WO2014030650A1 - 糖代謝能の測定方法及びそれに使用する組成物 - Google Patents
糖代謝能の測定方法及びそれに使用する組成物 Download PDFInfo
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- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
- G16H50/00—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics
- G16H50/30—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for calculating health indices; for individual health risk assessment
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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
- G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
- G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
- G01N33/502—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects
- G01N33/5038—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects involving detection of metabolites per se
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/08—Detecting, measuring or recording devices for evaluating the respiratory organs
- A61B5/0813—Measurement of pulmonary parameters by tracers, e.g. radioactive tracers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/08—Detecting, measuring or recording devices for evaluating the respiratory organs
- A61B5/083—Measuring rate of metabolism by using breath test, e.g. measuring rate of oxygen consumption
- A61B5/0836—Measuring rate of CO2 production
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/72—Signal processing specially adapted for physiological signals or for diagnostic purposes
- A61B5/7271—Specific aspects of physiological measurement analysis
- A61B5/7275—Determining trends in physiological measurement data; Predicting development of a medical condition based on physiological measurements, e.g. determining a risk factor
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
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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
- G01N33/483—Physical analysis of biological material
- G01N33/497—Physical analysis of biological material of gaseous biological material, e.g. breath
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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
- G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
- G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
- G01N33/5082—Supracellular entities, e.g. tissue, organisms
- G01N33/5088—Supracellular entities, e.g. tissue, organisms of vertebrates
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2400/00—Assays, e.g. immunoassays or enzyme assays, involving carbohydrates
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/04—Endocrine or metabolic disorders
- G01N2800/042—Disorders of carbohydrate metabolism, e.g. diabetes, glucose metabolism
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/56—Staging of a disease; Further complications associated with the disease
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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
- G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
- G01N33/60—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances involving radioactive labelled substances
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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
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T436/00—Chemistry: analytical and immunological testing
- Y10T436/14—Heterocyclic carbon compound [i.e., O, S, N, Se, Te, as only ring hetero atom]
- Y10T436/142222—Hetero-O [e.g., ascorbic acid, etc.]
- Y10T436/143333—Saccharide [e.g., DNA, etc.]
- Y10T436/144444—Glucose
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T436/00—Chemistry: analytical and immunological testing
- Y10T436/20—Oxygen containing
- Y10T436/204998—Inorganic carbon compounds
Definitions
- the present invention relates to a method for measuring a subject's ability to metabolize glucose, and a composition suitably used for the method. Specifically, the present invention relates to a method for measuring and monitoring a subject's ability to metabolize glucose using a labeled C-breath test such as 13 C, and a composition suitably used for the method. The present invention also relates to a method for determining the pathological stage after the onset of diabetes and / or the pre-stage of the onset of diabetes by measuring the glucose metabolism ability of the subject using a labeled C-breath test (hereinafter referred to as the present specification). Then, the pathological stage after the onset of diabetes and the pre-stage of the onset of diabetes are collectively referred to as “diabetic pathological stage”).
- Diabetes diagnosis is usually performed by primary screening by urine glucose test or fasting blood glucose level test, and if these tests are positive, a glucose tolerance test is generally performed to reach a definitive diagnosis. Recently, there are cases where HbAlC and fructosamine in blood are tested before a glucose tolerance test using glucose.
- Patent Documents 2 and 3 performed breath test using labeled glucose as well 13 C and Patent Document 1, and 13 C in the breath calculated from 13 CO 2 concentration excreted in the breath 12 It is described that a diabetic patient, an insulin resistant patient or a glucose intolerant patient can be diagnosed by using a ratio with C ( 13 C / 12 C) as an index that is lower than that of a healthy subject .
- Patent Document 4 was administered labeled glucose at 2 H to the subject, to measure the total amount of deuterium water in the subject (2 H 2 O), the total amount of the deuterated water (2 H 2 O) Is a method of determining insulin resistance in a subject using the value obtained by dividing the amount of insulin by the area under insulin concentration or insulin concentration (insulin AUC) as an index.
- Patent Document 5 discloses a blood glucose level and insulin measured after administration of a test food. Describes how to determine the product of the area under insulin concentration (insulin AUC) and the area under glucose concentration (glucose AUC) from the concentration (“insulin AUC x glucose AUC”) and determine insulin resistance in the subject using this value as an index Has been.
- Another object of the present invention is to provide a composition for measuring glucose metabolic capacity for use in the above method.
- the present inventors have calculated the amount of isotope-labeled carbon dioxide (CO 2 ) excreted in exhaled air after administration of isotope-labeled glucose, and calculation from the amount from the behavior of the abundance of carbon dioxide gas contained in expiratory that (proportion of labeled CO 2 amount to unlabeled CO 2 amount or proportion of labeled CO 2 amount to the total amount of CO 2,) is a high precision glucose metabolism ability of a subject And, it was found that it can be measured quickly.
- the present inventors measured not only the pathological stage of patients who developed diabetes but also the state of the previous stage of developing diabetes by using the glucose metabolism ability of the subject thus measured as an index. It was found that can be monitored over time.
- the present inventors have found that the therapeutic effect of a drug (diabetic drug) on a diabetic patient can be determined by using the glucose metabolism ability of the subject as an index, and that it can be monitored over time. It was.
- the present invention has been completed based on such findings.
- Method for measuring glucose metabolism ability (1-1) Method for measuring glucose metabolism ability of a subject having the following steps (a) and (b): (A) A step of collecting exhaled breath by administering to a subject a composition containing glucose, which is converted into labeled carbon dioxide gas in vivo and labeled with at least one of the isotopes C discharged into the exhaled breath , and (b) obtaining a ratio of the labeled CO 2 amount to non-rate of the labeled amount of CO 2 for the labeled CO 2 amount or total amount of CO 2, contained in the breath.
- the step (b) is performed by obtaining, for example, ⁇ % 13 C ( 13 C concentration change amount: atom%) or ⁇ 13 C value ( ⁇ 13 C value change amount: ⁇ ), as will be described later. be able to.
- (1-3) The method for measuring glucose metabolism according to (1-1) or (1-2), wherein the isotope is
- a subject who is in a sugar-loaded state is a subject who ingested a saccharide, or a food or drink containing sugar or something that is metabolized to become sugar before step (a).
- the above food or drink is selected from the group consisting of proteins (including semi-digested proteins), amino acids, fats, electrolytes, trace elements, and vitamins in addition to sugars or metabolized sugar components
- the method for measuring sugar metabolism according to (1-6) which is a liquid, semi-liquid, or solid food or drink containing at least one selected from the above.
- diabetes stage the pre-stage of diabetes onset and / or the pathological stage after the onset of diabetes.
- a subject who has been determined to have enhanced glucose metabolism in the method for measuring glucose metabolism according to any one of (1-2) to (1-7) is in a stage before onset of diabetes
- the method of the present invention can be paraphrased as [2-a] to [2-g] below.
- a method for detecting a stage of diabetic condition in a subject having the following steps (a) to (c ′): (a) administering to the subject a composition comprising glucose (labeled C-glucose), which is converted into labeled carbon dioxide in the living body and labeled with at least one of the isotopes C discharged into the breath, as an active ingredient Collecting the exhaled breath, (b) obtaining a ratio of the labeled amount of CO 2 for the labeled amount of CO 2 ratio or the total amount of CO 2, to unlabeled CO 2 amount contained in the breath and, (c ′) “Percentage of labeled CO 2 amount relative to the amount of unlabeled CO 2 contained in exhaled breath or ratio of labeled CO 2 amount relative to total CO 2 amount” ( ⁇ % 13 C) of the subject obtained in the step (b) (the atom%) or delta 13 C value ( ⁇ )) (test value), the percentage of labeled CO 2 amount to unlabeled CO 2 amount
- a subject who is in a sugar-loaded state is a subject who has ingested a saccharide, or a food or drink containing sugar or a substance that is metabolized into sugar before step (a). Detection method to be described.
- the food or drink is selected from the group consisting of proteins (including semi-digested proteins), amino acids, fats, electrolytes, trace elements, and vitamins, in addition to sugars or metabolized sugar components
- the detection method according to [2-f] which is a liquid, semi-liquid, or solid food or drink containing at least one selected from the above.
- the method for detecting a diabetic stage of the present invention can also be carried out by the methods described in (2-3) to (2-6) below.
- At least one time point (t) after administration of the test sample is at least one time point 10 minutes or more after administration of the test sample, as described in (2-3) or (2-4) Method.
- (3-2) Compare the glucose metabolism ability measured before diabetes treatment with the glucose metabolism ability measured after diabetes treatment for the subject, and that the glucose metabolism ability after diabetes treatment is increased compared to before diabetes treatment.
- [3-a] A method for detecting diabetes treatment for diabetic patients, comprising the following steps (a ′), (b) and (d): (a ′) A composition containing glucose (labeled C-glucose), which is converted with labeled carbon dioxide in vivo and labeled with at least one of the isotopes C discharged into the breath, as an active ingredient Collecting exhaled breath by administering to a subject before and after (B) obtaining a non-labeled ratio of the labeled amount of CO 2 for CO 2 amount or proportion of labeled CO 2 amount to the total amount of CO 2, contained in the front and rear of the expiration of diabetes treatment and, (d) (b) in the step is obtained for subjects after diabetes therapeutic treatment "percentage of labeled CO 2 amount to unlabeled CO 2 amount contained in the breath or percentage of labeled CO 2 amount to the total amount of CO 2," (a ′) A composition containing glucose (labeled C-glucose), which is converted with labeled
- a subject in a sugar-loading state is a subject who ingested a saccharide, or a food or drink containing a sugar or a substance that is metabolized to become a sugar before step (a ′), [3-d] The detection method described in 1.
- the above food or drink is selected from the group consisting of proteins (including semi-digested proteins), amino acids, fats, electrolytes, trace elements, and vitamins in addition to sugars or metabolized sugar components
- the detection method according to [3-f] which is a liquid, semi-liquid, or solid food or drink containing at least one selected from the above.
- composition for measuring sugar metabolism ability (4-1) Glucose labeled with at least one of the isotopes C converted into labeled carbon dioxide in the living body and discharged into the exhaled breath as an active ingredient
- a composition for measuring sugar metabolic capacity (4-1) Glucose labeled with at least one of the isotopes C converted into labeled carbon dioxide in the living body and discharged into the exhaled breath as an active ingredient
- composition for measuring glucose metabolism ability according to (4-1) or (4-2), wherein the administration form of the composition is an oral administration form or an injection administration form.
- composition for measuring the disease state stage (composition for measuring the disease state stage of diabetes).
- composition for detecting the therapeutic effect of diabetes To detect the therapeutic effect of diabetes on a diabetic patient by the breath test of glucose labeled with at least one of the isotopes C converted into labeled carbon dioxide in the living body and discharged into the breath Use for the manufacture of a composition (composition for detecting the therapeutic effect of diabetes).
- a subject's ability to metabolize glucose can be measured and evaluated with high accuracy and speed.
- the accuracy and rapidity can be achieved by performing the method of the present invention on a subject under a glucose load condition and / or making the administration form of the labeled C-glucose as a test substance intravenous rather than oral. Can be further improved.
- the glucose metabolism ability of the subject thus measured as an index, not only the pathological stage of the patient who developed diabetes but also whether or not it is a stage before developing diabetes. It can be determined and its status (diabetes pathology, including pre-diabetes status) can be monitored over time.
- a stage of diabetic condition is preferably performed within 60 minutes, more preferably within 30 minutes from the start of the test (administration of a composition containing glucose labeled with at least one of the isotopes C as an active ingredient). Can be measured and evaluated. For this reason, according to the method of the present invention, it is not necessary to restrain the subject for a long time, and the physical and mental burden can be reduced.
- the therapeutic effect of the diabetes treatment on a diabetic patient who has been treated for diabetes is determined, and the therapeutic effect of diabetes is determined over time. Can be monitored.
- the determination is also preferably within 120 minutes, more preferably within 60 minutes from the start of the test (administration of a composition containing glucose labeled with at least one of the isotopes C as an active ingredient) according to the present invention. More preferably, it can be measured and evaluated in a short time such as within 30 minutes. Therefore, according to the method of the present invention, it is not necessary to restrain the subject for a long time when determining the effect of diabetes treatment, and the physical and mental burden can be reduced.
- the result of Experimental example 1 is shown.
- Each of the 4 groups of rats (1- 13 C-Glc administration group, 2- 13 C-Glc administration group, 3- 13 C-Glc administration group, and U- 13 C-Glc administration group) was given each 13 C-glucose solution.
- the change in exhaled ⁇ 13 C ( ⁇ ) measured after administration is shown.
- the vertical axis represents ⁇ 13 C ( ⁇ ) in exhaled breath
- the horizontal axis represents the breath collection time (t) (min) after each 13 C-glucose solution administration.
- the result of Experimental example 2 is shown.
- Rats 4 groups (A group: healthy group, B group: severe diabetes onset group, C group: moderate diabetes onset group, D group: pre-diabetes stage group, the same applies to FIGS. 3 and 4), respectively.
- the change of ⁇ 13 C ( ⁇ ) in exhaled breath measured after administration of the U- 13 C-glucose oral administration solution is shown.
- the vertical axis represents ⁇ 13 C ( ⁇ ) in exhaled breath
- the horizontal axis represents the breath collection time (t) (min) after administration of the U- 13 C-glucose oral administration solution.
- t breath collection time
- the “blood glucose level (mg / dL)” (horizontal axis) of 4 groups of rats and [ ⁇ 13 C ( ⁇ )-exhalation collection time (120 minutes) area under the curve (AUC)] were determined as the insulin concentration (ng /
- the result of Experimental example 2 is shown.
- the “blood glucose level (mg / dL)” (horizontal axis) of 4 groups of rats and ⁇ 13 C ( ⁇ ) (10 minutes) divided by the insulin concentration (ng / mL) of each group “ ⁇ 13 C ( ⁇ ) ) (10 minutes) / insulin ( ⁇ ⁇ min ⁇ mL / ng) ”(vertical axis).
- the result of Experimental example 3 is shown.
- 6 shows changes in exhaled ⁇ 13 C ( ⁇ ) measured after administration of an oral administration solution of U- 13 C-glucose at the age of each rat (ZDF Fatty, ZDF lean).
- the result of Experimental example 4 (2-1) is shown.
- the result of Experimental example 4 (2-2-1) is shown. Measurement was performed after oral administration of a glucose aqueous solution (450 mg / 4 mL / kg) and a U- 13 C-glucose aqueous solution (50 ⁇ mol / 4 mL / kg) simultaneously to the first group (control group) and the second group (diabetes group), respectively. Changes in exhaled ⁇ 13 C ( ⁇ ) are shown.
- enteral nutrient protein amino acid preparation: trade name “Racol (registered trademark) enteral solution”
- 13 C is described as an example of “at least one of isotopes C or O” used in the present invention.
- RSAM is first obtained from (Definition 2), which is the definition of ⁇ 13 C, and substituted into R in the above expression, and an approximation (Expression 7) for obtaining the 13 C concentration is obtained.
- Equation 8 can calculate the delta% 13 C from delta 13 C.
- composition for Measuring Sugar Metabolism The composition for measuring glucose metabolism according to the present invention is labeled with at least one of the isotopes C that are converted into labeled CO 2 gas in the living body and discharged into the exhaled breath. It contains glucose as an active ingredient.
- the labeled C-glucose used in the present invention after being administered to a subject, is sugar metabolized according to the ability of the body to metabolize the glucose, and is exhaled as carbon dioxide containing the label C reflecting the size of the subject's ability of sugar metabolism. Has the property of being discharged.
- the isotope used for labeling the carbon atom constituting glucose is not particularly limited, and specific examples thereof include 13 C and 14 C.
- Such isotopes may be radioactive or non-radioactive, but are preferably non-radioactive isotopes from the viewpoint of safety.
- a preferred example of such an isotope is 13 C.
- Isotope element-labeled glucose is labeled so that at least a part of CO 2 produced from the sugar metabolic pathway is labeled with an isotope.
- glucose a compound in which at least one carbon atom at the 1-position, 6-position, 2-position, 5-position, and 3-position or 4-position of glucose is labeled with an isotope, specifically, it can be exemplified 1-13 C-labeled glucose, 2-13 C-labeled glucose, 3- 13 C-labeled glucose.
- all the carbon atoms at the 1st, 2nd, 3rd, 4th, 5th and 6th positions of glucose may be labeled with isotopes.
- the method for labeling a compound such as glucose with an isotope such as 13 C, 14 C and 18 O is not particularly limited, and a commonly used method is widely adopted (Sasaki, “5.1 Clinical practice of stable isotopes”). Application to diagnosis ”: Chemistry 107“ Application of stable isotopes to medicine / pharmaceutics and biology ”pp.149-163 (1975) Nanedo; Sugawara, RADIOISOTOPES, 41, 45-48 (1992), etc.). Any of these isotope-labeled compounds, particularly 13 C-labeled glucose shown in the Examples, can be obtained commercially, and such commercially available products can also be used conveniently.
- the composition of the present invention may be any one as long as labeled C-glucose is absorbed into the body after administration and metabolized and then discharged into the breath as labeled carbon dioxide gas.
- the form, components other than labeled C-glucose, the blending ratio of each component, the preparation method of the composition, and the like are not particularly limited.
- the form may be an oral dosage form or an intravenous dosage form.
- liquid forms including syrups), suspensions and emulsions; tablets (including nakeds and coatings), chewable tablets, capsules, pills, powders (powder), fine granules
- Any oral dosage form can be employed, such as solid forms such as agents and granules.
- a dosage form liquid, suspension or emulsion
- An oral dosage form that is a non-invasive measurement method is preferred, and an intravenous dosage form is more preferred, as shown in Experimental Example 4, in that high measurement accuracy can be obtained.
- composition of the present invention is not limited to one having a pharmaceutical form, and may contain any labeled C-glucose as long as it does not interfere with the action and effect of the present invention. In combination, it may have a form of solid food, liquid food or liquid food.
- composition of the present invention may consist essentially of the above-mentioned labeled C-glucose, which is an active ingredient.
- each formulation form ( Depending on the administration form, it may be in a form in which arbitrary pharmaceutically acceptable carriers and additives usually used in the art are blended.
- the amount of labeled C-glucose to be blended as an active ingredient is not particularly limited and can be 1 to 95% by weight in 100% by weight of the composition, and can be adjusted as appropriate within this range. .
- compositions of the present invention in the form of a liquid, suspension or emulsion such as an infusion or an injection
- various carriers or additions in addition to purified water or distilled water for injection depending on the various forms.
- An agent can be used.
- isotonic agents eg, sodium chloride
- pH adjusters eg, hydrochloric acid, sodium hydroxide, etc.
- buffers eg, boric acid, sodium monohydrogen phosphate, sodium dihydrogen phosphate, etc.
- Preservatives for example, benzalkonium chloride, etc.
- thickeners for example, carboxyvinyl polymer, etc.
- composition of the present invention when the composition of the present invention is formed into a solid form such as a tablet, chewable tablet, capsule, pill, powder (powder), fine granule, and granule, various kinds of forms are used. Carriers or additives can be used.
- Carriers or additives such as lactose, sucrose, dextrin, mannitol, xylitol, sorbitol, erythritol, calcium dihydrogen phosphate, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc.
- Binders such as dry starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxy Disintegrators such as ethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, carmellose calcium, low-substituted hydroxypropylcellulose, carmellose, croscarmellose sodium, carboxymethyl starch sodium, crospovidone; Disintegration inhibitors such as stearic acid, cocoa butter, hydrogenated oil; absorption enhancers such as polysorbate 80, quaternary ammonium base, sodium lau
- Tablets can be made into tablets with a normal coating as necessary, for example, sugar-coated tablets, gelatin-encapsulated tablets, film-coated tablets, double tablets, multilayer tablets and the like.
- Capsules are prepared by mixing isotope-labeled glucose, which is an active ingredient, with the various carriers exemplified above and filling hardened gelatin capsules, soft capsules and the like according to a conventional method.
- the composition of the present invention is used as a sample to be administered to a subject (test sample) in the measurement method described later. Specifically, it is used as a test sample to be administered for measurement of glucose metabolism ability in a subject.
- the composition of the present invention is used as a test sample to be administered to measure and determine the pre-stage of diabetes onset and / or the pathological stage after the onset of diabetes for a subject. Furthermore, the composition of the present invention is used as a test sample to be administered to determine and monitor the effects of diabetes treatment on diabetic patients.
- the amount of labeled C-glucose (active ingredient) to be blended in the composition is the case. It can be adjusted and set as appropriate according to the conditions. In any case, the dose per dose is in the range of 5 mg / body to 50 mg / body, preferably 10 mg / body to 25 mg / body in terms of the amount of labeled C-glucose (active ingredient). Can be prepared.
- the measurement of the glucose metabolism is basically performed by administering the above composition containing labeled C-glucose as an active ingredient to mammals (subjects) including humans and collecting exhaled breath as shown below.
- the abundance ratio of carbon dioxide gas contained in the exhaled breath ratio of labeled CO 2 amount relative to unlabeled CO 2 amount, or ratio of labeled CO 2 amount relative to total CO 2 amount
- It can be performed through the step of measuring [step (b) of the method of the present invention].
- Step (a) A composition comprising glucose as an active ingredient (labeled C-glucose), which is labeled with at least one of the isotopes C that are converted into labeled carbon dioxide in the living body and discharged into the exhaled breath. recovering said exhalation administered to, and [(b) step] obtaining a ratio of the labeled CO 2 amount to the rate or total amount of CO 2 labeled amount of CO 2 to unlabeled CO 2 amount contained in the breath.
- labeled CO 2 amount to the rate or total amount of CO 2 labeled amount of CO 2 to unlabeled CO 2 amount contained in the breath.
- the labeled C-glucose used in the present invention is orally or intravenously administered to a subject, and then sugar is metabolized according to the subject's ability to metabolize glucose, and reflects the magnitude of the ability of sugar metabolism.
- the “carbon dioxide containing the label C” is discharged into the breath.
- the administration method of the composition of the present invention containing labeled C-glucose as an active ingredient is not particularly limited, and may be either oral administration or intravenous administration. Oral administration is preferable in terms of a non-invasive method, and intravenous administration is preferable in terms of high accuracy as shown in Experimental Example 4.
- the amount of labeled C-glucose (active ingredient) blended in the composition for measuring glucose metabolism ability of the present invention can be appropriately adjusted and set according to the case.
- the dose per administration is 5 mg / body or more in terms of the amount of labeled C-glucose (active ingredient). It can be prepared so as to be in the range of 50 g / body, preferably 10 mg / body to 25 g / body.
- the subject targeted by the present invention is a human or a non-human mammal as described above.
- mammals other than humans include mice, rats, guinea pigs, rabbits, dogs, cats, monkeys, pigs, cows, horses, etc., but preferably experiments with mice, rats, guinea pigs, rabbits, dogs, monkeys, etc. Is an animal.
- Such a subject may be fasted or non-fasted before being subjected to step (a).
- the sugar metabolic capacity can be measured with high accuracy in a short time. It is preferable to be in a fasted state, particularly in a sugar-loaded state.
- a subject who has been fasted is a carbohydrate (eg, glucose), or a food or drink containing a carbohydrate, or It is preferable to ingest foods and drinks including those that are metabolized to become carbohydrates to achieve a sugar-loaded state.
- carbohydrate eg, glucose
- a food or drink containing a carbohydrate or It is preferable to ingest foods and drinks including those that are metabolized to become carbohydrates to achieve a sugar-loaded state.
- the dose of these carbohydrates or foods and beverages include a ratio such that the amount of glucose administered into the body or the glucose produced by metabolism in the body is about 450 mg to 2 g / kg.
- food and drink containing carbohydrates or foods and drinks containing those that are metabolized to saccharides are not limited, but in addition to carbohydrates or components that are metabolized to saccharides, proteins (semi-digested proteins A liquid, semi-liquid, or solid food or drink containing at least one selected from the group consisting of amino acids, fats, electrolytes, trace elements and vitamins.
- proteins include glucose, sucrose (sucrose), maltose, sorbitol, oligosaccharide, carbohydrate, and the like without limitation. Glucose and maltodextrin are preferred.
- the 13 C content (atom%) [ 13 C concentration in exhaled air (% 13 C)] [(% 13 C) t ] in the exhaled breath collected t hours after administration of the reagent Further, according to Equation 6, the amount of change in 13 C concentration ( ⁇ % 13 C) is obtained by subtracting the 13 C concentration (atom%) [(% 13 C) 0 ] before administration of the 13 C-labeled compound.
- the labeled C content excreted into the exhaled breath after the administration of the composition for measuring glucose metabolic capacity containing labeled C-glucose as an active ingredient, or the corresponding ⁇ % 13 C (atom%) or ⁇ 13 C value ( ⁇ ) ) Reflects the subject's ability to metabolize glucose, as shown in the experimental examples described below, and according to the method of the present invention using the composition, the subject's ability to metabolize sugar is accurately and rapidly. Can be measured.
- the measurement and analysis of labeled carbon dioxide contained in the breath sample differs depending on whether the isotope used is radioactive or non-radioactive, but usually the liquid scintillation counter method, mass spectrometry, infrared spectroscopy, luminescence analysis
- the analysis can be carried out using a commonly used analytical technique such as a magnetic resonance spectrum method or the like. In view of measurement accuracy, infrared spectroscopy and mass spectrometry are preferred.
- step (b) "percentage of labeled CO 2 amount to unlabeled CO 2 amount contained in the breath or percentage of labeled CO 2 amount to the total amount of CO 2," ( ⁇ % 13 C (atom% ) or Using the ⁇ 13 C value ( ⁇ )) as an index, the subject's ability to metabolize glucose can be determined by the following method.
- (C-1) (b) "percentage of labeled CO 2 amount to non-rate of the labeled amount of CO 2 for the labeled CO 2 amount or total amount of CO 2, contained in the breath" of the subject obtained in step (delta% 13 C (the atom%) or delta 13 C value ( ⁇ )) (test value), the percentage of labeled CO 2 amount to unlabeled CO 2 amount contained in the "expiration corresponding obtained for healthy subjects or to the total amount of CO 2, It is compared with the “ratio of labeled CO 2 amount” ( ⁇ % 13 C (atom%) or ⁇ 13 C value ( ⁇ )) (control value).
- a healthy person means here the test subject (non-diabetic person) who is healthy regarding diabetes, ie, has not developed diabetes, and is not in the state before onset of diabetes.
- a subject whose sugar metabolic capacity is lower than that of a healthy person is determined to develop diabetes, and in the method of the present invention, the sugar metabolism capacity of a healthy person is determined to be healthy.
- Subjects with higher than ability are determined to be in the early stages of diabetes. That is, according to the method for measuring glucose metabolism capacity of the present invention, since it is possible to detect that the subject is in the stage before the onset of diabetes, the risk of the onset of diabetes can be determined, which contributes to the prevention of the onset of diabetes. Can do.
- these methods measure, in parallel with the method of the present invention using a breath test, a known or commonly used diagnostic method for diabetes (such as blood glucose level measurement, insulin resistance test, hemoglobin A1c). Can also be done.
- a known or commonly used diagnostic method for diabetes such as blood glucose level measurement, insulin resistance test, hemoglobin A1c.
- (IV) A method for measuring the pre-stage of diabetes onset and / or the pathological stage after onset of diabetes
- the glucose metabolism ability of the subject obtained by the glucose metabolism ability measurement method of the present invention described above is used as an index.
- the pre-stage of the onset of diabetes and / or the pathological stage after the onset of diabetes can be measured for the subject.
- step (c) based on the results obtained in step (c), it was determined that the glucose metabolism ability was reduced compared with the sugar metabolism ability of healthy subjects. Assuming that the subject is a diabetic patient (diabetic onset patient) and the subject determined to have increased (increased) glucose metabolism ability is a patient in the early stage of diabetes onset (pre-diabetic stage patient). Can be determined.
- Step (a) A composition comprising glucose as an active ingredient (labeled C-glucose), which is labeled with at least one isotope C that is converted into labeled carbon dioxide in the living body and discharged into the exhaled breath.
- [(C ') step] (b) "percentage of labeled CO 2 amount to non-rate of the labeled amount of CO 2 for the labeled CO 2 amount or total amount of CO 2, contained in the breath" of the subject obtained in step (delta% 13 C (atom%) or delta 13 C value ( ⁇ )) (the test value), the percentage of labeled CO 2 amount to unlabeled CO 2 amount contained in the "expiration corresponding obtained for healthy subjects or total CO 2,
- the test value is lower than the control value compared to the ratio of the amount of labeled CO 2 to the amount ”( ⁇ % 13 C (atom%) or ⁇ 13 C value ( ⁇ )) (control value)
- the subject is treated for diabetes.
- the method of the present invention is useful in that a patient in the pre-stage of diabetes onset (pre-diabetic stage patient), which was difficult to determine by conventional methods, can be distinguished from a healthy person.
- a patient in the pre-stage of diabetes onset pre-diabetic stage patient
- the degree of progression (severity) of diabetes when the degree of decrease in glucose metabolism ability is large, the degree of progression (severity) of diabetes is large, and the degree of decrease in glucose metabolism ability and the degree of progression of diabetes (seriousness). Therefore, according to the method of the present invention, the degree of progression (severity) of diabetes can be measured and evaluated from the degree of decrease in the ability of glucose metabolism and monitored. .
- Measurement of the pathological stage of diabetes can also be performed by the following method. According to this method, not only diabetic patients but also patients in the pre-stage of diabetes onset can be clearly and accurately distinguished from healthy individuals.
- the healthy group concentrates in the upper left column (blood glucose level of 150 mg / dl or less, [ ⁇ 13 C ( ⁇ ) (t) / insulin] 90 ⁇ ⁇ mL / ng or more).
- diabetic patients and patients in the pre-stage of diabetes onset concentrate at a particularly low value of [ ⁇ 13 C ( ⁇ ) (t) / insulin] 90 ⁇ ⁇ mL / ng or less.
- the healthy group concentrates in the upper left column (blood glucose level of 150 mg / dl or less, [ ⁇ 13 C ( ⁇ ) AUCt / insulin] 23000 ⁇ ⁇ min ⁇ mL / ng or more).
- diabetic patients and patients in the pre-stage of diabetes onset concentrate at particularly low values of [ ⁇ 13 C ( ⁇ ) AUCt / insulin] 23000 ⁇ ⁇ min ⁇ mL / ng or less.
- patients in the pre-stage of diabetes onset are concentrated in the region of [ ⁇ 13 C ( ⁇ ) AUCt / insulin] 23000 ⁇ ⁇ min ⁇ mL / ng or less and blood glucose level of 150 mg / dl or less.
- the test subject in the early stage of the onset of diabetes can be detected and distinguished from the healthy subject and the diabetic patient by the short-time test. By taking appropriate measures, it can be expected to prevent or prevent the onset of diabetes. In addition, by monitoring the subject over time, it is possible to manage and monitor the progress of diabetes onset and the degree and the severity of diabetes patients over time.
- the subject carried out before and after the treatment of diabetes, the labeled amount of CO 2 to unlabeled CO 2 amount contained in the "breath obtained before and after treatment of diabetes ratio, or the total proportion of labeled CO 2 amount to the amount of CO 2 "( ⁇ % 13 C (atom% ) or delta 13 C value ( ⁇ )) were compared to the values after treatment of diabetes than the value of pre-diabetes If it is high, it can be determined that there is a therapeutic effect on diabetes.
- Step (a ') A composition comprising glucose (labeled C-glucose), which is converted into labeled carbon dioxide in vivo and labeled with at least one of the isotopes C discharged into the breath, as an active ingredient Collecting exhaled breath by administering to a subject before and after diabetes treatment, [(B) step] obtaining a non percentage of labeled CO 2 amount to the labeled amount of CO 2 or proportion of labeled CO 2 amount to the total amount of CO 2, contained in the front and rear of the expiration of diabetes treatment, and [(d) Step ] (b) in the step is obtained for subjects after diabetes therapeutic treatment "percentage of labeled CO 2 amount to unlabeled CO 2 amount contained in the breath or percentage of labeled CO 2 amount to the total amount of CO 2," (delta% 13 C (atom%) or delta 13 C value ( ⁇ )) the proportion of the labeled CO 2 amount to unlabeled CO 2 amount contained in the corresponding "exhalation obtained for diabetes treatment the subject
- the method of the present invention it is possible to measure and evaluate the therapeutic effect of the diabetes treatment and monitor it for a diabetic patient who has been treated for diabetes, using the increase in glucose metabolism ability as an index.
- ⁇ 13 C ( ⁇ ) is, 13 C-glucose solution before administration (0 minute) and the breath sampling point exhaled in (t min) 13 CO 2/12 CO 2 concentration ratio after administration ([delta] 13 C value ), And the difference ( ⁇ 13 C t ⁇ 13 C 0 ) between the ⁇ 13 C value ( ⁇ 13 C t ) at each sampling point (t) and the ⁇ 13 C value ( ⁇ 13 C 0 ) before administration. (The same applies to the following experimental examples).
- FIG. 1 shows changes in exhaled ⁇ 13 C ( ⁇ ) measured after each 13 C-glucose solution was administered to each of the four groups of rats.
- the vertical axis represents ⁇ 13 C ( ⁇ ) during expiration.
- the abscissa represents the breath collection time (min) (t minutes) after administration of each 13 C-glucose solution.
- the ⁇ 13 C ( ⁇ ) value up to 30 minutes after administration of the glucose solution is higher in the group treated with 3- 13 C-Glc (- ⁇ -) and then in the group administered U- 13 C-Glc (-X-).
- Excretion The results, 1-13 C-glucose, 2-13 C-glucose, 3- 13 C-out of glucose and U- 13 C-glucose after administration into the body, the more early expiration as 13 CO 2
- the 13 C-glucose reflected in the ⁇ 13 C ( ⁇ ) value was found to be 3- 13 C-glucose and then U- 13 C-glucose. That is, the 13 C-glucose capable of measuring the ⁇ 13 C ( ⁇ ) value in a short time is preferably 3- 13 C-glucose and U- 13 C-glucose.
- exhaled breath was collected at each time point before (0 minutes) and after (10, 20, 30, 40, 50, 60, 80, 100, 120 minutes) administration of the oral administration solution of U- 13 C-glucose.
- ⁇ 13 C ( ⁇ ) was determined from the 13 CO 2 concentration discharged therein using a mass spectrometer for breath analysis (ABCA: manufactured by SerCon).
- FIG. 2 shows the changes in exhaled ⁇ 13 C ( ⁇ ) measured after the U- 13 C-glucose oral administration solution was administered to each of the four groups of rats.
- the vertical axis represents ⁇ 13 C ( ⁇ ) during expiration.
- the horizontal axis represents the breath collection time (minutes) after administration of the U- 13 C-glucose oral administration solution.
- the moderately diabetic group (C group:- ⁇ -) and the severely diabetic group (B group:- ⁇ -) 13 C ( ⁇ ) value was low.
- the pre-diabetes stage group (D group: -x-) had a higher ⁇ 13 C ( ⁇ ) value than both the healthy group and the diabetes onset group (medium onset diabetes group, severe diabetes onset group). .
- the AUC per insulin concentration (120 minutes) [AUC120 / insulin ( ⁇ ⁇ min ⁇ mL / ng)] is the pre-diabetes stage group (Group D: -x-) In the onset group (Group C:- ⁇ -) and the severe onset group of diabetes (Group B:- ⁇ -), the value was significantly lower in the diabetes onset group. Was clearly different. Furthermore, it was shown that as the blood glucose level rises, it shifts to the right side of the figure as the diabetes state stage progresses.
- diabetes pathological stage the pre-diabetes stage and the pathological stage of diabetes (collectively referred to as “diabetic pathological stage”) can be determined and monitored. Diabetes state stage determination using this parameter is difficult to discriminate by conventional methods, and is particularly useful for diagnosis of the stage before the onset of diabetes.
- FIG. 4 shows the correlation between “(10 minutes) / insulin ( ⁇ ⁇ mL / ng)” and “blood glucose level (mg / dL)” of each group.
- the vertical axis indicates “ ⁇ 13 C ( ⁇ ) (10 minutes) / insulin concentration” ( ⁇ ⁇ mL / ng), and the horizontal axis indicates the blood glucose level (mg / dL).
- the vertical axis is changed from “AUC120 / insulin ( ⁇ ⁇ min ⁇ mL / ng)” to “ ⁇ 13 C ( ⁇ ) (10 minutes) / insulin ( ⁇ ⁇ mL / ng)”. Even if it replaces, while being able to discriminate
- the measurement time point (t minutes) may be after 13 C-glucose administration, but in the sense of taking advantage of the present invention that the above can be performed in a short time, 120 C after 13 C-glucose administration. Within minutes, preferably within 60 minutes, more preferably within 30 minutes. Moreover, although not limited, it is preferable that at least 10 minutes or more have passed after 13 C-glucose administration.
- Diabetes state stage determination using this parameter is difficult to distinguish in a short time by the conventional method, and is particularly useful for diagnosis at the stage before the onset of diabetes.
- FIG. 7 shows the exhalation pattern (transition of ⁇ 13 C ( ⁇ ) during exhalation).
- test animals of (1), the first group (control group) and the second group (diabetes group) were each treated with U-glucose 30 minutes after oral administration of an aqueous glucose solution (450 mg / 4 mL / kg). 13 C-glucose aqueous solution (50 ⁇ mo / 4 mL / kg) was orally administered.
- aqueous glucose solution 450 mg / 4 mL / kg
- 13 C-glucose aqueous solution 50 ⁇ mo / 4 mL / kg
- exhaled air was collected and ⁇ 13 C ( ⁇ ) was measured from the 13 CO 2 concentration discharged into the exhaled air.
- FIG. 8 shows the exhalation pattern (transition of ⁇ 13 C ⁇ during exhalation).
- test animals of (1), the first group (control group) and the second group (diabetes group) were each given U- 13 C 30 minutes after oral administration of glucose aqueous solution (2 g / 4 mL / kg). -An aqueous glucose solution (50 ⁇ mol / mL / kg) was administered intravenously.
- aqueous glucose solution 50 ⁇ mol / mL / kg was administered intravenously.
- exhaled air was collected and ⁇ 13 C ( ⁇ ) was measured from the 13 CO 2 concentration discharged into the exhaled air.
- FIG. 10 shows the exhalation pattern (transition of ⁇ 13 C ( ⁇ ) during exhalation).
- FIG. 11 shows the exhalation pattern (transition of ⁇ 13 C ( ⁇ ) during exhalation).
- the vertical axis represents ⁇ 13 C ( ⁇ )
- the horizontal axis represents the breath collection time (min) after administration of U- 13 C-glucose.
- the first group (control group) and the second group (diabetes group) are initially treated (especially within 10 minutes after administration).
- the initial exhalation can be obtained by administering a carbohydrate in advance (sugar load) before administration of 13 C-glucose as a test substance, as shown in FIG. Overlapping of reactions was resolved.
- the first group The difference in exhalation response between the (control group) and the second group (diabetes group), especially the difference in exhalation response in the initial stage (for example, within 10 minutes after administration) further spread.
- breath test using 13 C- glucose in glucose tolerance conditions preferably breath test using 13 C- glucose under the conditions glucose load was administered carbohydrate in advance More preferably, the measurement accuracy of the diabetic stage can be improved by an exhalation test performed by intravenous administration of 13 C-glucose.
- Metformin (Wako Co., Ltd.), 300 mg / kg, which is an active ingredient of a biguanide diabetes therapeutic drug (generic name: Melvin), was orally administered to each group of rats every morning for 3 days. Three hours after administration on the third day, a U- 13 C-glucose solution prepared by the method described in Experimental Example 1 (1) was intravenously administered.
- the expiration pattern ( ⁇ 13 C in expiration) ( ⁇ ) is higher than that before administration of the therapeutic agent for diabetes by administering the therapeutic agent for diabetes. It was found that the glucose metabolism ability was enhanced. That is, it has been found that the therapeutic effect of a therapeutic drug for diabetes can be evaluated and determined using the breath test of the present invention.
- the therapeutic effect of the antidiabetic drug can be confirmed in a short period of time within 3 days.
- the measured HbA1c value about one month after the start of drug treatment is used as an index for determining the therapeutic effect of drugs.
- STZ rat As a type 1 diabetes group (STZ rat), rats that had been administered for 1 week after intravenous administration of STZ (streptozocin: SIGNA) 65 mg / mL / kg / were used.
- STZ streptozocin: SIGNA
- Insulin (SIGMA) 30U / body administered subcutaneously type 1 diabetic group, prior to insulin administration, 24 hours after 4 hours or administered dose, 1-13 was prepared by the method described in Experimental Example 1 (1) C -Glucose solution was administered intravenously (however, insulin was not administered to the control group, which is a healthy group). Then, each group of rats (control group, type 1 diabetes group, insulin administration 4h- diabetic group, insulin administration 24h- diabetic group) for each time point after administration and 1-13 C-glucose administration before (0 min) ( 10, 20, 30, 40, 50, 60, 80, 100, 120 minutes), and ⁇ 13 C ( ⁇ ) is calculated from the 13 CO 2 concentration discharged into the breath ( ABCA: manufactured by SerCon).
- FIG. 13 shows expiration patterns of rats in each group (control group:- ⁇ -, type 1 diabetes group:- ⁇ -, insulin administration 4h-diabetes group:- ⁇ -, insulin administration 24h-diabetes group:- ⁇ -).
- ⁇ 13 C ( ⁇ ) the vertical axis represents ⁇ 13 C ( ⁇ )
- the horizontal axis represents the breath collection time (minutes) after administration of 1 13 C-glucose.
- ⁇ 13 C ( ⁇ ) during the duration of the insulin effect showed almost the same value as the control group.
- the expiration pattern (change in ⁇ 13 C ( ⁇ )) showed a low value as the effect of insulin disappeared.
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Abstract
Description
(1)糖代謝能の測定方法
(1-1)下記(a)及び(b)の工程を有する、被験者の糖代謝能の測定方法:
(a)生体内で標識炭酸ガスに変換されて呼気中に排出される同位元素Cの少なくとも一つで標識されてなるグルコースを有効成分とする組成物を被験者に投与して呼気を採取する工程、および
(b)呼気に含まれる非標識CO2量に対する標識CO2量の割合、または総CO2量に対する標識CO2量の割合を求める工程。
(1-2)さらに下記(c)の工程を有する、(1-1)に記載する糖代謝能測定方法:
(c)(b)工程で得られる被験者の「呼気に含まれる非標識CO2量または総CO2量に対する標識CO2量の割合」(被験値)を、健常者について得られる「呼気に含まれる非標識CO2量に対する標識CO2量の割合、または総CO2量に対する標識CO2量の割合」(対照値)と比較し、被験値が対照値よりも低い場合を被験者について糖代謝能が低下していると決定し、被験値が対照値よりも高い場合を被験者について糖代謝能が亢進していると決定する工程。
(1-3)上記同位元素が13Cである、(1-1)または(1-2)に記載する糖代謝測定方法。
(2-1)(1-1)乃至(1-7)のいずれかに記載する糖代謝能測定方法により得られる被験者の糖代謝能を指標として、被験者について糖尿病発症の前段階または/および糖尿病発症後の病態ステージを検出する方法。
(a) 生体内で標識炭酸ガスに変換されて呼気中に排出される同位元素Cの少なくとも一つで標識されてなるグルコース(標識C-グルコース)を有効成分とする組成物を被験者に投与して呼気を採取する工程、
(b) 呼気に含まれる非標識CO2量に対する標識CO2量の割合、または総CO2量に対する標識CO2量の割合を求める工程、及び
(c’) 上記(b)工程で得られる被験者の「呼気に含まれる非標識CO2量に対する標識CO2量の割合、または総CO2量に対する標識CO2量の割合」(Δ%13C(atom%)またはΔ13C値(‰))(被験値)を、健常者について得られる対応する「呼気に含まれる非標識CO2量に対する標識CO2量の割合、または総CO2量に対する標識CO2量の割合」(Δ%13C(atom%)若しくはΔ13C値(‰))(対照値)と比較し、被験値が対照値よりも低い場合、当該被験者を糖尿病を発症していると決定し、被験値が対照値よりも高い場合、当該被験者を糖尿病発症の前段階にあると決定する工程。
(3-1)(1-1)乃至(1-6)のいずれかに記載する糖代謝能測定方法により得られる糖尿病患者の糖代謝能を指標として、糖尿病治療を受けた糖尿病患者に対する当該糖尿病治療の治療効果を検出する方法。
[3-a]下記(a’)、(b)及び(d)の工程を有する、糖尿病患者に対する糖尿病治療の検出方法:
(a’)生体内で標識炭酸ガスに変換されて呼気中に排出される同位元素Cの少なくとも一つで標識されてなるグルコース(標識C-グルコース)を有効成分とする組成物を、糖尿病治療の前後で被験者に投与して呼気を採取する工程、
(b)糖尿病治療の前後の呼気に含まれる非標識CO2量に対する標識CO2量の割合、または総CO2量に対する標識CO2量の割合を求める工程、及び
(d)(b)工程で、糖尿病治療処置後の被験者について得られる「呼気に含まれる非標識CO2量に対する標識CO2量の割合、または総CO2量に対する標識CO2量の割合」(Δ%13C(atom%)またはΔ13C値(‰))を、糖尿病治療処置前の被験者について得られる対応する「呼気に含まれる非標識CO2量に対する標識CO2量の割合、または総CO2量に対する標識CO2量の割合」(Δ%13C(atom%)またはΔ13C値(‰))(対照値)と比較し、被験値が対照値よりも高い場合の当該被験者については糖尿病治療効果があると決定し、被験値が対照値と同じ若しくはそれよりも低い場合の当該被験者については糖尿病治療効果がないと決定する工程。
(4-1)生体内で標識炭酸ガスに変換されて呼気中に排出される同位元素Cの少なくとも一つで標識されてなるグルコースを有効成分とする、糖代謝能を測定するための組成物。
(5-1)生体内で標識炭酸ガスに変換されて呼気中に排出される同位元素Cの少なくとも一つで標識されてなるグルコースの、呼気試験によって糖代謝能を測定するための組成物(糖代謝能測定用組成物)の製造のための使用。
(6-1)呼気試験によって糖代謝能を測定するために使用される、生体内で標識炭酸ガスに変換されて呼気中に排出される同位元素Cの少なくとも一つで標識されてなるグルコース、またはそれを有効成分とする組成物。
本発明の糖代謝能測定方法は、13C-呼気試験などの標識C-呼気試験を用いることを基礎とするものである。よって、本発明の説明に先だって、標識C-呼気試験に関連する用語およびその解析方法について説明する(「13C-呼気試験の実際 基礎と実践的応用 第8項:13C-呼気試験データ解析法」、松林恒夫、松山渉、13C医学応用研究会、pp.102-111)。
同位体の存在比を表す場合、同一元素の中で最も組成比の高い元素を分母にした同位体比(R)を用いる。従って炭素13(13C)のR値は、炭素12(12C)を分母とした次式で表される。
「Δ13C値(‰)」は、下式で示すように、試薬投与前のδ13C値(すなわち天然に存在する13Cのδ値)をback groundとして、試薬投与後のδ13C値から差し引いた値(Δ13C)を意味する。
呼気中の13C濃度(%13C:atom%)は下式で定義される。
呼気中の13C濃度(%13C)の変化量(Δ%13C)は、次式で定義されるように、投与t時間後の13C濃度〔(%13C)t〕から投与前0時間の13C濃度〔(%13C)0〕を差し引いて求められる。
13Cの天然存在比(R)は約0.011であり、標識試薬を投与した場合でも呼気中への増加量はわずかに+0.001~0.002程度である。そこで、天然存在比R→0とみなすことができ、%13CをRで表した(式4)は、次式で近似することができる。
本発明の糖代謝能測定用組成物は、生体内で標識CO2ガスに変換して呼気中に排出される同位元素Cの少なくとも一種で標識されてなるグルコースを有効成分とするものである。本発明で用いられる標識C-グルコースは、被験者に投与された後、体内の糖代謝能に応じて糖代謝され、被験者の糖代謝能の大きさを反映した標識Cを含む炭酸ガスとして呼気に排出される特性を有する。
前述する本発明の糖代謝能測定用組成物を用いることによって、被験者(ヒトまたはヒト以外の哺乳動物)の糖代謝能を測定することができる。
[(b)工程] 呼気に含まれる非標識CO2量に対する標識CO2量の割合または総CO2量に対する標識CO2量の割合を求める工程。
前述するように、前述する本発明の糖代謝能測定方法によって得られた被験者の糖代謝能を指標とすることで、当該被験者について糖尿病発症の前段階または/および糖尿病発症後の病態ステージを測定することができる。
[(b)工程]呼気に含まれる非標識CO2量に対する標識CO2量の割合、または総CO2量に対する標識CO2量の割合を求める工程、及び
[(c)工程](b)工程で得られる被験者の「呼気に含まれる非標識CO2量に対する標識CO2量の割合、または総CO2量に対する標識CO2量の割合」(Δ%13C(atom%)またはΔ13C値(‰))(被験値)を、健常者について得られる対応する「呼気に含まれる非標識CO2量に対する標識CO2量の割合、または総CO2量に対する標識CO2量の割合」(Δ%13C(atom%)若しくはΔ13C値(‰))(対照値)と比較し、被験値が対照値よりも低い場合、当該被験者について糖代謝能が低下していると決定し、被験値が対照値よりも高い場合、当該被験者について糖代謝能が亢進していると決定する工程。
前述するように、本発明の糖代謝能測定方法によって得られた被験者の糖代謝能を指標とすることで、糖尿病の治療を受けている被験者(糖尿病患者)に対する糖尿病治療の治療効果を検出し評価することができる。
[(b)工程]糖尿病治療の前後の呼気に含まれる非標識CO2量に対する標識CO2量の割合、または総CO2量に対する標識CO2量の割合を求める工程、及び
[(d)工程](b)工程で、糖尿病治療処置後の被験者について得られる「呼気に含まれる非標識CO2量に対する標識CO2量の割合、または総CO2量に対する標識CO2量の割合」(Δ%13C(atom%)またはΔ13C値(‰))を、糖尿病治療処置前の被験者について得られる対応する「呼気に含まれる非標識CO2量に対する標識CO2量の割合、または総CO2量に対する標識CO2量の割合」(Δ%13C(atom%)またはΔ13C値(‰))(対照値)と比較し、被験値が対照値よりも高い場合の当該被験者については糖尿病治療効果があると決定し、被験値が対照値と同じ若しくはそれよりも低い場合の当該被験者については糖尿病治療効果がないと決定する工程。
(1)13C-グルコース溶液の調製
(a)1-13C-グルコース(1位の炭素原子を13Cに置換したグルコース。MW:181,Cambridge Isotope Laboratory製)を生理食塩水で300μmol/mLになるように調製した。
(b)2-13C-グルコース(2位の炭素原子を13Cに置換したグルコース。MW:181,Cambridge Isotope Laboratory製)を生理食塩水で300μmol/mLになるように調製した。
(c)3-13C-グルコース(3位の炭素原子を13Cに置換したグルコース。MW:181,Cambridge Isotope Laboratory製)を生理食塩水で300μmol/mLになるように調製した。
(d)U-13C-グルコース(全ての炭素原子を13Cに置換したグルコース。MW:186,Cambridge Isotope Laboratory製)を生理食塩水で50μmol/mLになるように調製した。
被験動物として絶食させたラット(雄,SD系ラット)を4群にわけ(1群あたりn=4)、各群(1-13C-Glc投与群、2-13C-Glc投与群、3-13C-Glc投与群、及びU-13C-Glc投与群)のラットに、それぞれ上記で調製した各13C-グルコース溶液を1mL/kgずつ静脈内投与した。次いで、各13C-グルコース溶液の投与前(0分)と投与後の各時点(10,20,30,40,50,60,80,100,120分)で呼気を採取し、呼気中に排出された13CO2濃度からΔ13C(‰)を、呼気分析用質量分析計(ABCA:SerCon社製)を用いて求めた。
ラット4群にそれぞれ各13C-グルコース溶液を投与した後に測定した呼気中Δ13C(‰)の推移を図1に示す。図中、縦軸は呼気中Δ13C(‰)である。また横軸は各13C-グルコース溶液投与後の呼気採取時間(分)(t分)を示す。
(1)U-13C-グルコース経口投与液の調製
U-13C-グルコース(MW:186,Cambridge Isotope Laboratory製)を生理食塩水に溶解して50μmol/4mL濃度のU-13C-グルコース経口投与液を調製した。
被験動物として、表1に記載するA~Dの計4群のラット(雄,ZDFラット(LeanまたはFatty)、1群あたり、n=4~6)を用い、各群のラットを絶食させた後、上記で調製したU-13C-グルコース経口投与液を強制的に4mL/kgずつ経口投与した。
(3-1) 上記ラット4群に、それぞれU-13C-グルコース経口投与液を投与した後、測定した呼気中Δ13C(‰)の推移を図2に示す。図中、縦軸は呼気中Δ13C(‰)である。また横軸は、U-13C-グルコース経口投与液投与後の呼気採取時間(分)を示す。
(1)U-13C-グルコース経口投与液の調製
U-13C-グルコース(MW:186,Cambridge Isotope Laboratory製)を生理食塩水に溶解して50μmol/4mL濃度のU-13C-グルコース経口投与液を調製した。
被験動物として、絶食させたZDF Laenラット(非糖尿病ラット:健常群)(雄,n=4)とZDF Fattyラット(雄, n=4)を用い、ZDF Fattyラットについては9,10,13,及び23週齢の各時点で、またZDF Laenラットについては13週齢の各時点で、上記で調製した投与液を強制的に4mL/kg経口投与した。次いで、各群について、U-13C-グルコース経口投与液投与前(0分)と投与後の各時点(10,20,30,40,50,60,80,100,120分)で呼気を採取し、呼気中に排出された13CO2濃度からΔ13C(‰)を、呼気分析用質量分析計(ABCA:SerCon社製)を用いて測定した。
各週齢時(ZDF Fatty:9W,10W,13W,23W、ZDF Laen:13W)にU-13C-グルコース経口投与液を投与した後に測定した呼気中Δ13C(‰)の推移を図5に示す。図中、縦軸は呼気中Δ13C(‰)、また横軸はU-13C-グルコース経口投与液投与後の呼気採取時間(分)を示す。
(1)被験動物
被験動物として、糖尿病モデル動物であるOLETFラットとそのコントロールとしてLETOラットを用いた。具体的には、第1群(対照群:LETOラット,雄,n=5)と第2群(糖尿病群:OLETFラット,雄,n=6)を20時間絶食した後、下記の試験に供した。
(2-1) 絶食下での呼気パターン(呼気中Δ13C(‰)の推移)
絶食下の第1群(対照群)及び第2群(糖尿病群)に、それぞれU-13C-グルコース水溶液(50μmol/4mL/kg)を経口投与した。各群について、U-13C-グルコース投与前(0分)と投与後の各時点(10,20,30,40,50,60,80,100,120分)で呼気を採取し、呼気中に排出された13CO2濃度からΔ13C(‰)を呼気分析用質量分析計(ABCA:SerCon社製)を用いて測定した。図6に、その呼気パターン(呼気中Δ13C(‰)の推移)を示す。
(2-2-1)(1)の被験動物、第1群(対照群)及び第2群(糖尿病群)に、それぞれグルコース水溶液(450mg/4mL/kg)とU-13C-グルコース水溶液(50μmol/4mL/kg)を同時に経口投与した。
(2-1)と同様に、各群についてU-13C-グルコース投与前(0分)と投与後の各時点(10,20,30,40,50,60,80,100,120分)で呼気を採取し、呼気中に排出された13CO2濃度からΔ13C(‰)を測定した。図7にその呼気パターン(呼気中Δ13C(‰)の推移)を示す。
図6に示すように、絶食下では第1群(対照群)と第2群(糖尿病群)のΔ13C(‰)値の差は小さかった。一方、図7~11に示すように、糖負荷条件下では第1群(対照群)の呼気パターン(呼気中Δ13C(‰)の推移)は第2群(糖尿病群)の呼気パターン(呼気中Δ13C(‰)の推移)に比して有意に高いことが判明した。つまり、絶食下では、健常者群(対照群)と糖尿病群との呼気反応(呼気パターン、呼気中Δ13C(‰)の推移)の間に差はあるものの、その程度は小さいのに対して、糖負荷条件下での測定により、両者の呼気反応(呼気パターン、呼気中Δ13C(‰)の推移)の差が増大する。このことから、糖負荷条件下で測定することにより、糖尿病群が健常者群(対照群)と区別されてより判別しやすくなることが確認された。
(1)実験方法
被験動物として3群のZDFラット(A群:健常群(n=4)、B群:糖尿病重度発症群(n=6)、C群:糖尿病中度発症群(n=6))を用いた。なお、実験中、これらのZDFラットには、水及び餌料(糖質、脂質及び蛋白質含有)(MF:オリエンタル酵母社)を自由摂取させた。つまり、下記の実験は非絶食条件下で行った。
各3群(A群:健常群、B群:糖尿病重度発症群、C群:糖尿病中度発症群)の糖尿病治療薬投与前(無処置)のΔ13C(‰)の推移(A群:―◆―、B群:―■―、C群:―▲―)と糖尿病治療薬投与後のΔ13C(‰)の推移(B群:―□―、C群:―△―)を図12に示す。図中、縦軸はΔ13C(‰),横軸はU-13C-グルコース投与後の呼気採取時間(分)を示す。
被験動物として、対照群(Wistarラット,雄,n=3),及び1型糖尿病群(STZラット,雄,n=3)を用いた。なお、実験中、これらのラットには、水及び餌料(糖質、脂質及び蛋白質含有)(MF:オリエンタル酵母社)を自由摂取させた。つまり、下記の実験は非絶食条件下で行った。
Claims (13)
- 下記(a)及び(b)の工程を有する、被験者の糖代謝能の測定方法:
(a)生体内で標識炭酸ガスに変換されて呼気中に排出される同位元素Cの少なくとも一つで標識されてなるグルコースを有効成分とする組成物を被験者に投与して呼気を採取する工程、および
(b)非標識CO2量に対する標識CO2量の割合、または総CO2量に対する標識CO2量の割合を求める工程。 - さらに下記(c)の工程を有する請求項1に記載する糖代謝能測定方法:
(c)(b)工程で得られる被験者の「非標識CO2量に対する標識CO2量の割合、または総CO2量に対する標識CO2量の割合」(被験者)を、健常者について得られる「非標識CO2量に対する標識CO2量の割合、または総CO2量に対する標識CO2量の割合」(対照値)と比較し、被験値が対照値よりも低い場合を被験者について糖代謝能が低下していると決定し、被験者が対照値よりも高い場合を被験者について糖代謝能が亢進していると決定する工程。 - 糖負荷状態にある被験者を(a)工程に供することを特徴とする請求項1または2に記載する糖代謝能測定方法。
- 糖負荷状態にある被験者が(a)工程前に、糖質、または糖質を含む飲食品若しくは代謝されて糖質になるものを含む飲食品を摂取した被験者である請求項3に記載する糖代謝能測定方法。
- 請求項1乃至4のいずれかに記載する糖代謝能測定方法により得られる被験者の糖代謝能を指標として、被験者について糖尿病発症の前段階または/および糖尿病発症後の病態ステージを検出する方法。
- 請求項1乃至4のいずれかに記載する糖代謝能測定方法において糖代謝能が亢進していると決定された被験者を、糖尿病発症の前段階にあると決定する工程を有する、請求項5に記載する糖尿病病態ステージの検出方法。
- 請求項1乃至4のいずれかに記載する糖代謝能測定方法により得られる被験者の糖代謝能の指標として、「△13C(%)-呼気採取時間tまでの曲線下面積(△13C(‰)AUCt)」または被験試料投与後の少なくとも1つの時点(t)における△13C(‰)値(△13C(‰)AUCt/インスリン)または「△13C(‰)t/インスリン」)と血糖値との相関関係から、被験者について糖尿病発症の前段階または/および糖尿病発症後の病態ステージを検出する請求項5または6に記載する方法。
- 被験者について得られる「△13C(‰)AUCt/インスリン」または「△13C(‰)t/インスリン」が、健常者についても得られる「△13C(‰)AUCt/インスリン」または「△13C(‰)t/インスリン」よりも低値である場合、当該被験者について糖尿病発症前の前段階若しくは/及び糖尿病発症後の病態ステージであると決定する工程を有する請求項5乃至7のいずれかに記載する方法。
- 請求項1乃至4のいずれかに記載する糖代謝能測定方法により得られる糖尿病患者の糖代謝能を指標として、糖尿病患者に対する糖尿病治療効果を検出する方法。
- 被験者について糖尿病治療前に測定した糖代謝能と糖尿病治療後に測定した糖代謝能とを対比し、糖尿病治療前に測定した糖代謝能と比較して糖尿病治療後の糖代謝能が増加していることを指標として、当該被験者に対して糖尿病治療効果があると決定する工程を有する請求項9記載の方法。
- 生体内で標識炭酸ガスに変換されて呼気中に排出される同位元素Cの少なくとも一つで標識されてなるグルコースを有効成分とする、糖代謝能を測定するための組成物。
- 生体内で標識炭酸ガスに変換されて呼気中に排出される同位元素Cの少なくとも一つで標識されてなるグルコースを有効成分とする組成物の、糖代謝能を測定するための呼気試験における使用。
- 生体内で標識炭酸ガスに変換されて呼気中に排出される同位元素Cの少なくとも一つで標識されてなるグルコースを有効成分とする組成物の、糖尿病発症の前段階または/および糖尿病発症後の病態ステージを測定するための呼気試験における使用。
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WO2016006601A1 (ja) * | 2014-07-09 | 2016-01-14 | 大塚製薬株式会社 | 肝疾患被験者のエネルギー低栄養評価 |
WO2018088521A1 (ja) | 2016-11-11 | 2018-05-17 | 大塚製薬株式会社 | 肝の糖取込み能評価方法 |
WO2018097222A1 (ja) | 2016-11-25 | 2018-05-31 | 大塚製薬株式会社 | 栄養状態の評価方法 |
Families Citing this family (2)
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ES2813868T3 (es) | 2012-08-20 | 2021-03-25 | Otsuka Pharma Co Ltd | Composición para su uso en un método para medir la capacidad de metabolismo de los hidratos de carbono |
WO2014142248A1 (ja) | 2013-03-15 | 2014-09-18 | 大塚製薬株式会社 | 脂肪酸燃焼によるインスリン抵抗性の測定方法、並びにそれに使用する組成物 |
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Cited By (6)
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WO2016006601A1 (ja) * | 2014-07-09 | 2016-01-14 | 大塚製薬株式会社 | 肝疾患被験者のエネルギー低栄養評価 |
JPWO2016006601A1 (ja) * | 2014-07-09 | 2017-04-27 | 大塚製薬株式会社 | 肝疾患被験者のエネルギー低栄養評価 |
US10393730B2 (en) | 2014-07-09 | 2019-08-27 | Otsuka Pharmaceutical Co., Ltd. | Energy malnutrition evaluation for liver disease test subject |
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US11313861B2 (en) | 2016-11-11 | 2022-04-26 | Otsuka Pharmaceutical Co., Ltd. | Method of evaluating hepatic glucose uptake capacity |
WO2018097222A1 (ja) | 2016-11-25 | 2018-05-31 | 大塚製薬株式会社 | 栄養状態の評価方法 |
Also Published As
Publication number | Publication date |
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EP2887066A1 (en) | 2015-06-24 |
KR102105354B1 (ko) | 2020-04-29 |
CN104737016B (zh) | 2017-09-29 |
CA2882528A1 (en) | 2014-02-27 |
US20200096500A1 (en) | 2020-03-26 |
US20150204852A1 (en) | 2015-07-23 |
EP2887066A4 (en) | 2016-04-27 |
US10228365B2 (en) | 2019-03-12 |
CN104737016A (zh) | 2015-06-24 |
ES2813868T3 (es) | 2021-03-25 |
JPWO2014030650A1 (ja) | 2016-07-28 |
JP6352188B2 (ja) | 2018-07-04 |
KR20150042853A (ko) | 2015-04-21 |
EP2887066B1 (en) | 2020-08-05 |
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