Human glucagon-like peptide-1 mimics and their use in the treatment of diabetes and related conditions

Abstract

The present invention provides novel human glucagon-like peptide-1 (GLP-1) peptide mimics that mimic the biological activity of the native GLP-1 peptide and thus are useful for the treatment or prevention of diseases or disorders associated with GLP activity. Further, the present invention provides novel, chemically modified peptides that not only stimulate insulin secretion in type II diabetics, but also produce other beneficial insulinotropic responses. These synthetic peptide GLP-1 mimics exhibit increased stability to proteolytic cleavage making them ideal therapeutic candidates for oral or parenteral administration.

1 . An isolated polypeptide having a sequence of Formula I  
         A-X aa1 -X aa2 -X aa3 -X aa4 -X aa5 -X aa6 -X aa7 -X aa8 -X aa9 -Y-Z-B  I  wherein, X aa1-9  is a naturally or nonnaturally occurring amino acid residue; Y and Z are amino acid residues; wherein one of the substitutions at the alpha-carbon atoms of Y and Z may each independently be substituted with a primary substituent group selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl, heterocyclylalkyl said primary substituent optionally being substituted with a secondary substituent selected from a cycloalkyl, heterocyclyl, aryl or heteroaryl group; any of said primary or secondary substituents may further be substituted with one or more of, hydrogen, alkyl, cycloalkyl, arylalkyl, aryl, heterocyclyl, heteroaryl, alkenyl, alkynyl, halo, hydroxy, mercapto, nitro, cyano, amino, acylamino, azido, guanidino, amidino, carboxyl, carboxamido, carboxamido alkyl, formyl, acyl, carboxyl alkyl, alkoxy, aryloxy, arylalkyloxy, heteroaryloxy, heterocycleoxy, acyloxy, mercapto, mercapto alkyl, mercaptoaryl, mercapto acyl, halo, cyano, nitro, azido, amino, guanidino alkyl, guanidino acyl, sulfonic, sulfonamido, alkyl sulfonyl, aryl sulfonyl or phosphonic group; wherein, the primary or secondary substitutents may optionally be bridged by covalent bonds to form one or more fused cyclic or heterocyclic systems with each other; wherein, the other substitution at the alpha-carbon of Y may be substituted with hydrogen, alkyl, aminoalkyl, hydroxyalkyl or carboxyalkyl; wherein, the other substitution at the alpha-carbon of Z may be substituted with hydrogen, alkyl, aminoalkyl, hydroxyalkyl or carboxyalkyl; A and B are optionally present; wherein A is present and A is hydrogen, an amino acid or peptide containing from about 1 to about 15 amino acid residues, an R group, an R—C(O) (amide) group, a carbamate group RO—C(O), a urea R 4 R 5 N—C(O), a sulfonamido R—SO 2 , or a R 4 R 5 N—SO 2 ; wherein R is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl and heteroaryloxyalkyl; wherein R 4  and R 5  are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl and heteroaryloxyalky; wherein the alpha-amino group of X aa1  is substituted with a hydrogen or an alkyl group, said alkyl group may optionally form a ring with A; wherein B is present and B is OR 1 , NR 1 R 2 , or an amino acid or peptide containing from 1 to 15 amino acid residues, terminating at the C-terminus as a carboxamide, substituted carboxamide, an ester, a free carboxylic acid or an amino-alcohol; wherein R 1  and R 2  are independently chosen from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl or heteroaryloxyalkyl.    
     
     
         2 . The isolated polypeptide of  claim 1  wherein the substitutions made at the alpha-carbon atoms of Y and Z are selected from the group consisting of heteroarylarylmethyl, arylheteroarylmethyl or biphenylmethyl forming biphenylalanine residues, any of which is also optionally substituted with one or more, hydrogen, alkyl, cycloalkyl, arylalkyl, aryl, heterocyclyl, heteroaryl, alkenyl, alkynyl, halo, hydroxy, mercapto, nitro, cyano, amino, acylamino, azido, guanidino, amidino, carboxyl, carboxamido, carboxamido alkyl, formyl, acyl, carboxyl alkyl, alkoxy, aryloxy, arylalkyloxy, heteroaryloxy, heterocycleoxy, acyloxy, mercapto, mercapto alkyl, mercaptoaryl, mercapto acyl, halo, cyano, nitro, azido, amino, guanidino alkyl, guanidino acyl, sulfonic, sulfonamido, alkyl sulfonyl, aryl sulfonyl and phosphonic group.  
     
     
         3 . The isolated polypeptide of  claim 1  wherein B is an amino acid or peptide containing 1 to about 10 amino acid residues.  
     
     
         4 . The isolated polypeptide of  claim 3  wherein B is an amino acid or peptide containing 1 to about 5 amino acid residues.  
     
     
         5 . The isolated polypeptide of  claim 1  wherein X aa1 , X aa2  and X aa3  are N—H or N-alkylated amino acid residues.  
     
     
         6 . The isolated polypeptide of  claim 5  wherein X aa1 , X aa2  and X aa3  are N—H or N-methylated amino acid residues.  
     
     
         7 . The isolated polypeptide of  claim 1  wherein the other substitution at the alpha-carbon of Y is substituted with hydrogen, methyl or ethyl; and wherein, the other substitution at the alpha-carbon of Z is substituted with hydrogen, methyl or ethyl.  
     
     
         8 . The isolated polypeptide of  claim 1  wherein X aa1  is naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is a primary substituent selected from the group consisting of heterocyclylalkyl, heteroaryl, heteroarylalkyl and arylalkyl, said primary substituent optionally being substituted with secondary substituent selected from heteroaryl or heterocyclyl; and in which the other substitution at the alpha-carbon is hydrogen or alkyl; X aa2  is naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is an alkyl or cycloalkyl where the alkyl group may optionally form a ring with the nitrogen of X aa2 ; and wherein the other substitution at the alpha-carbon is hydrogen or alkyl; X aa3  is a naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is selected from the group consisting of a carboxyalkyl, bis-carboxyalkyl, sulfonylalkyl, heteroalkyl and mercaptoalkyl; and wherein the other substitution at the alpha-carbon is hydrogen or alkyl; X aa4  is a naturally or nonnaturally occurring amino acid residue in which the alpha-carbon is not substituted, or in which one of the substitutions at the alpha-carbon is selected from the group consisting of aminoalkyl, carboxyalkyl heteroarylalkyl and heterocycylalkyl; X aa5  is a naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is an alkyl or hydroxyalkyl, and in which the other substitution at the alpha-carbon is hydrogen or alkyl; X aa6  is a naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is selected from the group consisting of alkyl, aryl, heteroaryl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl group, and wherein the other substitution at the alpha-carbon is hydrogen or alkyl; X aa7  is a naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is a hydroxylalkyl group; X aa8  is a naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is selected from the group consisting of alkyl, hydroxylalkyl, heteroarylalkyl and carboxamidoalkyl, and in which the other substitution at the alpha-carbon is hydrogen or alkyl; X aa9  is a naturally or nonnaturally occurring amino acid residue in which one of the substitutions at alpha-carbon is selected from the group consisting of carboxylalkyl, bis-carboxylalkyl, carboxylaryl, sulfonylalkyl, carboxylamidoalkyl and heteroarylalkyl; and wherein A is hydrogen, an amino acid or peptide containing from about 1 to about 5 amino acid residues, an R group, an R—C(O) amide group, a carbamate group RO—C(O), a urea R 4 R 5 N—C(O), a sulfonamido R—SO 2  or a R 4 R 5 N—SO 2 .  
     
     
         9 . The isolated polypeptide of  claim 8  wherein X aa1  is an amino acid residue selected from the group consisting of L-His, D-His, L-N-Methyl-His, D-N-Methyl-His, L-4-ThiazolylAla and D-4-ThiazolylAla; X aa2  is an amino acid residue selected from the group consisting of L-Ala, D-Ala, L-Pro, Gly, D-Ser, D-Asn, L-N-Methyl-Ala, D-N-Methyl-Ala, L-4-ThioPro, L-Pro(t-4-OH), L-2-Pip, L-2-Azt, Aib, S— or R-Iva and Acc 3 ; X aa3  is an amino acid residue selected from the group consisting of L-Glu, L-N-Methyl-Glu, L-Asp, D-Asp, L-His, L-Gla, L-Adp, L-Cys and L-4-ThiazolylAla; X aa4  is an amino acid residue selected from the group consisting of Gly, L-His, L-Lys and L-Asp; X aa5  is an amino acid residue selected from the group consisting of L-Thr, D-Thr, L-Nle, L-Met, L-Nva and L-Aoc; X aa6  is an amino acid residue selected from the group consisting of L-Phe, L-Tyr, L-Tyr(Bzl), Tyr(3-NO 2 ), L-Nle, L-Trp, L-Phe(penta-Fluoro), D-Phe(penta-Fluoro), Phe(2-Fluoro), Phe(3-Fluoro), Phe(4-Fluoro), Phe(2,3-di-Fluoro), Phe(3,4-di-Fluoro), Phe(3,5-di-Fluoro), L-Phe(2,6-di-Fluoro), Phe(3,4,5-tri-Fluoro), Phe(2-Iodo), Phe(2-OH), Phe(2-OMethyl), Phe(3-OMethyl), Phe(3-Cyano), Phe(2-Chloro), Phe(2-NH 2 ), Phe(3-NH 2 ), Phe(4-NH 2 ), Phe(4-NO 2 ), Phe(4-Methyl), Phe(4-Allyl), Phe(n-butyl), Phe(4-Cyclohexyl), Phe(4-Cyclohexyloxy), Phe(4-Phenyloxy), 2-NaphthylAla, 2-PyridylAla, L-4-ThiazolylAla, L-2-Thi, L-α-Me-Phe, D-α-Me-Phe, L-α-Et-Phe, D-α-Et-Phe, L-α-Me-Phe(2-Fluoro), D-α-Me-Phe(2-Fluoro), L-α-Me-Phe(2,3-di-Fluoro), D-α-Me-Phe(2,3-di-Fluoro), L-α-Me-Phe(2,6-di-Fluoro), D-α-Me-Phe(2,6-di-Fluoro), L-α-Me-Phe(penta-Fluoro) and D-α-Me-Phe(penta-Fluoro); X aa7  is an amino acid residue selected from the group consisting of L-Thr, D-Thr, L-Ser and L-hSer; X aa8  is an amino acid residue selected from the group consisting of L-Ser, L-hSer, L-His, L-Asn and L-α-Me-Ser; and X aa9  is an amino acid residue selected from the group consisting of L-Asp, L-Glu, L-Gla, L-Adp, L-Asn and L-His.  
     
     
         10 . The isolated polypeptide of  claim 1  wherein Y is selected from the group consisting of L-Bip, D-Bip, L-Bip(2-Me), D-Bip(2-Me), L-Bip(2′-Me), L-Bip(2-Et), D-Bip(2-Et), L-Bip(3-Et), L-Bip(4-Et), L-Bip(2-n-Propyl), L-Bip(2-n-Propyl, 4-OMe), L-Bip(2-n-Propyl,2′-Me), L-Bip(3-Me), L-Bip(4-Me), L-Bip(2,3-di-Me), L-Bip(2,4-di-Me), L-Bip(2,6-di-Me), L-Bip(2,4-di-Et), L-Bip(2-Me, 2′-Me), L-Bip(2-Et, 2′-Me), L-Bip(2-Et, 2′-Et), L-Bip(2-Me,4-OMe), L-Bip(2-Et,4-OMe), D-Bip(2-Et, 4-OMe), L-Bip(3-OMe), L-Bip(4-OMe), L-Bip(2,4,6-tri-Me), L-Bip(2,3-di-OMe), L-Bip(2,4-di-OMe), L-Bip(2,5-di-OMe), L-Bip(3,4-di-OMe), L-Bip(2-Et,4,5-di-OMe), L-Bip(3,4-Methylene-di-oxy), L-Bip(2-Et, 4,5-Methylene-di-oxy), L-Bip(2-CH 2 OH, 4-OMe), L-Bip(2-Ac), L-Bip(3-NH-Ac), L-Bip(4-NH-Ac), L-Bip(2,3-di-Chloro), L-Bip(2,4-di-Chloro), L-Bip(2,5-di-Chloro), L-Bip(3,4-di-Chloro), L-Bip(4-Fluoro), L-Bip(3,4-di-Fluoro), L-Bip(2,5-di-Fluoro), L-Bip(3-n-Propyl), L-Bip(4-n-Propyl), L-Bip(2-iso-Propyl), L-Bip(3-iso-Propyl), L-Bip(4-iso-Propyl), L-Bip(4-tert-Butyl), L-Bip(3-Phenyl), L-Bip(2-Chloro), L-Bip(3-Chloro), L-Bip(2-Fluoro), L-Bip(3-Fluoro), L-Bip(2-CF 3 ), L-Bip(3-CF 3 ), L-Bip(4-CF 3 ), L-Bip(3-NO 2 ), L-Bip(3-OCF 3 ), L-Bip(4-OCF 3 ), L-Bip(2-OEt), L-Bip(3-OEt), L-Bip(4-OEt), L-Bip(4-SMe), L-Bip(2-OH), L-Bip(3-OH), L-Bip(4-OH), L-Bip(2-CH 2 —COOH), L-Bip(3-CH 2 —COOH), L-Bip(4-CH 2 —COOH), L-Bip(2-CH 2 —NH 2 ), L-Bip(3-CH 2 —NH 2 ), L-Bip(4-CH 2 —NH 2 ), L-Bip(2-CH 2 —OH), L-Bip(3-CH 2 —OH), L-Bip(4-CH 2 —OH), L-Phe[4-(1-propargyl)], L-Phe[4-(1-propenyl)], L-Phe[4-n-Butyl], L-Phe[4-Cyclohexyl], Phe(4-Phenyloxy), L-Phe(penta-Fluoro), L-2-(9,10-Dihydrophenanthrenyl)-Ala, 4-(2-Benzo(b)furan)-Phe, 4-(4-Dibenzofuran)-Phe, 4-(4-Phenoxathiin)-Phe, 4-(2-Benzo(b)thiophene)-Phe, 4-(3-thiophene)-Phe, 4-(3-Quinoline)-Phe, 4-(2-Naphthyl)-Phe, 4-(1-Naphthyl)-Phe, 4-(4-(3,5-dimethylisoxazole))-Phe, 4-(2,4-dimethoxypyrimidine)-Phe, homoPhe, Tyr(Bzl), Phe(3,4-di-Chloro), Phe(4-Iodo), 2-Naphthyl-Ala, L-α-Me-Bip and D-α-Me-Bip; Z is selected from the group consisting of L-Bip, D-Bip, L-Bip(2-Me), D-Bip(2-Me), L-Bip(2′-Me), L-Bip(2-Et), D-Bip(2-Et), L-Bip(3-Me), L-Bip(4-Me), L-Bip(3-OMe), L-Bip(4-OMe), L-Bip(4-Et), L-Bip(2-n-Propyl,2′-Me), L-Bip(2,4-di-Me), L-Bip(2-Me, 2′-Me), L-Bip(2-Me,4-OMe), L-Bip(2-Et,4-OMe), D-Bip(2-Et,4-OMe), L-Bip(2,6-di-Me), L-Bip(2,4,6-tri-Me), L-Bip(2,3,4,5,-tetra-Me), L-Bip(3,4-di-OMe), L-Bip(2,5-di-OMe), L-Bip(3,4-Methylene-di-oxy), L-Bip(3-NH-Ac), L-Bip(2-iso-Propyl), L-Bip(4-iso-Propyl), L-Bip(2-Phenyl), L-Bip(4-Phenyl), L-Bip(2-Fluoro), L-Bip(4-CF 3 ), L-Bip(4-OCF 3 ), L-Bip(2-OEt), L-Bip(4-OEt), L-Bip(4-SMe), L-Bip(2-CH 2 —COOH), D-Bip(2-CH 2 —COOH), L-Bip(2′-CH 2 —COOH), L-Bip(3-CH 2 —COOH), L-Bip(4-CH 2 —COOH), L-Bip(2-CH 2 —NH 2 ), L-Bip(3-CH 2 —NH 2 ), L-Bip(4-CH 2 —NH 2 ), L-Bip(2-CH 2 —OH), L-Bip(3-CH 2 —OH), L-Bip(4-CH 2 —OH), L-Phe(3-Phenyl), L-Phe[4-n-Butyl], L-Phe[4-Cyclohexyl], Phe(4-Phenyloxy), L-Phe(penta-Fluoro), L-2-(9,10-Dihydrophenanthrenyl)-Ala, 4-(3-Pyridyl)-Phe, 4-(2-Naphthyl)-Phe, 4-(1-Naphthyl)-Phe, 2-Naphthyl-Ala, 2-Fluorenyl-Ala, L-α-Me-Bip, D-α-Me-Bip, L-Phe(4-NO 2 ) and L-Phe(4-Iodo); A is selected from the group consisting of H, Acetyl, β-Ala, Ahx, Gly, Asp, Glu, Phe, Lys, Nva, Asn, Arg, Ser, Thr, Val, Trp, Tyr, Caprolactam, L-Bip, L-Ser(Bzl), 3-PyridylAla, Phe(4-Me), Phe(penta-Fluoro), 4-Methylbenzyl, 4-Fluorobenzyl, n-propyl, n-hexyl, cyclohexylmethyl, 6-hydroxypentyl, 2-Thienylmethyl, 3-Thienylmethyl, penta-Fluorobenzyl, 2-naphthylmethyl, 4-biphenylmethyl, 9-Anthracenylmethyl, benzyl, (S)-(2-amino-3-phenyl)propyl, methyl, 2-aminoethyl and (S)-2-Aminopropyl; and B is selected from the group consisting of OH, NH 2 , Trp-NH 2 , 2-NaphthylAla-NH 2 , Phe(penta-Fluoro)-NH 2 , Ser(Bzl)-NH 2 , Phe(4-NO 2 )—NH 2 , 3-PyridylAla-NH 2 , Nva-NH 2 , Lys-NH 2 , Asp-NH 2 , Ser-NH 2 , His-NH 2 , Tyr-NH 2 , Phe-NH 2 , L-Bip-NH 2 , D-Ser-NH 2 , Gly-OH, β-Ala-OH, GABA-OH and APA-OH.  
     
     
         11 . The isolated polypeptide of  claim 1  wherein such polypeptide is a 10-mer to 15-mer and such polypeptide and binds to and activates the GLP-1 receptor.  
     
     
         12 . An isolated polypeptide having a sequence of Formula I  
         A-X aa1 -X aa2 -X aa3 -X aa4 -X aa5 -X aa6 -X aa7 -X aa8 -X aa9 -Y-Z-B  I  wherein, X aa1-9  is a naturally or nonnaturally occurring amino acid residue; Y and Z are amino acid residues; wherein one of the substitutions at the alpha-carbon atoms of Y and Z may each independently be substituted with a primary substituent group selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl, said primary substituent optionally being substituted with a secondary substituent selected from a cycloalkyl, heterocyclyl, aryl or heteroaryl group; any of said primary or secondary substituents may further be substituted with one or more of, hydrogen, alkyl, cycloalkyl, arylalkyl, aryl, heterocycle, heteroaryl, alkenyl, alkynyl, halo, hydroxy, mercapto, nitro, cyano, amino, acylamino, azido, guanidino, amidino, carboxyl, carboxamido, carboxamido alkyl, formyl, acyl, carboxyl alkyl, alkoxy, aryloxy, arylalkyloxy, heteroaryloxy, heterocycleoxy, acyloxy, mercapto, mercapto alkyl, mercaptoaryl, mercapto acyl, halo, cyano, nitro, azido, amino, guanidino alkyl, guanidino acyl, sulfonic, sulfonamido, alkyl sulfonyl, aryl sulfonyl or phosphonic group; wherein, the primary or secondary substitutents may optionally be bridged by covalent bonds to form one or more fused cyclic or heterocyclic systems with each other; wherein, the other substitution at the alpha-carbon of Y may be substituted with hydrogen, alkyl, aminoalkyl, hydroxyalkyl or carboxyalkyl; wherein, the other substitution at the alpha-carbon of Z may be substituted with hydrogen, alkyl, aminoalkyl, hydroxyalkyl or carboxyalkyl; A and B are optionally present; wherein A is not present, and X aa1  is an R group, an R—C(O) (amide) group, a carbamate group RO—C(O), a urea R 4 R 5 N—C(O), a sulfonamido R—SO 2 , or a R 4 R 5 N—SO 2 ; wherein R is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl, heteroaryloxyalkyl and heteroarylalkoxyalkyl; wherein R 4  and R 5  are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl and heteroaryloxyalkyl; wherein B is present and B is OR 1 , NR 1 R 2 , or an amino acid or peptide containing from 1 to 15 amino acid residues, terminating at the C-terminus as a carboxamide, substituted carboxamide, an ester, a free carboxylic acid or an amino-alcohol; and wherein R 1  and R 2  are independently chosen from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl or heteroaryloxyalkyl.    
     
     
         13 . The isolated polypeptide of  claim 12  wherein the substitutions upon the alpha-carbon atoms of Y and Z are selected from the group consisting of heteroarylarylmethyl, arylheteroarylmethyl or biphenylmethyl forming biphenylalanine residues, any of which is also optionally substituted with one or more, hydrogen, alkyl, cycloalkyl, arylalkyl, aryl, heterocyclyl, heteroaryl, alkenyl, alkynyl, halo, hydroxy, mercapto, nitro, cyano, amino, acylamino, azido, guanidino, amidino, carboxyl, carboxamido, carboxamido alkyl, formyl, acyl, carboxyl alkyl, alkoxy, aryloxy, arylalkyloxy, heteroaryloxy, heterocycleoxy, acyloxy, mercapto, mercapto alkyl, mercaptoaryl, mercapto acyl, halo, cyano, nitro, azido, amino, guanidino alkyl, guanidino acyl, sulfonic, sulfonamido, alkyl sulfonyl, aryl sulfonyl and phosphonic group.  
     
     
         14 . The isolated polypeptide of  claim 12  wherein B is an amino acid or peptide containing 1 to about 10 amino acid residues.  
     
     
         15 . The isolated polypeptide of  claim 14  wherein B is an amino acid or peptide containing 1 to about 5 amino acid residues.  
     
     
         16 . The isolated polypeptide of  claim 12  wherein X aa2  and X aa3  are N—H or N-alkylated amino acid residues.  
     
     
         17 . The isolated polypeptide of  claim 16  wherein X aa2  and X aa3  are N—H or N-methylated amino acid residues.  
     
     
         18 . The isolated polypeptide of  claim 12  wherein the other substitution at the alpha-carbon of Y is substituted with hydrogen, methyl or ethyl, and wherein the other substitution at the alpha-carbon of Z is substituted with hydrogen, methyl or ethyl.  
     
     
         19 . The isolated polypeptide of  claim 12  wherein R, R 4  and R 5  are heteroarylalkyl or heterocycloalkyl, or R, R 4  and R 5  are cycloalkyl, cycloalkylalkyl, heterocycle, aryl, arylalkyl or aryloxyalkyl substituted with heteroaryl or heterocycle.  
     
     
         20 . The isolated polypeptide of  claim 12  wherein X aa2  is a naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is an alkyl or cycloalkyl where the alkyl group may optionally form a ring with the nitrogen of X aa2 , and wherein the other substitution at the alpha-carbon is hydrogen or alkyl; X aa3  is a naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is selected from the group consisting of a carboxyalkyl, bis-carboxyalkyl, sulfonylalkyl, heteroalkyl and mercaptoalkyl; and wherein the other substitution at the alpha-carbon is hydrogen or alkyl; X aa4  is a naturally or nonnaturally occurring amino acid residue in which the alpha-carbon is not substituted, or in which one of the substitutions at the alpha-carbon is selected from the group consisting of aminoalkyl, carboxyalkyl heteroarylalkyl and heterocycylalkyl; X aa5  is a naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is an alkyl or hydroxyalkyl, and in which the other substitution at the alpha-carbon is hydrogen or alkyl; X aa6  is a naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is selected from the group consisting of alkyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, heterocyclealkyl, arylalkyl and heteroarylalkyl, and wherein the other substitution at the alpha-carbon is hydrogen or alkyl; X aa7  is a naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is a hydroxylalkyl group; X aa8  is a naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is selected from the group consisting of alkyl, hydroxylalkyl, heteroarylalkyl and carboxamidoalkyl, and in which the other substitution at the alpha-carbon is hydrogen or alkyl; and X aa9  is a naturally or nonnaturally occurring amino acid residue in which one of the substitutions at alpha-carbon is selected from the group consisting of carboxylalkyl, bis-carboxylalkyl, carboxylaryl, sulfonylalkyl, carboxylamidoalkyl and heteroarylalkyl.  
     
     
         21 . The isolated polypeptide of  claim 20  wherein X aa2  is an amino acid residue selected from the group consisting of L-Ala, D-Ala, L-Pro, Gly, D-Ser, D-Asn, L-N-Methyl-Ala, D-N-Methyl-Ala, L-4-ThioPro, L-Pro(t-4-OH), L-2-Pip, L-2-Azt, Aib, S— or R-Iva and Acc 3 ; X aa3  is an amino acid residue selected from the group consisting of L-Glu, L-N-Methyl-Glu, L-Asp, D-Asp, L-His, L-Gla, L-Adp, L-Cys and L-4-ThiazolylAla; X aa4  is an amino acid residue selected from the group consisting of Gly, L-His, L-Lys and L-Asp; X aa5  is an amino acid residue selected from the group consisting of L-Thr, D-Thr, L-Nle, L-Met, L-Nva and L-Aoc; X aa6  is an amino acid residue selected from the group consisting of L-Phe, L-Tyr, L-Tyr(Bzl), Tyr(3-NO 2 ), L-Nle, L-Trp, L-Phe(penta-Fluoro), D-Phe(penta-Fluoro), Phe(2-Fluoro), Phe(3-Fluoro), Phe(4-Fluoro), Phe(2,3-di-Fluoro), Phe(3,4-di-Fluoro), Phe(3,5-di-Fluoro), L-Phe(2,6-di-Fluoro), Phe(3,4,5-tri-Fluoro), Phe(2-Iodo), Phe(2-OH), Phe(2-OMethyl), Phe(3-OMethyl), Phe(3-Cyano), Phe(2-Chloro), Phe(2-NH 2 ), Phe(3-NH 2 ), Phe(4-NH 2 ), Phe(4-NO 2 ), Phe(4-Methyl), Phe(4-Allyl), Phe(n-butyl), Phe(4-Cyclohexyl), Phe(4-Cyclohexyloxy), Phe(4-Phenyloxy), 2-NaphthylAla, 2-PyridylAla, L-4-ThiazolylAla, L-2-Thi, L-α-Me-Phe, D-α-Me-Phe, L-α-Et-Phe, D-α-Et-Phe, L-α-Me-Phe(2-Fluoro), D-α-Me-Phe(2-Fluoro), L-α-Me-Phe(2,3-di-Fluoro), D-α-Me-Phe(2,3-di-Fluoro), L-α-Me-Phe(2,6-di-Fluoro), D-α-Me-Phe(2,6-di-Fluoro), L-α-Me-Phe(penta-Fluoro) and D-α-Me-Phe(penta-Fluoro); X aa7  is an amino acid residue selected from the group consisting of L-Thr, D-Thr, L-Ser and L-hSer; X aa8  is an amino acid residue selected from the group consisting of L-Ser, L-hSer, L-His, L-Asn and L-α-Me-Ser; and X aa9  is an amino acid residue selected from the group consisting of L-Asp, L-Glu, L-Gla, L-Adp, L-Asn and L-His.  
     
     
         22 . The isolated polypeptide of  claim 12  wherein Y is selected from the group consisting of L-Bip, D-Bip, L-Bip(2-Me), D-Bip(2-Me), L-Bip(2′-Me), L-Bip(2-Et), D-Bip(2-Et), L-Bip(3-Et), L-Bip(4-Et), L-Bip(2-n-Propyl), L-Bip(2-n-Propyl, 4-OMe), L-Bip(2-n-Propyl,2′-Me), L-Bip(3-Me), L-Bip(4-Me), L-Bip(2,3-di-Me), L-Bip(2,4-di-Me), L-Bip(2,6-di-Me), L-Bip(2,4-di-Et), L-Bip(2-Me, 2′-Me), L-Bip(2-Et, 2′-Me), L-Bip(2-Et, 2′-Et), L-Bip(2-Me,4-OMe), L-Bip(2-Et,4-OMe), D-Bip(2-Et,4-OMe), L-Bip(3-OMe), L-Bip(4-OMe), L-Bip(2,4,6-tri-Me), L-Bip(2,3-di-OMe), L-Bip(2,4-di-OMe), L-Bip(2,5-di-OMe), L-Bip(3,4-di-OMe), L-Bip(2-Et,4,5-di-OMe), L-Bip(3,4-Methylene-di-oxy), L-Bip(2-Et, 4,5-Methylene-di-oxy), L-Bip(2-CH 2 OH, 4-OMe), L-Bip(2-Ac), L-Bip(3-NH-Ac), L-Bip(4-NH-Ac), L-Bip(2,3-di-Chloro), L-Bip(2,4-di-Chloro), L-Bip(2,5-di-Chloro), L-Bip(3,4-di-Chloro), L-Bip(4-Fluoro), L-Bip(3,4-di-Fluoro), L-Bip(2,5-di-Fluoro), L-Bip(3-n-Propyl), L-Bip(4-n-Propyl), L-Bip(2-iso-Propyl), L-Bip(3-iso-Propyl), L-Bip(4-iso-Propyl), L-Bip(4-tert-Butyl), L-Bip(3-Phenyl), L-Bip(2-Chloro), L-Bip(3-Chloro), L-Bip(2-Fluoro), L-Bip(3-Fluoro), L-Bip(2-CF 3 ), L-Bip(3-CF 3 ), L-Bip(4-CF 3 ), L-Bip(3-NO 2 ), L-Bip(3-OCF 3 ), L-Bip(4-OCF 3 ), L-Bip(2-OEt), L-Bip(3-OEt), L-Bip(4-OEt), L-Bip(4-SMe), L-Bip(2-OH), L-Bip(3-OH), L-Bip(4-OH), L-Bip(2-CH 2 —COOH), L-Bip(3-CH 2 —COOH), L-Bip(4-CH 2 —COOH), L-Bip(2-CH 2 —NH 2 ), L-Bip(3-CH 2 —NH 2 ), L-Bip(4-CH 2 —NH 2 ), L-Bip(2-CH 2 —OH), L-Bip(3-CH 2 —OH), L-Bip(4-CH 2 —OH), L-Phe[4-(1-propargyl)], L-Phe[4-(1-propenyl)], L-Phe[4-n-Butyl], L-Phe[4-Cyclohexyl], Phe(4-Phenyloxy), L-Phe(penta-Fluoro), L-2-(9,10-Dihydrophenanthrenyl)-Ala, 4-(2-Benzo(b)furan)-Phe, 4-(4-Dibenzofuran)-Phe, 4-(4-Phenoxathiin)-Phe, 4-(2-Benzo(b)thiophene)-Phe, 4-(3-thiophene)-Phe, 4-(3-Quinoline)-Phe, 4-(2-Naphthyl)-Phe, 4-(1-Naphthyl)-Phe, 4-(4-(3,5-dimethylisoxazole))-Phe, 4-(2,4-dimethoxypyrimidine)-Phe, homoPhe, Tyr(Bzl), Phe(3,4-di-Chloro), Phe(4-Iodo), 2-Naphthyl-Ala, L-α-Me-Bip and D-α-Me-Bip; Z is selected from the group consisting of L-Bip, D-Bip, L-Bip(2-Me), D-Bip(2-Me), L-Bip(2′-Me), L-Bip(2-Et), D-Bip(2-Et), L-Bip(3-Me), L-Bip(4-Me), L-Bip(3-OMe), L-Bip(4-OMe), L-Bip(4-Et), L-Bip(2-n-Propyl,2′-Me), L-Bip(2,4-di-Me), L-Bip(2-Me, 2′-Me), L-Bip(2-Me,4-OMe), L-Bip(2-Et,4-OMe), D-Bip(2-Et,4-OMe), L-Bip(2,6-di-Me), L-Bip(2,4,6-tri-Me), L-Bip(2,3,4,5,-tetra-Me), L-Bip(3,4-di-OMe), L-Bip(2,5-di-OMe), L-Bip(3,4-Methylene-di-oxy), L-Bip(3-NH-Ac), L-Bip(2-iso-Propyl), L-Bip(4-iso-Propyl), L-Bip(2-Phenyl), L-Bip(4-Phenyl), L-Bip(2-Fluoro), L-Bip(4-CF 3 ), L-Bip(4-OCF 3 ), L-Bip(2-OEt), L-Bip(4-OEt), L-Bip(4-SMe), L-Bip(2-CH 2 —COOH), D-Bip(2-CH 2 —COOH), L-Bip(2′-CH 2 —COOH), L-Bip(3-CH 2 —COOH), L-Bip(4-CH 2 —COOH), L-Bip(2-CH 2 —NH 2 ), L-Bip(3-CH 2 —NH 2 ), L-Bip(4-CH 2 —NH 2 ), L-Bip(2-CH 2 —OH), L-Bip(3-CH 2 —OH), L-Bip(4-CH 2 —OH), L-Phe(3-Phenyl), L-Phe[4-n-Butyl], L-Phe[4-Cyclohexyl], Phe(4-Phenyloxy), L-Phe(penta-Fluoro), L-2-(9,10-Dihydrophenanthrenyl)-Ala, 4-(3-Pyridyl)-Phe, 4-(2-Naphthyl)-Phe, 4-(1-Naphthyl)-Phe, 2-Naphthyl-Ala, 2-Fluorenyl-Ala, L-α-Me-Bip, D-α-Me-Bip, L-Phe(4-NO 2 ) and L-Phe(4-Iodo); and B is selected from the group consisting of OH, NH 2 , Trp-NH 2 , 2-NaphthylAla-NH 2 , Phe(penta-Fluoro)-NH 2 , Ser(Bzl)-NH 2 , Phe(4-NO 2 )—NH 2 , 3-PyridylAla-NH 2 , Nva-NH 2 , Lys-NH 2 , Asp-NH 2 , Ser-NH 2 , His-NH 2 , Tyr-NH 2 , Phe-NH 2 , L-Bip-NH 2 , D-Ser-NH 2 , Gly-OH, 1-Ala-OH, GABA-OH and APA-OH.  
     
     
         23 . The isolated polypeptide of  claim 12  wherein such polypeptide is a 10-mer to 15-mer and such polypeptide and binds to and activates the GLP-1 receptor.  
     
     
         24 . An isolated polypeptide having a sequence of Formula I  
         A-X aa1 -X aa2 -X aa3 -X aa4 -X aa5 -X aa6 -X aa7 -X aa8 -X aa9 -Y-Z-B  I  wherein, X aa1-9  is a naturally or nonnaturally occurring amino acid residue; Y is an amino acid residue; wherein one of the substitutions at the alpha-carbon atom of Y may independently be substituted with a primary substituent group selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl, said primary substituent optionally being substituted with a secondary substituent selected from a cycloalkyl, heterocyclyl, aryl or heteroaryl group; any of said primary or secondary substituents may further be substituted with one or more of, hydrogen, alkyl, cycloalkyl, arylalkyl, aryl, heterocyclyl, heteroaryl, alkenyl, alkynyl, halo, hydroxy, mercapto, nitro, cyano, amino, acylamino, azido, guanidino, amidino, carboxyl, carboxamido, carboxamido alkyl, formyl, acyl, carboxyl alkyl, alkoxy, aryloxy, arylalkyloxy, heteroaryloxy, heterocyclyloxy, acyloxy, mercapto, mercapto alkyl, mercaptoaryl, mercapto acyl, halo, cyano, nitro, azido, amino, guanidino alkyl, guanidino acyl, sulfonic, sulfonamido, alkyl sulfonyl, aryl sulfonyl or phosphonic group; wherein, the primary or secondary substitutents may optionally be bridged by covalent bonds to form one or more fused cyclic or heterocyclic systems with each other; wherein, the other substitution at the alpha-carbon of Y may be substituted with hydrogen, alkyl, aminoalkyl, hydroxyalkyl or carboxyalkyl; A and B are optionally present; wherein A is present and A is hydrogen, an amino acid or peptide containing from about 1 to about 15 amino acid residues, an R group, an R—C(O) (amide) group, a carbamate group RO—C(O), a urea R 4 R 5 N—C(O), a sulfonamido R—SO 2  or a R 4 R 5 N—SO 2 ; wherein R is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl and heteroaryloxyalkyl; wherein R 4  and R 5  are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl and heteroaryloxyalky; wherein the alpha-amino group of X aa1  is substituted with a hydrogen or an alkyl group, said alkyl group may optionally form a ring with A; wherein B is not present and Z is OR 1 , NR 1 R 2  or an amino-alcohol; and wherein R 1  and R 2  are independently chosen from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl or heteroaryloxyalkyl.    
     
     
         25 . The isolated polypeptide of  claim 24  wherein the substitutions upon the alpha-carbon atoms of Y are selected from the group consisting of heteroarylarylmethyl, arylheteroarylmethyl or biphenylmethyl forming biphenylalanine residues, any of which is also optionally substituted with one or more, hydrogen, alkyl, cycloalkyl, arylalkyl, aryl, heterocyclyl, heteroaryl, alkenyl, alkynyl, halo, hydroxy, mercapto, nitro, cyano, amino, acylamino, azido, guanidino, amidino, carboxyl, carboxamido, carboxamido alkyl, formyl, acyl, carboxyl alkyl, alkoxy, aryloxy, arylalkyloxy, heteroaryloxy, heterocycleoxy, acyloxy, mercapto, mercapto alkyl, mercaptoaryl, mercapto acyl, halo, cyano, nitro, azido, amino, guanidino alkyl, guanidino acyl, sulfonic, sulfonamido, alkyl sulfonyl, aryl sulfonyl and phosphonic group.  
     
     
         26 . The isolated polypeptide of  claim 24  wherein B is an amino acid or peptide containing 1 to about 10 amino acid residues.  
     
     
         27 . The isolated polypeptide of  claim 26  wherein B is an amino acid or peptide containing 1 to about 5 amino acid residues.  
     
     
         28 . The isolated polypeptide of  claim 24  wherein X aa1 , X aa2  and X aa3  are N—H or N-alkylated amino acid residues.  
     
     
         29 . The isolated polypeptide of  claim 24  wherein X aa1 , X aa2  and X aa3  are N—H or N-methylated amino acid residues.  
     
     
         30 . The isolated polypeptide of  claim 24  wherein the other substitution at the alpha-carbon of Y is substituted with hydrogen, methyl or ethyl.  
     
     
         31 . The isolated polypeptide of  claim 24  wherein X aa1  is naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is a primary substituent selected from the group consisting of heterocyclylalkyl, heteroaryl, heteroarylalkyl, and arylalkyl, said primary substituent optionally being substituted with secondary substituent selected from heteroaryl or heterocyclyl, and wherein the other substitution at the alpha-carbon is hydrogen or alkyl; X aa2  is naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is an alkyl or cycloalkyl where the alkyl group may optionally form a ring with the nitrogen of X aa2 , and wherein the other substitution at the alpha-carbon is hydrogen or alkyl; X aa3  is a naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is selected from the group consisting of a carboxyalkyl, bis-carboxyalkyl, sulfonylalkyl, heteroalkyl and mercaptoalkyl, and wherein the other substitution at the alpha-carbon is hydrogen or alkyl; X aa4  is a naturally or nonnaturally occurring amino acid residue in which the alpha-carbon is not substituted, or in which one of the substitutions at the alpha-carbon is selected from the group consisting of aminoalkyl, carboxyalkyl heteroarylalkyl and heterocycylalkyl; X aa5  is a naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is an alkyl or hydroxyalkyl, and wherein the other substitution at the alpha-carbon is hydrogen or alkyl; X aa6  is a naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is selected from the group consisting of alkyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, heterocyclealkyl, arylalkyl and heteroarylalkyl group, and wherein the other substitution at the alpha-carbon is hydrogen or alkyl; X aa7  is a naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is a hydroxylalkyl group; X aa8  is a naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is selected from the group consisting of alkyl, hydroxylalkyl, heteroarylalkyl and carboxamidoalkyl, and wherein the other substitution at the alpha-carbon is hydrogen or alkyl; X aa9  is a naturally or nonnaturally occurring amino acid residue in which one of the substitutions at alpha-carbon is selected from the group consisting of carboxylalkyl, bis-carboxylalkyl, carboxylaryl, sulfonylalkyl, carboxylamidoalkyl and heteroarylalkyl; and wherein A is hydrogen, an amino acid or peptide containing from about 1 to about 5 amino acid residues, an R group, an R—C(O) (amide) group, a carbamate group RO—C(O), a urea R 4 R 5 N—C(O), a sulfonamido R—SO 2  or a R 4 R 5 N—SO 2 .  
     
     
         32 . The isolated polypeptide of  claim 24  wherein, X aa1  is an amino acid residue selected from the group consisting of L-His, D-His, L-N-Methyl-His, D-N-Methyl-His, L-4-ThiazolylAla and D-4-ThiazolylAla; X aa2  is an amino acid residue selected from the group consisting of L-Ala, D-Ala, L-Pro, Gly, D-Ser, D-Asn, L-N-Methyl-Ala, D-N-Methyl-Ala, L-4-ThioPro, L-Pro(t-4-OH), L-2-Pip, L-2-Azt, Aib, S- or R-Iva and Acc 3 ; X aa3  is an amino acid residue selected from the group consisting of L-Glu, L-N-Methyl-Glu, L-Asp, D-Asp, L-His, L-Gla, L-Adp, L-Cys and L-4-ThiazolylAla; X aa4  is an amino acid residue selected from the group consisting of Gly, L-His, L-Lys and L-Asp; X aa5  is an amino acid residue selected from the group consisting of L-Thr, D-Thr, L-Nle, L-Met, L-Nva and L-Aoc; X aa6  is an amino acid residue selected from the group consisting of L-Phe, L-Tyr, L-Tyr(Bzl), Tyr(3-NO 2 ), L-Nle, L-Trp, L-Phe(penta-Fluoro), D-Phe(penta-Fluoro), Phe(2-Fluoro), Phe(3-Fluoro), Phe(4-Fluoro), Phe(2,3-di-Fluoro), Phe(3,4-di-Fluoro), Phe(3,5-di-Fluoro), L-Phe(2,6-di-Fluoro), Phe(3,4,5-tri-Fluoro), Phe(2-Iodo), Phe(2-OH), Phe(2-OMethyl), Phe(3-OMethyl), Phe(3-Cyano), Phe(2-Chloro), Phe(2-NH 2 ), Phe(3-NH 2 ), Phe(4-NH 2 ), Phe(4-NO 2 ), Phe(4-Methyl), Phe(4-Allyl), Phe(n-butyl), Phe(4-Cyclohexyl), Phe(4-Cyclohexyloxy), Phe(4-Phenyloxy), 2-NaphthylAla, 2-PyridylAla, L-4-ThiazolylAla, L-2-Thi, L-α-Me-Phe, D-α-Me-Phe, L-α-Et-Phe, D-α-Et-Phe, L-α-Me-Phe(2-Fluoro), D-α-Me-Phe(2-Fluoro), L-α-Me-Phe(2,3-di-Fluoro), D-α-Me-Phe(2,3-di-Fluoro), L-α-Me-Phe(2,6-di-Fluoro), D-α-Me-Phe(2,6-di-Fluoro), L-α-Me-Phe(penta-Fluoro) and D-α-Me-Phe(penta-Fluoro); X aa7  is an amino acid residue selected from the group consisting of L-Thr, D-Thr, L-Ser and L-hSer; X aa8  is an amino acid residue selected from the group consisting of L-Ser, L-hSer, L-His, L-Asn and L-α-Me-Ser; and X aa9  is an amino acid residue selected from the group consisting of L-Asp, L-Glu, L-Gla, L-Adp, L-Asn and L-His.  
     
     
         33 . The isolated polypeptide of  claim 24  wherein Y is selected from the group consisting of L-Bip, D-Bip, L-Bip(2-Me), D-Bip(2-Me), L-Bip(2′-Me), L-Bip(2-Et), D-Bip(2-Et), L-Bip(3-Et), L-Bip(4-Et), L-Bip(2-n-Propyl), L-Bip(2-n-Propyl, 4-OMe), L-Bip(2-n-Propyl,2′-Me), L-Bip(3-Me), L-Bip(4-Me), L-Bip(2,3-di-Me), L-Bip(2,4-di-Me), L-Bip(2,6-di-Me), L-Bip(2,4-di-Et), L-Bip(2-Me, 2′-Me), L-Bip(2-Et, 2′-Me), L-Bip(2-Et, 2′-Et), L-Bip(2-Me,4-OMe), L-Bip(2-Et,4-OMe), D-Bip(2-Et, 4-OMe), L-Bip(3-OMe), L-Bip(4-OMe), L-Bip(2,4,6-tri-Me), L-Bip(2,3-di-OMe), L-Bip(2,4-di-OMe), L-Bip(2,5-di-OMe), L-Bip(3,4-di-OMe), L-Bip(2-Et,4,5-di-OMe), L-Bip(3,4-Methylene-di-oxy), L-Bip(2-Et, 4,5-Methylene-di-oxy), L-Bip(2-CH 2 OH, 4-OMe), L-Bip(2-Ac), L-Bip(3-NH-Ac), L-Bip(4-NH-Ac), L-Bip(2,3-di-Chloro), L-Bip(2,4-di-Chloro), L-Bip(2,5-di-Chloro), L-Bip(3,4-di-Chloro), L-Bip(4-Fluoro), L-Bip(3,4-di-Fluoro), L-Bip(2,5-di-Fluoro), L-Bip(3-n-Propyl), L-Bip(4-n-Propyl), L-Bip(2-iso-Propyl), L-Bip(3-iso-Propyl), L-Bip(4-iso-Propyl), L-Bip(4-tert-Butyl), L-Bip(3-Phenyl), L-Bip(2-Chloro), L-Bip(3-Chloro), L-Bip(2-Fluoro), L-Bip(3-Fluoro), L-Bip(2-CF 3 ), L-Bip(3-CF 3 ), L-Bip(4-CF 3 ), L-Bip(3-NO 2 ), L-Bip(3-OCF 3 ), L-Bip(4-OCF 3 ), L-Bip(2-OEt), L-Bip(3-OEt), L-Bip(4-OEt), L-Bip(4-SMe), L-Bip(2-OH), L-Bip(3-OH), L-Bip(4-OH), L-Bip(2-CH 2 —COOH), L-Bip(3-CH 2 —COOH), L-Bip(4-CH 2 —COOH), L-Bip(2-CH 2 —NH 2 ), L-Bip(3-CH 2 —NH 2 ), L-Bip(4-CH 2 —NH 2 ), L-Bip(2-CH 2 —OH), L-Bip(3-CH 2 —OH), L-Bip(4-CH 2 —OH), L-Phe[4-(1-propargyl)], L-Phe[4-(1-propenyl)], L-Phe[4-n-Butyl], L-Phe[4-Cyclohexyl], Phe(4-Phenyloxy), L-Phe(penta-Fluoro), L-2-(9,10-Dihydrophenanthrenyl)-Ala, 4-(2-Benzo(b)furan)-Phe, 4-(4-Dibenzofuran)-Phe, 4-(4-Phenoxathiin)-Phe, 4-(2-Benzo(b)thiophene)-Phe, 4-(3-thiophene)-Phe, 4-(3-Quinoline)-Phe, 4-(2-Naphthyl)-Phe, 4-(1-Naphthyl)-Phe, 4-(4-(3,5-dimethylisoxazole))-Phe, 4-(2,4-dimethoxypyrimidine)-Phe, homoPhe, Tyr(Bzl), Phe(3,4-di-Chloro), Phe(4-Iodo), 2-Naphthyl-Ala, L-α-Me-Bip and D-α-Me-Bip; and A is selected from the group consisting of H, Acetyl, β-Ala, Ahx, Gly, Asp, Glu, Phe, Lys, Nva, Asn, Arg, Ser, Thr, Val, Trp, Tyr, Caprolactam, L-Bip, L-Ser(Bzl), 3-PyridylAla, Phe(4-Me), Phe(penta-Fluoro), 4-Methylbenzyl, 4-Fluorobenzyl, n-propyl, n-hexyl, cyclohexylmethyl, 6-hydroxypentyl, 2-Thienylmethyl, 3-Thienylmethyl, penta-Fluorobenzyl, 2-naphthylmethyl, 4-biphenylmethyl, 9-Anthracenylmethyl, benzyl, (S)-(2-amino-3-phenyl)propyl, methyl, 2-aminoethyl and (S)-2-Aminopropyl.  
     
     
         34 . An isolated polypeptide of  claim 24  wherein said polypeptide is a 10-mer to 15-mer and said polypeptide binds and activates a GLP-1 receptor.  
     
     
         35 . An isolated polypeptide having a sequence of Formula I  
         A-X aa1 -X aa2 -X aa3 -X aa4 -X aa5 -X aa6 -X aa7 -X aa8 -X aa9 -Y-Z-B  I  wherein, X aa1-9  is a naturally or nonnaturally occurring amino acid residue; Y is an amino acid residue; wherein one of the substitutions at the alpha-carbon atom of Y may each independently be substituted with a primary substituent group selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl, said primary substituent optionally being substituted with a primary or secondary substituent selected from a cycloalkyl, heterocycle, aryl or heteroaryl group; any of said secondary substituents may further be substituted with one or more of, hydrogen, alkyl, cycloalkyl, arylalkyl, aryl, heterocycle, heteroaryl, alkenyl, alkynyl, halo, hydroxy, mercapto, nitro, cyano, amino, acylamino, azido, guanidino, amidino, carboxyl, carboxamido, carboxamido alkyl, formyl, acyl, carboxyl alkyl, alkoxy, aryloxy, arylalkyloxy, heteroaryloxy, heterocycleoxy, acyloxy, mercapto, mercapto alkyl, mercaptoaryl, mercapto acyl, halo, cyano, nitro, azido, amino, guanidino alkyl, guanidino acyl, sulfonic, sulfonamido, alkyl sulfonyl, aryl sulfonyl or phosphonic group; wherein, the primary or secondary substitutents may optionally be bridged by covalent bonds to form one or more fused cyclic or heterocyclic systems with each other; wherein, the other substitution at the alpha-carbon of Y may be substituted with hydrogen, alkyl, aminoalkyl, hydroxyalkyl or carboxyalkyl; A and B are optionally present; wherein A is not present, and X aa1  is an R group, an R—C(O) (amide) group, a carbamate group RO—C(O), a urea R 4 R 5 N—C(O), a sulfonamido R—SO 2  or a R 4 R 5 N—SO 2 ; wherein R is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl, heteroaryloxyalkyl and heteroarylalkoxyalkyl; wherein R 4  and R 5  are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl and heteroaryloxyalky; wherein B is not present and Z is OR 1 , NR 1 R 2  or an amino-alcohol; and wherein R 1  and R 2  are independently chosen from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl or heteroaryloxyalkyl.    
     
     
         36 . The isolated polypeptide of  claim 35  wherein the substitutions upon the alpha-carbon atoms of Y are selected from the group consisting of heteroarylarylmethyl, arylheteroarylmethyl or biphenylmethyl forming biphenylalanine residues, any of which is also optionally substituted with one or more, hydrogen, alkyl, cycloalkyl, arylalkyl, aryl, heterocycle, heteroaryl, alkenyl, alkynyl, halo, hydroxy, mercapto, nitro, cyano, amino, acylamino, azido, guanidino, amidino, carboxyl, carboxamido, carboxamido alkyl, formyl, acyl, carboxyl alkyl, alkoxy, aryloxy, arylalkyloxy, heteroaryloxy, heterocycleoxy, acyloxy, mercapto, mercapto alkyl, mercaptoaryl, mercapto acyl, halo, cyano, nitro, azido, amino, guanidino alkyl, guanidino acyl, sulfonic, sulfonamido, alkyl sulfonyl, aryl sulfonyl and phosphonic group.  
     
     
         37 . The isolated polypeptide of  claim 35  wherein X aa2  and X aa3  are N—H or N-alkylated amino acids residues.  
     
     
         38 . The isolated polypeptide of  claim 37  wherein X aa2  and X aa3  are N—H or N-methylated amino acid residues.  
     
     
         39 . The isolated polypeptide of  claim 35  wherein the other substitution at the alpha-carbon of Y is substituted with methyl or ethyl.  
     
     
         40 . The isolated polypeptide of  claim 35  wherein R, R 4  and R 5  are heteroarylalkyl or heterocycloalkyl, or R, R 4  and R 5  are cycloalkyl, cycloalkylalkyl, heterocycle, aryl, arylalkyl or aryloxyalkyl substituted with heteroaryl or heterocycle.  
     
     
         41 . The isolated polypeptide of  claim 35  wherein X aa2  is naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is an alkyl or cycloalkyl where the alkyl group may optionally form a ring with the nitrogen of X aa2 , and wherein the other substitution at the alpha-carbon is hydrogen or alkyl; X aa3  is a naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is selected from the group consisting of a carboxyalkyl, bis-carboxyalkyl, sulfonylalkyl, heteroalkyl and mercaptoalkyl, and wherein the other substitution at the alpha-carbon is hydrogen or alkyl; X aa4  is a naturally or nonnaturally occurring amino acid residue in which the alpha-carbon is not substituted, or in which one of the substitutions at the alpha-carbon is selected from the group consisting of aminoalkyl, carboxyalkyl heteroarylalkyl and heterocycylalkyl; X aa5  is a naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is an alkyl or hydroxyalkyl, and wherein the other substitution at the alpha-carbon is hydrogen or alkyl; X aa6  is a naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is selected from the group consisting of alkyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, heterocyclealkyl, arylalkyl and heteroarylalkyl, and wherein the other substitution at the alpha-carbon is hydrogen or alkyl; X aa7  is a naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is a hydroxylalkyl group; X aa8  is a naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is selected from the group consisting of alkyl, hydroxylalkyl, heteroarylalkyl and carboxamidoalkyl, and wherein the other substitution at the alpha-carbon is hydrogen or alkyl; and X aa9  is a naturally or nonnaturally occurring amino acid residue in which one of the substitutions at alpha-carbon is selected from the group consisting of carboxylalkyl, bis-carboxylalkyl, carboxylaryl, sulfonylalkyl, carboxylamidoalkyl and heteroarylalkyl.  
     
     
         42 . The isolated polypeptide of  claim 41  wherein X aa2  is an amino acid residue selected from the group consisting of L-Ala, D-Ala, L-Pro, Gly, D-Ser, D-Asn, L-N-Methyl-Ala, D-N-Methyl-Ala, L-4-ThioPro, L-Pro(t-4-OH), L-2-Pip, L-2-Azt, Aib, S— or R-Iva and Acc 3 ; X aa3  is an amino acid residue selected from the group consisting of L-Glu, L-N-Methyl-Glu, L-Asp, D-Asp, L-His, L-Gla, L-Adp, L-Cys and L-4-ThiazolylAla; X aa4  is an amino acid residue selected from the group consisting of Gly, L-His, L-Lys and L-Asp; X aa5  is an amino acid residue selected from the group consisting of L-Thr, D-Thr, L-Nle, L-Met, L-Nva and L-Aoc; X aa6  is an amino acid residue selected from the group consisting of L-Phe, L-Tyr, L-Tyr(Bzl), Tyr(3-NO 2 ), L-Nle, L-Trp, L-Phe(penta-Fluoro), D-Phe(penta-Fluoro), Phe(2-Fluoro), Phe(3-Fluoro), Phe(4-Fluoro), Phe(2,3-di-Fluoro), Phe(3,4-di-Fluoro), Phe(3,5-di-Fluoro), L-Phe(2,6-di-Fluoro), Phe(3,4,5-tri-Fluoro), Phe(2-Iodo), Phe(2-OH), Phe(2-OMethyl), Phe(3-OMethyl), Phe(3-Cyano), Phe(2-Chloro), Phe(2-NH 2 ), Phe(3-NH 2 ), Phe(4-NH 2 ), Phe(4-NO 2 ), Phe(4-Methyl), Phe(4-Allyl), Phe(n-butyl), Phe(4-Cyclohexyl), Phe(4-Cyclohexyloxy), Phe(4-Phenyloxy), 2-NaphthylAla, 2-PyridylAla, L-4-ThiazolylAla, L-2-Thi, L-α-Me-Phe, D-α-Me-Phe, L-α-Et-Phe, D-α-Et-Phe, L-α-Me-Phe(2-Fluoro), D-α-Me-Phe(2-Fluoro), L-α-Me-Phe(2,3-di-Fluoro), D-α-Me-Phe(2,3-di-Fluoro), L-α-Me-Phe(2,6-di-Fluoro), D-α-Me-Phe(2,6-di-Fluoro), L-α-Me-Phe(penta-Fluoro) and D-α-Me-Phe(penta-Fluoro); X aa7  is an amino acid residue selected from the group consisting of L-Thr, D-Thr, L-Ser and L-hSer; X aa8  is an amino acid residue selected from the group consisting of L-Ser, L-hSer, L-His, L-Asn and L-α-Me-Ser; and X aa9  is an amino acid residue selected from the group consisting of L-Asp, L-Glu, L-Gla, L-Adp, L-Asn and L-His.  
     
     
         43 . The isolated polypeptide of  claim 35  wherein Y is selected from the group consisting of L-Bip, D-Bip, L-Bip(2-Me), D-Bip(2-Me), L-Bip(2′-Me), L-Bip(2-Et), D-Bip(2-Et), L-Bip(3-Et), L-Bip(4-Et), L-Bip(2-n-Propyl), L-Bip(2-n-Propyl, 4-OMe), L-Bip(2-n-Propyl,2′-Me), L-Bip(3-Me), L-Bip(4-Me), L-Bip(2,3-di-Me), L-Bip(2,4-di-Me), L-Bip(2,6-di-Me), L-Bip(2,4-di-Et), L-Bip(2-Me, 2′-Me), L-Bip(2-Et, 2′-Me), L-Bip(2-Et, 2′-Et), L-Bip(2-Me,4-OMe), L-Bip(2-Et,4-OMe), D-Bip(2-Et,4-OMe), L-Bip(3-OMe), L-Bip(4-OMe), L-Bip(2,4,6-tri-Me), L-Bip(2,3-di-OMe), L-Bip(2,4-di-OMe), L-Bip(2,5-di-OMe), L-Bip(3,4-di-OMe), L-Bip(2-Et,4,5-di-OMe), L-Bip(3,4-Methylene-di-oxy), L-Bip(2-Et, 4,5-Methylene-di-oxy), L-Bip(2-CH 2 OH, 4-OMe), L-Bip(2-Ac), L-Bip(3-NH-Ac), L-Bip(4-NH-Ac), L-Bip(2,3-di-Chloro), L-Bip(2,4-di-Chloro), L-Bip(2,5-di-Chloro), L-Bip(3,4-di-Chloro), L-Bip(4-Fluoro), L-Bip(3,4-di-Fluoro), L-Bip(2,5-di-Fluoro), L-Bip(3-n-Propyl), L-Bip(4-n-Propyl), L-Bip(2-iso-Propyl), L-Bip(3-iso-Propyl), L-Bip(4-iso-Propyl), L-Bip(4-tert-Butyl), L-Bip(3-Phenyl), L-Bip(2-Chloro), L-Bip(3-Chloro), L-Bip(2-Fluoro), L-Bip(3-Fluoro), L-Bip(2-CF 3 ), L-Bip(3-CF 3 ), L-Bip(4-CF 3 ), L-Bip(3-NO 2 ), L-Bip(3-OCF 3 ), L-Bip(4-OCF 3 ), L-Bip(2-OEt), L-Bip(3-OEt), L-Bip(4-OEt), L-Bip(4-SMe), L-Bip(2-OH), L-Bip(3-OH), L-Bip(4-OH), L-Bip(2-CH 2 —COOH), L-Bip(3-CH 2 —COOH), L-Bip(4-CH 2 —COOH), L-Bip(2-CH 2 —NH 2 ), L-Bip(3-CH 2 —NH 2 ), L-Bip(4-CH 2 —NH 2 ), L-Bip(2-CH 2 —OH), L-Bip(3-CH 2 —OH), L-Bip(4-CH 2 —OH), L-Phe[4-(1-propargyl)], L-Phe[4-(1-propenyl)], L-Phe[4-n-Butyl], L-Phe[4-Cyclohexyl], Phe(4-Phenyloxy), L-Phe(penta-Fluoro), L-2-(9,10-Dihydrophenanthrenyl)-Ala, 4-(2-Benzo(b)furan)-Phe, 4-(4-Dibenzofuran)-Phe, 4-(4-Phenoxathiin)-Phe, 4-(2-Benzo(b)thiophene)-Phe, 4-(3-thiophene)-Phe, 4-(3-Quinoline)-Phe, 4-(2-Naphthyl)-Phe, 4-(1-Naphthyl)-Phe, 4-(4-(3,5-dimethylisoxazole))-Phe, 4-(2,4-dimethoxypyrimidine)-Phe, homoPhe, Tyr(Bzl), Phe(3,4-di-Chloro), Phe(4-Iodo), 2-Naphthyl-Ala, L-α-Me-Bip and D-α-Me-Bip.  
     
     
         44 . The isolated polypeptide of  claim 35  wherein such polypeptide is a 10-mer to 15-mer and such polypeptide and binds to and activates the GLP-1 receptor.  
     
     
         45 . A method of making a polypeptide recognized by the family of B G-protein coupled receptors wherein the polypeptide mimics the activity of a polypeptide receptor agonist, said polypeptide having the formula  
       
         
           
           
               
               
           
         
         the method comprising replacing an address sequence of the polypeptide receptor agonist with Y and Z, wherein Y and Z are amino acid residues; wherein one of the substitutions at the alpha-carbon atoms of Y and Z may each independently be substituted with a primary substituent group selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl, heterocyclyl said primary substituent optionally being substituted with a secondary substituent selected from a cycloalkyl, heterocyclyl, aryl or heteroaryl group; any of said primary or secondary substituents may further be substituted with one or more of, hydrogen, alkyl, cycloalkyl, arylalkyl, aryl, heterocyclyl, heteroaryl, alkenyl, alkynyl, halo, hydroxy, mercapto, nitro, cyano, amino, acylamino, azido, guanidino, amidino, carboxyl, carboxamido, carboxamido alkyl, formyl, acyl, carboxyl alkyl, alkoxy, aryloxy, arylalkyloxy, heteroaryloxy, heterocycleoxy, acyloxy, mercapto, mercapto alkyl, mercaptoaryl, mercapto acyl, halo, cyano, nitro, azido, amino, guanidino alkyl, guanidino acyl, sulfonic, sulfonamido, alkyl sulfonyl, aryl sulfonyl or phosphonic group; wherein, the primary or secondary substitutents may optionally be bridged by covalent bonds to form one or more fused cyclic or heterocyclic systems with each other; wherein, the other substitution at the alpha-carbon of Y may be substituted with hydrogen, alkyl, aminoalkyl, hydroxyalkyl or carboxyalkyl; wherein, the other substitution at the alpha-carbon of Z may be substituted with hydrogen, alkyl, aminoalkyl, hydroxyalkyl or carboxyalkyl; and wherein X aa1 -X aan  is a message sequence capable of inducing receptor mediated signal transduction.  
       
     
     
         46 . The method of  claim 45  wherein the polypeptide mimics the activity of an endogenous polypeptide receptor agonist.  
     
     
         47 . The method of  claim 45  wherein the polypeptide receptor agonist is GLP-1.  
     
     
         48 . The method of  claim 45  further comprising replacing the message sequence of the polypeptide receptor agonist with a variant message sequence capable of inducing receptor mediated signal transduction.  
     
     
         49 . A pharmaceutical composition comprising a polypeptide of  claim 1  and a pharmaceutically acceptable carrier therefor.  
     
     
         50 . A pharmaceutical combination comprising a polypeptide of  claim 49  and at least one therapeutic agent selected from the group consisting of an antidiabetic agent, an anti-obesity agent, an anti-hypertensive agent, an anti-atherosclerotic agent and a lipid-lowering agent.  
     
     
         51 . The combination of  claim 50  wherein the antidiabetic agent is at least one agent selected from the group consisting of a biguanide, a GPR119 agonist, a sulfonyl urea, a glucosidase inhibitor, a PPAR γ agonist, a PPAR α/γ dual agonist, an aP2 inhibitor, a DP4 inhibitor, an insulin sensitizer, a glucagon-like peptide-1 (GLP-1), insulin and a meglitinide.  
     
     
         52 . The combination of  claim 51  wherein the antidiabetic agent is at least one agent selected from the group consisting of metformin, glyburide, glimepiride, glipyride, glipizide, chlorpropamide, gliclazide, acarbose, miglitol, pioglitazone, troglitazone, rosiglitazone, insulin, farglitizar, isaglitazone, reglitizar, balaglitazone, (Z)-1,4-bis{4-[(3,5-Dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy} but-2-ene, rivoglitazone, rafaegron, repaglinide, nateglinide, (S)-2-benzyl-4-oxo-4-(cis-perhydroisoindol-2-yl)butyric acid calcium salt, tesaglitizar, L-phenylalanine, N-[(1Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]-4-[3-(5-methyl-2-phenyl-4-oxazolyl)propyl], benzamide, 5-[(2,4-dioxo-5-thiazolidinyl)methyl]-2-methoxy-N-[[4-(trifluoromethyl)phenyl]methyl], exenatide, 8-37-glucagon-like peptide I (human)-N-[3-(1H-imidazol-4-yl)-1-oxopropyl]-26-L-arginine-34-[N6-(1-oxooctyl)-L-lysine], and vildagliptin.  
     
     
         53 . The combination of  claim 50  wherein the anti-obesity agent is at least one agent selected from the group consisting of a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin reuptake inhibitor, a dopamine reuptake inhibitor, a serotonin and dopamine reuptake inhibitor, a thyroid receptor beta compound, and an anorectic agent.  
     
     
         54 . The combination of  claim 53  wherein the anti-obesity agent is at least one agent selected from the group consisting of orlistat, cetilistat, rafabregon, N-[4-[2-[[(2S)-3-[(6-amino-3-pyridinyl)oxy]-2-hydroxypropyl]amino]ethyl]phenyl]-4-(1-methylethyl)-benzenesulfonamide, sibutramine, topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine and mazindol.  
     
     
         55 . The combination of  claim 50  wherein the lipid lowering agent is at least one agent selected from the group consisting of an MTP inhibitor, cholesterol ester transfer protein, an HMG CoA reductase inhibitor, a squalene synthetase inhibitor, a fibric acid derivative, an upregulator of LDL receptor activity, a lipoxygenase inhibitor, or an ACAT inhibitor.  
     
     
         56 . The combination of  claim 55  wherein the lipid lowering agent is at least one agent selected from the group consisting of pravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, nisvastatin, visastatin, fenofibrate, gemfibrozil, clofibrate, avasimibe, N-[2,6-bis(1-methylethyl)phenyl]-2-(tetradecylthio)-acetamide, 3-(13-hydroxy-10-oxotetradecyl)-5,7-dimethoxy-1(3H)-isobenzofuranone, torcetrapib, and (3 alpha,4 alpha,5 alpha)-4-(2-propenylcholestan-3-ol).  
     
     
         57 . A method for treating or delaying the progression or onset of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, Syndrome X, diabetic complications, elevated blood levels of free fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, atherosclerosis or hypertension, which comprises administering to a mammalian species in need of treatment a therapeutically effective amount of a polypeptide of  claim 1 .  
     
     
         58 . The method of  claim 57  further comprising administering, a therapeutically effective amount of at least one additional therapeutic agent selected from the group consisting of an antidiabetic agent, an anti-obesity agent, a anti-hypertensive agent, an anti-atherosclerotic agent and a lipid-lowering agent.  
     
     
         59 . A method for treating or delaying the progression or onset of diabetes or a diabetes-related condition comprising administering a therapeutically effective amount of an isolated polypeptide comprising the amino acid sequence of SEQ ID NO: 456.  
     
     
         60 . The method of  claim 59  wherein said isolated peptide is administered as a pharmaceutical composition.  
     
     
         61 . The method of  claim 59  wherein said diabetes-related condition is a condition selected from the group consisting of diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, Syndrome X, diabetic complications, elevated blood levels of free fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, atherosclerosis and hypertension.  
     
     
         62 . The method of  claim 59  further comprising administering, a therapeutically effective amount of at least one additional therapeutic agent selected from the group consisting of an antidiabetic agent, an anti-obesity agent, a anti-hypertensive agent, an anti-atherosclerotic agent and a lipid-lowering agent.  
     
     
         63 . The method of  claim 62  wherein the antidiabetic agent is at least one agent selected from the group consisting of a biguanide, a sulfonyl urea, a glucosidase inhibitor, a peroxisome proliferator-activated receptor (PPAR) γ agonist, a PPAR α/γ dual agonist, an adipocyte lipid binding protein (aP2) inhibitor, a dipeptidyl peptidase 4 (DP4) inhibitor, an insulin sensitizer, a glucagon-like peptide-1 (GLP-1), insulin and a meglitinide.  
     
     
         64 . The method of  claim 63  wherein the antidiabetic agent is at least one agent selected from the group consisting of metformin, glyburide, glimepiride, glipyride, glipizide, chlorpropamide, gliclazide, acarbose, miglitol, pioglitazone, troglitazone, rosiglitazone, insulin, farglitizar, isaglitazone, reglitizar, balaglitazone, (Z)-1,4-bis{4-[(3,5-Dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy} but-2-ene, rivoglitazone, rafaegron, repaglinide, nateglinide, (S)-2-benzyl-4-oxo-4-(cis-perhydroisoindol-2-yl)butyric acid calcium salt, tesaglitizar, L-phenylalanine, N-[(1Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]-4-[3-(5-methyl-2-phenyl-4-oxazolyl)propyl], 5-[(2,4-dioxo-5-thiazolidinyl)methyl]-2-methoxy-N-[[4-(trifluoromethyl)phenyl]methyl]-benzamide, exenatide, 8-37-glucagon-like peptide I (human)-N-[3-(1H-imidazol-4-yl)-1-oxopropyl]-26-L-arginine-34-[N6-(1-oxooctyl)-L-lysine], and vildagliptin.  
     
     
         65 . The method of  claim 62  wherein the anti-obesity agent is at least one agent selected from the group consisting of a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin reuptake inhibitor, a dopamine reuptake inhibitor, a serotonin and dopamine reuptake inhibitor, a thyroid receptor beta compound, and an anorectic agent.  
     
     
         66 . The method of  claim 65  wherein the anti-obesity agent is at least one agent selected from the group consisting of orlistat, cetilistat, rafabregon, N-[4-[2-[[(2S)-3-[(6-amino-3-pyridinyl)oxy]-2-hydroxypropyl]amino]ethyl]phenyl]-4-(1-methylethyl)-benzenesulfonamide, sibutramine, topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine and mazindol.  
     
     
         67 . The method of  claim 62  wherein the lipid lowering agent is at least one agent selected from the group consisting of a microsomal triglyceride transfer protein (MTP) inhibitor, cholesterol ester transfer protein, a hydroxy-3-methyl-glutaryl-coenzyme A (HMG CoA) reductase inhibitor, a squalene synthetase inhibitor, a fibric acid derivative, an upregulator of low-density lipoprotein (LDL) receptor activity, a lipoxygenase inhibitor, or an acyl coenzyme A-cholesterol acyltransferase (ACAT) inhibitor.  
     
     
         68 . The method of  claim 67  wherein the lipid lowering agent is at least one agent selected from the group consisting of pravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, nisvastatin, visastatin, fenofibrate, gemfibrozil, clofibrate, avasimibe, N-[2,6-bis(1-methylethyl)phenyl]-2-(tetradecylthio)-acetamide, 3-(13-hydroxy-10-oxotetradecyl)-5,7-dimethoxy-1(3H)-isobenzofuranone, torcetrapib, and (3 alpha,4 alpha,5 alpha)-4-(2-propenylcholestan-3-ol).  
     
     
         69 . The method of  claim 59  wherein the isolated polypeptide is selected from the group consisting of SEQ ID NOs: 1-23, 25-27, 31-32, 34-140, 142-145, 148, 150, 153-155, 157-160, 162, 164, 166, 168-227, 231-234, 236, 238-271, 276-290, 292, 294-295, 274-455, and 457-517.  
     
     
         70 . A method for treating or delaying the progression or onset of diabetes or a diabetes-related condition comprising administering a therapeutically effective amount of an isolated polypeptide selected from the group consisting of SEQ ID NOs: 1-23, 25-27, 31-32, 34-140, 142-145, 148, 150, 153-155, 157-160, 162, 164, 166, 168-227, 231-234, 236, 238-271, 276-290, 292, 294-295, 274-455, and 457-517.  
     
     
         71 . An isolated polypeptide comprising the amino acid sequence of SEQ ID NO: 518 wherein said polypeptide binds and activates a GLP-1 receptor.  
     
     
         72 . A pharmaceutical composition comprising a polypeptide of  claim 71 , and a pharmaceutically acceptable carrier.  
     
     
         73 . A pharmaceutical combination comprising a polypeptide of  claim 71  and at least one therapeutic agent selected from the group consisting of an antidiabetic agent, an anti-obesity agent, an anti-hypertensive agent, an anti-atherosclerotic agent and a lipid-lowering agent.  
     
     
         74 . The combination of  claim 73  wherein the antidiabetic agent is at least one agent selected from the group consisting of a biguanide, a sulfonyl urea, a glucosidase inhibitor, a peroxisome proliferator-activated receptor (PPAR) γ agonist, a PPAR α/γ dual agonist, an adipocyte lipid binding protein (aP2) inhibitor, a dipeptidyl peptidase 4 (DP4) inhibitor, an insulin sensitizer, a glucagon-like peptide-1 (GLP-1), insulin and a meglitinide.  
     
     
         75 . The combination of  claim 74  wherein the antidiabetic agent is at least one agent selected from the group consisting of metformin, glyburide, glimepiride, glipyride, glipizide, chlorpropamide, gliclazide, acarbose, miglitol, pioglitazone, troglitazone, rosiglitazone, insulin, farglitizar, isaglitazone, reglitizar, balaglitazone, (Z)-1,4-bis{4-[(3,5-Dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy} but-2-ene, rivoglitazone, rafaegron, repaglinide, nateglinide, (S)-2-benzyl-4-oxo-4-(cis-perhydroisoindol-2-yl)butyric acid calcium salt, tesaglitizar, L-phenylalanine, N-[(1Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]-4-[3-(5-methyl-2-phenyl-4-oxazolyl)propyl], 5-[(2,4-dioxo-5-thiazolidinyl)methyl]-2-methoxy-N-[[4-(trifluoromethyl)phenyl]methyl]-benzamide, exenatide, 8-37-glucagon-like peptide I (human)-N-[3-(1H-imidazol-4-yl)-1-oxopropyl]-26-L-arginine-34-[N6-(1-oxooctyl)-L-lysine], and vildagliptin.  
     
     
         76 . The combination of  claim 73  wherein the anti-obesity agent is at least one agent selected from the group consisting of a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin reuptake inhibitor, a dopamine reuptake inhibitor, a serotonin and dopamine reuptake inhibitor, a thyroid receptor beta compound, and an anorectic agent.  
     
     
         77 . The combination of  claim 76  wherein the anti-obesity agent is at least one agent selected from the group consisting of orlistat, cetilistat, rafabregon, N-[4-[2-[[(2S)-3-[(6-amino-3-pyridinyl)oxy]-2-hydroxypropyl]amino]ethyl]phenyl]-4-(1-methylethyl)-benzenesulfonamide, sibutramine, topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine and mazindol.  
     
     
         78 . The combination of  claim 73  wherein the lipid lowering agent is at least one agent selected from the group consisting of a microsomal triglyceride transfer protein (MTP) inhibitor, cholesterol ester transfer protein, a hydroxy-3-methyl-glutaryl-coenzyme A (HMG CoA) reductase inhibitor, a squalene synthetase inhibitor, a fibric acid derivative, an upregulator of low-density lipoprotein (LDL) receptor activity, a lipoxygenase inhibitor, or an acyl coenzyme A-cholesterol acyltransferase (ACAT) inhibitor.  
     
     
         79 . The combination of  claim 78  wherein the lipid lowering agent is at least one agent selected from the group consisting of pravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, nisvastatin, visastatin, fenofibrate, gemfibrozil, clofibrate, avasimibe, N-[2,6-bis(1-methylethyl)phenyl]-2-(tetradecylthio)-acetamide, 3-(13-hydroxy-10-oxotetradecyl)-5,7-dimethoxy-1(3H)-isobenzofuranone, torcetrapib, and (3 alpha,4 alpha,5 alpha)-4-(2-propenylcholestan-3-ol).  
     
     
         80 . The isolated polypeptide of  claim 71  wherein said polypeptide is selected from the group consisting of SEQ ID NOs: 24, 28, 29, 30, 33, 141, 146, 147, 149, 151, 152, 156, 161, 163, 165, 167, 228, 229, 230, 235, 237, 272, 273, 274, 275, 291, 293 and 296.  
     
     
         81 . A pharmaceutical composition comprising a polypeptide of  claim 80 , and a pharmaceutically acceptable carrier.  
     
     
         82 . A pharmaceutical combination comprising a polypeptide of  claim 80  and at least one therapeutic agent selected from the group consisting of an antidiabetic agent, an anti-obesity agent, an anti-hypertensive agent, an anti-atherosclerotic agent and a lipid-lowering agent.  
     
     
         83 . The combination of  claim 82  wherein the antidiabetic agent is at least one agent selected from the group consisting of a biguanide, a sulfonyl urea, a glucosidase inhibitor, a PPAR γ agonist, a PPAR α/γ dual agonist, an aP2 inhibitor, a DP4 inhibitor, an insulin sensitizer, a GLP-1, insulin and a meglitinide.  
     
     
         84 . The combination of  claim 83  wherein the antidiabetic agent is at least one agent selected from the group consisting of metformin, glyburide, glimepiride, glipyride, glipizide, chlorpropamide, gliclazide, acarbose, miglitol, pioglitazone, troglitazone, rosiglitazone, insulin, farglitizar, isaglitazone, reglitizar, balaglitazone, (Z)-1,4-bis{4-[(3,5-Dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy} but-2-ene, rivoglitazone, rafaegron, repaglinide, nateglinide, (S)-2-benzyl-4-oxo-4-(cis-perhydroisoindol-2-yl)butyric acid calcium salt, tesaglitizar, L-phenylalanine, N-[(1Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]-4-[3-(5-methyl-2-phenyl-4-oxazolyl)propyl], 5-[(2,4-dioxo-5-thiazolidinyl)methyl]-2-methoxy-N-[[4-(trifluoromethyl)phenyl]methyl]-benzamide, exenatide, 8-37-glucagon-like peptide I (human)-N-[3-(1H-imidazol-4-yl)-1-oxopropyl]-26-L-arginine-34-[N6-(1-oxooctyl)-L-lysine], and vildagliptin.  
     
     
         85 . The combination of  claim 82  wherein the anti-obesity agent is at least one agent selected from the group consisting of a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin reuptake inhibitor, a dopamine reuptake inhibitor, a serotonin and dopamine reuptake inhibitor, a thyroid receptor beta compound, and an anorectic agent.  
     
     
         86 . The combination of  claim 85  wherein the anti-obesity agent is at least one agent selected from the group consisting of orlistat, cetilistat, rafabregon, N-[4-[2-[[(2S)-3-[(6-amino-3-pyridinyl)oxy]-2-hydroxypropyl]amino]ethyl]phenyl]-4-(1-methylethyl)-benzenesulfonamide, sibutramine, topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine and mazindol.  
     
     
         87 . The combination of  claim 82  wherein the lipid lowering agent is at least one agent selected from the group consisting of an MTP inhibitor, cholesterol ester transfer protein, an HMG CoA reductase inhibitor, a squalene synthetase inhibitor, a fibric acid derivative, an upregulator of LDL receptor activity, a lipoxygenase inhibitor, or an ACAT inhibitor.  
     
     
         88 . The combination of  claim 87  wherein the lipid lowering agent is at least one agent selected from the group consisting of pravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, nisvastatin, visastatin, fenofibrate, gemfibrozil, clofibrate, avasimibe, N-[2,6-bis(1-methylethyl)phenyl]-2-(tetradecylthio)-acetamide, 3-(13-hydroxy-10-oxotetradecyl)-5,7-dimethoxy-1(3H)-isobenzofuranone, torcetrapib, and (3 alpha,4 alpha,5 alpha)-4-(2-propenylcholestan-3-ol).  
     
     
         89 . An isolated polypeptide selected from the group consisting of: SEQ ID Nos: 24, 28, 29, 30, 33, 141, 146, 147, 149, 151, 152, 156, 161, 163, 165, 167, 228, 229, 230, 235, 237, 272, 273, 274, 275, 291, 293 and 296.  
     
     
         90 . A pharmaceutical composition comprising a polypeptide of  claim 89 , and a pharmaceutically acceptable carrier.  
     
     
         91 . A pharmaceutical combination comprising a polypeptide of  claim 89  and at least one therapeutic agent selected from the group consisting of an antidiabetic agent, an anti-obesity agent, an anti-hypertensive agent, an anti-atherosclerotic agent and a lipid-lowering agent.  
     
     
         92 . The combination of  claim 91  wherein the antidiabetic agent is at least one agent selected from the group consisting of a biguanide, a sulfonyl urea, a glucosidase inhibitor, a PPAR γ agonist, a PPAR α/γ dual agonist, an aP2 inhibitor, a DP4 inhibitor, an insulin sensitizer, a glucagon-like peptide-1 (GLP-1), insulin and a meglitinide.  
     
     
         93 . The combination of  claim 92  wherein the antidiabetic agent is at least one agent selected from the group consisting of metformin, glyburide, glimepiride, glipyride, glipizide, chlorpropamide, gliclazide, acarbose, miglitol, pioglitazone, troglitazone, rosiglitazone, insulin, farglitizar, isaglitazone, reglitizar, balaglitazone, (Z)-1,4-bis{4-[(3,5-Dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy} but-2-ene, rivoglitazone, rafaegron, repaglinide, nateglinide, (S)-2-benzyl-4-oxo-4-(cis-perhydroisoindol-2-yl)butyric acid calcium salt, tesaglitizar, L-phenylalanine, N-[(1Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]-4-[3-(5-methyl-2-phenyl-4-oxazolyl)propyl], benzamide, 5-[(2,4-dioxo-5-thiazolidinyl)methyl]-2-methoxy-N-[[4-(trifluoromethyl)phenyl]methyl], exenatide, 8-37-glucagon-like peptide I (human)-N-[3-(1H-imidazol-4-yl)-1-oxopropyl]-26-L-arginine-34-[N6-(1-oxooctyl)-L-lysine], and vildagliptin.  
     
     
         94 . The combination of  claim 91  wherein the anti-obesity agent is at least one agent selected from the group consisting of a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin reuptake inhibitor, a dopamine reuptake inhibitor, a serotonin and dopamine reuptake inhibitor, a thyroid receptor beta compound, and an anorectic agent.  
     
     
         95 . The combination of  claim 94  wherein the anti-obesity agent is at least one agent selected from the group consisting of orlistat, cetilistat, rafabregon, N-[4-[2-[[(2S)-3-[(6-amino-3-pyridinyl)oxy]-2-hydroxypropyl]amino]ethyl]phenyl]-4-(1-methylethyl)-benzenesulfonamide, sibutramine, topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine and mazindol.  
     
     
         96 . The combination of  claim 92  wherein the lipid lowering agent is at least one agent selected from the group consisting of an MTP inhibitor, cholesterol ester transfer protein, an HMG CoA reductase inhibitor, a squalene synthetase inhibitor, a fibric acid derivative, an upregulator of LDL receptor activity, a lipoxygenase inhibitor, or an ACAT inhibitor.  
     
     
         97 . The combination of  claim 96  wherein the lipid lowering agent is at least one agent selected from the group consisting of pravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, nisvastatin, visastatin, fenofibrate, gemfibrozil, clofibrate, avasimibe, N-[2,6-bis(1-methylethyl)phenyl]-2-(tetradecylthio)-acetamide, 3-(13-hydroxy-10-oxotetradecyl)-5,7-dimethoxy-1(3H)-isobenzofuranone, torcetrapib, and (3 alpha,4 alpha,5 alpha)-4-(2-propenylcholestan-3-ol).