WO2014028607A1

WO2014028607A1 - Low glycemic index nutritional compositions for preserving muscle mass and improving body composition in diabetics

Info

Publication number: WO2014028607A1
Application number: PCT/US2013/054925
Authority: WO
Inventors: Suzette Pereira; Padmavathy KRISHNAN DESAI; Neile Edens
Original assignee: Abbott Laboratories
Priority date: 2012-08-14
Filing date: 2013-08-14
Publication date: 2014-02-20

Abstract

Nutritional compositions that include a combination of Curcumin and epigallocatechin gallate (EGCg) are provided. The nutritional compositions may be formulated as low glycemic index nutritional compositions. The nutritional compositions may be administered to an individual, particularly an insulin resistant, pre-diabetic, or diabetic individual, to preserve muscle mass and decrease fat deposition, thereby improving overall body composition leading to increased strength and functionality as well as improved blood glucose control and insulin sensitivity.

Description

LOW GLYCEMIC INDEX NUTRITIONAL COMPOSITIONS FOR PRESERVING MUSCLE MASS AND IMPROVING BODY COMPOSITION

IN DIABETICS

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of U.S. Provisional Patent Application No. 61/682,984, filed August 14, 2012, the entire content of which is incorporated by reference herein.

FIELD

[0002] The present disclosure relates to low glycemic index nutritional compositions that include a combination of Curcumin and epigallocatechin gallate (EGCg) and to methods of using the compositions. More particularly, the present disclosure relates to low glycemic index nutritional compositions that include Curcumin and EGCg for preventing skeletal muscle mass loss and improving body composition in diabetic individuals.

BACKGROUND OF THE DISCLOSURE

[0003] There are numerous metabolic defects generally associated with diabetes. Several large epidemiological studies have shown that insulin resistance, pre-diabetes, and diabetes are significantly correlated with decreased lean body mass, strength, and frailty. This correlation has been found in both men and women across a wide span of ages. The loss of skeletal muscle may lead to a number of further problems in these individuals, including mobility and dexterity issues.

[0004] Further, adipose tissue serves as a major depot for energy storage. The lipid biosynthetic and catabolic pathways are tightly regulated in normal physiological conditions, but become dysfunctional during diabetes and obesity. Enhanced adipose tissue lipolysis and improved whole body fat oxidation and energy expenditure is known to contribute to improved body composition.

[0005] Conventional treatment for diabetes, both pharmaceuticals and nutritionals, mainly target the metabolic disturbances like blood glucose control, improvement of insulin sensitivity, etc. No emphasis, however, has been placed on the loss of lean body mass and fat deposition disturbances due to diabetes.

[0006] Accordingly, there is a need in the art for nutritional compositions and methods for treating and managing the loss of muscle mass and fat deposition in insulin resistant, pre-diabetic and diabetic individuals. Further, it would be advantageous if the compositions could be used as a meal replacement or dietary supplement by diabetic individuals to improve body composition thereby increasing strength and functionality as well as improving blood glucose control and insulin sensitivity.

SUMMARY

[0007] The present disclosure is generally directed to low glycemic index nutritional compositions that include a combination of Curcumin and EGCg. The nutritional compositions prevent skeletal muscle mass loss and improve body composition in diabetic individuals without undesirable increases in blood sugar levels. Particularly, the combination of Curcumin and EGCg has been found to increase muscle mass as measured by muscle fiber cross section and increase lipolysis in adipose tissue as measured by glycerol levels in diabetic individuals.

[0008] The present disclosure is directed to a method of preventing skeletal muscle mass loss in a diabetic individual in need thereof. The method comprises administering a nutritional composition comprising Curcumin and epigallocatechin gallate to the diabetic individual.

[0009] The present disclosure is further directed to a method of increasing skeletal muscle mass in a diabetic individual in need thereof. The method comprises administering a nutritional composition comprising Curcumin and epigallocatechin gallate to the diabetic individual.

[0010] The present disclosure is further directed to a method of increasing lipolysis in adipose tissue of a diabetic individual in need thereof. The method comprises administering a nutritional composition comprising Curcumin and epigallocatechin gallate to the diabetic individual.

[0011] The present disclosure is further directed to a low glycemic nutritional composition comprising Curcumin and epigallocatechin gallate. In one exemplary embodiment, the Curcumin is formulated as bioavailable Curcumin.

[0012] It has been discovered that the combination of Curcumin and EGCg, when utilized in low glycemic nutritional compositions, imparts improved body composition to an individual as it preserves lean body mass and decreases fat mass via increasing lipolysis in adipose tissue. Particularly, the combination of Curcumin and EGCg provides a surprisingly synergistic effect on preventing muscle atrophy in the milieu of diabetes, thereby increasing skeletal muscle mass and preventing further skeletal muscle mass loss. Surprisingly, the individual ingredients did not have an effect on muscle mass, although they have been shown to be efficacious in other types of muscle atrophy (e.g., sarcopenia, cachexia, and the like).

[0013] Further, the combination of Curcumin and EGCg provides increased glycerol levels suggesting that lipolysis is increased with their administration. This cycle could sensitize regulatory control over lipid metabolism linked to increased energy expenditure. The nutritional compositions of the present disclosure target muscle mass loss due to diabetes, which will help decrease fat deposition, leading to improved body composition as well as improved blood glucose control and insulin sensitivity. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] FIG. 1 is a graph depicting muscle fiber cross section area (CSA) measurements in obese diabetic rats as analyzed in Example 1.

[0015] FIG. 2 is a graph depicting metabolomic analysis on adipose tissue as analyzed in Example 1.

DETAILED DESCRIPTION OF THE DISCLOSURE

[0016] The nutritional compositions of the present disclosure comprise a combination of Curcumin and EGCg. When used in a low glycemic index environment, the combination provides increased skeletal muscle mass and increased lipolysis in adipose tissue without an increase in blood sugar levels in diabetic individuals.

[0017] These and other features of the nutritional compositions, as well as some of the many optional variations and additions, are described in detail hereafter.

[0018] The terms "nutritional composition" or "nutritional product" as used herein, unless otherwise specified, refer to nutritional liquids and nutritional powders, the latter of which may be reconstituted to form a nutritional liquid, all of which comprise one or more of fat, protein, and carbohydrate and are suitable for oral consumption by a human.

[0019] The terms "liquid nutritional composition" and "nutritional liquid" are used interchangeably herein, and unless otherwise specified, refer to nutritional products in ready-to-drink liquid form and concentrated form.

[0020] The term "nutritional powder" as used herein, unless otherwise specified, refers to nutritional formulations in fiowable or scoopable form that can be reconstituted with water or another aqueous liquid prior to consumption and includes both spray dried and dry mixed/dry blended powders.

[0021] The term "low glycemic index nutritional composition" as used herein, unless otherwise specified, refers to a nutritional composition having a glycemic index of less than 55. The glycemic index of a composition is defined as the incremental area under the two-hour blood glucose response curve (AUC) following a 12-hour fast and ingestion of a composition with a certain quantity of available carbohydrate (usually 50 g). The AUC of the test composition is divided by the AUC of the standard (either glucose or white bread, giving two different definitions) and multiplied by 100. The average GI value is calculated from data collected in 10 human subjects. Both the standard and test composition must contain an equal amount of available carbohydrate. The result gives a relative ranking for each tested composition. A lower glycemic index suggests slower rates of digestion and absorption of the composition's carbohydrates and may also indicate greater extraction from the liver and periphery of the products of carbohydrate digestion. A lower glycemic response usually equates to a lower insulin demand, and may improve long-term blood glucose control and blood lipids.

[0022] The term "Curcumin" as used herein, unless otherwise specified, refers to Curcumin, "bioavailable Curcumin," and derivatives and analogs thereof.

[0023] The term "bioavailable" as used herein, unless otherwise specified, refers to the ability of a compound to enter into and remain in the bloodstream of an individual such that the substance can be absorbed into cells in the body. As the degree of bioavailability of a compound increases, the compound becomes more likely to enter into and remain in the bloodstream where it can be absorbed and used by the body. As the degree of bioavailability of a compound decreases, the compound becomes more likely to go directly into the gastrointestinal area and be expelled from the body before entering the bloodstream.

[0024] The terms "fat" and "oil" as used herein, unless otherwise specified, are used interchangeably to refer to lipid materials derived or processed from plants or animals. These terms also include synthetic lipid materials so long as such synthetic materials are suitable for oral administration to humans.

[0025] The terms "susceptible" and "at risk" as used herein, unless otherwise specified, mean having little resistance to a certain condition or disease, including being genetically predisposed, having a family history of, and/or having symptoms of the condition or disease.

[0026] The term "shelf stable" as used herein, unless otherwise specified, refers to a liquid nutritional composition that remains commercially stable after being packaged and then stored at 18-24°C for at least 3 months, including from about 6 months to about 24 months, and also including from about 12 months to about 18 months.

[0027] The terms "retort packaging" and "retort sterilizing" are used interchangeably herein, and unless otherwise specified, refer to the common practice of filling a container, most typically a metal can or other similar package, with a liquid nutritional composition and then subjecting the liquid-filled package to the necessary heat sterilization step, to form a sterilized, retort packaged, liquid nutritional product.

[0028] The term "aseptic packaging" as used herein, unless otherwise specified, refers to the manufacture of a packaged product without reliance upon the above-described retort packaging step, wherein the liquid nutritional composition and package are sterilized separately prior to filling, and then are combined under sterilized or aseptic processing conditions to form a sterilized, aseptically packaged, liquid nutritional product.

[0029] All percentages, parts and ratios as used herein, are by weight of the total composition, unless otherwise specified. All such weights as they pertain to listed ingredients are based on the active level and, therefore, do not include solvents or by-products that may be included in commercially available materials, unless otherwise specified.

[0030] All references to singular characteristics or limitations of the present disclosure shall include the corresponding plural characteristic or limitation, and vice versa, unless otherwise specified or clearly implied to the contrary by the context in which the reference is made. [0031] All combinations of method or process steps as used herein can be performed in any order, unless otherwise specified or clearly implied to the contrary by the context in which the referenced combination is made.

[0032] The various embodiments of the nutritional compositions of the present disclosure may also be substantially free of any optional or selected ingredient or feature described herein, provided that the remaining nutritional composition still contains all of the required ingredients or features as described herein. In this context, and unless otherwise specified, the term "substantially free" means that the selected nutritional composition contains less than a functional amount of the optional ingredient, typically less than 1%, including less than 0.5%, including less than 0.1%, and also including zero percent, by weight of such optional or selected ingredient.

[0033] The nutritional compositions may comprise, consist of, or consist essentially of the elements of the nutritional compositions as described herein, as well as any additional or optional element described herein or otherwise useful in nutritional composition applications.

Product Form

[0034] The nutritional compositions used in the methods of the present disclosure may be formulated and administered in any known or otherwise suitable oral product form. Any solid, semi-solid, liquid, semi-liquid, or powder form, including combinations or variations thereof, are suitable for use herein, provided that such forms allow for safe and effective oral delivery to the individual of the Curcumin and EGCg ingredients as also defined herein. The nutritional compositions may be formulated to include only the essential ingredients described herein, or may be modified with optional ingredients to form a number of different product forms.

[0035] The nutritional compositions used in the methods of the present disclosure include a combination of Curcumin and EGCg. In some embodiments, the nutritional compositions may be formulated to further comprise at least one of fat, protein, and carbohydrate, and preferably also contain additional vitamins, minerals, or combinations thereof. [0036] The nutritional compositions may be formulated with sufficient kinds and amounts of nutrients to provide a sole, primary, or supplemental source of nutrition, or to provide a specialized nutritional composition, including specialized nutrition to individuals in need of preserving skeletal muscle mass and/or improved body composition.

Nutritional Solids

[0037] The nutritional solids will include Curcumin and EGCg and may be in any form, including nutritional bars, nutritional tablets, nutritional pellets, extruded solids, and the like, but are typically in the form of flowable or substantially flowable particulate formulations, or at least particulate formulations. Particularly suitable nutritional solid product forms include spray dried, agglomerated or dryblended powder compositions. In many embodiments, the compositions can easily be scooped and measured with a spoon or similar other device, wherein the compositions can easily be reconstituted by the intended user with a suitable aqueous liquid, typically water, to form a nutritional composition for immediate oral or enteral use. In this context, "immediate" use generally means within about 48 hours, most typically within about 24 hours, preferably right after reconstitution.

Nutritional Liquids

[0038] Nutritional liquids will include Curcumin and EGCg and will include both concentrated and ready-to-feed nutritional liquids. These nutritional liquids are most typically formulated as suspensions, emulsions or clear or substantially clear liquids.

[0039] Nutritional emulsions suitable for use may be aqueous emulsions comprising proteins, fats, and carbohydrates. These emulsions are generally flowable or drinkable liquids at from about 1°C to about 25°C and are typically in the form of oil-in-water, water-in-oil, or complex aqueous emulsions, although such emulsions are most typically in the form of oil-in-water emulsions having a continuous aqueous phase and a discontinuous oil phase. [0040] The nutritional emulsions may be and typically are shelf stable. The nutritional emulsions typically contain up to 95% by weight of water, including from about 50%) to 95%o, also including from about 60%> to about 90%>, and also including from about 70% to about 85%, of water by weight of the nutritional emulsions. The nutritional emulsions may have a variety of product densities, but most typically have a density greater than 1.03 g/ml, including greater than 1.04 g/ml, including greater than 1.055 g/ml, including from about 1.06 g/ml to about 1.12 g/ml, and also including from about 1.085 g/ml to about 1.10 g/ml.

[0041] The nutritional emulsion may have a pH ranging from about 3.5 to about 8, but are most advantageously in a range of from about 4.5 to about 7.5, including from about 5.5 to about 7.3, including from about 6.2 to about 7.

[0042] Although the serving size for the nutritional liquid can vary depending upon a number of variables, a typical serving size is generally at least 2 mL, or even at least 5 mL, or even at least 10 mL, or even at least 25 mL, including ranges from 2 mL to about 300 mL, including from about 4 mL to about 250 mL, and including from about 10 mL to about 240 mL.

Curcumin

[0043] The nutritional compositions of the present disclosure include Curcumin. As used herein, the term "Curcumin" includes isolated Curcumin or analogues or derivatives thereof, as described herein, or any combinations thereof. Curcumin also refers to the compound having a systematic name of (lE,6E)-l,7-bis (4-hydroxy-3-methoxyphenyl)-l,6-heptadiene-3,5-dione and having the formula:

Curcumin is the principal Curcuminoid of turmeric. In addition to the keto form shown above, Curcumin may also be in enol form. Other naturally occurring

Curcuminoids of turmeric include bis-demethoxyCurcumin (one methoxy group removed from Curcumin structure) and demethoxyCurcumin (both methoxy groups removed from Curcumin structure).

[0044] Conventionally, some Curcumin products have suffered lower bioavailability when taken orally, and thus when formulated at higher concentrations to counter its inherent poor bioavailability to achieve the desired systemic delivery, the products often take on an intense undesirable yellow color. The term "Curcumin," as used herein, includes Curcumin that has been formulated as "bioavailable

Curcumin," which may exhibit an improved bioavailability as compared to conventionally used Curcumin. As such, Curcumin formulated as bioavailable Curcumin can be utilized at lower concentrations in the nutritional compositions and methods of the present disclosure, while still maintaining its anti-inflammatory, antioxidative, and anti-amyloidogenic activity.

[0045] The term "bioavailable Curcumin" may refer to Curcumin and derivatives and analogs thereof, including natural and synthetic derivatives of Curcumin, as well as any combination of one or more of Curcumin, a Curcumin derivative, and a Curcumin analog that has been processed or otherwise manipulated to improve the biovailability thereof. In particular, in one exemplary embodiment, the term "bioavailable Curcumin" may encompass compounds having a 1,7-bis (4- hydroxyphenyl)-l,6-heptadiene-3,5-dione skeleton, or a 1 ,7-bis(4-hydroxyphenyl) hept-4-en-3-one skeleton, wherein the phenyl groups independently may bear one or more alkoxy residues, especially one methoxy residue in the 3-position. In some embodiments, additional Curcuminoids, such as demethoxyCurcumin and

bisdemethoxyCurcumin, may also be present in the nutritional compositions. When present, demethoxyCurcumin and bisdemethoxyCurcumin may be present as part of a complex with Curcumin, for example, Curcumin C3 complex, available from Sabinsa Corporation (East Windsor, New Jersey).

[0046] The "bioavailable Curcumin" used in certain exemplary

compositions herein shows improved oral bioavailability as compared to "non- bioavailable Curcumin." The term "non-bioavailable Curcumin," as used herein, refers to Curcumin that has not been processed or otherwise manipulated in an effort to improve the bioavailability thereof, and does not mean that the Curcumin has no bioavailability. The oral bioavailability can be determined in experiments involving oral administration of the bioavailable Curcumin (and administration of a

corresponding amount of non-bioavailable Curcumin) to an individual and measuring the level of Curcumin in a biological sample obtained from the individual over time, wherein the biological sample may be derived from a body fluid, for example, serum, plasma, whole blood, or cerebrospinal fluid, or from a tissue (e.g., brain, liver, kidney, or heart). For analysis, the Curcumin level in the examined body fluid or tissue may be plotted against time, and the area under the curve (AUC), for example, the total area under the curve from t = 0 (time of administration) to t = infinity (AUC0- infinity), or the area under the curve within a defined period (e.g. from t = 0 to t = 6 hours (AUC0-6H)) may be calculated. In general, a higher AUC relative to the AUC obtained by administration of non-bioavailable Curcumin indicates an improved bioavailability. The absolute bioavailability may be calculated from the resulting AUC data as a percentage based on the corresponding AUC data obtained from intravenous administration of Curcumin.

[0047] In one exemplary embodiment, the amount of Curcumin in the blood, determined as AUC0-6H after a single oral administration to a human or an animal subject, such as a rat, of a dose or serving of a composition containing bioavailable Curcumin of the present disclosure corresponding to 20 milligrams of total Curcumin is significantly higher than after oral administration of the same amount of non- bioavailable Curcumin in the composition, including at least 2 times higher, at least 3 times higher, at least 4 times higher, at least 6 times higher, at least 8 times higher, at least 10 times higher, or at least 15 times higher, and, for example, up to 30 times higher.

[0048] As used herein, the amount of Curcumin in the blood being

"significantly higher" means a statistically significant increase of this parameter in subjects after oral administration of 20 mg of bioavailable Curcumin in the nutritional composition of the present disclosure as compared to the control 20 mg of non- bioavailable Curcumin. A statistical test known in the art, such as ANOVA or Student's t-test, may be used to determine the significance of this difference, wherein the p-value is at least <0.1, <0.5, <0.01, <0.005, <0.001 or O.OOOl .

[0049] Curcumin can be prepared in a number of ways including, for example, using Meltrex® or similar melt-extrusion technology to prepare extruded solids and improve the bioavailability of the Curcumin as compared to Curcumin not produced by melt extrusion. Meltrex® or similar melt-extrusion technology methods are known in the art and can be applied to produce bioavailable Curcumin by one skilled in the art based on the disclosure herein.

[0050] In another embodiment, Curcumin can be co-supplemented with piperine (generally extracted from black pepper) to increase the bioavailability and hence the absorbability of Curcumin. In one embodiment, the piperine is co- supplemented in an amount of about 20 mg to increase the bioavailability of the Curcumin.

[0051] In another embodiment, the Curcumin may be solubilized in an oil having an HLB of from about 0.7 to about 14 (polar oils) such that the resulting oil mixture provides increased bioavailability of Curcumin. One suitable polar oil for dissolving the Curcumin is a medium chain triglyceride (MCT) oil.

[0052] In one embodiment of the present disclosure, the Curcumin comprises a mixture of Curcuminoids (e.g., Curcumin, demethoxyCurcumin and bisdemethoxyCurcumm). In one embodiment of the present disclosure, the Curcumin comprises a mixture of Curcuminoids (e.g., Curcumin, demethoxyCurcumin and bisdemethoxyCurcumm) obtained from the rhizomes of Curcuma Longa, and may be formulated as bioavailable Curcumin. In another embodiment, the Curcumin is obtained using Meltrex® technology (Abbott Nutrition, Columbus, Ohio). In yet another embodiment, the Curcumin is Meriva Bioavailable Curcumin, commercially available from Idena SPA (Milan, Italy). In one exemplary embodiment, the

Curcumin is Longvida Optimized Curcumin, commercially available from Verdure Sciences (Noblesville, Indiana). In one exemplary embodiment, the Curcumin is Theracurmin CR-011L, commercially available from Theravalues Corporation (Tokyo, Japan). In one exemplary embodiment, the Curcumin is Curqlife Curcumin, commercially available from Interhealth Nutraceuticals (Benicia, California).

[0053] The Curcumin concentration in the nutritional compositions may range from at least 0.001%, including from about 0.001% to about 3.36%, including from about 0.002%> to about 3.36%, including from about 0.005%) to about 1.87%, also including from about 0.03% to about 0.935%), also including from about 0.1% to about 0.467%), and also including from about 0.234%> to about 0.3%, by weight of the nutritional composition. Exemplary embodiments of the present disclosure include nutritional compositions having Curcumin in amounts ranging from about 0.002% to about 0.25%, from 0.002% to about 0.234%, from about 0.005% to about 0.467%, from about 0.03% to about 0.935%, from about 0.1% to about 1.9%, from about 0.1% to about 1.87%, and from about 0.3% to about 3.36%, by weight of the nutritional composition.

[0054] The nutritional compositions of the present disclosure desirably include sufficient Curcumin to provide an individual with at least 1 milligram, including at least 3 milligrams, including from about 10 milligrams to about 10,000 milligrams, including from about 100 milligrams to about 4000 milligrams, including from about 400 milligrams to about 2000 milligrams, including from about 1200 milligrams to about 1800 milligrams, per day of Curcumin. The total daily amount of Curcumin may be administered to an individual in a single undivided dose or serving, or may be split into multiple (e.g., two, three, four) doses or servings per day.

Catechins and Epigallocatechin Gallate (EGCg)

[0055] In addition to the Curcumin, the nutritional compositions of the present disclosure additionally include one or more catechins. In one exemplary embodiment, the nutritional composition comprises epigallocatechin gallate

("EGCg"). As used herein, "catechin" is meant to refer to flavonoid phytochemical compounds that appear predominantly in green tea and, to a lesser extent, in black tea, grapes, wine, and chocolate. Examples of other suitable catechins, in addition to EGCg, that can be used in the practice of the present disclosure include gallocatechin ("GC"), epigallocatechin ("EGC"), epicatechin ("EC"), and epicatechin gallate ("ECG"), as well as mixtures of these and other catechins. The catechins used in the nutritional compositions of the present disclosure can be prepared from lipid extracts from green tea leaves. The catechins can be purified to any suitable level, such as about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 85%, about 90%, and/or about 95%. One example of a suitable catechin is an extract (e.g., an 80% catechin extract) of Camellia sinensis. Another example of a suitable catechin is Sunphenon® 90D (e.g., a 40% catechin extract) available from Taiyo (Mie, Japan).

[0056] Generally, the catechins, and specifically EGCg, may be present in the nutritional compositions in an amount of from about 0.1% to about 10%, including from about 0.1 % to about 5%, including from about 0.1 % to about 3%, including from about 0.1% to about 2% by weight of the nutritional composition. In one specific embodiment, the catechins, and specifically EGCg may be present in the nutritional compositions in an amount of up to 1 gram/serving of the nutritional composition.

Macronutrients

[0057] In one exemplary embodiment, the nutritional composition may further comprise one or more macronutrients in addition to the Curcumin and EGCg described herein. Such macronutrients include proteins, lipids, carbohydrates, and combinations thereof. In one exemplary embodiment, the nutritional composition is formulated as a nutritional formulation containing all three macronutrients.

[0058] Macronutrients suitable for use herein include any protein, lipid, or carbohydrate or source thereof that is known for or otherwise suitable for use in an oral nutritional composition, provided that the macronutrient is safe and effective for oral administration and is otherwise compatible with the other ingredients in the nutritional composition.

[0059] The concentration or amount of the one or more lipid, carbohydrate, and protein in the nutritional composition can vary considerably depending upon the particular product form (e.g., bars or other solid dosage forms, milk or soy-based liquids/emulsions or other clear beverages, reconstitutable powders etc.) and the various other compositions and targeted dietary needs. These one or more

macronutrients are most typically formulated within any of the embodied ranges described in the following tables.

Each numerical value preceded by the term "about"

Each numerical value preceded by the term "about"

Carbohydrate

[0060] Exemplary carbohydrates suitable for use in the nutritional compositions may be simple, complex, or variations or combinations thereof. Non- limiting examples of suitable carbohydrates include hydrolyzed or modified or resistant starch or cornstarch, maltodextrin, isomaltulose, sucromalt, glucose polymers, sucrose, corn syrup, corn syrup solids, rice-derived carbohydrate, glucose, fructose, lactose, high fructose corn syrup, honey, sugar alcohols (e.g., maltitol, erythritol, sorbitol), and combinations thereof.

[0061] Exemplary carbohydrates suitable for use herein also include soluble dietary fiber, non-limiting examples of which include gum Arabic, sodium

carboxymethyl cellulose, guar gum, citrus pectin, low and high methoxy pectin, oat and barley glucans, carrageenan, psyllium and combinations thereof. Insoluble dietary fiber is also suitable as a carbohydrate source herein, non-limiting examples of which include oat hull fiber, pea hull fiber, soy hull fiber, soy cotyledon fiber, sugar beet fiber, cellulose, corn bran, and combinations thereof.

[0062] It should be understood by one skilled in the art that in the low glycemic index nutritional composition embodiments, the carbohydrates for use in the compositions should be selected to maintain an overall glycemic index of less than 55.

Protein

[0063] In one exemplary embodiment, the nutritional composition comprises at least one source of protein. In one exemplary embodiment, the nutritional composition comprises at least one source of protein in an amount sufficient to provide about 5 grams to about 50 grams of protein per serving of the nutritional composition. In certain exemplary embodiments, the nutritional composition comprises about 5 grams to about 40 grams, about 10 grams to about 35 grams, or about 15 grams to about 30 grams of protein per serving. In one exemplary embodiment, the composition comprises about 1% to about 30% of at least one source of protein by weight of the composition. In one exemplary embodiment, the composition comprises about 1% to about 20%> of at least one source of protein by weight of the composition. In one exemplary embodiment, the composition comprises about 1% to about 15%, about 1% to about 10%, about 1% to about 7%, or about 1%) to about 5% of at least one source of protein by weight of the composition. Any source of protein may typically be used in the nutritional compositions so long as it is suitable for oral administration and is otherwise compatible with any other selected ingredients or features in the nutritional composition.

[0064] Exemplary proteins suitable for use in the nutritional formulations 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, egg albumen), cereal (e.g., rice, corn), vegetable (e.g., soy, pea, potato), proteins derived from algae, beans (e.g., black, white), sorghum, millet or combinations thereof. The proteins for use herein can also include, or be entirely or partially replaced by, free amino acids known for use in nutritional products, non-limiting examples of which include L-tryptophan, L- glutamine, L-tyrosine, L-methionine, L-cysteine, taurine, L-arginine, L-carnitine, and combinations thereof.

Fat

[0065] In one exemplary embodiment, the nutritional composition comprises at least one source of fat. In certain exemplary embodiments, the nutritional composition comprises no fat, or essentially no fat (i.e., less than 0.5 grams of fat per serving). In one exemplary embodiment, the nutritional composition comprises about 0.5 grams to about 45 grams of at least one source of fat per serving. In other exemplary embodiments, the nutritional composition comprises about 2 grams to about 35 grams, about 5 grams to about 30 grams, about 10 grams to about 25 grams, or about 15 grams to about 20 grams of at least one source of fat per serving. In one exemplary embodiment, the nutritional composition comprises about 0.5% to about 30% of at least one source of fat by weight of the nutritional composition. In certain exemplary embodiments, the nutritional composition comprises about 1% to about 30%, about 5% to about 25%, about 10% to about 20%, or about 12% to about 18% of at least one source of fat by weight of the nutritional composition. In certain exemplary embodiments, the nutritional composition comprises about 1% to about 18%), about 1.5% to about 10%>, or about 2% to about 5% of at least one source of fat by weight of the nutritional composition. In certain exemplary embodiments, the nutritional composition includes only a small amount of fat, including less than 1 % fat by weight of the nutritional composition, or less than 0.5%>, or even 0%> fat by weight of the nutritional composition. In certain embodiments, the nutritional composition comprises about 0.1% to about 1% fat by weight of the nutritional composition.

[0066] Exemplary sources of fat suitable for use in the nutritional compositions include, but are not limited to, coconut oil, fractionated coconut oil, soy oil, corn oil, olive oil, safflower oil, high oleic safflower oil, high GLA-safflower oil, MCT oil (medium chain triglycerides), sunflower oil, high oleic sunflower oil, palm oil, palm kernel oil, palm olein, canola oil, flaxseed oil, borage oil, cottonseed oil, evening primrose oil, blackcurrant seed oil, transgenic oil sources, fungal oils, marine oils (e.g., tuna, sardine) and so forth.

Optional Ingredients

[0067] The nutritional compositions may further comprise other optional ingredients that may modify the physical, nutritional, chemical, hedonic or processing characteristics of the products or serve as pharmaceutical or additional nutritional components when used in a targeted population. Many such optional ingredients are known or otherwise suitable for use in other nutritional products and may also be used in the nutritional compositions described herein, provided that such optional ingredients are safe and effective for oral administration and are compatible with the essential and other ingredients in the composition.

[0068] Non-limiting examples of such other optional ingredients include preservatives, anti-oxidants, buffers, pharmaceutical actives, sweeteners, colorants, flavors, flavor enhancers, thickening agents and stabilizers, emulsifying agents, prebiotics, lubricants, and combinations thereof.

[0069] The nutritional compositions may further include one or more minerals, non-limiting examples of which include phosphorus, sodium, chloride, magnesium, manganese, iron, copper, zinc, iodine, calcium, potassium, chromium, chromium picolinate, molybdenum, selenium, and combinations thereof.

[0070] The nutritional compositions may also include one or more additional vitamins, non-limiting examples of which include carotenoids (e.g., beta-carotene, zeaxanthin, lutein, lycopene), biotin, choline, inositol, folic acid, pantothenic acid, choline, Vitamin A, thiamine (Vitamin Bl), riboflavin (Vitamin B2) niacin (Vitamin B3), pyridoxine (Vitamin B6), cyanocobalamin (Vitamin B12), ascorbic acid

(Vitamin C), Vitamin D, Vitamin E, Vitamin K, and various salts, esters, or other derivatives thereof, and combinations thereof.

[0071] In some embodiments of the present disclosure, the nutritional compositions including the combination of Curcumin and EGCg additionally comprise HMB, and preferably calcium HMB, which means that the nutritional compositions are either formulated with the addition of calcium HMB, most typically as a monohydrate, or are otherwise prepared so as to contain HMB in the finished composition. Any source of HMB is suitable for use herein provided that the finished product contains HMB, although such a source is preferably calcium HMB and is most typically added as such to the nutritional compositions during formulation.

[0072] Although calcium HMB monohydrate is the generally preferred source of HMB for use in the nutritional compositions disclosed herein, other suitable sources may include HMB as the free acid, a salt, an anhydrous salt, an ester, a lactone, or other product forms that otherwise provide a bioavailable form of HMB from the nutritional compositions. Non- limiting examples of suitable salts of HMB for use herein include HMB salts, hydrated or anhydrous, of sodium, potassium, magnesium, chromium, calcium, or other non-toxic salt form. Calcium HMB monohydrate is preferred and is commercially available from Technical Sourcing International (TSI) of Salt Lake City, Utah.

[0073] When utilized, the concentration of HMB in the nutritional compositions may range up to 20%, including from about 0.01% to about 10%>, including from about 0.01% to about 8%, and also including from about 0.08%> to about 5.0%), and also including from about 0.08%> to about 3%, and also including from about 0.1% to about 2.5%, by weight of the nutritional composition. In some specific embodiments, the nutritional compositions include about 0.38%> or about 0.71%, by weight HMB.

[0074] The nutritional compositions of the present disclosure desirably include sufficient HMB to provide an individual with from about 0.1 grams to about 10 grams, including from about 0.5 grams to about 10 grams, including from about 1 gram to about 8 grams, including from about 2 grams to about 7 grams, and also including from about 3 grams to about 6 grams, per day of HMB. In one specific embodiment, the daily intake of HMB by the individual is about 3 grams. The total daily HMB may be contained in one, two, three, or more servings of the nutritional composition. Methods of Manufacture

[0075] The nutritional products for use herein may be manufactured by any known or otherwise suitable method for making the nutritional product form selected. When manufactured as nutritional liquids, the nutritional liquids may either be suitably sterilized by aseptic sterilization or by retort sterilization. Nutritional liquids may be prepared, for example, by any of the well known methods of formulating nutritional liquids by way of retort, aseptic packaging, or hot fill processing methods. Such methods are well known in the nutrition formulation and manufacturing arts.

[0076] In one suitable manufacturing process, for example, at least three separate slurries are prepared, including a protein-in-fat (PIF) slurry, a carbohydrate- mineral (CHO-MIN) slurry, and a protein-in-water (PIW) slurry. The PIF slurry is formed by heating and mixing the oil (e.g., canola oil, corn oil, etc.) and then adding an emulsifier (e.g., lecithin), fat soluble vitamins, and a portion of the total protein (e.g., intact pea protein concentrate, milk protein concentrate, etc.) with continued heat and agitation. The CHO-MIN slurry is formed by adding with heated agitation to water: minerals (e.g., potassium citrate, dipotassium phosphate, sodium citrate, etc.), trace and ultra trace minerals (TM/UTM premix), thickening or suspending agent. The resulting CHO-MIN slurry is held for 10 minutes with continued heat and agitation before adding additional minerals (e.g., potassium chloride, magnesium carbonate, potassium iodide, etc.), and/or carbohydrates (e.g., synthetic sweetener, glycerine, etc.). The PIW slurry is then formed by mixing with heat and agitation the remaining protein, if any.

[0077] The resulting slurries are then blended together with heated agitation and the pH adjusted to 6.6-7.0, after which the composition is subjected to high- temperature short-time (HTST) processing during which the composition is heat treated, emulsified and homogenized, and then allowed to cool. Water soluble vitamins and ascorbic acid are added, the pH is adjusted to the desired range if necessary, flavors are added, and water is added to achieve the desired total solid level. The composition is then aseptically packaged to form an aseptically packaged nutritional emulsion. This emulsion can then be further diluted, heat-treated, and packaged to form a ready-to-feed or concentrated liquid.

[0078] In another embodiment, the nutritional composition is a solid nutritional composition such as a nutritional powder. Any methods known in the nutritional art for preparing nutritional powders may be used herein. By way of example, the nutritional powders can be prepared by drying the heated, homogenized liquid nutritional composition described above, such as by spray drying.

Methods of Use

[0079] The nutritional compositions as described herein comprise a combination of Curcumin and EGCg. By utilizing the combination in the nutritional compositions, and particularly in low glycemic index nutritional compositions, the nutritional compositions can be administered to diabetic individuals, as well as individuals having similar metabolic dysfunctions, to improve body composition by preserving lean body mass and decreasing fat mass via increasing lipolysis in adipose tissue. Surprisingly, the low glycemic index nutritional compositions including the combination of Curcumin and EGCg have a synergistic effect on preventing muscle atrophy in diabetic individuals, thereby preventing skeletal muscle mass loss, and further even increasing skeletal muscle mass in the individual. Accordingly, the low glycemic index nutritional compositions comprising Curcumin and EGCg may be useful in the treatment or prevention of sarcopenia, cachexia, or disease associated wasting, including, but not limited to wasting associated with cancer, HIV/ AIDS, congestive heart failure, chronic obstructive pulmonary disorder (COPD), and renal failure. The combination also targets muscle mass loss following periods of extended muscle disuse (e.g., hospitalization and rehabilitation).

[0080] Additionally, the low glycemic nutritional compositions including the combination of Curcumin and EGCg may be used in methods for improving body composition in diabetic individuals. Particularly, the combination of Curcumin and EGCg decreases fat deposition leading to improved blood glucose control and insulin sensitivity. [0081] The combination of Curcumin and EGCg may be administered to a subset of individuals in need of improved body composition. Some individuals that are in specific need of improved body composition may include infants, pediatrics, teens, or adults who have insulin resistance, pre-diabetes, and/or diabetes (infants, pediatrics, teens, or adults susceptible to or at elevated risk of insulin resistance, prediabetes, or diabetes), infants, pediatrics, teens, or adults who experience an extended period of muscle disuse such as during hospitalization or rehabilitation (infants, pediatrics, teens, or adults susceptible to or at elevated risk of experiencing extended periods of muscle disuse), and the like. Preterm infants, infants, pediatrics, teens, adults, and older adults may be susceptible to or at elevated risk for experiencing these diseases and conditions due to family history, age, environment, and/or lifestyle. Based on the foregoing, because some of the method embodiments of the present disclosure are directed to specific subsets or subclasses of identified individuals (that is, the subset or subclass of individuals "in need" of assistance in addressing one or more specific conditions noted herein), not all individuals will fall within the subset or subclass of individuals as described herein for certain diseases or conditions.

[0082] The individual desirably consumes at least one serving of the nutritional composition daily, and in some embodiments, may consume two, three, or even more servings per day. Each serving is desirably administered as a single, undivided dose, although the serving may also be divided into two or more partial or divided servings to be taken at two or more times during the day. The methods of the present disclosure include continuous day after day administration, as well as periodic or limited administration, although continuous day after day administration is generally desirable. The methods of the present disclosure are preferably applied on a daily basis, wherein the daily administration is maintained continuously for at least 3 days, including at least 5 days, including at least 1 month, including at least 4 weeks, including at least 8 weeks, including at least 2 months, including at least 6 months, desirably for at least 18-24 months, desirably as a long term, continuous, daily, dietary supplement. [0083] These compositions may be administered as a dietary supplement. Particularly, the methods of the present disclosure may be employed such that the composition is administered before, during, or after intake of a meal.

EXAMPLES

[0084] The following examples illustrate specific embodiments and or features of the nutritional compositions of the present disclosure. The examples are given solely for the purpose of illustration and are not to be construed as limitations of the present disclosure, as many variations thereof are possible without departing from the spirit and scope of the disclosure. All exemplified amounts are weight

percentages based upon the total weight of the composition, unless otherwise specified.

[0085] The exemplified compositions are nutritional products prepared in accordance with manufacturing methods well known in the nutrition industry for preparing nutritional compositions.

Example 1

[0086] In this Example, the effects of nutritional compositions including Curcumin and/or EGCg on muscle mass and fat deposition in diabetic rats were evaluated.

[0087] A chronic 6-week feeding study was carried out on Zucker Diabetic Fatty (ZDF) rats (5 weeks old) whose diets were supplemented with one of a combination of Curcumin C3 complex and EGCg; a control non-supplemented diet group; Curcumin C3 complex; and EGCg.

Experimental groups: 4 groups (n=12 per group)

1. Control 5008 rat chow diet

2. 5008 diet + Curcumin (Sabinsa) 1% diet (500 mg/kg BW)

3. 5008 diet + EGCg (Teavigo) 0.75% diet (375 mg/kg BW) 4. Curcumin 1% diet + EGCg 0.75% diet

[0088] At the end of the 6-week feeding period, animals were sacrificed and gastrocnemius muscles were isolated, fixed and mounted in OCT medium and frozen in isopentane. Muscles were cryosectioned and mounted on slides to measure muscle fiber cross section area by microscopy following H&E staining. Increase in muscle fiber cross section area (CSA) is an early indicator of muscle hypertrophy and correlated with increase in muscle mass and strength. Results are shown in the FIG. 1 as well as in the table below.

* Significant Change

[0089] As shown in FIG. 1, the chronic feeding of a combination of Curcumin and EGCg to obese diabetic rats resulted in a significant increase in muscle fiber cross section area significantly as compared to the control group or either individual ingredient alone. This indicates that the combination of Curcumin and EGCg has a synergistic effect on preventing muscle atrophy in the milieu of diabetes, inflammation and metabolic syndrome. Surprisingly, the individual ingredients did not have an effect on muscle mass as measured by muscle fiber cross section area (CSA) although they have been shown to be efficacious in other types of muscle atrophy (sarcopenia, cachexia, etc.). [0090] Additionally, adipose tissue from the animals was isolated, frozen in liquid N₂, and tissue extracts were prepared to remove protein, to dislodge small molecules bound to the protein and/or physically trapped in the precipitated protein matrix, and to recover metabolites using methodologies available from Metabolon, Inc. (Durham, North Carolina). Adipose tissue extract samples were split into equal parts for analysis on GC/MS and LC/MS/MS platforms. Metabolon software was used to match ions to an in-house Metabolon library of standards for metabolite identification and quantification by peak area integration. Results are shown in FIG. 2. Box plots were used to convey the spread of the data with the middle 50% of the data represented by the boxes and the whiskers reporting the range of the data. The solid bar across the box represents the median value of those measured while the + is the mean. Data are scaled such that the median value measured across all samples was set to 1.0. Any outliers are shown as dots outside the whiskers of the plot.

[0091] As shown in FIG. 2, metabolomic analysis on the adipose tissue samples indicated that glycerol levels increased significantly with the combination of Curcumin and EGCg treatment as compared to either ingredient alone or compared to the control. This suggests that lipolysis was increased in the adipose tissue, indicating a decrease in fat deposition and/or increase in fat utilization that could lead to decrease in inflammation and metabolic syndrome.

Examples 2-6

[0092] Examples 2-6 illustrate aseptically processed liquid nutritional emulsions of the present disclosure, the ingredients of which are listed in the table below. All ingredient amounts are listed as kg per 1000 kg batch of product, unless otherwise specified.

Claims

WHAT IS CLAIMED IS:

1. A method of preventing skeletal muscle mass loss in a diabetic individual in need thereof comprising administering to the diabetic individual a nutritional composition comprising Curcumin and epigallocatechin gallate.

2. The method of claim 1 wherein the Curcumin is bioavailable Curcumin.

3. The method of claim 1 wherein the nutritional composition comprises from about 0.001% to about 10.0% by weight of Curcumin.

4. The method of claim 1 wherein the nutritional composition comprises from about 0.1% to about 10% by weight of epigallocatechin gallate.

5. The method of claim 1 wherein the nutritional composition further comprises at least one of protein, carbohydrate, and fat.

6. The method of claim 1 wherein the nutritional composition is a low glycemic index nutritional composition.

7. The method of claim 1 wherein the nutritional composition further comprises at least one of protein and carbohydrate, and from 0 wt% to about 1 wt% lipid.

8. A method of increasing skeletal muscle mass in a diabetic individual in need thereof comprising administering to the diabetic individual a nutritional composition comprising Curcumin and epigallocatechin gallate.

9. The method of claim 8 wherein the Curcumin is bioavailable Curcumin.

10. The method of claim 8 wherein the nutritional composition comprises from about 0.001 ) to about 3.36%> by weight of Curcumin.

11. The method of claim 8 wherein the nutritional composition comprises from about 0.1% to about 10% by weight of epigallocatechin gallate.

12. The method of claim 8 wherein the nutritional composition further comprises at least one of protein, carbohydrate, and fat.

13. The method of claim 8 wherein the nutritional composition is a low glycemic index nutritional composition.

14. A method of increasing lipolysis in adipose tissue of a diabetic individual in need thereof comprising administering to the diabetic individual a nutritional composition comprising Curcumin and epigallocatechin gallate.

15. The method of claim 14 wherein the Curcumin is bioavailable Curcumin.

16. The method of claim 14 wherein the nutritional composition comprises from about 0.001% to about 3.36% by weight of Curcumin.

17. The method of claim 14 wherein the nutritional composition comprises from about 0.1% to about 10% by weight of epigallocatechin gallate.

18. The method of claim 14 wherein the nutritional composition further comprises at least one of protein, carbohydrate, and fat.

19. The method of claim 14 wherein the nutritional composition is a low glycemic index nutritional composition.

20. A low glycemic nutritional composition comprising Curcumin and

epigallocatechin gallate.

21. The low glycemic nutritional composition of claim 20 comprising from about 0.001 ) to about 3.36%> by weight of Curcumin.

22. The low glycemic nutritional composition of claim 20 comprising from about 0.1% to about 10% by weight of epigallocatechin gallate.

23. The low glycemic nutritional composition of claim 20 further comprising at least one of protein, carbohydrate, and fat.

24. A composition comprising Curcumin and EGCg for use in treating or preventing sarcopenia, cachexia, or disease associated wasting in an individual in need thereof.

25. The composition according to claim 24, wherein the individual in need thereof is a diabetic human.

26. The composition according to claim 24, further comprising about 0.001% to about 3.36%) of Curcumin by weight of the composition and about 0.1 % to about 10%> of epigallocatechin gallate.

27. The composition according to any one of claims 24-26, wherein the composition further comprises about 1% to about 30%> of at least one source of protein by weight of the nutritional composition.