WO2005118630A2

WO2005118630A2 - Peptides for the treatment of diabetes

Info

Publication number: WO2005118630A2
Application number: PCT/EP2005/052406
Authority: WO
Inventors: Ulla Ribel; Torben Elm; Per Franklin Nielsen; Peter Andreas Nicolai Reumert Wagtmann; Peter Schulz-Knappe; Michael JÜRGENS; Michael Schrader; Hans-Dieter Zucht
Original assignee: Novo Nordisk A/S
Priority date: 2004-05-26
Filing date: 2005-05-26
Publication date: 2005-12-15
Also published as: WO2005118630A3

Abstract

DPP IV-regulated peptides were found in the blood plasma of pigs treated with a DPP IV inhibitor. The peptides are 12-21 amino acids in length and are termed SIP (Salivary-Intestinal Peptides). Also disclosed are related human peptides. The peptides are capable of exerting a blood glucose lowering effect and can be used for the treatment of diabetes.

Description

PEPTIDES FOR THE TREATMENT OF DIABETES

FIELD OF THE INVENTION The present invention relates to novel peptides termed Salivary-Intestinal Peptides (SIP) and derivatives and analogues thereof, and to methods of treating diabetes comprising the administration of said peptides.

BACKGROUND OF THE INVENTION Certain peptides, such as insulin and GLP-1 , can lower blood glucose levels upon administration to patients with diabetes. It has been shown that some peptides, including GLP-1 , have a short half-life in the body due to rapid inactivation by the action of an enzyme called

Dipeptidyl Peptidase IV (DPP IV, also known as CD26). DPP IV catalytically removes two amino acids from the N-terminus of peptides having a praline or alanine at position 2. The half-lives of such peptides can be protracted by engineering analogues or derivatives that are resistant to cleavage by DPP IV. This may be achieved by replacing the praline or alanine at position 2 by another amino acid that is not a substrate for DPP IV. Alternatively, such peptides can be modified by attachment of a large bulky group that prevents DPP IV from coming close enough to cleave the peptide. Physiologically, a function of DPP IV appears to be to rapidly inactivate peptides that modulate important physiological processes. In connection with ingestion of meals, for example, GLP-1 and gastric inhibitory peptide (GIP) are produced by cells in the intestine, and these peptides are secreted into the blood stream. They are carried in the blood to the pancreas, where pancreatic cells respond to these peptides by secreting insulin, which acts on tissues to promote uptake of sugar from the blood. Since it is crucial to maintain a very narrow regulation of blood glucose levels, it is necessary to avoid that GLP-1 and GIP act on the pancreas for too long, causing production of excessive insulin levels. One way to achieve this is by rapid, DPP IV- mediated inactivation of GLP-1 and GIP. This rapid, DPP IV-mediated inactivation, however, causes that wild-type GLP-1 is not suitable as a therapeutic agent. On the other hand, modified analogues of GLP-1 , engineered to resist degradation by DPP IV, are very useful for treatment of some diabetes patients. Other patients suffering from diabetes do not respond well to GLP-1 ; they may instead be treated with insulin. Still other patients are not optimally treated by either GLP-1 , insulin or, indeed, other currently known therapeutic agents. Consequently, there is a need for additional therapeutic modalities for many patients with diabetes. Furthermore, currently used therapeutic peptides, including GLP-1 and insulin, are all administered by injection. Many patients would prefer to avoid injections, and instead take medication orally. Thus, there is a need in the art for novel therapeutic peptides that are orally available for use in diabetes care.. Considering the fact that some peptides that regulate blood-glucose levels, such as GLP-1 and GIP are substrates of DPP IV and are regulated by DPP IV, it may be speculated that additional peptides exist that similarly are cleaved by DPP IV and which participate in the blood glucose regulation. A set of experiments were performed to identify peptides that are present in plasma from pigs treated with a DPP IV-inhibitor, but are absent in plasma from untreated pigs. This experiment resulted in the identification of novel peptides that are present in plasma of pigs only when DPP IV-activity has been suppressed. These peptides were desig- nated "DPP IV-regulated peptides". Subsequent experiments revealed that some of these DPP IV-regulated peptides are directly cleaved by DPP IV in vitro. Other peptides were not directly cleaved by DPP IV; rather, they appeared to be upregulated in plasma via an indirect pathway initiated upon inhibition of DPP IV.

SUMMARY OF THE INVENTION The present inventors have surprisingly found novel peptides in the blood plasma which are DPP IV substrates and which appear to participate in the blood glucose regulation. An embodiment of the invention provides a peptide according to formula I

1 2 3 4 5 6 7 8 9 10 11 Pro-Xaa-Xaa-Xaa-Xaa-Xaa-Pro-Xaa-Gly-Pro-Pro-

12 13 14 15 16 17 18 19 20 21 [I]

Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa

wherein

Xaa at position 2 is Pro, Gly or Aib,

Xaa at position 3 is Pro or Gly,

Xaa at position 4 is Pro or Ala,

Xaa at position 5 is Arg, Lys or Gly Xaa at position 6 is Pro or Lys,

Xaa at position 8 is Pro or Gin,

Xaa at position 12 is Pro or Gin,

Xaa at position 13 is Pro, Gly, Gin or absent,

Xaa at position 14 is Pro, Gly , Ala or absent, Xaa at position 15 is Pro, Gly or absent, Xaa at position 16 is Pro, Gly, Gin, Arg, Lys or absent, Xaa at position 17 is Pro, Gly, Leu or absent, Xaa at position 18 is Pro, Gly, Gin or absent, Xaa at position 19 is Gly, Gin, Arg or absent, Xaa at position 20 is Pro, Gly or absent, Xaa at position 21 is Pro or absent; derivatives thereof; which peptide is capable of exerting a blood glucose lowering effect; and pharmaceutically acceptable salts or solvates thereof.

Accordingly, in one embodiment, the invention relates to a peptide of formula I

1 2 3 4 5 6 7 8 9 10 11 Pro-Xaa-Xaa-Xaa-Xaa-Xaa-Pro-Xaa-Gly-Pro-Pro-

12 13 14 15 16 17 18 19 20 21 [I]

Pro-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa

wherein

Xaa at position 2 is Pro, Gly or Aib,

Xaa at position 3 is Pro or Gly,

Xaa at position 4 is Pro or Ala,

Xaa at position 5 is Arg, Lys or Gly Xaa at position 6 is Pro or Lys,

Xaa at position 8 is Pro or Gin,

Xaa at position 13 is Pro, Gin or absent, Xaa at position 14 is Gly , Ala or absent, Xaa at position 15 is Pro, Gly or absent, Xaa at position 16 is Pro, Gly, Arg, Lys or absent, Xaa at position 17 is Pro, Leu or absent, Xaa at position 18 is Pro, Gin or absent, Xaa at position 19 is Gly, Gin or absent, Xaa at position 20 is Pro, Gly or absent, Xaa at position 21 is Pro or absent; derivatives thereof; and pharmaceutically acceptable salts or solvates thereof. In one embodiment, the invention relates to the use of the peptides of the present invention in therapy. In one embodiment, the invention relates to pharmaceutical compositions comprising one or more of the peptides of the present invention. In one embodiment, the present invention relates to therapeutic methods comprising the administration of peptides of the present invention. In one embodiment, the present invention relates to the use of peptides of the present invention in the manufacture of medicaments. In one embodiment, the invention relates to nucleic acid constructs encoding the peptides of the present invention, to vectors comprising said nucleic constructs, to host cells transformed with said vectors, and to methods of making peptides of the present invention using said nucleic acid constructs, vectors and/or host cells. In one embodiment, the invention relates to specific antibodies raised against the peptides of the present invention.

DESCRIPTION OF THE DRAWINGS

Figure 1 : pSIP-2 and Aib-analogue incubated with DPP IV. The MALDI-MS spectra show (top) sample withdrawn at T=0, (middle) sample withdrawn at T=10 min., and (bottom) sam- pie withdrawn at T=10 min from a parallel incubation of an analog of pSIP-2, where the amino acid in position 2 is Aib. The middle spectrum demonstrates removal of the two N- terminal amino acids due to the action of DPP IV. Theoretical molecular weight of pSIP-2 and the Aib-analog is 1942.2 and 1930.2 amu, respectively. Figure 2: Wistar rats fasted overnight were aneastesized with hypnorm/dormicum and admin- istered 250ug/kg of peptides i.v. as indicated at time=0. At various time points, blood samples were taken, and blood sugar measured by standard methods. The peptides given were: prpp-1/4367-008=pSIP-1 ; prpp-2/90-0015=pSIP-2.

Figure 3: CD26-/- mice were fasted over night and administered peptides (1 mg/kg) by ga- vage at t= -5 min. At t=0, the mice were given an OGTT by gavage (2 g/kg of glucose). Blood glucose was measured at various time-points (-5, 0, 10, 20, 30, 60, 90 and 120 minutes).

Datapoints shown are mean±SE (n=5). The peptides used were: prpp 04367-008 = pSIP-1 ; prpp-90-0155=pSIP-2. Figure 4: Area under the curves of the data shown in Figure 3. The peptides used were: prpp 04367-008 = pSIP-1 ; prpp-90-0155=pSIP-2. The values in the different groups of animals were compared using Dunnett's Multiple Comparison Test.

Figure 5: Alignment of a pSIP-1 , pSIP-2 and human Salivatin. The underlined part of Sali- vatin represents the internal fragment designated hSIP-2.

Figure 6: CD26-/- mice were fasted over night and administered the human hSIP-2 peptide (1 mg/kg) or vehicle by gavage at t= -5 min. At t=0, the mice were given an OGTT by gavage (2 g/kg of glucose). Blood glucose was measured at various time-points (-5, 0, 10, 20, 30, 60, 90 and 120 minutes). Datapoints shown are mean±SEM (n=6). The values in the two groups of animals were compared using the Student's T-Test.

Figure 7: CD26-/- mice were fasted over night and administered the human Salivatin or the human hSIP-2 peptide (1 mg/kg) or vehicle by gavage at t= -5 min. At t=0, the mice were given an OGTT by gavage (2 g/kg of glucose). Blood glucose was measured at various time- points (-5, 0, 10, 20, 30, 60, 90 and 120 minutes). Datapoints shown are mean±SEM (n=6). The statstical significance was determined using Tukey's post test.

Figure 8: Area under the curves of the data shown in Figure 6. The peptide used was SIP-2. The control group was given vehicle. Data are mean±SEM (n=6). The values in the two groups of animals were compared using the Student's T-Test.

DEFINITIONS In the present context "a" is intended to indicate one or more. A "peptide derivative" is the peptide obtained by modification of one or more amino acid residues of a peptide by chemical means, e.g., by alkylation, acylation, ester formation, or amide formation. The term "peptide analogue" is intended to indicate the peptide obtained by deleting and/or adding and/or substituting one or more amino acid residue with another amino acid residue, which may be codable or non-codable, from a parent sequence. Typically 10 or less, such as 5 or less, such as 3 or less, such as 2 or less amino acid residues have been altered relative to the parent peptide. The term "isolated" when used in relation to the peptides of the present invention re- fers to a peptide that has been separated from at least about 50 percent of polynucleotides, lipids, carbohydrates or other materials (i.e., contaminants) with which it is naturally associated. Preferably, the isolated polypeptide is substantially free from any other contaminating polypeptides or other contaminants that are found in its natural environment which would interfere with its therapeutic, diagnostic, prophylactic or research use. It is preferred to provide the peptides of the present invention in a highly purified form, i.e. greater than 95%, such as greater than 99% pure. When used in this context, the term "isolated" does not exclude the presence of the same polypeptide in an alternative physiological form, such as dimmers or alternatively derivatised forms. The term "ortholog" is intended to indicate a peptide obtained from one species, which peptide is the functional counterpart of a peptide from a different species. In the present context, the term "peptide" is intended to indicate two or more amino acids which are bonded by a peptide bond. Said amino acids may be codable or non- codable, and the term also includes peptide derivatives, wherein one or more amino acid in the peptide has been chemically substituted, e.g. by PEG or a lipophilic group. The terms "peptide" and "polypeptide" are used interchangeably ane are intended to indicate the same. In the present context, a peptide is said to be a DPP IV-regulated peptide if it is found at increased levels in an organism administered a DPP IV-inhibitor, compared to an organism not exposed to a DPP IV-inhibitor. In the present context, a peptide is said to be a DDP IV substrate if it is broken down by DPP IV. This may be quantified in an assay as described in example 2. A peptide which is more than 20%, such as more than 30%, such as more than 40%, such as more than 50%, such as more than 60% broken down after 10 minutes at 25°C is said to be a DPP IV substrate. In the present context, a peptide is said to exert a blood glucose lowering effect if it is capable of lowering the blood glucose level in a subject_? This effect may depend on the administration route, i.e. some compounds may exert a blood glucose lowering effect when administered parenterally but not when administered orally. A compound which is capable of lowering the blood glucose level when administered by at least one route is said to exert blood glucose lowering effect. Preferably, said subject is a mammal, such as a mouse, a rat, a dog, a pig or a human. Aib is short for the un-natural amino acid amino isobutyric acid. As used herein, the term "solvate" is a complex of defined stoichiometry formed by a solute (in casu, a peptide according to the present invention) and a solvent. Solvents may be, by way of example, water, ethanol, or acetic acid. In the present context, the term "pharmaceutically acceptable salt" is intended to indicate salts which are not harmful to the patient. Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts. Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hy- droiodic, phosphoric, sulfuric, nitric acids and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cin- namic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p- aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids and the like. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference. Examples of metal salts include lithium, sodium, potassium, magnesium salts and the like. Examples of ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hy- droxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts and the like. A "therapeutically effective amount" of a peptide as used herein means an amount sufficient to cure, alleviate or partially arrest the clinical manifestations of a given disease and its complications. An amount adequate to accomplish this is defined as "therapeutically effective amount". Effective amounts for each purpose will depend on the severity of the disease or injury as well as the weight and general state of the subject. It will be understood that determining an appropriate dosage may be achieved using routine experimentation, by con- structing a matrix of values and testing different points in the matrix, which is all within the ordinary skills of a trained physician or veterinary. The term "treatment" and "treating" as used herein means the management and care of a patient for the purpose of combating a condition, such as a disease or a disorder. The term is intended to include the full spectrum of treatments for a given condition from which the patient is suffering, such as administration of the active compound to alleviate the symptoms or complications, to delay the progression of the disease, disorder or condition, to alleviate or relief the symptoms and complications, and/or to cure or eliminate the disease, disorder or condition as well as to prevent the condition, wherein prevention is to be understood as the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of the active peptides to prevent the onset of the symptoms or complications. The patient to be treated is preferably a mammal, in particular a human being, but it may also include animals, such as dogs, cats, cows, sheep and pigs. The term "identity" as known in the art, refers to a relationship between the se- quences of two or more peptides, as determined by comparing the sequences. In the art, "identity" also means the degree of sequence relatedness between peptides, as determined by the number of matches between strings of two or more amino acid residues. "Identity" measures the percent of identical matches between the smaller of two or more sequences with gap alignments (if any) addressed by a particular mathematical model or computer pro- gram (i.e., "algorithms"). Identity of related polypeptides can be readily calculated by known methods. Such methods include, but are not limited to, those described in Computational Molecular Biology, Lesk, A. M., ed., Oxford University Press, New York, 1988; Biocomputing: Informatics and Genome Projects, Smith, D. W., ed., Academic Press, New York, 1993; Computer Analysis of Sequence Data, Part 1 , Griffin, A. M., and Griffin, H. G., eds., Humana Press, New Jersey, 1994; Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; Sequence Analysis Primer, Gribskov, M. and Devereux, J., eds., M. Stockton Press, New York, 1991 ; and Carillo et al., SIAM J. Applied Math., 48:1073 (1988). Preferred methods to determine identity are designed to give the largest match between the sequences tested. Methods to determine identity are described in publicly avail- able computer programs. Preferred computer program methods to determine identity between two sequences include, but are not limited to, the GCG program package, including GAP (Devereux et al., Nucl. Acid. Res., 12:387 (1984); Genetics Computer Group, University of Wisconsin, Madison, Wis.), BLASTP, BLASTN, and FASTA (Altschul et al., J. Mol. Biol., 215:403-410 (1990)). The BLASTX program is publicly available from the National Center for Biotechnology Information (NCBI) and other sources (BLAST Manual, Altschul et al. NCB/NLM/NIH Bethesda, Md. 20894; Altschul et al., supra). The well known Smith Waterman algorithm may also be used to determine identity. For example, using the computer algorithm GAP (Genetics Computer Group, University of Wisconsin, Madison, Wis.), two polypeptides for which the percent sequence iden- tity is to be determined are aligned for optimal matching of their respective amino acids (the "matched span", as determined by the algorithm). A gap opening penalty (which is calculated as 3.times. the average diagonal; the "average diagonal" is the average of the diagonal of the comparison matrix being used; the "diagonal" is the score or number assigned to each perfect amino acid match by the particular comparison matrix) and a gap extension penalty (which is usually {fraction (1/10)} times the gap opening penalty), as well as a comparison matrix such as PAM 250 or BLOSUM 62 are used in conjunction with the algorithm. A standard comparison matrix (see Dayhoff et al., Atlas of Protein Sequence and Structure, vol. 5, supp.3 (1978) for the PAM 250 comparison matrix; Henikoff et al., Proc. Natl. Acad. Sci USA, 89:10915-10919 (1992) for the BLOSUM 62 comparison matrix) is also used by the algo- rithm. Preferred parameters for a polypeptide sequence comparison include the following: Algorithm: Needleman et al., J. Mol. Biol, 48:443-453 (1970); Comparison matrix: BLOSUM 62 from Henikoff et al., Proc. Natl. Acad. Sci. USA, 89:10915-10919 (1992); Gap Penalty: 12, Gap Length Penalty: 4, Threshold of Similarity: 0. The GAP program is useful with the above parameters. The aforementioned parameters are the default parameters for polypeptide comparisons (along with no penalty for end gaps) using the GAP algorithm. Other exemplary algorithms, gap opening penalties, gap extension penalties, comparison matrices, thresholds of similarity, etc. may be used,, including those set forth in the Program Manual, Wisconsin Package, Version 9, September, 1997. The particular choices to be made will be apparent to those of skill in the art and will depend on the specific comparison to be made, such as DNA to DNA, protein to protein, protein to DNA; and additionally, whether the comparison is between given pairs of sequences (in which case GAP or BestFit are generally preferred) or between one sequence and a large database of sequences (in which case FASTA or BLASTA are preferred).

DESCRIPTION OF THE INVENTION The invention is partly based on the discovery of the following peptides in plasma from pigs: (pSIP-l) PPGARPPPGPPPPGPPPPGP; (pSIP-2) PPGARPPPGPPPPAGGLQQGP; (pSIP-3) PGARPPPGPPPPP; and (pSIP-4) PPGARPPPGPPPP, and by searching public sequence databases for human genes encoding peptides similar to those listed above, we identified human counteφarts of the pig peptides. These human peptides have the following sequence: (hSIP-1) PPPPGKPQGPPQGPPQGGRP. (hSIP-2) PPPPGKPQGPPPQGGRPQGP The presence of praline at position 2 and 4 of hSIP-1 indicates that they may be cleaved by DPP IV. hSIP-1 and hSIP-2 are internal fragments of a previously described preo- teins. For example, hSIP-2 is an internal fragment of a peptide of 47 amino acids called Salivatin or peptide-C. However, it has not previously been known that one active fragment of Salivatin is actually hSIP-2. The discovery of pSIP-1-4 from pig plasma allowed the prediction that an active part of Salivatin is the sequence designated as hSIP-2. As the peptides are expressed by the salivary gland and the peptides are active in the gastro-intestinal tract, the peptides are termed SIP (Salivary- Intestinal Peptides). In more general terms, a SIP peptide is a peptide with a sequence as defined in formula [I]. These SIP peptides have not previously been described in the art. The peptides are pre- sent in plasma from pigs treated with a DPP IV-inhibitor, but not in plasma from untreated pigs, indicating that they are DPP IV-regulated peptides. Some of these peptides are directly cleaved by DPP IV, suggesting that DPP IV-mediated cleavage confers a short half-life to the peptides. This was confirmed by in vitro experiments using synthetic versions of pSIP-1 and pSIP-2. These peptides were rapidly cleaved by DPP IV in vitro. However, it was found that the half-life of the peptides, in the presence of DPP IV, can be drastically prolonged by mutation of the Praline at position 2, and probably by acylation at different positions, or by mutation and acyla- tion in combination. Modified versions of the peptides may have significant advantages over unmodified peptides. However, both the wild-type form, and analogues and/or derivatives of said peptides, have potential as therapeutics and are equally covered by the embodiments of this invention. Peptides similar to the ones identified in pig plasma were discovered. These human or mouse peptides are related by sequence to the pig peptides, and share the praline at position 2 and/or 4, potentially rendering them sensitive to DPP IV. One such human peptide is hSIP-2. In one embodiment, the invention relates to peptides produced in the salivary glands and found in saliva of mammals, such as pigs, humans, mice, dogs and rats, and that exhibit more than 70% sequence identity to any of the pSIP-1 -4 peptides or the hSIPI -2 peptides. Preferably, these peptides should be DPP IV substrates or DPP IV-regulated peptides, and able to exert a blood sugar lowering effect. In one embodiment, the peptides of the present invention are DPP IV substrates. In one embodiment, the peptides of the present invention exert a glucose lowering effect. In one embodiment, the peptides of the present invention are DPP IV substrates and exert a glucose lowering effect. In one embodiment, the peptides of the present invention are DPP IV-regulated pep- tides that exert a glucose lowering effect. In one embodiment, the invention relates to peptides with the sequences (pSIP-1) PPGARPPPGPPPPGPPPPGP; (p-SIP-2) PPGARPPPGPPPPAGGLQQGP; (p-SIP-3) PGARPPPGPPPPP; (p-SIP-4) PPGARPPPGPPPP; (hSIP-1) PPPPGKPQGPPQGPPQGGRP, and (hSIP-2) PPPPGKPQGPPPQGGRPQGP and to peptides having at least 60%, such as having at least 70%, such as at least 75%, such as at least 80%, such as at least 90% identity to said sequences. This embodiment also relates to derivatives of said peptides. Preferably, said peptides are DPP IV-regulated peptides, or DPP IV-substrates, and/or capable of exerting a blood glucose lowering effect. In order to prolong the circulation time of SIP peptides in the body, i.e. to protract the SIP peptides, one or more of the amino acid residues in the SIP peptide may be derivatised. In one embodiment, the invention relates to said SIP derivatives. Typical examples of such derivatives include peptides wherein the ε-amino group of one or more Lys or the N-terminal amino group has been substituted with a lipophilic group or a PEG group, optionally via a spacer. Other examples include Cι.₆esters, amides, Cι-₆alkylamides, Cι-₆dialkylamides and Fmoc derivatives of said SIP. In one embodiment of the invention the SIP derivative only has one lipophilic substituent attached to the peptide. In one embodiment of the invention the lipophilic substituent comprises from 4 to 40 carbon atoms. In one embodiment of the invention the lipophilic substituent comprises from 8 to 25 carbon atoms. In one embodiment of the invention he lipophilic substituent comprises from 12 to 20 carbon atoms. In one embodiment of the invention the lipophilic substituent is attached to an amino acid residue in such a way that a carboxyl group of the lipophilic substituent forms an amide bond with an amino group of the amino acid residue. In one embodiment of the invention the lipophilic substituent is attached to a Lys residue. In one embodiment of the invention the lipophilic substituent is attached to an amino acid residue in such a way that an amino group of the lipophilic substituent forms an amide bond with a carboxyl group of the amino acid residue. In one embodiment of the invention the lipophilic substituent is attached to the SIP peptide by means of a spacer. In one embodiment of the invention the spacer is an unbranched alkane α,α> dicarboxylic acid group having from 1 to 7 methylene groups, such as two methylene groups which spacer forms a bridge between an amino group of the SIP peptide and an amino group of the lipophilic substituent. In one embodiment of the invention the spacer is an amino acid residue except a Cys residue, or a dipeptide. Examples of suitable spacers includes β-alanine, gamma- aminobutyric acid (GABA), ε-glutamic acid, succinic acid, Lys, Glu or Asp, or a dipeptide such as Gly-Lys. When the spacer is succinic acid, one carboxyl group thereof may form an amide bond with an amino group of the amino acid residue, and the other carboxyl group thereof may form an amide bond with an amino group of the lipophilic substituent. When the spacer is Lys, Glu or Asp, the carboxyl group thereof may form an amide bond with an amino group of the amino acid residue, and the amino group thereof may form an amide bond with a carboxyl group of the lipophilic substituent. When Lys is used as the spacer, a further spacer may in some instances be inserted between the ε-amino group of Lys and the lipophilic substituent. In one embodiment, such a further spacer is succinic acid which forms an amide bond with the ε-amino group of Lys and with an amino group present in the lipophilic substituent. In another embodiment such a further spacer is Glu or Asp which forms an amide bond with the ε-amino group of Lys and another amide bond with a carboxyl group present in the lipophilic substituent, that is, the lipophilic substituent is a N^ε-acylated lysine residue. In one embodiment of the invention the spacer is selected from the list consisting of β-alanine, gamma-aminobutyric acid (GABA), ε-glutamic acid, Lys, Asp, Glu, a dipeptide containing Asp, a dipeptide containing Glu, or a dipeptide containing Lys. In one embodiment of the invention the spacer is β-alanine. In one embodiment of the invention the spacer is gamma-aminobutyric acid (GABA). In one embodiment of the invention the spacer is ε- glutamic acid. In one embodiment of the invention a carboxyl group of the parent SIP peptide forms an amide bond with an amino group of a spacer, and the carboxyl group of the amino acid or dipeptide spacer forms an amide bond with an amino group of the lipophilic substituent. In one embodiment of the invention an amino group of the parent SIP peptide forms an amide bond with a carboxylic group of a spacer, and an amino group of the spacer forms an amide bond with a carboxyl group of the lipophilic substituent. In one embodiment of the invention the lipophilic substituent comprises a partially or completely hydrogenated cyclopentanophenathrene skeleton. In one embodiment of the invention the lipophilic substituent is an straight-chain or branched alkyl group. In one embodiment of the invention the lipophilic substituent is the acyl group of a straight-chain or branched fatty acid. In one embodiment of the invention the acyl group of a lipophilic substituent is se- lected from the group comprising CH₃(CH₂)_nCO-, wherein n is 4 to 38, such as CH₃(CH₂)₆CO-, CH₃(CH₂)₈CO-, CH₃(CH₂)ι₀CO-, CH₃(CH₂)i₂CO-, CH₃(CH₂)ι CO-, CH₃(CH₂)ι₆CO-, CH₃(CH₂)ι₈CO-, CH₃(CH₂)₂oCO- and CH₃(CH₂)₂₂CO-. In one embodiment of the invention the lipophilic substituent is an acyl group of a straight-chain or branched alkane oc,ω-dicarboxylic acid. In one embodiment of the invention the acyl group of the lipophilic substituent is selected from the group comprising HOOC(CH₂)_mCO-, wherein m is 4 to 38, such as HOOC(CH₂)₁₄CO-, HOOC(CH₂)₁₆CO-, HOOC(CH₂)ι₈CO-, HOOC(CH₂)₂₀CO- and

In one embodiment of the invention the lipophilic substituent is a group of the for- mula CH₃(CH₂)p((CH₂)_qCOOH)CHNH-CO(CH₂)₂CO-, wherein p and q are integers and p+q is an integer of from 8 to 40, such as from 12 to 35. In one embodiment of the invention the lipophlic substituent is a group of the formula CH₃(CH₂)_rCO-NHCH(COOH)(CH₂)₂CO-, wherein r is an integer of from 10 to 24. In one embodiment of the invention the lipophilic substituent is a group of the for- mula CH₃(CH₂)_sCO-NHCH((CH₂)₂COOH)CO-, wherein s is an integer of from 8 to 24. In one embodiment of the invention the lipophilic-substituent is a group of the formula COOH(CH₂)_tCO- wherein t is an integer of from 8 to 24. In one embodiment of the invention the lipophilic substituent is a group of the formula -NHCH(COOH)(CH₂)₄NH-CO(CH₂)uCH₃, wherein u is an integer of from 8 to 18. In one embodiment of the invention the lipophilic substituent is a group of the formula -NHCH(COOH)(CH₂)₄NH-COCH((CH₂)₂COOH)NH-CO(CH₂)_wCH₃, wherein w is an integer of from 10 to 16. In one embodiment of the invention the lipophilic substituent is a group of the formula -NHCH(COOH)(CH₂)₄NH-CO(CH₂)₂CH(COOH)NH-CO(CH₂)χCH₃, wherein x is an inte- ger of from 10 to 16. In one embodiment of the invention the lipophilic substituent is a group of the formula -NHCH(COOH)(CH₂)₄NH-CO(CH₂)2CH(COOH)NHCO(CH2)yCH₃, wherein y is zero or an integer of from 1 to 22. In one embodiment of the invention the lipophilic substituent is N-Lithocholoyl. In one embodiment of the invention the lipophilic substituent is N-Choloyl. In one embodiment of the invention the SIP derivative has one lipophilic substituent. In one embodiment of the invention the SIP derivative has two lipophilic substituents. In one embodiment of the invention the SIP derivative has three lipophilic substituents. In one embodiment of the invention the SIP derivative has four lipophilic substituents. Peptides of the present invention can be used to raise antibodies that specifically bind to the peptides of the present invention. In the present context, "antibodies" include monoclonal and polyclonal antibodies, and antigen-binding fragments thereof, such as F(ab')₂ and Fab fragments, including genetically engineered antibodies. Antibodies are said to be specific if they bind to a peptide of the present invention with a K_a greater than or equal to 10⁷ M^"1. Methods for preparing antibodies are disclosed in e.g. Hurrell J.G.R. (Ed.) Monoclonal Hybridoma Antibodies: Techniques and Applications, CRC Press, Boca Raton, Florida, 1982 and Sambrok, Molecular Cloning: A Laboratory Manual, Cold Spring Harbour, New York, 1989. Antibodies raised against peptides of the present invention may be used e.g. in diagnostic assays and for affinity purification. Administration of these peptides to mice or rats resulted in a significant lowering of blood glucose, indicating that the peptides hold promise as therapeutic agents for the treatment of diabetes or other complications involving abnormal glucose or lipid metabolism. Most remarkably, some of the peptides are active also when administered orally, suggesting their use in tablet form. In one embodiment, the invention relates to a method for the treatment Type I diabetes, Type II diabetes, obesity, impaired glucose tolerance or impaired fasting glucose toler-,, ance, the method comprising administering to a patient in need thereof a therapeutically effective amount of a peptide of the present invention, optionally in combination with one or more other therapeutically active agents. In one embodiment, the present invention relates to the use of a peptide of the present invention in the manufacture of a medicament for the treatment of Type I diabetes, Type II diabetes, obesity, impaired glucose tolerance or impaired fasting glucose tolerance. In one embodiment, said other therapeutically active agent optionally to be administered together with SIP peptides in the methods of the present invention is selected from agents normally used in the treatment of glyco- or lipid-metabolic disorders. Suitable additional compounds may be selected from antidiabetic agents, antihyperlipidemic agents, an- tiobesity agents, antihypertensive agents and agents for the treatment of complications resulting from or associated with diabetes. Suitable antidiabetic agents include insulin, GLP-1 (glucagon like peptide-1) derivatives such as those disclosed in WO 98/08871 (Novo Nordisk A/S), which is incorporated herein by reference, as well as orally active hypoglycemic agents. Suitable orally active hypoglycemic agents preferably include imidazolines, sulfony- lureas, biguanides, meglitinides, oxadiazolidinediones, thiazolidinediones, insulin sensrtizers, α-glucosidase inhibitors, agents acting on the ATP-dependent potassium channel of the pancreatic β-cells e.g. potassium channel openers such as those disclosed in WO 97/26265, WO 99/03861 and WO 00/37474 (Novo Nordisk A/S) which are incorporated herein by reference, potassium channel openers, such as ormitiglinide, potassium channel blockers such as nateglinide or BTS-67582, glucagon antagonists such as those disclosed in WO 99/01423 and WO 00/39088 (Novo Nordisk A/S and Agouron Pharmaceuticals, Inc.), all of which are incorporated herein by reference, GLP-1 agonists such as those disclosed in WO 00/42026 (Novo Nordisk A/S and Agouron Pharmaceuticals, Inc.), which are incorporated herein by reference, DPP-IV (dipeptidyl peptidase-IV) inhibitors, PTPase (protein tyrosine phos- phatase) inhibitors, glucokinase activators, such as those described in WO 02/08209 to

Hoffmann La Roche, inhibitors of hepatic enzymes involved in stimulation of gluconeogene- sis and/or glycogenolysis, glucose uptake modulators, GSK-3 (glycogen synthase kinase-3) inhibitors, compounds modifying the lipid metabolism such as antihyperlipidemic agents and antilipidemic agents, compounds lowering food intake, and PPAR (peroxisome proliferator- activated receptor) and RXR (retinoid X receptor) agonists such as ALRT-268, LG-1268 or ■ LG-1069. Other examples of suitable additional therapeutically active agents include insulin or insulin analogues, sulfonylurea e.g. tolbutamide, chlorpropamide, tolazamide, glibenclamide, glipizide, glimepiride, glicazide, glyburide, biguanide e.g. metformin, meglitinide e.g. repag- linide or senaglinide/nateglinide. Other examples of suitable additional therapeutically active agents include thia- zolidinedione insulin sensitizer e.g. troglitazone, ciglitazone, pioglitazone, rosiglitazone, is- aglitazone, darglitazone, englitazone, CS-011/CI-1037 or T 174 or the compounds disclosed in WO 97/41097 (DRF-2344), WO 97/41119, WO 97/41120, WO 00/41121 and WO 98/45292 (Dr. Reddy's Research Foundation), which are incorporated herein by reference. Other examples of suitable additional therapeutically active agents include insulin sensitizer e.g. such as Gl 262570, YM-440, MCC-555, JTT-501 , AR-H039242, KRP-297, GW-409544, CRE-16336, AR-H049020, LY510929, MBX-102, CLX-0940, GW-501516 or the compounds disclosed in WO 99/19313 (NN622/DRF-2725), WO 00/50414, WO 00/63191 , WO 00/63192, WO 00/63193 (Dr. Reddy's Research Foundation) and WO 00/23425, WO 00/23415, WO 00/23451 , WO 00/23445, WO 00/23417, WO 00/23416, WO 00/63153, WO 00/63196, WO 00/63209, WO 00/63190 and WO 00/63189 (Novo Nordisk A/S), which are incorporated herein by reference. Other examples of suitable additional therapeutically active agents include α-glucosidase inhibitor e.g. voglibose, emiglitate, miglitol or acarbose. Other examples of suitable additional therapeutically active agents include glycogen phosphorylase inhibitor e.g. the compounds described in WO 97/09040 (Novo Nordisk A/S). Other examples of suitable additional therapeutically active compounds include a glucokinase activator. Other examples of suitable additional therapeutically active agents include an agent acting on the ATP-dependent potassium channel of the pancreatic β-cells e.g. tolbutamide, glibenclamide, glipizide, glicazide, BTS-67582 or repaglinide. Other examples of suitable additional therapeutically active agents include nateglinide. Other examples of suitable additional therapeutically active agents include an anti- hyperlipidemic agent or a antilipidemic agent e.g. cholestyramine, colestipol, clofibrate, gem- fibrozil, lovastatin, pravastatin, simvastatin, prabucol or dextrothyroxine. Other examples of said additional therapeutically active agents include antiobesity compounds or appetite regulating agents. Such compounds may be selected from the group consisting of CART (cocaine amphetamine regulated transcript) agonists, NPY (neuropeptide Y) antagonists, MC3 (melanocortin 3) agonists, MC4 (melanocortin 4) agonists, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF (corticotropin releasing factor) agonists, CRF BP (corticotropin releasing factor binding protein) antagonists, urocortin agonists, β3 adrenergic agonists such as CL-316243, AJ-9677, GW-0604, LY362884, LY377267 or AZ- 40140, MSH (melanocyte-stimulating hormone) agonists, MCH (melanocyte-concentrating hormone) antagonists, CCK (cholecystokinin) agonists, serotonin reuptake inhibitors (fluoxet- ine, seroxat orcitalopram), serotonin and norepinephrine reuptake inhibitors, 5HT (serotonin) agonists, bombesin agonists, galanin antagonists, growth hormone, growth factors such as prolactin or placental lactogen, growth hormone releasing compounds, TRH (thyreotropin releasing hormone) agonists, UCP 2 or 3 (uncoupling protein 2 or 3) modulators, chemical uncouplers, leptin agonists, DA (dopamine) agonists (bromocriptin, doprexin), lipase/amylase inhibitors, PPAR modulators, RXR modulators, TR β agonists, adrenergic CNS stimulating agents, AGRP (agouti related protein) inhibitors, H3 histamine antagonists such as those disclosed in WO 00/42023, WO 00/63208 and WO 00/64884, which are incorporated herein by reference, exendin-4, GLP-1 agonists and ciliary neurotrophic factor. Further antiobesity agents are bupropion (antidepressant), topiramate (anticonvulsant), ecopipam (dopamine D1/D5 antagonist), naltrexone (opioid antagonist), and peptide YY₃.₃₆ (Batterham et al, Nature 418, 650-654 (2002)). In one embodiment, the antiobesity agent is leptin. In one embodiment, the antiobesity agent is peptide YY₃.₃₆. In one embodiment, the antiobesity agent is a serotonin and norepinephrine reuptake inhibitor e.g. sibutramine. In one embodiment, the antiobesity agent is a lipase inhibitor e.g. orlistat. In one embodiment, the antiobesity agent is an adrenergic CNS stimulating agent e.g. dexamphetamine, amphetamine, phentermine, mazindol phendimetrazine, diethyl- propion, fenfluramine or dexfenfluramine. Other examples of suitable additional therapeutically active agents include anti- hypertensive agents. Examples of antihypertensive agents are β-blockers such as alprenolol, atenolol, timolol, pindolol, propranolol and metoprolol, ACE (angiotensin converting enzyme) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and ramipril, calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil, and α-blockers such as doxazosin, urapidil, prazosin and terazosin. In one embodiment of methods of the present invention, the compound of the peptide invention is administered in combination with more than one of the above-mentioned compounds e.g. in combination with metformin and a sulfonylurea such as glyburide; a sul- fonylurea and acarbose; nateglinide-.and metformin; acarbose and metformin; a sulfonylurea, metformin and troglitazone; insulin and a sulfonylurea; insulin and metformin; insulin, metformin and a sulfonylurea; insulin and troglitazone; or insulin and lovastatin. When a peptide of the present invention is administered in combination with another therapeutically active agent, said administration may be either simultaneously or sequentially, and it may use regimes with identical or different administration intervals for the individual compounds administered. The peptide can be produced by a method which comprises culturing a host cell containing a DNA sequence encoding the polypeptide and capable of expressing the poly- peptide in a suitable nutrient medium under conditions permitting the expression of the peptide, after which the resulting peptide is recovered from the culture. The medium used to culture the cells may be any conventional medium suitable for growing the host cells, such as minimal or complex media containing appropriate supplements. Suitable media are available from commercial suppliers or may be prepared from published recipes (e.g. in catalogues of the American Type Culture Collection). The peptide produced by the cells may then be recovered from the culture medium by conventional procedures including separating the host cells from the medium by centrifugation or filtration, precipitating the proteinaceous components of the supernatant or filtrate by means of a salt, e.g. ammonium sulphate, purification by a variety of chromatographic procedures, e.g. ion exchange chromatography, gel filtration chromatography, affinity chromatography, or the like, dependent on the type of peptide in question. The DNA sequence encoding the parent peptide may suitably be of genomic or cDNA origin, for instance obtained by preparing a genomic or cDNA library and screening for DNA sequences coding for all or part of the peptide by hybridisation using synthetic oligonu- cleotide probes in accordance with standard techniques (see, for example, Sambrook, J, Fritsch, EF and Maniatis, T, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, New York, 1989). The DNA sequence encoding the peptide may also be prepared synthetically by established standard methods, e.g. the phosphoamidite method described by Beaucage and Caruthers, Tetrahedron Letters 22 (1981), 1859 - 1869, or the method described by Matthes et al., EMBO Journal 3 (1984), 801 - 805. The DNA sequence may also be prepared by polymerase chain reaction using specific primers, for instance as described in US 4,683,202 or Saiki etal., Science 239 (1988), 487 - 491. The DNA sequence may be inserted into any vector which may conveniently be subjected to recombinant DNA procedures, and the choice of vector will often depend on the host cell into which it is to be introduced. Thus, the vector may be an autonomously replicating vector, i.e. a vector which exists as an extrachromosomal entity, the. replication of which is independent of chromosomal replication, e.g. a plasmid. Alternatively, the vector may be one which, when introduced into a host cell, is integrated into the host cell genome and replicated together with the chromosome(s) into which it has been integrated. The vector is preferably an expression vector in which the DNA sequence encoding the peptide is operably linked to additional segments required for transcription of the DNA, such as a promoter. The promoter may be any DNA sequence which shows transcriptional activity in the host cell of choice and may be derived from genes encoding proteins either homologous or heterologous to the host cell. Examples of suitable promoters for directing the transcription of the DNA encoding the peptide of the invention in a variety of host cells are well known in the art, cf. for instance Sambrook etal., supra. The DNA sequence encoding the peptide may also, if necessary, be operably connected to a suitable terminator, polyadenylation signals, transcriptional enhancer sequences, and translational enhancer sequences. The recombinant vector of the invention may further comprise a DNA sequence enabling the vector to replicate in the host cell in question. The vector may also comprise a selectable marker, e.g. a gene the product of which complements a defect in the host cell or one which confers resistance to a drug, e.g. ampicil- lin, kanamycin, tetracyclin, chloramphenicol, neomycin, hygromycin or methotrexate. To direct a parent peptide of the present invention into the secretory pathway of the host cells, a secretory signal sequence (also known as a leader sequence, prepro sequence or pre sequence) may be provided in the recombinant vector. The secretory signal sequence is joined to the DNA sequence encoding the peptide in the correct reading frame. Secretory signal sequences are commonly positioned 5' to the DNA sequence encoding the peptide. The secretory signal sequence may be that normally associated with the peptide or may be from a gene encoding another secreted protein. The procedures used to ligate the DNA sequences coding for the present peptide, the promoter and optionally the terminator and/or secretory signal sequence, respectively, and to insert them into suitable vectors containing the information necessary for replication, are well known to persons skilled in the art (cf., for instance, Sambrook etal.., supra). The host cell into which the DNA sequence or the recombinant vector is introduced may be any cell which is capable of producing the present peptide and includes bacteria, yeast, fungi and higher eukaryotic cells. Examples of suitable host cells well known and used in the art are, without limitation, E. coli, Saccharomyces cerevisiae, or mammalian BHK or CHO cell lines. The peptides of the present invention may also be synthesized synthetically by standard solid-phase peptide chemistry. Regardless of the production method, the resulting SIP peptide can be further deri- vatised, for example by acylation by methods known in the art.

PHARMACEUTICAL COMPOSITIONS Another object of the present invention is to provide a pharmaceutical formulation comprising an SIP protein compound which is present in a concentration from 10^"15 mg/ml to 200 mg/ml, such as e.g. 10^"10 mg/ml to 5 mg/ml and wherein said formulation has a pH from 2.0 to 10.0. The formulation may further comprise a buffer system, preservative(s), tonicity agent(s), chelating agent(s), stabilizers and surfactants. In one embodiment of the invention the pharmaceutical formulation is an aqueous formulation, i.e. formulation comprising water. Such formulation is typically a solution or a suspension. In a further embodiment of the invention the pharmaceutical formulation is an aqueous solution. The term "aqueous formulation" is defined as a formulation comprising at least 50 %w/w water. Likewise, the term "aqueous solution" is defined as a solution comprising at least 50 %w/w water, and the term "aqueous suspension" is defined as a suspension comprising at least 50 %w/w water. In another embodiment the pharmaceutical formulation is a freeze-dried formulation, whereto the physician or the patient adds solvents and/or diluents prior to use. In another embodiment the pharmaceutical formulation is a dried formulation (e.g. freeze-dried or spray-dried) ready for use without any prior dissolution. In a further aspect the invention relates to a pharmaceutical formulation comprising an aqueous solution of an SIP protein, and a buffer, wherein said SIP protein is present in a concentration from 0.1-100 mg/ml, and wherein said formulation has a pH from about 2.0 to about 10.0. In a another embodiment of the invention the pH of the formulation is selected from the list consisting of 2.0, 2.1 , 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1 , 3.2, 3.3, 3.4, 3.5,

3.6, 3.7, 3.8, 3.9, 4.0, 4.1 , 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1 , 5.2, 5.3, 5.4, 5.5, 5.6,

5.7, 5.8, 5.9, 6.0, 6.1 , 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1 , 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1 , 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1 , 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8,

9.9, and 10.0. In a further embodiment of the invention the buffer is selected from the group consisting of sodium acetate, sodium carbonate, citrate, glycylglycine, histidine, glycine, lysine, arginine, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, and tris(hydroxymethyl)-aminomethan, bicine, tricine, malic acid, succinate, maleic acid, fu- maric acid, tartaric acid, aspartic acid or mixtures thereof. Each one of these specific buffers constitutes an alternative embodiment of the invention. In a further embodiment of the invention the formulation further comprises a pharmaceutically acceptable preservative. In a further embodiment of the invention the preservative is selected from the group consisting of phenol, o-cresol, m-cresol, p-cresol, methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, 2-phenoxyethanol, butyl p- hydroxybenzoate, 2-phenylethanol, benzyl alcohol, chlorobutanol, and thiomerosal, bronopol, benzoic acid, imidurea, chlorohexidine, sodium dehydroacetate, chlorocresol, ethyl p- hydroxybenzoate, benzethonium chloride, chlorphenesine (3p-chlorphenoxypropane-1 ,2-diol) or mixtures thereof. In a further embodiment of the invention the preservative is present in a concentration from 0.1 mg/ml to 20 mg/ml. In a further embodiment of the invention the preservative is present in a concentration from 0.1 mg/ml to 5 mg/ml. In a further embodiment of the invention the preservative is present in a concentration from 5 mg/ml to 10 mg/ml. In a further embodiment of the invention the preservative is present in a concentration from 10 mg/ml to 20 mg/ml. Each one of these specific preservatives constitutes an alternative embodiment of the invention. The use of a preservative in pharmaceutical compositions is well-known to the skilled person. For convenience, reference is made to Remington: The Science and Practice of Pharmacy, 20^th edition, 2000. In a further embodiment of the invention the formulation further comprises an isotonic agent. In a further embodiment of the invention the isotonic agent is selected from the group consisting of a salt (e.g. sodium chloride), a sugar or sugar alcohol, an amino acid (e.g. L-glycine, L-histidine, arginine, lysine, isoleucine, aspartic acid, tryptophan, threonine), an alditol (e.g. glycerol (glycerine), 1 ,2-propanediol (propyleneglycol), 1 ,3-propanediol, 1,3- butanediol) polyethyleneglycol (e.g. PEG400), or mixtures thereof. Any sugar such as mono-, di-, or polysaccharides, or water-soluble glucans, including for example fructose, glucose, mannose, sorbose, xylose, maltose, lactose, sucrose, trehalose, dextran, pullulan, dextrin, cyclodextrin, soluble starch, hydroxyethyl starch and carboxymethylcellulose-Na may be used. In one embodiment the sugar additive is sucrose. Sugar alcohol is defined as a C4-C8 hydrocarbon having at least one -OH group and includes, for example, mannitol, sorbitol, inositol, galactitol, dulcitol, xylitol, and arabitol. In one embodiment the sugar alcohol additive is mannitol. The sugars or sugar alcohols mentioned above may be used individually or in combination. There is no fixed limit to the amount used, as long as the sugar or sugar alcohol is soluble in the liquid preparation and does not adversely effect the stabilizing effects achieved using the methods of the invention. In one embodiment, the sugar or sugar alcohol concentration is between about 1 mg/ml and about 150 mg/ml. In a further embodiment of the invention the isotonic agent is present in a concentration from 1 mg/ml to 50 mg/ml. In a. further embodiment of the invention the isotonic agent is present in a concentration from 1 mg/ml to 7 mg/ml. In a further embodiment of the invention the isotonic agent is present in a concentration from 8 mg/ml to 24 mg/ml. In a further embodiment of the invention the isotonic agent is present in a concentration from 25 mg/ml to 50 mg/ml. Each one of these specific isotonic agents constitutes an alternative embodiment of the invention. The use of an isotonic agent in pharmaceutical compositions is well-known to the skilled person. For convenience reference is made to Remington: The Science and Practice of Pharmacy, 20^th edition, 2000. In a further embodiment of the invention the formulation further comprises a chelating agent. In a further embodiment of the invention the chelating agent is selected from salts of ethylenediaminetetraacetic acid (EDTA), citric acid, and aspartic acid, and mixtures thereof. In a further embodiment of the invention the chelating agent is present in a concentration from 0.1 mg/ml to 5mg/ml. In a further embodiment of the invention the chelating agent is present in a concentration from 0.1 mg/ml to 2mg/ml. In a further embodiment of the invention the chelating agent is present in a concentration from 2mg/ml to 5mg/ml. Each one of these specific chelating agents constitutes an alternative embodiment of the invention. The use of a chelating agent in pharmaceutical compositions is well-known to the skilled person. For convenience reference is made to Remington: The Science and Practice of Pharmacy, 20* edition, 2000. In a further embodiment of the invention the formulation further comprises a stabilizer. The use of a stabilizer in pharmaceutical compositions is well-known to the skilled person. For convenience, reference is made to Remington: The Science and Practice of Pharmacy, 20^th edition, 2000. More particularly, compositions of the invention are stabilized liquid pharmaceutical compositions whose therapeutically active components include a polypeptide that possibly exhibits aggregate formation during storage in liquid pharmaceutical formulations. By "aggregate formation" is understood a physical interaction between the polypeptide molecules that results in formation of oligomers, which may remain soluble, or large visible aggregates that precipitate from the solution. By "during storage" is intended a liquid pharmaceutical compo- sition or formulation that once prepared is not immediately administered to a subject. Rather, following preparation, it is packaged for storage, either in a liquid form, in a frozen state, or in a dried form for later reconstitution into a liquid form or other form suitable for administration to a subject. By "dried form" is understood that the liquid pharmaceutical composition or formulation is dried either by freeze drying (i.e., lyophilization; see, for example, Williams and Polli (1984) J. Parenteral Sci. Technol. 38:48-59), spray drying (see Masters (1991) in Spray- Drying Handbook (5th ed; Longman Scientific and Technical, Essez, U.K.), pp. 491-676; Broadhead et al. (1992) Drug Devel. Ind. Pharm. 18:1169-1206; and Mumenthaler et al. (1994) Pharm. Res. 11 :12-20), or air drying (Carpenter and Crowe (1988) Cryobiology 25:459-470; and Roser (1991) Biopharm. 4:47-53). Aggregate formation by a polypeptide during storage of a liquid pharmaceutical composition can adversely affect biological activity of that polypeptide, resulting in loss of therapeutic efficacy of the pharmaceutical composition. Furthermore, aggregate formation may cause other problems such as blockage of tubing, membranes, or pumps when the polypeptide-containing pharmaceutical composition is administered using an infusion system. The pharmaceutical compositions of the invention may further comprise an amount of an amino acid base sufficient to decrease aggregate formation by the polypeptide during storage of the composition. By "amino acid base" is understood an amino acid or a combination of amino acids, where any given amino acid is present either in its free base form or in its salt form. Where a combination of amino acids is used, all of the amino acids may be pre- sent in their free base forms, all may be present in their salt forms, or some may be present in their free base forms while others are present in their salt forms. In one embodiment, amino acids to use in preparing the compositions of the invention are those carrying a charged side chain, such as arginine, lysine, aspartic acid, and glutamic acid. Any stereoi- somer (i.e., L, D, or DL isomer) of a particular amino acid (e.g. glycine, methionine, histidine, imidazole, arginine, lysine, isoleucine, aspartic acid, tryptophan, threonine and mixtures thereof) or combinations of these stereoisomers, may be present in the pharmaceutical compositions of the invention so long as the particular amino acid is present either in its free base form or its salt form. In one embodiment the L-stereoisomer is used. Compositions of the invention may also be formulated with analogues of these amino acids. By "amino acid ana- logue" is understood a derivative of the naturally occurring amino acid that brings about the desired effect of decreasing aggregate formation by the polypeptide during storage of the liquid pharmaceutical compositions of the invention. Suitable arginine analogues include, for example, aminoguanidine, ornithine and N-monoethyl L-arginine, suitable methionine analogues include ethionine and buthionine and suitable cysteine analogues include S-methyl-L cysteine. As with the other amino acids, the amino acid analogues are incorporated into the compositions in either their free base form or their salt form. In a further embodiment of the invention the amino acids or amino acid analogues are used in a concentration, which is sufficient to prevent or delay aggregation of the protein. In a further embodiment of the invention the formulation further comprises a stabilizer selected from the group of high molecular weight polymers or low molecular compounds. In a further embodiment of the invention the stabilizer is selected from polyethylene glycol (e.g. PEG 3350), polyvinyl alcohol (PVA), polyvinylpyrrolidone, carboxy- /hydroxycellulose or derivates thereof (e.g. HPC, HPC-SL, HPC-L and HPMC), cyclodextrins, sulphur-containing substances as monothioglycerol, thioglycolic acid and 2- methylthioethanol, and different salts (e.g. sodium chloride). Each one of these specific stabilizers constitutes an alternative embodiment of the invention. The pharmaceutical compositions may also comprise additional stabilizing agents, which further enhance stability of the therapeutically active polypeptide therein. Stabilizing agents of particular interest to the present invention include, but are not limited to, methionine and EDTA, which protect the polypeptide against oxidation, and a nonionic surfactant, which protects the polypeptide against aggregation associated with freeze- thawing or mechanical shearing. In a further embodiment of the invention the formulation further comprises a surfactant. In a further embodiment of the invention the surfactant is selected from a detergent, ethoxylated castor oil, polyglycolyzed glycerides, acetylated monoglycerides, sorbitan fatty acid esters, polyoxypropylene-polyoxyethylene block polymers (eg. poloxamers such as Pluronic^® F68, poloxamer 188 and 407, Triton X-100 ), polyoxyethylene sorbitan fatty acid esters, polyoxyethylene and polyethylene derivatives such as alkylated and alkoxylated derivatives (tweens, e.g. Tween-20, Tween-40, Tween-80 and Brij-35), monoglycerides or ethoxylated derivatives thereof, diglycerides or polyoxyethylene derivatives thereof, alcohols, glycerol, lectins and phospholipids (eg. phosphatidyl serine, phosphatidyl choline, phosphatidyl ethanolamine, phosphatidyl inositol, diphosphatidyl glycerol and sphingomyelin), derivates of phospholipids (eg. dipalmitoyl phosphatidic acid) and lysophospholipids (eg. palmitoyl lysophosphatidyl-L-serine and 1 -acyl-sn-glycero-3- phosphate esters of ethanolamine, choline, serine or threonine) and alkyl, alkoxyl (alkyl ester), alkoxy (alkyl ether)- derivatives of lysophosphatidyl and phosphatidylcholines, e.g. lauroyl and myristoyl derivatives of lysophosphatidylcholine, dipalmitoylphosphatidylcholine, and modifications of the polar head group, that is cholines, ethanolamines, phosphatidic acid, serines, threonines, glycerol, inositol, and the positively charged DODAC, DOTMA, DCP, BISHOP, lysophosphatidylserine and lysophosphatidylthreonine, and glycerophospholipids (eg. cephalins), glyceroglycolipids (eg. galactopyransoide), sphingoglycolipids (eg. ceramides, gangliosides), dodecylphosphocholine, hen egg lysolecithin, fusidic acid derivatives- (e.g. sodium tauro-dihydrofusidate etc.), long-chain fatty acids and salts thereof C6-C12 (eg. oleic acid and caprylic acid), acylcarnitines and derivatives, N^α-acylated derivatives of lysine, arginine or histidine, or side-chain acylated derivatives of lysine or arginine, N^α-acylated derivatives of dipeptides comprising any combination of lysine, arginine or histidine and a neutral or acidic amino acid, N^α-acylated derivative of a tripeptide comprising any combination of a neutral amino acid and two charged amino acids, DSS (docusate sodium, CAS registry no [577-11-7]), docusate calcium, CAS registry no [128-49- 4]), docusate potassium, CAS registry no [7491 -09-0]), SDS (sodium dodecyl sulphate or sodium lauryl sulphate), sodium caprylate, cholic acid or derivatives thereof, bile acids and salts thereof and glycine or taurine conjugates, ursodeoxycholic acid, sodium cholate, sodium deoxycholate, sodium taurocholate, sodium glycocholate, N-Hexadecyl-N,N- dimethyl-3-ammonio-1-propanesulfonate, anionic (alkyl-aryl-sulphonates) monovalent surfactants, zwitterionic surfactants (e.g. N-alkyl-N,N-dimethylammonio-1-propanesulfonates, 3-cholamido-1-propyldimethylammonio-1-propanesulfonate, cationic surfactants (quaternary ammonium bases) (e.g. cetyl-trimethylammonium bromide, cetylpyridinium chloride), nonionic surfactants (eg. Dodecyl β-D-glucopyranoside), poloxamines (eg. Tetronic's), which are tetrafunctional block copolymers derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine, or the surfactant may be selected from the group of imidazoline derivatives, or mixtures thereof. Each one of these specific surfactants constitutes an alternative embodiment of the invention. The use of a surfactant in pharmaceutical compositions is well-known to the skilled person. For convenience, reference is made to Remington: The Science and Practice of Pharmacy, 20* edition, 2000. It is possible that other ingredients may be present in the pharmaceutical formulation of the present invention. Such additional ingredients may include wetting agents, emulsifiers, antioxidants, bulking agents, tonicity modifiers, chelating agents, metal ions, oleaginous vehicles, proteins (e.g., human serum albumin, gelatine or proteins) and a zwitterion (e.g., an amino acid such as betaine, taurine, arginine, glycine, lysine and histidine). Such additional ingredients, of course, should not adversely affect the overall stability of the pharmaceutical formulation of the present invention. Pharmaceutical compositions containing a SIP protein according to the present invention may be administered to a patient in need of such treatment at several sites, for ex- ample, at topical sites, for example, skin and mucosal sites, at sites which bypass absoφ- tion, for example, administration in an artery, in a vein, in the heart, and at sites which involve absorption, for example, administration in the skin, under the skin, in a muscle or in the abdomen. Administration of pharmaceutical compositions according to the invention may be through several routes of administration, for example, lingual, sublingual, buccal, in the mouth, oral, in the stomach and intestine, nasal, pulmonary, for example, through the bronchioles and alveoli or a combination thereof, epidermal, dermal, transdermal, vaginal, rectal, ocular, for examples through the conjunctiva, uretal, and parenteral to patients in need of such a treatment. Compositions of the current invention may be administered in several dosage forms, for example, as solutions, suspensions, emulsions, microemulsions, multiple emulsion, foams, salves, pastes, plasters, ointments, tablets, coated tablets, rinses, capsules, for example, hard gelatine capsules and soft gelatine capsules, suppositories, rectal capsules, drops, gels, sprays, powder, aerosols, inhalants, eye drops, ophthalmic ointments, ophthal- mic rinses, vaginal pessaries, vaginal rings, vaginal ointments, injection solution, in situ transforming solutions, for example in situ gelling, in situ setting, in situ precipitating, in situ crystallization, infusion solution, and implants. Compositions of the invention may further be compounded in, or attached to, for example through covalent, hydrophobic and electrostatic interactions, a drug carrier, drug de- livery system and advanced drug delivery system in order to further enhance stability of the SIP protein, increase bioavailability, increase solubility, decrease adverse effects, achieve chronotherapy well known to those skilled in the art, and increase patient compliance or any combination thereof. Examples of carriers, drug delivery systems and advanced drug delivery systems include, but are not limited to, polymers, for example cellulose and derivatives, polysaccharides, for example dextran and derivatives, starch and derivatives, poly(vinyl alcohol), acrylate and methacrylate polymers, polylactic and polyglycolic acid and block copolymers thereof, polyethylene glycols, carrier proteins, for example albumin, gels, for example, thermogelling systems, for example block co-polymeric systems well known to those skilled in the art, micelles, liposomes, microspheres, nanoparticulates, liquid crystals and dispersions thereof, L2 phase and dispersions there of, well known to those skilled in the art of phase behaviour in lipid-water systems, polymeric micelles, multiple emulsions, self- emulsifying, self-microemulsifying, cyclodextrins and derivatives thereof, and dendrimers. Compositions of the current invention are useful in the formulation of solids, semisol- ids, powder and solutions for pulmonary administration of SIP protein, using, for example a metered dose inhaler, dry powder inhaler and a nebulizer, all being devices well known to those skilled in the art. Compositions of the current invention are specifically useful in the formulation of controlled, sustained, protracting, retarded, and slow release drug delivery systems. More specifically, but not limited to, compositions are useful in formulation of parenteral controlled release and sustained release systems (both systems leading to a many-fold reduction in number of administrations), well known to those skilled in the art. Even more preferably, are controlled release and sustained release systems administered subcutaneous. Without limiting the scope of the invention, examples of useful controlled release system and compositions are hydrogels, oleaginous gels, liquid crystals, polymeric micelles, microspheres, nanoparticles, Methods to produce controlled release systems useful for compositions of the current invention include crystallization, condensation, co-crystallization, precipitation, co- precipitation, emulsification, dispersion, high pressure homogenisation, encapsulation, spray drying, microencapsulating, coacervation, phase separation, solvent evaporation to produce microspheres, extrusion and supercritical fluid processes. General reference is made to

Handbook of Pharmaceutical Controlled Release (Wise, D.L, ed. Marcel Dekker, New York, 2000) and Drug and the Pharmaceutical Sciences vol. 99: Protein Formulation and Delivery (MacNally, E.J., ed. Marcel Dekker, New York, 2000). Parenteral administration may be performed by subcutaneous, intramuscular, in- traperitoneal or intravenous injection by means of a syringe, optionally a pen-like syringe. Alternatively, parenteral administration can be performed by means of an infusion pump. A further option is a composition which may be a solution or suspension for the administration of the SIP protein in the form of a nasal or pulmonal spray. As a still further option, the pharmaceutical compositions containing the SIP protein of the invention can also be adapted to transder al administration, e.g. by needle-free injection or from a patch, optionally an ionto- phoretic patch, or transmucosal, e.g. buccal, administration. The term "stabilized formulation" refers to a formulation with increased physical stability, increased chemical stability or increased physical and chemical stability. The term "physical stability" of the protein formulation as used herein refers to the tendency of the protein to form biologically inactive and/or insoluble aggregates of the protein as a result of exposure of the protein to thermo-mechanical stresses and/or interaction with interfaces and surfaces that are destabilizing, such as hydrophobic surfaces and interfaces. Physical stability of the aqueous protein formulations is evaluated by means of visual inspection and/or turbidity measurements after exposing the formulation filled in suitable containers (e.g. cartridges or vials) to mechanical/physical stress (e.g. agitation) at different temperatures for various time periods. Visual inspection of the formulations is performed in a sharp focused light with a dark background. The turbidity of the formulation is characterized by a visual score ranking the degree of turbidity for instance on a scale from 0 to 3 (a formulation showing no turbidity corresponds to a visual score 0, and a formulation showing visual turbid- ity in daylight corresponds to visual score 3). A formulation is classified physical unstable with respect to protein aggregation, when it shows visual turbidity in daylight. Alternatively, the turbidity of the formulation can be evaluated by simple turbidity measurements well- known to the skilled person. Physical stability of the aqueous protein formulations can also be evaluated by using a spectroscopic agent or probe of the conformational status of the pro- tein. The probe is preferably a small molecule that preferentially binds to a non-native con- former of the protein. One example of a small molecular spectroscopic probe of protein structure is Thioflavin T. Thioflavin T is a fluorescent dye that has been widely used for the detection of amyloid fibrils. In the presence of fibrils, and perhaps other protein configurations as well, Thioflavin T gives rise to a new excitation maximum at about 450 nm and enhanced emission at about 482 nm when bound to a fibril protein form. Unbound Thioflavin T is essentially non-fluorescent at the wavelengths. Other small molecules can be used as probes of the changes in protein structure from native to non-native states. For instance the "hydrophobic patch" probes that bind preferentially to exposed hydrophobic patches of a protein. The hydrophobic patches are gener- ally buried within the tertiary structure of a protein in its native state, but become exposed as a protein begins to unfold or denature. Examples of these small molecular, spectroscopic probes are aromatic, hydrophobic dyes, such as antrhacene, acridine, phenanthroline or the like. Other spectroscopic probes are metal-amino acid complexes, such as cobalt metal complexes of hydrophobic amino acids, such as phenylalanine, leucine, isoleucine, methion- ine, and valine, or the like. The term "chemical stability" of the protein formulation as used herein refers to chemical covalent changes in the protein structure leading to formation of chemical degradation products with potential less biological potency and/or potential increased immunogenic properties compared to the native protein structure. Various chemical degradation products can be formed depending on the type and nature of the native protein and the environment to which the protein is exposed. Elimination of chemical degradation can most probably not be completely avoided and increasing amounts of chemical degradation products is often seen during storage and use of the protein formulation as well-known by the person skilled in the art. Most proteins are prone to deamidation, a process in which the side chain amide group in glutaminyl or asparaginyl residues is hydrolysed to form a free carboxylic acid. Other degradations pathways involves formation of high molecular weight transformation products where two or more protein molecules are covalently bound to each other through transami- dation and/or disulfide interactions leading to formation of covalently bound dimer, oligomer and polymer degradation products (Stability of Protein Pharmaceuticals, Ahem. T . & Man- ning M.C., Plenum Press, New York 1992). Oxidation (of for instance methionine residues) can be mentioned as another variant of chemical degradation. The chemical stability of the protein formulation can be evaluated by measuring the amount of the chemical degradation products at various time-points after exposure to different environmental conditions (the formation of degradation products can often be accelerated by for instance increasing tempera- ture). The amount of each individual degradation product is often determined by separation of the degradation products depending on molecule size and/or charge using various chromatography techniques (e.g. SEC-HPLC and/or RP-HPLC). Hence, as outlined above, a "stabilized formulation" refers to a formulation with increased physical stability, increased chemical stability or increased physical and chemical stability. In general, a formulation must be stable during use and storage (in compliance with recommended use and storage conditions) until the expiration date is reached. In one embodiment of the invention the pharmaceutical formulation comprising the SIP protein is stable for more than 6 weeks of usage and for more than 3 years of storage. In another embodiment of the invention the pharmaceutical formulation comprising the SIP protein is stable for more than 4 weeks of usage and for more than 3 years of storage. In a further embodiment of the invention the pharmaceutical formulation comprising the SIP proteinis stable for more than 4 weeks of usage and for more than two years of storage. In an even further embodiment of the invention the pharmaceutical formulation comprising the SIP protein is stable for more than 2 weeks of usage and for more than two years of storage.

EXAMPLES

Example 1 SIPs exist in plasma from pigs treated with DPP IV inhibitor but not in vehicle treated plasma from pigs

Minipigs were given 50 mg/kg of val-pyr ( DPP IV inhibitor) or a similar volume of vehicle to control animals by i.v. injection at time -15 minutes. At time 0, the pigs were allowed to eat 2 g of glucose pr gram of body weight. At various time points before and after giving the glucose blood samples were taken from the animals for measuring of blood-glucose levels and for peptide analysis in the plasma fraction of the blood. Plasma was separated by chromatography and each fraction analyzed by mass-spectrometry. Each peptide in the sample was identified by its unique mass which is a reflection of the peptide's unique sequence. pSIP-1 and pSIP-2 were present only in plasma from pigs given the DPP IV-inhibitor and absent ip controls. This experiment led to the discovery of pSIP-1 and pSIP-2 as DPP IV-regulated peptides. The amino acid sequences of the peptides were obtained by direct MS/MS sequencing of the peptides, and are indicated in the text above.

Example 2 Assessment of DPP IV sensitivity of SIP peptides pSIP-1 and pSIP-2 were prepared using standard solid-phase peptide synthesis using methods well known in the art. Synthetic peptides corresponding to the wild-type sequence of pSIP-1 and -2 were prepared as well as analogues in which the proline at position 2 was replaced by a particular variant of Alanine termed Aib (aminoisobutyric acid). This substitution is known to change a peptide from being a DPP IV substrate into not being a DPP IV substrate. Consequently, these analogues were expected to be resistant to DPP IV- mediated cleavage. The DPP IV-sensitivity of the peptides was tested by incubating them in a solution of DPP IV in vitro, followed by standard mass spectrometry analysis (MALDI-MS). More specifi- cally, the experiment was performed at a enzyme/substrate ratio of 1 :50 and aliquots were withdrawn for MALDI-MS at given time intervals. After incubation for 10 minutes, more than 50% of the wild-type peptides were cleaved by DPP IV, whereas the two analogues remained intact. The results showed that pSIP-1 and pSIP-2 are both very good substrates of DPP IV, while the two analogues are not. This is also a confirmation of the in vivo results showing DPP IV sensitivity of pSIP-1 and pSIP-2 discussed in example 1. The data obtained for pSIP-2 and its Aib (aminoisobutyric acid) analogue is shown in figure 1.

Example 3 Blood glucose lowering effect of SIP when administered i.v. To test the glucose-lowering activity of the peptides in plasma, a rat model was used where endogenous glucose levels are raised slightly by anesthetizing the animals with hyp- norm/dormicum. In wistar rats this leads to an increase in blood glucose levels of about 1 mmol/L. Administration of GLP-1 (7-36) amide, as a positive control, decreased blood glucose back towards normal levels. Administration of either pSIP-1 or pSIP-2 also caused a signifi- cant lowering of blood glucose levels, as shown in Figure 2. In contrast, administration of vehicle had no effect. Therefore, it is concluded that SIP peptides can cause a lowering of blood glucose levels.

Example 4 Blood glucose lowering effect of SIP when administered orally To test the glucose-lowering effect of the peptides when administered orally, the peptides were administered by gavage to mice followed by a glucose challenge. As it has been shown that some SIP peptides are DPP IV substrates, mice lacking the gene encoding DPP IV (also known as CD26-/- mice) were used in this experiment. Mice given pSIP-1 had markedly lower blood glucose excursion after oral glucose challenge than mice given pSIP-2, or vehicle (figure 3). By taking the area under the curve of the data in figure 3, one can obtain a quantitative measure of the glucose excursions in the different experimental groups ,as depicted in figure 4. Using Dunnett's Multiple Comparison Test it was found that area under the curve (AUC) for pSIP-1 was significantly lower (p<0.05) than AUC for vehicle. It is thus concluded, that certain SIP peptides, such as pSIP-1 , are orally available peptides that can be used for lowering blood-glucose, optionally in combination with a DPP IV inhibitor.

Claims

1. A peptide according to formula I

5 1 2 3 4 5 6 7 8 9 10 11 Pro-Xaa-Xaa-Xaa-Xaa-Xaa-Pro-Xaa-Gly-Pro-Pro-

12 13 14 15 16 17 18 19 20 21 [I] Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa0 wherein Xaa at position 2 is Pro, Gly or Aib, Xaa at position 3 is Pro or Gly, Xaa at position 4 is Pro or Ala,5 Xaa at position 5 is Arg, Lys or Gly Xaa at position 6 is Pro or Lys, Xaa at position 8 is Pro or Gin, Xaa at position 12 is Pro or Gin, Xaa at position 13 s Pro, Gly, Gin or absent,0 Xaa at position 14 is Pro, Gly, Ala or absent, Xaa at position 15 s Pro, Gly or absent, Xaa at position 16 s Pro, Gly, Gin, Arg, Lys or absent, Xaa at position 17 s Pro, Gly, Leu or absent, Xaa at position 18 s Pro, Gly, Gin or absent,5 Xaa at position 19 s Gly, Gin, Arg or absent, Xaa at position 20 is Pro, Gly or absent, Xaa at position 21 s Pro or absent; derivatives thereof; which peptide is capable of exerting a blood glucose lowering effect;0 and pharmaceutically acceptable salts or solvates thereof.

2. A peptide of claim 1 , according to formula I

10 11 Pro-Xaa-Xaa-Xaa-Xaa-Xaa-Pro-Xaa-Gly-Pro-Pro-

12 13 14 15 16 17 18 19 20 21 [ I ]

Pro-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa

wherein

Xaa at position 2 is Pro, Gly or Aib, Xaa at position 3 is Pro or Gly, Xaa at position 4 is Pro or Ala, Xaa at position 5 is Arg, Lys or Gly Xaa at position 6 is Pro or Lys, Xaa at position 8 is Pro or Gin,

Xaa at position 13 s Pro, Gin or absent,

Xaa at position 14 s Gly , Ala or absent, Xaa at position 15 s Pro, Gly or absent,

Xaa at position 16 is Pro, Gly, Arg, Lys or absent,

Xaa at position 17 s Pro, Leu or absent,

Xaa at position 18 s Pro, Gin or absent,

Xaa at position 19 s Gly, Gin or absent, Xaa at position 20 s Pro, Gly or absent,

Xaa at position 21 s Pro or absent; derivatives thereof; which peptide is capable of exerting a blood glucose lowering effect; and pharmaceutically acceptable salts or solvates thereof.

3. A peptide according to any of the following sequences

(pSIP-1) PPGARPPPGPPPPGPPPPGP;

(p-SIP-2) PPGARPPPGPPPPAGGLQQGP;

(p-SIP-3) PGARPPPGPPPPP; (p-SIP-4) PPGARPPPGPPPP;

(h-SIP-1) PPPPGKPQGPPQGPPQGGRP; and

(hSIP-2) PPPPGKPQGPPPQGGRPQGP, or a peptides having at least 60%, identity to any of said sequences, and derivatives thereof, which peptides are capable of exerting a blood glucose lowering effect.

4. A peptide according to any of the claims 1- 3 selected from (pSIP-1) PPGARPPPGPPPPGPPPPGP;

(p-SIP-2) PPGARPPPGPPPPAGGLQQGP; (p-SIP-3) PGARPPPGPPPPP; (p-SIP-4) PPGARPPPGPPPP;

(h-SIP-1) PPPPGKPQGPPQGPPQGGRP; (hSIP-2) PPPPGKPQGPPPQGGRPQGP P(Aib)GARPPPGPPPPGPPPPGP; P(Aib)GARPPPGPPPPAGGLQQGP.

5. A peptide according to any of claims 1 -4 in an isolated form.

6. A peptide according to any of claims 1 -5 for use in therapy

7. A therapeutic method for the treatment of Type I diabetes, Type II diabetes, obesity, impaired glucose tolerance or impaired fasting glucose tolerance, the method comprising administering to a patient in need thereof a therapeutically effective amount of a peptide according to any of claims 1 -5, optionally in combination with one or more other therapeutically active agents.

8. The use of a peptide according to any of claims 1 -5 in the manufacture of a medicament for the treatment of Type I diabetes, Type II diabetes, obesity, impaired glucose tolerance or impaired fasting glucose tolerance.

9. A pharmaceutical composition comprising a peptide according to any of claims 1 -5.

10. A nucleic acid construct encoding a peptide according to any of claims 1 -5.

11. A vector comprising the vector according to claim 10.

12. A host cell comprising the vector according to claim 11.

13. Antibodies that specifically binds to a peptide according to any of claims 1-5.