Medicament for treatment of non-insulin dependent diabetes mellitus, hypertension and/or metabolic syndrome

Abstract

A dietary supplement or medicament comprising a substance including the chemical structure of bicyclo [3.2.1]octan or the chemical structure of kaurene. The medicament is useful for the treatment of non-insulin dependent diabetes mellitus, hypertension and/or the metabolic syndrome. The possible substances include steviol, isosteviol or stevioside.

Claims

1. A method of treating non-insulin dependent diabetes mellitus and/or the metabolic syndrome, said method comprises administering a substance selected from the group consisting of steviol and isosteviol to a patient in need thereof in a therapeutically effective amount.

2. The method according to claim 1, wherein the substance is steviol.

3. The method according to claim 1, wherein the substance is isosteviol.

4. The method according to claim 1, wherein the substance is isolated from a plant source.

5. The method according to claim 1, wherein the substances provides an insulin stimulating effect that is dependent on the plasma glucose concentration.

6. The method according to claim 5, wherein the plasma glucose concentration is above 6 mmol/l.

7. The method according to claim 1, wherein the substance controls, regulates and adjusts the plasma glucose concentration to a normal level in a non-insulin dependent diabetes mellitus patient.

8. The method according to claim 1, wherein at plasma glucose concentrations above 6 mmol/l, the treatment provides an elevated plasma insulin concentration resulting in an immediate suppression of the plasma glucose concentration thereby keeping this at a normal level.

9. The method according to claim 1, wherein the treatment is a stimulation of the insulin secretion in a mammal afflicted with non-insulin dependent diabetes mellitus, wherein the stimulation of the insulin secretion is initiated by the presence of a plasma glucose concentration of 6 mmol/l or larger.

10. The method according to claim 1, wherein the substance is administered orally.

11. The method according to claim 1, wherein the substance is administered intravenously, subcutaneously or intramuscularly.

12. The method according to claim 1, wherein the substance is administered in combination with at least one soy protein or in combination with at least one isoflavone.

13. The method according to claim 1, wherein the substance is administered in combination with at least one soy protein.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) The invention is further illustrated by the following examples and the accompanying drawings that are intended to illustrate preferred features and properties of the invention, wherein:

(2) FIG. 1 shows the chemical structure of steviol, isosteviol and stevioside,

(3) FIG. 2a shows the effect of stevioside on blood glucose during i.v. glucose tolerance test in normal Wistar rats,

(4) FIG. 2b shows the effect of stevioside on blood glucose during i.v. glucose tolerance test in GK rats,

(5) FIG. 3a shows the effect of stevioside on glucose-induced release during i.v. glucose tolerance test in normal Wistar rats,

(6) FIG. 3b shows the effect of stevioside on glucose-induced release during i.v. glucose tolerance test in GK rats,

(7) FIG. 4a shows the effect of stevioside on glucose-stimulated insulin secretion from isolated mouse islets,

(8) FIG. 4b shows the effect of steviol on glucose-stimulated insulin secretion from isolated mouse islets,

(9) FIG. 5a shows the effect of an i.v. bolus injection of glucose on plasma glucagon levels during an intravenous glucose tolerance test in GK rats,

(10) FIG. 5b shows the effect of an i.v. bolus injection of glucose and stevioside on plasma glucagon levels during a glucose tolerance test in GK rats,

(11) FIG. 6a shows the systolic blood pressure during 6 weeks treatment of GK rats with stevioside,

(12) FIG. 6b shows the diastolic blood pressure in GK rats treated with stevioside.

(13) FIG. 7a shows the effect of 10.sup.3 mmol/l stevioside on the insulin secretion from isolated mouse islets in the presence of glucose ranging between 0 and 16.7 mmol/l,

(14) FIG. 7b shows the effect of 10.sup.6 mmol/l steviol on the insulin secretion from isolated mouse islets in the presence of glucose ranging between 0 and 16.7 mmol/l,

(15) FIG. 8 a-d shows the acute effects of stevioside in type II diabetic patients, and

(16) FIG. 9a-g shows the effects of the action of the combination of stevioside and soy based dietary supplementation in diabetic GK-rats.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

(17) Careful structural chemistry studies by the inventors have revealed that all potential substances for stimulating the insulin secretion extracted from the leaves of Stevia rebaudiana share the common unique skeletal structure of bicycle [3.2.1] octan of the formula I:

(18) ##STR00002##
This bicyclo [3.2.1] octan can be found in e.g. steviol, isosteviol and in stevioside. The formula I structure has also been recognised in glucosilsteviol, gymnemic acid, steviolbioside, Rebaudioside A, Rebaudioside B, Rebaudioside C, Rebaudioside D, Rebaudioside E and Dulcoside A.

(19) All these substances also share the common structure of formula II:

(20) ##STR00003##
which is the basic structure in kaur-16-en-18-oic acid.

(21) These specific structures of the formula I or II are recognized in several chemical compounds, which have been shown to have a highly potent insulin stimulating effect on isolated mouse pancreatic -cell, and these structures of formula I and II are evidently the active parts of the molecules in causing the stimulating task.

(22) This assumption is further confirmed by the fact that tests have shown that steviol having the smallest skeletal structure stimulate one insulin secretion to a greater extent than e.g. the glycoside stevioside having a much larger skeletal structure. Also, the inventors of the present invention have succeeded in purifying the different Rebaudiosides from Stevia rebaudiana and preclinical animal studies indicate the same stimulatory effect on insulin secretion.

(23) Consequently this indicates that other compounds including the structures of the formula I or II, such as e.g. analogues, derivates and metabolites of the compounds mentioned above, can be used alternatively.

(24) Studies and tests on rats have disclosed that the insulin stimulating effect of these substances is dependent on the concentration of the plasma glucose.

(25) The substances comprising the chemical structures, which includes the formula I or II, did not cause an insulin release as long as the plasma glucose concentration was below approximately 6 mmol/l. At plasma glucose concentration above 6 mmol/l, the stimulating effect of the compounds provided an elevated plasma insulin concentration resulting in an immediate suppression of plasma glucose concentration thereby keeping this at a normal level.

(26) In addition to the above findings, the present inventors have surprisingly found that the substances comprising the chemical structures including the formula I or II also have the capabilities of reducing the glucagon concentration in the blood.

(27) This characteristic nature and qualities of the substances make them an obvious choice as a component in a medicament for the treatment of especially non-insulin dependent diabetes mellitus (NIDDM).

(28) The finding that e.g. intravenously administered stevioside inhibited blood glucose responses to intravenous glucose in NIDDM rats (GK rats) but not in normal rats supports this fact. This finding is new and surprisingly has neither been expected nor demonstrated in earlier studies that have only been concerned with normal pancreatic islet cells.

(29) As a further example of the unique action of the substances according to the invention, stevioside infusion at normal blood glucose did not cause any hypoglycemia irrespective of it being given as a bolus or at a constant intravenous infusion.

(30) Due to the insulin secretory stimulating effect induced by a slightly elevated plasma glucose concentration, the simultaneous plasma glucagon reducing effect and the inhibited blood glucose response, these substances are able to control, regulate and adjust the plasma glucose concentration of a NIDDM patient to a normal level.

(31) As a consequence of the glucose-dependency the substances only act when needed, e.g. after the patient has increased blood glucose after having eaten. In NIDDM patients treated with medicaments including these substances hypoglycemia will not occur and hypoglycemia will be counteracted.

(32) Therefore, the substances provide a self-regulatory system responding only at elevated plasma glucose concentration.

(33) The substances are preferably used in medicaments for oral medication. When taken orally, the glycosylated substances can be partially metabolised but the basic skeletal structure of the formula I or II will not be changed and the different characteristic effects mentioned above will be preserved.

(34) The treatment with a medicament including these substances provides an attractive alternative to different types of drugs available and presently used today for the treatment of NIDDM, such drugs being drugs for stimulating the insulin secretion (sulphonylureas or repaglinide), drugs for improving the insulin sensitivity (biguanides and thiazolidinediones) or drugs for retarding gastrointestinal carbohydrate absorption (-glucosidase inhibitors).

(35) The potential of these new substances has for the first time also been tested in human NIDDM studies and the beneficial and advantageously combined multiple effects in humans of a single substance according to the invention has been demonstrated and will be further described in the examples.

(36) The above-mentioned human tests have been conducted by orally administrating the substances, but within the scope of the invention the substances can optionally be used in the preparation of medicaments for intravenous, subcutaneous or intramuscular medication.

(37) The substances further bring along the blood pressure reducing effect. In long-term experiments stevioside acutely suppresses blood pressure in diabetic rat. This important discovery is of the benefit to the diabetic patients that have developed hypertension in relation to or besides their disease.

(38) When at least one of the substances according to the invention is combined in a medicament also comprising at least one soy protein alone or in combination with at least one isoflavone, it is possible to manufacture a combined preparation of a drug for the treatment of patients with the metabolic syndrome in accordance with the previously definition. Such a medicament may advantageously be used in prophylactic treatment of patient in a risk group. For example, a slow-release drug on the basis composition mentioned above provides a convenient treatment for the patient with the metabolic syndrome.

(39) The inventors of the present invention have demonstrated that the combination of the substances according to the invention and at least one soy protein have a new unexpected and surprisingly synergistic effect surpassing the additive effect of the single components of the medicament thereby providing a completely new and very important medicament for therapeutic or prophylactic treatment of the metabolic syndrome.

(40) The present inventors have used the combination of the substances according to the invention and at least one soy protein as a dietary supplementation in human studies. The test results significantly proved, as will be seen in the following examples, that such combination has a beneficial impact on cardiovascular risk markers in type II diabetic subjects.

(41) Stevioside at a dose as high as 15 g/kg body weight was not lethal to either mice, rats or hamsters (Toskulkao C., Chaturat L., Temcharoen P., Glinsukon T. Acute toxicity of stevioside, a natural sweetener, and its metabolite, steviol, in several animal species. Drug Chem. Toxicol. 1997 February-May; 20 (1-2), p. 31-44). In rats and mice, LD.sub.50 values of steviol were higher than 15 g/kg body weight while the LD.sub.50 for hamsters were 5-6 g/kg body weight. The latter was accompanied with degeneration of the proximal tubular cells, which correlated to increases in blood urea nitrogen and creatinine. Stevioside is excreted by the urine (Melis M. S. Renal excretion of stevioside in rats. J. Nat. Prod. 1992 May; 55 (5), p. 688-90) and is not metabolised in the isolated perfused rat liver (Ishii-Iwamoto E. L., Bracht A. Stevioside is not metabolised in the isolated perfused rat liver. Res. Commun. Mol. Pathol. Pharmacol. 1995 February; 87 (2), p. 167-75).

(42) Stevioside and steviol showed no mutagenic effect on a number of Salmonella typhirmurium strains (Klongpanichpak S., Temcharoen P., Toskulkao C., Apibal S., Glinsukon T. Lack of mutagenicity of stevioside and steviol in Salmonella typhimurium TA 98 and TA 100. J. Med. Assoc. Thai 1997 September; 80 Suppl. 1, p. 121-128; Suttajit M., Vinitketkaumnuen U., Meevatee U., Buddhasukh D. Mutagenicity and human chromosomal effect of stevioside, a sweetener from Stevia rebaudiana Bertoni. Environ. Health Perspect 1993 October; 101 Suppl. 3, p. 53-56). In another study, it was confirmed that stevioside was not mutagenic whereas steviol, however, produced dose-related positive responses in some mutagenicity test (Matsui M., Matsui K., Kawasaki Y., Oda Y., Noguchi T., Kitagawa Y., Sawada M., Hayashi M., Nohmi T., Yoshihira K., Ishidate M. Jr., Sofuni T. Evaluation of the genotoxicity of stevioside and steviol using six in vitro and one in vivo mutagenicity assays. Mutagenesis 1996 November; 11 (6), p. 573-579).

(43) Stevioside is not carcinogenic in F344 rats (Toyoda K., Matsui H., Shoda T., Uneyama C., Takada K., Takahashi M. Assessment of the carcinogenicity of stevioside.in F344 rats. Food Chem. Toxicol. 1997 June; 35 (6), p. 597-603). Doses as high as 2.5 g/kg body weight/day had no effect on growth or reproduction in hamsters (Yodyingyuad V., Bunyawong S. Effect of stevioside on growth and reproduction. Hum. Reprod. 1991 January; 6 (1), p. 158-165).

(44) To the knowledge of the inventors, no observations or reports showing potential toxic effects in humans have been published.

(45) It will be recognised by the skilled artisan that rearranged structures of the formula II are within the scope of the invention, and such rearrangements might occur naturally in the gastro intestinal tract. As example can be mentioned that rearrangement may occur at the C16 forming a double bond to the C15 and thereby leaving a single bond open for substitution at position 17. A COOH group at position 18 is open for a number of reactions such as reaction with alcohol, as well as a number of substituents can be provided at any point of the formula II structure. Also, other substituents such as e.g. saccharides, at the various C-atoms and the structures may be anticipated.

EXAMPLES

(46) In the following examples, the type II diabetic Goto-Kakizaki (GK) rats originated from Takeda Chemical Ind., Tokyo, Japan and were bred locally.

(47) The normal Wistar rats and the NMRI mice were available from Bomholtg{dot over (a)}rd Breeding and Research Centre Ltd., Ry, Denmark.

(48) The rats had a weight of 300-350 g and the mice a weight of 22-25 g. The animals were kept on a standard pellet diet and tap water ad libitum.

(49) The stevioside is obtained from the Japanese company WAKO-TriCHEM.

(50) The abbreviation IAUC means Incremental Area Under the Curve (above basal).

Example 1

(51) As examples of the effects of a compound including the chemical formulas II, stevioside was tested on normal Wistar rats and on GK rats. 2.0 g glucose/kg body weight and 0.2 g stevioside/kg body weight were dissolved in 0.9% saline and infused intravenously. The plasma glucose and insulin levels were measured over a period of 2 hours.

(52) The results are shown in FIGS. 2a, 2b, 3a and 3b, were the O-O series (n=6 for Wistar and n=14 for GK) illustrate glucose infused alone and the {circle around (2)}-{circle around (2)} series (n=6 for Wistar and n=12 for GK) illustrate the combined glucose and stevioside infusion. Data are given as meanSEM.

(53) After administration of the glucose load, plasma glucose raised immediately and plasma insulin raised abruptly. When stevioside was added together with the glucose, a diminished glucose response was found in the GK-rat and a significant decrease was observed already after 30 min. In the GK rat, stevioside caused a pronounced increase in the insulin response compared to the Wistar rat. The stevioside-induced insulin response was delayed and increased throughout the whole test. The insulin response was monophasic.

(54) This discovery of stevioside having a blood glucose reducing effect in the type II diabetic rat indicates that stevioside and compounds having a similar chemical structure can be used in a medicament for the treatment of NIDDM in man.

Example 2

(55) Islet from 6-10 NMRI mice were isolated and incubated in the presence of 16.7 mmol/l and 10.sup.9-10.sup.3 mol/l stevioside or 10.sup.9-10.sup.3 mol/l steviol.

(56) The results of these tests are illustrated in FIGS. 4a and 4b where each column represents meanSEM from 24 incubations of single islets. Black bars in FIG. 4a indicate that stevioside is present and hatched bars indicate that stevioside is absent.

(57) Black bars in FIG. 4b indicate that steviol is present and hatched bars indicate that steviol is absent.

(58) The figures show that stevioside and steviol are capable of potentiating glucose-stimulated insulin secretion. Further tests confirmed that a stimulatory effect was found already at a very low concentration (above 0.1 nM).

Example 3

(59) During a glucose tolerance test, an intravenous bolus of stevioside of 0.2 g/kg body weight was injected in GK rats (the {circle around (2)}-{circle around (2)} serie (n=6)). GK rats receiving 0.9% saline intravenously served as controls (the O-O serie (n=6)). Glucose 2.0 g/kg body weight was administered as a bolus at timepoint 0 min. The plasma glucagon responses are shown as meanSEM in FIGS. 5a (control) and 5b (GK). The plasma glucagon was suppressed in the stevioside treated GK rat.

Example 4

(60) GK rats were treated with stevioside 0.025 g/kg body weight/24 h for 6 weeks. Stevioside was administered in the drinking water. GK rats receiving drinking water with 0.111 g D-glucose/kg body weight/24 h served as controls. Systolic (FIG. 6a, control: O-O series, stevioside-treated: {circle around (2)}-{circle around (2)} series) and diastolic (FIG. 6b, control: O-O series, stevioside-treated: {circle around (2)}-{circle around (2)} series) blood pressures were measured on the tail.

(61) The figures show a 10-15% decrease in the blood pressure detectable after 2 weeks of treatment and the effect hereafter was stable and consistent during the study period.

Example 5

(62) The influence of the maximal stimulatory doses of 10.sup.3 mol/l stevioside and 10.sup.6 mol/l steviol was studied in NMRI mouse islets over a range between 0 and 16.7 mmol/l glucose. Both stevioside (FIG. 7a) and steviol (FIG. 7b) potentiated insulin secretion at and above 8.3 mmol/l and indicated that the initiating level for stimulating insulin secretion was between 3.3 mmol/l and 8.3 mmol/l of glucose. Black bars in FIG. 7a indicate that stevioside is present and hatched bars indicate that stevioside is absent. Black bars in FIG. 7b indicate that steviol is present and hatched bars indicate that steviol is absent.

Example 6

(63) Twenty type II diabetic patients (6 female/14 males) with a mean age of 63.67.5 years participated in a controlled randomised double blind crossover trial. They were supplemented for 6 weeks with soy protein for (50 g/day) with high levels of isoflavones (minimum 165 mg/day) and cotyledon fibers (20 g/day) or placebo (casein 50 g/day) and cellulose (20 g/day) separated by a 3 week wash-out period.

(64) This dietary supplement significantly reduced LDL-Cholesterol by 10% (p<0.05), LDL/HDL ratio by 12% (p<0.05), Apo B-100 by 30% (p<0.01), triglycerides by 22% (p<0.05) and homocystein by 14% (p<0.01). No change was observed in HDL-Cholesterol, Factor VIIc, von Willebrandt factor, fibrinogen, PAI-1, HbA1c or 24 hour blood pressure.

(65) The results indicate beneficial effects of dietary supplementation with soy protein on cardiovascular risk markers in type II diabetic subjects. The improvement is also seen in individuals with near-normal lipid values. Ingestion of soy product has been shown to further improve the effectiveness of low-fat diets in non-diabetic subjects and the dietary supplementation in type II diabetic patients may provide an acceptable and effective option for blood lipid control, thereby postponing or even preventing drug therapy.

Example 7

(66) Twelve type II diabetic patients (4 female/8 males) with a mean age of 65.81.6 years, a diabetes duration of 6.01.3 years, a mean body mass index of 28.51.0, and a mean glycated hemoglobin HbA1c of 7.40.4 percent were included in the study.

(67) The experiment was an acute, paired, cross-over study in which two test meals were served during the experiments (A: Standard meal supplemented with 1 g of stevioside given orally; B: Standard meal given together with 1 g of gelatine (placebo) given orally. The total energy content of the test meals was 1725 kJ (protein 16 E %, fat 30 E %, carbohydrate 54 E %).

(68) Blood samples were drawn from an antecubital vein 30 minutes before and 240 minutes after ingestion of the test meal. The arterial blood pressure was continuously monitored during the experiment. Students paired t-test was used for comparing the effects of stevioside with placebo on the parameters measured. Data are given as meanSEM.

(69) Stevioside reduced the postprandial blood glucose response by 185% (p<0.004) compared to placebo (absolute IAUC 63855 vs. 52264 mmol/l240 min; p<0.02) as seen in FIG. 8a. Stevioside tended to stimulate the insulin response in type II diabetic patients (enhance the area under the insulin response curve (IAUC)), however the difference did not reach statistical significance (p=0.09) (FIG. 8b).

(70) Stevioside significantly reduced the postprandial glucagon levels compared to placebo (34846 vs. 28133; p=0.02) (FIG. 8c).

(71) Stevioside significantly reduced the postprandial glucagon like peptide-1 (GLP-1) levels compared to placebo (2208253 vs. 1529296; p<0.045) (FIG. 8d).

Example 8

(72) Four test diets (A: Standard carbohydrate rich laboratory animal diet (Altromin); n=12 (Alt). B: Altromin supplemented with stevioside (Altromin+Stevioside); n=12; (Alt+Ste). C: Soy plus 20% Altromin; n=12; (Soy). D: Soy plus 20% Altromin plus stevioside; n=12; (Soy+Ste)) were administered for four weeks to four groups of adult rats. Each experimental group consisted of twelve female Goto-Kakizaki wish an age of 9 weeks. The rats received the stevioside (0.025 g/kg body weight/day) with the drinking water. By the end of the third experimental week intra-arterial catheters were implanted into the carotid artery thereby enabling blood sampling during a 240 minutes glucose-tolerance test which was carried out by the end of the experiment at week 4. Blood samples were drawn after a bolus infusion of 2.0 g D-glucose/kg body weight. Plasma concentrations of glucose, insulin, and glucagon were measured during the glucose tolerance test. Immediately before the glucose tolerance test fasting levels of triglycerides and cholesterol were determined. Concomitantly, the systolic blood pressure was measured using a tail cuff.

(73) Effects on Plasma-Glucose:

(74) As seen at FIG. 8 and in Table I below stevioside reduced the incremental area (IAUC) under the glucose response curve during the glucose tolerance testing both in the Altromin (p<0.05) and in the soy+20% Altromin group (Soy) (p<0.001). The relative effect of stevioside was more pronounced in the group receiving soy+20% Altromin group compared to the group receiving Altromin. The combination of soy and stevioside synergistically reduced the area under the glucose response curve compared to the Altromin group (p<0.0001) (FIG. 9a.).

(75) (Plasma glucose was measured using MPR 3, 166 391, Glucose/GOD-PAP Method from Boehringer Mannheim)

(76) Effects on Plasma Insulin:

(77) The group receiving soy+stevioside (Soy+Ste) has reduced incremental area under the insulin response curve compared to the Altromin+stevioside group (Alt+Ste) as seen in FIG. 9 and in Table I below. Considering the concomitant blood glucose responses this indicates that soy increases the insulin sensitivity. Stevioside did not alter the insulin responses in the Altromin and soy diets when studying the total response curve from 0 to 240 minutes. However, in both groups supplementation of the diets with stevioside significantly improved the first phase insulin responseswhich is subdued as a characteristic feature of type II diabetes. The combination of soy+stevioside synergistically improved the first phase insulin response (p<0.05) (FIG. 9b).

(78) (Plasma insulin was measured using Sensitive Rat Insulin RIA, Cat #SRI-13K from Linco)

(79) Effects on Plasma Glucagon:

(80) Stevioside significantly reduced the area under the plasma-glucagon response curve during the glucose tolerance test in both the groups receiving Altromin (p<0.003) and soy (p<0.01) (see FIG. 9c and Table I below).

(81) (Plasma glucagon was measured using Glucagon RIA. Cat #GL-32K from Linco)

(82) Effects on Blood Pressure:

(83) A marked significant suppression of the systolic blood pressure (p<0.05) (Table I) is elicited by stevioside in combination with either Altromin (=28 mmHg) or soy (=21 mmHg) as depicted in FIG. 9d.

(84) (Blood pressure was measured using TSE Non-Invasive Blood Pressure Monitoring System from Technical Scientific Equipment GmbK)

(85) Effects on Body Weight:

(86) The initial weights in the four groups did not differ (FIG. 5). Apparently the combination of soy and stevioside prevented weight gain as seen in FIG. 9e.

(87) Effects on Triglyceride and Cholesterol:

(88) Stevioside causes a significant suppression of the fasting triglyceride levels in combination with either Altromin (p<0.05) or soy (p<0.02) (Table I). Soy significantly reduced the fasting triglyceride levels with or without supplementation of stevioside (p<0.05 and p<0.002, respectively) (Table I). Stevioside given in combination with soy synergistically reduced the fasting total cholesterol levels compared to diets containing Altromin alone (p<0.0001). Soy alone also reduced the total cholesterol levels compared to Altromin alone (p<0.002) (FIG. 9f. and FIG. 9g) (Table I).

(89) (Plasma cholesterol was measured GOD-PAP from Roche and triglycerides was measured using GHOD-PAP from Roche)

(90) Stevioside exerts beneficial effects in type II diabetes i.e. reduces blood glucose, suppresses glucagon and improve first phase insulin secretion. The results also indicates that soy improves insulin sensitivity, a characteristic feature of the metabolic syndrome. Stevioside exerts a pronounced blood pressure reduction both with as well as without the presence of soy. The combination of stevioside and soy has a synergistic suppressive effect on blood glucose levels, enhances first phase insulin secretion, suppresses fasting plasma triglycerides and total cholesterol and the combination of soy and stevioside seems to prevent weight gain. The combination of stevioside and soy appears to possess the potential of an effective treatment of a number of the characteristic features of the metabolic syndrome i.e. type II diabetes, hypertension, dyslipidemia and obesity.

(91) TABLE-US-00001 TABLE I IAUC IUAC p-glucose p-insulin IAUC IAUC Change in blood (mM (ng/ml p-insulin p-glucagon pressure (mmHg) Triglycerides Cholesterol Group 240 min) 240 min) (ng/ml 30 min) (pg/ml 240 min) From week 0 to 4 (mM) (mM) Altromin 991 96 317 55 11 4 21918 1467 5 4 0.72 0.10 2.51 007 Altromin + 757 53 375 42 19 4 17023 1449 23 6 0.50 0.04 2.28 0.18 Stevioside Soy + 20% Altromin 820 75 218 22 9 2 26200 2410 8 3 0.49 0.04 2.13 0.08 Soy + 20% Altromin + 439 56 248 27 24 5 17229 1819 13 5 0.37 0.02 1.84 0.06 Stevioside Table I: Areas under the p-glucose, -insulin and -glucagon response curves during the glucose tolerance test in the four experimental groups. Change in systolic blood pressure at start and at end of the study period. Fasting plasma-triglyceride and -total cholesterol concentrations by the end of the study.