Patent Description:
Insulin resistance (IR) is a pathological condition in which cells fail to respond normally to the hormone insulin. The body produces insulin when glucose starts to be released into the bloodstream from the digestion of carbohydrates in the diet. Normally this insulin response triggers glucose being taken into body cells, to be used for energy, and inhibits the body from using fat for energy. The concentration of glucose in the blood decreases as a result, staying within the normal range of approximately <NUM> mmol/L (mM) even when a large amount of carbohydrates is consumed. However, when the body produces insulin under conditions of IR, the cells are resistant to the insulin and are unable to use it as effectively, leading to high blood sugar. Beta cells in the pancreas subsequently increase their production of insulin, further contributing to a high blood insulin level. This can contribute to the development of pre-diabetes followed by type <NUM> diabetes.

<CIT> describes a combination of zinc and vitamin D for use in improving insulin sensitivity, treating or preventing an impaired glucose tolerance, type II diabetes, gestational diabetes mellitus, or preventing a condition associated with any of these conditions in a subject. <NPL>, investigates the role between vitamin D status and insulin sensitivity in adults using data collated from studies in the literature.

The worldwide high prevalence of overweight and obesity within an aging population creates challenges for society and health care systems. For instance, in The Netherlands at present more than <NUM>% of the over <NUM> year old population is overweight and more than <NUM>% is obese. Overweight, obesity and aging are all associated with a higher risk of IR.

It is thus important to find a method to ameliorate insulin resistance or, in other words, how to increase insulin sensitivity, by improvement of the management of insulin sensitivity during aging and especially in conditions of overweight and obesity.

<NPL> have shown that a high-protein, leucine and vitamin D enriched oral nutritional supplement (ONS) preserves skeletal muscle mass compared to an iso-caloric control supplement in older obese adults participating in a calorie restriction diet and resistance exercise program during a <NUM>-week randomised controlled study.

For the present invention, the inventors surprisingly found that said composition did not show a significant effect on glucose uptake, but synergistically decreased insulin resistance, increased insulin sensitivity and decreased fasting insulin levels in obese or overweight older adults during a lifestyle intervention. A hypocaloric diet in combination with resistance exercise resulted in significant weight loss, improved fasting glucose levels and improved plasma HbA1c. Surprisingly, addition of the composition according to the invention on top of lifestyle intervention and hypocaloric diet did not have any effects on plasma glucose levels but showed additional benefits by decreasing insulin resistance, increasing insulin sensitivity and decreasing fasting insulin levels. These findings are particularly of value for those subjects that suffer or are at risk of increased insulin resistance, impaired insulin sensitivity and increased fasting insulin levels.

The invention pertains to a nutritional product for therapeutic use in decreasing fasting insulin levels, increasing insulin sensitivity or decreasing insulin resistance, in older obese or overweight adults of at least <NUM> years of age preferably during a lifestyle intervention, such as participating in a weight loss program involving a physical exercise regimen and a hypo-caloric dietary regimen, wherein said product comprises per serving between <NUM> - <NUM> kcal, preferably <NUM> - <NUM> kcal; between <NUM> and <NUM> proteinaceous matter, preferably <NUM>- <NUM> proteinaceous matter; and at least <NUM> microgram vitamin D. Preferably the serving is administered at least once per day as a single shot. Lifestyle intervention is preferably defined as any intervention including exercise, diet and/or a weight loss program. The lifestyle intervention is preferably a weight loss program involving a physical exercise regime and a hypocaloric dietary regime. The invention particularly pertains to obese or overweight adults of at least <NUM> years of age who are participating in a weight loss program, said older adult preferably following a hypocaloric diet in combination with an exercise regimen, preferably resistance exercise training. Preferably the serving is administered at least once per day as a single shot.

Preferably, the invention pertains to a nutritional composition or product with the above characteristics, in conjunction with a weight loss program for therapeutic use in decreasing fasting insulin levels, increasing insulin sensitivity or decreasing insulin resistance, in older obese or overweight adults of at least <NUM> years of age. Preferably the composition is administered at least once a day, in a single shot, to adults that suffer from overweight or obesity and/or adults suffering from a disease or condition selected from the group consisting of pre-diabetes type <NUM>, or diabetes type <NUM>.

In a preferred embodiment, said adults are fed <NUM> - <NUM> dry weight of the nutritional composition daily, in a single dose or as multiple doses, wherein the nutritional composition has an energy density of between <NUM> and <NUM> kcal per <NUM> dry weight, and, in terms of dry weight: between <NUM> and <NUM> wt% proteinaceous matter, including between <NUM> and <NUM> wt% leucine as free amino acid, peptide and/or salt thereof, less than 50wt% carbohydrates, and between <NUM> and <NUM> wt% dietary fiber, between <NUM> and <NUM> microgram vitamin D. Preferably the serving is administered at least once per day as a single shot.

The older obese or overweight adult is preferably suffering from a disease or condition selected from the group consisting of pre-diabetes type <NUM>, or diabetes type <NUM>.

Throughout the specification and claims, the older adult is a human being.

Obesity is defined as an unhealthy excess of body fat, which increases the risk of medical illness and premature mortality. BMI, calculated as body weight (in kg) divided by the square of height (in m), has been widely used and accepted as a simple method to classify medical risk by weight status. The classification 'overweight' is reserved for BMI of <NUM> - <NUM>, while 'obesity' is characterized by a BMI of <NUM> or higher. The prevalence of obesity (defined as BMI of <NUM> or higher) among older adult is rising in The Netherlands. At present, more than <NUM>% of the population above <NUM> years of age is obese. As the prevalence of both ageing and obesity is increasing, obese older adult are a significant target population for research. Obesity is clearly related to metabolic risk factors for cardiovascular diseases and diabetes mellitus.

Prediabetes is the precursor stage before diabetes mellitus in which not all of the symptoms required to diagnose diabetes are present, but blood sugar is abnormally high. Adults suffering from prediabetes are at increased risk for diabetes and cardiovascular disease (CVD). Prediabetes is associated with obesity. It is thus a metabolic diathesis or syndrome, and it usually involves no symptoms but impaired fasting blood sugar and impaired glucose tolerance which are similar in clinical definitions for diabetes.

The inventors surprisingly found that a nutritional supplement, specifically designed for older adults is particularly useful in decreasing fasting insulin levels, increasing insulin sensitivity and decreasing insulin resistance in older adults belonging to the group of pre-diabetes type <NUM> or diabetes type <NUM> during a weight loss program involving exercise or training. The results are reported in the clinical evidence further below.

In the context of this application, the term "at least" also includes the starting point of the open range. For example, an amount of "at least <NUM> wt%" means any amount equal to <NUM> weight % or above.

The term 'proteinaceous matter' comprises all protein, in intact or hydrolyzed form, di- and tripeptides as well as free amino acids, and salts thereof. It includes a protein or any part derivable of a protein, such as but not limited to non-hydrolyzed protein, native protein, hydrolyzed protein, peptides, such as oligopeptides and dipeptides, and amino acids. Leucine as non-protein bound free amino acid is part of proteinaceous matter, but for instance citrulline, and creatine would not fall within the definition.

In the context of this application, the older adult is an older adult human of the age of <NUM> years or more, more preferably of <NUM> years or more, in particular of the age of <NUM> or more, more in particular of the age of <NUM> or more.

In the context of this application the term "daily dose" means the serving size indicating the amount of the nutrition information which is administered to the older adult per day. Preferably a daily dose is limited to between <NUM> and <NUM> kcal, even more preferably between <NUM> and <NUM> kcal per day. Preferably the daily dose is given in <NUM> to <NUM> servings per day, more preferably <NUM> or <NUM> servings, or most preferably <NUM> serving per day.

It is preferred that the nutritional composition of the invention comprises predominantly fast-digestible protein (referring to the rate of appearance in the circulation of the amino acids following whey ingestion) and to consume the nutritional composition at least once in a single shot per day. With 'fast-digestible protein' it is understood to include hydrolyzates of any protein source (including vegetable proteins and milk protein sources), free amino acids, and/or whey protein. Since the taste of whey protein is most appreciated, this protein source is preferred. As further detailed below, it is preferred that the composition is leucine-enriched.

In the context of this application the term serving or administration at once means that the serving is preferably consumed as a shot within a time span of <NUM> minutes, more preferably within <NUM> minutes, even more preferably within <NUM> minutes.

In the context of the invention, with a 'weight loss program' it is understood a program involving (a) a dietary calorie restriction (i.e. a hypocaloric dietary regimen) in conjunction with (b) a physical exercise regimen.

The older adults are advised to adhere to a protocol of dietary restriction in terms of limited daily caloric intake, i.e. a 'hypo-caloric' or low-caloric dietary regimen. According to dietary guidelines, such a hypo-caloric dietary regimen preferably involves a restriction of the total daily caloric intake of a human being that is <NUM> - <NUM>% of his or her average total daily intake. The average total daily intake of the target group of older adults is well-documented, and it is considered within the ambits of the skilled person's knowledge to determine a suitable meal plan and the caloric restrictions of a hypocaloric dietary regime. According to FAO publication; Human energy requirements, Report of a Joint FAO/WHO/UNU Expert Consultation Rome, <NUM>-<NUM> October <NUM> the energy requirements of humans have been established. As summarised in the below table, cited from this report, the energy requirements depend on the age, bodyweight (BMI), and physical activity level (PAL). The content of the above report is herewith considered incorporated by reference.

According to the present invention the term "hypocaloric diet" preferably means a diet that delivers the daily energy expenditure (total energy expenditure; TEE) or less (in calories) when calculated without the physical exercise program. TEE may also be referred to in the art as the 'TDEE' (i.e. total daily energy expenditure). For instance, an overweight male between <NUM> and <NUM> years old has a TEE of <NUM> kcal/kg body weight. According to the invention, a hypo-caloric diet will thus provide at most <NUM> kcal/kg body weight. Dependent on patient's age and gender, the skilled person can straightforwardly calculate the caloric consequences of a hypo-caloric diet for an overweight or obese person from these tables. It is preferred that the hypo-caloric diet provides <NUM> - <NUM> %, preferably <NUM> - <NUM> %, more preferably <NUM>- <NUM> % of the TEE of the targeted subject. Additionally or alternatively, in terms of absolute numbers the hypo-caloric diet may involve a caloric content of more than <NUM> kcal below estimated needs of the targeted subject, preferably assessed in terms of TEE or in accordance with WHO guidelines, more preferably a hypo-caloric diet of <NUM> - <NUM> kcal below estimated needs of the targeted subject (preferably assessed through TEE or WHO guidelines), dependent on the subjects age, gender, BMI and daily activities. TEE may for instance be assessed by means of the doubly labelled water method (TEEDLW). This method is widely regarded as the 'gold standard' for estimating TEE in free-living individuals. Reference is made to for instance <NPL>, its contents herein incorporated by reference. TEE can also be estimated by methods such as indirect calorimetry of formulas such as the Harrison and Benedict multiplied with a physical activity score.

The physical exercise regimen involves any physical exercise or activity other than or in addition to daily living activities that contributes to a negative energy balance or an activity that costs calories during that activity. Physical activity examples can be, but not limited to, resistance exercise, aerobic exercise or flexibility training or combinations thereof. Endurance training is not recommended, at least not as the sole source of physical exercise It is preferred that the physical exercise regimen involves at least resistance exercise, due to its well-known effects on muscle mass maintenance and stimulation of muscle mass increase. Activity patterns could vary from engaging in the above one or more physical activities for a minimum of <NUM> time per week but preferably <NUM> times per week and more preferably <NUM> or more times per week, including at least some form of resistance exercise. There are ACSM/AHA Guidelines for flexibility, endurance and resistance exercise which can be of help to the skilled person to determine a suitable physical exercise regimen, and these are considered incorporated by reference here. The physical exercise regimen involves daily physical exercise activities as described above, preferably comprising resistance exercise. The physical exercise regimen is preferably in accordance with ACSM/AHA guidelines, their contents herein incorporated by reference. In a preferred embodiment, the physical exercise regimen involves resistance exercise according to ACSM/AHA Guidelines.

Depending on the design of the hypocaloric diet, within the weight loss program, the composition for use according to the invention preferably has a low caloric content, i.e. preferably not exceeding <NUM> kcal/<NUM> (i.e. at most <NUM> kcal per ml) or preferably not exceeding <NUM> kcal/<NUM> (i.e. at most <NUM> kcal per ml). In an embodiment, the composition preferably has per serving a caloric content between <NUM>-<NUM> kcal preferably between <NUM> and <NUM> kcal, particularly <NUM> - <NUM> kcal of the composition administered to the older adult. In one embodiment, the composition has a caloric content of at most <NUM>, preferably between <NUM> and <NUM> kcal fed to the older adult per day. In one embodiment, the composition has a caloric content of at most <NUM>, preferably between <NUM> and <NUM> kcal per daily dose. A serving preferably involves <NUM> - <NUM>, more preferably <NUM> - <NUM>; and. /or <NUM> - <NUM> dry matter, more preferably <NUM> - <NUM> dry matter. Unless specified otherwise, as a guide the skilled person could convert the relative amounts of the various ingredients in terms of caloric content to volume assuming a serving of <NUM> kcal and <NUM>.

An embodiment of the invention thus pertains to a nutritional composition for therapeutic use in decreasing fasting insulin levels, increasing insulin sensitivity or decreasing insulin resistance, in older obese or overweight adults of at least <NUM> years of age participating in a weight loss program, said composition comprising per daily dose between <NUM> and <NUM> proteinaceous matter, at least <NUM> microgram vitamin D and between <NUM> - <NUM> kcal energy content, wherein preferably at least <NUM> wt%, more preferably between <NUM> and <NUM> wt% of the total proteinaceous matter is leucine (as the sum of all leucine bound or in free form). The proteinaceous matter preferably comprises at least <NUM> wt%, more preferably at least <NUM> wt% whey protein, based on proteinaceous matter.

An embodiment of the invention thus pertains to a nutritional composition for use in decreasing fasting insulin levels, increasing insulin sensitivity or decreasing insulin resistance, in older obese or overweight adults of at least <NUM> years of age participating in a weight loss program, comprising per serving between <NUM> - <NUM> kcal; between <NUM> and <NUM> proteinaceous matter; and at least <NUM> microgram vitamin D, wherein the proteinaceous matter preferably comprises at least <NUM> wt%, more preferably at least <NUM>% whey protein (based on proteinaceous matter) and wherein preferably at least <NUM> wt%, more preferably between <NUM> and <NUM> wt% of the total proteinaceous matter is leucine (as the sum of all leucine bound or in free form).

The preferred proteinaceous matter is detailed further on.

Since food intake is reduced during a weight loss program the composition according to the invention is preferably enriched with nutritional ingredients like vitamins and minerals. In a preferred embodiment according to the invention the composition used in the weight loss program comprises all nutritional ingredients recommended according to the nutritional guidelines for the older adults including calcium source and vitamin D source. Preferably a serving of the composition for use according to the invention comprises calcium in an amount between <NUM> and <NUM>. A serving of the composition for use according to the invention comprises at least <NUM> microgram vit D, preferably between <NUM> and <NUM> microgram and even more preferably between <NUM> and <NUM> microgram vit D (per serving). The RDA [recommended daily allowance] of vitamin D is about <NUM> microgram on basis of low sun exposure. Due to low sun light exposure of many older adults the inventors believe that high doses of vit D are particularly useful in the older adult target group. A serving for use according to the invention comprises at least <NUM>, more preferably at least <NUM> and even more preferably at least <NUM> microgram vitamin D per 100kcal of the serving. The term 'vitamin D' in the context of the invention refers to all physiological forms of vitamin D and its metabolite (i.e. <NUM> OHD), either D<NUM>, D<NUM>, D<NUM> or D<NUM>, in particular D<NUM> and D<NUM>, or any mixture thereof. In the context of this application, <NUM> IU of vitamin D is the biological equivalent of <NUM>µg. Hence, <NUM>,<NUM> IU is the biological equivalent of <NUM>µg.

The protein or proteinaceous content of the composition comprises a sufficient amount of protein to assure at least a protein intake of between <NUM> and <NUM> protein, preferably between <NUM> and <NUM> and even more preferably between <NUM> and <NUM> protein per serving. In the preferred embodiment the serving(s) are consumed at or around breakfast, since most breakfasts are low in protein, or around the moment of exercise. Alternatively, in a preferred embodiment a daily protein intake as supplemented to the older adults provides at least <NUM> proteinaceous matter / kg body weight, preferably at least <NUM>, even more preferably more than <NUM> and most preferably at least <NUM> proteinaceous matter per kg body weight. In a most preferred embodiment, there is less than <NUM> proteinaceous matter per kg body weight provided.

The source of proteinaceous matter may be provided separately, in the form of a meal, a food supplement, a drink, or in any other form or may be combined in a single nutritional composition.

The proteinaceous matter originates from high quality protein, preferably high in branched chain amino acids. Proteins such as vegetable proteins soy or pea, more preferably animal protein such as egg or dairy, even more preferably fast digestible animal protein, such as whey protein are used. The amino acids are essentially L-amino acids as only L-amino acids are metabolically relevant in the context of this invention. The protein fraction is preferably high in branched chain amino acids (leucine, valine, isoleucine). An advantage of providing these amino acids in the form of protein is to avoid the adverse sensory impact of added amino acids, but also to create a favourable physiological response due to the high protein composition.

The nutritional composition according to the invention comprises <NUM> - <NUM> of proteinaceous matter per serving. Preferably, the composition comprises at least about <NUM>, at least about <NUM>, and most preferably at least about <NUM> of proteinaceous matter per serving. In a most preferred embodiment, there is less than <NUM> proteinaceous matter per serving.

According to another embodiment, the nutritional composition according to the invention comprises at least about <NUM> en% of proteinaceous matter per <NUM> kcal. Preferably, the composition comprises between <NUM> and <NUM> en% of proteinaceous matter per <NUM> kcal. Preferably at least about <NUM>, <NUM>, or <NUM> en%, at least about <NUM> en%, at least about <NUM> en%, at least about <NUM> en%, and most preferably at least about <NUM> en% of proteinaceous matter per <NUM> kcal.

According to a preferred embodiment, the proteinaceous matter according to the invention comprises between <NUM> and <NUM> wt% whey protein, preferably at least about <NUM> wt% of whey protein, preferably at least about <NUM> wt% of whey protein, preferably at least about <NUM> wt%, and most preferably about <NUM> wt% of whey protein. Whey protein is considered a fast protein referring to the rate of appearance in the circulation of the amino acids following whey ingestion. In addition, whey protein is inherently high in branched chain amino acids (leucine, valine, isoleucine).

The whey protein may be provided as an intact whey protein, a hydrolysed whey protein, a microparticular whey protein, a nanoparticular whey protein, a micellar whey protein, and the like. Preferably, the whey protein is an intact whey protein, i.e. a whey protein in its intact form, such as present in fresh milk. As a source of whey protein to be used in the present invention, any commercially available whey protein source may be used, i.e. whey obtained by any process for the preparation of whey known in the art, as well as whey protein fractions prepared thereof, or in the form of proteins that constitute the bulk of the whey, i.e. being β-lactoglobulin, α-lactalbumin and serum albumin. The whey protein may be provided as liquid whey, or whey in powder form, such as whey protein isolate (WPI) or whey protein concentrate (WPC). Whey protein concentrate is rich in whey proteins, but also contains other components such as fat, lactose and glycomacroprotein (GMP), a casein-related non-globular protein. Typically, whey protein concentrate is produced by membrane filtration. On the other hand, whey protein isolate consists primarily of whey proteins with minimal amounts of fat and lactose. Whey protein isolate usually requires a more rigorous separation process such as a combination of microfiltration and ultra-filtration or ion exchange chromatography. It is generally understood that a whey protein isolate refers to a mixture in which at least <NUM> wt% of the solids are whey proteins. A whey protein concentrate is understood as having a percentage of whey proteins between the initial amount in the by-product (about <NUM> wt%) and a whey protein isolate. In particular, sweet whey, obtained as a by-product in the manufacturing of cheese, acid whey, obtained as a by-product in the manufacturing of acid casein, native whey, obtained by milk microfiltration or rennet whey, obtained as a by-product in the manufacturing of rennet casein, may be used as a source of whey proteins.

Furthermore, whey proteins may originate from all kinds of mammalian animal species, such as, for instance cows, sheep, goats, horses, buffalo's, and camels. Preferably, the whey protein is of bovine origin.

Preferably, the whey protein source is available as a powder, preferably the whey protein source is a WPC or WPI.

According to another embodiment, the proteinaceous matter according to the invention comprises at least about <NUM> wt% of essential amino acids (EAA), preferably at least about <NUM> wt%, and more preferably at least about <NUM> wt% of EAA. Essential amino acids are amino acids selected from the group of isoleucine (Ile), leucine (Leu), lysine (Lys), methionine (Met), phenylalanine (Phe), threonine (Thr), tryptophan (Trp), histidine (His) and valine (Val). Since native whey protein and casein protein comprise (depending on the source) maximum about <NUM> and <NUM> wt% of EAA, respectively, it may be necessary to add EAAs to the nutritional composition, such as in the form of amino acids or peptides, to arrive at the preferred amount of at least <NUM> wt%.

According to another embodiment, the proteinaceous matter according to the invention comprises total leucine, total valine and total isoleucine in a total leucine:valine:isoleucine weight ratio of about <NUM>-<NUM>:<NUM>:<NUM>, preferably about <NUM>:<NUM>:<NUM>. Alternatively, the weight ratio of leucine : (valine + isoleucine) is about <NUM> or higher, preferably <NUM> or higher. Suitable valine and isoleucine levels may be provided by the whey protein, or may be provided by added amino acids, either in free form as bases or salts, or as peptides.

The composition of the present invention preferably involves the use of an anabolic amino acid-derived stimulus, which is defined as a chemical compound derived from or which is a precursor to an amino acid (hence, amino acid derived).

Preferably, the anabolic amino acid-derived stimulus is one or more selected from the group of L-leucine, β-hydroxy-β-methylbutyrate, β-hydroxy-β-methylbutyrate free acid, calcium-β-hydroxy-β-methylbutyrate, hydroxyl iso caproic acid, ketoisocaproic acid, citrulline, and creatine. Most preferably, the anabolic amino acid-derived stimulus is an amino acid selected from the group of L-leucine, β-hydroxy-β-methylbutyrate and citrulline. β-hydroxy-β-methylbutyrate and citruline have an improved effect on the palatability and hence compliance of the product compared to L-leucine. It is particularly preferred to use β-hydroxy-β-methylbutyrate or citrulline or both in concentrations higher than <NUM>/<NUM>. L-leucine (hereafter also called leucine, since the R-form of leucine is biologically not relevant in the context of this invention) is an essential amino acid, being part of a diverse number of proteins and, together with valine and isoleucine, belongs to the group of branched-chain amino acids. Leucine may be used as a free amino acid, or in a bound form, such as a dipeptide, an oligopeptide, a polypeptide or as part of a protein. Common protein sources of leucine are dairy proteins such as whey, casein, micellar casein, caseinate, and glycomacroprotein (GMP), and vegetable proteins such as wheat, rice, pea, lupine and soy proteins. Said sources of protein may provide intact proteins, hydrolysates or mixtures thereof, hereafter further called proteinaceous matter.

In one embodiment, anabolic amino acid is provided in a daily dosage of <NUM> to <NUM>. In one embodiment, it is preferred to provide at least leucine. When leucine is provided as anabolic amino acid, the proteinaceous matter preferably comprises at least about <NUM> wt% of leucine, based on the total weight of the proteinaceous matter. Preferably, said proteinaceous matter comprises between <NUM> and <NUM> wt% of leucine. In a preferred embodiment part of the leucine may be replaced by one or more amino acid derived stimuli mentioned above, preferably anabolic amino acids selected from the group consisting of β-hydroxy-β-methylbutyrate, β-hydroxy-β-methylbutyrate free acid, calcium-β-hydroxy-β-methylbutyrate, hydroxyl iso caproic acid and ketoisocaproic acid, creatine and citrulline.

Preferably, at least about <NUM> %, preferably at least about <NUM> %, preferably at least about <NUM> % of total leucine is provided in free form, relative to the total amount of leucine. In the context of this application, with "free form" includes a peptide comprising <NUM> to <NUM> amino acids, preferably <NUM> to <NUM> amino acids, more preferably <NUM> amino acid. Preferably, leucine is a free amino acid, either as a base, a salt or a chelate. It is preferred that at most <NUM> %, more preferably at most <NUM> % of the leucine is provided as in free form, most preferably as a free amino acid.

Citrulline is an α-amino acid. Citrulline, in the form of citrulline malate, is sold as a performance-enhancing athletic dietary supplement which was suggested to promote aerobic energy production (human study) and to increase athletic performance and decreasing muscle soreness (human study). In the human body, citrulline is produced from ornithine and carbamoyl phosphate in one of the central reactions in the urea cycle. It is also produced from arginine in the body as a by-product of the reaction catalyzed by NOS family. Citrulline is also capable of promoting muscle protein synthesis and has been described in human and animal studies [see e.g. <CIT>]. Citrulline is commercially available and can be obtained, e.g. from Ajinomoto, Kyowa, and Biocodex. In one embodiment, citrulline is provided in a daily dosage between <NUM> to <NUM>, preferably between <NUM> and <NUM>, and even more preferably between <NUM> and <NUM>.

Creatine (N-(amino-imino-methyl)-N-methyl-glycine; methylglycocyamine) is a nitrogenous organic acid that is produced in vertebrates, in particular the human body from L-arginine, glycine, and L-methionine and helps to supply energy to muscles. Creatine is commercially available and can be obtained, e.g. from Sigma Aldrich, Alfa Aesar, and Aminolabs. In one embodiment, creatine is provided in a daily dosage of <NUM> to <NUM>, preferably between <NUM>-<NUM>, even more preferably between <NUM> and <NUM>.

Preferably, the anabolic amino acid-derived stimulus is provided in a daily dosage of <NUM> to <NUM>, preferably <NUM> to <NUM>. Preferably, such daily dosage is administered as a single serving.

In one embodiment, any combination of leucine, β-hydroxy-β-methylbutyrate and citrulline, citrulline, and creatine is provided in a daily dosage of <NUM> to <NUM>, preferably <NUM> to <NUM>.

According to one embodiment, the anabolic amino acid-derived stimulus in combination with vitamin D is used for the manufacture of a medicament. In the context of this application, a medicament is an embodiment of the invention which does not, or does not substantially contain caloric components, such as carbohydrates, fat and proteinaceous matter, other than the components according to the invention.

The medicament may be administered sequentially or simultaneously with said caloric components, in particular a protein source. Said caloric components may be provided separately, in the form of a meal, a food supplement, a drink, or in any other form.

According to an alternative embodiment, the anabolic amino acid-derived stimulus in combination with vitamin D is used for the manufacture of a nutritional composition. In the context of this application, a nutritional composition is an embodiment of the invention which contains, or substantially contains caloric components, such as carbohydrates, fat and proteinaceous matter, other than the components according to the invention.

According to one embodiment, the anabolic amino acid-derived stimulus in combination with vitamin D is used in combination with a source of proteinaceous matter to provide the necessary amino acids to prevent and/or treat a loss of muscle mass, a loss of muscle function, or both, in the older adult targeted.

According to a preferred embodiment, the nutritional composition according to the invention comprises at least one of a source of fat and a source of carbohydrates. The presence of one or both of these components effectively prohibits the excessive use of the protein as an energy source instead. Preferably the composition according to the invention comprises at least <NUM> en% carbohydrates and/or fat.

The total amount of energy supplied by the fat and/or carbohydrates (digestible and indigestible) preferably match the total energy supplied by the proteinaceous matter. Therefore, the total amount fat and/or carbohydrates preferably is at most about <NUM> en%, preferably at most about <NUM> en %, preferably at most about <NUM> en%, preferably at most about <NUM> en%.

In a preferred embodiment, the nutritional composition according to the invention comprises a source of fat and a source of carbohydrates, preferably in an amount of about <NUM> of fat and about <NUM> of digestible carbohydrates per <NUM> kcal.

With regard to the type of fat, a wide choice is possible, provided the fat is of food quality. The fat may either be an animal fat or a vegetable fat or both. Although animal fats such as lard or butter have essentially equal caloric and nutritional values and can be used interchangeably, vegetable or marine oils are highly preferred in the practice of the present invention due to their readily availability, absence of cholesterol and lower concentration of saturated fatty acids. The fat may include a source of medium chain fatty acids, such as medium chain triglycerides (MCT, mainly <NUM> to <NUM> carbon atoms long), a source of long chain fatty acids, such as long chain triglycerides (LCT) and phospholipid-bound fatty acids such as phospholipid-bound EPA or DHA, or any combination of the two types of sources. Unsaturated preferably mono-unsaturated, most preferably mono and poly-unsaturated LCT sources, such as canola oil, rapeseed oil, sunflower oil, soybean oil, olive oil, coconut oil, palm oil, linseed oil, marine oil or corn oil are beneficial because it is known that these LCTs may have beneficial effects in the human body. In a preferred embodiment according to the invention, the composition comprises a source of long chain poly unsaturated fatty acids (IcPUFA). Preferably the PUFA comprises at least <NUM>% alpha linolenic acid (C18, n3), eicosopentaenoic acid (EPA, C20, n3), or docosahexaenoic acid (C22, n3 DHA).

With regard to the type of carbohydrates, a wide choice is possible, provided the carbohydrates are of food quality. The digestible carbohydrates positively influence the energy level of a subject, and add to the advantageous effect of the nutritional composition according to the invention. The digestible carbohydrate may comprise either simple or complex carbohydrates, or any mixture thereof. Suitable for use in the present invention are glucose, fructose, sucrose, lactose, trehalose, palatinose, corn syrup, malt, maltose, isomaltose, partially hydrolysed corn starch, maltodextrins, glucose oligo- and poly-saccharides. More preferably sugars with a low glycemic index (GI) are used. Low GI sugars are sugars that are slowly released in the blood compared to glucose. Examples are fructose, palatinose, isomaltulose or maltodextrins. Preferably carbohydrates are used with a GI below <NUM>.

The composition for use according to the invention may optionally be fortified with dietary fibres or non-digestible carbohydrates such as galacto-oligosaccharides, fructooligosaccharides, inulin, and pectin (hydrolysed pectin, low-viscosity pectin (a pectin degradation product with a DP of <NUM> - <NUM>), or other pectin degradation products). In an embodiment of the present invention, the composition according to the invention comprises <NUM>/serving to <NUM>/serving of non-digestible carbohydrates, preferably <NUM>/serving to <NUM>/serving. The dietary fibres include non-digestible oligosaccharides having a DP of <NUM> to <NUM>, preferably <NUM> to <NUM>. More preferably, these oligosaccharides do not contain substantial amounts (less than <NUM> weight %) of saccharides outside these DP ranges, and they are soluble.

Preferably, the nutritional composition further comprises one or more dietary fibres, preferably having a degree of polymerization [DP] of <NUM> to <NUM>, more preferably a DP of <NUM> to <NUM>, more preferably DP <NUM> - <NUM>. The composition preferably comprises one or more dietary fibres selected from the group of short chain galactooligosaccharides (GOS), preferably having a DP <NUM> - <NUM>, preferably DP <NUM> - <NUM>, long chain fructooligosaccharides (FOS), including inulin (preferably having an average DP <NUM> - <NUM>), and low-viscosity pectin (preferably having an average DP <NUM> - <NUM>). The low-viscosity providing pectin such as Herbapekt SF <NUM>-LV has a molecular weight of about <NUM>,<NUM> Dalton to ensure its solubility. Due to the low viscosity it can be used in very high dosage without having a major influence on the texture of the desired product which is a beneficial effect of this type of pectin. In one embodiment, the composition preferably comprises at least one fiber selected from the group consisting of GOS and FOS, more preferably a mixture of GOS and FOS.

The nutritional composition according to the invention can advantageously be used for the prevention or treatment of a disease or condition involving decreasing fasting insulin levels, increasing insulin sensitivity or decreasing insulin resistance, in an older adult as defined here above, preferably an older adult participating in a weight loss program. Alternatively, the nutritional composition according to invention can advantageously be used for the prevention or treatment of a disease or condition selected from the group of (pre)-diabetes type <NUM>, or diabetes type <NUM>, in an older adult, preferably an older adult participating in a weight loss program. The weight loss program preferably comprises resistance exercise. The composition is preferably part of a hypocaloric diet, wherein the older adult receives (i) at least <NUM> kcal, preferably <NUM> - <NUM> kcal less than the daily energy expenditure (TEE) of the older adult, or (ii) <NUM> - <NUM> %, preferably <NUM> - <NUM> %, more preferably <NUM>- <NUM> % of the TEE of the older adult. The older adult preferably suffers from overweight or obesity.

Clinical study shows decreased fasting insulin levels, increased insulin sensitivity and decreased insulin resistance during a weight loss program in older adult.

Men and women (<NUM> to <NUM> years old, inclusive) with obesity (BMI higher than <NUM>/m<NUM>, or when BMI higher than <NUM>/m<NUM> with waist circumference higher than <NUM> (women) and > <NUM> (men)) being ambulant (pre-) type <NUM> diabetes patient were recruited from the Dutch population. Subjects were excluded from participation if they had had any malignant disease during the last five years, participated in any weight loss program three months before start of the study, it was potentially unsafe to participate in the resistance training program according to a physiotherapist, or if they were not able to comply fully with study protocol.

A randomized, controlled, double-blinded, parallel-group, single-centre study design was applied. All subjects were enrolled in a <NUM>-week hypo-caloric weight loss diet and participated in a resistance exercise program. Subjects were randomly assigned to receive one of the study products (test or control) and stratified for gender.

All subjects followed a hypo-caloric weight loss diet of <NUM> kcal below estimated needs per day. Subjects had to take the study product once or twice daily throughout the <NUM>-week intervention period; once daily at the days when no training takes place and twice-daily at the training days. The study product was taken in the morning, just before breakfast. At the training days, the second serving was taken after the training. The product had to be consumed completely, preferably as a bolus within <NUM>, maximally <NUM> minutes.

The test product involved a nutritional supplement comprising a whey protein and was enriched with leucine. Per serving it contained <NUM> total protein of which <NUM> whey protein, <NUM> total leucine, <NUM> carbohydrates, <NUM> fibre and <NUM> fat, a caloric content of about <NUM> kcal per serving. The control product contained no protein. Taste and appearance of the control product were similar to test product and both products provided an energetic value of <NUM> kcal per serving.

The resistance exercise program was performed <NUM> times per week for a period of <NUM> weeks. The training started with a short warm up and was followed by several arm, leg and core strength exercises. The number of repetitions and intensity of the training was adapted to the personal ability of the participant.

At baseline and after <NUM> weeks, a <NUM>-hour oral glucose tolerance test (OGTT) was conducted. Cannulas were placed at least <NUM> minutes before the first blood sample were taken. Subjects had to consume a sugar solution (<NUM> sugar dissolved in <NUM>) within <NUM> minutes. To determine plasma glucose and insulin, a venous blood sample was drawn immediately (t=<NUM>) prior to intake of the sugar solution and <NUM>, <NUM>, <NUM> and <NUM> minutes after intake of the sugar solution. HbA1c was also measured in baseline plasma from all subjects.

Homa-IR is method that quantifies a degree of basal insulin resistance in a subject. For the calculation the fasting glucose (FPG) and fasting insulin (FPI) values are used in the following formula: HOMA-IR = (FPI × FPG)/<NUM> where FPI is fasting plasma insulin concentration (mU/I) and FPG is fasting plasma glucose (mmol/l).

The Matsuda index is an index that reflects whole-body insulin sensitivity as calculated from the plasma glucose and plasma insulin response during an oral glucose tolerance test (OGTT). The index is calculated according the following formula: (<NUM>,<NUM>/square root of [fasting glucose x fasting insulin] x [mean glucose x mean insulin during OGTT]). It has been shown that the calculation of the index has a high correlation with the rate of whole body glucose disposal during an hyper-insulinaemic euglycemic clamp (<NPL>.

Outcome parameters were analysed using a repeated measures mixed model with a random effect for subjects and a fixed factor for study group, sex and use of SU-derivatives at study start (screening) yes/no.

The Intention-to-Treat dataset was described as the primary dataset in the protocol and the Statistical Analysis Plan.

Subject characteristics are presented in Table <NUM> and showed no significant differences between groups.

AS shown in <FIG>, both the control group and the test group loss weight during the intervention.

The glucose concentrations at the individual time points of the oral glucose tolerance test, both at week <NUM> and week <NUM>, are presented below, and visualized in <FIG> and <FIG>, respectively. No statistically significant differences between groups were observed for the effect on the concentration of fasting glucose (Table <NUM>) or HbA1c (Table <NUM>) and the area under the curves of both glucose as shown in said <FIG>.

However, the fasting insulin concentration was decreased in the test group and increased in the control group, which was a statistically significantly difference between study groups (Table <NUM>). The results are plotted in <FIG>.

Further, there is an improvement on insulin sensitivity and a decrease in insulin resistance due to the intervention, as shown in <FIG>, respectively. The results are statistically significant.

According to one embodiment, the invention concerns a solid nutritional composition, suitable as a supplement within a calorie restriction protocol, comprising per <NUM> of dry matter:.

According to one embodiment the invention concerns a nutritional composition, suitable as a meal replacement in a caloric restriction setting during a weight loss program, comprising per serving:.

According to a further embodiment the invention concerns a nutritional composition, suitable as snack replacer in a weight loss therapy, comprising per serving:.

Claim 1:
A nutritional product for use in
a) decreasing fasting insulin levels; or
b) increasing insulin sensitivity; or
c) decreasing insulin resistance
in obese or overweight adults of at least <NUM> years of age,
said product comprising per serving between <NUM> - <NUM> kcal; between <NUM> and <NUM> proteinaceous matter; and at least <NUM> microgram vitamin D.