GLP-1 as a diagnostic test to determine β-cell function and the presence of the condition of IGT and type-II diabetes

• US 6,884,579 B2
• Filed: 10/26/2001
• Issued: 04/26/2005
• Est. Priority Date: 06/15/1999
• Status: Expired due to Fees

• Current Assignee: Amylin Pharmaceuticals Incorporated (Bristol-Myers Squibb Company)
• Original Assignee: Amylin Pharmaceuticals Incorporated (Bristol-Myers Squibb Company)
• Inventors: Holst, Jens J., Vilsboll, Tina
• Primary Examiner(s): Nolan, Patrick J.
• Application Number:
  US10/055,259
• Publication Number:
  US 20030091507A1
• Time in Patent Office: 1,278 Days
• Field of Search: 435/6
• US Class Current: 435/6.13
• CPC Class Codes: A61K 49/0004 Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions

Abstract

Since glucagon-like peptide-1 (GLP-1) is the most potent insulinotropic hormone known and has been shown to stimulate insulin secretion strongly in patients with type II diabetes, this invention uses GLP-1 or its biologically active analogues in β-cell stimulatory tests in order to test β-cell function in a simple way. The test provides information about insulin secretory capacity, is easy and reproducible and has insignificant side effects.

Claims

1. A method of detecting impaired glucose tolerance of individuals by evaluation of β

-cells secretory capacity, comprising;

infusing the individual with glucose and a glucagon-like peptide-1 or its biologically active analogue expressed by a polynucleotide wherein said analogue binds to the glucagon-like peptide amide receptor protein and has a corresponding effect on insulin secretion as GLP-1 (7-36) amide; and

thereafter

measuring the insulin and C-peptide responses against standard responses of healthy subjects to determine if the individual has impaired β

-cell function.

2. The method of claim 1 wherein the glucagon-like peptide-1 is selected from (a) a peptide which comprises the amino acid sequence of glucagon-like peptide-1, and (b) a variant peptide comprising an amino acid sequence that differs from the sequence of glucagon-like peptide-1 by one or more substitutions, deletions or insertions wherein said variant binds to the glucagon-like peptide-1 amide receptor protein and has a corresponding biological affect on insulin secretion as GLP-1 (7-36) amide.

3. The method of claim 2 wherein the glucagon-like peptide-1 is glucagon-like peptide-1 (7-37) which has the sequence His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly (SEQ. ID NO:

3).

4. The method of claim 2 wherein the glucagon-like peptide-1 is glucagon-like peptide-1 (7-36) amide which has the sequence His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg (NH₂) (SEQ. ID NO:

4).

5. The method of claim 2 wherein the glucagon-like peptide-1 is a variant peptide in which the combination of the substitutions, deletions and insertions in the amino acid sequence does not differ by more than ten amino acids from the amino acid sequence of glucagon-like peptide-1.

6. The method of claim 1, further comprising using an agent which enhances the half-life in vivo of the compound.

7. The method of claim 1 wherein the patient is simultaneously infused with a combined glucose/GLP-1 or its biologically active analogue.

8. The method of claim 1 wherein the patient is first infused with glucose and then later with GLP-1.

9. The method of claim 1 wherein the dose of GLP-1 is a bolus dose intravenously administered at from 0.05 nmol to 100 nmol.

10. The method of claim 1 wherein the dose is a bolus subcutaneous method at from 10 nmol to 1000 nmol.

11. The method of claim 1 wherein the patient is infused with a dose of GLP-1 or a biologically active analogue continuously infused by I.V. at from 0.1 pmol/kg/min to 10 pm/kg/min.

12. The method of claim 1 wherein dosing is continuous subcutaneous infusion at a dose of from 0.5 to 50 pm/kg/min.