Method for predicting the risk of a subject for contracting diabetes mellitus and/or metabolic syndrome or for diagnosing metabolic syndrome in a subject

Abstract

Subject of the present invention is a method for predicting the risk of getting a cardiovascular event in a female subject comprising determining the level of pro-neurotensin or fragments thereof of at least 5 amino acids in a bodily fluid obtained from said female subject; and correlating said level of pro-neurotensin or fragments thereof with the a risk for getting a cardiovascular event, wherein an elevated level is predictive for an enhanced risk of getting a cardiovascular event.

1 .- 18 . (canceled) 
     
     
         19 . A method comprising contacting a sample of a bodily fluid from a fasting non-diabetic subject with a level pro-neurotensin 1-117 of 78 pmol/l or above with a binder that binds to pro-neurotensin 1-117. 
     
     
         20 . A method according to  claim 19 , wherein said binder is an antibody that is full-length immunoglobulin, or fragments therein containing at least the F-variable domain of heavy and/or light chain. 
     
     
         21 . A method of  claim 20  which comprises the additional step of producing a complex of pro-neurotensin 1-117 and said antibody in an amount of 78 pmol/l or above. 
     
     
         22 . A method of  claim 21  which comprises the additional step of determining the level of complex of pro-neurotensin 1-117 and said antibody by detecting binding between pro-neurotensin 1-117 and said antibody. 
     
     
         23 . A method of  claim 19 , wherein the sample of bodily fluid is selected from the group consisting of a blood sample, a plasma sample, a cerebrospinal fluid sample, a serum sample, a urine sample or an extract of the aforementioned samples. 
     
     
         24 . A method according to  claim 19 , wherein the sample of bodily fluid is from a subject which is a fasting non-diabetic and non-prediabetic (non-IFG) subject. 
     
     
         25 . A method according to  claim 19 , wherein the blood sample has a blood glucose level of less than 6.1 mmol/l but more than 5.4 mmol/l or a blood glucose level of less than 5.4 mmol/l. 
     
     
         26 . A method according to  claim 19 , wherein the level of pro-neurotensin 1-117 in the bodily fluid is between 78-150 pmol/l. 
     
     
         27 . A method according to  claim 19  wherein the level of pro-neurotensin 1-117 in the bodily fluid is 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149 or 150 pmol/l. 
     
     
         28 . A method comprising:
 A) determining the level of pro-neurotensin 1-117 or fragments thereof of at least 5 amino acids or pro-neurotensin 1-117 comprising peptides in a sample of bodily fluid obtained from a fasting non-diabetic subject; and   B) determining whether the fasting non-diabetic subject has an enhanced risk of contracting diabetes mellitus and/or metabolic syndrome based on the level of pro-neurotensin 1-117 or fragments thereof of at least 5 amino acids or proneurotensin 1-117 comprising peptides determined in the bodily fluid obtained from said fasting non-diabetic subject, wherein a level of pro-neurotensin 1-117 or fragments thereof or pro-neurotensin 1-117 comprising peptides above a threshold level of 78 pmol/L is predictive for an enhanced risk of contracting diabetes mellitus and/or metabolic syndrome.   
     
     
         29 . A method of  claim 28  wherein the level of pro-neurotensin 1-117 or fragments thereof of at least 5 amino acids or pro-neurotensin 1-117 comprising peptides in said sample of bodily fluid is determined by a) contacting said sample with an antibody that binds to pro-neurotensin 1-117 or fragments thereof of at least 5 amino acids or pro-neurotensin 1-117 comprising peptides and b) detecting binding between the antibody and pro-neurotensin 1-117 or fragments thereof of at least 5 amino acids or pro-neurotensin 1-117 comprising peptides. 
     
     
         30 . A method of  claim 28  comprising the additional step of recording when a sample of bodily fluid obtained from said fasting non-diabetic subject has a fasting level of pro-neurotensin 1-117 or fragments thereof of at least 5 amino acids or proneurotensin 1-117 comprising peptides that is elevated over a threshold level of 78 pmol/l. 
     
     
         31 . A method according to  claim 28 , comprising the additional step of measuring the blood glucose level of a fasting non-diabetic subject, wherein the fasting non-diabetic subject selected has a blood glucose of a) less than 6.1 mmol/l but more than 5.4 mmol/l or b) less than 5.4 mmol/l. 
     
     
         32 . A method according to  claim 28 , comprising the additional step of determining at least one clinical parameter selected from the group consisting of age, gender, systolic blood pressure, diastolic blood pressure, antihypertensive treatment (AHT), body mass index, waist circumference, waist-hip-ratio, smoker status, diabetes heredity and previous cardiovascular disease (CVD). 
     
     
         33 . A method according to  claim 28 , comprising the additional step of
 determining the level of at least one further marker selected from triglycerides, HDL cholesterol or subfractions thereof, LDL cholesterol or subfractions thereof, Cystatin C, insulin, CRP, vasopressin or its precursors or fragments thereof, or BNP or its precursors or fragments thereof, in a sample of bodily fluid obtained from a fasting non-diabetic subject; and   determining whether the fasting non-diabetic subject has an enhanced risk of contracting diabetes mellitus and/or metabolic syndrome based on   
       a) the level of pro-neurotensin 1-117 or fragments thereof of at least 5 amino acids or pro-neurotensin 1-117 comprising peptides determined in the bodily fluid obtained from said fasting non-diabetic subject, and 
       b) the level of at least one further marker selected from triglycerides, HDL cholesterol or subfractions thereof, LDL cholesterol or subfractions thereof, Cystatin C, insulin, CRP, vasopressin or its precursors or fragments thereof, or BNP or its precursors or fragments thereof. 
     
     
         34 . A method according to  claim 28 , wherein the level of pro-neurotensin 1-117 is determined. 
     
     
         35 . A method for identifying a fasting non-diabetic subject at risk for contracting diabetes mellitus, a metabolic syndrome, or both; the improvement comprising: determining the level of pro-neurotensin 1-117 or fragments thereof of at least 5 amino acids in a bodily fluid of said fasting non-diabetic subject. 
     
     
         36 . A method of monitoring the course of treatment of a subject treated with preventive and/or therapeutic measures for diabetes mellitus and/or metabolic syndrome, said method comprising
 A) determining the level of pro-neurotensin 1-117 or fragments thereof of at least 5 amino acids or pro-neurotensin 1-117 comprising peptides in a sample of bodily fluid obtained from a subject to be treated with preventive and/or therapeutic measures for diabetes mellitus and/or metabolic syndrome;   B) determining the level of pro-neurotensin 1-117 or fragments thereof of at least 5 amino acids or pro-neurotensin 1-117 comprising peptides in a sample of bodily fluid obtained from a subject after treatment with preventive and/or therapeutic measures for diabetes mellitus and/or metabolic syndrome; and   C) evaluating the response of said subject to preventive and/or therapeutic measures based on the difference in the level of pro-neurotensin 1-117 or fragments thereof of at least 5 amino acids or pro-neurotensin 1-117 comprising peptides determined in steps A and B.   
     
     
         37 . A method according to  claim 36 , wherein an increase in pro-neurotensin 1-117 or fragments thereof of at least 5 amino acids or pro-neurotensin 1-117 comprising peptides determined in Step B indicates a poor response of said subject to preventive and/or therapeutic measures and a decrease in pro-neurotensin 1-117 or fragments thereof of at least 5 amino acids or pro-neurotensin 1-117 comprising peptides determined in Step B indicates a favorable response of said subject to preventive and/or therapeutic measures. 
     
     
         38 . A method for stratifying subjects into risk groups for getting diabetes mellitus and/or metabolic syndrome comprising performing the method according to  claim 28  on more than one fasting non-diabetic subject. 
     
     
         39 . A method of prevention or treatment of diabetes mellitus and/or metabolic syndrome in a subject comprising administering to said subject a binder to neurotensin or a neurotensin receptor which reduces the bioactivity of neurotensin to 70% or less. 
     
     
         40 . The method according to  claim 39 , wherein the binder to neurotensin is selected from the group consisting of antibodies e.g. IgG, a typical full-length immunoglobulin, or antibody fragments containing at least the F-variable domain of heavy and/or light chain as e.g. chemically coupled antibodies (fragment antigen binding) including but not limited to Fab-fragments including Fab minibodies, single chain Fab antibody, monovalent Fab antibody with epitope tags, e.g. Fab-V5Sx2; bivalent Fab (mini-antibody) dimerized with the CH3 domain; bivalent Fab or multivalent Fab, e.g. formed via multimerization with the aid of a heterologous domain, e.g. via dimerization of dHLX domains, e.g. Fab-dHLX-FSx2; F(ab′)2-fragments, scFv-fragments, multimerized multivalent or/and multi specific scFv-fragments, bivalent and/or bispecific diabodies, BITE® (bispecific T-cell engager), trifunctional antibodies, polyvalent antibodies, e.g. from a different class than G; single-domain antibodies, e.g. nanobodies derived from camelid or fish immunoglobulines. 
     
     
         41 . The method according to  claim 39 , wherein the binder to a neurotensin receptor is selected from the group consisting of antibodies e.g. IgG, a typical full-length immunoglobulin, or antibody fragments containing at least the F-variable domain of heavy and/or light chain as e.g. chemically coupled antibodies (fragment antigen binding) including but not limited to Fab-fragments including Fab minibodies, single chain Fab antibody, monovalent Fab antibody with epitope tags, e.g. Fab-V5Sx2; bivalent Fab (mini-antibody) dimerized with the CH3 domain; bivalent Fab or multivalent Fab, e.g. formed via multimerization with the aid of a heterologous domain, e.g. via dimerization of dHLX domains, e.g. Fab-dHLX-FSx2; F(ab′)2-fragments, scFv-fragments, multimerized multivalent or/and multi specific scFv-fragments, bivalent and/or bispecific diabodies, BITE® (bispecific T-cell engager), trifunctional antibodies, polyvalent antibodies, e.g. from a different class than G; single-domain antibodies, e.g. nanobodies derived from camelid or fish immunoglobulines, or a peptide antagonist e.g. [D-Trp11]-Neurotensin, [Tyr(Me)11]-Neurotensin, or a non-peptide antagonist, e.g. Levocabastine, SR-48692 (NTS1 selective), SR-142948 (unselective), SR-142948A, CP 96345, [3H]SR-48692, SR-48527 and SR-49711, or a binder scaffold e.g. tetranectin-based non-Ig scaffolds, fibronectin scaffolds, lipocalin-based scaffolds, ubiquitin scaffolds, transferring scaffolds, protein A scaffolds, ankyrin repeat based scaffolds, microproteins, preferably microproteins forming a cystine knot scaffolds, Fyn SH3 domain based scaffolds, EGFR-A-domain based scaffolds and Kunitz domain based scaffolds. 
     
     
         42 . A point-of-care device for performing a method according to  claim 28 .