WO2019048423A1 - Supplémentation en l-sérine chez des sujets prédiabétiques - Google Patents
Supplémentation en l-sérine chez des sujets prédiabétiques Download PDFInfo
- Publication number
- WO2019048423A1 WO2019048423A1 PCT/EP2018/073723 EP2018073723W WO2019048423A1 WO 2019048423 A1 WO2019048423 A1 WO 2019048423A1 EP 2018073723 W EP2018073723 W EP 2018073723W WO 2019048423 A1 WO2019048423 A1 WO 2019048423A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- serine
- diabetes
- autoantibodies
- subjects
- beta
- Prior art date
Links
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 title claims abstract description 213
- 229960001153 serine Drugs 0.000 title claims description 106
- 230000009469 supplementation Effects 0.000 title description 10
- 206010018429 Glucose tolerance impaired Diseases 0.000 title description 6
- 208000001280 Prediabetic State Diseases 0.000 title description 3
- 201000009104 prediabetes syndrome Diseases 0.000 title description 3
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims abstract description 62
- 230000037396 body weight Effects 0.000 claims abstract description 62
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 claims abstract description 31
- 230000003820 β-cell dysfunction Effects 0.000 claims abstract description 10
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims description 64
- 239000000203 mixture Substances 0.000 claims description 63
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 37
- 239000008103 glucose Substances 0.000 claims description 37
- 102000004877 Insulin Human genes 0.000 claims description 30
- 108090001061 Insulin Proteins 0.000 claims description 30
- 229940125396 insulin Drugs 0.000 claims description 30
- 210000004369 blood Anatomy 0.000 claims description 29
- 239000008280 blood Substances 0.000 claims description 29
- 230000002265 prevention Effects 0.000 claims description 16
- 108091006550 Zinc transporters Proteins 0.000 claims description 14
- 235000013305 food Nutrition 0.000 claims description 14
- 230000008595 infiltration Effects 0.000 claims description 11
- 238000001764 infiltration Methods 0.000 claims description 11
- 238000011161 development Methods 0.000 claims description 10
- 210000004153 islets of langerhan Anatomy 0.000 claims description 9
- 235000013361 beverage Nutrition 0.000 claims description 7
- 230000004064 dysfunction Effects 0.000 claims description 7
- 102000006449 Class 8 Receptor-Like Protein Tyrosine Phosphatases Human genes 0.000 claims description 6
- 108010044226 Class 8 Receptor-Like Protein Tyrosine Phosphatases Proteins 0.000 claims description 6
- 210000004698 lymphocyte Anatomy 0.000 claims description 6
- 102000008214 Glutamate decarboxylase Human genes 0.000 claims description 5
- 108091022930 Glutamate decarboxylase Proteins 0.000 claims description 5
- 239000000047 product Substances 0.000 claims description 5
- 230000000069 prophylactic effect Effects 0.000 claims description 5
- 230000002950 deficient Effects 0.000 claims description 4
- 210000003705 ribosome Anatomy 0.000 claims description 4
- 239000013589 supplement Substances 0.000 claims description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 6
- 201000010099 disease Diseases 0.000 abstract description 5
- 241000282412 Homo Species 0.000 abstract description 4
- 235000007882 dietary composition Nutrition 0.000 abstract description 2
- 238000011321 prophylaxis Methods 0.000 abstract description 2
- 241000699670 Mus sp. Species 0.000 description 37
- 206010012601 diabetes mellitus Diseases 0.000 description 22
- 238000011282 treatment Methods 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000002417 nutraceutical Substances 0.000 description 14
- 235000021436 nutraceutical agent Nutrition 0.000 description 14
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 14
- 238000007446 glucose tolerance test Methods 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 230000002829 reductive effect Effects 0.000 description 11
- 239000002775 capsule Substances 0.000 description 10
- 238000000528 statistical test Methods 0.000 description 10
- 230000018109 developmental process Effects 0.000 description 9
- 150000002632 lipids Chemical class 0.000 description 9
- 210000000496 pancreas Anatomy 0.000 description 9
- 239000003826 tablet Substances 0.000 description 9
- 238000000692 Student's t-test Methods 0.000 description 8
- 238000005259 measurement Methods 0.000 description 8
- 229940024606 amino acid Drugs 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- YDNKGFDKKRUKPY-JHOUSYSJSA-N C16 ceramide Natural products CCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)C=CCCCCCCCCCCCCC YDNKGFDKKRUKPY-JHOUSYSJSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- 241000699666 Mus <mouse, genus> Species 0.000 description 6
- CRJGESKKUOMBCT-VQTJNVASSA-N N-acetylsphinganine Chemical compound CCCCCCCCCCCCCCC[C@@H](O)[C@H](CO)NC(C)=O CRJGESKKUOMBCT-VQTJNVASSA-N 0.000 description 6
- 150000001413 amino acids Chemical class 0.000 description 6
- 229940106189 ceramide Drugs 0.000 description 6
- ZVEQCJWYRWKARO-UHFFFAOYSA-N ceramide Natural products CCCCCCCCCCCCCCC(O)C(=O)NC(CO)C(O)C=CCCC=C(C)CCCCCCCCC ZVEQCJWYRWKARO-UHFFFAOYSA-N 0.000 description 6
- 235000015872 dietary supplement Nutrition 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- VVGIYYKRAMHVLU-UHFFFAOYSA-N newbouldiamide Natural products CCCCCCCCCCCCCCCCCCCC(O)C(O)C(O)C(CO)NC(=O)CCCCCCCCCCCCCCCCC VVGIYYKRAMHVLU-UHFFFAOYSA-N 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- 210000002966 serum Anatomy 0.000 description 6
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 5
- 239000005695 Ammonium acetate Substances 0.000 description 5
- 235000019257 ammonium acetate Nutrition 0.000 description 5
- 229940043376 ammonium acetate Drugs 0.000 description 5
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 5
- 238000013270 controlled release Methods 0.000 description 5
- 235000005911 diet Nutrition 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 201000001119 neuropathy Diseases 0.000 description 5
- 230000007823 neuropathy Effects 0.000 description 5
- 208000033808 peripheral neuropathy Diseases 0.000 description 5
- 150000003408 sphingolipids Chemical class 0.000 description 5
- 230000003442 weekly effect Effects 0.000 description 5
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 4
- 206010022489 Insulin Resistance Diseases 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 235000019577 caloric intake Nutrition 0.000 description 4
- 230000037213 diet Effects 0.000 description 4
- 239000007937 lozenge Substances 0.000 description 4
- 238000004949 mass spectrometry Methods 0.000 description 4
- 239000000902 placebo Substances 0.000 description 4
- 229940068196 placebo Drugs 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 235000020772 multivitamin supplement Nutrition 0.000 description 3
- 235000016709 nutrition Nutrition 0.000 description 3
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 3
- 230000008092 positive effect Effects 0.000 description 3
- 230000008929 regeneration Effects 0.000 description 3
- 238000011069 regeneration method Methods 0.000 description 3
- 238000012762 unpaired Student’s t-test Methods 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- RYCNUMLMNKHWPZ-SNVBAGLBSA-N 1-acetyl-sn-glycero-3-phosphocholine Chemical compound CC(=O)OC[C@@H](O)COP([O-])(=O)OCC[N+](C)(C)C RYCNUMLMNKHWPZ-SNVBAGLBSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 208000023275 Autoimmune disease Diseases 0.000 description 2
- 210000002237 B-cell of pancreatic islet Anatomy 0.000 description 2
- 208000028698 Cognitive impairment Diseases 0.000 description 2
- 206010012289 Dementia Diseases 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 239000001828 Gelatine Substances 0.000 description 2
- 102000051325 Glucagon Human genes 0.000 description 2
- 108060003199 Glucagon Proteins 0.000 description 2
- 208000000913 Kidney Calculi Diseases 0.000 description 2
- 206010029148 Nephrolithiasis Diseases 0.000 description 2
- 208000000474 Poliomyelitis Diseases 0.000 description 2
- CWRILEGKIAOYKP-SSDOTTSWSA-M [(2r)-3-acetyloxy-2-hydroxypropyl] 2-aminoethyl phosphate Chemical compound CC(=O)OC[C@@H](O)COP([O-])(=O)OCCN CWRILEGKIAOYKP-SSDOTTSWSA-M 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 208000010877 cognitive disease Diseases 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000002596 correlated effect Effects 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 230000006806 disease prevention Effects 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 230000007717 exclusion Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 230000037406 food intake Effects 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 208000004104 gestational diabetes Diseases 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 2
- 229960004666 glucagon Drugs 0.000 description 2
- 230000014101 glucose homeostasis Effects 0.000 description 2
- 150000002402 hexoses Chemical class 0.000 description 2
- 230000001900 immune effect Effects 0.000 description 2
- 239000006194 liquid suspension Substances 0.000 description 2
- 238000001325 log-rank test Methods 0.000 description 2
- UOXRPRZMAROFPH-IESLQMLBSA-N lysophosphatidylinositol Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@@H](O)COP(O)(=O)OC1[C@H](O)[C@@H](O)C(O)[C@@H](O)[C@H]1O UOXRPRZMAROFPH-IESLQMLBSA-N 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 235000020786 mineral supplement Nutrition 0.000 description 2
- 229940029985 mineral supplement Drugs 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 208000020016 psychiatric disease Diseases 0.000 description 2
- 238000001959 radiotherapy Methods 0.000 description 2
- 235000018770 reduced food intake Nutrition 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 239000000310 rehydration solution Substances 0.000 description 2
- 230000008439 repair process Effects 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 201000009032 substance abuse Diseases 0.000 description 2
- 231100000736 substance abuse Toxicity 0.000 description 2
- 208000011117 substance-related disease Diseases 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 230000004584 weight gain Effects 0.000 description 2
- 235000019786 weight gain Nutrition 0.000 description 2
- PORPENFLTBBHSG-MGBGTMOVSA-N 1,2-dihexadecanoyl-sn-glycerol-3-phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(O)=O)OC(=O)CCCCCCCCCCCCCCC PORPENFLTBBHSG-MGBGTMOVSA-N 0.000 description 1
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 description 1
- ZPDQFUYPBVXUKS-YADHBBJMSA-N 1-stearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)COP(O)(=O)OC[C@H](N)C(O)=O ZPDQFUYPBVXUKS-YADHBBJMSA-N 0.000 description 1
- YPMOAQISONSSNL-UHFFFAOYSA-N 8-hydroxyoctyl 2-methylprop-2-enoate Chemical compound CC(=C)C(=O)OCCCCCCCCO YPMOAQISONSSNL-UHFFFAOYSA-N 0.000 description 1
- 238000009020 BCA Protein Assay Kit Methods 0.000 description 1
- 101100337060 Caenorhabditis elegans glp-1 gene Proteins 0.000 description 1
- 102000004031 Carboxy-Lyases Human genes 0.000 description 1
- 108090000489 Carboxy-Lyases Proteins 0.000 description 1
- -1 Cholesteryl ester Chemical class 0.000 description 1
- 108020004705 Codon Proteins 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- 108010011459 Exenatide Proteins 0.000 description 1
- 208000002705 Glucose Intolerance Diseases 0.000 description 1
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- 102000003746 Insulin Receptor Human genes 0.000 description 1
- 108010001127 Insulin Receptor Proteins 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 125000002842 L-seryl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])O[H] 0.000 description 1
- 101500016415 Lophius americanus Glucagon-like peptide 1 Proteins 0.000 description 1
- 108010006519 Molecular Chaperones Proteins 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 102000005157 Somatostatin Human genes 0.000 description 1
- 108010056088 Somatostatin Proteins 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- ATBOMIWRCZXYSZ-XZBBILGWSA-N [1-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-3-hexadecanoyloxypropan-2-yl] (9e,12e)-octadeca-9,12-dienoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC ATBOMIWRCZXYSZ-XZBBILGWSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- 230000002424 anti-apoptotic effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 235000021311 artificial sweeteners Nutrition 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 230000006470 autoimmune attack Effects 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- JUFFVKRROAPVBI-PVOYSMBESA-N chembl1210015 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(=O)N[C@H]1[C@@H]([C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO[C@]3(O[C@@H](C[C@H](O)[C@H](O)CO)[C@H](NC(C)=O)[C@@H](O)C3)C(O)=O)O2)O)[C@@H](CO)O1)NC(C)=O)C(=O)NCC(=O)NCC(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 JUFFVKRROAPVBI-PVOYSMBESA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 239000008199 coating composition Substances 0.000 description 1
- 239000005515 coenzyme Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000000306 component Substances 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 150000001982 diacylglycerols Chemical class 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 235000008242 dietary patterns Nutrition 0.000 description 1
- 229940090124 dipeptidyl peptidase 4 (dpp-4) inhibitors for blood glucose lowering Drugs 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000003797 essential amino acid Substances 0.000 description 1
- 235000020776 essential amino acid Nutrition 0.000 description 1
- 235000020774 essential nutrients Nutrition 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 229960001519 exenatide Drugs 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 235000012041 food component Nutrition 0.000 description 1
- 235000012631 food intake Nutrition 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 230000004153 glucose metabolism Effects 0.000 description 1
- 230000004190 glucose uptake Effects 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 235000006486 human diet Nutrition 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000012528 insulin ELISA Methods 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 208000001921 latent autoimmune diabetes in adults Diseases 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 235000021097 low calorie intake Nutrition 0.000 description 1
- 238000012067 mathematical method Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 210000005087 mononuclear cell Anatomy 0.000 description 1
- 235000021096 natural sweeteners Nutrition 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 210000004923 pancreatic tissue Anatomy 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 150000003905 phosphatidylinositols Chemical class 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000000291 postprandial effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 239000003642 reactive oxygen metabolite Substances 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- NHXLMOGPVYXJNR-ATOGVRKGSA-N somatostatin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N1)[C@@H](C)O)NC(=O)CNC(=O)[C@H](C)N)C(O)=O)=O)[C@H](O)C)C1=CC=CC=C1 NHXLMOGPVYXJNR-ATOGVRKGSA-N 0.000 description 1
- 229960000553 somatostatin Drugs 0.000 description 1
- 210000002325 somatostatin-secreting cell Anatomy 0.000 description 1
- 230000006829 sphingolipid biosynthesis Effects 0.000 description 1
- 230000004137 sphingolipid metabolism Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
Definitions
- the present invention relates to supplementary dietary compositions comprising L- serine for use in subjects with occurrence of islet lymphocyte infiltration (insulitis), dysfunction and/or loss of beta cells, as well as islet autoantibody/autoantibodies, to deaccelerate or prevent the progression from pre-type 1 diabetes, or other related disorders, to established type 1 diabetes in humans.
- This prophylactic treatment is particularly relevant for subjects that are predisposed for type 1 diabetes.
- the daily dose ranges from 10-400 mg/kg bodyweight per day.
- Type 1 diabetes is an autoimmune disease in which the insulin producing beta cells are either destroyed by autoreactive T cells or dysfunctional leading to insulin deficiency. Insulitis, beta-cell dysfunction and/or loss, as well as the occurrence of islet autoantibodies, may be observed in subjects with pre-type 1 diabetes, and the severity is correlated with increased risk of developing established type 1 diabetes.
- Type 1 diabetes incidence is increasing worldwide, highlighting the need for effective and affordable prevention strategies.
- the NOD mouse has for many years been the preferred animal model for studying type 1 diabetes as an autoimmune disease, as it develops diabetes spontaneously with similarities to human type 1 diabetes.
- L-serine can be made de novo through the phosphorylated pathway and is as such classified as a non-essential amino acid, however an external supply of L-serine is necessary for the required level of sphingolipid synthesis in the central nervous system.
- an external supply of L-serine is necessary for the required level of sphingolipid synthesis in the central nervous system.
- both type 2 diabetes patients and patients with gestational diabetes have reduced levels of L-serine in serum. This suggest that a lack of L-serine is associated with type 2 diabetes.
- WO 2007/060924 discloses the treatment and/or prevention of type 2 diabetes with a combination dosage of L-serine and L-glycine, which may normalize the function of the pancreatic beta cell of the diabetic state, but do not show prevention of the disease initiation of type 1 diabetes.
- WO 2007/060924 do not disclose any effect of L- serine alone for either type 2 diabetes nor type 1 diabetes. Dietary supplementation of the sphingolipid precursor L-serine is known to increase serum sphingolipid levels, particularly relevant for type 2 diabetes, however the effect of L-serine on the development of the early stages of type 1 diabetes, such as pre- diabetes, have so far not been investigated.
- WO2011/104298 discloses the use of L-serine in treatment and prevention of diseases associated with elevated levels of deoxy-sphingolipids. Although mentioning both type 1 and type 2 diabetes in the field of invention, WO2011/104298 do not provide any enabling data on type 1 diabetes, and in particular not on the prevention of the development of type 1 diabetes in pre-diabetic subjects, nor prevention of beta-cell dysfunction, beta-cell loss and/or development of multiple islet autoantibodies.
- the present inventors tested the potential of chronic L-serine supplementation to prevent insulitis, beta-cell dysfunction and/or loss, and thus the occurrence of multiple islet autoantibodies and thereby progression to type 1 diabetes. This is a whole new method of action of this amino acid, and thus lead the inventors to use L-serine as an active ingredient for preventing type 1 diabetes in pre-type 1 diabetic subjects.
- the experimental tests in NOD mice showed that L-serine reduced insulitis, HOMA-IR, blood glucose, GTT (glucose intolerance) and diabetes incidence.
- the invention therefore relates to a composition comprising L-serine for use in the prophylactic prevention of beta-cell dysfunction, beta-cell loss and/or development of multiple islet autoantibodies in a human subject with pre-type 1 diabetes.
- the present invention relates to a method of preventing beta-cell dysfunction and loss, and thereby the presence of multiple islet auto-antibodies, and thus deaccelerating or preventing the progression from pre-type 1 diabetes to established type 1 diabetes in human subjects by oral supplementation of the nonessential amino acid L-serine.
- a dietary supplement composition comprising L-serine may deaccelerate or prevent the progression to type 1 diabetes in a human subject with pre-type 1 diabetes.
- human subjects being selected from the group consisting of a) subjects with lymphocyte infiltration of islets, dysfunction and/or loss of beta cells, measured by insulitis, HOMA-IR, blood glucose and/or GTT. b) subjects with the signs of beta-cell death, including subjects with the
- INS-DRiPs insulin defective ribosomal products
- IAA insulin autoantibodies
- GADA glutamate decarboxylase autoantibodies
- ZnT8 autoantibodies to zinc transporter
- IA- 2A insulinoma-associated-protein-2 autoantibodies
- the daily dose ranges from 10-400 mg/kg bodyweight per day.
- the inventors showed that continued dietary supplementation of L-serine is protective against autoimmune diabetes - type 1 diabetes. They showed for example in Example 1 that L-serine is protective against autoimmune diabetes as developed in the NOD mice, and that this was associated with reduced immunological activity as
- the invention relates to a composition comprising L-serine for use in the prophylactic prevention of beta-cell dysfunction.
- the invention also relates to a composition comprising L-serine for use in the prophylactic prevention of beta-cell loss.
- the invention furthermore relates to a composition comprising L-serine for use in the prophylactic prevention of the development of multiple islet autoantibodies in a human subject with pre-type 1 diabetes.
- L-serine may reduce type 1 diabetic incidences, and thus that L-serine may be particularly relevant as a dietary supplement for subjects predisposed for developing type 1 diabetes.
- Serine (abbreviated as Ser or S) encoded by the codons UCU, UCC, UCA, UCG, AGU, and AGC is an a-amino acid that is used in the biosynthesis of proteins. It contains an a-amino group (which is in the protonated -NH +3 form under biological conditions), a carboxyl group (which is in the deprotonated -COO-form in physiological conditions), and a side chain consisting of a hydroxymethyl group, classifying it as a polar amino acid. It can be synthesized in the human body under normal physiological
- This compound is one of the naturally occurring proteinogenic amino acids. Only the L-stereoisomer appears naturally in proteins. It is not essential to the human diet, since it is synthesized in the body from other metabolites, including glycine.
- L-serine is typically produced by fermentation, with an estimated 100- 1000 tonnes per year produced - Ullmann's Encyclopaedia of Industrial Chemistry. Predisposition for type 1 diabetes
- the present invention relates to the use of L-serine for prevention of the development of type 1 diabetes in a human subject with pre-type 1 diabetes.
- pre-type 1 diabetes relates to the presence of insulitis, dysfunction and/or loss of beta cells, as well as islet autoantibody/autoantibodies.
- the invention is not related to treatment of human subject already diagnosed with or having type 1 diabetes, although such patients may also benefit from a daily intake of L-serine.
- the invention is not related to the treatment of a human subject diagnosed with type 2 diabetes.
- Type 1 diabetes is distinct from non-insulin dependent diabetes (NIDDM)/type 2 diabetes in that only the type 1 diabetes form involves specific destruction of the insulin producing beta cells of the islets of Langerhans.
- the destruction of beta cells appears to be a result of specific autoimmune attack, in which the patient's own immune system recognizes and destroys the beta cells, but not the surrounding alpha cells (glucagon producing) or delta cells (somatostatin producing) that comprise the pancreatic islet.
- the progressive loss of pancreatic beta cells results in insufficient insulin production and, thus, impaired glucose metabolism with attendant
- the invention only relates to the predisposition for type 1 diabetes, and the
- a human subject with pre-type 1 diabetes is a human subject selected from the group consisting of a) subjects with lymphocyte infiltration of islets, dysfunction and/or loss of beta cells, measured by insulitis, HOMA-IR, blood glucose and/or GTT b) Subjects the signs of beta-cell death, including subjects with the presence of insulin defective ribosomal products (INS-DRiPs) and subjects with presence of circulating unmethylated insulin DNA.
- INS-DRiPs insulin defective ribosomal products
- the present invention relates to a composition comprising L- serine for use in treatment of human subjects with presence of lymphocyte infiltration of islets, dysfunction and/or loss of beta cells and thus deacceleration or prevention of progression to established type 1 diabetes.
- the present invention relates to a composition comprising L- serine for use in treatment of human subjects with beta-cell dysfunction and/or loss of beta-cell function and thus deacceleration or prevention of progression to established type 1 diabetes. In one embodiment, the present invention relates to a composition comprising L- serine for use in treatment of human subjects with signs of beta-cell death and thus deacceleration or prevention of progression to established type 1 diabetes.
- subjects with the signs of beta-cell death including subjects with the presence of insulin defective ribosomal products (INS-DRiPs) and subjects with presence of circulating unmethylated insulin DNA.
- the present invention relates to a composition comprising L- serine for use in treatment of human subjects with presence of islets auto-antibodies and thus deacceleration or prevention of progression to established type 1 diabetes.
- subjects with presence of islets auto-antibodies includes subjects with the presence of islet cell autoantibodies (ICA), insulin autoantibodies (IAA), glutamate decarboxylase autoantibodies (GADA), autoantibodies to zinc transporter (ZnT8) and insulinoma-associated-protein-2 autoantibodies (IA-2A).
- L-serine can be any suitable for use in treatment of human subjects with presence of islets auto-antibodies and thus deacceleration or prevention of progression to established type 1 diabetes.
- subjects with presence of islets auto-antibodies includes subjects with the presence of islet cell autoantibodies (ICA),
- the daily dose range of the present invention contains L-serine in an amount sufficient to administer to a subject a dosage from about 10 mg to about 400 mg per kg bodyweight per day.
- the composition contains L-serine in an amount sufficient to administer to a subject a dosage from about 10 mg to about 40 mg per kg bodyweight per day.
- the composition contains L-serine in an amount sufficient to administer to a subject a dosage from about 40 mg to about 70 mg per kg body weight per day. In one embodiment, the composition contains L-serine in an amount sufficient to administer to a subject a dosage from about 70 mg to about 100 mg per kg bodyweight per day.
- the composition contains L-serine in an amount sufficient to administer to a subject a dosage from about 100 mg to about 130 mg per kg bodyweight per day. In one embodiment, the composition contains L-serine in an amount sufficient to administer to a subject a dosage from about 130 mg to about 160 mg per kg bodyweight per day.
- the composition contains L-serine in an amount sufficient to administer to a subject a dosage from about 160 mg to about 190 mg per kg bodyweight per day. In one embodiment, the composition contains L-serine in an amount sufficient to administer to a subject a dosage from about 190 mg to about 220 mg per kg bodyweight per day.
- the composition contains L-serine in an amount sufficient to administer to a subject a dosage from about 220 mg to about 250 mg per kg bodyweight per day.
- the composition contains L-serine in an amount sufficient to administer to a subject a dosage from about 250 mg to about 280 mg per kg bodyweight per day.
- the composition contains L-serine in an amount sufficient to administer to a subject a dosage from about 280 mg to about 310 mg per kg bodyweight per day.
- the composition contains L-serine in an amount sufficient to administer to a subject a dosage from about 310 mg to about 340 mg per kg bodyweight per day. In one embodiment, the composition contains L-serine in an amount sufficient to administer to a subject a dosage from about 340 mg to about 370 mg per kg bodyweight per day.
- the composition contains L-serine in an amount sufficient to administer to a subject a dosage from about 370 mg to about 400 mg per kg bodyweight per day. In one embodiment, the composition is administered to the subject in a dosage regime comprising an oral dose once daily.
- the composition is administered to the subject in a dosage regime comprising an oral dose twice-daily.
- a dosage regime comprising an oral dose twice-daily.
- composition contains L-serine in an amount sufficient to administer to a subject a dosage from about 5 mg to about 200 mg per kg bodyweight twice-daily, such as but not limited to 10-200 mg per kg bodyweight twice-daily, 20-200 mg per kg
- bodyweight twice-daily 30-200 mg per kg bodyweight twice-daily, 40-200 mg per kg bodyweight twice-daily, 50-200 mg per kg bodyweight twice-daily, 60-200 mg per kg bodyweight twice-daily, 70-200 mg per kg bodyweight twice-daily, 80-200 mg per kg bodyweight twice-daily, 90-200 mg per kg bodyweight twice-daily, 100-200 mg per kg bodyweight twice-daily, 110-200 mg per kg bodyweight twice-daily, 120-200 mg per kg bodyweight twice-daily, 130-200 mg per kg bodyweight twice-daily, 140-200 mg per kg bodyweight twice-daily, 160-200 mg per kg bodyweight twice-daily, 170-200 mg per kg bodyweight twice-daily, 180-200 mg per kg bodyweight twice-daily, 90-200 mg per kg bodyweight twice-daily, 10-20 mg per kg bodyweight twice-daily, 40-80 mg per kg bodyweight twice-d
- composition(s) according to the present invention must be administered for a time sufficient for the preventive effect to occur.
- the composition is administered for at least 3 months.
- the composition is administered for at least 4 months. In one embodiment, the composition is administered for at least 5 months. In one embodiment, the composition is administered for at least 6months. In one embodiment, the composition is administered for at least 7 months. In one embodiment, the composition is administered for at least 8 months. In one embodiment, the composition is administered for at least 9 months.
- the composition is administered for at least 10 months.
- the composition is administered for at least 11 months. In one embodiment, the composition is administered for at least 12 months.
- L-serine can be any organic radical.
- L-serine can prevent or delay the destruction of functional beta-cell mass in the subject with the previously described symptoms of pre-type 1 diabetes such that the intervention with L-serine, as described herein, enables the patient to retain pancreatic insulin production thereby eliminating or reducing the need for insulin injections.
- Weight and calorie intake are well known modulators of insulin resistance, and the inventors do find that L-serine treatment resulted in a small reduction in bodyweight, which could be explained by the trend to-wards lower calorie intake. ( Figure 8-11).
- the positive effects can be connected to the insulin secretory effect of L-serine as demonstrated in a beta-cell line.
- L-serine is a new possible therapeutic supplementation for subjects with lymphocyte infiltration, dysfunction and/or loss of beta cells, and thus the occurrence of multiple islet autoantibodies and may thereby deaccelerate or prevent progression to type 1 diabetes.
- the invention may have similar positive effects on latent autoimmune diabetes of adults, gestational diabetes, hypoglycaemia, and neuropathy as shown by its beneficial effect on diabetes development, degree of insulitis in NOD mice and positive effect on non-fasted blood glucose, GTT, and HOMA-IR.
- the inventors have demonstrated that dietary L-serine supplementation do not alter sphingolipid metabolism in pancreata from prediabetic NOD mice.
- L-serine in the preventing/delaying the progression from pre- autoimmune diabetes (pre-type 1 diabetes) to type 1 diabetes, it seems unlikely to include reduction of the level of deoxysphingolipids.
- the mechanism may however include that ingestion of L-Serine leads to increased insulin secretion, which would improve postprandial glucose levels and glucose tolerance as shown by improved glucose tolerance test by the inventor. This again leads to reduced beta-cell stress and reduced insulitis.
- administration of L-serine may be accompanied by administration of a compound that also promotes repair, production, and/or regeneration of beta cells.
- the agent that promotes the repair, production, and/or regeneration of beta cells may be, for example glulisine, glucagon's such as glucagon- like peptide-I (GLP- 1), DPP4 inhibitors, islet regeneration molecules, anti-apoptotic molecules and exendin-4.
- the present invention is further directed to provide the dietary supplement as a nutraceutical formulation aforementioned in the form of powders, tablets, capsules, soft gelatine capsules, controlled release capsules and tablets, lozenges and chewable preparations, liquid suspensions, suspensions in an edible supporting matrix or foodstuff and oral rehydration solutions.
- Nutraceutical formulation is a mean known to the skilled person and nutraceutical formulations enables consumption of an effective amount of the L-serine according to any of the diseases envisioned by the present invention.
- a nutraceutical is a pharmaceutical-grade and standardized nutrient, also known as dietary supplements or food additives by the FDA under the authority of the Federal Food, Drug, and Cosmetic Act.
- the formulations of the present invention can be prepared and administered in a wide variety of oral dosage forms. It is obvious to those skilled in the art that the dosage forms may comprise L-serine in combination with an effective amount of one or more dietary ingredients selected from the traditional group of minerals, fatty acids, amino acids and metabolites thereof, phytonutrients, vitamins and coenzymes.
- a multi-vitamin and mineral supplement may be added to the nutraceutical compositions of the present invention to obtain an adequate amount of an essential nutrient missing in some diets.
- the multi-vitamin and mineral supplement may also be useful for disease prevention and protection against nutritional losses and deficiencies due to lifestyle patterns and common inadequate dietary patterns sometimes observed in diabetes. Moreover, oxidant stress has been implicated in the development of insulin resistance.
- nutraceutical compatible carriers and excipients may be either solid or liquid. Solid form preparations include powders, tablets, capsules, soft gelatine capsules, controlled release capsules and tablets, lozenges and chewable preparations, and suspensions in an edible supporting matrix or foodstuff.
- Liquid preparations include liquid suspensions and oral rehydration solutions. These preparations may contain, in addition to the active component, colorants, flavours, stabilizers, buffers, artificial and natural sweeteners, thickeners, solubilizing agents, dispersants, sorbants, glidants, disintegrants, and the like.
- the nutraceutical compositions are preferably prepared in unit dosage form whereby the preparation is subdivided into unit doses containing appropriate quantities of the active component.
- the unit dosage form can be a packaged preparation containing discrete quantities of packaged tablets, lozenge, capsules, soft gelatin capsules, or controlled release capsules and tablets.
- the controlled release period is suitable for once-daily (i.e., once within a 24-hour period) dosing of an effective dose of the nutraceutical compositions.
- the tablets, lozenge, capsules, soft gelatin capsules, or controlled release capsules and tablets may be coated with any pharmaceutically acceptable coating.
- the coatings may be applied for such purposes as product identification, printability of tablet, light protection, aesthetic appearance, and patient compliance.
- Numerous pharmaceutically acceptable coating formulations have been developed by the pharmaceutical industry and are well known to the pharmaceutical scientist and are also commercially available.
- nutraceutical denotes a usefulness in both the nutritional and pharmaceutical field of application.
- nutraceutical compositions can find use as supplement to food and beverages, and as pharmaceutical formulations.
- nutraceutical composition also comprises food and beverages containing the above-specified active ingredients.
- one embodiment relates to a composition according to the invention, wherein the nutraceutical is a food or beverage or a supplement composition for a food or beverage.
- Lipid content in pancreas 10 ⁇ g tissue samples were analysed by mass spectrometry. Lipid amount is shown as pmol/mg protein. Data is mean ⁇ SD. Statistical tests: two- tailed unpaired Student's t-test, corrected for multiple comparisons using the Holm- Sidak method
- nutraceutical composition, and formulation are used interchangeably.
- Figure 2 - L-serine reduces insulitis score in NOD mice.
- mice Female NOD mice (Taconic Biosciences, Germantown, NY, USA) were housed at the Department of Experimental Medicine, Biocenter, University of Copenhagen, Denmark and kept in a specific Pathogen-Free (SPF) animal facility (temperature 22°C, 12 h light cycle, air change 16 times per hour, and humidity 55 ⁇ 10%). Three-week-old mice were acclimatized for one week with free access to standard chow diet Altromin 1320 (Altromin, Lü, Germany) and water.
- SPF Pathogen-Free
- mice Age and weight matched mice were divided in two groups, both with free access to Altromin 1320 (Altromin) and to water with or without the addition of L-serine (AppliChem, Darmstadt, Germany) 85.7g/L, or approximately 280mg/day/mouse. L-serine supplemented water was pH adjusted. Mice were treated from the age of four weeks and until the experiment was terminated at age 45 weeks. Mice were weighed each week and food and water intake were measured weekly by weighing of the food racks or water flask, respectively. The chow diet contained 3188kcal/kg, L-serine supplemented water was set to contain 342.8kcal/L. Sample sizes were based on previous studies with similar experimental settings.
- mice were inspected weekly for autoimmune diabetes using Freestyle Lite (Abbott Diabetes Care, Alameda, CA, USA) glucose monitoring. Diagnosis was based on two tail blood glucose measurements with an interval of two days > 12 mmol/L. Blood glucose values were measured between 9 AM and 5 PM, and used for evaluation of non-fasted blood glucose. Diabetic animals were killed.
- Freestyle Lite Abbott Diabetes Care, Alameda, CA, USA
- Pancreas from 13-week-old mice was dissected and fixed in 10% neutral buffered formalin overnight and embedded in paraffin. Then 5 ⁇ sections were cut and subsequently stained in H&E. Sections were evaluated in a blinded fashion using an BX53 microscope (Olympus America, Inc., Melville, NY, USA). 30 islets from each mouse were scored according to the following scale : 0, no infiltration ; 1, intact islets but with few mononuclear cells surrounding the islets; 2, peri-insulitis; 3, islet infiltration below 50%; 4, islet infiltration above 50%. HOMA
- HOMA-IR insulin resistance
- HOMA-Beta beta-cell function
- the mice were fasted for six hours and blood glucose measured as described above. Mice were killed by cervical dislocation and blood was collected immediately by heart puncture. Insulin concentration was measured in blood serum using Mercodia Mouse Insulin ELISA kit (Mercodia, U p psa l a, Swed e n ) .
- HOMA-IR was calculated as fasting serum insulin content mU /L x fasting blood glucose mM
- mice were fasted 6h and intraperitoneally injected with 0.01 ml 1 M glucose/g body weight. Blood was drawn from the tail and glucose concentrations were measured as described above at time 30, 45 60, 90, and 120 minutes. Incremental area under the curve (AUG) was calculated using the fasting blood glucose level prior to glucose administration as baseline.
- Lipid levels in pancreas was measured using mass spectrometry.
- Pancreatic samples lOmg were taken from the tail of the pancreas and immediately frozen in liquid nitrogen, and stored at -80°C, until further processing .
- 1 ml of ammonium acetate 155mM and 6 metal beads were added to lOmg of pancreas tissue, and tissue was disrupted two times for two minutes, using TissueLyzer II (Qiagen, H ilden, Germany) at a frequency of 30/sec.
- Samples were centrifuged at 5000g for 5min and protei n concentration was quantified using BCA protein assay kit (Thermo Fisher Scientific, Waltham, MA, USA) and Varioskan Flash (Thermo Fisher Scientific).
- Lipid extractions were performed at room temperature. First using 8ml glass vials, 5ml of Chloroform/Methanol 10 : 1, 900 ⁇ ammonium acetate 155mM, ⁇ of the homogenate, and ⁇ of 50nM SHexCer 30: 1 :2 standard (Avanti Polar Lipids, Inc, Alabaster, AL, USA). The lower organic) phase was discarded after shaking for 15 minutes at lOOOrpm. Second extraction was performed using 5ml of
- Chloroform/MeOH 2 1, shaking for 15 min as before.
- the lower phase was transferred to a new 8ml glass vial, where the solvent was evaporated using SpeedVac RVC 2-25 CD plus (Christ, Osterode, Germany).
- 1ml of Chloroform/MeOH 2 : 1 was added, and the sample shaken as described above, before being transferred to a new 1.5ml Eppendorf tube.
- Solvent was evaporated and 100ml of solvent B (described below) was added for the LC-MS run. Samples were shaken at 2000rpm for 15 min.
- the HPLC separation was performed using a (U)PLC system with vacuum degasser, Autosampler, NC pumps Ultimate 3000 (Thermo Fisher Scientific) and a silica column 150mm x 0,5mm, 3 ⁇ particle size, 1/16", YMC-Pack Silica (YMC, Kyoto, Japan).
- a column temperature 35°C and a flow rate of 25 ⁇ / ⁇ .
- the LC run was performed as following; 0 to O. lmin at 100%B, 0.1 to 0.5min at 90%B, 0.5 to 2min as linear gradient from 90%B to 30%B, 2min to 3min was kept at 30%B, 3 to 3.2min as linear gradient from 30%B to 100%B and it finally was kept at 100%B until 7min in order to clean the column.
- Solvent A 6mM ammonium acetate
- solvent B in 6mM ammonium acetate in acetonitrile/MeOH 100 : 2.
- mass spectrometry was performed on a Q Exactive Hybrid Quadrupole-Orbitrap Mass Spectrometer (Thermo Fisher Scientific).
- Lipid Xplorer version 1.2.4 https://wiki.mpi-cbg.de/lipidx/Main_Page) to extract data from the chromatogram, selecting a time range based on the eluted peaks. The final data was referred to the protein concentration previously measured for each sample. All solvents were HPLC-grade. Methanol, acetonitrile and water were supplied by (VWR, Radnor, PA, USA) and ammonium acetate by (Sigma Aldrich, Darmstadt, Germany).
- the mixed model analysis of non-fasted blood glucose levels and weight was performed using SAS Enterprise v7.11 (SAS institute Inc, NC, USA). Final model was adjusted for time, there was no time-diet interaction. The remaining statistical analysis was performed using Graphpad Prism version 6.01 (La Jolla, CA, USA) and data is shown as mean ⁇ SEM unless otherwise noted. The cumulative diabetes incidence was assessed using Mantel-Cox log-rank test. For comparisons between groups, a two-tailed unpaired Student's t-test was used. For multiple comparisons between two groups a two-tailed unpaired Student's t-test, corrected for multiple comparisons using the Holm-Sidak method was used. A p-value of less than 0.05 was considered significant.
- Example 1 Reduced diabetes incidence and insulitis in L-serine supplemented mice
- NOD mice were treated with water containing L-serine (85.7g/L) from age four weeks onwards. Treatment with L-serine significantly lowered the incidence of autoimmune diabetes to 43% (13/30) compared to controls 71% (35/49) ( Figure 1).
- L-serine significantly lowered the incidence of autoimmune diabetes to 43% (13/30) compared to controls 71% (35/49)
- Figure 1 we correlated this to the immunological activity in pancreas by looking at islet infiltration. Insulitis score was reduced in the L- serine supplemented group compared to control ( Figure 2). This was clearly seen from islets with insulitis score 4, which was 30% in the L-serine treated mice and 52.6% in controls ( Figure 3).
- Example 2 L-serine improves GTT, reduces HOMA-IR and non-fasted blood glucose
- HOMA-IR and HOMA-Beta is a mathematical method used to quantify insulin resistance and beta-cell function based on fasting insulin and glucose levels.
- Example 3 L-serine supplementation reduces bodyweight
- Example 4 L-serine supplementation has no effect on sphingolipids in pancreas. Next, we wanted to evaluate the effect of L-serine supplementation on the
- composition of sphingolipid in pancreas 10pg samples from the pancreatic tail were taken from mice age 45 weeks and analysed by mass spectrometry. Five sphingolipid species were identified in the pancreas (ceramide, hexose ceramide, dihexose ceramide, sphingomyeline, and sulfatide). Of these sulfatide, an insulin chaperone, trended towards reduced levels following L-serine treatment (Table 1). An additional 20 lipid species were identified in the pancreas with the large majority consisting of phosphatidyl choline. However, we find no differences between the groups.
- the placebo group includes 30 individuals that are predisposed to develop type 1 diabetes and they receive oral protein mix (not including L-serine) 10-400 mg/kg bodyweight per day for 3-12 months.
- the diabetes-status is evaluated at study enrollment and at study completion by a clinical examination and measurement of islet cell autoantibodies (ICA), insulin autoantibodies (IAA), glutamate decarboxylase autoantibodies (GADA), autoantibodies to zinc transporter (ZnT8) and insulinoma- associated-protein-2 autoantibodies (IA-2A), as well as measurement of fasting plasma glucose and insulin (HOMA-IR) as well as GTT.
- ICA islet cell autoantibodies
- IAA insulin autoantibodies
- GADA glutamate decarboxylase autoantibodies
- ZnT8 autoantibodies to zinc transporter
- IA-2A insulinoma- associated-protein-2 autoantibodies
- HOMA-IR fasting plasma glucose and insulin
- neuropathy such as diabetes or drug-induced neuropathy
- medical history of kidney stones or history of poliomyelitis or radiotherapy.
- Serious illness requiring systemic treatment and/or hospitalization until subject either completes therapy or is clinically stable on therapy, in the opinion of the site investigator, for at least 10 days prior to study entry.
- Example 6 Dosage regimen in humans - twice daily
- This randomized, double-blind, placebo-controlled study evaluates the benefits of oral L-serine diet-supplementation 5-200 mg/kg bodyweight twice daily for 3-12 months in 30 individuals that are predisposed to develop type 1 diabetes.
- the placebo group includes 30 individuals that are predisposed to develop type 1 diabetes and they receive oral protein mix (not including L-serine) 10-400 mg/kg bodyweight per day twice daily for 3-12 months.
- the diabetes-status is evaluated at study enrollment and at study completion by a clinical examination and measurement of islet cell autoantibodies (ICA), insulin autoantibodies (IAA), glutamate
- GADA decarboxylase autoantibodies
- ZnT8 autoantibodies to zinc transporter
- IA-2A insulinoma-associated-protein-2 autoantibodies
- HOMA-IR fasting plasma glucose and insulin
- neuropathy such as diabetes or drug-induced neuropathy
- medical history of kidney stones such as diabetic kidney stones
- poliomyelitis or radiotherapy any cause of neuropathy (such as diabetes or drug-induced neuropathy), medical history of kidney stones, or history of poliomyelitis or radiotherapy
Landscapes
- Health & Medical Sciences (AREA)
- Diabetes (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Engineering & Computer Science (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Epidemiology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
La présente invention concerne des compositions alimentaires de supplémentation comprenant de la L-sérine, en particulier destinées à être utilisées chez des sujets humains atteints de prédiabète de type 1, ou d'autres maladies associées chez l'être humain, dans le but de ralentir ou de prévenir la progression d'un diabète de type 1 établi. Ce traitement prophylactique est particulièrement pertinent pour des sujets présentant un dysfonctionnement et/ou une perte de cellules bêta, des signes de mort cellulaire des cellules bêta ou des auto-anticorps en îlots. La gamme posologique quotidienne est d'environ 10 mg à environ 400 mg par kg de poids corporel par jour.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DKPA201700490 | 2017-09-08 | ||
DKPA201700490 | 2017-09-08 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2019048423A1 true WO2019048423A1 (fr) | 2019-03-14 |
Family
ID=63452661
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2018/073723 WO2019048423A1 (fr) | 2017-09-08 | 2018-09-04 | Supplémentation en l-sérine chez des sujets prédiabétiques |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2019048423A1 (fr) |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011104298A1 (fr) * | 2010-02-24 | 2011-09-01 | Universität Zürich | Prévention et traitement de maladies provoquées par des niveaux élevés de désoxysphingolipides |
WO2016116582A1 (fr) * | 2015-01-23 | 2016-07-28 | Nestec S.A. | Traitement ou prévention de l'inflammation à l'aide de sérine |
-
2018
- 2018-09-04 WO PCT/EP2018/073723 patent/WO2019048423A1/fr active Application Filing
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011104298A1 (fr) * | 2010-02-24 | 2011-09-01 | Universität Zürich | Prévention et traitement de maladies provoquées par des niveaux élevés de désoxysphingolipides |
WO2016116582A1 (fr) * | 2015-01-23 | 2016-07-28 | Nestec S.A. | Traitement ou prévention de l'inflammation à l'aide de sérine |
Non-Patent Citations (1)
Title |
---|
YEA K ET AL: "Lysophosphatidylserine regulates blood glucose by enhancing glucose transport in myotubes and adipocytes", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, ELSEVIER, AMSTERDAM, NL, vol. 378, no. 4, 23 January 2009 (2009-01-23), pages 783 - 788, XP025841496, ISSN: 0006-291X, [retrieved on 20081206], DOI: 10.1016/J.BBRC.2008.11.122 * |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Kou et al. | Ampelopsin attenuates the atrophy of skeletal muscle from d-gal-induced aging rats through activating AMPK/SIRT1/PGC-1α signaling cascade | |
RU2563991C2 (ru) | Синергические комбинации каротиноидов и полифенолов | |
EP1827136B1 (fr) | Formulation destinee a etre administree par voie orale presentant un effet benefique sur le systeme cardiovasculaire | |
WO2018064468A1 (fr) | Alpha-cétobutyrate, alpha-cétoglutarate, et 2-hydroxybutyrate pour stimuler la croissance des cheveux | |
EP3095451B1 (fr) | Procédé de préparation d'un extrait de cerveau d'origine animale | |
DK2651251T3 (en) | A composition for the treatment of infertility | |
Li et al. | Chicory polysaccharides alleviate high-fat diet-induced non-alcoholic fatty liver disease via alteration of lipid metabolism-and inflammation-related gene expression | |
Wolff et al. | Moringa isothiocyanate-1 is bioaccessible and bioavailable as a stable unmodified compound | |
CN111344016A (zh) | 用于抑制胆碱向三甲胺(tma)的转化的方法 | |
WO2019048423A1 (fr) | Supplémentation en l-sérine chez des sujets prédiabétiques | |
TW201618802A (zh) | 用於調控pp2a甲基化反應並提供抗氧化及抗發炎活性之天然萃取物 | |
ES2678023T3 (es) | Factores extraídos de embriones de pez y uso de mezclas de los mismos en el control de la multiplicación y la diferenciación de células madre | |
WO2007050599A2 (fr) | Ginkgolides dans le traitement et la prevention du cancer de l'ovaire | |
CA3117566C (fr) | Procedes pour inhiber la conversion de la choline en trimethylamine (tma) | |
EP3804709A1 (fr) | Agent d'activation de l'autophagie | |
CN112969454A (zh) | 抑制胆碱向三甲胺(tma)的转化的方法 | |
EP2514429B1 (fr) | Agent antioxydant | |
JP6732351B1 (ja) | イソクエルシトリン組成物 | |
WO2013150771A1 (fr) | Composition et procédé pour inhibition sûre et efficace de lipase pancréatique chez les mammifères | |
US20240122946A9 (en) | Methods and compositions for treating 25-hydroxyvitamin d deficiency | |
EP2441450B1 (fr) | Composition antioxydante pour réduire le stress oxydatif et les effets secondaires attribuables à un traitement avec la lévothyroxine | |
Petrangolini et al. | Research Article Development of an Innovative Berberine Food-Grade Formulation with an Ameliorated Absorption: In Vitro Evidence Confirmed by Healthy Human Volunteers Pharmacokinetic Study | |
AU2008253777B2 (en) | Medicinal agent for treating patients suffering from diseases caused by the monoaminooxidase excessive activity and a method for treating patients suffering from diseases caused by the monoaminooxidase excessive activity | |
TW205542B (fr) | ||
IT202100016895A1 (it) | Vescicola fosfolipidica comprendente una miscela di berberina e naringenina e/o suoi derivati glicosidici, composizione e uso |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 18762845 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 18762845 Country of ref document: EP Kind code of ref document: A1 |