KR102445638B1 - Composition for preventing or treating diabetes comprising 11 alpha hydroxyprogesterone - Google Patents

Abstract

The present invention relates to a composition comprising 11 alpha hydroxyprogesterone and its use for preventing or treating diabetes, and preferably to a use for preventing, improving or treating type 2 diabetes or insulin resistance.

Description

A composition for preventing or treating diabetes comprising 11 alpha hydroxyprogesterone {Composition for preventing or treating diabetes comprising 11 alpha hydroxyprogesterone}

The present invention relates to a composition comprising 11 alpha hydroxyprogesterone, which is excellent in preventing or treating type 2 diabetes, as an active ingredient.

Type 2 diabetes mellitus (T2D) is occurring worldwide and its prevalence is expected to increase over several decades (Wild et al., 2004). The prevalence of type 2 diabetes is increasing particularly in Asia, and its etiology is lifestyle-dependent, which is attributed to sedentary lifestyle and diet leading to obesity (Zheng et al., 2018). Type 2 diabetes patients initially show insulin resistance in muscle, and then in fat and liver (Fernandez et al., 2001). Although insulin-mediated glucose transporter 4 (GLUT4) translocation promotes glucose utilization in muscle in general, the mechanism of type 2 diabetes is not triggered by muscle-specific knockout of the insulin receptor (IR), resulting in cellular suggesting that intracellular signaling is important for glycemic control (Bruning et al., 1998; Zisman et al., 2000).

Progesterone receptor membrane component 1 (Pgrmc1) is a novel progesterone-coupled receptor on the cell surface that, unlike typical progesterone receptors, has no direct gene-regulated transcriptional effects (Kasubuchi et al., 2017). In previous studies, PGRMC1 is known to contribute to cholesterol synthesis (Hughes et al., 2007; Rohe et al., 2009) and to bind to INSIG-1, a key regulator of cholesterol homeostasis (Suchanek et al., 2005). In addition, PGRMC1 was identified as a functional component of the glucagon-like peptide-1 receptor (GLP-1R) involved in circulating AMP (cAMP) accumulation in pancreatic β cells (Zhang et al., 2014). A recent study observed that Pgrmc1 inhibited fatty liver induced by a high-fat diet (Lee et al., 2018). Although the endocrine relevance of Pgrmc1 is emerging, challenges remain as to whether Pgrmc1 is associated with type 2 diabetes.

A previous study confirmed the protein interaction between PGRMC1 and insulin receptor beta (IRβ), and it was confirmed through cell lines that Pgrmc1 downregulation reduced glucose uptake without insulin treatment. However, levels of phosphorylated AKT, a central regulator of IRβ-GLUT4 signaling, were significantly increased (Hampton et al., 2018). Since plasma membrane IRβ and phosphorylated-AKT levels show contradictory results in Pgrmc1 regulation, we predicted that Pgrmc1 is involved in intracellular signaling that activates AKT phosphorylation. The present invention proceeds with a series of experiments concluding that Pgrmc1 in muscle inhibits glucose processing in muscle by inhibiting phosphorylated-AKT and membrane GLUT4 levels. Using 11α-hydroxyprogesterone, an endogenous hormone regulating PGRMC1 levels, we explored the role of PGRMC1 in type 2 diabetes and its potential for use in novel therapeutic approaches.

Korean Patent Publication No. 2005-008805 International Patent Publication No. 2002-072084

The present invention has been derived from the above needs, and the present inventors have completed the present invention by confirming the effect of a composition containing 11 alpha hydroxyprogesterone for preventing or improving diabetes, in particular, improving type 2 diabetes or insulin resistance.

In order to solve the above problems, the present invention relates to a pharmaceutical composition for preventing or treating diabetes or its complications comprising 11 alpha hydroxyprogesterone as an active ingredient.

In one embodiment of the present invention, diabetes is characterized in that it is type 2 diabetes.

In one embodiment of the present invention, 11 alpha hydroxyprogesterone is characterized in that it induces inhibition of PGRMC1, activation of Akt phosphorylation pathway, or increased expression of GLUT4.

In another embodiment of the present invention, the complication is diabetic heart disease, diabetic nephropathy, diabetic vascular disorder or diabetic neuropathy.

In addition, the present invention relates to a food composition for preventing or improving diabetes or its complications, comprising 11 alpha hydroxyprogesterone as an active ingredient.

In another embodiment of the present invention, the present invention relates to a pharmaceutical composition for preventing or treating insulin resistance comprising 11 alpha hydroxyprogesterone as an active ingredient.

In another example of the present invention, it relates to a food for preventing or improving insulin resistance, comprising 11 alpha hydroxyprogesterone as an active ingredient.

Since the composition comprising 11 alpha hydroxyprogesterone of the present invention has effects on sugar metabolism, PGRMC1, and phosphorylated Akt, it can be usefully used for preventing or treating diabetes.

1 shows the effect on the expression of PGRMC1 or phosphorylated Akt in the muscles of 11 alpha hydroxyprogesterone-treated mice according to an embodiment of the present invention.
Figure 2 shows the effect on the expression of membrane GLTU4 in the muscles of mice treated with 11 alpha hydroxyprogesterone according to an embodiment of the present invention.
3 shows the effect on glucose tolerance (A) or insulin resistance (B) in 11 alpha hydroxyprogesterone-treated mice according to an embodiment of the present invention.
4 shows the effect on the expression of phosphorylated Akt in the muscles of 11 alpha hydroxyprogesterone-treated Pgrmc1 KO mice according to an embodiment of the present invention.
5 shows the effect on the expression of membrane GLTU4 in the muscles of 11 alpha hydroxyprogesterone-treated Pgrmc1 KO mice according to an embodiment of the present invention.
6 shows the effect on glucose tolerance (A) or insulin resistance (B) in 11 alpha hydroxyprogesterone-treated Pgrmc1 KO mice according to an embodiment of the present invention.
7 shows the effect on the expression of PGRMC1 or phosphorylated Akt in the muscles of 11 alpha hydroxyprogesterone-treated high-fat diet (T2D) mice according to an embodiment of the present invention.
8 shows the effect on the expression of membrane GLTU4 in the muscles of 11 alpha hydroxyprogesterone-treated high-fat diet (T2D) mice according to an embodiment of the present invention.
9 shows the effect on glucose tolerance (A) or insulin resistance (B) in 11 alpha hydroxyprogesterone-treated high-fat diet (T2D) mice according to an embodiment of the present invention.
10 shows the effect on the expression of PGRMC1 or phosphorylated Akt in insulin-treated A204 muscle cells treated with 11 alpha hydroxyprogesterone according to an embodiment of the present invention.
11 shows the effect on the expression of membrane GLTU4 in insulin-treated A204 muscle cells treated with 11 alpha hydroxyprogesterone according to an embodiment of the present invention.
Figure 12 shows the effect on the extracellular acidification rate (ECAR, extracellular acidification rate) in 11 alpha hydroxyprogesterone-treated insulin-treated A204 muscle cells according to an embodiment of the present invention.

Hereinafter, preferred embodiments of the present invention will be described in detail. In addition, many specific details such as specific components are shown in the following description, which are provided to help a more general understanding of the present invention, and it is common in the art that the present invention can be practiced without these specific details. It will be self-evident to those who have the knowledge of And, in describing the present invention, if it is determined that a detailed description of a related known function or configuration may unnecessarily obscure the gist of the present invention, the detailed description thereof will be omitted.

As used herein, the term "prevention" or "prevention" means inhibiting or delaying the occurrence of a disease from the cause.

As used herein, the term "treatment" means to stop the progression of damage by inhibiting the progress and/or aggravation of symptoms even without complete cure, or to ameliorate some or all of the symptoms to guide them in the direction of healing.

In the present invention, the term “improvement” refers to any action in which symptoms are improved or beneficially changed.

In order to achieve the object of the present invention, the present invention provides a pharmaceutical composition for preventing or treating diabetes or its complications comprising 11 alpha hydroxyprogesterone as an active ingredient.

In the present invention, 11 alpha hydroxyprogesterone (11α-OHP) is an endogenous steroid that is 11α-hydroxyprogn-4-ene-3,20-dione and is a metabolite of progesterone. It is a weak antiandrogen and lacks androgen, estrogenic and progesterone activity. Local anti-androgen effects were discovered in the early 1950s in the treatment of androgen-dependent skin conditions, with some useful effects. 11 alpha hydroxyprogesterone is an epimer of 11β-hydroxyprogesterone and acts as a competitive inhibitor of isoforms 1 and 2 of 11β-hydroxysteroid dehydrogenase.

The diabetes relates to type 1 diabetes or type 2 diabetes, preferably type 2 diabetes, but is not limited thereto.

The complication relates to all complications caused by diabetes, and preferably relates to diabetic heart disease, diabetic nephropathy, diabetic vascular disorder or diabetic neuropathy, but is not limited thereto.

In another embodiment of the present invention, the present invention relates to a pharmaceutical composition for preventing or treating insulin resistance comprising 11 alpha hydroxyprogesterone as an active ingredient.

In one embodiment of the present invention, 11 alpha hydroxyprogesterone is characterized in that it induces inhibition of PGRMC1, activation of Akt phosphorylation pathway, or increased expression of GLUT4.

In addition, in the composition according to one embodiment of the present invention, the composition may include an additional component useful for diabetes, and the additional component may include any component known to have an effect on diabetes, including compounds and natural products.

The composition of the present invention may be prepared in any form of composition, including an appropriate carrier, excipient and diluent commonly used in the preparation of the composition, preferably in the form of a pharmaceutical composition, a health functional food composition or a cosmetic composition may be, but is not limited thereto.

The pharmaceutical composition of the present invention may be formulated in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories, and sterile injection solutions according to conventional methods, and powders , tablets, capsules, injections and liquids are more preferred. Such formulation may be performed by a method conventionally performed in the pharmaceutical field, and may be preferably formulated according to each disease or component using the method disclosed in Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA.

Carriers, excipients and diluents that may be included in the pharmaceutical composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose , methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil.

In the case of formulation, it may be prepared by additionally using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants.

Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and these solid preparations include at least one excipient, for example, starch, calcium carbonate, sucrose or lactose ( lactose), gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used.

Liquid formulations for oral administration include suspensions, solutions, emulsions, syrups, etc., and various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to water and liquid paraffin, which are commonly used simple diluents, may be included. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. As the non-aqueous agent and suspending agent, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used. As a base of the suppository, witepsol, macrogol, tween, cacao butter, laurin, glycerogelatin, and the like may be used.

The preferred dosage of the pharmaceutical composition of the present invention varies depending on the condition and weight of the patient, the severity of the disease, the drug form, the route and duration of administration, but may be appropriately selected by those skilled in the art. However, for a desirable effect, the pharmaceutical composition of the present invention may be included in an amount of 0.01 to 99.9% by weight, preferably 0.1 to 99% by weight per day. The daily dose may be about 0.1 to 1,000 mg/kg, preferably 100 to 300 mg/kg.

In addition, the present invention relates to a food composition for preventing or improving diabetes or its complications, comprising 11 alpha hydroxyprogesterone as an active ingredient.

In another example of the present invention, it relates to a food for preventing or improving insulin resistance, comprising 11 alpha hydroxyprogesterone as an active ingredient.

Health functional foods to which the composition can be added include, for example, various general foods, beverages, gum, tea, vitamin complexes, and the like.

In addition, the composition may be added to food or beverage for the purpose of preventing disease. At this time, the amount of the extract in the food or beverage may be added in 0.01 to 15% by weight of the total food weight, and the health beverage composition may be added in a ratio of 0.02 to 5 g, preferably 0.3 to 1 g based on 100 g. have.

The health functional beverage composition of the present invention is not particularly limited in other ingredients other than containing the extract as an essential ingredient in the indicated ratio, and may contain additional ingredients such as various flavoring agents or natural carbohydrates like a conventional beverage. have. Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose, and the like; disaccharides such as maltose, sucrose and the like; and polysaccharides such as conventional sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those mentioned above, natural flavoring agents such as taumatin, stevia extract, such as rebaudioside A, glycyrrhizine, and the like; and synthetic flavoring agents such as saccharin, aspartame and the like may be advantageously used. The proportion of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 g of the composition of the present invention. In addition to the above, the extract of the present invention contains various nutrients, vitamins, minerals (electrolytes), synthetic and natural flavors, colorants and thickeners (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective properties colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like. In addition, the extracts of the present invention may contain pulp for the production of natural fruit juice, fruit juice beverage and vegetable beverage. These components may be used independently or in combination. At this time, although the proportion of the additive is not very important, it is generally selected in the range of 0.01 to about 20 parts by weight per 100 parts by weight of the composition of the present invention.

Advantages and features of the present invention, and methods for achieving them, will become apparent with reference to the embodiments described below in detail. However, the present invention is not limited to the embodiments disclosed below, but will be implemented in a variety of different forms, and only these embodiments allow the disclosure of the present invention to be complete, and common knowledge in the technical field to which the present invention belongs It is provided to fully inform the possessor of the scope of the invention, and the present invention is only defined by the scope of the claims.

<Example>

1. Animals

C57BL/6J mice were bred in an aseptic facility at Chungnam National University by supplying a standard feed or a high-fat diet along with water unlimitedly while changing the light and shade every 12 hours. All mouse experiments were approved and performed in accordance with the Chungnam National University Facility Animal Management Committee (CNU-01145). As reported in a previous study (Lee et al., 2018), Pgrmc1 KO mice and wild-type inbred mice were used. Diabetes was induced by administration of streptozotocin (30 mg/kg) or a high-fat diet for 8 weeks (Skovso, 2014). A high fat diet (#D12492, Research Diets, In., New Brunswick, NJ, USA) consists of carbohydrates (20% kcal), protein (20% kcal) and fat (60% kcal).

2. Compounds

Insulin (I0908, Sigma), glucose (LS001-02, Welgene), glucose (G8270, Sigma), and 11α-hydroxyprogesterone (sc-287291, Santa Cruz) were used.

3. Assessing blood glucose levels and resistance

Blood glucose levels were measured by cutting off the tail with an Accu-Chek Active (Roche, 07124112) kit after fasting for a certain period of time. Mice were restrained from developing sympathetic disturbances to glucose levels before tail cutting. Glucose (2g/kg) and insulin (0.75U/kg) were intraperitoneally injected for tolerability testing.

4. Western Blotting

Protein samples were obtained by sequential procedures including tissue and cell mycosis, centrifugation and sonication. The concentration of the protein sample was measured with PRO-Measure solution (Intron, #21011), and the same amount of protein was loaded and separated by SDS-PAGE. The gel was blotted onto the membrane, and the membrane was blocked and then reacted with the primary antibody. The next day, the membrane was reacted with a secondary antibody. Results were detected with ECL solution (XLS025-0000, Cyanagen) and Chemi Doc (Fusion Solo, Vilber Lourmat).

As primary antibodies, β-ACTIN (Santa Cruz, sc-130656), PGRMC1 (CST, #13856), pAKT (CST, #4060) and GLUT4 (Santa Cruz, sc-53566) were used.

As the secondary antibody, Goat anti-rabbit IgG (BS-0295G-HRP) was used.

5. Cell Culture

All cell culture reagents were purchased from Welgene (Gyungsan, Korea). A204 human rhabdomyosarcoma cells were cultured at 37°C in an atmosphere of 5% CO2 using McCoy's culture medium (Welgene, LM005-01) supplemented with 5% FBS, penicillin (100 U/mol) and streptomycin (100 μg/ml). did. Cells were cultured in McCoy's medium without serum for 5 hours to remove insulin. Insulin (100 nM) was administered for 30 minutes.

6. Membrane Protein Isolation

Samples were lysed in a buffer containing sucrose (0.25M), Tris-HCl (20mM), and EDTA (pH 7.5, 1 mM). The supernatant was obtained by centrifugation (1,000 g, 10 min) and centrifuged again at 14,000 g for 20 minutes. The pellet was lysed with T-PER buffer and sonicated (Du et al., 2017).

6. Glycolytic Stress Test

A204 cells were infected and isolated from seahorse cell culture plates. Cells were cultured for 5 hours in McCoy's medium (glucose 4500 mg/L) without serum to remove endogenous hormones, and incubated for 1 hour in McCoy's medium (glucose 500 mg/L) without serum. It was decarboxylated in XFp medium (103575-100, Agilent technologies) containing equal amounts of glutamine, sodium pyruvate and glucose for 40 min to 1 hour, and cells were cultured. For the glycolytic stress test, glucose (25 mM) and oligomycin (2 μM) were used, and the extracellular acidification rate (ECAR) was measured. . Seahorse XFp analyzer (Agilent technologies) and Seahorse XFp, XFp FluxPak (103022-100, Agilent technologies) were used.

7. Statistical Analysis

Results are expressed as mean±standard deviation. Mean differences were obtained by Student's t-test, and one-way ANOVA followed by Dunnett's post-Dunnett analysis was performed with Graph Pad Software (GraphPad Inc., San Diego, CA).

<Test Example>

1. Mice treated with 11α-hydroxyprogesterone (11α-OHP) showed higher sensitivity to glucose clearance and insulin reactivity.

Mice were treated subcutaneously with 11α-OHP (3 mg/mouse) and fasted for 5 h prior to necropsy. Western blotting analysis confirmed a decrease in the expression of PGRMC1 in the muscles of 11α-OHP-treated mice (p<0.05, 41.2% vs. vehicle-treated mice (CON)) (Fig. 1). The expression of phosphorylated AKT was significantly increased in the muscles of 11α-OHP-treated mice (p<0.05, 1.45-fold vs. CON) ( FIG. 1 ).

As phosphorylation of AKT was triggered by insulin, the expression of membrane GLUT4 in the muscles of 11α-OHP-treated mice was also increased (p<0.05, 1.84-fold vs. CON) ( FIG. 2 ).

As glucose transport increased, 11α-OHP treated mice were observed to be resistant to hyperglycemia. In the glucose tolerance test, it was confirmed that the blood glucose level decreased after 0, 15, 30, 45, and 60 minutes after glucose injection in 11α-OHP-treated mice (p<0.05, 91.4, 87.8, 86.3, 82.7, and 84.4%, respectively, vs. CON) (Fig. 3A). Also, the insulin response was more sensitively increased in 11α-OHP-treated mice. In the insulin resistance test, it was confirmed that the blood glucose level decreased 15, 30, 45, 60, and 90 minutes after insulin injection in 11α-OHP-treated mice (p<0.05, 69.9, 54.8, 43.6, 38.2, and 49.2%, respectively, vs. CON) (Fig. 3B).

2. The hypoglycemic effect of 11α-OHP was mediated by Pgrmc1.

As it is predicted that 11α-OHP potentiates insulin action through Pgrmc1 inhibition, Pgrmc1 KO mice were introduced to identify the mechanistic target of 11α-OHP, and Pgrmc1 KO mice were treated with 11α-OHP (3 mg/mouse) subcutaneously. treatment and maintained fasting for 5 h prior to necropsy. Western blotting analysis confirmed that the expression of PGRMC1 was not detected. The expression of phosphorylated AKT was similar between control solvent-treated mice and 11α-OHP-treated Pgrmc1 KO mice ( FIG. 4 ). In addition, the expression of membrane GLUT4 was similar between control solvent-treated mice and 11α-OHP-treated Pgrmc1 KO mice. Consistently, blood glucose levels were similar between control solvent-treated mice and 11α-OHP-treated Pgrmc1 KO mice during glucose tolerance and insulin tolerance tests. These results are important because 11α-OHP did not show any effect on the molecular target of insulin and blood glucose levels in Pgrmc1 loss.

3. 11α-OHP improved glucose intolerance and insulin resistance in type 2 diabetes mellitus.

To induce type 2 diabetes, rats were fed a high-fat diet for 8 weeks and streptozotocin was administered to the rats (30 mg/kg) at 6 weeks. During type 2 diabetes induction, mice were exposed subcutaneously to 11α-OHP (3 mg/mouse x 15 times, total 45 mg/mouse). As a result, the expression of PGRMC1 was reduced in the muscles of 11α-OHP-treated mice (p<0.05, 68.1% vs. CON) ( FIG. 7 ). The expression of phosphorylated AKT was increased in the muscles of 11α-OHP-treated mice (p<0.05, 1.63-fold vs. CON) ( FIG. 7 ). In addition, an increase in membrane GLUT4 expression was observed in the muscles of 11α-OHP-treated mice (p<0.05, 1.82-fold vs. CON) ( FIG. 8 ). In addition, blood glucose levels were decreased in 11α-OHP-treated mice after 45, 60, and 90 minutes of glucose infusion (p<0.05, 87, 71.9, and 73%, respectively, vs. CON) ( FIG. 9 ). After 15 and 30 minutes of insulin injection in 11α-OHP-treated mice, blood glucose levels decreased (p<0.05, 86.2, and 73.2%, respectively, vs. CON) ( FIG. 9 ).

4. 11α-OHP increased membrane GLUT4 translocation and glycolysis in A204 myocytes.

To exclude intrinsic interference, an in vitro test was introduced and the effect of muscle-specific 11α-OHP was investigated. A204 cells, a rhabdomyosarcoma cell line, were treated with 11α-OHP for 24 hours and then incubated without serum for 5 hours to remove endogenous hormones and then treated with insulin (100 nM) for 30 minutes. Among the two 11α-OHP treatment concentrations (50 nM and 100 nM), a decrease in the expression of PGRMC1 was observed at 100 nM ((p<0.05, 78.2% vs. 0 nM of 11α-OHP treated cell (CON)) ( FIG. 10 ). The expression of phosphorylated AKT was observed to increase at 50 and 100 nM in 11α-OHP-treated cells (p<0.05, 1.32- and 1.71-fold vs. CON) ( FIG. 10 ). Increased membrane GLUT4 expression (p<0.05, 1.96-fold vs. CON) (FIG. 11).Extracellular acidification rate (ECAR) after glucose exposure in 11α-OHP-treated cells, as analyzed by real-time cell metabolites. , extracellular acidification rate) was increased (p<0.05, 1.72-fold vs. CON) (Fig. 11). These results indicate that 11α-OHP regulates glucose metabolism in muscle cells regardless of endocrine interference. will be.

Reference

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Du, K., Murakami, S., Sun, Y., Kilpatrick, CL, and Luscher, B. (2017). DHHC7 Palmitoylates Glucose Transporter 4 (Glut4) and Regulates Glut4 Membrane Translocation. J Biol Chem 292 , 2979-2991.

Fernandez, AM, Kim, JK, Yakar, S., Dupont, J., Hernandez-Sanchez, C., Castle, AL, Filmore, J., Shulman, GI, and Le Roith, D. (2001). Functional inactivation of the IGF-I and insulin receptors in skeletal muscle causes type 2 diabetes. Genes & development 15 , 1926-1934.

Hampton, K. K., Anderson, K., Frazier, H., Thibault, O., and Craven, R. J. (2018). Insulin Receptor Plasma Membrane Levels Increased by the Progesterone Receptor Membrane Component 1. Mol Pharmacol 94 , 665-673.

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Claims (12)

A pharmaceutical composition for preventing or treating type 2 diabetes mellitus or its complications comprising 11 alpha hydroxyprogesterone as an active ingredient delete [Claim 2] The pharmaceutical composition for preventing or treating type 2 diabetes mellitus or its complications according to claim 1, wherein 11 alpha hydroxyprogesterone inhibits PGRMC1, activates Akt phosphorylation pathway, or induces increased expression of GLUT4. The pharmaceutical composition for preventing or treating type 2 diabetes or its complications according to claim 1, wherein the complication is diabetic heart disease, diabetic nephropathy, diabetic vascular disorder or diabetic neuropathy. Food composition for preventing or improving type 2 diabetes or its complications comprising 11 alpha hydroxyprogesterone as an active ingredient delete [Claim 6] The food composition for preventing or improving type 2 diabetes mellitus or its complications according to claim 5, wherein 11 alpha hydroxyprogesterone inhibits PGRMC1, activates Akt phosphorylation pathway, or induces an increase in GLUT4 expression. The food composition for preventing or improving type 2 diabetes or its complications according to claim 5, wherein the complication is diabetic heart disease, diabetic nephropathy, diabetic vascular disorder or diabetic neuropathy. Pharmaceutical composition for preventing or treating insulin resistance comprising 11 alpha hydroxyprogesterone as an active ingredient The pharmaceutical composition for preventing or treating insulin resistance according to claim 9, wherein 11 alpha hydroxyprogesterone inhibits PGRMC1, activates Akt phosphorylation pathway, or induces increase in GLUT4 expression. Food composition for preventing or improving insulin resistance comprising 11 alpha hydroxyprogesterone as an active ingredient The food composition for preventing or improving insulin resistance according to claim 11, wherein 11 alpha hydroxyprogesterone inhibits PGRMC1, activates Akt phosphorylation pathway, or induces increased expression of GLUT4.

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