WO2012047800A1 - Procédés pour augmenter l'absorption de glucose par le muscle et réduire le temps de récupération du muscle employant un mélange d'acides aminés - Google Patents

Procédés pour augmenter l'absorption de glucose par le muscle et réduire le temps de récupération du muscle employant un mélange d'acides aminés Download PDF

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Publication number
WO2012047800A1
WO2012047800A1 PCT/US2011/054592 US2011054592W WO2012047800A1 WO 2012047800 A1 WO2012047800 A1 WO 2012047800A1 US 2011054592 W US2011054592 W US 2011054592W WO 2012047800 A1 WO2012047800 A1 WO 2012047800A1
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body weight
amino acid
muscle
individual
acid blend
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PCT/US2011/054592
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English (en)
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John L. Ivy
Neile K. Edens
Jeffrey L. Nelson
Lisa Ann Reaves
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Abbott Laboratories
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/142—Amino acids; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/175—Amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the present disclosure relates to methods for increasing muscle glucose uptake and decreasing muscle recovery time by administration of a composition comprising select amino acid blends.
  • Glucose uptake and transport into muscle cells may also be particularly important for the pre-diabetic and diabetic population, as it is well known that a decrease in muscle glucose uptake is one of the early symptoms of diabetes.
  • pre-diabetics and diabetics can more easily maintain a steady level of blood glucose and avoid unwanted glucose spikes.
  • the rate of glucose uptake into muscle cells has been primarily enhanced by the use of exogenous insulin, physical exertion and exercise, and/or carbohydrate loading. Although one or a combination of these options may result in an increase uptake of glucose into muscle cells and the resulting benefits, they may not be suitable for all adults. For example, hypoglycemic episodes may be associated with insulin use in some adults. Additionally, not all adults have the physical ability to perform exercise, nor the physical ability to ingest a large number of carbohydrate calories.
  • compositions and methods for easily and effectively increasing the uptake of glucose into muscle tissue and reduce muscle recovery time. Additionally, it would be very beneficial if the compositions and methods could be utilized by a wide variety of adults, irrespective of overall health condition and physical ability.
  • the present disclosure is directed to methods of increasing muscle glucose uptake and improving muscle glucose metabolism by administering a composition including a specific amino acid blend comprising isoleucine, leucine, valine, methionine, and cysteine.
  • a composition including a specific amino acid blend comprising isoleucine, leucine, valine, methionine, and cysteine.
  • the specific amino acid blend is utilized to increase the muscle recovery rate of an individual.
  • the present disclosure is specifically directed to a method of increasing glucose uptake in a muscle cell of an individual.
  • the method comprises administering to the individual a composition comprising an amino acid blend comprising isoleucine, leucine, valine, methionine, and cysteine in a molar ratio of about 97.65 :about 0.68:about 0.77:about 0.31 :about 0.59, respectively.
  • the present disclosure is further directed to a method of increasing the muscle recovery rate of an individual.
  • the method comprises administering to the individual a composition comprising an amino acid blend comprising isoleucine, leucine, valine, methionine, and cysteine in a molar ratio of about 97.65 :about 0.68:about
  • the present disclosure is further directed to a method of increasing the muscle glucose metabolism rate of an individual.
  • the method comprises administering to the individual a composition comprising an amino acid blend comprising isoleucine, leucine, valine, methionine, and cysteine in a molar ratio of about 97.65 :about 0.68:about 0.77:about 0.31 :about 0.59, respectively.
  • the present disclosure is further directed to a method of managing or treating diabetes or prediabetes in an individual.
  • the method comprises administering to the individual a composition comprising an amino acid blend comprising isoleucine, leucine, valine, methionine, and cysteine in a molar ratio of about 97.65 :about 0.68:about 0.77:about 0.31 :about 0.59, respectively.
  • the present disclosure is further directed to a method of managing or treating insulin resistance in an individual.
  • the method comprises administering to the individual a composition comprising an amino acid blend comprising isoleucine, leucine, valine, methionine, and cysteine in a molar ratio of about 97.65 :about 0.68:about
  • the present disclosure is further directed to a method of preventing or treating skeletal muscle loss in an individual.
  • the method comprises administering to the individual a composition comprising an amino acid blend comprising isoleucine, leucine, valine, methionine, and cysteine in a molar ratio of about 97.65 :about 0.68:about
  • the present disclosure is further directed to a method of increasing glucose uptake in a muscle cell of a diabetic athlete.
  • the method comprises administering to the individual a composition comprising an amino acid blend comprising isoleucine, leucine, valine, methionine, and cysteine in a molar ratio of about 97.65 :about 0.68:about 0.77:about 0.31 :about 0.59, respectively.
  • the glucose uptake, and hence the glucose metabolism rate, in muscle cells can be increased such that the time period for muscle recovery after a trauma or physical activity, such as after a workout, is reduced.
  • the specific amino acid blend increases glucose transport into muscle cells and reduces or eliminates that need for other means of increasing glucose transport into muscle cells, such as insulin use or ingestion of large amounts of
  • the specific amino acid blend is particularly useful for prediabetics and diabetics as they typically experience a significant decrease in muscle glucose metabolism as diabetes progresses.
  • these individuals can increase muscle glucose uptake, which allows them to control their blood glucose level without solely relying on insulin or methodologies that can interfere with digestion.
  • Figure 1 is a graph showing the glucose uptake in red and white gastrocnemius muscles from Sprague-Dawley rats during an oral glucose tolerance test.
  • Figure 2 is a graph showing the glucose uptake in red gastrocnemius muscles from Zucker obese rats during an oral glucose tolerance test.
  • Figure 3 is a graph showing the glucose uptake in the soleus muscle from Zucker obese rats during an oral glucose tolerance test.
  • Figure 4 is a graph showing the glucose uptake in response to the treatment of epitrochlearis muscles from rats with different doses of a specific amino acid blend.
  • Figure 5 is a graph showing the C2C12 myotubular glucose transport in response to treatment with various amino acid blends.
  • compositions and methods of the present disclosure are directed to specific blends of amino acids including isoleucine, leucine, valine, methionine, and cysteine for increasing the rate of muscle glucose uptake and metabolism.
  • the term "healthy individual” as used herein refers to a person who is in generally good health, and is not obese, a prediabetic or diabetic.
  • diabetes athlete refers to an athlete who is diabetic, prediabetic, or suffers from impaired glucose tolerance.
  • compositions of the present disclosure may also be substantially free of any optional or selected essential ingredient or feature described herein, provided that the remaining composition still contains all of the required ingredients or features as described herein.
  • substantially free means that the selected composition contains less than a functional amount of the optional ingredient, typically less than 0.1% by weight, and also including zero percent by weight of such optional or selected essential ingredient.
  • compositions and corresponding methods of the present disclosure can comprise, consist of, or consist essentially of the essential elements and limitations of the disclosure as described herein, as well as any additional or optional ingredients, components, or limitations described herein or otherwise useful in the compositions or methods.
  • compositions including the specific amino acid blends useful in the methods of the present disclosure may be formulated in any known or otherwise suitable product form for oral or parenteral administration.
  • Oral product forms are generally preferred and include any solid, liquid, or powder formulation suitable for use herein, provided that such a formulation allows for safe and effective oral delivery of the essential and other selected ingredients from the selected product form.
  • Non-limiting examples of solid nutritional product forms suitable for use herein include snack and meal replacement products, including those formulated as bars, sticks, cookies or breads or cakes or other baked goods, frozen liquids, candy, breakfast cereals, powders or granulated solids or other particulates, snack chips or bites, frozen or retorted entrees and so forth.
  • liquid product forms suitable for use herein include snack and meal replacement products, hot or cold beverages, carbonated or non carbonated beverages, juices or other acidified beverages, milk or soy-based beverages, shakes, coffees, teas, enteral feeding compositions, and so forth.
  • compositions are most typically formulated as suspensions or emulsions, but can also be formulated in any other suitable forms such as clear liquids, solutions, liquid gels, and so forth.
  • suitable oral product forms include semisolid or semi-liquid compositions (e.g., puddings, gels), as well as more conventional product forms such as capsules, tablets, caplets, pills, and so forth.
  • the quantity of the composition for providing an effective amount of the defined amino acid blend to the targeted user may be contained in one or a plurality of individual dosage forms, e.g., in one tablet or a plurality of tablets that may be administered in single or multiple dosages per day.
  • the amino acid blend may be formulated at concentrations most typically ranging from about 5 to about 50%, including from about 15 to about 33%, and also including from about 15 to about 25%, by weight of the product form, all in combination with excipients or other ingredients such as carbohydrates, acidulants, flavors, and colors.
  • compositions useful in the methods of the present disclosure comprise a select blend of branched chain amino acids and sulfur-containing amino acids, the former of which includes valine (VAL), leucine (LEU), and isoleucine (ILE), and the latter of which includes cysteine (CYS) and methionine (MET).
  • the compositions include a specific amino acid blend of at least isoleucine, leucine, valine, cysteine, and methionine, the quantity or amount of which should be sufficient to provide an increase in glucose uptake in a muscle cell of an individual, an increase in the muscle recovery rate of an individual, and/or an increase in muscle glucose metabolism rate in an individual upon administration.
  • the amino acid blend is present in the composition in an amount sufficient to provide an individual with from about 0.1 grams to about 50 grams per day, desirably from about 1 gram to about 15 grams per day of the amino acid blend.
  • the composition may be administered once, twice, three times or more daily to reach the desired level of amino acid blend intake per day.
  • the amino acid blend comprises isoleucine, leucine, valine, methionine, and cysteine in a molar ratio of about 97.65 :about 0.68:about
  • the amino acid blend comprises isoleucine, leucine, valine, methionine, and cysteine in a molar ratio of 96.49- 98.00:0.65-0.70:0.68-0.81 :0.26-0.38:0.55-0.62, respectively.
  • the composition contains from about 1.0 to about 200 mg/kg of body weight of isoleucine; from about 0.001 to about 10 mg/kg of body weight of leucine; from about 0.001 to about 10 mg/kg of body weight of valine; 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 body weight of the individual or subject patient to which the composition is administered.
  • the composition contains from about 120 to about 180 mg/kg of body weight of isoleucine; from about 0.25 to about 7.5 mg/kg of 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.
  • the composition contains from about 130 to about 170 mg/kg of 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 select amino acid blends may also be characterized as a weight ratio of the branched chain to sulfur-containing amino acids of at least about 10: 1 , including at least about 50: 1 , and also including at least about 100: 1 , and also including from 500: 1 to 10: 1.
  • the individual amino acids for use in the compositions and methods of the present disclosure can be provided in the form of natural, intact or hydrolyzed proteins, which may therefore include free amino acids as well as various polypeptides or intact proteins within the compositions or otherwise consumed as part of the methods, provided that such sources provide the requisite kind and amount of amino acids in the blends as described herein.
  • the amino acid blends for use in the methods and composition may therefore comprise from 0 to 100% , including from 50 to 100%, also including from 75 to 95%), also including from 90 to 100%, and also including 100%, on a molar or weight basis of the targeted amino acid blend in the form of free amino acids within the compositions or otherwise administered in the methods.
  • the amino acid blends may also be provided in the form of a blend of one or more of free amino acids, intact proteins, and hydrolyzed proteins or other protein fractions.
  • the amino acids in the defined blend may be in the L or R configuration, or a mixture thereof, although most amino acids for use in the formulation will typically be in the L configuration. Suitable amino acids described herein are commercially available from a number of different material suppliers, including Sigma- Aldrich Corporation (St. Louis, Missouri.) [0045]
  • the pH of the liquid composition is suitable for appropriate administration to a subject, such as by oral administration.
  • 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.
  • compositions of the present disclosure may further comprise one or more supplemental amino acids, 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), tryptophan (TRY), phenylalanine (PHE), and combinations thereof.
  • supplemental amino acids 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), tryptophan (TRY), phenylalanine (PHE), and combinations thereof.
  • the compositions may contain a sufficient amount of one or more (such
  • 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 body weight of each of 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 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 body weight of each of glycine, alanine, tyrosine, arginine, and tryptophan.
  • the compositions of the present disclosure contain little or no phenylalanine.
  • the composition may contain less than about 10 mg/kg of body weight of phenylalanine or less than about 5% by weight.
  • the composition contains less than about 5 mg/kg of body weight of phenylalanine.
  • the composition contains zero or less than about 1 mg/kg of body weight of phenylalanine.
  • compositions of the present disclosure including the amino acid blend 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 blend as described herein.
  • the optional macronutrients in combination with the other essential or added ingredients may 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, most suitably as a single, undivided serving or dose.
  • Carbohydrates suitable for use in the compositions of the present disclosure may be simple, complex, or variations or combinations thereof.
  • suitable carbohydrates include hydrolyzed or modified starch or cornstarch, maltodextrin, glucose polymers, sucrose, corn syrup, corn syrup solids, rice-derived carbohydrate, glucose, fructose, lactose, high fructose corn syrup, indigestible
  • oligosaccharides e.g., fructooligosaccharides
  • soluble or insoluble fiber honey
  • sugar alcohols e.g., maltitol, erythritol, sorbitol
  • Proteins suitable for use in the compositions include hydrolyzed, partially hydrolyzed or non- hydrolyzed proteins or protein sources, and can be derived from any known or otherwise suitable source such as milk (e.g., casein, whey), animal (e.g., meat, fish), cereal (e.g., rice, corn), vegetable (e.g., soy), or combinations thereof.
  • milk e.g., casein, whey
  • animal e.g., meat, fish
  • cereal e.g., rice, corn
  • vegetable e.g., soy
  • Fats suitable for use in the compositions include coconut oil, fractionated coconut oil, soy oil, corn oil, olive oil, safflower oil, high oleic safflower oil, MCT oil (medium chain triglycerides), sunflower oil, high oleic sunflower oil, palm and palm kernel oils, palm olein, canola oil, marine oils, cottonseed oils, structured lipids, and combinations thereof.
  • compositions of the present disclosure may vary considerably depending upon the particular product form (e.g., solid, liquid, powder) and the various other formulations and targeted dietary needs. These macronutrients are most typically formulated within any of the caloric ranges (embodiments A-D) described in the following table.
  • compositions including the amino acid blend of the present disclosure may further comprise other optional components that may modify the physical, chemical, aesthetic or processing characteristics of the products or serve as pharmaceutical or additional nutritional components when used in the targeted population.
  • 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 oral
  • Non-limiting examples of such optional ingredients include fibers, preservatives, anti-oxidants, emulsifying agents, buffers, pharmaceutical actives, additional nutrients as described herein, colorants, flavorants, thickening agents and stabilizers, emulsifying agents, lubricants, sweetening agents, vitamins, minerals and so forth.
  • compositions including the specific amino acid blends of the present disclosure may be prepared by any known or otherwise effective manufacturing technique for preparing the selected product form. Many such techniques are known for any given product form such as nutritional liquids or nutritional bars and can easily be applied by one of ordinary skill in the art to the nutritional products described herein.
  • compositions can likewise be prepared by any known or otherwise effective manufacturing technique for preparing the various pharmaceutical product forms. Many such techniques are known for any given pharmaceutical product form such as capsules, tablets, liquids, and so forth, and can easily be applied by one of ordinary skill in the art to the compositions described herein.
  • compositions may be prepared by dissolving each of the selected amino acids in water or a dilute acid solution, and then combining the different amino acid solutions to form a liquid embodiment of the present disclosure.
  • the compositions may be prepared by combining the different powder forms of the selected amino acids, along with any tablet forming materials or other excipients, and then dry blending the powders prior to processing it into the desired solid product form, e.g., tablet, capsule, caplet, and so forth.
  • compositions may be formulated as a nutritional liquid, including a juice or milk or soy-based liquid, comprising the selected amino acid blend.
  • a nutritional liquid including a juice or milk or soy-based liquid, comprising the selected amino acid blend.
  • Such an embodiment may be prepared by first forming an oil and fiber blend containing all formulation oils, any emulsifier, fiber and fat-soluble vitamins.
  • Additional slurries (typically a carbohydrate and two protein slurries) are prepared separately by mixing the carbohydrate and minerals together and the protein in water. The slurries are then mixed together with the oil blend. The resulting mixture is homogenized, heat processed, standardized with any water-soluble vitamins, flavored and the liquid terminally sterilized or aseptically filled or dried to produce a powder.
  • the solid product is then coated, to enhance palatability, and packaged for distribution.
  • the fat-soluble components are then blended together and mixed with any powdered premixes.
  • any liquid components are then mixed into the composition, forming a plastic like composition or dough.
  • the resulting plastic mass can then be shaped, without further physical or chemical changes occurring, by cold forming or extrusion, wherein the plastic mass is forced at relatively low pressure through a die, which confers the desired shape.
  • the resultant exudate is then cut off at an appropriate position to give products of the desired weight. If desired the solid product is then coated, to enhance palatability, and packaged for distribution.
  • the solid nutritional embodiments of the present invention may also be manufactured through a baked application or heated extrusion to produce solid product forms such as cereals, cookies, crackers, and similar other product forms.
  • solid product forms such as cereals, cookies, crackers, and similar other product forms.
  • compositions may, of course, be manufactured by other known or otherwise suitable techniques not specifically described herein without departing from the spirit and scope of the present invention.
  • present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive and all changes and equivalents also come within the description of the present invention.
  • compositions including the specific amino acid blend as described herein may be administered to individuals to increase the rate of glucose uptake in a muscle cell of the individual, to increase the rate of muscle recovery rate of an individual, to increase the rate of muscle glucose metabolism in an individual, or to increase the fuel supply to the muscles of an individual.
  • the individual may be a healthy individual, such as an athlete, who wants to speed muscle recovery after a trauma or physical exertion.
  • the individual may be an individual who is a prediabetic or has diabetes, has insulin resistance, or impaired glucose tolerance, or who wants to control and maintain safe blood glucose levels with the use of little or no insulin.
  • the individual may be an individual who suffers from skeletal muscle loss, cancer cachexia, sarcopenia,
  • HIV/AIDS HIV/AIDS, COPD, or a combination thereof.
  • compositions and methods of the present disclosure may be directed to any individual, including humans and other mammals such dogs, cats, rodents, cows, sheep, swine, goats, horses and other hoofed animals, and so forth. Healthy individuals at risk of type 2 diabetes may be administered the compositions as well.
  • compositions including the specific amino acid blend may be administered before, during, or after carbohydrate intake (such as from a meal, drink, or snack), or before, during or after exercise to increase the rate of muscle recovery and/or increase muscle glucose metabolism rates.
  • carbohydrate intake such as from a meal, drink, or snack
  • administration of the amino acid composition is conducted within about one hour of carbohydrate consumption and/or physical exertion by the subject.
  • the administration of the amino acid composition is conducted within about 30 minutes of carbohydrate
  • compositions including the specific amino acid blend may be used to increase muscle uptake of blood glucose to treat and/or manage glucose tolerance, diabetes, obesity, skeletal muscle loss, sarcopenia, muscle wasting diseases, cachexia due to cancer, HIV/ AIDS, COPD and combinations thereof, and/or symptoms and side effects thereof.
  • the compositions and methods may 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, decreased strength, body weight/poor or increased appetite, reflux, irregularity, stomach neuropathy, kidney failure, heart disease, stroke, and deteriorating eyesight.
  • the methods of the present disclosure as described herein are also intended to include the use of such methods in individuals unaffected by or not otherwise afflicted with glucose intolerance, diabetes, obesity, sarcopenia, muscle wasting diseases, etc., for the purpose of managing, preventing, minimizing, or delaying the development of such diseases or conditions over time.
  • the methods of the present disclosure preferably include continuous, daily administration of the compositions as described herein.
  • Such preventive methods may be directed at adults or others who are at risk of developing muscle wasting and/or diabetes.
  • administering increases muscle glucose metabolism.
  • Blood glucose levels may be determined using whole blood, blood plasma or blood serum. Unless otherwise indicated, blood glucose levels refer to analysis of whole blood.
  • Administration of the compositions decreases blood glucose levels after carbohydrate ingestion (compared to blood glucose levels after carbohydrate ingestion without administration of the amino acid compositions) in at least one of about 30 minutes after carbohydrate intake, about 60 minutes after carbohydrate intake, about 90 minutes after carbohydrate intake, and about 120 minutes after
  • the rate of glucose uptake in red gastrocnemius and white gastrocnemius muscles of Sprague-Dawley rats is analyzed following the administration of: (1) a carbohydrate-only solution; or (2) a carbohydrate solution including a specific amino acid blend of the present disclosure.
  • the carbohydrate-only solution administered is a 22.5% (by weight) glucose standard solution.
  • the carbohydrate solution including a specific amino acid blend is a 22.5%) (by weight) glucose standard solution (50 mL) including 5.28 mg of cysteine, 3.36 mg of methionine, 6.68 mg of valine, 944.8 mg of isoleucine, and 6.58 mg of leucine.
  • the amino acid blend is introduced into 45 mL of the 22.5% glucose solution while stirring at high speed for about 1.5 hours. After all of the amino acids are dissolved, the solution is brought up to 50 mL.
  • the amino acid blend has a molar ratio of
  • isoleucine leucine : valine methionine: cysteine of about 97.65:0.68:0.77:0.31 :0.59.
  • Sprauge Dawley rats are orally gavaged 8 ml/kg with either carbohydrate (CHO) or carbohydrate plus the 5 amino acid mixture (CHO-AA). Fifteen minutes after the gavage, a bolus containing 40 ⁇ 3 ⁇ 4 body weight 2-[l,2- 3 H] deoxyglucose ( 3 H-2-DG) and 20 ⁇ 3 ⁇ 4 body weight [U- 14 C] mannitol is injected by syringe via a tail vein.
  • CHO carbohydrate
  • CHO-AA 5 amino acid mixture
  • rats Sixty minutes after the oral gavage, rats are anesthetized with an intraperitoneal injection of sodium pentobarbital at which time the gastrocnemius is excised, sectioned into red and white muscle samples, freeze clamped in liquid nitrogen and stored at -80° C. Muscle samples are digested and read in a liquid scintillation counter preset for simultaneous counting of [ 3 H] and [ 14 C] DPM.
  • FIG. 1 there is shown a graph of the in vivo assay results of the glucose uptake measured in the red (RG) and white (WG) gastrocnemius muscles during the oral glucose tolerance test in the Sprague Dawley rats. As the graph indicates, both the RG and the WG have significantly greater glucose uptake following administration of the carbohydrate and amino acid blend as compared to the carbohydrate alone. This indicates that the amino acid blend increases the glucose uptake into the muscle cells.
  • skeletal muscle glucose uptake across different fiber types isolated from Zucker obese rats is analyzed following the administration of: (1) a carbohydrate-only solution; or (2) a carbohydrate solution including a specific amino acid blend of the present disclosure.
  • the carbohydrate-only solution is a 22.5% (by weight) glucose standard solution.
  • the carbohydrate solution including a specific amino acid blend is a 22.5% (by weight) glucose standard solution (50 mL) including 5.28 mg of cysteine, 3.36 mg of methionine, 6.68 mg of valine, 944.8 mg of isoleucine, and 6.58 mg of leucine.
  • the amino acid blend is introduced into 45 mL of the 22.5% glucose solution while stirring at high speed for about 1.5 hours. After all of the amino acids are dissolved, the solution is brought up to 50 mL.
  • the amino acid blend has a molar ratio of
  • isoleucine leucine : valine :methionine : cysteine of 97.65:0.68:0.77:0.31 :0.59.
  • Obese Zucker rats are orally gavaged 8 ml/kg with either carbohydrate (CHO) or carbohydrate plus a 5 amino acid mixture (CHO-AA). Fifteen minutes after the gavage, a bolus containing 40 ⁇ 3 ⁇ 4 body weight 2-[l,2- 3 H] deoxyglucose ( 3 H-2-DG) and 20 ⁇ Ci/kg body weight [U- 14 C] mannitol is injected by syringe via a tail vein.
  • CHO carbohydrate
  • CHO-AA 5 amino acid mixture
  • rats Sixty minutes after the oral gavage, rats are anesthetized with an intraperitoneal injection of sodium pentobarbital at which time the gastrocnemius and soleus muscle are excised, sectioned into red and white muscle samples (gastrocnemius muscle), freeze clamped in liquid nitrogen and stored at -80° C. Muscle samples are digested and read in a liquid scintillation counter preset for simultaneous counting of [ 3 H] and [ 14 C] DPM.
  • FIGS 2 and 3 there are shown graphs of the in vivo assay results of the glucose uptake measured in the red gastrocnemius muscle and the soleus muscle during the oral glucose tolerance test in the Zucker obese rats, an animal model used for the study of insulin resistance.
  • both the red gastrocnemius muscle and soleus muscle have significantly greater glucose uptake following administration of the carbohydrate and amino acid blend as compared to the carbohydrate alone. This indicates that the amino acid blend increases the glucose uptake into the different fiber types in insulin resistant muscle.
  • Sprauge Dawley rats are fasted for 8 hours and then anesthetized via an intraperitoneal (IP) injection of pentobarbital sodium (65 mg/kg body weight). The epitrochlearis muscle is then surgically dissected for in vitro incubation.
  • IP intraperitoneal
  • the isolated muscles are individually pre-incubated for 50 min at 29 °C in 1.5 ml of continuously gassed (95%02/5%C02) Krebs-Henseliet bicarbonate (KHB) buffer containing 0.1% BSA, 32 mM mannitol, and 8 mM glucose. Following the pre-incubation, muscles are washed for 10 min at 29 °C in fresh KHB buffer (1.5 ml) containing 0.1% BSA, 2 mM pyruvate, and 38 mM mannitol.
  • KHB Krebs-Henseliet bicarbonate
  • muscles are then incubated for 20 min at 29 °C in the uptake mediums containing different levels of the 5 amino acids with radioactive tracers (280 ⁇ / ⁇ [ 3 H] 2-deoxyglucose and 10 ⁇ / ⁇ [ 14 C]-mannitol). Following the last incubation period, muscles are blotted and freeze clamped with Wallenberg tongs cooled in liquid nitrogen. The muscles are stored at -80 °C until analysis.
  • radioactive tracers 280 ⁇ / ⁇ [ 3 H] 2-deoxyglucose and 10 ⁇ / ⁇ [ 14 C]-mannitol.
  • the amino acid mixture is based on the concentration of isoleucine within the incubation medium, and the ratios of each individual amino acid in the medium are kept the same among different doses. For the concentrations of the individual amino acids, see Table 1.
  • Glucose uptake in the incubated muscles is estimated by determining the incorporation rate of 3 H-labeled 2-deoxyglucose (2-DG) into the muscle fibers during the 20 minute incubation.
  • Frozen muscle samples are weighed (15-25 mg) and digested in 1 ml IN KOH at 60 °C for 20 minutes. Muscle homogenate then are neutralized with 1 ml IN HC1, and the neutralized supernatant are added into 6 ml BioSafe II scintillation cocktail (Research Products International, Mt. Prospect, IL). Samples are counted for 3 H and 14 C in an LS-6000 liquid scintillation spectrophotometer (Beckman, Fullerton, CA). Muscle 2-DG uptake is calculated as the difference between total muscle 2-DG and 2-DG in the extracellular space. The amount of 2-DG contained in the extracellular space is determined and corrected by the amount of [ 14 C]-mannitol retained in the tissue.
  • FIG. 4 there is shown graphs of the in vitro assay results of the glucose uptake in response to treatment of the epitrochlearis muscles with different doses of the specific amino acid blend.
  • the muscle has significantly greater glucose uptake following administration of the increased doses of the amino acid blend as compared to basal levels. This indicates that the amino acid blend increases the glucose uptake into the muscle.
  • glucose transport of C 2 C 12 myotubes is analyzed after treatment with various solutions, including insulin (100 nM in Krebs-Ringers-HEPES buffer with bovine serum albumin (BSA), glucose, and sodium bicarbonate (KRH-BGB), 5AA (14.4 mM isoleucine, 0.10 mM leucine, 0.11 mM valine, 0.05 mM methionine, and 0.09 mM cysteine), 4AA (0.10 mM leucine, 0.11 mM valine, 0.05 mM methionine, and 0.09 mM cysteine), ILE (14.4 mM isoleucine in KRH-BGB), and a basal treatment (KRH- BGB alone).
  • insulin 100 nM in Krebs-Ringers-HEPES buffer with bovine serum albumin (BSA), glucose, and sodium bicarbonate (KRH-BGB)
  • 5AA (14.4 mM isoleucine, 0.10 mM leucine
  • C 2 Ci 2 myoblast plates (6-well plates) are prepared at a concentration of ⁇ 6 X 10 4 cells/well (3 ml of suspension/well). Following preparation, the C 2 Ci 2 myoblast plates are differentiated to C 2 Ci 2 myotubes by replacing the growth medium with differentiation medium (DMEM, 2% Horse Serum (HS), L ⁇ alanyi ⁇ L-glutaraine at a final concentration of 1%, and Penicillin-Streptomycin (10,000 IU/10,000 ⁇ g/ml) solution at a final concentration of 1%. Once differentiated, the C 2 Ci 2 myotubes are subjected to a C 2 Ci 2 glucose transport assay.
  • DMEM Dulbecco's Modified Eagle Medium
  • FBS Fetal Bovine Serum
  • Penicillin-Streptomycin 10,000 IU/10,000 ⁇ g/ml
  • 0.5 ml of cell extraction buffer is added to each To well and a cell scraper is used to dislodge the treated cells from the plates.
  • 0.25 ml of the cell suspension is dispensed into a scintillation vial and the remaining cell suspension is dispensed into a separate tube for storage at ⁇ 20°C until protein testing (Bicinchoninic Acid (BCA)) could be completed.
  • BCA Protein testing
  • 15 ml of liquid scintillation fluid is added.
  • the wells including the insulin control and test amino acid-containing solution samples are then processed as the T 0 wells.
  • radioactive C2C12 glucose transport assay protein samples i.e., the 0.25 ml of cell extraction buffer that is not added to the scintillation vials, but is frozen and later tested for protein
  • a protein standard from the BCA kit is used to prepare the standard curve by making a series of 1 :2 dilutions in cell extraction buffer (2000 ⁇ g/ml through 125 ⁇ g/ml) and a 1 : 10 dilution of the 250 ⁇ g/ml standard (25 ⁇ g/ml).
  • Duplicate wells of a flat-bottom micro titer plate are loaded with 25 ⁇ of the prepared standards, blanks, and samples. Cell extraction buffer is used in the assay blank wells.
  • BCA reagents which is a 50: 1 mixture of kit components A and B
  • the working solution of BCA reagents is prepared. 290 ⁇ of BCA working reagent is added to each well of the microtiter plate and gently rocked to mix the samples.
  • the radioactive plate(s) are safely transferred to a 37°C incubator. Once the plate cools to room temperature, a microplate reader is used to read the absorbance at 562 nm.
  • the microplate reader's software program, quadratic curve is then used to evaluate the standards and calculate the ⁇ g/ml of protein for the controls and test samples from the C 2 C 12 glucose transport assay. To determine the protein concentration associated with each scintillation vial, the ⁇ g/ml of protein is divided by 4.
  • Examples 5-7 illustrate nutritional liquid embodiments of the present disclosure.
  • the ingredients for each exemplified composition are described in the following table. All ingredient amounts are listed as kg per 1000 kg batch of product, unless otherwise specified.
  • the amino acid blend is prepared by conventional methods as a powder comprising each of the identified amino acids.
  • the amino acid powder is added slowly, with agitation, to a kettle containing the specified amount of water. Once the amino acids are fully dispersed, the solution pH is reduced to 2.4 using an 80% phosphoric acid solution, and thereafter increased to 3.2 using a 45% KOH solution.

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Abstract

L'invention concerne des compositions et des procédés pour augmenter l'absorption de glucose par le muscle et réduire le temps de récupération du muscle chez un individu. Les compositions utiles pour ces procédés comprennent des mélanges d'acides aminés spécifiques comprenant de l'isoleucine, de la leucine, de la valine, de la cystéine et de la méthionine. Ces compositions peuvent être utilisées chez des individus sains et/ou des individus prédiabétiques ou diabétiques pour augmenter l'absorption de glucose par le muscle et réduire le temps de récupération du muscle. Certains procédés d'utilisation des mélanges d'acides aminés spécifiques sont destinés aux diabétiques pour réguler les teneurs en glucose dans le sang.
PCT/US2011/054592 2010-10-06 2011-10-03 Procédés pour augmenter l'absorption de glucose par le muscle et réduire le temps de récupération du muscle employant un mélange d'acides aminés WO2012047800A1 (fr)

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