13C glucose breath test for the diagnosis of diabetic indications and monitoring glycemic control

• US 6,878,550 B2
• Filed: 05/16/2003
• Issued: 04/12/2005
• Est. Priority Date: 05/06/1998
• Status: Expired due to Term

• Current Assignee: Paladin Labs Inc. (Endo International PLC)
• Original Assignee: Isotechnika Inc. (Endo International PLC)
• Inventors: Foster, Robert T., Yatscoff, Randall W., Lewanczuk, Richard, Aspeslet, Launa J.
• Primary Examiner(s): WALLENHORST, MAUREEN
• Application Number:
  US10/439,290
• Publication Number:
  US 20040038412A1
• Time in Patent Office: 697 Days
• Field of Search: 436/8, 436/14, 436/56, 436/173, 436/181, 436/814, 422/61, 435/14
• US Class Current: 436/56
• CPC Class Codes: A61B 5/0813 Measurement of pulmonary parameters by tracers, e.g. radioactive tracers
• CPC Class Codes: A61B 5/0836 Measuring rate of CO2 production
• CPC Class Codes: A61B 5/14532 for measuring glucose, e.g. by tissue impedance measurement
• CPC Class Codes: A61K 51/1206 Administration of radioactive gases, aerosols or breath tests
• CPC Class Codes: G01N 33/497 of gaseous biological material, e.g. breath
• CPC Class Codes: Y10T 436/104998 Glucose, ketone, nitrate standard or control
• CPC Class Codes: Y10T 436/13 Tracers or tags
• CPC Class Codes: Y10T 436/24 Nuclear magnetic resonance, electron spin resonance or other spin effects or mass spectrometry
• CPC Class Codes: Y10T 436/25875 Gaseous sample or with change of physical state

Abstract

Use of ¹³C glucose in an analytical assay to monitor glucose metabolism by measurement of labeled exhaled CO₂ is provided. A breath test and kit for performing the breath test are described for the diagnosis of diabetic indications and monitoring of glycemic control. The breath test utilizes the measurement of expired ¹³C-labeled CO₂ following the ingestion of a ¹³C-enriched glucose source.

Claims

1. A diagnostic kit for the determination of glycemic control in a subject comprising:

(a) a predetermined quantity of uniformly labeled ¹³C-enriched glucose; and

(b) a plurality of breath collection containers.

2. A diagnostic kit according to claim 1 wherein the determination of glycemic control is indicative for the diagnosis of diabetes.

3. A diagnostic kit according to claim 1 wherein the determination of glycemic control is indicative for the diagnosis of insulin resistance.

4. A diagnostic kit according to claim 1 wherein the determination of glycemic control is indicative for the diagnosis of gestational diabetes.

5. A diagnostic kit according to claim 1 wherein the determination of glycemic control is indicative for the determination of adequacy of antihyperglycemic therapy.

6. A diagnostic kit according to claim 1 further comprising a tube that is adapted for the transfer of the breath of a subject into the breath collection containers.

7. A diagnostic kit according to claim 1 further comprising a set of instructions wherein the instructions direct the subject to collect a first breath sample is a first breath collection container, ingest the uniformly labeled ¹³C-enriched glucose and collect a second breath sample in a second breath container at a time point that is about 90 minutes after ingestion of the uniformly labeled ¹³C-enriched glucose.

8. A diagnostic kit for the determination of glycemic control in normal, diabetic and insulin resistance subjects by comparing blood glucose levels with breath levels of ¹³C-enriched CO₂ comprising:

(a) a predetermined quality of uniformly labeled ¹³C-enriched glucose;

(b) a plurality of breath collection containers; and

(c) a blood sampling device.

9. A method of diagnosing a condition in a subject, said condition selected from the group consisting of diabetes, insulin resistance impaired glucose tolerance, impaired fasting glucose and gestational diabetes, said method comprising:

a) collecting a first breath sample from said subject in first breath collection container;

b) administering uniformly labeled ¹³C-enriched glucose to said subject;

c) collecting a second breath sample from said subject in a second breath container at a time point after administration of said uniformly labeled ¹³C-enriched glucose;

d) measuring the ¹³CO² in each of said first and second breath samples; and

e) comparing the amount of ¹³CO₂ in said second breath sample with the amount of ¹³CO₂ in said first breath sample, wherein the presence of less ¹³CO₂ in said second breath sample compared to normal control values indicates the presence of said condition.

10. The method of claim 9, wherein said comparison is made by choosing a cutoff of receiver operated characteristics (ROC) values wherein the sensitivity and specificity are such as to maximize diagnostic accuracy.

11. The method of claim 10, wherein said condition is insulin resistance and said cutoff of ROC values is 8 to 10.

12. The method of claim 11, wherein said ROC value is 9.

13. A method of predicting a subject'"'"'s risk of developing diabetes, said method comprising:

a) collecting a first breath sample from said subject in a first breath collection container;

b) administering uniformly labeled ¹³C-enriched glucose to said subject;

c) collecting a second breath sample from said subject in a second breath container at a time point after administration of said uniformly labeled ¹³C-enriched glucose;

d) measuring the ¹³CO₂ in each of said first and second breath samples; and

e) comparing the amount of ¹³CO₂ in said second breath sample with the amount of ¹³CO₂ in said first breath sample, wherein the presence of less ¹³CO₂ in said second breath sample compared to normal control values indicates risk of developing diabetes.

14. The method claim 13, wherein said comparison is made by choosing a cutoff of receiver operated characteristics (ROC) values wherein the sensitivity and specificity are such as to maximize diagnostic accuracy.

15. The method of claim 14, wherein said cutoff of ROC values is 8 to 10.

16. The method of claim 15, wherein said ROC value is 9.

20. A diagnostic kit according to claim 15, further comprising a set of instructions, wherein the instructions direct the subject to:

(i) collect a first breath sample in a first breath collection container;

(ii) ingest the uniformly labeled ¹³C-enriched glucose; and

(iii) collect a second breath sample in a second breath collection container at a time point that is after ingestion of the uniformly labeled ¹³C-enriched glucose.

17. A diagnostic kit for the diagnosis of insulin resistance in a subject comprising:

(a) a predetermined quantity of uniformly labeled ¹³C-enriched glucose; and

(b) a breath collection container.

18. A diagnostic kit according to claim 17 comprising at least two breath collection containers.

19. A diagnostic kit according to claim 18 further comprising a tube that is adapted for the transfer of the breath of a subject into the breath collection containers.

21. A diagnostic kit according to claim 17 further comprising analysis means for measuring ¹³CO₂ metabolized from said uniformly labeled ¹³C-enriched glucose in a breath sample.

22. A diagnostic kit according to claim 17, further comprising a blood sampling device.

23. A diagnostic kit for monitoring antihyperglycemic therapy in a subject comprising:

(a) a predetermined quantity of uniformly labeled ¹³C-enriched glucose; and

(b) a breath collection container.

24. A diagnostic kit according to claim 23, wherein the antihyperglycemic therapy is selected from the group consisting of diet, exercise, and pharmacological.

25. A diagnostic kit according to claim 23 comprising at least two breath collection containers.

26. A diagnostic kit according to claim 25 further comprising a tube that is adapted for the transfer of the breath of a subject into the breath collection containers.

27. A diagnostic kit according to claim 23 further comprising a set of instructions, wherein the instructions direct the subject to:

(i) collect a first breath sample in a first breath collection container;

(ii) ingest the uniformly labeled ¹³C-enriched glucose; and

(iii) collect a second breath sample in a second breath collection container at a time point that is after ingestion of the uniformly labeled ¹³C-enriched glucose.

28. A method of diagnosing insulin resistance in subject, said method comprising:

a) collecting a first breath sample from said subject in a first breath collection container;

b) administering uniformly labeled ¹³C-enriched glucose to said subject;

c) collecting a second breath sample from said subject in a second breath container at a time point after administration of said uniformly labeled ¹³C-enriched glucose;

d) measuring the ¹³CO₂ in each of said first and second breath samples;

e) comparing the amount of ¹³CO₂ in said second breath sample with the amount of ¹³CO₂ in said first breath sample to calculate a delta over baseline; and

f) diagnosing insulin resistance if the calculated delta over baseline for the subject is less than a standard delta over baseline of a normal individual or of a typical diabetic individual.

29. A method of diagnosing insulin resistance in a subject, said method comprising:

a) collecting a first breath sample from the subject in a first breath collection container;

b) administering uniformly labeled ¹³C-enriched glucose to the subject;

c) collecting a second breath sample from the subject in a second breath container at a first time point after administration of the uniformly labeled ¹³C-enriched glucose;

d) collecting a third breath sample from the subject in a third breath container at a second time point after administration of the uniformly labeled ¹³C-enriched glucose;

e) measuring the ¹³CO₂ in each of the first, second and third breath samples to generate a breath test curve;

f) determining a blood glucose level of the subject prior to administration of the uniformly labeled 13C-enriched glucose and at the first and second time point after administration to generate a blood glucose test curve;

g) diagnosing insulin resistance if the area between the breath test curve and the blood glucose test curve is less than that of a standard individual or of a typical diabetic individual.