Methods and compositions for delaying the onset of diabetes or reducing the risk of diabetes

Abstract

A method for delaying the onset of diabetes in an individual with diabetes or prediabetes, or reducing the risk of developing diabetes in an individual at risk of developing diabetes, comprising administering to the individual Bifidobacterium animalis subsp. lactis CECT 8145 (BPL1) and a carbohydrate blend. The carbohydrate blend comprises at least one carbohydrate source providing fast-acting glucose, at least one carbohydrate source providing slow-acting glucose, and at least one source of non-digestible carbohydrate or resistant starch. The nutritional composition comprises protein, fat, the carbohydrate blend, and BPL1.

Description

[Technical field]

[0001] The present invention is directed to methods and compositions suitable for delaying the onset of diabetes or pre-diabetes or reducing the risk of developing diabetes, for example in individuals at risk of developing diabetes. [Background technology]

[0002] The gut microbiota (microbes in the gut) plays a key role in host metabolism, and the importance of the gut microbiota has attracted widespread scientific interest in health and disease. Emerging evidence suggests a strong causal relationship between microbial imbalance and human diseases such as obesity and diabetes. Several studies have confirmed that adults with obesity and diabetes have reduced gut microbial diversity and altered microbiota composition compared to healthy individuals. The composition of the gut microbiota is also susceptible to nutritional changes or drugs. Therefore, modification of the composition of gut bacteria toward a "healthier" microbiota has become attractive as a possible therapeutic avenue.

[0003] Probiotics are defined as live microorganisms that confer a health benefit to the host when administered in adequate amounts. Postbiotics are defined as preparations of non-living microorganisms and / or their components that confer a health benefit to the host. They include any substance released or produced through the metabolic activity of a microorganism that has a direct or indirect beneficial effect on the host. One known probiotic is Bifidobacterium animalis subsp. Lactis CECT 8145 (BPL1) supplied by Archer Daniels Midland Company. BPL1 has been disclosed to have beneficial effects in both living (probiotic) and non-living (postbiotic) organisms in the management of metabolic changes associated with obesity and related diseases, including metabolic syndrome, hypertension, glycemia and type 2 diabetes. See WO 2015 / 007941. Various studies have described beneficial effects against obesity for the postbiotic heat-killed BPL1 or heat-treated BPL1 (hkBPL1 or BPL1HT) through different mechanisms of action, which involve: (i) reduction of body weight and mesenteric fat with an increase in lean body mass, (ii) stimulation of energy expenditure, and (iii) improvement of insulin sensitivity and dyslipidemia.

[0004] However, further improvements in the use of probiotics and / or postbiotics to obtain and / or maintain health benefits are needed. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Publication No. 2015 / 007941 Summary of the Invention [Problem to be solved by the invention]

[0006] Summary of the Invention It is therefore an object of the present invention to make further improvements in obtaining health benefits from probiotic or postbiotic BPL1.

[0007] In one embodiment, the present invention is directed to a method for delaying the onset of diabetes in an individual with diabetes or prediabetes, or reducing the risk of developing diabetes in an individual at risk of developing diabetes, comprising administering to the individual Bifidobacterium animalis subsp. lactis CECT 8145 (BPL1) and a carbohydrate blend comprising at least one carbohydrate source providing rapidly available glucose, at least one carbohydrate source providing slowly available glucose, and at least one source of non-digestible carbohydrate or resistant starch.

[0008] In another embodiment, the present invention is directed to a nutritional composition comprising protein, fat, a carbohydrate blend, and BPL1, wherein the carbohydrate blend comprises at least one carbohydrate source providing fast-release glucose, at least one carbohydrate source providing slow-release glucose, and at least one source of non-digestible carbohydrate or resistant starch. [Means for solving the problem]

[0009] The methods and compositions of the invention are advantageous in managing the metabolic changes associated with the onset and progression of diabetes, such as delaying the onset of diabetes or prediabetes, or reducing the risk of developing diabetes, in individuals, such as those at risk of developing diabetes. These and additional advantages will become more fully apparent upon reference to the detailed description that follows.

[0010] The detailed description of the present invention can be more fully understood with reference to the following drawings. [Brief description of the drawings]

[0011] [Figure 1] FIG. 1 shows the total fat mass in groups of insulin-resistant obese rats fed different diets for 4 weeks, including an OB group fed a high-fat diet, an OB+BPL1 HT group fed a high-fat diet supplemented with postbiotic (heat-killed) Bifidobacterium animalis subsp. lactis CECT 8145 (BPL1 HT), an OB+CBLEND group fed a high-fat diet supplemented with a carbohydrate blend according to the present invention (CBLEND), and an OB+BPL1 HT+CBLEND group fed a high-fat diet supplemented with both BPL1 HT and CBLEND, compared to a control group fed a low-fat diet (Lean), as described in Example 1. [Diagram 2] FIG. 2 shows glucagon-like peptide 1 (GLP-1) secretion in insulin-resistant obese rats in the OB, OB+BPL1 HT, OB+CBLEND, and OB+BPL1 HT+CBLEND groups after 4 weeks of feeding different diets compared to the Lean group, as described in Example 1. [Diagram 3] FIG. 3 shows short-chain fatty acids A (SCFA) detected in the cecum of the OB group, the OB+BPL1 HT group, the OB+CBLEND group, and the OB+BPL1 HT+CBLEND group after four weeks of feeding different diets compared to the Lean group, as described in Example 1. [Figure 4A] FIG. 4A shows glucose levels detected in the blood after oral glucose loading in groups of diabetic rats after 4 weeks of feeding different diets, including a DM group fed a high fat diet, a DM+BPL1 HT group fed a high fat diet supplemented with BPL1 HT, a DM+CBLEND group fed a high fat diet supplemented with CBLEND, and a DM+BPL1 HT+CBLEND group fed a high fat diet supplemented with both BPL1 HT and CBLEND, compared to a control group fed a low fat diet (Lean), as described in Example 2, i.e., a group of insulin-resistant obese rats treated with streptozotocin (STZ) (which causes early beta cell dysfunction and subsequent hyperglycemia, thus simulating the progression to type 2 diabetes). [Figure 4B] FIG. 4B shows the AUC of blood glucose in the DM group, the DM+BPL1 HT group, the DM+CBLEND group, and the DM+BPL1 HT+CBLEND group of diabetic rats compared to the Lean group, as described in Example 2. [Diagram 5] FIG. 5 shows the HbA1c levels detected in the blood in the DM group, DM+BPL1 HT group, DM+CBLEND group, and DM+BPL1 HT+CBLEND group of diabetic rats compared with the Lean group, as described in Example 2.

[0012] The drawings are presented for the purpose of illustrating certain features of the invention and are not to be construed as limiting the embodiments or scope of the invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] While the general inventive concept may be embodied in many different forms, specific embodiments of the invention are described in detail herein with the understanding that the present disclosure should be considered as an exemplification of the principles of the general inventive concept, and therefore it is not intended that the general inventive concept be limited to the specific embodiments illustrated and described herein.

[0014] As used herein, all percentages, parts and proportions are by weight of the total composition unless otherwise specified. As with listed ingredients, all such weights are based on the active level and, therefore, do not include solvents or by-products that may be included in commercially available materials, unless otherwise specified.

[0015] As set forth herein, the terms are for the purpose of describing the embodiments only and should not be construed as limiting the entire disclosure. Unless otherwise specified, "a", "an", "the", and "at least one" are used interchangeably. Furthermore, as used in the description and the appended claims, the singular forms "a", "an", and "the" include their plural forms unless the context clearly indicates otherwise.

[0016] Throughout this specification, when a range of values ​​is defined for a particular feature of the invention, the invention relates to and explicitly incorporates all specific subranges thereof. Furthermore, throughout this specification, when a group of materials is defined for a particular feature of the invention, the invention relates to and explicitly incorporates all specific subranges thereof. Any particular range or group should be understood as a shorthand way of referring to all individual members of the range or group, as well as all possible subranges or subgroups that may be contained therein.

[0017] The methods and nutritional compositions described herein may comprise, consist of, or consist essentially of the essential individual steps and elements described herein, as well as any additional or optional steps and elements described herein. Any combination of methods or processes used herein may be performed in any order unless otherwise specified or clearly indicated inconsistently by the context including the referenced combination.

[0018] Various embodiments of the nutritional compositions of the present invention may also be substantially free of any optional or selected ingredient or feature described herein, so long as the remaining nutritional composition still contains all of the required ingredients or features described herein. In this context, and unless otherwise specified, the term "substantially free" means that the selected nutritional composition contains less than a functional amount of any ingredient, typically less than 1% by weight (including less than 0.5% by weight, including less than 0.1% by weight, including zero% by weight) of such any essential element or selected essential element.

[0019] Unless otherwise specified herein, all exemplary embodiments, partial embodiments, specific embodiments, and optional embodiments are each an exemplary embodiment, partial embodiment, specific embodiment, and optional embodiment associated with all embodiments described herein.

[0020] In a first embodiment, the method is directed to a method of delaying the onset of diabetes in an individual with diabetes or prediabetes, or reducing the risk of developing diabetes in an individual at risk of developing diabetes. Diabetes is a chronic disease that occurs when either the pancreas does not produce enough insulin or the body is unable to effectively use the insulin it produces. Insulin is a hormone that regulates blood glucose. Hyperglycemia, also called raised blood glucose or raised blood sugar, is a common feature of uncontrolled diabetes and causes serious damage to many body systems over time. Type 2 diabetes (also called non-insulin-dependent diabetes or adult-onset diabetes, but can also develop in children and adolescents) results from the body's inability to use insulin effectively. The majority of people with diabetes have type 2 diabetes, often the result of excess weight and lack of exercise. Prediabetes is a serious health condition in which blood glucose levels are higher than normal, but not high enough to be diagnosed as type 2 diabetes. In some specific cases, individuals with prediabetes are insulin resistant, i.e., the individual's cells do not respond normally to insulin, so that glucose cannot be readily taken up into the cells. This results in elevated glucose levels in the blood. This can eventually lead to type 2 diabetes. Insulin resistance is typically asymptomatic. In fact, many people with prediabetes are asymptomatic and will likely develop type 2 diabetes without intervention.

[0021] Thus, in certain embodiments, an individual exhibits pre-diabetes or diabetes and the methods of the invention delay the onset of diabetes, hi other certain embodiments, an individual is at risk of developing diabetes, more specifically, is obese and / or exhibits insulin resistance, and the methods of the invention reduce the risk of developing diabetes in that individual.

[0022] The method of the present invention includes administering both BPL1 and a defined carbohydrate blend. The inventors have surprisingly and unexpectedly found that a diet including both BPL1 and a carbohydrate blend reduces the occurrence of metabolic activity leading to the development of diabetes and pre-diabetes to a greater extent than administration of either BPL1 or the carbohydrate blend individually. Thus, the method effectively manages the metabolic changes associated with the onset and progression of diabetes to delay the onset of diabetes or pre-diabetes or reduce the risk of developing diabetes in individuals at risk of developing diabetes.

[0023] The BPL1 used in the present invention can be a probiotic (i.e., living form) or a postbiotic (i.e., non-living form). Typically, postbiotic BPL1 is heat-treated to remove living cells. Surprisingly, as shown in the examples, heat-treating BPL1 to make it a postbiotic does not prevent the beneficial benefits of administering it with a carbohydrate blend. BPL1 is commercially available, for example, from Archer Daniels Midland Company, Chicago, IL, USA, or BPL1 can be prepared as described in Caimari et al., Journal Functional Foods (2017), 38:251-63, which is incorporated herein by reference.

[0024] In the context of the present invention, carbohydrate blend comprises at least one carbohydrate source that provides fast-acting glucose, at least one carbohydrate source that provides slow-acting glucose, and at least one non-digestible carbohydrate or resistant starch source.Carbohydrates that provide fast-acting glucose are rapidly absorbed in the duodenum and proximal regions of the small intestine, leading to a rapid rise in blood glucose and usually the appearance of hypoglycemia.Carbohydrates that provide slow-acting glucose are steadily but completely digested, resulting in the long-lasting release of glucose from the lumen of the small intestine into the bloodstream.Non-digestible carbohydrates or resistant starches are carbohydrates or parts thereof that are not digested in the upper digestive tract, but are fermented by gut microflora in the large intestine, producing short-chain fatty acids that advantageously provide the body with additional energy.

[0025] The terms "fast-acting glucose" and "slow-acting glucose", as used herein, reflect the rate at which glucose becomes available for absorption in the human small intestine according to an in vitro method developed by Englyst et al. (Am J Clin Nutr (1999) 69:448-454), known in the art and incorporated herein by reference. This in vitro method characterizes dietary carbohydrates with respect to their chemical composition and potential gastrointestinal fate. The percentage of glycemic carbohydrate available for absorption in the small intestine is measured as the sum of sugars and starches (including maltodextrins), excluding resistant starch. The Englyst method determines the percentage of fast-acting glucose, slow-acting glucose, and starch by measuring the amount of glucose released from carbohydrates or carbohydrate sources during incubation with digestive enzymes for a set period of time (20 minutes and 120 minutes) under standardized conditions. According to the Englyst method, for a carbohydrate or carbohydrate source, the amount of glucose measured at 20 minutes (G20) represents the "fast-acting glucose", while the difference between the amount of glucose measured at 120 minutes (G120) and the value of G20, i.e., G120-G20, represents the "slow-acting glucose". The Englyst method also allows the calculation of (i) rapidly digestible starch, which contributes to the amount of fast-acting glucose, (ii) slowly digestible starch, which contributes to the amount of slow-acting glucose, (iii) total starch, and (iv) resistant starch.

[0026] In certain embodiments, the at least one carbohydrate source providing fast-acting glucose comprises (i) monosaccharides, (ii) glucose and fructose units linked by α-1, β-2 glycosidic linkages, (iii) glucose and galactose units linked by αβ(1,4) glycosidic linkages, (iv) glucose units linked by α(1,4) glycosidic linkages, (v) glucose units linked by α(1,6) glycosidic linkages, or (vi) oligosaccharides having a random mixture of α(1,2), α(1,3), α(1,4) and α(1,6) glycosidic linkages, or a combination of two or more thereof.

[0027] In a more specific embodiment, at least one carbohydrate source that provides fast acting glucose in the carbohydrate blend comprises a monosaccharide.Examples of monosaccharides suitable for use in the carbohydrate blend to provide fast acting glucose include, but are not limited to, glucose, fructose, tagatose, galactose, mannose, and ribose.

[0028] In a further particular embodiment, at least one carbohydrate source providing fast acting glucose in the carbohydrate blend comprises glucose and fructose units linked by α-1, β-2 glycosidic bonds. One example of a carbohydrate containing glucose and fructose units linked by α-1, β-2 glycosidic bonds is sucrose.

[0029] In additional specific embodiments, at least one carbohydrate source providing fast acting glucose in the carbohydrate blend comprises galactose and glucose units linked by an αβ(1,4) glycosidic bond. One example of a carbohydrate containing galactose and glucose units linked by an αβ(1,4) glycosidic bond is lactose.

[0030] In additional specific embodiments, at least one carbohydrate source providing fast acting glucose in the carbohydrate blend comprises glucose units linked by α(1,4) glycosidic bonds. Examples of carbohydrates or carbohydrate sources having glucose units linked by α(1,4) glycosidic bonds include, but are not limited to, maltose, maltodextrin, and starch.

[0031] In additional specific embodiments, at least one carbohydrate source providing fast acting glucose in the carbohydrate blend comprises glucose linked by an α(1,6) glycosidic bond. One example of a carbohydrate having glucose units linked by an α(1,6) glycosidic bond is isomaltose.

[0032] In additional specific embodiments, at least one carbohydrate source providing fast acting glucose in the carbohydrate blend comprises oligosaccharides having a random mixture of α(1,2), α(1,3), α(1,4), and α(1,6) glycosidic linkages. One example of a carbohydrate source containing oligosaccharides having a random mixture of α(1,2), α(1,3), α(1,4), and α(1,6) glycosidic linkages is isomaltooligosaccharides. Suitable isomaltooligosaccharides that provide fast acting glucose and contain a mixture of oligosaccharides with a degree of polymerization (DP) of 3 or greater include, but are not limited to, isomaltose, panose, maltotetraose, isomaltotriose, isomaltotetraose, maltopentaose, isomaltopentaose, maltohexaose, isomaltohexaose, maltoheptaose, isomaltoheptaose, maltooctaose, isomaltooctaose, maltononaose and isomaltononaose.

[0033] In additional embodiments, the at least one carbohydrate source providing fast-acting glucose comprises glucose, fructose, tagatose, galactose, mannose, ribose, sucrose, maltose, isomaltose, lactose, isomaltooligosaccharides, maltodextrin, or starch, or a combination of two or more thereof.

[0034] In certain embodiments, at least one carbohydrate source in the blend that provides slow release glucose comprises (i) a glucose unit and a fructose unit linked by an α(1,6) glycosidic bond, (ii) two glucose units linked by an α(1,1) glycosidic bond, (iii) a glucose unit and a fructose unit linked by an α(1,5) glycosidic bond, or (iv) an oligosaccharide having alternating α(1,3) and α(1,6) glycosidic bonds, or a combination of two or more thereof.

[0035] In a more specific embodiment, at least one carbohydrate source providing slow release glucose in the carbohydrate blend comprises glucose and fructose units linked by an α(1,6) glycosidic bond. One example of a carbohydrate having glucose and fructose units linked by an α(1,6) glycosidic bond is isomaltulose.

[0036] In a further particular embodiment, at least one carbohydrate source providing slow release glucose in the carbohydrate blend comprises two glucose units linked by an α(1,1) glycosidic bond. One example of a carbohydrate having two glucose units linked by an α(1,1) glycosidic bond is trehalose.

[0037] In additional specific embodiments, at least one carbohydrate source providing slow release glucose in the carbohydrate blend comprises glucose and fructose units linked by an α(1,5) glycosidic bond. One example of a carbohydrate having glucose and fructose units linked by an α(1,5) glycosidic bond is leucrose. Leucrose is a disaccharide present in sucromalt.

[0038] In a further particular embodiment, at least one carbohydrate source providing slow release glucose in the carbohydrate blend comprises oligosaccharides having alternating α(1,3) and α(1,6) glycosidic linkages. One example of a carbohydrate containing oligosaccharides having alternating α(1,3) and α(1,6) glycosidic linkages is sucromalt.

[0039] In additional embodiments, the at least one carbohydrate source providing slow release glucose comprises isomaltulose, trehalose, sucromalt, or leucrose, or a combination of two or more thereof.

[0040] In certain embodiments, the at least one source of non-digestible carbohydrate or resistant starch contained in the carbohydrate blend comprises (i) oligosaccharides having a random mixture of α(1,2), α(1,3), α(1,4), and β glycosidic linkages, (ii) carbohydrates having linear chains of 2 to 60 fructose units linked by α(2,1) glycosidic linkages or fructose polymers linked by β(2,1) glycosidic linkages, or (iii) oligosaccharides having a random mixture of α(1,2), α(1,3), α(1,4), or α(1,6) glycosidic linkages, or a combination of two or more thereof.

[0041] In certain embodiments, at least one source of non-digestible carbohydrate or resistant starch comprises oligosaccharides having a random mixture of α(1,2), α(1,3), α(1,4) and β glycosidic bonds. One example of a carbohydrate source containing oligosaccharides having a random mixture of α(1,2), α(1,3), α(1,4) and β glycosidic bonds is digestion-resistant maltodextrin, i.e., typically resistant maltodextrin. The mixture of oligosaccharides that constitutes resistant maltodextrin is produced by thermal and enzymatic hydrolysis of starch (e.g., corn, wheat, rice, potato) and typically has a molecular weight of about 2,000 daltons. Examples of commercially available resistant maltodextrins include Nutriose® resistant maltodextrin from Roquette America, Inc. (Geneva, IL) and Fibersol® digestion-resistant maltodextrin from ADM / Matsutani LLC (Itasca, IL).

[0042] In additional specific embodiments, the at least one source of non-digestible carbohydrate or resistant starch comprises a carbohydrate having a linear chain of 2-60 fructose units or fructose polymers linked by β(2,1) glycosidic bonds. Examples of carbohydrates and carbohydrate sources containing carbohydrates having a linear chain of 2-60 fructose units or fructose polymers linked by β(2,1) glycosidic bonds include, but are not limited to, inulin and fructooligosaccharides.

[0043] In certain embodiments, the at least one source of non-digestible carbohydrate or resistant starch comprises oligosaccharides having a random mixture of α(1,2), α(1,3), α(1,4) and α(1,6) glycosidic linkages. One example of a carbohydrate source containing oligosaccharides having a random mixture of α(1,2), α(1,3), α(1,4) and α(1,6) glycosidic linkages is isomaltooligosaccharides. The isomaltooligosaccharides may be any one or more of the isomaltooligosaccharides previously described herein.

[0044] In additional embodiments, the at least one source of non-digestible carbohydrate or resistant starch comprises resistant maltodextrin, fructooligosaccharides, inulin, or isomaltooligosaccharides, or a combination of two or more thereof.

[0045] In additional embodiments, the carbohydrate blend comprises (i) at least one carbohydrate source providing fast-acting glucose selected from one or more of glucose, fructose, galactose, mannose, ribose, sucrose, lactose, maltose, isomaltose, maltodextrin, starch, or isomaltooligosaccharides, (ii) at least one carbohydrate source providing slow-acting glucose selected from one or more of isomaltulose, trehalose, leucrose, or sucromalt, and (iii) at least one source of non-digestible or resistant starch selected from one or more of resistant maltodextrin, fructooligosaccharides, inulin, or isomaltooligosaccharides. In a more specific embodiment, the carbohydrate blend comprises (i) at least one carbohydrate source providing fast-acting glucose selected from one or more of maltodextrin, isomaltose, or isomaltooligosaccharides, (ii) at least one carbohydrate source providing slow-acting glucose selected from one or more of isomaltulose, sucromalt, trehalose, or leucrose, and (iii) at least one source of non-digestible or resistant starch selected from one or more of resistant maltodextrin, fructooligosaccharides, inulin, or isomaltooligosaccharides. In a further embodiment, the carbohydrate blend comprises (i) at least one carbohydrate source providing fast-acting glucose selected from one or more of maltodextrin or isomalto-oligosaccharides, (ii) at least one carbohydrate source providing slow-acting glucose selected from one or more of isomaltulose or sucromalt, and (iii) at least one source of non-digestible or resistant starch selected from one or more of resistant starch, fructooligosaccharides, inulin or isomalto-oligosaccharides.

[0046] The specific carbohydrate source used in the carbohydrate blend may contain carbohydrates or portions thereof that provide one or more categories of glucose availability (i.e., fast acting glucose, slow acting glucose, and non-digestible glucose, i.e., non-digestible carbohydrates or resistant starch). Thus, according to the present invention, the carbohydrate source in the carbohydrate blend may contain one or more of carbohydrates that provide fast acting glucose, carbohydrates that provide slow acting glucose, and non-digestible carbohydrates or resistant starch. For example, a carbohydrate source that contains fast acting glucose and carbohydrates that provide non-digestible carbohydrates or resistant starch (e.g., via a fiber portion that is non-digestible carbohydrates or resistant starch) is isomaltooligosaccharide. An example of a carbohydrate source that contains carbohydrates that provide fast acting glucose and carbohydrates that provide slow acting glucose is sucromalt. Another such example is maltitol, which can be considered as the source of carbohydrates that provide slow-release glucose in the carbohydrate blend, and also as the source of carbohydrates that are non-digestible carbohydrates or resistant starch because they are digested slowly and are not completely digested.Therefore, a single source of carbohydrates can be used in the method of the present disclosure to provide one or more of the carbohydrates that provide fast-release glucose, the carbohydrates that provide slow-release glucose, and the non-digestible carbohydrates or resistant starch.

[0047] In another particular embodiment, the carbohydrate blend contains fructose, isomaltose, sucromalt, digestion-resistant maltodextrin, or fructooligosaccharides, or a combination of two or more thereof. In a more particular embodiment, the carbohydrate blend includes, but is not limited to, fructose, isomaltose, sucromalt, digestion-resistant maltodextrin, and fructooligosaccharides.

[0048] In certain embodiments, at least one carbohydrate source of the carbohydrate blend providing fast-release glucose provides between 5% and 70% of the total calories provided by carbohydrates in the nutritional composition, at least one carbohydrate source of the carbohydrate blend providing slow-release glucose provides between 20% and 85% of the total calories provided by carbohydrates in the nutritional composition, and at least one source of non-digestible carbohydrate or resistant starch of the carbohydrate blend provides between 5% and 35% of the total calories provided by carbohydrates in the nutritional composition. In a more specific embodiment, at least one carbohydrate source of the carbohydrate blend providing fast-release glucose provides between 25% and 60% of the total calories provided by carbohydrates in the nutritional composition, at least one carbohydrate source of the carbohydrate blend providing slow-release glucose provides between 20% and 50% of the total calories provided by carbohydrates in the nutritional composition, and at least one source of non-digestible carbohydrate or resistant starch of the carbohydrate blend provides between 15% and 35% of the total calories provided by carbohydrates in the nutritional composition.

[0049] In certain embodiments, BPL1 is administered together with a carbohydrate blend. Whether administered together or separately, BPL1 and the carbohydrate blend are administered in an amount effective to reduce metabolic changes leading to or accompanying the onset of prediabetes and / or diabetes, thereby delaying the onset of diabetes or prediabetes or reducing the risk of developing diabetes in individuals at risk of developing diabetes. In certain embodiments, BPL1 is administered in an amount effective to reduce the metabolic changes leading to or accompanying the onset of prediabetes and / or diabetes, thereby delaying the onset of diabetes or prediabetes or reducing the risk of developing diabetes in individuals at risk of developing diabetes. 5 ~10 15cfu per day and the carbohydrate blend is administered to the individual in a daily amount of about 5 to about 100 g, about 5 to about 50 g, or about 5 to about 30 g. In more particular embodiments, BPL1 and the carbohydrate blend are administered in combination in the amounts indicated, for example in a nutritional composition or dietary supplement. In particular embodiments, the nutritional composition contains protein and fat. In additional embodiments, BPL1 and the carbohydrate blend are administered at least once per day for a sustained period of time, for example at least 7 days, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 6 weeks, at least 12 weeks, or longer. In further embodiments, BPL1 and the carbohydrate blend are administered at least once per day as part of a routine daily nutritional supplementation.

[0050] In certain embodiments of the present invention, the nutritional composition comprises protein, fat, carbohydrate blend, and BPL1. The nutritional composition may be in liquid or powder form. The powder composition may be consumed as a powder or may be reconstituted with a liquid, such as water, for consumption. The concentrations and relative amounts of the protein, carbohydrate blend, and fat sources in the exemplary nutritional composition may vary widely, for example, depending on the particular dietary needs of the intended user. In certain embodiments, the nutritional composition is a powder and comprises about 10 to about 75% by weight, or about 10 to about 30% by weight, or about 40 to about 75% by weight, protein, about 5 to about 80% by weight, or about 35 to about 75% by weight, or about 5 to about 15% by weight, carbohydrate blend, and about 1 to about 30% by weight, or about 5 to 30% by weight, or about 1 to 15% by weight, fat. In another specific embodiment, the nutritional composition is liquid and comprises about 1 to about 15% or about 1 to about 10% by weight protein, about 1 to about 25% or about 5 to about 20% by weight carbohydrate, and about 0.1 to about 15% or about 0.1 to about 10% by weight fat.

[0051] In additional embodiments, the nutritional composition is a powder and comprises about 10 to about 75% by weight protein, about 5 to about 80% by weight carbohydrate blend, and about 1 to about 30% by weight fat. In additional embodiments, the powder composition may comprise about 10 to about 30% by weight protein, about 35 to about 75% by weight carbohydrate blend, and about 5 to about 30% by weight fat, or about 40 to about 75% by weight protein, about 5 to about 15% by weight carbohydrate blend, and about 1 to about 15% by weight fat.

[0052] In another particular embodiment, the nutritional composition is liquid and comprises about 1 to about 15% by weight protein, about 1 to about 25% by weight carbohydrate blend, and about 0.1 to about 10% by weight fat, with the majority of the composition being water. In an additional embodiment, the liquid nutritional composition comprises about 1 to about 10% by weight protein, about 0.1 to about 10% by weight fat, and about 5 to about 20% by weight carbohydrate blend.

[0053] In a particular embodiment, the nutritional composition comprises BPL1 and a carbohydrate blend in amounts such that a single intake provides a sufficient amount of each to obtain the improvements of the methods of the present invention. For example, in a more particular embodiment, a liquid composition prepared as a ready-to-drink liquid or reconstituted from a powder, for a serving size of about 8 oz, contains about 10 5 ~10 15 cfu BPL1 or, more specifically, about 10 8 ~10 12 cfu BPL1, and about 5 to about 100 g, about 5 to about 50 g, or about 5 to about 30 g of carbohydrate blend.

[0054] In additional specific embodiments, which make the compositions suitable for use according to certain embodiments of the inventive methods discussed herein, the carbohydrate blend of the nutritional composition comprises fructose, isomaltose, sucromalt, digestion-resistant maltodextrin, fructooligosaccharides, or a combination of two or more thereof. In more specific embodiments of the nutritional composition, the carbohydrate blend includes, but is not limited to, fructose, isomaltose, sucromalt, digestion-resistant maltodextrin, and fructooligosaccharides.

[0055] The protein contained in the nutritional composition can be any one or more proteins known for use in nutritional compositions. A wide variety of sources and types of protein can be used in the nutritional composition. For example, the source of protein can include, but is not limited to, complete proteins, hydrolyzed proteins, and partially hydrolyzed proteins, and can be obtained from any suitable source, such as milk (e.g., casein, whey), animals (e.g., meat, fish), grains (e.g., rice, brown rice, corn, barley, etc.), vegetables (e.g., soybeans, peas, yellow peas, broad beans, chickpeas, canola, potatoes, mung beans, ancient grains such as quinoa, amaranth, and chia, hemp, flax seeds, etc.), and combinations of two or more thereof. Protein can also contain natural or synthetic amino acids (often described as free amino acids) and / or one or a mixture of their metabolites known for use in nutritional products, either alone or in combination with the complete proteins, hydrolyzed proteins, and / or partially hydrolyzed proteins described herein.

[0056] More specific examples of sources of protein suitable for use in the nutritional compositions described herein include whey protein, whey protein concentrate, whey protein isolate, whey protein hydrolysate, acid casein, casein protein isolate, sodium caseinate, calcium caseinate, potassium caseinate, casein hydrolysate, milk protein concentrate, milk protein isolate, milk protein hydrolysate, skim milk powder, condensed skim milk, whole milk, partially skimmed or fully skimmed milk, whole egg powder, egg yolk powder, egg white powder, coconut milk, soy protein concentrate, soy protein isolate, soy protein hydrolysate, pea protein concentrate, pea protein isolate. Protein sources include, but are not limited to, pea protein hydrolysate, rice protein concentrate, rice protein isolate, rice protein hydrolysate, barley rice protein, broad bean protein concentrate, broad bean protein isolate, broad bean protein hydrolysate, collagen protein, collagen protein isolate, meat protein such as beef protein isolate and / or chicken protein isolate, potato protein, chickpea protein, canola protein, mung bean protein, quinoa protein, amaranth protein, chia protein, hemp protein, flax seed protein, earthworm protein, insect protein, and combinations of two or more thereof. The nutritional composition may contain any individual protein source or combinations of two or more of protein sources. In certain embodiments, the nutritional composition comprises at least one milk protein, or at least one plant protein, or at least one milk protein and at least one plant protein. In additional embodiments, the protein comprises a caseinate, such as sodium caseinate, calcium caseinate, potassium caseinate, or casein hydrolysate, a milk protein concentrate, a soy protein, more specifically a soy protein isolate, or a combination of two or more thereof.

[0057] The nutritional composition of the present invention also comprises fat.The term "fat" as used herein refers to lipids, fats, oils, and combinations thereof, unless otherwise specified.The sources of fat suitable for use in nutritional composition include, but are not limited to, algae oil, canola oil, linseed oil, borage oil, safflower oil, high oleic safflower oil, high gamma linolenic acid (GLA) safflower oil, corn oil, soybean oil, sunflower oil, high oleic sunflower oil, cottonseed oil, coconut oil, fractionated coconut oil, medium chain triglyceride (MCT) oil, palm oil, palm kernel oil, palm olein, lecithin, and long chain polyunsaturated fatty acids such as docosahexaenoic acid (DHA), arachidonic acid (ARA), docosapentaenoic acid (DPA), eicosapentaenoic acid (EPA), and combinations thereof. The nutritional composition may include any individual source of fat or a combination of two or more sources of fat. In certain embodiments, the fat comprises high oleic sunflower oil, soybean oil, or a combination thereof.

[0058] In a specific embodiment, the liquid nutritional composition is either prepared as a ready-to-drink liquid or reconstituted from a powder composition and has a neutral pH, i.e., a pH of about 6 to 8, or more specifically, a pH of about 6 to 7.5. In a more specific embodiment, the nutritional composition has a pH of about 6.5 to 7.2, or more specifically, a pH of about 6.8 to 7.1.

[0059] The nutritional composition may further comprise one or more additional ingredients that may modify the physical, chemical, aesthetic, or processing properties of the nutritional composition or may serve as additional nutritional ingredients. Non-limiting examples of additional ingredients include preservatives, emulsifiers (e.g., lecithin), buffers, sweeteners including artificial sweeteners (e.g., saccharin, aspartame, acesulfame K, sucralose), natural sweeteners, colorants, flavorings, thickeners, stabilizers, and the like. In certain embodiments, the nutritional composition contains myo-inositol, which may increase insulin sensitivity. In certain embodiments, the nutritional composition may comprise about 0.1 to about 5% by weight of myo-inositol.

[0060] Additionally, the nutritional compositions may further contain vitamins or related nutrients, non-limiting examples of which include vitamin A, vitamin B12, vitamin C, vitamin D, vitamin K, thiamine, riboflavin, pyridoxine, niacin, folic acid, pantothenic acid, biotin, choline, inositol, salts and derivatives thereof, and combinations thereof. Water-soluble vitamins may be added in the form of a water-soluble vitamin (WSV) premix and / or oil-soluble vitamins may be added in one or more oil carriers as desired.

[0061] In additional embodiments, the nutritional composition may further contain one or more minerals, non-limiting examples of which include calcium, phosphorus, magnesium, zinc, manganese, sodium, potassium, molybdenum, chromium, chloride, and combinations thereof.

[0062] The nutritional composition may be formed using any technique known in the art. In one embodiment, the nutritional composition may be formed by (a) preparing an aqueous solution containing protein and carbohydrate, (b) preparing an oil blend containing fat and oil-soluble components, and (c) mixing the aqueous solution and the oil blend together to form an emulsified liquid nutritional composition. BPL1 may be added at any point in the process as desired, for example to the aqueous solution or to the emulsified blend. If a powdered product is desired, the composition may be dried by spray drying or other methods. Alternatively, the powdered product may be formed by dry mixing the powdered ingredients.

[0063] The following examples demonstrate aspects of the methods and compositions of the present invention. EXAMPLES

[0064] The following examples demonstrate the beneficial effects of BPL1 in combination with the described carbohydrate blends in managing metabolic changes associated with the progression of diabetes. The results of the examples are expressed as mean ± standard error of the mean (SEM). Statistical analysis was performed using one-way analysis. Multiple comparisons of means were performed by Fisher's LSD test. p<0.05 was considered statistically significant.

[0065] The examples used heat-killed BPL1 (BPL1 HT) from Archer Daniels Midland Company (ADM) (Chicago, IL, USA) and were obtained from ADM as described in Caimari et al., Journal Functional Foods (2017), 38:251-63. Briefly, in the process disclosed by Caimari et al., BPL1 strains were isolated from the feces of healthy breast-fed infants. The BPL1 strains were grown anaerobically, then inactivated by heat treatment (autoclaving at 121°C for 20 minutes), collected by centrifugation, mixed with maltodextrin and freeze-dried. Once obtained, the heat-killed BPL1 strain powder was standardized taking into account the total cfu content obtained in the culture and the grams of powder recovered by combining with maltodextrin.

[0066] In the examples, Wistar rats weighing 200-250 g were used, purchased from Envigo (France). The animals were housed in a climate-controlled room at 22±2° C. with 50±10% humidity and a 12-h dark / 12-h light cycle prior to the experiments described herein, and were fed standard rodent chow AIN93M and demineralized water ad libitum.

[0067] A rat model of type 2 diabetes was used that reproduces the natural history and metabolic characteristics of human type 2 diabetes. In this rat model, a diabetic pattern is achieved by combining (1) feeding a high-fat (HF) diet, which induces obesity and insulin resistance, and (2) streptozotocin (STZ) treatment, which induces early beta cell dysfunction and subsequent hyperglycemia. More specifically, feeding rats a high-fat diet for a period of 10 weeks produces obese rats, as used in Example 1, with a condition similar to the prediabetic state in humans, characterized by insulin resistance, obesity, moderate hyperglycemia, hypertriglyceridemia, hypercholesterolemia, and compensatory hyperinsulinemia with reduced glucose elimination rate. The development of a diabetic disease pattern is achieved by injecting insulin-resistant rats with low doses of STZ, which induces overt hyperglycemia, as described in more detail in Example 2.

[0068] Example 1 This example demonstrates the improvements provided by the methods and compositions of the present invention in obese subjects who had been fed a high fat (HF) diet for 10 weeks prior to the start of the study. More specifically, obese high fat diet-fed rats were used in this example as described above to evaluate the effect of administering BPL1 (heat treated, BPL1 HT) and a carbohydrate blend (CBLEND) to obese rats. The obese rats were divided into four groups according to the diets they were fed, with the macronutrient profile of each diet shown in Table 1.

[0069] - OB group, continued HF diet, no additional supplementation.

[0070] - OB+BPL1 HT group, continued HF diet, 10 10 cfu / day of heat-treated BPL1 were supplemented.

[0071] - OB+CBLEND group, the HF diet was continued but supplemented with the carbohydrate blend (CBLEND) described in Table 1 instead of the traditional carbohydrates sucrose and cornstarch.

[0072] - OB+BPL1 HT+CBLEND group, continued HF diet, 10 10 Heat-killed BPL1 cfu / day and carbohydrate blends were supplemented in place of the traditional carbohydrates sucrose and cornstarch.

[0073] Obese animals were fed their respective diets for a period of four weeks. A low-fat control group (Lean group) was fed AIN93M throughout the study, including the first 10 weeks of feeding.

[0074] [Table 1]

[0075] The source of protein in all diets was calcium caseinate. The source of fat in the AIN93M low fat diet included soybean fat and the source of fat in the high fat (HF) diet included lard fat.

[0076] Body composition was measured at the end of the 4-week feeding period (day 28) using magnetic resonance imaging (EchoMRI system, EchoMRI, Houston, TX, USA). In addition, blood samples were collected after meals to analyze glucagon-like peptide-1 (GLP-1) in plasma using an ELISA kit (Mercodia, Uppsala, Sweden). Cecums were also collected, weighed, and frozen on day 28 of the study to evaluate cecal short-chain fatty acids (SCFAs). SCFAs were derivatized and analyzed by liquid chromatography tandem mass spectrometry (LC-MS / MS). The total SCFA content in the cecum was quantified, and the results were expressed as cecal wet weight content in μg as described in Zeng et al., J Chrom B Analyt Technol Biomed Life Sci (2018), 1083:137-145.

[0077] FIG. 1 shows the fat mass of each group of animals in g fat mass / 100 g body weight. Animals from the OB group showed a higher amount of fat mass compared to animals from the Lean group. No significant difference was observed when comparing the OB group with the OB+BPL1 HT group. In contrast, both the OB+CBLEND group and the OB+BPL1 HT+CBLEND group had significantly lower fat content than the OB and OB+BPL1 HT groups. Significantly, the OB+BPL1 HT+CBLEND group showed the lowest fat content compared to the remaining obese treatment groups, more specifically, the OB+BPL1 HT+CBLEND group had 36%, 34%, and 15% lower fat mass than the OB, OB+BPL1 HT, and OB+CBLEND groups, respectively. In FIG. 1, a p-value of <0.05 was considered significant, and ( * ) indicates statistical significance versus the OB group, (#) indicates statistical significance versus the OB+BPL1 HT group. Differences between the OB+CBLEND and OB+BPL1 HT+CBLEND groups are indicated with p-values ​​below the columns.

[0078] GLP-1 is an incretin synthesized and released in intestinal L-cells, with nutrient intake as the main stimulus. GLP-1 has been shown to suppress appetite and play a major role in regulating energy metabolism in both normal and obese individuals. As shown in Figure 2, in this experiment, GLP-1 secretion was not affected by the HF diet and showed similar levels in the OB and Lean groups. The addition of BPL1 HT to the HF diet also did not significantly affect the secretion of GLP-1 by the OB+BPL1 HT group. However, the GLP-1 levels in the OB+CBLEND group and the OB+BPL1 HT+CBLEND were significantly higher than the other two groups. Significantly, in the OB+BPL1 HT+CBLEND group, the combination of slowly digestible carbohydrates and BPL1 HT showed the highest plasma GLP-1 concentration, 23% higher than that observed in the OB+CBLEND. In Figure 2, a p-value of <0.05 was considered significant, and ( *) indicates statistical significance versus the OB group, and (#) indicates statistical significance versus the OB+BPL1 HT group.

[0079] It has been demonstrated that the increase in SCFA production by fermentation of non-digestible carbohydrates promotes the activation of L cells in the small intestine and increases the secretion of GLP-1. As shown in FIG. 3, when the total SCFA content was analyzed in the cecal samples, an increase that achieved statistical significance was observed in the OB+CBLEND group compared to the OB group and the OB+BPL1 HT group. However, the highest total SCFA content was observed in the OB+BPL1 HT+CBLEND group, which was significantly higher than the other three groups. In FIG. 3, a p-value of <0.05 was considered significant, and ( * ) indicates statistical significance versus the OB group, (#) indicates statistical significance versus the OB+BPL1 HT group, and (φ) indicates statistical significance versus the OB+CBLEND group.

[0080] In summary, the combination of BPL1 HT and carbohydrate blend resulted in a decrease in body fat mass, an increase in postprandial GLP-1, and an increase in total cecal SCFAs compared to BPL1 HT alone and compared to carbohydrate blend alone, as follows:

[0081] [Table 2]

[0082] These results indicate that the combination of BPL1 and a carbohydrate blend can attenuate metabolic conditions associated with the development of diabetes and prediabetes in obese subjects.

[0083] Example 2 This example shows the effect of BPL1 and carbohydrate blend in regulating the progression of diabetes. Rats were fed with each diet as shown in Table 1. After 4 weeks of feeding, obese rats fed with each experimental diet (HF-containing diet with or without BPL1 HF and / or CBLEND) were fasted for 12 hours to induce the decrease in secretory capacity of pancreatic beta cells and compensate for existing insulin resistance, as described in Example 1, and then a single dose of STZ (30 mg / kg body weight) in citrate buffer (50 mmol / L, pH 4.5) was administered intraperitoneally to induce diabetic state.

[0084] The diets for each of the diabetic animal groups are shown in Table 1 and are designated as follows:

[0085] - DM group, continued HF diet, no additional supplementation.

[0086] - DM+BPL1 HT group, continued HF diet, 10 10 cfu / day of heat-killed BPL1 was replenished.

[0087] - DM+CBLEND group, continued HF diet, supplemented with carbohydrate blend instead of traditional carbohydrates sucrose and cornstarch.

[0088] - DM+BPL1 HT+CBLEND group, continued HF diet, 10 10 cfu / day heat-killed BPL1 and a carbohydrate blend was supplemented in place of the traditional carbohydrates sucrose and cornstarch.

[0089] A low fat control group of animals (Lean group) was fed AIN93M throughout the study.

[0090] Animals continued on their respective diets for 4 weeks after STZ injection and then underwent an oral glucose tolerance test (OGTT). Diabetic animals fasted for 12 hours were given a glucose load of 2.5 g / kg body weight. The glucose load was administered via oral gavage. Blood samples were taken before (t=0) and after (15, 30, 60, 90, 120, and 180 min) glucose administration. Upon completion of the study, blood HbA1c was measured using a clinical chemistry analyzer (Pentra 400, Horiba ABX, Montpellier, France).

[0091] 4A and 4B show the glucose response and area under the curve (AUC) as a function of time, respectively. As shown in FIG. 4A, the Lean group showed a lower postprandial glucose response compared to the remaining groups, while the DM and DM+BPL1 HT groups showed the highest response. In contrast, the DM+BPL1 HT+CBLEND group showed the lowest glycemic response among the diabetic groups over the measurement period. FIG. 4B shows that the AUC in the DM+CBLEND group was significantly lower compared to the DM group, but no statistical difference was found between the DM+CBLEND group and the DM+BPL1 HT. The lowest value of AUC was obtained in the DM+BPL1 HT+CBLEND group, which was significantly lower than both the DM and DM+BPL1 HT groups, as well as 17% lower than the DM+CBLEND group. In FIG. 4B, a p-value of <0.05 was considered significant, and ( * ) indicates statistical significance versus the DM group, (#) indicates statistical significance versus the DM+BPL1 HT group. Differences between the DM+CBLEND group and the DM+BPL1 HT+CBLEND group are indicated by p-values ​​below the columns.

[0092] Concerning blood glucose level, glycated hemoglobin (HbA1c), which increases with the progression of diabetes, is recognized as a diagnostic tool. In this experiment, an increase in HbA1c was observed in all groups compared to the Lean group. As shown in FIG. 5, when comparing diabetic groups, the lowest value of HbA1c was obtained in the DM+BPL1 HT+CBLEND group, and the value was significantly different from both the DM group and the DM+BPL1 HT group, and tended to be lower (p=0.10) compared to the DM+CBLEND group. The DM+BPL1 HT+CBLEND group had HbA1c that was 2%, 2%, and 1% lower than the DM, DM+BPL1 HT, and DM+CBLEND groups, respectively. Those skilled in the art understand that these reductions have important relevance. For example, every 1% reduction in HbA1c on average is associated with a 21% reduction in diabetes-related deaths, a 14% reduction in myocardial infarction, and a 14% reduction in microvascular complications (see Stratton et al. (2000) Br Med J, 321:405-12). In FIG. 5, a p-value of <0.05 was considered significant, and * ) indicates statistical significance versus the DM group, (#) indicates statistical significance versus the DM+BPL1 HT group. Differences between the DM+CBLEND group and the DM+BPL1 HT+CBLEND group are indicated by p-values ​​below the columns.

[0093] In summary, the combination of BPL1 HT and carbohydrate blend resulted in a reduction in both postprandial glucose response and blood HbA1c compared to BPL1 HT alone and compared to carbohydrate blend alone, as follows:

[0094] [Table 3]

[0095] These results indicate that the combination of BPL1 and a carbohydrate blend can alleviate the metabolic conditions associated with the onset of diabetes in diabetic subjects.

[0096] The present application has been illustrated by the description of its embodiments and examples, and while the embodiments and examples have been described in considerable detail, such description is not intended to restrict or in any way limit the scope of the appended claims to such details. Additional advantages and modifications will be readily apparent to those skilled in the art. Thus, the invention in its broader aspects is not limited to the specific details, representative methods or compositions, or illustrative examples shown and described. Accordingly, departures may be made from such details without departing from the spirit or scope of the general inventive concept.

Claims

1. A composition comprising Bifidobacterium animalis subsp. Lactis CECT 8145 (BPL1) and a carbohydrate blend, The carbohydrate blend comprises at least one source of carbohydrates providing fast-acting glucose, at least one source of carbohydrates providing slow-acting glucose, and at least one source of indigestible carbohydrates or resistant starch. A composition for slowing the progression of diabetes in individuals with diabetes or prediabetes, or for reducing the risk of developing diabetes in individuals at risk of developing diabetes.

2. The source of at least one carbohydrate that provides the rapid-acting glucose is (i) Monosaccharides, (ii) Glucose units and fructose units linked by α-1, β-2 glycosidic bonds, (iii) Glucose units and galactose units linked by αβ(1,4) glycosidic bonds, (iv) Glucose units linked by α(1,4) glycosidic bonds, (v) Glucose units linked by α(1,6) glycosidic bonds, or (vi) Oligosaccharides having a random mixture of α(1,2), α(1,3), α(1,4), and α(1,6) glycosidic bonds, The composition according to claim 1, or comprising two or more combinations thereof.

3. The composition according to claim 1, wherein the source of at least one carbohydrate that provides the rapid-acting glucose comprises glucose, fructose, tagatose, galactose, mannose, ribose, sucrose, maltose, isomaltose, lactose, isomaltoligosaccharide, maltodextrin, or starch, or two or more combinations thereof.

4. The composition according to claim 1, wherein the source of at least one carbohydrate that provides the slow-release glucose comprises (i) glucose units and fructose units linked by α(1,6) glycosidic bonds, (ii) two glucose units linked by α(1,1) glycosidic bonds, (iii) glucose units and fructose units linked by α(1,5) glycosidic bonds, (iv) oligosaccharides having alternating α(1,3) and α(1,6) glycosidic bonds, or two or more combinations thereof.

5. The composition according to claim 1, wherein at least one source of the slow-release glucose comprises isomaltose, trehalose, scromalt, or leucrose, or a combination of two or more thereof.

6. The aforementioned source of at least one indigestible carbohydrate or resistant starch is (i) Oligosaccharides having a random mixture of α(1,2), α(1,3), α(1,4) and β-glycosidic bonds, (ii) Carbohydrates having a linear chain of 2 to 60 fructose units, or a fructose polymer linked by β(2,1) glycosidic bonds, (iii) Oligosaccharides having a random mixture of α(1,2), α(1,3), α(1,4), and α(1,6) glycosidic bonds, The composition according to claim 1, or comprising two or more combinations thereof.

7. The composition according to claim 1, wherein the source of at least one non-digestible carbohydrate or indigestible starch comprises indigestible maltodextrin, fructooligosaccharide, inulin, or isomaltoligosaccharide, or a combination of two or more thereof.

8. The composition according to claim 1, wherein the carbohydrate blend comprises fructose, isomaltose, scromalt, digestion-resistant maltodextrin, fructooligosaccharides, or a combination of two or more thereof.

9. The composition according to claim 1, wherein the carbohydrate blend comprises fructose, isomaltose, scromalt, digestion-resistant maltodextrin, and fructooligosaccharides.

10. The composition according to claim 1, wherein the source of at least one carbohydrate providing the fast-acting glucose provides 5% to 70% or 25% to 60% of the total calories supplied by the carbohydrates in the nutritional composition, the source of at least one carbohydrate in the carbohydrate blend providing the slow-acting glucose provides 20% to 85% or 20% to 50% of the total calories supplied by the carbohydrates in the nutritional composition, and the source of at least one non-digestible carbohydrate or resistant starch in the carbohydrate blend provides 5% to 35% or 15% to 35% of the total calories supplied by the carbohydrate blend.

11. The composition according to claim 1, wherein the BPL1 is an inanimate object.

12. The composition according to claim 1, wherein the individual is obese, exhibits insulin resistance, and / or exhibits prediabetes or diabetes.

13. The composition is about 10 ５ ~10 １５ cfu BPL1, or about 10 ８ ~10 １２ The composition according to claim 1, which provides a daily amount of cfu BPL1.

14. The composition according to claim 13, wherein the composition provides about 5 g to about 100 g, about 5 g to about 50 g, or about 5 g to about 30 g of a carbohydrate blend.

15. The composition according to claim 1, wherein a single serving of approximately 237 ml of liquid composition contains approximately 10⁵ to 10¹⁵ cfu of BPL1, or approximately 10⁸ to 10¹² cfu of BPL1, and contains approximately 5 to approximately 100 g, approximately 5 to approximately 50 g, or approximately 5 to approximately 30 g of a carbohydrate blend.

16. The composition according to claim 1, wherein the composition further comprises protein and fat.

17. The composition according to claim 16, wherein the composition is a powder and comprises about 10 to about 75% by weight of protein, about 1 to about 30% by weight of fat, and about 5 to about 80% by weight of a carbohydrate blend, or about 10 to about 30% by weight of protein, about 5 to about 30% by weight of fat, and about 35 to about 75% by weight of a carbohydrate blend, or about 40 to about 75% by weight of protein, about 1 to about 15% by weight of fat, and about 5 to about 15% by weight of a carbohydrate blend.

18. The composition according to claim 16, wherein the composition is liquid and comprises about 1 to about 15% by weight of protein, about 0.1 to about 15% by weight of fat, and about 1 to about 25% by weight of a carbohydrate blend, or about 1 to about 10% by weight of protein, about 0.1 to about 10% by weight of fat, and about 5 to about 20% by weight of a carbohydrate blend.

19. A nutritional composition comprising protein, fat, a carbohydrate blend, and Bifidobacterium animalis subspecies lactis CECT 8145 (BPL1), wherein the carbohydrate blend comprises at least one carbohydrate source providing rapid glucose, at least one carbohydrate source providing slow-release glucose, and at least one indigestible carbohydrate or resistant starch.

20. The source of at least one carbohydrate that provides the rapid-acting glucose is (i) Monosaccharides, (ii) Glucose units and fructose units linked by α-1, β-2 glycosidic bonds, (iii) Glucose units and galactose units linked by αβ(1,4) glycosidic bonds, (iv) Glucose units linked by α(1,4) glycosidic bonds, (v) Glucose units linked by α(1,6) glycosidic bonds, or (vi) Oligosaccharides having a random mixture of α(1,2), α(1,3), α(1,4), and α(1,6) glycosidic bonds, The nutritional composition according to claim 19, or comprising two or more combinations thereof.

21. The nutritional composition according to claim 20, wherein the source of at least one carbohydrate that provides the rapid-acting glucose comprises glucose, fructose, tagatose, galactose, mannose, ribose, sucrose, maltose, isomaltose, lactose, isomaltoligosaccharide, maltodextrin, or starch, or two or more combinations thereof.

22. The nutritional composition according to claim 19, wherein the source of at least one carbohydrate that provides the slow-release glucose comprises (i) glucose units and fructose units linked by α(1,6) glycosidic bonds, (ii) two glucose units linked by α(1,1) glycosidic bonds, (iii) glucose units and fructose units linked by α(1,5) glycosidic bonds, or (iv) oligosaccharides having alternating α(1,3) and α(1,6) glycosidic bonds, or two or more combinations thereof.

23. The nutritional composition according to claim 19, wherein the source of at least one carbohydrate that provides the slow-release glucose comprises isomaltose, trehalose, scromalt, or leucrose, or a combination of two or more thereof.

24. The aforementioned source of at least one indigestible carbohydrate or resistant starch is (i) Oligosaccharides having a random mixture of α(1,2), α(1,3), α(1,4) and β-glycosidic bonds, (ii) Carbohydrates having a linear chain of 2 to 60 fructose units, or a fructose polymer linked by β(2,1) glycosidic bonds, (iii) Oligosaccharides having a random mixture of α(1,2), α(1,3), α(1,4), and α(1,6) glycosidic bonds, The nutritional composition according to claim 19, or comprising two or more combinations thereof.

25. The nutritional composition according to claim 24, wherein the source of at least one indigestible carbohydrate or indigestible starch comprises indigestible maltodextrin, fructooligosaccharide, inulin, or isomaltoligosaccharide, or a combination of two or more thereof.

26. The nutritional composition according to claim 19, wherein the carbohydrate blend comprises fructose, isomaltose, scromalt, digestion-resistant maltodextrin, fructooligosaccharides, or a combination of two or more thereof.

27. The nutritional composition according to claim 19, wherein the carbohydrate blend comprises fructose, isomaltose, scromalt, digestion-resistant maltodextrin, and fructooligosaccharides.

28. The nutritional composition according to claim 19, wherein the source of at least one carbohydrate providing the fast-acting glucose provides 5% to 70% or 25% to 60% of the total calories supplied by the carbohydrates in the nutritional composition, the source of at least one carbohydrate in the carbohydrate blend providing the slow-acting glucose provides 20% to 85% or 20% to 50% of the total calories supplied by the carbohydrates in the nutritional composition, and the source of at least one non-digestible carbohydrate or indigestible starch in the carbohydrate blend provides 5% to 35% or 15% to 35% of the total calories supplied by the carbohydrate blend.

29. The nutritional composition according to claim 19, wherein the nutritional composition is a powder and comprises about 10 to about 75% by weight of protein, about 1 to about 30% by weight of fat, and about 5 to about 80% by weight of the carbohydrate blend; or about 10 to about 30% by weight of protein, about 5 to about 30% by weight of fat, and about 35 to about 75% by weight of the carbohydrate blend; or about 40 to about 75% by weight of protein, about 1 to about 15% by weight of fat, and about 5 to about 15% by weight of the carbohydrate blend.

30. The nutritional composition according to claim 19, wherein the nutritional composition is a liquid and comprises about 1 to about 15% by weight of protein, about 0.1 to about 15% by weight of fat, and about 1 to about 25% by weight of the carbohydrate blend; or about 1 to about 10% by weight of protein, about 0.1 to about 10% by weight of fat, and about 5 to about 20% by weight of the carbohydrate blend.

31. The nutritional composition according to claim 19, wherein the BPL1 is an inanimate object.

32. The nutritional composition according to claim 19, further comprising myo-inositol.

33. The liquid composition, provided in a size of approximately 237 ml, is approximately 10 ５ ~10 １５ cfu BPL1, or about 10 ８ ~10 １２ The nutritional composition according to claim 19, comprising cfu BPL1 and a carbohydrate blend in an amount of about 5 to about 100 g, about 5 to about 50 g, or about 5 to about 30 g.

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