Gip-glp-1 dual agonist compounds and methods

Abstract

The present invention relates to truncated GIP analogues which comprise one or more substitutions as compared to wild-type GIP and which may have the property of an altered, preferably increased GLP-1 activity, e.g. as assessed in in vitro efficacy assays. The invention provides GIP-GLP-1 dual agonist compounds and associated methods.

1 . A method of treating a disease or condition in a patient in need thereof comprising administering an effective amount of a GIP analogue represented by the general Formula I′:
   R 1 -Tyr-X2-X3-Gly-Thr-Phe-X7-Ser-X9-X10-X11-X12-X13-X14-X15-X16-Lys-Ala-X19-X20-X21-X22-X23-X24-Trp-Leu-X27-X28-X29-X30-X31-X32-X33-X34-X35-X36-X37-X38-X39-X40-X41-X42-R 2   (I′) (SEQ ID NO: 61)
 
 or a pharmaceutically acceptable salt thereof, 
 wherein 
 R 1  is Hy-, Ac or pGlu; 
 X2 is Ala, Aib or Gly; 
 X3 is Glu or Asp; 
 X7 is Thr, Ser, or Ile; 
 X9 is Asp or Glu; 
 X10 is Tyr, Leu or Ser; 
 X11 is Ser or Leu; 
 X12 is Ile or Lys; 
 X13 is Ala, Tyr or Aib; 
 X14 is Met, Leu or Ser; 
 X15 is Asp or Glu; 
 X16 is Lys, Gly, Ser or Glu; 
 X19 is Gln, Ala, Glu or Lys; 
 X20 is Gln, Lys, Arg or His; 
 X21 is Asp, Ala or Glu; 
 X22 is Phe or 1Nal; 
 X23 is Val, Ile or Leu; 
 X24 is Asn, Glu, Arg or Lys; 
 X27 is Leu, Val, Ile, Lys, Glu or Ser; 
 X28 is Ala, Ser, Arg or Aib; 
 X29 is Gln, Aib, Lys, Gly or Ala; 
 X30 is Lys, Gly, Pro or absent; 
 X31 is Gly, Pro, Ser, Glu or absent; 
 X32 is Lys, Ser or absent; 
 X33 is Lys, Ser, Glu or absent; 
 X34 is Asn, Gly, Ala, Lys or absent; 
 X35 is Asp, Ala, Pro, Glu or absent; 
 X36 is Trp, Pro, Lys or absent; 
 X37 is Lys, Pro, Glu or absent; 
 X38 is His, Pro, Ser, Lys or absent; 
 X39 is Asn, Ser or absent; 
 X40 is Ile or absent; 
 X41 is Thr or absent; 
 X42 is Gln or absent; and 
 R 2  is —NH 2  or —OH, 
 wherein the disease or condition is selected from the group consisting of a stomach and/or bowel-related disorder, a metabolic disease or disorder, a diabetes-related disorder, and an obesity-related disorder. 
 
     
     
         2 . The method of  claim 1 , wherein the GIP analogue is represented by the general Formula I(b)′:
   R 1 -Tyr-X2-X3-Gly-Thr-Phe-X7-Ser-X9-X10-X11-X12-X13-X14-X15-X16-Lys-Ala-X19-X20-X21-Phe-X23-X24-Trp-Leu-X27-X28-X29-X30-X31-X32-X33-X34-X35-X36-X37-X38-X39-X40-X41-X42-R 2   (I(b)′) (SEQ ID NO: 63)
 
 or a pharmaceutically acceptable salt thereof, 
 wherein 
 R1 is Hy-, Ac or pGlu; 
 X2 is Ala, Aib or Gly; 
 X3 is Glu or Asp; 
 X7 is Thr or Ser; 
 X9 is Asp or Glu; 
 X10 is Tyr or Leu; 
 X11 is Ser or Leu; 
 X12 is Ile or Lys; 
 X13 is Ala, Tyr or Aib; 
 X14 is Leu or Ser; 
 X15 is Asp or Glu; 
 X16 is Lys, Ser or Glu; 
 X19 is Gln, Ala, Glu or Lys; 
 X20 is Gln, Lys, Arg or His; 
 X21 is Asp, Ala or Glu; 
 X23 is Val, Ile or Leu; 
 X24 is Asn, Glu, Arg or Lys; 
 X27 is Leu, Glu, Val or Ile; 
 X28 is Ala, Ser, Arg or Aib; 
 X29 is Gln, Gly, Aib or Ala; 
 X30 is Lys, Gly, Pro or absent; 
 X31 is Gly, Pro, Ser, Glu or absent; 
 X32 is Lys, Ser or absent; 
 X33 is Lys, Ser, Glu or absent; 
 X34 is Asn, Gly, Ala, Lys or absent; 
 X35 is Asp, Ala, Pro, Glu or absent; 
 X36 is Trp, Pro, Lys or absent; 
 X37 is Lys, Pro, Glu or absent; 
 X38 is His, Pro, Ser, Lys or absent; 
 X39 is Asn, Ser or absent; 
 X40 is Ile or absent; 
 X41 is Thr or absent; 
 X42 is Gln or absent; and 
 R 2  is —NH 2  or —OH. 
 
     
     
         3 . A method of treating a disease or condition in a patient in need thereof comprising administering an effective amount of a GIP analogue represented by the general Formula II′:
   R 1 -Tyr-X2-Glu-Gly-Thr-Phe-X7-Ser-Asp-X10-X11-X12-X13-Leu-X15-X16-Lys-Ala-X19-X20-X21-Phe-X23-X24-Trp-Leu-X27-X28-X29-X30-Y1-R 2   (II′) (SEQ ID NO: 64),
 
 or a pharmaceutically acceptable salt thereof, 
 wherein 
 R1 is Hy-, Ac or pGlu; 
 X2 is Aib or Gly; 
 X7 is Thr, Ile or Ser; 
 X10 is Tyr or Leu; 
 X11 is Ser or Leu; 
 X12 is Ile or Lys; 
 X13 is Ala, Tyr or Aib; 
 X15 is Asp or Glu; 
 X16 is Ser, Glu or Lys; 
 X17 is Ile or Lys; 
 X19 is Gln or Ala; 
 X20 is Lys, His or Arg; 
 X21 is Ala, Asp or Glu; 
 X23 is Val or Ile; 
 X24 is Asn, Lys or Glu; 
 X27 is Leu, Glu, Val or Ile; 
 X28 is Aib, Ala, Ser or Arg; 
 X29 is Gln, Aib, Ala, Gly or Lys; 
 X30 is Lys, Gly or absent; 
 Y1 is Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser, Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser, Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser, Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or absent; and 
 R 2  is —NH 2  or —OH, 
 wherein the disease or condition is selected from the group consisting of a stomach and/or bowel-related disorder, a metabolic disease or disorder, a diabetes-related disorder, and an obesity-related disorder. 
 
     
     
         4 . The method of  claim 3 , wherein the GIP analogue is represented by the general Formula II(a)′:
   R 1 -Tyr-X2-Glu-Gly-Thr-Phe-X7-Ser-Asp-X10-X11-Ile-X13-Leu-X15-X16-Lys-Ala-X19-X20-X21-Phe-X23-X24-Trp-Leu-X27-X28-X29-X30-Y1-R 2   (II(a)′) (SEQ ID NO: 65)
 
 wherein 
 R 1  is Hy-, Ac or pGlu; 
 X2 is Aib or Gly; 
 X7 is Thr, Ile or Ser; 
 X10 is Tyr or Leu; 
 X11 is Ser or Leu; 
 X13 is Ala, Tyr or Aib; 
 X15 is Asp or Glu; 
 X16 is Ser, Glu or Lys; 
 X19 is Gln, Lys, Ala or Glu; 
 X20 is Lys, His or Arg; 
 X21 is Ala, Asp or Glu; 
 X23 is Val or Ile; 
 X24 is Asn, Lys or Glu; 
 X27 is Leu, Glu, Val or Ile; 
 X28 is Aib, Ala, Ser or Arg; 
 X29 is Gln, Aib, Ala or Gly; 
 X30 is Lys, Gly or absent; 
 Y1 is Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser, Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser, Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser, Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or absent; and 
 R 2  is —NH 2  or —OH. 
 
     
     
         5 . The method of  claim 4 , wherein the GIP analogue is represented by the general Formula II(b)′:
   R 1 -Tyr-Aib-Glu-Gly-Thr-Phe-X7-Ser-Asp-Tyr-Ser-Ile-X13-Leu-X15-X16-Lys-Ala-Gln-X20-X21-Phe-X23-Glu-Trp-Leu-X27-X28-Ala-X30-Y1-R 2   (II(b)′) (SEQ ID NO: 66)
 
 or a pharmaceutically acceptable salt thereof, 
 wherein 
 R 1  is Hy-, Ac or pGlu; 
 X7 is Thr or Ser; 
 X13 is Ala or Tyr; 
 X15 is Asp or Glu; 
 X16 is Lys, Glu or Ser; 
 X20 is Lys, His or Arg; 
 X21 is Ala, Asp or Glu; 
 X23 is Val or Ile; 
 X27 is Leu, Glu or Val; 
 X28 is Arg or Ser; 
 X30 is Lys, Gly or absent; 
 Y1 is Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser, Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser, Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser, Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or absent; and 
 R 2  is —NH 2  or —OH. 
 
     
     
         6 . The method of  claim 4 , wherein the GIP analogue is represented by the general Formula II(c)′:
   R 1 -Tyr-Aib-Glu-Gly-Thr-Phe-X7-Ser-Asp-Tyr-Ser-Ile-X13-Leu-X15-X16-Lys-Ala-Gln-X20-X21-Phe-Val-X24-Trp-Leu-X27-Ala-X29-X30-Y1-R 2   (II(c)) (SEQ ID NO: 67)
 
 or a pharmaceutically acceptable salt thereof, 
 wherein 
 R 1  is Hy-, Ac or pGlu; 
 X7 is Thr or Ser; 
 X13 is Ala, Aib or Tyr; 
 X15 is Asp or Glu; 
 X16 is Glu, Lys or Ser; 
 X20 is Lys, His or Arg; 
 X21 is Ala, Asp or Glu; 
 X24 is Glu or Asn; 
 X27 is Leu, Glu or Val; 
 X29 is Gln or Aib; 
 X30 is Lys, Gly or absent; 
 Y1 is Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser, Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser, Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser, Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or absent; and 
 R 2  is —NH 2  or —OH. 
 
     
     
         7 . The method of  claim 5 , wherein the GIP analogue is represented by the general Formula II(d)′:
   R 1 -Tyr-Aib-Glu-Gly-Thr-Phe-X7-Ser-Asp-Tyr-Ser-Ile-X13-Leu-X15-X16-Lys-Ala-Gln-X20-Ala-Phe-Val-Glu-Trp-Leu-X27-Ala-Gln-X30-Y1-R 2   (II(d)) (SEQ ID NO: 68)
 
 or a pharmaceutically acceptable salt thereof, 
 wherein 
 R 1  is Hy-, Ac or pGlu; 
 X7 is Thr or Ser; 
 X13 is Ala, Aib or Tyr; 
 X15 is Asp or Glu; 
 X16 is Glu, Lys or Ser; 
 X20 is Lys, His or Arg; 
 X27 is Leu, Glu or Val; 
 X30 is Lys, Gly or absent; 
 Y1 is Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser, Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser, Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser, Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser or absent; and 
 R 2  is —NH 2  or —OH. 
 
     
     
         8 . The method of  claim 1 , wherein the amino acid sequence X1-X29 has no more than 6 amino acid differences from the sequence Y-Aib-EGTFTSDYSIYLDKKAQRAFVEWLLAQ (SEQ ID NO: 70). 
     
     
         9 . The method of  claim 1 , wherein the amino acid sequence X1-X29 has no more than 6 amino acid differences from the sequence Y-Aib-EGTFTSDYSIYLEKKAAKEFVEWLLSA (SEQ ID NO: 71). 
     
     
         10 . The method of  claim 1 , wherein the amino acid sequence X1-X29 has no more than 5 amino acid differences from sequence Y-Aib-EGTFTSDYSIYLDEKAAKEFIEWLESA (SEQ ID NO: 72). 
     
     
         11 . The method of  claim 1  wherein:
 X24 is Glu and/or X21 is Ala; or 
 X7 is Thr and X14 is Leu; or 
 X7 is Thr, X14 is Leu and X18 is Ala; or 
 X2 is Aib, X7 is Thr and X14 is Leu; or 
 X2 is Aib, X7 is Thr, X14 is Leu and X13 and/or X29 is Aib; or 
 X2 is Aib, X7 is Thr, X14 is Leu and X24 is Glu; or 
 X2 is Aib, X7 is Thr, X14 is Leu, X24 is Glu and X29 is Gln; or 
 X2 is Aib, X7 is Thr, X14 is Leu, X21 is Ala, X24 is Glu and X29 is Gln; or 
 X2 is Aib, X7 is Thr, X14 is Leu, X24 is Glu, X27 is Leu and X28 is Ser; or 
 X2 is Aib, X7 is Thr, X14 is Leu, X24 is Glu, X27 is Glu and X28 is Ser; or 
 X2 is Aib, X7 is Thr, X14 is Leu, X20 is His, X24 is Glu, X27 is Leu and X28 is Ser. 
 
     
     
         12 - 21 . (canceled) 
     
     
         22 . A method of treating a disease or condition in a patient in need thereof comprising administering an effective amount of a GIP analogue selected from:
 Hy-Y-Aib-EGTFISDYSIYLEKKAAKEFVNWLLAQK-NH 2  (SEQ ID NO: 3) (Compound 1);   Hy-Y-Aib-EGTFTSDYSI-Aib-LDKKAQRAFVEWLLAQGPSSGAPPPS-NH 2  (SEQ ID NO: 4) (Compound 2);   Hy-Y-Aib-EGTFTSDYSIYLDKKAQRAFVNWLLA-Aib-K-NH 2  (SEQ ID NO: 7) (Compound 5);   pGlu-YAEGTFTSDYSIYLDKKAQRAFVNWLLA-Aib-K-NH 2  (SEQ ID NO: 8) (Compound 6);   Hy-YGEGTFTSDYSIYLDKKAQRAFVNWLLA-Aib-K-NH 2  (SEQ ID NO: 9) (Compound 7);   Hy-Y-Aib-EGTFSSDYSIYLDKKAQRAFVNWLLA-Aib-K-NH 2  (SEQ ID NO: 10) (Compound 8);   Hy-Y-Aib-EGTFTSDLSIYLDKKAQRAFVNWLLA-Aib-K-NH 2  (SEQ ID NO: 11) (Compound 9);   Hy-Y-Aib-EGTFTSDYLIYLDKKAQRAFVNWLLA-Aib-K-NH 2  (SEQ ID NO: 13) (Compound 11);   Hy-Y-Aib-EGTFTSDYSIALDKKAQRAFVNWLLA-Aib-K-NH 2  (SEQ ID NO: 14) (Compound 12);   Hy-Y-Aib-EGTFTSDYSIYSDKKAQRAFVNWLLA-Aib-K-NH 2  (SEQ ID NO: 15) (Compound 13);   Hy-Y-Aib-EGTFTSDYSIYLEKKAQRAFVNWLLA-Aib-K-NH 2  (SEQ ID NO: 16) (Compound 14);   Hy-Y-Aib-EGTFTSDYSIALEKKAQRAFVNWLLA-Aib-K-NH 2  (SEQ ID NO: 17) (Compound 15);   Hy-Y-Aib-EGTFTSDYSIYLDSKAQRAFVNWLLA-Aib-K-NH 2  (SEQ ID NO: 18) (Compound 16);   Hy-Y-Aib-EGTFTSDYSIYLDEKAQRAFVNWLLA-Aib-K-NH 2  (SEQ ID NO: 19) (Compound 17);   Hy-Y-Aib-EGTFTSDYSIYLDSKAKRAFVNWLLA-Aib-K-NH 2  (SEQ ID NO: 20) (Compound 18);   Hy-Y-Aib-EGTFTSDYSIYLDKKAQKEFVNWLLA-Aib-K-NH 2  (SEQ ID NO: 21) (Compound 19);   Hy-Y-Aib-EGTFTSDYSIYLDKKAQRAFVKWLLA-Aib-K-NH 2  (SEQ ID NO: 22) (Compound 20);   Hy-Y-Aib-EGTFTSDYSIYLDKKAQRAFVNWLVA-Aib-K-NH 2  (SEQ ID NO: 23) (Compound 21);   Hy-Y-Aib-EGTFTSDYSIYLDKKAQRAFVNWLKA-Aib-K-NH 2  (SEQ ID NO: 25) (Compound 23);   Hy-Y-Aib-EGTFTSDYSIYLDKKAQRAFVNWLL-Aib-K-NH 2  (SEQ ID NO: 26) (Compound 24);   Hy-Y-Aib-EGTFTSDYSIYLDKKAEKAFVNWLLA-Aib-K-NH 2  (SEQ ID NO: 29) (Compound 27);   Hy-Y-Aib-EGTFTSDYSIYLDKKAQRAFVNWLLA-Aib-GPSSGAPPPS-NH 2  (SEQ ID NO: 30) (Compound 28);   Hy-Y-Aib-EGTFTSDYSIYLDKKAQRAFVNWLLA-Aib-GPSSGAPPS-NH 2  (SEQ ID NO: 31) (Compound 29);   Hy-Y-Aib-EGTFTSDYSIYLEKKAAKEFVNWLLAQK-NH 2  (SEQ ID NO: 32) (Compound 30);   Hy-Y-Aib-EGTFTSDYSIYLDK-K(15-carboxy-pentadecanoyl-isoGlu)-AQRAFVNWLLA-Aib-K-NH 2  (SEQ ID NO: 35) (Compound 31);   Hy-Y-Aib-EGTFTSDYSI-Aib-LDK-K(Hexadecanoyl-isoGlu)-AQRAFVEWLLAQGPSSGAPPPS-NH 2  (SEQ ID NO: 36) (Compound 32);   Hy-Y-Aib-EGTFTSDYSIYLDK-K(hexadecanoyl-isoGlu)-AQRAFVEWLLAQGPSSGAPPPS-NH 2  (SEQ ID NO: 37) (Compound 33);   Hy-Y-Aib-EGTFTSDYSIYLDE-K(hexadecanoyl-isoGlu)-AAKEFIEWLESA-NH 2  (SEQ ID NO: 38) (Compound 34);   Hy-Y-Aib-EGTFTSDYSIYLDK-K(hexadecanoyl-isoGlu)-AQRAFVNWLLA-Aib-KPSSGAPPPS-NH 2  (SEQ ID NO: 39) (Compound 35);   Hy-Y-Aib-EGTFTSDYSIALDK-K(hexadecanoyl-isoGlu)-AQRAFVNWLVA-Aib-KPSSGAPPPS-NH 2  (SEQ ID NO: 40) (Compound 36);   Hy-Y-Aib-EGTFTSDYSIYLE-KKAAKDFVEWLLSA-NH 2  (SEQ ID NO: 41) (Compound 37);   Hy-Y-Aib-EGTFTSDYSIYLE-KKAAHDFVEWLLSA-NH 2  (SEQ ID NO: 93) (Compound 38);   Hy-Y-Aib-EGTFTSDYSIYLEKKAQKEFVEWLLSA-NH 2  (SEQ ID NO: 42) (Compound 39);   Hy-Y-Aib-EGTFTSDYSIYLDEKAAKDFVEWLLSA-NH 2  (SEQ ID NO: 43) (Compound 40);   Hy-Y-Aib-EGTFTSDYSIYLESKAAHDFVEWLLSA-NH 2  (SEQ ID NO: 44) (Compound 41);   Hy-Y-Aib-EGTFTSDYSIYLDKKAAHDFVEWLLSA-NH 2  (SEQ ID NO: 45) (Compound 42);   Hy-Y-Aib-EGTFTSDYSIYLEKKAAKEFVEWLLSA-NH 2  (SEQ ID NO: 46) (Compound 43);   Hy-Y-Aib-EGTFTSDYSIYLDSKAAHDFVEWLLRA-NH 2  (SEQ ID NO: 47) (Compound 44);   Hy-Y-Aib-EGTFTSDYSKYLDS-K(Hexadecanoyl-isoGlu)-AAHDFVEWLLSA-NH 2  (SEQ ID NO: 48) (Compound 45);   Hy-Y-Aib-EGTFTSDYSIYLEK-K(Hexadecanoyl-isoGlu)-AAKEFVEWLLSA-NH 2  (SEQ ID NO: 49) (Compound 46);   Hy-Y-Aib-EGTFTSDYSIYLDS-K(Hexadecanoyl-isoGlu)-AAHDFVEWLLRA-NH 2  (SEQ ID NO: 50) (Compound 47);   Hy-Y-Aib-EGTFTSDYSIYLDE-K(Hexadecanoyl-isoGlu)-AAKDFVEWLESA-NH 2  (SEQ ID NO: 51) (Compound 48);   Hy-Y-Aib-EGTFTSDYSKYLDE-K(Hexadecanoyl-isoGlu)-AAKDFIEWLESA-NH 2  (SEQ ID NO: 52) (Compound 49);   Hy-Y-Aib-EGTFTSDYSIYLDE-K(Hexadecanoyl-isoGlu)-AAKDFIEWLESA-NH 2  (SEQ ID NO: 53) (Compound 50);   Hy-Y-Aib-EGTFTSDYSKYLDS-K(Hexadecanoyl-isoGlu)-AAHDFVEWLLRA-NH 2  (SEQ ID NO: 54) (Compound 51);   Hy-Y-Aib-EGTFTSDYSIYLDE-K(Hexadecanoyl-isoGlu)-AAKDFVEWLLSA-NH 2  (SEQ ID NO: 55) (Compound 52);   Hy-Y-Aib-EGTFTSDYSIYLDS-K(Hexadecanoyl-isoGlu)-AAHDFVEWLLSAGPSSGAPPPS-NH 2  (SEQ ID NO: 56) (Compound 53);   Hy-Y-Aib-EGTFTSDYSIYLEK-K-(Hexadecanoyl-isoGlu)-AAKEFVEWLLSAGPSSGAPPPS-NH 2  (SEQ ID NO: 57) (Compound 54);   Hy-Y-Aib-EGTFTSDYSIYLDSKAAHDFVEWLLSAGPSSGAPPPS-NH 2  (SEQ ID NO: 58) (Compound 55); and   Hy-Y-Aib-EGTFTSDYSIYLDE-K(Hexadecanoyl-isoGlu)-AAHDFVEWLLSA-NH 2  (SEQ ID NO: 69) (Compound 57),   or a pharmaceutically acceptable salt thereof,   wherein the disease or condition is selected from the group consisting of a stomach and/or bowel-related disorder, a metabolic disease or disorder, a diabetes-related disorder, and an obesity-related disorder.   
     
     
         23 . The method according to  claim 1  with a lipophilic substituent conjugated to one or more of positions 15, 16, 17, 19, 20, 24, 27, 28 and 30. 
     
     
         24 - 43 . (canceled) 
     
     
         44 . The method of  claim 1 , wherein the disease or condition is a stomach and/or bowel-related disorder. 
     
     
         45 . The method of  claim 1 , wherein the disease or condition is a metabolic disease or disorder. 
     
     
         46 . The method of  claim 45 , wherein the metabolic disease or disorder is selected from diabetes and obesity. 
     
     
         47 . The method of  claim 1 , wherein the disease or condition is a diabetes-related disorder. 
     
     
         48 . The method of  claim 1 , wherein the disease or condition is an obesity-related disorder. 
     
     
         49 . The method of  claim 47 , wherein the diabetes-related disorder is selected from insulin resistance, glucose intolerance, increased fasting glucose, pre-diabetes, type 1 diabetes, type 2 diabetes, gestational diabetes hypertension, dyslipidemia, or a combination thereof. 
     
     
         50 . The method of  claim 47 , wherein the diabetes-related disorder is selected from atherosclerosis, arteriosclerosis, coronary heart disease, peripheral artery disease and stroke; or is associated with a condition selected from atherogenic dyslipidemia, blood fat disorders, elevated blood pressure, hypertension, a prothrombotic state, and a proinflammatory state, or a combination thereof. 
     
     
         51 . The method of  claim 50 , wherein the blood fat disorder is selected from high triglycerides, low HDL cholesterol, high LDL cholesterol, plaque buildup in artery walls, or a combination thereof. 
     
     
         52 . The method of  claim 50 , wherein the prothrombotic state is selected from high fibrinogen levels in the blood and high plasminogen activator inhibitor-1 levels in the blood. 
     
     
         53 . The method of  claim 50 , wherein the proinflammatory state is an elevated C-reactive protein level in the blood. 
     
     
         54 . The method of  claim 48 , wherein the obesity-related disorder is selected from obesity linked inflammation, obesity linked gallbladder disease and obesity induced sleep apnea. 
     
     
         55 - 67 . (canceled)