Peptides for treatment of diabetes

Abstract

To provide agents and their use in the treatment of endocrine, nutritional and / or metabolic diseases in a mammal.SOLUTION: The present disclosure provides novel peptides which stimulate β-cell proliferation, have ability to rescue β-cells from apoptosis induced by glucotoxic conditions, and stimulate insulin secretion from rat INS-1 β-cells as well as isolated mouse pancreatic islets.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] Technical Field The present disclosure relates to peptides useful for the treatment of diabetes and related disorders.

Background Art

[0002] Background Insulin, a peptide hormone produced by β cells in the islets of Langerhans of the pancreas, is released in response to an increase in blood glucose level. Thus, glucose is removed from the blood by insulin-dependent stimulation of glucose transporters located in the cell membranes of target tissues such as adipose tissue, skeletal muscle, and the liver. Insulin binds to and activates the membrane-bound insulin receptor (IR), thereby initiating a cascade of intracellular signaling events and regulating multiple biological processes such as glucose and lipid metabolism, to exert a biological effect.

[0003] Currently, the treatment of both type 1 and type 2 diabetes mainly relies on insulin treatment. Adjuvant drugs to insulin treatment are long-acting glucagon-like peptide 1 (GLP-1) receptor agonists, i.e., derivatives that act on the same receptor as GLP-1. GLP-1 is a metabolic hormone that stimulates insulin secretion. GLP-1 is known to increase insulin sensitivity in both α and β cells; increase β cell mass, insulin expression, post-translational modification, and secretion; and decrease glucagon secretion from the pancreas, in addition to increasing glucose-dependent insulin secretion from the pancreas. Other pharmaceuticals used adjunctively to insulin treatment for the purpose of lowering plasma glucose levels include DPP-IV inhibitors, metformin, SGLT-2 inhibitors, and sulfonylureas.

[0004] Weight gain, as well as certain drawbacks such as an increased risk of cancer and hypoglycemia, are associated with long-term use of insulin. Accordingly, there is a growing need in the art for novel non-insulin compounds that can treat diabetes not only by addressing insulin resistance and hyperglycemia, but also by reducing related and consequential complications.

[0005] Therefore, it is highly desirable to identify novel compounds that can restore glucose metabolism and treat diabetes and related disorders. Multiple approaches can be envisioned, but none are obvious to those of ordinary skill in the art. SUMMARY OF THE INVENTION

[0006] Summary The inventors have discovered a peptide that has the ability to stimulate β-cell proliferation, rescue β-cells from apoptosis induced by glucotoxic conditions, and stimulate insulin secretion from rat INS-1 β-cells and isolated mouse islets. Further, the inventors have found that in a glucose tolerance test, the peptide reduces plasma glucose levels in vivo and delays the onset of diabetic disease in BB lyp / lyp rats, a model of type 1 diabetes. Thus, the peptides of the present disclosure are suitable for use in the treatment of endocrine, trophic, and metabolic diseases and disorders.

[0007] In one aspect, the present disclosure provides a) a peptide or peptidomimetic comprising an amino acid sequence of the general formula: KX2LAX5X6X7X8IX 10 LX 12 YGIK (SEQ ID NO:140) wherein (wherein X2 is C, P or G; X5 is E or G; X6 is C, D or I; X7 is D, I, S or G; X8 is S, D or G; X10 is E or G; X 12 is S or T, provided that as a condition, if X 12 is T, the peptide contains no more than 25 amino acids, as a condition, X2 is P, X5 is E, X6 is I, X7 is D, X8 is S, X 10 is E, X 12 is S, the peptide contains no more than 85 amino acid residues), or CLAEIDSC (SEQ ID NO:142), CFKPLAEIDSIECSYGIK (SEQ ID NO:143), KPLAEGDIELSYGIK (SEQ ID NO:147), KPLAEIELSYGIK (SEQ ID NO:148), KCLAEIDSCELSYGIK (SEQ ID NO:155), and CFKPLAEIDSIEC (SEQ ID NO:156) its bioactive fragments and / or variants selected from the group consisting of; b) a polynucleotide encoding the peptide of a) upon expression; c) a vector containing the polynucleotide of b); d) a cell containing the polynucleotide of b) or the vector of c), relates to a medicament comprising or consisting of.

[0008] In one aspect, the present disclosure a) Amino acid sequences GDPNDGRGDSVVYGLR (SEQ ID NO:137), VDTYDGGISVVYGLR (SEQ ID NO:138), VDTYDGDGSVVYGLR (SEQ ID NO:139), VDVPEGDISLAYGLR (SEQ ID NO:157), LDGLVRAYDNISPVG (SEQ ID NO:158), GDPNGDISVVYGLR (SEQ ID NO:159), VDVPNGDISLAYRLR (SEQ ID NO:160), VDVPEGDISLAYRLR (SEQ ID NO:161), V(beta-D)TYDGDISVVYGLR (SEQ ID NO:167), VDTY(beta-D)GDISVVYGLR (SEQ ID NO:168), VDTYDG(beta-D)ISVVYGLR (SEQ ID NO:169) a peptide or peptidomimetic comprising or consisting of; b) a polynucleotide encoding the peptide of a) upon expression; c) a vector comprising the polynucleotide of b); d) a cell comprising the polynucleotide of b) or the vector of c), relates to a medicament comprising.

[0009] In one aspect, the present disclosure relates to a composition comprising the medicament described earlier herein.

[0010] In one aspect, the present disclosure relates to a medicament for use as a medicine, or a composition comprising the above medicament.

[0011] In one aspect, the present disclosure is for use in the treatment of endocrine diseases, nutritional diseases and / or metabolic diseases in mammals, a) (i) General formula: KX2LAX5X6X7X8IX 10 LX 12 YGIK (SEQ ID NO:140) a peptide or peptidomimetic comprising or consisting of the amino acid sequence represented by (wherein, X2 is C, P or G; X5 is E or G; X6 is C, D or I; X7 is D, I, S or G; X8 is S, D or G; X 10 is E or G; X 12 is S or T, provided that if X 12 is T, the peptide contains no more than 25 amino acid residues); (ii) A peptide comprising the amino acid sequence represented by the general formula: VDZ3Z4Z5GZ7Z8SZ 10 Z 11 YGLR (SEQ ID NO:68) wherein (wherein Z3 is T or V; Z4 is Y or P; Z5 is D or N; Z7 is D or G; Z8 is I or G; Z 10 is V or L; Z 11 is V or A), and (iii) A peptide comprising or consisting of an amino acid sequence selected from the group consisting of KCLAECDSIELSYGIK (SEQ ID NO:141), CLAEIDSC (SEQ ID NO:142), CFKPLAEIDSIECSYGIK (SEQ ID NO:143), KPLAEIELSYGIK (SEQ ID NO:148), KCLAEIDSCELSYGIK (SEQ ID NO:155), and CFKPLAEIDSIEC (SEQ ID NO:156); b) A polynucleotide encoding the peptide of a) upon expression; c) A vector containing the polynucleotide of b); d) A cell containing the polynucleotide of b) or the vector of c), Relates to a drug containing

[0012] In one aspect, the present disclosure relates to a method for treating endocrine diseases, nutritional diseases and / or metabolic diseases, including administering to an individual in need of a therapeutically effective amount of the drug described herein.

[0013] In one aspect, the present disclosure relates to the use of the drug described herein for the manufacture of a medicament for the treatment of endocrine diseases, nutritional diseases and / or metabolic diseases.

[0014] In one aspect, the present disclosure relates to a method for delaying the onset of diabetes, including administering to an individual in need of a therapeutically effective amount of the drug described herein.

[0015] In one aspect, the present disclosure relates to a method for reducing blood glucose levels, including administering to an individual in need of a therapeutically effective amount of the drug described herein.

[0016] In one aspect, the present disclosure relates to a method for improving the morphology of beta cells, such as an in vitro method, including administering to an individual in need of a therapeutically effective amount of the drug described herein.

[0017] In one aspect, the present disclosure relates to a method for improving the viability of beta cells, including administering to an individual in need of a therapeutically effective amount of the drug described herein.

[0018] In one aspect, the present disclosure relates to the use of the drug described herein for the preparation of a diagnostic composition for the diagnosis of pancreatic diseases, disorders or injuries in an individual. BRIEF DESCRIPTION OF THE DRAWINGS

[0019]

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Mode for Carrying Out the Invention

[0020] Detailed Description This disclosure is as defined in the claims.

[0021] In one aspect, the present disclosure provides a general formula: a) KX2LAX5X6X7X8IX 10 LX 12 YGIK (SEQ ID NO:140) (wherein, X2 is C, P or G; X5 is E or G; X6 is C, D or I; X7 is D, I, S or G; X8 is S, D or G; X 10 is E or G; X 12 is S or T, provided that if X 12 is T, the peptide contains no more than 25 amino acids, As a condition, X2 is P, X5 is E, X6 is I, X7 is D, X8 is S, X 10 is E, X 12 is S, then the peptide contains no more than 85 amino acid residues); b) a polynucleotide encoding the peptide of a) upon expression; c) a vector containing the polynucleotide of b); d) a cell containing the polynucleotide of b) or the vector of c), relates to a peptide or peptide analog containing the amino acid sequence shown.

[0022] In one embodiment, the present disclosure provides a general formula: KX2LAX5X6X7X8IX 10 LSYGIK (SEQ ID NO:162) (wherein, X2 is C, P or G; X5 is E or G; X6 is C, I or absent; X7 is D, G or absent; X8 is S, G or absent; X 10 is E or G, where absent means that amino acid X5 is coupled to amino acid X 10 ). relates to a peptide or peptide analog containing the amino acid sequence shown.

[0023] In one embodiment, the present disclosure provides KX2LAX5IX 10 LSYGIK (SEQ ID NO:163) (wherein, X2 is C, P or G; X5 is E or G; X 10 is E or G) relates to a peptide containing the amino acid sequence shown.

[0024] In one embodiment, the present disclosure relates to a) i) a peptide comprising or consisting of the amino acid sequences of SEQ ID NO: 136, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, and 156; ii) any one of the peptide's bioactive sequence variants of i), wherein any one amino acid is modified for another proteinogenic or non-proteinogenic amino acid, provided that no more than 5 amino acids are so modified; iii) a bioactive fragment of any one of the peptides of i) or ii) comprising at least 10 consecutive amino acids of any one of i) or ii), a peptide selected from the group consisting of; b) a polynucleotide encoding the peptide of a) upon expression; c) a vector comprising the polynucleotide of b); d) a cell comprising the polynucleotide of b) or the vector of c), and relates to a medicament comprising the same.

[0025] In one embodiment, the present disclosure relates to a) a peptide comprising or consisting of an amino acid sequence selected from the group consisting of GDPNDGRGDSVVYGLR (SEQ ID NO: 137), VDTYDGGISVVYGLR (SEQ ID NO: 138), VDTYDGDGSVVYGLR (SEQ ID NO: 139), VDVPEGDISLAYGLR (SEQ ID NO: 157), LDGLVRAYDNISPVG (SEQ ID NO: 158), GDPNGDISVVYGLR (SEQ ID NO: 159), VDVPNGDISLAYRLR (SEQ ID NO: 160), VDVPEGDISLAYRLR (SEQ ID NO: 161); b) a polynucleotide encoding the peptide of a) upon expression; c) a vector comprising the polynucleotide of b); d) a cell comprising the polynucleotide of b) or the vector of c), Relates to a medicament containing

[0026] In one embodiment, the present disclosure provides a general formula: VDVPZ5GDISLAYZ 13 LR(SEQ ID NO:164) (wherein, Z5 is E or N; Z 13 is R or G) and relates to a peptide containing the amino acid sequence represented by

[0027] In one embodiment, the present disclosure provides a general formula: VDVTYDGZ7Z8SVVYGLR(SEQ ID NO:165) (wherein, Z7 is D or G; Z8 is I or G) and relates to a peptide containing the amino acid sequence represented by

[0028] In one embodiment, the present disclosure provides a general formula: GDPNZ5Z6Z7Z8Z9SVVYGLR(SEQ ID NO:166) (wherein, Z5 is D or G; Z6 is D or G; Z7 is I or R; Z8 is G or absent; Z9 is D or absent) and relates to a peptide containing the amino acid sequence represented by

[0029] As used herein, the term "absent", for example, "X6 is C, I or absent", should be understood to mean that the amino acid residues directly adjacent to the absent amino acid are directly linked to each other by a conventional amide bond.

[0030] As used herein, the term "peptide analog" refers to a peptide that contains or consists of a non-naturally occurring peptide.

[0031] As used herein, the term "amino acid" includes the standard 20 genetically encoded amino acids and the corresponding stereoisomers in the "D" form (compared to the natural "L" form), omega amino acids and other naturally occurring amino acids, non-conventional amino acids (e.g., α,α-disubstituted amino acids, N-alkyl amino acids, etc.), and chemically derived amino acids (see below).

[0032] When an amino acid is specifically listed, such as "alanine" or "Ala" or "A", it refers to both L-alanine and D-alanine unless expressly stated otherwise. Other non-conventional amino acids may be suitable components of the peptides of the present disclosure as long as the desired functional properties are retained by the peptides. For the peptides shown, each encoded amino acid residue is represented, as appropriate, by a one-letter designation corresponding to the common name of the conventional amino acid.

[0033] Chemical derivatives of one or more amino acids can be achieved by reaction with functional side chain groups. Such derivatives include, for example, those molecules in which the free amino group is derivatized to form an amine hydrochloride, p-toluenesulfonyl group, carboxybenzyloxy group, t-butyloxycarbonyl group, chloroacetyl group or formyl group. The free carboxyl group may be derivatized to form salts, methyl and ethyl esters, or other types of esters and hydrazides. The free hydroxyl group may be derivatized to form O-acyl or O-alkyl derivatives. Also included as chemical derivatives are those peptides containing naturally-derived amino acid derivatives of the 20 standard amino acids. For example, it may be substituted with 4-hydroxyproline in place of proline; with 5-hydroxylysine in place of lysine; with 3-methylhistidine in place of histidine; with homoserine in place of serine and with ornithine in place of lysine. As long as the essential activity is maintained, the derivatives also include peptides containing one or more additions or deletions. Other included modifications are amidation, amino-terminal acylation (e.g., acetylation or thioglycolic acid amidation), terminal carboxyl amidation (e.g., with ammonia or methylamine) and similar terminal modifications.

[0034] Some of the peptides of the present disclosure share amino acid sequence similarity with partial regions of the naturally-occurring osteopontin protein. In some embodiments, the peptide may be regarded as an active fragment of the naturally-occurring osteopontin protein, or a variant such as a fragment.

[0035] Some of the peptides of the present disclosure share amino acid sequence similarity with partial regions of the naturally-occurring tenascin protein. In some embodiments, the peptide may be regarded as an active fragment of the naturally-occurring tenascin protein, or a variant such as a fragment.

[0036] A "fragment" includes at least 5 adjacent amino acids of an amino acid sequence, such as at least 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 adjacent amino acids of an amino acid sequence. Thus, the fragment may have an amino acid length of 15 or less, such as 14, 13, 12, 11, 10, 9, 8, 7, 6 or 5 amino acids in length.

[0037] In one embodiment, the peptide has an amino acid length not exceeding 85, not exceeding 80, not exceeding 75, not exceeding 70, not exceeding 65, not exceeding 60, not exceeding 55, not exceeding 50, not exceeding 45, not exceeding 40, not exceeding 35, not exceeding 30, not exceeding 28, not exceeding 26, not exceeding 24, not exceeding 22, not exceeding 20, not exceeding 19, not exceeding 18, not exceeding 17, not exceeding 16, not exceeding 15, not exceeding 14, not exceeding 13, not exceeding 12, not exceeding 11, not exceeding 10, etc.

[0038] In another embodiment, the peptide has an amino acid length between 5 and 30, such as between 5 and 20, between 8 and 20, between 8 and 16, between 10 and 15, etc.

[0039] In yet another embodiment, the fragment has an amino acid length of less than 15, such as less than 14, less than 13, less than 12, less than 11, less than 10, less than 9, less than 8, less than 7, less than 6, less than 5.

[0040] The term "variant" refers to a peptide that does not share 100% amino acid sequence identity with the parent peptide, i.e., one or more amino acids must be mutated. "Mutated" refers to modifying the amino acid at a specified position within the parent peptide. For example, the amino acid at the specified position may be deleted, modified, substituted, or may be a site of insertion / addition of one or more amino acids. It will be appreciated by those skilled in the art that the substitution can be conservative or non-conservative.

[0041] In one embodiment, the peptide variant has no more than 5 amino acids modified with another proteinogenic or non-proteinogenic amino acid, and has a sequence including or consisting of an amino acid with no more than 4 amino acids, no more than 3 amino acids, no more than 2 amino acids, no more than 1 amino acid, etc., being modified. In one embodiment, one or more amino acids are conservatively substituted. "Conservatively substituted" refers to the substitution of one amino acid with another amino acid having similar properties (such as size, hydrophobicity, etc.) such that the function of the peptide is not significantly modified. Thus, "conservative substitution" is an intended combination such as Gly, Ala; Val, Ile, Leu; Asp, Glu; Asn, Gln; Ser, Thr; Lys, Arg; and Phe, Tyr, etc.

[0042] In another embodiment, the peptide includes or consists of one or more additional amino acids inserted at the N- and / or C-terminus of the sequence and / or internally. In one embodiment, at least 2 additional amino acids are inserted, such as at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 15, or at least 20 additional amino acids. The additional amino acids may be amino acids from the corresponding positions of wild-type human osteopontin (SEQ ID NO: 66) or from the corresponding positions of wild-type murine osteopontin (SEQ ID NO: 134). The term "corresponding position" of wild-type osteopontin means the same as where the additional amino acids are present at equivalent positions in the above wild-type osteopontin (as an image, in the amino acid sequence of SEQ ID NO: 1, the italicized underlined sequence of SEQ ID NO: 66 is replaced).

[0043] In another embodiment, the peptide is selected from the group consisting of SEQ ID NO:1, 136, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 67, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 135, 137, 138, 139, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 167, 168 and 169; [Chemical formula] TIFF2025090703000003.tif242166 TIFF2025090703000004.tif243166 TIFF2025090703000005.tif244166 TIFF2025090703000006.tif178166 selected from the group consisting of

[0044] In one embodiment, the peptide is derived from osteopontin, such as mammalian osteopontin variants and / or fragments.

[0045] In one embodiment, the peptide is of non-natural origin, such as a peptide containing non-proteinogenic amino acid residues.

[0046] In some embodiments, the peptide is further conjugated to a moiety selected from the group consisting of PEG, monosaccharides, fluorophores, chromophores, radioactive compounds, and cell-penetrating peptides. In one embodiment, the fluorophore is lucifer yellow, biotin, 5,6-carboxytetramethylrhodamine (TAMRA), indodicarbocyanine (C5), Alexa Fluor® 488, Alexa Fluor® 532, Alexa Fluor® 647, ATTO 488, ATTO 532, 6-carboxyfluorescein (6-FAM), Alexa Fluor® 350, DY-415, ATTO 425, ATTO 465, Bodipy® FL, fluorescein isothiocyanate, Oregon Green® 488, Oregon Green® 514, Rhodamine Green™, 5'-tetrachloro-fluorescein, ATTO 520, 6-carboxy-4',5'-dichloro-2',7'-dimethoxyfluorescein, Yakima Yellow™ dye, Bodipy® 530 / 550, hexachlorofluorescein, Alexa Fluor® 555, DY-549, Bodipy® TMR-X, cyanine phosphoramidite (cyanine 3, cyanine 3.5, cyanine 5, cyanine 5.5, cyanine 7.5) Selected from the group consisting of ATTO 550, Rhodamine Red (trademark), ATTO 565, Carboxy-X-Rhodamine, Texas Red (Sulforhodamine 101 Acid Chloride), LightCycler (registered trademark) Red 610, ATTO 594, DY-480-XL, DY-610, ATTO 610, LightCycler (registered trademark) Red 640, Bodipy 630 / 650, ATTO 633, Bodipy 650 / 665, ATTO 647N, DY-649, LightCycler (registered trademark) Red 670, ATTO 680, LightCycler (registered trademark) Red 705, DY-682, ATTO 700, ATTO 740, DY-782, IRD 700, IRD 800, CAL Fluor (registered trademark) Gold 540nm, CAL Fluor (registered trademark) Gold 522nm, CAL Fluor (registered trademark) Gold 544nm, CAL Fluor (registered trademark) Orange 560nm, CAL Fluor (registered trademark) Orange 538nm, CAL Fluor (registered trademark) Orange 559nm, CAL Fluor (registered trademark) Red 590nm, CAL Fluor (registered trademark) Red 569nm, CAL Fluor (registered trademark) Red 591nm, CAL Fluor (registered trademark) Red 610nm, CAL Fluor (registered trademark) Red 590nm, CAL Fluor (registered trademark) Red 610nm, CAL Fluor (registered trademark) Red 635nm, Quasar (registered trademark) 570nm, Quasar (registered trademark) 548nm, Quasar (registered trademark) 566nm (Cy 3), Quasar (registered trademark) 670nm, Quasar (registered trademark) 647nm, Quasar (registered trademark) 670nm, Quasar (registered trademark) 705nm, Quasar (registered trademark) 690nm, Quasar (registered trademark) 705nm (Cy 5.5), Pulsar (registered trademark) 650 Dyes, SuperRox (registered trademark) Dyes).

[0047] In another embodiment, the peptide is further modified, such as by being glycosylated, or by PEGylation, amidation, esterification, acylation, acetylation and / or alkylation.

[0048] In one embodiment, the peptide comprises, or consists of, tandem repeats that can include, or consist of, any one or more of the amino acid sequences of the sequences described herein.

[0049] In one embodiment, the peptide is cyclic. The cyclic structure can be achieved by any suitable synthetic method. Thus, heterodetic linkages can include, but are not limited to, formation via disulfide bridges, cysteine bridges, alkylene bridges or sulfide bridges.

[0050] In a further embodiment, the peptide comprises, or consists of, a fusion. For example, the peptide may comprise a fusion of the amino acid sequence of SEQ ID NO:1 or 136.

[0051] The term "fusion" of a peptide relates to the amino acid sequence corresponding to, for example, SEQ ID NO:1 or 136 (or a fragment or variant thereof) fused to any other peptide. For example, the peptide may be fused to a polypeptide such as glutathione-S-transferase (GST) or protein A to facilitate purification of the peptide. Examples of such fusions are well known to those skilled in the art. Similarly, the peptide may be fused to an oligo-histidine tag such as His6, or to an epitope recognized by an antibody such as the well-known Myc tag epitope. Fusions to any variant or derivative of the peptide are also included within the scope of the present disclosure.

[0052] Alternatively, the fused moiety may be a lipophilic molecule or peptide domain capable of facilitating intracellular uptake of the polypeptide, as is known to those skilled in the art.

[0053] Novel peptide In one embodiment, the present disclosure relates to a peptide comprising, or consisting of, an amino acid sequence selected from the group consisting of KPLAEIDSIELSYGIK (SEQ ID NO: 136), GDPNDGRGDSVVYGLR (SEQ ID NO: 137), VDTYDGGISVVYGLR (SEQ ID NO: 138), VDTYDGDGSVVYGLR (SEQ ID NO: 139), VDVPEGDISLAYGLR (SEQ ID NO: 157), LDGLVRAYDNISPVG (SEQ ID NO: 158), GDPNGDISVVYGLR (SEQ ID NO: 159), VDVPNGDISLAYRLR (SEQ ID NO: 160), VDVPEGDISLAYRLR (SEQ ID NO: 161), or variants or fragments thereof.

[0054] In one embodiment, the present disclosure relates to a peptide comprising, or consisting of, an amino acid sequence selected from the group consisting of KCLAECDSIELSYGIK (SEQ ID NO: 141), CLAEIDSC (SEQ ID NO: 142), CFKPLAEIDSIECSYGIK (SEQ ID NO: 143), KPLAEDISIELSYGIK (SEQ ID NO: 145), KPLAEIGDIELSYGIK (SEQ ID NO: 146), KPLAEGDIELSYGIK (SEQ ID NO: 147), KPLAEIELSYGIK (SEQ ID NO: 148), KPLAEIDSIELTYGIK (SEQ ID NO: 149), KPLAEIDGIELSYGIK (SEQ ID NO: 150), KPLAEIDGIELTYGIK (SEQ ID NO: 151), KPLAEIGSIELSYGIK (SEQ ID NO: 152), KGLAEIDSIELSYGIK (SEQ ID NO: 153), KPLAGIDSIGLSYGIK (SEQ ID NO: 154), KCLAEIDSCELSYGIK (SEQ ID NO: 155) and CFKPLAEIDSIEC (SEQ ID NO: 156), or variants or fragments thereof.

[0055] In one embodiment, the present disclosure relates to a medicament comprising a peptide comprising the amino acid sequence KPLAEIDSIELSYGIK (SEQ ID NO: 136), or variants or fragments thereof, or consisting of the same.

[0056] In one embodiment, the present disclosure relates to a medicament comprising a peptide comprising the amino acid sequence KPLAGIDSIGLSYGIK (SEQ ID NO: 154), or variants or fragments thereof, or consisting of the same.

[0057] In one embodiment, the present disclosure relates to a medicament comprising a peptide comprising the amino acid sequence KGLAEIDSIELSYGIK (SEQ ID NO: 153), or variants or fragments thereof, or consisting of the same.

[0058] In one embodiment, the present disclosure relates to a medicament comprising a peptide comprising the amino acid sequence KCLAECDSIELSYGIK (SEQ ID NO: 141), or variants or fragments thereof, or consisting of the same.

[0059] In one embodiment, the present disclosure relates to a medicament comprising a peptide comprising the amino acid sequence KPLAEIDGIELTYGIK (SEQ ID NO: 151), or variants or fragments thereof, or consisting of the same.

[0060] In one embodiment, the present disclosure relates to a medicament comprising a peptide comprising the amino acid sequence KPLAEIGSIELSYGIK (SEQ ID NO: 152), or variants or fragments thereof, or consisting of the same.

[0061] In one embodiment, the present disclosure relates to a medicament comprising a peptide comprising the amino acid sequence KPLAEIELSYGIK (SEQ ID NO: 148), or variants or fragments thereof, or consisting of the same.

[0062] In one embodiment, the present disclosure b) a peptide or peptidomimetic comprising, or consisting of, the amino acid sequences GDPNDGRGDSVVYGLR (SEQ ID NO:137), VDTYDGGISVVYGLR (SEQ ID NO:138), VDTYDGDGSVVYGLR (SEQ ID NO:139), VDVPEGDISLAYGLR (SEQ ID NO:157), LDGLVRAYDNISPVG (SEQ ID NO:158), GDPNGDISVVYGLR (SEQ ID NO:159), VDVPNGDISLAYRLR (SEQ ID NO:160), VDVPEGDISLAYRLR (SEQ ID NO:161), V(beta-D)TYDGDISVVYGLR (SEQ ID NO:167), VDTY(beta-D)GDISVVYGLR (SEQ ID NO:168), VDTYDG(beta-D)ISVVYGLR (SEQ ID NO:169); b) a polynucleotide encoding the peptide of a) upon expression; c) a vector comprising the polynucleotide of b); d) a cell comprising the polynucleotide of b) or the vector of c), relating to a medicament comprising the same.

[0063] In some embodiments, the variant comprises, or consists of, a sequence in which any one amino acid is modified with another proteinogenic or non-proteinogenic amino acid, provided that no more than 5 amino acids are so modified, no more than 4 amino acids, no more than 3 amino acids, no more than 2 amino acids, no more than 1 amino acid, etc. are modified. In some embodiments, one or more amino acids are conservatively substituted.

[0064] In some embodiments, the peptide comprises, or consists of, one or more additional amino acids inserted at the N- and / or C-terminus of the sequence, and / or internally. In one embodiment, at least 2 additional amino acids are inserted, such as at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 15, or at least 20 additional amino acids.

[0065] In some embodiments, the peptide has an amino acid length of no more than 85, such as no more than 80, no more than 75, no more than 70, no more than 65, no more than 60, no more than 55, no more than 50, no more than 45, no more than 40, no more than 35, no more than 30, no more than 28, no more than 26, no more than 24, no more than 22, no more than 20, no more than 19, no more than 18, no more than 17, no more than 16, no more than 15, no more than 14, no more than 13, no more than 12, no more than 11, no more than 10 amino acids.

[0066] In some embodiments, the peptide is further conjugated to a moiety that can be selected from the group consisting of PEG, monosaccharides, fluorophores, chromophores, radioactive compounds, and cell-penetrating peptides.

[0067] In one embodiment, the peptide is further modified, such as by glycosylation, or by PEGylation, amidation, esterification, acylation, acetylation and / or alkylation.

[0068] In some embodiments, the peptide comprises, or consists of, tandem repeats that can include any one or more of the amino acid sequences of the sequences described hereinabove.

[0069] In one embodiment, the peptide is cyclic. The cyclic structure can be achieved by any suitable synthetic method. Thus, examples of heterodetic linkages include, but are not limited to, formation via cysteine crosslinking, disulfide crosslinking, alkylene crosslinking, or sulfide crosslinking.

[0070] Indications The agents of the present disclosure are suitable for use in the treatment of endocrine, nutritional, and metabolic diseases and disorders.

[0071] In one embodiment, the mammal in need of treatment of the endocrine disease, nutritional disease, and / or metabolic disease is a human.

[0072] In some embodiments, the endocrine disease, nutritional disease, and / or metabolic disease is selected from the group consisting of diabetes, type 1 diabetes, type 2 diabetes, malnutrition-related diabetes, disorders of glucose regulation and pancreatic endocrinology, insulin resistance syndrome, impaired glucose tolerance, hyperglycemia, hyperinsulinemia, and any combination thereof.

[0073] In some embodiments, the endocrine disease, nutritional disease, and / or metabolic disease is selected from the group consisting of diabetes, thyroid disorders, disorders of glucose regulation and pancreatic endocrinology, endocrine gland disorders, malnutrition, nutritional deficiencies, obesity, overnutrition, and metabolic disorders.

[0074] In one embodiment, diabetes is selected from the group consisting of type 1 diabetes, type 2 diabetes, malnutrition-related diabetes, identified diabetes, and unidentified diabetes.

[0075] In one embodiment, the disorders of glucose regulation and pancreatic endocrinology are selected from the group consisting of non-diabetic hypoglycemic coma and disorders of pancreatic endocrinology.

[0076] In one embodiment, the disorders of obesity and overnutrition are selected from the group consisting of localized adiposity, overnutrition, and sequelae of overnutrition.

[0077] In one embodiment, the nutritional deficiency disorder is selected from the group consisting of disorders of aromatic amino acid metabolism, disorders of branched-chain amino acid metabolism and fatty acid metabolism, disorders of amino acid metabolism, lactose intolerance, disorders of carbohydrate metabolism, disorders of sphingolipid metabolism, lipid storage disorders, disorders of glycosaminoglycan metabolism, disorders of glycoprotein metabolism, disorders of lipoprotein metabolism, hyperlipidemia, disorders of purine and pyrimidine metabolism, disorders of porphyrin and bilirubin metabolism, disorders of mineral metabolism, cystic fibrosis, amyloidosis, reduction in body fluid volume, disorders of body fluid, electrolyte and acid-base balance, and post-treatment endocrine and metabolic disorders.

[0078] Composition In one aspect, the present disclosure relates to a composition comprising the agent described herein.

[0079] In one aspect, the present disclosure is for use in the treatment of endocrine diseases, nutritional diseases and / or metabolic diseases in mammals, a) (i) General formula: KX2LAX5X6X7X8IX 10 LX 12 YGIK (SEQ ID NO:140) a peptide comprising or consisting of the amino acid sequence represented by (wherein, X2 is C, P or G; X5 is E or G; X6 is C, D or I; X7 is D, I, S or G; X8 is S, D or G; X 10 is E or G; X 12 is S or T, provided that if X 12 is T, the peptide contains no more than 25 amino acid residues); and (ii) General formula: VDZ3Z4Z5GZ7Z8SZ 10 Z 11YGLR (SEQ ID NO:68) A peptide comprising or consisting of the amino acid sequence shown (wherein Z3 is T or V; Z4 is Y or P; Z5 is D or N; Z7 is D or G; Z8 is I or G; Z 10 is V or L; Z 11 is V or A), and (iii) A peptide comprising or consisting of an amino acid sequence selected from the group consisting of KCLAECDSIELSYGIK (SEQ ID NO:141), CLAEIDSC (SEQ ID NO:142), CFKPLAEIDSIECSYGIK (SEQ ID NO:143), KPLAEIELSYGIK (SEQ ID NO:148), KCLAEIDSCELSYGIK (SEQ ID NO:155), and CFKPLAEIDSIEC (SEQ ID NO:156), A peptide or peptide analog selected from the group consisting of; b) A polynucleotide encoding the peptide of a) upon expression; c) A vector containing the polynucleotide of b); d) A cell containing the polynucleotide of b) or the vector of c), Relates to a medicament selected from the group consisting of.

[0080] In one aspect, the present disclosure relates to a composition for use in the treatment of endocrine, nutritional and / or metabolic diseases comprising a medicament described herein. In one embodiment, the composition is a pharmaceutical composition.

[0081] In one embodiment, the agent further comprises a second active ingredient. The second active ingredient may be selected from the group consisting of insulin, glucagon-like peptide-1 (GLP-1), biguanide, forskolin compound, sulfonylurea, dipeptidyl peptidase-4 (DPP4) inhibitor, alpha-glucosidase inhibitor, thiazolidinedione, meglitinide, and sodium-glucose cotransporter-2 (SGLT2) inhibitor.

[0082] Other methods In one aspect, the present disclosure relates to a method of treating an endocrine disorder, a nutritional disorder, and / or a metabolic disorder, comprising administering to a subject in need of the agent described herein.

[0083] In one aspect, the present disclosure relates to the use of an agent for the manufacture of a medicament for use in the treatment of an endocrine disorder, a nutritional disorder, and / or a metabolic disorder in a mammal.

[0084] In one aspect, the present disclosure relates to a polynucleotide encoding the peptide described herein upon expression. In one aspect, the present disclosure relates to a vector comprising the polynucleotide encoding the peptide described herein upon expression. In one aspect, the present disclosure relates to a cell comprising the polynucleotide or the vector encoding the peptide described herein upon expression.

[0085] In one aspect, the present disclosure relates to a method for increasing insulin secretion, comprising administering to an individual in need of a therapeutically effective amount of the peptide described herein. In one embodiment, the method is an in vitro method.

[0086] In one aspect, the present disclosure relates to a method for reducing blood glucose levels, comprising administering to an individual in need of a therapeutically effective amount of the peptide described herein. In one embodiment, the method is an in vitro method. In one embodiment, insulin secretion is increased. In another embodiment, intracellular glucose uptake is increased. In yet another embodiment, insulin production is increased. In another embodiment, glucagon production is decreased.

[0087] In one aspect, the present disclosure relates to a method for improving the morphology of β-cells, such as an in vitro method, comprising administering to an individual in need of a therapeutically effective amount of the peptide described herein.

[0088] In one aspect, the present disclosure relates to a method for improving the viability of β-cells, comprising administering to an individual in need of a therapeutically effective amount of the peptide described herein.

[0089] In one aspect, the present disclosure relates to a method for delaying the onset of diabetes, as well as diabetes-related disorders and diseases, comprising administering to an individual in need of a therapeutically effective amount of the peptide described herein.

[0090] In one embodiment of the present disclosure, the agent may further comprise a detectable moiety. For example, the detectable moiety may 99m Tc, 111 In, 67 Ga, 68 Ga, 72 As, 89 Zr, 123 I and 201 Tl, and may comprise or consist of a radioisotope such as a radioisotope selected from the group consisting of. Thus, the binding moiety may be coupled to a nanoparticle having the ability for multi-imaging (e.g., SPECT, PET, MRI, optical or ultrasound). Alternatively, the detectable moiety may comprise or consist of a paramagnetic isotope, such as paramagnetic isotopes 157 Gd, 55Mn, 162 Dy, 52 Cr and 56 is selected from the group consisting of Fe.

[0091] If the agent contains a detectable moiety, the detectable moiety may be detectable by contrast techniques such as SPECT, PET, MRI, optical, or ultrasound contrast.

[0092] In one aspect, the present disclosure relates to the use of the agents described herein for the preparation of a diagnostic composition for the diagnosis of a disease, disorder, or injury of the pancreas in an individual.

[0093] Item 1.a) A peptide, wherein the peptide or peptide analog has the general formula: KX2LAX5X6X7X8IX 10 LX 12 YGIK (SEQ ID NO:140) A peptide comprising the amino acid sequence shown by (wherein, X2 is C, P or G; X5 is E or G; X6 is C, D or I; X7 is D, I, S or G; X8 is S, D or G; X 10 is E or G; X 12 is S or T, provided that if X 12 is T, the peptide contains no more than 25 amino acid residues, provided that if X2 is P, X5 is E, X6 is I, X7 is D, X8 is S, X 10 is E, and X 12 is S, the peptide contains no more than 85 amino acid residues), or a bioactive fragment and / or variant represented by SEQ ID NO:140; b) a polynucleotide encoding the peptide of a) upon expression; c) a vector containing the polynucleotide of b); d) a cell containing the polynucleotide of b) or the vector of c), A medicament comprising the same.

[0094] 2. General formula: VDVPZ5GDISLAYZ 13 LR(SEQ ID NO:164) (wherein, Z5 is E or N; Z 13 is R or G) A medicament comprising a peptide containing the amino acid sequence represented by the formula.

[0095] 3. General formula: VDTYDGZ7Z8SVVYGLR(SEQ ID NO:165) (wherein, Z7 is D or G; Z8 is I or G) A medicament comprising a peptide containing the amino acid sequence represented by the formula.

[0096] 4. General formula: GDPNZ5Z6Z7Z8Z9SVVYGLR(SEQ ID NO:166) (wherein, Z5 is D or G; Z6 is D or G; Z7 is I or R; Z8 is G or absent; Z9 is D or absent) A medicament comprising a peptide containing the amino acid sequence represented by the formula.

[0097] 5. a) A peptide comprising, or consisting of, an amino acid sequence selected from the group consisting of GDPNDGRGDSVVYGLR (SEQ ID NO:137), VDTYDGGISVVYGLR (SEQ ID NO:138), VDTYDGDGSVVYGLR (SEQ ID NO:139), VDVPEGDISLAYGLR (SEQ ID NO:157), LDGLVRAYDNISPVG (SEQ ID NO:158), GDPNGDISVVYGLR (SEQ ID NO:159), VDVPNGDISLAYRLR (SEQ ID NO:160), VDVPEGDISLAYRLR (SEQ ID NO:161); b) A polynucleotide encoding the peptide of a) upon expression; c) A vector containing the polynucleotide of b); d) A cell containing the polynucleotide of b) or the vector of c), The medicament according to items 2 to 4, comprising the same.

[0098] 6. The medicament according to item 1, wherein the peptide has the general formula: KX2LAX5X6X7X8IX 10 LSYGIK (SEQ ID NO:162) (wherein, X2 is C, P or G; X5 is E or G; X6 is C, I or absent; X7 is D, G or absent; X8 is S, G or absent; X 10 is E or G) and comprising, or consisting of, the amino acid sequence represented thereby.

[0099] 7. The medicament according to item 1, wherein the peptide has the general formula: KX2LAX5IX 10 LSYGIK (SEQ ID NO:163) (wherein, X2 is C, P or G; X5 is E or G; X10 is E or G) The agent according to item 6, comprising the amino acid sequence shown in .

[0100] 8.a) Peptides or peptide analogs comprising or consisting of the amino acid sequences GDPNDGRGDSVVYGLR (SEQ ID NO:137), VDTYDGGISVVYGLR (SEQ ID NO:138), VDTYDGDGSVVYGLR (SEQ ID NO:139), VDVPEGDISLAYGLR (SEQ ID NO:157), LDGLVRAYDNISPVG (SEQ ID NO:158), GDPNGDISVVYGLR (SEQ ID NO:159), VDVPNGDISLAYRLR (SEQ ID NO:160), VDVPEGDISLAYRLR (SEQ ID NO:161), V(beta-D)TYDGDISVVYGLR (SEQ ID NO:167), VDTY(beta-D)GDISVVYGLR (SEQ ID NO:168), VDTYDG(beta-D)ISVVYGLR (SEQ ID NO:169) and; b) A polynucleotide encoding the peptide of a) upon expression; c) A vector comprising the polynucleotide of b); d) A cell comprising the polynucleotide of b) or the vector of c), and; an agent.

[0101] 9. The agent according to any one of the preceding items, which is non-naturally derived, for example, contains non-proteinogenic amino acid residues.

[0102] 10. The agent according to any one of the preceding items, which is conjugated to a moiety.

[0103] 11. The agent according to any one of the preceding items, wherein the moiety is selected from the group consisting of polyethylene glycol (PEG), monosaccharides, fluorophores, chromophores, radioactive compounds, and cell-penetrating peptides.

[0104] 12. A drug according to any one of the preceding items, which is further modified, such as being glycosylated, or by PEGylation, amidation, esterification, acylation, acetylation and / or alkylation.

[0105] 13. A drug according to any one of the preceding items, which contains or consists of tandem repeats.

[0106] 14. A drug according to any one of the preceding items, wherein the tandem repeat contains or consists of any one or more amino acid sequences of the sequences described in the preceding item.

[0107] 15. A drug according to any of the preceding items, which is fused to another polypeptide.

[0108] 16. A drug according to any one of the preceding items, wherein the polypeptide is selected from the group consisting of glutathione - S - transferase (GST) and protein A.

[0109] 17. A drug according to any of the preceding items, which is fused to a tag.

[0110] 18. A drug according to any one of the preceding items, wherein the tag is an oligo - histidine tag.

[0111] 19. A drug according to any of the preceding items, wherein the drug is cyclic, such as the peptide being cyclic.

[0112] 20. A drug according to any of the preceding items, wherein the peptide or peptide analog can form at least one intramolecular cysteine bridge, for example, to form a cyclic or partially cyclic peptide.

[0113] 21. The peptide or peptide analog comprises, or consists of, an amino acid sequence selected from the group consisting of KCLAECDSIELSYGIK (SEQ ID NO:141), CLAEIDSC (SEQ ID NO:142), CFKPLAEIDSIECSYGIK (SEQ ID NO:143), KPLAEDISIELSYGIK (SEQ ID NO:145), KPLAEIGDIELSYGIK (SEQ ID NO:146), KPLAEGDIELSYGIK (SEQ ID NO:147), KPLAEIELSYGIK (SEQ ID NO:148), KPLAEIDSIELTYGIK (SEQ ID NO:149), KPLAEIDGIELSYGIK (SEQ ID NO:150), KPLAEIDGIELTYGIK (SEQ ID NO:151), KPLAEIGSIELSYGIK (SEQ ID NO:152), KGLAEIDSIELSYGIK (SEQ ID NO:153), KPLAGIDSIGLSYGIK (SEQ ID NO:154), KCLAEIDSCELSYGIK (SEQ ID NO:155), and CFKPLAEIDSIEC (SEQ ID NO:156), or variants or fragments thereof, and is the agent according to any of the preceding items.

[0114] 22. The peptide or peptide analog comprises, or consists of, the amino acid sequence KPLAEIDSIELSYGIK (SEQ ID NO:136), or variants or fragments thereof, and is the agent according to any of the preceding items.

[0115] 23. The peptide or peptide analog comprises, or consists of, the amino acid sequence KPLAGIDSIGLSYGIK (SEQ ID NO:154), or variants or fragments thereof, and is the agent according to any of the preceding items.

[0116] 24. The peptide or peptide analog comprises, or consists of, the amino acid sequence KGLAEIDSIELSYGIK (SEQ ID NO:153), or variants or fragments thereof, and is the agent according to any of the preceding items.

[0117] 25. The agent according to any one of the preceding items, wherein the peptide or peptide analog contains, or consists of, the amino acid sequence KCLAECDSIELSYGIK (SEQ ID NO: 141), or a variant or fragment thereof.

[0118] 26. The agent according to any one of the preceding items, wherein the peptide or peptide analog contains, or consists of, the amino acid sequence KPLAEIDGIELTYGIK (SEQ ID NO: 151), or a variant or fragment thereof.

[0119] 27. The agent according to any one of the preceding items, wherein the peptide or peptide analog contains, or consists of, the amino acid sequence KPLAEIGSIELSYGIK (SEQ ID NO: 152), or a variant or fragment thereof.

[0120] 28. The agent according to any one of the preceding items, wherein the peptide or peptide analog contains, or consists of, the amino acid sequence KPLAEIELSYGIK (SEQ ID NO: 148), or a variant or fragment thereof.

[0121] 29. The agent according to any one of the preceding items, wherein the variant contains, or consists of, a sequence in which any one amino acid is modified with another proteinogenic or non-proteinogenic amino acid, provided that no more than 5 amino acids are so modified.

[0122] 30. The agent according to any one of the preceding items, wherein the variant contains, or consists of, a sequence in which no more than 5 amino acids, such as no more than 4 amino acids, no more than 3 amino acids, no more than 2 amino acids, or no more than 1 amino acid, are modified with another proteinogenic or non-proteinogenic amino acid.

[0123] 31. The agent according to any one of the preceding items, wherein one or more amino acids are conservatively substituted.

[0124] 32. The agent according to any one of the preceding items, wherein the peptide or peptidomimetic comprises, or consists of, one or more additional amino acids inserted at the N- and / or C-terminus of the sequence and / or internally.

[0125] 33. The agent according to any one of the preceding items, wherein the peptide or peptidomimetic comprises one additional amino acid conjugated to either the N- or C-terminus.

[0126] 34. The agent according to any of the preceding items, comprising no more than 85 amino acids, such as no more than 80, no more than 75, no more than 70, no more than 65, no more than 60, no more than 55, no more than 50, no more than 45, no more than 40, no more than 35, no more than 30, no more than 28, no more than 26, no more than 24, no more than 22, no more than 20, no more than 19, no more than 18, no more than 17, no more than 16, no more than 15, no more than 14, no more than 13, no more than 12, no more than 11, no more than 10 amino acids.

[0127] 35. The agent according to any one of the preceding items, conjugated to the N- or C-terminus of the peptide and comprising at least 2 additional amino acids, such as at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 15, or at least 20 amino acids.

[0128] 36. The agent according to any one of the preceding items, further comprising a detectable moiety.

[0129] 37. The agent according to any one of the preceding items, wherein the detectable moiety comprises, or consists of, a radioisotope.

[0130] 38. The radioisotope is 99m Tc, 111 In, 67 Ga, 68 Ga, 72 As,89 Zr, 123 I and 201 Tl, and is a drug according to any one of the preceding items.

[0131] 39. The detectable part is detectable by a contrast technique such as SPECT, PET, MRI, optical or ultrasonic contrast, and is a drug according to any one of the preceding items.

[0132] 40. Use of a drug according to any one of the preceding items for the preparation of a diagnostic composition for the diagnosis of pancreatic diseases, disorders or injuries in an individual.

[0133] 41. A composition comprising a drug according to any one of the preceding items.

[0134] 42. A composition according to any one of the preceding items, which is a pharmaceutical composition.

[0135] 43. A drug or composition according to any one of the preceding items for use as a medicine.

[0136] 44. For use in the treatment of endocrine diseases, nutritional diseases and / or metabolic diseases in mammals, a) (i) General formula: KX2LAX5X6X7X8IX 10 LX 12 YGIK (SEQ ID NO:140) A peptide comprising or consisting of the amino acid sequence represented by (wherein, X2 is C, P or G; X5 is E or G; X6 is C, D or I; X7 is D, I, S or G; X8 is S, D or G; X 10 is E or G; X 12 is S or T, but as a condition, X 12if T, the peptide contains no more than 25 amino acid residues); or a bioactive fragment and / or variant thereof represented by SEQ ID NO: 140; (ii) General formula: VDZ3Z4Z5GZ7Z8SZ 10 Z 11 YGLR (SEQ ID NO: 68) a peptide comprising or consisting of the amino acid sequence represented by (wherein Z3 is T or V; Z4 is Y or P; Z5 is D or N; Z7 is D or G; Z8 is I or G; Z 10 is V or L; Z 11 is V or A): a peptide selected from the group consisting of; b) a polynucleotide encoding the peptide of a) upon expression; c) a vector containing the polynucleotide of b); d) a cell containing the polynucleotide of b) or the vector of c), a medicament selected from the group consisting of.

[0137] 45. The medicament or composition for use according to item 44, wherein the peptide comprises or consists of an amino acid sequence selected from the group consisting of KCLAECDSIELSYGIK (SEQ ID NO: 141), CLAEIDSC (SEQ ID NO: 142), CFKPLAEIDSIECSYGIK (SEQ ID NO: 143), KPLAEIELSYGIK (SEQ ID NO: 148), KCLAEIDSCELSYGIK (SEQ ID NO: 155), and CFKPLAEIDSIEC (SEQ ID NO: 156).

[0138] 46. A medicament or composition for use according to any one of the preceding items, wherein the peptide is selected from the group consisting of SEQ ID NO: 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, and 156.

[0139] 47. A medicament or composition for use according to any one of the preceding items, wherein the peptide is selected from the group consisting of SEQ ID NO: 1, 136, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 67, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 135, 137, 138, 139, 157, 158, 159, 160, 161, 167, 168 and 169.

[0140] 48. A medicament or composition for use according to any one of the preceding items, wherein the medicament contains a second or additional active ingredient.

[0141] 49. The pharmaceutical or composition for use according to item 48, wherein the second or further active ingredient is selected from the group consisting of insulin, glucagon-like peptide-1 (GLP-1), sulfonylurea, dipeptidyl peptidase-4 (DPP4) inhibitor, alpha-glucosidase inhibitor, thiazolidinedione, meglitinide and sodium-glucose cotransporter-2 (SGLT2) inhibitor.

[0142] 50. The pharmaceutical or composition for use according to any of the preceding items for use in the treatment of endocrine diseases, nutritional diseases and / or metabolic diseases in mammals.

[0143] 51. The pharmaceutical or composition for use according to item 50, wherein the mammal is a human.

[0144] 52. The pharmaceutical or composition for use according to any one of the preceding items, wherein the endocrine disease, nutritional disease and / or metabolic disease is selected from the group consisting of diabetes, type 1 diabetes, type 2 diabetes, malnutrition-related diabetes, glucose regulation and pancreatic endocrine disorders, insulin resistance syndrome, impaired glucose tolerance, hyperglycemia, hyperinsulinemia, and any combination thereof.

[0145] 53. The pharmaceutical or composition for use according to any one of the preceding items, wherein the endocrine disease, nutritional disease and / or metabolic disease is selected from the group consisting of diabetes, thyroid disorders, glucose regulation and pancreatic endocrine disorders, endocrine gland disorders, malnutrition, nutritional deficiencies, obesity, overnutrition, and metabolic disorders.

[0146] 54. The pharmaceutical or composition for use according to any one of the preceding items, wherein the diabetes is selected from the group consisting of type 1 diabetes, type 2 diabetes, malnutrition-related diabetes, specified diabetes, and unspecified diabetes.

[0147] 55. A medicament or composition for use according to any one of the preceding items, wherein the disorder of glucose regulation and pancreatic endocrine is selected from the group consisting of non-diabetic hypoglycemic coma and disorder of pancreatic endocrine.

[0148] 56. A medicament or composition for use according to any one of the preceding items, wherein the disorder of obesity and overnutrition is selected from the group consisting of localized adiposis, overnutrition, and sequelae of overnutrition.

[0149] 57. A medicament or composition for use according to any one of the preceding items, wherein the disorder of nutritional deficiency is selected from the group consisting of disorders of aromatic amino acid metabolism, disorders of branched-chain amino acid metabolism and fatty acid metabolism, disorders of amino acid metabolism, lactose intolerance, disorders of carbohydrate metabolism, disorders of sphingolipid metabolism, lipid storage disorders, disorders of glycosaminoglycan metabolism, disorders of glycoprotein metabolism, disorders of lipoprotein metabolism, hyperlipidemia, disorders of purine and pyrimidine metabolism, disorders of porphyrin and bilirubin metabolism, disorders of mineral metabolism, cystic fibrosis, amyloidosis, reduction of body fluid volume, disorders of body fluid, electrolyte and acid-base balance, and endocrine and metabolic disorders after treatment.

[0150] 58. A method for treating endocrine diseases, nutritional diseases and / or metabolic diseases, comprising administering to a subject in need of a medicament according to any one of the preceding items.

[0151] 59. Use of a medicament according to any one of the preceding items for the manufacture of a medicament for use in the treatment of endocrine diseases, nutritional diseases and / or metabolic diseases in mammals.

[0152] 60. A method for delaying the onset of diabetes and diabetes-related disorders and diseases, comprising administering to an individual in need of a therapeutically effective amount of a medicament according to any one of the preceding items.

[0153] 61. A method for reducing blood glucose levels, comprising administering to an individual in need of a therapeutically effective amount of a medicament according to any one of the preceding items.

[0154] 62. The method according to item 61, wherein the insulin secretion is increased.

[0155] 63. The method according to item 61, wherein the intracellular uptake of glucose is increased.

[0156] 64. The method according to item 61, wherein the insulin production is increased.

[0157] 65. The method according to item 61, wherein the glucagon production is decreased.

[0158] 66. A method for improving the viability of beta cells, comprising administering to an individual in need of a therapeutically effective amount of the agent according to any one of the preceding items.

[0159] 67. A method for improving the morphology of beta cells, comprising administering to an individual in need of a therapeutically effective amount of the agent according to any one of the preceding items.

[0160] 68. A method for stabilizing or improving the viability and / or morphology of pancreatic islets, comprising administering to an individual in need of a therapeutically effective amount of the agent according to any one of the preceding items.

[0161] Examples The present disclosure is further illustrated by the following examples, which should not be construed as limiting the present disclosure. These examples demonstrate that the exemplary peptides of the present disclosure have the ability to stimulate beta cell proliferation and protect and rescue beta cells from apoptosis induced by glucotoxic conditions. It is also demonstrated that the exemplary peptides have the ability to stimulate insulin secretion from rat beta cells and isolated mouse pancreatic islets, and that the peptides reduce glucagon levels. Furthermore, the examples demonstrate that the peptides reduce plasma glucose levels in vivo in a glucose tolerance test and that the peptides delay the onset of type 1 diabetes in BB lyp / lyp rats.

[0162] Example 1: Design of Peptides Novel peptides were designed according to the following rational structure-activity studies. In FOL-005 (SEQ ID NO:1), the peptide was designed around the RGD site but mutated to create different structures that could potentially interact with different integrins. Sequences similar to FOL-005 were identified in the third fibronectin type III repeat domain (TNfn3) of tenascin C and were found to be moderately similar to the mutant RGD site of FOL-005. One peptide was designed from this sequence and designated FOL-014. The X-ray crystal structure of the tenascin 3 TNfn3 domain (PDB code 1 TEN, Leahy et al. (1992) Science 258(5084):987-91) was analyzed. The FOL-014 (SEQ ID NO:136) sequence extends across the entire third beta sheet and in front of a beta turn. FOL-014 variants were designed to allow for structural modification and stabilization of the three-dimensional molecular structure. Specifically, the peptide variants had side chains covering the exposed beta turn region and several cyclic variants, maintaining the geometric structure.

[0163] All peptides were synthesized by solid-phase peptide synthesis using multiple peptide manufacturers. The peptide variants were mainly provided by Biopeptide Inc. located in California.

[0164] Example 2: FOL-005 and FOL-014 Induced the Proliferation of INS-1 Cells To examine whether FOL-005 and FOL-014 could induce the proliferation of beta cells, the inventors used INS-1 cells. Rat INS-1 cells were seeded in 96-well plates in supplemented RPMI medium and the medium was changed to RPMI without supplementation 2 hours later.

[0165] During the proliferation experiment, cells were incubated under different test conditions (FOL-005, FOL-014, with coating, or in solution, 48-hour incubation), and during the last 20 hours of the culture period, the cells were pulse-labeled with 1 μCi / well [methyl-3H] thymidine. Subsequently, the cells were harvested onto glass fiber filters using a FilterMate harvester. The filters were air-dried, and the bound radioactivity was measured using a liquid scintillation counter. To test whether FOL-005 affects β-cell proliferation, INS-1 cells were treated with increasing amounts of soluble FOL-005 (0.06 - 6 μM) for 48 hours, and proliferation was measured by the incorporation of radiolabeled thymidine into newly synthesized DNA. FOL-005 stimulated the proliferation of INS-1 cells (Figure 1A). Wells coated with either FOL-005 or FOL-014, blocked later with bovine serum albumin (BSA), and then added with INS-1 cells also stimulated proliferation compared to the control (Ctrl) coating wells (Figures 1B - C).

[0166] This demonstrated that FOL-005 and FOL-014 interact with β-cells and induce proliferation.

[0167] Example 3: FOL-005 protected β-cells from glucotoxicity Since glucotoxicity in pancreatic β-cells is an established process in type 2 diabetes, the inventors next examined the protective effect of FOL-005 on β-cells under glucotoxic conditions. First, the inventors confirmed that 20 mM glucose induced cell apoptosis in INS cells after 48 hours of exposure. RPMI medium containing high glucose (20 mM) induced more annexin V-positive cells and greater caspase-3 activity in INS cells compared to cells incubated in medium containing 5 mM glucose (Figures 2A - B). Exposure of INS-1 cells to 20 mM glucose for the same time as FOL-005 decreased cell apoptosis as detected by both annexin V staining and caspase-3 activity (Figures 2A - B). The percentage of apoptosis in INS-1 cells was measured with a caspase-3 assay kit or stained with an annexin V apoptosis detection kit and 7-AAD. Caspase-3 activity was measured by fluorescence at an excitation wavelength of 380 nm and an emission wavelength of 440 nm. Thereafter, caspase-3 activity was normalized to the protein concentration of each well. Measurement of annexin V-stained cells was performed using a CyAn ADP flow cytometer and analyzed with Summit V4.3 software.

[0168] In conclusion, while it is well known that glucotoxicity induces β-cell apoptosis, glucotoxicity-induced apoptosis was reduced in the presence of FOL-005.

[0169] Example 4: FOL-005 induced insulin secretion from INS-1 cells To examine the stimulatory effect of FOL-005 on insulin secretion, INS-1 β cells were used in the following experiments. Cells were seeded overnight in cRPMI and then washed with PBS and pre-incubated at 37 °C for 60 minutes in Krebs Ringer bicarbonate buffer (KRB) (pH 7.4) supplemented with 10 mM HEPES and 0.1% bovine serum albumin. After pre-incubation, the buffer was exchanged and INS-1 cells were incubated under different test conditions (0 mM, 5 mM or 20 mM glucose) and stimulated with peptide FOL-005 or FOL-015 (SEQ ID NO:158) for 60 minutes at 37 °C or left untreated. Immediately after incubation, aliquots of the buffer were removed and frozen for the next insulin assay using an insulin radioimmunoassay kit.

[0170] From the results, it was demonstrated that β cells stimulated with the FOL-005 peptide secreted more insulin under glucose-free conditions compared to unstimulated control cells or cells stimulated with the FOL-015 control peptide (Figure 3A). INS-1 β cells exposed to glucose (5 mM or 20 mM) responded with increased insulin secretion after stimulation with the FOL-005 peptide (6 μM) (Figure 3B). INS-1 cells stimulated with 6 μM FOL-005 peptide in the presence of 20 mM glucose responded with more insulin secretion compared to FOL-005-stimulated cells incubated with 5 mM glucose (Figure 3B).

[0171] Example 5: FOL-005 induced insulin secretion from mouse islets Mouse islets were isolated from 8-week-old male C57BL / 6J mice (Taconic). Mice were sacrificed by overdose of isoflurane and cervical dislocation. 3 ml of 0.9 U / ml collagenase P was injected into the pancreatic duct to inflate the pancreas. The pancreas was then removed and the collagen was digested at 37 °C for 19 minutes. The sample was shaken vigorously to disrupt the tissue. The digest was treated with Ca 2+ and Mg 2+It was transferred into ice-cold Hank's balanced salt solution (HBSS) containing . The suspension was allowed to stand for 10 minutes to sediment the islets, and the islets were washed 4 times with fresh HBSS. Then, the islets were selected and sorted according to size. Islets (n = 3 per well of a 96-well plate) were pre-incubated at 37 °C for 10 minutes in KRB buffer (pH 7.4) supplemented with 10 mM HEPES and 0.1% bovine serum albumin. After pre-incubation, the buffer was exchanged, and the islets were incubated at 37 °C for 60 minutes under different test conditions (untreated Ctrl, FOL-005 peptide, or GLP-1) in fresh KRB buffer containing 0.1% bovine serum albumin. Immediately after incubation, an aliquot of the buffer was taken out and frozen for the next insulin assay.

[0172] From the results, it was demonstrated that isolated mouse islets stimulated with GLP-1 (100 nM) or FOL-005 (6 μM) secreted more insulin compared to unstimulated control islets (Figure 3C).

[0173] Example 6: FOL-014 induced insulin secretion from INS-1 cells Using INS-1 β cells, the stimulating effect of FOL-014 on insulin secretion was examined. The cells were seeded overnight and then washed with PBS and pre-incubated at 37 °C for 60 minutes in Krebs-Ringer bicarbonate buffer (KRB) (pH 7.4) supplemented with 10 mM HEPES and 0.1% bovine serum albumin. After pre-incubation, the buffer was exchanged, and the INS-1 cells were incubated in fresh KRB buffer supplemented with 10 mM HEPES and 0.1% bovine serum albumin and stimulated with the peptide FOL-014 at 37 °C for 60 minutes or left untreated. Immediately after incubation, an aliquot of the buffer was taken out and frozen for the next insulin assay.

[0174] From the results, it was demonstrated that β cells stimulated with the FOL-014 peptide secreted more insulin compared to unstimulated control cells (Figure 4A).

[0175] Example 7: FOL-014 induced insulin secretion from mouse islets Mouse islets were isolated from 8-week-old C57BL / 6J male mice as described in Example 5. Thereafter, the islets were sorted and selected according to size. Islets (n = 5 per well of a 96-well plate) were pre-incubated in 200 μl of KRB buffer (pH 7.4) supplemented with 10 mM HEPES and 0.1% bovine serum albumin at 37°C for 10 minutes. After pre-incubation, the buffer was exchanged and the islets were incubated at 37°C for 60 minutes under different test conditions (untreated Ctrl, FOL-014 peptide, and GLP-1) in fresh KRB buffer containing 0.1% bovine serum albumin. Immediately after incubation, an aliquot of the buffer was removed and frozen for the subsequent insulin assay.

[0176] The results showed that mouse islets stimulated with FOL-014 (6 μM) secreted more insulin compared to unstimulated control islets (Figure 4B). GLP-1 (100 nM) or FOL-014 (0.6 μm) did not affect insulin secretion (Figure 4B).

[0177] Examples 8 - 11: Stimulation of insulin secretion from INS-1 cell line by FOL-014, FOL-005 and related peptides Materials and methods: Unless otherwise noted, rat INS-1 β cells (60 - 70 passages) were cultured in cRPMI medium (RPMI 1640 supplemented with 10% fetal bovine serum, 50 IU / ml penicillin, 50 mg / L streptomycin, 10 mM HEPES, 2 mM L-glutamine, 1 mM sodium pyruvate, and 50 μM beta-mercaptoethanol) at 37°C and 5% CO2. INS-1 cells were seeded in 96-well plates in cRPMI medium (2×10 3After incubating overnight in (cells / well), the cells were washed with PBS and pre-incubated at 37 °C for 120 minutes in Krebs-Ringer bicarbonate buffer (pH 7.4) supplemented with 10 mM HEPES, 0.1% bovine serum albumin, and 2.8 mM glucose. After pre-incubation, the buffer was exchanged with fresh Krebs-Ringer buffer supplemented with the specific glucose concentrations and peptides for the individual experiments described below as previously described. Immediately after incubation at 37 °C for 60 minutes, an aliquot of the buffer was removed and frozen for the next insulin ELISA assay.

[0178] Example 8. Insulin secretion induced by FOL-014 is non-linearly dose-dependent Insulin release from INS-1 cells was measured after exposure to increasing concentrations of FOL-014 and compared to the stimulatory effects of GLP-1 and untreated controls at high glucose concentration (16.7 mM). All concentrations of FOL-014 tested induced significantly higher insulin release compared to untreated controls. FOL-014 elicited insulin release within the same range as 100 mM GLP-1 at 6 nM and above. At concentrations in the range of 0.6 - 60 nM, insulin secretion increased linearly with increasing FOL-014 concentration. Exposure to FOL-014 concentrations of 600 nM and above did not increase insulin secretion (Figure 5).

[0179] The results demonstrated that FOL-014 significantly increased insulin secretion from INS-1 β-cells in vitro in a non-linearly dose-dependent manner.

[0180] Example 9. The ability of FOL-014 to induce insulin secretion is glucose-dependent Insulin release from INS-1 cells was measured after exposure to increasing concentrations of glucose and 60 nM FOL-014. In untreated control samples, at high concentrations of glucose, glucose at 11.1 mM or higher increased insulin secretion. In the presence of FOL-014, insulin secretion was already significantly increased in a glucose-dependent manner from 5.5 mM glucose (Figure 6).

[0181] The results also demonstrated that the presence of FOL-014 significantly increased insulin secretion from INS-1 β-cells in vitro in a glucose concentration-dependent manner, and that FOL-014 was effective at slightly higher glucose levels.

[0182] Example 10. FOL-014 or FOL-005 in combination with GLP-1 increased insulin secretion compared to either peptide alone Insulin secretion from INS-1 cells was measured after exposure to FOL-005, FOL-014, GLP-1, or combinations thereof, and expressed as a percentage relative to untreated controls. The effect of the combination of GLP-1 and FOL-014 resulted in a significantly higher insulin release rate than GLP-1 alone or FOL-014 alone. The additive effect of the combination of FOL-005 and GLP-1 was less pronounced but increased insulin secretion compared to GLP-1 alone. The experiments were performed in the presence of 16.7 mM glucose (Figure 7).

[0183] The results demonstrated that the combination of GLP-1 and FOL-014 can further enhance insulin secretion from INS-1 cells in vitro compared to each peptide alone. Furthermore, the combination of FOL-005 and GLP-1 tended to increase insulin secretion.

[0184] Example 11. The ability of novel peptide analogs to induce insulin secretion in pancreatic β-cell lines was investigated A novel peptide analog derived from either FOL-005 or FOL-014 was tested for its ability to induce insulin secretion in two separate INS-1 cell lines in the presence of 16.7 mM glucose. In addition to FOL-005, FOL-014, and GLP-1, high glucose (16.7 mM) and low glucose (2.8 mM) controls (not shown) were included in each experiment, and the peptide concentration was 100 nM. To correct for variation between experiments, all values were normalized to the mean value of the high glucose control in each individual experiment and expressed as a percentage. Next, the analogs were ranked according to performance (Figures 11A and 11B). Peptide analogs that induced an insulin response below the high glucose control mean value were considered non-functional and thus excluded (not shown).

[0185] The results demonstrated the ability of multiple novel peptide analogs to increase insulin secretion from INS-1 β cells in vitro.

[0186] Example 12. FOL-014 increases insulin secretion from mouse-derived pancreatic islets Twelve-week-old male C57 / b16 mice were euthanized by isoflurane and cervical dislocation. After clamping the hepatic duct, 3 ml of 0.9 U / ml collagenase P was injected into the bile duct to inflate the pancreas. Subsequently, the pancreas was removed and digested at 37°C for 19 minutes. The sample was shaken vigorously to disrupt the tissue. The digest was quickly transferred into ice-cold Hank's balanced salt solution containing Ca 2+ and Mg 2+ The suspension was allowed to stand for 8 minutes to sediment the pancreatic islets, and the pancreatic islets were washed 4 times in the same manner. Subsequently, the pancreatic islets were sorted and selected according to size.

[0187] Freshly isolated islets were seeded into 5 groups in a 96-well plate and pre-incubated at 37 °C for 1 hour in Krebs Ringer bicarbonate buffer (pH 7.4). The islets were incubated at 37 °C for 1 hour in Krebs Ringer buffer solution supplemented with 0.6 or 6 μM FOL-014, or 100 nM GLP-1, or left unsupplemented as a control. Immediately after incubation, the medium was removed for assays of insulin and glucagon using Mercodia's ELISA kit. The effect of FOL-014 on insulin (Figures 8A and B) and glucagon (Figures 8C and D) secretion from isolated mouse islets was measured in the presence of low glucose (2.8 mM; Figures 8A and C) or high glucose (16.7 mM; Figures 8B and D) concentrations. A significant effect of FOL-014 was observed in the presence of high glucose for insulin and in the presence of both high and low glucose for glucagon. The effect of FOL-014 was different from that of GLP-1, which increased insulin secretion even in low glucose samples, but glucagon secretion could not be inhibited under low glucose conditions.

[0188] The results demonstrated that FOL-014 increased insulin secretion and inhibited glucagon secretion in islets.

[0189] Example 13. FOL-014 decreased plasma glucose levels in an intraperitoneal glucose tolerance test (IPGTT) in mice Whole blood was collected from 10-week-old wild-type male C57b1 / 6 mice for glucose and insulin measurements. Mice were classified into three groups after a 4-hour fast and received an intraperitoneal injection (ip) of either saline, 30 nmol / kg peptide (Figure 9A) or 200 nmol / kg peptide (Figure 9B). Fifteen minutes after FOL-014 or saline (control) injection, mice were administered 2 g glucose / kg ip. Blood glucose concentrations were measured at 5, 15, 30, 45, and 60 minutes after glucose injection. Statistical calculations were performed using the Student's t-test. The 200 nmol / kg dose of FOL-014 significantly decreased plasma glucose levels as measured by the area under the curve, compared to the control. In addition, the difference was significant at 15, 30, and 45 minutes. At the 30 nmol / kg dose, FOL-014 decreased plasma glucose levels and showed a significant effect 45 minutes after glucose injection.

[0190] The results demonstrated that FOL-014 can decrease plasma glucose levels in a glucose tolerance test performed in healthy wild-type mice.

[0191] Example 14. FOL-014 Delayed the Onset of Type 1 Diabetes in BB lyp / lyp Rats BB lyp / lyp rats were randomized for placebo (sodium chloride, 9 mg / ml) or FOL-014 treatment three times a week starting on day 40 until the onset of type 1 diabetes defined as plasma glucose levels ≥ 11.1 mM. A 100 nmol / kg dose of FOL-014 peptide or placebo (saline) in saline was administered subcutaneously and discontinued immediately if the animals exceeded the critical plasma glucose level. The difference between FOL-014-treated animals and placebo-treated animals was significant both when represented as the mean age of onset of type 1 diabetes (Figure 10A) and when described as the percentage of type 1 diabetes-onset animals per day (Figure 10B).

[0192] The results demonstrated that FOL-014 treatment significantly delayed the onset of type 1 diabetes in BB lyp / lyp rats.

[0193] Example 15. FOL-005 and FOL-014 showed organ-specific distribution patterns in mice C57Bl / 6 mice were subcutaneously injected with H 3 labeled FOL-005 and euthanized at 1 hour (Figure 12A) or 2 hours (Figure 12B) after injection. After dividing the whole body, the distribution of the labeled peptide was visualized. Strong binding was revealed in the pancreas and the injection site. Using a Pearl Trilogy Small Animal Imaging System, the in vivo biodistribution and tissue localization of two Cy7.5-labeled peptides, FOL-005 (Figure 12C) and FOL-014 (Figure 12D), in NMRI nude mice by subcutaneous injection were examined. High peptide accumulation was revealed in the pancreatic tissue area. The same distribution pattern was found after i.v. administration (not shown). The dose of each peptide was 10 nmol / mouse. Mice were imaged before injection of the labeled peptide, and at 5 minutes, 20 minutes, 50 minutes, 60 minutes, 2 hours, 4 hours, 6 hours, 24 hours, and 48 hours after administration.

[0194] Example 16. Tissue-specific imaging for diagnostic use The agent prepared as defined earlier in this specification is labeled by conjugation to a suitable contrast probe or moiety using methods known to those of ordinary skill in the art. The conjugated peptide probe agent is then administered to a subject, and then the biodistribution is monitored, for example, up to 48 hours after administration. The conjugated agent is thus used as a diagnostic or predictive tool for examining pancreatic conditions. To that end, the conjugated agent is suitable for detecting, diagnosing, or monitoring diseases, disease processes and progression, susceptibility, and for measuring the effectiveness of treatment. The agent is particularly suitable for monitoring the diabetic state of a subject. The conjugated agent is also used for monitoring diseases, specifically diabetes, and / or for predicting the risk of its onset. The test is used alone or in combination with other tests known to those of ordinary skill in the art, such as blood tests, genetic tests, urine tests, and biopsies.

[0195] Example 17: Overview of Sequences [Table 1] TIFF2025090703000008.tif245165TIFF2025090703000009.tif242166TIFF2025090703000010.tif236166TIFF2025090703000011.tif236166TIFF2025090703000012.tif243166TIFF2025090703000013.tif233166

Claims

1. a) i) VDTYDGGISVVYGLR (SEQ ID NO: 138), VDTYDGDGSVVYGLR (SEQ ID NO: 139), VDVPEGDISLAYGLR (SEQ ID NO: 157), LDGLVRAYDNISPVG (SEQ ID NO: 158), GDPNGDISVVYGLR (SEQ ID NO: 159), VDVPNGDISLAYRLR (SEQ ID NO: 160), VDVPEGDISLAYRLR (SEQ ID NO: 161), V (Beta-D) TYDGDISVVYGLR (SEQ ID NO: 167), VDTY (Beta-D) GDISVVYGLR (SEQ VDTYDG(beta-D)ISVVYGLR (SEQ ID NO: 169); ii) a peptide consisting of the amino acid sequence GDPNDGRGDSVVYGLR (SEQ ID NO: 137); A peptide selected from the group consisting of: b) a polynucleotide which upon expression encodes the peptide of a); c) a vector comprising the polynucleotide of b); or d) a cell comprising the polynucleotide of b) or the vector of c); A drug comprising:

2. 2. The agent of claim 1, wherein the agent is conjugated to a moiety selected from the group consisting of polyethylene glycol (PEG), a monosaccharide, a fluorophore, a chromophore, a radioactive compound, and a cell-penetrating peptide.

3. 3. The agent according to claim 1 or 2, wherein the agent is further modified by being glycosylated or by being PEGylated, amidated, esterified, acylated, acetylated and / or alkylated.

4. The agent of any one of claims 1 to 3, wherein the agent comprises or consists of a tandem repeat.

5. The agent according to any one of claims 1 to 4, wherein the agent is fused to another polypeptide selected from the group consisting of glutathione-S-transferase (GST) and protein A, or is fused to a tag.

6. The drug of any one of claims 1 to 5, wherein the drug is cyclic.

7. The medicament according to any one of claims 1 to 6, wherein the medicament comprises a second or further active ingredient selected from the group consisting of insulin, glucagon-like peptide-1 (GLP-1), sulfonylureas, dipeptidyl peptidase-4 (DPP4) inhibitors, alpha-glucosidase inhibitors, thiazolidinediones, meglitinides and sodium glucose cotransporter-2 (SGLT2) inhibitors.

8. An agent according to any one of claims 1 to 7 for use as a medicine.

9. 1. A medicament for use in the treatment of an endocrine and / or metabolic disorder in a mammal, said medicament comprising: a) (i) VDTYDGGISVVYGLR (SEQ ID NO: 138), VDTYDGDISVVYGLR (SEQ ID NO: 1), VDTYDGDISVVYGL (SEQ ID NO: 3), VDTYDGDISVVYG (SEQ ID NO: 6), GDISVVYGLR (SEQ ID NO: 26), VDTYDGRGDSVVYGLR (SEQ ID NO: 67), VDVPNGDISLAYGLR (SEQ ID NO: 69), VDVPNGDISLAYGL (SEQ ID NO:71), DVPNGDISLAYGLR(SEQ ID NO: 72), VDVPNGDISLAYG (SEQ ID NO: 74), PNGDISLAYGLR (SEQ ID NO: 81), VDVPNGDISLA (SEQ ID NO: 83), GDISLAYGLR (SEQ ID NO: 94), VDVPNGDIS (SEQ ID NO: 96), CLAEIDSC (SEQ ID NO: 142), CFKPLAEIDSIECSYGIK (SEQ ID NO: 143), KPLAEGDIELSYGIK (SEQ ID NO: 147), KPLAEIELSYGIK (SEQ ID NO: 148), KCLAEIDSCELSYGIK (SEQ ID NO: 155), CFKPLAEIDSIEC (SEQ ID NO: 156), VDTYDGDGSVVYGLR (SEQ ID NO: 139), VDVPEGDISLAYGLR (SEQ ID NO: 157), LDGLVRAYDNISPVG (SEQ ID NO: 158), GDPNGDISVVYGLR (SEQ ID NO: 159), VDVPNGDISLAYRLR (SEQ ID NO: 160), VDVPEGDISLAYRLR (SEQ ID NO: 161), V (Beta-D) TYDGDISVVYGLR (SEQ ID NO: 167), VDTY (Beta-D) GDISVVYGLR (SEQ ID SEQ ID NO:168), VDTYDG(beta-D)ISVVYGLR (SEQ ID NO:169); (ii) a peptide or peptide analog consisting of the amino acid sequence GDPNDGRGDSVVYGLR (SEQ ID NO: 137); A peptide selected from the group consisting of: b) a polynucleotide which upon expression encodes the peptide of a); c) a vector comprising the polynucleotide of b); or d) a cell comprising the polynucleotide of b) or the vector of c); A pharmaceutical comprising a drug comprising:

10. The method of claim 9, wherein the agent is cyclic.

11. 11. The pharmaceutical for use according to claim 9 or 10, wherein the medicament comprises a second or further active ingredient selected from the group consisting of insulin, glucagon-like peptide-1 (GLP-1), sulfonylureas, dipeptidyl peptidase-4 (DPP4) inhibitors, alpha-glucosidase inhibitors, thiazolidinediones, meglitinides and sodium glucose cotransporter-2 (SGLT2) inhibitors.

12. The medicament for use according to any of claims 9 to 11, wherein the endocrine and / or metabolic disease is selected from the group consisting of diabetes, type 1 diabetes, type 2 diabetes, malnutrition-related diabetes, specified diabetes, unspecified diabetes, disorders of glucose regulation and pancreatic endocrinology, insulin resistance syndrome, impaired glucose tolerance, hyperglycemia, hyperinsulinemia, and any combination thereof.

13. The medicament for use according to any of claims 9 to 12, wherein the endocrine and / or metabolic disease is selected from the group consisting of thyroid disorders, endocrine gland disorders, malnutrition, nutritional deficiencies, obesity, overnutrition, and metabolic disorders.

14. 14. The medicament for use according to any of claims 9 to 13, wherein the endocrine and / or metabolic disease is selected from the group consisting of non-diabetic hypoglycemic coma, disorders of the endocrine pancreas, localized adiposity, hypernutrition, sequelae of hypernutrition, disorders of aromatic amino acid metabolism, disorders of branched chain amino acid metabolism and fatty acid metabolism, disorders of amino acid metabolism, lactose intolerance, disorders of carbohydrate metabolism, disorders of sphingolipid metabolism, lipid accumulation disorders, disorders of glycosaminoglycan metabolism, disorders of glycoprotein metabolism, disorders of lipoprotein metabolism, lipemia, disorders of purine and pyrimidine metabolism, disorders of porphyrin and bilirubin metabolism, disorders of mineral metabolism, cystic fibrosis, amyloidosis, hypovolemia, disorders of fluid, electrolyte and acid-base balance, and post-treatment endocrine and metabolic disorders.

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