JP2019132839A - Method of determining mean red blood cell age - Google Patents

Abstract

To provide means that allow for easily and accurately deriving mean red blood cell age without making diagnosis that imposes burdens on patients.SOLUTION: A method disclosed herein comprises a step of plugging an average blood glucose (AG) level and a hemoglobin A1c (HbA1c) level of a subject into a formula selected from a group of formulas below to determine mean red blood cell age (MRBC). In the formulas, MRBC represents mean red blood cell age (day), HbA1c represents a hemoglobin A1c level, Kg represent a saccharification rate (dL/mg/day), and AG represents an average blood glucose level (mg/dL).SELECTED DRAWING: None

Description

  The present invention relates to a method for determining an average erythrocyte age, and a system and program for determining an average erythrocyte age.

  Low control of blood glucose levels is important in diabetic patients, and monitoring of blood glucose levels is essential, but plasma glucose levels easily vary with diet and other factors. The hemoglobin A1c (HbA1c) value, which indicates the ratio of glycated hemoglobin to total hemoglobin, rises and falls reflecting the average of blood glucose levels in the past one to several months, and is therefore used as a biomarker for average blood glucose (AG) values.

In order to estimate the average blood glucose level from the hemoglobin A1c value, many studies on the premise of a linear relationship have been reported. For example, Nathan et al., 2008 (Non-patent Document 1) shows the following equation (1): Proposed:

  The formula (1) is widely used among doctors at the recommendation of the American Diabetes Association (ADA). In addition, the linear relational expression proposed so far including the above-described formula (1) is functional and effective in actual clinical use, but includes some mathematical contradictions.

First, in these formulas, hemoglobin is glycated even in the absence of glucose in the plasma (AG = 0 mg / mL). When these equations are graphed, it is necessary to pass through the origin.
Second, in these equations, the hemoglobin A1c value exceeds the theoretical limit value of 100%. Even when erythrocytes are immersed in saturated sugar water (about 200,000 mg / mL), the hemoglobin A1c value should not exceed 100%.

On the other hand, mean erythrocyte age (M _RBC ) is known as a biomarker in diagnosis of hemolytic anemia (Non-patent Document 2), gastrointestinal bleeding (for example, bleeding due to colorectal cancer), and the like. For example, the lifespan of red blood cells is normally about 120 days, but if there is bleeding or hemolytic disease, the amount of red blood cells produced from the bone marrow increases, which increases 6 to 8 times the normal value. In hemolytic anemia, it is shortened to 100 days or less. If there is a tendency for the amount of red blood cells in the blood to become deficient, that is, if there is a tendency for red blood cells to decompose or metabolize due to some factor and a shortage of red blood cells, hematopoietic stem cells in the bone marrow tissue proliferate and differentiate. Increase the production of red blood cells. Therefore, unless there is a serious hematopoietic abnormality, a large amount of bleeding, or hemolysis, the blood red blood cell count does not change greatly. Therefore, it has been difficult to detect abnormalities such as hemorrhage and hemolysis in the body from the blood red blood cell count.

Conventional methods for measuring red blood cell lifetime include the administration of radioactive isotope ⁵¹ Cr and artificially chemically modified red blood cells (for example, biotin label) as an injection to the human body, and measuring the rate of decrease in their blood levels. There are ways to be used clinically. However, these methods also have the risk of serious side effects such as the problem of internal exposure in subjects and anaphylactic shock caused by repeated administration of chemically modified red blood cells that are immunologically foreign, and are limited according to the severity of the disease It has been used only for purpose. Against this background, development of a non-radioactive and safe red blood cell lifetime measurement method has been awaited.

Nathan, DM, Kuenen, J., Borg, R., Zheng, H., Schoenfeld, D., Heine, RJ, 2008. Translating the A1C assay into estimated average glucose values. Diabetes Care 31 (8), 1473-1478 . Usuki Kensuke, 2015, Hemolytic anemia: Diagnosis and treatment, Journal of the Japan Society for Internal Medicine, 104, 7, pp. 1389-1396 Shrestha, RP, Horowitz, J., Hollot, CV, Germain, MJ, Widness, JA, Mock, DM, Veng-Pedersen, P., Chait, Y., 2016. Models for the red blood cell lifespan. J Pharmacokinet Pharmacodyn 43 (3), 259-274. Beach, K. W., 1979. A theoretical model to predict the behavior of glycosylated hemoglobin levels. J Theor Biol 81 (3), 547-561. Higgins, P. J., Bunn, H. F., 1981. Kinetic analysis of the nonenzymatic glycosylation of hemoglobin. J Biol Chem 256 (10), 5204-5208. Ladyzynski, P., Wojcicki, JM, Bak, M., Sabalinska, S., Kawiak, J., Foltynski, P., Krzymien, J., Karnafel, W., 2008. Validation of hemoglobin glycation models 22 using glycemia monitoring in vivo and culturing of erythrocytes in vitro. Ann Biomed Eng 36 (7), 1188-1202. Lledo-Garcia, R., Mazer, N. A., Karlsson, M. O., 2013.A semi-mechanistic model of the relationship between average glucose and HbA1c in healthy and diabetic subjects.J Pharmacokinet Pharmacodyn 40 (2), 129-142. Malka, R., Nathan, D. M., Higgins, J. M., 2016.Mechanistic modeling of hemoglobin glycation and red blood cell kinetics enables personalized diabetes monitoring.Sci Transl Med 8 (359), 359ra130.

  In order to eliminate some mathematical contradictions of the linear relational expression, the present inventor searched for a more accurate relational expression between the average blood glucose level and the hemoglobin A1c value. A nonlinear relational expression (formula (21) described later) was successfully obtained. Furthermore, based on this relational expression, the inventors succeeded in deriving a relational expression or an approximate expression thereof that can easily and accurately determine the average erythrocyte age from the average blood glucose level and the hemoglobin A1c value.

  Accordingly, an object of the present invention is to propose a relational expression that can determine the average erythrocyte age from the average blood glucose level and hemoglobin A1c value of the subject or an approximate expression thereof, and a method for determining the average erythrocyte age using these expressions And providing a system and program for determining mean erythrocyte age.

The measurement principle of the present invention is a method for measuring the life of red blood cells by utilizing the fact that red blood cells newly born in the body undergo continuous saccharification non-enzymatically through blood glucose for 120 days.
The longer nascent red blood cells are exposed to blood glucose, the higher the blood glucose concentration, and the higher the blood glucose concentration, the more saccharification progresses. Changes to a stable bond. Thereby, saccharification accumulates irreversibly. Therefore, the longer the red blood cell life, the more saccharification proceeds.
Since the mechanism of erythrocyte glycation is a non-enzymatic reaction, it is not affected by qualitative and quantitative changes in other enzymes, proteins, etc., and stable saccharification occurs continuously in the body. It can also be reproduced in a test tube. The present invention provides a technique for measuring erythrocyte lifetime utilizing such a constant, non-enzymatic saccharification reaction in a living body.
As described above, homeostasis is maintained so that the amount of red blood cells in human blood is always kept constant. Therefore, when continuous hemorrhage or hemolysis occurs in the body, the bone marrow tissue attempts to regenerate red blood cells to return to a normal value. In this case, the supply and demand (metabolism) rate of red blood cells increases, and the life of red blood cells becomes shorter than usual. Therefore, this red blood cell has a short exposure time with glucose in the blood, that is, the red blood cell ends its life with low glycation.
The technique of the present invention is a method for calculating the lifetime of erythrocytes from the exposure time of erythrocytes to blood glucose using the aforementioned non-enzymatic glycation mechanism of erythrocytes physiologically present in the human body.

Said subject is according to the invention,
[1] A method of determining an average erythrocyte age based on a subject's average blood glucose (AG) value and hemoglobin A1c (HbA1c) value;
[2] The subject's average blood glucose (AG) value and hemoglobin A1c (HbA1c) value are expressed by the following formulas (30), (34), and (35):
_{Wherein, M RBC} is the mean red blood cell age (day), HbA1c is hemoglobin A1c value, _{k g} is the glycation rate (dL / mg / day), AG is an average blood glucose level (mg / dL) is there]
Determining the mean erythrocyte age (M _RBC ) by substituting into an expression selected from the group consisting of:
[3] (1) Means for inputting an average blood glucose (AG) value and a hemoglobin A1c (HbA1c) value;
(2) Calculation means for calculating an average erythrocyte age based on the inputted average blood glucose level and hemoglobin A1c value;
(3) means for outputting the calculated mean erythrocyte age;
A system for determining mean erythrocyte age, comprising:
[4] The computing means is represented by the following formula (30), (34), or (35):
_{Wherein, M RBC} is the mean red blood cell age (day), HbA1c is hemoglobin A1c value, _{k g} is the glycation rate (dL / mg / day), AG is an average blood glucose level (mg / dL) is there]
The system of [3], which calculates an average erythrocyte age based on at least one of
[5] A program for determining an average red blood cell age (M _RBC ) for causing a computer to function as the following means (1), means (2), and means (3):
(1) Means for inputting an average blood glucose (AG) value and a hemoglobin A1c (HbA1c) value;
(2) Calculation means for calculating an average red blood cell age (M _RBC ) based on the inputted average blood glucose level and hemoglobin A1c value;
(3) means for outputting the calculated mean erythrocyte age;
[6] The computing means is represented by the following formula (30), (34), or (35):
_{Wherein, M RBC} is the mean red blood cell age (day), HbA1c is hemoglobin A1c value, _{k g} is the glycation rate (dL / mg / day), AG is an average blood glucose level (mg / dL) is there]
The program according to [5], wherein an average erythrocyte age is calculated based on at least one of the following:
Can be solved.

  According to the present invention, the average erythrocyte age can be determined more easily and accurately in a less invasive manner than conventional methods by blood glucose level measurement and blood sampling, regardless of conventional isotope administration or chemically modified erythrocyte injection administration. .

In diabetic patients, blood vessels become fragile, and when they become severe, tissue bleeding may occur. Such hemorrhage is relatively inconvenient, such as sensitive detection of red blood cells in the stool if it is in the gastrointestinal tract, but it is difficult to detect if bleeding or hemolysis occurs outside the gastrointestinal tract, It could not be discovered until the medical condition became serious.
The method of the present invention can detect the life of erythrocytes, that is, the presence of bleeding and hemolysis, only by a test method usually applied to diabetic patients, such as measurement of HbA1c in blood and measurement of blood glucose concentration of diabetic patients. it can. In other words, this is a new technique that can determine the life span of red blood cells only from data of examination methods performed on normal diabetic patients. The technology of the present invention having such a specification is the first method that can calculate the red blood cell lifetime without performing any additional or invasive treatment on the patient.
On the other hand, at the site of bone marrow transplantation, the erythrocyte supply rate from the transplanted bone marrow can be monitored by using the method of the present invention. Since the method of the present invention has no risk of exposure to radiation or repeated administration of drugs, the lifetime of red blood cells can be continuously measured.
Since the technology of the present invention is a method constituted by such specifications, it is possible to easily measure the life of red blood cells in the clinical field without requiring special medical facilities and specialists for radiation handling. ing.

FIG. 1A is a probability density function p (t) of red blood cells, and FIG. 1B is a normalized red blood cell lifetime distribution. FIG. 2A shows a three-compartment model of hemoglobin glycation and FIG. 2B shows a simplified two-compartment model. FIG. 3A is a graph that visualizes the relationship between the average blood glucose and HbA1c shown in Equation (21), and FIG. 3B is a graph that partially enlarges it. FIG. 4A is a graph showing an approximation of the relationship between average blood glucose and HbA1c together with the original complete relational expression (21), and FIG. 4B is a graph in which it is partially enlarged. FIG. 5 is a graph showing the relationship between the mean erythrocyte age (M _RBC ) and iA1c / (1000-2 / 3 × iA1c).

In the method for determining the average erythrocyte age of the present invention (hereinafter sometimes referred to as the method of the present invention), the average erythrocyte age (M _RBC ) is calculated from the average blood glucose (AG) value obtained from the subject and the hemoglobin A1c (HbA1c) value. Can be determined. In the present invention, as will be described later, a plurality of specific approximate expressions that can determine the average erythrocyte age are provided. However, the essence of the present invention is not limited to these individual approximate expressions. This is based on a new technical idea that the average age of red blood cells can be obtained from two test values, ie, the hemoglobin A1c value and the hemoglobin A1c value.

  The average blood glucose level and hemoglobin A1c level can be obtained by a conventional method. In particular, the average blood glucose level can be measured over time over a long period of time with a continuous blood glucose measurement device that can be worn on the body. HbA1c is a ratio of glycated hemoglobin to total hemoglobin. In each formula in this specification, 100% is assumed to be 1 (for example, 0.055 if 5.5%). use.

A relational expression of an average blood glucose level, a hemoglobin A1c value, and an average erythrocyte age or an approximate expression thereof (hereinafter, the relational expression in the present invention or an approximate expression thereof) used in the method of the present invention or the system or program of the present invention described later In particular, the approximate expression is a relational expression (21) between the average blood sugar level and the hemoglobin A1c value, as will be described in detail in the examples described later:
Wherein, HbA1c is hemoglobin A1c value, AG is an average blood glucose (mg / dL), k _g is the glycation rate (dL / mg / day), α, β is a parameter of the gamma distribution ]
It is derived based on.

Here, the equation (21) is the probability of erythrocyte death according to the gamma distribution determined by the present inventor among the three types of distribution proposed by Shrestha et al., 2016 (Non-patent Document 3). Density function p (t):
[Where α and β are parameters of the gamma distribution, and Γ means Euler's gamma function]
It is based on.

The relational expression or the approximate expression thereof in the present invention is not limited to the following, for example,
_{Wherein, M RBC} is the mean red blood cell age (day), HbA1c is hemoglobin A1c value, _{k g} is the glycation rate (dL / mg / day), AG is an average blood glucose level (mg / dL) is there]
Can be mentioned.

  Equation (30), which is a hyperbolic approximation of equation (21), approximation equation (34) of equation (21), and equation (35), which is a linear approximation of equation (21), are all used to determine the average erythrocyte age. Although it is an approximate expression that can be performed, it is an approximation close to Expression (21) that gives a new and accurate nonlinear relationship between AG and HbA1c in the steady state, and in that it is a nonlinear approximation, Expression (30 ) And (34) are preferable, and (30) is more preferable because it is the closest approximation.

As shown in Table 1 described later, k _g (saccharification rate, unit: dL / mg / day) in the above formula is reported as 6 to 10 × 10 ⁻⁶ dL / mg / day as an estimated value, For example, it can select suitably in this range. Moreover, in a certain group, average erythrocyte age, hemoglobin A1c value, and average blood glucose level can be measured, and _kg can be determined based on the measured average blood glucose level. Furthermore, as an application mode of the present invention, even if the average erythrocyte age still contains k _g , the relative level can be determined with respect to the normal value. In this mode, k _g is specified. You can get useful information without doing it.

The system for determining the average erythrocyte age of the present invention (hereinafter sometimes referred to as the present invention system) is not limited to the above-described relational expression in the present invention or an approximate expression thereof.
(1) means for inputting an average blood glucose (AG) value and a hemoglobin A1c (HbA1c) value (hereinafter referred to as input means);
(2) Calculation means (hereinafter referred to as calculation means) for calculating the mean erythrocyte age (M _RBC ) by substituting the inputted average blood glucose level and hemoglobin A1c into the relational expression in the present invention described above or an approximate expression thereof. Called);
(3) means for outputting the calculated mean erythrocyte age (hereinafter referred to as calculation means);
Can be included.

  The input means in the system of the present invention is not particularly limited as long as the average blood glucose level and hemoglobin A1c value can be input so that the calculation means can be used. For example, a keyboard, a touch panel, an optical reader, voice recognition An apparatus etc. can be mentioned.

  Further, as will be described later, in a device incorporating the system of the present invention in a continuous blood glucose measurement device, the continuous blood glucose device itself can function as an input means, and the average blood glucose level output from the continuous blood glucose device is Input can be made so that the computing means can be used. In this case, the hemoglobin A1c value can be input separately by the various input means (for example, a keyboard) exemplified above.

  The calculation means in the system of the present invention is not limited to the following from the average blood glucose level and hemoglobin A1c input from the input means, but for example, based on the relational expression in the present invention or its approximate expression An arithmetic means capable of calculating the age of red blood cells can be given, and examples thereof include a CPU of a computer.

  The output means in the system of the present invention is not particularly limited as long as it can be output so that the average erythrocyte age calculated by the arithmetic means can be recognized by the system user or can be used by another device. For example, a display, a printer, a speaker, etc. can be mentioned. Further, when the average erythrocyte age calculated by the calculation means is used in another apparatus (for example, a comprehensive diagnosis system), a transmission means to the apparatus can be used as the output means.

  The system of the present invention includes the input means, calculation means, and output means described above. For example, the system of the present invention can be configured as one integrated device, or can be configured to be incorporated in another device. Furthermore, it is possible to adopt a configuration (for example, a cloud system) connected via a communication line (for example, the Internet).

  As a configuration incorporated in another device, for example, a device incorporating the system of the present invention in a continuous blood glucose measurement device can be cited. In the apparatus, the average erythrocyte age can be calculated only by inputting the hemoglobin A1c value.

  As an aspect connected via a communication line, the input means and the output means can be installed in a place where the system user can use, and the operation means can be installed in an arbitrary place.

The program for determining the mean erythrocyte age according to the present invention (hereinafter sometimes referred to as the present program) is a program for causing a computer to function as the input means, calculation means, and output means. For the “input means”, “calculation means”, and “output means” in the program of the present invention, the description in the system of the present invention can be applied as it is.
A computer-readable recording medium that records the program of the present invention is also included in the present invention.

  Hereinafter, although the process is concretely demonstrated about each formula which this inventor derived in this invention, these do not limit the scope of the present invention.

<< 1. Red blood cell life
The probability density function p (t) of erythrocyte death is expressed as follows according to the gamma distribution that the present inventor determined to be most preferable among the three distributions proposed by Shrestha et al., 2016 (Non-patent Document 3). Can be expressed as:
[Where α and β are parameters of the gamma distribution, and Γ means Euler's gamma function]

The number of red blood cells decreases according to p (t).
[Where R (t) is the number of red blood cells t days after the birth of red blood cells, and R ₀ (/ day) is the rate of red blood cell production]
A graph visualizing p (t) and R (t) is shown in FIG.

In FIG. 1, FIG. 1A is a probability density function p (t) of red blood cells, and FIG. 1B is a normalized red blood cell lifetime distribution, both of which are examples of each. Since the present inventor assumed a constant erythrocyte production rate R ₀ , the lifetime distribution is the same as the current age distribution of erythrocytes. The solid line, alpha = 7.83, beta = 12.72, life expectancy = 99. Day 59, a M _RBC = 56. 16 days, the dotted line, alpha = 46.38, beta = 2.77, average life = 128. Day 47, a M _RBC = 65. 62 days.

Red blood cell count (RBC) is calculated as follows:
The following equation derived from equation (5) was used.

The average erythrocyte age (M _RBC ) can be calculated as follows.
Therefore, M _RBC is
It becomes.

<< 2. Hemoglobin Saccharification >>
FIG. 2 shows two models of hemoglobin glycation. FIG. 2A is a three-compartment model of hemoglobin glycation, and FIG. 2B is a simplified two-compartment model. HbA _ald is an aldimine complex (intermediate), and k ₁ , k ₂ , k ₃ , and k _g are rate constants.

It is assumed that hemoglobin glycation follows a three compartment model (FIG. 2A).
[ _Wherein [G] is the glucose concentration (same as AG in steady state) and HbA _ald is the aldimine complex (intermediate) concentration)
Since dHbA _ald / dt can be ignored in the steady state, and Hb (t) + HbA _ald + HbA1c is a constant, the following equation is established.
Thus, hemoglobin is glycated in proportion to intact hemoglobin, and the model can be simplified to a two-compartment model (FIG. 2B).
[In the formula, k _g is the saccharification rate (dL / mg / day)]
Equation (16) shows that the total saccharification rate is the product of k ₁ (power to convert to HbA _ald ) and k ₃ / (k ₂ + k ₃ ) (retained fraction to convert to HbA1c). . Table 1 shows estimated values of _kg reported in the past (Non-Patent Documents 4 to 8).

[Where Hb (t) is the value of non-glycated hemoglobin in t-day-old red blood cells, and Hb ₀ is the value of intact hemoglobin at the time of red blood cell birth]
Therefore,
Indicates the percentage of glycated hemoglobin in t-day-old red blood cells.

The collected blood contains red blood cells of various ages. Here, it is assumed that the hemoglobin synthesis rate (R ₀ Hb ₀ ) does not vary.
Therefore, HbA1c is
It becomes.

A graph visualizing the relationship between the average blood glucose (AG) and HbA1c represented by formula (21) is shown in FIG.
FIG. 3A shows AG and HbA1c under conditions of α = 40, β = 4, M _RBC = 82 (gray thick solid line), α = 6, β = 12, M _RBC = 42 (black thin solid line). To show the complete relationship. The _kg was 8 × 10 ⁻⁶ .
FIG. 3B expands the relationship in the physiological range and shows them with their tangent lines (dashed lines) at AG = 200.

<< 3. Section Origin-Tangent >>
The tangent lines of the formula (21) around AG ₀ are as follows (x and y indicate AG and HbA1c at the tangent lines, respectively), and indicate positive intercepts:
FIG. 3B shows a graph visualizing the relationship in Expression (21) and Expression (22).
The tangent at AG ₀ = 0 is obtained by using the Taylor expansion.

<< 4. Approximation of derivation relationship >>
Equation (21) gives the exact relationship between AG and HbA1c. However, this equation is too complicated to obtain the inverse function needed to convert HbA1c to AG. We also want to reduce the two parameters α and β to one parameter _MRBC .

First, equation (23) gives the following linear approximation (FIG. 4).
From this equation, M _RBC can be easily obtained [Equation (35)].

As a better approximation, Taylor expansion gives:
Substituting equation (25) into equation (21),
Since α >> 1,
This equation gives a two-dimensional (2D) approximation (FIG. 4).

When x approaches 0 infinitely
(27) can be reorganized as follows:
This equation gives a hyperbolic approximation (FIG. 4).

Thus, the following inverse function can be easily derived.
Using this equation, M _RBC can be determined:

  An approximation of the relationship between mean blood glucose (AG) and HbA1c is shown in FIG. 4 together with the original complete relationship (original: equation (21) under conditions of α = 40, β = 4). In FIG. 4, “hyperbolic” is a hyperbolic approximation of equation (28), “2D” is a two-dimensional approximation of equation (27), and “linear” is a linear approximation of equation (24).

When the formula (25) is substituted into the formula (21), the following formula can be derived from the quadratic approximation.
When x approaches 0 infinitely
So that
Substituting
Therefore, M _RBC is
It becomes.

<< 5. Discussion >>
The inventor has succeeded in proposing an equation (21) for a new and accurate nonlinear relationship between AG and HbA1c in steady state, and derived the intercept in the linear relationship between AG and HbA1c. Was presented (FIG. 3). This is the first equation showing the relationship between AG and HbA1c based on accurate red blood cell lifetime distribution (Shrestha et al., 2016). The previously proposed linear relationship is an approximation of a non-linear relationship.

  The present inventor's formula (21) indicates that AG increases and accelerates as HbA1c increases. Equation (29), which is a hyperbolic approximation, shows that the change in AG value between 13% -18% of HbA1c is 1.12 times greater than the change in AG value between 5% -10% of HbA1c. This relationship is worth considering for physicians who interact with diabetics in actual clinical settings.

  Approximation is a kind of technique. There are many functions close to a certain function within a certain range. We need to determine and select an appropriate formula. The present inventor succeeded in approximating the formula (21) proposed by the present person to the hyperbolic function (28). This approximate hyperbolic function was very close to the original function (21) (FIG. 4). In addition, a plurality of approximate expressions could be obtained.

<< 6. Verification of approximate expression >>
(1) Determination of glycation rate ( _kg ) 31 erythrocyte creatine (EC) values and hemoglobin A1c values (International Federation of Clinical Chemistry (IFCC) units) for 31 patients with hemolytic anemia and 76 non-anemic individuals. The average erythrocyte age (M _RBC ) and iA1c / (1000-2 / 3 × iA1c) were calculated from these measured values.

Regarding the hemoglobin A1c value, the National Glycohemoglobin Standardization Program (NSGP) unit (HbA1c _NGSP ) used in clinical practice and the iA1c can be converted by the following conversion formula.

Further, the _MRBC was calculated by the following formula proposed by the present inventors.

Further, iA1c / (1000-2 / 3 × iA1c) is based on the following equation derived from the approximate equation (30).

FIG. 5 shows the relationship between the calculated mean red blood cell age (M _RBC ) and iA1c / (1000-2 / 3 × iA1c). In FIG. 5, Δ indicates a hemolytic anemia patient, and ○ indicates a non-anemic patient. As shown in FIG. 5, a linear relationship was observed.

Subsequently, the saccharification rate ( _kg ) was calculated by two methods (slope method and direct method). Table 2 shows the glycation rate ( _kg ) calculated by each method for the entire population (ie, hemolytic anemia patients and non-anemic) and the non-anemic population.

In the slope method, the slope of the regression line passing through the origin (horizontal axis: M _RBC , vertical axis: iA1c / (1000-2 / 3 × iA1c)) was obtained by the least square model with respect to the equation (39).
In the direct method, it was directly calculated by the following formula obtained by modifying the formula (39).
In addition, as a mean blood glucose (AG) value, 100 mg / dL, which is a normal value excluding diabetic patients, was used from a plurality of past reports.

As shown in Table 2, the four types of saccharification rates ( _kg ) were about 7 × 10 ⁻⁶ , but according to FIG. 5, since the data was not stable in patients with severe hemolytic anemia, Of the saccharification rates shown in Fig. 2, there was a possibility that the values for the whole population / direct method were not accurate. Therefore, it was determined to 7.0 × 10 ⁻⁶ from the three types of saccharification rates ((6.94 to 6.99) × 10 ⁻⁶ ) excluding the values of the whole population / direct method.

(2) Comparison of the average erythrocyte age determined from the approximate expression of the present invention and the average erythrocyte age measured using ⁵¹ Cr From the approximate expression (30) of the present invention, based on the three cases reported in the past The obtained average erythrocyte age (M _RBC ) and the average erythrocyte age measured using ⁵¹ Cr are summarized in Table 3.

Herranz (Herranz, L., Grande, C., Janez, M., Pallardo, F., 1999. Red blood cell autoantibodies with a shortened erythrocyte life span as a cause of lack of relation between glycosylated hemoglobin and mean blood glucose levels in Diabetes Care 22 (12), 2085-2086.) and Ishii (Ishii Tax, Nobuhiro Taine, Kiyohiko Negishi, Shigehiro Katayama, 2001, blood glucose level due to subclinical autoimmune hemolysis and one example of type 2 diabetes showed discrepancy between HbA1c values, diabetes, Vol. 44 No. 2, 157-160), the measurements were performed twice, because the HbA1c is changed, separately calculates M _RBC, The average value was also obtained.
Herranz and Ishii determined the average blood glucose (AG) value by calculating the average value from data obtained by self-monitoring of blood glucose (SMBG).
Hiratani (Kazuyuki Hiratani, Toshizuka Totsuka, Shinichiro Suemori, Hideho Wada, Masafumi Koga, 2016, a case of type 2 diabetes mellitus complicated with oral erythrocytosis in which HbA1c showed a pseudo-low value due to invisible hemolysis In Diabetes, Vol. 59, No. 10, 719-723), an average blood glucose (AG) value was determined by continuous glucose measurement (CGM).
The red blood cell lifetime measurements using ⁵¹ Cr-, normal values of M _RBC is of about 60 ^days, according the normal range of the measured erythrocyte life (half-life) using 51 Cr-within Herranz 28 to 30 days, according to the Ishii The average age of red blood cells (M _RBC ) was calculated by multiplying 2.14 (= 60/28) [Equation (41)] because it was 30 ± 5 days and according to Hiratani it was 26-40 days.

The M _RBC calculated from iA1c [average value in column (e) of Table 3] was 36.95 ± 5.93, and the M _RBC calculated from ⁵¹ Cr [average value in column (g) of Table 3] was 41.29 ± 2.22. It was. The result of the pair t test was t, −0.9278; df, 2; p (bilateral), 0.4514, and there was no significant difference between the two, confirming the accuracy of the approximate expression of the present invention.

  The average erythrocyte age that can be calculated by the present invention can be used as a biomarker in the diagnosis of hemolytic anemia, gastrointestinal bleeding (for example, bleeding due to colorectal cancer), and the like.

Claims (6)

  A method of determining an average erythrocyte age based on a subject's average blood glucose (AG) value and hemoglobin A1c (HbA1c) value. The average blood glucose (AG) value and hemoglobin A1c (HbA1c) value of the test subjects are represented by the following formulas (30), (34), and (35):
_{Wherein, M RBC} is the mean red blood cell age (day), HbA1c is hemoglobin A1c value, _{k g} is the glycation rate (dL / mg / day), AG is an average blood glucose level (mg / dL) is there]
The method of claim 1, wherein the mean age of red blood cells (M _RBC ) is determined by substituting into an expression selected from the group consisting of: (1) Means for inputting an average blood glucose (AG) value and a hemoglobin A1c (HbA1c) value;
(2) Calculation means for calculating an average erythrocyte age based on the inputted average blood glucose level and hemoglobin A1c value;
(3) means for outputting the calculated mean erythrocyte age;
A system for determining an average red blood cell age. The computing means is represented by the following formula (30), (34), or (35):
_{Wherein, M RBC} is the mean red blood cell age (day), HbA1c is hemoglobin A1c value, _{k g} is the glycation rate (dL / mg / day), AG is an average blood glucose level (mg / dL) is there]
The system according to claim 3, wherein an average red blood cell age is calculated based on at least one of the following. A program for determining mean red blood cell age (M _RBC ) for causing a computer to function as the following means (1), means (2), and means (3):
(1) Means for inputting an average blood glucose (AG) value and a hemoglobin A1c (HbA1c) value;
(2) Calculation means for calculating an average red blood cell age (M _RBC ) based on the inputted average blood glucose level and hemoglobin A1c value;
(3) A means for outputting the calculated average erythrocyte age. The calculation means is the following formula (30), (34), or (35):
_{Wherein, M RBC} is the mean red blood cell age (day), HbA1c is hemoglobin A1c value, _{k g} is the glycation rate (dL / mg / day), AG is an average blood glucose level (mg / dL) is there]
The program according to claim 5, wherein an average erythrocyte age is calculated based on at least one of the following.