WO2021009182A1 - Diagnostic prédictif pour la présence de diabète et de tolérance au glucose modifié - Google Patents
Diagnostic prédictif pour la présence de diabète et de tolérance au glucose modifié Download PDFInfo
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Classifications
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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
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/689—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to pregnancy or the gonads
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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
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
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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
- G01N2800/36—Gynecology or obstetrics
- G01N2800/368—Pregnancy complicated by disease or abnormalities of pregnancy, e.g. preeclampsia, preterm labour
Definitions
- Type 2 diabetes mellitus is a chronic metabolic disease caused by reduced or no insulin secretion or also by reduced sensitivity of the tissue to insulin.
- DM today presents a challenge for healthcare systems all over the world.
- IDF International Diabetes Federation
- Chronic hyperglycemia is a characteristic common in all subtypes of this disease and is associated with long-term damage which increases the morbidity and mortality rate and causes the disfunction of various organs, such as renal insufficiency, blindness and amputation of the limbs.
- Gestational diabetes mellitus is a condition characterized by glycemia values which are higher than the norm and which suggest a diagnosis of diabetes, said condition occurring during pregnancy in women who, prior thereto, were not diabetic.
- gestational diabetes The problems associated with gestational diabetes are not linked primarily to the symptoms which are typical of diabetes, but more so to the increased risk of pre-eclampsia. Furthermore, gestational diabetes, if it is not correctly managed, results in an increased risk of macrosomia and icterus for the newborn baby.
- the newborn baby is also exposed to an increased risk of overweight and the development of type 2 diabetes.
- the causes of gestational diabetes are to be found in an insulin insufficiency in the context of insulin resistance.
- the risk factors include overweight, preceding gestational diabetes, a family history of type 2 diabetes and polycystic ovary syndrome.
- the laboratory tests used to diagnose DM are glycated hemoglobin (HbA1 c), fasting plasma glucose (FG) and plasma glucose 2 hours (2hG) after a 75g oral glucose tolerance test (OGTT) (Sacks DB et al. Guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus. Clin Chem. 2011 ; 57:e1 -e47).
- HbA1 c constitutes hitherto the reference test for glycemic monitoring since it reflects directly the average glycemia and is very closely related to long term complications of DM.
- numerous recent studies indicate that the current evaluation of HbA1 c alone or of fasting glycemia does not manage to highlight the response to glycemic or fructose "peaks" and therefore represents a measurement which is unsuitable or not complete enough for characterization of a pre-diabetic condition or for indicating the possible diabetic evolution (Rodriguez-Segade S et al., Prediabetes defined by HbA1 c and by fasting glucose: differences in risk factors and prevalence. Acta Diabetol.
- gestational diabetes is performed by means of prenatal screening during the 24th to 28th week of pregnancy, with the measurement of the plasma glucose 2 hours (2hG) after a 75g oral glucose tolerance test (OGTT) (Sacks DB et al. Guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus. Clin Chem. 2011 ; 57:e1 -e47).
- OGTT oral glucose tolerance test
- HbA1 c is not recommended in certain clinical situations which influence the metabolism of the hemoglobin (Cavagnolli G et al. Factors affecting A1 C in non-diabetic individuals: Review and meta- analysis. Clin Chim Acta. 2015; 445:107-14) owing to the possible interference of these situations with the results, resulting in an incorrect interpretation thereof.
- recent studies have shown a divergence between the levels of HbA1 c in different ethnic groups for the same glycemia levels, although the reasons for this divergence are not entirely clear.
- Glycated albumin is a laboratory test which has assumed a certain importance for glycemic monitoring in DM in recent years (Kohzuma T et al. , Glycated albumin assay kit: a new diagnostic test for diabetes mellitus. Mol Diagn Ther. 2010; 14:49-51 ).
- GA is one of the fructosamines which, for measurement thereof, does not require prior fasting and reflects the short-term glycemia owing to the half-life of the albumin, which is equal to about 3 weeks.
- GA Compared to HbA1 c, GA is not influenced by the presence of hemolytic processes and Hb abnormalities (Kim C et al., Association between iron deficiency and A1 C Levels among adults without diabetes in the National Health and Nutrition Examination Survey, 1999-2006. Diabetes Care. 2010; 33:780-5). Furthermore, in conditions such as anemia, pregnancy, postprandial hyperglycemia and DM which uses insulin, GA appears to be a better glycemic marker than HbA1 c, in particular suitable for diabetic patients undergoing hemodialysis. Recently studies carried on patients with type 1 diabetes (Nathan DM et al. DCCT/EDIC Research Group.
- Albumin is a protein of 66.7 kDa, composed of a single polypeptide chain which contains 585 amino acids, 17 disulfide bridges and 3 homologous domains which are connected in a helical structure (Anguizola J et al. Glycation of human serum albumin. Clin Chim Acta. 2013; 425:64-76). It is the main plasma protein, representing about
- the albumin passes through the physiological process of glycation, where glycation is a non-enzymatic spontaneous reaction in which a reducing sugar is added to a free amine group, typically lysine or arginine present inside the proteins, also known as Maillard reaction.
- the first stage of this reaction involves the formation of an unstable and reversible product known as Schiff base, which is formed by the binding of a carbonyl group of an acyclic carbohydrate with the N-terminal amino acid.
- This intermediate product may undergo a change in its form and result in a stable and irreversible compound, known as Amadori product.
- the set of compounds formed by the non-enzymatic glycation of the proteins is called "fructosamine".
- GA is the main constituent, representing about 80% of all the glycations in plasma (Anguizola J et al., citation).
- the extracellular proteins such as albumin
- the concentration of glucose and the exposure time of the proteins to the sugar are the determining factors for glycations, which is equivalent to saying that the glycation depends on the degree and the duration of the hyperglycemia.
- the glycated proteins are subject to further oxidizing and irreversible events which result in stable and heterogenous compounds known as final advanced glycation products.
- AGE Advanced Glycation End-products
- the AGE receptors are present in cells of various tissues, such as macrophages, muscles, endothelial and glial cells. They are expressed as membrane molecules forming the superfamily of immunoglobulins and act as signal transduction receptors, initiating an inflammatory cascade. As a result of this cascade, there is a greater production of reactive species of the oxygen, which is directly associated with pathogenesis and long-term complications in DM.
- fructosamine has been used in clinical practice when it was necessary to evaluate short-term glycemia (Raghav A, Ahmad J. Glycated serum albumin: a potential disease marker and an intermediate index of diabetes control. Diabetes Metab Syndr. 2014; 8:245-51 ).
- this test has a low accuracy since it is influenced by all the plasma proteins or also by other molecules present in the blood, such as bilirubin, uric acid and substances with a low molecular weight.
- the test for fructosamine is not available in all the laboratories and there do not exist consolidated international standards for the analysis.
- GA may be measured by means ion-exchange high performance liquid chromatography (HPLC), boron affinity chromatography, immunological assays (radioimmunological dosing and immune-absorbent assay linked to the enzyme), colorimetric method with thiobarbituric acid and enzymatic methods which use proteinase and ketamine oxidase. No method is however available in the laboratory routine (Furusyo N, Hayashi J. Glycated albumin and diabetes mellitus. Biochim Biophys Acta. 2013; 1830:5509-14).
- GA is measured using a three-step enzymatic method based on a specific proteinase for the albumin and the ketamine oxidase.
- Hb and ascorbic acid which are typically present in analysis samples, result however in interference during the reading.
- GA is predictive of the microvascular complications both in type 1 DM and type 2 DM.
- GA appears to be a good marker only in type 2 DM.
- the mechanisms involved in the development of atherosclerosis and cardiovascular diseases in the type 1 DM could explain these results.
- the degree, the type of modification and the variable combination of the alterations in structure and circular form of the albumin give rise to the variation of its binding affinity for different molecules, as observed in opposite directions.
- GA shows a substantial loss of binding affinity for various ligands. In particular, it is drastically altered in relation to bilirubin and long-chain fatty acids.
- the binding affinity for iron increases, while for copper the variation is ambivalent.
- the binding capacity of GA is moreover also reduced in relation to important drugs such as furosemide, ibuprofen and warfarin, although in the case of the latter an increased affinity or no modification is also reported.
- HbA1 c is, however, still not sufficient per se for reflecting the average glycemic values.
- Methylglyoxal is an oxidizing substance, the value of which increases in proportion to the progression of the glycemia.
- the levels of MGO in the healthy organism are controlled by an enzymatic system which detoxifies the organism, converting 99% of the MGO into less reactive products.
- MGO metal-oxidative stress
- the MGO which is typically measured is that bound to the amino acids of the proteins by means of the spontaneous Maillard reaction.
- Other techniques for measuring the MGO detect the total levels of MGO.
- the present invention relates to a method which highlights the propensity for development of diabetes or other sugar-related diseases as well as the propensity for development of gestational diabetes, said method comprising the simultaneous evaluation and the combined interpretation of the percentage of GA and the levels of MGO in a biological sample obtained from a subject.
- Said biological sample is preferably a blood sample and said subject is a human subject. Description of the figures
- Figure 1 MGO values measured in relation to the levels of GA%.
- Figure 2 graphical correlation between values of GA% and MGO in the same subjects.
- Figure 3 (A) MGO values and (B) absolute values of GA measured in the general control population (GP) and in the population of women at the 27th week of pregnancy in the presence of gestational diabetes (TO) and at the 38th week of pregnancy in the same subjects in whom the measurement had been carried out 12 weeks previously (T12).
- GP general control population
- TO gestational diabetes
- Figure 4 GA%, values measured at different times in two different general populations.
- Glycated albumin (GA)
- the method used in the present invention which is sensitive and reproducible, is based on the immunometric method which makes use of the monoclonal antibodies which bind specifically the glycated albumin.
- the analyses are carried out on glycated albumin and total albumin using the ELISA technique.
- the ELISA assay was carried out using specific kits for GA and total albumin.
- GA% (glycated albumin/total album in)*100
- Methylglyoxal is an oxidizing substance, the value of which increases in proportion to the progression of the blood values of glucose, fructose and other sugars, considering also the peaks thereof reached and the corresponding downwards trends.
- a peak of sugars following a meal or the consumption of desserts or fructose produces the immediate increase thereof, said increase reaching the pre-load values in a few hours, while the drop in the base values, recorded during fasting, which may be upwardly biased in subjects with a high glucose sensitivity, occurs during the course of a few days of controlled diet.
- the MGO values indicate the possible toxic effect of peaks of sugars (both of fructose and glucose) in the blood, in an individual subject, thus making it possible to define whether a single person has, in relation to a certain quantity of sugars consumed, a normal response or one indicating the possibility of glucose intolerance.
- a blood level of MGO defined control level, equal to 0.200 pg/ml.
- Said control level defines two groups of subjects, namely subjects characterized by an MGO level ⁇ said control level and subjects characterized by an MGO level > said control level.
- the authors of the present invention have surprisingly shown that a combined analysis of GA% and MGO is able to predict the risk of developing diabetes, in the medium term and long term, while providing also a classification of the risk (moderate risk or high risk in the long term).
- a method which comprises the following steps is therefore claimed: - making available a biological sample from a subject; - measuring, in said sample, the levels of total albumin, glycated albumin and MGO;
- GA% is calculated as follows:
- GA% (glycated albumin/total album in)*100
- (6D) diabetic subjects undergoing treatment who report a diet that is highly inadequate and unsuitable for effective control of the blood values, with probable recent excesses of sugars.
- said biological sample is first classified as low GA%, intermediate GA% or high GA%.
- the same biological sample is also classified as low MGO or high MGO.
- said GA% classification meets the following criteria:
- said MGO classification meets the following criteria:
- the sample is taken from pregnant women in the 24th to 28th week of pregnancy, preferably in the 27th week of pregnancy: in one embodiment, the sample was repeated in the 38th week.
- the present invention provides a predictive diagnostic method able to identify, in a blood sample obtained from a woman in the 4th week of pregnancy onwards, a predisposition for developing gestational diabetes.
- a variation in the levels of GA% and/or MGO was in fact observed in blood samples in which the glycemia and glycated hemoglobin levels were within the parameters considered to be normal.
- kits which comprises a GA-specific ELISA test, a total albumin specific ELISA test and an ELISA test for measuring the methylglyoxal bound to the protein amino acids and the instructions for reading said tests is also described.
- said kit also includes a test tube and at least one lancing device.
- said instructions which are supplied on an analog or digital medium together with the kit, or are made available in other ways, for example on-line, comprise the parameters for correct reading of the tests and preferably comprise the indications given in Table 2.
- GA and MGO proved to be indicators of a predisposition for the development of gestational diabetes, when measured in blood samples in which the glycemia and glycated hemoglobin values were absolutely within the norm.
- MGO mesenchymal glycational diabetes
- a close correlation has also been shown to exist between the measured values of MGO and the anthropometric values of the fetus, where the higher the MGO values, the greater the risk that the newborn baby will be affected by macrosomia.
- the method according to the present invention it is possible to detect, much further in advance compared to the methods of the prior art, the presence in a sample of an altered sensitivity to sugars.
- As a result of such early detection it is possible to implement in good time those changes to diet and lifestyle which are able to prevent the development of diabetes. Understanding in advance the effects of the sugars on the organism is undoubtedly helpful for a correct choice as to how to use them.
- With the method according to the present invention it is possible surprisingly to determine the impact of the sugars on the organism of a specific subject in advance of any damage induced by them.
- the method according to the present invention highlights critical situations which the analysis values typically used, namely fasting glycemia and glycated hemoglobin values, recognize only partially and often too late.
- the method according to the present invention is therefore useful for all subjects because it provides information for defining a personalized dietary regime.
- the method proves to be useful not only for healthy subjects but also for those subjects who have already been diagnosed with diabetes.
- the method according to the present invention is undoubtedly useful for evaluating the possible damage due to peaks of fructose and glucose, while the glycemia and glycated hemoglobin readings have proved to be not entirely satisfactory for detecting the effects of glycemic peaks following meals or immediately after the consumption of sugary substances.
- the method according to the present invention avoids the use of the glycemic load curve, avoiding the disturbances which are often reported by the subjects exposed to the same, linked with the consumption of the glucose solution which has a taste which may be unpleasant or produce nausea.
- Example 1 evaluation of MGO and GA, first group of subjects tested 84 non-selected standard subjects and 12 known diabetic or pre diabetic subjects were evaluated.
- Figure 1 shows the MGO values measured in relation to 3 groups of GA%, as defined above. Low levels of MGO correspond to very high values of GA%.
- kits are based on the sandwich use of antibodies conjugated to HRP enzyme.
- a specific antibody for the analyte covers the surface of the well in which the sample will be loaded.
- the standards and the samples are added to the wells and washed with washing buffer.
- a specific antibody conjugated with the biotin which recognizes and specifically binds the analyte is used as detection antibody.
- the color intensity of the reaction occurring with the substrate added to the reaction is proportional to the quantity of analyte bound in the well.
- the absorbance is measured using a spectrophotometer at 450 nm in a microplate reader and then the concentration of the analyte is calculated by means of interpolation of the absorbance on a calibration curve.
- MGO was measured with OxiSelectTM Methylglyoxal (MG) Competitive ELISA Kit - Catalog No.: STA-811 - Cell Biolabs, San Diego, CA, USA, an enzyme immunoassay developed for the detection and quantization of MG-H1 (methylglyoxal-hydro-imidazolone) protein adducts.
- An anti- MG antibody covers the surface of the well of the ELISA plate.
- Samples containing the standard MG or MGBSA protein adducts are added to the pre-absorbed MG conjugate plate. After a short incubation, an anti- MG antibody is added, followed by a secondary HRP-conjugated antibody.
- the content of the MG protein adducts in the unknown samples are determined by comparing the absorbances of the samples with those of the MG-BSA standard curve at known concentration.
- the analysis carried out following the first heuristic evaluations, confirmed the alignment with international data and the evidence of the fact that diabetics do not show high levels of MGO; however, subjects enjoying excellent physical health, with correct glycemia values, but with possible intolerance to sugars (defined for example by clinical knowledge or familiarity), show an increase in MGO following the administration of sugars, as if it were - even though per se an alarm signal - still a manifestation of possible compensation.
- the algorithm according to the present invention classifies Gly04 in class 5, i.e. subject with a high risk of diabetes, with the need for pharmacological treatment and significant dietary and nutritional commitment. It is worth noting that such a subject has a glycemia lower than 110 mg/dl and an HbA1 c equal to 44 mmol/mol, values not indicative of pathology.
- the subject from whom the Gly04 sample was obtained was monitored over time. The same subject did not follow the recommended dietary regime and became diabetic in the following months, with the need for antidiabetic drug therapy.
- the algorithm according to the present invention classifies Gly14 in class 1 D, i.e. diabetic subject undergoing appropriate treatment. The subject's medical history confirms the result.
- the sample indicated with Gly20 was obtained from a subject, followed one year later by a further sample, Gly99.
- the subject had been undergoing treatment with a low dosage of metformin (500 mg twice a day) for at least 3 years and showed glycemia values still at levels of between 140 and 150 mg/dl, with 52 mmol/mol glycated Hb.
- metformin 500 mg twice a day
- Hb 52 mmol/mol glycated Hb.
- the subject maintained glycemia and glycated hemoglobin values which were consistent.
- Table 3 shows the distribution of the measured MGO values in relation to the 3 groups of GA%, as defined above.
- Figure 4 shows the comparison between the data obtained in the first and second group of subjects tested
- the left column shows the GA% values measured in the 96 subjects belonging to the second group, while the right column shows the GA% measured in the 84 subjects belonging to the first group.
- the results obtained in different subjects and at different times are perfectly comparable, confirming the validity of the GA values used as a reference standard in the present invention.
- the mean fasting glycemia value the mean HbA1 C value
- the GA and MGO values the mean fasting glycemia and HbA1 values were within the norm. This implies that routine blood tests, under fasting conditions, cannot diagnose gestational diabetes.
- MGO values all above the level of 0.200 ng/ml, are significantly higher than those of the general population with a clear correlation between high MGO values and the appearance of the clinical characteristic, with high statistical significance P ⁇ 0.001.
- the percentage values of GA measured in the 27th week were within the norm for 26 out of 30 women. Three women instead had GA values between 1.15 and 2.95 and one woman had a GA value above 2.95. In summary, 4 out of 30 women already showed a dietary inadequacy which during the remaining 12 weeks, under strict dietary control, for all 30 women studied showed GA values below 1.15%, i.e. normal in relation to the percentage of GA against total albumin, although significantly higher p ⁇ 0.001 in absolute value, than those of the general population.
- the MGO and GA measurements were repeated 12 weeks later, at the 38th week of pregnancy.
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Abstract
La présente invention concerne un procédé de détermination de la propension au développement du diabète ou d'autres maladies liées au sucre, ledit procédé comprenant l'évaluation simultanée et l'interprétation combinée du pourcentage d'albumine glyquée (GA) et des niveaux 5 de méthylglyoxal (MGO) dans un échantillon biologique obtenu d'un sujet. La présente invention concerne en outre un procédé de détermination de la propension au développement du diabète gestationnel, ledit procédé comprenant l'évaluation simultanée et l'interprétation combinée du pourcentage d'albumine glyquée (GA%) et des niveaux de 10 méthylglyoxal (MGO) dans un échantillon biologique obtenu à d'un sujet entre la 4e à la 38e semaine de grossesse.
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EP4086633A3 (fr) * | 2021-05-04 | 2023-02-15 | GEK S.r.l. | Procédé de pronostic |
CN116519811A (zh) * | 2022-01-24 | 2023-08-01 | 杭州凯莱谱精准医疗检测技术有限公司 | 预测妊娠个体血糖值的系统 |
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