O-acetylserine for use in the prevention and treatment of glucose intolerance and related diseases

Abstract

O-acetylserine for use in the prevention and treatment of glucose intolerance and related diseases. The present application relates to O-acetylserine or a salt or a derivative thereof for use in the treatment and / or prevention of glucose intolerance and / or one or more diseases related to glucose intolerance in an individual. The present application also relates to a composition comprising O-acetylserine or a salt or a derivative thereof and a physiologically acceptable carrier for use in the treatment and / or prevention of glucose intolerance and / or one or more diseases related to glucose intolerance in an individual.

Description

Technical Field

[0001] This invention relates to the field of prevention and / or treatment of metabolic disorders (e.g., glucose intolerance or prediabetes, and diseases associated with glucose intolerance, such as type 2 diabetes). Existing technology

[0002] Type 2 diabetes mellitus (T2DM) is a disease characterized by chronic hyperglycemia resulting from the body's inefficient use of insulin. It is often a consequence of overweight and inactivity, such as obesity developed in response to changes in nutrition and lifestyle. Therefore, risk factors associated with T2DM include, in particular, overweight, advanced age, poor diet and excessive or poor nutrition, inactivity, smoking, or a family history of diabetes (Vazquez et al., Comparison of body mass index, waist circumference, and waist / hip ratio in predicting incident diabetes: a meta-analysis. Epidemiol Rev 2007, 29:115-28; Diabetes Prevention Program Research Group. Long-term effects of lifestyle intervention or metaformin on diabetes development and microvascular complications over 15-year follow-up: the Diabetes Prevention Program Outcomes Study. Lancet Diabetes Endocrinol 2015, 3:866-75).

[0003] Type 2 diabetes mellitus (T2DM) is the most common form of diabetes worldwide, accounting for 90% of all cases (World Health Organization. 1999. Definition, diagnosis and classification of diabetes mellitus and its complications: report of a WHO consultation. Part 1, Diagnosis and classification of diabetes mellitus). Diabetes is a genuine public health problem due to its global prevalence (which doubled between 1980 and 2014, from 4.7% to 8.5% in the adult population (World Diabetes Report, World Health Organization, 2016, ISBN: 9789242565256)), high treatment costs, and its complications. This is because, in the long term, diabetes can affect the heart, blood vessels, eyes, kidneys, and nerves, and increase the risk of heart disease and myocardial infarction. Therefore, the prevention and treatment of T2DM is a highly relevant area of ​​therapeutic research with significant economic and social implications (IDF Diabetes Atlas – 8th Edition, 2017).

[0004] Today, health and dietary recommendations target prediabetes, and while rarely prescribed, preventative treatment is recommended for individuals at high risk of developing type 2 diabetes. Prediabetes (the early and reversible stage of diabetes) is particularly characterized by impaired glucose tolerance.

[0005] Impaired glucose tolerance is a risk factor for type 2 diabetes, which is a prediabetes stage. Impaired glucose tolerance, or prediabetes, or intermediate hyperglycemia, is a glucose disorder. Individuals with impaired glucose tolerance have blood glucose levels that are higher than normal but not high enough to warrant a diagnosis of diabetes. It is possible to characterize impaired glucose tolerance by detecting decreased insulin sensitivity or increased insulin resistance.

[0006] Prediabetes is a stage in which the trend toward diabetes can often be reversed to restore normal blood sugar levels. In some cases, this predisposing state of type 2 diabetes can be reversed through physical activity and dietary adjustments.

[0007] Generally, physical activity combined with a balanced diet can lower blood glucose and prevent progression to type 2 diabetes mellitus (T2DM). However, the projected increase in type 2 diabetes cases in the coming years suggests that these lifestyle interventions are insufficient. Therefore, it appears that lifestyle rebalancing is often impractical or inadequate and may be combined with oral medications prescribed to control blood glucose levels. However, the number of these medications is limited, and some are not recommended for use in children and adolescents, who are increasingly developing glucose intolerance. For example, metformin may be prescribed, which is commonly used to treat T2DM. In addition, there are contraindications and undesirable side effects such as nausea, vomiting, diarrhea, abdominal pain, or loss of appetite. These undesirable effects are a reason for frequent discontinuation of treatment (McGovern et al., Comparison of medication adherence and persistence in type 2 diabetes: A systematic review and meta-analysis. Diabetes Obesity and Metabolism, 2017, 20(4): 1040-1043). Long-term metformin use is associated with an increased risk of vitamin B6 and B12 deficiency (which may be accompanied by neurological complications) (Porter et al., Hyperglycemia and Metformin Use Are Associated With B Vitamin Deficiency and Cognitive Dysfunction in Older Adults. J. Clin. Endocrinol. Metab., 2019, 104(10):4837-4847).

[0008] Therefore, early targeting of reversible prediabetes and, in particular, glucose intolerance appears to be essential to prevent its progression to type 2 diabetes.

[0009] There is a need for novel compounds or compositions for controlling glucose homeostasis in the body. There is also a need for novel compounds or compositions that enable targeting glucose intolerance.

[0010] There is a need for novel compounds or compositions that are harmless and suitable for administration to children and adolescents.

[0011] There is a need for novel treatments for the prevention and / or treatment of glucose intolerance. There is also a need for novel treatments for the prevention and / or treatment of diseases associated with or caused by glucose intolerance (e.g., especially type 2 diabetes). Therefore, there is a need for novel compounds or compositions for the prevention and / or treatment of prediabetes.

[0012] Therefore, there is still a need for prevention and / or treatment of postprandial hyperglycemia.

[0013] There is a need for treatment and / or prevention of diseases associated with impaired glucose tolerance, particularly type 2 diabetes.

[0014] The objective of this invention is to satisfy all or some of these needs.

[0015] Invention Statement

[0016] This invention proposes an anabolic metabolite, O-acetylserine, for use in the treatment and / or prevention of glucose intolerance. This invention also proposes O-acetylserine for use in the treatment and / or prevention of one or more diseases associated with glucose intolerance, particularly type 2 diabetes. Invention Overview

[0018] The objective of this invention is to provide novel substances for use in therapeutic methods for the prevention and / or treatment of glucose intolerance and / or diseases associated with glucose intolerance in individuals.

[0019] Surprisingly, the inventors observed a protective effect of O-acetylserine (or OAS) on glucose homeostasis. OAS limits the development of glucose intolerance induced by obesity-promoting (fat- or sugar-rich) diets and precedes the establishment of type 2 diabetes mellitus (T2DM). Therefore, the prevention and treatment of glucose intolerance makes it possible to prevent and treat T2DM.

[0020] Therefore, according to a first aspect, the present invention relates to O-acetylserine or its salts or derivatives thereof for use in individuals in the treatment and / or prevention of glucose intolerance and / or one or more diseases associated with glucose intolerance.

[0021] In one particular implementation, the disease associated with impaired glucose tolerance is type 2 diabetes.

[0022] In addition, the individual may be overweight or obese.

[0023] In one particular embodiment, the O-acetylserine is a bacterial biosynthetic metabolite, particularly a biosynthetic metabolite of bacteria in the gut microbiota, and more particularly a biosynthetic metabolite of the bacterial strain Streptococcus salivarius.

[0024] According to a second aspect, the present invention relates to compositions comprising O-acetylserine or its salts or derivatives thereof and a physiologically acceptable carrier, for use in an individual in the treatment and / or prevention of glucose intolerance and / or one or more diseases associated with glucose intolerance.

[0025] In one particular implementation, the disease associated with impaired glucose tolerance is type 2 diabetes.

[0026] In addition, the individual may be obese.

[0027] According to one embodiment, the O-acetylserine is a bacterial biosynthesis, particularly a biosynthesis of bacteria in the gut microbiota, and more particularly a biosynthesis of the bacterial strain Streptococcus salivarius.

[0028] According to the present invention, the composition may be a composition for oral administration, particularly in the form of powder, granules, food, beverage, pharmaceutical product, nutritional supplement, food additive, food supplement, capsule or gelatin capsule.

[0029] In one particular embodiment, the composition further comprises additional active substances, specifically selected from metabolites, antioxidants, fish oil, DHA, EPA, vitamins, minerals, phytonutrients, proteins, lipids, probiotics, additional active substances that allow for the prevention and / or treatment of glucose intolerance, and combinations thereof. Brief description of the attached diagram

[0031] Figure 1 The final body weight (left) and epididymal adipose tissue weight of the mice studied after 12 weeks of dietary regimens and treatments are presented: control group receiving the control dietary regimen, untreated HFD group receiving a high-fat diet (HFD), and HFD group treated with O-acetylserine (HFD+OAS).

[0032] The diagram on the left shows the average weight of mice in each group, expressed in grams (vertical axis). The mouse groups are indicated on the horizontal axis, from left to right: Control; HFD; and HFD+OAS. The weight difference between the control and HFD groups was statistically significant (*p<0.05).

[0033] The diagram on the right shows the mean weight of epididymal adipose tissue in each group of mice, expressed in grams (vertical axis). The mouse groups are indicated on the horizontal axis, from left to right: Control; HFD; and HFD+OAS. The difference in epididymal adipose tissue weight between the control group and either the HFD or HFD+OAS group was statistically significant (p < 0.0001).

[0034] Figure 2 The results of glucose tolerance tests at 5 weeks post-study are presented for each of the studied mouse groups: the control group receiving a control diet, the untreated HFD group receiving a high-fat diet (HFD), and the HFD group treated with O-acetylserine (HFD+OAS).

[0035] On the left, the curves show the change in mean glucose concentration (in mg / dL) in mouse plasma over time (in minutes) (x-axis) for each mouse group after oral glucose loading (y-axis). The control group is represented by the curve with the symbol ○, the HFD group by the curve with the symbol ●, and the HFD+OAS group by the curve with the symbol ■. The differences between the control group and the HFD and HFD+OAS groups were significant (with ****p<0.0001, ***p<0.001, **p<0.01, and *p<0.05, respectively, at t=15 min, t=30 min, t=60 min, t=90 min, and t=120 min).

[0036] On the right, the bars represent the area under the curve (in mg / dl / min) of the curve from the left-hand schematic for each mouse group indicated from left to right on the horizontal axis (vertical axis): Control; HFD; and HFD+OAS. The difference in area under the curve between the control group and the HFD and HFD+OAS groups was significant (p < 0.0001).

[0037] Figure 3 The results of glucose tolerance tests at 9 weeks post-study are presented for each of the studied mouse groups: the control group receiving a control diet, the untreated HFD group receiving a high-fat diet (HFD), and the HFD group treated with O-acetylserine (HFD+OAS).

[0038] On the left, the curves show the change in mean glucose concentration (in mg / dL) in mouse plasma over time (in minutes) (x-axis) for each mouse group after oral glucose loading (y-axis). The control group is represented by the curve with the symbol ○, the HFD group by the curve with the symbol ●, and the HFD+OAS group by the curve with the symbol ■. The differences between the control group and the HFD and HFD+OAS groups were significant (with ****p<0.0001, ***p<0.001, **p<0.01, and *p<0.05, respectively, at t=15 min, t=30 min, t=60 min, and t=90 min). From t=60 min onwards, the differences between the control group and the HFD+OAS group were no longer significant, and at t=30 min, the differences between the HFD group and the HFD+OAS group were significant. $$$$ p<0.0001).

[0039] On the right, the bars represent the area under the curve (in mg / dl / min) of the curve from the left-hand schematic for each mouse group indicated from left to right on the x-axis (y-axis): Control; HFD; and HFD+OAS. Differences in area under the curve between each mouse group were significant (*p<0.0001, between control and HFD; *p<0.05, between HFD and HFD+OAS; and *p<0.05, between control and HFD+OAS).

[0040] Figure 4 The results of glucose tolerance tests after 5 days of study are presented for each of the studied mouse groups: the control group received a standard diet and did not receive O-acetylserine, while the OAS group received a standard diet and a daily dose of O-acetylserine (OAS).

[0041] On the left, the curves show the change in mean plasma glucose concentration (in mg / dL) in mice over time (in minutes) (x-axis) for each mouse group after oral glucose loading at t0 (y-axis). The control group is represented by the curve with the symbol ■, and the OAS group is represented by the curve with the symbol ●. The differences between the control group and the OAS group were significant (with ****p<0.0001 and *p<0.05, respectively, at t=15 min, t=30 min, and t=60 min).

[0042] On the right, the bars represent the area under the curve (in mg / dL / min) of the curve from the left-hand schematic for each mouse group indicated from left to right on the x-axis (y-axis): Control; OAS. The differences in area under the curve between each mouse group were significant (****p<0.0001).

[0043] Figure 5 The results of the glucose tolerance test after the study were presented for each mouse group: the control group received only an oral glucose load at t0, while the OAS group received a dose of O-acetylserine (OAS) at t0 in addition to the oral glucose load.

[0044] On the left, the curves show the change in mean plasma glucose concentration (in mg / dL) in mice over time (in minutes) (x-axis) for each mouse group after oral glucose loading at t0 (y-axis). The control group is represented by the curve with the symbol ■, and the OAS group is represented by the curve with the symbol ●. The difference between the control group and the OAS group was significant (with ***p<0.001 at t=15 minutes).

[0045] On the right, the bars represent the area under the curve (in mg / dL / min) of the curve from the left-hand schematic for each mouse group indicated from left to right on the x-axis (y-axis): Control; OAS. The differences in area under the curve between each mouse group were significant (*p<0.05). Invention Details

[0047] The inventors conducted in-depth research to identify the ability of O-acetylserine to treat and / or prevent glucose intolerance and / or glucose intolerance-related diseases in subjects with such need. In particular, the inventors demonstrated the ability of OAS to treat and / or prevent glucose intolerance in mice.

[0048] This is because, as described in the experimental section below, the inventors demonstrated that treatment with OAS in a mouse model subjected to an obesity-inducing diet resulted in the regulation of glucose metabolism, particularly improvement in glucose intolerance (especially obesity-related glucose intolerance). Therefore, they demonstrated the usefulness of OAS in improving metabolic disorders in vivo, especially those caused by obesity.

[0049] definition

[0050] The terms used in this specification are used in their conventional meaning in the technical field considered and in accordance with the context of the description in which these terms are used. Some terms are further discussed below or elsewhere in the specification to provide supplementary guidance regarding the invention and its implementation. The following definitions are provided for the purposes of this specification and the claims.

[0051] The description of different embodiments of the invention includes embodiments containing the terms "comprising," "having," "consisting of," and "substantially consisting of." The words "having" and "comprising," or variations thereof, should be understood to mean including the specified element (e.g., a component of a composition or a step of a method), but not excluding other elements. The term "consisting of" means including the specified element, excluding any supplementary elements. The expression "substantially consisting of" means including the specified element and possibly other elements when said other elements do not substantially affect the basic and novel features of the invention. Depending on the context, the term "comprising" can also strictly indicate the specified feature, integer, step, or component, and therefore in this case, it can be replaced by "consisting of."

[0052] Type 2 diabetes, or T2DM, is a chronic disease that occurs when the pancreas does not produce enough insulin (the hormone that regulates blood sugar) or when the body is unable to use the insulin it produces effectively. Prior to T2DM, there is usually impaired glucose tolerance.

[0053] In this document, the terms "approximately" or "roughly" used with respect to numerical values ​​refer to a conventional range of error for the value under consideration, as commonly determined by those skilled in the art. Thus, reference to the term "approximately" with respect to a specific value or parameter includes and describes that value or parameter. The term "approximately" means ±10% of a given value. However, whenever the value in question refers to an indivisible object that loses its identity upon subdivision, then "approximately" means ±1% of said indivisible object.

[0054] The terms “individual” or “patient” as used in this text specifically refer to mammals. Mammals considered include, but are not limited to: domesticated animals (e.g., cattle, sheep, cats, dogs, and horses), primates (e.g., humans and non-humans), rabbits, and rodents (e.g., mice and rats). According to a particular implementation, the individual or patient is a human.

[0055] "Dysglucose intolerance" refers to a pathophysiological condition in which an individual's blood glucose levels are higher than normal but lower than the diagnostic threshold for type 2 diabetes. Dysglucose intolerance can be detected by measuring fasting blood glucose and by monitoring blood glucose levels during an oral glucose tolerance test (or OGTT).

[0056] Obesity refers to a pathophysiological state in which an individual has an excess of adipose tissue, typically induced by an obese dietary regime (particularly involving excessive consumption of high-calorie foods), genetic predisposition, or insufficient or absent physical activity. Individuals declared obese have a body mass index (BMI) higher than 30. According to the official definition of the World Health Organization (WHO), BMI is a risk indicator of health associated with being overweight or underweight. BMI is calculated by dividing an individual's weight (in kilograms) by the square of their height (in meters). BMI values ​​are associated with a specific body type according to the classification given by the WHO.

[0057] Unlike obese individuals, overweight individuals are those whose condition is not pathophysiological. Overweight individuals often also have excess adipose tissue. Generally, an individual is considered overweight when their body mass index (BMI) is between 25 and 30.

[0058] Prediabetes refers to a pathophysiological state characterized, in particular, by elevated blood glucose levels relative to normal but below the defining threshold for type 2 diabetes. Fasting blood glucose: (i) between 0.70 and 1.10 g / L is considered normal, (ii) between 1.10 and 1.25 g / L is considered a sign of prediabetes, and (iii) >1.25 g / L is considered a sign of diabetes. Prediabetes typically does not induce symptoms but is frequently associated with obesity, dyslipidemia, and hypertension. These are risk factors for cardiovascular disease. Prediabetes is particularly characterized by impaired glucose tolerance.

[0059] In the context of this invention, the terms “prevention” and “slowing the progression of…” (and variations thereof) relating to a physiological condition or disease refer to preventive treatment of said disease or condition, for example, in individuals suspected of having the disease or condition or at risk of developing it. Prevention includes, but is not limited to, preventing or slowing the development of said disease, and / or maintaining one or more symptoms of said disease at a desired or lower level. The term “prevention” does not require the complete elimination of the possibility or probability of said disease or condition occurring. More precisely, the term refers to reducing the risk or probability of a given phenomenon (i.e., in this invention, glucose intolerance or a disease associated with glucose intolerance, such as prediabetes or type 2 diabetes) to a lower level. As noted, prevention can be complete, i.e., the absence of detectable symptoms or disease, or partial, such that fewer symptoms are present or the symptoms are of lower intensity.

[0060] "Glucose homeostasis" refers to the blood glucose balance characteristic of an individual for normal blood glucose levels. Normal fasting blood glucose balance in humans is between approximately 0.70 g / L and approximately 1.10 g / L (i.e., between 70 mg / dL and 110 mg / dL). Blood glucose levels below 0.70 g / L indicate hypoglycemia, while blood glucose levels above 1.10 g / L but below 1.26 g / L indicate moderate hyperglycemia, which can manifest as glucose intolerance.

[0061] "Salts of O-acetylserine" refers to salts of O-acetylserine prepared using physiologically acceptable acids or bases. However, acids or bases useful for, for example, the purification or separation of OAS can also be used. As salts of O-acetylserine, the hydrochloride salt of O-acetyl-L-serine can be mentioned.

[0062] "Derivatives of O-acetylserine" refers to physiologically acceptable O-acetylserine that has undergone one or more modifications (e.g., substitution or intramolecular migration). As an example of modifications (particularly substitutions) to O-acetylserine derivatives according to the invention, it can be mentioned that at least one hydrogen atom of the amino group of OAS is substituted to form an amide functional group. As an example, further or alternative modifications (particularly substitutions) to O-acetylserine derivatives according to the invention may involve the methyl group of OAS being substituted with an alkyl group, particularly (C1-C6) alkyl, which is optionally substituted, particularly with a halogen, specifically selected from F and Cl. As an example, further or alternative modifications (particular substitutions) to O-acetylserine derivatives according to the invention may involve the proton of the carboxyl group -COOH of OAS being substituted to form an ester functional group. Suitable OAS derivatives according to the invention are OAS compounds having the same activity as OAS (particularly the same activity for the prevention and / or treatment of glucose intolerance and / or diseases associated with glucose intolerance in individuals). As a derivative of O-acetylserine, N-acetylserine can be mentioned.

[0063] As used herein, the terms “therapeuticly effective amount” and “preventively effective amount” refer to the amount that provides therapeutic benefit in the treatment, prevention, or management of a pathological process under consideration. A specific therapeutically effective amount may be readily determined by the physician or may vary depending on factors such as the type and stage of the pathological process under consideration, past medical history, the patient’s sex, weight, and age, their dietary regimen, and the administration of other therapeutic agents.

[0064] Within the scope of this invention, the term "significantly" as used in a changing context means that the observed change is noteworthy or statistically significant.

[0065] Within the scope of this invention, the expressions “substantially similar,” “not substantially different,” “obviously similar,” or “not obviously different” (or any other variation) used in connection with a feature of the invention are intended to define an entire set of embodiments of the invention associated with that feature, which are broadly but not entirely identical to embodiments including that feature.

[0066] The "oral glucose tolerance test" or "OGTT test" is a method that allows measurement of the body's ability to use glucose. The OGTT test is well known to technicians. It can be performed, for example, using the experimental protocol described in Nagy et al., Study of In VivoGlucose Metabolism in High-fat Diet-fed Mice Using Oral Glucose Tolerance Test (OGTT) and Insulin Tolerance Test (ITT). J. Vis. Exp. (131), e56672, doi:10.3791 / 56672 (2018).

[0067] Within the scope of this invention, the terms "treatment," "therapy," or "therapeutic" refer to the administration or ingestion of an active substance, O-acetylserine, or its salts or derivatives, or a composition containing such an active substance, for the purpose of curing, alleviating, reducing, weakening, or improving a disease or pathological disorder or one or more related symptoms, or for the purpose of preventing or slowing the progression of such symptoms or the disease, or for the purpose of stopping the development of such symptoms or the disease or the pathological disorder in a statistically significant manner. More specifically, "treatment" includes any method for obtaining a beneficial effect or desired outcome in an individual with respect to a state of impaired glucose tolerance. Beneficial or desired clinical outcomes may include, but are not limited to: attenuation or improvement of glucose intolerance, a disease associated with glucose intolerance (e.g., prediabetes or type 2 diabetes), or one or more symptoms of such a disease; reduction or decrease in the severity of glucose intolerance, a disease associated with glucose intolerance, or one or more symptoms of such a disease; stabilization of glucose intolerance, a disease associated with glucose intolerance, or one or more symptoms of such a disease, i.e., no exacerbation; prevention of glucose intolerance, a disease associated with glucose intolerance, or one or more symptoms of such a disease; prevention of the spread of glucose intolerance, a disease associated with glucose intolerance, or one or more symptoms of such a disease; slowing of the progression of glucose intolerance, a disease associated with glucose intolerance, or one or more symptoms of such a disease; reduction in the recurrence of glucose intolerance, a disease associated with glucose intolerance, or one or more symptoms of such a disease; and interruption of glucose intolerance, a disease associated with glucose intolerance, or one or more symptoms of such a disease. In other words, as used herein, “treatment” includes any cure, improvement, attenuation, or interruption of glucose intolerance, a disease associated with glucose intolerance, or one or more symptoms of such a disease. “Attenuation” of a symptom or disease means a reduction in the severity or frequency of said disease or symptom, or the elimination of said disease or symptom.

[0068] As used in this specification and claims, the singular forms “un,” “une,” “le,” and “la” include the plural, unless the context clearly indicates otherwise.

[0069] The expression "physiologically acceptable carrier" is intended to refer to any substance or composition compatible with the body of the individual to whom the active substance of the invention is to be administered. In particular, a physiologically acceptable carrier is a substance or composition to which administration to an individual does not result in significant adverse effects. It can be, for example, a non-toxic solvent, such as water or a saline solution. Specifically, such a carrier is compatible with oral or rectal administration and is preferably suitable for oral administration.

[0070] The list of sources, ingredients and components indicated below should be understood as being described so that any combination and mixture thereof are also considered to be within the scope of the invention.

[0071] It should be understood that each maximum numerical limit given in this specification includes each lower numerical limit as expressly stated herein. Each minimum numerical limit given in this specification includes any higher numerical limit as expressly stated herein. Each numerical range given throughout this specification includes each narrower numerical range included within such a wider numerical range as expressly stated herein.

[0072] All lists referred to in the specification, such as lists of ingredients, are intended and should be interpreted as Markush groups. Therefore, all lists can be interpreted and understood as elements “selected from groups consisting of: ... a list of elements ... " and combinations and mixtures thereof.

[0073] Trade names of the various ingredients used in this specification may be mentioned below. The inventors do not intend to limit themselves to materials under specific trade names. In the following description, materials equivalent to those indicated herein by trade name (e.g., those obtained from different sources under different names or reference numbers) may be substituted and used.

[0074] O-acetylserine

[0075] This invention relates to O-acetylserine (OAS) or its salts or derivatives thereof for use in the treatment and / or prevention of glucose intolerance in an individual. The invention also relates to OAS or its salts or derivatives thereof for use in the treatment and / or prevention of one or more diseases associated with glucose intolerance in an individual.

[0076] In particular, the present invention relates to O-acetylserine (OAS) or a salt thereof, or N-acetylserine (NAS), for use in the treatment and / or prevention of glucose intolerance in an individual. The present invention also relates to OAS or a salt thereof, or N-acetylserine (NAS), for use in the treatment and / or prevention of one or more diseases associated with glucose intolerance in an individual.

[0077] O-acetylserine (C5H9NO4) is an intracellular secondary metabolite of sulfur-containing amino acids in certain bacteria or plants, and it has the following formula:

[0078] [Table 1]

[0079]

[0080] It is a non-proteinogenic α-amino acid derived from serine through acetylation starting from acetyl-CoA under the action of serine O-acetyltransferase. It is an intermediate in the biosynthesis of cysteine ​​in bacteria and plants, which convert it to cysteine ​​via cysteine ​​synthase.

[0081] The inventors have identified OAS in the supernatant fraction of Streptococcus salivarius strains by mass spectrometry analysis.

[0082] This symbiotic species is predominantly found in the oral cavity and secondarily in the human digestive tract. Strains of *Streptococcus salivarius* are capable of synthesizing OAS.

[0083] OAS also exists in a wide variety of plants.

[0084] In humans, this molecule has been found in the prostate, urine, and blood, and is a source of bacteria (especially those in the gut microbiota) and food.

[0085] OAS is referred to as HMDB0003011 in the Human Metabolites Database HMDB 4.0 (http: / / www.hmdb.ca / metabolites / HMDB0003011) and corresponds to the number CAS5147-00-2.

[0086] The O-acetylserine according to the present invention can also exist in the form of a salt of OAS.

[0087] In particular, OAS can be in the form of O-acetyl-L-serine hydrochloride (OAS.HCl). The salt OAS.HCl (C5H9NO4.HCl) is referred to by the number CAS 66638-22-0.

[0088] The O-acetylserine according to the present invention may also exist in the form of a derivative of OAS or in the form of a salt of a derivative of OAS.

[0089] In particular, OAS can be in the form of N-acetylserine (NAS). OAS can also be in the form of a salt of NAS.

[0090] Suitable OAS according to the present invention are particularly known from Sigma-Aldrich under Commercial Reference No. A6262_ It is sold as a chemical product.

[0091] Suitable derivatives of OAS according to the present invention, particularly N-acetylserine, are available from Sigma-Aldrich under commercial reference number [notation missing]. It is sold as a chemical product.

[0092] According to a particular embodiment, the O-acetylserine according to the invention is a bacterial biosynthetic metabolite, particularly a biosynthetic metabolite of bacteria in the gut microbiota, and more particularly a biosynthetic metabolite of the bacterial strain Streptococcus salivarius.

[0093] In some embodiments, OAS, or its salts or derivatives, may be included in the composition.

[0094] Composition

[0095] Furthermore, the present invention also relates to compositions comprising O-acetylserine or its salts or derivatives according to the invention, and at least one physiologically acceptable carrier, for use in individuals in the treatment and / or prevention of glucose intolerance and / or one or more diseases associated with glucose intolerance.

[0096] The described composition shall be administered to the individual in need of it in a therapeutically effective amount. This amount shall be determined by a healthcare professional based on the characteristics of each individual.

[0097] In some embodiments, the composition is suitable for administration with or outside of meals, preferably outside of meals. In some embodiments, the composition may be suitable for administration at at least one daily dose, particularly as a single daily dose.

[0098] According to certain embodiments, the composition can be applied continuously daily during the considered application period. Alternatively, the composition can be applied over a period of one, two, or more consecutive days, followed by a break period of at least one, two, or more consecutive days. The application period and the break period can constitute a cycle. The composition can be applied over at least one cycle, or even two, three, or more consecutive cycles.

[0099] The composition may be administered over a period of at least five weeks, or at least six weeks, or at least seven weeks, or at least eight weeks, or at least nine weeks.

[0100] The composition may be applied at the following times: during a period of at least two consecutive days, particularly during a period of at least five consecutive days, at a weekly interval, and during a period of at least one to at least twelve weeks, particularly during a period of at least one to at least ten weeks, particularly during a period of at least two to at least five weeks, and particularly during a period of at least three weeks.

[0101] According to certain embodiments, the composition may be applied over a period of at least two consecutive days at weekly intervals, particularly over a period of at least five consecutive days at weekly intervals.

[0102] As physiologically acceptable carriers that can be used to formulate the compositions of the present invention, references may be made in a non-limiting manner to water, saline buffers, especially phosphate buffers, sodium bicarbonate, juice, dairy products, especially milk or yogurt, infant food compositions, thickeners such as glyceryl monostearate, sweeteners, coating agents such as rapeseed oil, soybean oil, peanut oil, soy lecithin or fish gelatin, diluents such as lactose, lactose monohydrate or starch, binders such as povidone, gelling starch, gum, sucrose, polyethylene glycol (PEG) 4000 or PEG 6000, dispersants such as microcrystalline cellulose or sodium carboxymethyl starch, such as sodium carboxymethyl starch type A, lubricants such as magnesium stearate, fluidizing agents such as anhydrous colloidal silica, etc.

[0103] Physiologically acceptable carriers can be any substance used to prepare a pharmaceutical Galenian form, and include coating materials, film-forming materials, fillers, disintegrants, release modifiers, support materials, diluents, binders, and other auxiliaries. Conventionally used physiologically acceptable carriers include substances such as sucrose, mannitol, sorbitol, starch and starch derivatives, lactose, lubricants such as magnesium stearate, disintegrants, and buffers. Suitable physiologically acceptable carriers also include, for example, water, saline solutions, alcohols, oils, preferably vegetable oils, polyethylene glycol, gelatin, lactose, amylose, magnesium stearate, surfactants, aromatic oils, fatty acids, monoglycerides and diglycerides, hydroxymethyl cellulose, polyvinylpyrrolidone, etc. The pharmaceutical composition may contain excipients such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorants, flavorings, and / or aromatic substances.

[0104] Liquid forms are contemplated for this invention. These may include emulsions, solutions, suspensions, and syrups. Solid forms are also contemplated, such as suppositories, tablets, lozenges, pills, gelatin capsules, powders, effervescent formulations, sugar-coated pills, granules, or capsules.

[0105] Furthermore, the compositions according to the invention may contain any additives or excipients conventionally used in the art for the intended use of the composition. Therefore, the compositions of the invention may further contain at least one selected from sweeteners, stabilizers, antioxidants, additives, flavoring agents, and / or coloring agents. The formulation of the compositions of the invention is carried out by methods commonly used in the art (especially for producing sugar-coated tablets, gelatin capsules, gelling agents, controlled-release hydrogels, emulsions, foaming agents, syrups, liquids, tablets, capsules, or suppositories).

[0106] This composition is suitable for administration via oral, sublingual, nasal, or rectal routes, especially via oral administration.

[0107] In one embodiment, the composition may be in the form of a food supplement, beverage supplement, nutritional product, medical food, or nutritional health composition.

[0108] The composition may also be in the form of a nutritional or nutritional health composition.

[0109] In particular, the composition can be a food supplement.

[0110] Food supplements can be available in particular in the form of capsules, gelatin capsules, soft capsules, tablets, sugar-coated tablets, pills, pastes, lozenges, gums, drinkable solutions or emulsions, syrups or gels.

[0111] Compositions suitable for use in this invention can be formulated, in particular, in the form of food supplements selected from the following: dairy products, dairy beverages, yogurt, fruit and vegetable juices or their concentrates, powders, soy or grain-based beverages, breakfast cereals such as muesli cereal, fruit and vegetable juice powders, cereals and / or chocolate bars, confectionery, spreads, milk powder, smoothies, ice cream, reconstituted fruit-based products, food bars, sauces, sports supplements (including dairy and non-dairy sports supplements), desserts, frozen foods, soups, liquid suspensions, tablets, gums or candies.

[0112] Advantageously, the composition according to the invention prepared for oral administration can be coated with a gastric acid-resistant coating to ensure that the O-acetylserine of the invention contained in the composition can pass through the stomach unimpaired. Therefore, the release of the OAS according to the invention can occur initially in the upper intestine.

[0113] According to a particular embodiment, the oral composition suitable for use in this invention may be selected from powders, granules, foods, beverages, pharmaceutical products, nutritional supplements, food additives, food supplements, capsules, and gelatin capsules.

[0114] In another embodiment of the invention, the composition can be administered rectally. Specifically, the composition for rectal administration can be prepared in the form of suppositories, enemas, or foams.

[0115] In one embodiment, the composition may further comprise at least one additional active substance selected from: metabolites, antioxidants, fish oil, DHA, EPA, vitamins, minerals, phytonutrients, proteins, lipids, probiotics, and combinations thereof.

[0116] As alternative probiotic active substances, strains of probiotics from the following categories may be mentioned: Streptococcus, Lactobacillus, Lactococcus, Bifidobacterium, Veillonella, Desemzia, Coprococcus, Collinsella, Citrobacter, Turicibacter, and Suttella. rella), Subdoligranulum, Sporobacter, Sporacetigenium, Ruminococcus, Roseburia, Proteus, Propionobacterium, Leuconostoc, Weissella, Pediococcus, Prevotella, Parabacteroides ), *Papillibacter*, *Oscillospira*, *Melissococcus*, *Dorea*, *Dialister*, *Clostridium*, *Cedecea*, *Catenibacterium*, *Butyrivibrio*, *Buttiauxella*, *Bulleidia*, *Bilophila*, *Bacteroides*, anaerobic bacteria *Anaerovorax*, *Anaerostopes*, *Anaerofilum*, *Enterobacteriaceae*, *Fermicutes*, *Atopobium*, *Alistipes*, *Acinetobacter*, *Slackie*, *Shigella*, *Shewanella*, *Serratia*, *Mahella*, *Lachnospira*Klebsiella, Idiomarina, Fusobacterium, Faecalibacterium, Eubacterium, Enterococcus, Enterobacter, or Eggerthella.

[0117] As suitable plant nutrients for the present invention, carotenoids, polyphenols, or resveratrol may be mentioned. As suitable antioxidants for the present invention, vitamin C, glutathione, caffeine, or tocopherol may be mentioned. As suitable vitamins for the present invention, vitamins A, B, C, or D may be mentioned. As minerals, iron, magnesium, calcium, zinc, copper, or sodium may be mentioned.

[0118] In particular, the composition may contain at least one additional active substance that allows for the prevention and / or treatment of glucose intolerance. This additional active substance that allows for the prevention and / or treatment of glucose intolerance is different from OAS or its salts or derivatives.

[0119] According to one embodiment, the composition according to the invention comprises O-acetylserine or its salt or derivatives according to the invention, at least one physiologically acceptable carrier, and at least one additional active substance that allows for the prevention and / or treatment of glucose intolerance.

[0120] In particular, the additional active substance can be any antidiabetic molecule, especially metformin. Glucose intolerance can be treated with inhibitors of alpha-glucosidase (acarbose, voglibose), or inhibitors of pancreatic lipase (orlistat), or meglitinides (nateglinide), or intestinal glucagon mimics (liraglutide).

[0121] Metformin (C4H) 11 N5 is an oral antidiabetic drug of the normoglycemic family of biguanides used in the treatment of type 2 diabetes and recommended for prediabetic patients who are at the highest risk of developing type 2 diabetes.

[0122] According to one aspect, compared to a composition containing only metformin, administering OAS or its salt or derivative with metformin in the same composition enables a reduction in the amount of metformin in the composition, while having an equivalent effect on the prevention and / or treatment of glucose intolerance and / or diseases associated with glucose intolerance.

[0123] According to a particular embodiment, the composition is not a nutritional composition comprising a mixture of oligosaccharides consisting of N-acetylated oligosaccharides, galacto-oligosaccharides, and sialylated oligosaccharides.

[0124] According to another embodiment, the compositions of the present invention are not intended for use in reducing and / or preventing excessive accumulation of fat mass in infants or young children, and / or for preventing health disorders associated with excessive accumulation of fat mass in infants or young children at later ages, such as obesity at later ages, and related comorbidities.

[0125] Glucose intolerance and related diseases

[0126] As noted above, the OAS or its salts or derivatives according to the invention, or the compositions according to the invention, are used in therapeutic methods for the prevention and / or treatment of glucose intolerance and / or one or more diseases associated with glucose intolerance in an individual.

[0127] The individual or patient considered according to the present invention can be a mammal. The mammals targeted by the present invention can be selected, for example, from: domesticated animals (e.g., cattle, sheep, cats, dogs, and horses, especially cats and dogs), primates (e.g., human and non-human primates), rabbits, and rodents (e.g., mice and rats). According to one embodiment, the individual or patient targeted by the present invention can be a human.

[0128] The OAS, salts thereof, or derivatives thereof, or compositions according to the present invention are particularly suitable for use in the therapeutic treatment of prediabetes and / or diseases or conditions associated with prediabetes or symptoms of prediabetes.

[0129] Glucose intolerance, or prediabetes, can be asymptomatic. However, it can be associated with obesity, dyslipidemia with high triglyceride levels and / or low HDL cholesterol levels, and hypertension. Glucose intolerance and prediabetes are associated with an increased risk of cardiovascular disease. Prediabetes and glucose intolerance are considered early stages of type 2 diabetes.

[0130] Glucose intolerance, or prediabetes, can be diagnosed using a variety of methods known to different technicians. In particular, glucose intolerance in humans is diagnosed based on two criteria:

[0131] - Fasting blood glucose, and

[0132] - Blood glucose levels two hours after oral glucose intake.

[0133] Therefore, glucose intolerance can be diagnosed if (i) blood glucose is between 6.1 and 6.9 mmol / L (110-125 mg / dL) on an empty stomach, and if (ii) blood glucose is between 7.8 mmol / L and 11.0 mmol / L (140 mg / dL to 199 mg / dL) two hours after oral ingestion of 75 g of glucose.

[0134] Blood glucose levels two hours after glucose intake are measured using an oral glucose tolerance test (OGTT). Such a test is described in Hjellestad et al., HbA1c versus oral glucose tolerance test as a method to diagnose diabetes mellitus in vascular surgery patients, Cardiovascular Diabetology, 12:79 (2013).

[0135] Type 2 diabetes often follows glucose intolerance or prediabetes. Type 2 diabetes (or T2DM) is a condition associated with glucose intolerance or prediabetes.

[0136] According to one embodiment, the OAS or its salt or derivatives or compositions according to the invention may be particularly suitable for use in therapeutic treatments for the prevention and / or treatment of type 2 diabetes.

[0137] T2DM can be diagnosed using a variety of methods known to different technicians. In particular, T2DM can be diagnosed if one or more of the following criteria are met:

[0138] - Fasting blood glucose,

[0139] - Blood glucose level two hours after oral glucose ingestion, or

[0140] -Postprandial or random blood glucose

[0141] - Glycated hemoglobin A1C (HbA1C).

[0142] Therefore, a diagnosis of T2DM is made if: (i) fasting blood glucose is greater than or equal to 7.0 mmol / L (126 mg / dL), or if (ii) two hours after oral ingestion of 75 g glucose, blood glucose is greater than or equal to 11.1 mmol / L (200 mg / dL), or if (iii) random plasma blood glucose is greater than 11.1 mmol / L (200 mg / dL), or if (iv) glycated hemoglobin A1c (HbA1c) level is greater than or equal to 48 mmol / mol (equivalent to 6.5%).

[0143] According to one embodiment, the present invention also relates to a therapeutic method for preventing and / or treating glucose intolerance and / or diseases associated with glucose intolerance in individuals in need, comprising at least one step of administering OAS or its salts or derivatives to the individual or administering a composition according to the present invention to the individual.

[0144] According to one embodiment, the present invention also relates to a therapeutic method for preventing and / or treating prediabetes and / or diseases associated with prediabetes in individuals in need, comprising at least one step of administering OAS or its salts or derivatives to the individual or administering a composition according to the present invention to the individual.

[0145] According to one embodiment, the present invention also relates to a therapeutic method for preventing and / or treating type 2 diabetes in individuals in need, comprising at least one step of administering OAS or its salts or derivatives to the individual or administering a composition according to the present invention to the individual.

[0146] The method according to the invention may include a step of diagnosing glucose intolerance, prediabetes, or type 2 diabetes prior to the step of administering the active substance of the invention. Such a diagnosis can be made by any diagnostic method known to those skilled in the art for this purpose, and in particular by the method described above.

[0147] Furthermore, the method according to the present invention may include the steps of observing the reduction, inhibition or improvement of symptoms or blood glucose markers of impaired glucose tolerance, prediabetes or type 2 diabetes.

[0148] According to one particular embodiment, the individual or patient considered for use in this invention may be overweight or obese.

[0149] Uses or methods according to the invention may include administering the OAS, or its salts, or derivatives or compositions thereof, according to the invention to an individual or patient in need via any suitable route. Administration via, for example, oral, sublingual, nasal, or rectal routes may be mentioned. Preferably, administration of the OAS, or its salts, or derivatives or compositions thereof, according to the invention may be performed via an oral route.

[0150] According to one embodiment, the OAS or its salt or derivatives or compositions according to the invention can be administered at at least one daily dose, particularly two or three daily doses. More specifically, at least one daily dose.

[0151] The OAS, salt, derivative, or composition according to the invention can be taken with or without meals. Within a 24-hour period, the OAS, salt, derivative, or composition according to the invention can be taken at any time. In particular, the OAS, salt, derivative, or composition according to the invention can be taken in the morning, and especially at breakfast time.

[0152] In particular, the application of the OAS or its salt or derivatives or compositions according to the invention can be taken outside of meals, especially as a daily dose.

[0153] The duration of administration of the OAS or its salts or derivatives or compositions according to the invention depends on several factors, such as the patient's age, weight and sex, the presence of other pathological disorders, dietary regimen, and is adjusted by those skilled in the art based on common practice in the field.

[0154] The appropriate time period for applying the OAS or its salt or derivatives or compositions according to the invention may be at least five weeks, or at least six weeks, or at least seven weeks, or at least eight weeks, or at least nine weeks.

[0155] During the application period, the OAS or its salt or derivatives or compositions according to the invention may be applied continuously daily, or may be applied over a period of one or more days, followed by a period of one or more days of interruption, and if necessary, followed by one or more cycles of application and interruption.

[0156] According to certain embodiments, the OAS, its salt, or its derivatives or compositions according to the invention can be applied over a continuous period of one, two, or more days, followed by a continuous interruption period of at least one, two, or more days. The application period and the interruption period can constitute a cycle. The application of the OAS, its salt, or its derivatives or compositions according to the invention can be carried out over at least one cycle, or even over two, three, or more consecutive cycles.

[0157] Therefore, the OAS, its salt, or its derivatives or compositions according to the invention can be applied over a continuous period of at least two days at weekly intervals. According to one embodiment, the application can be performed over a continuous period of at least five days at weekly intervals. The application can continue for two weeks, three weeks, or more weeks, as indicated above.

[0158] According to one embodiment, the OAS, or its salt, or its derivatives, or compositions according to the invention can be administered in a therapeutically effective amount or dose. Specifically, the OAS, or its salt, or its derivatives, or compositions according to the invention can be administered at a daily dose equivalent to a dose varying from at least about 70 mg / kg / day to at least about 2000 mg / kg / day. Specifically, doses suitable for the invention can be from at least about 100 mg / kg / day to at least about 1000 mg / kg / day, and particularly from at least about 200 mg / kg / day to at least about 500 mg / kg / day.

[0159] According to another aspect, the present invention also relates to the use of the OAS, or its salts, or derivatives thereof, or compositions according to the present invention, in the preparation of pharmaceuticals. In particular, the present invention relates to the use of the OAS, or its salts, or derivatives thereof, or compositions according to the present invention, in the preparation of pharmaceuticals that enable the prevention and / or treatment of glucose intolerance and / or one or more diseases associated with glucose intolerance.

[0160] It should be understood that this invention encompasses all such variations, combinations, and arrangements in which one or more limitations, elements, provisions, descriptive terms, etc., of one or more of the claims listed below can be incorporated into another claim dependent on the same basic claim (or, as the case may be, any other claim), unless otherwise stated or unless it would be obvious to a person skilled in the art that a contradiction or inconsistency would occur. When elements are presented in a list form (e.g., in a Markush group or similar style), it should be understood that each subgroup of elements is also disclosed, and any element may be deleted from that group. It should be understood that, generally, when the invention or an aspect of the invention is specified as containing a particular element, feature, etc., certain embodiments of the invention or certain aspects of the invention consist of or substantially consist of such elements, features, etc. For simplicity, these embodiments are not always described in the same number of words. It should also be understood that any embodiment or aspect of the invention may be expressly excluded from the claims, whether or not such particular exclusion is mentioned in the description. Publications and other documents cited to describe the background of the invention and to provide supplementary details about its implementation are incorporated herein by reference.

[0161] The present invention will be described in more detail below through the following embodiments, which are presented by way of example only and do not limit the invention.

[0162] The present invention will be described in more detail below through the following embodiments, which are presented by way of example only. Example

[0163] Example 1: Preventive effect of the active substance according to the invention on healthy individuals

[0164] Seven-week-old male C57BL / 6JRj mice from the Janvier laboratory were fed using the standard diet regimen used in laboratory animal housing.

[0165] The first group, consisting of 10 mice that did not receive OAS treatment, served as the control group.

[0166] The second group, consisting of 10 mice, was treated with a daily dose of 1000 mg / kg of OAS for 5 days. The OAS used was a product marketed by Sigma-Aldrich under the name A6262_SIGMA (CAS No. 66638-22-0). This group was the OAS treatment group.

[0167] The oral glucose tolerance test (OGTT) was performed on each of the two mouse groups.

[0168] The test involved tracking plasma glucose concentrations in mice for 120 minutes following an oral glucose load. Therefore, at T0 (fasting blood glucose), glucose (2.5 g / kg) was administered orally to the animals. A drop of blood was drawn from the tail every 15 to 30 minutes during the 90-minute period to measure blood glucose using a band glucometer (Accu-Check Perfoma, available at pharmacies).

[0169] On day 5 of treatment, mice in the OAS treatment group underwent an oral glucose tolerance test (OGTT) 2 hours after receiving a dose of 500 mg / kg. At the time of the OGTT test, mice in the treatment group received 500 mg / kg of OAS concurrently with an oral glucose load.

[0170] The control group received only oral glucose loading.

[0171] Fasting blood glucose levels tended to be lower in the OAS treatment group, and blood glucose levels at 15, 30, and 60 minutes after oral glucose loading were significantly lower in the OAS treatment group compared to the control group.

[0172] The results of the test showed that 5 days of treatment with OAS reduced fasting blood glucose in the treatment group and significantly reduced hyperglycemia induced by oral glucose loading. Figure 4 ).

[0173] This treatment significantly reduced hyperglycemia, with a lower area under the curve (AUC) compared to the control group. Figure 4 This confirms the effect of O-acetylserine on regulating postprandial hyperglycemia and, therefore, the preventive effect of the active substance according to the invention in the development of insulin resistance and / or prediabetes.

[0174] Example 2: Prevention of postprandial blood glucose in healthy individuals by a single dose of the active substance according to the invention. effect

[0175] Seven-week-old male C57BL / 6JRj mice from the Janvier laboratory were fed using the standard diet regimen used in laboratory animal housing.

[0176] The first group, consisting of 5 mice that did not receive OAS treatment, served as the control group.

[0177] The second group, consisting of 5 mice, was treated with a single dose of OAS at 1000 mg / kg. The OAS used was a product marketed by Sigma-Aldrich under the name A6262_SIGMA (CAS No. 66638-22-0). This group was the OAS treatment group.

[0178] The oral glucose tolerance test (OGTT) was performed on each of the two mouse groups.

[0179] The test involved tracking plasma glucose concentrations in mice for 120 minutes following an oral glucose load. Therefore, at T0 (fasting blood glucose), glucose (2.5 g / kg) was administered orally to the animals. A drop of blood was drawn from the tail every 30 minutes during the 120-minute period to measure blood glucose using a band glucometer (Accu-Check Perfoma, available at pharmacies).

[0180] During the OGTT test, the OAS treatment group received a dose of 1000 mg / kg OAS concurrently with an oral glucose load. The control group received only an oral glucose load. Blood glucose levels 15 minutes after the oral glucose load were significantly lower in the OAS treatment group compared to the control group.

[0181] The results of the test showed that, after 15 minutes, a single dose of OAS significantly reduced the hyperglycemia induced by oral glucose loading. Figure 5 This treatment significantly reduced hyperglycemia, with a lower area under the curve (AUC) compared to the control group. Figure 5 A single dose of O-acetylserine can reduce postprandial hyperglycemia. Therefore, this confirms the preventive effect of a single dose of the active substance according to the invention in the development of insulin resistance and / or prediabetes.

[0182] Example 3: Effect of the active substance according to the present invention on individuals with HFD

[0183] The effects of the active substances according to the invention were also tested in individuals under obesity-inducing dietary regimes.

[0184] Seven-week-old male C57BL / 6JRj mice from Janvier's laboratory were fed a high-fat diet (HFD, 45% lipids and 20% sucrose) for 12 weeks. This diet is comparable to an obesity-inducing diet that favors glucose intolerance.

[0185] During the 12-week dietary regimen, the first group of 10 mice receiving this diet were treated with a daily dose of OAS at a frequency of 200 mg / kg / day every 5 days / week. The OAS used was a product marketed by Sigma-Aldrich under the name A6262_SIGMA (CAS No. 66638-22-0). This group was the HFD+OAS group.

[0186] The second group, consisting of nine mice that received the HFD dietary regimen, did not receive OAS treatment. This is the HFD group.

[0187] The last group of nine mice that did not receive a special diet or OAS treatment served as the control group.

[0188] Compared to mice not fed the HFD diet (control group), mice on the HFD diet showed significantly greater weight gain (*p<0.05) and significantly increased fat accumulation in the epididymis (****p<0.0001) after 12 weeks of the diet. These characteristics are signs of obesity in mice. Figure 1 ).

[0189] Oral glucose tolerance test (OGTT) was performed on each of the three mouse groups.

[0190] The test involved tracking plasma glucose concentrations in mice for 120 minutes following an oral glucose load. Therefore, at T0 (fasting blood glucose), glucose (2 g / kg) was administered orally to the animals. A drop of blood was drawn from the tail every 30 minutes during the 120-minute period to measure blood glucose using an Accu-Check Perfoma (available at pharmacies).

[0191] Glucose tolerance is the body’s ability to regulate blood sugar back to normal after a glucose load.

[0192] Oral glucose tolerance tests (OGTTs) were performed at 5 and 9 weeks after the start of the obesity-inducing diet. Results of this test showed that glucose intolerance was established from week 5 in mice on the HFD diet. Treatment with oral glucose tolerance assays (OAS) had no visible effect after 5 weeks in the HFD+OAS group. Figure 2However, after 9 weeks, the treatment significantly reduced glucose intolerance, with a similar area under the curve (AUC) to the control group. Figure 3 ).

[0193] In summary, treatment with O-acetylserine enables the regulation of glucose metabolism in the body, particularly improving glucose intolerance associated with obesity-promoting dietary regimes.

Claims

1. Use of O-acetylserine or its salts in the preparation of a medicament for the treatment and / or prevention in an individual of glucose intolerance and / or one or more diseases associated with glucose intolerance, said diseases associated with glucose intolerance being selected from prediabetic states and type 2 diabetes.

2. The use of O-acetylserine according to claim 1, wherein the disease associated with glucose intolerance is type 2 diabetes.

3. The use of O-acetylserine according to claim 1 or 2, wherein the individual is overweight or obese.

4. Use of O-acetylserine according to claim 1 or 2, wherein the O-acetylserine is a bacterial synthetic metabolite.

5. The use of O-acetylserine according to claim 4, wherein the synthetic metabolite is a bacterial strain *Streptococcus salivarius* (…). Streptococcus salivarius Synthetic metabolites of ).

6. Use of a composition comprising O-acetylserine or a salt thereof and a physiologically acceptable carrier in the preparation of a medicament for the treatment and / or prevention in an individual of glucose intolerance and / or one or more diseases associated with glucose intolerance, said diseases associated with glucose intolerance being selected from prediabetic states and type 2 diabetes.

7. Use of the composition according to claim 6, wherein the disease associated with glucose intolerance is type 2 diabetes.

8. Use of the composition according to claim 6 or 7, wherein the individual is obese.

9. Use of the composition according to claim 6 or 7, wherein the O-acetylserine is a bacterial synthetic metabolite.

10. Use of the composition according to claim 9, wherein the O-acetylserine is a synthetic metabolite of the bacterial strain Streptococcus salivarius.

11. Use of the composition according to claim 6 or 7, wherein the composition is a composition for oral administration.

12. Use of the composition according to claim 6 or 7, wherein the composition further comprises an additional active substance.

13. Use of the composition according to claim 12, wherein the additional active substance is selected from metabolites, antioxidants, vitamins, minerals, phytonutrients, proteins, lipids, probiotics, additional active substances for the prevention and / or treatment of glucose intolerance, and combinations thereof.

14. Use of the composition according to claim 12, wherein the additional active substance is fish oil.

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