WO2016068468A2 - Method of extracting organ metabolic functions using oral glucose tolerance tests and device therefor - Google Patents

Abstract

The present invention relates to a method of extracting organ metabolic functions using oral glcucose tolerance tests, and a device therefor. According to the present invention, the method of extracting organ metabolic functions using oral glucose tolerance tests (OGTTs) comprises: a step of measuring an amount of change over time in plasma glucose and plasma insulin at a regular time interval after a subject has consumed a certain quantity of a glucose solution; a step of extracting parameters associated with organ metabolism in a human body by applying the amount of change over time of the measured glucose and insulin to a human body organ function model; and a step of diagnosing the metabolic function state of the subject using the extracted parameters. The present invention may present grounds for determining exact metabolic functions and evidence of diseases since the present invention can ascertain the status of previously unidentifiable metabolic functions in the human body of a subject or patient, by extracting glucose absorption function in the gastrointestinal tract, glucose treatment function in the liver, insulin secretion function relative to blood glucose in the pancreas, and glucose metabolic function in the peripheral tissues.

Description

Long term metabolic function extraction method using oral glucose tolerance test and its device

The present invention relates to a method and apparatus for extracting long-term metabolic function using oral glucose loading test, and more particularly, long-term metabolic function using oral glucose loading test that can accurately diagnose the state of metabolic function in the human body of a subject or patient. An extraction method and apparatus therefor.

Oral glucose tolerance tests (OGTTs) are a test method for determining glucose processing ability by measuring blood sugar after taking a predetermined sugar, and are mainly used to diagnose diabetes mellitus (DM).

Blood glucose data and changes in insulin induced by oral glucose tolerance tests (OGTTs) include information about intestinal absorption, glucose and insulin liver control, pancreatic insulin secretion, and glucose and insulin control of peripheral tissues.

Thus, an appropriate dynamic model may represent the above information from oral glucose tolerance tests (OGTTs).

However, the diagnosis of existing diabetes is based on the blood glucose level after 12 hours of fasting and the blood glucose level of 2 hours after ingestion of glucose.These diagnostic criteria are based on physiological mechanisms and are simply based on epidemiological data. There was a problem that accurate mechanism diagnosis was difficult.

The background technology of the present invention is disclosed in Korean Patent Registration No. 10-0902282 (2009.06.10 notification).

The technical problem to be achieved by the present invention is to provide a method and apparatus for extracting long-term metabolic function using oral glucose loading test that can accurately diagnose the state of the metabolic function in the human body of a subject or patient.

According to an embodiment of the present invention for achieving the above technical problem, in the long-term metabolic function extraction method using oral glucose loading test (OGTTs), after the subject ingested a certain amount of glucose solution in the plasma at a certain time interval and Measuring a change amount of insulin in plasma over time, extracting a parameter related to organ metabolism of the human body by applying the measured change in glucose and insulin over time to a human organ function model, and extracting the extracted parameter Diagnosing the metabolic function state of the subject.

The human organ function model includes a glucose compartment and an insulin compartment, and the glucose compartment comprises a glucose compartment produced in the liver and a blood glucose compartment in the plasma, and the insulin compartment includes plasma insulin, hepatic insulin, peripheral insulin, It may consist of the liver receptor and peripheral receptor compartments.

The extracted parameters include gastrointestinal glucose uptake, insulin reduction rate, number of receptors in liver, number of receptors in peripheral tissues, glucose sensitivity for insulin secretion, glucose response to insulin secretion, maximum insulin secretion rate, maximum insulin dependent glucose in peripheral tissues And at least one of absorption rate, maximum glucose production rate in liver, insulin dependent liver glucose production reduction rate, and glucose absorption rate absorbed into liver.

In the diagnosing the metabolic function state of the subject, it may be determined whether the metabolic function of the subject is normal by comparing the extracted parameter with a reference value.

According to another embodiment of the present invention, in the long-term metabolic function extraction device using oral glucose loading test (OGTTs), after the subject ingested a certain amount of glucose liquid at a time interval between the plasma glucose and plasma insulin at a time Measuring unit for measuring the amount of change according to the modeling unit for modeling the human organ function model consisting of a glucose compartment and insulin compartment, organ metabolism of the human body by applying the measured change amount of glucose and insulin over time to the human organ function model And a parameter extracting unit for extracting a related parameter, and a diagnostic unit for diagnosing the metabolic function state of the subject using the extracted parameters.

Thus, according to the present invention, by extracting the gastrointestinal glucose absorption function, liver glucose processing function, pancreas blood glucose insulin secretion function, terminal tissue glucose metabolism function of the human body metabolism function of the subject or patient that could not be previously known Knowing the condition can provide accurate judgments of metabolic function and provide evidence of the disease.

In addition, the metabolic function of each individual can be identified and applied to an appropriate health care system, and new diagnostic criteria based on physiological mechanisms, rather than the existing diabetes criteria, can be established.

In addition, it can be used in various parts such as medical examination of hospitals, wellness platform that is currently of national interest, and other personal health care programs.

1 is a block diagram of an apparatus for extracting metabolic function using oral glucose tolerance test (OGTTs) according to an embodiment of the present invention.

FIG. 2A is a diagram illustrating a human organ function model based on a physiological system according to an exemplary embodiment of the present invention, and FIG. 2B illustrates a part to which Equations 6 to 20 are applied in the human organ function model shown in FIG. 2A. will be.

Figure 3 shows the changes in glucose and insulin during the OGTTs test.

Figure 4 is a flow chart of the metabolic function extraction method using oral glucose tolerance test (OGTTs) according to an embodiment of the present invention.

Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings. The terms used are terms selected in consideration of functions in the embodiments, and the meaning of the terms may vary depending on the intention or precedent of the subject or operator. Therefore, the meaning of the terms used in the embodiments to be described later, according to the definition if specifically defined herein, and if there is no specific definition should be interpreted to mean generally recognized by those skilled in the art.

Metabolic function extraction device using oral glucose loading test (OGTTs) according to an embodiment of the present invention using the physiological model to change the concentration of glucose and insulin of oral glucose loading test (OGTTs) used for the diagnosis of conventional diabetes Extracts the metabolic functions of the gastrointestinal tract, liver, pancreas and other tissues (muscles / fats) in the human body.

1 is a block diagram of an apparatus for extracting metabolic function using oral glucose tolerance test (OGTTs) according to an embodiment of the present invention.

As shown in FIG. 1, the apparatus 100 for extracting metabolic functions using oral glucose tolerance test (OGTTs) according to an embodiment of the present invention includes a measuring unit 110, a modeling unit 120, a parameter extraction unit 130, and a diagnostic unit. 140.

First, the measuring unit 110 measures a change amount according to time of glucose and insulin at predetermined time intervals after a subject ingests a predetermined amount of glucose solution.

The modeling unit 120 models a human organ function model based on a physiological system composed of a glucose compartment and an insulin compartment.

The parameter extractor 130 extracts a parameter related to organ metabolism of the human body by applying the measured change amount of glucose and insulin over time to the human organ function model.

The diagnosis unit 140 diagnoses the metabolic function state of the subject using the extracted parameters.

Hereinafter, a human organ function model based on a physiological system for extracting metabolic function according to an embodiment of the present invention will be described with reference to FIGS. 2A and 2B.

FIG. 2A is a diagram illustrating a human organ function model based on a physiological system according to an embodiment of the present invention, and FIG. 2B illustrates a part to which Equations 6 to 20 are applied in the human organ function model shown in FIG. 2A. will be.

First, subjects consume a certain amount of glucose solution for oral glucose tolerance test (OGTTs) and then at each time point (minimum 30 minutes, 60 minutes, 90 minutes, 120 minutes, 180 minutes: up to 24 minutes at each time point). Changes in plasma glucose and plasma insulin (in addition, gastric inhibitory peptides, gastrointestinal hormones such as glucagon-like peptide-1, and glucagon) are measured.

As shown in FIG. 2A, a physiological system-based human organ functional model according to an embodiment of the present invention is divided into a compartment of glucose and insulin, and again, glucose is divided into two compartments (G [ 0], G [1]), and insulin consists of five compartments I [0], I [1], I [2], [3], I [4].

The glucose model is divided into the plasma glucose compartment (G [0]) and the glucose compartment produced by the liver (G [1]).

Glucose, first taken through the mouth and then absorbed by the gut, is delivered to the liver. Second, hepatic glucose, part of which is absorbed from the gastrointestinal tract and part of which is produced from the liver, is delivered to the plasma through the bloodstream.

Plasma glucose is consumed or excreted through the brain, peripheral tissues, urine, or other organs that do not require insulin, or are absorbed by peripheral tissues that require insulin.

The insulin model is divided into five compartments: plasma insulin, hepatic insulin, peripheral insulin, liver receptor and peripheral receptor. The insulin model likewise utilizes the amount of insulin reduction in the plasma insulin, liver receptor and peripheral receptor compartments. Insulin is produced in the pancreas in response to plasma glucose and delivered to and removed from the liver to which insulin insulins are bound.

In the peripheral space, plasma insulin is delivered to the non-secretory cell interstitial space that is bound to insulin receptors on peripheral tissues (mainly muscle and fat) and decreases linearly.

For modeling a human organ function model according to an embodiment of the present invention, an initial value may be set as in Equations 1 to 5 below.

1. Initial value setting

In Equation 1, V [0] is a plasma volume, which is calculated at a ratio of 0.04505 L / kg of body weight. In Equation 2, V [1] is liver plasma volume and is calculated at a ratio of 0.00495 L / kg of body weight. In Equation 3, V [2] is the peripheral insulin volume and is calculated at a ratio of 0.15 L / kg of body weight. Body surface area (BSA) shown in Equation 4 is calculated using the Du Bois formula, Cardiac output (Cardiac output, CO, L / min) and the heart rate (HR) and Calculated using body surface area (BSA).

Table 1 shows the units of each component shown in the equations (1) to (5).

2. Gut glucose absorption of the stomach

In Equation 6 G [4] means the amount of glucose (glucose) remaining in the stomach (Gut), Equation 7 shows the glucose absorption rate of the stomach. In Equation 7, 'F0' refers to the gut glucose absorption rate (gut glucose absorption rate), the total glucose is assumed to be 75g. The model assumes no glucose remains after 600 minutes.

3. Pancreas insulin production

Equation 8 shows the ratio of insulin secreted from the pancreas, 'Ins' means the insulin production quantity (insulin production quantity), F4 ~ F6 parameters control insulin production. F4 is the maximum insulin secretion half activation concentration of glucose, which means glucose sensitivity for insulin secretion. F5 is the glucose response to insulin secretion as the "Hill coefficient" and F6 represents the maximum insulin secretion rate.

4. Insulin compartments

In Equation 9, I [0] is plasma insulin, I [1] in Equation 10 is liver insulin, and I [2] in Equation 11 is peripheral insulin. Indicates. In Equation 12, I [3] is liver receptor insulin, and in Equation 13, I [4] refers to peripheral receptor insulin. 'CO' refers to cardiac output as described above, and hepatic blood flow is calculated as 30% of cardiac output based on existing physiological knowledge.

In Equations 9 to 13, F1 to F3 parameters are used, 'F1' is an insulin degradation rate, 'F2' is a receptor number on liver, and 'F3' is a peripheral tissue. Receptor number on peripheral tissue.

5. Brain, Urine glucose uptake

Brain glucose uptake is assumed to be constant over time, and was set to 60 mg / min as shown in Equation 14. In other words, it is assumed that the brain consumes 60 mg of glucose per minute.

Equation 15 represents the urine glucose uptake rate. As shown in Equation 15, Urine glucose uptake is considered only when the blood glucose (G [0]) is greater than 200 mg / dl. Similarly, if blood glucose (G [0]) is less than 200 mg / dl, it is not considered.

6. Glucose compartments

Glucose compartment basically consists of two compartments (G [0] and G [1]), where G [0] in Equation 17 is plasma glucose and G [ 1] is liver glucose in the liver. In this model, G [2] and G [3] were additionally considered. G [2] is the peripheral glucose consumption and G [3] is the liver glucose production.

As shown in Equation 19, G [2] is determined by F3 and F7, 'F3' is the number of peripheral tissue insulin receptors, and 'F7' is the maximum insulin dependent glucose uptake rate in peripheral tissue. in peripheral tissue).

As shown in Equation 20, G [3] is determined by F2, F8, F9 and F10, 'F2' is the number of receptors in the liver, 'F8' is the maximum glucose production rate in the liver, and 'F9' is generated from the liver. The maximum insulin dependent inhibition rate of glucose production from liver, 'F10' means glucose uptake rate into the liver (glucose uptake rate into the liver).

Table 2 shows the definitions and units of F0 to F10 shown in the above equations.

And Table 3 shows the definition and units of G0 to G4, Gut, I0 to I4, Ins shown in the above equations.

Figure 3 shows the changes in glucose and insulin during the OGTTs test.

3 shows that even if the same amount of glucose (75g) ingested in each group has a different characteristic, the male (●) is larger than the female (○) changes in glucose and insulin is greater. In particular, the insulin value at 180 minutes was significantly lower for men than for women.

In diabetic patients (q), the change in the value of glucose and insulin is different. Basal plasma glucose was much higher in the diabetic category, and oral glucose load caused hyperglycaemia by increasing plasma glucose levels. However, the increase in insulin was small and reached the peak value later than normal.

In FIG. 3, the solid line represents the line corrected by the model of the present invention. In males, the R ² values for glucose and insulin were 0.99 and 0.97, respectively, and 0.97 and 0.94 for females and 0.96 and 0.86 for diabetic patients, respectively.

Table 4 shows the fitted parameters and F7 / F3 shows the rate of peripheral glucose transfer to insulin receptor (I [4]). F9 / F2 represents the transmission rate of hepatic glucose to the insulin receptor (I [3]).

[Revision 29.10.2015 under Rule 91]

A number of calibrated parameters, including F0, F4, F6, and apparent endogenous glucose production (EGP) showed obvious gender differences.

However, no gender differences were seen in the diabetic group. Thus, all data do not distinguish gender in the diabetic group.

The parameters (F4, F6, F8, F9, F10, F9 / F2) differed significantly between normal males and diabetic patients, and the parameters (F0, F2, F4, F6, F8, F9, F10, F9 / F2) had a big difference. And, the difference between the pancreas and liver was noticeable between normal cases and diabetics.

The model according to an embodiment of the present invention can explain many important physiological aspects of normal people and diabetics. In particular, the model according to an embodiment of the present invention shows the difference between men and women according to the absorption rate of glucose in the stomach, endogenous glucose production (EGP), glucose sensitivity in the pancreas, the maximum insulin production capacity.

Figure 4 is a flow chart of the metabolic function extraction method using oral glucose tolerance test (OGTTs) according to an embodiment of the present invention.

First, the subject consumes a certain amount of glucose solution for oral glucose tolerance test (OGTTs), and then at each time point (e.g., every 30 minutes), glucose in plasma (G [0]), and the amount of change in insulin in plasma (I [0]) is measured (S410).

Next, the parameter extraction unit 120 applies parameters of the measured plasma glucose (G [0]) and plasma insulin (I [0]) over time to the human organ function model to determine parameters related to organ metabolism in the human body. It is extracted (S420).

That is, the time-varying amount of the plasma glucose (G [0]) and the plasma insulin (I [0]) is applied to Equations 6 to 20 to extract unknown parameters related to long-term metabolism.

Here, unknown parameters include gastrointestinal glucose uptake (F [0]), insulin reduction rate (F [1]), liver receptor count (F [2]), peripheral tissue receptor count (F [3]), glucose Insulin maximum secretion half activation concentration (F [4]), glucose sensitivity for insulin secretion (F [5]), glucose response to insulin secretion and maximum insulin secretion rate (F [6]), maximum insulin in peripheral tissues Dependent glucose uptake (F [7]), maximum glucose production rate in liver (F [8]), maximum ratio of insulin dependent glucose produced from liver (F [9]), glucose uptake absorbed into liver (F [10] ]) Extract at least one of them.

Next, the diagnosis unit 130 diagnoses the metabolic function state of the subject using the extracted parameters (S430).

The diagnosis unit 130 compares the extracted parameter with a reference value to determine whether the metabolic function of the subject is normal, wherein the reference value may use the corrected parameter shown in Table 4.

That is, even men and women with normal blood glucose who do not have diabetes, the extracted parameters are compared with the corrected parameters shown in Table 4, and if the parameters are out of the range of the corrected parameters, the condition can be diagnosed. .

For example, if the maximum glucose production rate (F [8]) in the liver is outside the range shown in Table 4, treatment for the glucose production rate in the liver can be progressed even before the diabetic patient.

As described above, according to an embodiment of the present invention, a state of metabolic function may be extracted from each organ by using a physiological system-based human organ function model.

That is, according to an embodiment of the present invention, by extracting the gastrointestinal glucose absorption function, hepatic glucose processing function, pancreas blood glucose insulin secretion function, terminal tissue glucose metabolism function, the subject or patient in the human body of the subject could not be known Knowing the status of metabolic function can provide accurate judgment of metabolic function and the basis of disease.

In addition, the metabolic function of each individual can be identified and applied to an appropriate health care system, and new diagnostic criteria based on physiological mechanisms, rather than the existing diabetes criteria, can be established.

In addition, it can be used in various parts such as medical examination of hospitals, wellness platform that is currently of national interest, and other personal health care programs.

The present invention has been described above with reference to the preferred embodiments described with reference to the drawings, but is not limited thereto. Accordingly, the invention should be construed by the description of the claims, which are intended to cover obvious variations that can be derived from the described embodiments.

Claims (8)

In the method of extracting long-term metabolic function using oral glucose loading test (OGTTs), Measuring a change over time of plasma glucose and plasma insulin at a predetermined time interval after the subject ingests a certain amount of glucose solution, Extracting a parameter related to organ metabolism of the human body by applying the measured change in glucose and insulin over time to the human organ functional model, and Diagnosing the metabolic function state of the subject using the extracted parameters. The method of claim 1, The human organ function model is, Consists of glucose compartment and insulin compartment, The glucose compartment, Consists of the glucose compartment produced by the liver and the blood glucose compartment in plasma, The insulin compartment, A method for extracting long-term metabolic function consisting of plasma insulin, hepatic insulin, peripheral insulin, liver receptor and peripheral receptor compartments. The method of claim 2, The extracted parameter is Gastrointestinal glucose uptake rate, insulin reduction rate, number of receptors in liver, number of receptors in peripheral tissues, glucose sensitivity for insulin secretion, glucose response to insulin secretion, maximum insulin secretion rate, maximum insulin dependent glucose uptake in peripheral tissues, maximum in liver A method for extracting long-term metabolic function comprising at least one of glucose production rate, maximum ratio of insulin dependent glucose produced from liver, and glucose absorption rate absorbed into liver. The method of claim 3, Diagnosing the metabolic function state of the subject, Long-term metabolic function extraction method for determining whether the metabolic function of the subject is normal by comparing the extracted parameter with a reference value. In the long-term metabolic function extraction device using oral glucose loading test (OGTTs), Measuring unit for measuring the amount of change in the plasma glucose and plasma insulin over time at a certain time interval after the subject ingested a certain amount of glucose solution, Modeling unit for modeling the human organ functional model consisting of glucose compartment and insulin compartment, A parameter extracting unit extracting a parameter related to organ metabolism of the human body by applying the measured change in glucose and insulin over time to the human organ functional model, and And a diagnosis unit for diagnosing the metabolic function state of the subject using the extracted parameters. The method of claim 5, The glucose compartment, Consists of the glucose compartment produced by the liver and the blood glucose compartment in plasma, The insulin compartment, Long term metabolic function extraction device consisting of plasma insulin, hepatic insulin, peripheral insulin, liver receptor and peripheral receptor compartments. The method of claim 6, The extracted parameter is Gastrointestinal glucose uptake rate, insulin reduction rate, number of receptors in liver, number of receptors in peripheral tissues, glucose sensitivity for insulin secretion, glucose response to insulin secretion, maximum insulin secretion rate, maximum insulin dependent glucose uptake in peripheral tissues, maximum in liver A method for extracting long-term metabolic function comprising at least one of glucose production rate, maximum ratio of insulin dependent glucose produced from liver, and glucose absorption rate absorbed into liver. The method of claim 7, wherein The diagnostic unit, The apparatus for extracting long-term metabolic function by comparing the extracted parameter with a reference value to determine whether the subject's metabolic function is normal.

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