CN114617924B

CN114617924B - Composition for treating type 2 diabetes

Info

Publication number: CN114617924B
Application number: CN202110712931.4A
Authority: CN
Inventors: 胡天宝; 何宗源; 胡薇
Original assignee: Beijing Jingyihesheng Pharmaceutical Technology Co ltd
Current assignee: Beijing Jingyihesheng Pharmaceutical Technology Co ltd
Priority date: 2021-06-25
Filing date: 2021-06-25
Publication date: 2022-12-30
Anticipated expiration: 2041-06-25
Also published as: CN114617924A

Abstract

The invention belongs to the technical field of traditional Chinese medicines, and particularly relates to a composition for treating type 2 diabetes and a preparation method thereof. The composition comprises the following components in parts by weight: 5-10 parts of poria with hostwood, 1-5 parts of rhizoma alismatis, 1-5 parts of cassia twig, 1-10 parts of raw bighead atractylodes rhizome, 0.2-0.8 part of honey-fried licorice root, 1-10 parts of coptis chinensis and 1-5 parts of pericarpium trichosanthis. The preparation method comprises decocting the raw materials in water, filtering to obtain decoction, concentrating, and drying. The composition has simple prescription and definite drug effect, can eliminate insulin resistance, and has obvious effects of reducing blood sugar and improving blood fat metabolism.

Description

Composition for treating type 2 diabetes

Technical Field

The invention belongs to the technical field of traditional Chinese medicines, and particularly relates to a composition for treating type 2 diabetes and a preparation method thereof.

Background

Diabetes is a series of metabolic disorder syndromes of sugar, protein, water, electrolyte and the like caused by hypofunction of pancreatic islets, insulin resistance, beta cell dysfunction and the like due to the action of various factors such as genetic factors, environmental factors, constitutional factors, metabolic factors, immune dysfunction and the like and various pathogenic factors on an organism. Among them, type 1 diabetes is mainly manifested as typical "more than three and one less" symptoms, i.e., polydipsia, polyphagia, diuresis and emaciation; while the type 2 diabetes patients are usually hidden and slow in onset, the symptoms of more than three and one less than three are light, even some patients have no obvious symptoms, and the patients are diagnosed when the blood sugar is higher due to physical examination. Diabetes mellitus, which causes various complications including hypertension, stroke, heart disease, renal failure, peripheral nerve injury, etc., has been a chronic disease that frequently endangers the health of human bodies and accompanies life.

The Western medicine for treating type 2 diabetes mainly comprises biguanide hypoglycemic drugs, alpha-glycosidase inhibitors acarbose and voglibose, insulin sensitizers rosiglitazone and pioglitazone, insulin secretagogue sulfonylureas and glinides and insulin. All the above treatments are maintenance treatments, and the pathology cannot be fundamentally improved. The traditional Chinese medicine adopts holistic concept and treatment based on syndrome differentiation to treat the disease and obtain obvious curative effect, avoids the side effect of chemical drugs on organisms to a certain extent, and is worthy of further discussion and research.

Diabetes belongs to the category of diabetes in traditional Chinese medicine, and the disease name is first seen in emperor's internal classic: the summary of the pyretic disease of the splenic fever … … and the sorghum disease of the experiential people is caused by high nutrition. The expression "two yang nodes, called Xiao", is a high generalization of the understanding of Xiaoke disease from Nei Jing. The two yang sources are the stomach of foot yangming and the large intestine of hand yangming. Stomach and intestine heat accumulation can cause hunger and thirst. The lung heat damaging the body fluid, thirst and polydipsia become the upper half of the body fluid; the stomach-fire is strong and the trough and hunger are eliminated; kidneys do not control water, and frequent urination is descending and dispersing. The principle of diabetes treatment is described in the book "medical consciousness and Sanxiao": for upper warmer, it is advisable to moisten lung and clear stomach; for middle energizer, it is advisable to clear stomach and nourish kidney; for lower energizer, it is advisable to nourish kidney and lung.

The Chinese patent application CN109730692A discloses a five-stage grading monitoring template for type 2 diabetes and a nutrient traditional Chinese medicine composition, wherein the development of diabetes is divided into five stages, namely a first stage: insulin resistance; and a second stage: insulin resistance with hypersecretion of insulin; and a third stage: insulin resistance and insulin hypersecretion aggravate, blood sugar begins to be abnormal, and diabetes mellitus is hidden; a fourth stage: identifiable type 2 diabetes; the fifth stage: type 2 diabetes is associated with low insulin, a high stage of diabetic complications. Different traditional Chinese medicine formulas are adopted at different stages, and although the medicine is more meticulous, the problem of poor compliance is undoubtedly brought.

Chinese patent application CN111000969A discloses a pharmaceutical composition for treating simple obesity and a preparation method thereof, wherein the pharmaceutical composition comprises radix bupleuri, radix paeoniae alba, cassia twig, yongbai, rhizoma atractylodis macrocephalae, fructus aurantii immaturus, cortex magnoliae officinalis, pericarpium citri reticulatae, poria cocos, grifola, rhizoma alismatis, rhizoma coptidis, red yeast rice, hawthorn, endothelium corneum gigeriae galli, radix astragali preparata, semen brassicae preparata, fructus perillae, semen raphani preparata, melon sunflower, radix glycyrrhizae preparata, ginger, chinese dates, radix salviae miltiorrhizae and cortex moutan. The prepared pharmaceutical composition can reduce weight, relieve symptoms, and prevent and treat complications such as diabetes, lipid metabolism disorder and cardiovascular disease. However, the medicine is complex in taste and inconvenient in clinical use, and the blood sugar reducing effect needs to be improved.

Disclosure of Invention

Aiming at the problems in the prior art, the invention provides the composition which has simple prescription and definite drug effect, can eliminate insulin resistance and obviously reduce blood sugar and blood fat and the preparation method thereof.

The purpose of the invention is realized by the following technical scheme:

a composition for treating type 2 diabetes comprises the following components in parts by weight: 5-10 parts of poria with hostwood, 1-5 parts of rhizoma alismatis, 1-5 parts of cassia twig, 1-10 parts of raw bighead atractylodes rhizome, 0.2-0.8 part of honey-fried licorice root, 1-10 parts of coptis chinensis and 1-5 parts of pericarpium trichosanthis.

Preferably, the composition comprises the following components in parts by weight: 5-10 parts of poria with hostwood, 1-5 parts of rhizoma alismatis, 1-5 parts of cassia twig, 1-5 parts of raw bighead atractylodes rhizome, 0.3-0.6 part of honey-fried licorice root, 1-5 parts of coptis chinensis and 1-5 parts of pericarpium trichosanthis.

The efficacy of each medicine in the formula of the invention is as follows:

poria with hostwood: sweet, bland and mild. It enters heart, lung, spleen and kidney meridians. Induce diuresis and drain dampness, invigorate spleen, resolve phlegm, calm heart and induce tranquilization. Fu Shen has the actions of inducing diuresis and excreting dampness, but its property is mild, and inducing diuresis without damaging healthy qi, so it is the essential herb for inducing diuresis and excreting dampness. It is indicated for dysuria and retention of water-dampness, whether it is due to cold-dampness, damp-heat or spleen deficiency with dampness accumulation.

Rhizoma alismatis: sweet and cold in nature. It enters kidney and bladder meridians. Induce diuresis and drain dampness, purge heat. Can be used for treating dysuria, edema, diarrhea, stranguria with turbid urine, leukorrhagia, and phlegm and fluid retention.

Cassia twig: pungent, sweet and warm. Enter heart, lung and bladder meridians. Induce sweating to release exterior, warm and dredge meridians, activate yang to transform qi. Can be used for treating wind-cold exterior syndrome.

White atractylodes rhizome: bitter and sweet in taste and warm in nature. It enters spleen and stomach meridians. Invigorate spleen, replenish qi, dry dampness, induce diuresis, stop sweating, prevent abortion. Can be used for treating spleen deficiency, anorexia, abdominal distention, diarrhea, phlegm retention, dizziness, palpitation, edema, spontaneous perspiration, and threatened abortion. Tu Bai Zhu strengthens spleen, harmonizes stomach and prevents abortion. Can be used for treating spleen deficiency, anorexia, diarrhea, loose stool, and threatened abortion.

Licorice root: is neutral in nature and sweet in taste, enters twelve meridians and is a tonifying Chinese herbal medicine. The raw licorice can clear away heat and toxic materials, moisten lung and relieve cough, and harmonize the property of the medicines; prepared licorice root, radix Glycyrrhizae Praeparata has the effect of tonifying spleen and qi.

Coptis chinensis: clear heat and dry dampness, purge fire and remove toxicity. Can be used for treating damp-heat distention, fullness, emesis, acid regurgitation, dysentery, jaundice, hyperpyrexia, coma, excessive heart-fire, vexation, insomnia, hematemesis, hemorrhage, conjunctival congestion, toothache, diabetes, carbuncle, furuncle, etc.; it is indicated for eczema, eczema and purulent ear canal. Huang Lian (Chinese goldthread) processed with wine is good at clearing heat in upper energizer. It can be used for treating conjunctival congestion and aphtha.

And (3) snakegourd peel: clear lung heat and resolve phlegm, promote qi circulation, relieve chest stuffiness and dissipate nodulation.

Preferably, the composition comprises the following components in parts by weight: 8 parts of poria with hostwood, 1.5 parts of rhizoma alismatis, 3 parts of cassia twig, 4 parts of raw bighead atractylodes rhizome, 0.5 part of honey-fried licorice root, 4 parts of coptis chinensis and 2 parts of pericarpium trichosanthis.

Preferably, the mass ratio of the poria with hostwood, the rhizoma alismatis to the liquorice is 15-18:1-5:1;

preferably, the mass ratio of the poria with hostwood, the rhizoma alismatis and the snakegourd peel is 2-5 to 1:1.

It is a further object of the present invention to provide a process for preparing the above composition, comprising the steps of: decocting Poria, alismatis rhizoma, ramulus Cinnamomi, atractylodis rhizoma, radix Glycyrrhizae Preparata, coptidis rhizoma and pericarpium Trichosanthis in water, filtering to obtain decoction, concentrating, and drying.

Preferably, soaking for 20-40min before decocting; the drying is vacuum drying under reduced pressure.

Preferably, the ratio of the volume of the added water to the total mass of the poria with hostwood, the rhizoma alismatis, the cassia twig, the raw rhizoma atractylodis macrocephalae, the honey-fried licorice root, the coptis chinensis and the trichosanthes bark is 8-12:1mL/g; preferably, the decoction time is 20-40min.

Preferably, the preparation method further comprises adding 0.2-0.5% of complex enzyme into the obtained decoction before concentration, adjusting pH to 5-7, performing enzymolysis at 40-60 deg.C for 1-2 hr, and inactivating enzyme at 100 deg.C.

Preferably, the compound enzyme is a mixture of cellulase, pectinase and bromelain in a mass ratio of 2-4.

The invention also aims to provide application of the composition or the composition prepared by the preparation method in preparing a medicament for treating type 2 diabetes.

Compared with the prior art, the invention has the beneficial effects that:

(1) The poria with hostwood disclosed by the invention is sweet in taste and neutral in nature, and has the effects of tonifying spleen, promoting diuresis and eliminating dampness. It is a monarch drug for relieving the spleen stagnation because the spleen fails to transport and clear yang fails to ascend, which results in lung failing to disperse and descend. Rhizoma alismatis is sweet and light in taste and cold in nature, and can promote diuresis, eliminate dampness, clear heat, dissolve turbidity and reduce blood fat; the bighead atractylodes rhizome is warm in nature, sweet in taste and slightly bitter, the two medicines are combined with the poria with hostwood in nature, and the two medicines are used as ministerial medicines and can help the poria with hostwood to promote diuresis, remove retained fluid and invigorate spleen. Cassia twig, ramulus Cinnamomi is pungent and sweet in flavor and warm in nature, and has the functions of warming yang and inducing diuresis; the liquorice has sweet taste and mild nature, and can tonify spleen and qi, and the cassia twig and the liquorice have the functions of warming yang, promoting diuresis and relieving fluid retention; coptis chinensis and trichosanthes kirilowii Maxim bark can clear away the heat of lung and stomach, and are used for banking up and generating gold; the four medicines are used as adjuvant medicines. The four medicines of the poria with hostwood, the cassia twig, the bighead atractylodes rhizome and the honey-fried licorice root strengthen the effects of warming yang and resolving fluid retention, promoting diuresis and excreting dampness, and can warm and tonify spleen and kidney, thus fundamentally solving the problem of spleen failure in transportation. The whole formula adopts the large method of inducing diuresis and excreting dampness and warming yang to resolve retention of fluid, so as to relieve the spleen dampness and also consider the upper energizer, which is the function of dredging the upper energizer, promoting the body fluid to descend and harmonizing the stomach-qi.

(2) The components supplement each other, wherein the poria with hostwood, the rhizoma alismatis and the liquorice have obvious treatment effect on the type 2 diabetes, and the traditional Chinese medicine composition is suitable for patients with type 2 diabetes and obesity, and is characterized by hypodynamia, thirst without desire for drinking, difficult urination, swollen tongue, thick white and greasy fur and floating and slippery pulse, and is applicable to diabetes mellitus water-dampness internal stagnation.

Drawings

FIG. 1 shows glycated hemoglobin (HbA 1 c) values before and after inclusion in a patient;

figure 2 shows plasma total cholesterol and total triglyceride values before and after inclusion in a patient.

Detailed Description

Example 1

A composition for treating type 2 diabetes comprises the following components in parts by weight: 5 parts of poria with hostwood, 1 part of rhizoma alismatis, 1 part of cassia twig, 2 parts of raw bighead atractylodes rhizome, 0.3 part of honey-fried licorice root, 1 part of coptis chinensis and 1 part of trichosanthes bark.

The preparation method comprises the following steps:

soaking Poria, alismatis rhizoma, ramulus Cinnamomi, atractylodis rhizoma, radix Glycyrrhizae Preparata, coptidis rhizoma and pericarpium Trichosanthis in 10 times of water for 20min, decocting for 40min, filtering to obtain decoction, concentrating, and vacuum drying under reduced pressure.

Example 2

A composition for treating type 2 diabetes comprises the following components in parts by weight: 10 parts of poria with hostwood, 3 parts of rhizoma alismatis, 5 parts of cassia twig, 8 parts of raw bighead atractylodes rhizome, 0.6 part of honey-fried licorice root, 8 parts of coptis chinensis and 4 parts of pericarpium trichosanthis.

The preparation method comprises the following steps:

soaking Poria, alismatis rhizoma, ramulus Cinnamomi, atractylodis rhizoma, radix Glycyrrhizae Preparata, coptidis rhizoma and pericarpium Trichosanthis in 8 times of water for 40min, decocting for 20min, filtering to obtain decoction, concentrating, and vacuum drying under reduced pressure.

Example 3

A composition for treating type 2 diabetes comprises the following components in parts by weight: 8 parts of poria with hostwood, 1.5 parts of rhizoma alismatis, 3 parts of cassia twig, 4 parts of raw bighead atractylodes rhizome, 0.5 part of honey-fried licorice root, 4 parts of coptis chinensis and 2 parts of pericarpium trichosanthis.

The preparation method comprises the following steps:

soaking Poria, alismatis rhizoma, ramulus Cinnamomi, atractylodis rhizoma, radix Glycyrrhizae Preparata, coptidis rhizoma and pericarpium Trichosanthis in 12 times of water for 30min, decocting for 30min, filtering to obtain decoction, concentrating, and vacuum drying under reduced pressure.

Example 4

The preparation method comprises the following steps:

soaking Poria, alismatis rhizoma, ramulus Cinnamomi, atractylodis rhizoma, radix Glycyrrhizae Preparata, coptidis rhizoma and pericarpium Trichosanthis in 10 times of water for 30min, decocting for 30min, filtering to obtain decoction, adding 0.3% complex enzyme into the decoction, adjusting pH to 6, performing enzymolysis at 50 deg.C for 1.5h, inactivating enzyme at 100 deg.C, concentrating, and vacuum drying under reduced pressure. Wherein the compound enzyme is a mixture of cellulase, pectinase and bromelain in a mass ratio of 3.5.

Comparative example 1

The difference between this comparative example and example 3 is that cassia twig was removed, and the number of parts of snakegourd peel was adjusted to 5 parts, and the rest was the same as example 3.

Comparative example 2

The difference between this comparative example and example 3 is that the peel of snakegourd fruit was removed, the number of parts of cassia twig was adjusted to 5 parts, and the rest was the same as example 3.

Comparative example 3

The difference between the comparative example and the example 3 is that the mixture ratio of the poria with hostwood, the alisma orientale and the liquorice is different, and the rest is consistent with the example 3. The specific method comprises the following steps:

a composition for treating type 2 diabetes comprises the following components in parts by weight: 6 parts of poria with hostwood, 3 parts of rhizoma alismatis, 3 parts of cassia twig, 4 parts of raw bighead atractylodes rhizome, 1 part of honey-fried licorice root, 4 parts of coptis chinensis and 2 parts of pericarpium trichosanthis.

The preparation method comprises the following steps:

Comparative example 4

The difference between this comparative example and example 3 is that the trichosanthes bark was adjusted to be scutellaria, and the rest was the same as example 3. The specific method comprises the following steps:

a composition for treating type 2 diabetes comprises the following components in parts by weight: 8 parts of poria with hostwood, 1.5 parts of rhizoma alismatis, 3 parts of cassia twig, 4 parts of raw bighead atractylodes rhizome, 0.5 part of honey-fried licorice root, 4 parts of coptis chinensis and 2 parts of scutellaria baicalensis.

The preparation method comprises the following steps:

soaking Poria, alismatis rhizoma, ramulus Cinnamomi, atractylodis rhizoma, radix Glycyrrhizae Preparata, coptidis rhizoma and Scutellariae radix in 12 times of water for 30min, decocting for 30min, filtering to obtain decoction, concentrating, and vacuum drying under reduced pressure.

Comparative example 5

The difference between the comparative example and the example 4 is that the used compound enzyme is a mixture of cellulase, pectinase and papain with the mass ratio of 2.

Test example 1 animal pharmacodynamic test

1.1 purpose of experiment: the composition has blood sugar lowering effect on type 2 diabetes model rats.

1.2 Experimental animals and groups: male SD rats, weighing 200 ± 20g, were 12 groups, blank group, model group, positive group, example 1 to example 4 group, comparative 1 to 5 group, 10 animals each.

1.3 establishment of model rat

Except for free diet of blank group, feeding rats of other groups with high-sugar high-fat feed (10% sucrose, 2% cholesterol, 10% lard, 10% egg yolk powder and 68% basal feed), injecting 30mg/kg of STZ solution into abdominal cavity of rat after 4 weeks, collecting blood from tail vein after normal feeding for 72h, measuring blood sugar, wherein the blood sugar value is higher than 11mmmol/L, and modeling is successful.

1.4 test methods

And (5) performing intragastric administration. The concentrated solution (30 g/kg based on crude drug amount) prepared by the groups of examples 1-4 and comparative examples 1-5 is administered to the corresponding group, and the concentrated solution with the corresponding dosage is continuously concentrated to 4mL before the administration by gastric lavage; the model group and the blank group are given distilled water with the same volume, the positive control group is given metformin hydrochloride tablet suspension of 150mg/kg and the administration volume of 2mL/100g, and the administration is carried out once a day for 3 weeks by continuous intragastric administration. After the last administration for 12h, pentobarbital sodium is injected into the abdominal cavity to anaesthetize the rat, and the eyeball blood collection is carried out to measure the fasting blood glucose value and the insulin level before and after the administration; insulin sensitivity index = -ln (blood glucose value x insulin level); and triglyceride and cholesterol levels were determined.

(2) Analysis of results

SPSS13.0 statistical software is adopted for data processing, variance analysis and t test are adopted for comparison among groups, and P <0.05 is a difference with statistical significance. The results are shown in Table 1.

TABLE 1 blood sugar, insulin sensitivity index and blood lipid levels of each group

Note: different letters in the same column represent a statistical difference between the corresponding groups, P < 0.05.

Test example 2 clinical test

According to the guideline of clinical research on new drugs in Chinese medicine, 37 type 2 diabetes patients were included for clinical observation, wherein 15 male patients accounted for 41%, 22 female patients accounted for 59%, and the sex differences were not statistically significant (P > 0.05). Patients with the greatest age were 75 years, the smallest 43 years, and the mean age was 61.8 ± 8.5 years (mean ± standard deviation).

37 patients took the concentrate prepared in example 3, one dose per day, which was 240g in terms of crude drug amount. The administration is continued for 3 months.

18 of the 37 patients had a cut point with a glycated hemoglobin (HbA 1 c) ratio of less than 6.5% after the treatment, with a standard reaching rate of 49%; after 34 patients are treated, the HbA1c ratio is reduced compared with that before treatment, and the obvious effective rate is 92%;3 patients were not effective. The results are shown in Table 2.

TABLE 2 Overall therapeutic Effect

Statistically, the HbA1c of the patients before treatment (0 month) is 7.7 + -1.7 (mean + -standard deviation), the HbA1c of the patients after treatment (3 months) is significantly reduced to 6.7 + -1.1, the difference is statistically significant, and the results are shown in FIG. 1, n =37, ^**** P<0.0001。

in addition to the significant reduction in the main therapeutic index HbA1c, the blood lipid index of the patient was significantly reduced after treatment. As shown in fig. 2, the total cholesterol of the patients before treatment (month 0) was 5.11 ± 2.13mmol/L (mean ± sd), and after treatment (month 3) it dropped to 4.57 ± 2.13mmol/L, with statistical differences (fig. 2, n =37, ^* P<0.05 ); the total triglycerides was 1.98 ± 1.05mmol/L, significantly decreased to 1.27 ± 0.72mmol/L, the difference was statistically significant (fig. 2, n =37, ^*** P<0.001)。

the above detailed description is specific to one possible embodiment of the present invention, and the embodiment is not intended to limit the scope of the present invention, and all equivalent implementations or modifications without departing from the scope of the present invention should be included in the technical scope of the present invention.

Claims

1. The composition for treating type 2 diabetes is characterized by comprising the following components in parts by weight: 5-10 parts of poria with hostwood, 1-5 parts of rhizoma alismatis, 1-5 parts of cassia twig, 1-10 parts of raw bighead atractylodes rhizome, 0.2-0.8 part of honey-fried licorice root, 1-10 parts of coptis chinensis and 1-5 parts of pericarpium trichosanthis; the mass ratio of the poria with hostwood, the rhizoma alismatis and the radix glycyrrhizae preparata is 15-18:1-5:1; the mass ratio of the poria with hostwood, the rhizoma alismatis and the trichosanthes bark is 2-5 to 1:1.

2. The composition according to claim 1, wherein the composition consists of the following components in parts by weight: 5-10 parts of poria with hostwood, 1-5 parts of rhizoma alismatis, 1-5 parts of cassia twig, 1-5 parts of raw bighead atractylodes rhizome, 0.3-0.6 part of honey-fried licorice root, 1-5 parts of coptis chinensis and 1-5 parts of pericarpium trichosanthis.

3. The composition according to claim 1, wherein the composition consists of the following components in parts by weight: 8 parts of poria with hostwood, 1.5 parts of rhizoma alismatis, 3 parts of cassia twig, 4 parts of raw bighead atractylodes rhizome, 0.5 part of honey-fried licorice root, 4 parts of coptis chinensis and 2 parts of pericarpium trichosanthis.

4. A method of preparing a composition according to any one of claims 1 to 3, comprising the steps of: decocting Poria, alismatis rhizoma, ramulus Cinnamomi, atractylodis rhizoma, radix Glycyrrhizae Preparata, coptidis rhizoma and pericarpium Trichosanthis in water, filtering to obtain decoction, and concentrating, or concentrating and drying to obtain oral preparation.

5. The method for preparing according to claim 4, wherein the oral preparation is a granule.

6. The preparation method according to claim 4, wherein the soaking is performed for 20-40min before the decoction; the drying is vacuum drying under reduced pressure.

7. The preparation method of claim 4, wherein the ratio of the volume of the added water to the total mass of the poria with hostwood, the rhizoma alismatis, the cassia twig, the raw rhizoma atractylodis macrocephalae, the honey-fried licorice root, the coptis chinensis and the trichosanthes bark is 8-12:1mL/g.

8. The preparation method according to claim 4, wherein the decoction time is 20-40min.

9. The preparation method according to claim 4, further comprising adding 0.2-0.5% of complex enzyme into the obtained decoction before concentration, adjusting pH to 5-7, performing enzymolysis at 40-60 deg.C for 1-2h, and inactivating enzyme at 100 deg.C.

10. The preparation method according to claim 9, wherein the complex enzyme is a mixture of cellulase, pectinase and bromelain in a mass ratio of 2-4.

11. Use of a composition according to any one of claims 1 to 3 or a composition prepared by a process according to any one of claims 4 to 10 in the manufacture of a medicament for the treatment of type 2 diabetes.