Use of a novel polypeptide in the treatment or prevention of insulin resistance

Abstract

The application discloses application of a novel polypeptide in treatment or prevention of insulin resistance. The amino acid sequence of the polypeptide is shown in SEQ ID NO:1; or contains the sequence shown in SEQ ID NO:1; or a polypeptide derivative with deletion, insertion or substitution of one or more amino acids and with the same biological function as the polypeptide molecule. The polypeptide has the use in preparation of medicines for preventing and / or treating insulin resistance, lowering blood sugar level, stimulating glycogen synthesis and inhibiting gluconeogenesis.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of biomedicine, and in particular to a novel polypeptide for treating or preventing insulin resistance. BACKGROUND

[0002] Metabolic syndrome includes diabetes, obesity, hypertension and dyslipidemia, and the key factor is that the body develops insulin resistance (IR).

[0003] Insulin is an important metabolic hormone produced by pancreatic beta cells, which regulates glucose, lipid and protein metabolism, and promotes energy balance, growth and aging. The insulin signaling (IS) pathway is damaged, leading to decreased insulin sensitivity, thereby inducing IR.

[0004] The causes of IR are multifaceted and complex, and there is still controversy in science. However, given the heterogeneity of its mechanism, a diversified strategy to improve insulin sensitivity and / or activate the insulin signaling pathway can help improve IR and thus contribute to personalized medicine. SUMMARY

[0005] The present application aims to provide a novel polypeptide for treating or preventing insulin resistance.

[0006] To achieve the above-mentioned purpose, the present application provides a polypeptide, characterized in that the amino acid sequence of the polypeptide is as follows:

[0007] 1) as shown in SEQ ID NO: 1;

[0008] 2) containing the sequence shown in SEQ ID NO: 1;

[0009] 3) a polypeptide derivative of the sequence of 1) above, which lacks, inserts or substitutes one or more amino acids and has the same biological function as the polypeptide molecule described in (a) or (b).

[0010] Further, the nucleic acid sequence of the polypeptide is as shown in SEQ ID NO: 2.

[0011] The present application also protects the use of the polypeptide in the preparation of a medicament for preventing and / or treating insulin resistance.

[0012] The present application also protects the use of the polypeptide in the preparation of a medicament for reducing blood glucose levels.

[0013] The present application also protects the use of the polypeptide in the preparation of a medicament for glycogen synthesis agonists and gluconeogenesis inhibitors.

[0014] Further, the polypeptide has any one of the following functions:

[0015] directly inhibiting the exocytosis of ATG7; and / or

[0016] activating a signal transduction factor in the IS pathway; and / or

[0017] increasing glycogen synthesis; and / or

[0018] reducing glucose production, inhibiting gluconeogenesis; and / or

[0019] regulating glucose metabolism.

[0020] Further, the dosage form of the drug is any pharmaceutically acceptable dosage form.

[0021] KTADKKLLLEQAANE. SEQ ID NO: 1.

[0022] AAGACTGCAGATAAGAAGCTCCTT TTG GAACAAGCAGCAAATGAG. SEQ ID NO: 2.

[0023] The present application also protects a pharmaceutical composition, characterized in that it comprises the polypeptide and a pharmaceutically acceptable carrier or excipient.

[0024] The present application first discovered that the autophagy-related factor ATG7 is exocytosed into the circulatory system of the body and participates in the regulation of glucose metabolism. On the basis of this discovery, the inventors of the present application found through creative research that the Aap1 polypeptide of the present application can prevent ATG7 protein from being exocytosed outside the cell, thereby affecting glucose metabolism.

[0025] The Aap1 polypeptide is derived from the 97-111th amino acid sequence of human ATG7 protein or an ATG7 fragment containing the above-mentioned amino acid sequence, which can specifically inhibit the exocytosis of ATG7, promote glycogen synthesis, inhibit gluconeogenesis, and thus improve the symptoms of insulin resistance; it only affects glucose metabolism, so it has less side effects and a longer half-life. BRIEF DESCRIPTION OF DRAWINGS

[0026] Figure 1 Figure 1 shows the exocytosis of the autophagy-related factor ATG7. Wherein a is the promotion of glucose to exocytose ATG7 outside the cell; the left side of b is the promotion of insulin to be taken up by the cell; the right side of b is the promotion of glucagon to exocytose ATG7 outside the cell.

[0027] Figure 2The ATG7 is involved in the metabolic regulation diagram of glucose. Wherein a is that the ATG7 protein promotes the increase of glycogen synthesis of primary hepatocytes; b is that the ATG7 protein reduces the glucose production of primary hepatocytes.

[0028] Figure 3 The Aap1 inhibits the excretion of ATG7. Wherein, a is a schematic diagram of ATG7 protein mutation; b is that ATG7-NM mutation inhibits its secretion to the extracellular; c is a schematic diagram of Aap1 design; d is that Aap1 inhibits the secretion of ATG7 to the extracellular.

[0029] Figure 4 The Aap1 regulates the insulin signal pathway to affect the metabolism of glucose. Wherein, a is that Aap1 regulates the insulin signal pathway in HepG2 cells; b is that Aap1 reduces the glucose tolerance of C57 mice. DETAILED DESCRIPTION

[0030] The embodiments of the present application are described in detail below, examples of which are shown in the accompanying drawings, wherein the same or similar notations represent the same or similar elements or elements having the same or similar functions throughout. The embodiments described below by reference to the drawings are exemplary and are intended to explain the present application, and cannot be understood as a limitation of the present application. If the specific techniques or conditions are not mentioned in the embodiments, the techniques or conditions described in the literature in the art or according to the product manual are used. If the reagents or instruments used are not mentioned by the manufacturer, they are all conventional products that can be obtained by purchase.

[0031] I. General methods involved in the embodiments.

[0032] 1. Immunoprecipitation experiment: centrifuge the cell culture solution at 800 rpm, 4°C, for 5 min, quantitatively take the supernatant, add the corresponding antibody, incubate at 4°C overnight, add protein A / G-beads, incubate at 4°C for 4-6 hours. After the immunoprecipitation reaction, centrifuge at 4°C, 700g for 5 min, discard the supernatant, wash the protein A / G-beads for 3 times, then add 2x SDS loading buffer 40μL, 95°C for 10 min, and detect and analyze by Western blotting.

[0033] 2. Culture of primary hepatocytes: after the C57 mice are killed by cervical dislocation, the liver is taken, cut and ground, centrifuged, trypsinized, centrifuged, and inoculated on rat tail collagen.

[0034] 3. Hepatic glycogen detection: the primary cultured hepatocytes are detected for hepatic glycogen, and the specific experimental steps are described in the reagent kit manual.

[0035] 4. Glucose production assay: Primary cultured fetal hepatocytes or hepatocytes were incubated in glucose production medium (sugar-free DMEM without phenol red, 20 mM sodium lactate and 2 mM sodium pyruvate) for 4 hours, and the supernatant was collected to determine the glucose concentration. The specific experimental steps are described in the kit instructions. The protein concentration of the sample was determined by BCA method, and the sample was calibrated.

[0036] 5. In vivo blood glucose level detection: The mouse tail tip was cut, and the Roche blood glucose meter and blood glucose test paper were used to detect the blood glucose level in the mouse.

[0037] 6. Glucose tolerance test: The mice were fasted for 16 hours, and then intraperitoneally injected with glucose at 1 g per kilogram of body weight. The blood glucose level was measured at 0, 15, 30, 50, 120 minutes. The area under the curve (AUC) of the IPGTT result was calculated using the blood glucose levels at 0 (BG0), 30 (BG30), 60 (BG60), 90 (BG90) and 120 (BG120) minutes by the following formula: AUC (min·mg / dL) = 30 min x [1 / 2 x (BG0+BG120) + 1 x (BG30+BG60+BG90)].

[0038] 7. Cell culture and transfection: Human hepatoma cell line HepG2 was cultured with 10% FBS, 1% NEAA in MEM medium, human hepatoma cell line Huh7 was cultured with 10% FBS in DMEM medium, and primary hepatocytes were cultured with 15% FBS in DMEM medium. All transfections were completed using Lipofectamin 3000 (Invitrogen).

[0039] 8. Plasmid construction and point mutation: GFP-ATG7, GFP-NM, GFP-CM were constructed according to the kit instructions. The sequence of ATG7 is shown in SEQ ID NO: 3, the sequence of NM is shown in SEQ ID NO: 4 (wherein 313-315 bp of GCN represents GCT / GCA / GCC / GCG), and the sequence of CM is shown in SEQ ID NO: 5 (wherein 1714-1716 bp can also be TCA / TCC / TGC / AGT / AGC).

[0040] ATG7 WT (SEQ ID NO: 3):

[0041] ATGGCGGCAGCTACGGGGGATCCTGGACTCTCTAAACTGCAGTTTGCCCCTTTTAGTAGTGCCTTGGATGTTGGGTTTT

[0042] GGCATGAGTT GACCCAGAAG AAGCTGAACG AGTATCGGCT GGATGAAGCT CCCAAGGACA TTAAGGGTT ATTACTACAA

[0043] TGGTGACTCT GCTGGGCTGC CAGCTCGCTT AACATTGGAG TTCAGTGCTT TTGACATGAG TGCTCCCACC CAGCCCGT

[0044] TGCTGCCCAG CTATTGGAAC ACTGTATAAC ACCAACACAC TCGAGTCTTT CAAGACTGCA GATAAGAAGC TCCTTTTGG

[0045] AACAAGCAGC AAATGAGATA TGGGAATCCA TAAAATCAGG CACTGCTCTT GAAAACCCTGT ACTCCTCAAC AAGTTCCT

[0046] CCTCTTGACA TTTGCAGATC TAAAGAAGTA CCACTTCTAC TATTGGTTTT GCTATCCTGCC CTCTGTCTTC CAGAGAGT

[0047] TTACCTCTCA TTCAGGGGCC AGTGGGTTTG GATCAAAGGT TTTCACTAAA ACAGATTGAA GCACTAGAGT GTGCATATG

[0048] ATAATCTTTG TCAAACAGAA GGAGTCACAG CTCTTCCTTA CTTCTTAATC AAGTATGATG AGAACATGGT GCTGGTTTC

[0049] CTTGCTTAAA CACTACAGTG ATTTCTTCCA AGGTCAAAGG ACGAAGATAACA ATTGGTGTAT ATGATCCCTG TAACTTA

[0050] GCCCAGTACC CTGGATGGCC TTTGAGGAAT TTTTTGGTCC TAGCAGCCCA CAGATGGAGT AGCAGTTTCC AGTCTGTTG

[0051] AAGTTGTTTGCTTCCGTGACCGTACCATGCAGGGGGCGAGAGACGTTGCCCACAGCATCATCTTCGAAGTGAAGCTTCC

[0052] AGAAATGGCATTTAGCCCAGATTGTCCTAAAGCAGTTGGATGGGAAAAGAACCAGAAAGGAGGCATGGGACCAAGGATG

[0053] GTGAACCTCAGTGAATGTATGGACCCTAAAAGGTTAGCTGAGTCATCAGTGGATCTAAATCTCAAACTGATGTGTTGGA

[0054] GATTGGTTCCTACTTTAGACTTGGACAAGGTTGTGTCTGTCAAATGTCTGCTGCTTGGAGCCGGCACCTTGGGTTGCAA

[0055] TGTAGCTAGGACGTTGATGGGTTGGGGCGTGAGACACATCACATTTGTGGACAATGCCAAGATCTCCTACTCCAATCCT

[0056] GTGAGGCAGCCTCTCTATGAGTTTGAAGATTGCCTAGGGGGTGGTAAGCCCAAGGCTCTGGCAGCAGCGGACCGGCTCC

[0057] AGAAAATATTCCCCGGTGTGAATGCCAGAGGATTCAACATGAGCATACCTATGCCTGGGCATCCAGTGAACTTCTCCAG

[0058] TGTCACTCTGGAGCAAGCCCGCAGAGATGTGGAGCAACTGGAGCAGCTCATCGAAAGCCATGATGTCGTCTTCCTATTG

[0059] ATGGACACCAGGGAGAGCCGGTGGCTTCCTGCCGTCATTGCTGCAAGCAAGAGAAAGCTGGTCATCAATGCTGCTTTGG

[0060] GATTTGACACATTTGTTGTCATGAGACATGGTCTGAAGAAACCAAAGCAGCAAGGAGCTGGGGACTTGTGTCCAAACCA

[0061] CCCTGTGGCATCTGCTGACCTCCTGGGCTCATCGCTTTTTGCCAACATCCCTGGTTACAAGCTTGGCTGCTACTTCTGC

[0062] AATGATGTGGTGGCCCCAGGAGATTCAACCAGAGACCGGACCTTGGACCAGCAGTGCACTGTGAGTCGTCCAGGACTGG

[0063] CCGTGATTGCAGGAGCCCTGGCCGTGGAATTGATGGTATCTGTTTTGCAGCATCCAGAAGGGGGCTATGCCATTGCCAG

[0064] CAGCAGTGACGATCGGATGAATGAGCCTCCAACCTCTCTTGGGCTTGTGCCTCACCAGGTTCTTGATCAATATGAACGA

[0065] GAAGGATTTAACTTCCTAGCCAAGGTGTTTAATTCTTCACATTCCTTCTTAGAAGACTTGACTGGTCTTACATTGCTGCATCAAGAAACCCAAGCTGCTGAGATCTGGGACATGAGCGATGATGAGACCATCTGA。

[0066] ATG7 NM(SEQ ID NO:4),其中的N代表A,T,G,C:

[0067] ATGGCGGCAGCTACGGGGGATCCTGGACTCTCTAAACTGCAGTTTGCCCCTTTTAGTAGTGCCTTGGATGTTGGGTTTT

[0068] GGCATGAGTTGACCCAGAAGAAGCTGAACGAGTATCGGCTGGATGAAGCTCCCAAGGACATTAAGGGTTATTACTACAA

[0069] TGGTGACTCT GCTGGGCTGC CAGCTCGCTT AACATTGGAG TTCAGTGCTT TTGACATGAG TGCTCCCACC CAGCCCGT

[0070] TGCTGCCCAG CTATTGGAAC ACTGTATAAC ACCAACACAC TCGAGTCTTT CAAGACTGCA GATAAGAAGC TCCTT G CN G

[0071] AACAAGCAGC AAATGAGATA TGGGAATCCA TAAAATCAGG CACTGCTCTT GAAAACCCTG TACTCCTCA ACAAGTTCCT

[0072] CCTCTTGACA TTTGCAGATC TAAAGAAGTA CCACTTCTAC TATTGGTTTT GCTATCCTGC CCTCTGTCTT CCAGAGAGT

[0073] TTACCTCTCA TTCAGGGGCC AGTGGGTTTG GATCAAAGGT TTTCACTAAA ACAGATTGAA GCACTAGAGT GTGCATATG

[0074] ATAATCTTTG TCAAACAGAA GGAGTCACAG CTCTTCCTTA CTTCTTAATC AAGTATGATG AGAACATGGT GCTGGTTTC

[0075] CTTGCTTAAA CACTACAGTG ATTTCTTCCA AGGTCAAAGG ACGAAGATAA CAATTGGTGT ATATGATCCC TGTAACTTA

[0076] GCCCAGTACC CTGGATGGCC TTGAGGAATT TTTTGGTCCT AGCAGCCCAC AGATGGAGTA GCAGTTTCCA GTCTGTTG

[0077] AAGTTGTTTG CTTCCGTGAC CGTACCATGC AGGGGGCGAG AGACGTTGCC CACAGCATCA TCTTCGAAGT GAAGCTTCC

[0078] AGAAATGGCATTTAGCCCAGATTGTCCTAAAGCAGTTGGATGGGAAAAGAACCAGAAAGGAGGCATGGGACCAAGGATG

[0079] GTGAACCTCAGTGAATGTATGGACCCTAAAAGGTTAGCTGAGTCATCAGTGGATCTAAATCTCAAACTGATGTGTTGGA

[0080] GATTGGTTCCTACTTTAGACTTGGACAAGGTTGTGTCTGTCAAATGTCTGCTGCTTGGAGCCGGCACCTTGGGTTGCAA

[0081] TGTAGCTAGGACGTTGATGGGTTGGGGCGTGAGACACATCACATTTGTGGACAATGCCAAGATCTCCTACTCCAATCCT

[0082] GTGAGGCAGCCTCTCTATGAGTTTGAAGATTGCCTAGGGGGTGGTAAGCCCAAGGCTCTGGCAGCAGCGGACCGGCTCC

[0083] AGAAAATATTCCCCGGTGTGAATGCCAGAGGATTCAACATGAGCATACCTATGCCTGGGCATCCAGTGAACTTCTCCAG

[0084] TGTCACTCTGGAGCAAGCCCGCAGAGATGTGGAGCAACTGGAGCAGCTCATCGAAAGCCATGATGTCGTCTTCCTATTG

[0085] ATGGACACCAGGGAGAGCCGGTGGCTTCCTGCCGTCATTGCTGCAAGCAAGAGAAAGCTGGTCATCAATGCTGCTTTGG

[0086] GATTTGACACATTTGTTGTCATGAGACATGGTCTGAAGAAACCAAAGCAGCAAGGAGCTGGGGACTTGTGTCCAAACCA

[0087] CCCTGTGGCATCTGCTGACCTCCTGGGCTCATCGCTTTTTGCCAACATCCCTGGTTACAAGCTTGGCTGCTACTTCTGC

[0088] AATGATGTGGTGGCCCCAGGAGATTCAACCAGAGACCGGACCTTGGACCAGCAGTGCACTGTGAGTCGTCCAGGACTGG

[0089] CCGTGATTGCAGGAGCCCTGGCCGTGGAATTGATGGTATCTGTTTTGCAGCATCCAGAAGGGGGCTATGCCATTGCCAG

[0090] CAGCAGTGACGATCGGATGAATGAGCCTCCAACCTCTCTTGGGCTTGTGCCTCACCAGGTTCTTGATCAATATGAACGA

[0091] GAAGGATTTAACTTCCTAGCCAAGGTGTTTAATTCTTCACATTCCTTCTTAGAAGACTTGACTGGTCTTACATTGCTGCATCAAGAAACCCAAGCTGCTGAGATCTGGGACATGAGCGATGATGAGACCATCTGA。

[0092] ATG7 CM(SEQ ID NO:5)

[0093]

[0094] 9. Western blotting: Cells were lysed in RIPA lysis buffer for 30 min at 4°C, then centrifuged at 13000 rpm for 20 min at 4°C, and the supernatant was taken. The protein concentration of the sample was determined by BCA method and adjusted to the same concentration. Add loading buffer, mix well, then 95°C for 10 min, protein SDS polyacrylamide gel electrophoresis, electrotransfer to PVDF membrane, block with 5% skim milk at room temperature for 1 hour, dilute the primary antibody to the appropriate concentration, incubate at 4°C overnight. Wash 3 times with PBST, incubate the secondary antibody at room temperature for 1-4 hours, wash 3 times with PBST, and develop with ECL.

[0095] II. Antibodies, kits and drugs used in the experiments in the examples.

[0096] 1. Glycogen detection kit from BIOVISION.

[0097] 2. Glucose detection kit from Sigma.

[0098] III. Commercial antibodies used in the experiments in the examples are from the following companies respectively.

[0099] 1. Rabbit anti-ATG7 antibody, mouse anti-GFP antibody, and mouse anti-α-tubulin antibody from Sigma.

[0100] 2. Rabbit anti-AKT phosphorylation antibody and rabbit anti-GFP antibody from CST.

[0101] IV. Unless otherwise specified, other drugs and reagents used in the examples are from Sigma.

[0102] V. Experimental animals: C57 mice from Beijing Vital River Laboratory Animal Technology Co., Ltd.

[0103] VI. Aap1 peptide (KTADKKLLLEQAANE, SEQ ID NO: 1) was synthesized directly by Shanghai Qiangyao Biotechnology Co., Ltd.

[0104] Example 1: Immunoprecipitation experiment to detect autophagy-related factor ATG7 exosome

[0105] 1.1 Glucose concentration affects ATG7 exosome

[0106] HepG2 cells were given no glucose culture or normal glucose culture for 24 hours, and the expression level of ATG7 in the culture solution was detected by immunoprecipitation experiment, see General Method 1 and 7.

[0107] Results show that compared with HepG2 cells cultured without glucose, the protein level of ATG7 in the culture medium of cells cultured with normal glucose is significantly decreased; the protein level of ATG7 in the cells is significantly increased, see Fig. 1 a. Figure 1

[0108] 1.2 Insulin inhibits the exocytosis of ATG7.

[0109] HepG2 cells were stimulated with insulin (100 ng / ml) for 4 hours, and the expression level of ATG7 in the culture medium was detected by immunoprecipitation, see General Methods 1 and 7.

[0110] Results show that compared with control cells (HepG2 cells without insulin), the protein level of ATG7 in the culture medium of cells stimulated with insulin is significantly decreased; the protein level of ATG7 in the cells is significantly increased, see Fig. 1 b, left panel. Figure 1

[0111] 1.3 Glucagon promotes the exocytosis of ATG7.

[0112] HepG2 cells were stimulated with glucagon (2 ng / ml) for 1 hour, and the expression level of ATG7 in the culture medium was detected by immunoprecipitation, see General Methods 1 and 7.

[0113] Results show that compared with control cells (HepG2 cells without glucagon), the protein level of ATG7 in the culture medium of cells stimulated with glucagon is significantly increased; the protein level of ATG7 in the cells is significantly decreased, see Fig. 1 b, right panel. Figure 1

[0114] Example 2 ATG7 is involved in the metabolic regulation of glucose

[0115] 2.1 Detection of glucose metabolism in primary hepatocytes.

[0116] 2.1.1 Culture of primary hepatocytes, see General Method 2.

[0117] 2.1.2 Detection of glycogen synthesis and glucose production in primary hepatocytes, see General Methods 3 and 4.

[0118] Primary hepatocytes were stimulated with ATG7 protein (2 μΜ) for 24 hours, and the expression level of ATG7 in the culture medium was detected by immunoprecipitation, see General Methods 1 and 7.

[0119] Results show that after being given ATG7 protein (2 μΜ), the glycogen synthesis in primary hepatocytes is increased, and the glucose production is decreased, see Fig. 2 a and b. The control is: primary hepatocytes without ATG7 protein. Figure 2

[0120] ​​​​Example 3 Polypeptide Aap1 of the present application inhibits the exosome of ATG7

[0121] 3.1 ATG7 NM site mediates its exosome.

[0122] Huh7 cells were transfected with ATG7 wild type (WT), 104 site mutant plasmid (NM) and 571 site mutant plasmid (CM, ATG7 E1 active site) respectively, and the expression level of ATG7 in the culture solution was detected by immunoprecipitation, see general methods 7 and 8. CM is a positive control of mutant plasmid, which proves that only the 104 site mediates the exosome of ATG7.

[0123] The results show that the 104 site mutation mediates the exosome of ATG7, see Figure 3 a and 3b of.

[0124] 3.2 Aap1 inhibits the exosome of ATG7.

[0125] Based on the 104 site-mediated exosome of ATG7, Aap1 was designed and synthesized. After Huh7 cells were transfected with GFP-ATG7 for 24 hours, Aap1 was given for 24 hours, and the expression level of ATG7 in the culture solution was detected.

[0126] The results show that Aap1 inhibits the exosome of ATG7, see Figure 3 c and d of.

[0127] Example 4 Aap1 regulates insulin signaling pathway to affect glucose metabolism

[0128] 4.1 Aap1 promotes insulin signaling pathway.

[0129] After HepG2 cells were given Aap1 (2 μM), WB detection was performed, see general method 7.

[0130] The results show that after Aap1 is given, the expression level of ATG7 in the cells is significantly increased, and the downstream signal AKT is activated, see Figure 4 a of.

[0131] 4.2 C57 mice were injected intraperitoneally with Aap1 (0.5 mg / kg, n = 5), and 24 hours later, glucose tolerance test was performed, see general method 6.

[0132] The results show that after C57 mice are given Aap1, the glucose tolerance is reduced, see Figure 4 b of.

[0133] Although the embodiments of the present application have been shown and described above, it is understood that the above-described embodiments are exemplary and are not to be construed as limiting the present application, and that changes, modifications, substitutions and variations can be made by those skilled in the art without departing from the spirit and scope of the present application.

Claims

1. A polypeptide, characterized in that The amino acid sequence of the polypeptide is shown in SEQ ID NO:

1.

2. The polypeptide according to claim 1, characterized in that The nucleic acid sequence of the polypeptide is shown in SEQ ID NO:

2.

3. Use of the polypeptide according to claim 1 in the preparation of a drug for lowering blood sugar levels.

4. The use according to claim 3, characterized in that The polypeptide has any of the following functions: Directly inhibiting the exocytosis of ATG7; and / or Activate signaling factors in the IS pathway; and / or Increased glycogen synthesis; and / or Reduce glucose production and inhibit gluconeogenesis; and / or Regulates glucose metabolism.

5. The use according to claim 3, characterized in that The dosage form of the drug is any therapeutically acceptable dosage form.

6. A pharmaceutical composition, characterized in that The invention comprises the polypeptide according to claim 1 or 2 and a pharmaceutically acceptable carrier or excipient.

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