CN112386696A - Target for treating insulin resistance and application thereof - Google Patents
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Abstract
The invention belongs to the technical field of insulin resistance, and discloses a target for treating insulin resistance and application thereof. The target has the characteristic that the expression of the target is gradually reduced in the occurrence and development processes of insulin resistance, the sensitivity of the type II diabetes mellitus patient to insulin can be restored by restoring the expression of the target, and the concentration of blood sugar and blood glycosylated hemoglobin is reduced. The target is SBP2 of adipose tissue macrophages. The invention can achieve the purpose of treating insulin resistance by the medicament for restoring SBP2 expression in a targeted manner, and the targeted medicament for restoring SBP2 expression has the effect of treating diabetic eye disease and other complications.
Description
Technical Field
The invention relates to the technical field of insulin resistance, in particular to a target for treating insulin resistance and application thereof.
Background
Obesity is one of the most important public health issues of this century. Insulin resistance caused by obesity is an important factor in the development of a number of major chronic diseases such as type II diabetes, hyperlipidemia, cardiovascular disease and certain cancers. Adipose tissue inflammation is an important mechanism for the generation and acceleration of local and systemic insulin resistance during obesity development. The presence of inflammatory-inhibiting adipose tissue-associated macrophages in adipose tissue converts to pro-inflammatory during obesity, promoting the infiltration of adipose tissue macrophages and the formation of the inflammatory tissue microenvironment. Transformation and infiltration of adipose tissue-associated macrophages contribute to the production of insulin resistance by a variety of factors.
The Sec insert (SECIS) binding protein 2SBP2(SBP2 is collectively referred to as selenocysteine insertion sequence-binding protein 2, Selenocysteine insert binding protein 2) is a protein encoded by SECISBP 2. Physiologically, it interacts with the SECIS RNA of selenoprotein to recruit translation and assembly factors into the mRN a-protein complex. Thus, SBP2 is considered to be an essential factor for selenoprotein translation in mammalian cells. In some metabolic diseases, SBP2 expression and activity are regulated by aberrant mutations. Homozygous missense mutations in SBP2 may result in abnormal thyroid hormone metabolism. Nonsense gene mutations that produce an early stop codon (R128X) may arrest early in the synthesis of the full-length molecule. Complex heterozygous mutations in the SBP2DNA sequence (R120X/R770X) inhibit the binding of SBP2 to Sec insertion elements and block the function of SBP2 in selenoprotein translation. This induces intracellular ROS production. SBP2 mutations may result in aberrant monocyte cytokine secretion. Previous studies detected a decrease in selenoprotein stability in the SBP2 mutant mouse model due to loss of SBP2 expression. However, the role of SBP2 in the progression of insulin resistance during obesity remains to be examined.
Disclosure of Invention
The invention aims to provide a target for treating insulin resistance and application thereof. The expression of the insulin resistance treatment target point abdominal adipose tissue macrophage SBP2 can obviously improve the insulin resistance of obese and diabetic mice; the medicament for restoring the expression of abdominal adipose tissue macrophage SBP2 can be used as a novel medicament for treating insulin resistance; the medicine for restoring the expression of abdominal adipose tissue macrophage SBP2 can be used as a new medicine for treating diabetic complications caused by hyperglycemia.
The technical scheme of the invention is as follows: a target for treating insulin resistance, which has the characteristic that the expression of the target is gradually reduced in the occurrence and development processes of insulin resistance, and the sensitivity of type II diabetics to insulin can be restored by restoring the expression of the target, so that the blood sugar and the concentration of blood glycosylated hemoglobin are reduced.
Among the aforementioned targets for treating insulin resistance, the target is SBP 2.
Among the aforementioned targets for treating insulin resistance, the target is SBP2 of macrophages in abdominal adipose tissue.
The use of the aforementioned target for the treatment of insulin resistance in the treatment of an insulin resistance drug, said drug targeting said target.
The target point for treating insulin resistance is applied to the medicine for treating insulin resistance, and the medicine can restore the expression of the target point.
In the application of the target for treating insulin resistance in the medicine for treating insulin resistance, the medicine is a traditional Chinese medicine, a traditional Chinese medicine compound, a compound or a biological product.
In the application of the target point for treating insulin resistance in the medicine for treating insulin resistance, the Chinese herbal compound is Tangning Tongluo.
An application of a targeted medicine for recovering SBP2 expression in preparing a medicine for treating diabetic complications caused by hyperglycemia.
In the application of the targeted drug for recovering the SBP2 expression in preparing the drug for treating diabetic complications caused by hyperglycemia, the targeted drug for recovering the SBP2 expression is a traditional Chinese medicine, a traditional Chinese medicine compound, a compound or a biological product.
In the application of the targeted drug for recovering SBP2 expression in preparing the drug for treating diabetic complications caused by hyperglycemia, the traditional Chinese medicine compound is Tangning Tongluo, and the complications are diabetic eye diseases.
The invention relates to a Tangning Tongluo (TNTL), namely a Chinese medicinal preparation for treating diabetes and a preparation method thereof, and a medicament in the patent application with the application number of 201410052627.1.
A novel target point for insulin resistance therapy is SBP2 of macrophages in abdominal adipose tissue. By restoring SBP2 expression, insulin sensitivity in obese and type II diabetic patients can be restored, and blood glucose and glycated hemoglobin concentration in blood can be reduced. Insulin resistance in obese or type II diabetic patients can be treated by restoring the expression of the protein.
SBP2 is a selenoprotein secondary insert binding protein 2 in adipose tissue, mediates the correlation between translation and synthesis of selenoproteins with antioxidant properties, and is inhibited from expression by saturated fatty acids during the production and development of insulin resistance.
The recovery of the expression of the adipose tissue macrophage SBP2 is realized by a traditional Chinese medicine compound with targeting property.
The Chinese herbal compound can be used for treating diabetic complications such as diabetic eye disease caused by hyperglycemia.
The therapeutic targets of insulin resistance described above are achieved by the following experiments,
in a mouse model of obesity induced by high-fat diet, the expression of the adipose tissue SBP2 is inhibited along with the development of the disease course; this inhibition is mainly manifested in adipose tissue macrophages.
In a mouse model of obesity induced by high-fat diet, the siRNA of SBP2 loaded by nano-carrier can inhibit the expression of the siRNA in macrophages of adipose tissues, so that the generation and the development of insulin resistance can be accelerated, and the concentration of blood sugar and glycosylated hemoglobin in blood can be increased.
In a spontaneous type II diabetes mouse model, the expression of the SBP2 plasmid is restored in fat tissue macrophages by injection, so that the insulin sensitivity can be restored, and the blood sugar and the concentration of glycosylated hemoglobin in blood can be reduced.
The use of a targeted Chinese medicinal compound can remarkably improve the insulin sensitivity of diabetic mice, reduce the concentration of blood sugar and glycosylated hemoglobin in blood, and prompt the effect of treating insulin resistance.
A Chinese medicinal composition has effects in reducing blood sugar and concentration of glycosylated hemoglobin in blood, and can be used for inhibiting diabetic complications such as diabetic retinopathy caused by hyperglycemia.
SBP2 deficiency in adipose tissue macrophages drives insulin resistance in obesity. Proinflammatory activation and accumulation of Adipose Tissue Macrophages (ATM) are closely associated with increasing the risk of insulin resistance in obese patients. Here we describe the novel role of selenocysteine insertion sequence binding, protein 2(SBP2), in maintaining insulin sensitivity in obesity. SBP2 was inhibited in diet-induced obese mouse ATM and was associated with adipose tissue inflammation. Loss of SBP2 triggers metabolic activation of ATM, induces intracellular reactive oxygen species and inflammatory bodies, and subsequently promotes IL1 bata-associated local proliferation and infiltration of pro-inflammatory macrophages. SBP2 in obese mice, knock-out of specific ATM, could promote insulin resistance by increasing adipose tissue inflammation and expansion. Re-expression of SBP2 improved insulin sensitivity. Finally, a herbal formulation that specifically induces SBP2 expression in ATM has been shown to improve hyperglycemic diabetic patients through clinical observations of experimental improvement in insulin sensitivity. The present invention identifies SBP2 in ATM as a new target for the treatment of insulin resistance in obesity.
An omics method is used for assisting in identifying macrophage-derived MIP-1 gamma as a therapeutic target of a plant product TNTL in diabetic retinopathy. The inflammatory response of retinal endothelial cell dysfunction is thought to play an important role in Diabetic Retinopathy (DR). To date, anti-inflammatory therapy has been less than ideal as a result of DR therapy. The invention aims to explore a herbal formula Tangning Tongluo (TNTL) as a novel anti-inflammatory in DR treatment. We observed that high doses of TNTL had a hypoglycemic effect in the mouse type I diabetes model, whereas it inhibited the incidence of DR at non-hypoglycemic doses. TNTL restores blood-retinal barrier integrity, inhibits retinal neovascularization, and attenuates retinal ganglion cell degeneration. Transcriptomic analysis of the hyperglycemic mouse retinal tissue with or without TNTL revealed a significant suppression of the inflammatory retinal microenvironment. TNTL treatment inhibits pro-inflammatory macrophages in the retina, leading to inactivation of endothelial cell migration, restoration of endothelial cell monolayer integrity and prevention of leakage. Cytokine array analysis showed that TNTL significantly inhibited the secretion of MIP1 gamma by pro-inflammatory macrophages. TNTL prevention of endothelial dysfunction may be mediated by inhibition of the MIP1 γ/CCR1 axis. More specifically, TNTL inhibits the release of MIP1 γ by pro-inflammatory macrophages, which in turn inhibits activation of CCR 1-related signaling pathways in endothelial cells. Our findings suggest that TNTL may be an alternative treatment for DR and also a major source of potential drug candidates in the retinal microenvironment for DR targeting the MIP1 γ/CCR1 axis.
Compared with the prior art, the expression of the abdominal adipose tissue macrophage SBP2 serving as the insulin resistance treatment target point can obviously improve the insulin resistance of obese and diabetic mice, and the medicine for recovering the expression of the abdominal adipose tissue macrophage SBP2 can be used as a new medicine for treating the insulin resistance. The medicine for restoring the expression of abdominal adipose tissue macrophage SBP2 can be used as a new medicine for treating diabetic complications caused by hyperglycemia.
Drawings
FIG. 1 is a graph showing that the expression of SBP2 is inhibited in response to the occurrence and development of insulin resistance in obese mice;
FIG. 2 is a graph showing that siRNA of SBP2 loaded on nanocarriers can accelerate the development process of insulin resistance in obese mice;
FIG. 3 is a graph showing the sensitivity of over-expression of SBP2 in restoring insulin resistance in type II diabetic mice;
FIG. 4 is a graph showing the ability of a herbal composition targeted to the adipose tissue macrophage SBP2 to restore insulin resistance in type II diabetic mice;
FIG. 5 is a graph showing the inhibition of diabetic ocular complications by TNTL.
Detailed Description
The present invention is further illustrated by the following examples, which are intended to be purely exemplary of the invention and are not intended to be limiting.
Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Although methods and materials similar or equivalent to those described herein can be used in the experimental or practical applications, the materials and methods are described below. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
Example 1. A target for treating insulin resistance, which has the characteristic that the expression of the target is gradually reduced in the occurrence and development processes of insulin resistance, and the sensitivity of type II diabetics to insulin can be restored by restoring the expression of the target, so that the blood sugar and the concentration of blood glycosylated hemoglobin are reduced.
The target point is SBP 2.
The target is SBP2 of abdominal adipose tissue macrophages.
Use of a target for the treatment of insulin resistance in the treatment of an insulin resistance drug, said drug targeting said target.
The drug can restore expression of the target.
The medicine is a Chinese herbal compound.
The Chinese herbal compound is Tangning Tongluo. The invention relates to a Tangning Tongluo (TNTL), namely a Chinese medicinal preparation for treating diabetes and a preparation method thereof, and a medicament in the patent application with the application number of 201410052627.1.
An application of a targeted medicine for recovering SBP2 expression in preparing a medicine for treating diabetic complications caused by hyperglycemia.
The targeted medicine for recovering SBP2 expression is a Chinese herbal compound.
The Chinese herbal compound is Tangning for dredging collaterals, and the complication is diabetic eye disease.
Example 2. Expression of SBP2 during development and progression of insulin resistance
Disease model of high fat diet induced insulin resistance in mice: the procedure of this experiment was started after the mice had acclimatized for one week. Mice were divided into two groups, one group was given normal diet (NCD) and one group was given High Fat Diet (HFD), and the expression of SBP2 was observed in abdominal adipose tissues of high fat diet mice at 2, 4, and 8 weeks, respectively, and the results are shown in fig. 1A. In 4-week-HFD-administered mice, yellow adipose tissue (BAT), abdominal adipose tissue (epiWAT) and subcutaneous adipose tissue (ingWAT) were separately harvested and tested for SBP2 expression, as shown in FIG. 1B. Cells of abdominal adipose tissues of mice administered with NCD and HFD were separated by cell sorting technique, and changes in expression of SBP2 in adipocytes, fat extract fraction (SVF) and adipose tissue macrophages (F4/80+) were examined, and the results are shown in FIG. 1C. Expression of SBP2 was detected by real-time fluorescent PCR. The results show that with the production of insulin resistance, the expression of SBP2 in adipose tissues is reduced; this decrease is mainly manifested in macrophages in abdominal adipose tissue.
Example 3. The targeted inhibition of the expression of the adipose tissue SBP2 accelerates the generation and development of insulin resistance of mice with high fat diet
Disease model of high fat diet induced insulin resistance in mice: one week after the mice acclimated to the environment, High Fat Diet (HFD) was started, and at the same time, the mice were divided into two groups, one group was given nano empty vector (Mock), and one group was given siRNA loaded with SBP2 (6 μ g/mouse, SBP2 KD). The nanocarrier was administered by intraperitoneal injection twice weekly. After the experiment was completed, body weight was measured, and the results are shown in fig. 2A. Fasting Blood Glucose (FBG) was measured and the results are shown in fig. 2B. A unit of recombinant insulin was intraperitoneally injected and its insulin sensitivity was determined, and the results are shown in FIG. 2C. Serum was collected and glycated hemoglobin (Hb1Ac) was measured, and the results are shown in FIG. 2D. The results show that the inhibition of the expression of the adipose tissue macrophage SBP2 has no significant effect on the body weight of the mice with high-fat diet, but improves the increase of fasting plasma glucose and glycosylated hemoglobin, so that the mice are less sensitive to insulin.
Example 4. Overexpression of SBP2 improves insulin resistance in type II diabetic mice
Disease model of idiopathic type two diabetic mice: the db/db mice begin to develop type two diabetic symptoms of obesity, insulin resistance and elevated blood glucose at 6-8 weeks of age, and the db/db mice 6-10 weeks of age are divided into two groups, one group is given plasmid vectors and the other group is given SBP2 overexpression plasmids (6-8 mug/mouse). The plasmid was administered by intraperitoneal injection twice weekly. Plasmids were purchased from Genecopiea, USA. After the experiment was completed, body weight was measured, and the results are shown in fig. 3A. Fasting Blood Glucose (FBG) was measured and the results are shown in fig. 3B. The insulin sensitivity was determined by intraperitoneal injection of one unit of recombinant insulin, and the results are shown in FIG. 3C. Serum was collected and glycated hemoglobin (Hb1Ac) was measured, and the results are shown in FIG. 3D. The results show that the recovery of SBP2 expression has no significant effect on the body weight of type II diabetic mice, but reduces fasting plasma glucose and glycated hemoglobin and improves insulin sensitivity.
Example 5. TNTL enhancement of insulin sensitivity in type II diabetic mice by improving SBP2 expression
Disease model of idiopathic type two diabetic mice: db/db mice begin to develop symptoms of diabetes of type two, obesity, insulin resistance and elevated blood glucose at 6-8 weeks of age, and db/db mice 6-10 weeks of age are divided into 4 groups, one group is given nano empty vector (Mock) while TNTL is being given, one group is given nano vector SBP2 loaded siRNA (6-8. mu.g/mouse, SBP2KD), and one group is given nano vector SBP2 loaded siRNA (6-8. mu.g/mouse) while TNTL is being given. Administration of the nanocarriers is shown in example 2. TNTL was administered by gavage, gavage 3.6g/kg daily. After the experiment was completed, body weight was measured, and the results are shown in fig. 4A. Fasting Blood Glucose (FBG) was measured and the results are shown in fig. 4B. A unit of recombinant insulin was intraperitoneally injected and its insulin sensitivity was determined, and the results are shown in FIG. 4C. Serum was collected and glycated hemoglobin (Hb1Ac) was measured, and the results are shown in FIG. 4D. The result shows that TNTL can effectively reduce the fasting blood sugar and the concentration of glycosylated hemoglobin of the type II diabetic mice and improve the insulin sensitivity of the type II diabetic mice. The TNTL function can be antagonized by the siRNA of SBP2, which indicates that the pharmacological action has targeting property and the function is generated by the targeted improvement of the expression of macrophage SBP2 in abdominal adipose tissue.
Example 6. TNTL inhibition of diabetic ocular complications
8-week-old male C57BL/J mice were randomly divided into 6 groups, normal, model, TNTL (0.9,1.8,3.6g/kg), insulin. In addition to the normal group, 5 mice were injected with Streptozotocin (STZ) at 55mg/kg i.p. on fasting condition for five consecutive days. After two days of stabilization, the study included measuring random blood glucose at 18.0-25.0 mmol/d. TNTL treatment group was gavaged orally daily for 8 weeks. Mice in the normal group and the model group are respectively perfused with equivalent distilled water. After 8 weeks, each group of mice was sacrificed and retinal vascular permeability was measured by Evans Blues method; the eye was removed and the retina was detached for vascular plating and pericytes, endothelial cells and anucleated vessels were counted. The results show that TNTL significantly increased the ratio of pericytes to endothelial cells on retinal vessels in diabetic mice, returned to normal group levels (FIGS. 5A and 5B), decreased the number of anucleated vessels (FIGS. 5A and 5C), and decreased fundus leakage of Evans Blues (FIG. 5D), suggesting decreased retinal permeability. These results indicate that TNTL can ameliorate retinopathy caused by hyperglycemia and is significantly better than insulin treatment.
Claims (10)
1. A target for the treatment of insulin resistance, comprising: the target has the characteristic that the expression of the target is gradually reduced in the occurrence and development processes of insulin resistance, the sensitivity of the type II diabetes mellitus patient to insulin can be restored by restoring the expression of the target, and the concentration of blood sugar and blood glycosylated hemoglobin is reduced.
2. The target of claim 1 for the treatment of insulin resistance, which is characterized by: the target point is SBP 2.
3. The target of claim 2 for the treatment of insulin resistance, which is characterized by: the target is SBP2 of abdominal adipose tissue macrophages.
4. The use of the target for treating insulin resistance according to claim 2 or 3 in a medicament for treating insulin resistance, wherein: the drug targets the target.
5. The use of the target for treating insulin resistance according to claim 4 in a medicament for treating insulin resistance, wherein: the drug can restore expression of the target.
6. The use of the target for treating insulin resistance according to claim 4 or 5 in a medicament for treating insulin resistance, wherein: the medicine is a traditional Chinese medicine, a traditional Chinese medicine compound, a compound or a biological product.
7. The use of the target for treating insulin resistance according to claim 6 in a medicament for treating insulin resistance, wherein: the Chinese herbal compound is Tangning Tongluo.
8. An application of a targeted medicine for recovering SBP2 expression in preparing a medicine for treating diabetic complications caused by hyperglycemia.
9. The use of the targeted drug for restoring SBP2 expression according to claim 8 in the preparation of a medicament for treating diabetic complications caused by hyperglycemia, wherein: the targeted medicine for recovering SBP2 expression is a traditional Chinese medicine, a traditional Chinese medicine compound, a compound or a biological product.
10. The use of the targeted drug for restoring SBP2 expression according to claim 9 in the preparation of a medicament for treating diabetic complications caused by hyperglycemia, wherein: the Chinese herbal compound is Tangning for dredging collaterals, and the complication is diabetic eye disease.
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| 贵州百灵: ""贵州百灵:关于糖宁通络胶囊研发项目的进展公告"", 《HTTPS://DATA.EASTMONEY.COM/NOTICES/DETAIL/002424/AN201709270915089872,%7BGPMC%7D.HTML》 * |
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Application publication date: 20210223 |