Use of mulberry extract for controlling postprandial glucose response

Abstract

The present invention relates to the use of mulberry extract for controlling postprandial glucose response. A method for reducing postprandial glucose from a balanced meal comprising orally administering to an individual a composition comprising a mulberry extract along with the meal. The post-prandial glucose is reduced relative to post-prandial glucose resulting from the administration of a corresponding composition comprising mulberry extract prior to subsequent administration of the equalization meal.

Description

[0001] This application is a divisional application of PCT application PCT / EP2021 / 060744, filed on April 23, 2021, entitled "Use of mulberry extract for controlling postprandial glucose response". The date of entry into the Chinese national phase of the PCT application was September 21, 2022, and the application number was 202180023167.8.

[0002] This invention relates generally to the use of mulberry extract for reducing postprandial glucose (PPG) response. More specifically, it relates to the use of mulberry extract, administered with meals, for reducing postprandial glucose (PPG) response. This invention also relates to compositions comprising mulberry extract, administered with meals, for the treatment and / or prevention of diseases associated with elevated postprandial glucose in an individual. Background Technology

[0003] Diabetes is a metabolic disorder characterized by high blood sugar levels caused by the body's inability to produce or use insulin. Hyperglycemia can lead to a variety of clinical complications, including blindness, amputation, heart attack, or stroke.

[0004] The most common types of diabetes are insulin-dependent diabetes mellitus (type 1 diabetes, T1D) and non-insulin-dependent diabetes mellitus (type 2 diabetes, T2D). T2D is by far the most prevalent type, and the increase in type 2 diabetes (T2D) is primarily driven by the increasing rate of obesity.

[0005] In addition, prediabetes symptoms are defined as blood sugar levels that are higher than normal but not high enough to be diagnosed as diabetes. These prediabetes symptoms largely contribute to the significant increase in the number of people with diabetes.

[0006] Insulin resistance (low insulin sensitivity) also occurs in pregnant individuals. This is because hormonal changes help ensure the transport of nutrients from the pregnant subject to the fetus. As mentioned above, in response to insulin resistance, the pancreas may secrete more insulin to compensate. These individuals are considered to have impaired glucose tolerance (hereinafter referred to as IGT). Ultimately, the pancreas may be unable to keep up with the body's increased demand for insulin, leading to type 2 diabetes. Any degree of impaired glucose tolerance that begins or is initially identified during pregnancy is called gestational diabetes mellitus (GDM).

[0007] The pathophysiology of type 2 diabetes is complex and multifactorial. Obesity, a sedentary lifestyle, and / or aging can lead to insulin resistance, resulting in an increase in circulating insulin concentration over time. At some point, blood glucose dysregulation begins, leading to impaired glucose tolerance (IGT) or impaired fasting glucose (IFG), and can ultimately result in type 2 diabetes. Therefore, IGT and IFG refer to metabolic states that lie between normal glucose homeostasis and diabetes.

[0008] Further testing, namely the oral glucose tolerance test (OGTT), can be performed to assess whether the patient has diabetes or impaired glucose tolerance (IGT). The OGTT involves administering a glucose drink containing 75g of glucose. Blood glucose levels are measured one and two hours after administration of the drink.

[0009] Glucose is an essential nutrient for the human body, and its circulating levels must be carefully maintained constant to supply adequate amounts to surrounding tissues. The liver plays a central role in glucose homeostasis by balancing the uptake and storage of glucose generated via glycogenolysis with the release of glucose via glycogenolysis and gluconeogenesis. Abnormal glucose homeostasis is a hallmark of type 2 diabetes. Patients with type 2 diabetes exhibit increased hepatic glucose production (HGP), which is considered a major cause of fasting hyperglycemia and is associated with decreased plasma glucose clearance (Gastaldelli A, et al., Diabetes 2000; 49:1367-1373), and also with a 25% to 45% reduction in glycogen synthesis compared to non-diabetic individuals (Roden M, et al., Best Pract Res Clin Endocrinol Metab. 2003; 17:365-83).

[0010] Optimal glycemic control is fundamental to diabetes management. Fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) levels are associated with the risk of complications and contribute to the measured glycated hemoglobin (A1C) value. A1C levels >7.0% are associated with a significantly increased risk of both microvascular and cardiovascular (CV) complications. PPG is a significant component of overall hyperglycemia and is likely a major component in patients closer to their A1C targets and in older adults.

[0011] PPG is determined by several factors, such as the total calorie value of a meal, macronutrient composition, and carbohydrate quality (e.g., glycemic index / load), all of which can be monitored and controlled. However, many other factors involved in diseases such as T2D are more complex because they cannot be controlled and are variable between individuals. These other factors include gastric emptying rate, intestinal absorption rate, enteroendocrine incretin secretion, incretin sensitivity, pancreatic β-cell insulin secretion function, hepatic glucose production, glucose effectiveness, glucose uptake in all tissues (especially the brain, fat, liver, and muscle), insulin sensitivity, and renal glucose reabsorption.

[0012] Limiting postprandial blood glucose spikes in individuals with diabetes constitutes an important goal of overall glycemic control strategies. Uncontrolled PPG is common in diabetes. It leads to overall hyperglycemia and is associated with adverse outcomes. Therefore, identifying treatment options targeting PPG is a key component of achieving and maintaining glycemic control in patients with type 1 diabetes (T1D) and type 2 diabetes (T2D), and can prevent individuals with prediabetes from progressing to a diagnosed diabetes condition.

[0013] Evidence demonstrates the importance of both postprandial glucose (PPG) and postprandial insulin (PPI) in the management and prevention of type 2 diabetes. PPG has been shown to be a major cause of total glucose fluctuations in patients with T2D (i.e., well-controlled diabetes or prediabetes) with HbA1c <8%. Postprandial hyperinsulinemia has been shown to be a marker of prediabetes and metabolic syndrome (M. Shanik et al., Diabetes Care, February 2008; 31(Supplement 2): S262-S268). Prediabetes status is rapidly increasing worldwide and is primarily associated with age and BMI. Controlling PPG and / or PPI responses in overweight and obese individuals who are also at risk for T2D appears to be key to preventing the disease.

[0014] Actual treatment for T2D includes several classes of drugs that can be used alone or in combination with insulin.

[0015] Alpha-glucosidase inhibitors slow down carbohydrate digestion, delay glucose absorption, and reduce postprandial blood glucose spikes. Common side effects include abdominal pain, diarrhea, and flatulence. The antidiabetic drug acarbose is an alpha-glucosidase inhibitor. However, due to its ability to also inhibit alpha-amylase activity, gastrointestinal side effects, specifically flatulence and diarrhea, have been reported.

[0016] Mulberry leaves have been used in traditional Chinese medicine for centuries as a common treatment for a variety of ailments, including diabetes, atherosclerosis, and cancer, as well as to enhance the immune system through their potent antioxidant activity. Studies have shown that mulberry plant material contains a variety of physiologically active components, including flavonoids, polyphenols, polysaccharides, 1-deoxymyopicrin (DNJ), identified as an α-glucosidase inhibitor, buckwheat alkaloids, GABA, and more.

[0017] WO2013 / 078658 reported the effect of mulberry juice on blood glucose levels after consuming high glycemic index carbohydrates. EP3145332 A1 reported a reduction in postprandial glucose and insulin spikes after administration of a composition comprising a combination of white kidney bean extract (1,200 mg), white mulberry extract (600 mg), and green coffee extract (400 mg), administered 15 minutes prior to a carbohydrate meal.

[0018] There is a long-standing need in the food industry to further improve nutritional solutions for individuals with diabetes or at risk of developing type 2 diabetes.

[0019] Alternative solutions to reduce postprandial glucose response instead of taking capsules or pills may be attractive to consumers and increase consumer compliance.

[0020] The purpose of this invention is to improve upon existing technologies and provide novel, advantageous nutritional solutions for improving PPG distribution in individuals, specifically individuals with diabetes or at risk of developing T2D. Summary of the Invention

[0021] As will be described in more detail later herein, the inventors conducted a study that surprisingly and unexpectedly showed that administering mulberry leaf extract (MLE) with a balanced meal provided a significant reduction in PPG compared to administering MLE before meals. Also surprisingly, it was found that ingesting compositions containing MLE extract, added in powder or granule form to a balanced meal, provided a significant reduction in PPG compared to administering the same amount of 1-deoxymyotrophic lateral jelly (DNJ) only five minutes before meals.

[0022] Therefore, in one non-limiting embodiment, the present invention provides a method for reducing postprandial glucose from meals. The method includes administering a composition containing mulberry extract (ME) to an individual along with a balanced meal.

[0023] In a preferred embodiment, the mulberry extract is mulberry leaf extract (MLE).

[0024] In another aspect, the present invention provides a ME for treating and / or preventing diseases associated with elevated PPG concentrations in an individual, wherein the ME is provided together with a balanced meal.

[0025] In another aspect, the present invention relates to the use of ME for reducing an individual's PPG concentration after consuming a balanced meal, wherein the ME is provided together with the balanced meal.

[0026] In one implementation, the individual has at least one condition selected from overweight, obesity, diabetes, gestational diabetes mellitus (GDM), and prediabetes.

[0027] ME extract is applied with meals, i.e., during meals, for example, as part of a meal. Preferably, the ME-containing composition is in the form of powder or granules, which can be added to meals, for example, sprinkled on meals. In a preferred embodiment, the ME-containing composition is applied as powder or granules sprinkled on a balanced meal.

[0028] In one embodiment, the composition can typically be administered to an individual in amounts providing about 50 mg ME per serving to about 2 g ME per serving, for example about 100 mg ME per serving to about 2 g ME per serving, preferably about 100 mg ME per serving to about 1 g ME per serving, such as about 100 mg ME per serving to about 500 mg ME per serving, such as about 250 mg ME per serving.

[0029] ME may have a DNJ concentration of at least 1 wt% (dry weight), at least 2 wt% (dry weight), at least 3 wt% (dry weight), at least 4 wt% (dry weight), for example, about 5 wt% (dry weight). In another embodiment, ME may have a DNJ concentration of at least 5 wt% (dry weight), for example, at least 6 wt% (dry weight). In one embodiment, the composition containing ME comprises at least 1 mg DNJ / g dry weight composition, preferably at least 2 mg DNJ / g dry weight composition, preferably at least 3 mg DNJ / g dry weight composition, preferably at least 4 mg DNJ / g dry weight composition, more preferably at least 5 mg DNJ / g dry weight composition, such as at least 6 mg DNJ / g dry weight composition.

[0030] In one embodiment, the composition may be administered to an individual in amounts providing up to about 1 mg DNJ / serving to about 100 mg DNJ / serving, such as about 5 mg DNJ / serving to about 50 mg DNJ / serving, preferably about 10 mg DNJ / serving to about 30 mg DNJ / serving, or about 10 mg DNJ / serving to about 20 mg DNJ / serving, such as about 10 mg ME / serving to about 15 mg ME / serving, such as about 12.5 mg DNJ / serving.

[0031] In one embodiment, the composition containing 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.

[0032] In one embodiment, postprandial glucose achieved by administering a composition containing ME with a balanced meal is lower than that achieved by administering the composition containing ME, containing an equal amount of DNJ, and in the form of a beverage before the meal (e.g., administering ME about five to about thirty minutes before the meal).

[0033] In another embodiment, this disclosure provides a method for treating or preventing at least one condition in which reduced PPG is beneficial. The method comprises orally administering a composition containing ME along with a balanced meal to an individual who needs or is at risk for that condition.

[0034] The at least one condition being treated or prevented is preferably selected from obesity, prediabetes, type 2 diabetes, and gestational diabetes.

[0035] Advantageously, ME according to the invention, when applied with a balanced meal, provides a significant reduction in postprandial glucose compared to ME applied before (e.g., at least 5 minutes before) the meal.

[0036] Additional features and advantages are described herein and will become apparent from the detailed embodiments and accompanying drawings described below. Attached Figure Description

[0037] Figure 1 The graph shows the postprandial glucose shift (above baseline) over time for the following substances: water 5 minutes before a standardized balanced meal, "control (white dot)"; mulberry leaf extract (MLE) diluted in water 5 minutes before a standardized balanced meal, "before (gray triangle)"; and MLE consumed with a standardized balanced meal, "during (black dot)". Detailed Implementation

[0038] definition

[0039] The following provides some definitions. However, definitions may be located in the “Implementation” section below, and the title “Definitions” above does not imply that such disclosures in the “Implementation” section are not definitions.

[0040] All percentages are by weight of the total weight of the composition unless otherwise stated. Similarly, all ratios are by weight unless otherwise stated. As used herein, “about,” “approximately,” and “substantially” should be understood to refer to a number within a range of values, such as -10% to +10% of the mentioned number, preferably -5% to +5%, more preferably -1% to +1%, and most preferably -0.1% to +0.1%.

[0041] Furthermore, all numerical ranges herein should be understood to include all integers or fractions within that range. Additionally, these numerical ranges should be understood to support claims involving any number or subset of numbers within that range. For example, disclosures of 1 to 10 should be understood to support 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 mentioned endpoints.

[0042] As used herein and in the appended claims, the singular form of a word includes the plural form unless the context clearly specifies otherwise. Therefore, references to “an,” “a,” and “the” generally include the plural form of the corresponding term. For example, references to “ingredient” or “method” include references to multiple 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.”

[0043] Similarly, the terms “comprise,” “comprises,” and “comprising” are used to interpret them inclusively rather than exclusively. Likewise, the terms “comprise” and “or” should be considered inclusive unless the context explicitly prohibits this interpretation. However, embodiments provided in this disclosure may not contain any elements not explicitly disclosed herein. Therefore, a disclosure of one embodiment defined by the term “comprise” is also a disclosure of multiple embodiments “consistent substantially of the disclosed components” and “consistent with the disclosed components.” “Consistent substantially of” means that the embodiment or its components contain more than 50% by weight of the individual identified components, preferably at least 75% by weight of the individual identified components, more preferably at least 85% by weight of the individual identified components, most preferably at least 95% by weight of the individual identified components, for example at least 99% by weight of the individual identified components.

[0044] The term "example" as used herein (especially when followed by a list of terms) is for illustrative purposes only and should not be considered exclusive or comprehensive. Any embodiment disclosed herein may be combined with any other embodiment disclosed herein unless expressly indicated otherwise.

[0045] "Animals" includes, but is not limited to, mammals, including but not limited to rodents; aquatic mammals; domesticated animals such as dogs and cats; farm animals such as sheep, pigs, cattle, and horses; and humans. When using "animals," "mammals," or their plural forms, these terms also apply to any animal capable of having an effect as indicated or intended to be indicated by the context of the paragraph, such as an animal benefiting from reduced postprandial glucose. While the terms "individual" or "subject" are commonly used herein to refer to humans, this disclosure is not limited thereto. Therefore, the terms "individual" or "subject" refer to any animal, mammal, or human that may benefit from the methods and compositions disclosed herein.

[0046] The relative terms “improvement,” “reduction,” “enhancement,” etc., refer to the effect of the methods disclosed herein on postprandial glucose, particularly the application of a composition containing WPM before the administration of a meal (e.g., about thirty minutes before the meal), as opposed to the application of the same formulated meal without the application of WPM (e.g., without WPM about one hour after the meal), or as opposed to the application of WPM at the same time as the administration of the same formulated meal (i.e., at approximately the same time).

[0047] As used herein, the term "treatment" means applying the compositions disclosed herein to an individual suffering from a condition to alleviate, reduce, or improve at least one symptom associated with the condition and / or slow, reduce, or halt the progression of the condition. The term "treatment" includes both preventative or deterrent treatment (preventing and / or delaying the development of a target pathological condition or disorder) and curative, therapeutic, or disease-modifying treatment, including therapeutic measures to cure, delay, or alleviate symptoms of a diagnosed pathological condition or disorder and / or halt its progression; and treatment of patients at risk of or suspected of having the disease, as well as treatment of patients who are ill or have been diagnosed with a disease or medical condition. The term "treatment" does not necessarily mean that an individual is treated until fully recovered. The term "treatment" also refers to health maintenance and / or promotion in individuals who do not have the disease but may be prone to developing unhealthy conditions. The term "treatment" is also intended to include intensifying or otherwise enhancing one or more major preventative or therapeutic measures. As a non-limiting example, treatment may be administered by a patient, caregiver, physician, nurse, or other healthcare professional.

[0048] The term "prevention" refers to the application of the compositions disclosed herein to an individual who does not exhibit any symptoms of the condition in order to reduce or prevent the development of at least one symptom associated with the condition. Furthermore, "prevention" includes reducing the risk, incidence, and / or severity of the condition or disorder. As used herein, "effective amount" is the amount in an individual that treats or prevents a defect, treats or prevents a disease or medical condition, or more generally, the amount that reduces symptoms, manages disease progression, or provides nutritional, physiological, or medical benefits to an individual.

[0049] "Overweight" is defined as a person's Body Mass Index (BMI) being between 25 kg / m². 2 With 30kg / m 2 Between. "Obesity" is defined as a BMI of at least 30 kg / m². 2 For example, 30-39.9 kg / m 2 .

[0050] "Diabetes" encompasses both type 1 and type 2 forms of the disease. Non-limiting examples of risk factors for diabetes include: a waist circumference greater than 40 inches for men or greater than 35 inches for women; blood pressure of 130 / 85 mmHg or higher; triglycerides greater than 150 mg / dL; fasting blood glucose greater than 100 mg / dL; or high-density lipoprotein (HDL) less than 40 mg / dL for men or less than 50 mg / dL for women. Therefore, an "individual at risk for diabetes" may have one or more of these factors.

[0051] "Prediabetes" means that an individual has at least one of the following characteristics: a glycated hemoglobin (A1C) level between 5.7% and 6.4%, a fasting blood glucose level between 100 mg / dL and 125 mg / dL (5.6 mmol / L to 7.0 mmol / L), or a blood glucose level between 140 mg / dL and 199 mg / dL (7.8 mmol / L to 11.0 mmol / L).

[0052] As used herein, “application” includes another person providing the mentioned composition to an individual so that the individual can consume the composition, and also includes only the act of the individual consuming the mentioned composition himself.

[0053] As used in this article, “subsequently” means at least about five minutes later, preferably at least about ten minutes later.

[0054] The terms “food,” “food product,” and “food composition” mean a composition intended for ingestion by an individual (such as a human) and to provide that individual with at least one nutrient. “Food” and related terms include any food, feed, snack, food supplement, therapeutic, meal substitute, or meal replacement, whether intended for human or animal use. Animal food includes food or feed intended for any domesticated or wild species. In a preferred embodiment, food for animals refers to granular, extruded, or dried food, such as extruded pet food, such as food for dogs and cats.

[0055] As used herein, the terms “serving” or “unit dosage” are interchangeable and refer to a physically discrete unit suitable as a unit dose for use in human and animal individuals, each unit preferably containing a predetermined amount of the WPM-containing composition disclosed herein, in association with a pharmaceutically acceptable diluent, carrier, or medium, sufficient to produce the 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. In one embodiment, the unit dosage form may be a predetermined amount of liquid contained in a container such as a bottle.

[0056] Implementation Plan

[0057] One aspect of this disclosure is a method for reducing PPG from meals. The method involves orally administering a composition containing ME to an individual along with a balanced meal.

[0058] In another embodiment, this disclosure provides a method for treating or preventing at least one condition in which reduced PPG is beneficial. The method comprises orally administering a composition containing ME along with a balanced meal to an individual who needs or is at risk for it. The at least one condition being treated or prevented is preferably selected from prediabetes and type 2 diabetes (T2D).

[0059] In another aspect of this disclosure, a method for reducing postprandial insulin (PPI) from meals is provided, the method comprising orally administering a composition containing ME to an individual along with a balanced meal.

[0060] In another embodiment, this disclosure provides a method for treating or preventing at least one condition in which a reduced PPI is beneficial. The method comprises orally administering a composition containing ME along with a balanced meal to an individual who needs or is at risk for it. The at least one condition being treated or prevented is preferably selected from prediabetes and type 2 diabetes (T2D).

[0061] In a preferred embodiment, the composition containing ME is orally administered to an individual in the form of a powder or granule composition, which is added to a meal, preferably sprinkled on the meal.

[0062] As used herein, a “meal” means one or more food products consumed substantially at the same time as each other; preferably, the meal provides one or more proteins, one or more carbohydrates, one or more fats, and at least one micronutrient; more preferably, the meal provides one or more proteins, one or more carbohydrates, one or more fats, one or more vitamins, and one or more minerals. Preferably, a meal includes multiple food products. As used herein, a “balanced meal” means a meal that provides all proteins, carbohydrates, fats, vitamins, and minerals in amounts and proportions suitable for maintaining an individual’s health or growth. The amounts and proportions of proteins, carbohydrates, fats, vitamins, and minerals suitable for maintaining health or growth can be determined in accordance with current food and nutrition regulations and any specific requirements for an individual, such as based on age, physical activity, and / or sex. For example, the Institute of Medicine (IOM) Food and Nutrition Committee, in its current recommendations on energy, macronutrients, and fluids, recommends acceptable macronutrient distributions for active individuals of carbohydrates (45%–65% of energy), protein (10%–35% of energy), and fat (20%–35% of energy). In one embodiment, a balanced meal provides 45-65% of total calories from carbohydrates, 20-35% from fat, and 10-35% from protein. In one embodiment, the meal 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. The meal can be any meal, such as breakfast, lunch, or dinner.

[0063] In some embodiments, the meal is breakfast. For example, the composition containing ME may be administered to an individual along with breakfast. In other embodiments, the meal is lunch. In still other embodiments, the meal is dinner (i.e., supper).

[0064] In one embodiment, the PPG achieved by applying the ME-containing composition together with a balanced meal is lower than the PPG achieved by applying the same amount of ME extract (the same amount of DNJ) before applying the balanced meal (e.g., at least 5 minutes before the meal, such as applying ME about 5 to 30 minutes before the meal).

[0065] Studies have shown that mulberry plant extracts contain a variety of physiologically active components, including flavonoids, polyphenols, polysaccharides, 1-deoxymyopicrin (DNJ), identified as an α-glucosidase inhibitor, buckwheat alkaloids, and GABA. 1-Deoxymyopicrin (DNJ) is considered to be the main active ingredient that works through effective α-glucosidase inhibition.

[0066] The mulberry extract applicable to this invention can be from any Morus genus, 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 formed between white and red mulberry, long-fruited mulberry (Morus laevigata), and combinations thereof.

[0067] The mulberry extract applicable to this invention can be derived from different parts of the mulberry tree, including bark (trunk, branches, or roots), roots, buds, branches, young shoots, leaves, fruits, or combinations thereof. The mulberry extract can be in the form of, for example, a dry powder, such as a powder ground from different parts of the tree. The starting plant material for the mulberry extract can be fresh, frozen, or dried mulberry material. The extract can be used in liquid or dry concentrated solid form. Typically, such extracts comprise at least about 1% by weight / volume of 1-DNJ.

[0068] In a preferred embodiment, the mulberry extract (ME) is mulberry leaf extract (MLE).

[0069] Mulberry extract can be prepared using procedures well known in the art. References in this regard include: 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), pp. 309-315; 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 CN104666427.

[0070] Mulberry leaf extract is also available commercially from companies such as Karallief Inc, USA, ET-Chem.com, China, Nanjing NutriHerb BioTech Co., Ltd, China, or Phynova Group Ltd.

[0071] The compositions of the present invention typically contain about 1% to about 50%, including about 2% to about 30%, such as about 5% to about 20%, and also contain about 10% to about 15% of mulberry extract, based on the weight of the compositions.

[0072] In one embodiment of the invention, the composition contains at least 1 mg 1-deoxynojirimycin (DNJ) / g dry weight, preferably at least 1 mg DNJ / g dry weight, preferably at least 2 mg DNJ / g dry weight, preferably at least 3 mg DNJ / g dry weight, preferably at least 4 mg DNJ / g dry weight, more preferably at least 5 mg DNJ / g dry weight, such as at least 6 mg DNJ / g dry weight. In one embodiment of the invention, the composition contains about 1 mg DNJ / g dry weight to about 20 mg DNJ / g dry weight, preferably about 2 mg DNJ / g dry weight to about 10 mg DNJ / g dry weight, and in another embodiment, the composition contains about 5 mg DNJ / g dry weight to about 10 mg DNJ / g dry weight, preferably about 5 mg DNJ / g dry weight to about 8 mg DNJ / g dry weight, such as about 6 mg DNJ / g dry weight to about 7 mg DNJ / g dry weight.

[0073] In one embodiment, the composition is administered to an individual in a dose providing at least about 1 mg DNJ per dose, preferably at least about 5 mg DNJ per dose, and more preferably at least about 10 mg DNJ per dose. In some embodiments, up to 50 mg DNJ is administered per dose of the composition. In some embodiments, up to 100 mg DNJ is administered per dose of the composition.

[0074] The ME-containing compositions according to the invention are intended to be consumed with a balanced meal. They can be added to or mixed into a meal, or consumed with a meal. In a preferred embodiment, the ME-containing compositions according to the invention are in the form of powder or granules intended to be added to or mixed into a meal (preferably sprinkled on the meal). The inventors have surprisingly found that, compared to applying a composition containing MLE (containing the same amount of DNJ) before subsequent meal administration (e.g., 5 minutes or more before the meal), ingestion of a composition containing MLE extract (approximately 12.5 mg of DNJ) sprinkled on a balanced meal in powder or granule form provides a significant reduction in postprandial glucose.

[0075] ME compositions may contain excipients, emulsifiers, stabilizers, and mixtures thereof, and the final formulation is preferably in powder / granule form.

[0076] The compositions of the present invention may also contain filler materials to enhance the volumetric properties of the composition. These filler materials may include any such materials suitable for the composition.

[0077] Filler materials may include any nutrient or non-nutrient components that increase volume and will in most cases be substantially inert and will not significantly negate the glycemic benefits of the composition. Filler materials most commonly include fiber and / or carbohydrates with a low glycemic index.

[0078] The filler material, including any carbohydrate and / or fiber filler, may indicate that the finished product is sufficient to provide the desired volume or flow properties, but by weight of the composition, most typically comprise about 30% to about 95%, preferably about 40% to about 95%, more preferably about 50% to about 90%, and most preferably about 75% to about 90%.

[0079] Suitable carbohydrate sources for use as filler materials in the compositions of the present invention include those with low glycemic index, such as fructose and low-DE maltodextrin, because such components do not introduce a high glycemic load into the composition. Other suitable filler materials include any dietary fiber suitable for human or animal use, including soluble and insoluble fibers, especially soluble fibers. The beneficial effects of soluble fiber on glucose 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.

[0080] Non-limiting examples of commercially available filler materials used in this document include (Taiyo International, Inc.) This is a water-soluble dietary fiber produced through enzymatic hydrolysis of guar beans; Fibersol 2 TM(Archer Daniels Midland Company), which contains resistant maltodextrin and polydextrose.

[0081] In one embodiment, the composition of the present invention comprises mulberry extract and soluble fiber. In a preferred embodiment, the ME-containing composition according to the present invention is in the form of powder or granules, and further comprises soluble fiber selected from polydextrose, resistant maltodextrin (such as soluble corn fiber Fibersol-2), and combinations thereof.

[0082] The composition may also contain other fillers, stabilizers, anti-caking agents, antioxidants, or combinations thereof.

[0083] Compositions containing ME may also contain one or more additional components, such as minerals; vitamins; salts; or functional additives, including, for example, palatants, colorants, emulsifiers, antimicrobial agents, or other preservatives. Non-limiting examples of minerals suitable for use in the compositions disclosed herein include calcium, phosphorus, potassium, sodium, iron, chloride, boron, copper, zinc, magnesium, manganese, iodine, selenium, chromium, molybdenum, fluorides, and any combination thereof. Non-limiting examples of vitamins suitable for use in 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), 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) comprising salts, esters, or derivatives thereof. Vitamin C, vitamin D, vitamin B3, and / or vitamin B12 are particularly useful in the compositions. In one preferred embodiment, the composition is supplemented with one or more vitamins and / or minerals selected from vitamin C, vitamin B3, zinc, or any combination thereof. In another preferred embodiment, the composition is supplemented with one or more vitamins and / or minerals selected from vitamin D and chromium, or combinations thereof. Vitamin D may preferably be in the form of vitamin D3.

[0084] In one embodiment, the composition is administered to an individual in an amount providing at least about 10 mg DNJ per serving, such as about 12.5 mg DNJ per serving, and about 0.5 μg vitamin D per serving to about 1.5 μg vitamin D per serving, such as about 0.75 μg vitamin D per serving, and about 0.05 mg chromium per serving to about 0.15 mg chromium per serving, such as about 0.075 mg chromium per serving.

[0085] The individual can be a mammal, such as a human, canine, feline, equine, goat, bovine, sheep, pig, deer, or primate. Preferably, the individual is a human.

[0086] All references to treatment herein include curative, palliative, and preventative treatment. Treatment may also include halting the progression of disease severity. Both human and veterinary treatments are within the scope of this disclosure. Preferably, the composition comprising ME is used to provide a therapeutically effective amount or a preventatively effective amount of ME, specifically providing a particulate or unit dosage form of a therapeutically effective amount or a preventatively effective amount of DNJ.

[0087] In view of the above, the embodiments provided herein are methods for reducing glucose response from meals, the method comprising: orally administering a composition containing ME to an individual along with a balanced meal.

[0088] The individual's PPG is preferably lower than that caused by oral administration of a composition containing ME, containing the same amount of DNJ, and administered before (e.g., at least 5 minutes before) a meal.

[0089] The individual preferably has at least one condition selected from obesity, type 2 diabetes, type 1 diabetes, prediabetes, and gestational diabetes. The composition containing ME is preferably in the form of a powder. The composition may preferably be applied to the individual in an amount containing about 50 mg / part to about 2 g / part, for example about 100 mg / part to about 2 g / part, preferably about 100 mg / part to about 1 g / part, such as about 100 mg / part to about 500 mg / part, such as about 250 mg / part.

[0090] The composition may preferably be administered to an individual in amounts comprising about 1 mg DNJ / serving to about 100 mg DNJ / serving, for example about 5 mg DNJ / serving to about 50 mg DNJ / serving, preferably about 10 mg DNJ / serving to about 30 mg DNJ / serving, or about 10 mg DNJ / serving to about 20 mg DNJ / serving, such as about 10 mg ME / serving to about 15 mg ME / serving, such as about 12.5 mg DNJ / serving. The composition may contain ME and at least one additional component selected from soluble fiber, vitamins, and minerals.

[0091] In a preferred embodiment, the mulberry extract is a mulberry leaf extract (MLE) containing at least 5% by weight DNJ.

[0092] Meals can be any balanced meal, such as breakfast, lunch, or dinner.

[0093] Another embodiment provided herein is a method for treating or preventing a condition in which reduced postprandial glucose from meals is beneficial. This method comprises orally administering a composition containing mulberry extract (ME) to an individual along with a balanced meal. The condition is preferably selected from obesity, prediabetes, and diabetes.

[0094] In another embodiment, the present invention relates to a composition comprising mulberry extract for the treatment and / or prevention of conditions associated with elevated plasma PPG concentrations in individuals who need or are at risk of such conditions, wherein the ME is provided with a balanced meal.

[0095] The disease can be selected from metabolic syndrome, glucose intolerance, prediabetes, gestational diabetes, and type 2 diabetes. In one implementation plan, the individual in need or at risk may be overweight or obese.

[0096] In a preferred embodiment, the composition containing mulberry leaf is used for obese, prediabetic, or diabetic patients. "Prediabetic patients" are individuals exhibiting insulin resistance or impaired glucose tolerance and are predisposed to developing type 2 diabetes later in life, for example, due to family history or genetic factors. Therefore, using the composition containing mulberry leaf according to the invention, administered with meals, will reduce the risk and / or development of insulin resistance, metabolic syndrome, impaired glucose tolerance, and type 2 diabetes in those individuals.

[0097] In other respects, the present invention relates to the use of mulberry extract for reducing plasma postprandial glucose concentration in individuals following a balanced meal, wherein the mulberry extract is provided with the meal (e.g., added to the meal in powder / granule form).

[0098] In one implementation, the individual has at least one condition selected from obesity, diabetes, and prediabetes.

[0099] In one implementation, ME is administered to an individual in a dose providing at least about 5 mg of DNJ, preferably at least about 10 mg of DNJ.

[0100] Non-limiting embodiments:

[0101] Example 1

[0102] The following non-limiting examples present clinical data that developed and support the concepts of the present invention.

[0103] In a controlled crossover trial, the effect of mulberry leaf extract, consumed either immediately before or with a meal, on postprandial glucose response to a standardized balanced meal was tested in 30 individuals. Subjects consumed (a) 200 ml of water (control), consumed 5 minutes before the standardized meal; (b) 250 mg of mulberry leaf extract (normalized to contain 5% DNJ) dissolved in 200 ml of water, consumed 5 minutes before the standardized balanced meal; or (c) 250 mg of mulberry leaf extract (normalized to contain 4.5–5% DNJ) in powder form, added to the standardized whole meal. A continuous glucose monitoring system (FreeStyle) was used. Abbott measured subcutaneous interstitial glucose concentrations before (fasting glucose) and after (up to 180 minutes) consuming test products and standardized meals.

[0104] The standardized balanced meals consumed by the test individuals consisted of white rice, white bread, seasonings, and chicken as a protein source (approximately 75g of uncooked rice, 25g of bread, 80g of curry sauce, and 80g of chicken) containing 55-65kcal% carbohydrates and at least 15kcal% protein and 15kcal% fat.

[0105] The study population consisted of 30 healthy adult men and women (19 women and 11 men) with a BMI ranging from 20.4 to 27.8 kg / m². 2 .

[0106] Figure 1 The changes in interstitial glucose levels (mean of 30 individuals) over time for the following substances are shown: water 5 minutes before a standardized balanced meal (“Control”); mulberry leaf extract (MLE) diluted in water 5 minutes before a standardized balanced meal (“Before”); and MLE powder added to a standardized balanced meal (“During”). Time 0 corresponds to the intake of the standardized balanced meal.

[0107] Compared with the control, mulberry leaf extract (MLE) administered precisely before and during a standardized meal significantly reduced the iCmax of the postprandial glucose curve (during: -0.84 mM, p < 0.01; before: -0.56 mM, p < 0.01). The Tmax of MLE administered before and during the standardized meal group was also significantly delayed compared with the control.

[0108] Compared with the control, MLE administered 5 minutes before and with a meal also significantly reduced postprandial glucose iAUC (before: -16%, p<0.01; during: -32%, p<0.01). Surprisingly, the postprandial glucose iAUC was significantly lower in the case of MLE administered with a standardized balanced meal (during) than the postprandial glucose iAUC observed for MLE administered before a standardized balanced meal (before) (-19%, p<0.01).

[0109] These results show that MLE administered with a meal significantly reduces postprandial glucose response (PPG) and demonstrates that MLE administered with a balanced meal is more effective at reducing postprandial glucose than MLE administered 5 minutes before a balanced meal.

[0110] Example 2

[0111] The following non-limiting examples provide examples of compositions comprising an MLE suitable for use according to the present invention.

[0112] Example 2A

[0113] Element weight% Mulberry leaf extract (standardized to contain 5% by weight DNJ) 13,125 Calcium carbonate (leveling agent) 0,020 Pyridine carboxylate (chromium source) 0,064 Vitamin D3 0,00075 Polydextrose Balance to 100% Total 100,000000

[0114] Example 2B

[0115]

[0116]

[0117] Example 3

[0118] A randomized, double-blind, crossover study evaluated the effect of MLE compositions taken with meals on postprandial glucose (PPG) response in patients with type 2 diabetes.

[0119] In a controlled crossover trial, the effect of mulberry extract, when consumed with a meal, on the postprandial glucose response of a meal compared to placebo (confirmatory) and active control (acarbose) was tested in patients with type 2 diabetes. Subjects consumed (a) placebo powder sprinkled on the test meal (negative control), (b) a mulberry leaf extract composition (250 mg mulberry leaf extract, normalized to contain 5% DNJ) (2 g of the composition according to Example 2 (2B)) sprinkled on the test meal (test product), or (c) 100 mg acarbose tablets consumed with the test meal (active control).

[0120] Participants were divided into three roughly equal-sized groups and randomized to sequences ABC, BCA, or CAB, where A = test, B = placebo, and C = acarbose. The study lasted approximately 6 months. Participants were enrolled for up to 32 days, including a screening period of up to 2 weeks, 3 treatment visits, and a washout period of 1 week (±4 days) between visits. Participants were assessed at the study site at screening (day -14 to day -1), the first visit (day 1), the second visit (day 7 ± 4), and the third visit (day 14 ± 4). The study product (test product, matched placebo, or acarbose) was consumed with a standardized mixed meal on the morning of the study visit after a fasting period of at least 10 hours. Participants were instructed to consume the entire test meal within approximately 15 minutes. Blood samples were drawn before meals (-30 minutes, and exactly before the start of the meal [-15 minutes]), and immediately after the meal (t=0 minutes) and after meals (15, 30, 45, 60, 90, 120, 150, 180, and 240 minutes) to assess glycemic parameters and paracetamol concentrations. Observations included the area under the curve (iAUC 0–3 h) of the postprandial glycemic shift induced by a standardized meal along with the spray-on MLE composition (test product) relative to the postprandial glycemic shift observed when placebo was administered with the meal.

[0121] It should be understood that various changes and modifications to the currently preferred embodiments described herein will be apparent to those skilled in the art. These changes and modifications can be made without departing from the spirit and scope of the invention and without diminishing its intended advantages. Therefore, such changes and modifications are intended to be covered by the appended claims.

Claims

1. A method for reducing postprandial glucose from a balanced meal, the method comprising: The composition containing mulberry extract (ME) is administered orally to an individual along with the balanced meal.

2. The method of claim 1, wherein the individual has at least one condition selected from overweight, obesity, type 1 diabetes, type 2 diabetes, gestational diabetes, and prediabetes.

3. A method for treating or preventing at least one condition, wherein reduced postprandial glucose and / or postprandial insulin from meals is beneficial to said at least one condition, said method comprising: The composition containing mulberry extract is administered orally with a balanced meal to individuals who need it or are at risk of it.

4. The method of claim 3, wherein the at least one condition is selected from overweight, obesity, prediabetes, gestational diabetes, and diabetes.

5. The method according to any one of claims 1 to 4, wherein the composition comprising the ME is in the form of powder or granules and is mixed into or added to the balanced meal.

6. The method according to any one of claims 1 to 5, wherein the composition is applied to the individual in an amount containing from about 1 mg to about 100 mg of 1-deoxynojirimycin (DNJ) per part, preferably in an amount containing from about 5 mg DNJ per part to about 50 mg DNJ per part, preferably from about 10 mg DNJ per part to about 30 mg DNJ per part, or from about 10 mg DNJ per part to about 20 mg DNJ per part, such as from about 10 mg DNJ per part to about 15 mg DNJ per part.

7. The method according to any one of claims 1 to 6, wherein the composition comprises the mulberry extract and at least one additional component selected from fiber, vitamins, minerals, and any combination thereof.

8. The method according to any one of claims 1 to 7, wherein the mulberry extract is a mulberry leaf extract.

9. The method according to any one of claims 1 to 8, wherein the postprandial glucose of the individual is reduced relative to the postprandial glucose when a composition comprising mulberry extract, containing the same amount of DNJ, is administered prior to the balanced meal.

10. A composition comprising mulberry extract (ME) for treating or preventing at least one condition associated with increased postprandial glucose response and / or postprandial insulin response in an individual who has a need for or is at risk therefor, wherein the composition comprising ME is provided to the individual together with a balanced meal.

11. The ME-containing composition according to claim 10, wherein the condition is selected from: overweight, obesity, prediabetes, type 1 diabetes, type 2 diabetes and gestational diabetes.

12. A composition containing ME, said composition for reducing postprandial glucose from a balanced meal, wherein said composition containing mulberry extract is provided to the individual along with the meal.

13. The ME-containing composition used according to any one of claims 10 to 12, wherein the composition is in the form of powder or granules.

14. The ME-containing composition used according to any one of claims 10 to 13, wherein the ME-containing composition is mixed into or added to the balanced meal.

15. The ME-containing composition used according to any one of claims 10 to 14, wherein the composition comprises about 1 mg DNJ / part of the composition to up to about 100 mg DNJ / part of the composition, preferably about 5 mg DNJ / part of the composition to about 50 mg DNJ / part of the composition, preferably about 10 mg DNJ / part of the composition to about 30 mg DNJ / part of the composition, or about 10 mg DNJ / part of the composition to about 20 mg DNJ / part of the composition, such as about 10 mg DNJ / part of the composition to about 15 mg DNJ / part of the composition.

16. The composition comprising ME used according to any one of claims 1 to 15, wherein the ME is mulberry leaf extract (MLE).

17. The ME-containing composition used according to any one of claims 10 to 16, wherein the ME-containing composition is provided in the form of a powder or granules, the powder or granules comprising the ME and at least one additional component selected from soluble fibers, vitamins, minerals and binders.

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