Details for Patent: 6,890,898

Title:	Method of regulating glucose metabolism, and reagents related thereto
Abstract:	The present invention provides methods and compositions for modification and regulation of glucose and lipid metabolism, generally to reduce insulin resistance, hyperglycemia, hyperinsulinemia, obesity, hyperlipidemia, hyperlipoprotein-emia (such as chylomicrons, VLDL and LDL), and to regulate body fat and more generally lipid stores, and, more generally, for the improvement of metabolism disorders, especially those associated with diabetes, obesity and/or atherosclerosis.
Inventor(s):	Bachovchin; William W. (Melrose, MA), Plaut; Andrew G. (Lexington, MA), Drucker; Daniel (Toronto, CA)
Assignee:	Trustees of Tufts College (Medford, MA) 1149336 Ontario Inc. (Toronto, CA) New England Medical Center Hospitals, Inc. (Boston, MA)
Filing Date:	Jul 03, 2002
Application Number:	10/190,267
Claims:	1. A method for modifying glucose metabolism of an animal, comprising conjointly administering to the animal an inhibitor of dipeptidylpeptidase IV or a pharmaceutically acceptable salt thereof, in an amount sufficient to modify the glucose metabolism of an animal but not sufficient to suppress the immune system of the animal, and one or more other therapeutic agents, wherein the other therapeutic agent is selected from insulin, M1 receptor antagonists, prolactin inhibitors, agents acting on an ATP-dependent channel of .beta.-cells, metformin, and glucosidase inhibitors. 2. A method for treating Type II diabetes in an animal, comprising conjointly administering to the animal an inhibitor of dipeptidylpeptidase IV or a pharmaceutically acceptable salt thereof, in an amount sufficient to treat Type II diabetes but not sufficient to suppress the immune system of the animal, and one or more other therapeutic agents, wherein the other therapeutic agent is selected from insulin, M1 receptor antagonists, prolactin inhibitors, agents acting on an ATP-dependent channel of .beta.-cells, metformin, and glucosidase inhibitors. 3. The method of claim 1 or 2, wherein administering the inhibitor reduces one or more of insulin resistance, glucose intolerance, hyperglycemia, hyperinsulinemia, obesity, hyperlipidemia, or hyperlipoproteinemia. 4. The method of claim 1 or 2, Wherein the inhibitor bas an EC.sub.50 for modification of glucose metabolism which is at least one order of magnitude less than its EC.sub.50 for immunosuppression. 5. The method of claim 1 or 2, wherein the inhibitor has an EC.sub.50 for inhibition of glucose tolerance in the nanomolar or less range. 6. The method of claim 1 or 2, wherein the inhibitor has an EC.sub.50 for immunosuppression in the .mu.M or greater range. 7. The method of claim 1 or 2, wherein the inhibitor has a K.sub.i for DPIV inhibition of 10 nM or less. 8. The method of claim 1 or 2, wherein the inhibitor has a K.sub.i for DPIV inhibition of 1.0 nM or less. 9. The method of claim 1 or 2, wherein the inhibitor is peptidomimetic of a peptide selected from Pro-Pro, Ala-Pro, and (D)-Ala-(L)-Ala. 10. The method of claim 1 or 2, wherein the inhibitor has a molecular weight less than 7500 amu. 11. The method of claim 1 or 2, wherein the inhibitor is administered orally. 12. The method of claim 1 or 2, wherein the inhibitor is represented by the general formula: ##STR39## wherein A represents a 4-8 membered heterocycle including the N and a C.alpha. carbon; Z represents C or N; W represents CN, --CH.dbd.NR.sub.5, a functional group which reacts with an active site residue of the targeted protease, or ##STR40## R.sub.1 represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, or an amino-protecting group, or ##STR41## R.sub.2 is absent or represents one or more substitutions to the ring A, each of which can independently be a halogen, a lower alkyl, a lower alkenyl, a lower alkynl, a carbonyl, a thiocarbonyl, an amino, an acylamino, an amido, a cyano, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido, --(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.m OH, --(CH.sub.2).sub.m --O-lower alkyl, --(CH.sub.2).sub.m --O-lower alkenyl, --(CH.sub.2).sub.n --O--(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.m --SH, --(CH.sub.2).sub.m --S-lower alkyl, --(CH.sub.2).sub.m --S-lower alkenyl, or --(CH.sub.2).sub.n --S--(CH.sub.2).sub.m --R.sub.7 ; if Z is N, R.sub.3 represents hydrogen, if Z is C, R.sub.3 represents hydrogen or a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, an amino, an acylamino, an amido, a cyano, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido, --(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.m --OH, --(CH.sub.2).sub.m --O-lower alkyl, --(CH.sub.2).sub.m --O-lower alkenyl, --(CH.sub.2).sub.n --O--(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.m --SH, --(CH.sub.2).sub.m --S-lower alkyl, --(CH.sub.2).sub.m --S-lower alkenyl, or --(CH.sub.2).sub.n --S--(CH.sub.2).sub.m --R.sub.7 ; R.sub.5 represents a hydrogen, an alkyl, an alkenyl, an alkynyl, --C(X.sub.1)(X.sub.2)X.sub.3, --(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.n --OH, --(CH.sub.2).sub.n --O-alkyl, --(CH.sub.2).sub.n --O-alkenyl, --(CH.sub.2).sub.n --O-alkynyl, --(CH.sub.2).sub.n --O--(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.n --SH, --(CH.sub.2).sub.n --S-alkyl, --(CH.sub.2).sub.n --S-alkenyl, --(CH.sub.2).sub.n --S-alkynyl, --(CH.sub.2).sub.n --S--(CH.sub.2).sub.m --R.sub.7, --C(O)C(O)NH.sub.2, or --C(O)C(O)OR'.sub.7 ; R.sub.6 represents hydrogen, a halogen, an alkyl, an alkenyl, an alkynyl, an aryl, --(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.m --OH, --(CH.sub.2).sub.m --O-alkyl, --(CH.sub.2).sub.m --O-alkenyl, --(CH.sub.2).sub.m --O-alkynyl, --(CH.sub.2).sub.m --O--(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.m --SH, --(CH.sub.2).sub.m --S-alkyl, --(CH.sub.2).sub.m --S-alkenyl, --(CH.sub.2).sub.m --S-alkynyl, or --(CH.sub.2).sub.m --S--(CH.sub.2).sub.m --R.sub.7, ##STR42## R.sub.7 represents, for each occurrence, a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle; R.sub.7 represents, for each occurrence, hydrogen, or a substituted or unsubstituted alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl or heterocyclyl; R.sub.8 and R.sub.9 each independently represent hydrogen, alkyl, alknyl, --(CH.sub.2).sub.m --R.sub.7, --C(.dbd.O)-alkyl, --C(.dbd.O)-alkenyl, --C(.dbd.O)-alkynyl, or --C(.dbd.O)--(CH.sub.2).sub.m --R.sub.7, or R.sub.8 and R.sub.9 taken together with the N atom to which they are attached complete a heterocyclic ring having from 4 to 8 atoms in the ring structure; R.sub.50 represents O or S; R.sub.51 represents N.sub.3, SH, NH.sub.2, NO.sub.2 or OR'.sub.7 ; R.sub.52 represents hydrogen, a lower alkyl, an amine, OR'.sub.7, or a pharmaceutically acceptable salt, or R.sub.51 and R.sub.52 taken together with the phosphorous atom to which they are attached complete a heterocyclic ring having from 5 to 8 atoms in the ring structure; X.sub.1 represents a halogen; X.sub.2 and X.sub.3 each represent a hydrogen or a halogen; Y.sub.1 and Y.sub.2 can independently or together be OH, or a group capable of being to a hydroxyl group, including cyclic derivatives where Y.sub.1 and Y.sub.2 are connected via a ring having from 5 to 8 atoms in the ring structure; m is zero or an integer in the range of 1 to 8; and n is an integer in the range of 1 to 8. 13. The method of claim 12, wherein W represents CN, --CH.dbd.NR.sub.5, ##STR43## R.sub.5 represents H, an alkyl, an alkenyl, an alkynyl, --C(X.sub.1)(X.sub.2)X.sub.3, --(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.n --OH, --(CH.sub.2).sub.n --O-alkyl, --(CH.sub.2).sub.n --O-alkenyl, --(CH.sub.2).sub.n --O-alkynyl, --(CH.sub.2).sub.n --O--(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.n --SH, --(CH.sub.2).sub.n --S-alkyl, --(CH.sub.2).sub.n --S-alkenyl, --(CH.sub.2).sub.n --S-alkynyl, --(CH.sub.2).sub.n --S--(CH.sub.2).sub.m --R.sub.7, --C(O)C(O)NH.sub.2, or --C(O)C(O)OR'.sub.7 ; R.sub.7 represents, for each occurrence, a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl or heterocyclyl; R.sub.7 represents, for each occurrence, hydrogen, or a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle; and Y.sub.1 and Y.sub.2 can independently or together be OH, or a group capable of being hydrolyzed to a hydroxyl group, including cyclic derivatives where Y.sub.1 and Y.sub.2 are connected via a ring having from 5 to 8 atoms in the ring structure; R.sub.50 represents O or S; R.sub.51 represents N.sub.3, SH, NH.sub.2, NO.sub.2 or OR'.sub.7 ; R.sub.52 represents hydrogen, a lower alkyl, an amine, OR'.sub.7, or a pharmaceutically acceptable salt, or R.sub.51 and R.sub.52 taken together with the phosphorous atom to which they are attached complete a heterocyclic ring having from 5 to 8 atoms in the ring structure; X.sub.1 represents a halogen; X.sub.2 and X.sub.3 each represent a hydrogen or a halogen; m is zero or an integer in the range of 1 to 8; and n is an integer in the range of 1 to 8. 14. The method of claim 13, wherein the ring A is represented by the formula ##STR44## wherein n is an integer of 1 or 2. 15. The method of claim 13, wherein W represents ##STR45## 16. The method of claim 13, wherein R.sub.1 represents ##STR46## wherein R.sub.36 is a small hydrophobic group and R.sub.38 is hydrogen, or, R.sub.36 and R.sub.38 together form a 4-7 membered heterocycle including the N and the C.alpha. carbon, as defined for above; and R.sub.40 represents a C-terminally linked amino acid residue or amino acid analog, or C-terminally linked peptide or peptide analog, or an amino-protecting group. 17. The method of claim 13, wherein R.sub.2 is absent, or represents a small hydrophobic group. 18. The method of claim 13, wherein R.sub.3 is a hydrogen, or a small hydrophobic group. 19. The method of claim 12, wherein R.sub.5 is a hydrogen, or a halogenated lower alkyl. 20. The method of claim 13, wherein X.sub.1 is a fluorine, and X.sub.2 and X.sub.3, if halogens, are fluorine. 21. The method of claim 12, wherein the inhibitor is represented by the general formula: ##STR47## wherein R.sub.1 represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, or ##STR48## R.sub.6 represents hydrogen, a halogen, an alkyl, an alkenyl, an alkynyl, an aryl, --(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.m --OH, --(CH.sub.2).sub.m --O-alkyl, --(CH.sub.2).sub.m --O-alkenyl, --(CH.sub.2).sub.m --O-alkynyl, --(CH.sub.2).sub.m --O--(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.m --SH, --(CH.sub.2).sub.m --S-alkyl, --(CH.sub.2).sub.m --S-alkenyl, --(CH.sub.2).sub.m --S-alkynyl, --(CH.sub.2).sub.m --S--(CH.sub.2).sub.m --R.sub.7, ##STR49## R.sub.7 represents an aryl, a cycloalkyl, a cycloalkenyl, or a heterocycle; R.sub.8 and R.sub.9 each independently represent hydrogen, alkyl, alkenyl, --(CH.sub.2).sub.m --R.sub.7, --C(.dbd.O)alkyl, --C(.dbd.O)-alkenyl, --C(.dbd.O)-alkynyl, --C(.dbd.O)--(CH.sub.2).sub.m --R.sub.7, or R.sub.8 and R.sub.9 taken together with the N atom to which they are attached complete a heterocyclic ring having from 4 to 8 atoms in the ring structure; R.sub.11 and R.sub.12 each independently represent hydrogen, an alkyl, or a pharmaceutically acceptable salt, or R.sub.11 and R.sub.12 taken together with the O-B-O atoms to which they are attached complete a heterocyclic ring having from 5 to 8 atoms in the ring structure; m is zero or an integer in the range of 1 to 8; and n is an integer in the range of 1 to 8. 22. The method of claim 12, wherein the inhibitor is represented by the general formula: ##STR50## wherein R.sub.1 represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, or ##STR51## R.sub.6 represents hydrogen, a halogen, an alkyl, an alkenyl, an alkynyl, an aryl, --(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.m --OH, --(CH.sub.2).sub.m --O-alkyl, --(CH.sub.2).sub.m --O-alkenyl, --(CH.sub.2).sub.m --O-alkynyl, --(CH.sub.2).sub.m --O--(CH.sub.2).sub.m --R.sub.7, --(C).sub.m --SH, --(CH.sub.2).sub.m --S-alkyl, --(CH.sub.2).sub.m --S-alkenyl, --(CH.sub.2).sub.m --S-alkynyl, --(CH.sub.2).sub.m --S--(CH.sub.2).sub.m --R.sub.7, ##STR52## R.sub.7 represents an aryl, a cycloalkyl, a cycloalkenyl, or a heterocycle; R.sub.8 and R.sub.9 each independently represent hydrogen, alkyl, alkenyl, --(CH.sub.2).sub.m --R.sub.7, --C(.dbd.O)-alkyl, --C(.dbd.O)-alkenyl, -C(.dbd.O)-alkynyl, --C(.dbd.O)--(CH.sub.2).sub.m --R.sub.7, or R.sub.8 and R.sub.9 taken together with the N atom to which they are attached complete a heterocyclic ring having from 4 to 8 atoms in the ring structure; m is zero or an integer in the range of 1 to .sub.8 ; and n is an integer in the range of 1 to 8. 23. The method of claim 1 or 2, wherein the inhibitor is represented by the general formula: ##STR53## wherein R.sub.1 represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, or ##STR54## R.sub.6 represents hydrogen, a halogen, an alkyl, an alkenyl, an alkynyl, an aryl, --(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.m --OH, --(CH.sub.2).sub.m --O-alkyl, --(CH.sub.2).sub.m --O-alkenyl, --(CH.sub.2).sub.m --O-alkynyl, --(CH.sub.2).sub.m --O--(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.m --SH, --(CH.sub.2).sub.m --S-alkyl, --(CH.sub.2).sub.m --S-alkenyl, --(CH.sub.2).sub.m --S-alkynyl, --(CH.sub.2).sub.m --S--(CH.sub.2).sub.m --R.sub.7, ##STR55## R.sub.7 represents an aryl, a cycloalkyl, a cycloalkenyl, or a heterocycle; R.sub.8 and R.sub.9 each independently represent hydrogen, alkyl, alkenyl, --(CH.sub.2).sub.m --R.sub.7, --C(.dbd.O)-alkyl, --C(.dbd.O)-alkenyl, --C(.dbd.O)-alkynyl, --C(.dbd.O)--(CH.sub.2).sub.m --R.sub.7, or R.sub.8 and R.sub.9 taken together with the N atom to which they are attached complete a heterocyclic ring having from 4 to 8 atoms in the ring structure; X.sub.1, X.sub.2 and X.sub.3 each represent a hydrogen or a halogen; m is zero or an integer in the range of 1 to 8; and n is an integer in the range of 1 to 8. 24. The method of claim 13, wherein the inhibitor is represented by the general formula: ##STR56## wherein A represents a 4-8 membered heterocycle including an N and a C.alpha. carbon; W represents CN, --CH.dbd.NR.sub.5, ##STR57## R.sub.2 is absent or represents one or more substitutions to the ring A, each of which can independently be a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, an amino, an acylamino, an amido, a cyano, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido, --(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.m --OH, --(CH.sub.2).sub.m --O-lower alkyl, --(CH.sub.2).sub.m --O-lower alkenyl, --(CH.sub.2).sub.n --O--(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.m --SH, --(CH.sub.2).sub.m --S-lower alkyl, --(CH.sub.2).sub.m --S-lower alkenyl, or --(CH.sub.2).sub.n --S--(CH.sub.2).sub.m --R.sub.7 ; R.sub.3 represents a hydrogen or a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, an amino, an acylamino, an amido, a cyano, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido, --(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.m --OH, --(CH.sub.2).sub.m --O-lower alkyl, --(CH.sub.2).sub.m --O-lower alkenyl, --(CH.sub.2).sub.n --O--(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.m --SH, --(CH.sub.2).sub.m --S-lower alkyl, --(CH.sub.2).sub.m --S-lower alkenyl, or (CH.sub.2).sub.n --S--(CH.sub.2).sub.m --R.sub.7 ; R.sub.5 represents a hydrogen, an alkyl, an alkenyl, an alkynyl, --C(X.sub.1)(X.sub.2)X.sub.3, --(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.n --OH, --(CH.sub.2).sub.n --O-alkyl, --(CH.sub.2).sub.n --O-alkenyl, --(CH.sub.2).sub.n --O-alkynyl, --(CH.sub.2).sub.n --O--(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.n --SH, --(CH.sub.2).sub.n --S-alkyl, --(CH.sub.2).sub.n --S-alkenyl, --(CH.sub.2).sub.n --S-alkynyl, --(CH.sub.2).sub.n --S--(CH.sub.2).sub.m --R.sub.7, --C(O)C(O)NH.sub.2, or --C(O)C(O)OR'.sub.7 ; R.sub.7 represents, for each occurrence, a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl or heterocyclyl; R'.sub.7 represents, for each occurrence, hydrogen, or a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl or heterocyclyl; R.sub.32 is a small hydrophobic group; R.sub.30 represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, or an amino-protecting group; R.sub.50 represents O or S; R.sub.51 represents N.sub.3, SH, NH.sub.2, NO.sub.2 or OR'.sub.7 ; R.sub.52 represents hydrogen, a lower alkyl, an amine, OR'.sub.7, or a pharmaceutically acceptable salt, or R.sub.51 and R.sub.52 taken together with the phosphorous atom to which they are attached complete a heterocyclic ring having from 5 to 8 atoms in the ring structure; X.sub.1 represents a halogen; X.sub.2 and X.sub.3 each represent a hydrogen or a halogen; Y.sub.1 and Y.sub.2 can independently or together be OH, or a group capable of being hydrolyzed to a hydroxyl group, including cyclic derivatives where Y.sub.1 and Y.sub.2 are connected via a ring having from 5 to 8 atoms in the ring structure; m is zero or an integer in the range of 1 to 8; and n is an integer in the range of 1 to 8. 25. A method for modifying metabolism of a peptide hormone in an animal, comprising conjointly administering to the animal one or more inhibitors of dipeptidylpeptidase IV (DPIV) or a pharmaceutically acceptable salt thereof, in a amount sufficient to modify the metabolism of a peptide hormone but not sufficient to suppress the immune system of the animal, and one or more other therapeutic agents, wherein the other therapeutic agent is selected from insulin, M1 receptor antagonists, prolactin inhibitors, agents acting on an ATP-dependent channel of .beta.-cells, metformin, and glucosidase inhibitors, and the peptide hormone is selected from growth hormone-releasing factor (GHRF), vasoactive intestinal peptide (VIP), peptide histidine isoleucine (PHI), pituitary adenylate cyclase activating peptide (PACAP), gastric inhibitory peptide (GIP), helodermin, Peptide YY, and neuropeptide Y. 26. A method for modifying glucose metabolism of an animal, comprising conjointly administering to the animal, a boronyl peptidomimetic of a peptide selected from Pro-Pro, Ala-Pro, and (D)-Ala-(L)-Ala or a pharmaceutically acceptable salt thereof, in an amount sufficient to modify glucose metabolism but not sufficient to suppress the immune system of the animal, and one or more other therapeutic agents, wherein the other therapeutic agent is selected from insulin, M1 receptor antagonists, prolactin inhibitors, agents acting on an ATP-dependent channel of .beta.-cells, metformin, and glucosidase inhibitors. 27. The method of claim 26, wherein the boronyl peptidomimetic is represented in the general formula: ##STR58## wherein each A independently represents a 4-8 membered heterocycle including the N and a C.alpha. carbon; R.sub.2 is absent or represents one or more substitutions to the ring A, each of which can independently be a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, an amino, an acylamino, an amido, a cyano, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido, --(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.m --OH, --(CH.sub.2).sub.m --O-lower akyl, --(CH.sub.2).sub.m --O-lower alkenyl, --(CH.sub.2).sub.n --O--(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.m --SH, --(CH.sub.2).sub.m --S-lower alkyl, --(CH.sub.2).sub.m --S-lower alkenyl, or --(CH.sub.2).sub.n --S--(CH.sub.2).sub.m --R.sub.7 ; R.sub.3 represents hydrogen or a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, an amino, an acylamino, an amido, a cyano, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido, --(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.m --OH, --(CH.sub.2).sub.m --O-lower alkyl, --(CH.sub.2).sub.m --O-lower alkenyl, --(CH.sub.2).sub.n --O--(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.m --SH, --(CH.sub.2).sub.m --S-lower alkyl, --(CH.sub.2).sub.m --S-lower alkenyl, or --(CH.sub.2).sub.n --S--(CH.sub.2).sub.m --R.sub.7 ; R.sub.6 represents hydrogen, a halogen, an alkyl, an alkenyl, an alkynyl, an aryl, --(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.m --OH, --(CH.sub.2).sub.m --O-alkyl, --(CH.sub.2).sub.m --O-alkenyl, --(CH.sub.2).sub.m --O-alkynyl, --(CH.sub.2).sub.m --O--(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.m --SH, --(CH.sub.2).sub.m --S-alkyl, --(CH.sub.2).sub.m --S-alkenyl, --(CH.sub.2).sub.m --S-alkynyl or --(CH.sub.2).sub.m --S--(CH.sub.2).sub.m --R.sub.7 ; R.sub.7 represents, for each occurrence, a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle; R.sub.30 represents a C-terminally linked amino acid residue or amino acid analog, or C-terminally linked peptide or peptide analog, or an amino-protecting group, or ##STR59## R.sub.32 represents a small hydrophobic group; R.sub.62 represents lower alkyl or halogen; Y.sub.1 and Y.sub.2 can independently or together be OH, or a group capable of being hydrolyzed to a hydroxyl group, including cyclic derivatives where Y.sub.1 and Y.sub.2 are connected via a ring having from 5 to 8 atoms in the ring structure; m is zero or an integer in the range of 1 to 8; and n is an integer in the range of 1 to 8. 28. The method of claim 27, wherein administering the boronyl peptidomimetic reduces one or more of insulin resistance, glucose intolerance, hyperglycemia, hyperinsulinemia, obesity, hyperlipidemia, or hyperlipoproteinemia. 29. The method of claim 27, wherein the boronyl peptidomimetic has an EC.sub.50 for modification of glucose metabolism which is at least one order of magnitude less than its EC.sub.50 for immunosuppression. 30. The method of claim 27, wherein the boronyl peptidomimetic has an EC.sub.50 for inhibition of glucose tolerance in the nanomolar or less range. 31. The method of claim 27, wherein the boronyl peptidomimetic has an EC.sub.50 for inhibition of glucose tolerance of 10 nM or less. 32. The method of claim 27, wherein the boronyl peptidomimetic has an EC.sub.50 for immunosuppression in the .mu.M or greater range. 33. The method of claim 27, wherein the boronyl peptidomimetic is administered orally. 34. A method for modifying glucose metabolism in a glucose intolerant animal, comprising conjointly administering to the animal one or more protease inhibitors which inhibit DPIV-mediated proteolysis with a K.sub.i in the nanomolar or less range or a pharmaceutically acceptable salt thereof, in an amount sufficient to modify glucose metabolism but not sufficient to suppress the immune system of the animal, and one or more other therapeutic agents, wherein the other therapeutic agent is selected from insulin, M1 receptor antagonists, prolactin inhibitors, agents acting on an ATP-dependent channel of .beta.-cells, metformin, and glucosidase inhibitors. 35. A method for treating Type II diabetes in a glucose in a tolerant animal, comprising conjointly administering to the animal one or more DPIV inhibitors or a pharmaceutically acceptable salt thereof, in an amount sufficient to treat Type II diabetes but not sufficient to suppress the immune system of the animal, and one or more other therapeutic agents, wherein the other therapeutic agent is selected from insulin, M1 receptor antagonists, prolactin inhibitors, agents acting on an ATP-dependent channel of .beta.-cells, metformin, and glucosidase inhibitors. 36. A method for modifying metabolism of a peptide hormone in a glucose intolerant animal, comprising conjointly administering to the animal one or more inhibitors of dipeptidylpeptidase IV (DPIV) or a pharmaceutically acceptable salt thereof, in an amount sufficient to modify the metabolism of a peptide hormone but not sufficient to suppress the immune system of the animal, and one or more other therapeutic agents, wherein the other therapeutic agent is selected from insulin, M1 receptor antagonists, prolactin inhibitors, agents acting on an ATP-dependent channel of .beta.-cells, metformin, acid glucosidase inhibitors, and the inhibitor inhibits DPIV with a K.sub.i in the nanomolar or less range, in an amount sufficient to increase the plasma half-life of the peptide hormone, which peptide hormone is selected from growth hormone-releasing factor (GHRF), vasoactive intestinal peptide (VIP), peptide histidine isoleucine (PHI), pituitary adenylate cyclase activating peptide (PACAP), gastric inhibitory peptide (GIP), helodermin, Peptide YY and neuropeptide Y. 37. A method for modifying glucose metabolism of a glucose intolerant animal, comprising conjointly administering to the animal a boronyl peptidomimetic inhibitor of a peptide selected from Pro-Pro, Ala-Pro, and (D)-Ala-(L)-Ala or a pharmaceutically acceptable salt thereof, in an amount sufficient to modify glucose metabolism of a glucose intolerant animal but not sufficient to suppress the immune system of the animal, and one or more other therapeutic agents, wherein the other therapeutic agent is selected from insulin, M1 receptor antagonists, prolactin inhibitors, agents acting on an ATP-dependent channel of .beta.-cells, metformin, and glucosidase inhibitors. 38. The method of claim 34, 35, 36 or 37 wherein administering the inhibitor reduces one or more of insulin resistance, glucose intolerance, hyperglycemia, hyperinsulinemia, obesity, hyperlipidemia, or hyperlipoproteinemia. 39. The method of claim 34, 35, 36 or 37 wherein the inhibitor has an EC.sub.50 for modification of glucose metabolism which is at least one order of magnitude less than its EC.sub.50 for immunosuppression. 40. The method of claim 34, 35, 36 or 37 wherein the inhibitor has an EC.sub.50 for inhibition of glucose tolerance in the nanomolar or less range. 41. The method of claim 34, 35, 36 or 37 wherein the inhibitor has an EC.sub.50 for immunosuppression in the .mu.M or greater range. 42. The method of any of claim 34, 35, 36 or 37 wherein the inhibitor has a K.sub.i for DPIV inhibition of 10 nM or less. 43. The method of claim 34, 35, 36 or 37 wherein the inhibitor is peptidomimetic of a peptide selected from Pro-Pro, Ala-Pro, and (D)-Ala-(L)-Ala. 44. The method of claim 34, 35, 36 or 37 wherein the inhibitor has a molecular weight less than 7500 amu. 45. The method of claim 34, 35, 36 or 37 wherein the inhibitor is administered orally. 46. The method of claim 34, 35, 36 or 37 wherein the inhibitor is represented by the general Formula VII: ##STR60## wherein, A represents a 4-8 membered heterocycle including a N and a C.alpha. carbon; Z represents C or N; W represents CN, --CH.dbd.NR.sub.5, ##STR61## R.sub.1 represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, or an amino-protecting group, ##STR62## R.sub.2 is absent or represents one or mare substitutions to the ring A, each of which can independently be a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, an amino, an acylamino, an amido, a cyano, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido, --(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.m --OH, --(CH.sub.2).sub.m --O-lower alkyl, --(CH.sub.2).sub.m --O-lower alkenyl, --(CH.sub.2).sub.n --O--(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.m --SH, --(CH.sub.2).sub.m --S-lower alkyl, --(CH.sub.2).sub.m --S-lower alkenyl, or --(CH.sub.2).sub.n --S--(CH.sub.2).sub.m --R.sub.7 ; if Z is N, R.sub.3 represents a hydrogen; if Z is C, R.sub.3 represents a hydrogen or a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, an amino, an acylamino, an amido, a cyano, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido, --(CH.sub.2).sub.m --R.sub.7, --(C.sub.2).sub.m --OH, --(CH.sub.2).sub.m --O-lower alkyl, --(CH.sub.2).sub.m --O-lower alkenyl, --(CH.sub.2).sub.n --O--(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.m --SH, --(CH.sub.2).sub.m --S-lower alkyl, --(CH.sub.2).sub.m --S-lower alkenyl, or --(CH.sub.2).sub.n --S--(CH.sub.2).sub.m --R.sub.7 ; R.sub.5 represents a hydrogen, an alkyl, an alkenyl, an alkynyl, --C(X.sub.1)(X.sub.2)X.sub.3, --(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.n --OH, --(CH.sub.2).sub.n --O-alkyl, --(CH.sub.2).sub.n --O-alkenyl, --(CH.sub.2).sub.n --O-alkynyl, --(CH.sub.2).sub.n --O--(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.n --SH, --(CH.sub.2).sub.n --S-alkyl, --(CH.sub.2).sub.n --S-alkenyl, --(CH.sub.2).sub.n --S-alkynyl, --(CH.sub.2).sub.n --S--(CH.sub.2).sub.m --R.sub.7, --C(O)C(O)NH.sub.2, or --C(O)C(O)OR'.sub.7 ; R.sub.6 represents a hydrogen, a halogen, an alkyl, an alkenyl, an alkynyl, an aryl, --(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.m --OH, --(CH.sub.2).sub.m --O-alkyl, --(CH.sub.2).sub.m --O-alkenyl, --(CH.sub.2).sub.m --O-alkynyl, --(CH.sub.2).sub.m --O--(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.m --SH, --(CH.sub.2).sub.m --S-alkyl, --(CH.sub.2).sub.m --S-alkenyl, --(CH.sub.2).sub.m --S-alkynyl, --(CH.sub.2).sub.m --S--(CH.sub.2).sub.m --R.sub.7, ##STR63## R.sub.7 represents, for each occurrence, a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl or heterocyclyl; R'.sub.7 represents, for each occurrence, hydrogen, or a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl or heterocyclyl; R.sub.8 and R.sub.9 each independently represent hydrogen, alkyl, alkenyl, --(CH.sub.2).sub.m --R.sub.7, --C(.dbd.O)-alkyl, --C(.dbd.O)-alkenyl, --C(.dbd.O)-alkynyl, or --C(.dbd.O)--(CH.sub.2).sub.m --R.sub.7, or R.sub.8 and R.sub.9 taken together with the N atom to which they are attached complete heterocyclic ring having from 4 to 8 atoms in the ring structure; R.sub.50 represents O or S; R.sub.51 represents N.sub.3, SH, NH.sub.2, NO.sub.2 or OR'.sub.7 ; R.sub.52 represents hydrogen, a lower alkyl, an amine, OR'.sub.7, or a pharmaceutically acceptable salt, or R.sub.51 and R.sub.52 taken together with the phosphorous atom to which they are attached complete a heterocyclic ring having from 5 to 8 atoms in the ring structure; X.sub.1 represents a halogen; X.sub.2 and X.sub.3 each represent a hydrogen or a halogen; m is zero or an integer in the range of 1 to 8; and n is an integer in the range of 1 to 8. 47. The method of claim 46, wherein W represents CN, --CH.dbd.NR.sub.5, ##STR64## R.sub.5 represents a hydrogen, an alkyl, an alkenyl, an alkynyl, --C(X.sub.1)(X.sub.2)X.sub.3, --(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.n --OH, --(CH.sub.2).sub.n --O-alkyl, --(CH.sub.2).sub.n --O-alkenyl, --(CH.sub.2).sub.n --O-alkynyl, --(CH.sub.2).sub.n --O--(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.n --SH, --(CH.sub.2).sub.n --S-alkyl, --(CH.sub.2).sub.n --alkenyl, --(CH.sub.2).sub.n --S-alkynyl, --(CH.sub.2).sub.n --S--(CH.sub.2).sub.m --R.sub.7, --C(O)C(O)NH.sub.2, or --C(O)C(O)OR'.sub.7 ; R.sub.7 represents, for each occurrence, a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl or heterocyclyl; R'.sub.7 represents, for each occurrence, hydrogen, or a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl or heterocyclyl; Y.sub.1 and Y.sub.2 can independently or together be hydroxyl, or taken together Y.sub.1 and Y.sub.2 are connected via a ring having from 5 to 8 atoms in the ring structure which is hydrolyzed to hydroxy groups under physiological conditions; R.sub.50 represents O or S; R.sub.51 represents N.sub.3, SH, NH.sub.2, NO.sub.2 or OR'.sub.7 ; R.sub.52 represents hydrogen, a lower alkyl, an amine, OR'.sub.7, or a pharmaceutically acceptable salt, or R.sub.51 and R.sub.52 taken together with the phosphorous atom to which they are attached complete a heterocyclic ring having from 5 to 8 atoms in the ring structure; X.sub.1 represents a halogen; and X.sub.2 and X.sub.3 each represent a hydrogen or a halogen. 48. The method of claim 46, wherein the ring A is represented by the formula ##STR65## wherein, n is an integer of 1 or 2. 49. The method of claim 46, wherein W represents ##STR66## 50. The method of claim 46, wherein R.sub.1 represents ##STR67## R.sub.36 represents a small hydrophobic group and R.sub.38 is hydrogen, or, R.sub.36 and R.sub.38 together form a 4-7 membered heterocycle including the N and the C.alpha.carbon, as defined for A above; and R.sub.40 represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, or an amino-protecting group. 51. The method of claim 46, wherein R.sub.2 is absent, or represents a small hydrophobic group. 52. The method of claim 46, wherein R.sub.3 is a hydrogen, or a small hydrophobic group. 53. The method of claim 46, wherein R.sub.5 is a hydrogen, or a halogenated lower alkyl. 54. The method of claim 46, wherein X.sub.1 is a fluorine, and X.sub.2 and X.sub.3, if halogens, are fluorine. 55. The method of claim 46, wherein the inhibitor is represented by the general formula (VIII): ##STR68## wherein, R.sub.1 represents a C-terminally linked amino acid residue or amino acid analog, or C-terminally linked peptide or peptide analog, ##STR69## R.sub.6 represents a hydrogen, a halogen, an alkyl, an alkenyl, an alkynyl, an aryl, --(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.m --OH, --(CH.sub.2).sub.m --O-alkyl, --(CH.sub.2).sub.m --O-alkenyl, --(CH.sub.2).sub.m --O-alkynyl, --(CH.sub.2).sub.m --O--(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.m --SH, --(CH.sub.2).sub.m --S-alkyl, --(CH.sub.2).sub.m --S-alkenyl, --(CH.sub.2).sub.m --S-alkynyl, --(CH.sub.2).sub.m --S--(CH.sub.2).sub.m --R.sub.7, ##STR70## R.sub.7 represents an aryl, a cycloalkyl, a cycloalkenyl, or a heterocycle; R.sub.8 and R.sub.9 each independently represent hydrogen, alkyl, alkenyl, --(CH.sub.2).sub.m --R.sub.7, --C(.dbd.O)-alkyl, --C(.dbd.O)-alkenyl, --C(.dbd.O)-alkynyl, or --C(.dbd.O)--(CH.sub.2).sub.m --R.sub.7, or R.sub.8 and R.sub.9 taken together with the N atom to which they are attached complete a heterocyclic ring having from 4 to 8 atoms in the ring structure; R.sub.11 and R.sub.12 each independently represent hydrogen, an alkyl, or a pharmaceutically acceptable salt, or R.sub.11 and R.sub.12 taken together with the O--B--O atoms to which they are attached complete a heterocyclic ring having from 5 to 8 atoms in the ring structure; m is zero or an integer in the range of 1 to 8; and n is an integer in the range of 1 to 8. 56. The method of claim 46, wherein the inhibitor is represented by the general Formula IX: ##STR71## wherein R.sub.1 represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, ##STR72## R.sub.6 represents a hydrogen, a halogen, an alkyl, an alkenyl, an alkynyl, an aryl, --(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.m --OH, --(CH.sub.2).sub.m --O-alkyl, --(CH.sub.2).sub.m ----O-alkenyl, --(CH.sub.2).sub.m --O-alkynyl, --(CH.sub.2).sub.m --O--(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.m --SH, --(CH.sub.2).sub.m S-alkyl, --(CH.sub.2).sub.m --S-alkenyl, --(CH.sub.2).sub.m --S-alkynyl, --(CH.sub.2).sub.m --S--(CH.sub.2).sub.m --R.sub.7, ##STR73## R.sub.7 represents an aryl, a cycloalkyl, a cycloalkenyl, or a heterocycle; R.sub.8 and R.sub.9 each independently represent hydrogen, alkyl, alkenyl, --(CH.sub.2).sub.m --R.sub.7, --C(.dbd.O)-alkyl, --C(.dbd.O)-alkenyl, --C(.dbd.O)-alkynyl, or --C(.dbd.O)--(CH.sub.2).sub.m --R.sub.7, or R.sub.8 and R.sub.9 taken together with the N atom to which they are attached complete a heterocyclic ring having from 4 to 8 atoms in the ring structure; m is zero or an integer in the range of 1 to 8; and n is an integer in the range of 1 to 8. 57. The method of claim 46, wherein the inhibitor is represented by the general formula: ##STR74## wherein, R.sub.1 represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, ##STR75## R.sub.6 represents a hydrogen, a halogen, an alkyl, an alkenyl, an alkynyl, an aryl, --(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.m --OH, --(CH.sub.2).sub.m --O-alkyl, --(CH.sub.2).sub.m --O-alkenyl, --(CH.sub.2).sub.m --O-alkynyl, --(CH.sub.2).sub.m --O--(CH.sub.2).sub.m R.sub.7, --(CH.sub.2).sub.m --SH, --(CH.sub.2).sub.m --S-alkyl, --(CH.sub.2).sub.m --S-alkenyl, --(CH.sub.2).sub.m --S-alkynyl, --(CH.sub.2).sub.m --S--(CH.sub.2).sub.m --R.sub.7, ##STR76## R.sub.7 represents an aryl, a cycloalkyl, a cycloalkenyl, or a heterocycle; R.sub.8 and R.sub.9 each independently represent hydrogen, alkyl, alkenyl, --(CH.sub.2).sub.m --R.sub.7, --C(.dbd.O)-alkyl, --C(.dbd.O)-alkenyl, --C(.dbd.O)-alkynyl, --C(.dbd.O)--(CH.sub.2).sub.m --R.sub.7, or R.sub.8 and R.sub.9 taken together with the N atom to which they are attached complete a heterocyclic ring having from 4 to 8 atoms in the ring structure; X.sub.1, X.sub.2 and X.sub.3 each represent a hydrogen or a halogen; m is zero or an integer in the range of 1 to 8; and n is an integer in the range of 1 to 8. 58. The method of claim 46, wherein the inhibitor is represented by the general Formula Xa or Xb: ##STR77## wherein, A represents a 4-8 membered heterocycle including a N and a C.alpha. carbon; W represents --CN, --CH.dbd.NR.sub.5, ##STR78## R.sub.5 represents a hydrogen, an alkyl, an alkenyl, an alkynyl, --(X.sub.1)(X.sub.2)X.sub.3, --(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.n --OH, --(CH.sub.2).sub.n --O-alkyl, --(CH.sub.2).sub.n --O-alkenyl, --(CH.sub.2).sub.n --O-alkynyl, --(CH.sub.2).sub.n --O--(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.n --SH, --(CH.sub.2).sub.n --S-alkyl, --(CH.sub.2).sub.n --S-alkenyl, --(CH.sub.2).sub.n --S-alkynyl, --(CH.sub.2).sub.n --S--(CH.sub.2).sub.m --R.sub.7, --C(O)C(O)NH.sub.2, or --C(O)C(O)OR'.sub.7 ; R.sub.7 represents, for each occurrence, a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl or heterocyclyl; R'.sub.7 represents, for each occurrence, hydrogen, or a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocyclyl; R.sub.32 is a small hydrophobic group; R.sub.30 represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, or an amino-protecting group; R.sub.50 represents O or S; R.sub.51 represents N.sub.3, SH, NH.sub.2, NO.sub.2 or OR'.sub.7 ; R.sub.52 represents hydrogen, a lower alkyl, an amine, OR'.sub.7, or a pharmaceutically acceptable salt, or R.sub.51 and R.sub.52 taken together with the phosphorous atom to which they are attached complete a heterocyclic ring having from 5 to 8 atoms in the ring structure; X.sub.1 represents a halogen; X.sub.2 and X.sub.3 each represent a hydrogen or a halogen; Y.sub.1 and Y.sub.2 can independently or together be OH, or a group capable of being hydrolyzed to a hydroxyl group, including cyclic derivatives where Y.sub.1 and Y.sub.2 are connected via a ring having from 5 to 8 atoms in the ring structure; m is zero or an integer in the range of 1 to 8; and n is an integer in the range of 1 to 8. 59. A method for treating Type II diabetes in an animal, comprising conjointly administering to the animal one or more inhibitors of a dipeptidylpeptidase or a pharmaceutically acceptable salt thereof, in an amount sufficient to treat Type II diabetes but not sufficient to suppress the immune system of the animal, and one or more other therapeutic agents, wherein the other therapeutic agent is selected from insulin, M1 receptor antagonist, prolactin inhibitors, agents acting on an ATP-dependent channel of .beta.-cells, metformin, and glucosidase inhibitor, and the inhibitor is represented by the general Formula I; ##STR79## wherein, A represented a 4-8 membered heterocycle including a N and a C.alpha.carbon; Z represents C or N; W represents CN, --CN.dbd.NR.sub.5 ; ##STR80## R.sub.1 represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, or an amino-protecting group, or ##STR81## R.sub.2 is absent or represents one or more substitutions to the A, each of which can independently be a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, an amino, an acylamino, an amido, a cyano a nitro, an azido, a sulfate, a sulfonate, a sulfonamido, --(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.m --OH, --(CH.sub.2).sub.m --O-lower alkyl, --(CH.sub.2).sub.m --O-lower alkenyl, --(CH.sub.2).sub.n --O--(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.m --SH, --(CH.sub.2).sub.m --S-lower alkyl, --(CH.sub.2).sub.m --S-lower alkenyl, or --(CH.sub.2).sub.n --S--(CH.sub.2).sub.m --R.sub.7 ; if Z is N, then R.sub.3 represents a hydrogen; if Z is C, then R.sub.3 represents a hydrogen or a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, an amino, an acylamino, an amido, a cyano, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido, --(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.m --OH, --(CH.sub.2).sub.m --O--lower alkyl, --(CH.sub.2).sub.m --O-lower alkenyl, --(CH.sub.2).sub.n --O--(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.m --SH, --(CH.sub.2)--.sub.m --S--lower alkyl, --(CH.sub.2).sub.m --S-lower alkenyl, or --(CH.sub.2).sub.n --S--(CH.sub.2).sub.m --R.sub.7 ; R.sub.5 represents a hydrogen, an alkyl, an alkenyl, an alkynyl, --C(X.sub.1)(X.sub.2)X.sub.3, --(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.n --OH, --(CH.sub.2).sub.n --O-alkyl, --(Ch.sub.2).sub.n --O-alkenyl, --(CH.sub.2).sub.n --O-alkynyl, --(CH.sub.2).sub.n --O--(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.n --SH, --(CH.sub.2).sub.n --S-alkyl, --(CH.sub.2).sub.n --S-alkenyl, --(CH.sub.2).sub.n --S-alkynyl, --(CH.sub.2).sub.n --S--(CH.sub.2).sub.m --R.sub.7, --C(O)C(O)NH.sub.2, or --C(O)C(O)OR'.sub.7 ; R.sub.6 represents a hydrogen, a halogen, an alkyl, an alkenyl, an alkynyl, an aryl, --(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.m --OH, --(CH.sub.2).sub.m --O-alkyl, --(CH.sub.2).sub.m --O-alkenyl, --(CH.sub.2).sub.m --O-alkynyl, --(CH.sub.2).sub.m --O--(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.m --SH, --(CH.sub.2).sub.m --S-alkyl, --(CH.sub.2).sub.m --S-alkenyl, --(CH.sub.2).sub.m --S-alkynyl, --(CH.sub.2).sub.m --S--(CH.sub.2).sub.m --R.sub.7 ; ##STR82## represents, for each occurrence, a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocyclyl; R'.sub.7 represents, for each occurrence, hydrogen, or a substituted of unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocyclyl; R.sub.8 and R.sub.9 each independently represent hydrogen, alkyl, alkenyl, --(CH.sub.2).sub.m --R.sub.7, --C(.dbd.O)--alkyl, --C(.dbd.O)-alkenyl, --C(.dbd.O)-alkynyl, or --C(.dbd.O)--(CH.sub.2).sub.m --R.sub.7, or R.sub.8 and R.sub.9 taken together with the N atom to which they are attached complete a heterocyclic ring having from 4 to 8 atoms in the ring structure; R.sub.50 represents O or S; R.sub.51 represents N.sub.3, SH, NH.sub.2, NO.sub.2 or OR'.sub.7; R.sub.52 represents hydrogen, a lower alkyl, an amine, OR'.sub.7, or a pharmaceutically acceptable salt, or R.sub.51 and R.sub.52 taken together with the phosphorous atom to which they are attached complete a heterocyclic ring having from 5 to 8 atoms in the ring structure; X.sub.1 represents a halogen; X.sub.2 and X.sub.3 each represent a hydrogen or a halogen; Y.sub.1 and Y.sub.2 can independently or together be OH or an alkoxyl, or taken together Y.sub.1 and Y.sub.2 are connected via a ring having from 5 to 8 atoms in the ring structure which is hydrolyzed to hydroxy groups under physiological conditions; m is zero or an integer in the range of 1 to 8; and n is an integer in the range of 1 to 8. 60. The method of claim 59, wherein the ring A is represented by the formula ##STR83## wherein, n is an integer of 1 or 2. 61. The method of claim 59, wherein W represents. ##STR84## 62. The method of claim 59, wherein R.sub.1 represents ##STR85## R.sub.36 represents a small hydrophobic group and R.sub.38 is hydrogen, or, R.sub.36 and R.sub.38 together form a 4-7 membered heterocycle including the N and a C.alpha. carbon; and R.sub.40 represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, or an amino-protecting group. 63. The method of claim 59, wherein R.sub.2 is absent, or represents a small hydrophobic group. 64. The method of claim 59, wherein R.sub.3 is a hydrogen, or a small hydrophobic group. 65. The method of claim 59, wherein R.sub.5 is a hydrogen, or a halogenated lower alkyl. 66. The method of claim 59, wherein X.sub.1 is a fluorine, and X.sub.2 and X.sub.3, if halogens, are fluorine. 67. The method of claim 59, wherein the inhibitor is represented by the general Formula (II): ##STR86## wherein, R.sub.1 represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, ##STR87## R.sub.6 represents a hydrogen, a halogen, an alkyl, an alkenyl, an alkynyl, an aryl, --(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.m --OH, --(CH.sub.2).sub.m --O-alkyl, --(CH.sub.2).sub.m --O-alkenyl, --(CH.sub.2).sub.m --O-alkynyl, --(CH.sub.2).sub.m --O--(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.m --SH, --(CH.sub.2).sub.m --S-alkyl, --(CH.sub.2).sub.m --S-alkenyl, --(CH.sub.2).sub.m --S-alkynyl, --(CH.sub.2).sub.m --S--(CH.sub.2).sub.m --R.sub.7, ##STR88## R.sub.7 represents an aryl, a cycloalkyl, a cycloalkenyl, or a heterocycle; R.sub.8 and R.sub.9 each independently represent hydrogen, alkyl, alkenyl, --(CH.sub.2).sub.m --R.sub.7, --C(.dbd.O)-alkyl, --C(.dbd.O)-alkenyl, --C(.dbd.O)-alkynyl, or --C(.dbd.O)--(CH.sub.2).sub.m --R.sub.7, or R.sub.8 and R.sub.9 taken together with the N atom to which they are attached complete a heterocyclic ring having from 4 to 8 atoms in the ring structure; R.sub.11 and R.sub.12 each independently represent hydrogen, an alkyl, or a pharmaceutically acceptable salt, or R.sub.11 and R.sub.12 taken together with the O--B--O atoms to which they are attached complete a heterocyclic ring having from 5 to 8 atoms in the ring structure; m is zero or an integer in the range of 1 to 8; and n is an integer in the range of 1 to 8. 68. The method of claim 59, wherein the inhibitor is represented by the general Formula III: ##STR89## wherein, R.sub.1 represents a C-terminally linked amino acid residue or amino acid analog, or C-terminally linked peptide or peptide analog, ##STR90## R.sub.6 represents a hydrogen, a halogen, an alkyl, an alkenyl, an alkynyl, an aryl, --(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.m --OH, --(CH.sub.2).sub.m --O-alkyl, --(CH.sub.2).sub.m --O-alkenyl, --(CH.sub.2).sub.m --O-alkynyl, --(CH.sub.2).sub.m --O--(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.m --SH, --(CH.sub.2).sub.m --S-alkyl, --(CH.sub.2).sub.m --S-alkenyl, --(CH.sub.2).sub.m --S-alkynyl, --(CH.sub.2).sub.m --S--(CH.sub.2).sub.m --R.sub.7, ##STR91## R.sub.7 represents an aryl, a cycloalkyl, a cycloalkenyl, or a heterocycle; R.sub.8 and R.sub.9 each independently represent hydrogen, alkyl, alkenyl, --(CH.sub.2).sub.m --R.sub.7, --(.dbd.O)-alkyl, --C(.dbd.O)-alkenyl, --C(.dbd.O)-alkynyl, or --C(.dbd.O)--(CH.sub.2).sub.m --R.sub.7, or R.sub.8 and R.sub.9 taken together with the N atom to which they are attached complete a heterocyclic ring having from 4 to 8 atoms in the ring structure; m is zero or an integer in the range of 1 to .sub.8 ; and n is an integer in the range of 1 to 8. 69. The method of claim 59, wherein the inhibitor is represented by the general formula: ##STR92## wherein, R.sub.1 represents a C-terminally linked amino acid residue or amino acid analog, or C-terminally linked peptide or peptide analog, or an amino protecting group, or ##STR93## R.sub.6 represents a hydrogen, a halogen, an alkyl, an alkenyl, an alkynyl, an aryl, --(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.m --OH, --(CH.sub.2).sub.m --O-alkyl, --(CH.sub.2).sub.m --O-alkenyl, --(CH.sub.2).sub.m --O-alkynyl, --(CH.sub.2).sub.m --O--(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.m --SH, --(CH.sub.2).sub.m --S-alkyl, --(CH.sub.2).sub.m --S-alkenyl, --(CH.sub.2).sub.m --S-alkynyl, --(CH.sub.2).sub.m --S--(CH.sub.2).sub.m --R.sub.7, ##STR94## R.sub.7 represents an aryl, a cycloalkyl, a cycloalkenyl, or a heterocycle; R.sub.8 and R.sub.9 each independently represent hydrogen, alkyl, alkenyl, --(CH.sub.2).sub.m --R.sub.7, --C(.dbd.O)-alkyl, --C(.dbd.O)-alkenyl, --C(.dbd.O)-alkynyl, --C(.dbd.O)(CH.sub.2).sub.m --R.sub.7, or R.sub.8 and R.sub.9 taken together with the N atom to which they are attached complete a heterocyclic ring having from 4 to 8 atoms in the ring structure; X.sub.1, X.sub.2 and X.sub.3 each represent a hydrogen or a halogen; m is zero or an integer in the range of 1 to 8; and n is an integer in the range of 1 to 8. 70. The method of claim 59, wherein the inhibitor is represented by the general Formula IVa or IVb: ##STR95## wherein, A represents a 4-8 membered heterocycle including an N and a C.alpha. carbon; W represents CN, --CH.dbd.NR.sub.5, ##STR96## R.sub.2 is absent or represents one or more substitutions to the ring A, each of which can independently be a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, an amino, an acylamino, an amido, a cyano, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido, --(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.m --OH, --(CH.sub.2).sub.m --O-lower alkyl, --(CH.sub.2).sub.m --O-lower alkenyl, --(CH.sub.2).sub.n --O--(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.m --SH, --(CH.sub.2).sub.m --S-lower alkyl, --(CH.sub.2).sub.m --S-lower alkenyl, or --(CH.sub.2).sub.n --S--(CH.sub.2).sub.m --R.sub.7 ; R.sub.3 represents a hydrogen or a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, an amino, an acylamino, an amido, a cyano, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido, --(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.m --OH, --(CH.sub.2).sub.m --O-lower alkyl, --(CH.sub.2).sub.m --O-lower alkenyl, --(CH.sub.2).sub.n --O--(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.m --SH, --(CH.sub.2).sub.m --S-lower alkyl, --(CH.sub.2).sub.m --S-lower alkenyl, or --(CH.sub.2).sub.n --S--(CH.sub.2).sub.m --R.sub.7 ; R.sub.5 represents a hydrogen, an alkyl, an alkenyl, an alkynyl, --C(X.sub.1)(X.sub.2)X.sub.3, --(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.n --OH, --(CH.sub.2).sub.n --O-alkyl, --(CH.sub.2).sub.n --O-alkenyl, --(CH.sub.2).sub.n --O-alkynyl, --(CH.sub.2).sub.n --O--(CH.sub.2).sub.m --R.sub.7, --(CH.sub.2).sub.n --SH, --(CH.sub.2).sub.n --S-alkyl, --(CH.sub.2).sub.n --S-alkenyl, --(CH.sub.2).sub.n --S-alkynyl, --(CH.sub.2).sub.n --S--(CH.sub.2).sub.m --R.sub.7, --C(O)C(O)NH.sub.2, or --C(O)C(O)OR'.sub.7 ; R.sub.7 represents, for each occurrence, a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl or heterocyclyl; R'.sub.7 represents, for each occurrence, hydrogen, or a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl or heterocyclyl; R.sub.30 represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, or an amino-protecting group; R.sub.32 is a small hydrophobic group; R.sub.50 represents O or S; R.sub.51 represents N.sub.3, SH, NH.sub.2, NO.sub.2 or OR'.sub.7 ; R.sub.52 represents hydrogen, a lower alkyl, an amine, OR'.sub.7, or a pharmaceutically acceptable salt, or R.sub.51 and R.sub.52 taken together with the phosphorous atom to which they are attached complete a heterocyclic ring having from 5 to 8 atoms in the ring structure; X.sub.1 represents a halogen; X.sub.2 and X.sub.3 each represent a hydrogen or a halogen; m is zero or an integer in the range of 1 to 8; and n is an integer in the range of 1 to 8. 71. The method of claim 70, wherein the ring A is represented by the formula ##STR97## wherein, n is 1 or 2. 72. The method of claim 70, wherein R.sub.2 is absent, or represents a small hydrophobic group. 73. The method of claim 70, wherein R.sub.3 is a hydrogen, or a small hydrophobic group. 74. The method of claim 59, wherein the inhibitor is peptidomimetic of a peptide selected from Pro-Pro and Ala-Pro. 75. The method of claim 59, wherein the inhibitor has an EC.sub.50 for immunosuppression in the .mu.M or greater range. 76. The method of claim 59, wherein the inhibitor is administered orally. 77. The method of claim 59, wherein administering the inhibitor reduces one or more of insulin resistance, glucose intolerance, hyperglycemia, hyperinsulinemia, obesity, hyperlipidemia, or hyperlipoproteinemia. 78. A method of any one of claims 1, 2, 25, 26, 34, 35, 36, 37, or 59, wherein said conjointly administering is achieved by simultaneous dosing of the individual components. 79. A method of any one of claims 1, 2, 25, 26, 34, 35, 36, 37, or 59, wherein said conjointly administering is achieved by sequential dosing of the individual components. 80. A method of any one of claims 1, 2, 25, 26, 34, 35, 36, 37, or 59, wherein said conjointly administering is achieved by separate dosing of the individual components. 81. A method of any one of claims 1, 2, 25, 26, 34, 35, 36, 37, or 59, wherein said conjointly administering is achieved by doping the individual components in the same composition. 82. A method of any one of claims 1, 2, 25, 26, 34, 35, 36, 37, or 59, wherein the M1 receptor antagonist is selected from quaternary amines, tertiary amines, tricyclic amines, pirenzepine, methyl scopolamine, benztropine, hexahydro-sila-difenidol hydrochloride, (+/-)-3-quinuclidinyl xanthene-9-carboxylate hemioxalate, and atropine. 83. A method of any one of claims 1, 2, 25, 26, 34, 35, 36, 37, or 59, wherein said prolactin inhibitor is selected from d2 dopamine agonists, prolactin-inhibiting ergo alkaloids, and prolactin-inhibiting dopamine agonists. 84. A method of claim 80, wherein said prolactin-inhibiting dopamine agonist is selected from 2-bromo-alpha-ergocriptine, 6-methyl-8-beta-carbobenzyloxyaminomethyl-10-alpha-ergoline, 8-acylaminoergolines, 6-methyl-8-alpha-(N-acyl)amino-9-ergoline, 6-methyl-8-alpha-(N-phenylacetyl)amino-9-ergoline, ergocornine, 9,10-dihydroergocornine, D-2-halo-6-alkyl-8-substituted ergolines, D-2-bromo-6-methyl-8-cyanomethylergoline, carbidopa, benserazide, other dopadecarboxylase inhibitor L-dopa, and dopamine. 85. A method of any one of claims 1, 2, 25, 26, 34, 35, 36, 37, or 59, wherein said agent acting on an ATP-dependent channel of .beta.-cells is selected from glibenclamide, glipizide, gliclazide, and AG-EE 623 ZW. 86. A method of any one of claims 1, 2, 25, 26, 34, 35, 36, 37, or 59, wherein said glucosidase inhibitor is acarbose. 87. A method of any one of claims 1, 2, 25, 26, 34, 35, 36, 37, or 59, comprising conjointly administering to the animal a composition comprising a pharmaceutically acceptable carrier, an inhibitor of dipeptidylpeptidase IV, or a pharmaceutically acceptable salt thereof, and one or more other therapeutic agent, wherein the other therapeutic agent is selected from insulin, M1 receptor antagonists, prolactin inhibitors, agents acting on an ATP-dependent channel of .beta.-cells, metformin, and glucosidase inhibitors. 88. A method of any one of claims 1, 2, 25, 26, 34, 35, 36, 37, or 59, wherein the other therapeutic agent is metformin.