice can be prepared by feeding the common diet for 8 weeks.
2. C57BL/6 mice are respectively taken and a C57BL/6 mouse model with abnormal glucose tolerance and a C57BL/6 mouse control animal model are prepared according to the method of the step 1.
The results of the blood glucose test are shown in FIG. 1.
3. A Liver SIRT5 OE mouse is taken and a Liver SIRT5 OE mouse animal model with abnormal sugar tolerance and a Liver SIRT5 OE mouse control animal model are prepared according to the method of the step 1.
Example 2 Western blot analysis of the level of malonylation of lysine (kmal) and the amount of expression of SIRT5 protein in primary hepatocytes from C57BL/6 mice
1. Isolation of C57BL/6 mouse Primary hepatocytes
C57BL/6 mice were fasted for 6 hours and then anesthetized with 10% chloral hydrate, exposing the liver and identifying the hepatic portal vein and inferior vena cava; starting a peristaltic pump, quickly placing the indwelling needle into the hepatic portal vein, perfusing with a front perfusion solution for warm bath at 37 ℃, cutting off the inferior vena cava to release perfusion pressure, and perfusing the indwelling needle with the volume of 75 mL/vein; replacing low-sugar DMEM digestive juice containing type IV collagenase, and continuously and slowly perfusing, wherein the perfusion volume is 75 mL/piece; after the collagen structure of the liver is fully digested, quickly cutting the whole liver into a 10cm culture dish containing 10mL of DMEM dispersion liquid; replacing the mixture into a biological safety cabinet, shearing the liver according to strict aseptic requirements, adding 10% fetal calf serum, blowing and beating the hepatocyte suspension, filtering the mixture by using a 70-75 mu m filter screen, centrifuging the mixture in a centrifuge at the temperature of 4 ℃ and the rpm of 50 for 2min, removing the supernatant, washing the cells by using a low-temperature DMEM/F-12 washing solution containing 10% fetal calf serum, and repeating the centrifugal washing for 4 times; and after the final centrifugation, sucking and removing the supernatant, namely the C57BL/6 mouse primary hepatocytes.
2. Culture of C57BL/6 mouse Primary hepatocytes
After completion of step 1, the obtained C57BL/6 mouse primary hepatocytes were resuspended in a DMEM medium containing 10% FBS and 1% penicillin-streptomycin to obtain a concentration of 4.5X 108L of C57BL/6 mouse primary hepatocyte resuspension. The C57BL/6 mouse primary hepatocyte resuspension solution was plated in 6-well cell culture plates at 37 ℃ in 5% CO2Culturing in a constant temperature incubator for 6-8 hours to ensure that the cells are fully attached to the wall, then absorbing and removing the old culture medium, washing with PBS once, and replacing with serum-free DMEM culture medium to continue culturing to fully maintain the cell morphology and activity.
3. Stimulation with sodium oleate
After completion of step 2, sodium oleate was added to the C57BL/6 mouse primary hepatocytes cultured in serum-free DMEM medium to a final concentration of 0 μ M, 25 μ M, 50 μ M, 100 μ M, 200 μ M or 400 μ M, and after incubation for 2h, the cells were collected.
4、Western blot
Western blot was performed by taking the cells collected in step 3, according to the method described in the literature (Du, Y.et al., SIRT5 nucleotides, metabolic-related proteins and peptides in ob/ob mic. EBioMedicine36, 347-. Among them, anti-malonyl lysine was purchased from PTM Biolabs (Chicago, IL) under the catalog number PTM-901. anti-SIRT 5 antibody was purchased from ProteinTech (Rosemont, IL) under catalog number 15122-1-AP. Anti-beta-actin antibodies and sodium oleate were purchased from Sigma-Aldrich (st louis, MI) under the product catalog numbers a2228 and O7501, respectively. The secondary antibody was purchased from Beijing Huaxing Bochuang Gene technology, Inc., under the product catalog number HX2031 or HX 2032.
The result of Western blot analysis is shown in FIG. 2. The results show that the expression level of SIRT5 protein is obviously reduced and the expression level of malonyl lysine is obviously increased after C57BL/6 mouse primary hepatocytes are stimulated by sodium oleate, and the free fatty acid (such as sodium oleate) can reduce the expression of SIRT5 protein in the hepatocytes, so that the malonyl modification level of lysine in the hepatocytes is increased.
Example 3 detection of sugar tolerance in mouse model with impaired glucose tolerance and mouse control animal model
The mice to be tested were the C57BL/6 mouse model with impaired glucose tolerance, the C57BL/6 mouse control animal model, the Liver SIRT5 OE mouse model with impaired glucose tolerance or the Liver SIRT5 OE mouse control animal model prepared in example 1.
1. Taking a mouse to be detected, and injecting glucose into the abdominal cavity after fasting for 6 hours, wherein the injection dose is 1g of glucose/kg of body weight; and collecting tail vein blood respectively at 0min, 15min, 30min, 45min, 60min, 90min and 120min after glucose injection.
2. After the step 1 is finished, respectively taking tail vein blood, and detecting blood sugar by adopting a Roche glucometer.
The detection results are shown in figure 3(A is a C57BL/6 mouse control animal model and a Liver SIRT5 OE mouse control animal model, B is a C57BL/6 mouse model and a Liver SIRT5 OE mouse model, WT is a C57BL/6 mouse, and Liver SIRT5 OE is a Liver SIRT5 OE mouse). The results show that the glucose tolerance of the C57BL/6 mouse control animal model and the Liver SIRT5 OE mouse control animal model has no obvious difference; compared with an animal model with abnormal glucose tolerance of a C57BL/6 mouse, the sugar tolerance of the animal model with abnormal glucose tolerance of the Liver SIRT5 OE mouse is obviously improved, and the blood glucose is lower after the same load of glucose is injected into the abdominal cavity.
Example 4 sugar tolerance and pyruvate tolerance assays in C57BL/6 mouse animal models with impaired glucose tolerance and in Liver SIRT5 OE mouse animal models with impaired glucose tolerance
The mice to be tested are C57BL/6 mice or Liver SIRT5 OE mice prepared in example 1.
1. The mice to be tested were taken and fed on a high fat diet for 4 weeks.
2. After the step 1 is finished, taking the mouse to be tested, and injecting glucose into the abdominal cavity after fasting for 6 hours, wherein the injection dose is 1g of glucose/kg of body weight; and collecting tail vein blood at 0min, 15min, 30min, 45min, 60min and 90min after glucose injection.
3. And (3) after the step 2 is finished, respectively taking tail vein blood, and detecting the blood sugar by adopting a Roche glucometer.
The results are shown in A in FIG. 4 (WT is C57BL/6 mouse, Liver SIRT5 OE is Liver SIRT5 OE mouse). The results indicate that when high fat diet was extended to 12 weeks, the glucose tolerance of Liver SIRT5 OE mice was significantly improved compared to C57BL/6 mice, as evidenced by a significant decrease in blood glucose levels following intraperitoneal injection of the same load of glucose.
4. After the step 1 is completed, taking the mice to be tested, and injecting pyruvic acid injection (the injection dose is 2g pyruvic acid/kg body weight) into the abdominal cavity of all animals after fasting for 6 hours; and collecting tail vein blood at 0min, 15min, 30min, 45min, 60min, 90min and 120min after injection of the pyruvic acid injection. And respectively taking tail vein blood, and detecting blood sugar by adopting a Roche glucometer.
Pyruvic acid is a gluconeogenic raw material. Thus, when the animal is starved, the higher the blood glucose, the stronger the gluconeogenic function, given the same dose of pyruvic acid. The pyruvate tolerance test is the current gold standard for studying gluconeogenesis.
The results are shown in B in FIG. 4 (WT was C57BL/6 mouse, and Liver SIRT5 OE was Liver SIRT5 OE mouse). The results indicate that blood glucose was significantly reduced in the Liver SIRT5 OE mice, i.e., gluconeogenic function was significantly reduced in the Liver SIRT5 OE mice, when pyruvate was administered as compared to the C57BL/6 mice.
Example 5, Glycoisogen assay in C57BL/6 mouse animal models with impaired glucose tolerance and Liver SIRT5 OE mouse animal models with impaired glucose tolerance
1. The C57BL/6 mouse model with abnormal sugar tolerance or the Liver SIRT5 OE mouse model with abnormal sugar tolerance prepared in the example 1 is taken and fed with high fat diet for 4 weeks to obtain the mouse to be tested.
2. Isolation of Primary hepatocytes from mice to be tested
After the step 1 is finished, a mouse to be tested is anesthetized by 10% chloral hydrate after fasting for 6 hours, the liver is exposed, and the hepatic portal vein and the inferior vena cava are identified; starting a peristaltic pump, quickly placing the indwelling needle into the hepatic portal vein, perfusing with a front perfusion solution for warm bath at 37 ℃, cutting off the inferior vena cava to release perfusion pressure, and perfusing the indwelling needle with the volume of 75 mL/vein; replacing low-sugar DMEM digestive juice containing type IV collagenase, and continuously and slowly perfusing, wherein the perfusion volume is 75 mL/piece; after the collagen structure of the liver is fully digested, quickly cutting the whole liver into a 10cm culture dish containing 10mL of DMEM dispersion liquid; replacing the mixture into a biological safety cabinet, shearing the liver according to strict aseptic requirements, adding 10% fetal calf serum, blowing and beating the hepatocyte suspension, filtering the mixture by using a 70-75 mu m filter screen, centrifuging the mixture in a centrifuge at the temperature of 4 ℃ and the rpm of 50 for 2min, removing the supernatant, washing the cells by using a low-temperature DMEM/F-12 washing solution containing 10% fetal calf serum, and repeating the centrifugal washing for 4 times; and after the final centrifugation is finished, sucking and removing the supernatant to obtain the primary hepatocytes of the mouse to be detected.
3. Culture of primary hepatocytes of mouse to be detected
After step 2 was completed, the DMEM medium containing 10% FBS and 1% penicillin-streptomycin was added to the obtained primary hepatocytes of the mouse to be tested to resuspend the cells to obtain a concentration of 4.5 × 108L of primary hepatocyte resuspension of mice to be tested. Spreading the heavy suspension of the primary hepatocytes of the mouse to be detected on a 6-well cell culture plate, and culturing at 37 deg.C with 5% CO2Culturing in a constant temperature incubator for 6-8 hr to make cells adhere to the wall, then removing the old culture medium, washing with PBS once, and replacing with noneSerum DMEM medium was continued for 24h to fully maintain cell morphology and viability.
4. Cellular gluconeogenesis detection
(1) After completion of step 3, the medium was replaced with sugar-free phenol red-free DMEM medium containing 10mM sodium pyruvate and 10mM sodium lactate at 37 ℃ with 5% CO2After incubation in the incubator for 4h, the supernatant 1 was collected.
(2) Taking the supernatant 1, centrifuging at 1500rpm for 3min, and collecting the supernatant 2.
(3) The amount of glucose produced in the supernatant 2 was measured using a glucose assay kit (GAGO20, Sigma).
The results are shown in FIG. 5(WT is C57BL/6 mouse, Liver SIRT5 OE is Liver SIRT5 OE mouse). The results indicate that the amount of glucose produced in hepatocytes was significantly reduced in Liver SIRT5 OE mice compared to C57BL/6 mice. It can be seen that the gluconeogenic function of hepatocytes in Liver SIRT5 OE mice was significantly reduced compared to C57BL/6 mice.
The present invention has been described in detail above. It will be apparent to those skilled in the art that the invention can be practiced in a wide range of equivalent parameters, concentrations, and conditions without departing from the spirit and scope of the invention and without undue experimentation. While the invention has been described with reference to specific embodiments, it will be appreciated that the invention can be further modified. In general, this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains. The use of some of the essential features is possible within the scope of the claims attached below.
Claims (10)
1. Application of the liver SIRT5 protein in preparing a product for improving sugar tolerance; the application is realized by over-expressing SIRT5 protein in liver.
2. Application of a liver SIRT5 gene in preparing a product for improving sugar tolerance; the application is realized by over-expressing SIRT5 gene in liver.
3. Use according to claim 1 or 2, characterized in that: said improved glucose tolerance is manifested by an increased ability of the body to regulate blood glucose concentration.
4. The application of the liver SIRT5 protein in preparing a product for inhibiting gluconeogenesis; the application is realized by over-expressing the SIRT5 protein in the liver.
5. Application of liver SIRT5 gene in preparing gluconeogenesis inhibiting product; the application is realized by over-expressing SIRT5 gene in liver.
6. Use according to claim 4 or 5, characterized in that: the inhibition of gluconeogenesis is manifested by a decrease in hepatic glucose production or a decrease in blood glucose.
7. Use according to claim 4 or 5, characterized in that: the inhibition of gluconeogenesis is manifested by an increase in pyruvate tolerance.
8. The application of the liver SIRT5 protein in preparing products for preventing and/or treating diabetes; the application is realized by over-expressing SIRT5 protein in liver.
9. The application of the liver SIRT5 gene in preparing products for preventing and/or treating diabetes mellitus; the application is realized by over-expressing SIRT5 gene in liver.
10. Use according to claim 1 or 2, characterized in that: the diabetes is type 2 diabetes.
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Citations (4)
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|---|---|---|---|---|
| US20070149466A1 (en) * | 2005-07-07 | 2007-06-28 | Michael Milburn | Methods and related compositions for treating or preventing obesity, insulin resistance disorders, and mitochondrial-associated disorders |
| CN101257897A (en) * | 2005-07-07 | 2008-09-03 | 西特里斯药业公司 | Methods and related compositions for treating or preventing obesity, insulin resistance disorders, and mitochondrial-associated disorders |
| US20080249103A1 (en) * | 2006-11-15 | 2008-10-09 | Sirtris Pharmaceuticals, Inc. | Sirtuin polymorphisms and methods of use thereof |
| CN103055313A (en) * | 2005-07-07 | 2013-04-24 | 西特里斯药业公司 | Methods and related compositions for treating or preventing obesity, insulin resistance disorders, and mitochondrial-associated disorders |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070149466A1 (en) * | 2005-07-07 | 2007-06-28 | Michael Milburn | Methods and related compositions for treating or preventing obesity, insulin resistance disorders, and mitochondrial-associated disorders |
| CN101257897A (en) * | 2005-07-07 | 2008-09-03 | 西特里斯药业公司 | Methods and related compositions for treating or preventing obesity, insulin resistance disorders, and mitochondrial-associated disorders |
| CN103055313A (en) * | 2005-07-07 | 2013-04-24 | 西特里斯药业公司 | Methods and related compositions for treating or preventing obesity, insulin resistance disorders, and mitochondrial-associated disorders |
| US20080249103A1 (en) * | 2006-11-15 | 2008-10-09 | Sirtris Pharmaceuticals, Inc. | Sirtuin polymorphisms and methods of use thereof |
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