Use of mulberry extract to improve sleep quality and / or subsequent behavioral outcomes

Abstract

The present invention generally relates to the use of mulberry extract to improve sleep quality and / or subsequent behavioral outcomes. More specifically, the disclosure relates to the administration of a dietary supplement comprising mulberry extract at a predetermined time before and / or simultaneously with the intake of a meal. Preferably, the meal is a balanced dinner.

Description

[Technical field]

[0001] The present invention generally relates to the use of mulberry extract to improve sleep quality and / or subsequent behavioral outcomes. More specifically, the disclosure relates to administration of a composition comprising mulberry extract at a predetermined time prior to and / or simultaneously with the ingestion of a meal. The combination of the composition and the meal has a lower glycemic load than the glycemic load of the meal alone. For example, the combination of the composition and the meal has a glycemic load of about 0-45. Preferably, the meal is a balanced dinner. [Background technology]

[0002] Sleep is a critical physiological function and is considered a key driver of health and well-being across the lifespan. Good quality sleep is associated with benefits for brain function, mood and mental performance, cardio-metabolic health, and immunity (Alvarez et al., 2004), whereas poor quality sleep can have negative consequences for health and well-being (Hublin et al., 2007).

[0003] The typical sleep architecture consists of two components: non-rapid eye movement (NREM) sleep (SWS) and rapid eye movement (REM) sleep. Overall, sleep quality is thought to be enhanced by the total duration of SWS, but both SWS and REM have been found to contribute jointly to next-day benefits, such as improved cognition. SWS and REM are associated with different physiological states, including different requirements in nocturnal energy metabolism, substrate oxidation, and glycemic control.

[0004] Sleep quality is strongly associated with cognitive function, mood, and next-day feelings of energy and vitality. From a scientific perspective, sleep has been consistently associated with benefits in human cognition and mood (for reviews, see Palmer & Alfano, 2017; Rasch & Born, 2013; Walker, 2009). Among the various sleep stages, it has been suggested that SWS duration in particular is more closely related to declarative memory, whereas REM sleep underlies the ability to synthesize abstract information, such as detecting patterns in newly acquired information (non-declarative; Rasch & Born, 2013; Walker, 2009). More recent insights into the role of each sleep stage suggest that SWS and REM may have complementary roles in the consolidation of newly acquired information (for various theories, see Rasch & Born, 2013).

[0005] Most of the evidence on the role of sleep on next-day performance comes from sleep deprivation studies, which suggest that both sleep interruption and sleep deprivation can negatively affect cognitive aspects including declarative memory, memory encoding, and recall, and cognitive flexibility, the ability to combine known information for new uses (Walker, 2009). Among the cognitive domains strongly affected by sleep, daytime levels of vigilance and subjective alertness are highly correlated with sleep duration (Jewett et al., 1999). Indeed, vigilance tasks have been consistently used as sensitive assessment measures of sleep deprivation (Basner & Dinges, 2011). Furthermore, sleep difficulties can have a significant negative impact on emotion regulation through a range of mechanisms, including a reduced ability to down-regulate amygdala activation to negative information. Specifically, several studies have found that sleep deprivation can lead to an almost 60% increase in amygdala activity when participants are presented with negative images (review, Palmer & Alfano, 2017).

[0006] The association between nocturnal glycemia and next-day benefits is not well understood. Experimentally inducing nocturnal hypoglycemia during deep sleep by stabilizing blood glucose at 2.2 mmol / L (40 mg / dL) with insulin infusion is associated with worse memory the next day (Jauch-Chara et al., 2007). Similarly, other studies manipulating blood glucose levels to remain within the range of 2.3–2.7 mmol / L (42–48 mg / dL) during deep sleep revealed lower levels of self-reported vitality and well-being conceptualized as satisfaction (minor symptom evaluation profile; King et al., 1998). It is noted that most studies relating nocturnal glycemia to cognitive / mood benefits have been conducted in diabetic patients. Thus, there is a notable gap in our understanding of how nocturnal glycemia is associated with next-day benefits in healthy populations.

[0007] To date, there is no clear evidence regarding the effect of dinner composition on next day benefits and the mechanisms by which dinner composition may affect subjective and objective cognitive performance and mood.

[0008] [Summary of the Invention] There is a lack of causal studies on blood glucose, carbohydrate metabolism, and sleep. The mechanism underlying the association between dinner carbohydrates and sleep quality remains unclear. Few studies have reported the association between glucose tolerance and sleep parameters under controlled diet or therapeutic glucose management, and most studies have used fasting parameters to investigate the relationship between sleep parameters and glycemic characteristics.

[0009] Overall, knowledge of the direct effect of nutrients on brain and their mode of action to promote sleep is accumulating, but there are still some scientific gaps in the impact of dietary deficiency and nutritional supplementation on sleep quality.There is no product that links improved glucose control with better sleep.Therefore, the inventors have investigated the relationship between nighttime glucose metabolism, sleep quality and next day benefits through clinical studies using state-of-the-art assessment scales of sleep and metabolism in healthy adults to better define nighttime glucose / carbohydrate profile.

[0010] As described in more detail later in this specification, the inventors have identified a nutritional solution to be consumed in the evening to improve sleep quality based on new scientific evidence on evening macronutrient composition and sleep health.In particular, new and developing science shows the importance of food protein and carbohydrate profile on sleep quality, which is mediated by nocturnal carbohydrate metabolism and brain function involved in the sleep-wake cycle.

[0011] A low glycemic index (GI) and fiber-rich dinner or a reduction in the glycemic response to the dinner (e.g., at least a 10%, preferably 20%, more preferably 30% reduction in the glycemic response to the dinner glycemic load (GL)) may improve the quality of sleep and the next day benefits in the general population with sleep complaints. However, the mechanism of action is not yet fully understood at present. Some of the identified modes of action may be related to how the hyperglycemic response to the dinner may lead to disruptions in glucose and carbohydrate metabolism during the night, which may reduce the quality of sleep. Postprandial hyperglycemia due to a high meal glycemic load and the resulting compensatory hyperinsulinemia may reduce plasma glucose to concentrations that impair brain glucose (3.8 mmol / L; 68 mg / dL) and induce the secretion of autonomic antagonist hormones such as adrenaline, cortisol, glucagon, and growth hormone. Symptoms of antagonistic hormone responses may include heart palpitations, tremors, cold sweats, anxiety, irritability, and hunger. Furthermore, hypoglycemic events have been shown to cause awakenings and substantially reduce sleep efficiency, even in healthy adults (Gais et al., 2003).

[0012] Thus, in a non-limiting embodiment, the present invention provides a method for improving sleep quality and / or subsequent behavioral outcomes. Also provided is a method for treating, preventing, and / or reducing at least one of the risk, incidence, or severity of at least one condition for which improved sleep quality is beneficial. The method comprises orally administering to an individual a composition comprising a mulberry extract (ME) at a predetermined time prior to and / or simultaneously with the ingestion of a meal. The combination of the composition and the meal has a glycemic load lower than that of the meal alone. For example, the combination of the composition and the meal has a glycemic load of about 0.0 to about 45.0, preferably about 11 to about 45, preferably about 20 to about 45, lower than that of the meal alone.

[0013] In any embodiment disclosed herein, preferably the meal is an evening meal, for example a balanced evening meal. Preferably, the total amount of mulberry extract is effective to better enhance sleep quality for an individual.

[0014] In some embodiments, the composition comprises mulberry leaf extract (MLE).

[0015] In some embodiments, the composition optionally further comprises an ingredient that reduces glycemic response.Preferably, the ingredient that reduces glycemic response is one or more of tryptophan (e.g., as free amino acid and / or in protein such as whey protein), glucosidase inhibitor such as 1-deoxynojirimycin (DNJ) (e.g., isolated or in mulberry leaf or fruit extract) or phloridzin (e.g., isolated or in apple extract), arginine-proline (AP) dipeptide (e.g., isolated or in milk protein hydrolysate), fiber, resistant starch, β-glucan, A-cyclodextrin, glucosidase (e.g., isolated and / or as part of composition such as mulberry leaf extract), polyphenol (e.g., anthocyanin), or amylase inhibitor (e.g., isolated and / or in composition such as white kidney bean or wheat albumin).

[0016] In an embodiment, the composition is administered to an individual in a serving that provides about 50 mg to about 2 g of ME per serving, e.g., about 100 mg to about 2 g of ME / serving, preferably about 100 mg to about 1 g of ME / serving, e.g., about 100 mg to about 500 mg of ME / serving, e.g., about 250 mg of ME / serving. Optionally, the total amount of ME in the composition and any ME in the diet is effective to better enhance the quality of sleep for the individual.

[0017] The concentration of DNJ in the ME may be at least 1% w / w (dry weight), at least 2% w / w, at least 3% w / w, at least 4% w / w, for example about 5% w / w. In another embodiment, the concentration of DNJ in the ME may be at least 5% w / w, for example at least 6% w / w. In one embodiment, the composition comprising ME comprises at least 1 mg DNJ per gram dry weight of the composition, preferably at least 2 mg DNJ per gram dry weight of the composition, preferably at least 3 mg DNJ, preferably at least 4 mg DNJ, more preferably at least 5 mg DNJ, for example at least 6 mg DNJ.

[0018] In one embodiment, the composition is administered to an individual in a serving providing about 1 mg to about 100 mg of DNJ per serving, e.g., about 5 mg to about 50 mg of DNJ / serving, preferably about 10 mg to about 30 mg of DNJ / serving, or about 10 mg to about 20 mg of DNJ / serving, e.g., about 10 mg to about 15 mg of ME / serving, e.g., about 12.5 mg of DNJ / serving.

[0019] In one embodiment, the composition comprising ME further comprises soluble fiber. In a preferred embodiment, the soluble fiber is selected from polydextrose or resistant starch. In one embodiment, the composition comprises ME and soluble fiber in a fiber:ME ratio of about 1:1 to about 20:1, preferably about 4:1 to about 10:1.

[0020] The inventors have recognized that whole meal replacements taken daily may result in poor consumer compliance in improving sleep.Instead, a particularly advantageous embodiment disclosed herein provides a composition (e.g., a food, a beverage such as a powdered or liquid beverage, or a dietary supplement) for consumption with dinner, which reduces the glycemic response to dinner and improves sleep quality.The compositions and methods disclosed herein can improve sleep quality by improving nocturnal glycemia during the first few hours of sleep (e.g., slow wave sleep (SWS)), which is most important for enhancing the restorative effects of sleep.

[0021] In certain non-limiting embodiments, the present disclosure provides a product that is a low calorie, optionally low volume (preferably about 100 mL to 250 mL) nutritional solution, the product including: (i) an ME that reduces the glycemic response to an evening meal to enhance sleep quality; (ii) an optional protein source that is rich in bioavailable tryptophan and enhances sleep quality; and (iii) optionally one or more supplemental ingredients that contribute to the onset of sleep.

[0022] In some embodiments, the product is provided as a dairy powder stick to be reconstituted with a water / dairy diluent, or as a powder product or RTD, or as a plant-based drink, and the product is taken orally with a standardized dinner. The product and meal can be taken from about 3 hours before bedtime to at least about 4 hours before bedtime.

[0023] Additional features and advantages are described in, and will be apparent from, the following detailed description and drawings. [Brief description of the drawings]

[0024] [Figure 1A]Postprandial glucose excursion by adding MLE before a meal or mixed with a meal. Figure 1A shows the postprandial glucose excursion (in mM) over time (in minutes) for three groups: water 5 min before a standardized balanced meal, "control (open circles)"; MLE diluted in water 5 min before a standardized balanced meal, "MLE before meal (grey triangles)"; MLE with a standardized balanced meal, "MLE during meal (black circles)". All data are shown as mean ± standard error of the mean (SEM). Asterisks (*) indicate significant differences (p<0.05) between the control and intervention groups, and $ indicates significant differences (p<0.05) between the "before meal" and "during meal" groups. [Figure 1B] Figure 1B shows postprandial glucose excursion by adding MLE before a meal or mixing it with a meal. Figure 1B is a graph showing the area under the ascending curve at 2 hours (iAUC 2h) of the three groups. All data are shown as mean ± standard error of the mean (SEM). Asterisks (*) indicate significant differences (p<0.05) between the control and intervention groups, and $ indicates significant differences (p<0.05) between the "before meal" and "with meal" groups. [Figure 1C] Figure 1C shows the postprandial glucose excursion by adding MLE before or mixed with the meal. Figure 1C is a graph showing the iCmax (incremental maximal glucose concentration) of glucose in mM for the three groups. All data are shown as mean ± standard error of the mean (SEM). Asterisks (*) indicate significant differences (p<0.05) between the control and intervention groups, and $ indicates significant differences (p<0.05) between the "before meal" and "with meal" groups. [Figure 1D] Figure 1D shows the postprandial glucose excursion by adding MLE before or mixed with a meal. Figure 1D is a graph showing the time to peak postprandial glucose response (min). All data are shown as mean ± standard error of the mean (SEM). Asterisks (*) indicate significant differences (p<0.05) between the control and intervention groups, and $ indicates significant differences (p<0.05) between the "before meal" and "with meal" groups. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0025] definition Some definitions are provided below. However, definitions may be found in the "Embodiments" section below, and the heading "Definitions" above does not imply that such disclosure in the "Embodiments" section is not a definition.

[0026] All percentages are by weight relative to the total weight of the composition unless otherwise specified.Similarly, all ratios are by weight unless otherwise specified.As used herein, "about", "approximately" and "substantially" are understood to refer to a number within a certain range of numerical values, for example, within the range of -10% to +10% of the reference number, preferably within the range of -5% to +5% of the reference number, more preferably within the range of -1% to +1% of the reference number, and most preferably within the range of -0.1% to +0.1% of the reference number.

[0027] Additionally, all numerical ranges herein should be understood to include all integers, whole or fractional numbers within that range. Additionally, these numerical ranges should be interpreted to support a claim directed to any number or subset of numbers within that range. For example, a disclosure of 1 to 10 should be interpreted to correspond to ranges of 1 to 8, 3 to 7, 1 to 9, 3.6 to 4.6, 3.5 to 9.9, etc. Ranges defined using "between" include the referenced endpoints.

[0028] As used in this specification and the appended claims, singular words include the plural unless the context clearly indicates otherwise. Thus, references to "a," "an," and "the" generally include the plural of the respective terms. For example, a reference to "an ingredient" or "a method" includes a plurality of such "ingredients" or "methods." The term "and / or" used in the context of "X and / or Y" should be interpreted as "X" or "Y" or "X and Y." Similarly, "at least one of X or Y" should be interpreted as "X" or "Y" or "both X and Y." Similarly, the words "comprise," "comprises," and "comprising" should be interpreted as inclusive rather than exclusive. In the same manner, the terms "include," "including," and "or" should all be construed as inclusive unless such interpretation is clearly prevented by the context. However, the embodiments provided by the present disclosure may not include any element not specifically disclosed herein. Thus, the disclosure of an embodiment defined using the term "comprising" is also the disclosure of an embodiment "consisting essentially of" and "consisting of" the disclosed components. "Consisting essentially of" means that the embodiment or components thereof contain more than 50% by weight of the individually identified components, preferably at least 75% by weight of the individually identified components, more preferably at least 85% by weight of the individually identified components, and most preferably at least 95% by weight of the individually identified components, for example at least 99% by weight of the individually identified components.

[0029] As used herein, the term "example," particularly when followed by a list of terms, is merely exemplary and illustrative and should not be considered as exclusive or comprehensive. All embodiments disclosed herein can be combined with any other embodiment disclosed herein, unless expressly stated otherwise.

[0030] "Animal" includes, but is not limited to, mammals, including rodents, aquatic mammals, domestic animals such as dogs and cats, livestock such as sheep, pigs, cows and horses, and humans. When "animal" or "mammal" or their plurals are used, these terms also apply to any animal that can obtain the effect indicated or intended to be indicated by the context of the section, for example, animals that can benefit from reduced postprandial blood glucose. Although the term "individual" or "subject" is often used herein to refer to humans, the disclosure is not so limited. Thus, the term "individual" or "subject" refers to any animal, mammal, or human that can benefit from the methods and compositions disclosed herein.

[0031] The relative terms "improve", "promote / enhance", "enhance" and the like refer to the effect of the methods disclosed herein on sleep quality, in particular the effect of administering a composition comprising mulberry extract at a predetermined time before and / or simultaneously with the consumption of dinner, as compared to the consumption of an identically formulated meal without the mulberry extract provided by the composition of the present invention. In some embodiments, sleep quality can be quantified by one or both of (a) the total duration of slow wave sleep (SWS) and / or (b) the total duration of REM sleep (rapid eye movement, REM). For example, improved sleep quality can be realized by one or both of a longer total SWS duration and / or total REM duration. In some embodiments, improvement in sleep quality is an improvement in one or more of: i) sleep efficiency (e.g., as assessed by actigraphy data); ii) change in sleep latency (e.g., actigraphy data); iii) change in wakefulness after sleep onset (e.g., by actigraphy); iv) change in total sleep duration (minutes, actigraphy); v) time in bed; vi) time spent in bed after waking (minutes). In other embodiments, sleep quality may be assessed by self-report (e.g., Karolinska Sleepiness Scale (KSS) or Epworth Sleepiness Scale (ESS)).

[0032] As used herein, the terms "treatment" and "treating" refer to administering a composition disclosed herein to a subject having a condition to attenuate, reduce or ameliorate at least one symptom associated with the condition and / or to slow, reduce or prevent the progression of the condition. The terms "treatment" and "treating" include both preventative or preventative treatments (treatments that prevent and / or delay the onset of the pathological condition or disorder of interest) and curative, therapeutic or disease-modifying treatments, including, for example, therapeutic measures to cure, delay, reduce symptoms and / or halt the progression of a diagnosed pathological condition or disorder, as well as treatment of patients at risk of or suspected of having a disease, and patients who are unwell or diagnosed with a disease or medical condition. The terms "treatment" and "treating" do not necessarily mean treating the subject until they are cured. The terms "treatment" and "treating" also refer to maintaining and / or promoting the health of an individual who is not afflicted with a disease but may be susceptible to an unhealthy condition. The terms "treatment" and "treating" are also intended to include the synergism or otherwise enhancement of one or more primary preventive or therapeutic measures. As a non-limiting example, treatment can be performed by the patient, a caregiver, a doctor, a nurse, or other medical professional. The terms "prevent" and "prevention" refer to administering a composition disclosed herein to a subject who does not exhibit any symptoms of the condition to reduce or prevent the occurrence of at least one symptom associated with the condition. Furthermore, "prevention" includes reducing the risk, incidence, and / or severity of a condition or disorder.

[0033] As used herein, an "effective amount" is an amount that treats or prevents a deficiency, treats or prevents a disease or medical condition in an individual, or, more generally, reduces the symptoms, manages the progression of a disease, or provides a nutritional, physiological, or medical benefit to the individual. As used herein, "administering" includes providing the referenced composition to an individual by another person so that the individual can ingest the composition, and also simply includes the act of the individual ingesting the referenced composition themselves.

[0034] The terms "food", "food product" and "food composition" refer to a composition intended for ingestion by an individual, such as a human, and providing the individual with at least one nutrient. "Food" and related terms include any food, feed, snack, supplement, treat, meal replacement, or meal replacement, whether intended for humans or animals. Dietary supplements can be fluorescent dietary supplements (ONS) and can be in the form of solid powders, powder sticks, capsules, or solutions. Animal foods include foods or feeds intended for any domestic or wild species. In a preferred embodiment, animal foods refer to pelleted, extruded, or desiccated foods, e.g., extruded pet foods, such as dog and cat foods.

[0035] In the context of this disclosure, the terms "beverage," "beverage product," and "beverage composition" refer to a portable liquid product or composition for consumption by an individual, such as a human, that provides hydration and may also contain one or more nutrients for the individual, and other ingredients that are safe for human consumption.

[0036] The terms "serving" or "unit dosage form" as used herein are interchangeable and refer to physically discrete units suitable as units of administration for human and animal subjects, each unit containing a predetermined amount of a composition comprising an ingredient that reduces glycemic response as disclosed herein, preferably with a pharma- ceutically acceptable diluent, carrier, or vehicle, in an amount sufficient to produce a desired effect. The specifications of the unit dosage form depend on the specific compound used, the effect to be achieved, and the pharmacodynamics associated with each compound in the host body. The term "additional" ingredient of the composition disclosed herein does not necessarily mean that the meal ingested with the composition includes a portion of the ingredient that reduces glycemic response. Instead, some embodiments of the meal ingested with the composition include a portion of the ingredient that reduces glycemic response, and some embodiments of the meal ingested with the composition do not include an ingredient that reduces glycemic response in some embodiments.

[0037] Embodiment One aspect of the present disclosure is a method of improving sleep quality and / or subsequent behavioral outcomes. The method includes orally administering a composition comprising a mulberry extract to an individual at a predetermined time prior to ingestion of a meal (e.g., about 30 minutes to about 1 hour prior to a meal) and / or simultaneously with ingestion of a meal by the individual. When the composition comprising a mulberry extract is administered prior to a meal, the composition can be provided in a form (e.g., capsule, liquid) that allows carbohydrates to be digested simultaneously with being present in the gastrointestinal tract.

[0038] The combination of the composition and a meal has a lower glycemic load than the meal alone. For example, the combination of the composition and a meal has a lower glycemic load than the meal, about 11 to about 45, preferably about 20 to 45.

[0039] Preferably, the meal is dinner.

[0040] Preferably, the total amount of mulberry extract in the composition and any mulberry extract in a balanced diet is effective to provide an individual with better sleep quality.

[0041] Subsequent behavioral outcomes enhanced by improved sleep quality include one or more of: (a) less frequent and / or less severe sleepiness, stress, tension / anxiety, fatigue / apathy or depression / low spirits, anger / hostility, subjective frustration, and / or (b) more and / or better falling asleep, relaxation, calmness, alertness, liveliness / energy, friendliness, cognition, memory, working memory, attention, vigilance, processing speed, fat utilization, weight control, immunity, subjective perception of mental, physical, temporal demands, subjective perception of performance, or next day mood.

[0042] In another embodiment, the present disclosure provides a method for treating, preventing, and / or reducing at least one of the risk, incidence, or severity of at least one condition for which improved sleep quality would be beneficial. The method includes orally administering to an individual a composition comprising a mulberry extract (ME) at a predetermined time prior to ingestion of a meal (e.g., about 30 minutes to about 1 hour prior to a meal) and / or simultaneously with ingestion of a meal by the individual. The combination of the composition and the meal has a lower glycemic load than the glycemic load of the meal alone. For example, in the combination of the composition and the meal, the glycemic load of the meal is about 11 to about 45, preferably about 20 to about 45.

[0043] In any of the embodiments disclosed herein, preferably the meal is an evening meal, such as a balanced evening meal.

[0044] The meal has a glycemic load of about 26.0 to about 58.5, e.g., at least about 27.0, at least about 28.0, at least about 29.0, at least about 30.0, at least about 31.0, at least about 32.0, at least about 33.0, at least about 34.0, at least about 35.0, at least about 36.0, at least about 37.0, at least about 38.0, at least about 39.0, or at least about 40.0. In some embodiments, the glycemic load of the meal is about 58.0 or less, about 57.0 or less, about 56.0 or less, about 55.0 or less, about 54.0 or less, about 53.0 or less, about 52.0 or less, about 51.0 or less, about 50.0 or less, about 49.0 or less, about 48.0 or less, about 47.0 or less, about 46.0 or less, or about 45.0 or less.

[0045] The combination of the composition and the meal has a glycemic load in the range of about 11.0 to about 45.0, e.g., about 20 to about 45.0, e.g., at least about 21.0, at least about 22.0, at least about 23.0, at least about 24.0, at least about 25.0, at least about 26.0, at least about 27.0, at least about 28.0, at least about 29.0, or at least about 30.0, lower than the glycemic load of the meal alone. In some embodiments, the glycemic load of the combination of the composition and the meal is about 45 or less, about 44.0 or less, about 43.0 or less, about 42.0 or less, about 41.0 or less, about 40.0 or less, about 39.0 or less, about 38.0 or less, about 37.0 or less, about 36.0 or less, or about 35.0 or less.

[0046] As another example, the glycemic load of a meal can be reduced by at least about 10%, such as by at least about 20%, preferably at least about 30.0%, and most preferably at least about 40.0% in combination with the meal.

[0047] Preferably, the composition further comprises an ingredient that reduces a glycemic response in an individual. Optionally, the total amount of the ingredients in the composition and any ingredients in the diet is effective to better enhance the quality of sleep of the individual.

[0048] In some embodiments, the ingredient that reduces the glycemic response is one or more of tryptophan (e.g., as a free amino acid and / or in a protein such as whey protein), a glucosidase inhibitor such as 1-deoxynojirimycin (DNJ) (e.g., isolated or in a mulberry leaf or fruit extract) or phlorizin (e.g., isolated or in an apple extract), arginine-proline (AP) dipeptide (e.g., isolated or in a milk protein hydrolysate), fiber, resistant starch, β-glucan, A-cyclodextrin, glucosidase (e.g., isolated and / or as part of a composition such as a mulberry leaf extract), polyphenols (such as anthocyanins), or amylase inhibitors (e.g., isolated and / or in a composition such as white kidney bean or wheat albumin).

[0049] In some embodiments, the composition is administered once a day (e.g., with dinner, preferably and not with other meals and / or at other times of the day) for a total duration of at least 3 days, preferably at least 1 week, and more preferably at least 2 weeks.

[0050] In some embodiments, the composition is a beverage administered to an adult with sleep complaints. In some embodiments, the composition is a cereal snack, a beverage containing cereal (e.g., an RTD beverage), a soup, a porridge, a broth, or a flan, and is administered to an adult. In some embodiments, the composition is administered to an infant.

[0051] In an embodiment, the composition is administered to an individual in a serving that provides about 50 mg to about 2 g of ME per serving, e.g., about 100 mg to about 2 g of ME / serving, preferably about 100 mg to about 1 g of ME / serving, e.g., about 100 mg to about 500 mg of ME / serving, e.g., about 250 mg of ME / serving. Optionally, the total amount of either ME in the composition and any ME in the diet is effective to better enhance the quality of sleep for the individual.

[0052] The concentration of DNJ in the ME may be at least 1% w / w (dry weight), at least 2% w / w, at least 3% w / w, at least 4% w / w, for example about 5% w / w. In another embodiment, the concentration of DNJ in the ME may be at least 5% w / w, for example at least 6% w / w. In one embodiment, the composition comprising ME comprises at least 1 mg DNJ per gram dry weight of the composition, preferably at least 2 mg DNJ per gram dry weight of the composition, preferably at least 3 mg DNJ, preferably at least 4 mg DNJ, more preferably at least 5 mg DNJ, for example at least 6 mg DNJ.

[0053] In one embodiment, the composition is administered to an individual in a serving providing about 1 mg to about 100 mg of DNJ per serving, e.g., about 5 mg to about 50 mg of DNJ / serving, preferably about 10 mg to about 30 mg of DNJ / serving, or about 10 mg to about 20 mg of DNJ / serving, e.g., about 10 mg to about 15 mg of ME / serving, e.g., about 12.5 mg of DNJ / serving.

[0054] Studies have shown that mulberry plant extracts contain a variety of physiologically active components, including flavonoids, polyphenols, polysaccharides, α-glucosidase inhibitors, fagomine, and 1-deoxynojirimycin (DNJ), identified as GABA. 1-deoxynojirimycin (DNJ) is believed to be the primary active component that acts through potent α-glucosidase inhibition.

[0055] Mulberry extracts applicable to the present invention may be from any genus Morus, including, but not limited to, white mulberry (Morus alba L.), black mulberry (Morus nigra L.), American mulberry (Morus celtidifolia Kunth), red mulberry (Morus rubra L.), hybrids of white and red mulberry, mountain mulberry (Morus australis), Himalayan mulberry (Morus laevigata), and combinations thereof.

[0056] Mulberry extracts applicable to the present invention may be derived from various parts of the mulberry tree, including bark (trunk, twigs, or root), roots, shoots, twigs, shoots, leaves, fruits, or combinations thereof. Mulberry extracts can be in the form of, for example, dry powders, such as dry powders ground from various parts of the tree. The plant raw material of the mulberry extract can be fresh, frozen, or dried mulberry material. The extract can be used as a liquid or a dry concentrated solid. Typically, such extracts contain at least about 1% w / v 1-DNJ.

[0057] In a preferred embodiment, the mulberry extract (ME) is a mulberry leaf extract (MLE).

[0058] Mulberry extract can be prepared by procedures well known in the art. In this embodiment, reference can be made to Chao Liu et al., Comparative analysis of 1-deoxynojirimycin contribution degree to α-glucosidase inhibitory activity and physiological distribution in Morus alba L, Industrial Crops and Products, 70(2015)p309-315; Wenyu Yang et al., Studies on the methods of analyzing and extracting total alkaloids in mulberry, Lishizhen Medicine and Material Medical Research, 2008(5); and Chinese Patent Application No. CN104666427.

[0059] Mulberry leaf extract is also commercially available, such as from Karallief Inc, USA, ET-Chem.com, China, Nanjing NutriHerb BioTech Co., Ltd, China, or Phynova Group Ltd.

[0060] The compositions of the present invention may typically comprise from about 1% to about 50%, including from about 2% to about 30%, for example from about 5% to about 20%, and also including from about 10% to about 15% by weight of the composition, of mulberry extract.

[0061] In one embodiment of the present invention, the composition comprises at least 1 mg of 1-deoxynojirimycin (DNJ) per gram of dry weight of the composition, preferably at least 1 mg of DNJ per gram of dry weight of the composition, preferably at least 2 mg of DNJ per gram of dry weight of the composition, preferably at least 3 mg of DNJ per gram of dry weight of the composition, preferably at least 4 mg of DNJ per gram of dry weight of the composition, more preferably at least 5 mg of DNJ per gram of dry weight of the composition, for example at least 6 mg of DNJ per gram of dry weight of the composition. In one embodiment of the present invention, the composition comprises about 1 to about 20 mg of DNJ per gram of dry weight of the composition, preferably about 2 mg to about 10 mg of DNJ per gram of dry weight of the composition. In one embodiment of the present invention, the composition comprises about 5 to about 10 mg of DNJ per gram of dry weight of the composition, preferably about 5 mg to about 8 mg of DNJ per gram of dry weight of the composition, for example about 6 mg to about 7 mg of DNJ per gram of dry weight of the composition.

[0062] In one embodiment, the composition is administered to an individual in servings that provide at least about 1 mg of DNJ per serving, preferably at least about 5 mg of DNJ per serving, more preferably at least about 10 mg of DNJ per serving. In some embodiments, up to 50 mg of DNJ is administered per serving of the composition. In some embodiments, up to 100 mg of DNJ can be administered per serving of the composition.

[0063] The composition comprising ME according to the present invention may be added to or mixed with food or taken in conjunction with food. In a preferred embodiment, the composition comprising ME according to the present invention is in the form of a powder or granules intended to be added to or mixed with food, preferably sprinkled on food.

[0064] As used herein, a "meal" refers to one or more food products, each of which is ingested substantially simultaneously, such that one or more proteins, one or more carbohydrates, one or more lipids, and at least one micronutrient are provided by the ingestion of the meal, more preferably one or more proteins, one or more carbohydrates, one or more lipids, one or more vitamins, and one or more minerals are provided by the ingestion of the meal. Preferably, a meal comprises a plurality of food products. As used herein, a "balanced meal" refers to a meal that provides all of the proteins, carbohydrates, lipids, vitamins, and minerals in amounts and proportions suitable for maintaining the health or growth of an individual. The amounts and proportions of proteins, carbohydrates, lipids, vitamins, and minerals suitable for maintaining health or growth can be determined in line with current food and nutrition regulations and any particular requirements of an individual based on, for example, age, physical activity, and / or sex.

[0065] For example, the current energy, macronutrient, and fluid recommendations of the Food and Nutrition Board of the Institute of Medicine (IOM) recommend acceptable macronutrient distribution ranges for active individuals as follows: carbohydrate (45-65% of energy), protein (10-35% of energy), and lipid (20-35% of energy). In one embodiment, a balanced diet provides 45-65% of total calories from carbohydrate, 20-35% of total calories from lipid, and 10-35% of total calories from protein. In one embodiment, the diet provides an individual with 200 kcal to 1,000 kcal, preferably 250 kcal to 900 kcal, more preferably 300 kcal to 850 kcal, and most preferably 350 kcal to 800 kcal.

[0066] In some embodiments, "dinner" refers to a meal consumed about 1.0 hours to about 6.0 hours before the onset of sleep, preferably about 2.0 hours to about 5.0 hours before the onset of sleep, more preferably about 2.5 hours to about 4.5 hours before the onset of sleep, and most preferably about 3.0 hours to about 4.0 hours before the onset of sleep.

[0067] In some embodiments, "dinner" refers to a meal consumed between about 4:30 pm and about 11:30 pm in the locale where the individual is located, preferably between about 5:00 pm and about 11:00 pm in the locale where the individual is located, more preferably between about 5:30 pm and about 10:30 pm in the locale where the individual is located, and most preferably between about 6:00 pm and about 10:00 pm in the locale where the individual is located.

[0068] Preferably, the food or dietary supplement according to the present invention is orally administered to an individual in a form selected from the group consisting of dairy and non-dairy beverages, and the unit dosage form is a predetermined amount of the beverage.

[0069] In some embodiments, the composition can be a ready-to-drink (RTD) beverage in a container, and the unit dosage form is a predetermined amount of the RTD beverage sealed in a container that is opened for oral administration. For example, the predetermined amount of the RTD beverage can include about 50 mg to about 2 g of ME. An RTD beverage is a liquid that can be consumed orally without the addition of additional ingredients. An RTD beverage can be low calorie and / or optionally low volume (e.g., about 100 mL to about 250 mL).

[0070] In other embodiments, the method includes forming a composition by reconstituting a powder unit dosage form containing ingredients that reduce glycemic response with water or milk, thereby forming a composition that is then orally administered to an individual (e.g., within about 10 minutes after reconstitution, within about 5 minutes after reconstitution, or within about 1 minute after reconstitution). The powder unit dosage form can be sealed in a sachet or other package that can be opened for reconstitution and subsequent oral administration. For example, a predetermined amount of powder can include about 50 mg to about 2 g of ME. A beverage reconstituted from the powder can be low calorie and / or low volume (e.g., about 100 mL to about 250 mL).

[0071] In some embodiments, a unit dosage form of a composition comprising ME may further comprise one or more of melatonin (e.g., about 0.1 to about 0.3 mg melatonin), for example as pistachio powder, vitamin B3 and vitamin B6 (e.g., about 15% NRV to about 2 mg), magnesium (e.g., about 40 mg magnesium), and / or zinc (e.g., about 15% NRV to about 15 mg). In some embodiments, the composition may further comprise one or more of gamma-aminobutyric acid (GABA), alpha-casozepine, or theanine.

[0072] The unit dosage form of the composition containing the ingredient that reduces glycemic response can further include excipients, emulsifiers, stabilizers, and mixtures thereof. The composition can include any nutritional or non-nutritive ingredient that adds bulk and, in most cases, will be substantially inert and will not significantly negate the glycemic effect of the composition. Filler materials most typically include fiber and / or carbohydrates with a low glycemic index.

[0073] Suitable carbohydrate sources for inclusion in the compositions disclosed herein include those with a low glycemic index, such as fructose and low DE maltodextrin. These raw materials do not introduce a high glycemic load into the composition. Other suitable composition ingredients include any dietary fiber suitable for human or animal use, including soluble and insoluble fiber, especially soluble fiber. The beneficial effects of soluble fiber on glycemic response have been widely reported. Non-limiting examples of suitable soluble fibers include FOS, GOS, inulin, resistant maltodextrin, partially hydrolyzed guar gum, polydextrose, and combinations thereof.

[0074] Non-limiting examples of commercially available fibers of the composition include Sunfiber® (Taiyo International, Inc.), a water-soluble dietary fiber produced by enzymatic hydrolysis of guar beans; Fibersol2™ (Archer Daniels Midland Company), a resistant maltodextrin; and polydextrose.

[0075] In one embodiment, the composition may also include tryptophan. In a preferred embodiment, the composition includes at least a portion of the tryptophan in the composition, preferably a protein including whey protein such as whey protein isolate, a mixture of whey protein and casein; or soy protein. In some embodiments, the dietary supplement is administered in a unit dosage form containing about 120 mg to about 5 g of tryptophan.

[0076] In one embodiment, the composition may include tryptophan, mulberry extract, and soluble fiber. In a preferred embodiment, the composition includes a soluble fiber selected from polydextrose, resistant maltodextrin (such as soluble corn fiber Fibersol-2), and combinations thereof.

[0077] The composition may also include other fillers, stabilizers, anti-caking agents, antioxidants, or combinations thereof.

[0078] The composition may further comprise one or more additional ingredients, such as minerals, vitamins, salts, or functional additives, such as palatants, colorants, emulsifiers, antimicrobial agents, or other preservatives. Non-limiting examples of minerals suitable for the compositions disclosed herein include calcium, phosphorus, potassium, sodium, iron, chloride, boron, copper, zinc, magnesium, manganese, iodine, selenium, chromium, molybdenum, fluoride, and any combination thereof. Non-limiting examples of vitamins suitable for the compositions disclosed herein include water soluble vitamins (such as thiamine (vitamin B1), riboflavin (vitamin B2), niacin (vitamin B3), pantothenic acid (vitamin B5), pyridoxine (vitamin B6), biotin (vitamin B7), myo-inositol (vitamin B8), folic acid (vitamin B9), cobalamin (vitamin B12), and vitamin C) and fat soluble vitamins (such as vitamin A, vitamin D, vitamin E, and vitamin K), including salts, esters, or derivatives thereof.

[0079] The individual may be a mammal, such as a human, dog, cat, horse, goat, cow, sheep, pig, deer, or a primate. Preferably, the individual is a human.

[0080] All references herein to treatment include curative, palliative, and prophylactic treatment. Treatment may also include arresting the progression of disease severity. Both human and animal treatments are within the scope of this disclosure. Preferably, the compositions are administered in servings or unit dosage forms that contain a therapeutically or prophylactically effective amount of ingredients that reduce glycemic response.

[0081] Non-limiting examples: Example 1 The following non-limiting examples present experimental data that develops and supports the concepts of embodiments provided by the present disclosure.

[0082] overview Introduction Dietary supplements containing whey protein premeal and mulberry leaf extract (MLE) have been reported to reduce the glucose response to meals. This study evaluated whether the efficacy of these two dietary supplements could be influenced by varying the timing of intake or by different whey protein structures in non-diabetic subjects.

[0083] Survey design and methods Two randomized crossover case-control studies were conducted. Thirty healthy subjects consumed 250 mg of mulberry leaf extract (MLE) before or with a fully balanced meal. Acute postprandial glycemic response (PPGR) was monitored with a continuous glucose monitoring (CGM) device.

[0084] result The supplement significantly reduced the glucose response to a standard meal at all time points. Taking MLE with a meal reduced PPGR to a greater extent than taking it before a meal (iAUC-16%, p=0.03).

[0085] conclusion This study confirmed that MLE premeals are an efficient solution to reduce the glucose response of complete meals and that the effectiveness of such premeals can be optimized by selecting the best administration timing or protein structure.

[0086] Detailed study design and methods Study Design and Subjects The study was a monocentric study with a crossover, randomized, and open-label design. The number of conditions in the study was three (see below). Subjects were randomly assigned to a series of Williams Latin squares balanced for study position and carryover effects to minimize potential bias. Eligible subjects were recruited after completing a health questionnaire and medical screening visit. After enrollment and before the start of the study visit, a CGM sensor was placed on the subject's non-dominant arm. On the day before each study visit, subjects were asked to refrain from drinking alcohol and performing strenuous exercise. Subjects were also asked not to take any medications, such as aspirin or vitamin C-containing dietary supplements, that may affect the CGM measurements. Because subjects could be tested using the same CGM sensor in all study conditions, randomization could be performed without any restrictions, such as blocking.

[0087] Thirty healthy volunteers aged 18-45 years were recruited to study the glycemic response after MLE ingestion. Key inclusion criteria were good health, BMI between 20-29.9 kg / m2, and ability to understand and sign the informed consent form. Key exclusion criteria were food allergies and intolerances to the study products, current smoking status, and contraindications to CGM sensor placement (e.g., hypersensitivity to skin). Screening of potential participants was performed by the study nurse and confirmed under medical responsibility. Sample size was estimated from two published studies reporting a 25% reduction in PPGR for either a rice-based standard diet or a 50 g maltodextrin challenge. Assuming similar effect sizes and variability, the calculated effect size was N=30 to reach a power of 80%.

[0088] Test meal 250 mg of mulberry (Morus alba) leaf extract (5% Reducose®, Phynova / DSM) containing 12.5 mg of DNJ was taken either before (mixed into the water) or during (sprinkled on the food) a standard meal consisting of 150 g cooked white jasmine rice, 25 g sliced ​​bread, 80 g curry sauce, and 80 g chicken breast slices. 200 mL of water was taken before the standard meal. The macronutrient composition of the standard meal is reported in the table in Figure 1.

[0089] [Table 1]

[0090] intervention In this study, participants arrived at the research center at 8:00 am (8:00 am) on the day of the study in a fasting state. Blood glucose readings from the CGM device were taken immediately before and after ingestion of the study product, and interstitial fluid glucose concentrations were continuously and automatically measured every 15 minutes up to 2 hours after the meal.

[0091] Subjects were asked to consume a standardized meal within 15 minutes from one of three groups: 1. Control: 200 mL of water 5 minutes before the standard meal 2. MLE pre-meal: 250 mg of MLE powder dissolved in 200 mL of water 5 minutes before a standard meal 3. MLE meal: 250 mg of MLE powder mixed in 200 mL of water 5 minutes before a standard meal

[0092] measurement Glucose responses were measured with a CGM device that measured interstitial fluid glucose concentrations every 15 minutes. At least 24 hours before the first visit, each subject was fitted with a sensor on their non-dominant arm and given a reader as well as instructions for its use. If a sensor was lost during the study, it was replaced and subjects were able to resume the study at their next study visit at least 24 hours after sensor insertion. Sensors were removed by study staff at the end of the study.

[0093] statistical analysis In these studies, the area under the curve of 2h-PPGR rise (iAUC) was the primary endpoint, calculated for each individual PPGR after a standard meal using the trapezoidal method. Additional endpoints of interest were the iCmax (incremental maximal glucose concentration) of blood glucose, the time to reach this value (Tmax), and all cross-sectional time points every 15 minutes after T0. At the beginning of each visit, subjects scanned the sensor with the reader immediately before and after ingestion of the test product, and the mean was calculated to determine baseline blood glucose (T0). Descriptive statistics (mean, SEM) were tabulated and visualized. Means were compared using paired t-tests with a significance level set at 5% (two-sided) according to established standards. Sensitivity analyses were performed using mixed models to impute possible missing data and to account for possible systematic study site or carryover effects. As none of these effects approached statistical significance, this analysis is not presented further.

[0094] result Baseline characteristics Participants (11 men, 19 women) were young (mean age ± SEM: 31 ± 1.3 years), lean (mean BMI ± SEM: 22.9 ± 0.4 kg / m2), and normoglycemic (mean fasting glucose ± SEM: 5 ± 0.09 mM). There were no missed visits, but two data points were lost due to problems with the CGM sensor. No subjects reported side effects of the intervention. The number of subjects considered in the analysis was N = 30.

[0095] Glucose response Mean PPGR parameters are tabulated for all interventions in the table in Figure 2 .

[0096] [Table 2]

[0097] Absolute values ​​of postprandial interstitial fluid glucose measured with the CGM device in the control and two MLE groups are shown in Figure 1A. Taking MLE before or during a meal reduced PPGR compared to the control. The 2h-iAUC plot (Figure 1B) shows that taking MLE before a meal significantly attenuated the glucose response by 22 ± 7% (p = 0.01), whereas taking MLE during a meal reduced the glucose response by 34 ± 7% (p < 0.01). Interestingly, the PPGR iAUC of MLE administered with a standardized balanced meal was significantly lower (-16 ± 7%, p = 0.03) than the postprandial glucose iAUC observed with MLE administered before a standardized balanced meal.

[0098] Comparing the maximum interstitial PPGR concentrations (Fig. 1C), iCmax was highest in the control group (2.44 ± 0.14 mM). MLE administered both immediately before and during the standardized meal significantly reduced iCmax of the PPGR curve compared to the control: MLE before meal (-0.56 ± 0.12 mM, p < 0.01) and MLE during meal (-0.84 ± 0.15 mM, p < 0.01). The time to reach the maximum blood glucose concentration (Tmax) was earliest in the control group (59 ± 7 min) (Fig. 1D), whereas MLE administered both immediately before and during the standardized meal was significantly delayed compared to the control: MLE before meal (+26 ± 9 min, p < 0.01) and MLE during meal (+28 ± 9 min, p < 0.01). When comparing iCmax and Tmax between the groups that took MLE during and before a standardized meal, there was a significant decrease in iCmax in the MLE meal group compared to the MLE before a meal group (-0.29 ± 0.12 mM, p = 0.02), but there was no difference in Tmax.

[0099] Discussion Studies evaluating the PPGR effect of MLE confirmed that MLE can reduce PPGR of a full meal. Compared to a previous study in which the same dose of 12.5 mg DNJ (in capsules) in co-ingestion with maltodextrin resulted in a 14% reduction in PPGR, the present study observed a similar reduction in PPGR of 16% when MLE was taken in solution before a meal. Similarly, a 24% reduction in PPGR was reported when MLE (8 mg DNJ) was taken with porridge. Interestingly, the present study demonstrated that the timing of administration is a key aspect in obtaining the optimal effect of MLE on PPGR. Indeed, MLE induced a stronger reduction in glucose response when mixed with a meal compared to taking it before a meal. Since DNJ, the active compound in MLE, acts as a competitive α-glucosidase inhibitor, it is reasonable to expect that the maximal effect would be observed when DNJ reaches the small intestine and simultaneously competes with dietary carbohydrates for binding to the α-glucosidase enzyme. In addition to attenuating total PPGR, this study also observed that MLE intake leads to a later maximum glucose peak (later Tmax).This observation may mean that MLE may delay glucose absorption in the gastrointestinal tract and possibly stimulate GLP-1 secretion.This effect has been observed with acarbose, another α-glucosidase inhibitor, which demonstrates delayed absorption and increased GLP-1 secretion.

[0100] Example 2 The following study investigated the effectiveness of nutritional interventions on sleep quality in healthy adults. The study was a double-blind, controlled, randomized, two-arm, crossover, group sequential design clinical trial. Subjects received two different nutritional interventions in a randomized order.

[0101] Research purpose: Primary Objective: To evaluate the effectiveness of nutritional interventions in improving objective sleep quality among healthy adults with sleep-related complaints. Primary Outcomes: Actigraphy parameters will be used to assess objective sleep quality: i) change in sleep efficiency (SE), calculated as (total sleep time / time in bed) x 100; ii) change in sleep latency (SOL), measured as the amount of time (in minutes) it takes a subject to fall asleep after going to bed.

[0102] Secondary objective: To evaluate the effectiveness of the nutritional intervention in improving subjective sleep quality. Outcomes: Change in self-reported sleep quality measured through questionnaires (e.g., Karolinska Sleepiness Scale (KSS), total sleep time, wake after sleep onset (WASO)).

[0103] Study Population: 45 subjects, both males and females, aged 25-50 years, with subjective and objective symptoms related to sleep, assessed as follows: Subjective sleep-related symptoms will be quantified via a sleep quality questionnaire (PSQI>5). Objective findings regarding sleep will mean sleep efficiency <85% over the 14-day screening period. To this end, an objective sleep monitoring device (actigraphy) will be used to screen subjects during the 2-week screening period.

[0104] Treatment administration: The investigational product (IP) was taken in combination with a standardized evening meal (glycemic load 55) and taken orally at least 4 hours and within 30 minutes of bedtime. The investigational product was taken once daily for a total of 2 weeks, i.e., 14 days (28 days total for both the investigational and control products).

[0105] Test Product: A beverage consumed during the evening meal, containing, per serving: 750 mg of mulberry leaf extract containing 1% (m / m) 1-deoxynojirimycin; 5.4g whey protein (providing 120mg tryptophan) Micronutrient fortification: zinc (1.337 mg), magnesium (12.39 mg), vitamin B3 (1.96 mg), and vitamin B6 (0.13 mg); Beverages containing.

[0106] Control product: a beverage consumed during the evening meal, with a low tryptophan content (4 g gluten hydrolysate) per protein equivalent serving.

[0107] The test and control products are provided as sachets containing a powder to be reconstituted with water to a final volume of 200-250 mL.

[0108] Dosing and duration: The test products are taken with meals, once daily, for a total of two weeks, or 14 days (28 days total for both test and control products).

[0109] The two intervention periods will be separated by a washout period of at least 4 weeks to ensure that subjects return to baseline sleep states and to ensure that there are no carryover effects, as well as by a washout period of at least 6 weeks to ensure that female subjects are at the same phase of their menstrual cycle.

[0110] During the intervention period, subjects will be provided with a customized meal consisting of dinner, a pre-dinner snack, and an after-dinner beverage. The dinner will be designed based on the local dietary guidelines, prepared from foods commonly consumed in the region, combining Asian and Western components. Serving sizes will be based on the estimated energy requirement (EER) calculated for adult men and women based on the Oxford formula (Henry, 2005), with total energy intake (TEI). A total of four different dinner menus will be provided to subjects, with serving sizes adjusted for men and women and otherwise standardized for macronutrient content. For this dinner, the carbohydrate profile will be designed to provide a glycemic load of 55±10%.

[0111] Statistical Analysis: Continuous variables will be summarized using appropriate descriptive statistics, including but not limited to number of observations (n), mean, standard deviation (SD), median, minimum, and maximum. Primary outcome measures: The effect of the intervention on the main sleep quality parameters (sleep efficiency and sleep latency) will be assessed by linear mixed-effects models adjusting for baseline values ​​of sleep quality parameters. Secondary Outcomes: Secondary sleep quality parameters will be analyzed as well as the primary sleep outcome.

[0112] result Sleep efficiency and sleep onset latency We observed a total sleep efficiency of 81% explained by the subject population with sleep concerns. After treatment, we observed a statistical trend of 1.4% improvement (p=0.09) in sleep efficiency compared to control.

[0113] Additionally, Table 1 below reports the "sleep onset latency" values ​​on days 4-6 and 13-14 post-dose, showing significant positive changes over these days.

[0114] [Table 3]

[0115] Secondary outcomes Point estimates for total sleep time were positive by 3.3 minutes (p=0.8). Since sleep efficiency is total sleep time divided by total time in bed, the positive / stable total sleep time highlights findings in sleep efficiency. After 13-14 days, treatment differences in wakefulness after sleep onset and total time in bed were significantly reduced by approximately 15 minutes (p=0.08) and 50 minutes (p=0.048), respectively (Tables 2 and 3).

[0116] [Table 4]

[0117] [Table 5]

[0118] Overall, sleep actigraphy findings on sleep quality suggest improved sleep efficiency with faster sleep onset and shorter wake times during the night.

[0119] The results also showed that the treatment statistically reduced the Karolinska Sleepiness Scale (KSS), a measure of same-day sleepiness (-0.46; p=0.002), indicating that taking the product has a secondary effect on improving sleep quality.

[0120] It should be understood that various changes and modifications to the presently preferred embodiments described herein will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the present subject matter and without diminishing its intended advantages. Accordingly, such changes and modifications are intended to be encompassed by the appended claims.

Claims

1. 1. A method for improving sleep quality and / or subsequent behavioral outcomes, said method comprising orally administering to an individual a composition comprising a mulberry extract at a predetermined time prior to and / or concurrently with the ingestion of a meal.

2. 1. A method for treating, preventing, and / or reducing at least one of the risk, incidence, or severity of at least one condition that would benefit from improved sleep quality, said method comprising orally administering to an individual a composition comprising a mulberry extract at a predetermined time prior to and / or concurrently with the ingestion of a meal.

3. 3. The method of claim 1 or 2, wherein the meal combination of said composition and said meal has a glycemic load lower than the glycemic load of said meal, between 0.0 and 45.

4. 3. The method of claim 1 or 2, wherein the meal combination of the composition and the meal has a glycemic load of 11 to 45, or 20.0 to 45.

0.

5. 3. The method of claim 1 or 2, wherein the meal is a dinner, preferably a balanced dinner.

6. 3. The method of claim 1 or 2, wherein the total amount of the mulberry extract in the composition and any mulberry extract in the diet is effective to better enhance sleep quality for an individual.

7. 3. The method of claim 1, wherein the mulberry extract is a mulberry leaf extract.

8. 3. The method of claim 1, wherein the composition further comprises an ingredient that reduces a glycemic response, the ingredient that reduces a glycemic response being one or more of tryptophan, a glucosidase inhibitor, 1-deoxynojirimycin (DNJ), arginine-proline (AP) dipeptide, fiber, resistant starch, β-glucan, A-cyclodextrin, glucosidase, polyphenols, and an amylase inhibitor.

9. 3. The method of claim 1, wherein the composition further comprises one or more of melatonin, vitamin B3, vitamin B6, magnesium, zinc, gamma-aminobutyric acid (GABA), alpha-casozepine, and theanine.

10. 3. The method of claim 1 or 2, wherein the composition comprises a protein having at least a portion of tryptophan, preferably a whey protein such as a whey protein isolate, a mixture of whey protein and casein, or a soy protein.

11. 3. The method of claim 1 or 2, wherein the composition is a liquid beverage, preferably a ready-to-drink beverage, or a beverage formed by reconstituting a powder with a diluent.

12. 3. The method of claim 1 or 2, wherein the individual is a mammal, preferably a companion animal or a human.

13. 3. The method of claim 1 or 2, wherein the composition is administered to the individual once daily for at least three days, at least one week, or at least two weeks.

14. 3. The method of claim 1 or 2, wherein the combination of the composition and the meal has a glycemic load that is at least 10% lower than the glycemic load of the meal alone.

15. 3. The method of claim 1 or 2, wherein the combination of the composition and the meal has a glycemic load that is at least 20%, at least 30%, or at least 40% lower than the glycemic load of the meal alone.

16. The method of claim 1 or 2, wherein the individual does not have a metabolic disorder.

17. 1. A unit dosage form of a composition for use in improving sleep quality and / or subsequent behavioral outcomes, and / or treating, preventing, and / or reducing at least one of the risk, incidence, or severity of at least one condition in which improved sleep quality is beneficial, wherein the composition comprises a mulberry extract and is provided to an individual at a predetermined time prior to and / or concurrently with the ingestion of a meal, the meal having a glycemic load that is at least 10% lower than the glycemic load of the meal alone.

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