MX2007011610A - Amino acid composition for improving glucose tolerance - Google Patents

Abstract

Disclosed are compositions, including low-calorie beverages or liquids, comprising isoleucine, leucine, valine, cysteine, and methionine, in specified amounts, weight ratios, or both. The compositions are especially useful in treating individuals afflicted with impaired glucose tolerance or diabetes.

Description

COMPOSITION OF AMINO ACIDS TO IMPROVE TOLERANCE TO GLUCOSE Field of the Invention The present invention relates to compositions comprising mixtures of selected amino acids and methods of using the compositions in afflicted individuals with impaired glucose tolerance or diabetes. BACKGROUND OF THE INVENTION Diabetes mellitus is a disorder of carbohydrate metabolism that results from insufficient production of or reduced sensitivity to insulin. In people who have diabetes, the normal ability of the body's cells to use glucose is inhibited, thereby increasing blood sugar levels. Because more glucose builds up in the blood, excess sugar levels are excreted in the urine. Corresponding symptoms of diabetes include increased urinary volume and frequency, thirst, hunger, weight loss, and weakness. There are two variations of diabetes. Type 1 diabetes is insulin-dependent diabetes mellitus for which insulin administration is required. In a patient suffering from type 1 diabetes, insulin is not secreted by the pancreas and therefore must be taken by injection or inhalation. Type 2 diabetes can be controlled by dietary restriction, oral antihyperglycemic agents, and / or insulin administration. Type 2 diabetes can be attributed to delayed pancreatic secretion of insulin and reduced sensitivity to the action of insulin in specific tissues. Complications of diabetes often involve the cardiovascular system, which is consequently responsible for the majority of deaths related to diabetes. Other serious complications include diabetic retinopathy, kidney disease, peripheral neuropathy, and / or frequent infection. The treatment of individuals afflicted with diabetes who can not produce insulin in their bodies involves the administration of a regular injection or inhalation of insulin. Insulin derived from the pancreatic extract of pigs, sheep, and oxen can be used for this purpose, although many individuals now use synthetic human insulin manufactured via recombinant DNA technology. One method of treating diabetes involves regulating or limiting the intake of calories and carbohydrates by placing an individual afflicted with diabetes on a restrictive diet designed to facilitate reaching and maintaining a normal body weight. While effective in theory, limited intake of calories and carbohydrates is often difficult, often resulting in poor compliance on the part of the patient. Medications are also used in certain diabetic individuals to help maintain blood glucose levels within acceptable target ranges. These medications generally stimulate the release of insulin by the pancreas, thus improving the body's ability to use insulin, and / or decreasing glucose production by the liver. These medications, however, are limited in that each can have limiting side effects, none being appropriate for non-diabetic individuals, and various medications often lose their effectiveness in many individuals after their prolonged use. Brief Description of the Invention The present invention is directed to compositions and methods of using these compositions to treat afflicted individuals with impaired glucose tolerance or diabetes. This invention is based on the discovery that the administration of certain combinations of amino acids, in defined amounts and / or proportions of weight, results in an astonishingly strong glycemic response to a carbohydrate load. One aspect of the present invention includes compositions comprising isoleucine, leucine, valine, cysteine, and methionine, in weight ratios of isoleucine to leucine, of isoleucine to valine, of isoleucine to cysteine, and of isoleucine to methionine, independently of at least about 10: 1. Another aspect of the present invention includes compositions for use in treating afflicted individuals with impaired glucose tolerance or diabetes, wherein such compositions comprise from about 1 to about 200 mg / kg body weight of isoleucine.; from about 0.001 to about 10 mg / kg body weight of leucine; from about 0.001 to about 10 mg / kg of valine body weight; from about 0.001 to about 10 mg / kg of body weight of cysteine; and from about 0.001 to about 10 mg / kg of methionine body weight, and wherein the weight ratios of isoleucine to leucine, of isoleucine to valine, of isoleucine to cysteine, and of isoleucine to methionine are each independently of less approximately 10: 1. Another aspect of the present invention includes compositions for use in treating afflicted individuals with impaired glucose tolerance or diabetes, wherein such compositions comprise from about 10 to about 200 mg / kg body weight of isoleucine; from about 0.01 to about 10 mg / kg of body weight of leucine; from about 0.01 to about 10 mg / kg of body weight of valine; from about 0.01 to about 10 mg / kg of body weight of cysteine; and from about 0.01 to about 10 mg / kg of methionine body weight. Another aspect of the present invention includes low calorie beverages or other liquids comprising (A) about 2% to about 98% carbohydrates, as a percentage of total calories, including at least one of maltitol, erythritol, sorbitol, xylitol, mannitol, glycerol, isolmalt, and lactitol, and (b) from about 2% to about 98% of a protein source including any mixture of amino acids as described herein, such as those comprising isoleucine, leucine, valine, cysteine, and methionine, in weight proportions of isoleucine to leucine, of isoleucine to valine, of isoleucine to cysteine, and of isoleucine to methionine independently of at least about 10: 1. These drinks or liquids have improved taste and are especially useful in treating afflicted individuals with impaired glucose tolerance or diabetes. Another aspect of the present invention is directed to a method of treating afflicted individuals with impaired tolerance to glucose or diabetes, wherein the method comprises administering to such individuals an effective amount of the compositions described herein. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a graph illustrating the changes in blood glucose concentrations at some time in Fatty Zucker rats (model with impaired glucose tolerance) after oral administration of a control solution (FIG. glucose) or an amino acid test solution (with glucose) according to one aspect of the present invention. Figure 2 is a graph illustrating changes in blood glucose concentrations in Zucker Diabetic Fatty rats (model with type 2 diabetes mellitus) after oral administration of a control solution (glucose) in a certain time. isoleucine solution (with glucose), or an amino acid test solution (with glucose) according to one aspect of the present invention. Figure 3 is a graph illustrating changes in blood glucose concentrations in a certain time in Fatty Zucker rats (model with impaired glucose tolerance) after oral administration of a control solution (glucose) or a amino acid test solution (with glucose) according to one aspect of the present invention. Detailed Description of the Invention The corresponding compositions and methods of the present invention are directed to compositions containing selected mixtures of branched chain amino acids and amino acids with sulfur. These and other essential or optional elements or limitations of the compositions and methods of the present invention are described in detail below. The compositions and methods of the present invention may comprise, consist of, or consist essentially of the essential elements and limitations of the invention described herein., as well as of any additional or optional ingredients, components, or limitations described herein or otherwise useful in a food or pharmaceutical application. All percentages, parts and proportions in accordance with the attached usage, are by weight of the total composition, unless otherwise specified. All weights that belong to the mentioned ingredients are based on the active level and, therefore, do not include solvents or by-products that can be included in commercially available materials, unless otherwise specified. All numerical ranges according to the attached used, whether or not they are expressly preceded by the term "approximately", is intended and understood to be preceded by this term, unless otherwise specified. All references to the unique features or limitations of the present invention will include the corresponding plural feature or limitation, and vice versa, unless otherwise specified or clearly implied to the contrary by the context in which the reference is made. All the combinations of the method or stages of the process according to the attached use can be made in any order, unless otherwise specified or clearly implicated on the contrary by the context in which the aforementioned combination is made. The compositions and methods of the present invention may also be substantially free of any optional ingredient described herein. In this context, the term "substantially free" means that the composition selected contains less than a functional amount of the optional ingredient, including zero percent by weight of such optional ingredient.

Product Form The compositions of the present invention can be formulated in the known or otherwise convenient manner of the product for oral or parenteral administration. Oral forms of the product are preferred and include any solid, liquid, or powdered formulation suitable for use herein, provided that such formulation allows safe and effective oral delivery of the essential ingredients and other selected ingredients of the formulation. selected form of the product. Non-limiting examples of solid forms of the food product suitable for use herein include food substitute products and snacks, including those formulated as bars, sticks, biscuits or breads or cakes or other baked goods, frozen liquids, sweets, cereals of breakfast, granulated powders or solids or other particles, flakes or snack snacks, and frozen or pastry entries, and so on. Non-limiting examples of liquid product forms suitable for use herein include food substitutes and snacks, hot or cold beverages, carbonated or non-carbonated beverages, juice or other acidified beverages, milk or soy-based beverages , smoothies, coffees, teas, whole food compositions, and so on. These liquid compositions are more typically formulated as suspensions or emulsions, but may also be formulated in any other convenient form such as solutions, liquid gels, and so forth. Other non-limiting examples of convenient oral forms of the product include semi-solid or semi-liquid compositions (e.g., puddings, gels), as well as more conventional product form eg capsules, tablets, dragees, pills, and so forth. The amount of the composition for providing an effective amount of the defined mixture of the amino acid to the target user can be contained in one or a plurality of individual dosage forms, for example, in a tablet or a plurality of tablets. For product forms such as tablets, tablets (eg, chewable, coated, etc.), gums, or gels, the amino acid mixture can be formulated in concentrations ranging more generally from about 5 to about 50%, including from about 15 to about 33%, and also including about 15 about 25%, by weight of the product form, all in combination with excipients or other ingredients such as carbohydrates, acidulants, flavors, and colors. The carbohydrates in these product forms preferably contain unreduced sugar, whose concentrations may range from about 5 to 100% by weight of carbohydrates. Non-limiting examples of acidulants in these embodiments include citric acid, malic acid, tartaric acid, lactic acid, or combinations thereof, to improve salivation and provide a masking taste for the bitter or acidic signs of amino acids. Mixture of Amino Acids The compositions of the present invention comprise a select mixture of branched chain amino acids and amino acids with sulfur, which includes valine (VAL), leucine (LEU), and isoleucine (ILE), and where the latter includes cysteine ( CYS) and methionine (MET). The compositions of the present invention therefore include a mixture of amino acids of at least isoleucine, leucine, valine, cysteine, and methionine, the amount or sum of which must be sufficient to provide an effective treatment for at least one of Impaired tolerance to glucose or diabetes. In one embodiment of the present invention, the composition contains from about 1.0 to about 200 mg / kg body weight of isoleucine; from about 0.001 to about 10 mg / kg body weight of leucine; from about 0.001 to about 10 mg / kg valine body weight; from about 0.001 to about 10 mg / kg of body weight of cysteine; and from about 0.001 to about 10 mg / kg of body weight of methionine. Body weight refers to the body weight of the subject or patient object to whom the composition is administered. In another embodiment of the present invention, the composition contains from about 120 to about 180 mg / kg body weight of isoleucine; from about 0.25 to about 7.5 mg / kg body weight of leucine; from about 0.25 to about 7.5 mg / kg of body weight of valine; from about 0.25 to about 7.5 mg / kg of body weight of cysteine; and from about 0.2 to about 5 mg / kg of body weight of methionine. In another embodiment of the present invention, the composition contains from about 130 to about 170 mg / kg body weight of isoleucine; from about 0.5 to about 5 mg / kg of body weight of leucine; from about 0.5 to about 5 mg / kg of body weight of valine; from about 0.5 to about 5 mg / kg of body weight of cysteine; and from about 0.3 to about 3 mg / kg of body weight of methionine. The amount of amino acids for use in the selected blends can also be characterized as a weight ratio of amino acids with branched chain sulfur of at least about 10: 1, including at least about 50: 1, and also including at least of approximately 100: 1, and also including from 500: 1 to 10: 1. The amount of amino acids for use in the selected blends can also be characterized by other weight-defined proportions of the amino acids that ultimately contribute to the efficacy of treating at least one of the impaired glucose tolerance or diabetes. In one embodiment of the present invention, the composition has proportions by weight of isoleucine to leucine, of isoleucine to valine, of isoleucine to cysteine, and of isoleucine to methionine independently of at least about 10: 1. In another embodiment, the weight ratio of at least one (such as at least two of, at least three of, at least four of, and all of) of isoleucine to leucine, of isoleucine to valine, of isoleucine to cysteine, and from isoleucine to methionine, is at least about 50: 1, including at least about 100: 1 and also including from about 50: 1 to about 500: 1. The individual amino acids for use in the compositions and methods of the present invention can be derived from or provided by a known amino acid source or other conventional manner, including amino acid esters or acylated derivatives, amino acids salified with inorganic or organic bases. The esterified forms are often derived from branched or linear chain alcohols, while the solidified forms frequently include hydrochlorides, sulfates, acetates, glutamates, and so forth. The individual amino acids used in the amino acid mixtures of the present invention include chemically discrete amino acids that do not bind to any protein or other structure of the polypeptide. Although less preferred, amino acids can also be provided by a synthetic polypeptide that provides the required amount and / or weight proportions of the amino acids in the defined mixture. Although the compositions may further comprise natural or intact proteins, or even polypeptide fragments thereof, the amino acids in such proteins or segments are not considered in the determination of the indispensable selection of amino acids, including amounts and / or weight ratios, in the amino acid mixture according to that defined herein. The amino acids in the defined mixture may be in the L or R configuration, or a mixture thereof, although most of the amino acids for use in the formulation will generally be in the L configuration. The amino acids used herein are commercially available from A number of different material suppliers, including Sigma-Aldrich Corporation, with its workplace at 3050 Spruce Street, St. Louis, Missouri. When a composition of the present invention is in liquid form, more generally as an oral liquid or beverage, or after a powder form is reconstituted to form an oral liquid composition, the pH of the liquid composition is convenient for proper administration to a subject, for example by oral administration. In such a liquid embodiment, the composition has a pH of from about 2.5 to about 8.0, including from about 2.7 to about 7.0, and also including from about 3.0 to about 5.5, and also including from about 3.0 to about 5.0. The compositions of the present invention may further comprise one or more complementary amino acids, the non-limiting examples of which include aspartic acid (ASP), threonine (THR), serine (SER), glutamic acid (GLU), proline (PRO), glycine (GLY) ), alanine (ALA), tyrosine (TYR), histidine (HIS), lysine (LYS), arginine (ARG), methionine (MET), tryptophan (TRY), phenylalanine (PHE), and combinations thereof. The compositions may contain a sufficient amount of one or more (such as at least about 2 or more, and at least about 5 or more) complementary amino acids to contribute to providing a treatment for at least one of the impaired tolerance to the glucose and diabetes. In one embodiment of the present invention, the composition contains one or more of from about 0.01 to about 30 mg / kg (including from about 1 to about 30 mg / kg and also including from about 5 to about 20 mg / kg) of the body weight of each of the aspartic acid and glutamic acid; from about 0.001 to about 10 mg / kg (including from about 0.1 to about 10 mg / kg and also including from about 0.5 to about 5 mg / kg) of the body weight of each of threonine, serine, proline, histidine, and lysine; and from about 0.001 to about 20 mg / kg (including from about 0.1 to about 20 mg / kg and also including from about 1 to about 10 mg / kg) of the body weight of each of glycine, alanine, tyrosine, arginine, and triptofan. In some cases, the compositions of the present invention contain little or no phenylalanine. For example, the composition may contain less than about 10 mg / kg of the phenylalanine body weight or less than about 5% by weight. In another embodiment, the composition contains less than about 5 mg / kg of body weight of phenylalanine. In another embodiment, the composition contains zero or less than about 1 mg / kg of body weight of phenylalanine. Macronutrients The compositions of the present invention may further comprise one or more other macronutrients including a fat source, a carbohydrate source, and a protein source, all in addition to the amino acid mixture as defined herein. Optional macronutrients in combination with the other essential ingredients or aggregates can provide up to about 1000 kcal of energy per serving or dose, including from about 25 kcal to about 900 kcal, also including from about 75 kcal to about 700 kcal, also including from about 100 kcal to about 500 kcal, also including from about 150 kcal to about 400 kcal, and also including from about 200 kcal to about 300 kcal, per serving or dose, preferably as a single portion or dose, undivided. Many different sources and types of proteins, lipids, and carbohydrates are known and can be used in the various products described herein, provided that the selected nutrients are safe and effective for oral administration and are compatible with the essential ingredients and other aggregates Suitable carbohydrates for use in the compositions of the present invention may be simple, complex, or variations or combinations thereof. Non-limiting examples of suitable carbohydrates include hydrolyzed or modified starch or cornstarch, maltodextrin, glucose polymers, sucrose, corn syrup, corn syrup solids, rice-derived carbohydrates, glucose, fructose, lactose, high fructose corn syrup , indigestible oligosaccharides (eg, fructooligosaccharides), soluble or insoluble fiber, honey, sugar alcohols (e.g., maltitol, erythritol, sorbitol), and combinations thereof. Suitable proteins for use in the compositions of the present invention, in addition to the component of the amino acid mixture according to that described herein, include hydrolyzed, partially hydrolyzed or non-hydrolyzed proteins or protein sources, and can be derived from any known or otherwise convenient source such as milk (e.g., casein, whey), animal (e.g., meat, fish), cereal (e.g., rice, corn), vegetables (e.g., soy), or combinations thereof. Suitable fats for use in the compositions of the present invention include coconut oil, fractionated coconut oil, soybean oil, corn oil, olive oil, safflower oil, high oleic safflower oil, MCT oil (triglycerides medium chain), sunflower oil, high oleic sunflower oil, palm and palm kernel oils, palm olein, cañola oil, marine oils, cottonseed oils, and combinations thereof. The concentration or amount of fats, proteins, and carbohydrates in the compositions of the present invention can vary considerably depending on the particular form of the product (eg, solid, liquid, powder) and the other formulations and dietary needs to be achieved . These macronutrients are most generally formulated within any calorific range (A-D modalities) described in the table below.

* Each numerical value is preceded by the term "approximately" Other Optional Ingredients The compositions of the present invention may further comprise other optional components that may modify the physical, chemical, aesthetic or process characteristics of the products or serve as pharmaceutical or nutritional components. additional when they are used in the designated population. Many such optional ingredients are known or otherwise suitable for use in medical food or other nutritional products or pharmaceutical dosage forms and may also be used in the compositions herein, provided that such optional ingredients are safe for the oral administration and are compatible with the essential ingredients and others in the form of the selected product. Non-limiting examples of such optional ingredients include preservatives, antioxidants, emulsifying agents, buffers, pharmaceutical actives, additional nutrients as described herein, dyes, flavors, thickening agents and stabilizers, emulsifying agents, lubricants, and so on. . The compositions of the present invention may further comprise a sweetening agent, preferably including at least one sugar alcohol such as maltitol, erythritol, sorbitol, xylitol I, mannitol, isolmalt, and lactitol, and also preferably including at least an artificial sweetener or high potency such as acesulfame K, aspartame, sucralose, saccharin, stevia, and tagatose. These sweetening agents, especially as a combination of a sugar alcohol and an artificial sweetener, are especially useful in formulating liquid beverage embodiments of the present invention having a desirable flavor profile. These sweetener combinations are especially effective in masking undesirable flavors sometimes associated with the addition of amino acids to a liquid beverage. Optional sugar alcohol concentrations in the beverage may range from at least about 0.01%, including from 0.1% to about 10%, and also including from about 1% to about 6%, by weight of the beverage. Optional concentrations of the artificial sweetener may range from about 0.01%, including from about 0.05% to about 5%, also including from about 0.1% to about 1.0%, by weight of the beverage. The compositions of the present invention may further comprise any variety of other vitamins or related nutrients, of which non-limiting examples include vitamin A, vitamin D, vitamin E, vitamin K, thiamin, riboflavin, pyridoxine, vitamin B12, carotenoids (eg, beta) -carotene, zeaxanthin, lutein, lycopene), niacin, folic acid, pantothenic acid, biotin, vitamin C, choline, inositol, salts and derivatives thereof, and combinations thereof.

The compositions may further comprise any variety of other additional minerals, the non-limiting examples of which include calcium, phosphorus, magnesium, iron, zinc, manganese, copper, sodium, potassium, molybdenum, chromium, chloride, and combinations thereof. Low Calorie Drink or Liquid The compositions of the present invention include low calorie beverages or other liquids formulated to mask or otherwise minimize the undesirable taste associated with the amino acid mixtures described herein. These low calorie beverages or liquids include those embodiments comprising from about 2% to about 98% of a protein source, as a percentage of total calories, including any mixture of amino acids as described herein, such as those comprising: solucin, leucine, valine, cysteine, and methionine, in weight proportions from soleucine to leucine, from soleucine to valine, from soleucine to cysteine, and from soleucine to methionine regardless of at least about 10: 1; and from about 2% to about 98% carbohydrates, as a percentage of total calories, including at least one of maltitol, erythritol, sorbitol, x i I t or I, mannitol, glycerol, isolmalt, and lactitol; wherein the nutritional liquid has a pH of from about 2.5 to about 8.0, preferably from about 2.5 to 4.6, and a heat density from about 8.1 kcal / 100 ml to about 40 kcal / 100 ml, including from about 16 kcal / 100 ml to about 32 Kcal / 100ml. These low calorie beverages or liquids preferably include erythritol, which concentrations may range from about 0.1 to about 10%, including from about 1 to about 5%, and also including from about 1.5 to about 3%, all by weight of the beverage or liquid. These low calorie beverages or liquids preferably include at least one additional sweetening agent, some non-limiting examples of which include acesulfame K, aspartame, sucralose, saccharin, stevia, and tagatose. These low calorie beverages or liquids may further comprise any one or more of the other optional ingredients or others as described herein. Manufacturing The compositions of the present invention can be prepared by any known manufacturing technique or otherwise effective to prepare the selected product form. Many such techniques are known for any given form of the product such as nutritional liquids or nutritional bars and can be readily applied by one skilled in the art to the nutritional products described herein. The compositions of the present invention can be further prepared by the known manufacturing technique or otherwise effective to prepare the various forms of the pharmaceutical product. Many such techniques are known for any form of the given pharmaceutical product such as capsules, tablets, liquids, and so forth, and can be readily applied by one skilled in the art to the compositions described herein. As a basic liquid formulation, the compositions of the present invention can be prepared by dissolving each of the selected amino acids in water or diluted in an acidic solution, and then combining the various amino acid solutions to form a liquid embodiment of the present invention. As a basic solid formulation, the compositions of the present invention can be prepared by combining the various powder forms of the selected amino acids, together with any tabletting material or other excipients, and then drying the powder mixture before processing it into the form of the desired solid product, for example, tablet, capsule, pill, and so on. In yet another embodiment, the compositions of the present invention can be formulated as a nutritional liquid, including a juice or milk or a soy-based liquid, comprising the selected mixture of the amino acid. Such an embodiment can be prepared first by forming an oil and the fiber mixture containing all the oils of the formulation, any emulsifier, fiber and fat-soluble vitamins. Additional suspensions (usually a carbohydrate and two protein suspensions) are prepared separately by mixing the carbohydrate and the minerals together and the protein in water. The suspensions are then mixed together with the oil mixture. The resulting mixture is homogenized, processed with heat, standardized with any water-soluble vitamin, flavor is applied and the thermally sterilized or aseptic liquid is filled or dried to produce a powder. The other product that forms such nutritional bars can be manufactured, for example, using cold extrusion technology as is commonly known and described in the art of bar making. To prepare such compositions, generally all the pulverized components are mixed together dry, generally including the mixture of amino acids and of any protein, premixes of vitamin, certain carbohydrates, and so on. The fat-soluble components are then mixed together and mixed with any powdered premix. Finally, any liquid component is then mixed in the composition, forming a plastic or paste type composition. The resulting plastic mass can then be formed, without other physical or chemical changes that occur, by cold forming or extrusion, where the plastic mass is forced at a relatively low pressure through a die, which confers the desired shape. The resulting exudate is then cut at an appropriate position to give products of the desired weight. If desired, the solid product is then covered, to improve palatability, and packaged for distribution. The solid nutritional modalities of the present invention can also be manufactured through a hot baking or extrusion application to produce the solid forms of the product such as cereals, biscuits, wafers, and other similar product forms. An expert in the techniques of manufacturing nutrition can select one of the many known or otherwise available manufacturing processes to produce the desired final product. The compositions of the present invention can, of course, be manufactured by other known and convenient techniques described not specifically herein without departing from the spirit and scope of the present invention. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive and that all changes and equivalents are also within the description of the present invention. The following non-limiting examples will further illustrate the compositions and methods of the present invention. Method of use The compositions of the present invention can be used in individuals afflicted with or otherwise at risk of developing impaired glucose tolerance or diabetes. These compositions can also be administered, however, in any individual as a source of nutrition, especially in those where a strong glycemic response is desirable. The compositions and methods of the present invention can be directed to any individual, including humans and other mammals such dogs, cats, rodents, cows, sheep, pigs, goats, horses and other animals with legs, and so on. Healthy individuals at risk for type 2 diabetes can be given the compositions as well. The compositions of the present invention can be administered before, during, or after the intake of carbohydrates (such as a meal, beverage, or snack) to improve glucose tolerance and reduce the glycemic response. In a modality, the administration of the amino acid composition is conducted in approximately one hour of carbohydrate consumption by the subject. In another embodiment, the administration of the amino acid composition is conducted in about 30 minutes of carbohydrate consumption by the subject. The compositions of the subject invention can be used to treat glucose tolerance, diabetes, obesity, and / or symptoms and side effects of glucose tolerance, diabetes, and obesity. Specifically, the compositions can be used to treat type 1 diabetes, type 2 diabetes and / or symptoms thereof. Symptoms and side effects of diabetes include one or more of high blood glucose levels, sleep habits such as insomnia, general energy level such as lethargy, strength, increased or poor body weight / appetite, reflux, irregularity, stomach neuropathy, kidney failure, heart disease, seizures, and impaired vision. In one aspect of the invention, administration of the compositions of the subject invention to a subject in need thereof, after, during, or prior to the ingestion of carbohydrates, lowers blood glucose levels compared to ingestion of carbohydrates without the administration of the compositions of the subject invention. Blood glucose levels can be determined using whole blood, blood plasma or blood serum. Unless otherwise indicated, blood glucose levels refer to the analysis of whole blood. Administration of amino acid compositions decreases blood glucose levels after carbohydrate ingestion (compared to blood glucose levels after ingestion of carbohydrates without administration of amino acid compositions) in at least one approximately 30 minutes after carbohydrate intake, approximately 60 minutes after carbohydrate intake, approximately 90 minutes after carbohydrate intake, and approximately 120 minutes after carbohydrate ingestion. In another aspect of the invention, administration of the compositions of the present invention to an individual before, during, or after the ingestion of carbohydrates, lowers blood glucose levels compared to the same intake of carbohydrates without the administration of carbohydrates. the compositions of the present invention, in at least about 5% in at least one of about 30 minutes after the ingestion of carbohydrates, of about 60 minutes after the ingestion of carbohydrates, of about 90 minutes after the ingestion of carbohydrates, and approximately 120 minutes after ingestion of carbohydrates. In another aspect of the invention, administration of the compositions of the present invention to a subject before, during, or after the ingestion of carbohydrates, lowers the blood glucose level compared to the same intake of carbohydrates without administration of carbohydrates. the compositions of the subject invention in at least about 10% in at least one of about 30 minutes after the ingestion of carbohydrates, about 60 minutes after the ingestion of carbohydrates, of about 90 minutes after the ingestion of carbohydrates , and approximately 120 minutes after the ingestion of carbohydrates. In yet another aspect of the invention, administration of the subject compositions to a subject prior to, during, or after the ingestion of carbohydrates, lowers blood glucose levels compared to the same carbohydrate intake without administration. of the compositions of the subject invention in at least about 20% in at least one of about 30 minutes after the ingestion of carbohydrates, of about 60 minutes after the ingestion of carbohydrates., approximately 90 minutes after the ingestion of carbohydrates, and approximately 120 minutes after the ingestion of carbohydrates.

EXAMPLES The following examples illustrate the specific embodiments of the compositions and methods of the present invention, including some convenient techniques for preparing the compositions. The examples are given only for the purpose of illustration and should not be construed as limitations of the present invention, as many variations thereof are possible without departing from the spirit and scope of the invention.

Examples 1-3 The examples 1-3 illustrate the liquid nutritional modalities of the present invention. Corresponding methods of using the compositions according to the methods of the present invention are also included. The ingredients for each exemplified composition are described in the following table. All ingredient quantities are listed as kilogram per batch of 1000 kilograms of the product, unless otherwise specified.

Low calorie drink * * Total calories: 72,432 kcal / 11 ounces (23 kcal / 100 mi) Each of the exemplified embodiments of the present invention in accordance with the aforementioned table, can be prepared, for example, according to the processing instructions and the following batch process. The amino acid mixture is prepared by conventional methods such as powder comprising each of the identified amino acids. The amino acid powder is added slowly, with stirring, to a boiler containing the specified amount of water. Once the amino acids are completely dispersed, the pH of the solution is reduced to 2.4 using an 80% phosphoric acid solution, and then increased to 3.2 using a 45% KOH solution. To the pH-adjusted mixture, the specified amounts of the premixed flavor mixture, citric acid, erythritol, powdered maltitol, 10% Acesulfame potassium solution, and liquid sucralose are added and allowed to mix thoroughly. The resulting mixture is then subjected to minimal homogenization pressure, processed to UHT (ultra high temperature) at 104 ° C for 5 seconds, and then filled warm aseptically in suitable containers at a temperature of 88-99 ° C. The pH of the final product is approximately 3.2. Each exemplified beverage has proportions by weight of isoleucine to leucine, isoleucine to valine, of isoleucine to cysteine, and of isoleucine to methionine, of at least about 10: 1. Each of the exemplified drinks is used to treat afflicted individuals with impaired tolerance to glucose. Each is administered, within one hour of the carbohydrate meal or other carbohydrate challenge, to such individuals to the extent necessary to provide 1-200 mg / kg body weight of isoleucine; 0.001-10 mg / kg body weight of leucine; 0.001-10 mg / kg body weight of valine; 0.001-10 mg / kg body weight of cysteine; and 0.001-10 mg / kg of the body weight of methionine. The blood glucose levels in these individuals who follow the carbohydrate meal or other carbohydrate challenge are reduced with respect to blood glucose levels without the administration of the beverage to at least 5-10% at less one approximately 30 minutes after the ingestion of carbohydrates, approximately 60 minutes after the ingestion of carbohydrates, approximately 90 minutes after the ingestion of carbohydrates, and approximately 120 minutes after the ingestion of carbohydrates.

Examples 4-6 Examples 4-6 illustrate some of the possible embodiments of the tablet of the present invention. Corresponding methods of using the tablets according to the methods of the present invention are also included. The tablets are made by methods well known in the techniques of the formulation.

* Amino Acid Mixture of Example 1 Each exemplified tablet has proportions by weight of isoleucine to leucine, of isoleucine to valine, of isoleucine to cysteine, and of isoleucine to methionine, of at least about 10: 1.

Each of the exemplified tablets is used to treat afflicted individuals with impaired tolerance to glucose. Each is administered, as single or multiple tablets, within one hour of the meal with carbohydrates or another carbohydrate challenge, to such individuals to the extent necessary to provide 1-200 mg / kg of body weight of isoleucine; 0.001-10 mg / kg body weight of leucine; 0.001-10 mg / kg body weight of valine; 0.001-10 mg / kg body weight of cysteine; and 0.001-10 mg / kg body weight of methionine. A typical dose is 25 tablets daily, taken orally in divided doses. These tablets can be swallowed whole or chewed, but are generally more chewed. The blood glucose levels in these individuals who follow the carbohydrate meal or other carbohydrate challenge are reduced with respect to blood glucose levels without the administration of the beverage to at least 5-10% at less one approximately 30 minutes after the ingestion of carbohydrates, approximately 60 minutes after the ingestion of carbohydrates, approximately 90 minutes after the ingestion of carbohydrates, and approximately 120 minutes after the ingestion of carbohydrates.

EXPERIMENT The following experiments are directed to the compositions of the present invention, and include the administration of these compositions to rats with impaired glucose tolerance (Fatty Zucker rats) or to rats with type 2 diabetes mellitus (Zucker Diabetic Fatty rats) and the evaluation Subsequent response to blood glucose in each animal.

Experiment 1 A formula and amino acid test control were prepared. The control is a 22.5% glucose solution. The amino acid test formula is prepared by weighing and dissolving each of the following amino acids in separate tubes: ASP (66.55 mg) is dissolved in 1.0 ml of 1N HCL; THR (7.21 mg) is dissolved in 1.0 ml of water; SER (7.97 mg) is dissolved in 1.0 ml of water; GLU (102.3 mg) is dissolved in 1.0 ml of 1N HCL; PRO (8.6 mg) is dissolved in 1.0 ml of water; GLY (29.15 mg) is dissolved in 1.0 ml of 1N HCL; ALA (33.27 mg) is dissolved in 1.0 ml of water; CYS (5.28 mg) is dissolved in 1.0 ml of 1N HCL; dissolves (6.68 mg) in 1.0 ml of water; MET (3.36 mg) is dissolved in 1.0 ml of water; I LE (7.34 mg) is dissolved in 1.0 ml of 1N HCL; LEU (6.58 mg) is dissolved in 1.0 ml of 1N HCL; TRY (33.55 mg) is dissolved in 1.0 ml of 1N HCL; PHE (20.8 mg) is dissolved in 1.0 ml of 1N HCL; HIS (6.9 mg) is dissolved in 1.0 ml of 1N HCL; LYS (11.8 mg) is dissolved in 1.0 ml of water; ARG (34.38 mg) is dissolved in 1.0 ml of water; TRP (9.46 mg) is dissolved in 1.0 ml of 1 N HCL. Each amino acid additive is contained within its own individual tube and mixed inside that tube until a clear solution is formed. Among the various amino acid solutions formed, those dissolved with HCL are then combined in a 50 ml beaker, after which 937.5 mg of ILE is added to the beaker and mixed until dissolved. Once the ILE is dissolved, all solutions of amino acids dissolved once in water are then added to the beaker, followed by 25 ml of a 45% glucose solution. The resulting glucose-containing mixture is stirred until thoroughly mixed, the pH of which is then adjusted to 7.0 +/- 1.0 with a 50% sodium hydroxide solution (a buffer can be added to stabilize the pH). The pH-adjusted mixture is transferred to a 50 ml volumetric flask and brought to volume with distilled water. The mixture is transferred to a vessel with a stir bar and stirring is continued while the syringes are filled. Fatty Zucker rats are received at the animal facility at least a week before testing. Each is weighed the day before the experiment and then assigned to one of two groups matched in body weight. Only rats weighing at least 300 gm are included in the study. After an overnight fast, each rat is weighed again and then dosed at 8ml / kg body weight (oral forced feeding) with the control or amino acid test solution. Blood glucose concentrations are then measured from the tail end of each animal at 30, 60, 90 and 120 minutes following forced feeding. The data from this experiment is summarized in Figure 1, which shows that the amino acid test mixture, when administered to rats, significantly reduces blood glucose concentrations relative to control within 60 minutes of feeding forced Experiment 2 The control formula (22.5% glucose solution) and the amino acid test formula described in experiment 1 are prepared and used later in this second experiment, together with a mixture of isoleucine according to what is described below.

In this second experiment, a high dose isoleucine mixture is prepared by adding L-isoleucine (1338.7 g) to a 50 ml beaker followed by 10 ml of 1N HCL. The contents of the beaker are mixed until dissolved, and then 25 ml of a 45% glucose solution is added with stirring. The pH of the resulting mixture is adjusted to 7.0 (+/- 1.0) with a 50% sodium hydroxide solution (a buffer can be added to stabilize the pH). The pH-adjusted mixture is transferred to a 50ml volumetric vessel and brought to volume with distilled water. The mixture is transferred to a stirring vessel and stirred continuously while the syringes are filled. Zucker Diabetic Fatty rats, a model of type 2 diabetes, are received at the animal facility at least one week before the test. Each is weighed the day before the experiment and then assigned to one of two matched groups in body weight. After an overnight fast, each rat is weighed and then dosed 8ml / kg body weight (oral forced feeding) with the glucose control, the amino acid test mixture, or isoleucine solution. Blood glucose concentrations are then measured from the tail end of each animal in 30, 60, 90 and 120 minutes after forced feeding. The data from this experiment are summarized in Figure 2. As shown in the illustrated data, the high dose isoleucine (isoleucine only) does not significantly affect blood glucose concentrations relative to the control, whereas the Amino acid test mix significantly decreases blood glucose concentrations relative to control within 60 minutes of forced feeding.

Experiment 3 To determine the minimum amino acid solution necessary to improve glycemia, a mixture of amino acids is prepared as follows (weigh each amino acid and place it in its own individual tube): CYS (5.28 mg) is dissolved in 1.0 ml of 1N HCL; VAL (6.68 mg) was dissolved in 1.0 ml of water; MET (3.36 mg) is dissolved in 1.0 ml of water; and LEU (6.58 mg) is dissolved in 1.0 ml of 1N HCL. Each tube is mixed until a clear solution is obtained. In a 50 ml beaker, ILE (927.5 mg) is dissolved in 10 ml of HCL. All acidic tubes dissolved in acid are added to the 50 ml beaker (use a pipette to transfer) and shaken. All amino acids dissolved once in water are then added to the beaker (transfer via the pipette), followed by 25 ml of 45% glucose solution. The resulting mixture is stirred until thoroughly mixed. The pH of the mixture is adjusted to about 7 with a 50% sodium hydroxide solution. A buffer can be added to stabilize the pH. The mixture is then transferred to a 50 ml volumetric flask and brought to volume with distilled water. The resulting mixture is compared to a control solution of 22.5% glucose in the following experiment.

Fatty Zucker rats are received at the animal facility at least one week before the test. Each is weighed the day before the experiment, and then assigned to one of two groups matched in body weight. Only rats weighing at least 300 gm are included in the study. After an overnight fast, the rats are weighed and dosed at 8ml / kg body weight (oral forced feeding) with the control or amino acid test mixture. Blood glucose concentrations are then measured from the tail end of each animal in 30, 60, 90 and 120 minutes from the tip of the tail.

The data from this experiment are summarized in Figure 3, which shows that the amino acid test mixture (combination of five amino acids) significantly decreases the concentration of glucose in the blood in relation to the control within 60 minutes after feeding forced

Claims (38)

1. A composition for treating individuals afflicted with diabetes or impaired glucose tolerance, comprising: from about 1 to about 200 mg / kg body weight of isoleucine; from about 0.001 to about 10 mg / kg body weight of leucine; from about 0.001 to about 10 mg / kg of valine body weight; from about 0.001 to about 10 mg / kg of body weight of cysteine; and from about 0.001 to about 10 mg / kg of methionine body weight, wherein the weight ratios of isoleucine to leucine, of isoleucine to valine, of isoleucine to cysteine, and of isoleucine to methionine are independently at least about 10. :1. The composition of claim 1, further comprising at least one of: from about 0.01 to about 30 mg / kg of the body weight of aspartic acid; from about 0.001 to about 10 mg / kg of threonine body weight; from about 0.001 to about 10 mg / kg of the body weight of serine; from about 0.01 to about 30 mg / kg of the body weight of glutamic acid; from about 0.001 to about 10 mg / kg of proline body weight; from about 0.001 to about 20 mg / kg of glycine body weight; from about 0.001 to about 20 mg / kg of the body weight of alanine; from about 0.001 to about 20 mg / kg of tyrosine body weight; from about 0.001 to about 10 mg / kg of histidine body weight; from about 0.001 to about 10 mg / kg of the body weight of lysine; from about 0.001 to about 20 mg / kg of the body weight of arginine; and from about 0.001 to about 20 mg / kg of body weight of tryptophan. The composition of claim 1, wherein the weight ratio of at least one of isoleucine to leucine, of isoleucine to valine, of isoleucine to cysteine, and of isoleucine to methionine is at least about 100: 1. 4. The composition of claim 1, comprising less than about 10 mg / kg of the phenylalanine body weight. The composition of claim 1, further comprising at least one of vitamins, minerals, carbohydrates, and fats. The composition of claim 5 comprising, as a percentage of total calories, about 10% to about 75% carbohydrates, about 20% to about 85% fat, and about 5% to about 70% proteins . The composition of claim 1, wherein the composition is an oral tablet. The composition of claim 1, wherein the composition is an oral liquid. 9. A composition for treating individuals afflicted with diabetes or impaired glucose tolerance, comprising isoleucine, leucine, valine, cysteine, and methionine; the composition has proportions by weight of isoleucine to leucine, of isoleucine to valine, of isoleucine to cysteine, and isoleucine to methionine independently of at least about 10: 1. The composition of claim 9, wherein the weight proportions of isoleucine to leucine, isoleucine to valine, isoleucine to cysteine, and isoleucine to methionine are independently at least about 100: 1. The composition of claim 9, which has proportions by weight of branched chain amino acids to the sulfur-containing amino acids of at least about 50: 1. The composition of claim 9, which comprises less than about 5% by weight of phenylalanine. The composition of claim 9, further comprising at least one of vitamins, minerals, carbohydrates, and fats. The composition of claim 13, which comprises, as a percentage of total calories, from about 10% to about 75% carbohydrates, from about 20% to about 85% of fats, and from about 5% to about 70% of protein. 15. The composition of claim 9, wherein the composition is an oral tablet. 16. The composition of claim 9, wherein the composition is an oral liquid. 17. A composition for treating individuals afflicted with diabetes or impaired glucose tolerance, comprising: from about 10 to about 200 mg / kg of the body weight of isoleucine; from about 0.01 to about 10 mg / kg of leucine body weight; from about 0.01 to about 10 mg / kg of valine body weight; from about 0.01 to about 10 mg / kg of the body weight of cysteine; and from about 0.01 to about 10 mg / kg of the body weight of methionine. The composition of claim 17, wherein the weight proportions of isoleucine to leucine, isoleucine to valine, isoleucine to cysteine, and isoleucine to methionine are independently at least about 10: 1. The composition of claim 17, wherein the weight proportions of at least one of isoleucine to leucine, of isoleucine to valine, of isoleucine to cysteine, and of isoleucine to methionine are at least about 100: 1. The composition of claim 17, which comprises less than about 10 mg / kg of the body weight of phenylalanine. The composition of claim 17, further comprising at least one of vitamins, minerals, carbohydrates, and fats. The composition of claim 17, which comprises, as a percentage of total calories, from about 10% to about 75% carbohydrates, from about 20% to about 85% fat, and from about 5% to about 70% of proteins 23. The composition of claim 17, wherein the composition is an oral tablet. The composition of claim 17, wherein the composition is an oral liquid. 25. A method for treating afflicted individuals with impaired glucose tolerance or diabetes, the method comprising administering to the individual an effective amount of a composition comprising from about 1.0 to about 200 mg / kg of the body weight of isoleucine, from about 0.001 to about 10 mg / kg of leucine body weight, from about 0.001 to about 10 mg / kg of valine body weight, from about 0.001 to about 10 mg / kg of body weight of cysteine, and from about 0.001 to about 10 mg / kg of body weight of methionine. 26. The method of claim 25, wherein the composition is administered orally. The method of claim 25, wherein the composition is administered in about one hour of carbohydrate ingestion by the individual. The method of claim 27, wherein administering the composition to a subject decreases blood glucose levels compared to blood glucose levels without administration of the composition by at least about 5% in at least one approximately 30 minutes after the ingestion of carbohydrates, approximately 60 minutes after the ingestion of carbohydrates, approximately 90 minutes after the ingestion of carbohydrates, and approximately 120 minutes after the ingestion of carbohydrates. 29. The method of claim 27, wherein administering the composition to a subject decreases blood glucose levels compared to blood glucose levels without administration of the composition by at least about 10% in the blood. approximately 60 minutes after the ingestion of carbohydrates. The method of claim 27, wherein the composition has weight proportions of isoleucine to leucine, isoleucine to valine, isoleucine to cysteine, and isoleucine to methionine independently of at least about 10: 1. 31. A nutritional liquid, comprising (A) from about 2% to about 98% of a protein source, as a percentage of total calories, including a mixture of amino acids comprising isoleucine, leucine, valine, cysteine, and methionine, in weight proportions of isoleucine to leucine, of isoleucine to valine, of isoleucine to cysteine, and of isoleucine to methionine independently of at least about 10: 1; and (B) from about 2% to about 98% carbohydrates, as a percentage of total calories, including at least one of maltitol, erythritol, sorbitol, xylitol, mannitol, glycerol, isolmalt, and lactitol; wherein the nutritional liquid has a pH of about 2.5 to about 8.0 and a heat density of about 8.1 kcal / 100 ml to about 40 kcal / 100 ml. 3

2. The nutritional liquid of claim 31, wherein the pH ranges from about 2.5 to about 4.6. 3

3. The nutritional liquid of claim 31, wherein the heat density ranges from about 16 kcal / 100 ml to about 32 kcal / 100 ml. 3

4. The nutritional liquid of claim 31, further comprising at least one of fats, minerals, and vitamins. 3

5. The nutritional liquid of claim 34, wherein the liquid comprises, as a percentage of total calories, from about 10% to about 75% carbohydrates, from about 20% to about 85% fat, and about 5% to approximately 70% of the protein source including the amino acid mixture. 3

6. The nutritional liquid of claim 31, wherein the liquid further comprises at least one of acesulfame K, aspartame, sucralose, saccharin, stevia, and tagatose. 3

7. The nutritional liquid of claim 31, wherein the liquid comprises erythritol. 3

8. The nutritional liquid of claim 37, wherein the liquid comprises from about 1% to about 10% by weight of erythritol.