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WO2016068468A2 - Procédé d'extraction de fonctions métaboliques d'organes à l'aide de tests oraux de tolérance au glucose et dispositif pour celui-ci - Google Patents

Procédé d'extraction de fonctions métaboliques d'organes à l'aide de tests oraux de tolérance au glucose et dispositif pour celui-ci Download PDF

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Publication number
WO2016068468A2
WO2016068468A2 PCT/KR2015/008858 KR2015008858W WO2016068468A2 WO 2016068468 A2 WO2016068468 A2 WO 2016068468A2 KR 2015008858 W KR2015008858 W KR 2015008858W WO 2016068468 A2 WO2016068468 A2 WO 2016068468A2
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WIPO (PCT)
Prior art keywords
glucose
insulin
liver
metabolic function
compartment
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PCT/KR2015/008858
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English (en)
Korean (ko)
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WO2016068468A3 (fr
Inventor
임채헌
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University of Ulsan Foundation for Industry Cooperation
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University of Ulsan Foundation for Industry Cooperation
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Priority claimed from KR1020150117400A external-priority patent/KR101840516B1/ko
Application filed by University of Ulsan Foundation for Industry Cooperation filed Critical University of Ulsan Foundation for Industry Cooperation
Priority to US15/522,778 priority Critical patent/US20170322220A1/en
Publication of WO2016068468A2 publication Critical patent/WO2016068468A2/fr
Publication of WO2016068468A3 publication Critical patent/WO2016068468A3/fr
Anticipated expiration legal-status Critical
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/66—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood sugars, e.g. galactose
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors

Definitions

  • 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 is provided.
  • Oral glucose tolerance tests 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 include information about intestinal absorption, glucose and insulin liver control, pancreatic insulin secretion, and glucose and insulin control of peripheral tissues.
  • an appropriate dynamic model may represent the above information from oral glucose tolerance tests (OGTTs).
  • 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.
  • 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.
  • OGTTs oral glucose loading test
  • 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.
  • 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.
  • the long-term metabolic function extraction device using oral glucose loading test 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.
  • OGTTs oral glucose loading test
  • 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.
  • FIG. 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.
  • OGTTs oral glucose tolerance test
  • 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
  • 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.
  • Metabolic function extraction device using oral glucose loading test 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.
  • FIG. 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.
  • OGTTs oral glucose tolerance test
  • 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 diagnosis unit 140 diagnoses the metabolic function state of the subject using the extracted parameters.
  • FIGS. 2A and 2B 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.
  • a physiological system-based human organ functional model 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.
  • 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.
  • 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.
  • an initial value may be set as in Equations 1 to 5 below.
  • V [0] is a plasma volume, which is calculated at a ratio of 0.04505 L / kg of body weight.
  • V [1] is liver plasma volume and is calculated at a ratio of 0.00495 L / kg of body weight.
  • 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).
  • Equation 6 means the amount of glucose (glucose) remaining in the stomach (Gut), Equation 7 shows the glucose absorption rate of the stomach.
  • '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.
  • 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.
  • I [0] is plasma insulin
  • I [1] in Equation 10 is liver insulin
  • I [2] in Equation 11 is peripheral insulin.
  • I [3] is liver receptor insulin
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • Table 2 shows the definitions and units of F0 to F10 shown in the above equations.
  • 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.
  • the solid line represents the line corrected by the model of the present invention.
  • 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]).
  • a number of calibrated parameters, including F0, F4, F6, and apparent endogenous glucose production (EGP) showed obvious gender differences.
  • 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.
  • 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.
  • FIG. 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.
  • OGTTs oral glucose tolerance test
  • 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).
  • OGTTs oral glucose tolerance test
  • 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).
  • Equation 6 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.
  • 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.
  • 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.
  • 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. .
  • a state of metabolic function may be extracted from each organ by using a physiological system-based human organ function model.
  • 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.

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Abstract

La présente invention concerne un procédé d'extraction de fonctions métaboliques d'organes à l'aide de tests oraux de tolérance au glucose, et un dispositif pour celui-ci. Selon la présente invention, le procédé d'extraction de fonctions métaboliques d'organes à l'aide de tests oraux de tolérance au glucose (OGTT) comprend les étapes suivantes : la mesure d'une quantité de changement au cours du temps dans le glucose plasmatique et l'insuline plasmatique à un intervalle de temps régulier après qu'un sujet a consommé une certaine quantité d'une solution de glucose; l'extraction des paramètres associés au métabolisme d'organe dans un corps humain par l'application de la quantité de changement au cours du temps du glucose et de l'insuline mesurés à un modèle de fonction d'un organe du corps humain; le diagnostic de l'état de fonction métabolique du sujet à l'aide des paramètres extraits. La présente invention peut présenter des raisons pour déterminer des fonctions métaboliques exactes et une preuve de maladies étant donné que la présente invention peut déterminer le statut de fonctions métaboliques précédemment non identifiables dans le corps humain d'un sujet ou patient, par extraction de la fonction d'absorption de glucose dans le tractus gastro-intestinal, la fonction de traitement du glucose dans le foie, la fonction de sécrétion d'insuline par rapport au glucose sanguin dans le pancréas, et la fonction métabolique du glucose dans les tissus périphériques.
PCT/KR2015/008858 2014-10-31 2015-08-25 Procédé d'extraction de fonctions métaboliques d'organes à l'aide de tests oraux de tolérance au glucose et dispositif pour celui-ci Ceased WO2016068468A2 (fr)

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US15/522,778 US20170322220A1 (en) 2014-10-31 2015-08-25 Method of extracting organ metabolic functions using oral glucose tolerance tests and device therefor

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KR10-2014-0150329 2014-10-31
KR20140150329 2014-10-31
KR1020150117400A KR101840516B1 (ko) 2014-10-31 2015-08-20 경구 당 부하 검사를 이용한 장기 대사 기능 추출 장치 및 그 방법
KR10-2015-0117400 2015-08-20

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JP4781710B2 (ja) * 2005-05-12 2011-09-28 シスメックス株式会社 治療効果予測システム及びそのプログラム
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AU2008242674A1 (en) * 2007-04-20 2008-10-30 Veridex, Llc A method for determining insulin sensitivity and glucose absorption
KR100902282B1 (ko) * 2007-05-15 2009-06-10 재단법인서울대학교산학협력재단 당뇨병 진단용 조성물, 이를 포함하는 당뇨병 진단 키트 및당뇨병 진단방법

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