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Definitions

• the present invention relates to a new medicament for the treatment of non-insulin dependent diabetes mellitus, hypertension and/or the metabolic syndrome.
• Non-insulin dependent diabetes mellitus comprises about 85 % of diabetes most commonly occurring at the age above 40 years. The incidence of non-insulin dependent diabetes mellitus is increasing and is at a global level expected to surpass 200 mill, subjects at year 2010.
• Diabetes is associated with increased morbidity and a 2-4-fold increase in mortality primarily due to cardiovascular diseases and strokes.
• Non-insulin dependent diabetes mellitus develops especially in subjects with insulin resistance and a cluster of cardiovascular risk factors such as obesity, hypertension and dyslipide- mia, a syndrome which first recently has been recognised and is named "The metabolic syndrome" (Albert! K.G., Zi met P.Z.; Definition, diagnosis and classification of diabetes mellitus and its complications”. Part 1: Diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet. Med. 1998 Jul;15(7), p. 539-53).
• a patient has in accordance with the WHO-definition (www.idi.org.au/whoreport.htm) the metabolic syndrome if insulin resistance and/or glucose intolerance is present together with two or more of the following components - reduced glucose tolerance or diabetes - insulin sensivity (under hyperinsulinaemic, euglycaemic conditions corresponding to a glucose uptake below the lower quartile for the background population)
• micro albuminuria urine albumin excretion: > 20 ⁇ g min "1 or albumin/creatinine ratio > 2,0 mg/ mol.
• plants provide a vast resource of compounds with the potential to become new antidiabetic agents .
• extracts of the leaves of Stevia rebaudiana Bertoni a herbaceous member of the Compositae family, have been used for many years in the treatment of diabetes among Indians in Paraguay and Brazil (Sakaguschi M. , Kan P Aspesquisas japonesas com Stevia rebaudiana (Bert) Bertoni e o estevioside. Cienc. Cultur. 34; p. 235-248,1982; Oviedo C.A., Franciani G. , Moreno R. , et al .
• Curi et al. found a slight suppression of plasma glucose when extracts of Stevia rebaudiana leaves were taken orally during a 3-day period. Furthermore, Oviedo et al . reported that tea prepared from the leaves caused a 35% reduction in blood glucose in man.
• control group demonstrated a significant increase in insulin output of about 16 times above the basal release value in the presence of 20 mmol/1 D-glucose increase. It is therefore uncertain whether the insulin releasing effect is due to the increased glucose level or the presence of stevioside.
• No diabetic islet cells were studied and the skilled person within the art will know that the mechanism for stimulating normal pancreatic islet cells either not functions at its optimum or not functions at all in the diabetic pancreatic cells, and that the study provided no certain indication of the possible use of stevioside in the treatment of non-insulin dependent diabetes mellitus, hypertension and/or the metabolic syndrome.
• the produced stevioside tablets were for no apparent reason and medical indication applied to patients in the Wuhan Second Hospital . No data on the influence of stevioside on blood glucose, insulin and/or blood pressure is revealed. It is stated that the tablets were effective to diabetes and hypertension during preliminary clinical observations. However, total lack of data on blood glucose, insulin and/or blood pressure i.e. lack of support by test results and the missing information of which types of diabetes that were treated makes this an unsupported and unconfirmed assertion.
• Glucagon a pancreatic islet hormone, acts as a diabetogenic hormone by increasing the hepatic glucose output thereby elevating blood glucose.
• Steviol has been found to be contained in the leaves of Stevia rebaudiana as well as other sweet-tasting glycosides e.g. Steviolbioside, Rebaudioside A,B,C,D and E, and Dulcoside (Bridel M. , Lavielle R. , Physiologie Vegetale: "Sur leismee'du Kaa' he'e (Stevia rebaudiana Bertoni) : II Les extra d'hydrolyse diastasique du stevioside, glucose et steviol". Acad. Sci. Paris 192, p.
• both stevioside and steviol have an antihyperglycemic, glucagonostatic and insulinotropic effect when administered intravenously to rats and a stimulatory effect on the insulin secretion from mouse islets in vitro .
• a substance or a composition of substances wherein the substance (s) includes a bicyclo [3.2.1] octan of the structural formula I shown in claim 1 or a kaurene structure of the structural formula II shown in claim 2 for the preparation of a medicament for the use in the treatment of non-insulin dependent diabetes mellitus.
• a substance or a composition of substances wherein the substance (s) includes a bicyclo [3.2.1] octan of the structural formula I shown in claim 1 or a kaurene structure of the structural formula II shown in claim 2 for the preparation of a medicament for the use in the simultaneous treatment of non-insulin dependent diabetes mellitus and hypertension .
• a substance or a composition of substances wherein the substance (s) include a bicyclo [3.2.1] octan of the structural formula I shown in claim 1 or a kaurene structure of the structural formula II shown in claim 2 in combination with at least one soy protein and at least one isoflavone for the preparation of a medicament for the use in the treatment of the metabolic syndrome.
• 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 ⁇ and Dulcoside A.
• 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/1.
• 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.
• 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.
• NIDDM non-insulin dependent diabetes mellitus
• 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.
• the substances provide a self-regulatory system responding only at elevated plasma glucose concentration.
• the substances are preferably used in medicaments for oral medication.
• 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.
• 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 sensivity (biguanides and thiazolidinediones) or drugs for retarding gastrointestinal carbohydrate absorption ( - glucosidase inhibitors) .
• drugs for stimulating the insulin secretion sulphonylureas or repaglinide
• drugs for improving the insulin sensivity biguanides and thiazolidinediones
• drugs for retarding gastrointestinal carbohydrate absorption - glucosidase inhibitors
• the above-mentioned human tests has 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.
• the substances further bring along the blood pressure reducing effect.
• 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.
• a medicament also comprising at least one soy protein alone or in combination with at least one isoflavone
• 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.
• a slow-release drug on the basis composition mentioned above provides a convenient treatment for the patient with the metabolic syndrome.
• 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.
• the inventors of the present invention has 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.
• 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 Feb- May;20(l-2), p. 31-44). In rats and mice, LD 50 values of steviol were higher than 15g/kg body weight while the LD 50 for hamsters were 5-6 g/kg body weight.
• 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 Feb;87(2), p. 167-75).
• Stevioside and steviol showed no mutagenic effect on a number of Salmonella typhimurium 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 Sep;80 Suppl. 1, p. 121-128; Suttajit M., Vinitketkaumn en U., Meevatee U., Buddhasukh D.
• 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 Jun.;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 Jan.,-6(1), p. 158-165).
• Fig. 1 shows the chemical structure of steviol, isosteviol and stevioside
• Fig. 2a shows the effect of stevioside on blood glucose during i.v. glucose tolerance test in normal Wistar rats
• Fig. 2b shows the effect of stevioside on blood glucose during i.v. glucose tolerance test in GK rats
• Fig. 3a shows the effect of stevioside on glucose-induced release during i.v. glucose tolerance test in normal Wistar rats
• Fig. 3b shows the effect of stevioside on glucose-induced release during i.v. glucose tolerance test in GK rats
• Fig. 4a shows the effect of stevioside on glucose-stimulated insulin secretion from isolated mouse islets
• Fig. 4b shows the effect of steviol on glucose-stimulated insulin secretion from isolated mouse islets
• 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
• 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
• Fig. 6a shows the systolic blood pressure during 6 weeks treatment of GK rats with stevioside
• Fig. 6b shows the diastolic blood pressure in GK rats treated with stevioside.
• Fig. 7a shows the effect of 10 "3 mmol/1 stevioside on the insulin secretion from isolated mouse islets in the presence of glucose ranging between 0 and 16,7 mmol/1,
• Fig. 7b shows the effect of 10 "6 mmol/1 steviol on the insulin secretion from isolated mouse islets in the presence of glucose ranging between 0 and 16,7 mmol/1,
• Fig. 8 a-d shows the acute effects of stevioside in type II diabetic patients
• Fig. 9a-g shows the effects of the action of the combination of stevioside and soy based dietary supplementation i diabetic GK-rats .
• GK rats originated from Takeda Chemical Ind. , Tokyo, Japan and were bred locally.
• the normal Wistar rats and the NMRI mice were available from Bomholtgard Breeding and Research Centre Ltd. , Ry, Denmark.
• 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 libi tum.
• the stevioside is obtained from the Japanese company WAKO- TriCHEM.
• the abbrevation IA ⁇ C means Incremental Area Under the Curve (above basal) .
• 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.
• Example 2 Islet from 6-10 NMRI mice were isolated and incubated in the presence of 16.7 mmol/1 and 10 "9 -10 "3 mol/1 stevioside or 10 "3 -10 ⁇ mol/1 steviol.
• Black bars in fig. 4b indicate that steviol is present and hatched bars indicate that steviol is absent .
• 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) .
• GK rats were treated with stevioside 0.025 g/kg body weight/24h for 6 weeks. Stevioside was administered in the drinking water. GK rats receiving drinking water with 0.111 g D-glucose/kg body weight/24h served as controls. Systolic (fig. 6a, control: 0-0 series, stevioside-treated: •-• series) and diastolic (fig. 6b, control: 0-0 series, stevioside- treated: •-• series) blood pressures were measured on the tail.
• 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.
• Examples 6 Twenty type II diabetic patients (6 female/14 males) with a mean age of 63.617.5 years participated in a controlled randomised double blind crossover trial. They were supplemented for 6 weeks with soy protein for (50g/day) with high levels of isoflavones (minimum 165 mg/day) and cotyledon fibers (20g/day) or placebo (casein 50g/day) and cellulose (20 g/day) separated by a 3 week wash-out period.
• 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
• 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.
• 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 ⁇ %, fat 30 E%, carbohydrate 54 E% ) .
• Stevioside reduced the postprandial blood glucose response by 18 ⁇ 5% (p ⁇ 0.004) compared to placebo (absolute IAUC 638+55 vs. 522 ⁇ 64 mmol/1 x 240 in; p ⁇ 0.02) as seen in fig. 8a.
• Stevioside significantly reduced the postprandial glucagon levels compared to placebo (348 ⁇ 46 vs. 281 ⁇ 33; p 0.02) (fig. 8c) .
• GLP-1 postprandial glucagon like peptide-1
• mice were administered for four weeks to four groups of adult rats. Each experimental group consisted of twelve female Goto-Kakizaki with an age of 9 weeks. The rats received the stevioside (0.025 g/kg body weight/day) with the drinking water.
• 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.).
• the group receiving soy + stevioside has reduced incremental area under the insulin response curve compared to the Altromin + stevioside group (Alt+Ste) as seen at 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 responses - which 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).
• Altromin p ⁇ 0.003
• soy p ⁇ 0.01
• 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).
• 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, supresses fasting plasma triglyceride 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.
• 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.

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• 2001
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