Protein and lipid biomarkers providing consistent improvement to the prediction of Type 2 diabetes

• US 9,810,697 B2
• Filed: 11/18/2015
• Issued: 11/07/2017
• Est. Priority Date: 10/29/2009
• Status: Expired due to Fees

• Current Assignee: True Health Diagnostics LLC (True Health Group LLC)
• Original Assignee: True Health Diagnostics LLC (True Health Group LLC)
• Inventors: McKenna, Michael P., Watkins, Steve M.
• Primary Examiner(s): COOK, LISA V
• Application Number:
  US14/945,200
• Publication Number:
  US 20170003297A1
• Time in Patent Office: 720 Days
• Field of Search: None
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: G01N 2800/042 Disorders of carbohydrate metabolism, e.g. diabetes, glucose metabolism
• CPC Class Codes: G01N 2800/50 Determining the risk of developing a disease
• CPC Class Codes: G01N 33/66 involving blood sugars, e.g. galactose
• CPC Class Codes: G01N 33/6893 related to diseases not provided for elsewhere
• CPC Class Codes: G01N 33/92 involving lipids, e.g. cholesterol , lipoproteins, or their receptors steroid hormones G01N33/743
• CPC Class Codes: G16H 50/50 for simulation or modelling of medical disorders
• CPC Class Codes: G16Z 99/00 Subject matter not provided for in other main groups of this subclass
• CPC Class Codes: Y02A 90/10 Information and communication technologies [ICT] supporting adaptation to climate change, e.g. for weather forecasting or climate simulation

Abstract

The invention relates to biomarkers associated with Diabetes, including protein and lipid metabolite biomarkers, methods of using the biomarkers to determine the risk that an individual will develop Diabetes, and methods of screening a population to identify persons at risk for developing Diabetes and other pre-diabetic conditions.

Claims

1. A method of treating a subject having an elevated risk for developing a diabetic condition, the method comprising:

(a) obtaining biomarker measurement data for an individual, wherein the biomarker measurement data is representative of measurements of biomarkers in at least one biological sample from the individual;

wherein said biomarkers comprise;

(i) glucose, (ii) at least three protein biomarkers selected from the group consisting of;

adiponectin, C-reactive protein, ferritin, glucose, hemoglobin A1c (HbA1c), insulin, and interleukin-2-receptor alpha (IL2RA) and (iii) at least one lipid metabolite selected from the group consisting of;

cholesteryl palmitoleate (CE16;

1n7), cholesteryl homo gamma linoleate (CE20;

3n6), cholesteryl linoleate (CE18;

2n6), cholesteryl palmitate (CE16;

0), cholesteryl petroselinate (CE18;

1n9), 1-linoleoyl-2-hydroxy-sn-glycero-3-phosphocholine (LY18;

2n6), and 1-oleoyl-2-hydroxy-sn-glycero-3-phosphocholine (LY18;

1n7 and LY18;

1n9);

(b) identifying the individual as having an elevated risk for developing a diabetic condition based on an output from a model, wherein the model is executed based on an input of the biomarker measurement data; and

(c) treating the individual identified as having an elevated risk for developing a diabetic condition with a treatment regimen to delay or prevent the onset of diabetes.

2. The method of claim 1, wherein the obtaining step comprises measuring the biomarkers in the at least one biological sample.

3. The method of claim 2, further comprising a step, prior to the measuring the biomarkers, of obtaining at least one biological sample from the individual.

4. The method of claim 1, wherein obtaining biomarker measurement data comprises obtaining data representative of a measurement of the level of at least one biomarker from a preexisting record.

5. The method of claim 1, wherein the evaluating step includes comparing the biomarker measurement data from the individual with biomarker measurement data of the same biomarkers from a population, and evaluating risk for the individual developing a diabetic condition from the comparison.

6. The method of claim 1, further comprising displaying the risk evaluation from (b) on a visual display.

7. The method of claim 1, further comprising printing or storing the risk evaluation on paper or an electronic storage medium.

8. The method of claim 1, further comprising advising said individual or a health care practitioner of said risk evaluation.

9. The method of claim 1, further comprising:

obtaining clinical measurement data for the individual for at least one clinical parameter selected from the group consisting of age, body mass index (BMI), diastolic blood pressure (DBP), family history (FHX), past gestational diabetes mellitus (GDM), height (HT), hip circumference (Hip), race, sex, systolic blood pressure (SBP), waist circumference (Waist), and weight (WT),

wherein the model is executed based on an input of the biomarker measurement data and the clinical measurement data.

16. The method of claim 1, wherein the individual has not been previously diagnosed as having Diabetes, pre-Diabetes, or a pre-diabetic condition.

17. The method of claim 1, wherein the individual has a pre-diabetic condition, and the method evaluates or calculates risk for the individual developing Diabetes.

18. The method of claim 1, wherein the individual is pregnant.

19. The method according to claim 1, wherein the diabetic condition is selected from the group consisting of Type 2 Diabetes, pre-Diabetes, Metabolic Syndrome, Impaired Glucose Tolerance, and Impaired Fasting Glycemia.

20. The method according to claim 1, wherein said at least one biological sample comprises whole blood, serum, or plasma.

21. The method according to claim 1, wherein at least one of said biomarker measurements is obtained by a method selected from the group consisting of immunoassay and enzymatic activity assay.

22. The method according to claim 1, wherein the method using said biomarkers has an area under the ROC curve, reflecting the degree of diagnostic accuracy for predicting development of the diabetic condition, of at least 0.75, 0.76, 0.77, 0.78, 0.79, 0.80, 0.81, 0.82, 0.83, 0.84, or 0.85.

23. The method according to claim 1, wherein the method using said biomarkers has an area under the ROC curve, reflecting the degree of diagnostic accuracy for predicting development of the diabetic condition, of at least 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, or 0.15 greater than a corresponding method wherein the biomarkers consist of the glucose and the protein biomarkers but not the lipid metabolites.

27. The method according to claim 1, wherein the treatment regimen comprises at least one therapeutic selected from the group consisting of:

INS, INS analogs, hypoglycemic agents, anti-inflammatory agents, lipid-reducing agents, calcium channel blockers, beta-adrenergic receptor blocking agents, cyclooxygenase-2 (COX-2) inhibitors, prodrugs of COX-2 inhibitors, angiotensin II antagonists, angiotensin converting enzyme (ACE) inhibitors, renin inhibitors, lipase inhibitors, amylin analogs, sodium-glucose cotransporter 2 inhibitors, dual adipose triglyceride lipase and PI3 kinase activators, antagonists of neuropeptide Y receptors, human hormone analogs, cannabinoid receptor antagonists, triple monoamine oxidase reuptake inhibitors, inhibitors of norepinephrine and dopamine reuptake, inhibitors of 11 Beta-hydroxysteroid dehydrogenase type 1 (11b-HSD1), inhibitors of Cortisol synthesis, inhibitors of gluconeogenesis, glucokinase activators, antisense inhibitors of protein tyrosine phosphatase-IB, islet neogenesis therapy, and betahistine.

28. The method according to claim 1, wherein the treatment regimen comprises at least one therapeutic at least one therapeutic selected from the group consisting of acarbose, metformin, troglitazone, and rosiglitazone.

10. A method of treating an individual at elevated risk for developing a diabetic condition, the method comprising:

(a) obtaining measurements of biomarkers from at least one biological sample isolated from the individual, wherein said biomarkers comprise;

(i) glucose, (ii) at least three protein biomarkers selected from the group consisting of;

adiponectin, C-reactive protein, ferritin, glucose, hemoglobin A1c (HbA1c), insulin, and interleukin-2-receptor alpha (IL2RA) and (iii) at least one lipid metabolite selected from the group consisting of;

cholesteryl palmitoleate (CE16;

1n7), cholesteryl homo gamma linoleate (CE20;

3n6), cholesteryl linoleate (CE18;

2n6), cholesteryl palmitate (CE16;

0), cholesteryl petroselinate (CE18;

1n9), 1-linoleoyl-2-hydroxy-sn-glycero-3-phosphocholine (LY18;

2n6), and 1-oleoyl-2-hydroxy-sn-glycero-3-phosphocholine (LY18;

1n7 and LY18;

1n9);

(b) calculating a risk for developing a diabetic condition from the output of a model, wherein the inputs to said model comprise said measurements of biomarkers, and wherein said model was developed by fitting data from a longitudinal study of a population of individuals and said fitted data comprises levels of said biomarkers and conversion to Diabetes in said selected population of individuals; and

(c) initiating a prophylactic regimen to delay or prevent the onset of a diabetic condition in the individual if the calculated risk indicates that the individual has an elevated risk for developing a diabetic condition.

11. The method of claim 10, wherein the obtaining step comprises measuring the biomarkers in the at least one biological sample.

12. The method of claim 10, further comprising displaying the calculated risk from (b) on a visual display.

13. The method of any one of claim 10, further comprising printing or storing the calculated risk on paper or an electronic storage medium.

14. The method of any one of claim 10, further comprising advising said individual or a health care practitioner of said risk evaluation.

15. The method of any one of claim 10, further comprising:

obtaining at least one clinical measurement for the individual for at least one clinical parameter selected from the group consisting of age, body mass index (BMI), diastolic blood pressure (DBP), family history (FHX), past gestational diabetes mellitus (GDM), height (HT), hip circumference (Hip), race, sex, systolic blood pressure (SBP), waist circumference (Waist), and weight (WT),

wherein the inputs to the model further comprise said at least one clinical measurement.

29. The method of claim 10, wherein the prophylactic regimen comprises at least one therapeutic selected from the group consisting of:

INS, INS analogs, hypoglycemic agents, anti-inflammatory agents, lipid-reducing agents, calcium channel blockers, beta-adrenergic receptor blocking agents, cyclooxygenase-2 (COX-2) inhibitors, prodrugs of COX-2 inhibitors, angiotensin II antagonists, angiotensin converting enzyme (ACE) inhibitors, renin inhibitors, lipase inhibitors, amylin analogs, sodium-glucose cotransporter 2 inhibitors, dual adipose triglyceride lipase and PI3 kinase activators, antagonists of neuropeptide Y receptors, human hormone analogs, cannabinoid receptor antagonists, triple monoamine oxidase reuptake inhibitors, inhibitors of norepinephrine and dopamine reuptake, inhibitors of 11 Beta-hydroxysteroid dehydrogenase type 1 (11b-HSD1), inhibitors of Cortisol synthesis, inhibitors of gluconeogenesis, glucokinase activators, antisense inhibitors of protein tyrosine phosphatase-IB, islet neogenesis therapy, and betahistine.

30. The method according to claim 10, wherein the prophylactic regimen comprises at least one therapeutic at least one therapeutic selected from the group consisting of acarbose, metformin, troglitazone, and rosiglitazone.

24. A kit comprising reagents for measuring a group of biomarkers, wherein the biomarkers comprise:

(i) glucose,

(ii) at least three protein biomarkers selected from the group consisting of;

adiponectin, C-reactive protein, ferritin, glucose, hemoglobin A1c (HbA1c), insulin, and interleukin-2-receptor alpha (IL2RA); and

(iii) at least one lipid metabolite selected from the group consisting of;

cholesteryl palmitoleate (CE16;

1n7), cholesteryl homo gamma linoleate (CE20;

3n6), cholesteryl linoleate (CE18;

2n6), cholesteryl palmitate (CE16;

0), cholesteryl petroselinate (CE18;

1n9), 1-linoleoyl-2-hydroxy-sn-glycero-3-phosphocholine (LY18;

2n6), and 1-oleoyl-2-hydroxy-sn-glycero-3-phosphocholine (LY18;

1n7 and LY18;

1n9).

25. The kit of claim 24, wherein at least one of the reagents comprises a detectable label.

26. The kit of claim 24, wherein the reagents for the protein biomarkers and lipid metabolites are attached to a solid support.