Method of measuring insulin resistance with fatty acid combustion, and composition used herein

• US 10,444,229 B2
• Filed: 03/13/2014
• Issued: 10/15/2019
• Est. Priority Date: 03/15/2013
• Status: Active Grant

• Current Assignee: Otsuka Pharmaceutical Company Limited (Otsuka Holdings Company Limited)
• Original Assignee: Otsuka Pharmaceutical Company Limited (Otsuka Holdings Company Limited)
• Inventors: Inada, Makoto, Kunizaki, Jun-ichi, Tobita, Kazuki, Motonari, Hiroshi, Sato, Tetsuya
• Primary Examiner(s): Soderquist, Arlen
• Application Number:
  US14/776,543
• Publication Number:
  US 20160146791A1
• Time in Patent Office: 2,042 Days
• Field of Search: 436129, 436133, 436181, 544 1
• CPC Class Codes: A61B 5/0836 Measuring rate of CO2 production
• CPC Class Codes: G01N 2458/15 Non-radioactive isotope labels, e.g. for detection by mass spectrometry
• CPC Class Codes: G01N 2560/00 Chemical aspects of mass spectrometric analysis of biological material
• CPC Class Codes: G01N 33/497 of gaseous biological material, e.g. breath
• CPC Class Codes: G01N 33/5088 of vertebrates

Abstract

This invention provides a method for measuring insulin resistance of a test subject, and a composition suitably used for the method.

A method for measuring insulin resistance of a test act comprising steps (a) and (b) below, the method using a composition for measuring insulin resistance comprising, as an active ingredient, a C_12-38 fatty acid labeled with at least one isotope of C, wherein the C_12-38 fatty acid is converted in the body into labeled carbon dioxide that is excreted in expired air,

• • (a) intravenously administering the composition to a test subject and collecting expired air; and
  • (b) determining the ratio of labeled CO₂ amount to unlabeled CO₂ amount contained in the expired air or the ratio of labeled CO₂ amount to total CO₂ amount contained in the expired air.

Claims

1. A method for measuring insulin resistance of a test subject, comprising

determining an area under a Δ

-labeled C(‰

)-expired air collection time t curve, based on a glucose metabolism ability measurement method having steps (i) and (ii) below (hereinafter referred to as “

AUCt[labeled C-glucose]”

),

determining an area under a Δ

-labeled C(‰

)-expired air collection time t curve, based on a method having steps (a) and (b) below (hereinafter referred to as “

AUCt[labeled C-fatty acid]”

),

using a value obtained by dividing the AUCt[labeled C-glucose] by the AUCt[labeled C-fatty acid] (AUCt[labeled C-glucose]/AUCt[labeled C-fatty acid]) as an index for the sugar/fatty acid combustion ratio,

determining a first index of the sugar/fatty acid combustion ratio under a fasting condition and a second index of the sugar/fatty acid combustion ratio under a feeding condition from the test subject, and

determining a difference between the first index and the second index, wherein the test subject'"'"'s insulin resistance is measured,

wherein

the method in which AUCt[labeled C-glucose] is determined has the steps of;

(i) intravenously administering a composition to a test subject and collecting expired air, the composition comprising, as an active ingredient, glucose labeled with at least one isotope of carbon, so that the glucose is converted in the body into labeled carbon dioxide that is excreted in expired air; and

(ii) determining the ratio of labeled CO₂ amount to unlabeled CO₂ amount contained in expired air or the ratio of labeled CO₂ amount to total CO₂ amount contained in expired air, and

the method in which AUCt[labeled C-fatty acid] is determined has the steps of;

(a) intravenously administering a composition comprising a C_12-38 fatty acid or a salt thereof labeled with at least one isotope of carbon to a test subject and collecting expired air, so that the C_12-38 fatty acid or salt thereof is converted in the body into labeled carbon dioxide that is excreted in expired air; and

(b) determining the ratio of labeled CO₂ amount to unlabeled CO₂ amount contained in expired air or the ratio of labeled CO₂ amount to total CO₂ amount contained in expired air.

4. The method according to any one of claims 1 to 3, wherein the isotope of C_12-38 fatty acid is ¹³C.

5. The method according to any one of claims 1 to 3, wherein the C_12-38 fatty acid is a C_12-18 saturated fatty acid or a C₁₈ unsaturated fatty acid.

6. The method according to any one of claims 1 to 3, wherein the C_12-38 fatty acid is at least one member selected from the group consisting of lauric acid, myristic acid, pentadecylic acid, stearic acid, oleic acid, and palmitic acid.

7. The method according to any one of claims 1 to 3, wherein the test subject has at least one condition selected from the group consisting of borderline diabetes, type II diabetes, liver cirrhosis, non-alcoholic steatohepatitis, and non-alcoholic fatty liver disease.

8. The method according to any one of claims 1 to 3, further comprising:

comparing a difference between the first index and the second index obtained from the test subject (test subject value) to a difference between the first index and the second index obtained from a healthy subject having a normal insulin resistance (control value), wherein when the test subject value is smaller than the control value, the insulin sensitivity of the test subject is decreased (insulin resistance).

2. A method for measuring insulin resistance of a test subject, comprising

determining an area under a Δ

-labeled C(‰

)-expired air collection time t curve, based on a method having steps (a) and (b) below (herein referred to as “

AUCt[labeled C-fatty acid]”

),

determining a blood glucose level of the test subject,

using a value obtained by dividing the reciprocal of the blood glucose level (1/blood glucose level) of the test subject by the AUCt[labeled C-fatty acid] (1/blood glucose level/AUCt[labeled C-fatty acid]) as an index for the sugar/fatty acid combustion ratio,

determining a first index of the sugar/fatty acid combustion ratio under a fasting condition and a second index of the sugar/fatty acid combustion ratio under a feeding condition for the test subject, and

determining a difference between the first index and the second index, wherein the test subject'"'"'s insulin resistance is measured,

wherein

the method in which AUCt[labeled C-fatty acid] is determined has the steps of;

(a) intravenously administering a composition comprising a C_12-38 fatty acid or a salt thereof labeled with at least one isotope of carbon to a test subject and collecting expired air, so that the C_12-38 fatty acid or a salt thereof is converted in the body into labeled carbon dioxide that is excreted in expired air; and

(b) determining the ratio of labeled CO₂ amount to unlabeled CO₂ amount contained in expired air or the ratio of labeled CO₂ amount to total CO₂ amount contained in expired air.

3. A method for measuring insulin resistance of a test subject, comprising

determining Ct[labeled C-fatty acid] (t=1-30 min) of Δ

-labeled C(‰

), based on a method having steps (a) and (b) below,

determining a blood glucose level of the test subject,

using a value obtained by dividing the reciprocal of the blood glucose level (1/blood glucose level) of the test subject by Ct[labeled C-fatty acid] (t=1-30 min) ([1/blood glucose level]/Ct[labeled C-fatty acid] (t=1-30 min)), as an index for the sugar/fatty acid combustion ratio,

determining a first index of the sugar/fatty acid combustion ratio under a fasting condition and a second index of the sugar/fatty acid combustion ratio under a feeding condition for the test subject, and

determining a difference between the first index and the second index, wherein the test subject'"'"'s insulin is measured,

wherein

the method in which Ct[labeled C-fatty acid] (t=1-30 min) is determined has the steps of;

(a) intravenously administering a composition comprising a C_12-38 fatty acid or a salt thereof labeled with at least one isotope of carbon to a test subject and collecting expired air at least one time point between 1 to 30 minutes after the composition administration, so that the C_12-38 fatty acid or a salt thereof is converted in the body into labeled carbon dioxide that is excreted in expired air; and

(b) determining the ratio of labeled CO₂ amount to unlabeled CO₂ amount contained in expired air or the ratio of labeled CO₂ amount to total CO₂ amount contained in expired air.