GIP agonist compounds and methods

1. A method of treating a metabolic disorder in an individual in need thereof, comprising administering to said individual (i) a GIP analogue in combination with (ii) a GLP-1 agonist;

whrerein the GIP analog is represented by the general Formula I:

(SEQ ID NO: 42)

R 1 -Tyr-X2-Glu-Gly-Thr-Phe-Ile-Ser-Asp-X10-

X11-X12-Glu-Leu-X15-X16-X17-X18-X19-X20-X21-

Phe-X23-X24-X25-Leu-X27-X28-X29-Y1-Y2-R 2

(I)

wherein

R 1 is H-, Ac or pGlu;

X2 is Aib, Ala, D-Ala, Gly, Ser, N-Me-Ser, Ac3c, Ac4c or Ac5c;

X10 is Tyr, Leu or Ser;

X11 is Ser or Leu;

X12 is Lys, ψ or Ile;

X15 is Asp or Glu;

X16 is Ser, Glu, Lys or ψ:

X17 is Ile, Lys, Gln, Arg or ψ:

X18 is His, Arg or Ala;

X19 is Gln, Lys, Ala or Glu;

X20 is Gln, Lys, Ala, His or Arg;

X21 is Ala, Leu, Asp or Glu;

X23 is Val or Ile;

X24 is Asn or Glu;

X25 is Tyr or Trp;

X27 is Leu, Glu, Ser, Lys or Val;

X28 is Ala, Ser or Arg;

X29 is Aib, Gly, Ala, Gln, Thr, Ser or Lys or is absent;

Y1 is Lys-Gly, Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 43), Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 44), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 45), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 46), Gly-Lys-Lys-Asn-Asp-Trp-Lys-His-Asn-Ile-Thr-Gln (SEQ ID NO: 47) or absent;

Y2 is ψ or is absent;

R 2 is —NH 2 or —OH;

wherein ψ is a residue independently selected from Lys, Arg, Orn and Cys and wherein the side chain of said residue is conjugated to a lipophilic substituent;

and wherein the GIP analogue contains one and only one residue ψ;

or a pharmaceutically acceptable salt thereof.

2. A method according to claim 1 wherein the metabolic disorder is diabetes or a diabetes related disorder, obesity, or an obesity related disorder.

3. A method according to claim 2 wherein the diabetes related disorder is selected from the group consisting of insulin resistance, glucose intolerance, increased fasting glucose, hypoglycemia, pre-diabetes, type 1 diabetes, type 2 diabetes, gestational diabetes hypertension, dyslipidemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral artery disease, stroke; or is a condition associated with atherogenic dyslipidemia, a blood fat disorder, elevated blood pressure, hypertension, a prothrombotic state, a proinflammatory state, hypoglycemia induced by insulin treatment, and combinations thereof.

4. A method according to claim 2 wherein the diabetes related disorder is osteoporosis including increased risk of bone fractures.

5. A method according to claim 3 wherein the blood fat disorder is high triglycerides, low HDL cholesterol, high LDL cholesterol, plaque buildup in artery walls; wherein the prothrombotic state comprises high fibrinogen levels in the blood or high plasminogen activator inhibitor-1 levels in the blood; or wherein the proinflammatory state comprises an elevated C-reactive protein level in the blood.

6. A method according to claim 2 wherein the obesity related disorder is selected from the group consisting of obesity linked inflammation, obesity linked gallbladder disease or obesity induced sleep apnea, atherogenic dyslipidemia, blood fat disorders, elevated blood pressure, hypertension, a prothrombotic state, and a proinflammatory state, and combinations thereof.

7. A method of treating osteoporosis in a subject in need thereof, comprising administering to the subject an effective amount of a GIP analogue, wherein the GIP analogue is represented by the general Formula I:

(SEQ ID NO: 42)

R 1 -Tyr-X2-Glu-Gly-Thr-Phe-Ile-Ser-Asp-X10-X11-X12-

Glu-Leu-X15-X16-X17-X18-X19-X20-X21-Phe-X23-X24-

X25-Leu-X27-X28-X29-Y1-Y2-R 2  (I)

wherein

R 1 is H—, Ac or pGlu;

X2 is Aib, Ala, D-Ala, Gly, Ser, N-Me-Ser, Ac3c, Ac 4 c or Ac5c;

X10 is Tyr, Leu or Ser;

X11 is Ser or Leu;

X12 is Lys, ψ or Ile;

X15 is Asp or Glu;

X16 is Ser, Glu, Lys or ψ;

X17 is Ile, Lys, Gln, Arg or ψ;

X18 is His, Arg or Ala;

X19 is Gln, Lys, Ala or Glu;

X20 is Gln, Lys, Ala, His or Arg;

X21 is Ala, Leu, Asp or Glu;

X23 is Val or Ile;

X24 is Asn or Glu;

X25 is Tyr or Trp;

X27 is Leu, Glu, Ser, Lys or Val;

X28 is Ala, Ser or Arg;

X29 is Aib, Gly, Ala, Gln, Thr, Ser or Lys or is absent;

Y1 is Lys-Gly, Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 43), Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 44), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 45), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 46), Gly-Lys-Lys-Asn-Asp-Trp-Lys-His-Asn-Ile-Thr-Gln (SEQ ID NO: 47) or absent;

Y2 is ψ or is absent;

R 2 is —NH 2 or —OH;

wherein ψ is a residue independently selected from Lys, Arg, Orn and Cys and wherein the side chain of said residue is conjugated to a lipophilic substituent;

and wherein the GIP analogue contains one and only one residue ψ;

or a pharmaceutically acceptable salt thereof.

8. A method according to claim 1 , wherein the GIP analogue is represented by the general Formula III:

(SEQ ID NO: 50)

R 1 -Tyr-Aib-Glu-Gly-Thr-Phe-Ile-Ser-Asp-

Tyr-Ser-Ile-Glu-Leu-X15-X16-X17-X18-X19-

X20-X21-Phe-Val-X24-X25-Leu-Leu-Ala-X29-

Y1-Y2-R 2

(III)

wherein

R 1 is H-, Ac or pGlu;

X15 is Asp or Glu;

X16 is Lys or ψ;

X17 is Ile or ψ;

X18 is His or Ala X19 is Gln or Ala;

X20 is Gln, Lys or Arg;

X21 is Ala, Asp or Glu;

X24 is Asn or Glu;

X25 is Tyr or Trp

X29 is Gln or is absent;

Y1 is Lys-Gly, Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 43), Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 44), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 45), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 46), Gly-Lys-Lys-Asn-Asp-Trp-Lys-His-Asn-Ile-Thr-Gln (SEQ ID NO: 47) or absent;

Y2 is ψ or is absent;

R 2 is —NH 2 or —OH;

wherein ψ is a residue independently selected from Lys, Arg, Orn and Cys and wherein the side chain of said residue is conjugated to a lipophilic substituent;

and wherein the GIP analogue contains one and only one residue ψ;

or a pharmaceutically acceptable salt thereof.

9. A method according to claim 8 , wherein the GIP analogue comprises one of the following residues or combinations of residues:

Asp15, Lys20;

Asp15, Arg20;

Asp15, Arg20, Glu24;

Asp15, Lys16;

Asp15, Lys16, Glu24;

Asp15, ψ16, Ala21;

Ala21, Glu24;

Asp15, Arg20, Gln29;

Asp15, Arg20, Gly29;

Asp15, Ile17, Arg20, Gly29;

Asp15, Ile17, Lys20, Gly29;

Asp15, Ala28;

Asp15, Ile17, Lys20, Ala28;

Asp15, Ile23, Glu24;

Asp15, ψ17, Lys20;

Asp15, ψ17, Arg20;

Asp15, ψ17, Arg20;

Asp15, ψ17, Arg20, Glu24;

Asp15, Lys 16, ψ17;

Asp15, Lys 16, ψ17, Glu24;

Asp15, ψ17, Ala21;

Ala21, ψ17, Glu24;

Asp15, Asp15, ψ17, Arg20, Gln29;

Asp15, ψ17, Arg20, Gly29;

Asp15, ψ17, Arg20, Gly29;

Asp15, Ile17, Lys20, Gly29;

Asp15; ψ17;

Asp15, ψ17, Ala28;

Asp15, Ile17, Lys20, Ala28;

Asp15, ψ17, Ile23, Glu24.

10. A method according to claim 8 , wherein ψ of the GIP analogue is a residue of Lys, Arg, Orn or Cys in which the side chain is conjugated to a substituent having the formula —Z 1 or —Z 2 —Z 1 .

11. A method according to claim 10 , wherein —Z 1 of the GIP analogue is a fatty chain having at a terminus a connection —X— to ψ or to Z 2 ;

wherein —X— is a bond, —CO—, —SO—, or —SO 2—;

and, optionally, Z 1 has a polar group at the end of the chain distal from connection —X—; said polar group comprising a carboxylic acid or a carboxylic acid bioisostere, a phosphonic acid, or a sulfonic acid group.

12. A method according to claim 11 , wherein Z 1 of the GIP analogue is a group of formula:

A—B—Alk—X— wherein

A is hydrogen or a carboxylic acid, a carboxylic acid bioisostere, a phosphonic acid, or a sulfonic acid group;

B is a bond or a linker;

X is a bond, acyl (—CO—), sulfinyl (—SO—), or sulfonyl (—SO 2 —); and

Alk is a fatty chain that may be optionally substituted with one or more substituents.

13. A method according to claim 12 , wherein Z 1 of the GIP analogue is:

A—B—C 16-20 alkylene—(CO)— wherein A is H or —COOH and B is a bond.

14. A method according to claim 10 , wherein Z 2 of the GIP analogue is a spacer bound at one terminus by Y, which is a nitrogen, oxygen or sulfur atom, and at the other terminus by X, which is a bond or an acyl (—CO—), sulfinyl (—SO—), sulfonyl (—SO 2 —) or absent.

15. A method according to claim 10 , wherein —Z 1− Z 2 of the GIP analogue is:

16. A method according to claim 8 , wherein the GIP analogue has the sequence:

(SEQ ID NO: 51)

Y-Aib-EGTFISDYSIELDKΨHQQDFVNWLLAQGPSSGAPPPS;

(SEQ ID NO: 52)

Y-Aib-EGTFISDYSIELDΨIHQQDFVNWLLAQGPSSGAPPPS;

(SEQ ID NO: 53)

Y-Aib-EGTFISDYSIELEKΨHQQDFVNWLLAQGPSSGAPPPS;

(SEQ ID NO: 54)

Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQGPSSGAPPPSΨ;

(SEQ ID NO: 55)

Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQΨ;

(SEQ ID NO: 56)

Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQKGΨ;

(SEQ ID NO:57)

Y-Aib-EGTFISDYSIELDKΨHQQDFVNYLLAQGPSSGAPPPS;

(SEQ ID NO: 58)

Y-Aib-EGTFISDYSIELDKΨHQQDFVNWLLAQGPSSGAPPPS;

(SEQ ID NO: 59)

Y-Aib-EGTFISDYSIELDKΨAAQDFVNWLLAQGPSSGAPPPS;

(SEQ ID NO: 60)

Y-Aib-EGTFISDYSIELEKΨAAKEFVNWLLAQGPSSGAPPPS;

(SEQ ID NO: 61)

Y-Aib-EGTFISDYSIELEKΨAQRAFVEWLLAQGPSSGAPPPS;

(SEQ ID NO: 62)

Y-Aib-EGTFISDYSIELEKIAQRAFVEWLLAQGPSSGAPPPSΨ;

(SEQ ID NO: 63)

Y-Aib-EGTFISDYSIELEKIAQRAFVEWLLAQΨ;

(SEQ ID NO: 64)

Y-Aib-EGTFISDYSIELDKΨAAQDFVNWLLAGPSSGAPPPS;

(SEQ ID NO: 65)

Y-Aib-EGTFISDYSIELDKIAAQDFVNWLLAGPSSGAPPPSΨ;

(SEQ ID NO: 66)

Y-Aib-EGTFISDYSIELDKKΨAQRAFVEWLLAQGPSSGAPPPS;

(SEQ ID NO: 67)

Y-Aib-EGTFISDYSIELDKKΨAQRAFIEWLLAQGPSSGAPPPS;

(SEQ ID NO: 68)

Y-Aib-EGTFISDYSIELDKIAQRAFIEWLLAGPSSGAPPPSKΨ;

(SEQ ID NO: 69)

Y-Aib-EGTFISDYSIELDKIAQKEFIEWLLAGPSSGAPPPSKΨ;

(SEQ ID NO: 70)

Y-Aib-EGTFISDYSIELDKIAAQDFIEWLLAGPSSGAPPPSKΨ;

(SEQ ID NO: 71)

Y-Aib-EGTFISDYSIELDKIAAQDFVEWLLAGPSSGAPPPSKΨ;

(SEQ ID NO: 72)

Y-Aib-EGTFISDYSIELDKIAQRAFIEWLLAQGPSSGAPPPSKΨ;

(SEQ ID NO: 73)

Y-Aib-EGTFISDYSIELDKKΨAAQAFVNWLLAGPSSGAPPPS;

(SEQ ID NO: 74)

Y-Aib-EGTFISDYSIELDKKΨAAQDFVNWLLAAGPSSGAPPPS;

(SEQ ID NO: 75)

Y-Aib-EGTFISDYSIELDKKΨAAQDFINWLLAGPSSGAPPPS;

(SEQ ID NO: 76)

Y-Aib-EGTFISDYSIELDKKΨAAQDFIEWLLAGPSSGAPPPS;

(SEQ ID NO: 77)

Y-Aib-EGTFISDYSIELDKKΨAAQDFIEWLLAGPSSGAPPPS;

(SEQ ID NO: 78)

Y-Aib-EGTFISDYSIELDKΨIAQRAFIEWLLAQGPSSGAPPPS;

(SEQ ID NO: 79)

Y-Aib-EGTFISDYSKΨELDKIAQRAFIEWLLAQGPSSGAPPPS;

(SEQ ID NO: 80)

Y-DAla-EGTFISDYSIELDKKΨAQRAFIEWLLAQGPSSGAPPPS;

(SEQ ID NO: 81)

Y-DAla-EGTFISDYSIELDKIAAQDFIEWLLAGPSSGAPPPSKW;

(SEQ ID NO: 82)

Y-Aib-EGTFISDYSIELDKKΨAAQDFIEWLLAQGPSSGAPPPS;

(SEQ ID NO: 83)

Y-Aib-EGTFISDYSIELDKKΨAAQDFINWLLAQGPSSGAPPPS;

or

(SEQ ID NO: 84)

Y-Aib-EGTFISDYSIELDKKΨAAQAFIEWLLAQGPSSGAPPPS.

17. A method according to claim 8 , wherein the GIP analogue has the sequence:

(SEQ ID NO: 1)

Y-Aib-EGTFISDYSIELDK-K(Hexadecanoyl-isoGlu)-

HQQDFVNWLLAQGPSSGAPPPS;

(SEQ ID NO: 2)

Y-Aib-EGTFISDYSIELD-K(Hexadecanoyl-isoGlu)-I

HQQDFVNWLLAQGPSSGAPPPS;

(SEQ ID NO: 3)

Y-Aib-EGTFISDYSIELEK-K(Hexadecanoyl-isoGlu)-

HQQDFVNWLLAQGPSSGAPPPS;

(SEQ ID NO: 4)

Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQGPSSGAPPPS-

K([19-carboxy-nonadecanoyl]-isoGlu-

Peg3-Peg3);

(SEQ ID NO: 5)

Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQGPSSGAPPPS-

K(Hexadecanoyl-isoGlu);

(SEQ ID NO: 6)

Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQ-

K(Hexadecanoyl-isoGlu);

(SEQ ID NO: 7)

Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQKG-K

(Hexadecanoyl-isoGlu);

(SEQ ID NO: 8)

Y-Aib-EGTFISDYSIELDK-K([19-carboxy-

nonadecanoyl]-isoGlu-Peg3-Peg3)-

HQQDFVNYLLAQGPSSGAPPPS;

(SEQ ID NO: 9)

Y-Aib-EGTFISDYSIELDK-K([19-carboxy-

nonadecanoyl]-isoGlu-Peg3-Peg3)-

HQQDFVNWLLAQGPSSGAPPPS;

(SEQ ID NO: 10)

Y-Aib-EGTFISDYSIELDK-K([19-carboxy-

nonadecanoyl]-isoGlu-Peg3-Peg3)-

AAQDFVNWLLAQGPSSGAPPPS;

(SEQ ID NO: 11)

Y-Aib-EGTFISDYSIELEK-K([19-carboxy-

nonadecanoyl]-isoGlu-Peg3-Peg3)-

AAKEFVNWLLAQGPSSGAPPPS;

(SEQ ID NO: 12)

Y-Aib-EGTFISDYSIELEK-K([19-carboxy-

nonadecanoyl]-isoGlu-Peg3-Peg3)-

AQRAFVEWLLAQGPSSGAPPPS;

(SEQ ID NO: 13)

Y-Aib-EGTFISDYSIELEKIAQRAFVEWLLAQ

GPSSGAPPPS-K([19-carboxy-

nonadecanoyl]-isoGlu-Peg3-Peg3);

(SEQ ID NO: 14)

[[H-]]Y-Aib-EGTFISDYSIELEKIAQRAFV

EWLLAQ-K([19-carboxy-nonadecanoyl]-

isoGlu-Peg3-Peg3);

(SEQ ID NO: 15)

[[H-]]Y-Aib-EGTFISDYSIELDK-K([19-

carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3)-

AAQDFVNWLLAGPSSGAPPPS;

(SEQ ID NO: 16)

[[H-]]Y-Aib-EGTFISDYSIELDKIAAQDFVNWLL

AGPSSGAPPPS-K([19-carboxy-nonadecanoyl]-

isoGlu-Peg3-Peg3);

(SEQ ID NO: 17)

Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-

nonadecanoyl]-isoGlu-Peg3-Peg3)-

AQRAFVEWLLAQGPSSGAPPPS;

(SEQ ID NO: 18)

Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-

nonadecanoyl]-isoGlu-Peg3-Peg3)-

AQRAFIEWLLAQGPSSGAPPPS;

(SEQ ID NO: 19)

Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-

nonadecanoyl)-[(Piperazine-1-yl)-

acetyl]-Peg3-Peg3)-AQRAFIEWLLAQ

GPSSGAPPPS;

(SEQ ID NO: 20)

Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-

nonadecanoyl)-[(Piperazine-1-yl)-

acetyl]-Peg3-Peg3)-AQRAFVEWLLA

QGPSSGAPPPS;

(SEQ ID NO: 21)

Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-

nonadecanoyl)-[(Piperazine-1-yl)-

acetyl]-Peg3-Peg3)-AQKEFVEWLLA

AGPSSGAPPPS

(SEQ ID NO: 22)

Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-

nonadecanoyl]-isoGlu-Peg3-Peg3)-

AQKEFVEWLLAAGPSSGAPPPS;

(SEQ ID NO: 23)

Y-Aib-EGTFISDYSIELDKIAQRAFIEWLLAGP

SSGAPPPS-K([19-Carboxy-nonadecanoyl]-

isoGlu-Peg3-Peg3);

(SEQ ID NO: 24)

Y-Aib-EGTFISDYSIELDKIAQKEFIEWLLAGPS

SGAPPPS-K([19-Carboxy-nonadecanoyl]-

isoGlu-Peg3-Peg3);

(SEQ ID NO: 25)

Y-Aib-EGTFISDYSIELDKIAAQDFIEWLLAGPS

SGAPPPS-K([19-Carboxy-nonadecanoyl]-

isoGlu-Peg3-Peg3);

(SEQ ID NO: 26)

Y-Aib-EGTFISDYSIELDKIAAQDFIEWLLAGP

SSGAPPPS-K((19-Carboxy-nonadecanoyl)-

[(Piperazine-1-yl)-acetyl]-Peg3-

Peg3);

(SEQ ID NO: 27)

Y-Aib-EGTFISDYSIELDKIAAQDFVEWLLAGPS

SGAPPPS-K([19-Carboxy-nonadecanoyl]-

isoGlu-Peg3-Peg3);

(SEQ ID NO: 28)

Y-Aib-EGTFISDYSIELDKIAQRAFIEWLLAQGP

SSGAPPPS-K([19-Carboxy-nonadecanoyl]-

isoGlu-Peg3-Peg3);

(SEQ ID NO: 29)

Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-

nonadecanoyl]-isoGlu-Peg3-Peg3)-

AAQAFVNWLLAGPSSGAPPPS;

(SEQ ID NO: 30)

Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-

nonadecanoyl]-isoGlu-Peg3-Peg3)-

AAQDFVNWLLAAGPSSGAPPPS;

(SEQ ID NO: 31)

Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-

nonadecanoyl]-isoGlu-Peg3-Peg3)-

AAQDFINWLLAGPSSGAPPPS;

(SEQ ID NO: 32)

Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-

nonadecanoyl]-isoGlu-Peg3-Peg3)-

AAQDFIEWLLAGPSSGAPPPS;

(SEQ ID NO: 33)

Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-

nonadecanoyl)-[(Piperazine-1-yl)-

acetyl]-Peg3-Peg3)-AAQDFIEWLLAGPSS

GAPPPS;

(SEQ ID NO: 34)

Y-Aib-EGTFISDYSIELD-K([19-Carboxy-

nonadecanoyl]-isoGlu-Peg3-Peg3)-

IAQRAFIEWLLAQGPSSGAPPPS;

(SEQ ID NO: 35)

Y-Aib-EGTFISDYS-K([19-Carboxy-

nonadecanoyl]-isoGlu-Peg3-Peg3)-

ELDKIAQRAFIEWLLAQGPSSGAPPPS;

(SEQ ID NO: 36)

Y-DAla-EGTFISDYSIELDK-K([19-Carboxy-

nonadecanoyl]-isoGlu-Peg3-Peg3)-

AQRAFIEWLLAQGPSSGAPPPS;

(SEQ ID NO: 37)

Y-DAla-EGTFISDYSIELDKIAAQDFIEWLLAG

PSSGAPPPS-K((19-Carboxy-nonadecanoyl)-

[(Piperazine-1-yl)-acetyl]-Peg3-Peg3);

(SEQ ID NO: 38)

Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-

nonadecanoyl]-isoGlu-Peg3-Peg3)-

AAQDFIEWLLAQGPSSGAPPPS;

(SEQ ID NO: 39)

Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-

nonadecanoyl]-isoGlu-Peg3-Peg3)-

AAQDFINWLLAQGPSSGAPPPS;

(SEQ ID NO: 40)

Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-

nonadecanoyl]-isoGlu-Peg3-Peg3)-

AAQAFIEWLLAQGPSSGAPPPS;

or

(SEQ ID NO: 41)

Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-

nonadecanoyl)-[(Piperazine-1-yl)-

acetyl]-Peg3-Peg3)-AAQAFIEWLLAQGP

SSGAPPPS.

18. A method according to claim 8 , wherein the GIP analogue has the sequence:

(SEQ ID NO: 1)

H-Y-Aib-EGTFISDYSIELDK-K(Hexadecanoyl-

isoGlu)-HQQDFVNWLLAQGPSSGAPPPS-NH 2

(SEQ ID NO: 2)

H-Y-Aib-EGTFISDYSIELD-K(Hexadecanoyl-

isoGlu)-IHQQDFVNWLLAQGPSSGAPPPS-NH 2 ;

(SEQ ID NO: 3)

H-Y-Aib-EGTFISDYSIELEK-K(Hexadecanoyl-

isoGlu)-HQQDFVNWLLAQGPSSGAPPPS-NH 2 ;

(SEQ ID NO: 4)

H-Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQG

PSSGAPPPS-K([19-carboxy-nonadecanoyl]-

isoGlu-Peg3-Peg3)-NH 2 ;

(SEQ ID NO: 5)

H-Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQG

PSSGAPPPS-K(Hexadecanoyl-isoGlu)-NH 2 ;

(SEQ ID NO: 6)

H-Y-Aib-EGTFISDYSIELDKIHQQDFVNWLI_AQ-

K(Hexadecanoyl-isoGlu)-NH 2 ;

(SEQ ID NO: 7)

H-Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQKG-

K(Hexadecanoyl-isoGlu)-NH 2 ;

(SEQ ID NO: 8)

H-Y-Aib-EGTFISDYSIELDK-K([19-carboxy-

nonadecanoyl]-isoGlu-Peg3-Peg3)-

HQQDFVNYLLAQGPSSGAPPPS-NH 2 ;

(SEQ ID NO: 9)

H-Y-Aib-EGTFISDYSIELDK-K([19-carboxy-

nonadecanoyl]-isoGlu-Peg3-Peg3)-

HQQDFVNWLLAQGPSSGAPPPS-NH 2  ;

(SEQ ID NO: 10)

H-Y-Aib-EGTFISDYSIELDK-K([19-carboxy-

nonadecanoyl]-isoGlu-Peg3-Peg3)-

AAQDFVNWLLAQGPSSGAPPPS-NH 2 ;

(SEQ ID NO: 11)

H-Y-Aib-EGTFISDYSIELEK-K([19-carboxy-

nonadecanoyl]-isoGlu-Peg3-Peg3)-

AAKEFVNWLLAQGPSSGAPPPS-NH 2 ;

(SEQ ID NO: 12)

H-Y-Aib-EGTFISDYSIELEK-K([19-carboxy-

nonadecanoyl]-isoGlu-Peg3-Peg3)-

AQRAFVEWLLAQGPSSGAPPPS-NH 2 ;

(SEQ ID NO: 13)

H-Y-Aib-EGTFISDYSIELEKIAQRAFVEWLLAQGP

SSGAPPPS-K([19-carboxy-nonadecanoyl]-

isoGlu-Peg3-Peg3)-NH 2 ;

(SEQ ID NO: 14)

H-Y-Aib-EGTFISDYSIELEKIAQRAFVEWLLAQ-

K([19-carboxy-nonadecanoyl]-isoGlu-

Peg3-Peg3)-NH 2 ;

(SEQ ID NO: 15)

H-Y-Aib-EGTFISDYSIELDK-K([19-carboxy-

nonadecanoyl]-isoGlu-Peg3-Peg3)-

AAQDFVNWLLAGPSSGAPPPS-NH 2 ;

(SEQ ID NO: 16)

H-Y-Aib-EGTFISDYSIELDKIAAQDFVNWLLA

GPSSGAPPPS-K([19-carboxy-nonadecanoyl]-

isoGlu-Peg3-Peg3)-NH 2 ;

(SEQ ID NO: 17)

H-Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-

nonadecanoyl]-isoGlu-Peg3-Peg3)-

AQRAFVEWLLAQGPSSGAPPPS-NH 2 ;

(SEQ ID NO: 18)

H-Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-

nonadecanoyl]-isoGlu-Peg3-Peg3)-

AQRAFIEWLLAQGPSSGAPPPS-NH 2 ;

(SEQ ID NO: 19)

H-Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-

nonadecanoyl)-[(Piperazine-1-yl)-acetyl]-

Peg3-Peg3)-AQRAFIEWLLAQGPSSGAPPPS-NH 2 ;

(SEQ ID NO: 20)

H-Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-

nonadecanoyl)-[(Piperazine-1-yl)-

acetyl]-Peg3-Peg3)-AQRAFVEWLLAQG

PSSGAPPPS-NH 2 ;

(SEQ ID NO: 21)

H-Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-

nonadecanoyl)-[(Piperazine-1-yl)-

acetyl]-Peg3-Peg3)-AQKEFVEWLLAAGPSSG

APPPS-NH 2 ;

(SEQ ID NO: 22)

H-Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-

nonadecanoyl]-isoGlu-Peg3-Peg3)-

AQKEFVEWLLAAGPSSGAPPPS-NH 2 ;

(SEQ ID NO: 23)

H-Y-Aib-EGTFISDYSIELDKIAQRAFIEWLLAGP

SSGAPPPS-K([19-Carboxy-nonadecanoyl]-

isoGlu-Peg3-Peg3)-NH 2 ;

(SEQ ID NO: 24)

H-Y-Aib-EGTFISDYSIELDKIAQKEFIEWLLAGP

SSGAPPPS-K([19-Carboxy-nonadecanoyl]-

isoGlu-Peg3-Peg3)-NH 2 ;

(SEQ ID NO: 25)

H-Y-Aib-EGTFISDYSIELDKIAAQDFIEWLLAGP

SSGAPPPS-K([19-Carboxy-nonadecanoyl]-

isoGlu-Peg3-Peg3)-NH 2 ;

(SEQ ID NO: 26)

H-Y-Aib-EGTFISDYSIELDKIAAQDFIEWLLAGP

SSGAPPPS-K((19-Carboxy-nonadecanoyl)-

r(PiDerazine-1-yl)-acetyll-Peg3-

Peg3)-NH 2 ;

(SEQ ID NO: 27)

H-Y-Aib-EGTFISDYSIELDKIAAQDFVEWLLAG

PSSGAPPPS-K([19-Carboxy-nonadecanoyl]-

isoGlu-Peg3-Peg3)-NH 2 ;

(SEQ ID NO: 28)

H-Y-Aib-EGTFISDYSIELDKIAQRAFIEWLLAQG

PSSGAPPPS-K([19-Carboxy-nonadecanoyl]-

isoGlu-Peg3-Peg3)-NH 2 ;

(SEQ ID NO: 29)

H-Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-

nonadecanoyl]-isoGlu-Peg3-Peg3)-

AAQAFVNWLLAGPSSGAPPPS-NH 2 ;

(SEQ ID NO: 30)

H-Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-

nonadecanoyl]-isoGlu-Peg3-Peg3)-

AAQDFVNWLLAAGPSSGAPPPS-NH 2 ;

(SEQ ID NO: 31)

H-Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-

nonadecanoyl]-isoGlu-Peg3-Peg3)-

AAQDFINWLLAGPSSGAPPPS-NH 2 ;

(SEQ ID NO: 32)

H-Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-

nonadecanoyl]-isoGlu-Peg3-Peg3)-

AAQDFIEWLLAGPSSGAPPPS-NH 2 ;

(SEQ ID NO: 33)

H-Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-

nonadecanoyl)-[(Piperazine-1-yl)-

acetyl]-Peg3-Peg3)-AAQDFIEWLLAGPSSG

APPPS-NH 2 ;

(SEQ ID NO: 34)

H-Y-Aib-EGTFISDYSIELD-K([19-Carboxy-

nonadecanoyl]-isoGlu-Peg3-Peg3)-

IAQRAFIEWLLAQGPSSGAPPPS-NH 2 ;

(SEQ ID NO: 35)

H-Y-Aib-EGTFISDYS-K([19-Carboxy-

nonadecanoyl]-isoGlu-Peg3-Peg3)-

ELDKIAQRAFIEWLLAQGPSSGAPPPS-NH 2 ;

(SEQ ID NO: 36)

H-Y-DAla-EGTFISDYSIELDK-K([19-Carboxy-

nonadecanoyl]-isoGlu-Peg3-Peg3)-

AQRAFIEWLLAQGPSSGAPPPS-NH 2 ;

(SEQ ID NO: 37)

H-Y-DAla-EGTFISDYSIELDKIAAQDFIEWLLAG

PSSGAPPPS-K((19-Carboxy-nonadecanoyl)-

[(PiDerazine-1-yl)-acetyl]-Peg3-Peg3)-NH 2 ;

(SEQ ID NO: 38)

H-Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-

nonadecanoyl]-isoGlu-Peg3-Peg3)-

AAQDFIEWLLAQGPSSGAPPPS-NH 2 ;

(SEQ ID NO: 39)

H-Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-

nonadecanoyl]-isoGlu-Peg3-Peg3)-

AAQDFINWLLAQGPSSGAPPPS-NH 2 ;

(SEQ ID NO: 40)

H-Y-Aib-EGTFISDYSIELDK-K([19-Carboxy-

nonadecanoyl]-isoGlu-Peg3-Peg3)-

AAQAFIEWLLAQGPSSGAPPPS-NH 2 ;

Or

(SEQ ID NO: 41)

H-Y-Aib-EGTFISDYSIELDK-K((19-Carboxy-

nonadecanoyl)-[(Piperazine-1-yl)-

acetyl]-Peg3-Peg3)-AAQAFIEWLLAQG

PSSGAPPPS-NH 2 .

19. A GIP analogue according to claim 1 , comprising one of the following residues or combinations of residues:

Aib2, Asp15, Lys20;

Aib2, Asp15, Arg20;

Aib2, Asp15, Arg20, Ile23;

Aib2, Ile12, Asp15, Arg20, Ile23, Glu24;

Ile12, Asp15, Ile23;

Ile12, Asp15, Ile23 Glu24;

Ile12, Asp15, Ala21, Ile23;

Aib2, Ala21, Ile23, Glu24;

Aib2, Asp15, Ile23;

Aib2, Asp15, Arg20, 11 e23, Gln29;

Aib2, Asp15, Arg20, Gly29;

Aib2, Asp15, Ile17, Arg20, Gly29;

Aib2, Asp15, Ile17, Lys20, Gly29;

DAla2, Asp15, Ile23;

DAla2, Asp15, Ile23, Ala28;

Aib2, Asp15, Ile17, Lys20, Ala28;

Asp15, Ile23, Glu24;

N-Me-Ser2, Asp15, Lys20;

N-Me-Ser2, Asp15, Arg20;

N-Me-Ser2, Asp15, Arg20, Ile23;

N-Me-Ser2, Ile12, Asp15, Arg20, Ile23, Glu24;

N-Me-Ser2, Ala21, Ile23, Glu24;

N-Me-Ser2, Asp15, Ile23;

N-Me-Ser2, Asp15, Arg20, 11 e23, Gln29;

N-Me-Ser2, Asp15, Arg20, Gly29;

N-Me-Ser2, Asp15, Ile17, Arg20, Gly29;

N-Me-Ser2, Asp15, Ile17, Lys20, Gly29;

N-Me-Ser2, Asp15, Ile23;

N-Me-Ser2, Asp15, Ile23, Ala28;

Ac 3 c2, Asp15, Lys20;

Ac3c2, Asp15, Arg20;

Ac3c2, Asp15, Arg20, Ile23;

Ac3c2, Ile12, Asp15, Arg20, Ile23, Glu24;

Ac3c2, Ala21, Ile23, Glu24;

Ac3c2, Asp15, Ile23;

Ac3c2, Asp15, Arg20, Ile23, Gln29;

Ac3c2, Asp15, Arg20, Gly29;

Ac3c2, Asp15, 11 e17, Arg20, Gly29;

Ac3c2, Asp15, 11 e17, Lys20, Gly29;

Ac3c2, Asp15, Ile23;

Ac3c2, Asp15, Ile23, Ala28

Ac4c2, Asp15, Lys20;

Ac4c2, Asp15, Arg20;

Ac4c2, Asp15, Arg20, Ile23;

Ac4c2, Ile12, Asp15, Arg20, Ile23, Glu24;

Ac4c2, Ala21, Ile23, Glu24;

Ac4c2, Asp15, 11 e23;

Ac4c2, Asp15, Arg20, Ile23, Gln29;

Ac4c2, Asp15, Arg20, Gly29;

Ac4c2, Asp15, Ile17, Arg20, Gly29;

Ac4c2, Asp15, Ile17, Lys20, Gly29;

Ac4c2, Asp15, Ile23;

Ac4c2, Asp15, Ile23, Ala28

Ac5c2, Asp15, Lys20;

Ac5c2, Asp15, Arg20;

Ac5c2, Asp15, Arg20, Ile23;

Ac5c2, Ile12, Asp15, Arg20, Ile23, Glu24;

Ac5c2, Ala21, Ile23, Glu24;

Ac5c2, Asp15, Ile23;

Ac5c2, Asp15, Arg20, Ile23, Gln29;

Ac5c2, Asp15, Arg20, Gly29;

Ac5c2, Asp15, Ile17, Arg20, Gly29;

Ac5c2, Asp15, Ile17, Lys20, Gly29;

Ac5c2, Asp15, Ile23; and

Ac5c2, Asp15, Ile23, Ala28.

20. A method according to claim 2 , wherein the diabetes related disorder is hypoglycemia induced by insulin treatment.

21. A method according to claim 13 , wherein Z 1 of the GIP analogue is:

A—B—C 16-20 alkylene—(CO)— wherein B is a bond, selected from:

17 -carboxy-heptadecanoyl HOOC—(CH 2 ) 16 —(CO)—;

19 -carboxy-nonadecanoyl HOOC—(CH 2 ) 18 —(CO)—;

Octadecanoyl H 3 C—(CH 2 ) 16 —(CO)—; or Eicosanoyl H 3 C—(CH 2 ) 18 —(CO)—.