WO2002022151A2 - Use of glp-1 and flp-2 peptides for treatment of bone disorders - Google Patents

Use of glp-1 and flp-2 peptides for treatment of bone disorders Download PDF

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WO2002022151A2
WO2002022151A2 PCT/EP2001/010714 EP0110714W WO0222151A2 WO 2002022151 A2 WO2002022151 A2 WO 2002022151A2 EP 0110714 W EP0110714 W EP 0110714W WO 0222151 A2 WO0222151 A2 WO 0222151A2
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glp
analogues
bone
derivatives
compounds
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WO2002022151A3 (en
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Dennis Bang Henriksen
Jens Juul Holst
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Immunodiagnostic Systems Nordic AS
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Osteometer Biotech AS
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Priority claimed from GB0022844A external-priority patent/GB0022844D0/en
Priority claimed from GB0029920A external-priority patent/GB0029920D0/en
Priority to DE60134251T priority Critical patent/DE60134251D1/de
Application filed by Osteometer Biotech AS filed Critical Osteometer Biotech AS
Priority to EP01982302A priority patent/EP1326630B1/en
Priority to JP2002526401A priority patent/JP5161412B2/ja
Priority to AU2002213925A priority patent/AU2002213925A1/en
Priority to DK01982302T priority patent/DK1326630T3/da
Publication of WO2002022151A2 publication Critical patent/WO2002022151A2/en
Publication of WO2002022151A3 publication Critical patent/WO2002022151A3/en
Priority to US10/391,460 priority patent/US6943151B2/en
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    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
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    • A61K38/22—Hormones
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    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
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Definitions

  • This invention relates to the use of glucagon-like peptide- 1 (GLP-1) as well as inducers, analogues and derivatives of GLP-1, and of glucagon-like peptide-2 (GLP-2) and inducers analogues and derivatives of GLP-2, in methods and compositions, in particular pharmaceutical formulations, for the treatment of diseases wherein bone resorption and/or insufficient bone formation is a factor, such as osteoporosis .
  • GLP-1 glucagon-like peptide- 1
  • GLP-2 glucagon-like peptide-2
  • inducers analogues and derivatives of GLP-2 in methods and compositions, in particular pharmaceutical formulations, for the treatment of diseases wherein bone resorption and/or insufficient bone formation is a factor, such as osteoporosis .
  • Glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) are fragments of the proglucagon molecule and the proglucagon molecule has a sequence of 160 a ino acids.
  • Proglucagon originates from preproglucagon which is synthesised in the L- ⁇ ells in the distal ileum, in the pancreas and in the brain. Processing of preproglucagon to give GLP-1 and GLP-2 occurs mainly in the L-cells.
  • the amino acid sequence of the proglucagon fragment 72-117 is given i.e. by Bell, G. I. et al . (Nature 304 368-371 (1983)).
  • the proglucagon fragment 78-108 is commonly referred to as GLP-1 (7-37) .
  • the proglucagon fragment 72-108 is in the present text also referred to as GLP-1 (1- 37) .
  • the proglucagon fragment of GLP-1 (7-36) amide is the naturally occurring form in humans and is usually referred to as GLP-1. Gutniak, M., N Engl . J. Med., 326:1316-22 (1992).
  • Gly8-GLP- 1(7-37) designates a fragment of GLP-1 formally derived from GLP-1 by replacing the amino acid residue in position 8 (Ala) by Gly.
  • GLP-1 (7-37) and analogues thereof have been disclosed, for example, Gln9-GLP-1 (7-37) , D-Gln9-GLP-1 (7-37) , acetyl-Lys9-GLP-l(7-37) , Thrl6-Lysl8-GLP-1 (7-37) , Lysl8-GLP- 1(7-37) and the like, and derivatives thereof including, for example, acid addition salts, carboxylate salts, lower alkyl esters, and amides (see e.g. WO 91/11457) .
  • GLP-1 Glucagon-like peptide-1
  • GLP-1 is known to stimulate insulin secretion and inhibit glucagon secretion and thereby lowers blood glucose, Andreasen, J. J. et al . (Digestion 55 221-228 (1994)).
  • the various disclosed forms of GLP-1 are known to stimulate insulin secretion and cAMP formation (see e.g., Mojsov, S. (Int. J. Peptide Protein Research 40 333- 343 (1992) ) ) .
  • Glucagon-like peptide-2 (GLP-2) is a 33 amino acid peptide fragment of proglucagon corresponding to the sequence of the proglucagon fragment 126-158.
  • GLP-2 shows remarkable homology in terms of amino acid sequence to glucagon and glucagon-like peptide-1 (GLP-1) .
  • GLP-1 glucagon and glucagon-like peptide-1
  • different mammalian forms of GLP-2 are highly conserved. For example, the human GLP-2 (hGLP-2)and the degu (a south American rodent) GLP-2 differ from rat GLP-2 (rGLP-2) by one and three amino acids respectively.
  • GLP-2 Various vertebrate forms of GLP-2 have been reported by many authors including Buhl et al . , J. Biol. Chem., 1988, 263 (18) :8621, Nishi and Steiner, Mol . Endocrinol . , , 1990, 4:1192-8, and Irwin and Wong, Mol. Endocrinol., 1995, 9(3):267-77. The sequences reported by these authors are incorporated by reference .
  • GLP-2 When given exogenously, GLP-2 can produce a marked increase in the proliferation of small intestinal epithelium of the test mice, apparently with no undesirable side effects
  • GLP-2 has also been shown to increase D-glucose maximal transport rate across the intestinal basolateral membrane (Cheeseman and Tseng, 1996, American Journal of Physiology 271 G477-G482) .
  • Osteoporosis is the most common bone disease in humans. It is a serious and frequent disease, which occurs worldwide. The single most important risk factor for osteoporosis is oestrogen deficiency, and it is estimated that up to one third of postmenopausal women will be affected if left untreated, Schlemmer, A. et al . , Eur. J. Endocrinol. 140:332-337 (1999). A primary event leading to osteoporotic bone loss is the increase in bone turnover associated with menopause. The acute increase in bone resorption seen with the decline in endogenous oestrogen production is followed by a coupled, but less accentuated increase in bone formation. This net imbalance between resorption and formation results in bone loss thereby increasing fracture risk.
  • GLP-1 peptide or GLP-2 peptide have an effect on loss of bone mass and/or insufficient bone formation in humans. Based on these observations it is now possible to provide a medicament and a method for the prophylaxis or treatment of diseases or disorders wherein bone resorption and/or insufficient bone formation is a factor, such as osteoporosis.
  • the present invention relates to the use of a composition comprising a glucagon-like peptide-1 (GLP-1) or an analogue or derivative thereof, and/or a glucagon-like peptide-2 (GLP-2) or an analogue or derivative thereof, to inhibit bone resorption and/or to promote bone formation.
  • GLP-1 glucagon-like peptide-1
  • GLP-2 glucagon-like peptide-2
  • an analogue is used to designate a peptide wherein one or more amino 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 amino acid residues have been added to the parent peptide.
  • analogue ' further includes mimetics so the said peptides which bind to the receptors for said peptides and activate said receptor to produce an output messenger or signal equivalent in kind to that produced upon binding of GLP-1 or GLP-2 respectively.
  • Such analogues may be adapted to resist degradation in the body to an extent greater than GLP-1 or GLP-2 and so may have a longer half life or may be orally administerable.
  • Such analogues will include pseudo- peptides modelled on GLP-1 or GLP-2 in which one or more amino acid residues have been substituted with structurally similar but peptidase resistant amino acid mimicking moieties .
  • amino acid residue designates the residue of an amino acid which can be coded for by the genetic code, via a triplet ("codon 1 ) of nucleotides.
  • the peptides to which the invention relates are referred to collectively as “GLP-1 peptides” and similarly collectively as “GLP-2 peptides'.
  • 'Derivatives' referred to herein include for example, acid addition salts, carboxylate salts, lower alkyl (e.g. Ci - C 6 , more preferably Ci -C 3 , esters and amides. Also included are substances formed by chemical modification of GLP-2 peptide which retain the bone resorption decreasing and/or bone formation increasing properties of GLP-2 at an equivalent or increased level.
  • the present invention relates to the use of a composition comprising a glucagon-like peptide-1 (GLP-1) or an analogue or derivative thereof, and/or a glucagon-like peptide-2 (GLP-2) or an analogue or derivative thereof, in the preparation of a medicament for the treatment of a disease wherein bone resorption and/or insufficient bone formation is a factor.
  • GLP-1 glucagon-like peptide-1
  • GLP-2 glucagon-like peptide-2
  • the disease is osteoporosis
  • the present invention relates to a method of inhibiting bone resorption and/or promoting bone formation, comprising, administering to a subject a compound selected from the group consisting of GLP-1, GLP-2, GLP-1 analogues, GLP-2 analogues, GLP-1 derivatives, GLP-2 derivatives, agonists of the GLP-1 or the GLP-2 receptor, agonists of the GLP-1 or the GLP-2 signal transduction cascade, compounds that stimulate synthesis of endogenous GLP-1 or GLP-2, compounds that stimulate release of endogenous GLP-1 or GLP-2, and pharmaceutically acceptable derivatives such as esters, amides or salts thereof.
  • a preferred embodiment of the present invention relates to a method wherein the composition is selected from the group consisting of GLP-2, GLP-2 analogues, GLP-2 derivatives, and pharmaceutically acceptable salts, esters or amides thereof,
  • the present invention relates to a method wherein the composition is administered orally.
  • Another aspect of the present invention relates to a method of prophylactically treating a subject at risk of developing a disease wherein bone resorption and/or insufficient bone formation is a factor, the method comprising the steps of
  • the present invention relates to a method of treatment wherein the disease is osteoporosis. In a further preferred embodiment, the present invention relates to a method wherein the subject is a human.
  • compositions used for inhibition of bone resorption and/or the promotion of bone formation comprising a compound selected from the group consisting of GLP-1, GLP-2, GLP-1 analogues, GLP-2 analogues, GLP-1 derivatives, GLP-2 derivatives, agonists of the GLP-1 or the GLP-2 receptor, agonists of the GLP-1 or the GLP-2 signal transduction cascade, compounds that stimulate synthesis of endogenous GLP-1 or GLP-2, compounds that stimulate release of endogenous GLP-1 or GLP-2, and pharmaceutically acceptable salts thereof.
  • the compound is an orally effective analogue or derivative.
  • a compound is on which stimulates endogenous production or release of GLP-1 or GLP- 2, it is not nutritionally effective or is not found as a component of foodstuffs.
  • the present invention relates to a pharmaceutical composition for use in the therapeutic or prophylactic treatment of a disease wherein bone resorption or insufficient bone formation is a factor, said composition comprising a compound selected from the group consisting of GLP-1, GLP-2, GLP-1 analogues, GLP-2 analogues, GLP-1 derivatives, GLP-2 derivatives, agonists of the GLP-1 or the GLP-2 receptor, agonists of the GLP-1 or the GLP-2 signal transduction cascade, compounds that stimulate synthesis of endogenous GLP-1 or GLP-2, compounds that stimulate release of endogenous GLP-1 or GLP- 2, and pharmaceutically acceptable salts thereof.
  • Fig.l shows in graphs A, B and C results obtained in Examples 1-3.
  • Fig. 1A shows the levels of GLP-1, GIP and S-CTX over a 2-3 hours period responding to oral fructose.
  • GIP Glucose- dependent Insulinotropic Polypeptide
  • S-CTX is a serum C-telopeptide fragment of collagen type I degradation.
  • Fig. IB shows the levels of GLP-1, GIP and S-CTX over a 2-3 hours period responding to oral long chain fatty acid
  • LCFA LCFA
  • Fig. 1C shows the levels of GLP- 2, GIP and S-CTX over a 2-3 hours period responding to oral protein.
  • Fig. 2 shows results obtained in Example 4.
  • the figure shows the levels of S-CTX, GLP-1 and GLP-2 in patients with short intestine but preserved colon over a 3 hours period responding to a normal meal.
  • Fig. 3 shows results obtained in Example 5. The figure shows the levels of S-CTX and GLP-2intact over a 7 hours period responding to a GLP-2 injection. DETAILED DESCRIPTION OF THE INVENTION
  • This invention comprises the use of glucagon-like peptide-1 (GLP-1) , analogues and derivatives of GLP-1, glucagon-like peptide-2 (GLP-2) , analogues and derivatives of GLP-2, for the treatment of diseases wherein bone resorption and/or insufficient bone formation is a factor, such as osteoporosis .
  • the skeleton is (among other things) a reservoir of nutrients, including minerals such as calcium and phosphate. This reservoir is usually well protected but in situations of insufficient access to nutrients giving rise to a decreasing extra cellular concentration of these nutrients the stores of these in the skeleton can be mobilised. Likewise, in situations of sufficient access to nutrients the metabolic machinery of the body is set to preserve the stores.
  • Such mobilisation of the stores can be achieved by stimulating osteoclastic bone resorption, and likewise resorption can be decreased when dietary availability of nutrients increases.
  • Such regulation of bone metabolism has previously been demonstrated for dietary intake of calcium. It has recently been observed that also oral glucose can decrease bone resorption, with a fully expressed decrease within 2 hours, GB Patent Application No. 0007492.2.
  • the nutrients that can inhibit bone resorption may be a sugar, a protein, or a fatty acid, or a triglyceride, or a mineral .
  • Fatty acids used were preferably long chain fatty acids.
  • the fragments of proglucagon produced in the intestine have a role in the inhibition of bone resorption and also a role in promoting bone formation (an anabolic bone effect) .
  • the proglucagon expressed in the ⁇ -cells of the endocrine pancreas and in the enteroendocrine L-cells of the intestine arises from the transcription of a single gene and the translation of identical mRNAs in these two tissues. Biologic diversity in the expression of the proglucagon gene occurs at the level of a remarkably tissue-specific alternative post-translational processing, resulting in the formation of the bioactive peptide glucagon in the pancreas and the reciprocal insulin-stimulating GLP-1 in the intestine.
  • glucagon and GLP sequences in intestine and pancreas, respectively, are retained as unprocessed proglucagon fragments: enteroglucagon (glicentin) in the intestine and the major proglucagon fragment in the pancreas, Habener, J. F., Diabetes Mellitus 68-78 (1996).
  • Glicentin or proglucagon fragment 1-69 is cleaved in the pancreas to GRPP (glicentin-related pancreatic polypeptide) and glucagon, whereas the major proglucagon fragment 72-158 is cleaved (processed) in the intestine to GLP-1 (proglucagon fragment 78-107) and GLP-2 (proglucagon fragment 126-158) fragments .
  • GLP-1 of the intestine is an anabolic hormone that among other things facilitates stimulation of insulin secretion and glucose uptake during feeding, whereas glucagon from pancreas is the most important catabolic hormone that acts during periods of fasting to break down glycogen (and thereby to increase glucose output by the liver) , skeletal muscle, and adipose tissue.
  • the proteolytic cleavage of the proglucagon in the intestine is part of a complicated process.
  • At least four peptides of GLP-1 result from the processing: two peptides of 37 and 36 amino acids, GLP-1 (1-37) and GLP-1 (1-36) amide; and two aminoterminally truncated isopeptides, GLP-1 (7-37) and GLP- 1 (7-36) amide.
  • GLP-1 1-37
  • GLP-1 (1-36) amide two aminoterminally truncated isopeptides
  • GLP-1 (7-37) and GLP- 1 (7-36) amide Only the two truncated GLP-ls have insulinotropic activities. Previously, no biologic activities have been found for either of the amino-terminally extended forms of GLP-1.
  • GLP-1 has been proven to be a potent glucose-dependent insulinotropic peptide distinct from GIP.
  • GIP Gastric Inhibitory Polypeptide which has been changed to Glucose- dependent Insulinotropic Polypeptide
  • GIP is an incretin that stimulates insulin secretion directly in a glucose-dependent manner.
  • amino acid sequence of GIP was determined in 1981 by
  • proglucagon 126-158 The intestinal processing of proglucagon also gives rise to GLP-2 corresponding to proglucagon 126-158. Only a single form is known in humans, Hartmann B et al . , Peptides 2000; 21(1) :73-80.
  • GLP-2 seems to share some of the effect of GLP-1 on gastrointestinal motility and secretion, Wojdemann, M. et al . , J Clin Endocrinol Metab 1999; 84 (7) :2513-2517 and Wo demann, M. et al, Scand J Gastroenterol 1998; 33 (8) : 828-832, but has no direct effect on the pancreatic islets.
  • GLP-2 has trophic effect on the intestinal mucosa, and may act physiologically as a growth factor involved in adaptive responses of the gut to surgery or nutritional variation, Drucker, D. J. et al . , Proc Natl Acad Sci USA 1996; 93 (15) :7911-7916 and Thulesen, J.
  • GLP-1 peptides Compounds which can be useful as GLP-1 peptides according to the present invention are described in International Patent Application No. WO 87/06941 which relates to a peptide fragment which comprises GLP-1 (7-37) and functional derivatives thereof and to its use as an insulinotropic agent .
  • GLP-1 analogues are described in International Patent Application No. WO 90/11296 which relates to peptide frag- ments 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.
  • Derivatives of naturally-occurring GLP-1 molecules are those peptides which are obtained by fragmenting a naturally- occurring sequence, or are synthesised based upon a knowledge of the sequence of the naturally-occurring amino acid sequence of the genetic material (DNA or RNA) which encodes this sequence.
  • the term "derivatives” also includes chemical modification of natural or unnatural GLP-1 or GLP-2 molecules. Processes for preparing these derivatives are well known to organic and peptide chemists of ordinary skill (see, e. g. WO 91/11457) .
  • GLP-1 receptor agonist and "GLP-2 receptor agonist” mean any molecule which on binding to the GLP-1 receptor, respectively the GLP-2 receptor result in activation of the GLP-1 receptor, respectively the GLP-2 receptor, and include for example GLP-1, GLP-2 or peptidic analogues of GLP-1 and GLP-2.
  • GLP-1 receptor and the GLP-2 receptor are G-protein coupled receptors.
  • methods commonly used in this field to identify G-protein coupled receptor agonists may be useful applied to the GLP-1 receptor respectively the GLP-2 receptor.
  • One useful methodology for assessing compounds for GLP-2 receptor agonist activity is disclosed in US Patent No. 6077949.
  • GLP-1 and of GLP-2 are not yet fully elucidated. It may be that one or both operates through a signal transduction cascade in which there may be active constituents either upstream or downstream or both from the GLP peptide. According to the invention, it is permissible to intervene at any point in such a cascade to produce a reduction in the rate of bone resorption and/or to promote the rate of bone formation by the mechanism of the cascade. This may involve stimulating the synthesis or release of endogenous GLP peptide or administering or triggering endogenous synthesis or release of another compound active in the cascade downstream from the GLP
  • peptide e.g. one produced in response to the GLP peptide binding to a receptor.
  • Osteoblasts are of mesenchymal origin derived from fibroblast colony forming units, as are chondrocytes, muscle cells and adipocytes. Osteoblasts are capable of secreting a number of factors (such as interleukins-6 and 11; MCS-F and GM-CSF) that can affect the development of osteoclasts. Osteoclasts develop from granulocye-macrophage colony forming units and their development is modulated by a variety of factors, including interleukins 1, 3, 6 and 11.
  • interleukin-6 because its production from osteoblasts is stimulated by PTH and vitamin D and because of its possible involvement in several diseases including primary hyperparathyroidism, multiple myeloma, rheumatoid arthritis, Paget's disease and hypogonadal osteoprosis.
  • Interleukin-6 production from osteoblasts is regulated by sex-hormones (androgens and estrogens) which act on the 11-6 promotor.
  • 11-6 in contrast to 11-11 in normal osteoclastic function is unclear but in certain pathologic states the 11-6 receptor is upregulated and 11-6 may then exert is effect.
  • GLP-1 and GLP-2 may play an important role in the regulation of both skeletal growth in the child, and skeletal remodelling in the adult.
  • GLP may act on receptors present in bone derived cells and stimulation of these cells with GLP leads to an increase in intracellular calcium concentration and cellular cAMP content, resulting in increased type I collagen synthesis and inhibition of PTH- stimulated bone resorption.
  • the invention includes the use of other fragments obtainable from the cleavage of the major proglucagon fragment which also have GLP-like activity.
  • subject includes a human or other mammal and including livestock and pets.
  • Administration may be via any route known to be effective by the physician of ordinary skill .
  • Parenteral administration may be performed by subcutaneous, intramuscular, intra- peritoneal or intravenous injection of a dosage form into the body by means of a sterile syringe, optionally a pen-like syringe or some other mechanical device such as an infusion pump.
  • a further option is a composition which may be a powder or a liquid for the administration in the form of a nasal or pulmonary spray.
  • the administration may be transdermally, e.g. from a patch.
  • Compositions suitable for oral, buccal, rectal and vaginal administration may also be provided. The oral route of administration is preferred for compounds used in the present invention which are orally effective.
  • Serum FSH was measured by IRMA (Coat-A-Count ® , DPC, Los Angeles, CA) .
  • Serum C-telopeptide fragments of collagen type I degradation (S-CTX) were measured by ELISA, serum CrossLapsTM assay (Osteometer BioTech A/S - Denmark) .
  • Serum osteocalcin was determined by ELISA, an assay which determines the N- terminal mid segment of the molecule.
  • Serum insulin and c- peptide were both assessed by RIA (Coat-A-Count ® for insulin and Double Antibody C-peptide for c-peptide both DPC, Los Angeles, CA) .
  • Example 1 Example 1
  • Oral fructose consisted of 75 g fructose dissolved in 300 ml water with juice of a half lemon added.
  • Oral fructose induced a reduction of 36 % in S-CTX after 2 hours ( Figure 1A) whereas the occurrence of GLP-1 was doubled to the level of 220 % after 2 hours compared to the baseline of 100 % at To.
  • the fragment of GLP-1 is one fragment of the major proglucagon fragment which is cleaved and activated in the intestine. According, the occurrence of the other parts or fragments are doubled to a similar level as GLP-1 and therefore can take part in the association of the reduction in S-CTX.
  • the level of GIP was almost maintained at the baseline .
  • Example 12 healthy women and men between 30-45, respectively 30-60, with the same in- and exclusion criteria as in Example 1 were included in a randomised, controlled cross over study comparing the effects of oral long chained fatty acids on GLP-1, on GIP and on bone turnover.
  • Oral long chained fatty acids consisted of 70 ml emulsion of long chained fatty acids (Calogen) .
  • Oral protein consisted of 40 g protein powder (Casilan) dissolved in 600 ml water.
  • Oral protein induced a reduction of 45 % in S-CTX after 2 hours (Figure 1C) whereas the occurrence of GLP-2 and GIP were both increased.
  • the level of GIP was increased from 8 pM to 17 pM and the occurrence of GLP-2 was increased from 36 pM to 57 pM after 1 hour decrease slightly after 2 hours to the level of 51 pM.
  • peripheral venous blood was collected 15 minute before the test meal and 10, 20, 30, 45, 60, 120 and 180 minutes after the start of the meal, which was completed in 15 minutes.
  • the normal mixed meal consisted of rye bread, toast, butter, cheese, jam, yoghurt, banana, and orange juice (total weight 755 g) , with an energy content of 3.92 MJ and a protein: carbohydrate : fat energy ratio of 10%: 52%: 37% evaluated from food tables .
  • a normal mixed meal induced a reduction of 40 % in S-CTX after 2 hours ( Figure 2) whereas the occurrence of GLP-1 and GLP-2 were both increased.
  • the level of GLP-1 was increased from 70 pM to 98 pM after 3 hours and the occurrence of GLP-2 was increased from 10 pM to 22 pM after 3 hours.
  • Blood samples were drawn at regular intervals before, during, and after the injection.
  • test persons received a subcutaneous bolus injection of 400 ⁇ g synthetic human GLP-2.
  • the GLP-2 injection induced a reduction of 33 % in S-CTX after 3 hours whereas the level of GLP-2 increased naturally after the injection to a peak after 1 hour indicating the association between GLP-2 and the reduction in S-CTX.

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PT1326630E (pt) 2008-09-02
US6943151B2 (en) 2005-09-13
US20040082507A1 (en) 2004-04-29
US20020037836A1 (en) 2002-03-28
WO2002024214A2 (en) 2002-03-28
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DK1414486T3 (da) 2010-08-30
PT1414486E (pt) 2010-07-21
EP1326630B1 (en) 2008-05-28
JP2004508410A (ja) 2004-03-18
ES2310192T3 (es) 2009-01-01
ES2345874T3 (es) 2010-10-05
ATE396738T1 (de) 2008-06-15
JP2004524268A (ja) 2004-08-12
CY1110721T1 (el) 2015-06-10
ATE466592T1 (de) 2010-05-15
WO2002024214A3 (en) 2004-02-19
EP1414486A2 (en) 2004-05-06
JP5189723B2 (ja) 2013-04-24
EP1970072A1 (en) 2008-09-17
AU2002213925A1 (en) 2002-03-26
DE60142084D1 (de) 2010-06-17
JP5161412B2 (ja) 2013-03-13
US6770620B2 (en) 2004-08-03
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