WO2010103585A1

WO2010103585A1 - Method for evaluating metabolic syndrome or constituent disease thereof

Info

Publication number: WO2010103585A1
Application number: PCT/JP2009/005508
Authority: WO
Inventors: 横田充弘; 谷村大輔
Original assignee: Yokota Mitsuhiro; Tanimura Daisuke
Priority date: 2009-03-08
Filing date: 2009-10-21
Publication date: 2010-09-16
Also published as: JPWO2010103585A1

Abstract

Disclosed is a novel measure (marker) useful for the evaluation of metabolic syndrome or a constituent disease thereof. The condition of a patient suffering from metabolic syndrome or a constituent disease thereof or the risk of metabolic syndrome or a constituent disease thereof can be evaluated by employing, as a measure, a value calculated from the following formula: (blood adiponectin level)/[(fasting insulin index)×(fasting blood glucose level)]×C (wherein "/" means division and "C" represents a constant).

Description

Method for evaluating metabolic syndrome or its constituent diseases

The present invention relates to a method for evaluating the morbidity or risk of developing metabolic syndrome or its constituent diseases (diabetes, hypertension, hyperlipidemia, arteriosclerosis). This application claims priority based on Japanese Patent Application No. 2009-54314 filed on Mar. 8, 2009, the entire contents of which are incorporated by reference.

Obesity, that is, accumulation of visceral fat, becomes the basis of metabolic syndrome through hypertension, hyperlipidemia, diabetes, etc., and increases future cardiovascular disease (Non-patent Document 1). Metabolic syndrome includes not only insulin resistance but also pathological conditions related to obesity such as oxidative stress (Non-patent Document 2) and adipose tissue hypoxia (Non-patent Document 3). It is an incentive for curing.

Adiponectin is secreted from adipocytes, and its blood concentration decreases with obesity and increases with obesity improvement. Therefore, it is regarded as an indicator of metabolic syndrome. Various studies to date have shown that adiponectin concentration decreases in the state of metabolic syndrome (Non-Patent Document 4), and the relationship between hypoadiponectinemia and cardiovascular disease has also been reported (Non-patent Document 4). Reference 5).

On the other hand, HOMA-IR (Homeostasis assessment-Insulin Resistance) is used as an index of insulin resistance. HOMA-IR is one of the indicators that have been conceived for easily examining the presence or absence of the underlying insulin resistance (Non-Patent Document 6), and fasting insulin value (μU / ml) x fasting blood glucose It is expressed as value (mg / dl) / 405. HOMA-IR is said to show a good correlation with the value of insulin resistance measured by the glucose clamp method, but it cannot always be a good index in hyperglycemia and non-obese individuals (Non-patent Document 7). In addition, a method for evaluating insulin resistance using a fasting insulin value, a fasting blood glucose level, and an adiponectin value has been proposed (Patent Document 1). According to this method, an evaluation result highly correlated with the conventional glucose clamp method is obtained.

JP 2006-98100 A

It is eager to provide a new index for simply and accurately evaluating metabolic syndrome. There is also a high need for evaluating the risk of developing metabolic syndrome in the future (risk of onset). Therefore, an object of the present invention is to find a new index (marker) useful for evaluating the morbidity or risk of developing metabolic syndrome or its constituent diseases, and to meet these demands.

The present inventors paid attention to blood adiponectin concentration and HOMA-IR, and analyzed the relationship between these indices and metabolic syndrome using a large-scale population. As a result, it was found that the value obtained by dividing the blood adiponectin concentration by HOMA-IR complements the characteristics of both blood adiponectin concentration and HOMA-IR, and can comprehensively evaluate the morbidity of metabolic syndrome. Moreover, it was shown that the said value is useful in predicting the risk of developing metabolic syndrome. Based on these findings, the following inventions are provided.
[1] The following calculation formulas (where / represents division and C represents a constant):
Blood adiponectin concentration / (fasting insulin value × fasting blood glucose level) × C
A method for evaluating the morbid state of metabolic syndrome or its constituent diseases, such as diabetes, hypertension, hyperlipidemia, or arteriosclerosis, using the value given by as an index.
[2] The following calculation formulas (where / represents division and C represents a constant):
Blood adiponectin concentration / (fasting insulin value × fasting blood glucose level) × C
A method for evaluating the risk of developing metabolic syndrome or a constituent disease thereof, such as diabetes, hypertension, hyperlipidemia, or arteriosclerosis, using the value given by as an index.
[3] The method according to [1] or [2], wherein C in the formula is any one of the following (1) to (3):
(1) a positive or negative integer,
(2) 1,
(3) 405.
[4] The following calculation formulas (where / represents division and C represents a constant):
Blood adiponectin concentration / (fasting insulin value × fasting blood glucose level) × C
A risk marker of diabetes syndrome, hypertension, hyperlipidemia or arteriosclerosis which is a metabolic syndrome or a constituent disease thereof.

The table | surface which shows the test subject's background and each test value of a large-scale analysis. Mean values ± standard deviation or% are shown. * The geometric mean was used because of the slope distribution. Statistical processing is based on Student's t-test. The table | surface which shows correlation with each test value and each parameter | index (blood adiponectin concentration, blood adiponectin concentration / HOMA-IR). Pearson's correlation coefficient is shown. Graph showing the incidence of metabolic syndrome by quartiles by blood adiponectin concentration (male on the left, female on the right). N in the graph represents the number of corresponding subjects. Evaluation was performed by 4 × 2 chi-square test. Graph showing the prevalence of metabolic syndrome by blood adiponectin concentration / HOMA-IR quartile (male on the left, female on the right). N in the graph represents the number of corresponding subjects. Evaluation was performed by 4 × 2 chi-square test. The geometric mean value of adiponectin and adiponectin / HOMA-IR according to the number of risk factors for metabolic syndrome. N in the graph represents the number of corresponding subjects. Error bars indicate standard error. One-way analysis of variance (ANOVA) was used for evaluation. Comparison of prediction of metabolic syndrome between adiponectin and adiponectin / HOMA-IR (male on the left and female on the right). The area under the curve (AUC) of the ROC curve (visitor operating characteristic curve) was evaluated.

The present invention provides a new index (marker) useful for evaluating metabolic syndrome or its constituent diseases. “Metabolic syndrome” refers to a condition in which insulin resistance, arteriosclerosis-induced lipoprotein abnormality, and hypertension are combined based on the accumulation of obesity and visceral fat, resulting in an increased risk of cardiovascular disease. The diagnostic criteria for metabolic syndrome are shown below. Unless otherwise specified, the International Diabetes Federation (IDF) standard is preferentially applied in this specification. The reason for this is that there is a debate about the determination of the abdominal circumference with respect to Japanese standards by eight academic societies such as the Japan Society of Internal Medicine (Oka R, Reassessment of the cutoff values of waist circumference and visceral fat area for identifying Japanese subjects at risk for the metabolic syndrome. See Diabetes Research and Clinical Practice. 2008; 79 (3): 474-481.).
(1) Japanese standards by eight academic societies such as the Japan Society of Internal Medicine (see Japan Internal Medicine Gold Magazine Vol. 94, No. 4, April 10, 2005)
In addition to the following (a), two or more of (b) to (d) are satisfied.
(a) Abdominal circumference: ≧ 85cm (male), ≧ 90cm (female)
(b) Neutral fat: ≧ 150 mg / dl and / or HDL-C: <40 mg / dl
(c) Blood pressure: ≧ 130 / 85mmhg
(d) Fasting blood glucose: ≧ 110mg / dl

(2) International Diabetes Federation (IDF) criteria (see Non-Patent Document 5)
In addition to the following (a), two or more of (b) to (e) are satisfied.
(a) Abdominal circumference: ≧ 90cm (male), ≧ 80cm (female)
(b) Neutral fat: ≧ 150mg / dl
(c) Fasting blood glucose: ≧ 100mg / dl
(d) HDL-C: <40mg / dl (male), <50mg / dl (female)
(e) Blood pressure: ≧ 130 / 85mmhg

“The constituent diseases” refer to diabetes, hypertension, hyperlipidemia or arteriosclerosis. Atherosclerosis includes cerebral arteriosclerosis and coronary atherosclerosis.

An index provided by the present invention (hereinafter, also referred to as “index of the present invention”) is obtained by dividing the blood adiponectin concentration by a value obtained by multiplying a fasting insulin value and a fasting blood glucose level, and the following formula ( Hereinafter, it is also expressed as “the mathematical formula of the present invention”). In the expression, / represents division.
Blood adiponectin concentration / (fasting insulin value × fasting blood glucose level) × C

In the above formula, C is a constant. The constant C is not particularly limited, but preferably the constant C is a positive or negative integer in order to facilitate calculation. A specific example of the constant C in this case is 1. The constant C can be set to 405. In this case, the above equation can be expressed as follows using HOMA-IR which is an index of insulin resistance.
Blood adiponectin concentration / HOMA-IR

The units of blood adiponectin concentration, fasting insulin level, and fasting blood glucose level are not particularly limited. For example, the unit of blood adiponectin concentration is μg / mL, the unit of fasting insulin value is μU / ml, and the unit of fasting blood glucose level is mg / dl.

The first aspect of the present invention provides a method for evaluating the morbidity of metabolic syndrome or its constituent diseases using the value given by the mathematical formula of the present invention as an index. “Evaluating the morbidity of the metabolic syndrome or its constituent diseases” means grasping the possibility or probability of suffering from these diseases. Therefore, when the method of the present invention is carried out, for example, evaluation / determination results such as low, high, and moderate possibility of suffering from the target disease are obtained. The result is very useful because it is not only an opportunity to receive a medical examination but also an opportunity to review lifestyle habits. Note that the evaluation / determination here can be automatically / mechanically performed irrespective of the judgment of a person having specialized knowledge such as a doctor or a laboratory technician, as is apparent from the judgment criteria.

The index of the present invention is useful not only for evaluating metabolic syndrome but also for evaluating the morbidity of its constituent diseases. In a preferred embodiment of the present invention, the index of the present invention is used to comprehensively evaluate the morbidity of metabolic syndrome. Used to do. That is, in this embodiment, metabolic syndrome is the target disease.

As is clear from the analysis results shown in the Examples section described later, if the value of the index of the present invention is low, the possibility of suffering from metabolic syndrome or a constituent disease thereof is high, and the value of the index of the present invention is high. This is less likely. Therefore, as a result of obtaining the value of the index of the present invention for the subject, it can be determined that the possibility of morbidity is high if the value is low, and conversely, if the value is high, morbidity is possible It can be determined that the property is low. In order to perform more accurate and useful determination, it is preferable to set a plurality of groups having different morbidity and associate the range of the index value of the present invention for each group. An example is shown below.

Group 1 (highly likely to be affected): index value ≦ a
Group 2 (moderately morbid): a <index value <b
Group 3 (low possibility of morbidity): b ≦ index value

Boundary values for dividing groups (a and b in the above example) should be derived from the results of a large-scale analysis for a large number of subjects including those with metabolic syndrome, as in the analysis described in the examples below. Can do. An example of the boundary value derived from the results of the examples described later (example divided into four groups) is as follows. In this example, “blood adiponectin concentration / HOMA-IR” is adopted as an index.
(For men)
Group 1 (very likely to be affected): index value <about 9
Group 2 (highly likely to be affected): about 9 ≤ index value <about 13
Group 3 (low chance of morbidity): about 13 ≤ index value <about 18
Group 4 (very unlikely): approx. 18 ≤ indicator value

(For women)
Group 1 (very likely to be affected): index value <about 7
Group 2 (highly likely to be affected): about 7 ≤ index value <about 13
Group 3 (low chance of morbidity): about 13 ≤ index value <about 27
Group 4 (very unlikely): approx. 27 ≤ indicator value

In the second aspect of the present invention, there is provided a method for evaluating the risk of developing metabolic syndrome or its constituent diseases using the value given by the mathematical formula of the present invention as an index. “Evaluating the onset risk of metabolic syndrome or its constituent diseases” means grasping the risk (susceptibility) of developing these diseases in the future. According to the method of the present invention, the risk of developing these diseases is determined, and preparation for future onset can be made. That is, important and meaningful suggestions are given from a preventive medical standpoint. Note that the evaluation / determination here can be automatically / mechanically performed irrespective of the judgment of a person having specialized knowledge such as a doctor or a laboratory technician, as is apparent from the judgment criteria.

As suggested by the analysis results shown in the Examples section described later, if the value of the index of the present invention is low, the risk of developing metabolic syndrome or a constituent disease thereof increases, and if the value of the index of the present invention is high, the same onset occurs. Risk is low. Therefore, as a result of obtaining the value of the index of the present invention for the subject, it can be determined that the onset risk is high if the value is low, and on the contrary, if the value is high, the onset risk is low. Can be determined. As in the case of the first aspect, in order to make more accurate and useful determination, a plurality of groups with different onset risks are set, and the ranges of the index values of the present invention are associated with each group. Good.

It is advisable to obtain the index value of the present invention over time (preferably periodically) and examine the variation. If it seems to change at a low value, it can be determined that the possibility of developing the disease in the future (ie, the risk of onset) is high. On the other hand, if it changes at a high value, it is usually determined that the onset risk is low. On the other hand, when a decrease in value is recognized, it can be considered that the risk of onset has increased. In this case, in addition to the determination result that the risk of onset is high, it is possible to promote improvement of lifestyle habits. As is clear from this example, it is extremely useful to examine the index value of the present invention over time and grasp the fluctuation, because it can give an opportunity to review the lifestyle and improve it.

It should be noted that the possibility of suffering from the metabolic syndrome or its constituent diseases (first aspect) or the risk of future onset (second aspect) is not evaluated by focusing on one but comprehensive It is also possible to evaluate the risk, ie the risk for metabolic syndrome or its constituent diseases.

¡Whole blood, plasma or serum is used as a sample when performing the method of the present invention. Preferably plasma or serum is used. Preparation of plasma and serum may be according to conventional methods. In the present specification, the adiponectin concentration in a blood sample is referred to as “blood adiponectin concentration”. The term “blood adiponectin concentration” is used as an expression encompassing the term “whole blood adiponectin concentration”, the term “plasma adiponectin concentration” and the term “serum adiponectin concentration”.

The blood adiponectin concentration is not limited to this, but is preferably measured using an immunological technique. According to the immunological technique, the adiponectin concentration can be measured quickly and with high sensitivity. Also, the operation is simple. In the measurement of adiponectin concentration by an immunological technique, a substance having a specific binding property to adiponectin is used. As the substance, an anti-adiponectin antibody is usually used. However, any substance that has a specific binding property to adiponectin and can measure the amount of the adiponectin can be used without being limited to the anti-adiponectin antibody.

Currently, ELISA (enzyme immunoassay: Enzyme -Linked Immuno Sorbent Assay) is mainly used as a method for measuring blood adiponectin concentration by immunological techniques. Another RIA method (radioimmunoassay Radio Immuno Assay) is also used. In addition, human adiponectin measurement kits based on the latex agglutination method (for example, Latex turbidometric immunassay (Otsuka Pharmaceutical)) have become widespread, and such kits may be used to measure the adiponectin concentration.

The measurement of fasting insulin level and fasting blood glucose level may be performed by a conventional method. Examples of methods for measuring fasting insulin levels include EIA (enzyme immunoassay: EnzymezyImmuno Assay) and IRMA (immunoradiometric assay: Immuno Radio Metric Assay). On the other hand, hexonase G-6-PDH method, electrode method, and glucose dehydrogenase method can be exemplified as a method for measuring fasting blood glucose level.

The scope of application of the present invention is not limited to Japanese. That is, the present invention can be applied to non-Japanese mongoloids and other races (such as cocaside). However, the present invention is particularly effective for a Japanese or a population genetically close to a Japanese (for example, a Chinese population or a Korean population is close to a Japanese population). Therefore, the subject in the present invention is preferably a Mongoloid (Japanese, Chinese, Korean, etc.), more preferably a Japanese.

In order to find a new index for metabolic syndrome that includes the pathophysiology based on obesity, we decided to focus on two indices, blood adiponectin concentration and HOMA-IR. In addition, we set a reference value for the elderly and considered future risk assessment.

1. Method The KING Study (NCT 00262691) is a prospective study of cardiovascular disease that started in 2004 and targeted 3975 Japanese general population (1712 men, 2263 women) over the age of 50. It is intended only for those who give explanations to the general residents of Kitanagoya City at the time of a health checkup and obtain consent. Blood was collected in all cases, and 3297 people (1456 men and 1841 women) who measured blood adiponectin concentration and blood insulin concentration were analyzed. As a diagnostic standard for metabolic syndrome, the International Diabetes Society (IDF) standard (Non-patent Document 8) was adopted.

2. Results The blood adiponectin concentration was clearly higher in women than in men, and higher in elderly than in young (Fig. 1). Furthermore, it strongly correlated with each component of metabolic syndrome (FIG. 1). In particular, it showed a strong correlation with HDL and triglycerides (Fig. 1). On the other hand, HOMA-IR tended to be higher for males than females (Figure 1). Moreover, it was strongly correlated with the components of each metabolic syndrome excluding total cholesterol (FIG. 2). In particular, there was a strong correlation with blood glucose, HbA1c, waist circumference, etc. (FIG. 2).

In “Blood Adiponectin Concentration / HOMA-IR”, it can be seen that the characteristics of both indicators are complemented and metabolic syndrome is comprehensively evaluated (FIG. 2).

When blood adiponectin concentrations were grouped by concentration and 4 groups were prepared, there was a significant difference in the prevalence of metabolic syndrome between the groups (FIG. 3). According to the value corrected with HOMA-IR, that is, “blood adiponectin concentration / HOMA-IR”, patients with metabolic syndrome among groups could be more accurately grouped (FIG. 4). It can be seen that in men, the prevalence of metabolic syndrome is 35% or more if adiponectin / HOMA-IR is less than 9.3, and the prevalence is less than 3% if it is 18.1 or more. In addition, it can be seen that in women, if the adiponectin / HOMA-IR is less than 6.7, the metabolic syndrome prevalence is 50% or more, and if it is 27.0 or more, the prevalence is less than 5%.

Since the subject was an elderly person aged 50 years or older, the above results indicate that adiponectin / HOMA-IR remains younger than 50 years if adiponectin / HOMA-IR remains below 9.3 for men and 6.7 for women. Sometimes it is an epidemiological prediction of the risk of developing metabolic syndrome. Thus, it was suggested that the value of adiponectin / HOMA-IR is useful as an index for risk assessment of metabolic syndrome.

As the number of risk factors for metabolic syndrome increased, the average value of adiponectin decreased. The average value of adiponectin / HOMA-IR was further reduced (FIG. 5). When the risk factor of metabolic syndrome was examined excluding hyperglycemia, the average value of adiponectin decreased and the average value of adiponectin / HOMA-IR further decreased as the number of risk factors possessed by metabolic syndrome increased (Not shown). On the other hand, the prediction of the incidence of metabolic syndrome by adiponectin / HOMA-IR was superior to that of adiponectin alone (FIG. 6).

As a result of large-scale analysis, an excellent index (marker) that can evaluate metabolic syndrome with a single item was found. This index can be said to be useful as an epidemiological index for the future development of metabolic syndrome.

The present invention provides a novel indicator for metabolic syndrome or its constituent diseases. By using the index, it is possible to evaluate the morbidity of the metabolic syndrome or its constituent diseases and the risk of developing these diseases in the future. Evaluation of the onset risk is extremely useful from the standpoint of preventive medicine, as it is an opportunity to encourage early consultation and an opportunity to review and improve lifestyle habits.

The present invention is not limited to the description of the embodiments and examples of the invention described above. Various modifications may be included in the present invention as long as those skilled in the art can easily conceive without departing from the description of the scope of claims.
The contents of papers, published patent gazettes, patent gazettes, and the like specified in this specification are incorporated by reference in their entirety.

Claims

The following formulas (where / represents division and C represents a constant):
Blood adiponectin concentration / (fasting insulin value × fasting blood glucose level) × C
A method for evaluating the morbid state of metabolic syndrome or its constituent diseases, such as diabetes, hypertension, hyperlipidemia, or arteriosclerosis, using the value given by as an index.
The following formulas (where / represents division and C represents a constant):
Blood adiponectin concentration / (fasting insulin value × fasting blood glucose level) × C
A method for evaluating the risk of developing metabolic syndrome or a constituent disease thereof, such as diabetes, hypertension, hyperlipidemia, or arteriosclerosis, using the value given by as an index.
The method according to [1] or [2], wherein C in the formula is any of the following (1) to (3):
(1) a positive or negative integer,
(2) 1,
(3) 405.
The following formulas (where / represents division and C represents a constant):
Blood adiponectin concentration / (fasting insulin value × fasting blood glucose level) × C
A risk marker of diabetes syndrome, hypertension, hyperlipidemia or arteriosclerosis which is a metabolic syndrome or a constituent disease thereof.