US20080131531A1 - Konjac Mannan and Ginseng Compositions and Methods and Uses Thereof - Google Patents
Konjac Mannan and Ginseng Compositions and Methods and Uses Thereof Download PDFInfo
- Publication number
- US20080131531A1 US20080131531A1 US11/960,033 US96003307A US2008131531A1 US 20080131531 A1 US20080131531 A1 US 20080131531A1 US 96003307 A US96003307 A US 96003307A US 2008131531 A1 US2008131531 A1 US 2008131531A1
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- United States
- Prior art keywords
- ginseng
- kjm
- treatment
- konjac
- diabetes
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Definitions
- the invention relates to compositions comprising Konjac-Mannan, Ginseng or both and methods of use and uses of these compositions, such as in lowering blood glucose including post-prandial and long-term effects.
- this invention is in the field of glucose and other heart disease risk factors management.
- the invention is concerned with dietary approaches to such management.
- compositions and methods of reducing blood glucose specifically
- Abnormal glucose tolerance and insulin resistance are related to multiple cardiovascular risk factors especially reduced HDL, elevated serum triglycerides and hypertension (Liese et al. (1998)). When clustered these abnormalities increase the risk of coronary heart disease (CHD) morbidity and mortality, an effect that is independent of other conventional risk factors (Trevisan et al. (1998)). Co-ocurrence is usually present in insulin-insensitive individuals (Himswarth (1936)) and is often described in relation to visceral adiposity (Haffner et al. (1986)) and lack of physical activity (Helmrich 1991)). The estimated prevalence ranges from 3% (Trevisan et al. (1998)) to approximately 30% (Liese et al. (1998); Reaven (1994)) depending on how this insulin resistance-dislipidemic syndrome is defined and in which population it is measured.
- Hyperglycemia and diabetes are strong and independent risk factors of both all-cause and cardiovascular (CVD) mortality (Wing et al. (1998)). These links are more pronounced when the diabetes is associated with other unfavorable risk factors such as hyperlipidemia (Goldsmith et al. (1994)), hypertension (Burt et al. (1995)), or a cluster of metabolic disorders (Stamler et al. (1993)). Since people with diabetes have almost twice the risk of dying from CVD (69.6%) compared to people in the general U.S. population (Gu et al. (1998)), the control of high glucose levels and other concomitant coronary heart disease (CHD) risk factors represents the most effective approach to prevention (Savage (1996)).
- CVD cardiovascular disease
- Tighter fasting and postprandial glycemic control results in a considerable reduction in CHD and all-cause mortality (Wei et al. (1998)), as well as fewer long-term microvascular complications both in type 1 (DCCT Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The diabetes control and complications trial. New Engl J Med 329:977-986 (1993)) and type 2 diabetes (UK Prospective Diabetes Study (UKPDS) Group: Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes: UKPDS 34 . Lancet 352:854-865, 1998).
- the present inventor has determined that the addition of high-viscosity fiber, in the form of a konjac-mannan mixture, or ginseng, or a composition comprising a konjac-mannan mixture and ginseng to a diet of an animal enhances conventional treatment outcomes, such as for diabetes and coronary heart disease, assessed primarily by total/HDL cholesterol, fructosamine, and sBP and secondarily by total, LDL, and HDL cholesterol; apolipoprotein A-1 (Apo A-1), B (Apo B) and their ratio; glucose; insulin; and systolic blood pressure (dBP).
- apolipoprotein A-1 Apo A-1
- B Apo B
- dBP systolic blood pressure
- the present invention provides a composition of matter for reducing blood glucose comprising a konjac-mannan mixture.
- a sufficient amount of the konjac-mannan mixture when given to an animal preferably at an appropriate time, reduces blood glucose in the animal, preferably postprandial blood glucose.
- the konjac-mannan mixture comprises konjac-mannan and a substance capable of increasing the viscosity of konjac-mannan from 50% to about 250% of konjac-mannan alone. More preferably the substance comprises about 5% to about 45% by weight of one or more such substances, preferably polysaccharides.
- composition as just mentioned comprises as the one or more polysaccharides xanthan, carragenan, acetan, guar, or xyloglucana.
- a composition according to the invention comprises consitituents with the particle size larger than about 1,000 angstroms.
- such a composition is used in controlling cholesterol levels, preferably lowering cholesterol levels.
- compositions according to the invention are formulated into a liquid, powder or formulated as part of a food.
- the compositions of the invention are formulated into pills, capsules and tablets
- the present invention provides a method for reducing blood glucose in an animal comprising administering to the animal a sufficient amount of a konjac-mannan mixture at an appropriate time in order to reduce blood glucose, preferably postprandial blood glucose, in the animal.
- the konjac-mannan mixture comprises konjac-mannan and a substance capable of increasing the viscosity of konjac-mannan to from about 50% to about 250% of konjac-mannan alone, preferably the substance comprises from about 5% to about 45% by weight of one or more polysaccharides, more preferably the one or more polysaccharides are selected from the group consisting of xanthan, carragenan, acetan, guar, or xyloglucana.
- the particle size of the constituents of a mixture of the invention are larger than about 1000 angstroms.
- a mixture according to the invention is administered orally in an amount of about 1 to about 4 grams per day, preferably the mixture is administered either prior to a meal or during the meal.
- the administration of a mixture according to the invention is by a liquid, a powder, or as a part of a food product.
- administration is by way of tablet, capsule or pill.
- composition of matter for reducing blood glucose comprising ginseng in one aspect of the invention a sufficient amount of ginseng, when given to an animal at an appropriate time reduces blood glucose, preferably postprandial blood glucose, in the animal.
- composition of matter for reducing blood glucose comprising an extract of ginseng, preferably American ginseng, a sufficient amount of which when given to an animal at an appropriate time reduces blood glucose in the animal.
- the ginseng is comprised of a ratio of protopanaxadiols (diols) relative to protopanaxatriols (triols) that is preferably greater than about 1.0, most preferably about 1.5 or greater and more preferably about 1.90 or greater.
- the diol/triol ratio is about 2.4 or greater.
- the composition is formulated into a liquid, powder or formulated as part of a food.
- the composition is formulated into tablets, capsules or pills.
- a method for reducing blood glucose in an animal comprising administering to the animal a sufficient amount of ginseng at an appropriate time in order to reduce blood glucose in the animal.
- a method for reducing blood glucose in an animal comprising administering to the animal a sufficient amount of an extract of ginseng at an appropriate time in order to reduce blood glucose in the animal.
- the ginseng or extract is administered before a meal or with a meal, more preferably the administration before meal occurs from about 1 to about 180 minutes before the meal.
- the amount of ginseng or extract of ginseng is at least about 1000 mg per administration.
- the amount of ginseng administered is between 1-9 g, preferably 1-4 g and most preferably 1-3 g.
- the ginseng comprises a ratio of diols/triols of greater than about 1.0, most preferably about 1.5 or greater and more preferably about 1.90 or greater. In another embodiment, the diols/triols ratio is about 2.4 or greater.
- the composition is administered as a food, a powder, or a liquid.
- the composition is formulated into tablets, capsules or pills.
- a composition of matter for reducing blood glucose comprising a konjac-mannan mixture of the invention and ginseng.
- a sufficient amount of konjac mannan and ginseng which when given to an animal at an appropriate time reduces blood glucose in the animal.
- the konjac-mannan mixture comprises konjac-mannan and a substance capable of increasing the viscosity of konjac-mannan from 50% to about 250% of konjac-mannan alone.
- the substance comprises about 10% to about 40% of one or more polysaccharides. More preferably the one or more polysaccharides are xanthan, carragenan, acetan, guar, or xyloglucana.
- the particle size of constituents within the mixture is larger than about 1,000 angstroms.
- the American ginseng is comprised of a ratio of diols/triols of greater than about 1.0, most preferably about 1.5 or greater and more preferably about 1.90 or greater. In another embodiment, the diol/triol ratio is about 2.4 or greater. According to yet another embodiment according to this aspect of the invention the composition is formulated into a liquid, powder or formulated as part of a food.
- the ginseng used in the compositions and methods of the invention can be any ginseng or extract thereof, for instance American, Asian, Chinese or other ginseng known in the art.
- the ginseng is preferably American ginseng.
- the ginseng or extract thereof has a diol/triol ratio of about 1.0, most preferably about 1.5 or greater and more preferably about 1.90 or greater. In another embodiment, the diol/triol ratio is about 2.4 or greater.
- the invention provides a method for determining whether a ginseng or extract thereof would be useful in controlling, modulating or lowering blood glucose, preferably postprandial blood glucose, by determining the diol/triol ratio of the ginseng or extract and selecting for one that has a diol/triol ratio of about 1.5 or greater.
- the selected extract can then be optionally tested for such activity using the traditional tests and assays described herein or known in the art.
- the selected ginseng can also be tested and selected for insulin, lipid profile, cholesterol and blood pressure control, modulation or decrease.
- the selected ginseng can be tested and selected for effectiveness in the treatment of diabetes and/or cardiovascular disease.
- compositions and methods of the invention can be applied to the treatment of long term diabetes, heart disease, and syndrome X.
- compositions and methods of the invention provide methods for increasing insulin sensitivity in an animal and of treating type 2 diabetes as well as for reducing systolic blood pressure or blood cholesterol and other lipids and apolipoproteins
- FIG. 1 is a histogram illustrating the effect of various fibres including Konjac mannan alone on glucose response in individuals in eleven individuals in comparison with a Konjac-mannan mixture of the present invention.
- FIG. 2 is a graph illustrating the post-meal blood glucose response of individuals histogram illustrating the effect of various fibres including Konjac mannan alone in comparison with a Konjac-mannan mixture of the present invention.
- FIG. 3 is a bar graph illustrating the composition of the placebo versus konjac biscuits used in Example 10.
- FIG. 4 illustrates the effect of konjac mannan versus placebo on blood glucose levels as described in Example 10.
- FIG. 4A is a linear graph illustrating glucose response to a test breakfast before 3-week treatment and
- FIG. 4B is a linear graph illustrating glucose response to a test breakfast after the 3 week treatment.
- FIG. 4C is a bar graph illustrating glucose area under the curve (AUC) before and after the 3-week treatment.
- FIG. 5 illustrates the effect of konjac mannan versus placebo on blood insulin levels as described in Example 10.
- FIG. 5A is a linear graph illustrating insulin response to a test breakfast before 3-week treatment and
- FIG. 5B is a linear graph illustrating insulin response to a test breakfast after the 3 week treatment.
- FIG. 5C is a bar graph illustrating insulin area under the curve (AUC) before and after the 3-week treatment.
- FIG. 6 illustrates the effect of highly refined konjac mannan versus the konjac mixture of the invention as described in Example 11.
- FIG. 6A is a linear graph illustrating absolute blood glucose levels.
- FIG. 6B is a linear graph illustrating incremental blood glucose levels.
- FIG. 6C is a bar graph illustration glucose area under the curve.
- FIG. 7 is a linear graph illustrating the results of Example 12 for the effect of konjac mannan, American ginseng and both konjac mannan and American ginseng on systolic blood pressure.
- FIG. 8 illustrated the effect of konjac mannan and ginseng treatment versus the separate treatments on blood glucose.
- FIGS. 8 A and B are linear graphs illustrating blood glucose levels versus time and changes therein as described in Example 13.
- FIG. 9 is a linear graph illustrating insulin levels versus time using various treatment regimes: placebo, ginseng, konjac mannan mix, and konjac mannan mix and ginseng.
- FIG. 10 is a bar graph illustrating the effect of various ginseng preparations with various diol/triol ratios on postpranial blood glucose levels.
- FIG. 11 illustrates a comparison of incremental change (linear graphs 11 A, C, and E) and area under the curve (AUC) ( FIGS. 11B , D, and F) in plasma glucose ( FIGS. 11A and B), insulin ( FIGS. 11C and D) and nitric oxide (Nox) ( FIGS. 11E and F).
- the present invention is related to compositions and methods for reducing blood glucose.
- the present inventor has found that a konjac mannan mixture, a ginseng composition, or a composition comprising konjac mannan and ginseng are effective in the reduction of blood glucose.
- the compositions of the invention are effective in controlling or modulating the lipid profile of an animal, blood pressure and insulin levels.
- compositions of the invention A enhances conventional treatment outcomes, such as for diabetes and coronary heart disease, assessed primarily by total/HDL cholesterol, fructosamine, and sBP and secondarily by total, LDL, and HDL cholesterol; apolipoprotein A-1 (Apo A-1), B (Apo B) and their ratio; glucose; insulin; and systolic blood pressure (dBP).
- animal means any member of the animal kingdom including preferably humans.
- postprandial means after any food intake.
- sufficient amount or “effective amount” means an amount of a composition, substance or reactant to give an observable result, including desired results.
- appropriate time means at a time at which administration of a substance or composition provides an observable result.
- prior to a meal means at any time after a meal and before a subsequent meal.
- “during a meal” means at any time after the commencement of consumption of one or more pieces of food by an animal, and can be coincident with commencement, and before the end of consumption of all food consumed by the animal, at one sitting or occasion and can be coincident with completion of consumption or immediately thereafter.
- a food means any substance or composition of substances or compounds which are consumed by an animal, preferably for some nutritional value.
- a meal means the consumption of one or more morsels or pieces of a food in a sitting where a sitting is the time taken to consume the one or more morsels or pieces of a food.
- diol/triol ratio(s) or “diols/triols” refers to protopanaxadiols (diols) relative to protopanaxatriols (triols).
- Konjac (Amorphophalus Konjac C. Koch) is a perennial plant belonging to the family Araceae. “Konnyaku”, which is made from the tuber of this plant, has been used traditionally for food in Japan for several hundred years.
- the predominant component of edible konnyaku is a glucomannan called konjac mannan (KJM).
- Edible konnyaku is made from the konjac flour, which is obtained from the dried tuber of this plant.
- KJM flour is obtained by grinding the tuber root of the Amorphophallus Konjac C. Koch . plant and is traditionally used as a food and remedy in the Far East.
- other findings have shown it to improve cholesterol levels (Arvill et al. (1995)), hypertension, and glycemia (Doi et al. (1979); Shima et al. (1982)).
- Konjac-mannan was chosen as the fibre because it represents a polysaccharide with one of the highest viscosities (Kiriyama et al. (1972)).
- the physiologically active component is a high molecular weight glucomannan polymer, which, when taken as a supplement, has been shown to have effects in lowering lipids (Arvill et al. (1995); Terasawa et al. (1979); Venter et al. (1987)), systolic blood pressure (sBP) (Arvill et al. (1995)), and glycemia (Doi et al. (1979); Shima et al. (1982)).
- konjac flour is boiled in water, treated with Fehling's solution to convert the mannan to its copper complex, and the latter is decomposed again into the mannan after purification, as disclosed in J. Agr. Chem. Soc. Japan, 6, 991-995 (1930).
- konjac flour is extracted with water, impurities are removed by precipitating with ethanol and redissolving the precipitate in water several times, and drying the precipitate finally obtained to obtain pure konjac mannan, as disclosed in Bull. Chem. Soc. Japan, 49, 298-322 (1927).
- Water-soluble konjac mannan capable of undergoing gelation when heated in an aqueous alkaline solution may be used as described in U.S. Pat. No. 3,973,008. Briefly it is obtained by extracting the ground tuber of the konjac plant with water, separating insoluble matter, dialyzing the solids-free liquid against water and then lyophilizing the dialyzed liquid to remove water.
- suitable konjac mannan preparation protocols for use herein. All such preparation methods are intended to be encompassed within the scope of the present invention.
- the present invention provides an improved konjac mannan composition.
- the konjac mannan composition or mixture of the invention preferably comprises konjac mannan and a substance that can increase the viscosity of the konjac mannan by 50-250%. Accordingly, in one aspect the present invention provides a composition of matter for reducing blood glucose comprising a konjac-mannan mixture. In another aspect of the invention, a sufficient amount of the konjac-mannan mixture, when given to an animal preferably at an appropriate time, reduces blood glucose in the animal, preferably postprandial blood glucose.
- the konjac-mannan mixture comprises konjac-mannan and a substance capable of increasing the viscosity of konjac-mannan from 50% to about 250% of konjac-mannan alone. More preferably the substance comprises about 5% to about 45% by weight of one or more such substances, preferably polysaccharides.
- composition as just mentioned comprises as the one or more polysaccharides xanthan, carragenan, acetan, guar, or xyloglucana.
- a composition according to the invention comprises consitituents with the particle size larger than about 1,000 angstroms.
- such a composition is used in controlling cholesterol levels, preferably lowering cholesterol levels.
- compositions according to the invention are formulated into a liquid, powder or formulated as part of a food.
- the compositions of the invention are formulated into pills, capsules and tablets
- the present invention provides a method for reducing blood glucose in an animal comprising administering to the animal a sufficient amount of a konjac-mannan mixture at an appropriate time in order to reduce blood glucose, preferably postprandial blood glucose, in the animal.
- the konjac-mannan mixture comprises konjac-mannan and a substance capable of increasing the viscosity of konjac-mannan to from about 50% to about 250% of konjac-mannan alone, preferably the substance comprises from about 5% to about 45% by weight of one or more polysaccharides, more preferably the one or more polysaccharides are selected from the group consisting of xanthan, carragenan, acetan, guar, or xyloglucana.
- the particle size of the constituents of a mixture of the invention are larger than about 1000 angstroms.
- a mixture according to the invention is administered orally in an amount of about 1 to about 4 grams per day, preferably the mixture is administered either prior to a meal or during the meal.
- the administration of a mixture according to the invention is by a liquid, a powder, or as a part of a food product.
- administration is by way of tablet, capsule or pill.
- a main ingredient of the ginseng is saponin.
- Various saponin are included in this ginseng, specifically there are twelve known kinds of ginsenside-Ro, -Ra, -Rb1, -Rb2, -Rc, -Rd, -Re, -Rf, -Rg1, -Rg2, -Rg3, -Rh. These are the ones (ginsenside-Rb1, -Rb2, -Rc) containing sapogenen and protopanaxadiol, and the ones (ginsenside-Re, Rf, -Rg1, -Rg2) containing sapogenen and protopanaxatriol.
- the main saponin in the crude drug is ginsenside-Rb1, -Rb2, -Rc, -Rg1.
- the ginsenside-Ro is the same as chikusetsusaponin V
- the ginsenside-Rb1 is the same as saponin D.
- the ginseng contains essential oil of 0.05%, beta.-elemene, panacene (C 15 H 24 ) and panaxynol as polyacetylene compound and further contains choline, vitamin B complex, fatty acid etc.
- ginseng there are known to be at least seven different types of ginseng and in the present disclosure a preferred form is American ginseng. There are many types of ginseng, American, Asian, and others known in the art, and various subspecies thereof. Not all have the same compositions or therapeutic effects, even within the same species. Effectiveness can also depend on the method of preparation of ginseng composition.
- the ginseng used in the compositions and methods of the invention can be any ginseng or extract thereof, for instance American, Asian, Chinese or other ginseng known in the art.
- the ginseng is preferably American ginseng.
- the ginseng or extract thereof has a diol/triol ratio of about 1.0, most preferably about 1.5 or greater and more preferably about 1.90 or greater. In another embodiment, the diol/triol ratio is about 2.4 or greater.
- the amount of ginseng or extract of ginseng is at least about 1000 mg per administration.
- the amount of ginseng administered is between 1-9 g, preferably 1-4 g and most preferably 1-3 g.
- the invention provides a method for determining whether a ginseng or extract thereof would be useful in controlling, modulating or lowering blood glucose, preferably postprandial blood glucose, by determining the diol/triol ratio of the ginseng or extract and selected for one that has a diol/triol ratio of about 1.5 or greater.
- the selected extract can then be optionally tested for such activity using the traditional tests and assays described herein or known in the art.
- the selected ginseng can also be tested and selected for insulin, lipid profile, cholesterol and blood pressure control, modulation or decrease.
- the selected ginseng can be tested and selected for effectiveness in the treatment of diabetes and/or cardiovascular disease.
- Ginseng preferably American Ginseng ( Panax quinquefolium L.) reduces postprandial blood glucose in nondiabetic and people with diabetes.
- at least 1000 mg of ginseng, preferably American ginseng is administered together or before the meal (up to 180 min) to see an effect on the postprandial blood glucose responses to a test meal. While in nondiabetic it is important to take ginseng before meal, in type 2 diabetes, the effect is seen irrespective of time of consumption (together with meal or up to 180 min before meal).
- Ginseng such as American ginseng with a profile of diol/triol ratio of greater than about 1.0, most preferably 1.5 or greater and more preferably 1.90 or greater. In another embodiment, the triols/diols ratio is about 2.4 or greater. In one embodiment the composition may be administered in the same manner as described above to produce glucose lowering effects. Ginseng with a particular ginsenosides profile may have an effect on increased secretion of the first phase insulin, similar to conventional diabetic drugs.
- Ginseng roots was selected by chemical composition analysis using HPLC. If ginseng extract is used, it can be prepared by the usual extraction procedure, by using a water and alcohol solution in ratio between 40% to 80% of water, with the rest being alcohol. Other ginseng, and extract preparation procedures are known in the art.
- the present invention shows for the first time, that ginseng (root or extract) with protopanaxadiols to protopanaxa triols ratio higher than about 1.0, most preferable 1.5, lowers the postprandial glycemic response in both healthy and diabetic individuals and in the long term reduces serum lipids and blood pressure and thus improves diabetes control.
- ginseng may potentate insulin secretion potentially through a modulation of autocoid metabolism linked to nitric oxide production.
- gut mediated hormone effects may play part in the mechanism of action of AM but this area has not yet been explored.
- the invention also comprises the administration of both ginseng (such as American Ginseng ( Panax quinquefolium L.) and konjac mannan, jointly.
- ginseng such as American Ginseng ( Panax quinquefolium L.) and konjac mannan
- the efficacy is not attainable by either treatment.
- the ginseng can be any ginseng or formulation thereof, preferably as described above, more preferably that has a diol/triol ratio of greater than about 1.5 or more.
- the konjac-mannan is preferably the konjac mannan mix as described above.
- the konjac mannan and ginseng can be prepared and administered in separate compositions or can be formulated into one composition.
- the possible mechanism of action for the hypoglycaemic effect of konjac/ginseng is to increase insulin secretion/sensitivity, and together with konjac mannan's ability to slow nutrient absorption and also improve insulin sensitivity these combined effects result in lower prolonged elevation of postprandial blood glucose and have applications in prevention and treatment of diabetes and heart disease.
- konjac mannan's ability to slow nutrient absorption and also improve insulin sensitivity result in lower prolonged elevation of postprandial blood glucose and have applications in prevention and treatment of diabetes and heart disease.
- compositions described herein can be prepared by per se known methods for the preparation of pharmaceutically acceptable compositions which can be administered to subjects, such that an effective quantity of the composition of the invention is combined in a mixture with a pharmaceutically acceptable vehicle, thereby allowing for the administration of a sufficient amount of the composition.
- Suitable vehicles are described, for example, in Remington's Pharmaceutical Sciences (Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., USA 1985).
- the compositions include, albeit not exclusively, solutions of the substances in association with one or more pharmaceutically acceptable vehicles or diluents, and contained in buffered solutions with a suitable pH and iso-osmotic with the physiological fluids.
- the effective or sufficient amount of a composition of the invention can vary depending on the individual, such as sex, age, and weight of the individual, and/or severity of a condition, such as diabetes. It may also in certain cases vary on the time of administration, i.e. post or pre meal and time it takes for the substance to clear or be metabolized by the body. It may also vary depending on whether the compositions are administered separately or with another substance that may modulate the effectiveness of the composition. For instance the effective amount of konjac mannan may vary depending on whether it is administered alone or in conjunction with a ginseng or another substance that may act synergistically with it. It may also vary depending on the concentration and mode of preparation of the konjac mannan being administered. The above similarly applied to the administration of ginseng.
- compositions in one aspect are administered orally, such as by liquid, powder or formulated as part of a food, such as a biscuit. It could be administered in the form of pills, capsules and tablets. Other forms of administration may also be suitable.
- compositions of the invention can be used in the modulation or control, preferably decrease, of blood glucose, preferably postprandial blood glucose.
- the compositions of the invention can also be used to modulate or control insulin levels in an animal, preferably decrease such levels.
- the compositions of the invention can also be used to modulate a lipid profile of a patient in need thereof. They can also be used to modulate blood pressure, preferably to lower blood pressure.
- the invention can be used in the treatment of animals, preferably humans, in need of controlling their glucose levels, such as in the management and treatment of diabetes.
- the compositions of the invention can be used in the management and treatment of cardiovascular disease and associated conditions, such as high blood pressure, high cholesterol level.
- the compositions of the invention, especially the ginseng compositions can be used to modulate or control nitric oxide levels in an animal.
- the study employed a double-blind, placebo-controlled, cross-over design, where all subjects were maintained on the same dosage of their medications throughout.
- the study began with an 8 week baseline period over which participants followed an NCEP Step 2 ad libitum diet: Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA; 285:2486-2497, 2001, documented by three non-consecutive days of food records every two weeks. This was followed by the experimental phase of the study that consisted of two successive 3 week treatment periods, separated by a two week washout interval over which another three day food record was obtained.
- NCEP National Cholesterol Education Program
- the first treatment period subjects were randomly assigned to either the KJM+ (Step 2 metabolically controlled diet enriched with fiber) or the control treatment (the same diet enriched with wheat bran [WB] fiber).
- the second treatment period the subjects were crossed-over. The study began with 5 subjects taking the KJM+ treatment and 6 the control.
- Both treatments consisted of a three-day rotating Step 2 diet with three meals per day provided under metabolic conditions. All foods were pre-weighed, packaged and couriered to participants for consumption at home or at work. The mean macronutrient profile conformed with a Step 2 diet. Energy intakes for weight maintenance were provided according to Lipid Research Clinics Tables with adjustment for physical activity (The Lipid Research Clinics Population Studies Data Book. Vol. 2. The prevalence study-nutrient intake. Washington D.C.: Government printing office (NIH publication no. 82-2014) (1982)). Total dietary fiber was administrated at 2 g/412 kJ (100 kcal), with a mean daily intake according to energy intake ranging from 24 g to a plateau of 50 g for those consuming 2500 Kcal per day or more. The actual diet consumed is presented in Table 2.
- KJM+ biscuits contained approximately 15% KJM flour of which 69% was the active high viscosity glucomannan, 15% other polysaccharides, and 16% excipients by weight.
- the KJM flour mix used in the biscuits comprised in % by weight: 69% KJM, 21% xanthan and 10% caragenan. Because KJM flour comprised half (1 g/412 kJ [100 kcal]) of the total fibre on the KJM+ treatment, approximately 0.7 g/412 kJ (100 kcal) was glucomannan.
- Wheat bran biscuits in contrast, had a lower proportion of fiber than KJM+ biscuits (Table 3). Approximately 14 g/day of wheat bran fibre derived from standardized American Association of Cereal Chemist hard red wheat bran was, therefore, added to the control (WB) diet to compensate for these fiber differences.
- Serum blood samples were immediately separated and stored in four aliquots at ⁇ 70° C. after collection. They were thawed at the end of the study for analysis of total cholesterol, HDL, and triglycerides (TRIG) measured enzymatically (McNamara et al. (1987); Warnick et al. (1982)). LDL content was estimated by the formula of Friedewald et al. (Friedewald et al. (1972)). Apolipoprotein (Apo) A1 and B were determined by rocket immunoelectrophoresis (Fruchart et al. (1982)).
- Fasting blood glucose was analyzed by a hexokinase method using a Cobas Mira Autoanalyzer (Roche Diagnostic, Mississauga, Canada). Serum fructosamine was analyzed in triplicate using the Cobas Fara II (Lloyd et al. (1984)) and plasma insulin in duplicate by radioimmunoassay with reagent from ICN Biomedicals, Inc. (Horsham, Pa.) (Livesey et al. (1980)). Finally, C-peptide was determined by radioimmunoassay (Kuzuya et al. (1976)).
- Results are expressed as mean ⁇ SEM, except for age, anthropometric measurements and nutrient intake (mean ⁇ SD). Data were analyzed by the Statistical Analysis System (SAS) (SAS Institute Inc.: SAS/STAT User's guide . Version 6, 4 th ed. Cary N.C.: SAS Institute Inc. 1989)). Differences in serum lipids, apolipoproteins, glycemia, blood pressure and body weight between the beginning (week-0) and end (week-3) of each treatment (control and KJM+) were assessed by two-tailed Student's t-test for paired data (PROC UNIVARIATE).
- SAS Statistical Analysis System
- ANCOVA covariance
- PROC GLM General Linear Model procedure
- HDL, Apo A-1, or triglycerides were not seen on HDL, Apo A-1, or triglycerides.
- HDL and Apo A-1 decreased insignificantly, for insignificant between treatment changes.
- triglycerides increased insignificantly, with no significant difference between treatments.
- Examples 1-4 illustrate that the addition of 0.7 g/412 kJ (100 kcal) of high viscosity glucomannan (KJM mix) in biscuit form to conventional CHD treatment (a low saturated fat diet combined with drug therapy) improved metabolic control beyond the effect of conventional treatment alone in high-risk individuals with type 2 diabetes.
- Step 2 diets were supplemented with soluble fibre from different dietary sources (Jenkins et al. (1993)) or fibre supplements (Anderson et al. (1986); Olson et al. (1997)). While such studies have reported reduced total and LDL concentrations, few, as has been the case for NCEP diets, have reported improved lipoprotein ratios. Out of the three lipid trials that used KJM+ (Arvill et al. (1995); Terasawa et al. (1979); Venter et al. (1987)) the former two did not show a significant change in these ratios. In contrast, Venter and coworkers (Venter et al.
- KJM has been shown to have a beneficial effect following both acute (Shima et al. (1982)) and long-term (Doi et al. (1979); Shima et al. (1982)) administration.
- KJM+ treatment compared to control, a 5.7 ⁇ 1.7% reduction was observed in serum fructosamine, a short-term marker of diabetes control, with no effect on either fasting glucose or insulin concentrations.
- KJM has been shown to have very high viscosity, approximately five times higher than guar gum (Ebihara et al. (1981)) and considerably more than pectin (Venter et al. (1987)). Consequently, in some studies it has been given at half the dosage relative to these other fibers (Ebihara et al. (1981)).
- the present inventors have further increased the viscosity of KJM by the addition of polysaccharides such xanthan, caragenan, acetan, guar or xyloglucena.
- a possible mechanism for the blood pressure lowering effect of soluble fibers may involve increased insulin sensitivity (Anderson et al. (1986)), which may reduce blood pressure by influencing sodium absorption in the distal tubule, increasing sympathetic nervous system activity and peripheral vascular resistance (Modan et al. (1985)).
- KJM+ supplementation in the high-risk diabetic study group of the examples demonstrated simultaneous improvement in all three diet-modifiable risk factors, indicating a reduction in overall CHD risk (Jenkins et al. (1995)).
- KJM+ supplemented therapy may lower required drug dosages and improve overall cost-effectiveness and acceptability of treatment.
- food should be the normal way to achieve an adequate fiber intake, fiber supplemented foods have advantages in the treatment of individuals at high risk for CHD and represent a possible intermediate step between diet and drug therapy.
- ITT impaired glucose tolerance
- the study employed a double-blind, placebo-controlled, cross-over design that was identical to that used in the previous study (Vuksan et al. (1999)) and Example 1. It began with an 8-week baseline period during which participants followed a National Cholesterol Education Program (NCEP) Step 2 (American Diabetes Association (ADA): Nutrition Recommendations and principles for people with diabetes mellitus. Diabetes Care 22:s42-s43, 1999)) ad libitum diet, documented by three non-consecutive days of food records every two weeks. This run-in phase was included to eliminate possible effects of dietary change on metabolic parameters. The experimental phase of the study followed.
- NCEP National Cholesterol Education Program
- ADA American Diabetes Association
- Both treatments consisted of a three-day rotating Step 2 diet with three meals per day provided under metabolic conditions. All foods were pre-weighed, packaged and couriered to participants for consumption at home or at work.
- the mean macronutrient profile closely conformed to a Step 2 diet (of calories ⁇ 30% from total fat, ⁇ 7% from saturated fat, and ⁇ 300 mg/day cholesterol) (American Diabetes Association (ADA): Nutrition Recommendations and principles for people with diabetes mellitus. Diabetes Care 22:s42-s43, (1999)).
- Energy intakes for weight maintenance were provided according to Lipid Research Clinics Tables with adjustment for physical activity (24).
- Total dietary fiber was administrated at 1.5 g/100 kcal, with a mean daily intake according to energy intake ranging from 24 g to a plateau of 40 g for those consuming 2800 kcal per day or more.
- the actual diet consumed is presented in Table 5.
- KJM+ enriched test biscuits whereas on the WB-control treatment they received an equal quantity of wheat bran control biscuits. Subjects were instructed to eat an equal amount of biscuits together with an 8 oz beverage, 3 times daily as a snack, including once at bedtime. Both were provided by Dicofarm S.p.A, Roma, Italy. They had similar nutrient profiles and were indistinguishable in taste and appearance.
- KJM+ biscuits contained approximately 10% KJM flour of which 69% was the active high viscosity glucomannan, 15% other polysaccharides, and 16% excipients by weight (Vuksan et al. (1999)).
- the KJM flour mixture of the KJM+ biscuits comprised 69%+17% xanthan, 9% caragenan, and 8% guar. Because KJM flour comprised half (0.75 g/100 kcal) of the total fibre on the KJM+ treatment, approximately 0.5 g/100 kcal (8-13 g/day) was glucomannan. Wheat bran biscuits, in contrast, had a lower proportion of total dietary fiber than KJM+ biscuits. Approximately 11 g/day of wheat bran fibre derived from standardized American Association of Cereal Chemist hard red wheat bran was, therefore, added to the WB-control diet to compensate for these fiber differences. Subjects were instructed to sprinkle the additional fiber on cereal, yoghurt, and/or other compatible foods to improve palatability.
- Serum fructosamine was analyzed in triplicate using Cobas Fara II and plasma insulin in duplicate by radioimmunoassay with reagent from ICN Biomedicals, Inc. (Horsham, Pa.). C-peptide was determined by radioimmunoassay.
- Results are expressed as mean ⁇ SEM, except for age, anthropometric measurements and nutrient intake (mean ⁇ SD). Data were analyzed by the Statistical Analysis System (SAS Institute, Cary, N.C.). Differences between the diets were assessed by two-tailed Student's t-test for paired data (univariate procedure). This same statistic also assessed differences in serum lipids, apolipoproteins, glycemia, blood pressure and body weight between the beginning (week-0) and end (week-3) of each treatment (WB-control and KJM+). Analysis of covariance (ANCOVA) with the facility of General Linear Model (GLM) procedure was used to test for differences in these same parameters between the two treatments.
- SAS Institute SAS Institute, Cary, N.C.
- Low-fat/high carbohydrate diets may still have promise as a therapeutic approach. Although there has been a shift away from their advocacy in favor of those rich in monounsaturated fat (American Diabetes Association (ADA): Nutrition Recommendations and principles for people with diabetes mellitus. Diabetes Care 22:s42-s43, 1999), these diets supplemented with fiber may have similar metabolic advantages. Guar gum, pectin, oat products, and psyllium added to high carbohydrate diets have been shown to improve total and LDL cholesterol significantly, with no improvement to triglycerides and slight or no adverse effects on HDL (Jenkins et al. (1978)). Both guar (Aro et al.
- KJM+ may be better suited than the other major soluble fibers in improving outcomes with high-carbohydrate/low-fat diets.
- meta-analyses use variance adjusted values that tend to underestimate effectiveness, KJM+ can be compared to other soluble fibers in terms of its lipid lowering ability per gram of fiber, using recent meta-analytical data (Brown et al. (1999)).
- Daily intake of glucommanan from KJM+ on this study produced an average net change in total and LDL cholesterol of ⁇ 0.084 and ⁇ 0.119 mmol/L per gram of fiber respectively.
- Contributions made by its theological properties may offer insight into the proposed mechanism by which the KJM+ supplemented biscuits had their beneficial effects.
- possibilities for its lipid lowering action may include an inhibition of cholesterol absorption in the jejunum (Venter et al. (1987) and bile acid absorption in the ileum (Kiriyama et al. (1974)) mediated by viscosity or less postprandial stimulation of HMG CoA reductase (Jenkins et al. (1993)).
- Other options include the generation of short chain fatty acids, predominantly propionate, by colonic microflora that may decrease hepatic cholesterol synthesis (Venter et al. (1990)).
- the improvement in glycemic control may be attributable to an effect of the gel forming KJM+ on rate of digestion. It has been suggested that decreases in glucose and insulin levels after the consumption of water-soluble fibers are related to slower rates of food absorption in the small intestine associated with increased viscosity (Jenkins et al. (1978)). This mechanism may explain why a reduction in serum fructosamine, but did not concomitant reductions in fasting glycemia and insulinemia were observed: KJM+ may be exerting its effect mainly postprandially.
- Results are presented as area under the glucose curve ( FIG. 1 ) and absolute and incremental blood glucose levels ( FIG. 2 ) for individual time points.
- Incremental and absolute glucose levels were significantly reduced on KJM mix treatment at time 30 (P ⁇ 0.05) compared to all other treatment.
- FIGS. 1 and 2 provide illustrations of the significant effects on blood glucose a konjac mannan mixture of the present invention has over the effects of individual saccharides and konjac mannan alone.
- the mixture of konjac mannan comprised konjac mannan and xanthan although, other saccharides which can be use include, carragenan, acetan, guar, or xyloglucana.
- Atherosclerosis and diabetes have been characterized as postprandial phenomena. Recent epidemiological analyses demonstrated that diets with a low glycemic load reduce their incidence.
- KJM mix to reduce postprandial glycemia in the insulin resistance syndrome (syndrome X) that underlies these diseases.
- 12 participants were studied (age: 55 ⁇ 4 y, BMI: 28 ⁇ 3 kg/m 2 ) who satisfied the criteria for the syndrome (IGT, reduced-HDL, elevated triglycerides and mild-hypertension) following 21 days of KJM mix supplementation.
- CompositeWhole Body ISI is hepatic & peripheral tissue insulin sensitivity
- FPG is fasting plama glucose (mg/dL)
- FPI is fasting plasma insulin ( ⁇ U/ml)
- G is mean glucose after glucose challenge
- I is mean insulin after glucose challenge.
- KJM glycemic control
- KJM 3 KJM 1
- KJM 1 KJM mix
- Results are presented as area under the glucose curve ( FIG. 6C ) and absolute and incremental blood glucose levels ( FIGS. 6A and 6B ) for individual time points.
- the results indicate that the area under the glucose curve for KJM 1 (68.4) was significantly lowered (by about 44%) (P ⁇ 0.015) than control treatment (120.5), and KJM 3 (P ⁇ 0.034) treatment (95.6) (lowered by about 21%).
- Incremental and absolute glucose levels were significantly reduced on KJM 1 treatment at time 60 (P ⁇ 0.02) and 90 minutes (P ⁇ 0.01) as compared to KJM 3 treatment.
- KJM 3 showed no significance difference at any time points, or for the area under the glucose curve.
- KJM mixed with polysaccharides such as xanthan in proportion to act synergistically is more effective on postprandial glycemia than highly refined KJM alone.
- KJM in mixture with other polysaccharides will express its efficacy in glycemic control of healthy individuals.
- Blood pressure was taken ⁇ 30 min, 0, 30, 60, 120, 240, 360, and 420 minutes after start of the test meals. Blood pressure was determined using conventional mercury sphygmomanometer device. Results are presented as systolic and diastolic blood pressure (See FIG. 7 ). When compared to the control treatment, systolic blood pressure (SBP) was significantly reduced after taking KJM MIX (at time 30, 60, 120, and 360 minutes); KJM MIX and AG combined (at 30, 60, 120, and 240 minutes), whereas AG lowered SBP only at 30 min and 120 min after start of test breakfast. The diastolic blood pressure was not different between four treatments.
- SBP systolic blood pressure
- KJM MIX and AG whether taken alone or in combination reduce SBP in type 2 diabetic individuals. Further, the effect of the combination of KJM and AG seems to be different than each individual component. This indicates that there is a different mechanism of action which might be beneficial and superior to either of the two components alone.
- Clinical blood pressure was measured using conventional mercury sphygmomanometer according to Joint National Council (JNC) VI criteria at ⁇ 30, 0, 30, 60, 120, 240, 360, 420 min. Subjects were asked to record their satiety levels throughout the day using a bipolar scale ranging from ⁇ 3 (extremely hungry), 0 (neutral), to +3 (uncomfortably full). The palatability of the meals was also recorded on a scale from 1 to 10, where 1 was “dislike extremely”, 5 “neutral” and 10 “delicious”. At each visit weight was measured using a beam scale and total body fat was measured with the Futrex 5000, using infrared technology. Additional samples were taken at the beginning and end of the study and measured for hemoglobin levels. This measurement was suggested by the Ethical Board of St Michael's Hospital as there was a concern regarding possible anemia.
- JNC Joint National Council
- KJM, and AG in the present study confirmed that they both beneficially affect postprandial glycemia.
- Postprandial blood glucose was lowered by two mechanisms that are different but complementary; ginseng increase insulin secretion and KJM mix reduces insulin levels (increases insulin sensitivity).
- the effect of the combination of KJM and AG seems to be different than each individual component. This indicates that there is a different mechanism of action which might be beneficial and superior to either of the two components alone.
- ginsengs with different diols/triols ratios were investigated.
- American ginseng was used, with composition of protopanaxadiols (Rb 1 , Rb 2 , Rc, and R) (diols) relative to protopanaxatriols (Rg 1 , Re, Rf) (triols), that had a ratio of above approximately 1.5 (i.e. Chinese ginseng with 1.91 ratio and American with 1.51 and 2.44 ratio).
- ginseng with a specific ginsenoside profile significantly decreases glucose.
- Ginseng profiles with weight ratios lower than 1.5 were also studied.
- ginseng was given with a 75 g oral glucose tolerance test (OGTT) and compared the results to a similar study done previously with ginseng with higher ratios ( FIG. 10 ).
- Normal subjects were studied with 3 different ginsengs; in a first study 12 (gender: 6 m: 6 f, age: 31 ⁇ 3 years, BMI: 28 ⁇ 2 kg/m 2 ) with Chinese ginseng with diols/triols ratio of 0.8; in the second and third studies, 10 (gender: 4 m: 6 f, age: 41 ⁇ 6 years, BMI: 26.1 ⁇ 0.4 kg/m 2 ) with AG with diols/triols ratio of 1.2 and 1.37, respectively.
- OGTT oral glucose tolerance test
- That part of ginseng's profile that gives improvement in human metabolism seems to be related to ginseng composition, mainly to ratios between main ginsneosides groups.
- the ginsenoside content of the 6 different ginseng grinded root and extracts used in the series of clinical studies was studied and found that reduction of blood glucose, lipids, and blood pressure; and also increase in insulin secretion, and nitric oxide, and reduction in oxidative stress had a high proportion of protopanaxadiols (Rb 1 , Rb 2 , Rc, and Rd) relative to protopanaxatriols (Rg 1 , Re, Rf).
- each bar represents ginseng with different diols/triols ratio. Once a ratio is reached of approximately 1.5 or higher the postprandial blood glucose is significantly reduced (letter b vs. a on graph).
- ginseng with ratio of above 1.5.
- ginseng had ratios of diols/triols of 2.44.
- Ginseng was administrated to 8 (gender: 3 m: 5 f, age: 34 ⁇ 3 years, BMI: 24.6 ⁇ 0.8 kg/m 2 ) healthy individuals.
- Data presenting reduction of postprandial blood glucose, and increase in plasma insulin and nitric oxide generation, relative to control. Data are presented in FIG. 11 .
- Glucose and insulin were measured by glucose oxidase method (67) and double antibody radioimmunoassay method respectively (68).
- Plasma NOx was measured as total nitrite (NO 2 ⁇ )+nitrate (NO 3 ⁇ ) concentrations by the chemiluminescence method (69,70) using a Sievers 280 NO Analyzer (Boulder Colo., USA). Points or bars with different letters are significantly different (repeated measures ANOVA adjusted for multiple pairwise comparisons with the Newman Keuls procedure, P ⁇ 0.05). Data are mean ⁇ SEM.
- the present inventor conducted four studies to determine the effect of American ginseng in humans were conducted (Table 8).
- ginseng is equally effective at doses above 3 g and when administered at any time together or before the challenge in diabetic subjects, but only when administered 40 minutes or more before the challenge in nondiabetic subjects.
- the third study showed that 1, 2, or 3 g of American ginseng compared to placebo reduced significantly the postprandial glycemic response to a 25 g oral glucose challenge when administered 40 minutes but not 20, 10, or 0 minutes before a glucose challenge in 12 nondiabetic subjects (Vuksan Am. J. Clin Nutr ,). Again there were no differences detected between the doses studied. The suggestion was that ginseng is equally effective at doses above 1 g, but needs to be administered a minimum of 40 minutes before the challenge in nondiabetic subjects.
- Konjac-mannan and wheat bran diets are based on actual intake. To convert kJ to kcal multiply by 2.39. ⁇ Based on the mean of four non-consecutive 3-day food records. ⁇ Differences between the konjac-mannan and wheat bran study periods were calculated by students paired t-test.
- LDL low-density lipoprotein
- HDL high-density lipoprotein
- Apo apolipoprotein.
- To convert cholesterol, triglycerides, and glucose to mg/dl multiply by 38.67, 88.57, and 18, respectively.
- Within treatment differences were assessed by paired t-test [( ⁇ ) P ⁇ .05; ( ⁇ ) P ⁇ .01; ( ⁇ ) P ⁇ .001], while between treatment differences by ANCOVA (PROC GLM). Lack of notation indicates no significant differences. [( ⁇ &) P ⁇ .05; ( ⁇ $) P ⁇ .01; ( ⁇ #) P ⁇ .001],
- ⁇ Android obesity is indicated by a wait-to-hip ratio grater than or equal to 0.9 for men, and 0.8 for women
- ⁇ Value represents 69% glucomannan polymer derived from KJM flour.
- Table 7 Shows the Test Breakfast used in Example 10.
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Abstract
Described are a number of compositions, namely a konjac mannan mixture, a ginseng composition, and a composition comprising konjac mannan and American ginseng. Methods of use of these compositions are described including their use for reducing blood glucose in non-diabetic and diabetic individuals, as well as reducing postprandial blood glucose in such individuals. Applications in the treatment of hyperlipidemia, high blood pressure, an increase in nitric oxide, Syndrome X and cardiovascular disease are also described. Various other applications of the compositions and methods are also described.
Description
- The invention relates to compositions comprising Konjac-Mannan, Ginseng or both and methods of use and uses of these compositions, such as in lowering blood glucose including post-prandial and long-term effects. In one aspect this invention is in the field of glucose and other heart disease risk factors management. In one aspect the invention is concerned with dietary approaches to such management. In another aspect it is concerned with compositions and methods of reducing blood glucose, specifically
- Abnormal glucose tolerance and insulin resistance are related to multiple cardiovascular risk factors especially reduced HDL, elevated serum triglycerides and hypertension (Liese et al. (1998)). When clustered these abnormalities increase the risk of coronary heart disease (CHD) morbidity and mortality, an effect that is independent of other conventional risk factors (Trevisan et al. (1998)). Co-ocurrence is usually present in insulin-insensitive individuals (Himswarth (1936)) and is often described in relation to visceral adiposity (Haffner et al. (1986)) and lack of physical activity (Helmrich 1991)). The estimated prevalence ranges from 3% (Trevisan et al. (1998)) to approximately 30% (Liese et al. (1998); Reaven (1994)) depending on how this insulin resistance-dislipidemic syndrome is defined and in which population it is measured.
- Hyperglycemia and diabetes are strong and independent risk factors of both all-cause and cardiovascular (CVD) mortality (Wing et al. (1998)). These links are more pronounced when the diabetes is associated with other unfavorable risk factors such as hyperlipidemia (Goldsmith et al. (1994)), hypertension (Burt et al. (1995)), or a cluster of metabolic disorders (Stamler et al. (1993)). Since people with diabetes have almost twice the risk of dying from CVD (69.6%) compared to people in the general U.S. population (Gu et al. (1998)), the control of high glucose levels and other concomitant coronary heart disease (CHD) risk factors represents the most effective approach to prevention (Savage (1996)). The importance of stronger nutrition-hygienic measures has been stressed repeatedly for the public at large (Stamler et al. (1993); National Cholesterol Education Program: Second report of the expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel II). Circulation. 1994; 89:1333-1445)). When these measures prove inadequate, an aggressive drug therapy is often required to meet the conventional treatment guidelines (National Cholesterol Education Program: Second report of the expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel II). Circulation. 1994; 89:1333-1445)). In the general population, this approach has been shown to be effective in lowering both the prevalence of hypertension (Burt et al. (1995)) and serum cholesterol levels (Johnson et al. (1993)), but has not reduced the incidence of diabetes (Harris et al. (1998)).
- Although it has been extensively described (Liese et al. (1998); Trevisan et al. (1998; Himswarth (1936); Haffner et al. (1986); Helmrich et al. (1994)), followed-up (Reaven (1994)), and had its prevalence determined (1,2), no specific recommendations for treatment of this syndrome have been proposed by health agencies. In practice, initial therapy of individual risk factors such as moderate dyslipidemia, hypertension or hyperglycemia is nonpharmacological. Treatment will often include behavioral changes to reduce body weight, increase physical activity, and moderate alcohol consumption. To achieve nutritional goals, there are three main approaches: a high-carbohydrate/low-fat diet (National Cholesterol Education Program: Second report of the expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel II) Circulation 89:1333-1445 (1994)), sharing calories between monounsaturated fat and complex carbohydrate at the expense of saturated fat (American Diabetes Association (ADA): Nutrition Recommendations and principles for people with diabetes mellitus. Diabetes Care 22:s42-s43 (1999)), or supplementing a high-carbohydrate/low-fat diet with exercise (Stefanick et al. (1998)).
- Tighter fasting and postprandial glycemic control results in a considerable reduction in CHD and all-cause mortality (Wei et al. (1998)), as well as fewer long-term microvascular complications both in type 1 (DCCT Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The diabetes control and complications trial. New Engl J Med 329:977-986 (1993)) and
type 2 diabetes (UK Prospective Diabetes Study (UKPDS) Group: Effect of intensive blood-glucose control with metformin on complications in overweight patients withtype 2 diabetes: UKPDS 34. Lancet 352:854-865, 1998). Effective dietary strategies shown to decrease (This OUT postprandialThis OUT) plasma glucose excursions include the use of high fibre and low glycemic index diets (Wolever et al. (1992); Jenkins et al. (1994)). The mechanism is presumed to involve slowing carbohydrate absorption (Jenkins et al. (1994)). Based on recent population studies these types of diets have been shown to have a protective role in preventing diabetes (Salmeron et al., Diabetes Care 20:545-550 (1997); Salmeron et al., JAMA 277:472-477 (1997)) and CHD (18). In the case of clinical studies however, it is the viscous water-soluble fibers, which increase the viscosity of digesta in the human gut (Eastwood et al. (1992)) that reduce glucose and lipid CHD risk factors (Anderson et al. (1986)). Whether soluble fibre is able to reduce a cluster of risk factors is speculative. Studies using soluble fibre as an adjunct to conventional treatment in individuals with two or more major CHD risk factors are scarce (Uuistupa et al. (1984)). - Evidence suggests that fibre may also be used in a therapeutic role. Recent epidemiological findings confirm the relationship between high dietary fiber intake and lower risk of developing both diabetes (Salmeron et al. (1997); Salmeron et al. (1997)) and CHD (Rimm et al. (1996)). Soluble dietary fiber, in particular, has been shown clinically to reduce the need for insulin, (Landin et al. (1992)) improve glycemia (Aro et al. (1981)), and reduce serum LDL-cholesterol (Brown et al. (1999)). Its viscosity is proposed as an important mechanistic factor (Jenkins et al. (1978)). However, to date, there is no clearly effective composition or method for reducing blood glucose.
- The present inventor has determined that the addition of high-viscosity fiber, in the form of a konjac-mannan mixture, or ginseng, or a composition comprising a konjac-mannan mixture and ginseng to a diet of an animal enhances conventional treatment outcomes, such as for diabetes and coronary heart disease, assessed primarily by total/HDL cholesterol, fructosamine, and sBP and secondarily by total, LDL, and HDL cholesterol; apolipoprotein A-1 (Apo A-1), B (Apo B) and their ratio; glucose; insulin; and systolic blood pressure (dBP).
- Accordingly, in one aspect the present invention provides a composition of matter for reducing blood glucose comprising a konjac-mannan mixture. In another aspect of the invention, a sufficient amount of the konjac-mannan mixture, when given to an animal preferably at an appropriate time, reduces blood glucose in the animal, preferably postprandial blood glucose. Preferably the konjac-mannan mixture comprises konjac-mannan and a substance capable of increasing the viscosity of konjac-mannan from 50% to about 250% of konjac-mannan alone. More preferably the substance comprises about 5% to about 45% by weight of one or more such substances, preferably polysaccharides.
- According to one embodiment a composition as just mentioned comprises as the one or more polysaccharides xanthan, carragenan, acetan, guar, or xyloglucana.
- According to another embodiment a composition according to the invention comprises consitituents with the particle size larger than about 1,000 angstroms. In one aspect such a composition is used in controlling cholesterol levels, preferably lowering cholesterol levels.
- Preferably, compositions according to the invention are formulated into a liquid, powder or formulated as part of a food. However, in another embodiment the compositions of the invention are formulated into pills, capsules and tablets
- According to another aspect the present invention provides a method for reducing blood glucose in an animal comprising administering to the animal a sufficient amount of a konjac-mannan mixture at an appropriate time in order to reduce blood glucose, preferably postprandial blood glucose, in the animal. Preferably the konjac-mannan mixture comprises konjac-mannan and a substance capable of increasing the viscosity of konjac-mannan to from about 50% to about 250% of konjac-mannan alone, preferably the substance comprises from about 5% to about 45% by weight of one or more polysaccharides, more preferably the one or more polysaccharides are selected from the group consisting of xanthan, carragenan, acetan, guar, or xyloglucana.
- According to one embodiment of the method, the particle size of the constituents of a mixture of the invention are larger than about 1000 angstroms.
- According to another embodiment of the invention, a mixture according to the invention is administered orally in an amount of about 1 to about 4 grams per day, preferably the mixture is administered either prior to a meal or during the meal.
- According to yet another embodiment of the method of the invention the administration of a mixture according to the invention is by a liquid, a powder, or as a part of a food product. In another embodiment administration is by way of tablet, capsule or pill.
- According to another aspect of the invention, there is provided a composition of matter for reducing blood glucose comprising ginseng in one aspect of the invention a sufficient amount of ginseng, when given to an animal at an appropriate time reduces blood glucose, preferably postprandial blood glucose, in the animal.
- According to another aspect of the invention, there is provided composition of matter for reducing blood glucose comprising an extract of ginseng, preferably American ginseng, a sufficient amount of which when given to an animal at an appropriate time reduces blood glucose in the animal. According to any of the ginseng compositions, whether root or extract, the ginseng is comprised of a ratio of protopanaxadiols (diols) relative to protopanaxatriols (triols) that is preferably greater than about 1.0, most preferably about 1.5 or greater and more preferably about 1.90 or greater. In another embodiment, the diol/triol ratio is about 2.4 or greater. In one embodiment, the composition is formulated into a liquid, powder or formulated as part of a food. In another embodiment the composition is formulated into tablets, capsules or pills.
- According to another aspect of the present invention there is provided a method for reducing blood glucose in an animal comprising administering to the animal a sufficient amount of ginseng at an appropriate time in order to reduce blood glucose in the animal. In another aspect, there is provided a method for reducing blood glucose in an animal comprising administering to the animal a sufficient amount of an extract of ginseng at an appropriate time in order to reduce blood glucose in the animal. According to either of these latter mentioned methods, preferably the ginseng or extract is administered before a meal or with a meal, more preferably the administration before meal occurs from about 1 to about 180 minutes before the meal.
- According to one embodiment of the method of the invention the amount of ginseng or extract of ginseng is at least about 1000 mg per administration. In another embodiment, the amount of ginseng administered is between 1-9 g, preferably 1-4 g and most preferably 1-3 g.
- According to another embodiment of the method of the invention the ginseng comprises a ratio of diols/triols of greater than about 1.0, most preferably about 1.5 or greater and more preferably about 1.90 or greater. In another embodiment, the diols/triols ratio is about 2.4 or greater.
- According to yet another embodiment of the method of the invention the composition is administered as a food, a powder, or a liquid. In another embodiment the composition is formulated into tablets, capsules or pills.
- According to another aspect of the present invention there is provided a composition of matter for reducing blood glucose comprising a konjac-mannan mixture of the invention and ginseng. In one embodiment of the invention a sufficient amount of konjac mannan and ginseng which when given to an animal at an appropriate time reduces blood glucose in the animal. Preferably the konjac-mannan mixture comprises konjac-mannan and a substance capable of increasing the viscosity of konjac-mannan from 50% to about 250% of konjac-mannan alone. Preferably the substance comprises about 10% to about 40% of one or more polysaccharides. More preferably the one or more polysaccharides are xanthan, carragenan, acetan, guar, or xyloglucana.
- According to one embodiment according to this aspect of the invention the particle size of constituents within the mixture is larger than about 1,000 angstroms.
- According to another embodiment according to this aspect of the invention the American ginseng is comprised of a ratio of diols/triols of greater than about 1.0, most preferably about 1.5 or greater and more preferably about 1.90 or greater. In another embodiment, the diol/triol ratio is about 2.4 or greater. According to yet another embodiment according to this aspect of the invention the composition is formulated into a liquid, powder or formulated as part of a food.
- According to another embodiment, the ginseng used in the compositions and methods of the invention can be any ginseng or extract thereof, for instance American, Asian, Chinese or other ginseng known in the art. In another embodiment, the ginseng is preferably American ginseng. In yet another embodiment of the invention, the ginseng or extract thereof has a diol/triol ratio of about 1.0, most preferably about 1.5 or greater and more preferably about 1.90 or greater. In another embodiment, the diol/triol ratio is about 2.4 or greater.
- In another embodiment, the invention provides a method for determining whether a ginseng or extract thereof would be useful in controlling, modulating or lowering blood glucose, preferably postprandial blood glucose, by determining the diol/triol ratio of the ginseng or extract and selecting for one that has a diol/triol ratio of about 1.5 or greater. The selected extract can then be optionally tested for such activity using the traditional tests and assays described herein or known in the art. In another embodiment, the selected ginseng can also be tested and selected for insulin, lipid profile, cholesterol and blood pressure control, modulation or decrease. In yet another embodiment the selected ginseng can be tested and selected for effectiveness in the treatment of diabetes and/or cardiovascular disease.
- According to another aspect of the present invention the compositions and methods of the invention can be applied to the treatment of long term diabetes, heart disease, and syndrome X. In addition the compositions and methods of the invention provide methods for increasing insulin sensitivity in an animal and of treating
type 2 diabetes as well as for reducing systolic blood pressure or blood cholesterol and other lipids and apolipoproteins - The details of the preferred embodiment of the present invention are set forth in the accompanying drawings and the description below. Once the details of the invention are known, numerous additional innovations and changes will become obvious to one skilled in the art.
- The invention will be better understood with reference to the drawings in which:
-
FIG. 1 is a histogram illustrating the effect of various fibres including Konjac mannan alone on glucose response in individuals in eleven individuals in comparison with a Konjac-mannan mixture of the present invention. -
FIG. 2 is a graph illustrating the post-meal blood glucose response of individuals histogram illustrating the effect of various fibres including Konjac mannan alone in comparison with a Konjac-mannan mixture of the present invention. -
FIG. 3 is a bar graph illustrating the composition of the placebo versus konjac biscuits used in Example 10. -
FIG. 4 illustrates the effect of konjac mannan versus placebo on blood glucose levels as described in Example 10.FIG. 4A is a linear graph illustrating glucose response to a test breakfast before 3-week treatment andFIG. 4B is a linear graph illustrating glucose response to a test breakfast after the 3 week treatment.FIG. 4C is a bar graph illustrating glucose area under the curve (AUC) before and after the 3-week treatment. -
FIG. 5 illustrates the effect of konjac mannan versus placebo on blood insulin levels as described in Example 10.FIG. 5A is a linear graph illustrating insulin response to a test breakfast before 3-week treatment andFIG. 5B is a linear graph illustrating insulin response to a test breakfast after the 3 week treatment.FIG. 5C is a bar graph illustrating insulin area under the curve (AUC) before and after the 3-week treatment. -
FIG. 6 illustrates the effect of highly refined konjac mannan versus the konjac mixture of the invention as described in Example 11.FIG. 6A is a linear graph illustrating absolute blood glucose levels.FIG. 6B is a linear graph illustrating incremental blood glucose levels.FIG. 6C is a bar graph illustration glucose area under the curve. -
FIG. 7 is a linear graph illustrating the results of Example 12 for the effect of konjac mannan, American ginseng and both konjac mannan and American ginseng on systolic blood pressure. -
FIG. 8 illustrated the effect of konjac mannan and ginseng treatment versus the separate treatments on blood glucose.FIGS. 8 A and B are linear graphs illustrating blood glucose levels versus time and changes therein as described in Example 13. -
FIG. 9 is a linear graph illustrating insulin levels versus time using various treatment regimes: placebo, ginseng, konjac mannan mix, and konjac mannan mix and ginseng. -
FIG. 10 is a bar graph illustrating the effect of various ginseng preparations with various diol/triol ratios on postpranial blood glucose levels. -
FIG. 11 illustrates a comparison of incremental change (linear graphs 11A, C, and E) and area under the curve (AUC) (FIGS. 11B , D, and F) in plasma glucose (FIGS. 11A and B), insulin (FIGS. 11C and D) and nitric oxide (Nox) (FIGS. 11E and F). - As described above, the present invention is related to compositions and methods for reducing blood glucose. In particular, the present inventor has found that a konjac mannan mixture, a ginseng composition, or a composition comprising konjac mannan and ginseng are effective in the reduction of blood glucose. In another embodiment, the compositions of the invention are effective in controlling or modulating the lipid profile of an animal, blood pressure and insulin levels. The compositions of the invention A enhances conventional treatment outcomes, such as for diabetes and coronary heart disease, assessed primarily by total/HDL cholesterol, fructosamine, and sBP and secondarily by total, LDL, and HDL cholesterol; apolipoprotein A-1 (Apo A-1), B (Apo B) and their ratio; glucose; insulin; and systolic blood pressure (dBP).
- As used herein “about” when referring to a value includes amounts that are within the scope of scientific certainty or uncertainty. Such amounts would include amounts that are effectively equivalent to the values stated. “About” when used in relation to diol/triol ratios means plus or minus 10% of the value.
- As used herein “animal” means any member of the animal kingdom including preferably humans.
- As used herein “postprandial” means after any food intake.
- As used herein “sufficient amount” or “effective amount” means an amount of a composition, substance or reactant to give an observable result, including desired results.
- As used herein “appropriate time” means at a time at which administration of a substance or composition provides an observable result.
- As used herein “prior to a meal” means at any time after a meal and before a subsequent meal.
- As used herein “during a meal” means at any time after the commencement of consumption of one or more pieces of food by an animal, and can be coincident with commencement, and before the end of consumption of all food consumed by the animal, at one sitting or occasion and can be coincident with completion of consumption or immediately thereafter.
- As used herein “a food” means any substance or composition of substances or compounds which are consumed by an animal, preferably for some nutritional value.
- As used herein “a meal” means the consumption of one or more morsels or pieces of a food in a sitting where a sitting is the time taken to consume the one or more morsels or pieces of a food.
- As used herein, “diol/triol ratio(s)” or “diols/triols” refers to protopanaxadiols (diols) relative to protopanaxatriols (triols).
- Konjac (Amorphophalus Konjac C. Koch) is a perennial plant belonging to the family Araceae. “Konnyaku”, which is made from the tuber of this plant, has been used traditionally for food in Japan for several hundred years. The predominant component of edible konnyaku is a glucomannan called konjac mannan (KJM). Edible konnyaku is made from the konjac flour, which is obtained from the dried tuber of this plant. KJM flour is obtained by grinding the tuber root of the Amorphophallus Konjac C. Koch. plant and is traditionally used as a food and remedy in the Far East. In addition to previous findings (Vuksan et al. (1999)), other findings have shown it to improve cholesterol levels (Arvill et al. (1995)), hypertension, and glycemia (Doi et al. (1979); Shima et al. (1982)).
- Konjac-mannan was chosen as the fibre because it represents a polysaccharide with one of the highest viscosities (Kiriyama et al. (1972)). The physiologically active component is a high molecular weight glucomannan polymer, which, when taken as a supplement, has been shown to have effects in lowering lipids (Arvill et al. (1995); Terasawa et al. (1979); Venter et al. (1987)), systolic blood pressure (sBP) (Arvill et al. (1995)), and glycemia (Doi et al. (1979); Shima et al. (1982)).
- Several techniques are known in the art for separating konjac mannan from konjac flour. In one, konjac flour is boiled in water, treated with Fehling's solution to convert the mannan to its copper complex, and the latter is decomposed again into the mannan after purification, as disclosed in J. Agr. Chem. Soc. Japan, 6, 991-995 (1930). In another, konjac flour is extracted with water, impurities are removed by precipitating with ethanol and redissolving the precipitate in water several times, and drying the precipitate finally obtained to obtain pure konjac mannan, as disclosed in Bull. Chem. Soc. Japan, 49, 298-322 (1927). Water-soluble konjac mannan capable of undergoing gelation when heated in an aqueous alkaline solution may be used as described in U.S. Pat. No. 3,973,008. Briefly it is obtained by extracting the ground tuber of the konjac plant with water, separating insoluble matter, dialyzing the solids-free liquid against water and then lyophilizing the dialyzed liquid to remove water. A person skilled in the art would be familiar with suitable konjac mannan preparation protocols for use herein. All such preparation methods are intended to be encompassed within the scope of the present invention.
- The present invention provides an improved konjac mannan composition.
- The konjac mannan composition or mixture of the invention preferably comprises konjac mannan and a substance that can increase the viscosity of the konjac mannan by 50-250%. Accordingly, in one aspect the present invention provides a composition of matter for reducing blood glucose comprising a konjac-mannan mixture. In another aspect of the invention, a sufficient amount of the konjac-mannan mixture, when given to an animal preferably at an appropriate time, reduces blood glucose in the animal, preferably postprandial blood glucose. Preferably the konjac-mannan mixture comprises konjac-mannan and a substance capable of increasing the viscosity of konjac-mannan from 50% to about 250% of konjac-mannan alone. More preferably the substance comprises about 5% to about 45% by weight of one or more such substances, preferably polysaccharides.
- According to one embodiment a composition as just mentioned comprises as the one or more polysaccharides xanthan, carragenan, acetan, guar, or xyloglucana.
- According to another embodiment a composition according to the invention comprises consitituents with the particle size larger than about 1,000 angstroms. In one aspect such a composition is used in controlling cholesterol levels, preferably lowering cholesterol levels.
- Preferably, compositions according to the invention are formulated into a liquid, powder or formulated as part of a food. However, in another embodiment the compositions of the invention are formulated into pills, capsules and tablets
- According to another aspect the present invention provides a method for reducing blood glucose in an animal comprising administering to the animal a sufficient amount of a konjac-mannan mixture at an appropriate time in order to reduce blood glucose, preferably postprandial blood glucose, in the animal. Preferably the konjac-mannan mixture comprises konjac-mannan and a substance capable of increasing the viscosity of konjac-mannan to from about 50% to about 250% of konjac-mannan alone, preferably the substance comprises from about 5% to about 45% by weight of one or more polysaccharides, more preferably the one or more polysaccharides are selected from the group consisting of xanthan, carragenan, acetan, guar, or xyloglucana.
- According to one embodiment of the method, the particle size of the constituents of a mixture of the invention are larger than about 1000 angstroms.
- According to another embodiment of the invention, a mixture according to the invention is administered orally in an amount of about 1 to about 4 grams per day, preferably the mixture is administered either prior to a meal or during the meal.
- According to yet another embodiment of the method of the invention the administration of a mixture according to the invention is by a liquid, a powder, or as a part of a food product. In another embodiment administration is by way of tablet, capsule or pill.
- A main ingredient of the ginseng is saponin. Various saponin are included in this ginseng, specifically there are twelve known kinds of ginsenside-Ro, -Ra, -Rb1, -Rb2, -Rc, -Rd, -Re, -Rf, -Rg1, -Rg2, -Rg3, -Rh. These are the ones (ginsenside-Rb1, -Rb2, -Rc) containing sapogenen and protopanaxadiol, and the ones (ginsenside-Re, Rf, -Rg1, -Rg2) containing sapogenen and protopanaxatriol. The main saponin in the crude drug is ginsenside-Rb1, -Rb2, -Rc, -Rg1. The ginsenside-Ro is the same as chikusetsusaponin V, and the ginsenside-Rb1 is the same as saponin D.
- Besides these, the ginseng contains essential oil of 0.05%, beta.-elemene, panacene (C15H24) and panaxynol as polyacetylene compound and further contains choline, vitamin B complex, fatty acid etc.
- There are known to be at least seven different types of ginseng and in the present disclosure a preferred form is American ginseng. There are many types of ginseng, American, Asian, and others known in the art, and various subspecies thereof. Not all have the same compositions or therapeutic effects, even within the same species. Effectiveness can also depend on the method of preparation of ginseng composition.
- According to another embodiment, the ginseng used in the compositions and methods of the invention can be any ginseng or extract thereof, for instance American, Asian, Chinese or other ginseng known in the art. In another embodiment, the ginseng is preferably American ginseng. In yet another embodiment of the invention, the ginseng or extract thereof has a diol/triol ratio of about 1.0, most preferably about 1.5 or greater and more preferably about 1.90 or greater. In another embodiment, the diol/triol ratio is about 2.4 or greater.
- According to one embodiment of the method of the invention the amount of ginseng or extract of ginseng is at least about 1000 mg per administration. In another embodiment, the amount of ginseng administered is between 1-9 g, preferably 1-4 g and most preferably 1-3 g.
- In another embodiment, the invention provides a method for determining whether a ginseng or extract thereof would be useful in controlling, modulating or lowering blood glucose, preferably postprandial blood glucose, by determining the diol/triol ratio of the ginseng or extract and selected for one that has a diol/triol ratio of about 1.5 or greater. The selected extract can then be optionally tested for such activity using the traditional tests and assays described herein or known in the art. In another embodiment, the selected ginseng can also be tested and selected for insulin, lipid profile, cholesterol and blood pressure control, modulation or decrease. In yet another embodiment the selected ginseng can be tested and selected for effectiveness in the treatment of diabetes and/or cardiovascular disease.
- Ginseng, preferably American Ginseng (Panax quinquefolium L.) reduces postprandial blood glucose in nondiabetic and people with diabetes. Preferably at least 1000 mg of ginseng, preferably American ginseng is administered together or before the meal (up to 180 min) to see an effect on the postprandial blood glucose responses to a test meal. While in nondiabetic it is important to take ginseng before meal, in
type 2 diabetes, the effect is seen irrespective of time of consumption (together with meal or up to 180 min before meal). - Ginseng, such as American ginseng with a profile of diol/triol ratio of greater than about 1.0, most preferably 1.5 or greater and more preferably 1.90 or greater. In another embodiment, the triols/diols ratio is about 2.4 or greater. In one embodiment the composition may be administered in the same manner as described above to produce glucose lowering effects. Ginseng with a particular ginsenosides profile may have an effect on increased secretion of the first phase insulin, similar to conventional diabetic drugs.
- Ginseng roots was selected by chemical composition analysis using HPLC. If ginseng extract is used, it can be prepared by the usual extraction procedure, by using a water and alcohol solution in ratio between 40% to 80% of water, with the rest being alcohol. Other ginseng, and extract preparation procedures are known in the art.
- The present invention shows for the first time, that ginseng (root or extract) with protopanaxadiols to protopanaxa triols ratio higher than about 1.0, most preferable 1.5, lowers the postprandial glycemic response in both healthy and diabetic individuals and in the long term reduces serum lipids and blood pressure and thus improves diabetes control. Not intending to be bound by a particular theory, studies conducted by the present inventors indicate that ginseng may potentate insulin secretion potentially through a modulation of autocoid metabolism linked to nitric oxide production. However, gut mediated hormone effects may play part in the mechanism of action of AM but this area has not yet been explored.
- The invention also comprises the administration of both ginseng (such as American Ginseng (Panax quinquefolium L.) and konjac mannan, jointly. A combination of selected ginseng, such as American Ginseng (Panax quinquefolium L.) and Konjac-Mannan fiber (Amorpophallus Konjac k) act jointly to reduce postprandial blood glucose in people with
Type 2 diabetes more than each individual material. The efficacy is not attainable by either treatment. The ginseng can be any ginseng or formulation thereof, preferably as described above, more preferably that has a diol/triol ratio of greater than about 1.5 or more. The konjac-mannan is preferably the konjac mannan mix as described above. The konjac mannan and ginseng can be prepared and administered in separate compositions or can be formulated into one composition. - While not wishing to be bound by any particular theory, the possible mechanism of action for the hypoglycaemic effect of konjac/ginseng is to increase insulin secretion/sensitivity, and together with konjac mannan's ability to slow nutrient absorption and also improve insulin sensitivity these combined effects result in lower prolonged elevation of postprandial blood glucose and have applications in prevention and treatment of diabetes and heart disease. Thus there are two products, operating through different pathways, that significantly reduce key risk factors for diabetes and cardiovascular disease.
- For the purposes of administration by means other than incorporation within a food, the compositions described herein can be prepared by per se known methods for the preparation of pharmaceutically acceptable compositions which can be administered to subjects, such that an effective quantity of the composition of the invention is combined in a mixture with a pharmaceutically acceptable vehicle, thereby allowing for the administration of a sufficient amount of the composition. Suitable vehicles are described, for example, in Remington's Pharmaceutical Sciences (Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., USA 1985). On this basis, the compositions include, albeit not exclusively, solutions of the substances in association with one or more pharmaceutically acceptable vehicles or diluents, and contained in buffered solutions with a suitable pH and iso-osmotic with the physiological fluids.
- One would appreciate that the effective or sufficient amount of a composition of the invention can vary depending on the individual, such as sex, age, and weight of the individual, and/or severity of a condition, such as diabetes. It may also in certain cases vary on the time of administration, i.e. post or pre meal and time it takes for the substance to clear or be metabolized by the body. It may also vary depending on whether the compositions are administered separately or with another substance that may modulate the effectiveness of the composition. For instance the effective amount of konjac mannan may vary depending on whether it is administered alone or in conjunction with a ginseng or another substance that may act synergistically with it. It may also vary depending on the concentration and mode of preparation of the konjac mannan being administered. The above similarly applied to the administration of ginseng.
- Such compositions in one aspect are administered orally, such as by liquid, powder or formulated as part of a food, such as a biscuit. It could be administered in the form of pills, capsules and tablets. Other forms of administration may also be suitable.
- Such composition can be used in the modulation or control, preferably decrease, of blood glucose, preferably postprandial blood glucose. In another aspect the compositions of the invention can also be used to modulate or control insulin levels in an animal, preferably decrease such levels. The compositions of the invention can also be used to modulate a lipid profile of a patient in need thereof. They can also be used to modulate blood pressure, preferably to lower blood pressure. In a preferred embodiment the invention can be used in the treatment of animals, preferably humans, in need of controlling their glucose levels, such as in the management and treatment of diabetes. In another embodiment, the compositions of the invention can be used in the management and treatment of cardiovascular disease and associated conditions, such as high blood pressure, high cholesterol level. In another embodiment, the compositions of the invention, especially the ginseng compositions, can be used to modulate or control nitric oxide levels in an animal.
- The following non-limiting examples are illustrative of the present invention:
- Eleven diabetic patients (5 men, 6 women) gave written informed consent to participate in the present study that was approved by the Human Ethic Committees of St. Michael's Hospital and the University of Toronto. All had hyperlipidemia, hypertension, and
type 2 diabetes (mean serum C-peptide 701±351 pmol/L), with a minimum of three years since the onset of all three conditions. They were taking medications to control each of the three risk factors, consuming a National Cholesterol Education Program (NCEP)Step 2 diet Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA; 285:2486-2497, 2001, not smoking, nor taking alcohol, and leading sedentary lifestyles at recruitment. Two participants had a history of atherosclerotic heart disease, but none had evidence of recent myocardial infarction, unstable angina, or congestive heart failure. Exclusion criteria were a family history of premature CHD, hypothyroidism, renal, hepatic, or gastrointestinal disease. Table 1 provides baseline demographic, anthropometric and clinical characteristics of the study participants. - The study employed a double-blind, placebo-controlled, cross-over design, where all subjects were maintained on the same dosage of their medications throughout. The study began with an 8 week baseline period over which participants followed an
NCEP Step 2 ad libitum diet: Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA; 285:2486-2497, 2001, documented by three non-consecutive days of food records every two weeks. This was followed by the experimental phase of the study that consisted of two successive 3 week treatment periods, separated by a two week washout interval over which another three day food record was obtained. During the first treatment period, subjects were randomly assigned to either the KJM+ (Step 2 metabolically controlled diet enriched with fiber) or the control treatment (the same diet enriched with wheat bran [WB] fiber). For the second treatment period, the subjects were crossed-over. The study began with 5 subjects taking the KJM+ treatment and 6 the control. - Both treatments consisted of a three-day
rotating Step 2 diet with three meals per day provided under metabolic conditions. All foods were pre-weighed, packaged and couriered to participants for consumption at home or at work. The mean macronutrient profile conformed with aStep 2 diet. Energy intakes for weight maintenance were provided according to Lipid Research Clinics Tables with adjustment for physical activity (The Lipid Research Clinics Population Studies Data Book. Vol. 2. The prevalence study-nutrient intake. Washington D.C.: Government printing office (NIH publication no. 82-2014) (1982)). Total dietary fiber was administrated at 2 g/412 kJ (100 kcal), with a mean daily intake according to energy intake ranging from 24 g to a plateau of 50 g for those consuming 2500 Kcal per day or more. The actual diet consumed is presented in Table 2. - The two treatments differed only in the type of fiber. On the KJM+ treatment, participants received KJM+ enriched biscuits, whereas on the control treatment they received an equal quantity of wheat bran (placebo) biscuits. Subjects were instructed to take biscuits together with an 8 oz beverage, 3 times daily as a snack, including once at bed-time. Both were produced and provided by Dicofarm S.p.A, Roma, Italy, (commercially available in Italy as “Dicoman®” biscuits). They had similar nutrient profiles (Table 2) and were indistinguishable in taste and appearance. KJM+ biscuits contained approximately 15% KJM flour of which 69% was the active high viscosity glucomannan, 15% other polysaccharides, and 16% excipients by weight. The KJM flour mix used in the biscuits comprised in % by weight: 69% KJM, 21% xanthan and 10% caragenan. Because KJM flour comprised half (1 g/412 kJ [100 kcal]) of the total fibre on the KJM+ treatment, approximately 0.7 g/412 kJ (100 kcal) was glucomannan. Wheat bran biscuits, in contrast, had a lower proportion of fiber than KJM+ biscuits (Table 3). Approximately 14 g/day of wheat bran fibre derived from standardized American Association of Cereal Chemist hard red wheat bran was, therefore, added to the control (WB) diet to compensate for these fiber differences.
- Any food from the metabolic diet together with study biscuits not consumed was brought to the clinic for weighing to measure compliance. Dietary changes found to occur during the first three-week treatment period were duplicated prior to food delivery for the second treatment period for each participant.
- Serum blood samples were immediately separated and stored in four aliquots at −70° C. after collection. They were thawed at the end of the study for analysis of total cholesterol, HDL, and triglycerides (TRIG) measured enzymatically (McNamara et al. (1987); Warnick et al. (1982)). LDL content was estimated by the formula of Friedewald et al. (Friedewald et al. (1972)). Apolipoprotein (Apo) A1 and B were determined by rocket immunoelectrophoresis (Fruchart et al. (1982)). Fasting blood glucose was analyzed by a hexokinase method using a Cobas Mira Autoanalyzer (Roche Diagnostic, Mississauga, Canada). Serum fructosamine was analyzed in triplicate using the Cobas Fara II (Lloyd et al. (1984)) and plasma insulin in duplicate by radioimmunoassay with reagent from ICN Biomedicals, Inc. (Horsham, Pa.) (Livesey et al. (1980)). Finally, C-peptide was determined by radioimmunoassay (Kuzuya et al. (1976)).
- Physical measurements were obtained by standard techniques. Blood pressure was taken and expressed as the mean of three measurements to the nearest 2 mm Hg on both arms. Fasting body weight was determined using a beam scale in light clothing, with an emptied bladder and in bare feet. Waist and hip circumferences were measured by soft non-stretchable tape on the narrowest and widest parts of the trunk.
- Energy and nutrient analysis of the diets was calculated using US Department of Agriculture data (The Agriculture Research Services. Composition of Foods, Agriculture Handbook No. 8. Washington, D.C., US Department of Agriculture, 1992). The nutrient composition of the treatment biscuits was analyzed, using the Prosky method to determine fiber content (Prosky et al. (1985)
- Results are expressed as mean ±SEM, except for age, anthropometric measurements and nutrient intake (mean ±SD). Data were analyzed by the Statistical Analysis System (SAS) (SAS Institute Inc.: SAS/STAT User's guide.
Version - All participants followed the experimental protocol with little difficulty. According to three-day food records collected over the baseline and washout periods, subjects ate their usual low-fat (<25% energy) and high-fiber (>27 g per day) diets (Table 3). In addition, during the treatment periods, returned food and biscuits from metabolic diets indicated that subjects consumed an average of 93% and 95% of diet calories prescribed on the KJM+ and control (WB) treatments respectively and 88% (137 g/day) KJM+ test and 91% (142 g/day) WB placebo biscuits. Consumption patterns translated into an insignificant decrease in body weight during both treatment periods (Table 4). There was no correlation between changes in weight and serum lipids, glucose or blood pressure (data not shown). The only side effect experienced was a transient complaint of flatulence and soft stools reported by 37% and 24% of participants during the KJM+ and the control (WB) treatments respectively, but none refused to continue the study.
- Blood lipids were improved during KJM+ treatment compared to control (Table 4). The primary lipid endpoint, total/HDL cholesterol, decreased significantly by 5.7±2.3% (P=0.034, α=0.05) during the KJM+ treatment compared to an insignificant increase of 4.7±4.4% (P=0.316, α=0.017) on control. The resultant between-treatment decrease of 10±4.0% on the KJM+ treatment was significant (P=0.028, α=0.05). The secondary endpoints of total and LDL cholesterol also fell significantly by 16±2.7% (P=0.001, α=0.005), 25±3.9% (P=0.001, α=0.005), during KJM+ treatment compared to 4.9±3.7% (P=0.20, α=0.006), and 4.8±5.9% (P=0.45, α=0.008) on control. Resultant between-treatment differences of 11±4.2% (P=0.025, α=0.005) and 19±6.8% (P=0.033, α=0.006), were insignificant, however, after correction by the Bonferroni-Hochberg procedure. The combined fall in total cholesterol and LDL on the KJM+ treatment indicated reclassification of the lipid status of 6 of the 11 subjects from elevated to normal cholesterolemia (<5.2 mmol/L) (2). Values for LDL, however, were derived from only 9 subjects, because two of the 11 participants had serum triglycerides levels over 4.5 mmo/L, not allowing for calculation by the Friedewald equation.
- Similar results were observed for Apo B and the Apo B/A-1 ratio. During KJM+ treatment both fell significantly by 14±3.4% (P=0.002, α=0.006) and 8.6±2.3% (P=0.004, α=0.007), compared to 3.0±5.0% (P=0.57, α=0.013) and 3.0±4.8% (P=0.55, α=0.01) on control respectively. These changes, however, resulted in an insignificant between-treatment difference of 11±4.3% (P=0.025, α=0.005) and 5.6±4.5% (P=0.24, α=0.008), after correction by the Bonferroni-Hochberg procedure.
- In contrast, such effects were not seen on HDL, Apo A-1, or triglycerides. During KJM+ and control treatments, HDL and Apo A-1 decreased insignificantly, for insignificant between treatment changes. Similarly, during both treatments, triglycerides increased insignificantly, with no significant difference between treatments.
- Improvements in glycemic control were observed on the KJM+ treatment compared to control (Table 4). The primary glycemic endpoint, serum fructosamine, was reduced insignificantly during both the KJM+ and control treatments by 6.1±2.4% (P=0.03, α=0.025), and 0.5±1.4% (P=0.751, α=0.05) respectively, after correction by the Bonferroni procedure. The resultant between treatment decrease of 5.7±1.7% on KJM+ was nevertheless significant (P=0.007, α=0.017). No significant differences between treatment regimes were seen for the secondary endpoints of insulin or glucose, although during the KJM+ treatment, fasting glycemia fell significantly by 11±3.0% (P=0.004, α=0.008) compared to 1.5±6.1% (=−0.804, α=0.013) on control.
- An improvement in blood pressure was also observed on the KJM+ treatment compared to control (Table 4). The primary blood pressure endpoint, sBP, decreased significantly on KJM+ supplementation by 5.5±1.4% (P=0.003, α=0.017), compared to 1.4±2.7% (P=0.62, α=0.03) on control, producing a significant between-treatment difference of 6.9±2.5% (P=0.021, α=0.025) or 9.4±3 mm Hg. During both treatments, diastolic blood pressure (dBP), however, remained virtually unchanged with no significant difference between treatments. The result was a reclassification in sBP status from moderately high to normotensive (<135 mmHg) in 5 of 11 subjects after the KJM+ treatment.
- Examples 1-4 illustrate that the addition of 0.7 g/412 kJ (100 kcal) of high viscosity glucomannan (KJM mix) in biscuit form to conventional CHD treatment (a low saturated fat diet combined with drug therapy) improved metabolic control beyond the effect of conventional treatment alone in high-risk individuals with
type 2 diabetes. Amelioration in three major CHD risk factors—hyperglycemia, hypertension, and hyperlipidemia—relative to a matched placebo control treatment as measured by the primary endpoints fructosamine, sBP, and total/HDL cholesterol respectively was observed. Differences between secondary glycemic, blood pressure, and lipid endpoints were insignificant after adjustment for multiple comparisons by the Bonferroni-Hochberg procedure. With greater power derived from a larger sample size, significance might have been achieved in these cases. - To achieve similar metabolic benefits, the recent dietary recommendations of the American Diabetes Association have changed their emphasis from encouraging carbohydrate and less processed fiber foods to increased consumption of monounsaturated fat (American Diabetes Association (ADA): Nutrition Recommendations and principles for people with diabetes mellitus. Diabetes care 22:S42-S43, 1999). Their reasoning is that fiber has only very modest effects on LDL cholesterol and does nothing to raise HDL cholesterol levels. Nevertheless, the diet usually prescribed for the management of CHD risk factors in people with diabetes resembles an
NCEP Step Step 1, of total calories <30% from total, <10% from saturated, and <10% from polyunsaturated, with <300 mg/day of cholesterol and forStep 2 the same except <7% of calories from saturated fat with <200 mg/day of cholesterol. In the two well-controlled clinical studies in this area, limitations of the diets are evident. Hunninghake et al., following hypercholesterolemic subjects on aStep 2 diet for three months, found that LDL was reduced by only 5% (Hunninghake et al. (1993)). Schaefer and colleagues found a reduction in LDL in subjects provided aStep 2 diet on a metabolic basis to be as much as 17%, but with adverse effects on other lipid parameters and no effect on total/HDL cholesterol ratio (Schaefer et al. (1995)). A high inter-subject variability in LDL reductions was also noticed. The present results, however, showed that KJM+ treatment resulted in an improvement in lipid ratios. The suggestion is that aStep 2 diet supplemented with KJM+ may confer additional benefits over this diet alone. - Improvements in blood lipid control have previously been shown when
Step 2 diets were supplemented with soluble fibre from different dietary sources (Jenkins et al. (1993)) or fibre supplements (Anderson et al. (1986); Olson et al. (1997)). While such studies have reported reduced total and LDL concentrations, few, as has been the case for NCEP diets, have reported improved lipoprotein ratios. Out of the three lipid trials that used KJM+ (Arvill et al. (1995); Terasawa et al. (1979); Venter et al. (1987)) the former two did not show a significant change in these ratios. In contrast, Venter and coworkers (Venter et al. (1987)) found 4.5 g/day glucomanan significantly improved both LDL and the LDL/HDL ratio in 18 hypercholesterolemic subjects. The present examples showed a more significant 10±4.0% decrease in the total/HDL ratio were noticed on the KJM+ treatment compared to control. The mechanism by which the KJM+ supplemented biscuits had this lipid lowering effect is not clear. While not wishing to be bound by any particular theory, possibilities include an inhibition of cholesterol absorption in the jejunum (Ebihara et al. (1989)) and bile acid absorption in the ileum (Kiriyama et al. (1974)) or less postprandial stimulation of HMG CoA reductase (Jenkins et al. (1993)). Other options include the generation of short chain fatty acids by colonic microflora, predominantly propionate, which may decrease hepatic cholesterol synthesis (Venter et al. (1990)). - Improvements in diabetes control after soluble fibre supplementation have been shown (Morgan et al. (1990)). KJM, in particular, has been shown to have a beneficial effect following both acute (Shima et al. (1982)) and long-term (Doi et al. (1979); Shima et al. (1982)) administration. In the present invention KJM+ treatment compared to control, a 5.7±1.7% reduction was observed in serum fructosamine, a short-term marker of diabetes control, with no effect on either fasting glucose or insulin concentrations. These results were not altered by excluding four subjects treated with insulin. An effect of the gel forming KJM+ on digestion may explain this finding. It has been suggested that decreases in glucose and insulin levels after the consumption of water-soluble fibers are related to slower rates of food absorption in the small intestine associated with increased viscosity (Ebihara et al. (1981)). KJM has been shown to have very high viscosity, approximately five times higher than guar gum (Ebihara et al. (1981)) and considerably more than pectin (Venter et al. (1987)). Consequently, in some studies it has been given at half the dosage relative to these other fibers (Ebihara et al. (1981)). The present inventors have further increased the viscosity of KJM by the addition of polysaccharides such xanthan, caragenan, acetan, guar or xyloglucena.
- Finally, although few studies have demonstrated an effect of fibre on blood pressure, significant reductions both in sBP and dBP have been reported after consumption of guar granulates (Landin et al. (1992)) and soluble dietary fibre supplements (Alison et al. (1992)). The same effect has been shown for KJM, but only on sBP (Arvill et al. (1995)). This last finding agrees with the results set out in the present examples, in which KJM treatment significantly reduced sBP by 6.9% compared to control but did not affect dPB. The commonly recommended oat bran, in contrast, has been shown to affect neither systolic nor diastolic blood pressure (Swain et al. (1990)). While not wishing to be bound by any particular theory, a possible mechanism for the blood pressure lowering effect of soluble fibers may involve increased insulin sensitivity (Anderson et al. (1986)), which may reduce blood pressure by influencing sodium absorption in the distal tubule, increasing sympathetic nervous system activity and peripheral vascular resistance (Modan et al. (1985)).
- The effect of KJM+ fibre supplements on the three CHD risk factors persist even in subjects who are taking conventional drug therapy concurrently. Consistent with the findings set forth in the examples, a combination of fiber and drugs has been shown to be more effective clinically than the drug given alone in improving metabolic control. Toumilehto and coworkers (Tuomilehto et al. (1989)) found that the viscous soluble fiber guar gum and gemfibrozil administered together reduced total cholesterol and LDL/HDL ratio significantly more than gemfibrozil and placebo. Elsewhere this same effect has been noticed for blood glucose and blood pressure. A significant reduction was found in postprandial blood glucose after consumption of sulfonylyurea (glibenclamide) and glucomannan with a test meal compared to sulfonylyurea alone with the same test meal (Shima et al. (1983)). Similarly, a significant decrease in diastolic blood pressure was noticed after administration of guar gum compared to placebo in patients receiving drug treatment for hypertension (Uuistupa et al. (1984)). Together these findings suggest that highly viscous soluble fibre may augment or potentiate the effect of drugs.
- In conclusion, the application of KJM+ supplementation in the high-risk diabetic study group of the examples demonstrated simultaneous improvement in all three diet-modifiable risk factors, indicating a reduction in overall CHD risk (Jenkins et al. (1995)). One of the benefits is that KJM+ supplemented therapy may lower required drug dosages and improve overall cost-effectiveness and acceptability of treatment. Although it is agreed that food should be the normal way to achieve an adequate fiber intake, fiber supplemented foods have advantages in the treatment of individuals at high risk for CHD and represent a possible intermediate step between diet and drug therapy.
- 278 free-living subjects were screened from the Canadian-Maltese Diabetes Study between the age of 45 and 65 years. This population is known to have one of the highest rates of diabetes (Katona et al. (1983)). Thirty eight of them satisfied the initial inclusion criteria: impaired glucose tolerance (IGT) (World Health Organization Diabetes Mellitus: Report of the World Health Organization Study Group. Technical report No. 727:9-15, 1985); clinical absence of CHD; body-mass index of less than 30 kg/m2; not taking medications for hyperglycemia, hyperlipidemia or hypertension; not smoking; nor consuming more than two alcoholic drinks per day. These subjects were further screened for the presence of the full multiple metabolic syndrome (Trevisan et al. (1998)) (syndrome X). This included moderate hypertension (>135/85 and less than 145/95 mm Hg), dyslipidemia (low-HDL [levels below 0.9 mmol/L for men and 1.2 mmol/L for women], and elevated triglycerides [greater than 2.3 mmol/L and less than 4.5 mmol/L]). Based on power analysis from the previous study (Vuksan et al. (1999)) and Example 1, eleven subjects (5 men, 6 women) who qualified were recruited. In addition to meeting the above criteria, their fasting (98±13 pmol/L) and 2-hour postprandial (439±68 pmol/L) plasma insulin levels was greater (p<0.05) than two standard deviation of the initial screening pool (71±8 and 316±47 pmol/L respectively). All eleven also had moderately high serum cholesterol (between 5.2 and 6.7 mmol/L) and were sedentary, with a mean (±SD) age of 55±4 years (range: 46-61 years); a BMI of 28±3 kg/m2; a waist-hip ratio of 0.98±0.2 (waist: 96±12 cm) in men and 0.91±0.4 (waist: 87±19 cm) in women. They gave written informed consent to participate in the current study that was approved by the Human Ethic Committees of St. Michael's Hospital and the University of Toronto.
- The study employed a double-blind, placebo-controlled, cross-over design that was identical to that used in the previous study (Vuksan et al. (1999)) and Example 1. It began with an 8-week baseline period during which participants followed a National Cholesterol Education Program (NCEP) Step 2 (American Diabetes Association (ADA): Nutrition Recommendations and principles for people with diabetes mellitus. Diabetes Care 22:s42-s43, 1999)) ad libitum diet, documented by three non-consecutive days of food records every two weeks. This run-in phase was included to eliminate possible effects of dietary change on metabolic parameters. The experimental phase of the study followed. This consisted of two successive 3-week treatment periods, separated by a two-week washout interval over which a
Step 2 diet was followed and documented by another three-day food record. During the first treatment period, subjects were randomly assigned to either the KJM+ (Step 2 metabolically controlled diet enriched with KJM+ fiber) or the control treatment (the same diet enriched with wheat bran [WB] fiber). For the second treatment period, the subjects were crossed-over. Blood collection, weight, blood pressure, and waist and hip measurements were done at the beginning and end of each 3-week treatment period. The study began with 5 subjects taking the KJM+ treatment and 6 the control. - Both treatments consisted of a three-day
rotating Step 2 diet with three meals per day provided under metabolic conditions. All foods were pre-weighed, packaged and couriered to participants for consumption at home or at work. The mean macronutrient profile closely conformed to aStep 2 diet (of calories <30% from total fat, <7% from saturated fat, and <300 mg/day cholesterol) (American Diabetes Association (ADA): Nutrition Recommendations and principles for people with diabetes mellitus. Diabetes Care 22:s42-s43, (1999)). Energy intakes for weight maintenance were provided according to Lipid Research Clinics Tables with adjustment for physical activity (24). Total dietary fiber was administrated at 1.5 g/100 kcal, with a mean daily intake according to energy intake ranging from 24 g to a plateau of 40 g for those consuming 2800 kcal per day or more. The actual diet consumed is presented in Table 5. - The two treatments differed only in the type of fiber. On the KJM+ treatment, participants received KJM+ enriched test biscuits whereas on the WB-control treatment they received an equal quantity of wheat bran control biscuits. Subjects were instructed to eat an equal amount of biscuits together with an 8 oz beverage, 3 times daily as a snack, including once at bedtime. Both were provided by Dicofarm S.p.A, Roma, Italy. They had similar nutrient profiles and were indistinguishable in taste and appearance. KJM+ biscuits contained approximately 10% KJM flour of which 69% was the active high viscosity glucomannan, 15% other polysaccharides, and 16% excipients by weight (Vuksan et al. (1999)). The KJM flour mixture of the KJM+ biscuits comprised 69%+17% xanthan, 9% caragenan, and 8% guar. Because KJM flour comprised half (0.75 g/100 kcal) of the total fibre on the KJM+ treatment, approximately 0.5 g/100 kcal (8-13 g/day) was glucomannan. Wheat bran biscuits, in contrast, had a lower proportion of total dietary fiber than KJM+ biscuits. Approximately 11 g/day of wheat bran fibre derived from standardized American Association of Cereal Chemist hard red wheat bran was, therefore, added to the WB-control diet to compensate for these fiber differences. Subjects were instructed to sprinkle the additional fiber on cereal, yoghurt, and/or other compatible foods to improve palatability.
- Any foods from the metabolic diet together with study biscuits not consumed during the study were returned to the clinic for weighing to measure compliance. Dietary changes found to occur during the first three-week treatment period were duplicated in the diets for the second treatment period for each participant.
- Laboratory methods were identical to those used in (Vuksan et al. (1999)). In brief, blood samples were separated immediately and stored as serum in four aliquots at −70° C. after collection. They were thawed at the end of the study for analysis of total cholesterol, HDL, and triglycerides measured enzymatically. LDL content was estimated by the formula of Friedewald et al. Apolipoprotein (Apo) A1 and B were determined by rocket immunoelectrophoresis. Fasting blood glucose was analyzed by a hexokinase method using a Cobas Mira Autoanalyzer (Roche Diagnostic, Mississauga, Canada). Serum fructosamine was analyzed in triplicate using Cobas Fara II and plasma insulin in duplicate by radioimmunoassay with reagent from ICN Biomedicals, Inc. (Horsham, Pa.). C-peptide was determined by radioimmunoassay.
- Results are expressed as mean ±SEM, except for age, anthropometric measurements and nutrient intake (mean ±SD). Data were analyzed by the Statistical Analysis System (SAS Institute, Cary, N.C.). Differences between the diets were assessed by two-tailed Student's t-test for paired data (univariate procedure). This same statistic also assessed differences in serum lipids, apolipoproteins, glycemia, blood pressure and body weight between the beginning (week-0) and end (week-3) of each treatment (WB-control and KJM+). Analysis of covariance (ANCOVA) with the facility of General Linear Model (GLM) procedure was used to test for differences in these same parameters between the two treatments. Control of individual variation from the repeat measures aspect of the design was addressed by incorporating the random subject effect as well as the starting measurement. Diet, sex, and phase effects were also incorporated in this model. Adjustment for multiple comparisons was made by the Bonferroni-Hochberg procedure (Hochberg (1988)). P-values for each endpoint were ordered sequentially and contrasted with the corresponding adjusted comparison-wise critical alpha (α) levels. The null hypotheses were rejected only if p-values were less than their corresponding α-values.
- All participants followed the experimental protocol with little difficulty. Returned food from metabolic diets indicated that subjects consumed an average of 96% and 95% of diet calories prescribed on the KJM+ and WB-control treatments respectively. Returned biscuits indicated they consumed 81% (97 g/day) of KJM+ and 86% (103 g/day) of WB-control biscuits. Consumption patterns translated into an insignificant decrease in body weight during both treatment periods with no difference between treatments (Table 6). The only side effect experienced was a transient complaint of flatulence and soft stools reported by 3 and 2 of the participants during the KJM+ and the WB-control treatments respectively, but none chose to discontinue the study.
- Blood lipids improved during KJM+ treatment compared to WB-control (Table 6). Total and LDL cholesterol fell significantly by 19±2.7% (P<0.0001) and 29±3.4% (P<0.0001) during KJM+ treatment compared to 6.3±3.4% (P=0.088) and 6.6±5.0% (P=0.231) on control. The between-treatment differences were 12.4±3.1% (P<0.005) and 22±3.9% (P<0.003) respectively. The combined fall in total cholesterol from 6.2±0.3 to 5.0±0.2 mmol/L and LDL from 3.9±0.2 to 2.8±0.2 mmol/L on KJM+ treatment indicated reclassification of the lipid status of the group (8 of 11 subjects) from elevated to normal cholesterolemia (National Cholesterol Education Program: Second report of the expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel II). Circulation 89:1333-1445, 1994)). Similar results were observed for Apo B. During KJM+ treatment Apo B fell significantly by 19±2.8% (P<0.0004) compared to 4.5±4.5% (P=0.34) on control, for a significant difference of 15.1±4.3% (P<0.0004) between the treatments.
- In contrast, such effects were not seen on Apo A-1, or triglycerides. During KJM+ and control treatments, HDL decreased significantly on both treatments (8.5±2.2%, P<0.04 on KJM+ diet and 9.6±2.2%, P<0.003 on WB-control, with an insignificant between-treatment change (P=0.98). Similarly, during both treatments, triglycerides increased insignificantly, with no significant difference between treatments.
- Despite this lack of effect of KJM+ treatment on HDL, Apo A-1, or triglycerides, the decreases in total cholesterol and Apo B were sufficient to improve lipid ratios. During KJM+ treatment total/HDL, LDL/HDL and Apo B/A-1 ratios decreased by 11±3.0% (P<0.005), 22±3.7% (P<0.0002) and 13±3.0% (P<0.003) respectively. This compares to an insignificant increase of 4.1±4.1% in total/HDL ratio, 0.2±6.3% in LDL/HDL ratio and 0.7±3.6% in Apo B/A-1 on WB-control. The resultant between-treatment differences were 15.2±3.4% (P<0.003) for total/HDL cholesterol, 22.2±4.1% (P<0.002) for LDL/HDL cholesterol, and 13.1±3.4% (P<0.0003) for Apo B/A-1.
- An improvement in glycemic control was observed on the KJM+ treatment compared to WB-control (Table 6). Serum fructosamine was reduced during the KJM+ treatment by 5.6±1.5% (P<0.003), compared to 0.39±1.3% (P=0.77) on control, with a between-treatment difference of 5.2±1.4% (P<0.002). No significant between-treatment differences were seen for insulin or glucose concentrations. On KJM+ however, fasting glycemia fell by 13±2.5% (P<0.0001) compared to 9.6±4.3% (P<0.05) on control.
- No change in systolic or diastolic blood pressure was observed on either treatment or between treatments (Table 6).
- All above results remained unchanged after adjustment for multiple comparisons by the Bonferroni-Hochberg procedure.
- These Examples demonstrate that the addition of 0.5 g/100 kcal (8-13 g/day) of high viscosity glucomannan in biscuit form to a high-carbohydrate/low-saturated
fat NCEP Step 2 diet improved metabolic control beyond diet alone in individuals with the insulin resistance-dyslipidemic syndrome. Significant reductions in hyperglycemia as measured by the short-term marker of glycemic control, fructosamine, were observed. Also observed were significant reductions in hyperlipidemia as measured by total, LDL, LDL/HDL and total/HDL cholesterol, apo B and apo B/A-1, relative to a matched WB-control treatment. These findings represent the first to demonstrate such improvements using soluble fiber in individuals with this particular cluster of risk factors that also includes the intermediate diabetic classification, IGT, syndrome X. - Because of the strong implications of this syndrome, a more aggressive approach has been suggested to achieve similar reductions. Diabetes and heart disease share common precursors for the development of atheroslerosis that often co-occur. Long before diabetes becomes manifest, the clustering of metabolic abnormalities exerts a synergistic effect on the atherosclerotic process (Haffner et al. (1990)). Based on findings from Trevisea and colleagues, cardiovascular disease (CVD) risk appears to increase linearly with an increase in the number of these risk factors. It is recommended therefore that insulin resistant patients have their CHD risk factors managed as if they have established coronary heart disease (Haffner et al. (1998)).
- Low-fat/high carbohydrate diets may still have promise as a therapeutic approach. Although there has been a shift away from their advocacy in favor of those rich in monounsaturated fat (American Diabetes Association (ADA): Nutrition Recommendations and principles for people with diabetes mellitus. Diabetes Care 22:s42-s43, 1999), these diets supplemented with fiber may have similar metabolic advantages. Guar gum, pectin, oat products, and psyllium added to high carbohydrate diets have been shown to improve total and LDL cholesterol significantly, with no improvement to triglycerides and slight or no adverse effects on HDL (Jenkins et al. (1978)). Both guar (Aro et al. (1981)) and KJM+ (Arvill et al. (1995); Vuksan et al. (1999)) supplementation have also been shown to improve other risk factors, including glycemia and blood pressure. This lead to support for the use of guar in the treatment of the multiple metabolic syndrome (Landin et al. (1992)). Evidence further suggests that supplementation with these soluble fibers may augment concurrent drug therapy. Improvements in these assorted risk factors following supplementation have been noticed beyond what was achieved by drugs alone in subjects receiving hypolipidemic (Aro et al. (1981); Vuksan et al. (1999); Tuomilehto et al. (1989)), hypoglycemic (Aro et al. (1981); Vuksan et al. (1999); Shima et al. (1983)), and hypotensive (Vuksan et al. (1999); Uuistupa et al. (1984)) medications.
- The ability of soluble fiber to improve a high carbohydrate/low fat diet is supported by the findings of these Examples. Total and LDL cholesterol were decreased and glycemic control was improved significantly. Also, although HDL, Apo A-1, and triglycerides were unaffected, as has been noticed with other fibers, this was balanced by the significant improvements in the other lipid endpoints, leading to significant reductions in all three lipid ratios: Total/HDL, LDL/HDL, and Apo B/A-1. Similar improvements in these ratios have rarely been reported using dietary interventions (Tuomilehto et al. (1989); Shima et al. (1983)). Overall, the present findings indicate that a Step-2 diet supplemented with KJM+ may confer additional benefits over the Step-2 diet alone, benefits that may be comparable to strategies using monounsaturated fat.
- KJM+ may be better suited than the other major soluble fibers in improving outcomes with high-carbohydrate/low-fat diets. Although meta-analyses use variance adjusted values that tend to underestimate effectiveness, KJM+ can be compared to other soluble fibers in terms of its lipid lowering ability per gram of fiber, using recent meta-analytical data (Brown et al. (1999)). Daily intake of glucommanan from KJM+ on this study produced an average net change in total and LDL cholesterol of −0.084 and −0.119 mmol/L per gram of fiber respectively. These reductions represent approximately triple the lipid lowering capacity of psyllium (−0.028 and −0.029 mmol/L respectively), oat products (−0.037 and −0.032 mmol/L respectively), and guar gum (−0.037 and −0.033 mmol/L respectively) (Brown et al. (1999)). In the case of pectin, they represent comparable total cholesterol lowering capacity (−0.070 mmol/L) and approximately twice the LDL lowering capacity (−0.055 mmol/L) (Brown et al. (1999)). The very high viscosity of KJM+ used in this present study may explain these differences. It has been shown to be approximately five times higher than that of guar gum (Ebihara et al. (1989)) and beta-glucan (Wood (1990)), and considerably more than that of pectin (Venter et al. (1987)).
- Contributions made by its theological properties may offer insight into the proposed mechanism by which the KJM+ supplemented biscuits had their beneficial effects. While not wishing to be bound to any particular theory, possibilities for its lipid lowering action may include an inhibition of cholesterol absorption in the jejunum (Venter et al. (1987) and bile acid absorption in the ileum (Kiriyama et al. (1974)) mediated by viscosity or less postprandial stimulation of HMG CoA reductase (Jenkins et al. (1993)). Other options include the generation of short chain fatty acids, predominantly propionate, by colonic microflora that may decrease hepatic cholesterol synthesis (Venter et al. (1990)). The improvement in glycemic control may be attributable to an effect of the gel forming KJM+ on rate of digestion. It has been suggested that decreases in glucose and insulin levels after the consumption of water-soluble fibers are related to slower rates of food absorption in the small intestine associated with increased viscosity (Jenkins et al. (1978)). This mechanism may explain why a reduction in serum fructosamine, but did not concomitant reductions in fasting glycemia and insulinemia were observed: KJM+ may be exerting its effect mainly postprandially.
- In conclusion, the results in these Examples support the role of KJM+ mix as a means for improving high-carbohydrate diets in the amelioration of the insulin resistance-dyslipidemic syndrome. Improved metabolic control resulted in the correction of several risk factors that characterize the syndrome and figure prominently in the etiology of atherosclerotic CHD.
- Ten healthy male (3) and female (6) volunteers (Age=37; BMI=26.3 kg/m2) were randomly assigned to consume either wheat bran control, psyllium fiber, xanthan, KJM alone (FMC Co.) or KJM mix (preparation: KJM 74%, xanthan 26%) on five separate occasions. Each of the treatments contained 5 grams of above-mentioned ingredients which was added to 75 g available carbohydrate (300 ml) derived from glucose drink Glucodex solution (Technolab, Quebec) drink. Capillary blood glucose was taken after 10-12 hrs fasting and 15, 30, 45, 60 and 90 minutes after start of the test meals. Blood glucose was analyzed using YSI 2300 instrument. Results are presented as area under the glucose curve (
FIG. 1 ) and absolute and incremental blood glucose levels (FIG. 2 ) for individual time points. The results indicated that the area under the glucose curve for KJM mix (39) was significantly lowered (P<0.011) than control treatment (113; p<0.02), psyllium (100; p<0.032), xanthan (81; p<0.041) and KJM alone (80; p<0.027). Incremental and absolute glucose levels were significantly reduced on KJM mix treatment at time 30 (P<0.05) compared to all other treatment. - In summary,
FIGS. 1 and 2 provide illustrations of the significant effects on blood glucose a konjac mannan mixture of the present invention has over the effects of individual saccharides and konjac mannan alone. The mixture of konjac mannan comprised konjac mannan and xanthan although, other saccharides which can be use include, carragenan, acetan, guar, or xyloglucana. - Atherosclerosis and diabetes have been characterized as postprandial phenomena. Recent epidemiological analyses demonstrated that diets with a low glycemic load reduce their incidence. To investigate the ability of KJM mix to reduce postprandial glycemia in the insulin resistance syndrome (syndrome X) that underlies these diseases, 12 participants were studied (age: 55±4 y, BMI: 28±3 kg/m2) who satisfied the criteria for the syndrome (IGT, reduced-HDL, elevated triglycerides and mild-hypertension) following 21 days of KJM mix supplementation. In a crossover design, participants were assigned to take a metabolically controlled NCEP Step-2 diet either with 0.7 g/100 kcal of KJM mix enriched biscuits (as outlined in Examples 5-8), or matched wheat bran control biscuits over two 21 day treatment periods (see
FIG. 3 for composition profiles). Venous blood samples were drawn at 0, 30, 45, 60, 90, 120, and 180 min after a standard breakfast (see Table 7), before (day-1) and after (day-3) chronic feeding of the KJM mix or wheat bran biscuits on each treatment period. Plasma glucose [FIG. 4A (day-1),FIG. 4B (day-3)] and insulin [FIG. 5A (day-1) andFIG. 5B (day-3)] concentration profiles were determined and whole body insulin sensitivity was calculated using both fasting and postprandial values, according to Matsuda and DeFronzo (Diabetes Care 1999; 22:1462-70). Area under the curves for glycemia (−23.5% versus 0.4±2.3%, P=0.000022) (FIG. 4C ) and insulinemia (−40.5±4.5% versus −2.0±2.9%, p=0.000012) (FIG. 5C ) were significantly reduced on the KJM mix treatment compared to wheat bran control treatment. These decreases translated into a significant increase in postprandial insulin sensitivity on KJM compared to control (55.9±9.2% versus 9.7±4.5%, P=0.00056). Insulin sensitivity index (ISI) was calculated as follows: -
Composite Whole Body ISI=10,000/(FPG×FPI)×(G×I) - Where 10,000 is the constant; CompositeWhole Body ISI is hepatic & peripheral tissue insulin sensitivity, FPG is fasting plama glucose (mg/dL); FPI is fasting plasma insulin (μU/ml); G is mean glucose after glucose challenge; and I is mean insulin after glucose challenge.
- From this it may be concluded that prolonged consumption of KJM improves glycemic control, as indicated by lower postprandial glycemia and insulinemia.
- To determine the effect, if any, of viscosity of KJM fiber preparations on KJM activity, the efficacy of the KJM mix compared with highly refined commercially available KJM RS (Opta Co., US) on lowering postprandial blood glucose levels was studied.
- First viscosity measurements were taken of 2 KJM fibers, commercially available highly purified KJM RS produced by Opta C. (KJM 3) and the same KJM mixed with 23% of xanthan (KJM 1). To determine the difference in viscosity over time, 1.5 g of each KJM sample was mixed with 150 ml of water. Theological measurements using a Synchro-electric Viscometer (D.W. Brookfield Ltd., Cooksville, ON) (Shear 0.6/12, spindle E) were taken at 15, 30, 45, 60, 90, 120, 180 min and 24 h. Relative viscosity was compared between the samples. The two KJM fibres from Opta Co. (KJM 3) or the KJM mix (KJM 1) were compared in vivo testing. In vitro analysis indicated that viscosity of KJM 1 (KJM mix) was significantly higher (42,000 cps) compared to commercially available most purified konjac RS fibre, KJM 3 (16,200 cps).
- For the in vivo study seven healthy male (4) and female (3) volunteers (Age=43; BMI=24.7 kg/m2) were randomly assigned to consume either wheat bran control, KJM RS (KJM 3) or KJM mixture treatment containing 23% of xanthan gum (KJM 1) on three separate occasions. Each of the treatments contained 3 grams of above-mentioned ingredients which was added to 50 g available carbohydrate (356 ml) derived from vanilla flavored Ensure™ drink (Ross Abbott Laboratories). Capillary blood glucose was taken fasting (i.e after a 10 to 12 hrs fast) and 15, 30, 45, 60 and 90 minutes after start of the test meals. Blood glucose was analyzed using YSI 2300 instrument. Results are presented as area under the glucose curve (
FIG. 6C ) and absolute and incremental blood glucose levels (FIGS. 6A and 6B ) for individual time points. The results indicate that the area under the glucose curve for KJM 1 (68.4) was significantly lowered (by about 44%) (P<0.015) than control treatment (120.5), and KJM 3 (P<0.034) treatment (95.6) (lowered by about 21%). There were significant differences between the two KJM fibers on time. Incremental and absolute glucose levels were significantly reduced onKJM 1 treatment at time 60 (P<0.02) and 90 minutes (P<0.01) as compared toKJM 3 treatment. When compared to thecontrol meal KJM 3 showed no significance difference at any time points, or for the area under the glucose curve. As such it can be concluded that KJM mixed with polysaccharides such as xanthan in proportion to act synergistically is more effective on postprandial glycemia than highly refined KJM alone. KJM in mixture with other polysaccharides will express its efficacy in glycemic control of healthy individuals. - The effect of the proprietary KJM MIX, AG, and their combination (AG&KJM MIX) on postprandial blood pressure regulation in
type 2 diabetic individuals as compared with wheat bran control was studied. Seventeen healthy male (10) and female (7) volunteers (Age=64.7; BMI=29.4 kg/m2) were randomly assigned to consume either wheat bran control, AG, KJM mixture treatment containing 27% of xanthan gum (KJM MIX), or combination of AG and KJM MIX, on four separate occasions. Each of the treatments contained 3 grams of above-mentioned ingredients which was added to 50 g available carbohydrate (356 ml) derived from vanilla flavored Ensure™ drink. Standardized lunch was served at 240 minutes time after start of breakfast. Blood pressure was taken −30 min, 0, 30, 60, 120, 240, 360, and 420 minutes after start of the test meals. Blood pressure was determined using conventional mercury sphygmomanometer device. Results are presented as systolic and diastolic blood pressure (SeeFIG. 7 ). When compared to the control treatment, systolic blood pressure (SBP) was significantly reduced after taking KJM MIX (attime type 2 diabetic individuals. Further, the effect of the combination of KJM and AG seems to be different than each individual component. This indicates that there is a different mechanism of action which might be beneficial and superior to either of the two components alone. - The effect of the proprietary KJM MIX, AG, and their combination (AG&KJM MIX) on postprandial blood pressure, blood glucose and insulin regulation in
type 2 diabetic individuals as compared with wheat bran control was studied. - Seven volunteers with
type 2 diabetes were recruited; duration of diabetes 8.4±4.9 yr, HbAlc 6.9±1%, 86.4±15.9 kg. The study utilized a crossover, double blind design. Four sets of breakfasts and lunches were administered in random order. Lunch was a standard meal, only the breakfast meal contained either wheat bran (control) or KJM mix with or without AG. The test days were randomized for each subject and were scheduled at least one week apart. The total test day spanned 7 hours. Blood samples were taken using an indwelling catheter at −30, 0, 5, 10, 15, 30, 45, 60, 90, 120, 150, 180, 240 (lunch), 270, 300, 330, 360, 390 and 420 min. Samples will be analyzed for glucose and insulin. - Clinical blood pressure was measured using conventional mercury sphygmomanometer according to Joint National Council (JNC) VI criteria at −30, 0, 30, 60, 120, 240, 360, 420 min. Subjects were asked to record their satiety levels throughout the day using a bipolar scale ranging from −3 (extremely hungry), 0 (neutral), to +3 (uncomfortably full). The palatability of the meals was also recorded on a scale from 1 to 10, where 1 was “dislike extremely”, 5 “neutral” and 10 “delicious”. At each visit weight was measured using a beam scale and total body fat was measured with the Futrex 5000, using infrared technology. Additional samples were taken at the beginning and end of the study and measured for hemoglobin levels. This measurement was suggested by the Ethical Board of St Michael's Hospital as there was a concern regarding possible anemia.
- The results indicated that weight and total body fat did not significantly differ for each intervention. Hemoglobin decreased significantly by 12.2 g/L. There were no differences between meals in palatability of either breakfast or lunch. The blood pressure results look promising.
- Postprandial blood glucose was significantly lower in all 3 interventions (KJM mix, AG, and its combination) compared to control wheat bran. The lowest results are found to be with combination of KJM mix and AG, indicating an additive effect of mixing the two compounds (
FIGS. 8A and 8 b). Insulin results indicated significantly higher insulin secretion, but lower on KJM mix and even lower when 2 compounds were combined. (FIG. 9 ) - Overall, the effect of KJM, and AG in the present study confirmed that they both beneficially affect postprandial glycemia. Postprandial blood glucose was lowered by two mechanisms that are different but complementary; ginseng increase insulin secretion and KJM mix reduces insulin levels (increases insulin sensitivity). The effect of the combination of KJM and AG seems to be different than each individual component. This indicates that there is a different mechanism of action which might be beneficial and superior to either of the two components alone. The fact that blood glucose was lowest on KJM mix and AG combination with lowest insulin secreted, indicate that this combination provides the most effective and economic intervention of all three. Saving insulin (insulin economy) to achieve lowest blood glucose results would be extremely beneficial in a diabetes therapy.
- There are a wide variety of ginsengs and not all, even ones within the same species will necessarily have the same effect. As such the composition profiles of various ginsengs and their effect on blood glucose and insulin was studied.
- The effect of ginsengs with different diols/triols ratios was investigated. In series of successful clinical studies American ginseng was used, with composition of protopanaxadiols (Rb1, Rb2, Rc, and R) (diols) relative to protopanaxatriols (Rg1, Re, Rf) (triols), that had a ratio of above approximately 1.5 (i.e. Chinese ginseng with 1.91 ratio and American with 1.51 and 2.44 ratio). As such ginseng with a specific ginsenoside profile significantly decreases glucose. Ginseng profiles with weight ratios lower than 1.5 were also studied.
- In the studies, ginseng was given with a 75 g oral glucose tolerance test (OGTT) and compared the results to a similar study done previously with ginseng with higher ratios (
FIG. 10 ). Normal subjects were studied with 3 different ginsengs; in a first study 12 (gender: 6 m: 6 f, age: 31±3 years, BMI: 28±2 kg/m2) with Chinese ginseng with diols/triols ratio of 0.8; in the second and third studies, 10 (gender: 4 m: 6 f, age: 41±6 years, BMI: 26.1±0.4 kg/m2) with AG with diols/triols ratio of 1.2 and 1.37, respectively. A single-blind, crossover design was used in which all subjects received control or 6 g, 40 min before a 75 g-OGTT. Control in the present study consisted of identical capsules containing cornstarch, whereas in the previous study it was the 75 g-OGTT done alone. Both protocols followed the Canadian Diabetes Association guidelines for the OGTT, with venous blood samples drawn at −40, 0, 15, 30, 45, 60, 90, and 120 min. Repeated measures analysis of variance demonstrated that there was no significant effect of the AG containing diols/triols ginsenosides with ratios lower then 1.5. on incremental change or area under the curve (AUC) for glycemia or insulinemia. That was in contrast with results where ginseng with ratios above approximately 1.5 had beneficial effects. One of the explanation for this discrepancy is that the level of total or specific active ginsenosides, possibly in diols fraction rather than triols fraction of ginseng. These data suggest that the ginsenoside profile of ginseng, particularly ratio between protopanaxadiols to protopanaxatriols of above 1.5, so this play a role in its effects. - That part of ginseng's profile that gives improvement in human metabolism seems to be related to ginseng composition, mainly to ratios between main ginsneosides groups. The ginsenoside content of the 6 different ginseng grinded root and extracts used in the series of clinical studies was studied and found that reduction of blood glucose, lipids, and blood pressure; and also increase in insulin secretion, and nitric oxide, and reduction in oxidative stress had a high proportion of protopanaxadiols (Rb1, Rb2, Rc, and Rd) relative to protopanaxatriols (Rg1, Re, Rf).
- The present study indicates that an optimal level of this ratio of ginseng to be effective should be higher then approximately 1.5 (
FIG. 10 ). - In
FIG. 10 , each bar represents ginseng with different diols/triols ratio. Once a ratio is reached of approximately 1.5 or higher the postprandial blood glucose is significantly reduced (letter b vs. a on graph). The first bar (area=167) is Chinese ginseng root with ratio 0.8. The second bar (area=196) is American ginseng extract (75% water:alcohol 25%) with ratio 1.2. The third bar (area=159) is American root ginseng with ratio 1.37. The fourth bar (area=159) is American root ginseng with ratio 1.37. The fifth bar represents (area=129) Chinese ginseng extract (59% water:41% alcohol) and ratio of 1.91 and this reduced blood glucose significantly. The sixth bar represents (area=142) American root ginseng with ratio 1.51 and this also reduced blood glucose significantly. The seventh bar represents (area=109) American ginseng root with ratio 2.44 and this reduced blood glucose significantly. - A further pilot study in healthy volunteers was conducted to explore the effect of the whole root ginseng versus an alcohol:water=55:45 extract, both with diols to triol ratio>1.5 with or without the addition of KJM mix. Results showed that both ginseng types and the KJM lowered the incremental glucose area and combining the ginseng with the KJM mix had an additional effect (results not shown).
- Other metabolic benefits such as increase in insulin secretion and nitric oxide generation (
FIG. 11 ) are demonstrated with ginseng with ratio of above 1.5. In this study ginseng had ratios of diols/triols of 2.44. Ginseng was administrated to 8 (gender: 3 m: 5 f, age: 34±3 years, BMI: 24.6±0.8 kg/m2) healthy individuals. Data presenting reduction of postprandial blood glucose, and increase in plasma insulin and nitric oxide generation, relative to control. Data are presented inFIG. 11 . - Comparison of incremental change and area under the curve (AUC) in plasma glucose, (
FIG. 11A , 11B), insulin (FIGS. 11C and 11D ) and nitric oxide (NOx) (FIGS. 11E and 11F ) following ginseng (diols/trials ratio=2.44)) taken 40 min before (Δ) or together (◯) with a 75 g oral glucose tolerance test (75 g-OGTT) or a 75 g-OGTT done alone previously (□) in 8 non-diabetic subjects. Glucose and insulin were measured by glucose oxidase method (67) and double antibody radioimmunoassay method respectively (68). Plasma NOx was measured as total nitrite (NO2 −)+nitrate (NO3 −) concentrations by the chemiluminescence method (69,70) using a Sievers 280 NO Analyzer (Boulder Colo., USA). Points or bars with different letters are significantly different (repeated measures ANOVA adjusted for multiple pairwise comparisons with the Newman Keuls procedure, P<0.05). Data are mean ±SEM. - The present inventor conducted four studies to determine the effect of American ginseng in humans were conducted (Table 8).
- In the first of these studies, the glycemic responses in 10 normal and 9
type 2 diabetic subjects was studied after the administration of 3 g American ginseng or placebo given 40 minutes before (−40 minutes) or together with a 25 g oral glucose challenge. It was observed that selected blood glucose concentrations and the area under the curve were reduced significantly when ginseng was administered either before or together with the challenge compared to placebo in the diabetic subjects and only when given before in the normal subjects (Vuksan, Arch. Intern. Med 2000; 160:1009-13. - Similar reductions in postprandial glycemia both in nondiabetic and diabetic subjects were observed, in three subsequent acute dosing and timing response studies that followed (Table 8). The first of these two studies showed that 3, 6, or 9 g of American ginseng compared to placebo significantly reduced the postprandial glycemic response to a 25 g oral glucose challenge when administered 0 (together with), 40, 80, or 120 minutes before a glucose challenge in 10 diabetic subjects (Vuksan, Diabetes Care 2000; 23:1221-6) and when administered 40, 80, or 120 minutes before the challenge in 10 nondiabetic subjects (Vuksan, J Am Coll Nutr 2000: 18:738-744). There were no differences observed in either study between the doses or the times of administration in their glycemic lowering effect. These data suggested that ginseng is equally effective at doses above 3 g and when administered at any time together or before the challenge in diabetic subjects, but only when administered 40 minutes or more before the challenge in nondiabetic subjects. The third study showed that 1, 2, or 3 g of American ginseng compared to placebo reduced significantly the postprandial glycemic response to a 25 g oral glucose challenge when administered 40 minutes but not 20, 10, or 0 minutes before a glucose challenge in 12 nondiabetic subjects (Vuksan Am. J. Clin Nutr,). Again there were no differences detected between the doses studied. The suggestion was that ginseng is equally effective at doses above 1 g, but needs to be administered a minimum of 40 minutes before the challenge in nondiabetic subjects.
- Having illustrated and described the principles of the invention in a preferred embodiment, it should be appreciated to those skilled in the art that the invention can be modified in arrangement and detail without departure from such principles. We claim all modifications coming within the scope of the following claims.
- All publications, patents and patent applications referred to herein are incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety.
-
TABLE 1 Baseline Characteristics of the Study Subjects According to Sex* MEN WOMEN CHARACTERISTICS (N = 5) (N = 6) Age - yr 62 ± 8 59 ± 7 Body weight - % desirable† 133 ± 33 143 ± 22 Android obesity - prevalence‡ 5 4 Baseline values: Serum total cholesterol - mmol/L 6.2 ± 0.4 5.9 ± 0.5 Glycosylated hemoglobin - % 7.4 ± 2.1 8.3 ± 3 Systolic/Diastolic pressure - mm Hg: 139/78 136/82 Known duration of: Diabetes - yr (self-reported) 11.5 ± 9 18.1 ± 6 Hypertension - yr 7.1 ± 3 6.0 ± 2 Hyperlipidemia - yr 6.3 ± 3 5.6 ± 2 Drug/insulin treatment - prevalence: Insulin 1 3 Sulfonylurea and/or Metformine 5 6 Diuretics 2 4 Other hypothensive 4 3 Lipid lowering medications§ 5 6 *Except for drug treatment, blood pressure, and android obesity values are expressed as mean ± SD. To convert values for cholesterol to mg/dl multiply by 38.67. †Values were assessed from Metropolitan Life Insurance tables, 1983. ‡Android obesity is indicated by a wait-to-hip ratio grater than 0.9 for men, and 0.8 for women §Bile acid sequestrant, nicotinic acid and/or coenzyme A reductase inhibitor -
TABLE 2 Average Intake of Energy and Nutrients in Eleven Subjects Before and During Study Periods.* Parameters Baseline† Konjac-mannan Wheat Bran P‡ Total energy, kJ/d 7671 ± 1760 8907 ± 2250 9134 ± 1006 .23 Total fat, % of energy 24.8 ± 6.2 23.4 ± 2.1 23.9 ± 1.6 .6 Saturated fat, % of energy 8.2 ± 2.4 4.1 ± .4 3.9 ± .2 .73 Monounsaturated fat, % of energy 7.3 ± 1.3 12.4 ± 1.9 12.6 ± 1.4 .35 Polyunsaturated fat, % of energy 9.1 ± 2.1 7.1 ± .2 7.6 ± .3 .24 Cholesterol, mg/4184 kJ 87 ± 17 44 ± 18 36 ± 11 .12 Total protein, % of energy 18.7 ± 4.2 15.5 ± 1.7 14.9 ± 2.1 .86 Available carbohydrate, % of energy 56.5 ± 14.3 60.5 ± 8.6 61.2 ± 6.5 .4 Sugar, % of energy 13.2 ± 17.2 11.2 ± .6 10.4 ± .3 .17 Total fiber, g/d 27.4 ± 14.2 39.3 ± 11.4 40.1 ± 12.5 .9 Water soluble, g/d 8.1 ± 2.7 23.1 ± 4.1 8.3 ± 2.4 <.001 Water insoluble, g/d 17.8 ± 4.2 16.7 ± 3.6 29.8 ± 4.8 <.001 Sodium, mg 4540 ± 1350 2820 ± 348 2708 ± 420 .878 Potassium, mg 1430 ± 850 3960 ± 450 4240 ± 664 .659 Calcium, mg 630 ± 442 1150 ± 185 1370 ± 246 .552 *Values are mean ± SD. Konjac-mannan and wheat bran diets are based on actual intake. To convert kJ to kcal multiply by 2.39. †Based on the mean of four non-consecutive 3-day food records. ‡Differences between the konjac-mannan and wheat bran study periods were calculated by students paired t-test. -
TABLE 3 Composition (g/100 g) of Konjac-mannan (KJM) and Wheat Bran biscuits, at the moisture content of 2.8 g/100 g. Total Dietary Fiber Glucomannan Biscuits Available from KJM Energy§ Type Protein Fat Carbohydrate* KJM flour Ash Dietary FiberH flourI (kJ/100 g) Wheat Bran 6.8 14.4 66.5 — 1.4 2.8 — 1011 Konjac-mannan 6.2 13.9 61.2 15.3 1.3 2.3 10.6 944 *Values are calculated by difference: 100 − (moisture + protein + fat + total dietary fiber + ash). Sucrose added is between 37-40% of total available carbohydrate. HAverage values for dietary fiber in wheat bran and flour analyzed by method of Prosky et al. (1985). ‡ Value represents 64% glucomannan polymer derived from KJM flour. §Values for available carbohydrate expressed as monosaccharide. To convert kJ to kcal multiply by 2.39. -
TABLE 4 Changes in Serum Lipids, Glycemia, Blood Pressure, Body Weight and 10-yrs. Coronary Heart Disease (CHD) Relative Risk during and between the Konjac-mannan and Control (Wheat Bran) Study Periods*. Konjac-mannan Wheat Bran Between-Treatments Risk factors Week-0 Week-3 Change, % Week-0 Week 3 Change, % Change, % P Cholesterol, mmol/L Total 6.10 ± 0.29 5.11 ± 0.28 −16 ± 2.7§ 5.81 ± 0.19 5.48 ± 0.19 −4.9 ± 3.7 −11 ± 4.3 0.0252 LDL 3.89 ± 0.25 3.04 ± 0.26 −25 ± 3.9§ 3.56 ± 0.18 3.29 ± 0.16 −4.8 ± 5.9 −19 ± 7 0.0331 HDL 1.07 ± 0.08 0.94 ± 0.06 −11 ± 2.2‡ 1.04 ± 0.10 0.95 ± 0.08 −8.9 ± 2.4‡ −2.2 ± 3 0.4924 Triglyceride, 2.53 ± 0.23 2.88 ± 1.38 18.7 ± 12.8 2.69 ± 0.44 2.96 ± 0.37 25.1 ± 14.7 −6.4 ± 14 0.6565 mmol/L Apolipoprotein, g/L Apo A-1 1.47 ± 0.07 1.37 ± 0.06 −6 ± 3.1 1.48 ± 0.08 1.48 ± 0.10 +0.7 ± 3.7 −6.7 ± 4.3 0.1541 Apo B 1.50 ± 0.09 1.28 ± 0.08 −14 ± 3.4‡ 1.48 ± 0.08 1.40 ± 0.07 −3.0 ± 5.0 −11 ± 4 0.0253 Lipid Ratios: Total/HDL 6.08 ± 0.48 5.69 ± 0.48 −5.7 ± 2.4† 6.06 ± 0.56 6.21 ± 0.53 4.7 ± 4.4 −−10 ± 4 0.0279 Apo B/Apo A-1 1.05 ± 0.09 0.96 ± 0.08 −8.6 ± 2.3‡ 1.05 ± 0.10 0.99 ± 0.08 −3.0 ± 4.5 −3.2 ± 5 0.2353 Glycemia: Glucose, mmol/L 9.63 ± 0.80 8.62 ± 0.95 −11 ± 3‡ 9.29 ± 0.74 8.99 ± 0.78 −1.5 ± 6.1 −9.7 ± 4 0.1413 Fructosamine, 3.43 ± 0.1 3.17 ± 0.2 −6.1 ± 2.4† 3.25 ± 0.2 3.25 ± 0.2 −0.5 ± 1.4 −5.7 ± 1.7 0.0069 mM Insulin, pmol/L 154 ± 38.6 150 ± 32.8 9.58 ± 9.7 142 ± 31 140 ± 31 2.1 ± 11 −7.5 ± 12 0.559 Blood pressure, mm Hg Systolic 139.5 ± 5.0 131.6 ± 4.9 −5.5 ± 1.4‡ 128.8 ± 4.0 130.4 ± 4.7 1.4 ± 2.7 −6.9 ± 2.5 0.0211 Diastolic 79.1 ± 2.0 77.5 ± 1.8 −1.6 ± 2.8 78.3 ± 1.6 78.4 ± 2.7 0.4 ± 3.6 −2 ± 5 0.7056 Body weight, kg 85.6 ± 19 85.0 ± 19 −0.6 ± 0.5 85.9 ± 19 85.3 ± 19 −0.6 ± 0.4 −0.1 ± 0.4 0.8991 CHD Realtive 1.77 ± 0.2 1.50 ± 0.2 −14 ± 2.7§ 1.56 ± 0.2 1.63 ± 0.3 8.7 ± 7.3 −22 ± 4.7 0.0107 Risk (10 yr) *Except body weight (mean ± SD) values are expressed as mean ± SEM. Abbreviations are defined as LDL, low-density lipoprotein; HDL, high-density lipoprotein; Apo, apolipoprotein. To convert cholesterol, triglycerides, and glucose to mg/dl multiply by 38.67, 88.57, and 18, respectively. To convert insulin to μU/ml, multiply by 0.1394. All means are for n = 11 except for LDL where n = 9, since two subjects had triglycerides above 4 mmol/L preventing calculation by Friedewald equation. Within treatment differences were assessed by paired t-test [(†) P < .05; (‡) P < .01; (§) P < .001], while between treatment differences by ANCOVA (PROC GLM). Lack of notation indicates no significant differences. [(†&) P < .05; (‡$) P < .01; (§#) P < .001], -
TABLE 5 Average Intake of Energy and Nutrients Before and During Study Periods in Eleven Subjects Parameters Baseline KJM WB Total energy (kcal/d) 2 070 ± 700 2 579 ± 628 2 355 ± 420 Total fat (% of energy) 30.5 ± 4.3 29.3 ± 3.2 28.7 ± 2.4 Saturated fat 7.2 ± 4.7 6.7 ± 0.8 6.4 ± 0.7 (% of energy) Monounsaturated 10.3 ± 5.1 12.7 ± 2.1 12.2 ± 2.6 fat (% of energy) Polyunsaturated 13.0 ± 5.7 9.9 ± 1.8 10.1 ± 0.9 fat (% of energy) Cholesterol (mg/d) 328 ± 102 219 ± 48 236 ± 77 Total protein 14.6 ± 8.2 16.2 ± 2.7 15.6 ± 3.2 (% of energy) Available 54.9 ± 21 54.5 ± 9.4 55.7 ± 7.3 carbohydrate (% of energy) Sugars (% of energy) 13.3 ± 3.6 11.2 ± 0.9 9.2 ± 1.4 Total fiber (g/d) 24.2 ± 11 34.7 ± 8.4 33.4 ± 9.6 Water soluble (g/d) 6.9 ± 3.2 23.4 ± 1.7 9.9 ± 3.2* Water insoluble (g/d) 17.3 ± 7.3 11.2 ± 3.8 23.1 ± 2.6* Sodium (mg) 5 810 ± 2 384 3 162 ± 648 3 380 ± 647 Potassium (mg) 3 882 ± 713 4 530 ± 611 4 840 ± 872 Calcium (mg) 1 366 ± 193 1 260 ± 238 1 487 ± 446 -
TABLE 6 Changes in Serum Lipids, Glycemia, Blood Pressure, and Body Weight during and between the Konjac-mannan (KJM) and Wheat Bran Control (WB-Control) Study Periods in Eleven Subjects KJM WB-Control Between-Treatments Risk factors Week-0 Week-3 Change, % Week-0 Week-3 Change, % Change, % P* Cholesterol (mmol/L) Total 6.2 ± 0.3 5.0 ± 0.2 −19 ± 2.69* 6.0 ± 0.2 5.6 ± 0.2 −6.3 ± 3.36 −12.4 ± 3.1 0.0038* LDL 3.9 ± 0.2 2.8 ± 0.2 −29 ± 3.37* 3.8 ± 0.2 3.5 ± 0.2 −6.6 ± 5.04 −22.3 ± 3.9 0.0017* HDL 1.0 ± 0.1 0.9 ± 0.1 −8.5 ± 2.19* 1.0 ± 0.1 0.9 ± 0.1 −9.6 ± 2.24* 1.2 ± 2.2 0.9812 Triglyceride 2.8 ± 0.2 3.0 ± 0.2 10.1 ± 9.92 2.9 ± 0.4 3.0 ± 0.3 12.1 ± 14 −1.6 ± 10 0.7317 (mmol/L) Apolipoprotein (g/L) Apo A-1 1.4 ± 0.1 1.4 ± 0.1 −6.5 ± 2.46* 1.5 ± 0.1 1.4 ± 0.1 −4.8 ± 3.38 −1.8 ± 3.1 0.3622 Apo B 1.6 ± 0.1 1.3 ± 0.1 −19 ± 2.78* 1.6 ± 0.1 1.5 ± 0.1 −4.5 ± 4.47 −15.1 ± 4.3 0.0003* Lipid Ratios: Total/HDL 6.5 ± 0.5 5.7 ± 0.4 −11 ± 3.02* 6.2 ± 0.4 6.4 ± 0.5 4.14 ± 4.16 −15.2 ± 3.4 0.0023* Apo B/Apo A-1 1.1 ± 0.1 1.0 ± 0.1 −13 ± 3.02* 1.1 ± 0.1 1.1 ± 0.1 0.72 ± 3.61 −13.1 ± 3.4 0.0002* LDL/HDL 4.2 ± 0.4 3.2 ± 0.3 −22 ± 3.72* 3.9 ± 0.3 3.9 ± 0.4 0.22 ± 6.27 −22.2 ± 4.1 0.0012* Glycemic Control: Glucose (mmol/L) 6.8 ± 0.5 5.9 ± 0.3 −13 ± 2.48* 6.6 ± 0.3 5.9 ± 0.4 −9.6 ± 4.27 −3.8 ± 3.6 0.7653 Fructosamine 286 ± 13.6 269 ± 11.9 −5.6 ± 1.46* 279 ± 11.7 278 ± 12.6 −0.39 ± 1.3 −5.2 ± 1.4 0.0013* (mM) Insulin (pmol/L) 94.8 ± 16.6 91.1 ± 16.5 0.91 ± 8.88 99.2 ± 16.5 88.5 ± 11.4 −3.0 ± 9.67 3.9 ± 8.9 0.9683 Blood pressure (mm Hg) Systolic 139 ± 2.0 135 ± 3.6 −2.9 ± 1.88 135 ± 2.6 138 ± 3.7 2.2 ± 2.5 −5.1 ± 2.2 0.448 Diastolic 85.4 ± 1.8 84.8 ± 1.5 −0.26 ± 2.55 85.5 ± 1.7 86.5 ± 1.5 1.33 ± 1.49 −1.4 ± 2.1 0.2647 Body weight (kg) 80.7 ± 5.1 80.6 ± 5 −0.17 ± 0.14 81 ± 5.3 80.6 ± 5.1 −0.29 ± 0.35 0.1 ± 0.2 0.5303 -
TABLE 7 Test Breakfast Compositions Placebo Breakfast Konjac Breakfast 49 g W. Bran Cookies 58 g Konjac Cookies 52 g Branflakes 69 g Branflakes 250 ml 2% Milk 250 ml 2% Milk8 g Butter 8 g Butter Macronutrient Composition Energy (Kcal) 673 678 Protein (%) 10.3 11.2 Total Fat (%) 29.0 28.6 Available Carbo (%) 61.1 59.2 Total Fiber (g) 13.0 13.1 Soluble Fiber (g) 7.2 1.4 -
TABLE 8 AUC Study Sample Treatments OGTT Reductions P value Study 1 10 NGT 3 g AG vs placebo @ 0 min 25 g — P = NS (Age: 34 ± 7years, 3 g AG vs placebo @ −40 min 18% P < 0.05 BMI: 25.6 ± 3 kg/m2) 9 T2DM 3 g AG vs placebo @ 0 min 25 g 19% P < 0.05 (Age: 62 ± 7years, 3 g AG vs placebo @ −40 min 22% P < 0.05 BMI: 29 ± 5 kg/m2, HbA1c: 7.6 ± 0.5%) Study 2 10 NGT Dosing: 3, 6, or 9 g AG vs placebo 25 g 26.6, 29.3, P < 0.05 (Age: 41 ± 13years, 38.5% for 3, 6, BMI: 24.8 ± 3.5 kg/m2) and 9 g Timing: −40 min vs −120 or −80 min — P = NS Study 3 10 T2DM Dosing: 3, 6, or 9 g AG vs placebo 25 g 19.7, 15.3, 15.9 P < 0.05 (Age: 63 ± 2years; % for 3,6, and BMI: 27.7 ± 1.5 kg/m2; 9 g HbA1c: 7.3 ± 0.3%) Timing: −120, −80, −40 or 0 min — P = NS Study 4 12NGT Dosing: 1, 2, or 3 g AG vs placebo 25 g 14.4, 10.6, 9.1 P < 0.05 (Age: 42 ± 7 years, % for 1, 2, and BMI: 24.1 ± 1.1 kg/m2) 3 g Timing: −40 min vs −20, −10 or 0 min 14.1, 15.0, 9.2 P < 0.05 % for −40 min AG, NGT, OGTT, T2DM, NS denote American ginseng, normal glucose tolerance, oral glucose tolerance test, type 2 diabetes mellitus, and nonsignificant respectively. P-values are for repeated measures analysis of variance (ANOVA) comparisons between absolute values. Values are mean ± SD. - * Values are calculated by difference: 100−(moisture+protein+fat+total dietary fiber+ash). Added sucrose was between 37-40% of total available carbohydrate.
- § Significant after adjustment of alpha level by the Bonferroni-Hochberg procedure. Null-hypotheses were rejected only if the p-values were less than their corresponding α-value. P-values for during treatment changes were assessed by paired t-test ∥ LDL values are for nine subjects, since two subjects had triglycerides above 4.5 mmol/L preventing calculation by Friedewald equation.
Table 5: Data are mean ±SD. KJM+ and WB-control diets are based on actual intake. Baseline values are based on the mean of four 3-day food records. *P<0.001 for differences between KJM+ and WB-control treatments (student's t-test for paired data)
Table 6: Data are expressed as mean ±SEM, except for body weight which is mean ±SD. Within-treatment differences (week-0 versus week-3) were assessed by paired Student's t-test and between-treatment differences by ANCOVA (GLM procedure). *Significant after adjustment of alpha level by the Bonferroni-Hochberg procedure. Null-hypotheses were rejected only if the p-values were less than their corresponding α-value. - Table 8: Is a comparison of 4 studies. See Example 16.
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Claims (20)
1-43. (canceled)
44. A composition of matter for reducing blood glucose comprising ginseng.
45. The composition of claim 44 wherein the ginseng is an extract of ginseng.
46. The composition according to claim 44 wherein the ginseng comprises a ratio of diols/triols of greater than about 1.5.
47. The composition according to claim 44 wherein the composition is formulated into a liquid, powder or food.
48. A method for the treatment or prevention of a disorder which benefits from reducing blood glucose in an animal comprising administering to the animal in need thereof a sufficient amount of ginseng.
49. The method according to claim 48 wherein the ginseng is an extract of ginseng.
50. The method according to claim 48 wherein the ginseng is administered before a meal or with a meal.
51. The method according to claim 48 wherein administration before the meal occurs from about 1 to about 180 minutes before the meal.
52. The method according to claim 48 wherein the amount of ginseng is at least about 1000 mg per administration.
53. The method according to claim 48 wherein the ginseng comprises a ratio of diols/triols of greater than about 1.5.
54. The method according to claim 48 wherein the ginseng is administered as a food, a powder, or a liquid.
55. The method according to claim 48 wherein the ginseng is American ginseng.
56. The method according to claim 48 wherein the disorder which benefits from reducing blood glucose is diabetes, heart disease, or syndrome X.
57. The method according to claim 48 wherein the method increases insulin sensitivity in an animal.
58. The method according to claim 48 wherein the disorder comprises type 2 diabetes.
59. The method according to claim 48 wherein the method reduces systolic blood pressure, blood cholesterol or lipids.
60. The method according to claim 48 wherein the method increases insulin secretion.
61. The method according to claim 48 wherein the animal comprises a human.
62. A method for the treatment or prevention of a disorder which benefits from reducing blood glucose in an animal comprising administering to the animal a sufficient amount of a composition comprising a konjac mannan mixture and ginseng.
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US10/296,196 US7326404B2 (en) | 2000-05-31 | 2001-05-31 | Konjac-mannan and ginseng compositions and methods and uses thereof |
PCT/CA2001/000774 WO2001091586A2 (en) | 2000-05-31 | 2001-05-31 | Konjac mannan and ginseng compositions and methods and uses thereof |
US11/960,033 US20080131531A1 (en) | 2000-05-31 | 2007-12-19 | Konjac Mannan and Ginseng Compositions and Methods and Uses Thereof |
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US7326404B2 (en) * | 2000-05-31 | 2008-02-05 | Vuksan Holdings Inc. | Konjac-mannan and ginseng compositions and methods and uses thereof |
DE602006009641D1 (en) * | 2005-04-07 | 2009-11-19 | Astrum Therapeutics Pty Ltd | COMPLEMENTARY COMPOSITIONS FOR REDUCING BLOOD SUGAR MIRRORS AND TREATING DIABETES |
US8062686B2 (en) | 2005-04-12 | 2011-11-22 | InovoBiologics, Inc. | Dietary supplement, and methods of use |
US8597709B2 (en) | 2005-04-12 | 2013-12-03 | Inovobiologic Inc. | Dietary supplement and methods of use |
EP1996176B1 (en) * | 2006-02-21 | 2010-05-19 | Astrum Therapeutics Pty, Ltd. | Compositions to reduce blood glucose levels and treat diabetes |
CA2676518A1 (en) * | 2008-08-29 | 2010-02-28 | Kraft Foods Global Brands Llc | Whey protein pre-load |
RS64061B1 (en) * | 2014-11-26 | 2023-04-28 | Omega Pharma Innovation And Dev Nv | A dietary fibre composition |
CN111513313A (en) * | 2020-04-13 | 2020-08-11 | 重庆市生物技术研究所有限责任公司 | Composition for enhancing bone mineral density, preparation and preparation method thereof |
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US20050020535A1 (en) | 2005-01-27 |
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