Claims for Patent: 7,407,934

Summary for Patent: 7,407,934

Title:	Methods for regulating postprandial blood glucose
Abstract:	Methods for treating conditions associated with elevated, inappropriate or undesired post-prandial blood glucose levels are disclosed which comprise administration of an effective amount of an amylin agonist alone or in conjunction with other anti-gastric emptying agents. Methods for reducing gastric motility and delaying gastric emptying for therapeutic and diagnostic purposes are also described.
Inventor(s):	Kolterman; Orville G. (Poway, CA), Young; Andrew A. (Alpine, CA), Rink; Timothy J. (La Jolla, CA), Brown; Kathleen Ann Keating (Wake Forest, NC)
Assignee:	Amylin Pharmaceuticals, Inc. (San Diego, CA)
Application Number:	10/643,681
Patent Claims:	1. A method of reducing or moderating a postprandial rise in plasma glucose in a mammal comprising administering to said mammal in need of reducing or moderating a postprandial rise in plasma glucose an amylin agonist analogue in an amount effective to reduce or moderate a postprandial rise in plasma glucose, wherein the amylin agonist analogue is a peptide having the amino acid sequence selected from the group consisting of a) .sup.1A.sub.1-X-Asn-Thr-.sup.5-Ala-Thr-Y-Ala-Thr-.sup.10Gln-Arg-Leu-B.sub- .1-Asn-.sup.15Phe-Leu-C.sub.1-D.sub.1-E.sub.1- .sup.20F.sub.1-G.sub.1-Asn-H.sub.1-Gly-.sup.25Pro-I.sub.1-Leu-J.sub.1-Pro- -.sup.30Thr-K.sub.1-Val-Gly-Ser-.sup.35Asn-Thr-Tyr-Z (SEQ ID NO:42) wherein A.sub.1 is Lys, Ala, Ser or hydrogen; B.sub.1 is Ala, Ser or Thr; C.sub.1 is Val, Leu or Ile; D.sub.1 is His or Arg; E.sub.1 is Ser or Thr; F.sub.1 is Ser, Thr, Gln or Asn; G.sub.1 is Asn, Gln or His; H.sub.1 is Phe, Leu or Tyr; I.sub.1 is Ile, Val, Ala or Leu; J.sub.1 is Ser, Pro, Leu, Ile or Thr; K.sub.1 is Asn, Asp or Gln; X and Y are independently selected residues having side chains which are chemically bonded to each other to form an intramolecular linkage, wherein said intramolecular linkage comprises a disulfide bond, a lactam or a thioether linkage; and Z is amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy, and provided that when (i) A.sub.1 is Lys, B.sub.1 is Ala, C.sub.1 is Val, D.sub.1 is Arg, E.sub.1 is Ser, F.sub.1 is Ser, G.sub.1 is Asn, H.sub.1 is Leu, I.sub.1 is Val, J.sub.1 is Pro and K.sub.1 is Asn; or (ii) A.sub.1 is Lys, B.sub.1 is Ala, C.sub.1 is Val, D.sub.1 is His, E.sub.1 is Ser, F.sub.1 is Asn, G.sub.1 is Asn, H.sub.1 is Leu, I.sub.1 is Val, J.sub.1 is Ser and K.sub.1 is Asn; then one or more of A.sub.1 to K.sub.1 is a D-amino acid and Z is selected from the group consisting of alkylamino, dialkylamino, cycloaklyamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy; b) .sup.1A.sub.1--X--Asn--Thr--.sup.5Ala--Thr--Y--Ala--Thr--.sup.10Gln--A- rg--Leu--B.sub.1--Asn--.sup.15Phe--Leu--C.sub.1--D.sub.1--E.sub.1--.sup.20- F.sub.1--G.sub.1--Asn--H.sub.1--Gly--.sup.25I.sub.1--J.sub.1--Leu--Pro--Pr- o--.sup.30Thr--K.sub.1--Val--Gly'Ser-.sup.35Asn--Thr--Tyr--Z (SEQ ID NO:44) wherein A.sub.1 is Lys, Ala, Ser or hydrogen; B.sub.1 is Ala, Ser or Thr; C.sub.1 is Val, Leu or Ile; D.sub.1 is His or Arg; E.sub.1 is Ser or Thr; F.sub.1 is Ser, Thr, Gln or Asn; G.sub.1 is Asn, Gln or His; H.sub.1 is Phe, Leu or Tyr; I.sub.1 is Ala or Pro; J.sub.1 is Ile, Val, Ala or Leu; K.sub.1 is Asn, Asp or Gln; X and Y are independently selected residues having side chains which are chemically bonded to each other to form an intramolecular linkage, wherein said intramolecular linkage comprises a disulfide bond, a lactam or a thioether linkage; and Z is amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy; and provided that when A.sub.1 is Lys, B.sub.1 is Ala, C.sub.1 is Val, D.sub.1 is Arg, E.sub.1 is Ser, F.sub.1 is Ser, G.sub.1 is Asn, H.sub.1 is Leu, I.sub.1 is Pro, J.sub.1 is Val and K.sub.1 is Asn (SEQ ID NO:41), then one or more of A.sub.1 to K.sub.1 is a D-amino acid and Z is selected from the group consisting of alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy; c) .sup.1A.sub.1-X-Asn-Thr-.sup.5Ala-Thr-Y-Ala-Thr-.sup.10Gln-Arg-Leu-B.sub.- 1-Asn-.sup.15Phe-Leu-C.sub.1-D.sub.1-E.sub.1- .sup.20F.sub.1-G.sub.1-Asn-H.sub.1-Gly-.sup.25Pro-I.sub.1-Leu-Pro-Pro-.su- p.30Thr-J.sub.1-Val-Gly-Ser-.sup.35Asn-Thr-Tyr-Z (SEQ ID NO:45) wherein A.sub.1 is Lys, Ala, Ser or hydrogen; B.sub.1 is Ala, Ser or Thr; C.sub.1 is Val, Leu or Ile; D.sub.1 is His or Arg; E.sub.1 is Ser or Thr; F.sub.1 is Ser, Thr, Gln or Asn; G.sub.1 is Asn, Gln or His; H.sub.1 is Phe, Leu or Tyr; I.sub.1 is Ile, Val, Ala or Leu J.sub.1 is Asn, Asp or Gln; and X and Y are independently selected residues having side chains which are chemically bonded to each other to form an intramolecular linkage wherein said intramolecular linkage comprises a disulfide bond, a lactam or a thioether linkage; and Z is amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy; provided that when A.sub.1 is Lys, B.sub.1 is Ala, C.sub.1 is Val, D.sub.1 is Arg, E.sub.1 is Ser, F.sub.1 is Ser, G.sub.1 is Asn, H.sub.1 is Leu, I.sub.1 is Val and J.sub.1 is Asn (SEQ ID NO:41), then one or more of A.sub.1 to J.sub.1 is a D-amino acid and Z is selected from the group consisting of alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy; and d) .sup.1A.sub.1-X-Asn-Thr-.sup.5Ala-Thr-Y-Ala-Thr-.sup.10Gln-Arg-Leu-B.sub.- 1-Asn-.sup.15Phe-Leu-C.sub.1- D.sub.1-E.sub.1-.sup.20F.sub.1-G.sub.1Asn-H.sub.1-Gly-.sup.25I.sub.1-J.su- b.1-Leu-K.sub.1-L.sub.1-.sup.30Thr-M.sub.1-Val-Gly-Ser-.sup.35Asn-Thr- Tyr-Z (SEQ ID NO:31) wherein A.sub.1 is Lys, Ala, Ser, Hydrogen or acetylated Lys; B.sub.1 is Ala, Ser or Thr; C.sub.1 is Val, Leu or Ile; D.sub.1 is His or Arg; E.sub.1 is Ser or Thr; F.sub.1 is Ser, Thr, Gln or Asn; G.sub.1 is Asn, Gln or His; H.sub.1 is Phe, Leu, or Tyr, I.sub.1 is Ala or Pro; J.sub.1 is Ile, Val, Ala, or Leu; K.sub.1 is Ser, Pro, Leu, Ile or Thr; L.sub.1 is Ser, Pro or Thr; M.sub.1 is Asn, Asp or Gln; X and Y are independently selected residues having side chains which are chemically bonded to each other to form an intramolecular linkage, wherein said intramolecular linkage comprises a disulfide bond, a lactam or a thioether linkage; and Z is an amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, arlyoxy or aralkyloxy; provided that (a) when A.sub.1 is Lys, B.sub.1 is Ala, C.sub.1 is Val, D.sub.1 is His, E.sub.1 is Ser, F.sub.1 is Ser, G.sub.1 is Asn, H.sub.1 is Phe, I.sub.1 is Ala, J.sub.1 is Ile, K.sub.1 is Ser, and M.sub.1 is Asn (SEQ ID NO:46); (b) when A.sub.1 is Lys, B.sub.1 is Ala, C.sub.1 is Ile, D.sub.1 is Arg, E.sub.1 is Ser, F.sub.1 is Ser, G.sub.1 is Asn, H.sub.1 is Leu, I.sub.1 is Ala, J.sub.1 is Ile, K.sub.1 is Ser, L.sub.1 is Pro, and M.sub.1 is Asn (SEQ ID NO:47); (c) when A.sub.1 is Lys, B.sub.1 is Ala, C.sub.1 is Val, D.sub.1 is Arg, E.sub.1 is Thr, F.sub.1 is Ser, G.sub.1 is Asn, H.sub.1 is Leu, I.sub.1 is Ala, J.sub.1 is Ile, K.sub.1 is Ser, L.sub.1 is Pro, and M.sub.1 is Asn (SEQ ID NO:48); (d) when A.sub.1 is Lys, B.sub.1 is Ala, C.sub.1 is Val, D.sub.1 is Arg, E.sub.1 is Ser, F.sub.1 is Ser, G.sub.1 is Asn, H.sub.1 is Leu, I.sub.1 is Pro, J.sub.1 is Val, K.sub.1 is Pro, L.sub.1 is Pro, and M.sub.1 is Asn (SEQ ID NO:41); (e) when A.sub.1 is Lys, B.sub.1 is Ala, C.sub.1 is Val, D.sub.1 is His, E.sub.1 is Ser, F.sub.1 is Asn, G.sub.1 is Asn, H.sub.1 is Leu, I.sub.1 is Pro, J.sub.1 is Val, K.sub.1 is Ser, L.sub.1 is Pro and M.sub.1 is Asn (SEQ ID NO:43); or (f) when A.sub.1 is Lys, B.sub.1 is Thr, C.sub.1 is Val, D.sub.1 is Arg, E.sub.1 is Ser, F.sub.1 is Ser, G.sub.1 is His, H.sub.1 is Leu, I.sub.1 is Ala, J.sub.1 is Ala, K.sub.1 is Leu, L.sub.1 is Pro and M.sub.1 is Asp (SEQ ID NO:49); then one or more of any of A.sub.1 to M.sub.1 is not an L-amino acid and Z is not amino. 2. The method of calim 1 wherein the amylin agonist analogue has the following amino acid sequence: .sup.1A.sub.1-X-Asn-Thr-.sup.5Ala-Thr-Y-Ala-Thr.sup.10Gln-Arg-Leu-B.sub.1- -Asn-.sup.15Phe-Leu-C.sub.1-D.sub.1-E.sub.1.sup.20F.sub.1- G.sub.1--Asn-H.sub.1Gly-.sup.25Pro-I.sub.1-Leu-Pro-J.sub.1-.sup.30Thr-K.s- ub.1-Val-Gly-Ser-.sup.35Asn-Thr--Tyr-Z (SEQ ID NO:40) wherein A.sub.1 is Lys, Ala, Ser or Hydrogen; B.sub.1 is Ala, Ser or Thr; C.sub.1 is Val Leu or Ile; D.sub.1 is His or Arg; E.sub.1 is Ser or Thr; F.sub.1 is Ser, Thr, Gln or Asn; G.sub.1 is Asn, Gln or His; H.sub.1 is Phe, Leu or Tyr; I.sub.1 is Ile, Val, Ala or Leu; J.sub.1 is Ser, Pro or Thr; K.sub.1 is Asn, Asp or Gln; X and Y are independently selected residues having side chains which are chemically bonded to each other to form an intramolecular linkage, wherein said intramolecular linkage comprises a disulfide bond, a lactam or a thieother linkage; and Z is an amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy; and provided that when A.sub.1 is Lys, B.sub.1 is Ala, C.sub.1 is Val, D.sub.1 is Arg, E.sub.1 is Ser, F.sub.1 is Ser, G.sub.1 is Asn, H.sub.1 is Leu, I.sub.1 is Val, J.sub.1 is Pro, and K.sub.1 is Asn; then one or more A.sub.1 to K.sub.1 is a D-amino acid and Z is selected from the group consisting of alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy. 3. The method of claim 1 wherein the amylin agonist analogue has the following amino acid sequence: .sup.1A.sub.1--X--Asn--Thr--.sup.5Ala--Thr--Y--Ala--Thr--.sup.10Gln--Arg'- Leu--B.sub.1--Asn--.sup.15Phe--Leu--C.sub.1--D.sub.1--E.sub.1.sup.20F.sub.- 1--G.sub.1--Asn--H.sub.1--Gly--.sup.25Pro--I.sub.1--Leu--J.sub.1--Pro--.su- p.30Thr--K.sub.1--Val--Gly--Ser--.sup.35Asn--Thr--Tyr--Z (SEQ ID NO:42) wherein A.sub.1 is Lys, Ala, Ser or hydrogen; B.sub.1 is Ala, Ser or Thr; C.sub.1 is Val, Leu, or Ile; D.sub.1 is His or Arg; E.sub.1 is Ser or Thr; F.sub.1 is Ser, Thr, Gln or Asn; G.sub.1 is Asn, Gln or His; H.sub.1 is Phe, Leu or Tyr; I.sub.1 is Ile, Val, Ala or Leu; J.sub.1 is Ser, Pro, Leu, Ile or Thr; K.sub.1 is Asn, Asp or Gln; X and Y are independently selected residues having side chains which are chemically bonded to each other to form an intramolecular linkage, wherein said intramolecular linkage comprises a disfulfide bond, a lactam or a thioether linkage; and Z is amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy, and provided that when (a) A.sub.1 is Lys, B.sub.1 is Ala, C.sub.1 is Val, D.sub.1 is Arg, E.sub.1 is Ser, F.sub.1 is Ser, G.sub.1 is Asn, H.sub.1 is Leu, I.sub.1 is Val, J.sub.1 is Pro and K.sub.1 is Asn; or (b) A.sub.1 is Lys, B.sub.1 is Ala, C.sub.1 is Val, D.sub.1 is His, E.sub.1 is Ser, F.sub.1 is Asn, G.sub.1 is Asn, H.sub.1 is Leu, I.sub.1 is Val, J.sub.1 is Ser and K.sub.1 is Asn; then one or more of A.sub.1 to K.sub.1 is a D-amino acid and Z is selected from the group consisting of alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy. 4. The method of claim 1 wherein the amylin agonist analogue has the following amino acid sequence: .sup.1A.sub.1-X-Asn-Thr-.sup.5Ala-Thr-Y-Ala-Thr-.sup.10Gln-Arg-Leu-B.sub.- 1-Asn-.sup.15Phe-Leu-C.sub.1-D.sub.1-E.sub.1-.sup.20F.sub.1- G.sub.1-Asn-H.sub.1-Gly-.sup.25I.sub.1-J.sub.1-Leu-Pro-Pro-.sup.30-Thr-K.- sub.1-Val-Gly-Ser-.sup.35Asn-Thr-Tyr-Z (SEQ ID NO:44) where A.sub.1 is Lys, Ala, Ser or hydrogen; B.sub.1 is Ala, Ser or Thr; C.sub.1 is Val, Leu or Ile; D.sub.1 is His or Arg; E.sub.1 is Ser or Thr; F.sub.1 is Ser, Thr, Gln or Asn; G.sub.1 is Asn, Gln or His; H.sub.1 is Phe, Leu or Tyr; I.sub.1 is Ala or Pro; J.sub.1 is Ile, Val, Ala or Leu; K.sub.1 is Asn, Asp or Gln; X and Y are independently selected residues having side chains which are chemically bonded to each other to form an intramolecular linkage, wherein said intramolecular linkage comprises a disulfide bond, a lactam or a thioether linkage; and Z is amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy; and provided that when A.sub.1 is Lys, B.sub.1 is Ala, C.sub.1 is Val, D.sub.1 is Arg, E.sub.1 is Ser, F.sub.1 is Ser, G.sub.1 is Asn, H.sub.1 is Leu, I.sub.1 is Pro, J.sub.1 is Val and K.sub.1 is Asn (SEQ ID NO:41); then one or more of A.sub.1 to K.sub.1 is a D-amino acid and Z is selected from the group consisting of alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy. 5. The method of claim 1 wherein the amylin agonist analogue has the following amino acid sequence: .sup.1A.sub.1-X-Asn-Thr-.sup.5Ala-Thr-Y-Ala-Thr-.sup.10Gln-Arg-Leu-B.sub.- 1-Asn-.sup.15Phe-Leu-C.sub.1-D.sub.1-E.sub.1-.sup.20F.sub.1- G.sub.1-Asn-H.sub.1-Gly-.sup.25Pro-I.sub.1-Leu-Pro-Pro-.sup.30Thr-J.sub.1- -Val-Gly-Ser-.sup.35Asn-Thr-Tyr-Z (SEQ ID NO:45) wherein A.sub.1 is Lys, Ala, Ser or hydrogen; B.sub.1 is Ala, Ser or Thr; C.sub.1 is Val, Leu or Ile; D.sub.1 is His or Arg; E.sub.1 is Ser or Thr; F.sub.1 is Ser, Thr, Gln or Asn; G.sub.1 is Asn, Gln, or His; H.sub.1 is Phe, Leu or Tyr; I.sub.1 is Ile, Val, Ala or Leu J.sub.1 is Asn, Asp or Gln; X and Y are independently selected residues having side chains where are chemically bonded to each other to from an intramolecular linkage wherein said intramolecular linkage comprises a disulfide bond, a lactam or a thioether linkage; and Z is amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy; and provided that when A.sub.1 is Lys, B.sub.1 is Ala, C.sub.1 is Val, D.sub.1 is Arg, E.sub.1 is Ser, F.sub.1 is Ser, G.sub.1 is Asn, H.sub.1 is Leu, I.sub.1 is Val and J.sub.1 is Asn (SEQ ID NO:41); then one or more of A.sub.1 to J.sub.1 is a D-amino acid and Z is selected from the group consisting of alkylamino, dialylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy. 6. The method of claim 1 wherein said amylin agonist analogue is any one of .sup.18Arg.sup.25,28Pro--h-amylin (SEQ ID NO:3), des-.sup.1Lys.sup.18Arg.sup.25,28Pro-h-amylin (SEQ ID NO:6), .sup.25,28,29Pro-h-amylin (SEQ ID NO:1), des-.sup.1Lys.sup.25,28,29Pro-h-amylin (SEQ ID NO:10), .sup.18Arg.sup.25,28,29Pro-h-amylin (SEQ ID NO:8), des-.sup.1Lys.sup.18Arg.sup.25,28,29Pro-h-amylin (SEQ ID NO:9), .sup.25Pro.sup.26Val.sup.28,29Pro-h-amylin (SEQ ID NO:7), or des-.sup.1Lys.sup.25Pro.sup.26Val.sup.28,29Pro-h-amylin (SEQ ID NO:38). 7. The method of claim 1 wherein the amylin agonist analogue is .sup.25,28,29Pro-h-amylin (SEQ ID NO:1). 8. The method of claim 1 wherein the mammal has diabetes. 9. The method of claim 8 wherein the diabetes is type 1. 10. The method of claim 8 wherein the diabetes is type 2. 11. The method of claim 2 wherein the mammal has diabetes. 12. The method of claim 11 wherein the diabetes is type 1. 13. The method of claim 11 wherein the diabetes is type 2. 14. The method of claim 3 wherein the mammal has diabetes. 15. The method of claim 14 wherein the diabetes is type 1. 16. The method of claim 14 wherein the diabetes is type 2. 17. The method of claim 4 wherein the mammal has diabetes. 18. The method of claim 17 wherein the diabetes is type 1. 19. The method of claim 17 wherein the diabetes is type 2. 20. The method of claim 17 wherein the mammal has diabetes. 21. The method of claim 20 wherein the diabetes is type 1. 22. The method of claim 20 wherein the diabetets is type 2. 23. The method of claim 20 wherein the mammal has diabetes. 24. The method of claim 23 wherein the diabetes is type 1. 25. The method of claim 23 wherein the diabetes is type 2. 26. The method of claim 23 wherein the amylin agonist analogue has the following amino acid sequence: .sup.1A.sub.1-X-Asn-Thr-Y-Ala-Thr-.sup.10Gln-Arg-Leu-B.sub.1-Asn-.sup.15P- he-Leu-C.sub.1-D.sub.1-E.sub.1- .sup.20F.sub.1-G.sub.1Asn-H.sub.1-Gly-.sup.25I.sub.1-J.sub.1-Leu-K.sub.1-- L.sub.1-.sup.30Thr-M.sub.1-Val-Gly-Ser-.sup.35Asn-Thr-Tyr-Z (SEQ ID NO:31) wherein A.sub.1 is Lys, Ala, Ser, Hydrogen or acetylated Lys; B.sub.1 is Ala, Ser or Thr; C.sub.1 is Val, Leu or Ile; D.sub.1 is His or Arg; E.sub.1 is Ser or Thr; F.sub.1 is Ser, Thr, Gln or Asn; G.sub.1 is Asn, Gln or His; H.sub.1 is Phe, Leu or Tyr, I.sub.1 is Ala or Pro; J.sub.1 is Ile, Val, Ala or Leu; K.sub.1 is Ser, Pro, Leu, Ile or Thr; L.sub.1 is Ser, Pro or Thr; M.sub.1 is Asn, Asp or Gln; X and Y are independently selected residues having side chains which are chemically bonded to each other to form an intramolecular linkage, wherein said intramolecular linkage comprises a disulfide bond, a lactam or a thioether linkage; and Z is an amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy; and provided that (a) when A.sub.1 is Lys, B.sub.1 is Ala, C.sub.1 is Val, D.sub.1 is His, E.sub.1 is Ser, F.sub.1 is Ser, G.sub.1 is Asn, H.sub.1 is Phe, I.sub.1 is Ala, J.sub.1 is Ile, K.sub.1 is Ser, L.sub.1 is Ser, and M.sub.1 is Asn (SEQ ID NO:46); (b) when A.sub.1 is Lys, B.sub.1 is Ala, C.sub.1 is Ile, D.sub.1 is Arg, E.sub.1 is Ser, F.sub.1 is Ser, G.sub.1 is Asn, H.sub.1 is Leu, L.sub.1 is Ala, J.sub.1 is Ile, K.sub.1 is Ser, L.sub.1 is Pro, and M.sub.1 is Asn (SEQ ID NO:47); (c) when A.sub.1 is Lys, B.sub.1 is Ala, C.sub.1 is Val, D.sub.1 is Arg, E.sub.1 is Thr, F.sub.1 is Ser, G.sub.1 is Asn, H.sub.1 is Leu, L.sub.1 is Ala, J.sub.1 is Ile, K.sub.1 is Ser, L.sub.1 is Pro, and M.sub.1 is Asn (SEQ ID NO:48); (d) when A.sub.1 is Lys, B.sub.1 is Ala, C.sub.1 is Val, D.sub.1 is Arg, E.sub.1 is Ser, F.sub.1 is Ser, G.sub.1 is Asn, H.sub.1 is Leu, I.sub.1 is Pro, J.sub.1 is Val, K.sub.1 is Pro, L.sub.1 is Pro, and M.sub.1 is Asn (SEQ ID NO:41); (e) when A.sub.1 is Lys, B.sub.1 is Ala, C.sub.1 is Val, D.sub.1 is His, E.sub.1 is Ser, F.sub.1 is Asn, G.sub.1 is Asn, H.sub.1 is Leu, I.sub.1 is Pro, J.sub.1 is Val, K.sub.1 is Ser, L.sub.1 is Pro and M.sub.1 is Asn (SEQ ID NO:43); or (f) when A.sub.1 is Lys, B.sub.1 is Thr, C.sub.1 is Val, D.sub.1 is Arg, E.sub.1 is Ser, F.sub.1 is Ser, G.sub.1 is His, H.sub.1 is Leu, I.sub.1 is Ala, J.sub.1 is Ala, K.sub.1 is Leu, L.sub.1 is Pro and M.sub.1 is Asp (SEQ ID NO:49); then one or more of any of A.sub.1 to M.sub.1 is not an L-amino acid and Z is not amino. 27. The method of claim 26 wherein the mammal has diabetes. 28. The method of claim 27 wherein the diabetes is type 1. 29. The method of claim 27 wherein the diabetes is type 2.