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

Abstract

The present patent application relates to O-acetylserine, or a salt or derivative thereof, for use in the treatment and / or prevention of impaired glucose tolerance and / or one or more diseases associated with impaired glucose tolerance in an individual, comprising O-acetylserine, or a salt or derivative thereof, and a physiologically acceptable vehicle. The present patent application also relates to a composition comprising O-acetylserine or a salt or derivative thereof and a physiologically acceptable vehicle for use in the treatment and / or prevention of impaired glucose tolerance and / or one or more diseases associated with impaired glucose tolerance in an individual.

Description

Technical Field

[0001] The present invention relates to the field of prevention and / or treatment of metabolic diseases such as glucose intolerance or prediabetes, and also diseases related to glucose intolerance such as type 2 diabetes.

Background Art

[0002] Type 2 diabetes (T2DM) is a disease characterized by chronic hyperglycemia caused by insufficient use of insulin by the body. This disease is generally a result of excessive body weight and lack of exercise (e.g., obesity), and develops in response to changes in diet and lifestyle. Thus, the risk factors associated with T2DM are, inter alia: overweight, advanced age, poor diet and excessive calorie intake or undernutrition, lack of exercise, smoking or family history (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 metformin 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] T2DM is the most common type 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 serious public health problem due to its global epidemic (doubling between 1980 and 2014, rising from 4.7% to 8.5% of the adult population (World Diabetes Report 2016, ISBN: 9789242565256)), high treatment costs, and complications. In fact, in the long term, diabetes can affect the heart, blood vessels, eyes, kidneys, and nerves, potentially increasing the risk of heart disease and myocardial infarction. Therefore, preventing and treating T2DM is a field of therapeutic research highly relevant to economic and social risks (IDF Diabetes Atlas - 8th Edition, 2017).

[0004] Today, recommendations for hygienic dietary measures are primarily for prediabetes and are not widely prescribed, although preventive treatment is recommended for those at high risk of developing type 2 diabetes. Prediabetes, an 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 develops during the pre-diabetic stage. Impaired glucose tolerance, or prediabetes or moderate hyperglycemia, is a disorder of blood glucose. Individuals with impaired glucose tolerance have blood glucose levels that are higher than normal but not high enough to be diagnosed as diabetes. Impaired glucose tolerance is characterized by the detection of decreased insulin sensitivity or increased insulin resistance.

[0006] Prediabetes is a stage where it is often still possible to reverse the tendency towards diabetes and return to normal blood glucose levels. In some cases, this precursory state to type 2 diabetes can be reversed through exercise and dietary adjustments.

[0007] Generally, physical activity combined with a balanced diet can lower blood sugar and prevent progression to T2DM. However, the expected increase in type 2 diabetes cases in the coming years suggests that these lifestyle adjustments are insufficient. Therefore, lifestyle rebalancing is often impractical or inadequate and can be combined with oral medications prescribed to control blood sugar levels. However, the number of these medications is small, and some are not recommended for children and adolescents with advanced impaired glucose tolerance. For example, metformin, which is commonly used to treat T2DM, may be prescribed. Furthermore, there are contraindications and side effects such as nausea, vomiting, diarrhea, abdominal pain, or loss of appetite.

[0008] These side effects are a frequent cause of 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 treatment is associated with an increased risk of vitamin B6 and B12 deficiencies and may be accompanied by neurological complications (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).

[0009] Early targeting of reversible prediabetic conditions, particularly impaired glucose tolerance, is considered essential for preventing progression to type 2 diabetes.

[0010] There is a need for novel compounds or compositions to control blood glucose homeostasis. There is also a need for novel compounds or compositions to target impaired glucose tolerance.

[0011] There is a need for novel compounds or compositions that may be safe for administration to children or adolescents.

[0012] There is a need for novel treatments to prevent and / or treat impaired glucose tolerance. In particular, there is a need for novel treatments to prevent and / or treat diseases associated with impaired glucose tolerance, such as type 2 diabetes, or diseases resulting from it. Therefore, there is a need for novel compounds or compositions to prevent and / or treat prediabetes.

[0013] Therefore, there is a need to prevent and / or treat postprandial hyperglycemia.

[0014] There is a need to treat and / or prevent diseases associated with impaired glucose tolerance, particularly type 2 diabetes.

[0015] The object of the present invention is to satisfy all or some of these requirements.

[0016] Disclosure of the invention This invention proposes O-acetylserine, a synthetic metabolite for use in the treatment and / or prevention of impaired glucose tolerance. The invention also proposes O-acetylserine for use in the treatment and / or prevention of one or more diseases associated with impaired glucose tolerance, particularly type 2 diabetes. [Overview of the Initiative]

[0017] The object of the present invention is to propose a novel substance for use in therapeutics for preventing and / or treating impaired glucose tolerance and / or diseases associated with impaired glucose tolerance in individuals.

[0018] Surprisingly, the inventors observed a preventive effect of O-acetylserine (or OAS) on glucose homeostasis. OAS limits the development of glucose intolerance induced by obesity-inducing diets (rich in fat or sugar) and precedes the development of T2DM. Therefore, prevention and treatment of glucose intolerance enable the prevention and treatment of T2DM.

[0019] Accordingly, according to a first aspect, the present invention relates to O-acetylserine, or a salt or derivative thereof, for use in the treatment and / or prevention of one or more diseases associated with impaired glucose tolerance in individuals.

[0020] In certain embodiments, the disease associated with impaired glucose tolerance is type 2 diabetes.

[0021] Furthermore, the individual may be overweight or obese.

[0022] In certain embodiments, O-acetylserine is a synthetic metabolite of bacteria, specifically a synthetic metabolite of bacteria in the gut microbiota, and more specifically, a synthetic metabolite of the bacterial strain Streptococcus salivarius.

[0023] According to a second aspect, the present invention relates to a composition comprising O-acetylserine, or a salt or derivative thereof, and a physiologically acceptable vehicle, for use in the treatment and / or prevention of one or more diseases associated with impaired glucose tolerance in an individual.

[0024] In certain embodiments, the disease associated with impaired glucose tolerance is type 2 diabetes.

[0025] Furthermore, the aforementioned individual may be obese.

[0026] According to one embodiment, O-acetylserine is a bacterial anabolic metabolite, specifically, an anabolic metabolite of bacteria in the gut microbiota, and more specifically, an anabolic metabolite of the bacterial strain Streptococcus salivarius.

[0027] According to the present invention, the composition may specifically be an oral composition in the form of a powder, granule, food product, beverage, pharmaceutical, nutraceutical product, food additive, food supplement, wafer capsule or gel capsule.

[0028] In certain embodiments, the composition also includes additional active agents, specifically, additional active agents selected from metabolites, antioxidants, fish oil, DHA, EPA, vitamins, minerals, phyto-nutrients, proteins, lipids, probiotics, additional active agents, and combinations thereof for preventing and / or treating glucose intolerance.

Brief Description of the Drawings

[0029] [Figure 1] Final body weights (left) and epididymal fat tissue weights of groups of mice tested after 12 weeks of diet and treatment: control group receiving a control diet, HFD group receiving an untreated high-fat diet (HFD), and HFD group treated with O-acetylserine (HFD+OAS). The left figure represents the average body weight of mice in each group in grams (y-axis). The groups of mice are shown on the x-axis, from left to right: control; HFD and HFD+OAS. The difference in body weight between the control group and the HFD group is statistically significant (*p<0.05). In the right figure, the average weight of epididymal fat tissue of each mouse group is represented in grams (y-axis). The mouse groups are shown on the x-axis, from left to right: control; HFD and HFD+OAS. The difference in epididymal fat tissue weight between the control group and the HFD group or the HFD+OAS group is statistically significant (****p<0.0001). [Figure 2]The results of the glucose tolerance test after a 5-week trial are shown for each mouse group in the study: the control group given a control diet, the HFD group given an untreated high-fat diet (HFD), and the HFD group treated with O-acetylserine (HFD+OAS). The curve on the left shows the change in mean plasma glucose concentration of mice in each mouse group after oral glucose loading, expressed as a function of time (minutes) (x axis) in mg / dL (y axis). The control group is represented by a curve containing the symbol "○", the HFD group by a curve containing the symbol "●", and the HFD+OAS group by a curve containing the symbol "■". The difference between one control group and the other HFD and HFD+OAS groups is significant (using **** p<0.0001, *** p<0.00, ** p<0.01, and * p<0.05 at t=15 min, t=30 min, t=60 min, t=90 min, and t=120 min, respectively). In the figure on the right, the bars, from left to right on the x-axis, represent the control, HFD, and HFD+OAS mouse groups, and the area under the curve in the left figure is expressed in mg / dL per minute (y-axis). The difference in the area under the curve between one control group and the other HFD and HFD+OAS groups is significant (**** p<0.0001). [Figure 3]The results of the glucose tolerance test after 9 weeks are shown for each mouse group in the study: the control group given a control diet, the HFD group given an untreated high-fat diet (HFD), and the HFD group treated with O-acetylserine (HFD+OAS). In the figure on the left, the curves represent the change in mean plasma glucose concentration of mice in each mouse group after oral glucose loading as a function of time (minutes) (x axis) in mg / dL (y axis). The control group is represented by a curve containing the symbol "○", the HFD group by a curve containing the symbol "●", and the HFD+OAS group by a curve containing the symbol "■". The difference between one control group and the other HFD and HFD+OAS groups is significant (using **** p<0.0001, *** p<0.001, ** p<0.01, and * p<0.05 at t=15 min, t=30 min, t=60 min, and t=90 min, respectively). From t=60 minutes, the difference between one control group and the other HFD+OAS group is no longer significant, and at t=30 minutes, the difference between one HFD group and the other HFD+OAS group is significant: * p < 0.0001. In the figure on the right, the bars represent the control, HFD, and HFD+OAS mouse groups from left to right on the x-axis, and the area under the curve in the left figure is represented by mg / dL per minute (y-axis). The difference in the area under the curve between each mouse group is significant (between the control group and the HFD group: **** p < 0.0001, between the HFD group and the HFD+OAS group: * p < 0.05, and between the control group and the HFD+OAS group: * p < 0.05). [Figure 4]The graph shows the results of the glucose tolerance test after 5 days of study for each mouse group of the study control: the control group received a normal diet and no O-acetylserine, while the OAS group also received a normal diet plus a daily dose of O-acetylserine (OAS). In the left figure, the curves represent the change in mean mouse plasma glucose concentration in each group of mice after oral glucose loading at t0, expressed as a function of time (minutes) (x-axis) in mg / dL (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 is significant (using **** p<0.0001 and * p<0.05 at t=15 min, t=30 min, and t=60 min, respectively). In the figure on the right, the bars, from left to right on the x-axis, represent the area under the curve in mg / dL per minute (y-axis) for each mouse group shown in the left figure, relative to the control group (OAS). The difference in the area under the curve between the mouse groups is significant (**** p<0.0001). [Figure 5] The graph shows the results of glucose tolerance tests after oral glucose loading for each mouse group studied: the control group received only oral glucose loading at t0, while the OAS group received both oral glucose loading and a dose of O-acetylserine (OAS) at t0. In the left graph, the curves represent the change in mean plasma glucose concentration for each mouse group after oral glucose loading at t0, as a function of time (minutes) (x-axis) in mg / dL (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 and OAS groups is statistically significant (using *** p<0.001 at t=15 minutes). In the right graph, the bars represent the area under the curves in mg / dL per minute (y-axis) for each mouse group, from left to right on the x-axis, representing the control and OAS groups, as shown in the left graph. The difference in the area under the curve between each mouse group is significant (* p<0.05).

[0030] Detailed explanation The inventors conducted extensive research to identify the ability of O-acetylserine to treat and / or prevent impaired glucose tolerance and / or diseases associated with impaired glucose tolerance in individuals requiring O-acetylserine. Specifically, the inventors demonstrated the ability of OAS to treat and / or prevent impaired glucose tolerance in mice.

[0031] In fact, as developed in the experimental section below, the inventors demonstrated that treatment with OAS enables the regulation of glucose metabolism, particularly with improvement of impaired glucose tolerance, especially impaired glucose tolerance associated with obesity, in a mouse model given an obesity-inducing diet. Thus, the inventors demonstrated the usefulness of OAS in the in vivo improvement of metabolic disorders caused by obesity.

[0032] definition The terms used herein are those used in the ordinary sense in the art being considered and in the context of this specification in which they are used. Furthermore, certain terms are discussed below or elsewhere to provide additional guidance with respect to the invention and its implementation. The following definitions are provided herein and in the claims.

[0033] The descriptions of various embodiments of the present invention include embodiments that include “comprising,” “having,” “consisting of,” and “consisting essentially of.” The words “have” and “comprises,” or variations such as “has,” “having,” “comprises,” or “comprising,” are understood to mean the inclusion of the indicated elements (such as elements of a composition or steps of a method) but not the exclusion of other elements.

[0034] The term "consists of" means the inclusion of the indicated elements, excluding any additional elements. The term "essentially consists of" means the inclusion of the described elements, and may include other elements if those other elements do not substantially affect the basic and novel features of the invention. Depending on the context, the term "contains" may also strictly refer to the indicated features, integers, steps, or components, in which case it may be replaced with "consists of".

[0035] The term "type 2 diabetes" or "T2DM" refers to a chronic disease that occurs when the pancreas does not produce enough insulin (a hormone that regulates blood sugar levels) or when the body cannot effectively use the insulin it produces. Typically, T2DM is preceded by impaired glucose tolerance.

[0036] As used herein with respect to numerical values, the terms “about” or “approximately” usually refer to the normal range of error of the value, as determined by those skilled in the art. A reference to the term “about” in relation to a specific value or parameter includes that value or parameter and is written as such. The term “about” refers to ±10% of a given value. However, whenever the value in question refers to an indivisible object that loses its identity when divided, “about” refers to ±1% of the indivisible object.

[0037] The terms "individual" and "patient" used in this text specifically refer to mammals. These mammals include, but are not limited to, livestock (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 certain embodiments, the individual, or patient, is a human being.

[0038] The term "impaired glucose tolerance" refers to a physiological and pathological condition in which an individual's blood glucose levels are above normal but below the diagnostic criteria for type 2 diabetes. Impaired glucose tolerance can be detected by measuring fasting blood glucose levels and monitoring blood glucose levels during an oral glucose tolerance test (OGTT).

[0039] The term "obesity" refers to a physiological and pathological condition in which an individual has a significant excess of adipose tissue, and is generally induced by obesity-inducing diets, particularly those involving excessive intake of calorie-rich foods, genetic predisposition, or insufficient or absent physical exercise. An individual declared obese has a body mass index (BMI) greater than 30. According to the official definition by the World Health Organization (WHO), BMI is an indicator of health risks 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 specific body types according to the classifications given by the WHO.

[0040] Unlike obese individuals, overweight individuals are those whose condition is not physiological or pathological. Overweight individuals also often have excess adipose tissue. An individual is generally considered overweight when their body mass index (BMI) is between 25 and 30.

[0041] The term "prediabetes" refers to a physiological and pathological condition characterized by elevated blood glucose levels compared to normal, but below the threshold defining type 2 diabetes. Fasting blood glucose levels are considered normal if (i) between 0.70 g / L and 1.10 g / L, (ii) between 1.10 g / L and 1.25 g / L as a sign of prediabetes, and (iii) above 1.25 g / L as a sign of diabetes. Prediabetes usually does not induce symptoms, but is often associated with obesity, dyslipidemia, and hypertension. Prediabetes is a risk factor for cardiovascular disease. Prediabetes is particularly characterized by impaired glucose tolerance.

[0042] In the context of the present invention, the terms “prevent,” “prevention,” and “slow progression” (and variations thereof) relating to physiological disorders or diseases refer, for example, to preventive measures for a disease or disorder in an individual who has the disease or disorder or is suspected to be at risk of developing the disease or disorder. Prevention includes, but is not limited to, preventing or delaying the onset of a disease and / or maintaining the symptoms of one or more diseases at a desirable or low level. The term “prevention” does not require the 100% elimination of the possibility or likelihood of the disease or disorder occurring. Rather, the term refers to reducing to a lesser extent the risk or likelihood of developing a given phenomenon, namely, a glucose intolerance such as a prediabetic state or type 2 diabetes, or a disease associated with glucose intolerance, as described in the present invention. As stated above, prevention may be complete, i.e., partial, such as having no detectable symptoms or disease, or having fewer or less severe symptoms.

[0043] The term "glucose homeostasis" refers to the blood glucose balance of an individual, which is characteristic of normal blood glucose levels. In humans, the normal fasting blood glucose balance is between approximately 0.70 g / L and 1.10 g / L (i.e., between 70 mg / dL and 110 mg / dL). Blood glucose levels below 0.70 g / L are characterized by hypoglycemia, while hyperglycemia, which is above 1.10 g / L but below 1.26 g / L, is characterized by moderate hyperglycemia and may indicate impaired glucose tolerance.

[0044] The term "O-acetylserine salt" refers to an O-acetylserine salt prepared with an acid or base that may be physiologically acceptable. However, acids or bases useful for the purification or isolation of OASs may also be used. The O-acetylserine salts that may be referred to may also be O-acetyl-L-serine hydrochloride salts.

[0045] The term "O-acetylserine derivative" refers to physiologically acceptable O-acetylserine that has undergone one or more modifications, such as substitution or intramolecular transfer. An example of modification of an O-acetylserine derivative according to the present invention, specifically substitution, is the substitution of at least one hydrogen atom of the amine group of OAS to form an amide functional group. An example of modification of an O-acetylserine derivative according to the present invention, specifically additive or alternative substitution, is the substitution of the methyl group of OAS with an alkyl group, specifically a (C1-C6) alkyl group (optionally, the alkyl group is substituted with a halogen, specifically selected from halogens, particularly fluorine and chlorine). An example of modification of an O-acetylserine derivative according to the present invention, specifically additive or alternative substitution, is the substitution of a proton of the carboxyl group-COOH of OAS to form an ester functional group. A suitable OAS derivative according to the present invention is an OAS compound having the same activity as OAS, specifically the same activity for preventing and / or treating impaired glucose tolerance and / or diseases associated with impaired glucose tolerance in individuals. An example of an O-acetylserine derivative is N-acetylserine.

[0046] As used herein, the terms “therapeutably effective dose” and “prophylactically effective dose” refer to the dose that provides therapeutic benefit in the treatment, prevention, or management of the pathological process in question. The specific therapeutically effective dose can be readily determined by a physician and may vary depending on factors such as the type and stage of the pathological process, the patient’s medical history, sex, weight and age, his or her diet, and the administration of other therapeutic agents.

[0047] For the purposes of this invention, the term “significantly” in the context of change means that the observed change is remarkable or statistically significant.

[0048] For the purposes of the present invention, the terms “substantially similar,” “substantially identical,” “essentially similar,” or “essentially identical” (or any variation thereof) used in relation to the features of the present invention are intended to define a set of embodiments of the present invention relating to a feature that is substantially identical but not entirely identical to an embodiment containing that feature.

[0049] The term “oral glucose tolerance test” or “OGTT test” refers to a test to measure the body’s ability to utilize glucose. The OGTT test is well known to those skilled in the art, and may be used, for example, by following the protocol described in Nagy et al., Study of In Vivo Glucose 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).

[0050] For the purposes of this invention, the terms “treat,” “treatment,” “therapy,” or “therapeutic” refer to the administration or consumption of an activator, O-acetylserine or its salts or derivatives, or a composition containing such activator, 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 delaying the progression of such symptoms or disease, or for the purpose of halting the occurrence of such symptoms or disease or pathological disorder in a statistically significant manner. Specifically, the terms “treat” or “treatment” include any method for obtaining a beneficial effect or desired outcome with respect to the pathophysiology of impaired glucose tolerance in an individual. Beneficial or desired clinical outcomes include alleviating or improving impaired glucose tolerance, diseases associated with impaired glucose tolerance, such as prediabetes or type 2 diabetes, or one or more symptoms of such diseases; impaired glucose tolerance, diseases associated with impaired glucose tolerance, or such This includes, but is not limited to, reducing or mitigating the severity of one or more symptoms of a disease; stabilizing, i.e., preventing worsening, of impaired glucose tolerance, impaired glucose tolerance-related diseases, or one or more symptoms of such diseases; preventing the spread of impaired glucose tolerance-related diseases, or one or more symptoms of such diseases; delaying the progression of impaired glucose tolerance-related diseases, or one or more symptoms of such diseases; reducing the recurrence of impaired glucose tolerance, impaired glucose tolerance-related diseases, or one or more symptoms of such diseases; and interrupting impaired glucose tolerance, impaired glucose tolerance-related diseases, or one or more symptoms of such diseases. In other words, as used herein, the term “treatment” includes any cure, improvement, reduction, or interruption of impaired glucose tolerance, impaired glucose tolerance-related diseases, or one or more symptoms of such diseases. “Reduction” of a symptomatic disease means a decrease in the severity or frequency of the disease or symptoms, or the disappearance of the disease or symptoms.

[0051] When used herein and in the claims, singular “a,” “an,” “one,” and “the” include the plural forms unless the context explicitly indicates otherwise.

[0052] The term “physiologically acceptable vehicle” is intended to refer to any substance or composition that is compatible with the body of an individual to whom the activator of the present invention is administered. Specifically, a physiologically acceptable vehicle is a substance or composition that does not cause significant adverse effects when administered to an individual. For example, a “physiologically acceptable vehicle” may be a non-toxic solvent such as water or saline solution. In particular, such a solvent is suitable for oral or rectal administration, and preferably for oral administration.

[0053] The following list of sources, ingredients, and components is understood to be described as being intended to be used in any combination and mixture thereof within the scope of the present invention.

[0054] Each maximum numerical limit given herein is understood to include its respective lower numerical limit, as if such lower numerical limits were explicitly written herein. Each minimum numerical limit given throughout this specification includes its respective higher numerical limit, as if such higher numerical limits were explicitly written herein. Each numerical range given throughout this specification includes its respective narrower numerical ranges contained within its wider numerical range, as if all such narrower numerical ranges were explicitly written herein.

[0055] All lists given herein, such as the list of components, are intended to be and should be interpreted as Marcsch groups. Thus, all lists can be understood and interpreted as being selected from the group consisting of elements ", a list of elements, and combinations and mixtures thereof."

[0056] Trade names of components, including the various components used herein, may be referenced below. The inventors do not intend to limit the materials to any particular trade name. Materials equivalent to those indicated herein by other trade names (for example, those obtained from other sources under different names or reference numbers) may be substituted and used in the following description.

[0057] O-acetylserine The present invention relates to O-acetylserine (OAS), or a salt or derivative thereof, for use in the treatment and / or prevention of impaired glucose tolerance in individuals. The present invention also relates to OAS, or a salt or derivative thereof, for use in the treatment and / or prevention of one or more diseases associated with impaired glucose tolerance in individuals.

[0058] Specifically, 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 impaired glucose tolerance in individuals. 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 impaired glucose tolerance in individuals.

[0059] O-acetylserine (C5H9NO4) is an intracellular secondary metabolite of sulfur-based amino acid metabolism in certain bacteria and plants, and is given the following formula: [ka] It has.

[0060] This is a non-protein α-amino acid derived from serine by acetylation using acetyl-CoA under the influence of serine O-acetyltransferase. It is an intermediate in bacterial and plant cysteine ​​biosynthesis and is converted to cysteine ​​by cysteine ​​synthase.

[0061] The inventors identified OAS in the culture supernatant fraction of the Streptococcus salivarius strain by mass spectrometry.

[0062] This symbiotic species is primarily found in the oral cavity and secondarily in the human digestive tract. The S. salivarius strain has the ability to synthesize OAS.

[0063] OAS is also present in various plants.

[0064] In humans, this molecule is found in the prostate, urine, and blood, and is of bacterial origin (particularly from gut microbiota) and dietary origin.

[0065] OAS is referenced as HMDB0003011 in the HMDB 4.0 Human Metabolite Database (http: / / www.hmdb.ca / metabolites / HMDB0003011) and corresponds to CAS number 5147-00-2.

[0066] The O-acetylserine according to the present invention can also be found as a salt of OAS.

[0067] Specifically, OAS may exist in the form of O-acetyl-L-serine hydrochloride (OAS.HCl).

[0068] The OAS.HCl(C5H9NO4.HCl) salt is referenced by CAS number 66638-22-0.

[0069] The O-acetylserine according to the present invention may also exist in the form of an OAS derivative or an OAS derivative salt.

[0070] Specifically, OAS may exist in the form of N-acetylserine (NAS). OAS may also exist in the form of a salt of NAS.

[0071] OAS suitable for use in accordance with the present invention is specifically marketed by Sigma-Aldrich under trade reference A6262_SIGMA (trademark registered).

[0072] OAS derivatives suitable for use in accordance with the present invention, specifically N-acetylserine, are specifically marketed by Sigma-Aldrich as a chemical product under trade reference A2638 (trademark registration).

[0073] According to certain embodiments, the O-acetylserine according to the present invention is a synthetic metabolite of bacteria, specifically a synthetic metabolite of bacteria in the gut microbiota, and more specifically a synthetic metabolite of the bacterial strain Streptococcus salivarius.

[0074] In certain embodiments, the composition may contain OAS or a salt or derivative thereof.

[0075] composition The present invention also relates to a composition for use in the treatment and / or prevention of impaired glucose tolerance and / or one or more diseases associated with impaired glucose tolerance in an individual, comprising O-acetylserine according to the present invention, or a salt or derivative thereof, and at least one physiologically acceptable vehicle.

[0076] The compositions described are administered to individuals in need in therapeutically effective doses. This dose is determined by a healthcare professional based on the characteristics of each individual.

[0077] In certain embodiments, the composition is suitable for administration during or outside of meals, preferably outside of meals. In certain embodiments, the composition may be suitable for administration at least once a day, particularly once a day.

[0078] According to certain embodiments, the composition may be administered daily for a period of time. Alternatively, the composition may be administered for one or more consecutive days, followed by a period of at least one or two consecutive days of interruption. The administration period and the interruption period may constitute a cycle. The composition may be administered in at least one cycle, and possibly two or three or more consecutive cycles.

[0079] The composition may be administered for at least 5 weeks, or at least 6 weeks, or at least 7 weeks, or at least 8 weeks, or at least 9 weeks.

[0080] The composition may be administered over a period of at least two consecutive days, particularly at least five consecutive days, one week, and from at least one week to at least twelve weeks, particularly from at least one week to at least ten weeks, particularly from at least two weeks to at least five weeks, and particularly at least three weeks.

[0081] According to certain embodiments, the composition may be administered for at least two consecutive days at one-week intervals, and particularly for at least five consecutive days at intervals of one week or more.

[0082] Physiologically acceptable vehicles that can be used to prepare the compositions of the present invention include, in a non-limiting manner, water, physiological saline buffer, especially phosphate buffer, 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, gelatinized starch, gum, sucrose, polyethylene glycol (PEG) 4000 or PEG 6000, dispersants such as microcrystalline cellulose such as sodium carboxymethyl starch type A or sodium carboxymethyl starch, lubricants such as magnesium stearate, and fluidizers such as anhydrous colloidal silica.

[0083] A physiologically acceptable vehicle may be any substance used in the pharmaceutical formulation, including coating materials, film-forming materials, fillers, disintegrants, release modifiers, support materials, diluents, binders, and other adjuvants. Typical physiologically acceptable vehicles include substances such as sucrose, mannitol, sorbitol, starch and starch derivatives, lubricants such as lactose and magnesium stearate, disintegrants, and buffers. Suitable physiologically acceptable vehicles also include, for example, water, saline solution, alcohol, oil, preferably vegetable oil, polyethylene glycol, gelatin, lactose, amylose, magnesium stearate, surfactants, fragrance oils, fatty acids, monoglycerides and diglycerides, hydroxymethylcellulose, and polyvinylpyrrolidone. The pharmaceutical composition may also contain auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts that affect osmotic pressure, buffers, colorants, fragrances, and / or aromatic substances.

[0084] The present invention envisions liquid forms, including emulsions, solutions, suspensions, and syrups. Solid forms such as suppositories, tablets, lozenges, gel capsules, powders, effervescent formulations, dragees, granules, or wafer capsules are also envisioned.

[0085] The compositions of the present invention may also contain any additives or excipients commonly used in the art with respect to the intended use of the compositions. Accordingly, the compositions of the present invention may also contain at least one selected from sweeteners, stabilizers, antioxidants, additives, flavorings and / or colorants. Formulation of the compositions of the present invention may be carried out by conventional processes used in the art, particularly for producing sugar-coated tablets, gel capsules, gels, controlled-release hydrogels, emulsions, foams, syrups, liquids, tablets, wafer capsules or suppositories.

[0086] This composition may be suitable for oral, sublingual, nasal, or rectal administration, particularly oral administration.

[0087] In one embodiment, the composition may be in the form of a nutritional supplement, a beverage supplement, a nutritional product, a medical food, or a nutritional supplement composition.

[0088] The composition may also be in the form of a nutritional or dietary supplement composition.

[0089] In particular, the composition may be a nutritional supplement.

[0090] Specifically, nutritional supplements may be in the form of wafer capsules, gel capsules, soft capsules, tablets, sugar-coated tablets, tablets, pastes, lozenges, gums, drinkable solutions or emulsions, syrups or gels.

[0091] Compositions suitable for use in the present invention may be particularly formulated in the form of food supplements selected from dairy products, dairy beverages, yogurt, fruit or vegetable juices or their concentrates, powders, soy or cereal-based beverages, breakfast cereals such as muesli flakes, fruit and vegetable juice powders, cereals and / or chocolate bars, confectionery, spreads, milk powder, smoothies, ice cream, reconstituted fruit products, food bars, sauces, sports supplements including dairy and non-dairy sports supplements, desserts, frozen foods, soups, liquid suspensions, tablets, gum or candy.

[0092] Advantageously, compositions according to the present invention intended for oral administration may be coated with a gastric juice-resistant coating so that the O-acetylserine of the present invention contained in the composition can pass through the stomach without being damaged. Thus, the release of the OAS according to the present invention can first occur in the upper intestinal tract.

[0093] According to certain embodiments, oral compositions suitable for use in the present invention may be selected from powders, granules, food products, beverages, pharmaceuticals, dietary supplements, food additives, dietary supplements, wafer capsules, or gel capsules.

[0094] In another embodiment of the present invention, the composition may be administered rectally. Specifically, the rectal composition may be prepared in the form of a suppository, enema, or foam.

[0095] In one embodiment, the composition may also include at least one additional activator selected from metabolites, antioxidants, fish oil, DHA, EPA, vitamins, minerals, phytonutrients, proteins, lipids, probiotics, and combinations thereof.

[0096] Probiotic active agents that may additionally be used include Streptococcus, Lactobacillus, Lactococcus, Bifidobacterium, Veillonella, Desemzia, Coprococcus, Collinsella, Citrobacter, Turicibacter, Sutterella, Subdoligranulum, Sporobac ter, Sporacetigenium, Ruminococcus, Roseburia, Proteus, Propionobacterium, Leuconostoc, Weissella, Pediococcus, Prevotella, Parabacteroides, Papilibacter, Oscillospira, Melissococcus, Dorea, Dialister, Clo Examples include strains of probiotic bacteria derived from stridium, cedecea, catenibacterium, butyrivibrio, buttiauxella, bulleidia, bilophila, bacteroides, anaerovorax, anaerostopes, anaerofilum, enterobacteriaceae, fermicutes, atopobium, alistipes, acinetobacter, slackie, shigella, shewanella, serratia, mahara, lachnospira, klebsiella, idiomarina, fusobacterium, faecalibacterium, eubacterium, enterococcus, enterobacter, or egggerthella.

[0097] Suitable plant nutrients for use in this invention include carotenoids, polyphenols, or resveratrol. Suitable antioxidants for use in this invention include vitamin C, glutathione, caffeine, or tocopherol. Suitable vitamins for use in this invention include vitamins A, B, C, or D. Suitable minerals include iron, magnesium, calcium, zinc, copper, or sodium.

[0098] Specifically, the composition may include at least one additional activator for preventing and / or treating impaired glucose tolerance. This at least one additional activator for preventing and / or treating impaired glucose tolerance is different from OAS or its salts or derivatives.

[0099] According to one embodiment, the composition according to the present invention comprises O-acetylserine, or a salt or derivative thereof, at least one physiologically acceptable vehicle according to the present invention, and at least one additional activator for preventing and / or treating impaired glucose tolerance.

[0100] Specifically, the additional activator may be any antidiabetic molecule, and may be metformin in particular. Impaired glucose tolerance can be treated with α-glucosidase inhibitors (acarbose, voglibose), pancreatic lipase inhibitors (orlistat), or glinides (nateglinide) or incretin mimetic drugs (liraglutide).

[0101] Metformin (C4H 11 N5) is an oral antidiabetic drug belonging to the euglycemic biguanide family used to treat type 2 diabetes and is recommended for prediabetic patients at the highest risk of developing type 2 diabetes.

[0102] According to one embodiment, administration of OAS or its salts or derivatives in the same composition as metformin has an equivalent effect on the prevention and / or treatment of impaired glucose tolerance and / or diseases associated with impaired glucose tolerance compared to a composition containing metformin alone, while simultaneously allowing for a reduction in the amount of metformin in the composition.

[0103] 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.

[0104] According to another embodiment, the compositions of the present invention are not intended to be used to reduce and / or prevent excessive accumulation of body fat in infants or young children, and / or to prevent later-life health problems associated with excessive accumulation of body fat in infants or young children, such as later-life obesity and associated comorbidities.

[0105] Impaired glucose tolerance and related diseases As described above, the OAS according to the present invention, or its salts or derivatives, or compositions according to the present invention, are used in therapies for preventing and / or treating one or more diseases associated with impaired glucose tolerance in individuals.

[0106] The individual or patient according to the present invention may be a mammal. The mammals to which the present invention is intended may be selected from, for example, livestock (e.g., cattle, sheep, cats, dogs, and horses, especially cats and dogs), primates such as humans and non-human primates, and rodents such as rabbits, mice, and rats. According to one embodiment, the individual or patient to which the present invention is intended may be a human.

[0107] The OAS or its salts or derivatives, or compositions according to the present invention may be particularly suitable for use in therapeutic measures to prevent and / or treat prediabetes and / or diseases or disorders associated with prediabetes, or symptoms of prediabetes.

[0108] Impaired glucose tolerance or prediabetes may be asymptomatic. However, impaired glucose tolerance or prediabetes may be associated with obesity, dyslipidemia with high triglyceride and / or low HDL cholesterol levels, and hypertension. Impaired glucose tolerance and prediabetes are associated with an increased risk of cardiovascular disease. Prediabetes and impaired glucose tolerance are considered early stages of type 2 diabetes.

[0109] Impaired glucose tolerance or prediabetes can be diagnosed by various methods known to those skilled in the art. Specifically, impaired glucose tolerance in humans is based on two criteria: - Fasting blood glucose level, and - Blood glucose level 2 hours after oral ingestion of glucose Diagnosis is made based on the following criteria.

[0110] Therefore, impaired glucose tolerance can be diagnosed in the following cases: (i) fasting blood glucose levels are between 6.1 mmol / L and 6.9 mmol / L (110 mg / dL to 125 mg / dL), and (ii) blood glucose levels 2 hours after oral glucose intake of 75 g are between 7.8 mmol / L and 11.0 mmol / L (140 mg / dL to 199 mg / dL).

[0111] Blood glucose levels two hours after glucose intake are measured by an oral glucose tolerance test (OGTT). Such tests are 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).

[0112] Typically, type 2 diabetes can develop after impaired glucose tolerance or prediabetes. Type 2 diabetes (or T2DM) is a disease associated with impaired glucose tolerance or prediabetes.

[0113] According to one embodiment, OAS or its salts or derivatives, or compositions according to the present invention, may be particularly suitable for use in therapeutic measures for the prevention and / or treatment of type 2 diabetes.

[0114] T2DM can be diagnosed by various methods known to those skilled in the art. Specifically, the following criteria: - Fasting blood glucose level, - Blood glucose level 2 hours after oral ingestion of glucose, or - Postprandial blood glucose levels or random blood glucose levels - Glycated hemoglobin A1C (HbA1C) A diagnosis of T2DM can be made if one or more of the following conditions are met.

[0115] Therefore, T2DM is diagnosed if (i) fasting blood glucose levels are 7.0 mmol / L (126 mg / dL) or higher, or (ii) 2 hours after 75 g oral glucose intake is 11.1 mmol / L (200 mg / dL) or higher, or (iii) random plasma glucose levels are 11.1 mmol / L (200 mg / dL) or higher, or (iv) glycated hemoglobin A1c (HbA1c) is 48 mmol / mol (equivalent to 6.5%) or higher.

[0116] According to one embodiment, the present invention also relates to a therapeutic treatment method for preventing and / or treating impaired glucose tolerance and / or diseases associated with impaired glucose tolerance in an individual in need, the therapeutic treatment method comprising at least one step of administering to the individual OAS or a salt or derivative thereof according to the present invention, or administering to the individual a composition according to the present invention.

[0117] According to one embodiment, the present invention also relates to a therapeutic treatment method for preventing and / or treating prediabetes and / or prediabetes-related diseases in an individual in need, comprising at least one step of administering to the individual OAS or a salt or derivative thereof according to the present invention, or administering to the individual a composition according to the present invention.

[0118] According to one embodiment, the present invention also relates to a therapeutic treatment method for preventing and / or treating type 2 diabetes in an individual in need, comprising at least one step of administering to the individual an OAS or a salt or derivative thereof according to the present invention, or administering to the individual a composition according to the present invention.

[0119] The method according to the present invention may include a step of diagnosing impaired glucose tolerance, prediabetes, or type 2 diabetes prior to the step of administering the activator of the present invention. Such a diagnosis may be made by any diagnostic method known to those skilled in the art for this purpose, and in particular via one of the above methods.

[0120] The method according to the present invention may also include a step of observing a decrease, suppression, or improvement in symptoms or blood glucose markers of impaired glucose tolerance, prediabetes, or type 2 diabetes.

[0121] According to certain embodiments, the individual or patient for the present invention may be overweight or obese.

[0122] The use or method of the present invention may include administering the OAS, its salts or derivatives, or compositions according to the present invention to an individual or patient in need via any suitable route of administration. Examples include oral, sublingual, nasal, and rectal administration. Preferably, the administration of the OAS, its salts or derivatives, or compositions according to the present invention may be done orally.

[0123] According to one embodiment, the OAS or its salt or derivative, or the composition according to the present invention, may be administered at least once a day, specifically two or three times a day, or more specifically, at least once a day.

[0124] The OAS, its salts or derivatives, or compositions according to the present invention may be taken during meals or outside of meals. The OAS, its salts or derivatives, or compositions according to the present invention can be taken at any time over a 24-hour period. Specifically, the OAS, its salts or derivatives, or compositions according to the present invention may be taken in the morning, particularly with breakfast.

[0125] Specifically, the administration of OAS or its salts or derivatives, or compositions according to the present invention, may be carried out outside of meals, particularly once a day.

[0126] The duration for which OAS or its salts or derivatives, or compositions according to the present invention are administered depends on several factors, such as the patient's age, weight and sex, the presence of other pathological disorders, and diet, and is adapted by those skilled in the art in accordance with the usual practices of the art.

[0127] The appropriate period for administering OAS or its salt or derivative, or composition according to the present invention, may be at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, or at least 9 weeks.

[0128] During the administration period, the OAS or its salt or derivative, or the composition according to the present invention, may be administered daily on a continuous basis, or the administration may be carried out over a period of one day or more, followed by a break of one day or more, and then, if applicable, one or more cycles of administration and breaks.

[0129] According to certain embodiments, the OAS or its salt or derivative, or the composition, according to the present invention may be administered for a continuous period of one or two days, followed by a continuous interruption period of at least one or two days. The administration and interruption periods may constitute a cycle.

[0130] The administration of OAS or its salt or derivative, or composition according to the present invention, may be carried out at least once, and further two, three or more consecutive cycles.

[0131] Therefore, the OAS or its salt or derivative according to the present invention, or the composition, may be administered for at least two consecutive days at intervals of more than one week. According to one embodiment, the administration may be performed for at least five consecutive days at intervals of one week. The administration may be continued for two weeks, three weeks or more as described above.

[0132] According to one embodiment, the OAS or its salt or derivative, or the composition according to the present invention, may be administered in a therapeutically effective amount or dose. Specifically, the OAS or its salt or derivative, or the composition according to the present invention, may be administered in a daily dose corresponding to a dose ranging from at least about 70 mg / kg per day to at least about 2000 mg / kg per day. In particular, doses suitable for use in the present invention may range from at least about 100 mg / kg per day to at least about 1000 mg / kg per day, and especially from at least about 200 mg / kg per day to at least about 500 mg / kg per day.

[0133] In another aspect, the present invention also relates to the use of OAS or salts or derivatives thereof according to the present invention, or compositions thereof, for the manufacture of pharmaceuticals. Specifically, the present invention relates to the use of OAS or salts or derivatives thereof according to the present invention, or compositions thereof, for the manufacture of pharmaceuticals for the prevention and / or treatment of one or more diseases related to impaired glucose tolerance and / or impaired glucose tolerance.

[0134] Unless otherwise indicated, or unless it would be obvious to those skilled in the art that such a conflict or inconsistency would arise, it should be understood that the present invention encompasses all variations, combinations, and permutations of one or more limitations, elements, clauses, descriptive terms, etc., of one or more of the claims listed below, which may be introduced into other claims (or, as such, any other claims) that depend on the same basic claim. Where items are presented in list form (e.g., a Markush group or similar form), it should be understood that each subgroup of the item is also disclosed, and any item may be removed from such group. In general, where an aspect(s) of the present invention is specified as including certain elements, features, etc., it should be understood that a particular embodiment or aspect of the invention consists of, or essentially consists of, such elements, features, etc. For simplicity, these embodiments are not necessarily described in many words. It should also be understood that any embodiment or aspect of the present invention may be expressly excluded from the claims, regardless of whether certain exclusions are described in the specification. Publications and other documents cited to provide background to the present invention and additional details relating to its implementation are incorporated herein by reference.

[0135] The present invention is described in more detail with the help of the following embodiments, which are provided purely for illustrative purposes and are not intended to limit the invention.

[0136] The present invention is described in more detail with the help of the following embodiments, which are provided purely for illustrative purposes. Examples [Example 1]

[0137] Preventive effect of treatment based on the activator according to the present invention on healthy individuals Seven-week-old male C57BL / 6JRj mice obtained from JanvierLabs were fed a standard diet used in pet shops. A group of 10 mice that had not been treated with OAS was used as the control group. A second group of 10 mice was treated with OAS at a daily dose of 1000 mg / kg for 5 days. The OAS used was the product marketed by Sigma-Aldrich under the name A6262_SIGMA (CAS number 66638-22-0). This group was the OAS-treated group.

[0138] Oral glucose tolerance tests (OGTTs) were performed on each of the two groups of mice.

[0139] This study involves monitoring plasma glucose levels for 120 minutes after mice receive an oral glucose load. Specifically, at T0 (fasting blood glucose level), glucose (2.5 g / kg) is administered orally to the animals. A drop of blood is collected from the tail every 15 to 30 minutes for 90 minutes, and blood glucose levels are measured using a strip glucose meter (Accu-Check Perfoma, available at pharmacies).

[0140] The aforementioned oral glucose tolerance test (OGTT) was performed on day 5 of the treatment, 2 hours after the OAS-treated group received a dose of 500 mg / kg. At the time of the OGTT, the mice in the treatment group also received 500 mg / kg of OAS along with oral glucose loading. The control group received only an oral glucose load. Fasting blood glucose levels tended to be lower in the OAS-treated group, and blood glucose levels 15, 30, and 60 minutes after oral glucose loading were significantly lower in the OAS-treated group compared to the control group.

[0141] The results of this study show that on day 5 of the OAS treatment, fasting blood glucose levels were reduced in the treatment group, and oral glucose loading-induced hyperglycemia was significantly reduced (Figure 4).

[0142] This treatment significantly reduced hyperglycemia with a lower area under the curve than the control group (Figure 4), demonstrating the effect of O-acetylserine in regulating postprandial hyperglycemia, and therefore the preventive effect of the activator according to the present invention in the establishment of insulin resistance and / or prediabetes. [Example 2]

[0143] Preventive effect of a single dose of the activator according to the present invention on postprandial blood glucose in healthy individuals. Seven-week-old male C57BL / 6JRj mice obtained from JanvierLabs were fed a standard pet shop diet. The first group of five mice that were not treated with OAS was used as the control group. The second group of five mice was treated with a single dose of OAS at 1000 mg / kg. The OAS used was the product marketed by Sigma-Aldrich under the name A6262_SIGMA (CAS number 66638-22-0). This group was the OAS-treated group.

[0144] Oral glucose tolerance tests (OGTTs) were performed on two separate groups of mice.

[0145] This study involves monitoring plasma glucose levels for 120 minutes after mice receive an oral glucose load. Therefore, at T0 (fasting blood glucose level), glucose (2.5 g / kg) is administered orally to the animals. A single drop of blood is collected from the tail every 30 minutes for 120 minutes, and blood glucose levels are measured using a blood glucose meter with a test strip (Accu-Chek Performa, available at pharmacies).

[0146] In the OGTT trial, the OAS-treated group received a dose of 1000 mg / kg of OAS along 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-treated group compared to the control group.

[0147] The results of this study show that a single dose of OAS administered 15 minutes later significantly reduces hyperglycemia induced by oral glucose loading (Figure 5). This treatment significantly reduces hyperglycemia with a smaller area under the curve than the control group (Figure 5). A single dose of O-acetylserine can reduce postprandial hyperglycemia. Therefore, this demonstrates the preventive effect of a single dose of the activator according to the present invention in the establishment of insulin resistance and / or prediabetes. [Example 3]

[0148] Action of the activator according to the present invention on HFD individuals The effects of the activator according to the present invention were also tested in individuals that received an obesity-inducing diet. Seven-week-old male C57BL / 6JRj mice obtained from JanvierLabs were fed a high-fat diet (HFD, 45% fat, 20% sucrose) for 12 weeks. This diet is comparable to an obesity-inducing diet that promotes impaired glucose tolerance. The first group of 10 mice fed this diet were treated with a dose of 200 mg / kg of OAS per day, 5 days a week, for 12 weeks. The OAS used was the product marketed by Sigma-Aldrich as A6262_SIGMA (CAS number 66638-22-0). This group was the HFD+OAS group. The second group of nine mice, fed an HFD diet, received no OAS treatment. This was the HFD group. The last group of nine mice were used as a control group and received no specific diet or OAS treatment.

[0149] Mice fed an HFD diet showed significantly higher body weight gain (* p<0.05) and significantly increased epididymal fat accumulation (**** p<0.0001) after 12 weeks compared to mice not fed an HFD diet (control group). These features indicate the establishment of obesity in mice (Figure 1).

[0150] An oral glucose tolerance test (OGTT) was performed on each of the three groups of mice. This study involves monitoring plasma glucose levels for 120 minutes after mice have received an oral glucose load. Therefore, at T0 (fasting blood glucose), glucose (2 g / kg) is administered orally to the animals. For 120 minutes, one drop of blood is collected from the tail every 30 minutes, and blood glucose levels are measured using a blood glucose meter with a test strip (Accu-Chek Performa, available at pharmacies).

[0151] Glucose tolerance is a reflection of the body's ability to regulate the return to normal blood glucose levels after glucose loading.

[0152] The aforementioned OGTT was performed at weeks 5 and 9 after the initiation of the obesity-inducing diet. The results of this study showed that the group of mice fed the HFD diet developed impaired glucose tolerance as early as week 5. Treatment with OAS did not have a noticeable effect in the HFD+OAS group after week 5 (Figure 2). However, after week 9, this treatment significantly reduced impaired glucose tolerance, with an area under the curve similar to that of the control group (Figure 3).

[0153] In conclusion, treatment with O-acetylserine significantly improves diet-associated glucose intolerance associated with obesity, enabling the regulation of glucose metabolism in vivo.

Claims

1. A composition for use in the treatment and / or prevention of one or more diseases associated with impaired glucose tolerance in an individual, comprising O-acetylserine or a salt thereof, or N-acetylserine or a salt thereof, and a physiologically acceptable vehicle.

2. A composition for use according to Claim 1, wherein the disease related to impaired glucose tolerance is type 2 diabetes mellitus.

3. A composition for use according to claim 1 or 2, wherein the individual is obese.

4. A composition for use according to any one of claims 1 to 3, wherein O-acetylserine is a bacterial synthetic metabolite.

5. A composition for use according to claim 4, wherein O-acetylserine is a synthetic metabolite of bacteria of the intestinal microbiota.

6. A composition for use according to claim 4 or 5, wherein O-acetylserine is a synthetic metabolite of the bacterial strain Streptococcus salivarius.

7. A composition for use according to any one of claims 1 to 6, wherein the composition is an oral composition.

8. A composition for use according to claim 7, wherein the composition is in the form of a powder, granules, food product, beverage, pharmaceutical, nutritional supplement, food additive, wafer capsule or gel capsule.

9. A composition for use according to any one of claims 1 to 8, wherein the composition also includes an additional activator.

10. A composition for use according to claim 9, wherein the additional activator is selected from metabolites, antioxidants, fish oil, DHA, EPA, vitamins, minerals, phytonutrients, proteins, lipids, probiotics, additional activators, and combinations thereof, for preventing and / or treating impaired glucose tolerance.

Images