Insulinotropic hormone GLP-1 (7-36) and uses thereof

• US 5,614,492 A
• Filed: 11/23/1993
• Issued: 03/25/1997
• Est. Priority Date: 05/05/1986
• Status: Expired due to Term

• Current Assignee: The General Hospital Corporation (Mass General Brigham, Inc.)
• Original Assignee: The General Hospital Corporation (Mass General Brigham, Inc.)
• Inventors: Habener, Joel F.
• Primary Examiner(s): Woodward, Michael P.
• Assistant Examiner(s): Prickril, Benet
• Application Number:
  US08/156,800
• Time in Patent Office: 1,218 Days
• Field of Search: 530/324, 530/303, 530/308, 514/12, 514/866
• US Class Current: 514/5.9
• CPC Class Codes: A61K 38/26 Glucagons
• CPC Class Codes: C07K 14/605 Glucagons

Abstract

Derivatives of glucagon-like peptide I (GLP-1) and especially GLP-1(7-36) have been found to have insulinotropic activity. The invention pertains to the use of GLP-1(7-36) for the treatment of type II diabetes mellitus.

Claims

1. A method for treating type II diabetes mellitus in an individual in need of such treatment, said method comprising

administering to said individual an effective amount of an insulinotropic molecule which is sufficient to treat said diabetes;

wherein said insulinotropic molecule is selected from the group consisting of;

(A) a glueagon-like peptide-1(7-36), GLP-1(7-36) having the amino acid 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; and

(B) a derivative of said GLP-1(7-36) (A), wherein said derivative is selected from the group consisting of;

(1) a pharmaceutically acceptable acid addition salt of said GLP-1(7-36);

(2) a pharmaceutically acceptable carboxylate salt of said GLP-1(7-36);

(3) a pharmaceutically acceptable lower alkyl ester of said GLP-1(7-36); and

,

(4) a pharmaceutically acceptable amide of said GLP-1(7-36);

and wherein (i) said insulinotropic molecule has an insulinotropic activity which exceeds the insulinotropic activity of glucagon-like peptide-1(1-36). GLP-1(1-36), or glucagon-like peptide-1(1-37), GLP-1(1-37); and

(ii) said insulinotropic molecule is combined in admixture with a suitable pharmaceutically acceptable carrier.

2. The method of treating type II diabetes mellitus of claim 1 wherein said insulinotropic molecule is said derivative (B) of said peptide GLP-1(7-36).

3. The method of treating type II diabetes mellitus of claim 1 wherein said insulinotropic molecule is peptide GLP-1(7-36).

4. The method of treating type II diabetes mellitus of claim 1, wherein said derivative (B) of said peptide GLP-1(7-36) is selected from the group consisting of a lower alkyl amide and a lower alkyl diamide.

13. The method of any of claims 1, 5 or 9, wherein said derivative is a pharmaceutically acceptable amide of said GLP-1(7-36).

14. The method of claim 13, wherein said derivative is GLP-1(7-36) amide.

15. The method of claim 1, wherein said administering is intravenous, intramuscular or subcutaneous administration.

5. A method for enhancing the expression of insulin in a pancreatic β

-type islet cell, comprising

providing to a mammalian pancreatic β

-type islet cell an effective amount of an insulinotropic molecule selected from the group consisting of;

(A) a glucagon-like peptide-1(7-36), GLP-1(7-36), having the amino acid 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; and

(B) a derivative of said GLP-1(7-36) (A), wherein said derivative is selected from the group consisting of;

(1) a pharmaceutically acceptable acid addition salt of said GLP-1(7-36);

(2) a pharmaceutically acceptable carboxylate salt of said GLP-1(7-36);

(3) a pharmaceutically acceptable lower alkyl ester of said GLP-1(7-36); and

,

(4) a pharmaceutically acceptable amide of said GLP-1(7-36);

wherein (i) said insulinotropic molecule has an insulinotropic activity which exceeds the insulinotropic activity of glucagon-like peptide-1(1-36), GLP-1(1-36) or glucagon-like peptide-1(1-37), GLP-1(1-37); and

(ii) said molecule is combined in admixture with a suitable pharmaceutically acceptable carrier.

6. The method of enhancing the expression of insulin of claim 5 wherein said insulinotropic molecule is said derivative (B) of said peptide GLP-1(7-36).

7. The method of enhancing the expression of insulin of claim 5 wherein said insulinotropic molecule is peptide GLP-1(7-36).

8. The method of enhancing the expression of insulin of claim 5, wherein said derivative (B) of said peptide GLP-1(7-36) is selected from the group consisting of a lower alkyl amide and a lower dialkyl amide.

9. A method for stimulating insulin secretion from the pancreas in an individual in a hyperglycemic state, said method comprising

administering to said individual an effective amount of an insulinotropic molecule which is sufficient to stimulate insulin secretion in said individual;

wherein said insulinotropic molecule is selected from the group consisting of;

(A) a glucagon-like peptide-1(7-36), GLP-1(7-36), having the amino acid 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; and

(B) a derivative of said GLP-1(7-36) (A), wherein said derivative is selected from the group consisting of;

(1) a pharmaceutically acceptable acid addition salt of said GLP-1(7-36);

(2) a pharmaceutically acceptable carboxylate salt of said GLP-1(7-36);

(3) a pharmaceutically acceptable lower alkyl ester of said GLP-1(7-36); and

,

(4) a pharmaceutically acceptable amide of said GLP-1(7-36);

and wherein (i) said insulinotropic molecule has an insulinotropic activity which exceeds the insulinotropic activity of glucagon-like peptide-1(1-36). GLP-1(1-36), or glucagon-like peptide-1(1-37). GLP-1(1-37); and

(ii) said molecule is combined in admixture with a suitable pharmaceutically acceptable carrier.

10. The method for stimulating insulin secretion of claim 9 wherein said insulinotropic molecule is said derivative (B) of said peptide GLP-1(7-36).

11. The method for stimulating insulin secretion of claim 9 wherein said insulinotropic molecule is peptide GLP-1(7-36).

12. The method for stimulating insulin secretion of claim 9 wherein said derivative (B) of said peptide GLP-1(7-36) is selected from the group consisting of a lower alkyl amide and a lower dialkyl amide.

16. The method of claim 9, wherein said administering is intravenous, intramuscular or subcutaneous administration.