CA2310513A1 - Compositions and methods for reducing blood glucose - Google Patents

Abstract

Described are a number of compoositions, namely a konjac mannan mixture, an American ginseng composition and a composition comprising konjac mannan and American ginseng. Methods of use of these compositions are described for reducing blood glucose in non-diabetic and diabetic individuals, as well as reducing postprandial blood glucose in such individuals. Various applications of the compositions and methods are also described.

Description

TITLE: COMPOSITIONS AND METHODS FOR REDUCING BLOOD GLUCOSE
FIELD OF THE INVENTION
This invention is in the field of glucose management and is concerned with dietary approaches to such management, more particularly it is concerned with compositions and methods of reducing blood glucose, specifically compositions comprising Konjac-Mannin and American Ginseng and methods of use of these compositions in lowering blood glucose including post-prandial.
BACKGROUND OF THE INVENTION
Abnormal glucose tolerance and Insulin resistance are related to multiple 1o cardiovascular risk factors especially reduced HDL, elevated serum triglycerides and hypertension (Liese et al. ( 1998)). When clustered these abnormalities increases 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 2o 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)).

-2-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 1o 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 22a42-s43 ( 1999)), or supplementing a high-carbohydrate/low-fat diet with exercise (Stefanick et al. (1998)).

-3-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 s 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).
Effective dietary strategies shown to decrease postprandial plasma glucose excursions o 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 t 5 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 fiber as an adjunct to conventional treatment in individuals with two or more major CHD risk factors are scarce (Uuistupa et al.
20 ( 1984)).
Evidence suggests that fiber 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 2s 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

-4-important mechanistic factor (Jenkins et al. (1978)). However, to date, there is no clearly effective composition or method for reducing postprandial blood glucose.
SUMMARY OF THE INVENTION
The present inventor has determined that the addition of high-viscosity fiber, in the form of a konjac-mannan mixture, or American ginseng, or a composition comprising a konjac-mannan mixture and American ginseng to a diet of an animal enhances conventional treatment outcomes, 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 diastolic blood pressure (dBP).
1o Accordingly, in one aspect the present invention provides a composition of matter for reducing blood glucose comprising a konjac-mannan mixture, a sufficient amount of which when given to an animal at an appropriate time reduces 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 from 50% to about 100% of konjac-mannan alone. More preferably the substance comprises about 10% to about 40% or one or more 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 2o comprises consitituents with the particle size larger than about 1,000 angstroms.
Preferably, compositions according to the invention are formulated into a liquid, powder or formulated as part of a food.
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 postprandial hood glucose in the animal. Preferably the konjac-mannan mixture comprises konjac-mannan and a

-5-substance capable of increasing the viscosity of konjac-mannan to from about 50% to about 100% of konjac-mannan alone, preferably the substance comprises from about 10%
to about 40% of one or more polysaccharides, more preferably the one or more polysaccharides are selected from 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 3 to about 4 grams per day, preferably the mixture is administered either prior to a meal or during the meal.
1o 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.
According to another aspect of the invention, there is provided a composition of matter for reducing blood glucose comprising American ginseng a sufficient amount of ~ 5 which when given to an animal at an appropriate time reduces 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 American ginseng a sufficient amount of which when given to an animal at an appropriate time reduces blood glucose in the 2o animal. According to either of these latter compositions, the American ginseng is comprised of a ratio of Rg 1/Rb 1 of greater than about 1.0, and preferably the composition is formulated into a liquid, powder or formulated as part of a food.
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 25 amount of American 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

-6-animal comprising administering to the animal a sufficient amount of an extract of American ginseng at an appropriate time in order to reduce blood glucose in the animal.
According to either of these latter mentioned methods, preferably the American 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 American ginseng or extract of American ginseng is at least about 1000 mg per administration.
According to another embodiment of the method of the invention the American 1 o ginseng comprises a ratio of Rg 1/Rb 1 of greater than about 1Ø
According to yet another embodiment of the method of the invention the composition is administered as a food, a powder, or a liquid.
According to another aspect of the present invention there is provided a composition of matter for reducing blood glucose comprising a konjac-mannan mixture and American ginseng a sufficient amount of 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 100% of konjac-mannan alone. Preferably the substance comprises about 10% to about 40% or 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 Rg 1/Rb 1 of greater than about 1Ø
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 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 lipids 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.
to BRIEF DESCRIPTION OF THE DRAWINGS
The invention will be better understood with reference to the drawings in which:
Figure 1 is a histogram illustrating the effect of various fibres including Konjac mannin alone on glucose response in individuals in comparison with a Konjac-mannin mixture of the present invention.
Figure 2 is a graph illustrating the post-meal blood glucose response of individuals histogram illustrating the effect of various fibres including Konjac mannin alone in comparison with a Konjac-mannin mixture of the present invention.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENT OF THE
INVENTION
2o 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.
As used herein "animal" means any member of the animal kingdom including preferably humans.
As used herein "postprandial" means after any food intake.

_g_ As used herein "sufficient 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 1o 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.
Konjac Mannan 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 2o 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 (Arvin 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 (Arvin et al. ( 1995);
Terasawa et al. (1979); Venter et al. (1987)), systolic blood pressure (sBP) (Arvin 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 1o 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 ~ 5 alkaline solution may be used as described in US 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.
Ginseng 2o A main ingredient of the ginseng is saponin. As the saponin included in this ginseng there have been known twelve kinds of ginsenside-Ro, -Ra, -Rbl, -Rb2, -Rc, -Rd, -Re, -Rf, -Rgl, -Rg2, -Rg3, -Rh. These are the one (ginsenside-Rbl, -Rb2, -Rc) containing sapogenen and protopanaxadiol, and the one (ginsenside-Re, Rf, -Rgl, -Rg2) containing sapogenen and protopanaxatriol. The main saponin in the crude drug is ginsenside-Rbl, -Rb2, -Rc, -Rgl.
25 The ginsenside-Ro is the same as chikusetsusaponin V, and the ginsenside-Rb 1 is the same as saponin D.

Besides these, the ginseng contains essential oil of 0.05%, .beta.-elemene, panacene (C_l5 H₂₄) and panaxynol as polyacetylene compound and further contains choline, vitamin B complex, fatty acid etc.
There are known to be at least seven diferent types of ginseng and in the present disclosure a prefered form is American ginseng.
American Ginseng (Panax quinquefolium L.) reduces postprandial blood glucose in nondiabetic and people with diabetes. Preferably at least 1000mg of 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 1o 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).
American ginseng with a profile of Rg 1/Rb 1 ratio of > 1.0_ is a prefered formulation and may be administered in the same manner as described above at posses glucose lowering effects. American ginseng with a particular ginsenosides profile may have an effect on increased secretion of the first phase insulin, similar to conventional diabetic drugs.
Konjac Mannan and Ginseng A combination of selected 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 then each individual material. The efficacy is not attainable 2o by either treatment. While not wishing to be bound by any particular theory, the possible mechanism of action for the hypoglycaemic effect of konjac/ginsneg 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.
Compositions 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 to pharmaceutically acceptable vehicles or diluents, and contained in buffered solutions with a suitable pH and iso-osmotic with the physiological fluids.
The following non-limiting examples are illustrative of the present invention:
EXAMPLES
t s GENERAL METHODS FOR EXAMPLES 1-4 Subjects 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 2o 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, 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 25 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.
Study Design 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, 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 1o 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 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. The study began with 5 subjects taking the KJM+ treatment and 6 the control.
Diet 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 2o 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 DC: Government printing office (NIH publication no. 82-2014) ( 1982)). Total dietary fiber was administrated at 2g/412 kJ ( 100kca1), with a mean daily intake according to energy intake ranging from 24g to a plateau of SOg for those consuming 2500Kca1 per day or more. The actual diet consumed is presented in Table 3.

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 8oz 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. Because KJM flour comprised half ( 1 g/412 kJ [ 100 kcal] ) of the total fibre on the KJM+ treatment, approximately 0.7g/412 kJ
( 100 kcal) was glucomannan. Wheat bran biscuits, in contrast, had a lower proportion of fiber than KJM+ biscuits (Table 2). Approximately 14g/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.
~ 5 Any food from the metabolic diet together with study biscuits not consumed were 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.
Laboratory Methods 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, Pennsylvania) (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-1o 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, DC, 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) Statistical Analyses 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.: SASlSTAT User's guide. Version 6, 4''' ed. Cary NC:
SAS
2o 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). Analysis of covariance (ANCOVA) with the facility of General Linear Model procedure (PROC GLM) was used to test for differences in these same parameters between the two treatments. Adjustment for multiple comparisons was made by the Bonferroni-Hochberg procedure (Hochberg ( 1988)) for primary (fructosamine, total/HDL

cholesterol ratio, and sBP) and secondary (body weight; total, LDL and HDL
cholesterol;
Apo A-l; Apo B; Apo A-1B ratio; glucose; insulin; and dBP) endpoints separately. P-values for each endpoint were ordered sequentially and contrasted with the corresponding adjusted comparisonwise critical alpha (a) levels. Null hypotheses were rejected only if the p-values were less than their corresponding a-values (Hochberg ( 1988)).
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. To test for confounding effects of body weight on study parameters, Pearson correlations were performed (PROC CORR
to procedure).

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 (>27g per day) diets (Table 2). 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% ( 137g/day) KJM+ test and 91 % ( 142g/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, a=0.05) during the KJM+ treatment compared to an insignificant increase of 4.7~4.4% (P=0.316, a=0.017) on control. The resultant between-treatment decrease of 10~4.0% on the KJM+ treatment was significant (P=0.028, a=0.05). The secondary endpoints of total and LDL cholesterol also fell significantly by 16~2.7%
(P=0.001, a=0.005), 25~3.9% (P=0.001, a=0.005), during KJM+ treatment compared to 4.9~3.7%
(P=0.20, a=0.006), and 4.8~5.9% (P=0.45, a=0.008) on control. Resultant between-to treatment differences of 11~4.2% (P=0.025, a=0.005) and 19~6.8% (P=0.033, a=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 (<5.2mmo1/L) (2). Values for LDL, however, were derived from only 9 subjects, because two ~ 5 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, a=0.006) and 8.6~2.3%
(P=0.004, a=0.007), compared to 3.0~5.0% (P=0.57, a=0.013) and 3.0~4.8 % (P=0.55, a=0.01) on 2o control respectively. These changes, however, resulted in an insignificant between-treatment difference of 11~4.3% (P=0.025, a=0.005) and 5.6~4.5% (P=0.24, a=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 _17_ 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, a=0.025), and 0.5~1.4% (P=0.751, a=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, a=0.017). No significant between treatment differences were seen for the 1o secondary endpoints of insulin or glucose, although during the KJM+
treatment, fasting glycemia fell significantly by 11~3.0% (P=0.004, a=0.008) compared to 1.5~6.1 % (P=0.804, a=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, a=0.017), compared to 1.4~2.7% (P=0.62, a=0.03) on control, producing a significant between-treatment difference of 6.9~2.5% (P=0.021, a=0.025) or 9.4~3 mm Hg. During both treatments, diastolic blood pressure (dBP), however, remained virtually unchanged with no significant difference 2o between treatments. The result was a reclassification in sBP status from moderately high to normotensive (< 135mmHg) in 5 of 11 subjects after the KJM+ treatment.

Examples 1-4 illustrate that the addition of 0.7g/412kJ (100kca1) of high viscosity glucomannan 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 1o 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 1 or 2 diet. The recommendations for these diets are as follows: for Step l, of total calories <30% from total, <10% from saturated, and <10% from polyunsaturated, with <300mg/day of cholesterol and for Step 2 the same except <7% of calories from saturated fat with <200mg/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 a Step 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 a Step 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.
These results are in agreement with our findings, but for KJM+ treatment an improvement in lipid ratios was also detected. The suggestion is that a Step 2 diet supplemented with KJM+
may confer additional benefits over this diet alone.
Lipids 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 1o show a significant change in these ratios. In contrast, Venter and coworkers (Venter et al.
(1987)) found 4.Sg/day glucomanan significantly improved both LDL and the LDL/HDL
ratio in 18 hypercholesterolemic subjects. These last findings are supported by those in the present examples, in which a 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, 2o predominantly propionate, which may decrease hepatic cholesterol synthesis (Venter et al.
( 1990)).
Glycemic control Improvements in diabetes control after soluble fibre supplementation have also 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. Our findings support these observations. On 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 1o been given at half the dosage relative to these other fibers (Ebihara et al. ( 1981 )).
Blood pressure 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 (Arvin 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 2o 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 1o 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.
2o GENERAL METHODS FOR EXAMPLES 5-8 Subjects 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/mz; 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)). 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)), eleven subjects (5 men, 6 women) who qualified were recruited. In addition to meeting the above criteria, their fasting (98~l3pmol/L) and 2-hour postprandial (439~68pmol/L) plasma insulin levels was greater (p<0.05) than two standard deviation of the initial screening pool (71~8 and 316~47pmo1/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 28~3kg/m2; a waist-hip ratio of 0.98~0.2 (waist: 96~l2cm) in men and 0.91~0.4 (waist: 87~l9cm) 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.
Study Design The study employed a double-blind, placebo-controlled, cross-over design that was 2o identical to that used on our previous study (Vuksan et al. (1999)). 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 22a42-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.
Diet t0 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 <300mg/day cholesterol) (American Diabetes Association (ADA): Nutrition Recommendations and principles for people with diabetes mellitus. Diabetes Care 22a42-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 l.Sg/100kca1, with a mean daily intake according to energy intake ranging from 24g to a plateau of 40g for those consuming 2800kca1 per day or more. The actual diet 2o 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 8oz 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)). Because KJM flour comprised half (0.75g/100 kcal) of the total fibre on the KJM+
treatment, approximately O.Sg/100 kcal (8-13g/day) was glucomannan. Wheat bran biscuits, in contrast, had a lower proportion of total dietary fiber than KJM+ biscuits.
Approximately 1 lg/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, yogurt, and/or other compatible foods to improve palatability.
o 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 Laboratory methods were identical to those used in our previous study (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 2o 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, Pennsylvania). C-peptide was determined by radioimmunoassay.

Statistical Analyses 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, NC). 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 to 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 comparisonwise critical alpha (a) levels. The null hypotheses were rejected only if p-values were less than their corresponding a-values.
EXAMPLE S
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 2o diet calories prescribed on the KJM+ and WB-control treatments respectively. Returned biscuits indicated they consumed 81 % (97g/day) of KJM+ and 86% ( 103g/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 5.0~0.2mmol/L and LDL from 3.9~0.2 to 2.8~0.2mmo1/L on KJM+ treatment indicated 1o 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 2o 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 to 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 betty 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 O.Sg/100kca1 (8-13g/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, although the clinical significance of the observed changes remains to be demonstrated. Also observed were significant reductions in hyperlipidemia as measured by total, LDL, LDL/HDL and total/HDL cholesterol, apo B and apo B/A-l, 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.
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 l0 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 22a42-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+
2o (Arvin 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 suggestion is 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 and our previous study (Vuksan et al. (1999)) produced an average net change in total and LDL
cholesterol of -0.084 and -0.1 l9mmol/L per gram of fiber respectively. These reductions 2o represent approximately triple the lipid lowering capacity of psyllium (-0.028 and -0.029mmol/L respectively), oat products (-0.037 and -0.032mmo1/L
respectively), and guar gum (-0.037 and -0.033mmo1/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 (-O.OSSmmol/L) (Brown et al. ( 1999)). The very high viscosity of KJM+ 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 rheological 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 to 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-2o 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.
Example 9 - Effect of Various Saccharides on Blood Glucose Figures 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 aor 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.
Example 10 - Chronic Feeding of Konjac-Mixture s 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 + to reduce postprandial glycemia in the insulin resistance syndrome that underlies these diseases, 12 participants were studied (age:55~4y, BMI:28~3kg/m2) who satisfied the criteria for the syndrome (IGT, reduced-HDL, elevated triglycerides and mild-hypertension) following 3 weeks of KJM+
supplementation. In a crossover design, participants were assigned to take a metabolically controlled NCEP Step-2 diet either with 0.7g/100kcal of KJM + enriched biscuits (as outlined in Examples 1-8, or matched wheat bran control biscuits over two 3-week treatment periods. Venous blood samples were drawn at 0, 30, 45, 60, 90, 120, and 180 min after a standard breakfast, before (week-0) and after (week-3) each treatment period.
Plasma glucose and insulin concentration profiles were determined and postprandial insulin sensitivity was calculated 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) 2o and insulinemia (-40.5~4.5% versus -2.0~2.9%, p=0.000012) were significantly reduced on the KJM+ treatment compared to control. 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). From this it may be concluded that prolonged consumption of KJM
improves glycemia.

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.

3~
Table l.- Baseline Characteristics of the Study Subjects According to Sex*
CHARACTERISTICS MEN W OMEN

(N = 5) (N = 6) Age - yr 628 597 Body weight - lo desirablet 13333 14322 Android obesity - prevalence 5 4 $

Baseline values:

Serum total cholesterol- mmol/L6.20.4 5.90.5 Glycosylated hemoglobin - % 7.42.1 8.33 Systolic/Diastolic pressure 139/78 136/82 - mm Hg:

Known duration of:

Diabetes - yr (self-reported) 11.59 18.16 Hypertension - yr 7.13 6.02 Hyperlipidemia - yr 6.33 5.62 Drug / insulin treatment -prevalence:

Insulin 1 3 Sulfonylurea and/or Metformine5 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.
fi 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 ~y r_~.

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Total energy (kcal/d) 2 070700 2 579628 2 355420 Total fat (% of energy) 30.54.3 29.33.2 28.72.4 Saturated fat (% of energy)7.24.7 6.70.8 6.40.7 Monounsaturated fat (% 10.35.1 12.72.1 12.22.6 of energy) Polyunsaturated fat (% 13.05.7 9.91.8 10.10.9 of energy) Cholesterol (mg/d) 328102 21948 236 77 Total protein (% of energy)14.68.2 16.22.7 15.63.2 Available carbohydrate 54.921 54.59.4 55.77.3 (% of energy) Sugars (% of energy) 13.33.6 11.20.9 9.21.4 Total fiber (g/d) 24.211 34.78.4 33.49.6 Water soluble (g/d) 6.93.2 23.41.7 9.93.2*

Water insoluble (g/d) 17.37.3 11.23.8 23.12.6*

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DETAILED LEGENDS OF THE TABLES
Table 1 * Except for drug treatment, blood pressure, and android obesity values are expressed as mean~SD.
~ Values were assessed using Metropolitan Life Insurance tables, 1983.
$ Android obesity is indicated by a wait-to-hip ratio grater than or equal to 0.9 for men, and 0.8 for women ~ Bile acid sequestrants and/or HMG-coenzyme A reductase inhibitors.
1 o Table 2 *Values are calculated by difference: 100 - (moisture + protein + fat + total dietary fiber +
ash). Added sucrose was between 37-40% of total available carbohydrate.
~ Average values for dietary fiber in wheat bran and flour analyzed by method of Prosky et al., 1985.
$ Value represents 69% glucomannan polymer derived from KJM flour.
Table 3 * Values are mean~SD. Konjac-mannan and wheat bran diets are based on actual intake.
Based on the mean of four 3-day food records.
$ Differences between Konjac-mannan and wheat bran study periods were calculated by 2o students t-test for paired data.
Table 4 *Except for body weight (mean~SD), all values are expressed as mean~SEM.
~ Between treatment differences assessed by ANCOVA (PROC GLM) $ Comparisonwise alpha (a) level was adjusted for multiple endpoint comparisons with the Bonferroni-Hochberg procedure for primary and secondary endpoints separately .

~ 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 a-value. P-values for during-treatment changes were assessed by paired t-test II 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 1o 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 ~5 adjustment of alpha level by the Bonferroni-Hochberg procedure. Null-hypotheses were rejected only if the p-values were less than their corresponding a-value.

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Claims

I CLAIM:

1. A composition of matter for reducing blood glucose comprising a konjac-mannan mixture, a sufficient amount of which when given to an animal at an appropriate time reduces postprandial blood glucose in the animal.
2. A composition according to claim 1 wherein the konjac-mannan mixture comprises konjac-mannan and a substance capable of increasing the viscosity of konjac-mannan from 50% to about 100% of konjac-mannan alone.
3. A composition according to claim 2 wherein the substance comprises about 10% to about 40% or one or more polysaccharides.
4. A composition according to claim 3 wherein the one or more polysaccharides are xanthan, carragenan, acetan, guar, or xyloglucana.
5. A composition according to any one of claims 1-4 wherein the particle size of constituents within the mixture is larger than about 1,000 angstroms.
6. The composition according to any one of claims 1-5 wherein the composition is formulated into a liquid, powder or formulated as part of a food.
7. 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 postprandial hood glucose in the animal.

8. A method according to claim 7 wherein the konjac-mannan mixture comprises konjac-mannan and a substance capable of increasing the viscosity of konjac-mannan to from about 50% to about 100% of konjac-mannan alone.
9. A method according to claim 8 wherein the substance comprises from about 10% to about 40% of one or more polysaccharides.
10. A method according to claim 9 wherein the one or more polysaccharides are selected from xanthan, carragenan, acetan, guar, or xyloglucana.
11. A method according to any one of claims 7-10 wherein the particle size of the constituents of the mixture are larger than about 1000 angstroms.
12. A method according to any one of claims 7-11 wherein the mixture is administered orally in an amount of about 3 to about 4 grams per day.
13. A method according to claim 12 wherein the mixture is administered either prior to a meal or during the meal.
14. A method according to any one of claims 7-13 wherein the administration is by a liquid, a powder, or as a part of a food product.
15. A composition of matter for reducing blood glucose comprising American ginseng a sufficient amount of which when given to an animal at an appropriate time reduces blood glucose in the animal.

16. A composition of matter for reducing blood glucose comprising an extract of American ginseng a sufficient amount of which when given to an animal at an appropriate time reduces blood glucose in the animal.
17. A composition according to claim 15 or 16 wherein the American ginseng is comprised of a ratio of Rg1/Rb1 of greater than about 1Ø
18. The composition according to any one of claims 15-17 wherein the composition is formulated into a liquid, powder or formulated as part of a food.
19. A method for reducing blood glucose in an animal comprising administering to the animal a sufficient amount of American ginseng at an appropriate time in order to reduce blood glucose in the animal.
20. A method for reducing blood glucose in an animal comprising administering to the animal a sufficient amount of an extract of American ginseng at an appropriate time in order to reduce blood glucose in the animal.
21. A method according to claim 19 or 20 wherein the American ginseng or extract is administered before a meal or with a meal.
22. A method according to claim 21 wherein administration before meal occurs from about 1 to about 180 minutes before the meal.
23. A method according to any one of claims 15-22 wherein the amount of American ginseng or extract of American ginseng is at least about 1000 mg per administration.

24. A method according to any one of the claims 15-23 wherein the American ginseng comprises a ratio of Rg1/Rb1 of greater than about 1Ø
25. A method according to any one of claims 15 to 24 wherein the composition is administered as a food, a powder, or a liquid.
26. A composition of matter for reducing blood glucose comprising a konjac-mannan mixture and American ginseng a sufficient amount of which when given to an animal at an appropriate time reduces blood glucose in the animal.
27 A composition according to claim 26 wherein the konjac-mannan mixture comprises konjac-mannan and a substance capable of increasing the viscosity of konjac-mannan from 50% to about 100% of konjac-mannan alone.
28. A composition according to claim 27 wherein the substance comprises about 10% to about 40% or one or more polysaccharides.
29. A composition according to claim 28 wherein the one or more polysaccharides are xanthan, carragenan, acetan, guar, or xyloglucana.
30. A composition according to any one of claims 26-29 wherein the particle size of constituents within the mixture is larger than about 1,000 angstroms.
31. A composition according to anyone of claims 26-30 wherein the American ginseng is comprised of a ratio of Rg1/Rb1 of greater than about 1Ø

32. The composition according to any one of claims 26-31 wherein the composition is formulated into a liquid, powder or formulated as part of a food.
33. A method for reducing blood glucose in an animal comprising administering to the animal a sufficient amount of a composition comprising a konjac mannan mixture and american ginseng at an appropriate time in order to reduce blood glucose in the animal.
34. A method according to claim 33 wherein the konjac-mannan mixture comprises konjac-mannan and a substance capable of increasing the viscosity of konjac-mannan from 50% to about 100% of konjac-mannan alone.
35. A method according to claim 34 wherein the substance comprises about 10%
to about 40% or one or more polysaccharides.
36. A method according to claim 35 wherein the one or more polysaccharides are xanthan, carragenan, acetan, guar, or xyloglucana.
37. A method according to any one of claims 33-36 wherein the particle size of constituents within the mixture is larger than about 1,000 angstroms.
33. A method according to anyone of claims 33-37 wherein the American ginseng is comprised of a ratio of Rg1/Rb1 of greater than about 1Ø
34. A method according to any one of claims 33-39 wherein the composition is formulated into a liquid, powder or formulated as part of a food.

41. A method for the treatment of long term diabetes, heart disease, and syndrome X
comprising anyone of the methods of claims 7-14, or 19-25, or 33-40.
42. A method of increasing insulin sensitivity in an animal comprising any one of the methods according to claims 7-14, or 19-25, or 33-40 in order to increase the animal's insulin sensitivity.
43. A method of treating type 2 diabetes comprising any one of the methods according to claims 7-14, or 19-25, or 33-40.
44. A method for reducing systolic blood pressure or blood cholesterol and lipids, comprising a method according to any one or claims 7-14, or 19-25, or 33-40.