JP2007099764A - Hypoglycaemic agent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new therapeutic method improving insulin resistance and fatty liver of a type 2 diabetic patient and preventing advance to metabolic syndrome such as arteriosclerosis. <P>SOLUTION: The sufficient hypoglycemic effect is obtained by simultaneous administration of an angiotensin II receptor antagonist and an islet-activating agent, especially, olmesartan or telmisartan and nateglinide. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

The present invention relates to a hypoglycemic agent and an insulin resistance therapeutic / preventive agent comprising a combination of an insulin secretagogue and an angiotensin II receptor antagonist.
The present invention also includes an insulin secretion promoter known as a hypoglycemic agent as an active ingredient, which is administered simultaneously with an angiotensin II receptor antagonist or an angiotensin II receptor antagonist at the same time. It is related with the pharmaceutical composition characterized by including.

In recent years, obesity has been shown to be a major risk factor for arteriosclerotic diseases, particularly coronary artery disease. That is, in obese individuals, various factors such as fatty acids and TNF-α are released from the accumulated visceral fat, which causes insulin resistance in skeletal muscle, liver and adipose tissue, and neutral fat in the liver. It has been reported to promote the synthesis of and cause hyperlipidemia.
In addition, insulin in the blood that has been compensated for by insulin resistance not only causes impaired glucose tolerance, but also diabetes, but also through peripheral vascularization through increased Na ion reabsorption and sympathetic nerve activation in the kidney. Increases resistance and eventually forms a hypertensive state.
Hyperlipidemia, diabetes and hypertension brought about by obesity are thought to cause vascular disorders based on arteriosclerosis such as cerebrovascular disorder and coronary artery disease, and to have a serious impact on life prognosis.
The basics of obesity treatment are exercise therapy and diet therapy, but there are a lot of factors to achieve the set goals due to various factors such as conflict with human fundamental desires, balance with working hours, and increased stress. There are difficulties. Surgical treatments such as gastric reduction and gastric bypass may be applied to extremely obese patients, but obesity often results in wound complications such as infection and lipolysis when laparotomy is performed. The current situation involves loss and pain. Therefore, there is a need for a combination of pharmaceuticals that can supplement diet / exercise therapy safely and simply.
Currently, pharmaceuticals used as anti-obesity drugs include central appetite suppressants such as mazindol and sibutramine, and orlistat, which is a pancreatic lipase inhibitor. Centrally acting drugs may cause serious side effects such as dry mouth, constipation, stomach discomfort, and sometimes hallucinations / visual hallucinations.Orlistat has side effects in the digestive tract such as diarrhea, incontinence, and paralysis. It recognized. In general, the effects of these anti-obesity drugs are moderate at doses that do not cause side effects, and the safety of long-term use has not yet been established. The current situation is that almost no recognition has been made.

With respect to insulin resistance, treatment using a biguanide agent or a peroxisome proliferation-related receptor (hereinafter abbreviated as PPAR) gamma agonist is widely performed. Regarding biguanides, it has been reported that non-insulin-dependent diabetic patients exhibit hypoglycemic and hyperlipidemic effects in addition to improving insulin resistance. However, the therapeutic effect by itself is inadequate, and in addition to gastrointestinal symptoms such as upper abdominal discomfort, nausea, and diarrhea, it has become clear that life-threatening side effects such as lactic acidosis are exhibited. Yes. Regarding PPAR gamma agonists, as with biguanides, it improves insulin resistance, hyperglycemia, hyperlipidemia and hypertension in non-insulin dependent diabetics, but is still satisfactory in terms of side effects (obesity, fulminant hepatitis) It's hard to say what you can do.
Japanese Patent Publication No. 4-15221 JP 2003-146907 A Special table 2002-535315 gazette

  The present invention improves insulin resistance and fatty liver by combined use of insulin secretagogues and angiotensin II receptor antagonists for patients with type 2 diabetes, and prevents the development of metabolic syndrome including arteriosclerosis It is an issue to provide new treatments for this purpose.

As a result of intensive studies, the inventors of the present application have made remarkable blood glucose lowering even for pathological conditions showing insulin resistance by simultaneously administering angiotensin II receptor antagonist and insulin secretagogue, particularly olmesartan or telmisartan, and nateglinide. It has been found that there is an action, and the present invention has been completed based on this.
More specifically, the present inventors have conducted extensive studies in view of the above problems, and as a result, by administering olmesartan or telmisartan, which is an angiotensin II receptor antagonist, blood glucose caused by nateglinide, which is an insulin secretagogue The present inventors have found that the lowering action is remarkably enhanced, and that combined administration of olmesartan and nateglinide significantly improves fatty liver, thereby completing the present invention.
That is, the present invention is as follows.

[1] A pharmaceutical composition comprising (1) an insulin secretion promoter or a pharmaceutically acceptable salt thereof as an active ingredient (2) an angiotensin II receptor antagonist or a pharmaceutically acceptable salt thereof.
[2] The pharmaceutical composition according to the above [1], wherein the insulin secretagogue is nateglinide.
[3] The pharmaceutical composition according to the above [1] or [2], wherein the angiotensin II receptor antagonist is olmesartan or telmisartan.
[4] The pharmaceutical composition according to the above [1] or [2], wherein the angiotensin II receptor antagonist is olmesartan.
[5] The pharmaceutical composition according to the above [1] or [2], wherein the angiotensin II receptor antagonist is telmisartan.
[6] A pharmaceutical composition comprising an insulin secretagogue or a pharmaceutically acceptable salt thereof, which is administered together with a pharmaceutical composition comprising an angiotensin II receptor antagonist or a pharmaceutically acceptable salt thereof.
[7] The pharmaceutical composition according to the above [6], wherein the angiotensin II receptor antagonist is olmesartan.
[8] The pharmaceutical composition according to the above [6], wherein the angiotensin II receptor antagonist is telmisartan.
[9] The pharmaceutical composition according to the above [6] to [8], wherein the insulin secretagogue is nateglinide.
[10] The pharmaceutical composition according to the above [6] to [9], wherein an insulin secretion promoter is administered after an angiotensin II receptor antagonist is administered in advance.
[11] An insulin resistance therapeutic / preventive agent comprising the pharmaceutical composition according to the above [1] to [10].
[12] A therapeutic and / or preventive agent for fatty liver comprising the pharmaceutical composition according to the above [1] to [10].
[13] An agent for enhancing blood glucose lowering action of an insulin secretagogue, comprising an angiotensin II receptor antagonist as an active ingredient.
[14] The blood glucose lowering effect enhancer according to [13] above, wherein the angiotensin II receptor antagonist is olmesartan or telmisartan.
[15] The blood glucose-lowering effect enhancer according to the above [13] to [14], wherein the insulin secretion promoter is nateglinide.

  According to the present invention, it has become possible to provide a drug for treating or preventing insulin resistance, and more effectively preventing or treating the development of metabolic syndrome, particularly in patients with type 2 diabetes.

  Embodiments of the present invention will be described below.

  The subject to which the drug of the present invention is administered is not particularly limited as long as it seeks prevention, amelioration, treatment, etc. of diseases caused by hyperglycemia, but it is applied to mammals, usually humans (patients).

  An insulin secretagogue is an active ingredient having the property of promoting the secretion of insulin from pancreatic β cells. Examples of insulin secretagogues include sulfonylureas (SU) (especially those that promote insulin secretion from pancreatic β-cells by transmitting insulin secretion signals via cell membrane SU receptors). Although not tolbutamide, chlorpropamide, tolazamide, acetohexamide, 4-chloro-N-[(1-pyrrolidinylamino) carbonyl] -benzenesulfonamide (glycopyramide), glibenclamide (glyburide), Gliclazide, 1-butyl-3-methanilylurea, carbutamide, glibonuride, glipizide, glyxone, glyxepide, glybuthiazole, glybazole, glyhexamide, grimidine, glipinamide, fenbutamide, and tolylcyclamide, or a pharmaceutically acceptable salt thereof And the like. (In the present invention, the “insulin secretion promoter” may include a pharmaceutically acceptable salt thereof.)

  In particular, nateglinide [chemical name: N- (trans-4-isopropylcyclohexanecarbonyl) -D-phenylalanine, hereinafter referred to as nateglinide. ] Have been shown to have excellent insulin secretion promotion and blood glucose lowering effects by oral administration, and are useful as antidiabetic drugs (Japanese Patent Publication No. 4-15221).

  An angiotensin II receptor antagonist is understood to be an active ingredient that binds to the angiotensin II receptor of the angiotensin II receptor subtype but does not result in activation of the receptor. As a result of the blockade of the angiotensin II receptor, these inhibitors can be used, for example, as antihypertensive drugs or in the treatment of congestive heart failure.

  Angiotensin II receptor antagonists include compounds with different structural characteristics, and non-peptide ones are basically preferred. Examples include compounds selected from the group consisting of valsartan, losartan, candesartan, eprosartan, irbesartan, olmesartan, tasosartan and telmisartan, or in each case a pharmaceutically acceptable salt thereof. (In the present invention, “angiotensin II receptor antagonist” may also include a pharmaceutically acceptable salt thereof.)

Preferred angiotensin II receptor antagonists include drugs already on the market, and the most preferable one is olmesartan (Japanese Patent Laid-Open No. 2003-146907), telmisartan (Japanese Patent Publication No. 2002-535315) or a pharmaceutically acceptable product thereof. Salt.
In the pharmaceutical composition or drug of the present invention, the insulin secretagogue and the angiotensin II receptor antagonist, or the angiotensin II receptor antagonist are used as they are or mixed with a pharmaceutically acceptable carrier, for example, powders, granules, etc. , Solid preparations such as tablets, capsules, syrups, emulsions, solutions such as injections (including subcutaneous injections, intravenous injections, intramuscular injections, infusions), sublingual tablets, buccals, lozenges, microcapsules Or as a drug such as a preparation or a suppository with a sustained-release coating, can be administered orally or parenterally. Especially, it is preferable to administer orally as a tablet.
As the pharmaceutically acceptable carrier, various organic or inorganic carrier substances commonly used as pharmaceutical materials can be used. In the case of a solid formulation, excipients, lubricants, binders, disintegrants, etc. In the case of liquid preparations, solvents, solubilizers, suspending agents, tonicity agents, buffers, soothing agents, etc. are appropriately used. Moreover, you may add additives, such as antiseptic | preservative, an antioxidant, a coloring agent, a sweetening agent, and a fragrance | flavor as needed.
The preparation of the above dosage form can be produced according to a preparation method known in the art.

  The ratio of the combination amount of the insulin secretagogue and the angiotensin II receptor antagonist in the pharmaceutical composition of the present invention is within a range where a more effective effect can be obtained by combining them. For example, nateglinide and olmesartan or telmisartan In the case of the combination, for nateglinide 1, the weight ratio is, for example, 0.01 to 10, preferably 0.1 to 1 for olmesartan, and 0.01 to 10, preferably 0.1 to 1 for telmisartan.

  The daily dose of the pharmaceutical composition or drug of the present invention varies depending on the degree of symptoms, age, sex, body weight, drug sensitivity, administration time, interval, administration route, etc. of the subject to be administered. The daily dose is a combination of about 0.001 to 1000 mg of nateglinide per kg body weight of a mammal and about 0.001 to 1000 mg of an angiotensin II receptor antagonist, preferably about 0.01 to 500 mg of nateglinide and about 0.01 to 500 mg of an angiotensin II receptor antagonist More preferably, it is a combination of about 0.1 to 300 mg of nateglinide and about 0.1 to 300 mg of an angiotensin II receptor antagonist. This can be administered, for example, in 1 to 3 divided doses as needed.

  EXAMPLES Hereinafter, the present invention will be described in more detail with reference to examples. However, the examples are described for explaining the present invention, and do not limit the present invention.

The hypoglycemic effect of nateglinide was examined in an oral glucose tolerance test using obese / insulin resistant rats treated with olmesartan for 4 weeks. We also investigated the effect of 6-week combined use of olmesartan and nateglinide on the accumulation of neutral fat in the liver using non-obese type 2 diabetes model rats.
As a result, in the Zucker Fatty rat, which is an obesity / insulin resistance model administered with olmesartan for 4 weeks, the hypoglycemic effect of nateglinide was clearly enhanced compared to the Zucker Fatty rat that did not receive olmesartan. Unexpectedly, the total amount of insulin secreted by nateglinide at this time was clearly reduced compared to Zucker Fatty rats that did not receive olmesartan.
In addition, nateglinide and olmesartan were administered to Goto-Kakizaki rats, a non-obese type 2 diabetes model, together for 6 weeks to examine the amount of triglyceride accumulated in the liver. Was clearly lower than that of the single agent.
The combined effect of nateglinide and telmisartan was also confirmed.
This will be described in more detail below.

<Enhanced action of nateglinide by olmesartan>
The efficacy of combined use of nateglinide and olmesartan was investigated using Zucker Fatty (ZF) rats with obesity and insulin resistance characteristics. ZF rats are insulin resistance model rats known to exhibit hyperinsulinemia and impaired glucose tolerance.
Male Zucker Fatty rats were introduced at 6 weeks of age and acclimated to restricted feeding twice a day for 1 hour each (9: 00-10: 00 am, 15: 00-16: 00 pm). After a 1-week acclimatization period, the rats were randomly divided into the following two groups, and 0.5% methylcellulose or 3 mg / kg olmesartan was administered over 4 weeks.
VEH group 0.5% methylcellulose once daily administration 8 cases
OLM group 3 mg / kg olmesartan orally administered once daily 8 patients were administered orally by gavage immediately before the first feeding every day. After a fasting overnight at 4 weeks after administration, an oral glucose tolerance test of 1 g / kg was performed, and glucose tolerance of each group was measured. At that time, the OLM group and the VEH group were further divided into two groups, respectively, as described below, and a glucose oral tolerance test was conducted in a total of 5 groups including normal rats of the same age as controls.
VEH / MC group 1g / kg glucose solution + 0.5% methylcellulose (MC) administration 4 cases
VEH / NAT group 1g / kg glucose solution + 50mg / kg nateglinide (NAT) administration 4 cases
OLM / MC group 1g / kg glucose solution + MC administration 4 cases
OLM / NAT group 1 g / kg glucose solution + 50 mg / kg NAT administration 4 cases Normal group 1 g / kg glucose solution + MC administration 4 cases
1g / kg glucose solution and 0.5% methylcellulose solution for rats in VEH / MC group, OLM / MC group and normal group, and 1g / kg glucose solution and 50mg for rats in VEH / NAT group and OLM / NAT group / kg nateglinide was orally administered, and blood was collected from the tail vein immediately before administration and 15, 30, 60, 120, and 180 minutes after administration, and blood glucose level and insulin level were measured according to a conventional method.

(result)
The results are shown in FIGS. 1-2 and Tables 1-2. In the VEH / MC group, blood glucose after glucose loading was significantly higher than that in the normal group, and increased to 221.2 ± 7.7 mg / dl 30 minutes after glucose loading (Figure 1). In addition, the blood insulin level at that time was also significantly higher than that in the normal group (FIG. 2).
On the other hand, in the OLM / MC group, the insulin secretion pattern after glucose loading and the total amount of insulin secretion up to 3 hours after glucose loading were the same as in the VEH / MC group (Figure 2, Table 2), but the increase in blood glucose was VEH・ It was suppressed compared to the MC group (Fig. 1), and the total blood glucose level up to 3 hours after glucose load was 466.6 ± 14.1mgh / dl in the VEH / MC group, compared with the OLM / MC group. It decreased to 418.1 ± 31.8 mgh / dl (Table 1). In the VEH / NAT group, the amount of insulin secretion was clearly increased to suppress the increase in blood glucose, and the degree of suppression of the increase in blood glucose was clearly stronger than in the OLM / MC group (FIGS. 1 and 2). On the other hand, in the OLM / NAT group, the total insulin secretion after glucose loading did not increase further compared to the VEH / MC group, VEH / NAT group, and OLM / MC group (Fig. 2, Table 2). ) The increase in blood sugar was most strongly suppressed and decreased to the normal level (Fig. 1).
From the above results, olmesartan was administered for 4 weeks to improve the sensitivity of whole body insulin and also enhance the hypoglycemic effect of nateglinide without additional increase of insulin, so combined use of nateglinide and olmesartan, This suggests the possibility of more strict blood glucose control and improvement of hyperinsulinemia (treatment and prevention of insulin resistance).

<Inhibitory effect of liver TG accumulation by combined use of olmesartan and nateglinide>
We investigated the effect of combined use of olmesartan and nateglinide on hepatic neutral fat accumulation in Goto-Kakizaki (GK) rats, a non-obese type 2 diabetes model. Male GK rats were introduced at 6 weeks of age and acclimated to restricted feeding twice a day for 1 hour each (9: 00-10: 00 am, 15: 00-16: 00 pm). After a 2-week acclimation period, the rats were randomly divided into 4 groups as described below and administered 0.5% methylcellulose, 3 mg / kg olmesartan or 50 mg / kg nateglinide for 6 weeks.
VEH group 0.5% methylcellulose administration 4 cases
NAT group 50mg / kg nateglinide administered twice daily 4 cases
OLM group 3 mg / kg olmesartan administered once daily 4 patients Combined group 50 mg / kg nateglinide administered twice daily, 3 mg / kg olmesartan once daily 4 patients
The VEH group received 0.5% methylcellulose immediately before each meal, the NAT group received 50 mg / kg nateglinide immediately before each meal, the OLM group received 3 mg / kg olmesartan before the first meal, and the second 0.5% methylcellulose is administered before meals, and the combination group is administered 50 mg / kg nateglinide and 3 mg / kg olmesartan before the first meal, and 50 mg / kg nateglinide and 0.5% methylcellulose before the second meal. did. After 6 weeks of administration, the liver was collected from each rat, the tissue was crushed and neutral fat was extracted with a chloroform / methanol solution, and the neutral fat content in the liver was measured by a conventional method.

(result)
The results are shown in Table 3. Liver triglyceride content was almost the same in the VEH group and NAT group, and a slight decrease was observed in the OLM group. However, when both drugs were used in combination, a significant reduction in liver triglyceride content was observed in the combination group. This suggests that the combination of nateglinide and olmesartan may be very effective in suppressing the development of fatty liver, which is also a risk factor for the development of insulin resistance and metabolic syndrome.

(Table 1) Sum of blood glucose up to 180 minutes after administration of 1 g / kg glucose and each drug
Mean ± standard error n = 4
Total blood glucose level (mg · hr / dl)
VEH / VEH group 466.6 ± 14.1
VEH / NAT group 343.8 ± 31.8
OLM / VEH group 418.1 ± 31.8
OLM / NAT group 320.8 ± 3.5
Normal group 362.5 ± 5.5

(Table 2) Average insulin secretion ± 1 standard error n = 4 up to 180 minutes after administration of 1 g / kg glucose and each drug
Total insulin secretion (ng · hr / ml)
VEH / VEH group 25.1 ± 1.4
VEH / NAT group 31.5 ± 2.5
OLM / VEH group 24.8 ± 0.3
OLM / NAT group 21.0 ± 2.8
Normal group 6.1 ± 0.7

(Table 3) Average triglyceride content in liver 6 weeks after drug administration ± standard error n = 4
Liver neutral fat content (μg / g tissue)
VEH group 423.4 ± 65.1
NAT group 485.2 ± 27.6
OLM group 361.0 ± 25.4
Combination group 239.7 ± 62.4

<Insulin resistance improvement effect by combined use of telmisartan and nateglinide>
Introduced 6-week-old male Zucker fatty (ZF) rats (Nippon Charles River) and acclimated to the rearing environment of the light-dark cycle with 7 to 19:00 as the dark period and 19 to 7 as the light period. From 2 days a day, limited feeding was started for 1 hour each (9-10 o'clock, 15-16 o'clock). At 10 weeks of age when food intake was stable, ZF rats were divided into four groups: the administration vehicle (VEH) group, the nateglinide (NAT) group, the telmisartan (TEL) group, and the combination group. Zucker lean (ZL) rats were used as normal controls.
In the VEH group and NAT group, 0.5% methylcellulose (MC) or 50 mg / kg NAT was orally administered immediately before each meal. In the TEL group, 5 mg / kg TEL was orally administered immediately before the first feeding, and MC was orally administered immediately before the second feeding. In the combination group, 50 mg / kg NAT and 5 mg / kg TEL were orally administered immediately before the first feeding, and 50 mg / kg NAT and MC were orally administered immediately before the second feeding.
Administration of each drug was repeated for 6 weeks from 10 to 16 weeks of age, and changes in blood glucose, plasma insulin, TG, and FFA were monitored. After 6 weeks of drug administration, a glucose tolerance test (OGTT) and an insulin tolerance test (ITT) were performed.
For OGTT, rats in each group were fasted for 17 hours from the end of feeding in the afternoon of the day before the test (16:00), and then a 2 g / kg glucose solution was orally administered under awakening. Blood was collected from the tail vein of rats at 30, 60, 120, and 180 minutes, and blood glucose and insulin were measured at each time point. As for ITT, as in OGTT, rats in each group were fasted for 17 hours from the end of feeding in the afternoon of the day before the test (16:00), and 0.5 U / kg of insulin (novolin, novonordisk) was awakened. Pharma Co., Ltd.) was subcutaneously administered, and blood was collected from the tail vein of rats before administration and at 15, 30, 60, 120, 180 minutes after administration, and blood glucose at each time point was measured.
Finally, blood, liver, epididymal fat, kidney and heart were collected from each rat, and plasma adiponectin concentration and organ weight were measured. In addition, 4 rats from each group were randomly selected to isolate the pancreatic islet, and the insulin content and insulin secretion response in the pancreatic islet were measured. Furthermore, the pancreas was removed from a rat different from the individual from which La Islet was isolated and fixed with 10% neutral formalin solution, followed by histopathological examination.

(result)
(1) Effects of drugs on diurnal fluctuations in blood glucose, insulin, TG, and FFA
The intake of ZF rats under restricted feeding twice a day was about 10 g per time and about 20 g per day, and there was no difference between groups throughout the experiment. FIG. 3 shows daily fluctuations of blood glucose, insulin, TG, and FFA in each group. Blood glucose levels in the VEH group were normal before morning feeding but increased significantly after meals, remained higher than those in the ZL group even before feeding in the afternoon, and again increased significantly after the afternoon meal . As for insulin, the VEH group was higher than the ZL group before feeding in the morning, increased further after meals, and the peak value was about 4 times that of the ZL group. In the ZL group, the postprandial peak was 30 minutes, while in the VEH group it was delayed by 60 minutes. TG was also higher in the VEH group before feeding in the morning than in the ZL group, and increased significantly after meals. FFA also remained higher in the VEH group than in the ZL group. NAT suppressed postprandial blood glucose elevation by increasing the postprandial insulin secretion peak to 30 minutes without increasing total insulin secretion. TEL did not affect blood glucose transition, but decreased insulin levels 60 minutes after meals.
The combined use of both drugs recovered the insulin level 30 minutes after meal in the same manner as in the NAT group, and decreased the insulin value 60 minutes after meal to the same level as in the TEL group. Along with this, the postprandial blood glucose level of the combination group tended to decrease more than that of the NAT and TEL groups. Regarding TG and FFA, there was a tendency to decrease in the drug administration group, and in particular, the tendency was lower in the combination group.

(2) Long-term combined effect of nateglinide and telmisartan Table 4 summarizes various pathological parameters in each group 6 weeks after drug administration. Body weight, HbA1c, fasting insulin, TG, and FFA were significantly increased in ZF rats compared to ZL rats. Fasting insulin, TG, and FFA tended to decrease in the NAT and TEL groups, and significantly decreased with the combination of both drugs.
In addition, both peripheral testicular fat weight and liver weight were increased in the VEH group compared to the ZL group, but there was no difference between the ZF groups. On the other hand, regarding kidney weight and heart weight, there was no significant difference between VEH group and ZL group, but kidney weight showed a decreasing trend in TEL group and combination group, and heart weight decreased in TEL group and combination group Was. Plasma adiponectin (which is supposed to improve insulin resistance) was significantly lower in the VEH group than in the ZL group, but increased in the NAT and TEL groups, but significantly increased in the combination group (Fig. 4).
The results of OGTT performed 6 weeks after drug administration are shown in FIG. The VEH group showed obvious glucose tolerance abnormalities, and insulin levels at this time were higher in the VEH group than in the ZL group both before and after the glucose load. The NAT group showed almost the same blood glucose transition as the VEH group, but the TEL group and the combination group showed a tendency to decrease the blood glucose level 30 to 60 minutes after glucose load, and the combined group had a total blood glucose area of up to 180 minutes It showed a tendency to be lower than each single administration group. Regarding insulin, the NAT group and the TEL group showed a tendency to suppress excessive secretion from 15 to 60 minutes after glucose loading, and in the combination group, insulin values and sugars before and after sugar loading and 30, 60 minutes after sugar loading. The total insulin area until 180 minutes after loading was significantly reduced.
FIG. 6 shows the results of ITT performed 6 weeks after drug administration. The ZL group showed a transient decrease in blood glucose after insulin administration, while the VEH group had attenuated the hypoglycemic effect of insulin. The NAT group and TEL group were lower than the VEH group, but no significant change was observed at any point. On the other hand, in the combination group, a significant decrease in blood glucose was observed 120 minutes after insulin administration, and the total blood glucose area until 180 minutes after insulin administration was also significantly decreased.
Furthermore, 6 weeks after drug administration, pancreas was collected from each group of rats and morphological changes and insulin content of pancreatic islets were observed. Cell detachment was observed, and the insulin content per unit protein tended to decrease compared to the ZL group (FIG. 7). This trend was similar in the NAT group, but in the TEL group and the combination group, fibrosis and b-cell loss were suppressed, and the insulin content was about 4 times that in the VEH group.
Therefore, glucose-dependent insulin secretion response (GSIS) was then measured using pancreatic islets isolated from rats at the end of drug administration (FIG. 8). The pancreatic islets of ZL rats showed an increase in glucose concentration-dependent insulin secretion, but in the VEH group, the secretion amount to 8.3 mM and 16.7 mM glucose stimulation decreased, and GSIS was attenuated. In the NAT group and the TEL group, insulin secretion by 2.8 mM and 8.3 mM glucose stimulation was similar to that in the VEH group, but the secretion by 16.7 mM glucose stimulation tended to increase compared to the VEH group. Furthermore, in the combination group, an upward trend of insulin secretion was observed after 8.3 mM glucose stimulation, and the secretion amount by 16.7 mM glucose stimulation was significantly increased, and recovery of GSIS was observed.

  From these facts, it is understood that the combined use of nateglinide and telmisartan strongly improves insulin resistance.

(Table 4) Pathological parameters after 6 weeks of drug administration

The blood glucose level transition after administration of 1 g / kg glucose and each drug is shown. 1 shows changes in insulin concentration in plasma after administration of 1 g / kg glucose and each drug. The influence of the drug on the circadian variation of blood glucose, insulin, TG and FFA is shown. CRF-1 was given from 9:00 to 10:00 am and from 15:00 to 16:00 pm, and changes in blood glucose, insulin, TG, and FFA were measured. Each drug was administered as follows immediately before feeding at 9:00 am and 15:00 pm. VEH group: AM / MC, PM / MC NAT group: AM / NAT, PM / NAT TEL group: AM / TEL, PM / MC Combination group: AM / NAT / TEL, PM / NAT / MC ZL group: AM / MC , PM / MC mean ± standard error, 6 patients in each group *: p <0.05 vs VEH (Dunnett) #: p <0.05, ##: p <0.01 vs ZL (Student's-t) The adiponectin concentration in plasma 6 weeks after administration is shown. Blood was collected from the inferior vena cava of rats after overnight fasting and the adiponectin concentration was measured. Mean ± standard error, 6 patients in each group *: p <0.05 vs VEH (Dunnett) #: p <0.05 vs ZL (Student’s-t) Shows glucose tolerance 6 weeks after administration. Rats fasted overnight were orally administered with a 2 g / kg glucose solution, and blood was collected from the tail vein over time after administration, and blood glucose and insulin concentrations were measured. a: blood glucose, b: total blood glucose area (0-180 minutes), c: insulin, d: total insulin area (0-180 minutes) mean ± standard error, 6 cases in each group *: p <0.05, **: p <0.01 vs VEH (Dunnett) #: p <0.05, ##: p <0.01 vs ZL (Student's-t) The results of an insulin tolerance test 6 weeks after administration are shown. Rats fasted overnight were administered subcutaneously with 0.5 U / kg of insulin, and blood was collected from the tail vein over time to measure blood glucose levels. a: blood glucose, b: total blood glucose area (0-180 minutes)) mean ± standard error, 6 patients in each group *: p <0.05 vs VEH (Dunnett) #: p <0.05, ##: p <0.01 vs ZL (Student's-t) The insulin content in the pancreatic islet 6 weeks after administration is shown. Insulin was extracted from pancreatic islets isolated from each rat and measured. The value obtained was corrected with the protein content extracted at the same time. Mean value ± standard error, 3 cases in each group 6 shows glucose-dependent insulin secretion response in pancreatic islets 6 weeks after administration. Glucose-dependent insulin secretion responses were measured using pancreatic islets isolated from each group of rats. Insulin secretion was corrected by the protein content of pancreatic islets. Mean ± standard error, 4 patients in each group *: p <0.05 vs VEH / 16.7 mM glucose stimulation (Dunnett) #: p <0.05 vs ZL / 8.3 mM glucose stimulation (Student's-t) ##: p <0.01 vs ZL /16.7 mM glucose stimulation (Student's-t)

Claims (15)

A pharmaceutical composition comprising (1) an insulin secretion promoter or a pharmaceutically acceptable salt thereof as an active ingredient (2) an angiotensin II receptor antagonist or a pharmaceutically acceptable salt thereof.   The pharmaceutical composition according to claim 1, wherein the insulin secretagogue is nateglinide.   The pharmaceutical composition according to claim 1 or 2, wherein the angiotensin II receptor antagonist is olmesartan or telmisartan.   The pharmaceutical composition according to claim 1 or 2, wherein the angiotensin II receptor antagonist is olmesartan.   The pharmaceutical composition according to claim 1 or 2, wherein the angiotensin II receptor antagonist is telmisartan.   A pharmaceutical composition comprising an insulin secretagogue or a pharmaceutically acceptable salt thereof, characterized by being administered together with a pharmaceutical composition comprising an angiotensin II receptor antagonist or a pharmaceutically acceptable salt thereof.   The pharmaceutical composition according to claim 6, wherein the angiotensin II receptor antagonist is olmesartan.   The pharmaceutical composition according to claim 6, wherein the angiotensin II receptor antagonist is telmisartan.   The pharmaceutical composition according to any one of claims 6 to 8, wherein the insulin secretagogue is nateglinide.   10. The pharmaceutical composition according to any one of claims 6 to 9, wherein an insulin secretagogue is administered after an angiotensin II receptor antagonist is administered in advance.   An insulin resistance treatment / prevention agent comprising the pharmaceutical composition according to claim 1.   A therapeutic or prophylactic agent for fatty liver comprising the pharmaceutical composition according to claim 1.   An agent for enhancing blood glucose lowering action of an insulin secretagogue, comprising an angiotensin II receptor antagonist as an active ingredient.   14. The blood glucose lowering effect enhancer according to claim 13, wherein the angiotensin II receptor antagonist is olmesartan or telmisartan.   15. The blood glucose lowering effect enhancer according to claim 13, wherein the insulin secretagogue is nateglinide.