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CN115245556A - Application of proteasome inhibitor ixazomide in preparation of medicine for treating diabetes - Google Patents

Application of proteasome inhibitor ixazomide in preparation of medicine for treating diabetes Download PDF

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CN115245556A
CN115245556A CN202110460520.0A CN202110460520A CN115245556A CN 115245556 A CN115245556 A CN 115245556A CN 202110460520 A CN202110460520 A CN 202110460520A CN 115245556 A CN115245556 A CN 115245556A
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diabetes
insulin resistance
medicament
insulin
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胡仁明
黄金雅
鹿斌
杨叶红
张召云
周丽诺
陈立立
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Huashan Hospital of Fudan University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin

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Abstract

The invention belongs to the technical field of biological medicines, and relates to a new application of proteasome inhibitor namely Sha Zuo m in pharmacy, in particular to an application of proteasome inhibitor namely ixazom in preparation of a medicine for treating diabetes, wherein the medicine is a medicine for improving insulin resistance of type 2 diabetes, reducing fasting blood glucose, reducing random blood glucose, reducing glycated hemoglobin, reducing blood fat or improving glucose tolerance. The invention also provides a method for improving insulin resistance by using in vitro cells, and provides a new tool and a new way for treating diabetes by using the ixazofamid as an active ingredient. The tissue chip treated by the ixazomide provides a series of gene targets related to diabetes, and provides a foundation for subsequent research and drug screening.

Description

Application of proteasome inhibitor ixazomide in preparation of medicine for treating diabetes
Technical Field
The invention belongs to the technical field of biology, and relates to application of ixazofamid in preparation of a medicament for treating diabetes, in particular to application of a proteasome inhibitor ixazofamid in preparation of a medicament for treating metabolic inflammation and insulin resistance.
Background
The prior art discloses that IDF global diabetes maps in 2019 show that global diabetes prevalence has risen to 9.3%, of which over 90% is type 2 diabetes, and that type 2 diabetes patients are mainly concentrated in asia-pacific regions, including china, and that, statistically, the total number of patients with chinese diabetes accounts for about one fourth of the world [1]. Diabetes and its complications have greatly exacerbated the global burden of death and disability, with diabetes having become the ninth leading cause of life expectancy in 2013 as a global disease burden study, and 8 years of life shortening in the U.S. as shown by 2016 closely related type 2 diabetes.
Studies have shown that insulin resistance and insufficient insulin secretion are two key factors in the onset of type 2 diabetes, but the specific mechanisms are not fully elucidated, and there is increasing evidence that type 2 diabetes is a chronic low grade inflammatory disease [3], an inflammatory disease called metabolic inflammation, which is a chronic inflammatory state mediated by classical inflammatory molecules and their associated signaling pathways triggered by an excess of nutrients and energy [4]. A cross-sectional study shows that inflammatory markers such as serum TNF-alpha, CRP, IL-6, SAA and the like of a type 2 diabetes patient are obviously increased compared with a non-diabetic healthy patient [5,6]. Moreover, prospective studies have found that non-diabetic healthy persons with high serum CRP and IL-6 are at 4-fold and 2-fold higher risk of developing type 2 diabetes than control people [7], and serum IL-1 beta and IL-6 are simultaneously increased at 3-fold higher risk of developing type 2 diabetes than control people [8], and the evidence fully indicates that inflammation is involved in the development of type 2 diabetes. In addition to the increase of the levels of inflammatory factors such as TNF-alpha, IL-6, IL-1 beta and the like in serum, the levels of proinflammatory factors such as local TNF-alpha and the like in liver, fat [9], muscle [10], pancreatic islet [11] and the like of a type 2 diabetes patient are also obviously increased, and meanwhile, macrophage infiltration is increased. In view of the above, it is well recognized that type 2 diabetes is essentially a chronic, low-grade inflammatory disease.
It has been studied how metabolic inflammation is initiated, and although adipocytes and islet beta cells themselves can synthesize and secrete inflammatory factors, the increase of inflammatory factors in type 2 diabetic patients mainly comes from M1-type macrophages infiltrated in fat, liver, muscle and islets of Langerhans [3], mainly fat and liver. Excessive energy intake causes fat accumulation in the body, free fatty acid is increased, the free fatty acid is combined with Toll-like receptors 2 or 4 (TLR 2/TLR 4) on the surfaces of macrophages, the macrophages are polarized to a proinflammatory M1 type [12], proinflammatory factors such as TNF-alpha and IL-1 beta are synthesized and secreted, the inflammatory factors are further combined with corresponding antibodies on the surfaces of insulin sensitive cells such as fat cells and liver cells, cells generate insulin resistance, and IL-1 beta can be combined with insulin beta cells to induce apoptosis, so that insulin secretion is insufficient. Meanwhile, inflammatory factors can further promote fat cells, macrophages and other chemotactic factors such as monocyte chemotactic protein 1 (MCP-1) and the like to secrete chemotactic monocytes, T lymphocytes and other infiltrating fat, so that inflammation is further expanded, and the infiltration degree of the macrophages in the fat is positively correlated with the obesity degree [13]. Meanwhile, the change of the dietary structure and the life style can also cause the disturbance of human intestinal flora, the decrease of the quantity of gram-positive bacteria, the increase of the quantity of negative bacteria and the increase of permeability among epithelial cells of the intestinal tract, thereby causing the increase of LPS in serum, and the combination of the LPS and TLR4 on the surfaces of macrophages at the parts of fat, liver and the like to activate the macrophages [14-16], and also can start metabolic inflammation.
Inflammation has also been studied to disclose the results of insulin resistance in type 2 diabetic patients, insulin acts by activating insulin signaling pathway, insulin recognizes and binds to insulin receptor IR on cell membrane, activates tyrosine kinase activity of IR, promotes tyrosine site phosphorylation of IR itself, phosphorylated IR recruits insulin receptor substrate IRs and promotes tyrosine phosphorylation thereof, further activates downstream AKT and other signaling pathways, inhibits gluconeogenesis, promotes glycolysis and glycogen synthesis [17], and lowers blood sugar. The specific molecular mechanism of insulin resistance caused by various inflammatory factors is mainly through activating IKK-beta/NF kB 18 and JNK (Jun N-terminal kinases) inflammatory signal pathways, which interfere with insulin signal pathways in the following two different ways. A large number of clinical tests and animal experiments prove that inhibiting IKK-beta can reduce phosphorylation level of nuclear factor kappa B (NF kappa B) and improve insulin resistance [18-20], NF kappa B is one of the most important nuclear transcription factors, normally, NF-kappa B and the inhibitor kappa B alpha (I kappa B alpha) protein are combined and free in cytoplasm, after inflammatory factors, free fatty acids or LPS are stimulated, I kappa B alpha protein kinase (IKK) is activated, serine sites of I kappa B alpha are phosphorylated, further ubiquitination is degraded by proteasomes, nuclear localization sequences of NF kappa B are released, the protein is transferred into nucleus to be used as a transcription factor to participate in transcription of proinflammatory factors such as TNF-alpha, IL-6 and the like [21], and the inflammatory factors further activate IKK-beta/NF kappa B and JNK signal pathways, so as to cause insulin resistance. Unlike IKK- β/nfkb, JNK inhibits IRS1 tyrosine phosphorylation by directly phosphorylating the serine site of IRS1, and the serine phosphorylated IRS1 is further ubiquitinated to be degraded by proteasomes, blocking the insulin signaling pathway, leading to insulin resistance [22].
Research proves that the type 2 diabetes, atherosclerosis, obesity and non-alcoholic fatty liver disease are all metabolic inflammatory diseases closely related to chronic low-grade inflammation, and researchers put forward a new concept of metabolic inflammatory syndrome: the patient had 2 of the above 4 metabolic syndromes (metabolic inflammation syndrome MIS) that could be diagnosed. [23-24] this concept is useful for both the treatment of different diseases and the prevention of different diseases. There are clinical studies to treat type 2 diabetes by anti-inflammatory therapy and preliminary results are obtained, for example, non-steroidal anti-inflammatory drugs can reduce blood sugar of type 2 diabetes and obese patients, but the dosage required for reducing blood sugar is about 10 times higher than the clinical common dosage, and meanwhile, high dosage can also cause a plurality of serious adverse reactions, such as liver function damage and deafness caused by salicylic acid, liver function damage and blood coagulation dysfunction caused by aspirin [25]. Therefore, these conventional anti-inflammatory agents have not been clinically used for the treatment of type 2 diabetes. In addition to non-steroidal anti-inflammatory drugs, specific inhibitors of inflammatory factors, such as anti-TNF α monoclonal antibodies, anti-IL 1 β monoclonal antibodies and IL-1 receptor antagonists, have been proposed, but clinical trials have shown that the effect of lowering blood sugar is weak [26], which is probably due to insufficient inhibition of an inflammatory factor alone to completely improve metabolic inflammation, and therefore, there is a need to find new anti-inflammatory targets for the treatment of type 2 diabetes and related metabolic diseases (MIS).
It is easy to see through the mechanism of insulin resistance caused by inflammation, proteasomes play a vital role in the process, can degrade ubiquitinated I kappa B alpha so as to activate NF kappa B, promote the transcription of inflammatory factors and cause insulin resistance, can degrade ubiquitinated IRS1 at the same time, block an insulin signal pathway and cause insulin resistance, and whether metabolic inflammation and insulin resistance of type 2 diabetes can be reversed by using proteasome inhibitors becomes a research focus in the industry.
Proteasome is an important component of the classical pathway ubiquitin proteasome pathway for degrading proteins in nucleated cells, and is a polymer composed of a plurality of subunits, including a barrel-shaped 20s core particle and two 19s regulatory subunits, wherein the core particle is composed of 4 isoheptane rings (two outer alpha rings and two inner beta rings) stacked axially, each ring is formed by connecting 7 subunits, wherein the beta 1, beta 2 and beta 5 subunits of the beta rings respectively contain peptidyl glutamyl hydrolase, tryptase and chymotrypsin-like activities, the protein is degraded into small molecular polypeptides, and the regulatory subunit is also composed of a plurality of subunits and has the functions of recognizing, binding ubiquitin on a substrate and transporting the substrate to the core particle [27]. Proteasomes are involved in regulating apoptosis, proliferation and other processes in organisms, proteasome inhibitors are used clinically as an effective anti-multiple myeloma drug, but in recent 10 years, more and more studies have found that proteasomes are also involved in antigen presentation, inflammatory response and metabolic regulation [28], and thus is type 2 diabetes a metabolic inflammatory disease, and is proteasome inhibitors a novel anti-inflammatory drug for treating type 2 diabetes? Known related studies have mostly focused on the treatment of chronic inflammatory diseases with proteasome inhibitors, including arthritis, encephalomyelitis, lupus erythematosus, etc. [30], several studies associated with diabetes have been inconsistent, and it has been reported that the proteasome inhibitor bortezomib can prevent NOD mice from developing type 1 diabetes, but that the blood glucose of the developed NOD mice cannot be reduced by a single week [30], curcumin, an extract of traditional Chinese medicine turmeric, can reduce blood glucose in db/db mice by inhibiting proteasome activity [31], rosiglitazone, a hypoglycemic agent, can inhibit proteasome activity [33], aghdam, etc. also, proteasome inhibitors have been found to improve diabetic nephropathy [33], but it has also been reported that proteasome inhibitors increase the stress of the endoplasmic reticulum of hepatocytes and reduce the level of AKT phosphorylation [34]. However, no direct evidence that proteasome inhibitors can improve metabolic inflammation and insulin resistance of type 2 diabetes has been found so far, and indirect evidence results are inconsistent.
Based on the basis and the current situation of the prior art, the inventor intends to provide a novel medicament for treating diabetes, and relates to application of ixazom in preparation of medicaments for treating diabetes, in particular to application of a proteasome inhibitor ixazom in preparation of medicaments for treating metabolic inflammation and insulin resistance.
Among the references relevant to the present invention are,
1.International Diabetes Federation.IDF Diabetes Atlas,9th edn.Brussels,Belgium:2019.Available at:https://www.diabetesatlas.org
2.Yan Zheng,Ley Sylvia-H,Hu Frank-B.Global aetiology and epidemiology of type 2 diabetes mellitus and its complications[J].NATURE REVIEWS ENDOCRINOLOGY,2018,14(2):88-98.
3.Marc-Y Donath,Shoelson Steven-E.Type 2 diabetes as an inflammatory disease[J].NATURE REVIEWS IMMUNOLOGY,2011,11(2):98-107.
4.Goekhan-S Hotamisligil.Inflammation and metabolic disorders[J].NATURE,2006,444(7121):860-867.
5.J-C Pickup,Chusney G-D,Thomas S-M,et al.Plasma interleukin-6,tumour necrosis factor alpha and blood cytokine production in type 2 diabetes[J].LIFE SCIENCES,2000,67(3):291-300.
6.E Leinonen,Hurt-Camejo E,Wiklund O,et al.Insulin resistance and adiposity correlate with acute-phase reaction and soluble cell adhesion molecules in type 2 diabetes[J].ATHEROSCLEROSIS,2003,166(PII S0021-9150(02)00371-42):387-394.
7.A-D Pradhan,Manson J-E,Rifai N,et al.C-reactive protein,interleukin 6,and risk of developing type 2 diabetes mellitus[J].JAMA,2001,286(3):327-334.
8.J Spranger,Kroke A,Mohlig M,et al.Inflammatory cytokines and the risk to develop type 2 diabetes-Results of the prospective population-based European Prospective Investigation into Cancer and Nutrition(EPIC)-Potsdam study[J].DIABETES,2003,52(3):812-817.
9.Katherine Samaras,Botelho Natalia-K,Chisholm Donald-J,et al.Subcutaneous and Visceral Adipose Tissue Gene Expression of Serum Adipokines That Predict Type 2 Diabetes[J].OBESITY,2010,18(5):884-889.
10.P Plomgaard,Nielsen A-R,Fischer C-P,et al.Associations between insulin resistance and TNF-alpha in plasma,skeletal muscle and adipose tissue in humans with and without type 2 diabetes[J].DIABETOLOGIA,2007,50(12):2562-2571.
11.Jan-A Ehses,Perren Aurel,Eppler Elisabeth,et al.Increased number of islet-associated macrophages in type 2 diabetes[J].DIABETES,2007,56(9):2356-2370.
12.C-N Lumeng,Bodzin J-L,Saltiel A-R.Obesity induces a phenotypic switch in adipose tissue macrophage polarization[J].J Clin Invest,2007,117(1):175-184.
13.S-P Weisberg,McCann D,Desai M,et al.Obesity is associated with macrophage accumulation in adipose tissue[J].JOURNAL OF CLINICAL INVESTIGATION,2003,112(12):1796-1808.
14.P-D Cani,Osto M,Geurts L,et al.Involvement of gut microbiota in the development of low-grade inflammation and type 2 diabetes associated with obesity[J].Gut Microbes,2012,3(4):279-288.
15.M-J Saad,Santos A,Prada P-O.Linking Gut Microbiota and Inflammation to Obesity and Insulin Resistance[J].Physiology(Bethesda),2016,31(4):283-293.
16.X Chen,Devaraj S.Gut Microbiome in Obesity,Metabolic Syndrome,and Diabetes[J].Curr Diab Rep,2018,18(12):129.
17.A Forand,Koumakis E,Rousseau A,et al.Disruption of the Phosphate Transporter Pit1 in Hepatocytes Improves Glucose Metabolism and Insulin Signaling by Modulating the USP7/IRS1 Interaction[J].Cell Rep,2016,16(10):2736-2748.
18.M-S Yuan,Konstantopoulos N,Lee J-S,et al.Reversal of obesity-and diet-induced insulin resistance with salicylates or targeted disruption of IKK beta[J].SCIENCE,2001,293(5535):1673-1677.
19.Amy Fleischman,Shoelson Steven-E,Bernier Raquel,et al.Salsalate Improves Glycemia and Inflammatory Parameters in Obese Young Adults[J].DIABETES CARE,2008,31(2):289-294.
20.Allison-B Goldfine,Fonseca Vivian,Jablonski Kathleen-A,et al.The Effects of Salsalate on Glycemic Control in Patients With Type 2 Diabetes A Randomized Trial[J].ANNALS OF INTERNAL MEDICINE,2010,152(6):346.
21.Hadi Khodabandehloo,Gorgani-Firuzjaee Sattar,Panahi Ghodratollah,et al.Molecular and cellular mechanisms linking inflammation to insulin resistance and beta-cell dysfunction[J].TRANSLATIONAL RESEARCH,2016,167(1):228-256.
22.V Aguirre,Uchida T,Yenush L,et al.The c-Jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307)[J].J Biol Chem,2000,275(12):9047-9054.
23.Hu R，Xie Y，Lu B,et al.Metabolic inflammatory syndrome:a novel concept of holistic integrative medicine for management metabolic diseases.AME Med J 2018；3:51.doi:10.21037/amj
24.Hu R，Xie Y，Lu B,et al.High detective rate of“metabolic inflammatory syndrome”in pateints with type 2diabetes.Chi J Endocrinol Metab.2016；32:27-32.
25.Rena G,K Sakamoto.Salicylic acid:old and new implications for the treatment of type 2diabetes[J].Diabetology international,2014,5(4):212-218.
26.Huang J,Y Yang,R Hu,et al.Anti-interleukin-1therapy has mild hypoglycaemic effect in type 2diabetes[J].Diabetes,obesity&metabolism,2018,20(4):1024-1028.
27.I Livneh,Cohen-Kaplan V,Cohen-Rosenzweig C,et al.The life cycle of the 26S proteasome:from birth,through regulation and function,and onto its death[J].Cell Res,2016,26(8):869-885.
28.
29.T Eleftheriadis,Pissas G,Antoniadi G,et al.A comparative analysis between proteasome and immunoproteasome inhibition in cellular and humoral alloimmunity[J].Int Immunopharmacol,2017,5048-54.
30.G Mondanelli,Albini E,Pallotta M-T,et al.The Proteasome Inhibitor Bortezomib Controls Indoleamine 2,3-Dioxygenase 1Breakdown and Restores Immune Regulation in Autoimmune Diabetes[J].Front Immunol,2017,8428.
31.S Weisberg,Leibel R,Tortoriello D-V.Proteasome inhibitors,including curcumin,improve pancreatic beta-cell function and insulin sensitivity in diabetic mice[J].Nutr Diabetes,2016,6e205.
32.X Wang,Hu Z,Hu J,et al.Insulin resistance accelerates muscle protein degradation:Activation of the ubiquitin-proteasome pathway by defects in muscle cell signaling[J].Endocrinology,2006,147(9):4160-4168.
33.S-Y Aghdam,Gurel Z,Ghaffarieh A,et al.High glucose and diabetes modulate cellular proteasome function:Implications in the pathogenesis of diabetes complications[J].Biochem Biophys Res Commun,2013,432(2):339-344.
34.T Otoda,Takamura T,Misu H,et al.Proteasome dysfunction mediates obesity-induced endoplasmic reticulum stress and insulin resistance in the liver[J].Diabetes,2013,62(3):811-824.。
disclosure of Invention
The invention aims to provide a novel medicament for treating diabetes based on the basis and the current situation of the prior art, and relates to application of ixazom in preparation of medicaments for treating diabetes, in particular to application of a proteasome inhibitor ixazom in preparation of medicaments for treating metabolic inflammation and insulin resistance.
The invention provides a novel medicine for treating or relieving diabetes, and particularly provides application of proteasome inhibitor ixazomide in preparation of medicines for treating metabolic inflammation and insulin resistance.
In order to solve the technical problems, the invention researches potential action targets of the isoxazomib for treating diabetes and metabolic inflammatory syndrome. Experimental results prove that the ixazofamid can reduce fasting blood glucose, random blood glucose, glycosylated hemoglobin and blood fat of a db/db mouse which is an animal model of type 2 diabetes, and improve the sugar tolerance of the mouse at the same time, and the results show that the blood glucose is reduced mainly by improving the insulin sensitivity of the db/db mouse, the administration is carried out orally, 2 times per week, after intervention for 6 weeks, the HOMA-IR index and fasting insulin level of the db/db mouse are obviously reduced, after insulin is injected in an abdominal cavity, the blood glucose reduction speed of a drug intervention group is obviously increased, in addition, the results show that Sha Zuo m obviously improves the phosphorylation level of an Akt signal pathway of liver insulin of the db/db mouse and the IRS1 protein content, and the experimental results prove that the I Sha Zuo m increases the insulin sensitivity of the type 2 diabetes mouse.
Furthermore, the invention manufactures a protein chip for db/db mouse livers intervened by ixazomycin, and 14 differential expression proteins are screened out, wherein 11 proteins are up-regulated and 3 proteins are down-regulated, the two most obvious up-regulated proteins TRAIL and Axl have the function of inhibiting inflammation, and the two most obvious down-regulated proteins have the function of promoting inflammatory reaction, which shows that the proteasome inhibitor inhibits the metabolic inflammation of type 2 diabetes mice through TRAIL or Axl, thereby improving insulin resistance and reducing blood sugar.
The invention provides application of proteasome inhibitor ixazofamid in preparing a medicament for treating diabetes, in particular application of the proteasome inhibitor ixazofamid in preparing a medicament for treating metabolic inflammation and insulin resistance.
Preferably, the medicament is a medicament for improving type 2 diabetes insulin resistance, reducing fasting glucose, reducing random blood glucose, reducing glycated hemoglobin, reducing blood lipid or improving glucose tolerance.
Preferably, the drug is a drug for increasing the phosphorylation level of liver Akt and the content of IRS1 protein.
Preferably, the drug is a drug for ameliorating metabolic inflammation.
Preferably, the medicament is capable of:
up-regulating TRAIL, axl, CD36, PF4, CD40, fas, IL-17F, IL-2Ra, OPN, IGFBP-6, I-TAC gene expression; or
Downregulating NOV, CTLA4, or CD6 gene expression.
The invention also provides a screening target of a group of diabetes drugs, and the screening target is selected from one or more of the following genes:
TRAIL, axl, CD36, PF4, CD40, fas, IL-17F, IL-2Ra, OPN, IGFBP-6, I-TAC, NOV, CTLA4 or CD6.
In a preferred embodiment of the invention, comparing tissue samples before and after treatment with Sha Zuo m, the results show up-regulation of TRAIL, axl, CD36, PF4, CD40, fas, IL-17F, IL-2Ra, OPN, IGFBP-6, I-TAC gene expression; simultaneously, expression of the NOV, CTLA4 or CD6 genes is down-regulated.
The invention also provides a method for relieving insulin resistance of in vitro cultured cells, which comprises the following steps:
(1) Collecting islet cells, and culturing in an in vitro cell culture medium; and/or
(2) And adding ixazofamid into the cell culture medium, and incubating.
On the other hand, the ixazomide can be used alone or together with other solvents and diabetes drugs to prepare drugs for treating or relieving diabetes.
Furthermore, the invention provides a pharmaceutical composition for treating diabetes, which contains ixazomide and a pharmaceutically common injection solvent.
Preferably, the pharmaceutical composition further comprises bortezomib.
The research of the invention proves that the proteasome inhibitor isoxazomib can improve the insulin resistance and reduce the blood sugar of db/db mice with type 2 diabetes, and simultaneously proves that metabolic inflammation of mice with type 2 diabetes can be inhibited through TRAIL or Axl, so that the insulin resistance is improved and the blood sugar is reduced. The Yi Sha Zuo rice provided by the invention can obviously improve clinical indexes of diabetes, improve insulin resistance of type 2 diabetes, reduce fasting blood glucose, reduce random blood glucose, reduce glycosylated hemoglobin, reduce blood fat or improve glucose tolerance, and provide a new intervention tool and approach for treatment of diabetes. The tissue chip treated by the ixazofamid provides a series of gene targets related to diabetes, and provides a foundation for subsequent research and drug screening.
Drawings
FIG. 1: modification of indexes of db/db mice by proteasome inhibitors i Sha Zuo m (ixazomib) and bortezomib (ps-341),
wherein, a, random blood sugar; b, fasting blood glucose; e, glycated hemoglobin and f, serum total cholesterol. Mice were unchanged in c, body weight and d, food intake.
FIG. 2 is a schematic diagram: IPGTT indicates that proteasome inhibitor intervention increases glucose tolerance in db/db mice.
FIG. 3: changes in blood glucose and insulin levels in mice by insulin and ixazofamid,
wherein, a, b, c, the proteasome inhibitor increases the rate of blood glucose decline in db/db mice after intraperitoneal injection of insulin; d, i Sha Zuo meters (ixazomib) reduces the HOMA-IR index in db/db mice; e, ixazomib Sha Zuo meters (ixazomib) reduced fasting insulin levels in db/db mice.
FIG. 4: modification of the content of blood glucose-related proteins by ixazofamid,
wherein, a, i Sha Zuo m (ixazomib) increases the liver p-Akt level and b, IRS1 protein content of db/db mouse; c, i Sha Zuo m (ixazomib) did not alter the liver IRS1 expression in db/db mice.
FIG. 5: a result graph of the difference protein,
wherein, the screening condition is as follows: p is less than 0.05 with a foldchange greater than 1.2 or less than 0.83; i13, i14, i7, i4 are i Sha Zuo m (ixazomib) intervention db/db mice; con2.14, con2.11, con2.13, con2.12 are control db/db mice.
FIG. 6: GO analysis suggested that i Sha Zuo meters (ixazomib) improved the liver inflammation profile of db/db mice.
Detailed Description
The technical solutions in the embodiments of the present application will be described clearly and completely below, and it should be understood that the described embodiments are only a part of the embodiments of the present application, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present application.
Example 1
The intervention of injecting ixazofamid into db/db mice of animal models of type 2 diabetes shows that the proteasome inhibitor of ixabendamide Sha Zuo m reduces fasting blood sugar, random blood sugar, glycosylated hemoglobin and blood fat of db/db mice and improves sugar tolerance.
In FIG. 1, it is shown that proteasome inhibitors i Sha Zuo m (ixazomib) and bortezomib (ps-341) reduced the a, random blood glucose in db/db mice; b, fasting blood glucose; e, glycated hemoglobin and f, serum total cholesterol. Mice were unchanged in c, body weight and d, food intake.
FIG. 2 shows that IPGTT indicates that proteasome inhibitor intervention increases glucose tolerance in db/db mice.
Example 2
The HOMA-IR index and fasting insulin level of db/db mice are obviously reduced after the intervention of 6 weeks after 2 times per week by oral administration, the blood sugar reduction speed of a drug intervention group is obviously increased after insulin is injected into an abdominal cavity, and the insulin sensitivity of the db/db mice is improved by using a proteasome inhibitor of i Sha Zuo m.
FIGS. 3 a, b, c, show that proteasome inhibitors increase the rate of blood glucose lowering in db/db mice following intraperitoneal injection of insulin; d shows that i Sha Zuo meters (ixazomib) reduces the HOMA-IR index in db/db mice; e showed that Sha Zuo meters (ixazomib) reduced fasting insulin levels in db/db mice.
FIG. 4 is a graph of a, i Sha Zuo meters (ixazomib) increased liver p-Akt levels and b, IRS1 protein content in db/db mice; c, i Sha Zuo m (ixazomib) did not change the liver IRS1 expression level in db/db mice.
Example 3
The Raybiotech Mouse Cytokine Array GS4000 protein chip shows that the proteasome inhibitor i Sha Zuo m can improve the liver inflammation of db/db mice.
Wherein, the differential protein screening conditions in fig. 5: p is less than 0.05 with a foldchange greater than 1.2 or less than 0.83; i13, i14, i7, i4 are i Sha Zuo m (ixazomib) intervention db/db mice; con2.14, con2.11, con2.13, con2.12 are control db/db mice.
Table one: 14 differentially expressed proteins are screened out by the protein chip
Figure BDA0003042251570000101
Among them, most proinflammatory proteins are down-regulated, and anti-inflammatory proteins are up-regulated. +: promoting inflammation; -: inhibiting inflammation; +/-: promoting and inhibiting inflammation; UK: unknown.

Claims (9)

1. Use of the proteasome inhibitor ixazomide in the preparation of a medicament for the treatment of metabolic inflammation and insulin resistance.
2. The use of claim 1, wherein the medicament is a medicament for improving type 2 diabetes insulin resistance, lowering fasting glucose, lowering random blood glucose, lowering glycated hemoglobin, lowering blood lipids, or increasing glucose tolerance.
3. The use of claim 1, wherein the agent is an agent that increases the level of phosphorylation of Akt in the liver and the level of IRS1 protein.
4. The use of claim 1, wherein the medicament is a medicament for ameliorating metabolic inflammation.
5. The use of claim 1, wherein the medicament is capable of: up-regulating TRAIL, axl, CD36, PF4, CD40, fas, IL-17F, IL-2Ra, OPN, IGFBP-6, I-TAC gene expression; alternatively, NOV, CTLA4, or CD6 gene expression is down-regulated.
6. The screening target of the diabetes drug is characterized in that the screening target is selected from one or more of the following genes:
TRAIL, axl, CD36, PF4, CD40, fas, IL-17F, IL-2Ra, OPN, IGFBP-6, I-TAC, NOV, CTLA4 or CD6.
7. A method for alleviating insulin resistance in cells cultured in vitro, the method comprising the steps of:
(1) Collecting islet cells, and culturing in an in vitro cell culture medium; and/or
(2) And adding ixazofamid into the cell culture medium, and incubating.
8. The pharmaceutical composition for treating diabetes is characterized by comprising ixazofamid and a pharmaceutically common injection solvent.
9. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition further comprises bortezomib or insulin.
CN202110460520.0A 2021-04-27 2021-04-27 Application of proteasome inhibitor ixazomide in preparation of medicine for treating diabetes Pending CN115245556A (en)

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