JP2016045185A - Method for predicting risk of onset of metabolic syndrome - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for diagnosing in an early stage and preventing a metabolic syndrome.SOLUTION: It has become possible that a subject who has equal to or less than 6.2 μg/mL of adiponectin density has high risk of onset of a metabolic syndrome within four years, by measurement of blood density of whole adiponectin of a subject. Therefore, it has become possible to predict in an early stage of risk of onset of a metabolic syndrome to people who are regarded as potential members of metabolic syndrome patients, so that the people who are potential members of metabolic syndrome can receive a proper medical instruction in an early stage, and as a result, risk of onset of a metabolic syndrome can be reduced.SELECTED DRAWING: Figure 2

Description

  The present invention is a method for predicting the risk of developing metabolic syndrome (abnormal sugar / lipid metabolism). In particular, the present invention relates to a method for predicting the risk of developing metabolic syndrome using the concentration of adiponectin in blood of male workers in middle age as an index.

The accumulation of cardiovascular disease risk factors based on visceral fat obesity, so-called metabolic syndrome, has been increasing in Japan in recent years and has become a serious medical and social problem. Traditionally, adipose tissue has been thought of as an organ only for storing extra energy, but as an endocrine organ that secretes various physiologically active substances, so-called adipocytokines, it controls in vivo immunity, inflammatory reactions, energy metabolism, etc. It is clear that
Adipocytokines are anti-inflammatory cytokines such as TNF-α that induces insulin resistance, PAI-1 that promotes thrombus formation, and HB-EGF that induces migration and proliferation of vascular smooth muscle, and have an appetite suppressive effect. Good adipokines such as leptin and adiponectin that improve insulin resistance are included. When visceral fat is accumulated, abnormal secretion of these adipocytokines occurs, which is thought to cause abnormal sugar / lipid metabolism.
Adiponectin, which is one of the good adipokines, is characterized by a decrease in blood concentration in obese patients, particularly visceral fat type obese patients, despite being specifically secreted from adipocytes. It has been reported that blood adiponectin level is inversely correlated with cardiovascular risk factors such as lipid, blood pressure and CRP, and hypoadiponectinemia is an independent risk factor for diabetes, hypertension and coronary artery disease.

  In basic research using mice deficient in the adiponectin gene, it has been revealed that adiponectin has an insulin resistance improving action, an anti-inflammatory action, and an anti-arteriosclerosis action. Adiponectin exerts a metabolic improvement effect by promoting fatty acid combustion and sugar utilization in the liver and skeletal muscle, which are energy consuming organs, and suppressing gluconeogenesis. Thiazolidine derivatives that are clinically used as insulin sensitizers are known to increase the blood concentration of adiponectin and are considered to be one of the mechanisms of their usefulness. Adiponectin has also been reported to act directly on cardiovascular cells and suppress cardiotrophy, ischemia-reperfusion injury, and remodeling after myocardial infarction, thereby acting cardioprotectively. As described above, adiponectin has attracted a great deal of attention not only as a biomarker for cardiovascular diseases based on metabolic syndrome but also as a target for new therapeutic agents (Patent Documents 1 and 2).

  In addition, adiponectin as a biomarker is used in patients with ischemic heart disease (IHD) suffering from PTCA (percutaneous transluminal coronary angiopathy). It is known to reduce heart disease). However, there is a sex difference in the blood concentration of adiponectin, making it difficult to use as a biomarker. For example, in humans, the concentration of high molecular weight adiponectin in blood is about twice as high as that of men in women. Furthermore, although it is suggested that adiponectin is more strongly involved in insulin resistance in men, there is a report that it is weakly related to insulin resistance in women (Non-patent Document 1). Thus, although adiponectin is known for its various effects, the standard as a biomarker was not very clear.

WO2010 / 03585 Special table 2011-521248 gazette

Yoshimasa Yoshimasa, 2005 Health and Labor Sciences Research Grant Subsidy for Children and Family Research Project “Study on Gender Differences in Cardiovascular Risk Factors”

  The present invention provides a method for predicting the risk of developing metabolic syndrome. Specifically, a cutoff value is set for adiponectin as a biomarker and used as an evaluation criterion for the risk of development. Objective.

Based on past epidemiological studies, metabolic syndrome (MetS) is regarded as a risk factor for type 2 diabetes, and it is considered that the onset of type 2 diabetes can be prevented by suppressing the onset of MetS. For this reason, various influencing factors contributing to the onset of MetS have been examined, and it is considered that the contribution of adipokine secreted from adipocytes is large. Among them, it is reported that the relationship between adiponectin and MetS is particularly strong. However, in these reports, reports from cross-sectional surveys occupy a large number, and there are few reports examining the cutoff value of adiponectin for the onset of MetS.
Therefore, the present inventor examined the cut-off value of adiponectin for the development of metabolic syndrome based on the results of a follow-up survey for 4 years from 2008 in male workers in Tokushima Prefecture. First, as shown in FIG. 1, the total adiponectin concentration in blood is divided into four regions (≦ 4.9, 5.0 to 6.6, 6.7 to 8.8, ≧ 8.9), The relative proportion of the health maintenance period (hereinafter, the time ratio calculated by the acceleration model in the survival time analysis method is used as the relative ratio of the health maintenance period) was calculated from the follow-up survey of the subject in question for 4 years. The relative ratio (TR) of the health maintenance period of subjects having a total adiponectin concentration of 8.9 μg / mL or more was taken as 1, and the relative ratio of the health maintenance periods of subjects in three lower adiponectin regions was calculated. As a result, the relative ratio of the health maintenance period shown in FIG. 1 was obtained. In the case of a subject having a total adiponectin concentration of 5.0 to 6.6 μg / mL, the relative ratio of the health maintenance period is greatly reduced with a statistically significant difference, and MetS is easily developed.
Therefore, the present inventors further investigated the adiponectin region and tried to calculate the cutoff value of adiponectin. If this cut-off value can be calculated, the relative ratio of the health maintenance period will decrease with respect to that value in the case of a subject who falls below that value.
As the survival time distribution used in the acceleration model, the present inventors examined using three types of distribution, Weibull distribution, exponential distribution, and gamma distribution. As a result, it was possible to obtain 6.2 μg / mL as a cutoff value. Using this value as an index and organizing the results of the 4-year follow-up survey, the relative ratio (TR) of the health maintenance period shown in FIG. 2 could be calculated. That is, a subject whose blood total adiponectin concentration is 6.2 μg / mL or less is calculated to have a TR value of 0.22, compared with a subject having a total adiponectin concentration higher than this value, and the risk of developing MetS is about It was shown to increase 4.5 times.
As described above, the present inventors have found the cut-off value of the total adiponectin concentration in blood as an index that can predict an increase in the risk of developing MetS, and completed the present invention.

That is, the gist of the present invention is as follows.
(1) In order to prevent the onset of metabolic syndrome (MetS), a method for selecting a subject who needs life guidance regarding exercise and diet,
A method for selecting a subject, comprising measuring a total adiponectin value in a blood sample of the subject and selecting a subject having an adiponectin value of 6.2 μg / mL or less.
(2) A method for preventing the onset of MetS, wherein subjects having a blood total adiponectin level of 6.2 μg / mL or less are selected and life guidance regarding exercise and meal is performed.
(3) A method for predicting the risk of developing MetS,
A method for predicting that MetS will develop in a subject having a blood total adiponectin level of 6.2 μg / mL or less in a shorter period than that of a subject who does not.

The present invention is a method for predicting the risk of developing metabolic syndrome in healthy individuals. That is, a constant threshold (6.2 μg / mL or less) is set for the blood concentration of adiponectin in healthy individuals, and subjects whose blood concentration of adiponectin deteriorates beyond this are shorter than subjects who do not It was shown that the metabolic syndrome was developed in time (TR is about 0.22).
Thus, if the value of the total adiponectin concentration is used as an index and attention is paid to fluctuations in the adiponectin concentration, it is possible to appropriately evaluate the prediction of the occurrence of metabolic syndrome in healthy individuals. Therefore, for a subject whose blood concentration of adiponectin is 6.2 μg / mL or less, the risk of onset can be clearly recognized. Therefore, the subject's behavior changes easily, and the subject actively acts to avoid the risk of onset. As a result, the subject in the previous stage of metabolic syndrome can appropriately perform exercise therapy, diet control, etc. at an early stage, and can greatly reduce the frequency of transition to metabolic syndrome.

It is the figure which computed the relative ratio (TR value) of the health maintenance period in four numerical ranges of the blood concentration of all the adiponectin, and performed the mutual comparison. It is the figure which classify | categorized the test subject with the numerical value whose blood concentration of all the adiponectin is 6.2 microgram / mL or less and the test subject with the higher value, and evaluated by said TR value. In subjects with a total blood adiponectin concentration of 6.2 μg / mL or less, the relative proportion of the healthy maintenance period is greatly reduced when compared with subjects with higher concentrations, which is reduced to about 4.5 times. It is shown that. That is, it has been shown that subjects whose blood total adiponectin concentration is 6.2 μg / mL or less are more likely to develop metabolic syndrome.

The “metabolic syndrome (MetS)” of the present invention is a well-known standard (a joint statement of IDF, NHLBI, AHA, World Heart Federation, International Academic Society Society, International Association). That is, when visceral fat accumulates excessively, lifestyle-related diseases such as diabetes, hypertension, and dyslipidemia are likely to occur simultaneously. Moreover, arteriosclerosis is said to progress rapidly even in the reserve group in which no disease is yet diagnosed.
In the present invention, “adiponectin” is one of adipocytokines secreted from adipocytes and is a protein consisting of 244 amino acids. In the blood, several types of multimers are formed based on trimers. It is reported to exist. Recently, it has been reported that the abundance ratio of high molecular weight adiponectin corresponding to 12-18 mer more reflects the disease state. In the present invention, since the total concentration of adiponectin reflects the disease state, the blood concentration of adiponectin is used without distinction between the total concentration of adiponectin and the concentration of high molecular weight adiponectin. When the concentration of the high molecular weight adiponectin is measured, the concentration is evaluated by converting it to the total concentration of adiponectin.
In addition, as a physiological activity of adiponectin, increased insulin sensitivity, suppression of arteriosclerosis, anti-inflammation, suppression of myocardial hypertrophy, and the like have been reported. The blood concentration of adiponectin is said to be inversely correlated with visceral fat mass, and the range of normal human values is reported to be 5-15 μg / ml as the total concentration of adiponectin.
The blood concentration of the adiponectin of the present invention can be measured and calculated according to a known method. For example, based on known methods such as biological methods using enzymes, antibodies, etc. (especially immunological methods), optical methods that can be used to measure blood glucose levels, from each blood (serum or plasma) sample, It can be measured according to a conventional method.
In the present invention, in the region where the total adiponectin concentration is 3.1 to 8.3 μg / ml, the survival time analysis was performed by setting a cutoff value for each 0.1 μg / ml. As a result, a numerical value of 6.2 μg / ml was found to be most appropriate for predicting the onset of MetS as a cut-off value.

  In the present invention, “life guidance” refers to a therapy for maintaining and improving health, and may include, for example, an intervention therapy related to intake of supplements and health supplements, exercise and / or nutrition. In particular, it refers to conducting appropriate life guidance regarding meals and exercise, and performing numerical management at a specific medical examination level. For example, in the numerical management of glucose metabolism abnormalities, appropriate lifestyle guidance so that HbA1c (NGSP value) is less than 5.6% and fasting blood glucose level is less than 100 mg / dL as the reference value for specific health guidance level And correction of obesity.

  EXAMPLES Next, although an Example is given and this invention is further demonstrated, this invention is not limited to these.

Examination of cut-off value in total adiponectin level (1) Evaluation subject a) Subject subject:
Tokushima male workers (20-60 years old) who received an epidemiological survey in 2008: 467 The following subjects are excluded from the subject.
(Exclusion criteria) Postprandial examinee, unblooded, measurement deficient, already diagnosed with MetS b) Analysis target:
365 people who could follow MetS onset or not c) Follow-up period:
4 years (2008-2012)
d) Evaluation data:
Data collected from subjects include blood glucose level, insulin concentration, other blood factors (adiponectin, free fatty acid, neutral fat (triglyceride), HDL-cholesterol, interleukin-6, interleukin-18, high sensitivity CRP, etc. ), Lifestyle (nutrient intake, activity level of daily life), background (age, history of drug use, past history, family history, drinking habits, smoking habits, etc.), body measurements (height, weight, waist circumference, hip circumference) Body fat percentage, blood pressure, etc.). Blood was collected after fasting for 10 hours or longer, and the factors in the blood were measured.

(2) Data processing a) Total adiponectin concentration in blood:
The serum of the subject was measured with a human adiponectin latex kit (Otsuka Pharmaceutical). The measured value was divided into four regions (4.9 or less, 5.0 to 6.6, 6.7 to 8.8, 8.9 or more), and 8.9 (μg / mL) The relative proportion of the health maintenance period of subjects having an adiponectin concentration of 1 or more was taken as 1, and the relative proportion of the health maintenance period of subjects in each adiponectin region below that was calculated. The result is shown in FIG.
b) Diagnostic Criteria Based on the criteria in Table 1 below, the presence or absence of metabolic syndrome (MetS) was diagnosed (a joint statement of IDF, NHLBI, AHA, World Heart federation, International Aesthetics Society Society, ).

［注記］上記５項目中、３項目以上該当するとメタボリックシンドロームと判定。

[Note] If 3 or more of the above 5 items are applicable, it is determined as metabolic syndrome.

c) Endpoint:
Number of MetS cases: 45 cases d) Adjustment factors:
Age, BMI, smoking habit, drinking habit, exercise habit

(3) Analysis method In order to obtain an index for predicting the onset of MetS in the range of the total adiponectin concentration of 3.1 to 8.3 μg / mL in FIG. 1, the representative is the representative of the total adiponectin concentration in blood and the number of onset of MetS. Evaluation was performed using the acceleration model, which is a typical survival analysis method, and applying the Weibull distribution, the exponential distribution, and the gamma distribution.
In addition, the data using log likelihood is modeled from the cut-off value candidates divided into two groups, a low-risk group (subject group with high adiponectin concentration) and a high-risk group (subject group with low adiponectin concentration). The one that fits in was selected.
a) Weibull distribution:
Table 5 below shows the five results in descending order of log likelihood, calculated using the Weibull distribution.

［注記］
調整因子は、年齢、ＢＭＩ、喫煙習慣、飲酒習慣、運動習慣である。
１）被験者を総アディポネクチン濃度で２群に区分する際のカットオフ値
２）ＭｅｔＳを発症するまでの健康維持期間の相対比率を表す。カットオフ値が６．２の場合、その値以下の被験者が４年以内にＭｅｔＳを発症する可能性が、より高い数値の被験者と比較して約４．５倍高いことを表している。

[Note]
The adjustment factors are age, BMI, smoking habit, drinking habit, and exercise habit.
1) Cut-off value when subject is divided into two groups based on total adiponectin concentration 2) Represents the relative proportion of health maintenance period until MetS develops. A cut-off value of 6.2 indicates that subjects below that value are about 4.5 times more likely to develop MetS within 4 years compared to higher numbers of subjects.

b) Exponential distribution:
Table 3 below shows five results calculated in exponential distribution in descending order of log likelihood.

［注記］
調整因子は、年齢、ＢＭＩ、喫煙習慣、飲酒習慣、運動習慣である。
１）は上記と同じ意味を表す。
２）も上記と同じであり、カットオフ値が６．２の場合、その値以下の被験者が４年以内にＭｅｔＳを発症する可能性は、より高い数値の被験者と比較して約３倍高いことを表している。

[Note]
The adjustment factors are age, BMI, smoking habit, drinking habit, and exercise habit.
1) represents the same meaning as above.
2) is the same as above, and when the cut-off value is 6.2, subjects below that value are about 3 times more likely to develop MetS within 4 years than those with higher numbers Represents that.

c) Gamma distribution:
Table 4 below shows the five results calculated in descending order of log likelihood.

［注記］
調整因子は、年齢、ＢＭＩ、喫煙習慣、飲酒習慣、運動習慣である。
１）は上記と同じ意味を表す。
２）も上記と同じであり、カットオフ値が６．２の場合、その値以下の被験者が４年以内にＭｅｔＳを発症する可能性は、より高い数値の被験者と比較して約４．５倍高いことを表している。

[Note]
The adjustment factors are age, BMI, smoking habit, drinking habit, and exercise habit.
1) represents the same meaning as above.
2) is the same as above, and when the cut-off value is 6.2, the possibility that a subject below that value will develop MetS within 4 years is about 4.5 as compared to a higher numerical subject. It represents that it is twice as expensive.

(4) Conclusion From the results of Tables 2 to 4, it was shown that the MetS onset can be predicted most appropriately when the cut-off value is 6.2 μg / mL in all three distributions examined.
In the above three distribution calculation methods, evaluation was performed using the Akaike Information Criterion (AIC) in order to determine which distribution method is optimal for obtaining the cut-off value of the adiponectin concentration. As a result, the Weibull distribution was selected with the smallest AIC (smaller is better). The 95% confidence interval under the Weibull distribution is as follows.

  From the above, in a population with many male workers in middle age, as shown in FIG. 2, subjects with a total adiponectin concentration of 6.2 μg / mL or less are at a higher risk of developing MetS than subjects who do not. It was 4.5 times (= 1 / 0.22) higher.

  According to the method for selecting patients with MetS onset according to the present invention, it is possible to select subjects with high risk of developing metabolic syndrome at an early stage using blood data of subjects (blood adiponectin concentration is 6.2 μg / mL or less). Therefore, improvement and treatment of eating habits and exercise habits can be started at the stage before the onset or at the early stage of the onset, and the transition to the metabolic syndrome can be avoided. That is, using the blood concentration of adiponectin as an index of 6.2 μg / mL as an index, it is predicted that the risk of developing MetS within about several years (about 4 years) is about 4.5 times higher for subjects with this value or less. it can. Therefore, the present invention is an invention of a method for selecting a subject that is extremely useful for the initial diagnosis and treatment of metabolic syndrome.

Claims (4)

A method of selecting subjects who need lifestyle guidance regarding exercise and / or diet for the prevention of the onset of metabolic syndrome (MetS),
A method for selecting a subject, comprising measuring a total adiponectin value in a blood sample of the subject and selecting a subject having an adiponectin value of 6.2 μg / mL or less.   6. A method for preventing the onset of MetS, comprising selecting a subject having a blood total adiponectin level of 6.2 μg / mL or less and providing life guidance regarding exercise and diet. A method for predicting the risk of developing MetS,
A method for predicting the onset of MetS with a higher probability in subjects with a blood total adiponectin level of 6.2 μg / mL or less than those who do not. For subjects whose blood adiponectin level is 6.2 μg / mL or less,
A method for reducing the risk of developing MetS, characterized by providing lifestyle guidance on exercise and / or meals.

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