JP6512590B2 - Method of predicting the risk of developing metabolic syndrome - Google Patents

Description

  The present invention is a method for predicting the risk of developing metabolic syndrome (glycolipid metabolism disorder). In particular, the present invention relates to a method of predicting the risk of developing metabolic syndrome using adiponectin concentration in blood of middle-aged male workers as an indicator.

In recent years, so-called metabolic syndrome has been increasing in Japan, and it has become a serious medical and social problem, as the weight of cardiovascular disease risk factor based on visceral fat type obesity is increasing. In the past, adipose tissue has been considered as an organ only for storing extra energy, but in recent years it controls in vivo immunity, inflammatory reactions, energy metabolism, etc. as endocrine organs that secrete various physiologically active substances, so-called adipocytokine. It is clear that you are doing.
Adipocytokines are inflammatory cytokines and TNF-α that causes insulin resistance, PAI-1 that promotes thrombus formation, and bad adipokines such as HB-EGF that causes migration and proliferation of vascular smooth muscle and anorectic action Good adipokine such as adiponectin which improves leptin and insulin resistance is included. In the state where visceral fat is accumulated, abnormal secretion of these adipocytokine occurs, which is considered to cause glucose / lipid metabolism abnormality.
Although adiponectin, which is one of the good adipokine, is specifically secreted from adipocytes, it is characterized in that the blood concentration is reduced in obese patients, particularly visceral fat type obese patients. Blood adiponectin levels are inversely correlated with risk factors for cardiovascular diseases such as lipid, blood pressure and CRP, and hypoadiponectinemia is reported to be an independent risk factor for diabetes, hypertension and coronary artery disease.

  In basic studies using mice in which the adiponectin gene has been deleted, it has been revealed that adiponectin has an insulin resistance improving action, an anti-inflammatory action, and an anti-atherosclerotic action. Adiponectin promotes fatty acid combustion and utilization of sugars in the liver and skeletal muscle which are energy consuming organs, and exerts a metabolism improving action by suppressing gluconeogenesis. Thiazolidine derivatives which 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 to act in a cardioprotective manner, suppressing cardiac hypertrophy, ischemia reperfusion injury and remodeling after myocardial infarction. From the above, adiponectin has drawn great attention not only as a biomarker in metabolic syndrome-based cardiovascular diseases, but also as a target for new therapeutic agents (Patent Documents 1 and 2).

  In addition, adiponectin as a biomarker is considered to be associated with increased risk of cardiovascular disease (myocardial infarction, narrowing) in patients with ischemic heart disease (IHD) who have undergone PTCA (percutaneous transluminal coronary angioplasty). It is known to reduce cardiovascular disease). However, there are gender differences in blood levels of adiponectin, making it difficult to use as a biomarker. For example, in humans, high molecular weight adiponectin levels in blood are about twice as high as in females in males. Furthermore, adiponectin is suggested to be more strongly involved in insulin resistance in men, but there is also a report that in women, the association with insulin resistance is weak (Non-patent Document 1). Thus, although adiponectin is known for its various effects, the criteria as a biomarker were not so clear.

WO 2010/03585 Japanese Patent Application Publication No. 2011-521248

Yasunao Yoshimasa, 2005 Grant-in-Aid for Health and Labor Science Research Grants for Children and Families Comprehensive Research Project Sharing Research Report "Study on sex differences in cardiovascular disease risk factors"

  The present invention provides a method for predicting the risk of developing metabolic syndrome, and more specifically, setting a cutoff value for adiponectin as a biomarker and using it as a criterion for evaluating the risk of developing To aim.

Metabolic syndrome (MetS) is considered as a risk factor for type 2 diabetes, according to past epidemiological surveys, and it is thought that suppressing the onset of MetS can prevent the onset of type 2 diabetes. For this reason, various influential factors contributing to MetS development are examined, and it is thought that the contribution of adipokine secreted from adipocytes is large. Among them, it is reported that adiponectin and MetS are particularly strongly associated. However, in these reports, reports from cross-sectional surveys account for a large number, and few reports have examined the adiponectin cutoff value for MetS onset.
Therefore, based on the results of the 4-year follow-up survey of male workers in Tokushima prefecture, the present inventor examined the cutoff value of adiponectin for the onset of metabolic syndrome. 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, 8.98.9), The relative proportion of the health maintenance period (hereinafter, the time ratio calculated by the accelerated model in the survival time analysis method is taken as the relative proportion of the health maintenance period) was calculated from the 4-year follow-up of the corresponding subjects. Assuming that the relative ratio (TR) of the healthy maintenance period of the subject with a total adiponectin concentration of 8.9 μg / mL or more was 1, the relative ratio of the healthy maintenance period of the subject with three adiponectin regions lower was calculated. As a result, the relative ratio of the health maintenance period shown in FIG. 1 was obtained. In the case of subjects with a total adiponectin concentration of 5.0 to 6.6 μg / mL, the relative proportion of the health maintenance period is significantly reduced with a statistically significant difference, and it is likely to develop MetS.
Therefore, the present inventors further reviewed the above adiponectin region and attempted to calculate the adiponectin cut-off value. If this cutoff value can be calculated, the relative proportion of the health maintenance period will be reduced in the case of a subject below that value based on that value.
The present inventors examined three types of survival time distributions used in the acceleration model, Weibull distribution, exponential distribution, and gamma distribution. As a result, 6.2 μg / mL could be obtained as a cutoff value. Using this value as an index and arranging the results of the 4-year follow-up, the relative proportion (TR) of the health maintenance period shown in FIG. 2 could be calculated. That is, a subject with a total adiponectin concentration in blood of 6.2 μg / mL or less has a TR value of 0.22 when compared with a subject with a total adiponectin concentration higher than this value, and the risk of developing MetS is about It was shown to increase by 4.5 times.
As described above, the present inventors have found a cutoff value of 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) A method of selecting a subject who needs daily life related exercise and diet for preventing the onset of metabolic syndrome (MetS),
A method of selecting a subject, comprising measuring a total adiponectin level in a blood sample of the subject and selecting a subject having an adiponectin level of 6.2 μg / mL or less.
(2) A method for preventing the onset of MetS, which comprises selecting subjects having a blood total adiponectin level of 6.2 μg / mL or less and giving living guidance on exercise and diet.
(3) A method of predicting the risk of developing MetS,
A method for predicting MetS onset in a subject whose total blood adiponectin level is 6.2 μg / mL or less in a shorter period than that of the non-subject.

The present invention is a method of predicting the risk of developing metabolic syndrome in healthy individuals. In other words, subjects who set blood levels of adiponectin in healthy individuals to a certain threshold (6.2 μg / mL or less) and whose blood levels of adiponectin got worse were shorter than those who did not. It was shown that metabolic syndrome was developed within a time (TR is about 0.22).
As described above, if attention is paid to the change in adiponectin concentration using the value of the above-mentioned total adiponectin concentration as an index, it is possible to appropriately evaluate the prediction of the onset of metabolic syndrome in a healthy subject. Therefore, for subjects with blood levels of adiponectin of 6.2 μg / mL or less, the risk of onset can be clearly recognized. Because of that, the behavior change of the subject is likely to occur, and the subject actively acts to avoid the risk of onset. As a result, subjects in the former stage of metabolic syndrome can appropriately perform exercise treatment, diet control, etc. at an early stage, and the frequency of transition to metabolic syndrome can be greatly reduced.

It is the figure which calculated the relative ratio (TR value) of the health maintenance period in four numerical ranges of the blood concentration of total adiponectin, and performed mutual comparison. It is the figure which divided the test subject in which the blood concentration of whole adiponectin has a numerical value below 6.2 micrograms / mL, and the test subject whose value is higher than it, and evaluated it by the above-mentioned TR value. Subjects with a total adiponectin concentration of 6.2 μg / mL or less in the blood had a significant reduction in the relative proportion of the health maintenance period when compared to subjects with higher concentrations, which was reduced by about 4.5 times. Is shown. That is, it is shown that a subject with a total adiponectin concentration in blood of 6.2 μg / mL or less is more likely to develop metabolic syndrome.

The “metabolic syndrome (MetS)” of the present invention refers to one that corresponds to a known standard (a joint statement of IDF, NHLBI, AHA, World Heart Federation, International Atherosclerosis Society, International Association for the Study of Obesity). That is, when visceral fat is excessively accumulated, lifestyle-related diseases such as diabetes, hypertension and dyslipidemia are easily caused. Furthermore, arteriosclerosis is said to progress rapidly even in the preparatory group that has not yet been diagnosed with disease.
In the present invention, “adiponectin” is one of the adipocytokine secreted from adipocytes, and is a protein consisting of 244 amino acids, and is based on a trimer in the blood, with several types of multimers It is reported to exist. Recently, it has also been reported that the abundance ratio of high molecular weight adiponectin corresponding to a 12-18-mer or the like more reflects the pathological condition. In the present invention, since the total concentration of adiponectin does not change in reflecting the pathological condition, the total concentration of adiponectin and the concentration of high molecular weight adiponectin are used without distinction as the blood concentration of adiponectin. In addition, when the concentration of high molecular weight adiponectin is measured, it is evaluated by converting it to the total concentration of adiponectin from the abundance ratio thereof.
In addition, as physiological activity of adiponectin, enhancement of insulin sensitivity, suppression of arteriosclerosis, anti-inflammatory, suppression of myocardial hypertrophy and the like have been reported. The blood concentration of adiponectin is inversely correlated to the visceral fat mass, and the range of normal values for humans is reported to be 5 to 15 μg / ml as the total concentration of adiponectin.
The blood concentration of adiponectin of the present invention can be measured and calculated according to known methods. For example, based on known methods such as biological methods (in particular, immunological methods) using enzymes, antibodies etc., optical methods that can be used to measure blood glucose levels, each from blood (serum to plasma) samples, It can be measured according to a conventional method.
In the present invention, survival time analysis was performed by setting a cutoff value every 0.1 μg / ml in a region of a total adiponectin concentration of 3.1 to 8.3 μg / ml. As a result, a value of 6.2 μg / ml was found to be the most suitable for predicting MetS onset as a cutoff value.

  In the present invention, “life guidance” refers to a therapy for maintaining and improving health, and can include, for example, intake of supplements and health supplements, and intervention therapy for exercise and / or nutrition. In particular, it refers to providing appropriate lifestyle guidance regarding diet and exercise, and performing numerical control at a specific medical checkup level. For example, for numerical control of glucose metabolism disorders, appropriate lifestyle guidance such 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 specified health guidance level And correction of obesity.

  EXAMPLES The present invention will next be described by way of examples, which should not be construed as limiting the invention thereto.

Examination of cutoff value in total adiponectin level (1) Evaluation target a) Target subject:
Tokushima male workers (20-60 years old) who received the 2008 epidemiological survey: 467 The following subjects were excluded from the study.
(Exclusion criteria) Post-meal examinees, uncollected persons, measurement value deficient persons, persons already diagnosed with MetS b) Analysis target:
365 people who were able to track the presence of MetS c) Follow-up period:
Four 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 in daily life), background (age, medication history, medical history, family history, drinking habits, smoking habits, etc.), physical measurement (height, weight, abdominal girth, hip area) , Body fat percentage, blood pressure etc.). Blood was collected after fasting for 10 hours or more, and factors in the blood were measured.

(2) Data processing a) Total adiponectin concentration in blood:
The serum of the subject was measured by a human adiponectin latex kit (Otsuka Pharmaceutical). Divide the measured values into four regions (4.9 or less, 5.0 to 6.6, 6.7 to 8.8, 8.9 or more), and use the acceleration model to obtain 8.9 (μg / g The relative ratio of the maintenance period of the subject of each adiponectin region below it was calculated by setting the relative ratio of the maintenance period of the subject having the above adiponectin concentration to 1. The results are 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 Atherosclerosis Society, International Association for the Study of Obesity) ).

［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 three or more of the above five items fall under the above, it is judged as metabolic syndrome.

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

(3) Analysis method In the total adiponectin concentration range of 3.1 to 8.3 μg / mL in FIG. 1, in order to obtain an index for predicting the onset of MetS, a representative is given for the total adiponectin concentration in blood and the number of MetS episodes. We evaluated by applying Weibull distribution, exponential distribution, and gamma distribution using an acceleration model, which is a typical survival time analysis method.
In addition, among the cutoff value candidates divided into two groups of low risk group (subject group with high concentration of adiponectin) and high risk group (subject group with low concentration of adiponectin), data is modeled using log likelihood I chose something that was true to me.
a) Weibull distribution:
The calculation was performed by the Weibull distribution, and five results are shown in Table 2 below 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）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]
Modulators are age, BMI, smoking habits, drinking habits, exercise habits.
1) Cut-off value when dividing test subjects into 2 groups by total adiponectin concentration 2) Express relative ratio of health maintenance period until MetS is developed. A cutoff value of 6.2 indicates that subjects below that value are about 4.5 times more likely to develop MetS in 4 years than subjects with higher numbers.

b) Exponential distribution:
Calculated by exponential distribution, five results are shown in the following Table 3 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]
Modulators are age, BMI, smoking habits, drinking habits, exercise habits.
1) represents the same meaning as described above.
2) The same as above, and with a cutoff value of 6.2, the probability that a subject below that value develops MetS within 4 years is about 3 times higher than the subject with a higher numerical value Represents that.

c) Gamma distribution:
Calculated by gamma distribution, five results are shown in Table 4 below 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]
Modulators are age, BMI, smoking habits, drinking habits, exercise habits.
1) represents the same meaning as described above.
2) The same as above, and with a cutoff value of 6.2, the probability that subjects below that value develop MetS within 4 years is approximately 4.5 compared to the higher number of subjects It represents twice as high.

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

  From the above, in a group with many male workers in middle age, subjects with a total adiponectin concentration of 6.2 μg / mL or less have a risk of developing MetS more than subjects without them, as shown in FIG. It was shown to be 4.5 times (= 1 / 0.22) higher.

  According to the patient sorting method for MetS onset of the present invention, subjects having a high risk of developing metabolic syndrome can be sorted at an early stage using blood data of subjects (the adiponectin concentration in blood is 6.2 μg / mL or less). Therefore, improvement and treatment of diet and exercise habit can be started at the early or early stage of onset, and transition to metabolic syndrome can be avoided. That is, it is predicted that the risk of developing MetS within several years (about 4 years) is about 4.5 times higher for subjects with numerical values lower than this, using a blood concentration of 6.2 μg / mL of adiponectin as an index it can. Therefore, the present invention is an invention of a method for screening subjects extremely useful for initial diagnosis and treatment of metabolic syndrome.

Claims (4)

A method of selecting subjects who need living guidance on exercise and / or diet in order to prevent metabolic syndrome (MetS) from developing within 4 years of blood collection for measuring blood total adiponectin levels. ,
And measuring the total adiponectin value of the subject's blood,
Selecting a subject having the total adiponectin value of 6.2 μg / mL or less,
Including and
The subject is male,
How to sort subjects. Were selected subjects with 6.2Myug / mL or less of the total adiponectin levels in the blood, include performing the lifestyle guidance relating to exercise and / or dietary to the subject,
The subject is male,
A method for preventing MetS from developing within 4 years of blood collection for measuring blood total adiponectin level .   A method of using a subject's blood total adiponectin level as an index showing the possibility of developing MetS within 4 years from blood collection for measuring blood total adiponectin level,
  If the total adiponectin level in blood is 6.2 μg / mL or less, it indicates that there is the possibility.
  The subject is male,
Method. For subjects with a total blood adiponectin level of 6.2 μg / mL or less,
Including giving lifestyle instruction on exercise and / or diet,
The subject is male,
A method for reducing the risk of MetS developing within 4 years of blood collection to measure total adiponectin levels in blood .

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