WO2019214494A1 - 基于尿液生物标志物的糖尿病早期无创检测系统和方法 - Google Patents

基于尿液生物标志物的糖尿病早期无创检测系统和方法 Download PDF

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WO2019214494A1
WO2019214494A1 PCT/CN2019/085080 CN2019085080W WO2019214494A1 WO 2019214494 A1 WO2019214494 A1 WO 2019214494A1 CN 2019085080 W CN2019085080 W CN 2019085080W WO 2019214494 A1 WO2019214494 A1 WO 2019214494A1
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urine
module
test strip
creatinine
urinary
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PCT/CN2019/085080
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English (en)
French (fr)
Inventor
赫斯奥·夫哈瑞
穆桑特·卢卡
马丁·阿尔贝托·贝尼托
萨拉斯瓦特·马扬克
塔塔奇·多洛塔·艾娃
赫斯奥夫·瑞塔·凯撒
张贯京
邹和群
葛新科
肖应芬
唐小浪
刘义
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深圳市贝沃德克生物技术研究院有限公司
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Publication of WO2019214494A1 publication Critical patent/WO2019214494A1/zh

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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
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54366—Apparatus specially adapted for solid-phase testing
    • G01N33/54386—Analytical elements
    • G01N33/54387—Immunochromatographic test strips
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
    • G01N21/27—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands using photo-electric detection ; circuits for computing concentration
    • 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
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/558—Immunoassay; Biospecific binding assay; Materials therefor using diffusion or migration of antigen or antibody
    • 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
    • G01N33/70—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving creatine or creatinine
    • 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 invention relates to the technical field of medical instruments, in particular to a non-invasive detection system and method for early diabetes based on urine biomarkers.
  • diabetes is primarily diagnosed by monitoring fasting or postprandial blood glucose.
  • current medical and home blood glucose measurements are mainly based on invasive methods, which are not conducive to the screening of diabetes in a large number of people, so that most people still have diabetes, and until the discovery, various complications have emerged.
  • diabetic patients need to frequently measure and control blood glucose concentrations in order to avoid diabetic complications.
  • Frequent blood collection for blood glucose concentration measurement brings huge economic burden and medical expenses to diabetic patients, on the other hand, it brings great physical and psychological pain to diabetic patients and increases the risk of infectious diseases.
  • Non-invasive urine test strips commonly used in the market due to limited measurement accuracy, often have false negatives, false positives, and cannot be widely promoted. In order to cope with the above situation, there is an urgent need for a non-invasive detection system for diabetes and its complications (diabetic nephropathy).
  • the invention provides a non-invasive detection system and method for early diabetes based on urine biomarkers, which can quantitatively detect various markers of diabetes and its complications in urine, improve detection accuracy and sensitivity, and reduce urine sugar concentration. Interference from external factors, true reflection of urine sugar concentration, simultaneous monitoring of diabetes and its complications.
  • the invention provides a non-invasive detection system for early diabetes based on urine biomarkers, comprising:
  • a transmitting module for emitting an incident spectrum of a predetermined wavelength
  • the test strip for detecting urine sugar is a dry chemical test strip comprising a urine diffusion layer, a filter layer, a hydrophilic layer and a reagent layer disposed in order from top to bottom, wherein the reagent layer has glucose oxidase, peroxidase, potassium iodide and polyethylene Pyrrolidone
  • the test strip for detecting urinary creatinine is a dry chemical test strip comprising a urine diffusion layer, a filter layer, a hydrophilic layer and a reagent layer disposed in order from top to bottom, wherein the reagent layer There are copper sulfate, sodium citrate, orange yellow, polyvinylpyrrolidone and tetramethylbenzidine
  • the test strip for detecting urinary cysteine protease inhibitor C is a dry chemical test strip, including successively lapped a sample
  • a spectrum receiving module configured to receive a spectral or fluorescent signal that has passed through the test strip and is attenuated, and converted into an analog electrical signal
  • a signal conversion module connected to the spectrum receiving module to convert the analog electrical signal into a digital signal
  • the data processing module is connected with the signal conversion module, and calculates the concentration values of urine sugar, urine creatinine, urinary cystatin C, and urine/creatinine ratio and/or urine in the urine sample according to the digital signal. Cystatin C/urinary creatinine ratio;
  • An output module coupled to the data processing module, for outputting concentration values and/or ratios.
  • the urine sample is from the urine that the subject empties urine at 0.5 to 2.5 hours after the meal and takes 2 to 4.5 hours after the meal.
  • the transmitting module comprises a spectral transmitting circuit and a transmitting power circuit
  • the spectral receiving module comprises a spectral receiving circuit and a receiving power circuit.
  • the data processing module comprises a microprocessor (MCU) and its peripheral circuits.
  • MCU microprocessor
  • the output module comprises a human-computer interaction module and a data communication module; a human-computer interaction module is configured to implement human-computer interaction, display output concentration values and/or ratios; and a data communication module for implementing remote information communication functions, The concentration values and/or ratios are transmitted to a remote data storage, analysis platform.
  • the invention also provides a non-diagnostic method for non-invasive detection of diabetes and its complications, comprising:
  • the detecting module drops urine into the reaction hole of the test strip, and the test strip reacts with urine sugar, urine creatinine and urinary cystatin C in urine;
  • the transmitting module emits an incident spectrum of a predetermined wavelength to the reacted test strip
  • the spectral receiving module receives the spectral or fluorescent signal that has passed through the test strip and is attenuated, and is converted into an analog electrical signal;
  • the signal conversion module converts the analog electrical signal into a digital signal
  • the data processing module calculates the concentration of urine glucose, urinary creatinine, urinary cystatin C, and urine glucose/creatinine ratio and/or urinary cysteine protease inhibitor in the urine sample based on the digital signal. C/urinary creatinine ratio;
  • the output module outputs concentration values and/or ratios.
  • the method further comprises: obtaining urine which is taken by the subject at 0.5 to 2.5 hours after the meal and taken at 2 to 4.5 hours after the meal.
  • the invention has the following technical effects: introducing urine creatinine as a reference, accurately reflecting the concentration of random urine sugar in the urine through the urine sugar/creatinine ratio, and eliminating the influence of external interference factors on the concentration of urine sugar; introducing the function evaluation index of urine Cystatin C, used to rule out false positive or false negative results in urine glucose test results due to kidney damage, and to evaluate renal function through urinary cystatin C, which can be used to monitor diabetic nephropathy at an early stage. Syndrome, the simultaneous monitoring of diabetes and its complications, so the present invention can achieve quantitative measurement, accuracy and sensitivity higher than the existing urine glucose test paper.
  • FIG. 1 is a schematic structural view showing a urine non-invasive detection system based on urine biomarkers in another embodiment of the present invention
  • FIG. 2 is a flow chart of a method for early detection of non-invasive diabetes in an embodiment of the present invention
  • FIG. 3 is a schematic view showing the structure of a test strip for urine sugar and urine creatinine in a non-invasive detection system for diabetes based on urine biomarkers according to an embodiment of the present invention
  • FIG. 4 is a schematic view showing the structure of a test strip for urinary cystatin C in a urine non-invasive detection system based on urine biomarkers in an embodiment of the present invention.
  • a urine biomarker-based early detection system for diabetes in an embodiment of the present invention includes: a transmitting module 10 for emitting an incident spectrum of a predetermined wavelength; and a detecting module 20 for passing a test strip and The urine glucose, urine creatinine and/or urinary cystatin C in the urine sample reacts and receives the incident spectrum; the spectral receiving module 30 receives the spectral or fluorescent signal that has passed through the test strip and is attenuated, and Converting to an analog electrical signal; the signal conversion module 40 is coupled to the spectral receiving module 30 to convert the electrical signal into a digital signal; the data processing module 50 is coupled to the signal conversion module 40 to calculate urine sugar in the urine sample based on the digital signal , urine creatinine, concentration of urinary cystatin C, and urine glucose/creatinine ratio and/or urinary cystatin C/urinary creatinine ratio; output module 60, and data processing module 50 Connection for outputting concentration values and/or ratios.
  • the urine biomarker-based early non-invasive detection system for diabetes in this example introduced urine creatinine as a reference.
  • the basis of the explanation is as follows:
  • glucose can pass freely through the glomerulus, that is, the glucose concentration in the original urine is consistent with the glucose concentration in the blood.
  • glucose is heavy by the renal tubular epithelial cells. absorb.
  • the renal sugar threshold (8.96) Mmmol / L -10.08mmol / L)
  • renal tubular epithelial cells to the limit of glucose absorption, glucose can not be completely reabsorbed back to the blood, there will be diabetes.
  • the concentration of urine sugar is susceptible to changes in urine volume, resulting in a randomized urine glucose concentration test.
  • the urinary creatinine content secreted by each person to the urine per unit time is certain.
  • the change of urine creatinine concentration in urine is directly affected by the external environment (such as excessive water intake).
  • the concentration of urinary creatinine decreases.
  • the concentration of urinary creatinine increases.
  • the urine sugar / urine creatinine ratio it is possible to eliminate the interference of the concentration of the urine solution due to factors such as excessive water intake, and accurately reflect the relative level of one of the solute of the urine solution - urine sugar.
  • urine sugar / urine creatinine (per unit time urine sugar content / urine volume) / (per unit time urine creatinine content / urine volume), because the individual urine creatinine content per unit time is constant, so through the urine sugar / urine Creatinine can rule out the effect of urine volume on urine sugar and accurately reflect the urine urine sugar content.
  • the urine biomarker-based early non-invasive detection system for diabetes in the present embodiment introduces a renal function evaluation index (specifically, a renal tubular function index) urinary cystatin C (Cystatin C) for excluding kidney damage. causes a false positive or false negative in the urine glucose test results.
  • a renal function evaluation index specifically, a renal tubular function index
  • urinary cystatin C (Cystatin C) for excluding kidney damage.
  • Cystatin C urinary cystatin C
  • the basis for this is as follows: Cystatin C is tissue-free and is produced at a constant rate in human cells. Cystatin C levels in the blood reflect glomerular filtration rate. Cystatin C in the blood can pass through the glomerular basement membrane at a constant rate, entering Cystatin in the original urine.
  • Cystatin C is completely reabsorbed in the renal tubules of healthy people.
  • Cystatin C is present in the urine.
  • a large number of studies have pointed out that when the kidney is damaged, the renal tubules will also be damaged at the same time, affecting the renal tubular reabsorption function. At the same time, these studies point out Cystatin in urine.
  • C can be used as an early biomarker for kidney disease, including diabetic nephropathy.
  • the transmitting module 10 includes a spectral transmitting circuit 11 and a transmitting power supply circuit 12 for transmitting light waves of a specific wavelength to the reacted test strip in real time; the detecting module 20 detects the test strip by detecting the test strip, and detects the test strip.
  • the strip consists of a thin sheet of sensitive chemical composition containing specific enzymes, substrates or antibodies that can react with urine sugar, urine creatinine and urinary Cystatin C for urine sugar, urine creatinine and urine in urine samples.
  • the cysteine protease inhibitor C reacts and emits an attenuated spectrum or fluorescence signal after being irradiated by the incident spectrum;
  • the spectrum receiving module 30 includes a spectrum receiving circuit 31 and a receiving power circuit 32 for receiving a spectral signal of a certain wavelength range.
  • the illumination spectrum When the spectral signal illuminates the test strip that reacts, the illumination spectrum will attenuate or fluoresce to some extent, calculate the optical loss rate or fluorescence intensity, and convert the reflected spectrum or fluorescent signal into an electrical signal; the signal conversion module 40, and the spectrum
  • the receiving module 30 is connected to convert the electrical signals related to the concentration of urine sugar, urine creatinine and urinary Cystatin C in the urine into a microprocessor capable of identifying The received digital signal;
  • the data processing module 50 is connected to the signal conversion module 40, and includes a microprocessor (MCU) 51 and its peripheral circuit 52 for analyzing and calculating the received urine sugar, urine creatinine, and urine Cystatin C information. Finally, the urine sample, urine creatinine, and urine Cystatin were obtained in the urine sample.
  • MCU microprocessor
  • the output module 60 is connected to the data processing module 50, and includes a human-computer interaction module 61 and a data communication module 62.
  • the human-computer interaction module 61 may further include an MCU, an LCM display circuit, and a keyboard input circuit. In the realization of human-computer interaction, the output concentration value and ratio are displayed, that is, urine sugar, urine creatinine, and urine Cystatin in urine.
  • the data communication module 62 further includes an MCU and a data communication circuit for implementing a telematics function, and transmitting the concentration value and the ratio to the remote data storage and analysis platform.
  • modules or circuits in the present invention are not limited to a specific circuit diagram configuration, because a module or a circuit for realizing respective functions can be selected by those skilled in the art according to the current technology.
  • the method for detecting urine biomarkers based on the urine biomarker for early detection of urine biomarkers is as shown in FIG. 2, and includes the following steps: S1.
  • the detection module drops urine into the reaction strip of the test strip, and tests The paper strip reacts with urine sugar, urine creatinine and urinary cysteine protease inhibitor C in the urine; S2.
  • the emission module emits an incident spectrum of a predetermined wavelength to the test strip after the reaction; S3.
  • the spectrum receiving module receives the passage Determining a sample strip and attenuating the spectral or fluorescent signal and converting it into an analog electrical signal; S4.
  • the signal conversion module converts the analog electrical signal into a digital signal; S5.
  • the data processing module calculates the Urine sugar, urine creatinine, urinary cystatin C concentration, and urine glucose/creatinine ratio and/or urinary cystatin C/urinary creatinine ratio; S6.
  • the output module outputs the concentration value and/or the ratio.
  • the dry biochemical test strip in the urine biomarker-based early non-invasive detection system for diabetes of the present invention is shown in Figs. 3 and 4.
  • the dry chemical test strip for detecting urine sugar and urine creatinine comprises, in order from top to bottom, an upper baffle (not shown), an intermediate layer and a bottom support (not shown).
  • the intermediate layer is provided with a urine diffusion layer, a filtration layer, a hydrophilic layer and a reagent layer in this order from top to bottom, wherein the reagent layer may be fused on the hydrophilic layer.
  • the urine sample is uniformly diffused in the urine diffusion layer of the porous polyester fiber material, passing through the filter layer (glass).
  • the fiber membrane filters out the impurities, reacts with the reagents in the reagent layer, generates a change in the absorbance value by changing the color of the test paper, detects the light loss, and obtains the content of the corresponding target substance in the urine.
  • Method for detecting urine creatinine test paper preparing a reagent layer of urine creatinine test paper by using copper sulfate, sodium citrate, orange yellow, polyvinylpyrrolidone and tetramethylbenzidine, and the specific preparation method is as follows: firstly immersing the reagent layer into liquid A (1000 ml) The solution contains 2mol/L Tris buffer, copper sulfate 0.4g-2g, sodium citrate 2-5g, orange 2mg0-200mg, and is made up with pure water, then taken out and dried at 70-100 ° C for 15-30min.
  • liquid B polyvinylpyrrolidone 10-20 g, tetramethylbenzidine 3-5 g, made up to volume with chloroform
  • urine is added to the test paper reaction well, creatinine and copper sulfate form a complex which can react with the colorants orange yellow and tetramethylbenzidine to develop color.
  • the creatinine concentration ranged from 0.6mmol/L to 28mmol/L, and the test paper showed four distinct color gradations from light yellow to dark green, namely light yellow-light green-grass green-dark green.
  • the reflected light is spectrally analyzed by a sensor (using a wavelength range of 580-650 nm) to detect light loss, and the concentration of creatinine in the urine is obtained.
  • the concentration of urinary creatinine is correlated with the color depth of the test strip after the reaction, that is, the correlation with the spectral intensity after attenuation by the test strip, and thus correlates with the converted analog electrical signal and digital signal.
  • the standard curve relationship between urine creatinine concentration and digital signal can be established by a series of gradient concentrations of standard urine creatinine and the corresponding digital signal intensity.
  • the concentration of urine creatinine in the tested sample can be calculated according to the standard curve.
  • Urine sugar test strip test method urinary glucose test paper is prepared by using glucose oxidase (GOD), peroxidase, potassium iodide and polyvinylpyrrolidone. Specifically, weigh 1200 U of peroxidase, 1200 U of glucose oxidase, 100 mg of potassium iodide, 100 mg of polyvinylpyrrolidone, and make up to 100 ml. The reagent layer was immersed in the solution and dried for 30 min.
  • GOD glucose oxidase
  • peroxidase peroxidase
  • potassium iodide potassium iodide
  • polyvinylpyrrolidone polyvinylpyrrolidone
  • the urine sugar reacts with the glucose oxidase on the test paper, residual gluconic acid and hydrogen peroxide; and hydrogen peroxide releases hydrogen radical [O:], oxygen under the catalysis of hydrogen peroxide and catalase.
  • the free radical reacts with the substrate potassium iodide, and the free iodine produced forms a brown complex with the polyvinylpyrrolidone.
  • Spectral analysis of the reflected light by the sensor (using a wavelength range of 550-750 nm) detects the light loss and obtains the urine sugar concentration in the urine.
  • the concentration of urine sugar is correlated with the color depth of the test strip after the reaction, that is, the correlation with the spectral intensity after attenuation by the test strip, and thus correlates with the converted analog electrical signal and the digital signal.
  • the concentration of urine sugar in the tested sample can be calculated according to the standard curve.
  • the dry immunofluorescence test strip for detecting urinary Cystatin C includes an upper baffle (not shown), an intermediate layer and a bottom support (not shown). Among them, the middle layer adheres to the sample pad (C in FIG. 4), the nitrocellulose membrane, and the water absorption pad from the left to the right, as shown in FIG. 4, and the detection line (C1) and the quality are provided on the nitrocellulose membrane.
  • the control line (C2), the specific antibody coated with the detection line is a monoclonal antibody against Cystatin C, and the specific antibody coated by the quality control line is a rabbit IgG antibody.
  • Individually packaged platinum porphyrin labeled antibodies are anti-microalbumin monoclonal antibodies and anti-rabbit IgG antibodies. Calculate Cystatin in urine samples by detecting the fluorescence intensity of the platinum and porphyrin on the nitrocellulose membrane The concentration of C.
  • Urine Cystatin C test strip test method urine Cystatin
  • the nitrocellulose membrane of the C test strip has a detection line and a quality control line in the detection area near the spotting hole.
  • the test line is coated with anti-Cystatin
  • the antibody of C is coated with rabbit IgG antibody on the quality control line.
  • the platinum porphyrin labeling solution contains platinum porphyrin labeled anti-Cystatain C antibody and platinum porphyrin labeled anti-rabbit IgG antibody.
  • the urine sample and the platinum porphyrin labeling solution are uniformly mixed in a certain ratio to make the platinum porphyrin-labeled antibody and the target protein in the urine (Cystatin).
  • urine Cystatin The concentration of C is correlated with the fluorescence intensity of the detection line on the test strip after the reaction, and then correlated with the converted analog electrical signal and digital signal, passing a series of gradient concentrations of standard urine Cystatin C and the corresponding digital signal intensity can establish a standard curve relationship between the concentration of urinary Cystatin C and the digital signal, and the concentration of urinary Cystatin C in the tested sample can be calculated according to the standard curve.
  • concentration of C is correlated with the fluorescence intensity of the detection line on the test strip after the reaction, and then correlated with the converted analog electrical signal and digital signal, passing a series of gradient concentrations of standard urine Cystatin C and the corresponding digital signal intensity can establish a standard curve relationship between the concentration of urinary Cystatin C and the digital signal, and the concentration of urinary Cystatin C in the tested sample can be calculated according to the standard curve.
  • Those skilled in the art can calculate the value of the urine Cystatin C concentration by the prior art through the understanding of the embodiments of the present invention, and
  • urine sugar / urine creatinine According to the measurement of urine sugar, urine creatinine, urine Cystatin C, urine sugar / urine creatinine and urine Cystatin C / urine creatinine: 1) If the urine sugar value or urine sugar / urine creatinine value exceeds the normal range (urine)
  • the normal range of sugar is 0-20mg/dL; the upper limit of the normal range of urine sugar/urinary creatinine is 50-100mg/g), but if the urine Cystatin C is not detected, the subject is judged to have diabetes, but not There are complications.
  • This kind of application can be used for large-scale screening of diabetic patients in the crowd, because the renal sugar threshold is certain, so when using this method to measure a certain amount of glucose in the urine, it means that the subject has or will have a certain degree The risk of diabetes; 2) For patients with diabetes, if the Cystatin C value exceeds the normal range ( ⁇ 0.15mg/dL), the patient is susceptible to diabetic nephropathy; 3) For diabetic patients with normal kidney function, use Determination of urine sugar, urine creatinine reaction test paper ( Figure 3, A, B) measurement, urine sugar, urine sugar / urine creatinine parameters can reflect the patient's blood sugar level to a certain extent, to a certain extent can reduce the pain of patients with fingers .
  • the method for monitoring the early detection of a non-invasive detection system for diabetes based on urine biomarkers of the present invention is that for a large-scale screening of a diabetic patient, preferably, the subject empties urine, meal at 0.5h-2.5h after a meal.
  • Urine, urine creatinine, and urinary Cystatin C were measured after 2h-4.5h.
  • urine is emptied at 1.5h after a meal, and urine is collected 3h after a meal.
  • the concentration of urine sugar in the collected urine reflects the average concentration of urine within 1.5h-3h after meal, which reflects the blood after meal.
  • Blood glucose (real-time) concentration for diabetic patients with predictive complications (diabetic nephropathy), preferably, the subject takes morning urine in the urine, measuring urine sugar, urinary inosine, and urine Cystatin C; For patients who have diabetes but no complications, the subject can take morning urine, postprandial urine, random urine test urine sugar, urine creatinine, and replace the measurement to a certain extent. blood sugar.
  • Table 1 shows the case of 10 samples detected using the system and method of the present invention.
  • No. 1-8 in the table is diabetic patients (glycated hemoglobin and postprandial blood glucose), and 9 and 10 are normal controls.
  • patient No. 6 has mild diabetic nephropathy (eGFR 87).
  • eGFR 87 mild diabetic nephropathy
  • the invention has the following technical effects: introducing urine creatinine as a reference, accurately reflecting the concentration of random urine sugar in the urine through the urine sugar/creatinine ratio, and eliminating the influence of external interference factors on the concentration of urine sugar; introducing the function evaluation index of urine Cystatin C, used to rule out false positive or false negative results in urine glucose test results due to kidney damage, and to evaluate renal function through urinary cystatin C, which can be used to monitor diabetic nephropathy at an early stage. Syndrome, the simultaneous monitoring of diabetes and its complications, so the present invention can achieve quantitative measurement, accuracy and sensitivity higher than the existing urine glucose test paper.

Abstract

一种基于尿液生物标志物的糖尿病早期无创检测系统和方法，系统包括：发射模块（10），用于发射预定波长的入射光谱；检测模块（20），用于通过试纸条与尿液样品中的尿糖、尿肌酐和/或尿半胱氨酸蛋白酶抑制剂C反应并接收入射光谱；光谱接收模块（30），用于接收通过试纸条并衰减后的光谱或荧光信号，并转换为模拟电信号；信号转换模块（40），与光谱接收模块（30）连接，将模拟电信号转换成数字信号；数据处理模块（50），与信号转换模块（40）连接，根据数字信号计算出尿液样品中的生物标志物的量值；输出模块（60），与数据处理模块（50）连接，用于输出量值。系统定量检测糖尿病及其并发症的多种标志物，提高检测准确性和灵敏度，减少干扰，真实反映尿糖浓度，同步监测糖尿病及其并发症。

Description

基于尿液生物标志物的糖尿病早期无创检测系统和方法 技术领域
本发明涉及医疗器械技术领域，尤其涉及一种基于尿液生物标志物的糖尿病早期无创检测系统和方法。
 背景技术
随着国民经济的快速发展，人民生活水平的提高，我国的肥胖人群也逐步增加；除肥胖人口的快速增加，老龄人口的增长也促进了糖尿病患者人群的增长。据统计，目前我国糖尿病患者已达1.2亿人，未来10年内我国的糖尿病患者人数将会突破2亿。同时，若糖尿病患者血糖控制不稳，会导致各种并发症，如糖尿病心血管疾病、糖尿病眼病、糖尿病肾病、糖尿病神经性疾病等。其中，糖尿病肾病是糖尿病最严重和最重要的慢性微血管并发症之一。据统计，30%～40%的2型糖尿病人将发展为糖尿病肾病，20%～40%的1型糖尿病患者在15～30年后也将发展为糖尿病肾病，会给我国带来越来越多的社会和经济负担。
目前，糖尿病主要是通过监测空腹或餐后血糖而进行初期诊断。然而，当前医用和家用血糖测量主要是基于有创方式进行，不利于对大范围人群进行糖尿病筛查，致使大多数人患了糖尿病仍然浑然不觉，等到发现时已出现各种并发症。同时，糖尿病患者为了避免糖尿病并发症，需要频繁地测量和控制血糖浓度。频繁的采血进行血液葡萄糖浓度的测量，一方面给糖尿病患者带来了巨大的经济负担和医疗费用，另一方面也给糖尿病患者带来了巨大的身体和心理痛苦和增加感染疾病的风险。而市场上普遍采用的无创尿糖试纸，由于测量精度受限，常常出现假阴性、假阳性，不能大规模推广。为了应对上述形势，迫切需要一种糖尿病及其并发症（糖尿病肾病）无创检测系统。
 技术问题
本发明提供一种基于尿液生物标志物的糖尿病早期无创检测系统和方法，能够定量检测尿液中的糖尿病及其并发症的多种标志物，提高检测准确性和灵敏度，减少尿糖浓度受外界因素的干扰，真实反映尿糖浓度，同步监测糖尿病及其并发症。
 技术解决方案
本发明提供一种基于尿液生物标志物的糖尿病早期无创检测系统，包括:
发射模块，用于发射预定波长的入射光谱；
检测模块，用于通过试纸条与尿液样品中的尿糖、尿肌酐和/或尿半胱氨酸蛋白酶抑制剂C反应并接收所述入射光谱，所述检测尿糖的试纸条为干式化学试纸条，包括从上至下依次设置的尿液扩散层、过滤层、亲水层和试剂层，其中所述试剂层上有葡萄糖氧化酶、过氧化物酶、碘化钾和聚乙烯吡络烷酮，所述检测尿肌酐的试纸条为干式化学试纸条，包括从上至下依次设置的尿液扩散层、过滤层、亲水层和试剂层，其中所述试剂层上有硫酸铜、柠檬酸钠、橙黄、聚乙烯吡咯烷酮和四甲基联苯胺，所述检测尿半胱氨酸蛋白酶抑制剂C的试纸条为干式化学试纸条，包括依次搭接的样品垫、硝酸纤维素膜和吸水垫，其中所述硝酸纤维素膜上有检测线和质控线，所述检测线上包被有抗半胱氨酸蛋白酶抑制剂C的抗体，所述质控线上包被有IgG抗体；
光谱接收模块，用于接收通过试纸条并衰减后的光谱或荧光信号，并转换为模拟电信号；
信号转换模块，与光谱接收模块连接，将模拟电信号转换成数字信号；
数据处理模块，与信号转换模块连接，根据数字信号计算出尿液样品中的尿糖、尿肌酐、尿半胱氨酸蛋白酶抑制剂C的浓度值，以及尿糖/尿肌酐比值和/或尿半胱氨酸蛋白酶抑制剂C/尿肌酐比值；
输出模块，与数据处理模块连接，用于输出浓度值和/或比值。
优选地，尿液样品来自受试者在餐后0.5~2.5h排空尿液，且在餐后2~4.5h所取的尿液。
优选地，发射模块包括光谱发射电路和发射电源电路；光谱接收模块包括光谱接收电路和接收电源电路。
优选地，数据处理模块包括微处理器（MCU）及其外围电路。
优选地，输出模块包括人机交互模块和数据通讯模块；人机交互模块，用于实现人机交互，显示输出的浓度值和/或比值；数据通讯模块，用于实现远程信息通讯功能，将浓度值和/或比值传输至远程数据存储、分析平台。
本发明还提供一种非诊断性的糖尿病及其并发症的无创检测方法，包括：
检测模块向试纸条反应孔滴加尿液，试纸条与尿液中的尿糖、尿肌酐和尿半胱氨酸蛋白酶抑制剂C反应；
发射模块向反应后的试纸条发射预定波长的入射光谱；
光谱接收模块接收通过试纸条并衰减后的光谱或荧光信号，并转换为模拟电信号；
信号转换模块将模拟电信号转换成数字信号；
数据处理模块根据数字信号计算出尿液样品中的尿糖、尿肌酐、尿半胱氨酸蛋白酶抑制剂C的浓度值，以及尿糖/尿肌酐比值和/或尿半胱氨酸蛋白酶抑制剂C/尿肌酐比值；
输出模块输出浓度值和/或比值。
优选地，在检测模块向试纸条反应孔滴加尿液前还包括：获取受试者在餐后0.5~2.5h排空尿液且在餐后2~4.5h所取的尿液。
 有益效果
本发明具有如下技术效果：引入尿肌酐作为参比，通过尿糖/尿肌酐比值准确反映尿液中随机尿糖的浓度，能排除外界干扰因素对尿糖浓度的影响；引入肾功能评价指标尿半胱氨酸蛋白酶抑制剂C，用于排除由于肾脏损伤，导致尿糖测试结果出现假阳性或假阴性，并且通过尿半胱氨酸蛋白酶抑制剂C评价肾功能，可以在早期监控糖尿病肾病并发症，实现糖尿病及其并发症的同步监测，因此本发明可以实现定量测量，准确性和灵敏度相较现有尿糖试纸更高。
 附图说明
图1为本发明另一个实施例中的基于尿液生物标志物的糖尿病早期无创检测系统的结构模式图；
图2为本发明一个实施例中的糖尿病早期无创检测方法的流程图；
图3为本发明一个实施例中的基于尿液生物标志物的糖尿病早期无创检测系统中尿糖和尿肌酐的检测试纸条结构示意图；
图4为本发明一个实施例中的基于尿液生物标志物的糖尿病早期无创检测系统中尿半胱氨酸蛋白酶抑制剂C的检测试纸条结构示意图。
 本发明的实施方式
下面通过具体实施例结合附图对本发明作进一步详细说明。
请参考图1，本发明一个实施例中的基于尿液生物标志物的糖尿病早期无创检测系统包括：发射模块10，用于发射预定波长的入射光谱；检测模块20，用于通过试纸条与尿液样品中的尿糖、尿肌酐和/或尿半胱氨酸蛋白酶抑制剂C反应并接收入射光谱；光谱接收模块30，用于接收通过试纸条并衰减后的光谱或荧光信号，并转换为模拟电信号；信号转换模块40，与光谱接收模块30连接，将电信号转换成数字信号；数据处理模块50，与信号转换模块40连接，根据数字信号计算出尿液样品中的尿糖、尿肌酐、尿半胱氨酸蛋白酶抑制剂C的浓度值，以及尿糖/尿肌酐比值和/或尿半胱氨酸蛋白酶抑制剂C/尿肌酐比值；输出模块60，与数据处理模块50连接，用于输出浓度值和/或比值。
本实施例的基于尿液生物标志物的糖尿病早期无创检测系统引入尿肌酐作为参比。其依据说明如下：肾脏在过滤血液杂质时，葡萄糖可以自由通过肾小球，也就是说原尿中葡萄糖浓度和血液中葡萄糖浓度一致，在肾小管重吸收过程中，葡萄糖被肾小管上皮细胞重吸收。当血糖浓度超过肾糖阈（8.96 mmol/L -10.08mmol/L），肾小管上皮细胞对葡萄糖的吸收达到极限，葡萄糖不能被完全重吸收回血液，便出现糖尿。然而，尿糖浓度易受尿液量变化的影响，导致随机尿糖浓度测试不准。每个人在单位时间内分泌至尿中的尿肌酐含量是一定的，尿液中尿肌酐的浓度变化直接受外界环境的影响（如水分摄取过多等），当排出的水分多,尿肌酐浓度降低；当排出的水分较少，尿肌酐浓度升高。通过尿糖/尿肌酐比值，可以排除因为水分摄取过多等因素对尿溶液浓度的干扰，准确反应尿溶液溶质之一-尿糖的相对水平。其中，尿糖/尿肌酐=（单位时间尿糖含量/尿液量）/（单位时间尿肌酐含量/尿液量），因为单位时间内个体尿肌酐含量是恒定的，所以通过尿糖/尿肌酐可以排除尿液量对尿糖的影响，准确反映尿液实时尿糖含量。
本实施例的基于尿液生物标志物的糖尿病早期无创检测系统引入肾功能评价指标（具体是肾小管功能指标）尿半胱氨酸蛋白酶抑制剂C（Cystatin C），用于排除由于肾脏损伤，导致尿糖测试结果出现假阳性或假阴性。同时，通过Cystatin C评价使用者的肾功能，可以用于早期检测糖尿病肾病并发症的发生。其依据说明如下：Cystatin C无组织特异性，在人体细胞内以恒定速度产生。血液中Cystatin C水平能反映肾小球滤过率。血液中Cystatin C能以恒定的速度通过肾小球基底膜，进入原尿中的Cystatin C在健康人肾小管处被完全重吸收。当肾小管发生损伤，尿液中就会有Cystatin C存在。大量的研究指出，当肾脏发生损伤，肾小管也会同时受损，影响肾小管重吸收功能。同时这些研究指出尿液中Cystatin C可作为肾病（包括糖尿病肾病）早期生物标志物。
更详细地，发射模块10包括光谱发射电路11和发射电源电路12，用于实时向发生反应后的试纸条发射特定波长的光波；检测模块20，通过检测试纸条进行检测，检测试纸条由敏感化学成分的薄片组成，薄片上含有能与尿糖、尿肌酐和尿Cystatin C发生特异的反应酶、底物或抗体，用于与尿液样品中的尿糖、尿肌酐和尿半胱氨酸蛋白酶抑制剂C反应并经入射光谱的照射后发出衰减后的光谱或荧光信号；光谱接收模块30，包括光谱接收电路31和接收电源电路32，用于接收一定波长范围的光谱信号，当光谱信号照射发生反应的试纸条后，照射光谱会发生一定程度衰减或发出荧光，计算光损失率或荧光强度，并将反射光谱或荧光信号转换为电信号；信号转换模块40，与光谱接收模块30连接，将尿液中尿糖、尿肌酐、尿Cystatin C浓度相关的电信号转换成微处理器能够识别和接收的数字信号；数据处理模块50，与信号转换模块40连接，包括微处理器（MCU）51及其外围电路52，将接收到的尿糖、尿肌酐、尿Cystatin C信息进行分析、计算，最后得到所测尿液样本中尿糖、尿肌酐、尿Cystatin C的浓度值以及尿糖/尿肌酐、尿Cystatin C/尿肌酐比值；输出模块60，与数据处理模块50连接，包括人机交互模块61和数据通讯模块62，其中，人机交互模块61进一步可以包括MCU、LCM显示器电路及键盘输入电路，用于实现人机交互，显示输出的浓度值和比值，即尿液中尿糖、尿肌酐、尿Cystatin C的浓度值，以及尿糖/尿肌酐、尿Cystatin C/尿肌酐比值测量数据结果；数据通讯模块62进一步可以包括MCU和数据通讯电路，用于实现远程信息通讯功能，将浓度值和比值传输至远程数据存储、分析平台。
需要说明的是，本发明中的模块或电路并不局限于特定电路图构造，因为用于实现各自功能的模块或电路，本领域的技术人员可以根据目前的技术进行选择。
本发明基于尿液生物标志物的糖尿病早期无创检测系统检测尿液生物标志物的方法流程图如图2所示，包括以下步骤：S1.检测模块向试纸条反应孔滴加尿液，试纸条与尿液中的尿糖、尿肌酐和尿半胱氨酸蛋白酶抑制剂C反应；S2.发射模块向反应后的试纸条发射预定波长的入射光谱；S3.光谱接收模块接收通过所述试纸条并衰减后的光谱或荧光信号，并转换为模拟电信号；S4.信号转换模块将所述模拟电信号转换成数字信号；S5.数据处理模块根据所述数字信号计算出所述尿液样品中的尿糖、尿肌酐、尿半胱氨酸蛋白酶抑制剂C的浓度值，以及尿糖/尿肌酐比值和/或尿半胱氨酸蛋白酶抑制剂C/尿肌酐比值；S6.输出模块输出所述浓度值和/或所述比值。
应当理解的是，本发明的糖尿病及其并发症的无创检测方法的应用范围并不局限于本发明中的具体构造的系统。
本发明的基于尿液生物标志物的糖尿病早期无创检测系统中的干式生化试纸条如图3和图4所示。
1）检测尿糖和尿肌酐的干式化学试纸条从上至下依次包括上层挡板（未示出）、中间层和底层支架（未示出）。中间层从上至下依次设有尿液扩散层、过滤层、亲水层和试剂层，其中试剂层可以融合在亲水层上。当向上层挡板两个相互独立的孔（图3中A和B）中分别加入尿液样本后，尿液样本在多孔聚酯纤维材料的尿液扩散层中均匀扩散，通过过滤层（玻璃纤维膜）滤掉杂质，与试剂层中的试剂发生反应，通过试纸颜色变化产生吸光值变化，检测光损失，得到尿液中相应目标物质的含量。
尿肌酐检测试纸检测方法：利用硫酸铜、柠檬酸钠、橙黄、聚乙烯吡咯烷酮和四甲基联苯胺制备尿肌酐检测试纸的试剂层，具体制备方法如下：先将试剂层充分浸入A液（1000ml溶液中含2mol/L Tris缓冲液，硫酸铜0.4g-2g，柠檬酸钠2-5g，橙黄2mg0-200mg，用纯水定容）后，取出并于70-100℃下干燥15-30min，然后将干燥后的试剂层浸入B液（聚乙烯吡咯烷酮10-20g，四甲基联苯胺3-5g，用氯仿定容），于70-100℃条件下干燥5-15min。当将尿液加入试纸反应孔中后，肌酐和硫酸铜生成络合物，该络合物可以与显色物橙黄和四甲基联苯胺发生反应显色。肌酐浓度在0.6mmol/L〜28mmol/L范围内，试纸呈现从浅黄到深绿的四级明显色阶，即淡黄-浅绿-草绿-深绿。通过传感器对反射光进行光谱分析（采用波长范围580-650nm），检测光损失，得到尿液中肌酐的浓度。具体地，尿肌酐的浓度与反应后试纸条的颜色深浅呈相关性，即与通过试纸条并衰减后的光谱强度呈相关性，进而与转换后的模拟电信号和数字信号呈相关性，通过一系列梯度浓度的标准品尿肌酐与对应的数字信号强度可以建立尿肌酐浓度与数字信号的标准曲线关系，根据标准曲线可以计算出测试的样本中尿肌酐的浓度。本领域技术人员通过本发明实施例的理解，能够通过现有技术计算出尿肌酐浓度值，在此不赘述。
尿糖检测试纸检测方法：利用葡萄糖氧化酶（GOD）、过氧化物酶、碘化钾、聚乙烯吡络烷酮配制尿葡糖糖试纸。具体来说，称取过氧化物酶1200U，葡萄糖氧化酶1200U，碘化钾100mg，聚乙烯吡络烷酮100mg，定容至100ml，将试剂层在溶液中浸泡，干燥30min。当将尿液加入试纸反应孔中后，尿糖与试纸上的葡萄糖氧化酶发生反应，残生葡萄糖酸和双氧水；双氧水再过氧化氢酶的催化下，释放出氧自由基[O：]，氧自由基与底物碘化钾发生显色反应，产生的游离碘与聚乙烯吡络烷酮形成棕色络合物。通过传感器对反射光进行光谱分析（采用波长范围550-750nm），检测光损失，得到尿液中尿糖浓度。具体地，尿糖的浓度与反应后试纸条的颜色深浅呈相关性，即与通过试纸条并衰减后的光谱强度呈相关性，进而与转换后的模拟电信号和数字信号呈相关性，通过一系列梯度浓度的标准品尿糖与对应的数字信号强度可以建立尿糖浓度与数字信号的标准曲线关系，根据标准曲线可以计算出测试的样本中尿糖的浓度。本领域技术人员通过本发明实施例的理解，能够通过现有技术计算出尿糖浓度值，在此不赘述。
2）检测尿Cystatin C的干式免疫荧光试纸条包括上层挡板（未示出）、中间层和底层支架（未示出）。其中，中间层从左到右依次粘有样品垫（图4中C）、硝酸纤维素膜、吸水垫三层，如图4所示，硝酸纤维素膜上设有检测线（C1）和质控线（C2），检测线包被的特异抗体为抗Cystatin C的单克隆抗体，质控线包被的特异抗体为兔IgG抗体。单独包装的铂卟啉标记抗体为抗微量白蛋白单克隆抗体和抗兔IgG抗体。通过检测硝酸纤维素膜上检测线和质控线铂卟啉荧光强度，计算出尿液样本中Cystatin C的浓度。
尿Cystatin C检测试纸检测方法：尿Cystatin C检测试纸条的硝酸纤维素膜在靠近点样孔的检测区域分别有检测线和质控线。检测线上包被有抗Cystatin C的抗体，质控线上包被有兔IgG抗体。同时，铂卟啉标记液中包含铂卟啉标记抗Cystatain C抗体和铂卟啉标记抗兔IgG抗体。检测时，将尿液样本和铂卟啉标记液以一定比例混合均匀，使铂卟啉标记抗体与尿液中目标蛋白（Cystatin C）充分结合，然后将混合液加入点样孔，3分钟后，将干式免疫荧光试纸条插入仪器，传感器发出光波（范围是400-420nm），读取检测线和质控线的荧光强度，根据荧光强度得出尿液中Cystatin C的浓度。具体地，尿Cystatin C的浓度与反应后试纸条上检测线的荧光强度呈相关性，进而与转换后的模拟电信号和数字信号呈相关性，通过一系列梯度浓度的标准品尿Cystatin C与对应的数字信号强度可以建立尿Cystatin C浓度与数字信号的标准曲线关系，根据标准曲线可以计算出测试的样本中尿Cystatin C的浓度。本领域技术人员通过本发明实施例的理解，能够通过现有技术计算出尿Cystatin C浓度值，在此不赘述。
根据尿糖、尿肌酐、尿Cystatin C、尿糖/尿肌酐和尿Cystatin C/尿肌酐的测量值作出判断：1）若尿液中尿糖值或尿糖/尿肌酐值超出正常范围（尿糖的正常范围为0-20mg/dL；尿糖/尿肌酐正常范围的上限值介于50-100mg/g），但未检测到尿Cystatin C，则判断受试者已患糖尿病，但未有并发症出现。此种应用可用于在人群中进行大规模初筛糖尿病患者，因为肾糖阈是一定的，所以当利用本方法测量出尿中有一定量葡萄糖时，说明受测人在一定程度上有或者将有患糖尿病的危险；2）对于已患糖尿病患者，若尿Cystatin C值超出正常范围（<0.15mg/dL），则说明患者易患糖尿病肾病；3）对于肾脏功能正常的糖尿病患者，可使用包含检测尿糖、尿肌酐的反应试纸（如图3中A、B）测量，尿糖、尿糖/尿肌酐参数可以在一定程度上反映患者血糖水平，在一定程度上可以减少患者扎手指的痛苦。
本发明的基于尿液生物标志物的糖尿病早期无创检测系统的监测推荐方法为，对于人群大规模筛查糖尿病患者，优选地，受试者在餐后0.5h-2.5h排空尿液，餐后2h-4.5h取次尿测量尿糖、尿肌酐、尿Cystatin C。例如，在餐后1.5h排空尿液，餐后3h采集尿液，所采集的尿液中的尿糖浓度反应了餐后1.5h-3h内尿液的平均浓度，更能反映餐后血液血糖（实时）浓度；对于糖尿病患者预测并发症（糖尿病肾病）发生，优选地，受试者取晨尿中段尿液，测量尿糖、尿肌苷、尿Cystatin C；对于已患糖尿病，但未出现并发症的患者，受试者可以在血糖相对稳定的情况下，取晨尿、餐后尿、随机尿检测尿糖、尿肌酐，在一定程度上代替测量血糖。
表1示出了使用本发明的系统和方法检测的10个样本的情况。
表1
Figure 813336dest_path_image001
。
注：表中1-8号为糖尿病患者（糖化血红蛋白及餐后血糖），9及10号为正常对照。其中，6号患者具有轻度糖尿病肾病（eGFR 87）。通过该方法检测，发现6号测试者尿Cystatin C值大于正常范围，暗示患有糖尿病肾病，不适用于用尿糖/尿肌酐值预测血糖浓度；其余患者无肾脏疾病；通过尿糖/尿肌酐值看，1-5及7、8号受试者尿糖/尿肌酐高于正常范围，暗示有不同程度糖尿病。
以上内容是结合具体的实施方式对本发明所作的进一步详细说明，不能认定本发明的具体实施只局限于这些说明。对于本发明所属技术领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干简单推演或替换。
 工业实用性
本发明具有如下技术效果：引入尿肌酐作为参比，通过尿糖/尿肌酐比值准确反映尿液中随机尿糖的浓度，能排除外界干扰因素对尿糖浓度的影响；引入肾功能评价指标尿半胱氨酸蛋白酶抑制剂C，用于排除由于肾脏损伤，导致尿糖测试结果出现假阳性或假阴性，并且通过尿半胱氨酸蛋白酶抑制剂C评价肾功能，可以在早期监控糖尿病肾病并发症，实现糖尿病及其并发症的同步监测，因此本发明可以实现定量测量，准确性和灵敏度相较现有尿糖试纸更高。

Claims (7)

  1. 一种基于尿液生物标志物的糖尿病早期无创检测系统，其特征在于，所述系统包括:
    发射模块，用于发射预定波长的入射光谱；
    检测模块，用于通过试纸条与尿液样品中的尿糖、尿肌酐和/或尿半胱氨酸蛋白酶抑制剂C反应并接收所述入射光谱，所述检测尿糖的试纸条为干式化学试纸条，包括从上至下依次设置的尿液扩散层、过滤层、亲水层和试剂层，其中所述试剂层上有葡萄糖氧化酶、过氧化物酶、碘化钾和聚乙烯吡络烷酮，所述检测尿肌酐的试纸条为干式化学试纸条，包括从上至下依次设置的尿液扩散层、过滤层、亲水层和试剂层，其中所述试剂层上有硫酸铜、柠檬酸钠、橙黄、聚乙烯吡咯烷酮和四甲基联苯胺，所述检测尿半胱氨酸蛋白酶抑制剂C的试纸条为干式化学试纸条，包括依次搭接的样品垫、硝酸纤维素膜和吸水垫，其中所述硝酸纤维素膜上有检测线和质控线，所述检测线上包被有抗半胱氨酸蛋白酶抑制剂C的抗体，所述质控线上包被有IgG抗体；
    光谱接收模块，用于接收通过所述试纸条并衰减后的光谱或荧光信号，并转换为模拟电信号；
    信号转换模块，与所述光谱接收模块连接，将所述模拟电信号转换成数字信号；
    数据处理模块，与所述信号转换模块连接，根据所述数字信号计算出所述尿液样品中的尿糖、尿肌酐、尿半胱氨酸蛋白酶抑制剂C的浓度值，以及尿糖/尿肌酐比值和/或尿半胱氨酸蛋白酶抑制剂C/尿肌酐比值；
    输出模块，与所述数据处理模块连接，用于输出所述浓度值和/或所述比值。
  2. 根据权利要求1所述的系统，其特征在于，所述尿液样品来自受试者在餐后0.5~2.5h排空尿液，且在餐后2~4.5h所取的尿液。
  3. 根据权利要求1所述的系统，其特征在于，所述发射模块包括光谱发射电路和发射电源电路；所述光谱接收模块包括光谱接收电路和接收电源电路。
  4. 根据权利要求1所述的系统，其特征在于，所述数据处理模块包括MCU及其外围电路。
  5. 根据权利要求1所述的系统，其特征在于，所述输出模块包括人机交互模块和数据通讯模块；所述人机交互模块，用于实现人机交互，显示输出的所述浓度值和/或所述比值；所述数据通讯模块，用于实现远程信息通讯功能，将所述浓度值和/或所述比值传输至远程数据存储、分析平台。
  6. 一种糖尿病早期无创检测方法，其特征在于，所述方法包括：
    检测模块向试纸条反应孔滴加尿液，试纸条与尿液中的尿糖、尿肌酐和尿半胱氨酸蛋白酶抑制剂C反应；
    发射模块向反应后的试纸条发射预定波长的入射光谱；
    光谱接收模块接收通过所述试纸条并衰减后的光谱或荧光信号，并转换为模拟电信号；
    信号转换模块将所述模拟电信号转换成数字信号；
    数据处理模块根据所述数字信号计算出所述尿液样品中的尿糖、尿肌酐、尿半胱氨酸蛋白酶抑制剂C的浓度值，以及尿糖/尿肌酐比值和/或尿半胱氨酸蛋白酶抑制剂C/尿肌酐比值；
    输出模块输出所述浓度值和/或所述比值。
  7. 根据权利要求6所述的方法，其特征在于，在所述检测模块向试纸条反应孔滴加尿液前还包括：
    获取受试者在餐后0.5~2.5h排空尿液且在餐后2~4.5h所取的尿液。
     
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