WO2023213813A1 - Composé destiné à être utilisé dans la régulation de l'absorption de saccharide par l'intermédiaire du tractus gastro-intestinal et compositions associées - Google Patents

Composé destiné à être utilisé dans la régulation de l'absorption de saccharide par l'intermédiaire du tractus gastro-intestinal et compositions associées Download PDF

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Publication number
WO2023213813A1
WO2023213813A1 PCT/EP2023/061553 EP2023061553W WO2023213813A1 WO 2023213813 A1 WO2023213813 A1 WO 2023213813A1 EP 2023061553 W EP2023061553 W EP 2023061553W WO 2023213813 A1 WO2023213813 A1 WO 2023213813A1
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WO
WIPO (PCT)
Prior art keywords
compound
acid
glucose
gastrointestinal tract
saccharide
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Application number
PCT/EP2023/061553
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English (en)
Inventor
Mireille Maria Johanna Petronella Elisabeth STHIJNS
Frederik Jan Troost
Art MUIJSENBERG
Original Assignee
Universiteit Maastricht
Academisch Ziekenhuis Maastricht
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Application filed by Universiteit Maastricht, Academisch Ziekenhuis Maastricht filed Critical Universiteit Maastricht
Publication of WO2023213813A1 publication Critical patent/WO2023213813A1/fr

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    • 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
    • A61K31/12—Ketones
    • 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
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 

Definitions

  • the present invention relates to a compound for use in the regulation of saccharide absorption via the gastrointestinal tract.
  • the present invention further relates to a composition comprising the compound according to the present invention.
  • d-glucose, d-galactose, and d-fructose are the most relevant monosaccharides.
  • monosaccharides must cross a layer of epithelial cells that are connected by tight junctions which do not allow permeation of monosaccharides in physiological concentrations. Because monosaccharides are hydrophilic, they cannot permeate cell membranes passively.
  • transporters in the luminal brush border membrane (BBM) and basolateral membrane (BLM) of small intestinal epithelial cells (lECs) are required.
  • BBM luminal brush border membrane
  • BBM basolateral membrane
  • transporters for d- glucose, d-galactose, and/or d-fructose expressed in the small intestine are well described in literature (see, for example: Koepsell H. Glucose transporters in the small intestine in health and disease. Pflugers Arch. 2020;472(9):1207-1248).
  • the present invention now provides for a compound regulating the saccharide absorption via the gastrointestinal tract.
  • the compound of the present invention decreases or increases the maximal saccharide uptake by the gastrointestinal tract.
  • the present invention provides hereto a method for treating mammalians suffering from obesity or improving exercise performance, respectively. It was found that by providing the compound of the present invention, the expression of gastrointestinal saccharide transporters is influenced, i.e.
  • the present invention provides hereto a compound for use in the regulation of saccharide absorption via the gastrointestinal tract, wherein the compound is selected from the group consisting of hydroxycinnamic acids, curcuminoids and derivatives thereof. It was found that the group of hydroxycinnamic acids and derivatives thereof resulted in increasing saccharide absorption via the gastrointestinal tract, thus being of particular use in the improvement of exercise performance of a mammalian. It was further found that the group of curcuminoids and derivatives thereof resulted in decreasing saccharide absorption via the gastrointestinal tract, thus being of particular use in the treatment of mammalians suffering from obesity.
  • saccharides such as d-glucose, d-galactose, d-fructose and ribose
  • transporters may be present in the luminal brush border membrane (BBM) and basolateral membrane (BLM) of small intestinal epithelial cells (lECs).
  • BBM luminal brush border membrane
  • BBM basolateral membrane
  • transporters may include (but are not limited to) transporters belonging to the SLC2 family with facilitative diffusion transporters (GLUTs) and the SLC5 family with Na + -d-glucose cotransporters (SGLTs).
  • GLUTs facilitative diffusion transporters
  • SGLTs Na + -d-glucose cotransporters
  • mammalian refers to an animal or human. Synonyms may include the terms ‘subject’ or ‘patient’.
  • the present invention relates to the use of a compound for use in the regulation of saccharide absorption via the gastrointestinal tract.
  • the saccharide absorption preferably comprises the saccharide absorption via the small intestine.
  • saccharide absorption may further refer to the absorption of monosaccharides, such as saccharides selected from the group consisting of d- glucose, d-glucose, d-galactose, d-fructose and pentoses, such as ribose, and combinations thereof.
  • the present invention relates to the use of a compound for improving exercise performance, wherein the compound is selected from the group consisting of hydroxycinnamic acids and derivatives thereof.
  • the hydroxycinnamic acid is preferably selected from the group consisting of cinnamic acid, coumaric acid, ferulic acid, caffeic acid, chlorgenic acid and rosemarinic acid.
  • caffeic acid In particular good results in increasing the saccharide absorption via the gastrointestinal tract are observed by using caffeic acid.
  • hydroxycinnamic acid is used as a compound for regulating saccharide absorption via the gastrointestinal tract
  • the amount and form of administration of hydroxycinnamic acid is preferably selected such that the bioaccessibility of hydroxycinnamic acid in the gastrointestinal tract, preferably the small intestine, is in the range of 100-400 pM hydroxycinnamic acid.
  • bioaccessibility of hydroxycinnamic acid refers to the amount of hydroxycinnamic acid released in the gastrointestinal tract. In other words, the amount of hydroxycinnamic acid available for absorption via the gastrointestinal tract. It is noted that the bioaccessibility depends on the amount administered and form of administration by the subject. A liquid formulation comprising a specific amount of hydroxycinnamic acid is expected to have a higher bioaccessibility than a solid formulation comprising the same amount of hydroxycinnamic acid.
  • the amount and form of administration of hydroxycinnamic acid is preferably selected such that the bioaccessibility of hydroxycinnamic acid in gastrointestinal tract, preferably the small intestine, is in the range of 125-350 pM, 150-300 pM or 175-250 pM hydroxycinnamic acid.
  • the amount and form of administration of hydroxycinnamic acid is preferably selected such that the bioaccessibility of hydroxycinnamic acid in gastrointestinal tract, preferably the small intestine is about 200 pM.
  • the present invention relates to a compound for treating obesity, wherein the compound is selected from the group consisting of curcuminoids and derivatives thereof.
  • the curcuminoid is preferably selected from the group consisting of curcumin, demethoxycurcumin, dibenzoylmethane and bisdemethoxycurcumin.
  • curcumin demethoxycurcumin
  • dibenzoylmethane dibenzoylmethane
  • bisdemethoxycurcumin bisdemethoxycurcumin.
  • curcuminoid is used as a compound for regulating saccharide absorption via the gastrointestinal tract
  • the amount and form of administration of curcuminoid is preferably selected such that the bioaccessibility of curcuminoid in the gastrointestinal tract, preferably the small intestine, is at least 100 pM curcuminoid.
  • bioaccessibility of curcuminoid refers to the amount of curcuminoid released in the gastrointestinal tract. In other words, the amount of curcuminoid available for absorption via the gastrointestinal tract. It is noted that the bioaccessibility depends on the amount administered and form of administration by the subject. A liquid formulation comprising a specific amount of curcuminoid is expected to have a higher bioaccessibility than a solid formulation comprising the same amount of curcuminoid.
  • the amount and form of administration of curcuminoid is preferably selected such that the bioaccessibility of curcuminoid in gastrointestinal tract, preferably the small intestine, is at least 125 pM, at least 150 pM, at least 175 pM, more preferably at least 200 pM or at least 400 pM curcuminoid.
  • the compound for use according to the present invention is preferably a nutraceutical.
  • the term ‘nutraceutical’ refers to any food or food ingredient (or feed or feed ingredient for animals) considered to provide medical or health benefits, including the prevention and treatment of a disease.
  • a nutraceutical may also be referred to as bioactive ingredient.
  • a food product may comprise a food ingredient that has bioactive potential at a higher concentration than actually consumed (i.e. the concentration of the ingredient as consumed when consuming the food product). Therefore, the compound for use according to the present invention is preferably a food ingredient (or feed ingredient) having bioactive properties administered in an amount such that the food ingredient (or feed ingredient) exhibits the bioactive properties in the mammalian (human or animal) body.
  • the present invention relates to a composition comprising the compound of the present invention.
  • the composition of the present invention is a food supplement.
  • a differentiated Caco-2 cell line transwell model system was used to determine glucose and fructose transepithelial transport.
  • Caco-2 cells were differentiated in a transwell set-up and exposed to the compound of interest at different concentrations and exposure times. After a 3-day differentiation with butyrate and BSA to induce differentiation of Caco-2 cells to an intestinal epithelial phenotype in transwells, the cells were exposed to different doses (100 pM, 200 pM and/or 400 pM) of the compounds of interest for 4 hours. After that the cells are apically exposed to physiological glucose (1 mM) and fructose (0.5 mM) concentrations for 30 minutes.
  • intestinal epithelial uptake of glucose and fructose was measured by determining the basolateral glucose and fructose spectrophotometrically by measuring absorbance (glucose amplex red assay) and fluorescence (NBD-labelled fructose).
  • saccharide transporters such as SGLT 1 and/or GLLIT5
  • the intestinal epithelial uptake of glucose and fructose as well as the expression of saccharide transporters SGLT 1 and GLLIT5 was measured for phlorizin and its aglucone phloretin, two known inhibitors of glucose transmembrane transport.
  • bisdemethoxycurcumin (200 pM) downregulates the glucose transepithelial transport (Figure 4A) and upregulates the fructose transepithelial transport ( Figure 4B).
  • Caffeic acid (200 pM) increases glucose transepithelial transport (Figure 2A).
  • Caffeic acid has a small therapeutic window, since 100 pM and 400 pM already decreases glucose uptake (Figure 2A).
  • An opposite pattern of fructose uptake has been seen as compared to glucose uptake for caffeic acid ( Figure 2B).
  • caffeic acid increases glucose transepithelial transport. It is further noted that caffeic acid significantly upregulates the expression of SGLT1 thus being a promising candidate for the upregulation of saccharide absorption via the gastrointestinal tract. As such, it can be concluded that caffeic acid is a promising candidate for improving exercise performance, in particular for improving exercise performance of endurance athletes.
  • Figure 1A glucose uptake results at different concentrations of dibenzoylmethane by measuring absorbance using a glucose amplex red assay
  • Figure 1 B fructose uptake results at different concentrations of dibenzoylmethane by measuring fluorescence using a NBD-labelled fructose
  • FIG. 2A glucose uptake results at different concentrations of caffeic acid by measuring absorbance using a glucose amplex red assay
  • FIG. 2B fructose uptake results at different concentrations of caffeic acid by measuring fluorescence using a NBD-labelled fructose
  • Figure 3 100 pM DBM has been shown to decrease SGLT1 expression in the differentiated Caco-2 cells;
  • Figure 4A glucose uptake results of phloretin (1 mM), phlorizin (500 pM), dibenzoylmethane (400 pM), curcumin (200 pM) and bisdemethoxycurcumin (200 pM) by measuring absorbance using a glucose amplex red assay;
  • Figure 4B fructose uptake results of phloretin (1 mM), phlorizin (500 pM), dibenzoylmethane (400 pM), curcumin (200 pM) and bisdemethoxycurcumin (200 pM) by measuring fluorescence using a NBD-labelled fructose;
  • Figure 5 SGLT1 expression results in differentiated Caco-2 cells of phloretin (1 mM), phlorizin (500 pM), dibenzoylmethane (400 pM), curcumin (200 pM), bisdemethoxycurcumin (200 pM) and caffeic acid (200 pM); and
  • FIG. 6 GLLIT5 expression results in differentiated Caco-2 cells of phloretin (1 mM), phlorizin (500 pM), dibenzoylmethane (400 pM), curcumin (200 pM) and bisdemethoxycurcumin (200 pM).

Abstract

La présente invention concerne un composé destiné à être utilisé dans la régulation de l'absorption de saccharides par l'intermédiaire du tractus gastro-intestinal, le composé étant choisi dans le groupe constitué par les acides hydroxycinnamiques, les curcuminoïdes et leurs dérivés. La présente invention concerne en outre une composition comprenant le composé selon la présente invention.
PCT/EP2023/061553 2022-05-03 2023-05-02 Composé destiné à être utilisé dans la régulation de l'absorption de saccharide par l'intermédiaire du tractus gastro-intestinal et compositions associées WO2023213813A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP22171356.3 2022-05-03
EP22171356 2022-05-03

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WO2023213813A1 true WO2023213813A1 (fr) 2023-11-09

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005113069A2 (fr) * 2004-05-14 2005-12-01 Research Development Foundation Utilisation de curcumine et d'analogues de curcumine comme inhibiteurs de l'acc2
EP2596704A1 (fr) * 2011-11-28 2013-05-29 Nestec S.A. Augmentation de la biodisponibilité d'acides hydroxycinnamiques
JP2014031330A (ja) * 2012-08-03 2014-02-20 Nippon Supplement Kk 高血糖等改善剤
KR20150035458A (ko) * 2013-09-26 2015-04-06 고려대학교 산학협력단 디벤조일메탄을 함유하는 비만 치료 또는 예방용 조성물

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005113069A2 (fr) * 2004-05-14 2005-12-01 Research Development Foundation Utilisation de curcumine et d'analogues de curcumine comme inhibiteurs de l'acc2
EP2596704A1 (fr) * 2011-11-28 2013-05-29 Nestec S.A. Augmentation de la biodisponibilité d'acides hydroxycinnamiques
JP2014031330A (ja) * 2012-08-03 2014-02-20 Nippon Supplement Kk 高血糖等改善剤
KR20150035458A (ko) * 2013-09-26 2015-04-06 고려대학교 산학협력단 디벤조일메탄을 함유하는 비만 치료 또는 예방용 조성물

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DOLATI SEPIDEH ET AL: "The Effect of Curcumin Supplementation and Aerobic Training on Anthropometric Indices, Serum Lipid Profiles, C-Reactive Protein and Insulin Resistance in Overweight Women: A Randomized, Double-Blind, Placebo-Controlled Trial", JOURNAL OF OBESITY & METABOLIC SYNDROME, vol. 29, no. 1, 30 March 2020 (2020-03-30), pages 47 - 57, XP055953205, ISSN: 2508-6235, DOI: 10.7570/jomes19055 *
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