ES2724728A1 - Composition for glucose metabolism regulation (Machine-translation by Google Translate, not legally binding) - Google Patents

Abstract

Composition for the regulation of glucose metabolism. The present invention relates to a composition for regulating glucose metabolism comprising as active ingredients one or more polyphenols at a concentration between 0.5 and 100 mg/g of the composition and dietary fibers, where the dietary fibers comprise one or more more sugars or derivatives thereof at a concentration of 50 to 600 mg/g based on the composition. The sugars especially comprise neutral sugars selected from the group comprising cellulose, glucose, xylose, galactose, arabinose and mannose and any combination thereof. The composition is used to treat or prevent diseases related to glucose metabolism disorders. (Machine-translation by Google Translate, not legally binding)

Description

DESCRIPTION

Composition for glucose metabolism regulation

TECHNICAL FIELD

The present invention belongs to the food and / or pharmaceutical sector, in particular, it relates to the functional composition of the ingredients.

STATE OF THE PRIOR ART OF THE INVENTION

High blood glucose levels stimulate insulin secretion by pancreatic beta cells. Insulin in turn stimulates the entry of glucose into the muscles and fat cells, which leads to the storage of glycogen and triglycerides and protein synthesis. Activation of insulin receptors in various cell types decreases circulating glucose levels by increasing glucose uptake and utilization, and by reducing liver glucose production. Alterations of this regulatory network can result in diabetes and associated pathological syndromes that affect a large and growing percentage of the human population.

Patients who have a glucose metabolism disorder may suffer from hyperglycemia, hyperinsulinemia and / or glucose intolerance. An example of a disorder that is often associated with aberrant glucose and / or insulin levels is insulin resistance, in which liver, fat and muscle cells lose their ability to respond to normal insulin levels in the blood.

In view of the prevalence and severity of diabetes and associated metabolic and non-metabolic disorders, treatment modalities that modulate, for example, glucose and / or insulin levels and improve the biological response to fluctuating levels remain of interest. of glucose in a patient. It is also important to reduce the risk of such diseases and disorders, especially type 2 diabetes.

Polyphenols are chemical compounds or substances found in a large amount of plant-derived foods. The term encompasses a wide variety of molecules with a common structure, characterized by having several hydroxyl groups attached to aromatic rings. However, polyphenols also include molecules with a phenol ring, as in the case of phenolic acids or phenolic alcohols.

Polyphenol Classification

Polyphenols are classified according to the number of phenol rings they contain, as well as the structural elements that bind these rings. As such, the main groups of polyphenols are:

Flavonoids: which have a diphenylpropane carbon skeleton and two benzene rings joined together by a linear chain of 3 carbon atoms. To date, more than 6,000 flavonoids have been identified in plants, and the list continues to grow. Flavonoids can be divided into 6 subclasses, depending on the oxidation state of the central pyranus ring. Flavonoids can be divided into Flavonols, Flavones, Flavanones, Lisoflavones, Anthocyanins and Flavanols.

Flavonols: which have a double bond between carbons 2 and 3, with a hydroxyl group in C3.

They are the most ubiquitous flavonoids in food, and quercetin is the most representative.

Flavones: They have a double bond between carbons 2 and 3, and are the least common flavonoids. They are found in parsley and celery.

Flavanones: They are characterized by having a saturated chain of 3 carbon atoms and an oxygen atom in carbon 4. They are found only in high concentrations in citrus fruits, although they are also present in tomatoes and in some aromatic plants such as mint.

Isoflavones: which are structurally similar to estrogens, and in the feet can bind to their receptors, so they are also known as phytoestrogens. Soy and its derivatives are the main sources of isoflavones.

Anthocyanins: which are the pigments responsible for the red, blue and purple coloring of fruits, flowers and other tissues and plant products

Flavanols: which have a saturated chain of 3 carbons, with a hydroxyl group in C3. They exist both as monomers and polymers, known as catechins and proanthocyanidins, respectively.

The main flavonoids in fruit are catechin and epicatechin, while galocatechin, epi-gallocatechin and epigallocatechin gallate are essentially found in tea. Catechins are found in fruits such as apricots and cherries and in other products such as tea, chocolate and white wine.

Phenolic acids: which are divided into two groups, those derived from benzoic acid and those derived from cinnamic acid.

Hydrobenzoic acids: found in very few plants consumed by humans, and therefore are not considered of particular interest for nutrition. Among them, gallic acid or egic acid stand out

Hydroxycinnamic acids: which are mainly represented by coumaric acid, caffeic acid and ferulic acid.

Phenolic alcohols: tyrosol and hydroxytyrosol are the main types. They are found mainly in olive oil. Tyrosol is also found in wine, both white and red, and in beer; Hydroxytyrosol, on the other hand, is found in red wine.

Stilbenes: the main stilbene present in the human diet is resveratrol, although the amount of these compounds ingested in the diet is small. Stilbenes are produced by plants in response to pathogens or certain stress conditions. They have been detected in more than 70 species of plants, such as grapes, berries and peanuts.

Lignans: Lignans are produced by the oxidative dimerization of two phenylpropane units. The main source of these compounds is flax seed.

The main source of food polyphenols is grape marc (GP). Grape pomace is a by-product of the winery consisting basically of grape seeds, skin and stems. It is rich in dietary fiber and polyphenols, including anthocyanins (in tintoGP), flavan-3-oles, flavonols, phenolic acids and stilbenes (Fontana, Antoniolli and Bottini, 2013), which provide a wide variety of possible biological activities (Yu and Ahmedna, 2013).

In recent years, interest in the use of GP to develop functional ingredients and other applications for the food industry has increased (Charalampia & Koutelidakis, 2016). But most of the scientific evidence related to the benefits of GP is derived from experiments performed in vitro and in animal models, often using a much higher concentration than that contained in biological fluids and diet, respectively. In addition, in some cases, the original GP compounds are tested instead of their derived metabolites, that would be responsible for the beneficial effects in vivo (D'Archivio, Filesi, Vari, Scazzocchio, and Masella, 2010).

Two human intervention studies have been published on the effects of GP inclusion in the human diet. Yubero et al. (2013) evaluated the effects of providing a supplement with GP extract (700 mg / day, 56 days) on cardiovascular risk and indicators of oxidative stress in healthy volunteers (n = 60). The results of this study showed that the supplement with GP extract was able to modulate the lipid profile, lowering total blood cholesterol and low density lipoprotein (LDL) cholesterol levels (Yubero et al., 2013). On the other hand, Urquiaga et al. (2015) investigated the effect of the contribution of a supplement with a GP flour (20 g / day, 16 weeks, approximately 10 g of dietary fiber / day) in male patients (n = 38) who presented at least one symptom of syndrome metabolic. The results of this study indicated a significant improvement in blood pressure, fasting glucose levels and protein damage after contribution with GP flour (Urquiaga et al., 2015).

DESCRIPTION OF THE INVENTION

The main object of this invention is a composition for regulating glucose metabolism comprising as active ingredients the following components:

a) one or more concentrations of polyphenols in a concentration between 0.5 and 100 mg / g of the composition;

b) dietary fibers, in which the dietary fibers comprise one or more sugars or derivatives thereof at a concentration of 50 to 600 mg / g based on the composition.

Preferably, the polyphenol compound or compounds comprise ellagic acid, flavanols or flavonols or any combination thereof, preferably ellagic acid, flavanols and flavanols. Preferably, the polyphenols comprise as catechin, epicatechin or proanthocyanidin flavanols or any combination thereof, preferably catechin, epicatechin and proanthocyanidin. Preferably the composition comprises as flavonols, myricetin, quercetin or any combination thereof, preferably micelin, quercetin and kaempferol.

One or more sugars or derivatives thereof are preferably sugars measured by hydrolysis of the alcohol insoluble residue (RIA) of the composition.

Preferably the sugars comprise neutral sugars and uronic acids. Preferably, the neutral sugars selected from the group comprising cellulose, glucose, xylose, galactose, arabinose and mannose and any combination thereof. Preferably, the neutral sugars are selected from the group consisting of cellulose, glucose, xylose, galactose, arabinose and mannose and any combination thereof.

Preferably, the total concentration of dietary fibers in the composition is from 50 to 850 mg / g, more preferably from 300 mg / g to 850 mg / g, even more preferably from 550 mg / g to 750 mg / g.

Preferably, the total concentration of one or more polyphenols is between 10 and 100 mg / g, more preferably between 20 and 50 mg / g. The total concentration is measured in mg of gallic acid / g.

Preferably, the total concentration of dietary fibers is at least 3 times greater than the concentration of polyphenols, more preferably between 5 and 30 times greater.

Preferably, the concentration of neutral sugars is 5 to 20 times higher than the concentration of uronic acids.

In a preferred embodiment of the invention, the composition comprises the following concentration of polyphenols by weight:

- ellagic acid: between 0.5 and 10 mg / g of the composition

- flavanols: between 0.2 and 20 mg / g of the composition

- flavonols: between 0.11 and 12 mg / g of the composition.

Preferably, the flavanols comprised by the composition are the following:

• catechin: between 0.05 and 5 mg / g of the composition

• epicatechin: between 0.05 and 5 mg / g of the composition

• proanthocyanidin: between 0.1 and 1O mg / g of the composition.

Preferably, the flavonols comprised by the composition are the following:

• myricetin: between 0.05 and 5 mg / g of the composition

• quercetin: between 0.05 and 5 mg / g of the composition

• kaempferol: between 0.01 and 2 mg / g of the composition.

Preferably, the sugars included in the dietary fibers are the following: - neutral sugars: between 150 and 550 mg / g of the composition

- Uronic acids: between 1 and 100 mg / g of the composition

- Lignin Klason: between 1 and 200 mg / g of the composition.

Preferably, the neutral sugars comprised by the composition are the following:

• cellulose: between 0.5 and 30 mg / g of the composition

• glucose: between 150 and 400 mg / g of the composition

• Xylose: between 0.1 and 5 mg / g of the composition

• galactose: between 0.5 and 30 mg / g of the composition

• arabinose: between 0.1 and 1O mg / g of the composition

• Mannose: between 0.5 and 30 mg / g of the composition

In a preferred embodiment of the invention, the composition comprises the following concentration of polyphenols by weight:

- ellagic acid: between 0.5 and 1O mg / g of the composition

- flavanols: between 0.2 and 20 mg / g of the composition

- flavonols: between 0.11 and 12 mg / g of the composition,

and where, the flavanols comprised by the composition are the following:

• catechin: between 0.05 and 5 mg / g of the composition

• epicatechin: between 0.05 and 5 mg / g of the composition

• proanthocyanidin: between 0.1 and 1O mg / g of the composition,

and where, the flavonols included in the composition are the following:

• myricetin: between 0.05 and 5 mg / g of the composition

• quercetin: between 0.05 and 5 mg / g of the composition

• kaempferol: between 0.01 and 2 mg / g of the composition.

In a preferred embodiment of the invention, the composition of sugars comprised of dietary fibers is as follows:

- neutral sugars: between 151.7 and 505 mg / g of the composition

- Uronic acids: between 1 and 100 mg / g of the composition

- Lignin Klason: between 1 and 200 mg / g of the composition;

wherein the neutral sugars included in the composition are the following:

• cellulose: between 0.5 and 30 mg / g of the composition

• glucose: between 150 and 400 mg / g of the composition

• Xylose: between 0.1 and 5 mg / g of the composition

• galactose: between 0.5 and 30 mg / g of the composition

• arabinose: between 0.1 and 1O mg / g of the composition

• Mannose: between 0.5 and 30 mg / g of the composition

All the sugars mentioned are preferably the natural forms of the sugars, e.g. RE- Glucose.

In a preferred embodiment of the invention, the composition is obtained from a dry grape extract.

A further object of this invention is a functional (nutritional) dietary supplement characterized in that it comprises the composition described above, in any of its variants, as a functional ingredient. The composition acts directly as a functional dietary supplement. The dietary supplement may consist entirely (100% of the total composition of the supplement) by the composition.

In another preferred embodiment, said dietary supplement is characterized in that it comprises at least between 100 mg and 5 g of the composition, preferably between 500 mg and 2 g.

Preferably, this dietary supplement is characterized in that it comprises, in addition to the composition as a functional ingredient, at least one physiologically acceptable substance having properties selected from the group consisting of: nutritive, antioxidant, therapeutic, flavoring, aromatic, coloring or other similar properties

It is also preferable that the edible dietary composition additionally contains at least one substance selected from the group consisting of: Vitamins (Vitamin A, Vitamin B1, Vitamin B2, Vitamin B3, Vitamin B6, Vitamin B9, Vitamin B12, Vitamin C, Vitamin E), dietary trace elements (for example, zinc, copper, magnesium, selenium, manganese), phytochemicals (for example, carotenoids, lutein, zeaxanthin, astaxanthin), collagen, type II collagen, Chondroitin Sulfate, Hyaluronic Acid, Omega-3 Fatty Acids , Hydroxitol, Glutathione, Glucosamine, phyto extracts enriched with proanthocyanidins and phyto extracts of other plant products (such as, optionally, pomegranate, green tea, olive, Polygonum cuspidatum).

Both the composition described in this specification and the dietary supplement that comprises it (as a functional ingredient) can directly be consumed by humans. As such, the scope of the present invention includes not only the use of the composition as a dietary supplement, but also the use of the composition as a functional ingredient in foods or in a dietary composition.

In this way, both the composition and the nutritional or dietary supplement described above, in any of its variants, can be packaged in bulk or in single doses. In general, the composition and dietary supplement can be packaged in cans, drums, cardboard boxes or any other type of packaging known in the field. When packaged in single doses, said composition and said composition comprising it can take the form of a tablet, a capsule or a pill.

It has been shown that the effect of the composition described herein, or of a dietary supplement comprising said composition, offers benefits for human health, especially with diseases related to glucose metabolism and the improvement of the parameters associated with related diseases. with glucose metabolism. For example, it has been shown how one benefits from the consumption of this composition, or the dietary supplement that contains it, by reduced blood sugar levels and an upregulated glucose metabolism. The effect is already significant even at low doses.

"Glucose metabolism regulation" is understood as the regulation of glucose processing and / or uptake. Preferably, regulation of glucose metabolism results in an increase or reduction of at least one of the circulating miRNAs selected from the group comprising miRNA-130a-3p, miRNA-122-5p, miRNA-34a-5p, miRNA-191 -5p and miRNA-342-3p, preferably at least 2, 3, 4 of these miRNAs, even more preferably all of these miRNAs. The miRNAs preferably have the sequences according to SEQ-ID Nos. 1 to 5. A regulation within the meaning of the invention is understood as a statistically significant change in the level of a circulating miRNA as indicated, for example, by a p value of p <0.05 as analyzed by the t-test for individual samples.

In a preferred embodiment, the regulation results in at least one significant change in the level of miRNA-191-5p and more preferably in the levels of miRNA-191-5p and miRNA-122-5p.

A "miRNA" (also called "microRNA", "mir-", "miR-" or "micro RNA") is a small non-coding RNA molecule (containing approximately 22 nucleotides) found in plants, animals and some virus, and that works in RNA silencing and posttranscriptional regulation of gene expression. The miRNAs work through base pairing with complementary sequences within mRNA molecules. As a result, these mRNA molecules are silenced by one or more of the following processes:

1) Rupture or cleavage of the mRNA chain in two parts, 2) destabilization of mRNA through shortening of its poly-Adenine tail (A) and 3) less efficient translation of mRNA into proteins in ribosomes. The miRNAs are well conserved in both plants and animals, and are believed to be a vital and evolutionarily ancient component of genetic regulation. It is understood by circulating miRNA that miRNA present in blood, blood serum or serum.

Influencing miRNA levels shows a strong influence of the composition on glucose metabolism.

Depending on the metabolic proposition, it may be necessary to determine if the composition also shows the effect described in 1, 2, 3, 4 or 5 of the miRNAs previously described in this person. The use of the compound may be restricted to these people.

The scope of the present invention further includes a food product characterized in that its composition comprises as a functional ingredient the described composition or the nutritional supplement that can be obtained thereof, mixed with at least one dietary ingredient. In a preferred composition of the food product, it comprises as a dietary ingredient one of the products selected from the group consisting of meat products, dairy products, dairy products, sauces, pasta, bakery and pastry products, and the like, and any combination thereof .

In another preferred embodiment, the food product is a beverage, and the nutritional composition or supplement comprising it is mixed with a physiologically acceptable liquid.

Another object of the present invention is the use of the described composition, or any of its variants, for the production of different functional products. These products include food and dietary supplements for human consumption. Said composition can be used to regulate glucose metabolism. In this way, the composition of the present invention can be used to prevent or treat diseases related to disorders in glucose metabolism. Treatment or prevention results in an increase in glucose metabolism. In particular embodiments, the glucose metabolism disorder is diabetes mellitus, especially type 2 diabetes.

Although it is not limited to any particular route of administration or dosage regimen, oral administration is preferred.

The composition can be used in a dosage of at least 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1 g or 1.4 g per day.

As an upper limit, a dose of 8 g, 7 g, 6 g, 5 g, 4 g, 3 g or 2 g per day is preferred. Each of these limits can be combined as the lower and upper limit of a preferred dosage.

More preferred is a dosage of 300 mg at 5 g per day, even more preferred a dosage of 1 g to 2 g per day. The present composition shows significant effects even at low doses, which can easily be included in a daily diet.

The doses correspond to an adult man or woman, preferably between the ages of 25 and 65, preferably adult women.

The person to be treated is preferably an adult man or woman, preferably between 25 and 65 years, more preferably an adult woman.

The duration of treatment is preferably at least 7 days, more preferably at least 14 days, even more preferably at least 21 days.

The duration of treatment is at least until the first regulation of significant effects of glucose metabolism can be measured as mentioned above. Another additional effect may be the improvement of fasting glucose levels. More preferably, the first effects are measured after at least 21 days. Therefore, the treatment can be terminated or suspended after 60 days, preferably after 40 days.

The treatment can be used to reduce the risk of the aforementioned diseases in healthy individuals.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

For a more complete understanding of the present invention, a reference is made to the following description made in connection with the accompanying drawings:

Fig. 1.2 Changes in the expression levels of five miRNAs related to glucose metabolism in all volunteers after the intake of the composition. Changes in magnitude (2-acq) expressed differences in miRNA before and after consuming the composition capsules. Samples were analyzed in triplicate. * indicates values significantly different from zero (p <0.05) as analyzed by t-test for individual samples.

DETAILED DESCRIPTION OF THE INVENTION

Although the present inventions have been described and illustrated together with several specific embodiments, those skilled in the art will appreciate that variations and modifications can be made without departing from the principles of the invention as illustrated, described and claimed herein. The present inventions can be incorporated in other specific forms without departing from their spirit or essential characteristics.

The described embodiments are considered in all aspects as illustrative and not restrictive. The scope of the invention, therefore, is indicated by the appended claims, rather than by the above description. All the changes that are found within the meaning and the equivalence range of the claims should be included within its scope.

Materials and methods

Composition

The composition contained high amounts of dietary fiber (659.7 mg / g of composition) and a moderate concentration of total polyphenols (37.44 mg of gallic acid / g of composition) (Table 1). Among the phenolic compounds, different phenolic acids, flavonols and flavanols were included (Table 1). Other chemical parameters analyzed in the composition were humidity (4.6%), total protein (8.7%), fat (0.8%) and ash (20.7%). The composition, dispensed in capsules containing 700 mg of composition / capsule. The composition could be obtained from red grapes used in the winemaking process, as described in Gil-Sánchez, l. (2017) to extract L1. The sugar content based on an alcohol insoluble residue of the composition is shown in Table 4.

The raw material for all extracts was the GP obtained after the vinification process of rosé or red wines. The red grapes used in winemaking were all of the Tempranillo variety, harvested in vineyards located in the Ribera de Duero Denomination of Origin. Fresh GP was used as raw material and underwent a distillation process to remove aromatic compounds and alcohol. The residue was extracted through the traditional solid-liquid extraction method using a hydroalcoholic solution (water-ethanol) as solvent. Solid-liquid extraction was performed by diffusion technique. Once the liquid polyphenolic extract was obtained, the resulting product was centrifuged and stabilized to displace possible solid residues. The solution rich in polyphenols was concentrated and finally dried by a spray drying process. Maltodextrin and silicon dioxide were used as encapsulation agents in the spray drying process. The humidity in the extract was around 4.6%. The process can also be carried out as described in ES2319032A1.

Analysis of flavanols, phenolic acids and flavonols

The composition (50 mg) was extracted with 50% acetonitrile (1 ml) in an ultrasonic bath for 30 minutes and further centrifuged at 6700xg for 5 minutes; the supernatant was collected and the residue was subjected to the same process another three times. The four supernatants were combined and evaporated to dryness under pressure. reduced The residue was recovered in 1 ml of acetonitrile-water (25:75, v / v) and analyzed by high performance liquid chromatography, by means of serial diode detection, electrospray ionization / mass spectrometry HPLC-DAD-ESI / MS) on a Hewlett-Packard 1100 chromatograph (Agilent Technologies, Waldbronn, Germany) equipped with a quaternary pump and a serial diode detector coupled to an HPChemStation data processing (rev.A.05.04). The HPLC system was connected through the serial diode detector cell output to an API 3200 Qtrap mass spectrometer (Applied Biosystems, Darmstadt, Germany), consisting of an ESI source and an ion trap mass analyzer Triple quadrupole controlled by Analyst 5.1 software.

The separation was performed on an Agilent Poroshell 120 EC-C18 column (2.7 ^ m, 150 mm x 4.6 mm) at 35 ° C, using (A) 0.1% formic acid and (B) acetonitrile as solvents, using different gradients for the analysis of flavanols and phenolic acids (0% B to 8% B in 5 min and 8 to 10% for 20 min, 10-14.5% B for 20 min, 14.5-60 % B for 10 min) and flavonols (isocratic 15% B for 5 min, 15-20% B for 5 min, 20-35% B for 10min, 35-50% B for 10min, 50-60% B for 7min) , using in both cases a flow rate of 0.5 mLmin-1. Double in-line detection was carried out by DAD at 280 and 370 nm as preferred wavelengths. Mass spectra were recorded between m / z 100 and m / z 1400 in the negative ion mode. The zero grade air served as a nebulizer gas (40 psi) and as a turbo gas (400C °) for solvent drying (30 psi). Nitrogen served as a curtain in (10psi) and collision gas (medium).

The quadrupoles were adjusted to the resolution of the unit and the mass spectrometer detector was programmed to perform a series of two consecutive analyzes: a complete high sensitivity survey (enhanced MS, EMS) and an improved product ion analysis (EPI ) to obtain the fragment pattern of the parent ion The EMS parameters were: 4500V ion spray voltage, potential offset (DP) -40V, input potential (EP) -7V and collision energy (CE) -20V; while the EPI settings were: DP -40V, EP -10V, CE -25V and CES 0V, for flavanols and phenolic acids; and: DP -40V, EP -10V, CE -25V and CES 0V, for flavonols.

Phenolic compounds were characterized according to their absorption and mass spectra and retention times compared to a data library, as well as authentic standards when available. The compounds were quantified from the areas of their chromatographic peaks recorded at 280 nm (phenolic acids and flavanols) and 370 nm (flavonols). For the quantification of the compound, were obtained Calibration curves for catechin, epicatechin, uercetin, gallic acid and ellagic acid. Flavonols were expressed as equivalents of quercetin and procyanidin dimers as epicatechin. All samples were analyzed in triplicate, and the results were expressed in milligrams of phenolic compound per gram of extract (spray dried product).

Anthocyanin analysis

Samples (50 mg) were extracted using 0.1% trifluoroacetic acid (TFA) -acetonitrile (1: 1, v / v) (1 ml) in an ultrasonic bath for 30 minutes and further centrifuged at 6700xg for 5 minutes; The supernatant was collected and the residue was subjected to the same process another three times. All supernatants were combined and evaporated to dryness under reduced pressure. The residue was recovered in 1 ml of 0.1% TFA-acetonitrile (75:25, v / v) and analyzed by HPLC-DAD-ESI / MS. An AQUA (Phenomenex) C18 column (5 ^ m, 150mmx4.6mm) was used at 35 ° C. The solvents were (A) 0.1% TFA and (B) acetonitrile, with the following elution gradient established: isocratic 10% B for 5 min, 10-15% B in 15 min, isocratic 15% B for 5 min, 15-18% B for 5 minutes, 18-35% B for 20 min, 35-60% B for 7 min. The flow rate was 0.5 mLmin-1. DAD was carried out at 280 and 520nm. Mass spectra were recorded between m / z 100 and m / z 900 in positive ion mode. Zero grade air served as a nebulizer (50 psi) and turbo gas (600 ° C) for solvent drying (40 psi). The nitrogen was the curtain (10 psi) and the collision gas (high). EMS and EPI analysis were also carried out. The parameters of the EMS mode were: ion spray voltage 5000V, DP 55V, EP 4V and CE 10V; The EPI parameters were: DP 5541V, EP 4V and CE 10V and collision energy dispersion (CES) 0V.

Analysis of cell wall components

From each extract, the alcohol insoluble residues (RIA) were obtained by immersing the samples in ethanol (96%) at 60 ° C and homogenizing with a mixer for 5 minutes. The materials were filtered through a sintered glass filter (No.3, Scientific Furnishingsltd, Chichester, United Kingdom) and reextracted twice for 1 minute in 96% ethanol at 20 ° C and filtered again.

The residues were resuspended in absolute alcohol (twice) and acetone (twice), filtered between times, and then air dried, after which they were stored in a sealed container at room temperature. The results were expressed in milligrams of RIA per gram of extract (spray dried product). The RIA amount corresponds to the amount of dietary fiber in the extract as used herein.

The polysaccharides present in the RIAs were extracted and the chemical composition of each fraction was determined. The RIAs were subjected to a 12molL-1 H2S04 treatment at room temperature for 3 h, followed by dilution at 0.6 molL-1 H2S04 hydrolysis at 100 ° C for 3 h (HF column in table 4), and also at 0.6 molL-1 H2S04 hydrolysis at 100 ° C for 3 h (HS column in table 4). Both hydrolyzed acids released different components of dietary fiber. The insoluble residues obtained after performing the acid hydrolysis, using 12 molL-1 H2S04 followed by 0.6 molL-1 H2S04, were gravimetrically quantified as Klason lignin. The hydrolysates were passed through an AG4x4 ion exchange resin column (Bio-Rad Laboratories, Richmond, CA, USA) to neutralize them. The neutral sugar composition of the hydrolysates was determined by HPLC using a microguard column (Aminex Carbo-P, Bio-Rad) in series with a carbohydrate analysis column (Aminex HPX-87P heavy metal, 300 mm x 7.8 mm, Bio-Rad) operated with a flow rate of 0.5 mLmin-1 using a refractive index detector. The amounts of sugars were calculated using the System Gold 7.0 software after calibration with standard sugars (Sigma, St Louis, MO, USA). Before neutralization, erythritol was added as an internal standard.

The uronic acid content was determined by the colorimetric method of mhydroxidiphenyl using D-galacturonic acid as standard.

Human intervention study design

The intervention study was carried out in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of the CSIC (Madrid, Spain). All volunteers gave their informed written consent before participating. The study involved 10 healthy women (age range 25-65 years, BMI <25 kg / m2). The participants did not suffer from diabetes, hypertension, dyslipidemia, acute or chronic inflammatory disease, infectious disease, cancer or a cardiovascular episode before entering the study.

They had not received any therapy with antibiotics, prebiotics, probiotics, symbiotics or vitamin supplements or any other medical treatment that could influence the intestinal microbiota during the 6 months before the start of the study or during the study (including the washing period). The volunteers followed an initial 10-day wash period (baseline) during which they maintained a low-polyphenol diet.

After this period, participants were instructed to take two capsules per day of the composition (1400 mg of composition / day) at breakfast for 21 days. Therefore, the average daily consumption of fiber and phenolic compounds, in the present study, was 923.58 mg and 54.42 mg, respectively. During the intervention period, they also maintained the restriction of foods rich in polyphenols in the diet. The volunteers completed a questionnaire about their dietary habits to verify the diet.

Professional experts took blood samples from the volunteers after fasting overnight, at three times: (a) after the initial wash period; (b) after 14 days of consumption of the composition; and (c) at the end of the composition intervention (21 days). The serum was separated into aliquots and immediately frozen at -80 ° C.

Measurement of biochemical and immunological parameters in plasma

The serum biochemical parameters were measured in plasma using an automated biochemical autoanalyzer in an accredited external laboratory. Tests included the measurement of glucose, uric acid, albumin, liver enzymes (glutamic oxaloacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT) and gamma-glutamyl transferase (y-GT), lipid metabolism (total cholesterol, cholesterol) High density lipoprotein (HDL), total cholesterol / HDL cholesterol ratio, LDL cholesterol, LDL cholesterol / HDL cholesterol ratio and triglycerides), proteins (C-reactive protein), basal hormones (insulin and leptin serum) and tumor necrosis factor ( TNF-a) TNF-a levels were determined using an ultrasensitive ELISA kit of human TNF-a (Invitrogen, Barcelona, Spain) following the manufacturer's recommended protocol, all determinations were carried out at least in duplicate. The results are shown in table 3.

Analysis of circulating plasma miRNAs 30

RNA extraction

Total RNA (including miRNA) was extracted from plasma samples corresponding to the initial and final time (21 days) of the intervention period of the composition, following the instructions of the miRCURY ™ RNA isolation kit for Biofluids (Exiqon, Vedbaek, Denmark). After extraction, the final concentration of total RNA enriched in miRNA was quantified using a NanoDrop-1000 spectrophotometer (Thermo Fisher Scientific Inc., Spain) and purity were evaluated by measuring the ratios of 260/280 nm and 260/230 nm. Samples were stored at -20oC until further analysis. The absence of serum hemolysis was verified by amplification of miR23a and miR454 as controls.

MiRNA screening using panels

Initially, plasma miRNA expression of volunteers # 8 and # 10 was analyzed. Two hundred ng of total RNA per panel was reverse transcribed using the miRCURY LNATM Universal RT PCR microRNA and the cDNA polyadenylation and synthesis kit (Exiqon , Vedbaek, Denmark).

For each sample, the cDNA was diluted, and a mixture was prepared with 45 µl of cDNA, 4455 µl of sterile nuclease-free water and 4500 µl of SYBR Green probe (Exiqon, Vedbaek, Denmark) and the mixture was added to ready-to-use PCR panels (10DL / well). The human miRNA panels I and II v4.0 contain 743 different miRNA targets and six reference gene assays (mirBase13) (Exiqon, Vedbaek, Denmark) were used for the miRNA test. The temperature protocol was performed as follows: enzymatic activation at 95 ° C for 10 minutes; 45 cycles of 95 ° C for 15 sec and 60 ° C for 60 sec. All reactions were carried out in a LightCycler® 480 real-time PCR equipment (Rache, Basel, Switzerland). Melting curves were analyzed after amplification and Cq values were calculated using a second derivative method (LightCycler® 480 Software 1.5, Rache). All reactions were performed in triplicate. UniSp5 and UniSp3 IPC were used for standardization of miRNAs Panel I and II, respectively. The data were calculated as a change in magnitude, according to the 2-AACq method, where -AACq = (CqmiRNA-CqUniSP) miRNA after ingestion - (CqmiRNA-CqUniSP) ctrl miRNA before intake.

The final results express the difference in magnitude between values before and after intake (variance).

mRNA validation

After the selection described above, we selected five modulated human circulating miRNAs (hsa-miR-122-5p, hsa-miR-34a-5p, hsa-miR-342-3p, hsa-miR-130a-3p and hsa-miR- 191-5p) related to glucose metabolism, insulin resistance status and biomarkers of type 2 diabetes (T2D) (Hernández-Alonso, Giardina, Salas-Salvado, Arcelin and Bullo, 2016; Jiao et al. , 2015;

Tome-Carneiro et al., 2013; Xiao et al., 2014; Ye et al., 2015) (Table 2). Real-time PCR detection was performed using specific SYBR blocked nucleic acid (LNA ™) probes (Exiqon, Vedbaek, Denmark), following the manufacturer's instructions on a LightCycler® 480 instrument (Roche). The temperature protocol was performed as follows: enzymatic activation at 95 oC for 10 minutes; 45 cycles of 95 oC for 15 sec. and 60 oC for 60 sec. All reactions were carried out in triplicate and Cq values and magnitude changes were calculated as indicated above.

Statistic analysis

Repeated measures of the ANOVA unidirectional variance analysis were performed to compare the data obtained from the volunteers at the three times (washing period and after 14 and 21 days consuming the composition). An analysis of unidirectional variance between groups was performed to study the different miRNA profiles among the subjects. The least significant differences in both cases were calculated using the Tukey test (p <0.05). The relationship between miRNA expression and fasting blood glucose levels was investigated using Pearson's correlation coefficient.

The STADISTICA 7.1 program was used to process this data. Finally, the principal component analysis (PCA) was performed to summarize the changes in the miRNA profiles of the volunteers. These tests were performed using IBM SPSS Statistics for Windows, Version 23.0; Ar monk, NT: IBM Corp.

Results

Compliance with the intervention

The recruitment of volunteers was carried out at the Food Science Research Institute (CIAL), Madrid (Spain), and the study was approved by the CSIC Ethics Committee. Initially, 11 healthy women gave their written informed consent, however, one participant dropped out of the study after the initial 14-day intervention period due to personal reasons.

Overall, the composition was well tolerated by volunteers, however, two participants reported mild episodes of increased intestinal gas and dyspepsia.

Modulation of miRNA by the supply of the composition

The regulation of miRNA expression profiles after delivery of the composition in the plasma samples of the two volunteers who showed the greatest decrease in glucose levels (volunteers # 8 and # 10) was analyzed. The microRNA screening showed some changes in the expression of several miRNAs from the different 734 target miRNAs. Based on these preliminary results, five miRNAs related to glucose metabolism (miRNA-130a-3p, miRNA-122-5p, miRNA -34a-5p, miRNA-191-5p and miRNA-342-3p) were selected for Subsequent quantitative analyzes using LNATM probes on samples from all study participants. Table 2 provides the main basic information about the miRNAs studied in the sample set.

In general, great variability was observed in the expression of the five miRNAs (Figures 1, 2), which reveals large differences between individuals. The miRNA-130a-3p decreased significantly after supplementation in five out of ten volunteers (# 6, # 7, # 8, # 9 and # 10), three of whom had the greatest decrease in plasma glucose after the intervention, while it was significantly increased in the case of volunteer # 4 who showed the lowest hypoglycemic effect. The expression level of miRNA-122-5p increased in three volunteers (# 5, # 6 and # 8) while it decreased significantly in four others (# 2, # 3, # 7 and # 10). In the case of miRNA-34a-5p, its expression was significantly modified for volunteer # 9, which suffered a significant decrease, and for volunteers # 8 and # 10, in whom an increase was observed. A significant change in the expression pattern of miRNA-191-5p was clearly observed for all volunteers. Specifically, the general trend observed was a significant decrease in the expression of this miRNA (7 out of 10 volunteers). However, the expression increased significantly in volunteers # 8 and # 10, along with volunteer # 5. Finally, in the case of miRNA-342-3p, a significant antagonistic effect was observed in its expression in volunteers # 1 and # 3 compared to # 8 and # 10.

Despite the large individual differences observed, volunteers # 8 and # 10 (who shared a similar decrease in blood glucose levels) showed the same trend in the miRNA expression pattern for four of the five miRNAs analyzed (miRNA -130a-3p, miRNA-34a-5p, miRNA-191-5p and miRNA-342-3p) (figures 1,2).

A principal component analysis (PCA) was performed to group subjects in relation to their miRNA expression pattern and glucose values. PCA analysis grouped volunteers # 8 and # 10, who were directly related to miRNA191-5p, this miRNA also correlates negatively with glucose variance. Volunteer patterns # 2 appear to be totally different from the rest of the volunteers, maintaining a direct link with miRNA-342-3p and miRNA-130-3p. Finally, the rest of the volunteers grouped very close.

Results

A significant decrease (p <0.05) was observed in fasting blood glucose levels after delivery of the composition (from 89.00 / - 1.84 mg / dL to 84.5 / - 2.61 mg / dL ). Accumulated evidence suggests that circulating miRNAs are useful biomarkers for the regulation of glucose metabolism or type 2 diabetes.

The expression of five specific miRNAs based on literature related to glucose metabolism (including miRNA-130a-3p, miRNA-122-5p, miRNA-34a-5p, miRNA-191-5p and miRNA-342-3p) are analyzed in plasma samples by real-time PCR. Significant changes (p <0.05) in the profile of circulating miRNA after supplementation with the composition suggest that the composition can modulate the expression of miRNAs, the regulation of gene expression at the post-transcriptional level and thus participate in the metabolism of glucose In addition, the statistical analysis confirmed high interindividual differences (p <0.001). A decrease in miRNA-342-3p expression levels has been previously found in patients with type 1 and type 2 diabetes (Collares et al., 2013; Fernández-Valverde, Taft and Mattick, 2011; Hezova et al., 2010 ). According to these studies, the study found an increase in miRNA-342-3p levels for volunteers # 8 and # 10. Similarly, miRNA-191-5p expression decreased in patients with type 1 diabetes (Zampetaki et al., 2010). Volunteers # 8 and # 1 showed a negative correlation between miRNA-191-5p and plasma glucose levels (Pearson test, p = 0.003). An antagonistic effect of miRNA-34a-5p on glucose metabolism has been described in the literature, and miRNA-34a-5p has been suggested as a marker to differentiate between non-diabetics and patients with early type-2 diabetes (Kong et al., 2011; Rokavec, Li, Jiang and Hermeking, 2014). In the study a possible protective effect was observed in the case of volunteer # 9, for which a significant reduction in miRNA-34a-5p was observed, coinciding with the decrease in blood glucose level in this volunteer after the consumption of composition. In contrast, volunteers # 8 and # 10, whose blood glucose levels decreased the most, showed an increase in miRNA-34a-5p. Similarly, these Antagonistic effects and interindividual differences were also detected in the expression of miRNA-122-5p (Fong et al., 2015).

Interindividual differences in miRNA profiles have been widely published in the literature (Flowers, Gadgil, Aouizerat and Kanaya, 2015; Geeleher, Huang, Gamazon, Golden and Seoighe, 2012; Ludwig et al., 2016; Lukiw, 2013) and that miRNAs are specific and precise regulators of homeostasis of the body. However, the miRNA differences described above associated with the delivery of the composition could indicate that the effects of the composition are mediated by miRNA modulation.

The composition tested in the present study did not cause any significant decrease in the levels of total cholesterol and LDL cholesterol.

In conclusion, the results of the present invention show that the supply of the composition (1.4 g, 2 capsules / day) for three weeks led to a significant decrease in fasting blood glucose levels. The positive in vivo regulation of the miRNAs related to the observed glucose metabolism followed by the supply of the composition suggests a possible beneficial effect thereof on the glucose metabolism, which contributes to reducing the risk of type 2 diabetes. The composition It can be considered a functional ingredient in the maintenance of human health.

Table 1

Composition PHENOLIC COMPOSITION (mg / g extract) Total Polyphenols (mg gallic acid / g) 37.44 Phenolic Acids

ellagic acid 5.64 ± 0.65 Flavanols

Catechin 0.28 ± 0.07 Epicatechin 1.03 ± 0.25 Proanthocyanidin 4.62 Flavonols

Myricetin 0.26 ± 0.01 Quercetin 0.34 ± 0.03 Kaempferol 0.16 ± 0.00

INSOLUBLE ALCOHOL RESIDUE COMPOSITION

(mg / g RIA)

RIA Rdto Total 660 Neutral Sugars 294.7 Uronic Acids 32.3 ± 1.0 Total Sugars 328.2 Lignin Klason 84.3 ± 1.1

Table 3

Before take After 14 After 21 Comp, days take days take comp, comp, Glucose (mg / dl) 89.00 ± 1.84b 87.10 ± 1.66ab 84.50 ± 2.61a Biochemistry Uric Acid (mg / dl ) 4.48 ± 0.35 4.49 ± 0.30 4.24 ± 0.29

Albumine (mg / dl) 4.46 ± 0.05 4.34 ± 0.04 4.49 ± 0.07 ASAT GOT (Ul / l) 19.10 ± 0.62 20.70 ± 2.55 19, 90 ± 1.73 ALAT GOT Enzymes (Ul / l) 17.00 ± 2.21 21.80 ± 6.82 20.30 ± 2.76

Gamma-GT (Ul / l) 13.30 ± 1.13 11.10 ± 1.31 11.60 ± 1.56 Total Cholesterol

_{(mg / dl)} 201.60 ± 7.70 196.90 ± 8.21 198.50 ± 9.00 Triglycerides (mg / dl) 82.50 ± 18.36 87.2 ± 19.22 91.10 ± 19.93

HDL Cholesterol Metabolism 59.40 ± 4.30 59.20 ± 3.55 58.60 ± 4.00 Lipid _{(mg / dl)}

Tot, Col, / HDL Col 3.57 ± 0.34 3.49 ± 0.37 3.56 ± 0.36 LDL Cholesterol

_{(mg / dl)} 125.40 ± 6.19 120.10 ± 6.63 121.60 ± 7.22 LDL Col / HDL Col 2.25 ± 0.24 2.15 ± 0.26 2.20 ± 0 , 26

Proteins ^{C-reactive protein}

_{(mg / l)} 3.82 ± 1.79 2.85 ± 1.55 2.60 ± 1.57 Hormones Insulin (^ IU / ml) 9.44 ± 1.88 10.15 ± 1.93 10, 52 ± 2.30 Baseline Serum Leptin (ng / ml) 12.12 ± 2.61 11.05 ± 19.93 11.47 ± 2.27 Markers

_Immuno TNF-a (pg / ml) 7.20 ± 0.68 8.01 ± 0.65 7.73 ± 0.33 a Means ± standard error when calculated. b Values followed by different letter codes are significantly different (p <0.05) according to the LSD test. The letter 'a' is assigned to the lowest value.

Table 4

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Claims (14)

1. Composition to regulate glucose metabolism, which comprises the following components as active ingredients: a) one or more polyphenols at a concentration of between 0.5 and 100 mg / g of the composition; b) dietary fibers, wherein the dietary fibers comprise one or more sugars or derivatives thereof at a concentration of 50 to 600 mg / g based on the composition. 2. Composition for use according to claim 1, wherein one or more polyphenols comprise ellagic acid, flavanols or flavonols or any combination thereof. 3. Composition for use according to any one of claims 1 or 2, wherein the sugars comprise neutral sugars and uronic acids. 4. Composition for use according to any one of claims 1 to 3, wherein the neutral sugars are selected from the group comprising cellulose, glucose, xylose, galactose, arabinose and mannose and any combination thereof. 5. Composition for use according to any one of claims 1 to 4, characterized in that it comprises the following concentration of polyphenols by weight: - ellagic acid: between 0.5 and 10 mg / g of the composition - flavanols: between 0.2 and 20 mg / g of the composition - flavonols: between 0.11 and 12 mg / g of the composition. 6. Composition for use according to any one of claims 1 to 5, characterized in that the sugars comprised by dietary fibers are as follows: - neutral sugars: between 150 and 550 mg / g of the composition - Uronic acids: between 1 and 100 mg / g of the composition - Lignin Klason: between 1 and 200 mg / g of the composition. 7. Composition for use according to any one of claims 3 to 6, characterized in that the neutral sugars comprised by the composition are as follows: - cellulose: between 0.5 and 30 mg / g of the composition - glucose: between 150 and 400 mg / g of the composition - Xylose: between 0.1 and 5 mg / g of the composition - galactose: between 0.5 and 30 mg / g of the composition - arabinose: between 0.1 and 10 mg / g of the composition - Mannose: between 0.5 and 30 mg / g of the composition. 8. Composition for use according to any one of claims 1 to 7, characterized in that the composition is used in a dosage of up to 8 g per day. 9. Composition for use according to any one of claims 1 to 8, characterized in that the regulation of glucose metabolism results in an increase or decrease in at least one of the circulating miRNAs selected from the group comprising miRNA130a. -3p, miRNA-122-5p, miRNA-34a-5p, miRNA-191-5p and miRNA-342-3p. 10. Dietary supplement comprising the composition described in any one of claims 1 to 9 as a functional ingredient. 11. Dietary supplement according to claim 10, characterized in that it comprises between 100 mg and 5 g of the composition. 12. Food product characterized in that its composition comprises as a functional ingredient the composition described in any one of claims 1 to 9 or the dietary supplement described in any one of claims 10 or 11 mixed together with at least one dietary ingredient. 13. Composition according to any one of claims 1 to 9 for treating or preventing glucose metabolism disorder or related diseases. 14. Use of the composition of any one of claims 1 to 9, for the production of functional products for human consumption.