GLP-1 DERIVATIVES

Abstract: Derivatives of GLP-1 and analogues thereof having a lipophilic substituent have interesting pharmacological properties, in particular they have a more protracted profile of action than GLP-1(7-37).

Description: GLP-1 DERIVATIVES FIELD OF THE INVENTION The present invention relates to novel derivatives of human glucagon- ke peptιde-1 (GLP-1) and fragments thereof and analogues of such fragments which have a protracted profile of action and to methods of making and using them BACKGROUND OF THE INVENTION Peptides are widely used in medical practice, and since they can be produced by recombinant DNA technology it can be expected that their importance will increase also in the years to come When native peptides or analogues thereof are used in therapy it is generally found that they have a high clearance A high clearance of a therapeutic agent is inconvenient in cases where it is desired to maintain a high blood level thereof over a prolonged period of time since repeated administrations will then be necessary Examples of peptides which have a high clearance are ACTH, corticotropin-releasing factor, angiotensm, calcitonin, insulin, glucagon, glucagon-hke peptιde-1 , glucagon-hke peptιde-2, insulin-like growth factor-1 , insulin-like growth factor-2, gastric inhibitory peptide, growth hormone- releasing factor, pituitary adenylate cyclase activating peptide, secretin, enterogastπn, somatostatin, somatotropm, somatomedin, parathyroid hormone thrombopoietin, erythropoietiπ, hypothalamic releasing factors, prolactin, thyroid stimulating hormones, endorphms, enkephalins, vasopressm, oxytocin, opiods and analogues thereof, superoxide dismutase, interferon, asparaginase, arginase, arginine deaminase, adenosine deaminase and nbonuclease In some cases it is possible to influence the release profile of peptides by applying suitable pharmaceutical compositions, but this approach has various shortcomings and is not generally applicable The hormones regulating insuiin secretion belong to the so-called enteromsular axis, designating a group of hormones, released from the gastrointestinal mucosa in response to the presence and absorption of nutrients in the gut, which promote an early and potentiated release of insulin The enhancing effect on insulin secretion, the so-called incretin effect, is probably essential for a normal glucose tolerance Many of the qastrointestinal hormones includinσ αastnn and secretiπ (cholecystokinin is not insulinotropic in man), are insu notropic, but the only physiologically important ones, those that are responsible for the incretin effect, are the glucose-dependent insulinotropic polypeptide, GIP, and glucagon-like peptιde-1 (GLP-1 ) Because of its insulinotropic effect, GIP, isolated in 1973 (1 ) immediately attracted considerable interest among diabetologists However, numerous investigations carried out during the following years clearly indicated that a defective secretion of GIP was not involved in the pathogenesis of insulin dependent diabetes mellitus (IDDM) or non insulin-dependent diabetes mel tus (NIDDM) (2) Furthermore, as an insulinotropic hormone, GIP was found to be almost ineffective in NIDDM (2) The other incretin hormone, GLP-1 is the most potent insulinotropic substance known (3) Unlike GIP, it is surprisingly effective in stimulating insulin secretion in NIDDM patients In addition, and in contrast to the other insulinotropic hormones (perhaps with the exception of secretin) it also potently inhibits glucagon secretion Because of these actions it has pronounced blood glucose lowering effects particularly in patients with NIDDM GLP-1 , a product of the proglucagon (4), is one of the youngest members of the secretin- VIP family of peptides, but is already established as an important gut hormone with regulatory function in glucose metabolism and gastrointestinal secretion and metabolism (5) The glucagon gene is processed differently in the pancreas and in the intestine In the pancreas (9), the processing leads to the formation and parallel secretion of 1 ) glucagon itself, occupying positions 33-61 of proglucagon (PG), 2) an N-terminal peptide of 30 ammo acids (PG (1-30)) often called g centin-related pancreatic peptide, GRPP (10, 11 ), 3) a hexapeptide corresponding to PG (64-69), 4) and, finally, the so-called major proglucagon fragment (PG (72-158)), in which the two glucagon-like sequences are buried (9) Glucagon seems to be the only biologically active product In contrast, in the intestinal mucosa, it is glucagon that is buried in a larger molecule, while the two glucagon-like peptides are formed separately (8) The following products are formed and secreted in parallel 1) glicentin, corresponding to PG (1-69), with the glucagon sequence occupying residues Nos 33-61 (12), 2) GLP-1 (7-36)amιde (PG (78-107))amιde (13), not as originally believed PG (72-107)amιde or 108, which is inactive) Small amounts of C-terminally glycine-extended but equally bioactive GLP-1 (7-37), (PG (78-108)) are also formed (14), 3) intervening peptιde-2 (PG (111- 22)amιde) (15), and 4) GLP-2 (PG (126-158)) (15, 16) A fraction of glicentin is cleaved further into GRPP (PG (1-30)) and oxyntomodulin (PG (33-69)) (17, 18) Of these peptides, GLP-1 , has the most conspicuous biological activities Being secreted in parallel with glicentin/enteroglucagon, it follows that the many studies of enteroglucagoπ secretion (6, 7) to some extent also apply to GLP-1 secretion, but GLP-1 is metabolised more quickly with a plasma half-life in humans of 2 mm (19) Carbohydrate or fat-rich meals stimulate secretion (20), presumably as a result of direct interaction of yet unabsorbed nutrients with the microvilli of the open-type L-cells of the gut mucosa. Endocrine or neural mechanisms promoting GLP-1 secretion may exist but have not yet been demonstrated in humans. The incretin function of GLP-1 (29-31) has been clearly illustrated in experiments with the GLP-1 receptor antagonist, exendin 9-39, which dramatically reduces the incretin effect elicited by oral glucose in rats (21 , 22). The hormone interacts directly with the β-cells via the GLP-1 receptor (23) which belongs to the glucagon/VIP/calcitonin famiiy of G-protein- coupled 7-transmembrane spanning receptors. The importance of the GLP-1 receptor in regulating insulin secretion was illustrated in recent experiments in which a targeted disruption of the GLP-1 receptor gene was carried out in mice. Animals homozygous for the disruption had greatly deteriorated glucose tolerance and fasting hyperglycaemia, and even heterozygous animals were glucose intolerant (24). The signal transduction mechanism (25) primarily involves activation of adenylate cyclase, but elevations of intracellular Ca 2+ are also essential (25, 26). The action of the hormone is best described as a potentiation of glucose stimulated insulin release (25), but the mechanism that couples glucose and GLP-1 stimulation is not known. It may involve a calcium-induced calcium release (26, 27). As already mentioned, the insulinotropic action of GLP-1 is preserved in diabetic β-cells. The relation of the latter to its ability to convey "glucose competence" to isolated insulin-secreting cells (26, 28), which respond poorly to glucose or GLP-1 alone, but fully to a combination of the two, is also not known. Equally importantly, however, the hormone also potently inhibits glucagon secretion (29). The mechanism is not known, but seems to be paracrine, via neighbouring insulin or somatostatin cells (25). Also the glucagonostatic action is glucose-dependent, so that the inhibitory effect decreases as blood glucose decreases. Because of this dual effect, if the plasma GLP-1 concentrations increase either by increased secretion or by exogenous infusion the molar ratio of insulin to glucagon in the blood that reaches the liver via the portal circulation is greatly increased, whereby hepatic glucose production decreases (30). As a result blood glucose concentrations decrease. Because of the glucose dependency of the insulinotropic and glucagonostatic actions, the glucose lowering effect is self-limiting, and the hormone, therefore, does not cause hypoglycaemia regardless of dose (31). The effects are preserved in patients with diabetes mellitus (32), in whom infusions of slightly supraphysiological doses of GLP-1 may completely normalise blood glucose values in spite of poor metabolic control and secondary failure to sulphonyiurea (33). The importance of the glucagonostatic effect is illustrated by the finding that GLP-1 also lowers blood glucose in type-1 diabetic patients without residual β-cell secretory capacity (34). In addition to its effects on the pancreatic islets, GLP-1 has powerful actions on the gastrointestinal tract Infused in physiological amounts, GLP-1 potently inhibits pentagastπn-induced as well as meal-induced gastric acid secretion (35, 36) It also inhibits gastric emptying rate and pancreatic enzyme secretion (36) Similar inhibitory effects on gastric and pancreatic secretion and motility may be elicited in humans upon perfusion of the ileum with carbohydrate- or lipid-containing solutions (37, 38). Concomitantly, GLP-1 secretion is greatly stimulated, and it has been speculated that GLP-1 may be at least partly responsible for this so-called "ileal-brake" effect (38) In fact, recent studies suggest that, physiologically, the ileal-brake effects of GLP-1 may be more important than its effects on the pancreatic islets Thus, in dose response studies GLP-1 influences gastric emptying rate at infusion rates at least as low as those required to influence islet secretion (39) GLP-1 seems to have an effect on food intake Intraventπcular administration of GLP-1 profoundly inhibits food intake in rats (40, 42) This effect seems to be highly specific Thus, N-terminally extended GLP-1 (PG 72-107)amιde is inactive and appropriate doses of the GLP-1 antagonist, exendm 9-39, abolish the effects of GLP-1 (41 ) Acute, peripheral administration of GLP-1 does not inhibit food intake acutely in rats (41 , 42) However, it remains possible that GLP-1 secreted from the intestinal L-cells may also act as a satiety signal Not only the insulinotropic effects but also the effects of GLP-1 on the gastrointestinal tract are preserved in diabetic patients (43), and may help curtailing meal-induced glucose excursions, but, more importantly, may also influence food intake Administered intravenously, continuously for one week, GLP-1 at 4 ng/kg/mm has been demonstrated to dramatically improve glycaemic control in NIDDM patients without significant side effects (44) The peptide is fully active after subcutaneous administration (45), but is rapidly degraded mainly due to degradation by dipeptidyl peptidase IV-like enzymes (46, 47) The ammo acid sequence of GLP-1 is given / a by Schmidt et al (Diabetologia 28 704-707 (1985). Although the interesting pharmacological properties of GLP-1 (7-37) and analogues thereof have attracted much attention in recent years only little is known about the structure of these molecules The secondary structure of GLP-1 in micelles has been described by Thorton ef al {Biochemistry 33 3532-3539 (1994)), but in normal solution, GLP-1 is considered a very flexible molecule Surprisingly, we found that deπvatisation of this relatively small and very flexible molecule resulted in compounds whose plasma profile were highly protracted and still had retained activity. GLP-1 and analogues of GLP-1 and fragments thereof are potentially useful a. in the treatment of type 1 and type 2 diabetes. However, the high clearance limits the usefulness of these compounds, and thus there still is a need for improvements in this field. Accordingly, it is one object of the present invention to provide derivatives of GLP-1 and analogues thereof which have a protracted profile of action relative to GLP-1 (7-37). It is a further object of the invention to provide derivatives of GLP-1 and analogues thereof which have a lower clearance than GLP-1 (7-37). It is a further object of the invention to provide a pharmaceutical composition comprising a compound according to the invention and to use a compound of the invention to provide such a composition. Also, it is an object of the present invention to provide a method of treating insulin dependent and non-insulin dependent diabetes mellitus References. 1 Pederson RA Gastric Inhibitory Polypeptide. In Walsh JH, Dockray GJ (eds) Gut peptides: Biochemistry and Physiology. Raven Press, New York 1994, pp. 217259. 2 Krarup T. Immunoreactive gastric inhibitory polypeptide Endocr Rev 1988;9 122-134. 3. ørskov C. Glucagon-like peptιde-1 , a new hormone of the enteroinsular axis Diabetologia 1992; 35:701-711. 4. Bell Gl, Sanchez-Pescador R, Laybourn PJ, Najanan RC. Exon duplication and divergence in the human preproglucagon gene. Nature 1983; 304. 368-371. 5. Hoist JJ. Glucagon-like peptιde-1 (GLP-1 ) - a newly discovered Gl hormone Gastroenterology 1994; 107: 1848-1855. 6. Hoist JJ. Gut glucagon, enteroglucagon, gut GLI, glicentin - current status. Gastroenterology 1983;84: 1602-1613. 7. Hoist JJ, ørskov C. Glucagon and other proglucagon-denved peptides. In Walsh JH, Dockray GJ, eds. Gut peptides: Biochemistry and Physiology Raven Press, New York, pp. 305-340, 1993 8. ørskov C, Hoist JJ, Knuhtsen S, Baldissera FGA, Poulsen SS, Nielsen OV Glucagon-like peptides GLP-1 and GLP-2, predicted products of the glucagon gene, are secreted separately from the pig small intestine, but not pancreas. Endocrinology 1986,119:1467-1475. 9. Hoist JJ, Bersani M, Johnsen AH, Kofod H, Hartmann B, ørskov C Proglucagon processing in porcine and human pancreas J Biol Chem, 1994, 269" 8827-1883 10 Moody AJ, Hoist JJ, Thim L, Jensen SL Relationship of glicentin to proglucagon and glucagon in the porcine pancreas Nature 1981 , 289 514-516 11 Thim L, Moody AJ, Purification and chemical characterisation of a glicentin-related pancreatic peptide (proglucagon fragment) from porcine pancreas Biochim Biophys Acta 1982:703.134-141 12. Thim L, Moody AJ The primary structure of glicentin (proglucagon) Regul Pept 1981 ,2:139-151 13. ørskov C, Bersani M, Johnsen AH, Højrup P, Hoist JJ Complete sequences of glucagon-like peptιde-1 (GLP-1 ) from human and pig small intestine. J. Biol Chem 1989,264 12826-12829 14 ørskov C, Rabenhøj L, Kofod H, Wettergren A, Hoist JJ Production and secretion of amidated and glycine-extended glucagon-like peptide- 1 (GLP-1 ) in man. Diabetes 1991 , 43: 535-539 15. Buhl T, Thim L, Kofod H, ørskov C, Harling H, & Hoist JJ. Naturally occurring products of proglucagon 111-160 in the porcine and human small intestine. J. Biol. Chem 1988;263:8621-8624. 16. ørskov C, Buhl T, Rabenhøj L, Kofod H, Hoist JJ Carboxypeptidase-B-hke processing of the C-terminus of glucagon-like peptιde-2 in pig and human small intestine FEBS letters, 1989,247 193-106 Hoist JJ Evidence that enteroglucagon (II) is identical with the C-terminal sequence (residues 33-69) of glicentin Biochem J 1980,187 337-343 Bataille D, Tatemoto K, Gespach C, Jornvall H, Rosseiin G, Mutt V Isolation of glucagon-37 (bioactive enteroglucagon/oxyntomoduhn) from porcine jejuno-ileum Characterisation of the peptide FEBS Lett 1982,146 79-86 ørskov C, Wettergren A, Hoist JJ The metabolic rate and the biological effects of GLP-1 7-36amιde and GLP-1 7-37 in healthy volunteers are identical Diabetes 1993,42 658-661 Elliott RM, Morgan LM, Tredger JA, Deacon S, Wright J, Marks V Glucagon-like peptιde-1 (7-36)amιde and glucose-dependent insulinotropic polypeptide secretion in response to nutrient ingestion in man acute post-prandial and 24-h secretion patterns J Endocnnol 1993, 138 159-166 Kolligs F, Fehmann HC, Goke R, Goke B Reduction of the incretin effect in rats by the glucagon-like peptιde-1 receptor antagonist exendin (9-39)amιde Diabetes 1995, 44 16-19 Wang 2, Wang RM, Owji AA, Smith DM, Ghatei M, Bloom SR Glucagon-like peptide- 1 is a physiological incretin in rat J Clin Invest 1995, 95 417-421 Thorens B Expression cloning of the pancreatic b cell receptor for the gluco-incretm hormone glucagon-like peptide 1 Proc Natl Acad Sci 1992,89 8641-4645 Scrocchi L, Auerbach AB, Joyner AL, Drucker DJ Diabetes in mice with targeted disruption of the GLP-1 receptor gene Diabetes 1996, 45 21A Fehmann HC, Goke R, Goke B Cell and molecular biology of the incretin hormones glucagon-hke peptιde-l (GLP-1 ) and glucose-dependent insulin releasing polypeptide (GIP) Endocrine Reviews, 1995, 16 390-410 26 Gromada J, Dissing S, Bokvist K, Renstrom E, Frøkjeer-Jensen J, Wulff BS, Rorsman P. Glucagon-like peptide I increases cytoplasmic calcium in insulin-secreting bTC3-cells by enhancement of tntracellular calcium mobilisation. Diabetes 1995; 44: 767-774. 27 Holz GG, Leech CA, Habener JF Activation of a cAMP-regulated Ca 2 -sιgnaiιng pathway in pancreatic β-cells by the insulinotropic hormone glucagon-like peptιde-1. J Biol Chem, 1996, 270. 17749-17759. 28. Holz GG, Kύhltreiber WM, Habener JF. Pancreatic beta-cells are rendered glucose competent by the insulinotropic hormone glucagon-like peptιde-1 (7-37) Nature 1993;361.362-365 29. ørskov C, Hoist JJ, Nielsen OV Effect of truncated glucagon-like peptide- 1 (proglucagon 78-107 amide) on endocrine secretion from pig pancreas, antrum and stomach. Endocrinology 1988,123.2009-2013. 30 Hvidberg A, Toft Nielsen M, Hilsted J, ørskov C, Hoist JJ Effect of glucagon-like peptide-1 (proglucagon 78-107amide) on hepatic glucose production in healthy man. Metabolism 1994;43: 104-108. 31. Qualmann C, Nauck M, Hoist JJ, ørskov C, Creutzfeldt W Insulinotropic actions of intravenous glucagon-like peptιde-1 [7-36 amide] in the fasting state in healthy subjects Acta Diabetologica, 1995, 32. 13-16. 32. Nauck MA, Heimesaat MM, ørskov C, Hoist JJ, Ebert R, Creutzfeldt W. Preserved incretin activity of GLP-1 (7-36amιde) but not of synthetic human GIP in patients with type 2-diabetes mellitus. J Clin Invest 1993;91.301-307 33 Nauck MA, Kleine N, ørskov C, Hoist JJ, Willms B, Creutzfeldt W. Normalisation of fasting hyperglycaemia by exogenous GLP-1 (7-36amιde) in type 2-dιabetic patients. Diabetologia 1993;36:741-744. 34. Creutzfeldt W, Kleine N, Willms B, ørskov C, Hoist JJ, Nauck MA. Glucagonostatic actions and reduction of fasting hyperglycaemia by exogenous glucagon-liem, peptide-1 (7-36amide) in type I diabetic patients. Diabetes Care 1996; 19: 580-586. 35. Schjoldager BTG, Mortensen PE, Christiansen J, ørskov C, Hoist JJ. GLP-1 (glucagon-like peptide-1 ) and truncated GLP-1 , fragments of human proglucagon, inhibit gastric acid secretion in man. Dig. Dis. Sci. 1989; 35:703-708. 36. Wettergren A, Schjoldager B, Mortensen PE, Myhre J, Christiansen J, Hoist JJ. Truncated GLP-1 (proglucagon 72-107amide) inhibits gastric and pancreatic functions in man. Dig Dis Sci 1993;38:665-673. 37. Layer P, Hoist JJ, Grandt D, Goebell H: Heal release of glucagon-like peptide-1 (GLP-1 ): association with inhibition of gastric acid in humans. Dig Dis Sci 1995; 40: 1074-1082. 38. Layer P, Hoist JJ. GLP-1 : A humoral mediator of the ileal brake in humans? Digestion 1993; 54: 385-386. 39. Nauck M, Ettler R, Niedereichholz U, ørskov C, Hoist JJ, Schmiegel W. Inhibition of gastric emptying by GLP-1 (7-36 amide) or (7-37): effects on postprandial glycaemia and insulin secretion. Abstract. Gut 1995; 37 (suppl. 2): A124. 40. Schick RR, vorm Walde T, Zimmermann JP, Schusdziarra V, Classen M. Glucagon-like peptide 1 - a novel brain peptide involved in feeding regulation, in Ditschuneit H, Gries FA, Hauner H, Schusdziarra V, Wechsler JG (eds.) Obesity in Europe. John Libbey & Company ltd, 1994; pp. 363-367. 41. Tang-Christensen M, Larsen PJ, Goke R, Fink-Jensen A, Jessop DS, Møller M, Sheikh S. Brain GLP-1 (7-36) amide receptors play a major role in regulation of food and water intake. Am. J. Physiol., 1996, in press. 42. Turton MD, O'Shea D, Gunn I, Beak SA, Edwards CMB, Meeran K, et al. A role for glucagon-like peptide-1 in the regulation of feeding. Nature 1996; 379: 69-72. 43 Willms B, Werner J, Creutzfeldt W, ørskov C, Hoist JJ, Nauck M Inhibition of gastric emptying by glucagon-like peptιde-1 (7-36 amide) in patients with type-2-dιabetes mellitus Diabetologia 1994, 37, suppl.1 A118 44 Larsen J, Jallad N, Damsbo P One-week continuous infusion of GLP-1 (7-37) improves glycaemic control in NIDDM. Diabetes 1996, 45, suppl 2 233A 45 Ritzel R, ørskov C, Hoist JJ, Nauck MA Pharmacokinetic, insulinotropic, and glucagonostatic properties of GLP-1 [7-36 amide] after subcutaneous injection in healthy volunteers. Dose-response relationships Diabetologia 1995, 38 720-725 46 Deacon CF, Johnsen AH, Hoist JJ Degradation of glucagon-like peptide-1 by human plasma in vitro yields an N-terminally truncated peptide that is a major endogenous metabolite in vivo J Clin Eπdocnnol Metab 1995, 80 952-957 47 Deacon CF, Nauck MA, Toft-Nielsen M, Pπdal L, Willms B, Hoist JJ 1995 Both subcutaneous and intravenously administered glucagon-like peptιde-1 are rapidly degraded from the ammo terminus in type II diabetic patients and in healthy subjects Diabetes 44 1 126-1 131 SUMMARY OF THE INVENTION Human GLP-1 is a 37 ammo acid residue peptide originating from preproglucagon which is synthesised / a in the L-cells in the distal ileum, in the pancreas and in the brain Processing of preproglucagon to give GLP-1 (7-36)amιde, GLP-1 (7-37) and GLP-2 occurs mainly in the L-cells A simple system is used to describe fragments and analogues of this peptide Thus, for example, Gly β -GLP-1 (7-37) designates a fragment of GLP-1 formally derived from GLP-1 by deleting the ammo acid residues Nos. 1 to 6 and substituting the naturally occurring ammo acid residue in position 8 (Ala) by Gly Similarly, Lys 3 (N etradecaπoyl)-GLP-1 (7-37) designates GLP-1 (7-37) wherein the ε-amtno group of the Lys residue in position 34 has been tetradecanoylated. Where reference in this text is made to C-terminally extended GLP- 1 analogues, the am o acid residue in position 38 is Arg unless otherwise indicated, the optional am o acid residue in position 39 is also Arg unless otherwise indicated and the optional ammo acid residue in position 40 is Asp unless otherwise indicated Also, if a C- terminally extended analogue extends to position 41 , 42, 43, 44 or 45, the am o acid sequence of this extension is as in the corresponding sequence in human preproglucagon unless otherwise indicated In its broadest aspect, the present invention relates to derivatives of GLP-1 and analogues thereof The derivatives according to the invention have interesting pharmacological properties, in particular they have a more protracted profile of action than the parent peptides In the present text, the designation "an analogue" is used to designate a peptide wherein one or more ammo acid residues of the parent peptide have been substituted by another amino acid residue and/or wherein one or more amino acid residues of the parent peptide have been deleted and/or wherein one or more ammo acid residues have been added to the parent peptide Such addition can take place either at the N-terminal end or at the C-terminal end of the parent peptide or both The term "derivative" is used in the present text to designate a peptide in which one or more of the am o acid residues of the parent peptide have been chemically modified, e g by alkylation, acylation, ester formation or amide formation The term 'a GLP-1 derivative" is used in the present text to designate a derivative of GLP-1 or an analogue thereof In the present text, the parent peptide from which such a derivative is formally derived is in some places referred to as the "GLP-1 moiety" of the derivative In a preferred embodiment, as descnbed in Claim 1 , the present invention relates to a GLP-1 derivative wherein at least one am o acid residue of the parent peptide has a lipophilic substituent attached with the proviso that if only one lipophilic substituent is present and this substituent is attached to the N-terminal or to the C-terminal ammo acid residue of the parent peptide then this substituent is an alkyl group or a group which has an ω-carboxyhc acid group. In another preferred embodiment, as descnbed in Claim 2, the present invention relates to a GLP-1 derivative having only one lipophilic substituent In another preferred embodiment, as described in Claim 3, the present invention relates to a GLP-1 derivative having only one lipophilic substituent which substituent is an alkyl group or a group which has an ω-carboxylic acid group and is attached to the N-terminal ammo acid residue of the parent peptide In another preferred embodiment, as described in Claim 4, the present invention relates to a GLP-1 derivative having only one lipophilic substituent which substituent is an alkyl group or a group which has an ω-carboxylic acid group and is attached to the C-terminal am o acid residue of the parent peptide In another preferred embodiment, as described in Claim 5, the present invention relates to a GLP-1 derivative having only one lipophilic substituent which substituent can be attached to any one ammo acid residue which is not the N-terminal or C-terminal ammo acid residue of the parent peptide In another preferred embodiment, as described in Claim 6, the present invention relates to a GLP-1 derivative wherein two lipophilic substituents are present In another preferred embodiment, as described in Claim 7, the present invention relates to a GLP-1 derivative wherein two lipophilic substituents are present, one being attached to the N-terminal ammo acid residue while the other is attached to the C-terminal ammo acid residue In another preferred embodiment, as described in Claim 8, the present invention relates to a GLP-1 derivative wherein two lipophilic substituents are present, one being attached to the N-terminal ammo acid residue while the other is attached to an ammo acid residue which is not N-terminal or the C-terminal ammo acid residue In another preferred embodiment, as described in Claim 9, the present invention relates to a GLP-1 derivative wherein two lipophilic substituents are present, one being attached to the C-terminal am o acid residue while the other is attached to an am o acid residue which is not the N-terminal or the C-terminal am o acid residue In further preferred embodiment, as described in Claim 10, the present invention relates to a derivative of GLP-1 (7-C), wherein C is selected from the group comprising 38, 39, 40, 41, 42, 43, 44 and 45 which derivative has just one lipophilic substituent which is attached to the C- terminal am o acid residue of the parent peptide In a further preferred embodiment, the present invention relates to a GLP-1 derivative wherein the lipophilic substituent comprises from 4 to 40 carbon atoms, more preferred from 8 to 25 carbon atoms In a further preferred embodiment, the present invention relates to a GLP-1 derivative wherein a lipophilic substituent is attached to an ammo acid residue in such a way that a carboxyl group of the lipophilic substituent forms an amide bond with an am o group of the ammo acid residue In a further preferred embodiment, the present invention relates to a GLP-1 deπvative wherein a lipophilic substituent is attached to an ammo acid residue in such a way that an ammo group of the lipophilic substituent forms an amide bond with a carboxyl group of the am o acid residue In a further preferred embodiment, the present invention relates to a GLP-1 derivative wherein a lipophilic substituent is attached to the parent peptide by means of a spacer In a further preferred embodiment, the present invention relates to a GLP-1 derivative wherein a lipophilic substituent - optionally via a spacer - is attached to the ε-ammo group of a Lys residue contained in the parent peptide In a further preferred embodiment, the present invention relates to a GLP-1 derivative wherein a lipophilic substituent is attached to the parent peptide by means of a spacer which is an unbranched alkane α,ω-dιcarboxylιc acid group having from 1 to 7 methylene groups, preferably two methylene groups which spacer forms a bridge between an ammo group of the parent peptide and an am o group of the lipophilic substituent. In a further preferred embodiment, the present invention relates to a GLP-1 derivative wherein a lipophilic substituent is attached to the parent peptide by means of a spacer which is an ammo acid residue except Cys, or a dipeptide such as Gly-Lys In the present text, the expression "a dipeptide such as Gly-Lys" is used to designate a dipeptide wherein the C- terminal ammo acid residue is Lys, His or Trp, preferably Lys, and wherein the N-terminal ammo acid residue is selected from the group comprising Ala, Arg, Asp, Asn, Gly, Glu, Gin, lie, Leu, Val, Phe and Pro In a further preferred embodiment, the present invention relates to a GLP-1 derivative wherein a lipophilic substituent is attached to the parent peptide by means of a spacer which is an am o acid residue except Cys, or is a dipeptide such as Gly-Lys and wherein a carboxyl group of the parent peptide forms an amide bond with an am o group of a Lys residue or a dipeptide containing a Lys residue, and the other ammo group of the Lys residue or a dipeptide containing a Lys residue forms an amide bond with a carboxyl group of the lipophilic substituent In a further preferred embodiment, the present invention relates to a GLP-1 derivative wherein a lipophilic substituent is attached to the parent peptide by means of a spacer which is an ammo acid residue except Cys, or is a dipeptide such as Gly-Lys and wherein an am o group of the parent peptide forms an amide bond with a carboxylic group of the ammo acid residue or dipeptide spacer, and an ammo group of the am o acid residue or dipeptide spacer forms an amide bond with a carboxyl group of the lipophilic substituent In a further preferred embodiment, the present invention relates to a GLP-1 derivative wherein a lipophilic substituent is attached to the parent peptide by means of a spacer which is an ammo acid residue except Cys, or is a dipeptide such as Gly-Lys and wherein a carboxyl group of the parent peptide forms an amide bond with an ammo group of the am o acid residue spacer or dipeptide spacer, and the carboxyl group of the ammo acid residue spacer or dipeptide spacer forms an amide bond with an am o group of the lipophilic substituent In a further preferred embodiment, the present invention relates to a GLP-1 derivative wherein a lipophilic substituent is attached to the parent peptide by means of a spacer which is an ammo acid residue except Cys, or is a dipeptide such as Gly-Lys, and wherein a carboxyl group of the parent peptide forms an amide bond with an am o group of a spacer which is Asp or Glu, or a dipeptide spacer containing an Asp or Glu residue, and a carboxyl group of the spacer forms an amide bond with an ammo group of the lipophilic substituent In a further preferred embodiment, the present invention relates to a GLP-1 derivative having a lipophilic substituent which comprises a partially or completely hydrogenated cyclopentanopheπathrene skeleton In a further preferred embodiment, the present invention relates to a GLP-1 derivative having a lipophilic substituent which is a straight-chain or branched alkyl group In a further preferred embodiment, the present invention relates to a GLP-1 derivative having a lipophilic substituent which is the acyl group of a straight-chain or branched fatty acid In a further preferred embodiment, the present invention relates to a GLP-1 derivative having a lipophilic substituent which is an acyl group selected from the group comprising CH 3 (CH 2 ) n CO-, wherein n is an integer from 4 to 38, preferably an integer from 4 to 24, more preferred selected from the group comprising CH 3 (CH 2 ) 6 CO-, CH 3 (CH 2 ) 8 CO-, CH 3 (CH 2 ) t0 CO-, CH 3 (CH 2 ) 12 CO-, CH 3 (CH 2 ), 4 CO-, CH 3 (CH 2 ) 1β CO-, CH 3 (CH 2 ) 18 CO-, CH 3 (CH 2 ) 20 CO- and CH^CH^CO- In a further preferred embodiment, the present invention relates to a GLP-1 derivative having a lipophilic substituent which is an acyl group of a straight-chain or branched alkane α,ω- dicarboxylic acid In a further preferred embodiment, the present invention relates to a GLP-1 derivative having a lipophilic substituent which is an acyl group selected from the group comprising HOOC(CH 2 ) m CO-, wherein m is an integer from 4 to 38, preferably an integer from 4 to 24, more preferred selected from the group comprising HOOC(CH 2 ) u CO-, HOOC(CH 2 ) 16 CO-, HOOC(CH 2 ) 18 CO-, HOOC(CH 2 ) 20 CO- and HOOC^H^CO- In a further preferred embodiment, the present invention relates to a GLP-1 derivative having a lipophilic substituent which is a group of the formula CH 3 (CH 2 ) p ((CH 2 ) < ,COOH)CHNH- CO(CH 2 ) 2 CO-, wherein p and q are integers and p+q is an integer of from 8 to 33, preferably from 12 to 28 In a further preferred embodiment, the present invention relates to a GLP-1 derivative having a lipophi c substituent which is a group of the formula CH 3 (CH 2 ) r CO- NHCH(COOH)(CH 2 ) 2 CO-, wherein r is an integer of from 10 to 24 In a further preferred embodiment, the present invention relates to a GLP-1 deπvative having a lipophilic substituent which is a group of the formula CH 3 (CH 2 ) s CO- NHCH((CH 2 ) 2 COOH)CO-, wherein s is an integer of from 8 to 24 In a further preferred embodiment, the present invention relates to a GLP-1 derivative having a lipophilic substituent which is a group of the formula COOH(CH 2 ),CO- wherein t is an integer of from 8 to 24 In a further preferred embodiment, the present invention relates to a GLP-1 derivative having a lipophilic substituent which is a group of the formula -NHCH(COOH)(CH 2 ) 4 NH- CO(CH 2 ) u CH 3 , wherein u is an integer of from 8 to 18 In a further preferred embodiment, the present invention relates to a GLP-1 derivative having a lipophilic substituent which is a group of the formula -NHCH(COOH)(CH 2 ) 4 NH- COCH((CH 2 ) 2 COOH)NH-CO(CH 2 ) w CH 3 , wherein w is an integer of from 10 to 16 In a further preferred embodiment, the present invention relates to a GLP-1 derivative having a lipophilic substituent which is a group of the formula -NHCH(COOH)(CH 2 ) 4 NH- CO(CH 2 ) 2 CH(COOH)NH-CO(CH 2 ) x CH 3 , wherein x is an integer of from 10 to 16 In a further preferred embodiment, the present invention relates to a GLP-1 derivative having a lipophilic substituent which is a group of the formula -NHCH(COOH)(CH 2 ) 4 NH- CO(CH 2 ) 2 CH(COOH)NHCO(CH 2 ) y CH 3 , wherein y is zero or an integer of from 1 to 22 In a further preferred embodiment, the present invention relates to a GLP-1 derivative having a lipophilic substituent which can be negatively charged Such a lipophilic substituent can for example be a substituent which has a carboxyl group In a further preferred embodiment, the present invention relates to a GLP-1 derivative the parent peptide of which is selected from the group comprising GLP-1 (1-45) or an analogue thereof In a further preferred embodiment, the present invention relates to a GLP-1 derivative derived from a GLP-1 fragment selected from the group comprising GLP-1 (7-35), GLP-1 (7- 36), GLP-1 (7-36)amιde, GLP-1 (7-37), GLP-1 (7-38), GLP-1 (7-39), GLP-1 (7-40) and GLP- 1 (7-41 ) or an analogue thereof In a further preferred embodiment, the present invention relates to a GLP-1 analogue derived from a GLP-1 analogue selected from the group compπsing GLP-1 (1-35), GLP-1(1-36), GLP-1 (1-36)amιde, GLP-1 (1-37), GLP-1 (1-38), GLP-1 (1-39), GLP-1 (1-40) and GLP-1 (1 -41 ) or an analogue thereof In a further preferred embodiment, the present invention relates to a GLP-1 derivative wherein the designation analogue comprises derivatives wherein a total of up to fifteen, preferably up to ten ammo acid residues have been exchanged with any α-amino acid residue In a further preferred embodiment, the present invention relates to a GLP-1 derivative wherein the designation analogue comprises derivatives wherein a total of up to fifteen, preferably up to ten ammo acid residues have been exchanged with any α-amino acid residue which can be coded for by the genetic code In a further preferred embodiment, the present invention relates to a GLP-1 derivative wherein the designation analogue comprises derivatives wherein a total of up to six am o acid residues have been exchanged with another α-amino acid residue which can be coded for by the genetic code In a further preferred embodiment, the present invention relates to a GLP-1 (A-B) derivative wherein A is an integer from 1 to 7 and B is an integer from 38 to 45 or an analogue thereof comprising one lipophilic substituent attached to the C-terminal ammo acid residue and, optionally, a second lipophilic substituent attached to one of the other ammo acid residues In a further preferred embodiment, a parent peptide for a derivative according to the invention is selected from the group comprising Arg 26 -GLP-1 (7-37), Arg 34 -GLP-1(7-37), Lys 36 - GLP-1 (7-37), Arg 28 "Lys^-GLP-I (7-37), Arg 26 ^Lys GLP-l (7-38), Arg 28 M Lys M -GLP-1 (7-39), Arg 2β34 Lys 40 -GLP-1(7-40), Arg 26 Lys 36 -GLP-1(7-37), Arg ϊ4 Lys 36 -GLP-1(7-37), Arg 26 Lys 3 -GLP- 1(7-39); Arg 34 Lys 40 -GLP-1(7-40), Arg 26 "Lys^-GLP-I (7-39), Arg 634 Lys 38 0 -GLP-1(7-40); Gly 8 Arg26-GLP-1(7-37); Gly 8 Arg 34 -GLP-1(7-37); Gly 8 Lys 3β -GLP-1(7-37); Gly β Arg 2634 Lys 36 - GLP-1 (7-37), Gly 8 Arg 2834 Lys 39 -GLP-1(7-39), Gly β Arg 2634 Lys 40 -GLP-1(7-40), Gly 8 Arg 26 Lys 36 - GLP-1(7-37), Gly 8 Arg 34 Lys 36 -GLP-1(7-37), Gly 8 Arg 26 Lys 39 -GLP-1(7-39); Gly β Arg 34 Lys 40 -GLP- 1(7-40), Gly 8 Arg 2834 Lys 3639 -GLP-1(7-39) and Gly β Arg 263 Lys 3540 -GLP-1(7-40). In a further preferred embodiment, a parent peptide for a derivative according to the invention is selected from the group comprising Arg 2634 Lys 38 GLP-1 (7-38); Arg a3 Lys 9 GLP- 1(7-39); Arg 26 M Lys 0 GLP-1 (7-40), Arg 2β3 Lys 41 GLP-1(7-41), Arg 26 "Lys^GLP-l (7-42), Arg 2634 Lys 3 GLP-1 (7-43), Arg 26 "Lys^GLP-l (7-44), Arg 263 Lys 45 GLP-1 (7-45); Arg 26 M Lys M GLP-1 (1-38), Arg 26 "Lys∞GLP-lf 1-39), Arg 263 Lys 0 GLP-1(1-40), Arg 2634 Lys 41 GLP-1(1-41), Arg 2634 Lys 42 GLP-1(1-42), Arg 28 ^Lys^GLP-l (1-43); Arg 2634 Lys GLP-1(1-44); Arg 2634 Lys 45 GLP-1(1-45), Arg 26 "Lys^GLP-l (2-38), Arg 26 ^Lys∞GLP-l (2-39), Arg 26 "Lys^GLP-l (2-40), Arg 26 M Lys 41 GLP-1 (2-41 ); Arg 26 M Lys 42 GLP-1 (2-42); Arg 26 ^Lys^GLP-l (2-43), Arg 26 Lys^GLP- 1(2-44), Arg 2W4 Lys 45 GLP-1 (2-45), Arg 26 Lys^GLP-l (3-38), Arg 2W4 Lys 3β GLP-1 (3-39); Arg^Lys^GLP- ^O), Arg 2634 Lys 1 GLP-1 (3-41 ), Arg 2634 Lys 42 GLP-1 (3-42), Arg 26 ^Lys^GLP-l (3-43), Arg 2634 Lys 44 GLP-1(3-44), Arg 26 "Lys^GLP-l (3-45), Arg 26 "Lys∞GLP-l (4-38), Arg 263 Lys 39 GLP-1 (4-39), Arg 26 "Lys^GLP-l (4-40); Arg 26 M Lys 41 GLP-1 (4-41 ), Arg 26 M Lys 2 GLP-1 (4-42), Arg 26 "Lys^GLP-l (4-43), Arg 2634 Lys 4 GLP-1 (4-44); Arg 26 M Lys 45 GLP-1 (4-45), Arg 26 ^Lys∞GLP-l (5-38), Arg 26 ^Lys∞GLP-l (5-39), Arg 26 "Lys^GLP-l (5-40), Arg 26 M Lys , GLP-1 (5-41), Arg 2634 Lys 42 GLP-1(5-42); Arg 26 M Lys 3 GLP-1 (5-43); Arg 26 "Lys^GLP-l (5-44); Arg 26 ^Lys^GLP-l (5-45), Arg 263 Lys 38 GLP-1 (6-38), Arg 26 "Lys∞GLP-l (6-39), Arg 26 "Lys^GLP-l (6-40), Arg 263 Lys 41 GLP-1(6-41), Arg 26 M Lys 42 GLP-1 (6-42), Arg 26 4 Lys 43 GLP-1 (6-43); Arg 2β ' 34 Lys 44 GLP-1(6-44); Arg 26 "Lys^GLP-l (6-45); Arg 26 Lys 38 GLP- 1(1-38), Arg s *Lys 3β GLP-1(1-38); Arg^Lys∞ GLP-IO-Sδ), Arg 2β Lys 38 GLP-1(7-38), Arg 3 Lys 38 GLP-1(7-38); Arg 2834 Lys 3β3B GLP-1 (7-38); Arg 26 ^Lys^GLP-l (7-38); Arg 26 Lys 39 GLP- 1(1-39), 1-39), Arg 26 Lys 39 GLP-1(7-39), Arg 4 Lys 39 GLP-1(7-39) and Arg 2634 Lys 3839 GLP-1(7-39). In a further preferred embodiment, the present invention relates to a GLP-1 derivative wherein the parent peptide is selected from the group comprising Arg 28 -GLP-1 (7-37), Arg 34 - GLP-1 (7-37), Lys 3β -GLP-1 (7-37), Arg 26 "Lys∞-GLP-I (7-37), Arg 2β Lys 36 -GLP-1 (7-37), Arg 34 Lys 36 -GLP-1 (7-37), Gly 8 Arg 2β -GLP-1 (7-37), Gly a Arg 34 -GLP-1 (7-37), Gly 8 Lys 3β -GLP-1 (7- 37), Gly 8 Arg 2634 Lys 36 -GLP-1 (7-37), Gly 8 Arg 26 Lys 38 -GLP-1 (7-37) and GI Arg^Lys∞-GLP-l (7- 37) In a further preferred embodiment, the present invention relates to a GLP-1 derivative wherein the parent peptide is selected from the group comprising Arg 2β Lys 38 -GLP-1(7-38), Arg 26 ^Lys^-GLP- 1 (7-38), Arg 263 Lys 3β M -GLP-1 (7-38), Gly 8 Arg 26 Lys 38 -GLP-1(7-38) and Gly β Arg 2β 34 Lys 3838 -GLP-1 (7-38) In a further preferred embodiment, the present invention relates to a GLP-1 derivative wherein the parent peptide is selected from the group comprising Arg 6 Lys 39 -GLP-1 (7-39), Arg 28 "Lys^-GLP-I (7-39), Gly 8 Arg 6 Lys 39 -GLP-1 (7-39) and Gly 8 Arg 2834 Lys 3639 -GLP-1 (7-39) In a further preferred embodiment, the present invention relates to a GLP-1 derivative wherein the parent peptide is selected from the group comprising Arg 3 Lys 40 -GLP-1 (7-40), Arg 28 "Lys^-GLP-I (7-40), Gly 8 Arg 3 Lys 40 -GLP-1(7-40) and Gly 8 Arg 2634 Lys 3640 -GLP-1(7-40) In a further preferred embodiment, the present invention relates to a GLP-1 derivative which is selected from the group comprising Lys 6 (N ε -tetradecanoyl)-GLP-1 (7-37), Lys 34 (N t -tetradecanoyl)-GLP-1 (7-37), Lys 6 4 -bιs(N'-tetradecanoyl)-GLP-1 (7-37), Gly 8 Lys 26 (N ε -tetradecanoyl)-GLP-1 (7-37), Gly 8 Lys 3 (N ε -tetradecanoyl)-GLP-1 (7-37), Gl Lys* 3 -bιs(N t -tetradecanoyl)-GLP-1 (7-37), Arg 2β Lys 34 (N ε -tetradecanoyl)-GLP-1(7-37), Lys 2β (N etradecanoyl)-GLP-1 (7-38), Lys 3 (N ε -tetradecanoyl)-GLP-1 (7-38), Lys 2634 -bιs(N ε -tetradecanoyl)-GLP-1 (7-38), Gly 8 Lys 28 (N ε -tetradecanoyl)-GLP-1 (7-38), Gly 8 Lys 3 (N etradecanoyl)-GLP-1 (7-38), Gly 8 Lys 2β ' 4 -bis(N E -tetradecanoyl)-GLP-1(7-38); Arg 26 Lys 34 (N ε -tetradecanoyl)-GLP-1(7-38); Lys 26 (N ε -tetradecanoyl)-GLP-1(7-39); Lys 34 (N ε -tetradecanoyl)-GLP- 1(7-39); Lys 263 -bis(N ε -tetradecanoyl)-GLP-1 (7-39); Gly 8 Lys 26 (N ε -tetradecanoyl)-GLP-1(7-39); Gly 8 Lys 3 (N ε -tetradecanoyl)-GLP-1(7-39); Gly 8 Lys 2634 -bis(N ε -tetradecanoyl)-GLP- 1(7-39); Arg 26 Lys 34 (N ε -tetradecanoyl)-GLP-1(7-39); Lys 6 (N ε -tetradecanoyl)-GLP-1 (7-40); Lys 34 (N ε -tetradecanoyl)-GLP-1(7-40); Lys 26 ' 34 -bis(N ε -tetradecanoyl)-GLP-1(7-40); Gly 8 Lys 26 (N etradecanoyl)-GLP-1(7-40); Gly β Lys 3 (N ε -tetradecanoyl)-GLP-1(7-40); Gly 8 Lys 26 ' 34 -bis(N E -tetradecanoyi)-GLP- 1(7-40); Arg 26 Lys 3 (N ε -tetradecanoyl)-GLP-1(7-40); Lys 2β (N e -tetradecanoyl)-GLP-1(7-36); Lys 34 (N ε -tetradecanoyl)-GLP-1(7-36); Lys 2634 -bis(N ε -tetradecanoyl)-GLP-1(7-36); Gly 8 Lys 2B (N ε -tetradecanoyl)-GLP-1 (7-36); Gly 8 Lys 3 (N ε -tetradecanoyl)-GLP-1(7-36); Gly β Lys 2634 -bis(N etradecanoyl)-GLP-1(7-36); Arg 26 Lys 34 (N ε -tetradecanoyl)-GLP-1(7-36); Lys 26 (N ε -tetradecanoyl)-GLP-1(7-35); Lys 3 (N t -tetradecanoyl)-GLP-1 (7-35); Lys 2634 -bis(N ε -tetradecanoyl)-GLP-1(7-35); Gly a Lys 26 (N ε -tetradecanoyl)-GLP-1(7-35); Gly 8 Lys 34 (N ε -tetradecanoyl)-GLP-1(7-35); Gly 8 Lys 283 -bis(N ε -tetradecanoyl)-GLP-1(7-35); Arg 26 Lys 34 (N ε -tetradecanoyl)-GLP-1 (7-35); Lys 28 (N ε -tetradecanoyl)-GLP-1(7-36)amide; Lys 34 (N ε -tetradecanoyl)-GLP-1(7-36)amide; Lys 28:j4 -bis(N ε -tetradecanoyl)-GLP-1(7-36)amide; Gly β Lys 2δ (N ε -tetradecanoyl)-GLP-1(7-36)amιde; Gly 8 Lys 3 (N ε -tetradecanoyl)-GLP-1 (7-36)amιde; Gly 8 Lys 2634 -bis(N t -tetradecanoyl)-GLP-1 (7-36)amide; Arg 25 Lys 34 (N ε -tetradecanoyl)-GLP-1(7-36)amide; Gly 8 Arg 6 Lys 34 (N ε -tetradecanoyl)-GLP-1 (7-37); Lys 26 ( N etradecanoy l)Arg M -G LP- 1 (7-37); Gly 8 Lys 26 (N ε -tetradecanoyl)Arg 34 -GLP-1 (7-37); Arg 2634 Lys 36 (N ε -tetradecanoyl)-GLP-1 (7-37); Gly 8 Arg 2634 Lys 36 (N ε -tetradecanoyl)-GLP-1 (7-37); Gly 8 Arg 26 Lys 34 (N ε -tetradecanoyl)-GLP-1 (7-38); Lys 26 (N ε -tetradecanoyl)Arg 34 -GLP-1(7-38); Gly 8 Lys 28 (N etradecanoyl)Arg 34 -GLP-1 (7-38); Arg 26 "Lys^N etradecanoylJ-GLP-l (7-38); Arg 2634 Lys 38 (N ε -tetradecanoyl)-GLP-1 (7-38); Gly 8 Arg 2634 Lys 36 (N ε -tetradecanoyl)-GLP-1 (7-38); Gly 8 Arg 26 Lys 3 (N ε -tetradecanoyl)-GLP-1 (7-39); Lys 26 (N ε -tetradecanoyl)Arg 34 -GLP-1(7-39); Gly 8 Lys 26 (N etradecanoyl)Arg 34 -GLP-1 (7-39); Arg 263 Lys 3β (N ε -tetradecanoyl)-GLP-1 (7-39); Gly 8 Arg 2634 Lys 36 (N ε -tetradecanoyl)-GLP-1 (7-39); Gly 8 Arg 26 Lys 34 (N ε -tetradecanoyl)-GLP-1 (7-40); Lys 26 (N ε -tetradecanoyl)Arg 34 -GLP-1 (7-40); Gly 8 Lys 26 (N ε -tetradecanoyl)Arg 34 -GLP-1 (7^0); Arg 2β ' 34 Lys 3β (N ε -tetradecanoyl)-GLP-1 (7-40); Gly 8 Arg 2634 Lys 38 (N ε -tetradecanoyl)-GLP-1 (7-40); Lys 2β (N ε -(ω-carboxynonadecanoyl))-GLP-1 (7-37); Lys 34 (N ε -(ω-carboxynonadecanoyl))-GLP-1 (7-37); Lys 2634 -bis(N ε -(ω-carboxynonadecanoyl))-GLP-1(7-37); Gly β Lys 28 (N ε -(ω-carboxynonadecanoyl))-GLP- 1 (7-37); Gly a Lys 34 (N ε -(ω-carboxynonadecanoyl))-GLP-1 (7-37); Gly 8 Lys 2634 -bis(N ε -(ω-carboxynonadecanoyl))-GLP-1(7-37); Lys 26 (N ε -(ω-carboxynonadecanoyl))-GLP-1 (7-38); Lys 34 (N e -(ω-carboxynonadecanoyl))-GLP-1 (7-38); Lys 2634 -bιs(N ε -(ω-carboxynonadecanoyl))-GLP-1 (7-38), Gly β Lys 26 (N ε -(ω-carboxynonadecanoyl))-GLP-1 (7-38), Gly 8 Lys 34 (N ε -(ω-carboxynonadecanoyl))-GLP-1(7-38), Gl Lys 2834 -bιs(N ε -(ω-carboxynonadecanoyl))-GLP-1 (7-38), Lys 26 (N ε -(ω-carboxynonadecanoyl))-GLP-1 (7-39), Lys 34 (N c -(ω-carboxynonadecanoyl))-GLP-1 (7-39), Lys 2S 3 -bιs(N ε -(ω-carboxynonadecanoyl))-GLP-1 (7-39), Gly 8 Lys 28 (N c -(ω-carboxynonadecanoyl))-GLP-1 (7-39), Gly 8 Lys 34 (N ε -(ω-carboxynonadecanoyl))-GLP-1 (7-39), Gly β Lys 2634 -bιs(N ε -(ω-carboxynonadecanoyl))-GLP-1 (7-39), Lys 26 (N ε -(ω-carboxynonadecanoyl))-GLP-1 (7-40), Lys 34 (N £ -(ω-carboxynonadecanoyl))-GLP-1 (7-40), Lys 2634 -bιs(N ε -(ω-carboxynonadecanoyl))-GLP-1 (7-40), Gly 8 Lys 26 (N ε -(ω-carboxynoπadecanoyl))-GLP-1 (7-40), Gly 8 Lys 3 (N ε -(ω-carboxynonadecanoyl))-GLP-1 (7-40), Gly B Lys 2β 34 -bιs(N ε -(ω-carboxynonadecanoyl))-GLP-1 (7-40), Lys 2β (N ε -(ω-carboxynonadecanoyl))-GLP-1(7-36), Lys 3 (N F -(ω-carboxynonadecanoyl))-GLP-1 (7-36), Lys 2634 -bιs(N ε -(ω-carboxynonadecanoyl))-GLP-1 (7-36), Gly 8 Lys 2β (N ε -(ω-carboxynonadecanoyl))-GLP-1 (7-36), Gly 8 Lys 34 (N ε -(ω-carboxynonadecanoyl))-GLP-1(7-36), Gly 8 Lys 2634 -bιs(N E -(ω-carboxynonadecanoyl))-GLP-1 (7-36), Lys 26 (N ε -(ω-carboxynonadecanoyl))-GLP-1 (7-36)amιde, Lys 3 (N ε -(ω-carboxynonadecanoyl))-GLP-1(7-36)amιde, Lys 26 ^-bisfN ω-carboxynonadecanoy J-GLP-l (7-36)amιde, Gly 8 Lys 26 (N ε -(ω-carboxynonadecanoyl))-GLP-1 (7-36)amιde, Gly 8 Lys 34 (N ε -(ω-carboxynonadecanoyl))-GLP-1 (7-36)amιde, Gly 8 Lys 2β 34 -bιs(N ε -(ω-carboxynonadecanoyl))-GLP-1 (7-36)amιde, Lys 26 (N ε -(ω-carboxynoπadecanoyl))-GLP-1 (7-35), Lys 34 (N ε -(ω-carboxynonadecanoyl))-GLP-1 (7-35), Lys 283 -bιs(N ε -(ω-carboxynonadecanoyl))-GLP-1 (7-35), Gly 8 Lys 26 (N c -(ω-carboxynonadecanoyl))-GLP-1 (7-35), Gly 8 Lys 34 (N ε -(ω-carboxynonadecanoyl))-GLP-1 (7-35), Gly 8 Lys 2β 34 -bis(N ε -(ω-carboxynonadecanoyl))-GLP-1 (7-35); Arg 26 Lys 3 (N ε -(ω-carboxynonadecanoyl))-GLP-1(7-37); Gly 8 Arg 26 Lys (N ε -(ω-carboxynonadecanoyl))-GLP-1(7-37); Lys 26 (N ε -(ω-carboxynonadecanoyl))Arg 34 -GLP-1 (7-37); Gly 8 Lys 26 (N ε -(ω-carboxynonadecanoyl))Arg 34 -GLP-1 (7-37); Arg 2634 Lys 36 (N ε -(ω-carboxynonadecanoyl))-GLP-1 (7-37); Gly 8 Arg 2634 Lys 36 (N ε -(ω-carboxynonadecanoyl))-GLP-1(7-37); Arg 2S Lys 34 (N ε -(ω-carboxynonadecanoyl))-GLP-1 (7-38); Gly 8 Arg 26 Lys 34 (N c -(ω-carboxynonadecanoyl))-GLP-1 (7-38); Lys 26 (N ε -(ω-carboxynonadecanoyl))Arg 34 -GLP-1 (7-38); Gly 8 Lys 26 (N ε -(ω-carboxynonadecanoyl))Arg 3 -GLP-1 (7-38); Arg 26 :54 Lys 36 (N ε -(ω-carboxynonadecanoyl))-GLP-1 (7-38); Arg 263 Lys 38 (N E -(ω-carboxynonadecanoyl))-GLP-1(7-38); Gly 8 Arg 2834 Lys 36 (N ε -(ω-carboxynonadecanoyl))-GLP-1(7-38); Arg 26 Lys 34 (N ε -(ω-carboxynonadecanoyl))-GLP-1 (7-39); Gly 8 Arg 26 Lys 34 (N ε -(ω-carboxynonadecanoyl))-GLP- 1(7-39); Lys 26 (N c -(ω-carboxynonadecanoyl))Arg 34 -GLP-1 (7-39); Gly 8 Lys 6 (N ε -(ω-carboxynonadecanoyl))Arg 34 -GLP-1 (7-39); Arg 26 - 34 Lys 36 (N ε -(ω-carboxynonadecanoyl))-GLP-1 (7-39); Gly 8 Arg 2634 Lys 3e (N ε -(ω-carboxynonadecanoyl))-GLP-1 (7-39); Arg 26 Lys 34 (N ε -(ω-carboxynonadecanoyl))-GLP-1 (7-40); Gly 8 Arg 26 Lys 34 (N ε -(ω-carboxynonadecanoyl))-GLP-1 (7-40); Lys 26 (N ε -(ω-carboxynonadecanoyl))Arg 34 -GLP-1 (7-40); Gly 8 Lys 26 (N ε -(ω-carboxynonadecaπoyl))Arg 34 -GLP-1(7-40); Arg 26:i4 Lys 36 (N ε -(ω-carboxynonadecanoyl))-GLP-1 (7-40); GI Arg 2β 34 Lys 6 (N ε -(ω-carboxynonadecanoyl))-GLP-1(7-40); Lys 26 (N e -(7-deoxycholoyl))-GLP-1(7-37); Lys 34 (N c -(7-deoxycholoyl))-GLP-1 (7-37); Lys 263 -bis(N ε -(7-deoxycholoyl))-GLP-1 (7-37); Gly 8 Lys 26 (N ε -(7-deoxycholoyl))-GLP-1 (7-37); Gly 8 Lys 34 (N ε -(7-deoxycholoyl))-GLP-1 (7-37); Gly 8 Lys 263 -bis(N t -(7-deoxycholoyl))-GLP-1 (7-37); Arg 26 Lys 3 (N e -(7-deoxycholoyl))-GLP-1 (7-37); Lys 2β (N E -(7-deoxycholoyl))-GLP-1(7-38); Lys 3 (N E -(7-deoxycholoyl))-GLP-1(7-38); Lys 26 ' 3 -bis(N ε -(7-deoxycholoyl))-GLP-1 (7-38); Gly 8 Lys 26 (N ε -(7-deoxycholoyl))-GLP-1 (7-38); Gly 8 Lys 34 (N ε -(7-deoxycholoyl))-GLP-1 (7-38); Gly 8 Lys 2634 -bis(N ε -(7-deoxycholoyl))-GLP-1 (7-38); Arg 2e Lys 3 (N E -(7-deoxychoioyl))-GLP-1 (7-38); Lys 26 (N E -(7-deoxycholoyl))-GLP-1 (7-39); Lys 34 (N ε -(7-deoxycholoyl))-GLP-1 (7-39); Lys 2634 -bis(N E -(7-deoxycholoyl))-GLP-1 (7-39); Gly 8 Lys 26 (N ε -(7-deoxycholoyl))-GLP-1(7-39); Gly a Lys 34 (N E -(7-deoxycholoyl))-GLP-1 (7-39); Gly 8 Lys 2634 -bis(N ε -(7-deoxycholoyl))-GLP-1 (7-39); Arg 26 Lys 34 (N ε -(7-deoxycholoyl))-GLP-1 (7-39); Lys 26 (N ε -(7-deoxycholoyl))-GLP-1 (7-40); Lys 34 (N ε -(7-deoxycholoyl))-GLP-1 (7-40); Lys 26 ' 34 -bis(N ε -(7-deoxycholoyl))-GLP-1 (7-40); Gly 8 Lys 26 (N ε -(7-deoxycholoyl))-GLP-1 (7-40); Gly 8 Lys 34 (N E -(7-deoxycholoyl))-GLP-1 (7-40); G!y e Lys 2634 -bis(N c -(7-deoxycholoyl))-GLP-1 (7-40); Arg 26 Lys 34 (N ε -(7-deoxycholoyl))-GLP-1 (7-40); Lys 26 ( N ε -(7-deoxycholoyl))-G LP- 1 (7-36 ) ; Lys 3 (N ε -(7-deoxycholoyl))-GLP-1 (7-36); Lys 2634 -bis(N e -(7-deoxycholoyl))-GLP-1(7-36); Gly 8 Lys 28 (N ε -(7-deoxycholoyl))-GLP-1 (7-36); Gly 8 Lys 34 (N ε -(7-deoxycholoyl))-GLP-1 (7-36); Gly 8 Lys 26 ' 3 -bis(N ε -(7-deoxycholoyl))-GLP-1 (7-36); Arg 26 Lys 34 (N ε -(7-deoxycholoyl))-GLP-1 (7-36); Lys 26 (N ε -(7-deoxycholoyl))-GLP-1(7-35); Lys 3 (N ε -(7-deoxycholoyl))-GLP-1 (7-35); Lys 26:i4 -bis(N E -(7-deoxycholoyl))-GLP-1 (7-35); Gly 8 Lys 26 (N ε -(7-deoxycholoyl))-GLP-1(7-35); Gly 8 Lys 34 (N ε -(7-deoxycholoyl))-GLP-1 (7-35); Gly β Lys 2β ' 34 -bis(N ε -(7-deoxycholoyl))-GLP-1 (7-35); Arg 26 Lys 34 (N E -(7-deoxycholoyl))-GLP-1 (7-35); Lys 26 (N E -(7-deoxycholoyl))-GLP-1 (7-36)amide; Lys 3 (N ε -(7-deoxychofoyl))-GLP-1(7-36)amide; Lys 63 -bis(N ε -(7-deoxycholoyl))-GLP-1 (7-36)amide; Gly 8 Lys 26 (N c -(7-deoxycholoyl))-GLP-1 (7-36)amide; Gly 8 Lys 34 (N ε -(7-deoxycholoyl))-GLP-1 (7-36)amide; Gly 8 Lys 263 -bis(N E -(7-deoxycholoyl))-GLP-1 (7-36)amide; Arg 26 Lys 34 (N ε -(7-deoxycholoyl))-GLP-1 (7-36)amide; Gly 8 Arg 26 Lys 34 (N ε -(7-deoxycholoyl))-GLP-1 (7-37); Lys 26 (N ε -(7-deoxycholoyl))Arg 34 -GLP-1 (7-37); Gly 8 Lys 26 (N ε -(7-deoxycholoyl))Arg 34 -GLP-1 (7-37); Arg 2634 Lys 36 (N ε -(7-deoxycholoyl))-GLP- 1 (7-37); GIy β Arg 63 Lys 36 (N £ -(7-deoxycholoyl))-GLP-1(7-37); Lys 26 (N ε -(choloyl))-GLP-1 (7-37); Lys 34 (N ε -(choloyl))-GLP-1 (7-37), Lys 2634 -bis(N ε -(choloyl))-GLP-1 (7-37); Gly 8 Lys 26 (N ε -(choloyl))-GLP-1 (7-37); Gly 8 Lys 34 (N E -(choloyl))-GLP-1 (7-37); Gly a Lys 2e 34 -bis(N E -(choloyl))-GLP-1 (7-37); Arg 26 Lys 34 (N ε -(choloyl))-GLP-1 (7-37); G!y 8 Arg 26 Lys 34 (N E -(7-deoxycholoyl))-GLP-1(7-38); Lys 26 (N ε -(7-deoxycholoyl))Arg 34 -GLP-1 (7-38); Gly 8 Lys 26 (N ε -(7-deoxycholoyl))Arg 3 -GLP-1 (7-38); Arg 2634 Lys 36 (N ε -(7-deoxycholoyl))-GLP-1 (7-38); Arg 2834 Lys 38 (N E -(7-deoxychotoyl))-GLP-1 (7-38); Gly 8 Arg 2634 Lys 3β (N ε -(7-deoxycholoyl))-GLP-1 (7-38); Lys 26 (N ε -(choloyi))-GLP-1(7-38); Lys 34 (N ε -(choloyl))-GLP-1 (7-38); Lys 26 :i4 -bis(N ε -(choloyl))-GLP-1 (7-38); Gly 8 Lys 26 (N E -(choloyl))-GLP-1(7-38); Gly 8 Lys 34 (N ε -(choloyl))-GLP-1(7-38); Gly 8 Lys 263 -bis(N ε -(choloyl))-GLP-1 (7-38); Arg 26 Lys 3 (N E -(choloyl))-GLP-1 (7-38); Gly 8 Arg 26 Lys 34 (N ε -(7-deoxycholoyl))-GLP-1 (7-39); Lys 26 (N ε -(7-deoxycholoyl))Arg 34 -GLP-1 (7-39), Gly 8 Lys 26 (N ε -(7-deoxycholoyl))Arg 34 -GLP-1 (7-39); Arg 2634 Lys 36 (N ε -(7-deoxycholoyl))-GLP-1 (7-39); Gly 8 Arg 2634 Lys 36 (N ε -(7-deoxycholoyt))-GLP-1 (7-39); Lys 26 (N E -(choloyl))-GLP-1 (7-39); Lys 34 (N ε -(choloyl))-GLP-1 (7-39); Lys 2634 -bιs(N E -(choloyl))-GLP-1 (7-39); Gly 8 Lys 26 (N E -(choloyl))-GLP-1 (7-39); Gly 8 Lys 34 (N ε -(choloyl))-GLP-1 (7-39); Gly 8 Lys 2634 -bis(N ε -(choloyl))-GLP-1 (7-39); Arg 26 Lys 34 (N ε -(choloyl))-GLP-1 (7-39); Gly 8 Arg 26 Lys 34 (N ε -(7-deoxycholoyl))-GLP-1 (7-40), Lys 26 (N E -(7-deoxycholoyl))Arg 34 -GLP-1 (7-40), Gly 8 Lys 6 (N ε -(7-deoxycholoyl))Arg 34 -GLP-1(7^0); Arg 2634 Lys 36 (N ε -(7-deoxycholoyl))-GLP-1 (7-40), Gly 8 Arg 83 Lys 3β (N ε -(7-deoxycholoyl))-GLP-1 (7-40), Lys 26 (N ε -(choloyl))-GLP-1 (7-40); Lys 34 (N E -(choloyl))-GLP-1 (7-40), Lys 2634 -bιs(N ε -(choloyl))-GLP-1 (7-40), Gly 8 Lys 26 (N E -(choloyl))-GLP-1 (7-40), GIy 8 Lys 34 (N ε -(choioyl))-GLP-1 (7-40); Gly β Lys 2634 -bis(N ε -(choloyl))-GLP-1 (7-40); Arg 2β Lys 3 (N ε -(choloyl))-GLP-1 (7-40), Lys 2β (N E -(choloyl))-GLP-1(7-36); Lys 34 (N ε -(choloyl))-GLP-1 (7-36); Lys 263 -bιs(N ε -(choloyl))-GLP-1 (7-36); Gly 8 Lys 26 (N ε -(choioyl))-GLP-1 (7-36); Gly 8 Lys 34 (N ε -(choloyl))-GLP-1 (7-36); Gly 8 Lys 2634 -bis(N ε -(choloyl))-GLP-1 (7-36), Arg 26 Lys 34 (N ε -(choloyl))-GLP- 1 (7-36); Lys 26 (N ε -(choloyl))-GLP-1(7-35); Lys 34 (N ε -(choloyl))-GLP-1 (7-35); Lys 26 ' 3 -bis(N ε -(choioyl))-GLP-1(7-35); Gly 8 Lys 26 (N ε -(choloy!))-GLP-1(7-35); Gly 8 Lys 34 (N ε -(choloyl))-GLP-1(7-35); Gly 8 Lys 26 ' 34 -bis(N ε -(choloyl))-GLP-1 (7-35); Arg 26 Lys 34 (N ε -(choloyl))-GLP-1(7-35); Lys 26 (N E -(choloyl))-GLP-1(7-36)amide; Lys 34 (N E -(choloyt))-GLP-1(7-36)amide; Lys 2534 -bis(N ε -(choloyl))-GLP-1(7-36)amide; Gly 8 Lys 2β (N ε -(choloyl))-GLP-1 (7-36)amide; Gly 8 Lys 3 (N ε -(choloyl))-GLP-1(7-36)amide; Gly 8 Lys 2634 -bis(N ε -(choloyl))-GLP-1(7-36)amide; Arg 26 Lys 34 (N ε -(choloyl))-GLP-1(7-36)amide; Gly 8 Arg 26 Lys 34 (N ε -(choloyl))-GLP-1(7-37); Lys 26 (N ε -(choioyl))Arg 3 -GLP-1 (7-37); Gly 8 Lys 26 (N ε -(choloyl))Arg 34 -GLP-1(7-37); Arg 2β34 Lys 36 (N ε -(choloyl))-GLP-1(7-37); Gly 8 Arg 26 ' 34 Lys 36 (N ε -(choloyl))-GLP-1(7-37); Lys 26 (N ε -(lithocholoyl))-GLP-1(7-37); Lys 34 (N ε -(lithocholoyl))-GLP-1 (7-37); Lys 26 ' 34 -bis(N ε -(lithocholoyl))-GLP-1(7-37); Gly 8 Lys 25 (N ε -(lithocholoyl))-GLP-1(7-37); Gly 8 Lys 34 (N ε -(lithocholoyl))-GLP-1(7-37); Gly 8 Lys 2834 -bis(N ε -(lithocholoyl))-GLP-1(7-37); Arg 26 Lys 3 (N ε -(lithocholoyl))-GLP-1 (7-37); Gly 8 Arg 26 Lys 34 (N ε -(choloyl))-GLP-1(7-38); Lys 2β (N ε -(choloyl))Arg 3 -GLP-1(7-38); Gly 8 Lys 2β (N ε -(choloyl))Arg 3 -GLP-1(7-38); Arg 26 - 34 Lys 36 (N ε -(choloyl))-GLP-1(7-38); Arg 2β3 Lys 38 (N ε -(choloyl))-GLP-1 (7-38); Gly 8 Arg 2βM Lys 3β (N E -(choloyl))-GLP-1(7-38); Lys 26 (N ε -(lithocholoyl))-GLP-1(7-38); Lys 3 (N ε -(lithocholoyl))-GLP-1(7-38); Lys 2634 -bis(N E -(lithocholoyl))-GLP-1(7-38); Gly 8 Lys 26 (N ε -(lithocholoyl))-GLP-1(7-38); Gly 8 Lys 34 (N ε -(lithocholoyl))-GLP-1(7-38); Gly 8 Lys 2634 -bis(N E -(lithocholoyl))-GLP-1(7-38); Arg 26 Lys l4 (N ε -(lithocholoyl))-GLP-1 (7-38); Gly 8 Arg 26 Lys 3 (N ε -(choloyl))-GLP-1(7-39); Lys 26 (N ε -(choloyl))Arg 34 -GLP-1(7-39); Gly 8 Lys 2β (N ε -(choloyl))Arg 34 -GLP-1(7-39); Arg 2634 Lys 3δ (N ε -(choloyl))-GLP-1(7-39); Gly 8 Arg 2634 Lys 36 (N E -(choloyl))-GLP-1 (7-39); Lys 26 (N ε -(lithocholoyl))-GLP-1(7-39); Lys 4 (N ε -(lithocholoyl))-GLP-1(7-39); Lys 263 -bis(N ε -(lithocholoyl))-GLP-1(7-39); Gly 8 Lys 26 (N E -(lithocholoyl))-GLP-1(7-39); Gly 8 Lys 34 (N ε -(lithocholoyl))-GLP-1 (7-39); Gly 8 Lys 26:M -bis(N ε -(lithocholoyl))-GLP-1(7-39); Arg 26 Lys 3 (N t -(lithocholoyl))-GLP- 1(7-39); Gly 8 Arg 26 Lys 3 (N ε -(choloyl))-GLP-1(7-40); Lys 26 (N ε -(chotoyl))Arg 34 -GLP-1(7-40); Gly 8 Lys 2β (N ε -(choloyl))Arg 34 -GLP-1 (7-40); Arg 2634 Lys 36 (N ε -(choloyl))-GLP-1(7-40); Gly 8 Arg 263 Lys 36 (N ε -(choloyl))-GLP-1 (7-40); Lys 26 (N E -(lithocholoyl))-GLP-1(7-40); Lys 34 (N ε -(lithocholoyl))-GLP-1(7-40); Lys 26 ' 34 -bis(N ε -(lithocholoyl))-GLP-1 (7-40); Gly 8 Lys 26 (N E -(lithocholoyl))-GLP-1(7-40); Gly 8 Lys 3 (N ε -(lithocholoyl))-GLP-1(7-40); Gly 8 Lys 2634 -bis(N ε -(lithocholoyl))-GLP-1(7-40); Arg 26 Lys 34 (N ε -(lithocholoyl))-GLP-1(7-37); Lys 26 (N ε -(lithocholoyl))-GLP-1 (7-36); Lys 3 (N c -(lithocholoyl))-GLP-1(7-36); Lys 2634 -bis(N ε -(lithocholoyl))-GLP-1(7-36); Gly 8 Lys 26 (N ε -(lithocholoyl))-GLP-1(7-36); Gly 8 Lys 34 (N ε -(lithocholoyl))-GLP-1 (7-36); Gly 8 Lys 2634 -bis(N ε -(lithocholoyl))-GLP-1 (7-36); Arg 26 Lys 34 (N ε -(lithocholoyl))-GLP-1 (7-36); Lys 26 (N E -(lithocholoyl))-GLP-1(7-35); Lys 34 (N ε -(lithocholoyl))-GLP-1 (7-35); Lys 2634 -bis(N ε -(lithocholoyl))-GLP-1 (7-35); Gly 8 Lys 26 (N ε -(lithocholoyl))-GLP-1 (7-35); Gly 8 Lys 3 (N ε -(lithocholoyl))-GLP-1 (7-35); Gly 8 Lys 2634 -bis(N E -(lithocholoyl))-GLP-1(7-35); Arg 2S Lys 34 (N ε -(lithocholoyl))-GLP-1 (7-35); Lys 26 (N E -(lithocholoyl))-GLP-1(7-36)amide; Lys 34 (N ε -(lithocholoyl))-GLP-1 (7-36)amide; Lys 2634 -bis(N ε -(lithocholoyl))-GLP-1 (7-36)amide; Gly 8 Lys 26 (N ε -(lithocholoyl))-GLP-1(7-36)amide; Gly 8 Lys 34 (N ε -(lithocholoyl))-GLP-1 (7-36)amide; Gly 8 Lys 26 ' 34 -bis(N ε -(lithocholoyl))-GLP-1 (7-36)amide; Arg 26 Lys 34 (N E -(lithocholoyl))-GLP-1(7-36)amide; Gly 8 Arg 26 Lys 34 (N ε -(lithocholoyl))-GLP-1 (7-37); Lys 28 (N ε -(lithocholoyl))Arg 3 -GLP-1(7-37); Gly β Lys 26 (N ε -(lithocholoyl))Arg 34 -GLP-1 (7-37); Arg 2β 34 Lys 3β (N ε -(lithocholoyl))-GLP-1(7-37); Arg 2β 4 Lys 38 (N ε -(lithocholoyl))-GLP-1 (7-37); Giy 8 Arg 2634 Lys 36 (N ε -(lithocholoyl))-GLP-1 (7-37); Gly 8 Arg 26 Lys 34 (N t -(lithocholoyl))-GLP-1(7-38); Lys 28 (N ε -(lithocholoyl))Arg 34 -GLP-1 (7-38); Gly 8 Lys 26 (N £ -(lithocholoyl))Arg 34 -GLP-1 (7-38); Arg 2δ34 Lys 3θ (N ε -(lithocholoyl))-GLP-1 (7-38); Arg 2634 Lys 38 (N ε -(lithocholoyl))-GLP-1 (7-38); Gly 8 Arg 2634 Lys 35 (N ε -(lithocholoyl))-GLP-1(7-38); Gly 8 Arg 26 Lys 4 (N ε -(lithocholoyl))-GLP-1 (7-39); Lys 6 (N ε -(lithocholoyl))Arg 34 -GLP-1 (7-39); Gly 8 Lys 26 (N ε -(lithocholoyl))Arg 34 -GLP-1 (7-39); Arg 2634 Lys 36 (N ε -(lithocholoyl))-GLP-1 (7-39); Gly 8 Arg 2634 Lys 36 (N ε -(lιthocholoyl))-GLP- 1 (7-39), Gly 8 Arg 26 Lys 3 (N ε -(lιthocholoyl))-GLP-1 (7-40), Lys 26 (N E -( thocholoyl))Arg 34 -GLP-1(7-40), Gly 8 Lys 26 (N E -( thocholoyl))Arg 3 -GLP-1 (7-40), Arg 263 Lys 36 (N E -(lιthocholoyl))-GLP-1 (7-40) and Gl Arg 2634 Lys 36 (N ε -(lιthochoioyl))-GLP-1 (7-40) In a further preferred embodiment, the present invention relates to a pharmaceutical composition comprising a GLP-1 derivative and a pharmaceutically acceptable vehicle or carrier In a further preferred embodiment, the present invention relates to the use of a GLP-1 derivative according to the invention for the preparation of a medicament which has a protracted profile of action relative to GLP-1 (7-37) In a further preferred embodiment, the present invention relates to the use of a GLP-1 derivative according to the invention for the preparation of a medicament with protracted effect for the treatment of non-insulin dependent diabetes mellitus In a further preferred embodiment, the present invention relates to the use of a GLP-1 derivative according to the invention for the preparation of a medicament with protracted effect for the treatment of insulin dependent diabetes mellitus In a further preferred embodiment, the present invention relates to the use of a GLP-1 derivative according to the invention for the preparation of a medicament with protracted effect for the treatment of obesity In a further preferred embodiment, the present invention relates to a method of treating insulin dependent or non-insulin dependent diabetes mellitus in a patient in need of such a treatment, comprising administering to the patient a therapeutically effective amount of a GLP-1 derivative according to claim 1 together with a pharmaceutically acceptable carrier DETAILED DESCRIPTION OF THE INVENTION To obtain a satisfactory protracted profile of action of the GLP-1 derivative, the lipophilic substituent attached to the GLP-1 moiety preferably comprises 4-40 carbon atoms, in particular 8-25 carbon atoms The lipophilic substituent may be attached to an ammo group of the GLP-1 moiety by means of a carboxyl group of the lipophilic substituent which forms an amide bond with an ammo group of the am o acid residue to which it is attached Alternatively, the lipophilic substituent may be attached to said am o acid residue in such a way that an ammo group of the lipophilic substituent forms an amide bond with a carboxyl group of the ammo acid residue As a further option, the lipophilic substituent may be linked to the GLP-1 moiety via an ester bond Formally, the ester can be formed either by reaction between a carboxyl group of the GLP-1 moiety and a hydroxyl group of the substituent-to-be or by reaction between a hydroxyl group of the GLP-1 moiety and a carboxyl group of the substituent-to-be As a further alternative, the lipophilic substituent can be an alkyl group which is introduced into a primary ammo group of the GLP-1 moiety In one preferred embodiment of the invention, the lipophilic substituent is attached to the GLP-1 moiety by means of a spacer in such a way that a carboxyl group of the spacer forms an amide bond with an ammo group of the GLP-1 moiety Examples of suitable spacers are succmic acid, Lys, Glu or Asp, or a dipeptide such as Gly-Lys When the spacer is succmic acid, one carboxyl group thereof may form an amide bond with an ammo group of the ammo acid residue, and the other carboxyl group thereof may form an amide bond with an ammo group of the lipophilic substituent When the spacer is Lys, Glu or Asp, the carboxyl group thereof may form an amide bond with an ammo group of the ammo acid residue, and the ammo 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-ammo group of Lys and the lipophilic substituent In one preferred embodiment, such a further spacer is succmic acid which forms an amide bond with the ε- ammo group of Lys and with an ammo group present in the lipophi c substituent In another preferred 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 lysme residue In another preferred embodiment of the present invention, the lipophilic substituent has a group which can be negatively charged One preferred group which can be negatively charged is a carboxylic acid group The parent peptide can be produced by a method which comprises cultuπng a host cell containing a DNA sequence encoding the polypeptide and capable of expressing the 5 polypeptide 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 Suit- 0 able media are available from commercial suppliers or may be prepared according to 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 centπfugation or filtration, precipitating the protemaceous components of the supernatant or filtrate by means of a salt, 5 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, 0 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 oligonucieotide probes in accordance with standard techniques (see, for example, Sambrook, J, Fπtsch, EF and Maniatis, T, Molecular Cloning A Laboratory Manual, Cold Spring Harbor Laboratory Press, New York, 1989) The DNA sequence encoding the peptide 5 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 ef a/ , EMBO Journal 3 (1984), 801 - 805. The DNA sequence may also be prepared by poiymerase chain reaction using specific pπmers, for instance as descnbed in US 4,683,202 or Saiki et al , Science 239 (1988), 487 - 30 491 The DNA sequence may be inserted into any vector which may conveniently be subjected to recomb ant 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, / 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 transcπption of the DNA, such as a promoter The promoter may be any DNA sequence which shows transcπptional 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 weii known in the art, cf for instance Sambrook et al , supra The DNA sequence encoding the peptide may also, if necessary, be operably connected to a suitable terminator, polyadenylation signals, transcπptional 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 ampicillin, kanamycin, tetracyciin, chloramphenicol, neomycin, hygromycm 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 et al , 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. Examples of compounds which can be useful as GLP-1 moieties according to the present invention are described in International Patent Application No. WO 87/06941 (The General Hospital Corporation) which relates to a peptide fragment which comprises GLP-1 (7-37) and functional derivatives thereof and to its use as an insulinotropic agent. Further GLP-1 analogues are described in International Patent Application No. 90/11296 (The General Hospital Corporation) which relates to peptide fragments which comprise GLP-1 (7-36) and functional derivatives thereof and have an insulinotropic activity which exceeds the insulinotropic activity of GLP-1 (1-36) or GLP-1 (1-37) and to their use as insulinotropic agents. International Patent Application No. 91/1 1457 (Buckley et al .) discloses analogues of the active GLP-1 peptides 7-34, 7-35, 7-36, and 7-37 which can also be useful as GLP-1 moieties according to the present invention. Pharmaceutical compositions Pharmaceutical compositions containing a GLP-1 derivative according to the present invention may be administered parenterally to patients in need of such a treatment. Parenteral administration may be performed by subcutaneous, intramuscular 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 powder or a liquid for the administration of the GLP-1 derivative in the form of a nasal or pulmonal spray As a still further option, the GLP-1 derivatives of the invention can also be administered transdermally, e.g. from a patch, optionally a lontophoretic patch, or transmucosally, e.g. bucally. Pharmaceutical compositions containing a GLP-1 derivative of the present invention may be prepared by conventional techniques, e.g. as described in Remington's Pharmaceutical Sciences, 1985 or in Remington: The Science and Practice of Pharmacy, 19 ,h edition, 1995. Thus, the injectable compositions of the GLP-1 derivative of the invention can be prepared using the conventional techniques of the pharmaceutical industry which involves dissolving and mixing the ingredients as appropriate to give the desired end product. According to one procedure, the GLP-1 derivative is dissolved in an amount of water which is somewhat less than the final volume of the composition to be prepared. An isotonic agent, a preservative and a buffer is added as required and the pH value of the solution is adjusted - if necessary - using an acid, e.g. hydrochloric acid, or a base, e g. aqueous sodium hydroxide as needed. Finally, the volume of the solution is adjusted with water to give the desired concentration of the ingredients. Examples of isotonic agents are sodium chloride, mannitol and glycerol. Examples of preservatives are phenol, m-cresol, methyl p-hydroxybenzoate and benzyl alcohol. Examples of suitable buffers are sodium acetate and sodium phosphate Further to the above-mentioned components, solutions containing a GLP-1 derivative according to the present invention may also contain a surfactant in order to improve the solubility and/or the stability of the GLP-1 derivative. A composition for nasal administration of certain peptides may, for example, be prepared as described in European Patent No. 272097 (to Novo Nordisk A/S) or in WO 93/18785. According to one preferred embodiment of the present invention, the GLP-1 derivative is provided in the form of a composition suitable for administration by injection. Such a composition can either be an injectable solution ready for use or it can be an amount of a solid composition, e.g. a lyophilised product, which has to be dissolved in a solvent before it can be injected The injectable solution preferably contains not less than about 2 mg/ml, preferably not less than about 5 mg/ml, more preferred not less than about 10 mg/ml of the GLP-1 derivative and, preferably, not more than about 100 mg/ml of the GLP-1 derivative The GLP-1 derivatives of this invention can be used in the treatment of various diseases The particular GLP-1 derivative to be used and the optimal dose level for any patient will depend on the disease to be treated and on a variety of factors including the efficacy of the specific peptide derivative employed, the age, body weight, physical activity, and diet of the patient, on a possible combination with other drugs, and on the severity of the case It is recommended that the dosage of the GLP-1 derivative of this invention be determined for each individual patient by those skilled in the art In particular, it is envisaged that the GLP-1 derivative will be useful for the preparation of a medicament with a protracted profile of action for the treatment of non-insulin dependent diabetes mellitus and/or for the treatment of obesity The present invention is further illustrated by the following examples which, however, are not to be construed as limiting the scope of protection The features disclosed in the foregoing description and in the following examples may, both separately and in any combination thereof, be material for realising the invention in diverse forms thereof EXAMPLES The following acronyms for commercially available chemicals are used: DMF N,N-Dιmethylformamιde NMP N-Methyl-2-pyrrolιdone EDPA N-Ethyl-N , N-dnsopropylamine EGTA Ethylene glycol-bιs(β-amιnoethyl ether)-N,N,N',N'-tetraacetιc GTP Guanosme 5'-tπphosphate TFA Trifluoroacetic acid THF Tetrahydrofuran Myr-ONSu: Tetradecanoic acid 2,5-dioxopyrrolidin-1-yl ester. Pal-ONSu: Hexadecanoic acid 2,5-dioxopyrrolidin-1-yl ester. Ste-ONSu Octadecanoic acid 2,5-dioxopyrrolidin-1-yl ester. HOOC-(CH 2 ) 6 -COONSu: ω-Carboxyheptanoic acid 2,5-dioxopyrrolidin-1 -yl ester. HOOC-(CH 2 ) 10 -COONSu ω-Carboxyundecanoic acid 2,5-dioxopyrrolidin-1-yl ester. HOOC-(CH 2 ) 12 -COONSu ω-Carboxytridecanoic acid 2,5-dioxopyrrolidin-1-yl ester. HOOC-(CH 2 ) 14 -COONSu ω-Carboxypentadecanoic acid 2,5-dioxopyrrolidin-1 -yl ester. HOOC-(CH 2 ) 16 -COONSu ω-Carboxyheptadecanoic acid 2,5-dioxopyrrolidin-1-yl ester. HOOC-(CH 2 ) 18 -COONSu ω-Carboxynonadecanoic acid 2,5-dioxopyrrolidin-1-yl ester. Abbreviations: PDMS: Plasma Desorption Mass Spectrometry MALDI-MS: Matrix Assisted Laser Desorption/lonisation Mass Spectrometry HPLC: High Performance Liquid Chromatography amu: atomic mass units Analytical Plasma Desorption Mass Spectrometry Sample preparation: The sample is dissolved in 0.1 % TFA/EtOH (1 :1 ) at a concentration of 1 μg/μl. The sample solution (5-10 μl) is placed on a nitrocellulose target (Bio-ion AB, Uppsala, Sweden) and allowed to adsorb to the target surface for 2 minutes. The target is subsequently rinsed with 2x25 μl 0.1 % TFA and spin-dried. Finally, the nitrocellulose target is piaced in a target carrousel and introduced into the mass spectrometer. MS analysis: PDMS analysis was carried out using a Bio-ion 20 time-of flight instrument (Bio-ion Nordic AB, Uppsala, Sweden). An acceleration voltage of 15 kV was applied and molecular ions formed by bombardment of the nitrocellulose surface with 252-Cf fission fragments were accelerated towards a stop detector. The resulting time-of-flight spectrum was calibrated into a true mass spectrum using the H + and NO * ions at m/z 1 and 30, respectively. Mass spectra were generally accumulated for 1 0x10 6 fission events corresponding to 15-20 minutes Resulting assigned masses all correspond to isotopically averaged molecular masses The accuracy of mass assignment is generally better than 0 1 % MALDi-MS MALDI-TOF MS analysis was carried out using a Voyager RP instrument (PerSeptive Biosystems Inc , Frammgham, MA) equipped with delayed extraction and operated in linear mode Aipha-cyano-4-hydroxy-cιnnamιc acid was used as matrix, and mass assignments were based on external calibration Example 1 Synthesis of Lys 26 (N ε -tetradecanoyl)-GLP-1 (7-37) The title compound was synthesised from GLP-1 (7-37) A mixture of GLP-1 (7-37) (25 mg, 7 45 μm), EDPA (26 7 mg, 208 μm), NMP (520 μl) and water (260 μl) was gently shaken for 5 mm at room temperature. To the resulting mixture was added a solution of Myr- ONSu (2 5 mg, 7 67 μm) in NMP (62.5 μl), the reaction mixture was gently shaken for 5 mm at room temperature and then allowed to stand for 20 mm An additional amount of Myr-ONSu (2.5 mg, 7.67 μm) in NMP (62.5 μl) was added and the resulting mixture gently shaken for 5 min After a total reaction time of 40 mm the reaction was quenched by the addition of a solution of glycine (12 5 mg, 166 μmol) in 50% aqueous ethanol (12.5 ml). The title compound was isolated from the reaction mixture by HPLC using a cyanopropyl column (Zorbax 300SB-CN) and a standard acetonitπle/TFA system, yield: 1 3 mg (corresponding to 4.9% of the theoretical yield) The column was heated to 65°C and the acetoπitπle gradient was 0-100% in 60 minutes The isolated product was analysed by PDMS and the m/z value for the protonated molecular ion was found to be 3567.9±3. The resulting molecular weight is thus 3566.9±3 amu (theoretical value: 3565.9 amu). The position of acylation (Lys26) was verified by enzymatic cleavage of the title compound with Staphylococcus aureus V8 protease and subsequent mass determination of the peptide fragments by PDMS In addition to the title compound two other GLP-1 derivatives were isolated from the reaction mixture by using the same chromatographic column and a more shallow gradient (35-38% acetonitrile in 60 minutes), see Examples 2 and 3. Example 2 Synthesis of Lys 34 (N ε -tetradecanoyl)-GLP-1 (7-37). The title compound was isolated by HPLC from the reaction mixture described in Example 1. PDMS analysis yielded a protonated molecular ion at m/z 3567.7±3. The molecular weight is thus found to be 3566.7±3 amu (theoretical value: 3565.9 amu). The acylation site was determined on the basis of the fragmentation pattern. Example 3 Synthesis of Lys 26 34 -bis(N E -tetradecanoyl)-GLP-1 (7-37). The title compound was isolated by HPLC from the reaction mixture described in Example 1. PDMS analysis yielded a protonated molecular ion at m/z 3778.4±3. The molecular weight is thus found to be 3777.4±3 amu (theoretical value: 3776.1 amu). Example 4 Synthesis of Lys 26 (N ε -tetradecanoyl)Arg 34 -GLP-1 (7-37). The title compound was synthesised from Arg 34 -GLP-1 (7-37). A mixture of Arg 34 -GLP-1 (7- 37) (5 mg, 1.47 μm), EDPA (5.3 mg, 41.1 μm), NMP (105 μl) and water (50 μl) was gently shaken for 5 min. at room temperature. To the resulting mixture was added a solution of Myr-ONSu (0.71 mg, 2.2 μm) in NMP (17.8 μl), the reaction mixture was gently shaken for 5 min. at room temperature and then allowed to stand for 20 min. After a total reaction time of 30 min. the reaction was quenched by the addition of a solution of glycine (25 mg, 33.3 μm) in 50% aqueous ethanol (2.5 ml). The reaction mixture was purified by HPLC as described in Example 1. PDMS analysis yielded a protonated molecular ion at m/z 3594.9±3. The molecular weight is thus found to be 3593.9±3 amu (theoretical value: 3593.9 amu). Example 5 Synthesis of Gly 8 Arg 2634 Lys 38 (N ε -tetradecanoyl)-GLP-1(7-37). The title compound was synthesised from Gly 8 Arg 26 34 Lys 36 -GLP-1 (7-37) which was purchased from QCB. A mixture of Gly 8 Arg 263 Lys 36 -GLP-1 (7-37) (1.3 mg, 0.39 μm), EDPA (1.3 mg, 10 μm), NMP (125 μl) and water (30 μl) was gently shaken for 5 mm. at room temperature. To the resulting mixture was added a solution of Myr-ONSu (0.14 mg, 0.44 μm) in NMP (3.6 ml), the reaction mixture was gently shaken for 15 mm. at room temperature. The reaction was quenched by the addition of a solution of glycine (0.1 mg, 1.33 μm) in 50% aqueous ethanol (10 μl). The reaction mixture was purified by HPLC, and the title compound (60 μg, 4%) was isolated. Example 6 Synthesis of Arg 63 Lys 36 (N E -tetradecanoyl)-GLP-1 (7-37)-OH. A mixture of Arg 2β 34 Lys 36 -GLP-1 (7-37)-OH (5.0 mg, 1 477 μmol), EDPA (5.4 mg, 41.78 μmol), NMP (105 μl) and water (50 μl) was gently shaken for 5 mm. at room temperature. . To the resulting mixture was added a solution of Myr-ONSu (0 721 mg, 2.215 μmoi) in NMP (18 μl). The reaction mixture was gently shaken for 5 m . at room temperature, and then allowed to stand for an additional 45 mm at room temperature. The reaction was quenched by the addition of a solution of glycine (2.5 mg, 33.3 μmol) in 50% aqueous ethanol (250 μl). The reaction mixture was purified by column chromatography using a cyanopropyl column (Zorbax 300SB-CN) and a standard acetonitπle/TFA system. The column was heated to 65°C and the acetonitrile gradient was 0-100% in 60 minutes. The title compound ( 1.49 mg, 28 %) was isolated, and the product was analysed by PDMS. The m/z value for the protonated molecular ion was found to be 3595 ± 3. The resulting molecular weight is thus 3594 ± 3 amu (theoretical value 3594 amu) Example 7 Synthesis of Lys 28 ' 34 bis(N ε -(ω-carboxynonadecanoyl))-GLP-1 (7-37)-OH. A mixture of GLP-1 (7-37)-OH (70 mg, 20.85 μmol), EDPA (75.71 mg, 585.8 μmol), NMP (1.47 ml) and water (700 μL) was gently shaken for 10 mm. at room temperature. To the resulting mixture was added a solution of HOOC-(CH 2 ) 18 -COONSu (27 44 mg, 62 42 μmol) in NMP (686 μl), the reaction mixture was gently shaken for 5 mm. at room temperature, and then allowed to stand for an additional 50 m . at room temperature. The reaction was quenched by the addition of a solution of glycine (34.43 mg, 458.7 μmol) in 50% aqueous ethanol (3 44 ml) The reaction mixture was purified by column chromatography using a cyanopropyl column (Zorbax 300SB-CN) and a standard acetonitπle/TFA system. The column was heated to 65°C and the acetonitrile gradient was 0-100% in 60 minutes. The title compound ( 8.6 mg, 10 %) was isolated, and the product was analysed by PDMS. The m/z value for the protonated molecular ion was found to be 4006 ± 3. The resulting molecular weight is thus 4005 ± 3 amu (theoretical value 4005 amu). Example 8 Synthesis of Arg 2834 Lys 36 (N ε -(ω-carboxynonadecanoyl))-GLP-1 (7-36)-OH. A mixture of Arg 28 34 Lys 3β -GLP-1 (7-36)-OH (5.06 mg, 1.52 μmol), EDPA (5.5 mg, 42.58 μmol), NMP (106 μl) and water (100 μl) was gently shaken for 5 m . at room temperature To the resulting mixture was added a solution of HOOC-(CH 2 ) 18 -COONSu (1 33 mg, 3.04 μmol) in NMP (33.2 μl), the reaction mixture was gently shaken for 5 mm. at room temperature, and then allowed to stand for an additional 2.5 h at room temperature. The reaction was quenched by the addition of a solution of glycine (2.50 mg, 33 34 μmol) in 50% aqueous ethanol (250 μl) The reaction mixture was purified by column chromatography using a cyanopropyl column (Zorbax 300SB-CN) and a standard acetonitπle/TFA system. The column was heated to 65°C and the acetonitrile gradient was 0-100% in 60 minutes. The title compound ( 0 46 mg, 8 %) was isolated, and the product was analysed by PDMS. The m/z value for the protonated molecular ion was found to be 3652 ± 3. The resulting molecular weight is thus 3651 ± 3 amu (theoretical value 3651 amu) Example 9 Synthesis of Arg 2634 Lys 38 (N ε -(ω-carboxynonadecanoyl))-GLP-1 (7-38)-OH A mixture of Arg 6 M Lys 38 -GLP-1(7-38)-OH (5.556 mg, 1.57μmol), EDPA (5.68 mg, 43.96 μmol), NMP (116.6 μl) and water (50 μl) was gently shaken for 10 m . at room temperature. To the resulting mixture was added a solution HOOC-(CH 2 ) 18 -COONSu (1.38 mg, 3.14 μmol) in NMP (34.5 μl), the reaction mixture was gently shaken for 5 min. at room temperature, and then allowed to stand for an additional 2.5 h at room temperature. The reaction was quenched by the addition of a solution of glycine (2.5 mg, 33.3 μmol) in 50% aqueous ethanol (250 μl). The reaction mixture was purified by column chromatography using a cyanopropyl column (Zorbax 300SB-CN) and a standard acetonitrile/TFA system. The column was heated to 65°C and the acetonitrile gradient was 0-100% in 60 minutes. The title compound (0.7 mg, 12 %) was isolated, and the product was analysed by PDMS. The m/z value for the protonated molecular ion was found to be 3866 ± 3. The resulting molecular weight is thus 3865 ± 3 amu (theoretical value 3865 amu). Example 10 Synthesis of Arg 3 Lys 28 (N ε -(ω-carboxynonadecanoyl))-GLP-1 (7-37)-OH. A mixture of Arg 34 -GLP-1 (7-37)-OH (5.04 mg, 1.489 μmol), EDPA (5.39 mg, 41.70 μmol), NMP (105 μl) and water (50 μl) was gently shaken for 10 min. at room temperature. To the resulting mixture was added a solution HOOC-(CH 2 ) 18 -COONSu (1.31 mg, 2.97 μmol) in NMP (32.8 μl), the reaction mixture was gently shaken for 5 min. at room temperature, and then allowed to stand for an additional 30 min. at room temperature. The reaction was quenched by the addition of a solution of glycine (2.46 mg, 32.75 μmol) in 50% aqueous ethanol (246 μl). The reaction mixture was purified by column chromatography using a cyanopropyl column (Zorbax 300SB-CN) and a standard acetonitrile/TFA system. The column was heated to 65°C and the acetonitrile gradient was 0-100% in 60 minutes. The title compound ( 1.2 mg, 22 %) was isolated, and the product was analysed by PDMS. The m/z value for the protonated molecular ion was found to be 3709 ± 3. The resulting molecular weight is thus 3708 ± 3 amu (theoretical value 3708 amu). Example 11 Synthesis of Arg 34 Lys 2β (N ε -(ω-carboxyheptadecanoyl))-GLP-1 (7-37)-OH. A mixture of Arg 34 -GLP-1 (7-37)-OH (5.8 mg, 1.714 μmol), EDPA (6.20 mg, 47.99 μmol), NMP (121.8 μl) and water (58 μl) was gently shaken for 10 min. at room temperature. To the resulting mixture was added a solution HOOC-(CH 2 ) 16 -COONSu (2.11 mg, 5.142 μmol) in NMP (52.8 μl), the reaction mixture was gently shaken for 5 min. at room temperature, and then allowed to stand for an additional 2 h at room temperature. The reaction was quenched by the addition of a solution of glycine (2.83 mg, 37 70 μmol) in 50% aqueous ethanol (283 μl). The reaction mixture was purified by column chromatography using a cyanopropyl column (Zorbax 300SB-CN) and a standard acetonitrile/TFA system. The column was heated to 65°C and the acetonitrile gradient was 0-100% in 60 minutes The title compound (0 81 mg, 13 %) was isolated, and the product was analysed by PDMS The m/z value for the protonated molecular ion was found to be 3681 ± 3. The resulting molecular weight is thus 3680 ± 3 amu (theoretical value 3680 amu). Example 12 Synthesis of Arg 26 4 Lys 36 (N ε -(ω-carboxyheptadecanoyl))-GLP-1 (7-37)-OH A mixture of Arg 2634 Lys 36 -GLP-1 (7-37)-OH (3.51 mg, 1 036 μmol), EDPA (3.75 mg, 29 03 μmol), NMP (73.8 μl) and water (35 μl) was gently shaken for 10 mm. at room temperature To the resulting mixture was added a solution HOOC-(CH 2 ) 16 -COONSu (1.27 mg, 3 10 μmol) in NMP (31.8 μl), the reaction mixture was gently shaken for 5 mm. at room temperature, and then allowed to stand for an additional 2 h and 10 m . at room temperature. The reaction was quenched by the addition of a solution of glycine (1.71 mg, 22.79 μmol) in 50% aqueous ethanol (171 μl). The reaction mixture was purified by column chromatography using a cyanopropyl column (Zorbax 300SB-CN) and a standard acetonitrile/TFA system. The column was heated to 65°C and the acetonitrile gradient was 0-100% in 60 minutes. The title compound (0 8 mg, 21 %) was isolated, and the product was analysed by PDMS. The m/z value for the protonated molecular ion was found to be 3682 ± 3 The resulting molecular weight is thus 3681 ± 3 amu (theoretical value 3681amu) Example 13 Synthesis of Arg 283 Lys 38 (N ε -(ω-carboxyheptadecanoyl))-GLP-1 (7-38)-OH A mixture of Arg 2634 Lys 38 -GLP-1 (7-38)-OH (5.168 mg, 1.459 μmol), EDPA (5.28 mg, 40.85 μmol), NMP (108.6 μl) and water (51.8 μl) was gently shaken for 10 m . at room temperature. To the resulting mixture was added a solution HOOC-(CH 2 ) 16 -COONSu (1.80 mg, 4.37 μmol) in NMP (45 μl), the reaction mixture was gently shaken for 10 m . at room temperature, and then allowed to stand for an additional 2 h and 15 m . at room temperature. The reaction was quenched by the addition of a solution of glycine (2.41 mg, 32 09 μmol) in 50% aqueous ethanol (241 μl) The reaction mixture was purified by column chromatography using a cyanopropyl column (Zorbax 300SB-CN) and a standard acetonitπle/TFA system. The column was heated to 65°C and the acetonitrile gradient was 0-100% in 60 minutes The title compound (0 8 mg, 14 %) was isolated, and the product was analysed by PDMS The m/z value for the protonated molecular ion was found to be 3838 ± 3 The resulting molecular weight is thus 3837 ± 3 amu (theoretical value 3837 amu) Example 14 Synthesis of Arg 2634 Lys 36 (N ε -(ω-carboxyheρtadecanoyl))-GLP-1 (7-36)-OH A mixture of Arg 2β 3 Lys 38 -GLP-1(7-36)-OH (24 44 mg, 7 34 μmol), EDPA (26.56 mg, 205.52 μmol), NMP (513 μl) and water (244 4 μl) was gently shaken for 5 mm at room temperature To the resulting mixture was added a solution HOOC-(CH 2 ) 16 -COONSu (9 06 mg, 22.02 μmol) in NMP (1 21 ml), the reaction mixture was gently shaken for 5 mm at room temperature, and then allowed to stand for an additional 30 mm at room temperature. The reaction was quenched by the addition of a solution of glycine (12.12 mg, 161 48 μmoi) in 50% aqueous ethanol (1 21 ml) The reaction mixture was purified by column chromatography using a cyanopropyl column (Zorbax 300SB-CN) and a standard acetonitπfe/TFA system. The column was heated to 65°C and the acetonitrile gradient was 0-100% in 60 minutes The title compound (7 5 mg, 28 %) was isolated, and the product was analysed by PDMS The m/z value for the protonated molecular ion was found to be 3625 ± 3 The resulting molecular weight is thus 3624 + 3 amu (theoretical value 3624 amu) Example 15 Synthesis of Arg 634 Lys 3β (N ε -(ω-carboxyundecanoyl))-GLP-1 (7-37)-OH. A mixture of Arg 2834 Lys 36 -GLP-1 (7-37)-OH (4 2 mg, 1.24 μmol), EDPA (4 49 mg, 34 72 μmol), NMP (88.2 μl) and water (42 μl) was gently shaken for 10 mm at room temperature. To the resulting mixture was added a solution HOOC-(CH 2 ) 10 -COONSu (1 21 mg, 3.72 μmol) in NMP (30.25 μl), the reaction mixture was gently shaken for 5 m . at room temperature, and then allowed to stand for an additional 40 mm at room temperature. The reaction was quenched by the addition of a solution of glycine (2.04 mg, 27.28 μmol) in 50% aqueous ethanol (204 μl). The reaction mixture was purified by column chromatography using a cyanopropyl column (Zorbax 300SB-CN) and a standard acetonitrile/TFA system. The column was heated to 65°C and the acetonitrile gradient was 0-100% in 60 minutes. The title compound (0.8 mg, 18 %) was isolated, and the product was analysed by PDMS. The m/z value for the protonated molecular ion was found to be 3598 ± 3. The resulting molecular weight is thus 3597 ± 3 amu (theoretical value 3597 amu). Example 16 Synthesis of Arg 2634 Lys 38 (N ε -(ω-carboxyundecanoyl))-GLP-1 (7-38)-OH. A mixture of Arg 263 Lys 38 -GLP-1 (7-38)-OH (5.168 mg, 1.46 μmol), EDPA (5.28 mg, 40.88 μmol), NMP (108.6 μl) and water (51.7 μl) was gently shaken for 10 min. at room temperature. To the resulting mixture was added a solution HOOC-(CH 2 ) 10 -COONSu (1.43 mg, 4.38 μmol) in NMP (35.8 μl), the reaction mixture was gently shaken for 5 min. at room temperature, and then allowed to stand for an additional 50 min. at room temperature. The reaction was quenched by the addition of a solution of glycine (2.41 mg, 32.12 μmol) in 50% aqueous ethanol (241 μl). The reaction mixture was purified by column chromatography using a cyanopropyl column (Zorbax 300SB-CN) and a standard acetonitrileTFA system. The column was heated to 65°C and the acetonitrile gradient was 0-100% in 60 minutes. The title compound (0.85 mg, 16 %) was isolated, and the product was analysed by PDMS. The m/z value for the protonated molecular ion was found to be 3753 ± 3. The resulting molecular weight is thus 3752 ± 3 amu (theoretical value 3752 amu). Example 17 Synthesis of Lys 263 bis(N ε -(ω-carboxyundecanoyl))-GLP-1 (7-37)-OH. A mixture of GLP-1 (7-37)-OH (10.0 mg, 2.98 μmol), EDPA (10.8 mg, 83.43 μmol), NMP (210 μl) and water (100 μl) was gently shaken for 10 min. at room temperature. To the resulting mixture was added a solution HOOC-(CH 2 ), 0 -COONSu (2.92 mg, 8.94 μmol) in NMP (73 μl), the reaction mixture was gently shaken for 5 min. at room temperature, and then allowed to stand for an additional 50 min. at room temperature. The reaction was quenched by the addition of a solution of glycine (4.92 mg, 65.56 μmol) in 50% aqueous ethanol (492 μl) The reaction mixture was purified by column chromatography using a cyanopropyl column (Zorbax 300SB-CN) and a standard acetonitnle/TFA system The column was heated to 65°C and the acetonitrile gradient was 0-100% in 60 minutes The title compound (1 0 mg, 9 %) was isolated, and the product was analysed by PDMS The m/z value for the protonated molecular ion was found to be 3781 ± 3 The resulting molecular weight is thus 3780 ± 3 amu (theoretical value 3780amu) Example 18 Synthesis of Arg 263 Lys 36 (N ε -(ω-carboxyundecanoyl))-GLP-1 (7-36)-OH. A mixture of Arg 2634 Lys 36 -GLP-1 (7-36)-OH (15 04 mg, 4 52 μmol), EDPA (16.35 mg, 126.56 μmol), NMP (315 8 μl) and water (150.4 μl) was gently shaken for 10 m . at room temperature To the resulting mixture was added a solution HOOC-(CH 2 ) 10 -COONSu (4 44 mg, 13 56 μmol) in NMP (1 1 1 μl), the reaction mixture was gently shaken for 5 m at room temperature, and then allowed to stand for an additional 40 mm at room temperature. The reaction was quenched by the addition of a solution of glycine (7 5 mg, 99 44 μmol) in 50% aqueous ethanol (750 μl). The reaction mixture was purified by column chromatography using a cyanopropyl column (Zorbax 300SB-CN) and a standard acetonitnle/TFA system. The column was heated to 65°C and the acetonitrile gradient was 0-100% in 60 minutes. The title compound (3.45 mg, 22 %) was isolated, and the product was analysed by PDMS The m/z value for the protonated molecular ion was found to be 3540 ± 3. The resulting molecular weight is thus 3539 ± 3 amu (theoretical value 3539 amu). Example 19 Synthesis of Arg 34 Lys 26 (N ε -(ω-carboxyundecanoyl))-GLP-1 (7-37)-OH. A mixture of Arg M -GLP-1 (7-37)-OH (5.87 mg, 1.73 μmol), EDPA (6.27 mg, 48 57 μmol), NMP (123.3 μl) and water (58 7 μl) was gently shaken for 10 mm. at room temperature To the resulting mixture was added a solution HOOC-(CH 2 ) 1Q -COONSu (1.70 mg, 5.20 μmol) in NMP (42.5 μl), the reaction mixture was gently shaken for 5 mm. at room temperature, and then allowed to stand for an additional 40 mm at room temperature. The reaction was quenched by the addition of a solution of glycine (2.86 mg, 286 μmol) in 50% aqueous ethanol (286 μl). The reaction mixture was purified by coiumn chromatography using a cyanopropyl column (Zorbax 300SB-CN) and a standard acetonitrile/TFA system. The coiumn was heated to 65°C and the acetonitrile gradient was 0-100% in 60 minutes. The title compound (1.27 mg, 20 %) was isolated, and the product was analysed by PDMS. The m/z value for the protonated molecular ion was found to be 3597 ± 3. The resulting molecular weight is thus 3596 ± 3 amu (theoretical value 3596 amu). Example 20 Synthesis of Arg 34 Lys 2β (N ε -(ω-carboxyheptaπoyl))-GLP-1 (7-37)-OH. A mixture of Arg 3 -GLP-1 (7-37)-OH (4.472 mg, 1.32 μmol), EDPA (4.78 mg, 36.96 μmol), NMP (94 μl) and water (44.8 μl) was gently shaken for 5 min. at room temperature. To the resulting mixture was added a solution HOOC-(CH 2 ) 6 -COONSu (1.07 mg, 3.96 μmol) in NMP (26.8 μl), the reaction mixture was gently shaken for 5 min. at room temperature, and then allowed to stand for an additional 1 h and 50 min. at room temperature. The reaction was quenched by the addition of a solution of glycine (2.18 mg, 29.04 μmol) in 50% aqueous ethanol (218 μl). The reaction mixture was purified by column chromatography using a cyanopropyl column (Zorbax 300SB-CN) and a standard acetonitrile/TFA system. The coiumn was heated to 65°C and the acetonitrile gradient was 0-100% in 60 minutes. The title compound (0.5 mg, 1 1 %) was isolated, and the product was analysed by PDMS. The m/z value for the protonated molecular ion was found to be 3540 ± 3. The resulting molecular weight is thus 3539 ± 3 amu (theoretical value 3539 amu). Example 21 Synthesis of Arg 2834 Lys 38 (N ε -(ω-carboxyheptanoyl))-GLP-1 (7-38)-OH. A mixture of Arg 2634 Lys 38 -GLP-1 (7-38)-OH (5.168 mg, 1.459 μmol), EDPA (5.28 mg, 40.85 μmol), NMP (108.6 μl) and water (51.6 μl) was gently shaken for 10 min. at room temperature. To the resulting mixture was added a solution HOOC-(CH 2 ) 6 -COONSu (1.18 mg, 4.37 μmol) in NMP (29.5 μl), the reaction mixture was gently shaken for 5 min. at room temperature, and then allowed to stand for an additional 1 h and 50 min. at room temperature. The reaction was quenched by the addition of a solution of glycine (2.40 mg, 32.09 μmol) in 50% aqueous ethanol (240 μl). The reaction mixture was purified by column chromatography using a cyanopropyl column (Zorbax 300SB-CN) and a standard acetonitrile/TFA system. The column was heated to 65°C and the acetonitrile gradient was 0-100% in 60 minutes. The title compound (0 5 mg, 9 %) was isolated, and the product was analysed by PDMS. The m/z value for the protonated molecular ion was found to be 3697 ± 3 The resulting molecular weight is thus 3695 ± 3 amu (theoretical value 3695 amu). Example 22 Synthesis of Arg 2634 Lys 36 (N ε -(ω-carboxyheptanoyl))-GLP-1 (7-37)-OH. A mixture of Arg 26 34 Lys 36 -GLP-1 (7-37)-OH (5.00 mg, 1 47 μmol), EDPA (5.32 mg, 41.16 μmol), NMP (105 μl) and water (50 μl) was gently shaken for 5 mm at room temperature. To the resulting mixture was added a solution HOOC-(CH 2 ) 6 -COONSu (1.19 mg, 4 41 μmol) in NMP (29.8 μl), the reaction mixture was gently shaken for 5 mm at room temperature, and then allowed to stand for an additional 2 h at room temperature The reaction was quenched by the addition of a solution of glycine (2 42 mg, 32.34 μmol) in 50% aqueous ethanol (242 μl) The reaction mixture was purified by column chromatography using a cyanopropyl column (Zorbax 300SB-CN) and a standard acetonitnle/TFA system The column was heated to 65°C and the acetonitrile gradient was 0-100% in 60 minutes. The title compound (0 78 mg, 15 %) was isolated, and the product was analysed by PDMS. The m/z value for the protonated molecular ion was found to be 3542 ± 3. The resulting molecular weight is thus 3541 ± 3 amu (theoretical value 3541 amu) Example 23 Synthesis of Arg 28 34 Lys 3β (N ε -(ω-carboxyheptanoyl))-GLP-1 (7-36)-OH. A mixture of Arg 283 Lys 36 -GLP-1 (7-36)-OH (5.00 mg, 1.50 μmoi), EDPA (5 44 mg, 42.08 μmol), NMP (210 μl) and water (50 μl) was gently shaken for 5 mm. at room temperature. To the resulting mixture was added a solution HOOC-(CH 2 ) β -COONSu (1.22 mg, 4.5 μmol) in NMP (30.5 μl), the reaction mixture was gently shaken for 5 mm. at room temperature, and then allowed to stand for an additional 2 h at room temperature. The reaction was quenched by the addition of a solution of glycine (2.47 mg, 33.0 μmol) in 50% aqueous ethanol (247 μl). The reaction mixture was purified by column chromatography using a cyanopropyl column (Zorbax 300SB-CN) and a standard acetonitrile/TFA system. The column was heated to 65°C and the acetonitrile gradient was 0-100% in 60 minutes. The title compound (0.71 mg, 14 %) was isolated, and the product was analysed by PDMS. The m/z value for the protonated molecular ion was found to be 3484 ± 3. The resulting molecular weight is thus 3483 ± 3 amu (theoretical value 3483 amu). Example 24 Synthesis of Lys 263 bis(N ε -(ω-carboxyheptanoyl))-GLP-1 (7-37)-OH. A mixture of GLP-1 (7-37)-OH (10 mg, 2.5 μmol), EDPA (10.8 mg, 83.56 μmol), NMP (210 μl) and water (100 μl) was gently shaken for 10 min. at room temperature. To the resulting mixture was added a solution HOOC-(CH 2 ) 6 -COONSu (2.42 mg, 8.92 μmol) in NMP (60.5 μl), the reaction mixture was gently shaken for 5 min. at room temperature, and then allowed to stand for an additional 2 h and 35 min. at room temperature. The reaction was quenched by the addition of a solution of glycine (4.92 mg, 65.54 μmol) in 50% aqueous ethanol (492 μl). The reaction mixture was purified by column chromatography using a cyanopropyl column (Zorbax 300SB-CN) and a standard acetonitrile/TFA system. The column was heated to 65°C and the acetonitrile gradient was 0-100% in 60 minutes. The title compound (2.16 mg, 24 %) was isolated, and the product was analysed by PDMS. The m/z value for the protonated molecular ion was found to be 3669 ± 3. The resulting molecular weight is thus 3668 ± 3 amu (theoretical value 3668 amu). Example 25 Synthesis of Arg^Lys 26 (N ε -(ω-carboxypentadecanoyl))-GLP-1 (7-37)-OH. A mixture of Arg 3 -GLP-1 (7-37)-OH (4.472 mg, 1.321 μmol), EDPA (4.78 mg, 36.99 μmol), NMP (93.9 μl) and water (44.7 μl) was gently shaken for 10 min. at room temperature. To the resulting mixture was added a solution HOOC-(CH 2 ) 14 -COONSu (1.519 mg, 3.963 μmol) in NMP (38 μl), the reaction mixture was gently shaken for 5 min. at room temperature, and then allowed to stand for an additional 1 h at room temperature. The reaction was quenched by the addition of a solution of glycine (2.18 mg, 29.06 μmol) in 50% aqueous ethanol (218 μl). The reaction mixture was purified by column chromatography using a cyanopropyl column (Zorbax 300SB-CN) and a standard acetonitrile/TFA system. The column was heated to 65°C and the acetonitrile gradient was 0-100% in 60 minutes. The title compound (0.58 mg, 12 %) was isolated, and the product was analysed by PDMS. The m/z value for the protonated molecular ion was found to be 3654 ± 3. The resulting molecular weight is thus 3653 ± 3 amu (theoretical value 3653 amu). Example 26 Synthesis of Arg 2634 Lys 36 (N ε -(ω-carboxyheptanoyl))-GLP-1 (7-36)-OH. A mixture of Arg 26 ' 3 Lys 36 -GLP-1 (7-36)-OH (5.00 mg, 1.50 μmol), EDPA (5.44 mg, 42.08 μmol), NMP (210 μl) and water (50 μl) was gently shaken for 5 min. at room temperature. To the resulting mixture was added a solution HOOC-(CH 2 ) 14 -COONSu (1.72 mg, 4.5 μmol) in NMP (43 μl), the reaction mixture was gently shaken for 5 min. at room temperature, and then allowed to stand for an additional 1 h at room temperature. The reaction was quenched by the addition of a solution of glycine (2.48 mg, 33 μmol) in 50% aqueous ethanol (248 μl). The reaction mixture was purified by column chromatography using a cyanopropyl column (Zorbax 300SB-CN) and a standard acetonitrile/TFA system. The column was heated to 65°C and the acetonitrile gradient was 0-100% in 60 minutes. The title compound (0.58 mg, 11 %) was isolated, and the product was analysed by PDMS. The m/z value for the protonated molecular ion was found to be 3596 ± 3. The resulting molecular weight is thus 3595 ± 3 amu (theoretical value 3595 amu). Example 27 Synthesis of lithocholic acid 2,5-dioxo-pyrrolidin-1-yl ester. To a mixture of lithocholic acid (5.44 g, 14.34 mmol), N-hydroxysuccinimide (1.78 g, 15.0 mmol), anhydrous THF (120 ml) and anhydrous acetonitrile (30 ml), kept at to 10 °C, was added a solution of N.N'-dicyclohexylcarbodiimide (3.44 g, 16.67 mmol) in anhydrous THF. The reaction mixture was stirred at ambient temperature for 16 h, filtered and concentrated in vacuo. The residue was dissolved in dichloromethane (450 ml), washed with a 10% aqueous Na 2 C0 3 solution (2x150 ml) and water (2x150 ml), and dried (MgS0 4 ). Filtered and the filtrate concentrated in vacuo to give a crystalline residue. The residue was recrystallised from a mixture of dichloromethane (30 ml) and n-heptane (30 ml to give the title compound (3.46 g, 51 %) as a crystalline solid. Example 28 Synthesis of Arg 34 Lys 25 (N E -lithocholyl)-GLP-1 (7-37)-OH. A mixture of Arg 34 -GLP-1(7-37)-OH (4.472 mg, 1.32 μmol), EDPA (4.78 mg, 36.96 μmol), NMP (94 μl) and water (44.8 μl) was gently shaken for 10 min. at room temperature. To the resulting mixture was added a solution of lithocholic acid 2,5-dioxo-pyrrolidin-1-yl ester (1.87 mg, 3.96 μmol) in NMP (46.8 μl), the reaction mixture was gently shaken for 5 min. at room temperature, and then allowed to stand for an additional 1 h at room temperature. The reaction was quenched by the addition of a solution of glycine (2.18 mg, 29.04 μmol) in 50% aqueous ethanol (218 μl). The reaction mixture was purified by column chromatography using a cyanopropyl column (Zorbax 300SB-CN) and a standard acetonitrile/TFA system. The column was heated to 65°C and the acetonitrile gradient was 0-100% in 60 minutes. The title compound (1.25 mg, 25 %) was isolated, and the product was analysed by PDMS. The m/z value for the protonated molecular ion was found to be 3744 +- 3. The resulting molecular weight is thus 3743 +- 3 amu (theoretical value 3743 amu). Example 29 Synthesis of N α -tetradecanoyl-Glu(ONSu)-OBu'. To a suspension of H-Glu(OH)-OBu' (2.5 g, 12.3 mmol), DMF (283 ml) and EDPA (1.58 g, 12.3 mmol) was added drop by drop a solution of Myr-ONSu (4.0 g, 12.3 mmol) in DMF (59 ml). The reaction mixture was stirred for 16 h at room temperature and then concentrated in vacuo to a total volume of 20 ml. The residue was partitioned between 5% aqueous citric acid (250 ml) and ethyl acetate (150 ml), and the phases were separated. The organic phase was concentrated in vacuo and the residue dissolved in DMF (40 ml). The resulting solution was added drop by drop to a 10% aqueous solution of citric acid (300 ml) kept at 0 °C. The precipitated compound was collected and washed with iced water and dried in a vacuum drying oven. The dried compound was dissolved in DMF (23 ml) and HONSu (1.5 g, 13 mmol) was added. To the resulting mixture was added a solution of N.N'-dicyclohexylcarbodiimide (2.44 g, 11.9 mmol) in dichloromethane (47 ml). The reaction mixture was stirred for 16 h at room temperature, and the precipitated compound was filtered off. The precipitate was recrystallised from n-heptane/2-propanol to give the title compound (3.03 g, 50%). Example 30 Synthesis of Glu 22 - 2330 Arg 26 ' 34 Lys 38 (N ε -(γ-glutamyl(N α -tetradecanoyl)))-GLP-1 (7-38)-OH. A mixture of Giu 22 ' 2330 Arg 26 :,4 Lys 38 -GLP-1 (7-38)-OH (1.0 mg, 0.272 μmol), EDPA (0.98 mg, 7.62 μmol), NMP (70 μl) and water (70 μl) was gently shaken for 5 min. at room temperature. To the resulting mixture was added a solution of N α -tetradecanoyl- Glu(ONSu)-OBu' , prepared as described in Example 29, (0.41 mg, 0.816 μmol) in NMP (10.4 μl), the reaction mixture was gently shaken for 5 min. at room temperature, and then allowed to stand for an additional 45 min. at room temperature. The reaction was quenched by the addition of a solution of glycine (0.448 mg, 5.98 μmol) in 50% aqueous ethanol (45 μl). A 0.5 % aqueous solution of ammonium acetate (0.9 ml) was added, and the resulting mixture was immobilised on a Varian 500 mg C8 Mega Bond Elut ® cartridge, the immobilised compound washed with 5% aqueous acetonitrile (10 ml), and finally liberated from the cartridge by eiutioπ with TFA (10 ml). The eluate was concentrated in vacuo. and the reaction mixture was purified by column chromatography using a cyanopropyl column (Zorbax 300SB-CN) and a standard acetonitrileTFA system. The column was heated to 65°C and the acetonitrile gradient was 0-100% in 60 minutes. The title compound (0.35 mg, 32 %) was isolated, and the product was analysed by PDMS. The m/z value for the protonated molecular ion was found to be 4012 ± 3. The resulting molecular weight is thus 401 1 ± 3 amu (theoretical value 401 1 amu). Example 31 Synthesis of Glu 23 - 26 Arg 3 Lys 38 (N E -(γ-glutamyl(N α -tetradecanoyl)))-GLP-1 (7-38)-OH. A mixture of Glu 23 ' 28 Arg 34 Lys 38 -GLP-1 (7-38)-OH (6.07 mg, 1.727 μmol), EDPA (6.25 mg, 48.36 μmol), NMP (425 μl) and water (425 μl) was gently shaken for 5 min. at room temperature. To the resulting mixture was added a solution of N etradecanoyl- Glu(ONSu)-OBu' , prepared as described in example 29, (2.65 mg, 5.18 μmol) in NMP (66.3 μl), the reaction mixture was gently shaken for 5 min. at room temperature, and then allowed to stand for an additional 45 min. at room temperature. The reaction was quenched by the addition of a solution of glycine (2.85 mg, 38.0 μmol) in 50% aqueous ethanol (285 μl). A 0.5 % aqueous solution of ammonium acetate (5.4 ml) was added, and the resulting mixture was immobilised on a Varian 500 mg C8 Mega Bond Elut ® cartridge, the immobilised compound washed with 5% aqueous acetonitrile (10 ml), and finally liberated from the cartridge by elution with TFA (10 ml). The eiuate was concentrated in vacuo. and the reaction mixture was purified by column chromatography using a cyanopropyl column (Zorbax 300SB-CN) and a standard acetonitrile/TFA system. The column was heated to 65°C and the acetonitrile gradient was 0-100% in 60 minutes. The title compound (0.78 mg, 12 %) was isolated, and the product was analysed by PDMS. The m/z value for the protonated molecular ion was found to be 3854 ± 3. The resulting molecular weight is thus 3853 ± 3 amu (theoretical value 3853 amu). Example 32 Synthesis of Lys 26 3 -bis(N E -(ω-carboxytridecanoyl))-GLP-1(7-37)-OH. A mixture of GLP-1 (7-37)-OH (30 mg, 8.9 μmol), EDPA (32.3 mg, 250 μmol), NMP (2.1 ml) and water (2.1 ml) was gently shaken for 5 min. at room temperature. To the resulting mixture was added a solution HOOC-(CH 2 ), 2 -COONSu (12.7 mg, 35.8 μmol) in NMP (318 μl), the reaction mixture was gently shaken for 1 h and 40 min. at room temperature. The reaction was quenched by the addition of a solution of glycine (3.4 mg, 44.7 μmol) in 50% aqueous ethanol (335 μl). The reaction mixture was purified by column chromatography using a cyanopropyl column (Zorbax 300SB-CN) and a standard acetonitrile/TFA system. The column was heated to 65°C and the acetonitrile gradient was 0-100% in 60 minutes. The title compound (10 mg, 29 %) was isolated, and the product was analysed by PDMS. The m/z value for the protonated molecular ion was found to be 3840 ± 3. The resulting molecular weight is thus 3839 ± 3 amu (theoretical value 3839 amu). Example 33 Synthesis of Lys 6 ' 3 -bis(N ε -(γ-glutamyl(N α -tetradecanoyl)))-GLP-1 (7-37)-OH. (NNC 90- 1167). A mixture of GLP-1 (7-37)-OH (300 mg, 79.8 μmol), EDPA (288.9 mg, 2.24 mmol), NMP (21 ml) and water (21 mi) was gently shaken for 5 min. at room temperature. To the resulting mixture was added a solution of N°-tetradecanoyl-Glu(ONSu)-OBu t , prepared as described in Example 29, (163 mg, 319.3 μmol) in NMP (4.08 ml), the reaction mixture was gently shaken for 5 min. at room temperature, and then allowed to stand for an additional 1 h at room temperature. The reaction was quenched by the addition of a solution of glycine (131 8 mg, 1 76 mmol) in 50% aqueous ethanol (13 2 ml) A 0 5 % aqueous solution of ammonium-acetate (250 ml) was added, and the resulting mixture was divided into four equal portions Each portion was eluted onto a Varian 500 mg C8 Mega Bond Elut ® cartridge, the immobilised compound washed with 0 1 % aqueous TFA (3 5 ml), and finally liberated from the cartridge by elution with 70% aqueous acetonitrile (4 ml) The combined eluates were diluted with 0 1 % aqueous TFA (300 ml) The precipitated compound was collected by centπfugation, washed with 0 1 % aqueous TFA (50 ml), and finally isolated by centπfugation To the precipitate was added TFA (60 ml), and the resulting reaction mixture was stirred for 1 h and 30 m at room temperature Excess TFA was removed in vacuo, and the residue was poured into water (50 ml) The precipitated compound was purified by column chromatography using a cyanopropyl column (Zorbax 300SB-CN) and a standard acetonitnle/TFA system The coiumn was heated to 65°C and the acetonitrile gradient was 0-100% in 60 minutes The title compound (27 3 mg, 8 %) was isolated, and the product was analysed by PDMS The m/z value for the protonated molecular ion was found to be 4036 ± 3 The resulting molecular weight is thus 4035 ± 3 amu (theoretical value 4035 amu) Example 34 Synthesis of Arg 2834 Lys 38 (N ε -(ω-carboxypentadecanoyl))-GLP-1 (7-38)-OH A mixture of Arg 634 Lys 38 -GLP-1 (7-38)-OH (30 mg, 8 9 μmol), EDPA (32 3 mg, 250 μmol), NMP (2 1 ml) and water (2 1 ml) was gently shaken for 5 mm at room temperature To the resulting mixture was added a solution HOOC-(CH 2 ) 14 -COONSu (13 7 mg, 35 8 μmol) in NMP (343 μl), the reaction mixture was gently shaken for 1 h at room temperature The reaction was quenched by the addition of a solution of glycine (3 4 mg, 44 7 μmol) in 50% aqueous ethanol (335 μl) The reaction mixture was purified by column chromatography using a cyanopropyl column (Zorbax 300SB-CN) and a standard acetonitnle/TFA system The column was heated to 65°C and the acetonitrile gradient was 0-100% in 60 minutes The title compound (4 8 mg, 14 %) was isolated, and the product was analysed by PDMS The m/z value for the protonated molecular ion was found to be 3894 + 3 The resulting molecular weight is thus 3893 ± 3 amu (theoretical value 3893 amu) Example 35 Synthesis of N α -hexadecanoyl-Glu(ONSu)-OBu' To a suspension of H-Glu(OH)-OBu' (4 2 g, 20 6 mmol), DMF (500 ml) and EDPA (2 65 g, 20 6 mmol) was added drop by drop a solution of Pal-ONSu (7 3 g, 20 6 mmol) in DMF (100 ml) The reaction mixture was stirred for 64 h at room temperature and then concentrated in vacuo to a total volume of 20 ml The residue was partitioned between 10% aqueous citric acid (300 ml) and ethyl acetate (250 ml), and the phases were separated The organic phase was concentrated in vacuo and the residue dissolved in DMF (50 ml) The resulting solution was added drop by drop to a 10% aqueous solution of citric acid (500 ml) kept at 0 °C The precipitated compound was collected and washed with iced water and dried in a vacuum drying oven The dried compound was dissolved in DMF (45 ml) and HONSu (2 15 g, 18 7 mmol) was added To the resulting mixture was added a solution of N,N'-dιcyclohexylcarbodιιmιde (3 5 g, 17 mmol) in dichloromethane (67 ml) The reaction mixture was stirred for 16 h at room temperature, and the precipitated compound was filtered off The precipitate was recrystallised from n-heptane/2-propanol to give the title compound (6 6 g, 72%) Example 36 Synthesis of Lys 2634 -bιs(N E -(γ-glutamyl(N°-hexadecanoyl)))-GLP-1 (7-37)-OH A mixture of GLP-1 (7-37)-OH (10 mg, 2 9 μmol), EDPA (10 8 mg, 83 4 μmol), NMP (0 7 ml) and water (0 7 ml) was gently shaken for 5 mm at room temperature To the resulting mixture was added a solution of N α -hexadecanoyl-Glu(ONSu)-OBu' , prepared as described in Example 33, (163 mg, 319 3 μmol) in NMP (4 08 ml), the reaction mixture was gently shaken 1 h and 20 mm at room temperature The reaction was quenched by the addition of a solution of glycine (4 9 mg, 65 6 μmol) in 50% aqueous ethanol (492 μl) A 0 5 % aqueous solution of ammonium-acetate (9 ml) was added, and the resulting mixture eluted onto a Varian 1g C8 Mega Bond Elut ® cartridge, the immobilised compound washed with 5% aqueous acetonitrile (10 ml), and finally liberated from the cartridge by elution with TFA (10 ml) The eluate was concentrated in vacuo, and the residue purified by column chromatography using a cyanopropyl column (Zorbax 300SB-CN) and a standard acetonitnle/TFA system The column was heated to 65°C and the acetonitrile gradient was 0-100% in 60 minutes. The title compound (2.4 mg, 20 %) was isolated, and the product was analysed by PDMS. The m/z value for the protonated molecular ion was found to be 4092 ± 3 The resulting molecular weight is thus 4091 ± 3 amu (theoretical value 4091 amu). Example 37 Synthesis of Arg 3 Lys 26 (N r -(γ-glutamyl(N α -hexadecanoyl)))-GLP-1 (7-37)-OH. A mixture of Arg 34 -GLP-1 (7-37)-OH (3 7 mg, 1 1 μmol), EDPA (4.0 mg, 30.8 μmol), acetonitrile (260 μl) and water (260 μl) was gently shaken for 5 mm. at room temperature. To the resulting mixture was added a solution of N α -hexadecanoyl-Glu(ONSu)-OBu l , prepared as described in Example 35, (1.8 mg, 3.3 μmol) in acetonitrile (44.2 μl), and the reaction mixture was gently shaken for 1 h and 20 mm. at room temperature The reaction was quenched by the addition of a solution of glycine (1.8 mg, 24 2 μmol) in 50% aqueous ethanol (181 μl). A 0.5 % aqueous solution of ammonium-acetate (12 ml) and NMP (300 μl) were added, and the resulting mixture eluted onto a Varian 1g C8 Mega Bond Elut ® cartridge, the immobilised compound washed with 5% aqueous acetonitrile (10 ml), and finally liberated from the cartridge by elution with TFA (6 ml) The eluate was allowed to stand for 2 h at room temperature and then concentrated in vacuo The residue was purified by column chromatography using a cyanopropyl column (Zorbax 300SB-CN) and a standard acetonitnle/TFA system The column was heated to 65°C and the acetonitrile gradient was 0-100% in 60 minutes. The title compound (0 23 mg, 6 %) was isolated, and the product was analysed by PDMS. The m/z value for the protonated molecular ion was found to be 3752 ± 3. The resulting molecular weight is thus 3751 ± 3 amu (theoretical value 3751 amu). Example 38 Synthesis of Arg 263 Lys 38 (N E -(γ-glutamyl(N α -tetradecanoyl)))-GLP-1 (7-38)-OH. A mixture of Arg β 34 Lys 38 -GLP-1 (7-38)-OH (14 mg, 4.0 μmol), EDPA (14.3 mg, 1 10.6 μmol), NMP (980 μl) and water (980 μl) was gently shaken for 5 mm. at room temperature. To the resulting mixture was added a solution of N α -tetradecanoyl-Glu(ONSu)-OBu' , prepared as described in Example 29, (12.1 mg, 23.7 μmol) in NMP (303 μl), and the reaction mixture was gently shaken for 2 h at room temperature The reaction was quenched by the addition of a solution of glycine (6.5 mg, 86.9 mmol) in 50% aqueous ethanol (652 μl). A 0.5 % aqueous solution of ammonium-acetate (50 ml) was added, and the resulting mixture eluted onto a Varian 1 g C8 Mega Bond Elut ® cartridge, the immobilised compound washed with 5% aqueous acetonitrile (15 ml), and finally liberated from the cartridge by elution with TFA (6 ml) The eluate was allowed to stand for 1 h and 45 mm. at room temperature and then concentrated in vacuo. The residue was purified by column chromatography using a cyanopropyl column (Zorbax 300SB-CN) and a standard acetonitnle TFA system. The column was heated to 65°C and the acetonitrile gradient was 0-100% in 60 minutes. The title compound (3.9 mg, 26 %) was isolated, and the product was analysed by PDMS. The m/z value for the protonated molecular ion was found to be 3881 ± 3. The resulting molecular weight is thus 3880 ± 3 amu (theoretical value 3880 amu). Example 39 Synthesis of Arg 2634 Lys 38 (N ε -(ω-carboxypentadecanoyl))-GLP-1 (7-38)-OH. A mixture of Arg 26 34 Lys 38 -GLP-1 (7-38)-OH (14 mg, 4.0 μmol), EDPA (14.3 mg, 11 1 μmol), NMP (980 μl) and water (980 μl) was gently shaken for 5 min. at room temperature. To the resulting mixture was added a solution of HOOC-(CH 2 ) 14 -COONSu (4.5 mg, 11.9 μmol) in NMP (1 14 μl), the reaction mixture was gently shaken for 1 h and 45 mm. at room temperature An additional solution of HOOC-(CH 2 ), 4 -COONSu (4.0 mg, 10 4 μmol) in NMP (100 μl) was added, and the resulting mixture was gently shaken for an additional 1 h and 30 mm. at room temperature. The reaction was quenched by the addition of a solution of glycine (1.5 mg, 19.8 μmol) in 50% aqueous ethanol (148 μl). The reaction mixture was purified by column chromatography using a cyanopropyl column (Zorbax 300SB-CN) and a standard acetonitrile/TFA system The column was heated to 65°C and the acetonitrile gradient was 0-100% in 60 minutes. The title compound (3.9 mg, 26 %) was isolated, and the product was analysed by PDMS. The m/z value for the protonated molecular ion was found to be 3809 ± 3. The resulting molecular weight is thus 3808 ± 3 amu (theoretical value 3808 amu). Example 40 Synthesis of Arg 2634 Lys 38 (N ε -(γ-glutamyl(N α -hexadecanoyl)))-GLP-1 (7-38)-OH. A mixture of Arg 2834 Lys 38 -GLP-1(7-38)-OH (14 mg, 4.0 μmol), EDPA (14.3 mg, 110.6 μmol), NMP (980 μl) and water (980 μl) was gently shaken for 5 min. at room temperature. To the resulting mixture was added a solution of N α -hexadecanoyl-Glu(ONSu)-OBu' , prepared as described in Example 35, (6.4 mg, 11.9 μmol) in NMP (160 μl), and the reaction mixture was gently shaken for 1 h and 20 min. at room temperature. The reaction was quenched by the addition of a solution of glycine (6.5 mg, 87 mmol) in 50% aqueous ethanol (653 μl). A 0.5 % aqueous solution of ammonium-acetate (50 ml) was added, and the resulting mixture eluted onto a Varian 1g C8 Mega Bond Elut ® cartridge, the immobilised compound washed with 5% aqueous acetonitrile (10 ml), and finally liberated from the cartridge by elution with TFA (6 ml). The eluate was allowed to stand for 1 h and 30 min. at room temperature and then concentrated in vacuo. The residue was purified by column chromatography using a cyanopropyl column (Zorbax 300SB-CN) and a standard acetonitrile/TFA system. The column was heated to 65°C and the acetonitrile gradient was 0-100% in 60 minutes. The title compound (7.2 mg, 47 %) was isolated, and the product was analysed by PDMS. The m/z value for the protonated molecular ion was found to be 3881 ± 3. The resulting molecular weight is thus 3880 ± 3 amu (theoretical value 3880 amu). Example 41 Synthesis of Arg ,8232630 ' 34 Lys 38 (N ε -hexadecanoyl)-GLP-1(7-38)-OH. A mixture of Arg ,823 ' 26 ' 30 - 34 Lys 38 -GLP-1(7-38)-OH (1.0 mg, 0.27 μmol), EDPA (0.34 mg, 2.7 μmoi) and DMSO (600 μl) was gently shaken for 5 min. at room temperature. To the resulting mixture was added a solution of Pal-ONSu (0.28 mg, 0.8 μmol) in NMP (7 μl). The reaction mixture was gently shaken for 5 min. at room temperature, and then allowed to stand for an additional 6 h at room temperature. The reaction was quenched by the addition of a solution of glycine (1.6 mg, 21.7 μmol) in 50% aqueous ethanol (163 μl). The reaction mixture was purified by column chromatography using a cyanopropyl column (Zorbax 300SB-CN) and a standard acetonitrile/TFA system. The column was heated to 65°C and the acetonitrile gradient was 0-100% in 60 minutes. The title compound ( 0.17 mg, 16 %) was isolated, and the product was analysed by MALDI-MS. The m/z value for the protonated molecular ion was found to be 3961 ± 3. The resulting molecular weight is thus 3960 ± 3 amu (theoretical value 3960 amu). Example 42 Synthesis of Arg 2δ ' 34 Lys 38 (N ε -(ω-carboxytridecanoyl))-GLP-1 (7-38)-OH. A mixture of Arg 6 34 Lys 38 -GLP-1 (7-38)-OH (14 mg, 4.0 μmol), EDPA (14.3 mg, 11 1 μmol), NMP (980 μl) and water (980 μl) was gently shaken for 5 min. at room temperature. To the resulting mixture was added a solution of HOOC-(CH 2 ) 12 -COONSu (4.2 mg, 11.9 μmol) in NMP (105 μl), the reaction mixture was gently shaken for 1 h and 50 min. at room temperature. The reaction was quenched by the addition of a solution of glycine (6.5 mg, 87 μmol) in 50% aqueous ethanol (652 μl). The reaction mixture was purified by column chromatography using a cyanopropyl column (Zorbax 300SB-CN) and a standard acetonitrileTFA system. The column was heated to 65°C and the acetonitrile gradient was 0-100% in 60 minutes. The title compound (5.8 mg, 39 %) was isolated, and the product was analysed by MALDI-MS. The m/z value for the protonated molecular ion was found to be 3780 ± 3. The resulting molecular weight is thus 3779 ± 3 amu (theoretical value 3781 amu). Example 43 Synthesis of Arg 3 Lys 26 (N ε -(γ-glutamyl(N' etradecanoyl)))-GLP-1 (7-37)-OH. A mixture of Arg 34 -GLP-1 (7-37)-OH (15 mg, 4.4 μmol), EDPA (16 mg, 124 μmol), NMP (2 ml) and water (4.8 ml ) was gently shaken for 5 min. at room temperature. To the resulting mixture was added a solution of N°-tetradecanoyl-Glu(ONSu)-OBu' , prepared as described in Example 29, (12.1 mg, 23.7 μmol) in NMP (303 μl), and the reaction mixture was gently shaken for 2 h at room temperature. The reaction was quenched by the addition of a solution of glycine (6.5 mg, 86.9 μmol) in 50% aqueous ethanol (652 μl). A 0.5 % aqueous solution of ammonium-acetate (50 ml) was added, and the resulting mixture eluted onto a Varian 1g C8 Mega Bond Elut ® cartridge, the immobilised compound washed with 5% aqueous acetonitrile (15 ml), and finally liberated from the cartridge by elution with TFA (6 ml). The eluate was allowed to stand for 1 h and 45 min. at room temperature and then concentrated in vacuo. The residue was purified by column chromatography using a cyanopropyl column (Zorbax 300SB-CN) and a standard acetonitrileTFA system. The column was heated to 65°C and the acetonitrile gradient was 0-100% in 60 minutes. The title compound (3.9 mg, 26 %) was isolated, and the product was analysed by MALDI-MS. The m/z value for the protonated molecular ion was found to be 3723 ± 3 The resulting molecular weight is thus 3722 ± 3 amu (theoretical value 3723 amu). Example 44 Synthesis of N α -octadecanoyl-Glu(ONSu)-OBu'. To a suspension of H-Glu(OH)-OBu' (2.82 g, 13.9 mmol), DMF (370 ml) and EDPA (1.79 g, 13.9 mmol) was added drop by drop a solution of Ste-ONSu (5.3 g, 13.9 mmol) in DMF (60 ml). Dichloromethane (35 ml) was added, and the reaction mixture was stirred for 24 h at room temperature and then concentrated in vacuo The residue was partitioned between 10% aqueous citric acid (330 ml) and ethyl acetate (200 ml), and the phases were separated. The organic phase was concentrated in vacuo and the residue dissolved in DMF (60 ml). The resulting solution was added drop by drop to a 10% aqueous solution of citric acid (400 ml) kept at 0 °C. The precipitated compound was collected and washed with iced water and dried in a vacuum drying oven The dried compound was dissolved in DMF (40 ml) and HONSu (1.63 g, 14.2 mmol) was added To the resulting mixture was added a solution of DCC (2.66 g, 12.9 mmol) in dichloromethane (51 ml). The reaction mixture was stirred for 64 h at room temperature, and the precipitated compound was filtered off. The precipitate was recrystallised from n-heptane/2-propanol to give the title compound (4.96 g, 68 %). Example 45 Synthesis of Arg 2834 Lys 38 (N ε -(γ-glutamyl(N α -octadecanoyl)))-GLP-1 (7-38)-OH A mixture of Arg 2β ' 34 -GLP-1(7-38)-OH (28 mg, 7.9 μmol), EDPA (28.6 mg, 221.5 μmol), NMP (1.96 ml) and water (1.96 ml ) was gently shaken for 5 m . at room temperature. To the resulting mixture was added a solution of N α -octadecanoyl-Glu(ONSu)-OBu l (17.93 g, 31.6 μmol), prepared as described in Example 44, in NMP (448 μl), and the reaction mixture was gently shaken for 2 h at room temperature. The reaction was quenched by the addition of a solution of glycine (13.1 mg, 174 μmol) in 50% aqueous ethanol (1.3 ml). A 0.5 % aqueous solution of ammonium-acetate (120 ml) was added, and the resulting mixture was divided into two equal portions. Each portion was eluted onto a Varian 5 g C8 Mega Bond Elut ® cartridge, the immobilised compound washed with 5% aqueous acetonitrile (25 ml), and finally liberated from the cartridge by elution TFA (25 ml). The combined eluates were allowed to stand for 1 h and 25 min. at room temperature and then concentrated in vacuo. The residue was purified by column chromatography using a cyanopropyl column (Zorbax 300SB-CN) and a standard acetonitrile/TFA system. The column was heated to 65°C and the acetonitrile gradient was 0-100% in 60 minutes. The title compound (3.6 mg, 11 %) was isolated, and the product was analysed by MALDI-MS. The m/z value for the protonated molecular ion was found to be 3940 ± 3. The resulting molecular weight is thus 3939 ± 3 amu (theoretical value 3937 amu). BIOLOGICAL FINDINGS Protraction of GLP-1 derivatives after s.c. administration The protraction of a number GLP-1 derivatives of the invention was determined by monitoring the concentration thereof in plasma after sc administration to healthy pigs, using the method described below. For comparison also the concentration in plasma of GLP-1 (7-37) after sc. administration was followed. The results are given in Table 1. The protraction of other GLP-1 derivatives of the invention can be determined in the same way. Pigs (50% Duroc, 25% Yorkshire, 25% Danish Landrace, app 40 kg) were fasted from the beginning of the experiment. To each pig 0.5 nmol of test compound per kg body weight was administered in a 50 μM isotonic solution (5 mM phosphate, pH 7.4, 0.02% Tween ® - 20 (Merck), 45 mg/ml mannitol (pyrogen free, Novo Nordisk). Blood samples were drawn from a catheter in vena juguiaris at the hours indicated in Table 1. 5 ml of the blood samples were poured into chilled glasses containing 175 μl of the following solution: 0.18 M EDTA, 1500 KIE/ml aprotinin (Novo Nordisk) and 3% bacitracin (Sigma), pH 7.4. Within 30 min, the samples were centrifuged for 10 min at 5-6000 * g. Temperature was kept at 4°C. The supernatant was pipetted into different glasses and kept at minus 20°C until use. The plasma concentrations of the peptides were determined by RIA using a monoclonal antibody specific for the N-terminal region of GLP-1 (7-37). The cross reactivities were less than 1 % with GLP-1 (1 -37) and GLP-1 (8-36)amιde and < 0 1 % with GLP-1 (9-37), GLP- 1 (10-36)amιde and GLP-1 (1 1 -36)amιde The entire procedure was carried out at 4°C The assay was carried out as follows 100 μl plasma was mixed with 271 μl 96% ethanol, mixed using a vortex mixer and centrifuged at 2600 * g for 30 mm The supernatant was decanted into Mmisorp tubes and evaporated completely (Savant Speedvac AS290) The evaporation residue was reconstituted in the assay buffer consisting of 80 mM NaH 2 P0 4 /Na 2 HP0 4l 0 1 % HSA (Orpha 20/21 , Behπng), 10 mM EDTA, 0 6 mM thiomersai (Sigma), pH 7 5 Samples were reconstituted in volumes suitable for their expected concentrations, and were allowed to reconstitute for 30 mm To 300 μi sample, 100 μl antibody solution in dilution buffer containing 40 mM NaH 2 P0 4 /Na 2 HP0 4 , 0 1 % HSA, 0 6 mM thiomersai, pH 7 5, was added A non-specific sample was prepared by mixing 300 μl buffer with 100 μl dilution buffer Individual standards were prepared from freeze dried stocks, dissolved in 300 μl assay buffer All samples were pre-incubated in Mmisorp tubes with antibody as described above for 72 h 200 μl tracer in dilution buffer containing 6-7000 CPM was added, samples were mixed and incubated for 48 h 1 5 ml of a suspension of 200 ml per litre of hepaπn-stabilised bovine plasma and 18 g per litre of activated carbon (Merck) in 40 mM NaH 2 P0 4 /Na 2 HP0 4 , 0 6 mM thiomersai, pH 7 5, was added to each tube Before use, the suspension was mixed and allowed to stand for 2 h at 4°C All samples were incubated for 1 h at 4°C and then centrifuged at 3400 * g for 25 mm Immediately after the centπfugation, the supernatant was decanted and counted in a γ- counter The concentration in the samples was calculated from individual standard curves The following plasma concentrations were found, calculated as % of the maximum concentration for the individual compounds (n=2) Table 1 " 'The test compounds are the title compounds of the examples with the numbers given As it appears from Table 1 , the GLP-1 derivatives of the invention have a protracted profile of action relative to GLP-1 (7-37) and are much more persistent in plasma than GLP-1 (7- 37). It also appears from Table 1 that the time at which the peak concentration in plasma is achieved varies within wide limits, depending on the particular GLP-1 derivative selected. Stimulation of cAMP formation in a cell line expressing the cloned human GLP-1 receptor In order to demonstrate efficacy of the GLP-1 derivatives, their ability to stimulate formation of cAMP in a cell line expressing the cloned human GLP-1 receptor was tested. An EC 50 was calculated from the dose-response curve. Baby hamster kidney (BHK) cells expressing the human pancreatic GLP-1 receptor were used (Knudsen and Pridal, 1996, Eur. J. Pharm. 318, 429-435). Plasma membranes were prepared (Adelhorst et al, 1994, J. Biol. Chem. 269, 6275) by homogenisation in buffer (10 mmol/l Tris-HCI and 30 mmol/l NaCl pH 7.4, containing, in addition, 1 mmol/I dithiothreitol, 5 mg/l leupeptin (Sigma, St. Louis, MO, USA), 5 mg/l pepstatin (Sigma, St. Louis, MO, USA), 100 mg/l bacitracin (Sigma, St. Louis, MO, USA), and 16 mg/l aprotinin (Novo Nordisk A/S, Bagsvaerd, Denmark)). The homogenate was centrifuged on top of a layer of 41 w/v% sucrose. The white band between the two iayers was diluted in buffer and centrifuged. Plasma membranes were stored at -80°C until used. The assay was carried out in 96-weil microtiter plates in a total volume of 140 μl. The buffer used was 50 mmol/l Tris-HCI, pH 7.4 with the addition of 1 mmol/l EGTA, 1.5 mmol/l MgS0 4l 1.7 mmol/l ATP, 20 mM GTP, 2 mmol/l 3-isobutyl-1-methylxanthine, 0.01 % Tween-20 and 0.1 % human serum albumin (Reinst, Behringwerke AG, Marburg, Germany). Compounds to be tested for agonist activity were dissolved and diluted in buffer, added to the membrane preparation and the mixture was incubated for 2 h at 37°C. The reaction was stopped by the addition of 25 μl of 0.05 mol/l HCl. Samples were diluted 10 fold before analysis for cAMP by a scintillation proximity assay (RPA 538, Amersham, UK). The following results were found: " ' The test compounds are the title compounds of the examples with the numbers given.

Claims: CLAIMS 1 A GLP-1 derivative wherein at least one am o acid residue of the parent peptide has a lipophilic substituent attached with the proviso that if oniy one lipophilic substituent is present and this substituent is attached to the N-terminal or to the C-terminal ammo acid residue of the parent peptide then this substituent is an alkyl group or a group which has an ω-carboxylic acid group 2 A GLP-1 derivative according to claim 1 , wherein only one lipophilic substituent is present 3 A GLP-1 derivative according to claim 2, wherein the lipophilic substituent is attached to the N-terminal ammo acid residue 4 A GLP-1 derivative according to claim 2, wherein the lipophilic substituent is attached to the C-terminal ammo acid residue 5 A GLP-1 derivative according to claim 2, wherein the lipophilic substituent is attached to an am o acid residue which is not the N-terminal or C-terminal ammo acid residue 6 A GLP-1 derivative according to claim 1 , wherein two lipophilic substituents are present 7 A GLP-1 derivative according to claim 6, wherein one of the lipophilic substituents is attached to the N-terminal am o acid residue while the other is attached to the C-termmal am o acid residue 8 A GLP-1 derivative according to claim 6, wherein one of the lipophilic substituents is attached to the C-terminal ammo acid residue while the other is attached to an am o acid residue which is not the N-terminal or C-terminal ammo acid residue 9 A GLP-1 derivative according to ciaim 6, wherein both lipophilic substituents are attached to ammo acid residues which are neither the N-terminal nor the C-terminal amino acid residue 10 A deπvative of GLP-1 (7-C), wherein C is selected from the group comprising 38, 39, 40, 41 , 42, 43, 44 and 45 which derivative has just one lipophilic substituent which is attached to the C-terminal amino acid residue. 1 1.A GLP-1 derivative according to any one of the preceding claims, wherein the lipophilic substituent comprises from 4 to 40 carbon atoms, more preferred from 8 to 25 carbon atoms. 12.A GLP-1 derivative according to any one of the preceding claims, wherein a 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. 13. A GLP-1 derivative according to any one of the claims 1-1 1 , wherein a 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. 14.A GLP-1 derivative according to any one of the preceding claims, wherein the lipophilic substituent is attached to the parent peptide by means of a spacer. 15.A GLP-1 derivative according to ciaim 14, wherein the spacer is an unbranched alkane α,ω-dicarboxylic acid group having from 1 to 7 methylene groups, preferably two methylene groups, which form a bridge between an amino group of the parent peptide and an amino group of the lipophilic substituent. 16.A GLP-1 derivative according to claim 14, wherein the spacer is an amino acid residue except Cys, or a dipeptide such as Gly-Lys. 17. A GLP-1 derivative according to claim 16, wherein a carboxyl group of the parent peptide forms an amide bond with an amino group of Lys or a dipeptide containing a Lys residue, and the other amino group of the Lys spacer or a dipeptide spacer containing a Lys residue forms an amide bond with a carboxyl group of the lipophilic substituent. 18. A GLP-1 derivative according to ciaim 16, wherein an amino group of the parent peptide forms an amide bond with a carboxylic group of the amino acid residue or dipeptide spacer, and an am o group of the ammo acid residue or dipeptide spacer forms an amide bond with a carboxyl group of the lipophilic substituent A GLP-1 derivative according to claim 16, wherein a carboxyl group of the parent peptide forms an amide bond with an ammo group of the am o acid residue spacer or dipeptide spacer, and a carboxyi group of the ammo acid residue spacer or dipeptide spacer forms an amide bond with an am o group of the lipophilic substituent A GLP-1 derivative according to claim 16, wherein a carboxyl group of the parent peptide forms an amide bond with an am o group of a spacer which is Asp or Glu, or a dipeptide spacer containing an Asp or Glu residue, and a carboxyl group of the spacer forms an amide bond with an ammo group of the lipophilic substituent A GLP-1 derivative according to any one of the preceding claims, wherein the lipophilic substituent comprises a partially or completely hydrogenated cyclopentanophenathrene skeleton A GLP-1 derivative according to any of the claims 1 -20, wherein the lipophilic substituent is an straight-chain or branched alkyl group A GLP-1 derivative according to any of the claims 1-20 wherein the lipophilic substituent is the acyl group of a straight-chain or branched fatty acid A GLP-1 derivative according to claim 23 wherein the acyl group is selected from the group comprising CH 3 (CH 2 ) n CO-, wherein n is 4 to 38, preferably CH 3 (CH 2 ) 6 CO-, CH 3 (CH 2 ) β CO-, CH 3 (CH 2 ), 0 CO-, CH 3 (CH 2 ) 12 CO-, CH 3 (CH 2 ) 14 CO-, CH 3 (CH 2 ) 16 CO-, CH 3 (CH 2 ) 18 CO-, CH 3 (CH 2 ) 20 CO- and CH^CH^CO- A GLP-1 derivative according to any one of the claims 1 -20 wherein the lipophilic substituent is an acyl group of a straight-chain or branched alkane α,ω-dιcarboxylιc acid A GLP-1 derivative according to claim 25 wherein the acyl group is selected from the group comprising HOOC(CH 2 ) m CO-, wherein m is from 4 to 38, preferably from 4 to 24, more preferred selected from the group comprising HOOC(CH 2 ), 4 CO-, HOOC(CH 2 ) 1β CO-, HOOC(CH 2 ) 18 CO-, HOOC(CH 2 ) 20 CO- and HOOC(CH 2 ) 22 CO- 7 A GLP-1 derivative according to any one of the claims 1-20, wherein the lipophilic substituent is a group of the formula CH 3 (CH 2 ) p ((CH 2 ) q COOH)CHNH-CO(CH 2 ) 2 CO-, wherein p and q are integers and p+q is an integer of from 8 to 33, preferably from 12 to 28 8 A GLP-1 derivative according to any one of the claims 1-20, wherein the lipophilic substituent is a group of the formula CH 3 (CH 2 ) r CO-NHCH(COOH)(CH 2 ) 2 CO-, wherein r is an integer of from 10 to 24 9 A GLP-1 deπvative according to any one of the claims 1-20, wherein the lipophilic substituent is a group of the formula CH 3 (CH 2 ) S CO-NHCH((CH 2 ) 2 COOH)CO-, wherein s is an integer of from 8 to 24 30 A GLP-1 derivative according to any one of the claims 1-20, wherein the lipophilic substituent is a group of the formula -NHCH(COOH)(CH 2 ) 4 NH-CO(CH 2 ) u CH 3 , wherein u is an integer of from 8 to 18 31 A GLP-1 derivative according to any one of the claims 1-20, wherein the lipophilic substituent is a group of the formula -NHCH(COOH)(CH 2 ) 4 NH-COCH((CH 2 ) 2 COOH)NH- CO(CH 2 ) w CH 3 , wherein w is an integer of from 10 to 16 32 A GLP-1 deπvative according to any one of the claims 1-20, wherein the lipophilic substituent is a group of the formula -NHCH(COOH)(CH 2 ) 4 NH-CO(CH 2 ) 2 CH(COOH)NH- CO(CH 2 ) x CH 3 , wherein x is an integer of from 10 to 16 33 A GLP-1 derivative according to any one of the claims 1-20, wherein the lipophilic substituent is a group of the formula -NHCH(COOH)(CH 2 ) 4 NH-CO(CH 2 ) 2 CH(COOH)NH- CO(CH 2 ) y CH 3 , wherein y is zero or an integer of from 1 to 22 34 A GLP-1 derivative according to any of claims 1-33, wherein the parent peptide is selected from the group comprising GLP-1 (1-45) or an analogue or a fragment thereof 35 A GLP-1 (A-B) derivative according to any one of the claims 1-33 wherein A is an integer from 1 to 7 and B is an integer from 38 to 45 or an analogue thereof comprising one lipophilic substituent attached to the C-terminai am o acid residue and, optionally, a second lipophilic substituent attached to one of the other ammo acid residues 36 A GLP-1 derivative according to claim 34, wherein the parent peptide is selected from the group comprising GLP-1 (7-35), GLP-1 (7-36), GLP-1 (7-36)amιde, GLP-1 (7-37), GLP-1 (7- 38), GLP-1 (7-39), GLP-1 (7-40) and GLP-1 (7-41 ) and an analogue thereof 37 A GLP-1 derivative according to claim 34, wherein the parent peptide is selected from the group comprising GLP-1 (1-35), GLP-1 (1-36), GLP-1 (1-36)amιde, GLP-1 (1-37), GLP-1 (1- 38), GLP-1 (1-39), GLP-1 (1-40), GLP-1 (1-41 ) and an analogue thereof 38 A GLP-1 derivative according to any of the preceding claims wherein the designation analogue comprises derivatives wherein a total of up to fifteen, preferably up to ten ammo acid residues have been exchanged with any α-amino acid residue 39 A GLP-1 derivative according to any of the preceding claims wherein the designation analogue comprises derivatives wherein a total of up to fifteen, preferably up to ten ammo acid residues have been exchanged with any α-amino acid residue which can be coded for by the genetic code 40 A GLP-1 derivative according to any of the preceding claims wherein the designation analogue comprises derivatives wherein a total of up to six ammo acid residues have been exchanged with any α-amino acid residue which can be coded for by the genetic code 41 A GLP-1 deπvative according to any of the preceding claims, wherein the parent peptide is selected from the group comprising Arg 28 -GLP-1 (7-37), Arg 34 -GLP-1 (7-37), Lys 36 -GLP- 1 (7-37), Arg 26 "Lys∞-GLP-I (7-37), Arg 2β 4 Lys 38 GLP-1 (7-38), Arg 26 ^Lys∞-GLP-I (7-39), Arg 28 ^Lys^-GLP-I (7-40), Arg 2β Lys 36 -GLP-1(7-37), Arg 34 Lys 3β -GLP-1 (7-37), Arg 26 Lys 39 - GLP-1 (7-39), Arg 34 Lys 40 -GLP-1 (7-40), Arg 28 ^Lys ^-GLP-I (7-39), Arg 2634 Lys 36 0 -GLP- 1 (7-40), Gly 8 Arg26-GLP-1 (7-37), Gly 8 Arg 3 -GLP-1 (7-37), Gly 8 Lys 36 -GLP- 1 (7-37), Gly 8 Arg 26 ^Lys^-GLP-I (7-37), Gly 8 Arg 2β ^Lys∞-GLP-I (7-39), Gly 8 Arg 26 ^Lys^-GLP-I (7- 40), Gly 8 Arg 26 Lys 36 -GLP-1(7-37), Gly 8 Arg 34 Lys 36 -GLP-1(7-37), Gly 8 Arg 26 Lys 39 -GLP-1 (7-39), Gly 8 Arg 34 Lys 40 -GLP-1(7-40), Gly 8 Arg 2634 Lys 3639 -GLP-1(7-39) and Gly 8 Arg 2634 Lys 36 0 -GLP- 1(7-40) 42 A GLP-1 derivative according to any of the claims 1-40, wherein the parent peptide is selected from the group comprising Arg 28 "Lys^GLP-l (7-38), Arg 263 Lys 39 GLP-1 (7-39), Arg 26 M Lys 0 GLP-1 (7-40), Arg 2β 4 Lys 41 GLP-1(7-41), Arg 26 M Lys 2 GLP-1 (7-42), Arg 2634 Lys 3 GLP-1 (7-43), Arg 26 "Lys^GLP-l (7-44), Arg 26 "Lys^GLP-l (7-45), Arg 26 M Lys M GLP-1 (1-38), Arg 2β34 Lys 39 GLP-1(1-39), Arg 26 ^Lys^GLP-^ 1-40), Arg 26 M Lys 41 GLP-1 (1-41), Arg 2634 Lys 2 GLP-1(1-42), Arg 28 "Lys^GLP-l (1-43), Arg 63 Lys 44 GLP-1(1-44), Arg 28 ^Lys^GLP-l (1-45), Arg 2β34 Lys 38 GLP-1(2-38), Arg 26 "Lys∞GLP-l (2-39), Arg 26 ^Lys^GLP- 1(2-40), Arg 26 M Lys 41 GLP-1 (2-41), Arg 2634 Lys 42 GLP-1 (2-42), Arg 2β34 Lys 43 GLP-1 (2-43), Arg 2β34 Lys 4 GLP-1 (2-44), Arg 26 M Lys 45 GLP-1 (2-45), Arg 26 ^Lys^LP-l (3-38), Arg 26 ^Lys∞GLP-l (3-39), Arg 2B34 Lys 40 GLP-1(3-40), Arg 26 M Lys 4, GLP-1 (3-41), Arg 26 M Lys 42 GLP-1 (3-42), Arg 26 ^Lys^GLP-l (3-43), Arg 26 "Lys^GLP- 1(3-44), Arg 26 M Lys 45 GLP-1 (3-45), Arg 2634 Lys 3β GLP-1 (4-38), Arg 263 Lys 39 GLP-1 (4-39), Arg 2634 Lys 40 GLP-1 (4-40), Arg 26 ^Lys 41 GLP-1 (4-41 ), Arg 2834 Lys 42 GLP-1 (4-42), Arg 26 ^Lys^GLP-l (4-43), Arg 26 "Lys^GLP-l (4-44), Arg 2634 Lys 45 GLP-1 (4-45), Arg 26 "Lys∞GLP-l (5-38), Arg 26 M Lys 39 GLP-1 (5-39), Arg 26 "Lys^GLP-l (5-40), Arg 26 ""Lys 41 GLP-1 (5-41), Arg 263 Lys 42 GLP-1 (5-42), Arg 26 ^Lys^GLP-l (5-43), Arg 2634 Lys 44 GLP-1 (5-44), Arg 26 M Lys 5 GLP-1 (5-45), Arg 26 "Lys∞GLP-l (6-38), Arg 26 ^Lys^GLP-l (6-39), Arg 28 "Lys^GLP-l (6-40), Arg 26 Lys 4, GLP-1(6-41), Arg 26 ^Lys^GLP-l (6-42), Arg 2β3 Lys 3 GLP-1 (6-43), Arg 2β34 Lys GLP-1 (6-44), Arg 2634 Lys 45 GLP-1 (6-45), Arg 26 Lys M GLP-1(1-38), Arg a4 Lys M GLP-1(1-38), Arg 263 Lys 3β3β GLP-1 (1-38), Arg 26 Lys 38 GLP-1 (7-38), Arg^Lys^GLP-l (7-38), Arg 26 Lys 3638 GLP-1 (7-38), Arg 2834 Lys 38 GLP-1 (7-38), Arg 26 Lys 39 GLP-1 ( 1 -39), Arg 34 Lys 9 GLP-1 (1 -39), Arg 2634 Lys 3β39 GLP-1(1-39), Arg 26 Lys 39 GLP-1(7-39), Arg 34 Lys 39 GLP-1(7-39) and Arg 28 "Lys^GLP-l (7-39). 43 A pharmaceutical composition comprising a GLP-1 derivative according to the present invention and a pharmaceutically acceptable vehicle or carrier 44 Use of a GLP-1 derivative according to the present invention for the preparation of a medicament which has a protracted profile of action relative to GLP-1 (7-37) 45. Use of a GLP-1 derivative according to the present invention for the preparation of a medicament with a protracted profile of action for the treatment of non-insulin dependent diabetes mellitus 46. Use of a GLP-1 deπvative according to the present invention for the preparation of a medicament with a protracted profile of action for the treatment of insulin dependent diabetes mellitus 47 Use of a GLP-1 derivative according to the present invention for the preparation of a medicament with a protracted profile of action for the treatment of obesity 48 A method of treating insulin dependent or non-msulm dependent diabetes mellitus in a patient in need of such a treatment, comprising administering to the patient a therapeutically effective amount of a GLP-1 derivative according to claim 1 together with a pharmaceutically acceptable carrier.

Inventors: KNUDSEN LISELOTTE BJERRE, NIELSEN PER FRANKLIN, SOERENSEN PER OLAF, KNUDSEN, LISELOTTE, BJERRE, NIELSEN, PER, FRANKLIN, SOERENSEN, PER, OLAF
Applicants: KNUDSEN LISELOTTE BJERRE, NIELSEN PER FRANKLIN, NOVONORDISK AS, SOERENSEN PER OLAF, KNUDSEN, LISELOTTE, BJERRE, NIELSEN, PER, FRANKLIN, NOVO NORDISK A/S, SOERENSEN, PER, OLAF
Application year: 1997
Main classification: C07K14
IPC codes: A61K31, A61K38, A61K47, A61P3, A61P5, C07K14