WO2017003166A1 - Composition pour le diagnostic précoce du diabète par analyse métabolomique - Google Patents

Composition pour le diagnostic précoce du diabète par analyse métabolomique Download PDF

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Publication number
WO2017003166A1
WO2017003166A1 PCT/KR2016/006937 KR2016006937W WO2017003166A1 WO 2017003166 A1 WO2017003166 A1 WO 2017003166A1 KR 2016006937 W KR2016006937 W KR 2016006937W WO 2017003166 A1 WO2017003166 A1 WO 2017003166A1
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diabetes
concentration
group
early diagnosis
early
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PCT/KR2016/006937
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English (en)
Korean (ko)
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박영자
메드리안노칼앤젤로
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고려대학교 산학협력단
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/62—Detectors specially adapted therefor
    • G01N30/72—Mass spectrometers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/62—Detectors specially adapted therefor
    • G01N30/72—Mass spectrometers
    • G01N30/7233—Mass spectrometers interfaced to liquid or supercritical fluid chromatograph
    • 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
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • 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
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6803—General methods of protein analysis not limited to specific proteins or families of proteins
    • G01N33/6806—Determination of free amino acids
    • 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
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6803—General methods of protein analysis not limited to specific proteins or families of proteins
    • G01N33/6848—Methods of protein analysis involving mass spectrometry
    • 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

Definitions

  • the present invention relates to a composition for diagnosing diabetes early, based on changes in metabolites in the blood.
  • the national R & D project supporting the present invention is a disease overcoming technology development project of the Ministry of Health and Welfare, research project number HI14C2686, metabolic research-based metabolic syndrome, new biomarker discovery and clinical significance securing project, supported by Korea University Industry-Academic Cooperation Group. It was.
  • type 2 diabetes occurs when the regulation of insulin secretion is smooth due to a lack of exercise, obesity, or stress, but insulin fails to function and blood glucose control fails.
  • the prevalence of diabetes in people aged 30 and over reaches 9.1%, and the prevalence increases rapidly after age 40, reaching 20% in their 50s. The rapid increase in prevalence is presumably due to changes in environmental factors such as improved nutrition and lack of exercise.
  • insulin-independent type 2 diabetes accounts for 90-95% of all diabetic patients.
  • people in developing countries gradually reduce physical activity and increase obesity. This is increasing at a frightening rate.
  • the proportion of fat in Korean diets has increased from 7.2% in 1969 to 18.5% in 2007 over the last decade, and the mortality rate from diabetes has increased rapidly from 7.4% in 1988 to 22.9% in 2007.
  • the existing diagnosis of diabetes is only diagnosed with blood glucose level or glycated hemoglobin level, but since this is a clinical sign after the progress of diabetes is sufficiently progressed, it is difficult to use it as an early diagnosis tool. Cannot be secured.
  • the present invention has been made to solve the above problems, an object of the present invention is to observe the changes in the metabolites in the blood of patients suspected of diabetes, based on their concentration changes, diabetic early diagnosis composition To provide.
  • the present invention provides a composition / kit for early diagnosis of diabetes, comprising a detection agent for a metabolite selected from the group consisting of leucine, lysine, proline, phenylalanine, cholesterol, and combinations thereof. .
  • the diabetes may be early diabetes or type 2 diabetes.
  • the concentration of the metabolite selected from the group consisting of proline and cholesterol when the concentration of the metabolite selected from the group consisting of proline and cholesterol is increased compared to the normal control, it may indicate an increased risk of developing diabetes.
  • the concentration of the metabolite selected from the group consisting of leucine, lysine, and phenylalanine may be reduced compared to the normal control, it may indicate an increased risk of developing diabetes.
  • the present invention comprises the steps of measuring the concentration of a metabolite selected from the group consisting of leucine, lysine, proline, phenylalanine, cholesterol and combinations thereof from a biological sample isolated from the subject; And it provides a method for providing information for the early diagnosis of diabetes, comprising the step of comparing the measured concentration of the metabolite with a normal control.
  • a metabolite selected from the group consisting of leucine, lysine, proline, phenylalanine, cholesterol and combinations thereof from a biological sample isolated from the subject.
  • the diabetes may be type 2 diabetes or early diabetes.
  • the biological sample may be blood, serum, or plasma.
  • the step of measuring the concentration of the metabolite may be measured by chromatography / mass spectrometry.
  • the present invention also provides a method for early diagnosis of diabetes, comprising administering the composition to a subject.
  • the present invention also provides the use of the composition for the early diagnosis of diabetes.
  • the present invention provides a biomarker for diagnosing early diabetes based on the change in the concentration of metabolites in the blood using metabolomics, and these can be applied as a leading material for the development of diabetes therapeutics.
  • 1 is a result of comparing the change in the concentration of leucine in the blood of the normal group (Pre-DM) and the diabetic group (DM) before the onset of diabetes using Q-TOF MS and QQQ MS.
  • 3 is a result of comparing the change in the concentration of valine in the blood of the normal group (Pre-DM) and the diabetic group (DM) before the onset of diabetes using Q-TOF MS and QQQ MS.
  • NDM non-diabetic group
  • PDM pre-diabetic group
  • DM type 2 diabetic group
  • NDM non-diabetic group
  • PDM pre-diabetic group
  • DM type 2 diabetic group
  • NDM non-diabetic group
  • PDM pre-diabetic group
  • DM type 2 diabetic group
  • FIG. 8 shows the results of comparing lysine concentration changes in blood of non-diabetic (NDM), pre-diabetic (PDM), and type 2 diabetic (DM) groups using Q-TOF MS.
  • NDM non-diabetic group
  • PDM pre-diabetic group
  • DM type 2 diabetic group
  • the present inventors collected blood before, during, and after the onset of diabetes by liquid chromatography. Through graphimetric / mass spectrometry, we observed changes in metabolite profiles, especially amino acids that are easily observed in the body, and confirmed their concentration changes.Leucine, Lysine, and Proline Obvious changes in concentrations of Phenylalanine, and Cholesterol were observed and used as biomarkers for early diagnosis of diabetes.
  • the present invention provides a composition / kit for early diagnosis of diabetes, comprising a detection agent for a metabolite selected from the group consisting of leucine, lysine, proline, phenylalanine, cholesterol, and combinations thereof, and more specifically, for early diagnosis of diabetes.
  • a detection agent for a metabolite selected from the group consisting of leucine, lysine, proline, phenylalanine, cholesterol, and combinations thereof, and more specifically, for early diagnosis of diabetes.
  • plasma biomarkers for leucine, lysine, proline, phenylalanine, cholesterol and combinations thereof are provided.
  • the term “detection agent” means an agent for quantitatively detecting leucine, lysine, proline, phenylalanine, or cholesterol from a biological sample isolated from a diabetic patient, and the agent is not particularly limited.
  • the component to be detected is an amino acid, it may be a primer, a probe, an aptamer, or an antibody capable of complementary binding, and for other components, it may be a reagent or a chemical that can quantify them.
  • the term “metabolite” refers to a metabolite obtained from a sample of biological origin, and preferably, a sample of biological origin from which the metabolite can be obtained is whole blood, more preferably plasma. .
  • whole blood can be pretreated to detect the metabolite.
  • whole blood can be pretreated to detect the metabolite.
  • it may include filtration, distillation, extraction, separation, concentration, inactivation of interference components, addition of reagents, and the like.
  • the metabolites may include substances produced by metabolic and metabolic processes or substances generated by chemical metabolism by biological enzymes and molecules.
  • the "diabetes" disease to be diagnosed with the composition of the present invention may preferably be early diabetes or type 2 diabetes.
  • the term "early diabetes” includes a condition in which blood sugar is slightly higher than normal but needs additional information before it is confirmed as diabetes. Most people have an early diabetes course before they are confirmed with type 2 diabetes. The rise in blood sugar levels in early diabetes is due to insulin resistance problems and does not automatically progress to diabetes, but is at risk of developing diabetes. Early determination of the progression from early diabetes to diabetes is very important from the perspective of preventive treatment. On the other hand, early diabetes may be a risk factor for the development of heart disease, and people with early diabetes, like those with type 2 diabetes, may be overweight, have high blood pressure, and have abnormal cholesterol concentrations.
  • type 2 diabetes refers to diabetes that occurs when insulin is normally secreted but fails to function properly, and is also referred to as "gender diabetes or insulin-independent diabetes".
  • Type 2 diabetes occurs when cells do not respond effectively to the insulin produced by the pancreas. This condition is called insulin resistance. Insulin-resistant patients initially produce more insulin to maintain normal blood sugar, which in turn causes the pancreas to lose its insulin requirements, resulting in elevated blood sugar. That is, in the pre-diabetic state (early stage), normal glucose tolerance is maintained (normal glucose tolerance), but after a certain time, the pancreatic beta cells to compensate for insulin resistance begins to fail, hyperglycemia (hyperglycemia), which results in type 2 diabetes. Therefore, there is a problem in that early diabetes, which can progress to type 2 diabetes, cannot be diagnosed early by the existing diabetes diagnosis method based on blood sugar, such as a fasting blood sugar test.
  • diagnosis refers to determining the susceptibility of an object to a particular disease or condition, determining whether an object currently has a particular disease or condition (eg, identifying early diabetes), Determining the prognosis of a subject with a particular disease or condition, or therametrics (eg, monitoring the condition of the subject to provide information about treatment efficacy).
  • the present invention comprises the steps of measuring the concentration of a metabolite selected from the group consisting of leucine, lysine, proline, phenylalanine, cholesterol and combinations thereof from a biological sample isolated from the subject; And it provides a method for providing information for the early diagnosis of diabetes, comprising the step of comparing the measured concentration of the metabolite with a normal control.
  • a metabolite selected from the group consisting of leucine, lysine, proline, phenylalanine, cholesterol and combinations thereof from a biological sample isolated from the subject.
  • the biological sample may include solid tissue samples such as blood and other liquid samples of biological origin, biopsy samples, tissue cultures or cells derived therefrom. More specifically, it may be tissue, extract, cell lysate, whole blood, plasma, serum, saliva, ocular fluid, cerebrospinal fluid, sweat, urine, milk, ascites fluid, synovial fluid, peritoneal fluid, and the like, more preferably whole blood, and more preferably Preferably plasma, but is not limited thereto.
  • the biological sample may be pretreated prior to use in detection and may include, for example, filtration, distillation, extraction, concentration, inactivation of interfering components, addition of reagents, and the like, including animals, preferably mammals, Most preferably it can be obtained from humans.
  • the concentration of the metabolite can be measured by chromatography / mass spectrometry.
  • Chromatography used in the present invention is Gas Chromatography, Liquid-Solid Chromatography (LSC), Paper Chromatography (PC), Thin-Layer Chromatography (TLC) ), Gas-solid chromatography (GSC), liquid-liquid chromatography (Liquid-Liquid Chromatography, LLC), foam chromatography (Foam Chromatography, FC), emulsion chromatography (Emulsion Chromatography, EC), Gas-Liquid Chromatography (GLC), Ion Chromatography (IC), Gel Filtration Chromatograhy (GFC) or Gel Permeation Chromatography (GPC)
  • the chromatography used in the present invention may be liquid chromatography
  • the mass spectrometer used in the present invention may be Q-TOF MS.
  • Metabolites of the present invention are separated from each component in the liquid chromatography, using the information obtained through the Q-TOF MS can identify the components through the structural information (elemental composition) as well as accurate molecular weight information.
  • diabetes can be diagnosed early by comparing the measured concentration of the metabolite with the normal control. Specifically, when the concentration of the metabolite selected from the group consisting of proline and cholesterol is increased compared to the normal control group, it indicates an increased risk of developing diabetes, on the contrary, the leucine, lysine, and phenylalanine are selected from the group consisting of If the concentration of the metabolite is reduced compared to the normal control, it indicates an increased risk of developing diabetes.
  • the term "increase in metabolic concentration” means that the metabolite concentration in the sample of a patient group having a high likelihood of developing diabetes is measurably increased as compared with a normal group before the onset of diabetes, preferably 70 It means increased by more than%, more preferably increased by more than 30%.
  • the term "reduction of metabolic concentration” means that the metabolite concentration in the blood of a patient group having a high likelihood of developing diabetes is measurably reduced as compared with a normal group before the onset of diabetes, preferably 40 It means reduced by more than%, more preferably reduced by more than 20%.
  • Example 1 on the basis of the results of Example 1, it was intended to confirm the biomarkers and their tendency to determine whether the progression to diabetes in the pre-diabetic state early.
  • Example 2-1 50 ⁇ l of the serum sample prepared in Example 2-1 was treated with 200 ⁇ l of acetonitrile (1: 4 v / v), and then centrifuged at 14,000 ⁇ g for 5 minutes. The samples were then analyzed by ultrafast liquid chromatography (C18 Synchronis aQ 1.9 ⁇ m 1002.1 mm (Thermo Scientific, MA, USA)) coupled with a Q-TOF 6550 mass spectrometer (Agilent, CA, USA). As a mobile phase, H 2 O and acetonitrile with 0.1% of formic aicd added respectively were used. As a% concentration of distilled water with respect to a solvent, 1 min in 95% distilled water and 55% distilled water by adding a straight tool.

Abstract

La présente invention concerne une composition pour le diagnostic précoce du diabète au moyen de l'analyse du métabolome et, plus spécifiquement, concerne des biomarqueurs qui permettent de diagnostiquer le stade précoce du diabète sur la base du changement de concentration de métabolome dans le sang en utilisant la métabolomique, et les biomarqueurs peuvent être appliqués à des matériaux tètes de série pour développer des agents thérapeutiques contre le diabète.
PCT/KR2016/006937 2015-06-29 2016-06-29 Composition pour le diagnostic précoce du diabète par analyse métabolomique WO2017003166A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110178035A (zh) * 2017-04-18 2019-08-27 深圳华大生命科学研究院 2型糖尿病标志物及其用途
CN113866285A (zh) * 2020-06-30 2021-12-31 上海透景生命科技股份有限公司 用于糖尿病诊断的生物标志物及其应用
CN114324662A (zh) * 2021-12-30 2022-04-12 中南大学 用于诊断或预防糖尿病的血清生物标志物、检测试剂及其应用

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KR102092821B1 (ko) * 2018-07-27 2020-03-24 한국과학기술원 뇌대사체를 이용한 대사 장애의 진단 또는 예후 예측 방법
KR102377089B1 (ko) * 2018-11-27 2022-03-21 대한민국 전당뇨 진단 키트 및 진단 방법
KR20200137312A (ko) 2019-05-29 2020-12-09 유리벳코리아 주식회사 눈물을 이용한 당뇨병 진단용 조성물
KR20210027879A (ko) 2019-09-03 2021-03-11 유리벳코리아 주식회사 알지네이트를 이용한 당 검출용 조성물 및 이를 이용한 당뇨병 진단용 키트
KR20210095071A (ko) * 2020-01-22 2021-07-30 계명대학교 산학협력단 당뇨 조기진단 또는 당뇨병성 합병증 진단을 위한 바이오마커 및 이의 용도
KR102480846B1 (ko) 2020-12-22 2022-12-23 유리벳코리아 주식회사 고양이 소변 내 단백뇨 진단을 위한 고체형 비드 및 이를 포함하는 단백뇨 진단 키트

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110178035A (zh) * 2017-04-18 2019-08-27 深圳华大生命科学研究院 2型糖尿病标志物及其用途
CN113866285A (zh) * 2020-06-30 2021-12-31 上海透景生命科技股份有限公司 用于糖尿病诊断的生物标志物及其应用
CN114324662A (zh) * 2021-12-30 2022-04-12 中南大学 用于诊断或预防糖尿病的血清生物标志物、检测试剂及其应用
CN114324662B (zh) * 2021-12-30 2022-09-16 中南大学 用于诊断或预防糖尿病的血清生物标志物的应用

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