CA2206012C - Novel compounds for the treatment and prevention of diabetes - Google Patents

Abstract

This invention is directed to a composition effective for the prevention, treatment, and cure of type II diabetes also known as non-insulin-dependent diabetes mellitus. The composition comprises extracts obtained from several medicinal plants proved effective in reducing blood glucose levels in diabetic animals. The possible mechanism of action of the composition involves a combination of increased expression of insulin receptors in hepatocytes and skeletal muscle, increased insulin secretion in pancreatic .beta. cells, an inhibition of .alpha.--glucohydrolase activity, and an increase in the levels of the GLUT (glucose transporter)2 protein in pancreatic B cells. The composition also proved effective in reducing blood glucose levels and restoring the general health of diabetic humans. A preferred composition for the treatment of type II diabetes is comprised of extracts obtained from Orthosiphon aristatus, Cornus officinalis, Trichosanthes kirilowii maxim, Ophiopogon japonicus, and Morus folium.

Description

NOVEL COMPOUNDS FOR THE TREATMENT AND PREVENTION OF DIABETES

The present invention relates to compositions for the treatment of type II
diabetes, also known as non-insulin-dependent diabetes mellitus. More specifically, it relates to compositions obtained from extracts of several known medicinal plants, including Orthosiphon aristatus, Cornus officinalis, Trichosanthes kirilowii maxim, Ophiopogonjaponicus, and Morus Folium.
BACKGROUND OF THE INVENTION

Full citations for references appear at the end of the Examples section.

Type II diabetes, also known as non-insulin-dependent diabetes mellitus (NIDDM), is much more common than insulin-dependent diabetes mellitus, affecting 80-90% of all persons with diabetes. Initially, NIDDM is often of gradual onset in middle age (over 40 years old).
However, later stages of this disease are very severe, resulting in various long term complications, such as kidney disease, heart disease, eye disease, nerve disease and others. The symptoms of NIDDM can be vague. The symptoms may include fatigue, nausea, frequent urination (particularly at night), and unusual thirst. Frequent urination is one way the body gets rid of excess glucose, and this loss of fluid leads to thirst. Obesity is an important factor in NIDDM. NIDDM develops in genetically predisposed individuals.

The pathological changes in the pancreatic islets of patients with NIDDM are not always apparent. Many patients with NIDDM have normal to high plasma insulin levels.
In these individuals, diabetes arises not from a shortage of insulin, but may arise from defects in the molecular machinery that mediates the action of insulin on its target cells.
NIDDM is not caused by (3 cell destruction but by other mechanisms, such as insulin resistance, down-regulation of insulin receptors, defects in insulin secretion from the pancreatic P cells and other changes to the glucose transporter system. The pancreas usually continues to produce some insulin in people with NIDDM. However, the insulin fails to limit the level of glucose in the blood. When insulin is present in the blood yet fails to maintain a normal level of glucose, the condition is called insulin resistance. Insulin resistance is an important factor in NIDDM.

A defect in the insulin receptors on the surface of cells may cause insulin resistance. In some cases there may not be a sufficient number of receptors on the cells for insulin. Or defects in the receptors may prevent insulin from binding to the cells. Insulin resistance may also involve the step after insulin binds with the insulin receptor. For example, insulin may bind to the receptor but the next step which should take place inside the cell does not occur and the cells do not perform their glucose-controlling task.

There are dozens of hypoglycaemic agents that control blood glucose. These hypoglycaemic agents are sulfonylureas or biguanides. Treatment of diabetic patients with sulfonylureas or biguanides (metformin) lowers the blood glucose level. When treatment with these substances is stopped, the blood glucose level increases. Therefore, these oral hypoglycaemic agents are for symptomatic relief, rather than a permanent treatment of NIDDM.

Sulfonylureas directly stimulate insulin release by closing adenosyl triphosphate (ATP)-sensitive potassium channels and depolarizing the cell membrane (Aguilar-Bryan et al 1995; Tan and Nelson 1996; Lubbos et al 1995). Sulfonylureas generally lower fasting blood glucose levels.
Metformin, on the other hand, enhances peripheral glucose uptake and reduces hepatic glucose output. This substance lowers blood glucose concentration in hyperglycaemic people (Goo et al 1996; Tan and Nelson 1996; Lubbos et al 1995). Various side effects have been reported by patients administered these oral hypoglycaemic agents. The main side effect of inetformin is lactic acidosis and increased cardiovascular mortality. Lactic acidosis is more common in patients with renal impairment and may be precipitated by tissue anoxia or ethanol ingestion.
Side effects of sulfonylureas include renal and hepatic disease, hypoglycaemia, loss of control of blood glucose, gastrointestinal disturbances, dermatological reactions, dizziness, drowsiness, headache and increased cardiovascular mortality (Howes et al 1996; Chan et al 1996; Saw et al 1996; Pogatsa 1995). When normal fasting blood glucose levels cannot be obtained with a combination of sulfonylureas and metformin, glycaemic control is often achieved by a long-acting insulin preparation, such as ultralente. When patients develop severe NIDDM, full insulin treatment is required. In these patients, sulfonylurea therapy is of little benefit and is typically stopped.

Insulin treatment also provides symptomatic relief rather than a cure. When treatment with insulin is stopped in patients with severe NIDDM, blood glucose levels increase. To date, no satisfactory method exists to treat or cure NIDDM without apparent toxicity to the patients.
Therefore, there is a need within the art to provide alterrlative treatments effective in the prevention and/or treatment of NIDDM. In U.S. 5,470,873, there is disclosed a composition for the treatment of NIDDM comprising maltol, which is obtained from Ginseng roots, and an extract obtained from Orthosiphon aristatus. These extracts were effective in regulating blood glucose levels in diabetic animals. However, the control of blood glucose levels by these extracts is not sufficient to normalize it, even though blood glucose levels after treatment with this composition are statistically lower than that of untreated groups. Nor was it determined whether this composition had any lasting affects on blood glucose levels following termination of the treatment. Therefore, in order to prevent severe long-term complications and to improve the control of blood glucose levels, a significant improvement of the maltol-Orthosiphon aristatus composition is required. These needs have been met by the composition of this invention which is obtained from several non-toxic medicinal plants.

SUMMARY OF THE INVENTION

This invention relates to compositions effective in the prevention, treatment, and cure of type II diabetes, also known as non-insulin-dependent diabetes mellitus (NIDDM). More specifically this invention relates to compositions effective in the prevention, treatment, and cure of NIDDM that are derived from non-toxic medicinal plants.

According to the present invention there is provided a composition comprising bioactive ingredients obtained from Orthosiphon aristatus and Morusfolium.
This invention also presents a composition of bio active ingredients obtained from Cornus officinalis, Trichosanthes kirilowii maxim, Ophiopogonjapanicus and Morusfolium. A further embodiment of this invention includes a composition of bioactive ingredients obtained from Orthosiphon aristatus, Cornus officinalis, Trichosanthes kirilowii maxim, Ophiopogon japonicus, and Morusfolium. This invention also embraces compositions comprising from about ( on a weight /weight basis):
1-100% Orthosiphon aristatus, 1-100% Cornus officinalis, 1-100% Trichosanthes kirilowii maxim, 1-100% Ophiopogonjapanicus, and 1-100% Morusfolium.

More specifically compositions of this invention include compositions comprising from about;
20-80% Orthosiphon aristatus, 2-40% Cornus officinalis, 2-40% Trichosanthes kirilowii maxim, 2-40% Ophiopogonjapanicus, and 2-60% Morusfolium.

This invention also is directed to a composition comprising of about 40%
Orthosiphon aristatus, of about 10% Cornus officinalis, of about 17% Trichosanthes kirilowii maxim, of about 13%
Ophiopogonjapanicus, and of about 20% Morusfolium.

This invention further relates to compositions effective in the prevention, treatment, or cure of non-insulin-dependent diabetes mellitus comprised of extracts obtained from Orthosiphon aristatus, Cornus officinalis, Trichosanthes kirilowii maxim, Ophiopogon japanicus, and Morusfolium, in the presence of a suitable carrier.

5 Another aspect of this invention includes a method for the treatment of non-insulin-dependent diabetes mellitus in a mammal comprising administering to the mammal a composition comprising extracts obtained from Morusfolium and at least one other extract obtained from Orthosiphon aristatus, Cornus officinalis, Trichosanthes kirilowii maxim, and Ophiopogonjapanicum..

This invention is also directed to a method for the prevention of NIDDM in a mammal susceptible to developing NIDDM comprising administering to the mammal a composition comprising extracts obtained from Orthosiphon aristatus, Cornus officinalis, Trichosanthes kirilowii maxim, Ophiopogon japanicus, and Morusfolium.

This invention is also directed to a method for curing NIDDM in a mammal comprising administering to the mammal a composition comprising extracts obtained from Orthosiphon aristatus, Cornus officinalis, Trichosanthes kirilowii maxim, Ophiopogonjapanicus, and Morus folium for a period of time effective in treating NIDDM, followed by discontinuing the treatment.

This invention is exemplified by the treatment and prevention of NIDDM using a combination of extracts obtained from Orthosiphon aristatus, Cornus officinalis, Trichosanthes kirilowii maxim, Ophiopogon japanicus, and Morusfolium which is termed GHP
700. However, this invention also discloses the treatment of NIDDM using plant extracts obtained from Orthosiphon aristatus and Morusfolium, or Cornus officinalis, Trichosanthes kirilowii maxim, Ophiopogonjapanicus, and Morusfolium, and therefore, this invention also relates to compositions comprising a combination of at least two extracts obtained from the group consisting of Orthosiphon aristatus, Cornus officinalis, Trichosanthes kirilowii maxim, Ophiopogonjapanicus, and Morusfolium, in the presence or absence of other compounds to be used for the treatment of NIDDM. Furthermore, by providing compositions effective in preventing, treating and curing NIDDM, this invention improves over US
5,470,873 which only discloses the treatment of NIDDM. It is not known whether or not the composition of US

5,470,873 is effective in the prevention or cure of NIDDM. The composition of this invention is also more effective in treating NIDDM than that of US 5,470,873 as lower blood glucose levels are obtained during the treatment periods (see Example 3).

BRIEF DESCRIPTION OF THE DRAWINGS
These and other features of the invention will become more apparent from the following description in which reference is made to the appended drawings wherein:

FIGURE 1 shows the rate of attachment of insulin to receptors obtained from GK
rats.

FIGURE 1A, partially purified receptors obtained from the liver of PBS-treated GK rats (*) and GHP 700 extract-treated GK rats (~). FIGURE IB, partially purified receptors obtained from the skeletal muscle of the hind limb of PBS-treated GK rats (+) and GHP 700 extract-treated GK rats (~). Data represents the mean of 10 animals/group.

FIGURE 2 shows the secretion of insulin in response to glucose from the perfused pancreas of PBS-treated GK rats (+) and GHP 700 extract-treated GK rats (~).

FIGURE 3 shows the effect of GHP 700 extract on blood glucose from oral loads of carbohydrates in normal WF rats.

FIGURE 4 shows the histological profile of the following tissues from WF rats:
Figure 4A
Esophagus; Figure 4B Stomach; Figure 4C Intestine; Figure 4D Liver, Figure 4E
Kidney, Figure 4F Lung; Figure 4G Heart; Figure 4H Cerebral Cortex (x250), after 7 months treatment with lOx's the regular dose of GHP 700.

DESCRIPTION OF THE PREFERRED EMBODIMENT

The compositions of this invention are effective in the prevention, treatment, and cure of NIDDM. These compositions are comprised of extracts obtained from Orthosiphon aristatus, Cornus officinalis, Trichosanthes kirilowii maxim, Ophiopogonjaponicus, and Morus Folium.

One such composition is referred to as GHP 700, however, other compositions are presented that are effective in treating NIDDM. It is to be understood that compositions comprising at least 2 or more extracts selected from the group consisting of Orthosiphon aristatus, Cornus officinalis, Trichosanthes kirilowii maxim, Ophiopogonjaponicus, and Morus Folium are encompassed by this invention.

Orthosiphon aristatus contains potassium sulfate, calcium salt, potassium salt, volatile oil, pentose, saponins, hexose, among other compounds (Oriental Materia Medica: A concise guide pp. 297). Due to the presence of potassium salt, which promotes diuresis, administration of this plant extract may result in the elimination of blood sugar and cleansing of peripheral tissues by excessive urination. These actions may improve control of blood glucose levels and improve insulin receptor regeneration. The leaves of this plant contain myoinositol. Orthosiphon aristatus has been used to eliminate kidney stones because its potassium salt promotes diuresis (Oriental Materia Medica: A concise guide pp. 297). Ophiopogonjaponicus contains monosaccharides, (3-sistostereol, saponin, and homoisoflavonoid (Watanabe et al 1997; Tomoda et al 1980; Koda et al 1971; Watanabe et al 1983; Boyang et al 1987). Saponin and flavonoid may enhance the immune system and may improve general health. Cornus officinalis contains triterpenoids, saponin, inidoidal glycoside, tartaric acid, malic acid and gallic acid (Yamahara et al 1973; Koda et al 1973). The enhancement of the immune system due to saponin and other compounds, may result in the prevention of infection and the promotion of good health. In addition, oleanic acid and ursolic acid (triterpenoids) may be antidiabetogenic agents. These agents lower blood glucose levels. Oleanolic acid and ursolic acid (triterpenoids) are considered as anti-diabetogenic agents (Yamahara et al 1973; Koda et al 1973).
Trichosanthes kirilowii maxim contains steroids and triterpenoids; glycosides; enzymes, such as P-galactosidase and a-mannosidase; and several amino acids, including alanine, valine, tyrosine, lysine, and y-aminobutyric acid (Kanaoka et al, 1982; Tamura et al 1986; Clinical Trials for GLO 223 as a treatment for AIDS. Amer. Fam. Phys 40:324, 1989). IDDM patients need to supplement their diets with rich nutrients because essential nutrients (e.g. amino acids) are lost by excessive urination. Thus, these substances may promote general health, and control thirst.

Morusfolium contains flavonoids, polysaccharides, betulinic acid, and a-amyrin (Hirakura et al 1985; Daigo et al 1986; Nomura et al 1983; Hikino 1983;
Nikaido 1984). It is thought that the blood glucose-lowering effect produced by M. folium may be related to the inhibition of the a-glucohydrolase catalysed enzymatic reactions (Hirakura et al 1985; Daigo et al 1986; Nomura et al 1983; Hikino 1983; Nikaido 1984). The active components contained in the water extract of M. folium may be potential candidates for an oral hypoglycaemic agent for the treatment of NIDDM, furthermore, this plant has been used for the control of blood pressure.

GHP 700 refers to a specific composition comprising 40% Orthosiphon aristatus, 10%
Cornus officinalis, 17% Trichosanthes kirilowii maxim, 13% Ophiopogon japanicus, and 20%
Morusfolium, however, the ratios (on a weight /weight basis) vary in accordance with the requirement of the patient. For example, hypoglyceamic patients typically require elevated levels of Morusfolium, in the range of 30-40%. Similarly, patients that over-eat also require higher amount of Morusfolium. Higher levels of Morusfolium are also used if a patient is hypoglyceamic and over-eats. Other variations may also be included for other patient requirements, for example, in obese patients, the amount of Orthosiphon aristatus is increased to about 60%. When the amounts of these plant extracts are varied, the proportions of the other plant extracts within the composition would be adjusted accordingly.
Therefore, the percent composition on a weight/weight basis of the plant extracts will vary depending upon the need at the time of treatment. It is to be understood that the percent composition of "GHP 700" is one example of a "typical" composition of these plant extracts, however, the actual amounts of each extract varies in accordance to the specific requirements of the treatment at hand.

An advantage of the treatment of NIDDM patients with compositions comprising several of these plant extracts, or GHP 700, is an increase in the synthesis and secretion of insulin.
Furthermore, GHP 700 up-regulates the number of insulin receptors and affects the transport of glucose by increasing the amount of glucose transporter protein (see Example 4). Administering GHP 700 does not result in hypoglycaemia even when high doses are used; thus, GHP 700 is a safe method of treatment. In contrast, treatment of patients with high doses of insulin or hypoglycaemic drugs may cause hypoglycaemia, occasionally leading to coma. It is also well known that biguanides (metformin) and sulfonylureas control blood glucose, but their use produces numerous side effects. Another drawback of the use of insulin is that the appropriate dosage of insulin is not always easy to control due to the variations in physical condition, diet and exercise between individuals. GHP 700 does not affect NIDDM patients in a uniform manner (see Table 6, Example 6). Genetic factors and environmental factors, such as diet and exercise, may vary the response of individuals to GHP 700. The administration of GHP 700 promotes general health as well as improves the control of blood glucose in NIDDM patients. In addition, the administration of GHP 700 does not result in hypoglycaemia in NIDDM patients regardless of the method of administration. The prevention of hypoglycaemia in these patients may be a result of the differing mechanisms involved in the control of blood glucose between GHP 700 and other hypoglycaemic agents.

Not only does GHP 700 control blood glucose, but it also promotes general health. For example, many conditions often associated with NIDDM are relieved, such as pain and stiffness in joints, the swelling of extremities, interrupted sleep, poor memory, urination, kidney discomfort, cracked and dry skin, among others. This improvement is probably a result of the supplement of nutrients GHP 700 provides. These nutrients are necessary for the promotion of good health in NIDDM patients. (see Example 6). In contrast, hypoglycaemic agents within the prior art do not promote general health.

Treatment of patients with GHP 700 significantly improves long-term complications often associated with NIDDM, such as neuropathy, renopathy and retinopathy. In addition, GHP

5 700 helps to protect against frequent infection, loss of body weight, and heart problems associated with diabetes. In contrast, other hypoglycaemic agents do not control complications that often accompany NIDDM.

Treatment of animals with GHP 700 results in lower levels of blood glucose, and 10 following termination of treatment these blood glucose levels remain low. A
period of time effective in treating NIDDM may be defined as the length of time of treatment that is required to reduce, and possibly stabilize, blood glucose levels. Such a period of time may vary from about 1 to 20 months, more preferably this time is from about 3 to 10 months.

The bio-active ingredients within the composition obtained from extracts from Morus Folium, along with at least one other extract obtained from Orthosiphon aristatus, Cornus officinalis, Trichosanthes kirilowii maxim, and Ophiopogonjaponicus, including the composition GHP 700, can be administered to effect prevention, treatment and cure of NIDDM. Such bio-active ingredients could be formulated as a pharmaceutical composition in the presence of a suitable carrier such as those used for the preparation of, but not limited to, solid, particulate or suspension formulations for tablets, capsules, elixir, parenteral, suppository, transdermal or topical administration. Suitable carriers include, but are not limited to magnesium stearate, starch, lactose, sucrose and cellulose for the formulation of tablets; aqueous gums, celluloses, silicates or oils and the dispersion or suspension of bio-active ingredient into gelatin capsules; liquid carriers including syrups, glycerin, peanut or olive oil, ethanol, saline and water in the case of elixirs; parenteral compositions could be formulated with a solution or suspension of the bio-active ingredients in a sterile aqueous carrier or parenterally acceptable oil such as polyethylene glycol, polyvinyl pyrrolidine, lecithin, arachis oil, sesame oil or the like; binding, and /or lubricating agents, for example polymeric glycols, gelatins or coca butter or other low melting vegetable or synthetic waxes or fats in the case of suppository compositions; aqueous or non-aqueous vehicles such as creams, ointments, liposome preparations, lotions, paste or medicated plaster, patch or membrane or the like for typical transdermal applications; and, for topical administration, pharmaceutical typically formulations include solutions, suspensions, ointments and solid inserts for example water, water miscible solvent mixtures including lower alkanols, or vegetable oils, emulsifying, preserving wetting and bodying agents such as polyethylene glycols, and antibacterial components. Furthermore, the bio-active ingredients may be administered in a timed release dosage unit form to permit sustained release of the bio-active ingredient. Such carriers may include glyceryl monostearate or glyceryl distearate, alone or in combination with a wax.

The pharmokinetic properties of the bio-active components must be determined to forlnulate dosing regimes that effectively treat NIDDM without significant adverse side effects. The bio-active ingredient may also be administered singly or in combination with other bio-active agents of interest.

Suitable dosages of the bio-active ingredients obtained from extracts from Morus Folium, along with at least one other extract obtained from Orthosiphon aristatus, Cornus officinalis, Trichosanthes kirilowii maxim, and Ophiopogon japonicus, including the composition GHP 700, in a suitable pharmaceutical carrier for use in the treatment of NIDDM
mammals including humans, according to the present invention, should not exceed about 50 mg/gm body weight. Preferably the dosage is in the range of 1-10 mg/gm body weight. It will be appreciated that the actual preferred dosages of the bio-active ingredients being administered will vary according to the particular composition formulated, the site and host being treated, and the mode of administration. Furthermore, the composition defined as GHP
700 not only refers to the specific composition of about 40% Orthosiphon aristatus, 10%
Cornus officinalis, 17% Trichosanthes kirilowii maxim, 13% Ophiopogon japanicus, and 20%
Morusfolium, but also other compositions where the ratios (on a weight /weight basis) vary in accordance with the requirement of the patient. Hypoglyceamic patients typically require elevated levels of Morusfolium, in the range of 30-40%, as do patients that over-eat, or patient that are hypoglyceamic and over-eat. Furthermore, obese patients require elevated amounts of Orthosiphon aristatus to about 60%. When the amounts of these plant extracts are varied, the proportions of the other plant extracts within the composition would be adjusted accordingly, and the percent composition on a weight/weight basis of the plant extracts will vary depending upon the need at the time of treatment. It is therefore to be understood that the percent composition of "GHP 700" is one example of a "typical" composition of these plant extracts, however, the actual amounts of each extract varies in accordance to the specific requirements of the treatment at hand.

Example 1: Effect of O. aristatus and M. folium Extract on the Blood Glucose levels in diabetic animals 1) Plant Extracts 0. aristatus was cultivated in Vietnam. The whole plant (including stems, leaves and roots) of O. aristatus was harvested and dried. M. folium was cultivated in Korea and the leaves of M. folium were harvested and dried. After drying, each component was powdered and O.
aristatus (50%) and M. folium (50%) (w/w) were mixed and extracted with water by boiling the mixture in a slow cooker. The water extract was filtered and used for the experiment.

2) Animal model system In order to test the effect of O. aristatus and M. folium on NIDDM, GK rats were used.
The GK rat is considered to be one of the best animal models for NIDDM and this model is characterized by impaired-glucose-insulin secretion and peripheral insulin resistance. Insulin secretion stimulated by glucose is markedly impaired in GK rats. Insulin response and sensitivity of glycogen synthesis, lipogenesis and DNA synthesis in hepatocytes from GK rats are markedly reduced as compared to non-diabetic control rats such as Wistar-Furth (WF). In GK rats, the islet structure was disrupted and areas of pronounced fibrosis were observed in the stroma. As the disease progressed, P cell degranulation was observed, but lymphocytic infiltration of the islet was not. Diabetic complications, such as neuropathy and nephropathy, were observed biochemically and morphologically.

In order to examine the effect that the composition obtained from O. aristatus and M.
folium extracts has on NIDDM, GK rats were treated with this extract in the following manner.
40 g of the extract was mixed with 200 ml of water and slowly boiled for 6 to 12 hours until 100 ml of the extract remained. 2.5 ml (1 g/rat:5g/kg body weight) of the extracted solution was intubated daily at 10:00 a.m. for 7 months. Control animals received the same volume of PBS.

The treatment of diabetic animals with this extract resulted in a decrease in the level of blood glucose when compared to PBS-treated animals (Table 1).

Table 1 The Effect of O. aristatus and M. folium Extract on the Blood Glucose Levels of GK rats Duration of Treatment O. aristatus & M. folium PBS
(months) Blood Incidence of Blood Glucose Incidence of Glucose Diabetes (mg/dl) Diabetes (mg/dl) Mellitus (%) Mellitus (%) 0 378 ~ 19 90(9/10) 381 17 90(9/10) 1 371 ~ 20 90 (9/10) 380 21 90 (9/10) 3 331 ~ 29 90(9/10) 384 19 90(9/10) 5 269 ~ 34 70(7/10) 401 18 90 (9/10) 7 236 t 36 50(5110) 395 zL 17 100(10/10) Example 2: Effect of C o icinalis, L kirilowii, O,ianonicus, M olium, and blood glucose levels in diabetic animals.
1) Plant Extract C. officinalis, T. kirilowii, O. japonicus, and M. folium were cultivated in Korea. The fruit of C. officinalis, the root of T. kirilowii, the stem root of O.
japonicus and the leaves of M.
folium were harvested and dried. After drying, each component was powdered and O. japonicus, C. officinalis, T. kirilowii, and M. folium (each at 25% w/w) were mixed and extracted with water by boiling the mixture in a slow cooker. The water extract was filtered and used for the experiment.

2) Animal model GK rats were used and treated as described in Example 1.

The treatment of diabetic animals with this extract resulted in a decrease in the level of blood glucose when compared to PBS-treated animals (Table 2). The effect on reduced levels of blood glucose levels was similar to that observed with O. aristatus and M.
folium (Table 1).

5 Table 2. The Effect of C. officinalis, T. kirilowii, O. japonicus, and M.
folium Extract on the Blood Glucose Levels of GK rats.

Duration of C. officinalis, PBS
Treatment T. kirilowii, O. japonicus, and 10 (months) M. folium Blood Glucose Incidence of Blood Glucose Incidence of (mg/dl) Diabetes (mg/dl) Diabetes Mellitus (%) Mellitus (%) 0 381 f 21 90(9/10) 380 18 90(9/10) 1 370 19 90(9/10) 383 17 90(9/10) 3 342 23 90(9/10) 390 16 90(9/10) 15 5 289 f 31 80(8/10) 402 18 90(9/10) 7 251 37 60(6/10) 396 17 100(10/10) Example 3: Effect of GHP 700 on the control of NIDDM in diabetic animals 1) Preparation of GHP 700 GHP 700 is made from the extract of five different plants combined in the following ratio weight:weight.

0. aristatus: 40%
0. japonicus: 13%
C. officinalis: 10%
T. kirilowii: 17%

M. folium: 20%

O. aristatus was cultivated in Vietnam. The whole plant (including stems, leaves and roots) of 0. aristatus was harvested and dried. C. officinalis, T. kirilowii, O.
japonicus, and M. folium were cultivated in Korea. The fruit of C. officinalis, the root of T.
kirilowii, the stem root of O.
japonicus and the leaves of M. folium were harvested and dried. After drying, each component was powdered and O. aristatus (40%), O. japonicus (13%), C. officinalis (10%), T. kirilowii (17%), and M. folium (20%) (w/w) were mixed and extracted with water by boiling the mixture in a slow cooker. The water extract was filtered and used for the experiment.

The use of O. japonicus, C. officinalis, O. aristatus, T. kirilowii, and M.
folium was based on previous information concerning the treatment of NIDDM patients with medicinal plants.

Traditional medicine indicates that these compounds are antidiabetic and diuretic agents.
Different combinations of the plant extracts were administered to patients and general observations were recorded in order to determine if there was any improvement of health or control of blood glucose levels.

2) Animal model system In order to test the effect GHP 700 has on NIDDM, GK rats were treated with in the following manner. GHP 700 (40 g) was mixed with 200 ml of water and slowly boiled for 6 to 12 hours until 100 ml of the extract remained. 2.5 ml (lg/rat:5g/kg body weight) of the extracted solution was intubated daily at 10:00 a.m. for 7 months. Control animals received the same volume of PBS.

The treatment of diabetic animals with GHP 700 resulted in a significant decrease in the level of blood glucose when compared to PBS-treated animals (Table 3).

Table 3. Effect of GHP 700 on GK rats.

DURATION

TREATMENT
(months) Blood Incidence of Blood Glucose Incidence of Glucose diabetes (%) (mg/dl) diabetes (mg/dl) Mellitis (%) 0 387 19 90 (18/20) 381 18 90 (18/20) 1 334 23 80 (16/20) 390 19 90 (18/20) 2 271 29 70 (14/20) 403 18 90 (18/20) 3 251 36 60 (12/20) 387 17 95 (19/20) 4 231 39 50(10/20) 393 17 95 (19/20) 5 201 43 35 (7/20) 395 19 95 (19/20) 6 175 36 25 ( 5/20) 389 17 95 (19/20) 7 146+41 15 ( 3/20) 394 18 95 (19/20) Mean non-fasting blood glucose levels of normal (non-diabetic) Wistar Furth rats, aged 3 months to 7 months, is 145f 17 mg/dl. Any GK rats with a blood glucose level of 230 mg/dl, 5 SD above the mean, were considered diabetic. Rats were treated at 12 weeks of age. Each group contains 20 animals.

It is apparent that GHP 700 improves the control of blood glucose, resulting in the treatment of NIDDM. When diabetic GK rats were treated with GHP 700 for approximately 4-5 months, the level of blood glucose of 35-50% of GK rats dropped to the normal range when compared to PBS-treated animals. All PBS-untreated animals remained hyperglycaemic.
Furthermore, when GK rats were treated with GHP 700 for approximately 7 months, most of the animals (85%) exhibited normal glycaemia, while all untreated animals remained hyperglycaemic. The blood glucose level of GHP 700-treated GK rats was lowered to 146 mg/dl (Table 3) compared to a blood glucose level of 185 mg/dl of DPD and OSA-treated GK rats (Table 4 of US 5,470,873). In addition, the following aspects are distinct from US 5,470,873.

1. GHP 700 contains the extract of M. folium, whereas the previous patent does not contain this extract. Mfolium contains compounds that inhibit the degradation of complex carbohydrates into monosaccharides by a-glucohydrolase (see Example 4). These inhibitory compounds lower blood glucose levels.

2. GHP 700 contains the extracts of O. japonicus, C. officinalis, and T.
kirilowii. These extracts contain substances that enhance the synthesis of GLUT2 protein in the pancreatic P cells (see Example 4). The extracts of these plants were not included in the previous patent.

3. The extracts of T. kirilowii and C. officinalis supply GHP 700 with rich nutritional supplements that may be essential for the promotion of good health and possibly the improvement of long-term complications associated with NIDDM (see Example 6).
The extracts of these plants were not included in the previous patent.

These observations indicate that GHP 700 is useful for the treatment of diabetes.

The administration of a combination of all five extracts is much more effective against NIDDM than the administration of a combination of O. aristatus and M. folium, or a combination of C. officinalis, T. kirilowii, O. japonicus and M. folium as the blood glucose levels of Tables 1, 2 and 3 indicate. A comparison of the blood glucose levels derived from experiments using the extract of O. aristatus alone, or in combination with maltol (see Table 4 of US 5,470,873) and the combinations illustrated in Tables 1 and 2 indicate that all five extracts together (Table 3) provide the most effective treatment for NIDDM.

3) Cure of NIDDM by GHP 700 Following treatment of GK rats with GHP 700 for 7 months (Table 3), treatment was terminated and blood glucose levels were monitored for a further 3 months. As Table 4 indicates, after treatment was terminated, syptoms did not return for the duration of the study (3 months).

Table 4 Effectiveness of GHP 700 on the Control of Blood Glucose Levels of GK
rats after Termination of Treatment Time elapsed after Blood Glucose (mg/dl) Incidence of Diabetes Termination of Treatment Mellitus (%) with GHP 700 (months) 0 146 41 15 (3/20) 1 158 39 20(4/20) 2 165 47 20 (4/20) 3 174 t 42 25 (5/20) 5) Prevention of NIDDM in Animals Table 5 provides data concerning the prevention of IDDM in GK rats. GK rats usually develop diabetes at 6 to 8 weeks of age. In this experiment, treatment of the GK rats with GHP 700 (as indicated above) began at 3 weeks of age: before the onset of NIDDM. As their blood glucose levels indicate, these animals did not develop diabetes and their blood glucose levels remain in the normal blood glucose range for the duration of the study. In the same study, PBS-treated GK
rats exhibited very high blood glucose levels and developed diabetes. Thus GHP
700 prevented the onset of NIDDM.

5 Table 5 Effect of GHP 700 on the Prevention of NIDDM in GK rats Age of animal Treatment with GHP 700 Treatment with PBS
(weeks) Blood Glucose Incidence of Blood Glucose Incidence of (mg/dl) Diabetes (mg/dl) Diabetes Mellitus (%) Mellitus (%) 10 3 147 31 0(0/20) 145 21 0(0/20) 5 156 27 0(0/20) 168 21 0(0/20) 7 165 34 5(1/20) 211 48 25 (5/20) 10 168 40 10 (2/20) 354 39 70 (14/20) On the basis of blood glucose levels, GHP 700 prevents NIDDM in GK rats when compared to PBS-treated GK rats. As Table 5 indicates, the blood glucose levels of GHP-treated GK rats are well within the normal range.

In summary, these results demonstrate that GHP 700 is effective in treating (Table 3), curing (Table 4) and preventing (Table 5) NIDDM in animals.

Example 4: Possible mechanisms involved in the prevention and treatment of NIDDM
using GHP 700 In order to determine the mechanisms involved in the lowering of the level of blood glucose in these diabetic animals we examined insulin receptors present on hepatocytes and skeletal muscle, the secretion of insulin in the pancreatic 0 cells, and inhibition of a-glucohydrolase catalysed enzymatic reactions, which prevents the degradation of complex carbohydrates to monosaccharides.

1) Effect of GHP 700 on the expression of insulin receptors NIDDM is a complex disorder associated with both insulin resistance and cell dysfunction. Decreased insulin-stimulated glucose uptake is characteristic of insulin resistance and diabetes. The mechanisms involved in insulin resistance in NIDDM is unclear, but may involve reduced insulin receptor numbers (secondary to hyperinsulinemia and hyperglycaemia), reduced tyrosine kinase activity of the insulin receptor, abnormalities distal to the receptor, and defects in the glucose transport system.

40 g of GHP 700 was mixed with 200 ml of water and slowly boiled for 6 to 12 hours until 100 ml of the extact remained. 2.5 ml (lg/rat:5g/kg body weight) of the extracted solution was intubated daily at 10:00 a.m. for 7 months. The animals were sacrificed by CO2 asphyxiation and the rate of insulin attachment to insulin receptors was measured (Klein et al, 1986; Vankatesan et al, 1991).

Glucose transport activity in NIDDM is decreased in both adipocytes and muscle. To determine the effect GHP 700 has on the expression of insulin receptors, we measured the rate at which insulin binds to receptors in GHP 700-treated GK rats. Briefly, insulin receptors were purified from control and GHP 700-treated GK rats using wheatgerm agglutinin (WGA) agarose (Klein et al 1986; Burant et al 1986; Vankatesan et al 1991). The rate at which insulin binds to solubilized receptors was determined using 125I-labelled insulin.

The rate at which insulin binds to partially purified insulin receptors from hepatocytes and muscles significantly increased in the GHP 700-treated group when compared to the PBS-treated control group (Figures 1 A, 1 B). Without wishing to be bound by theory, this difference may be a result of the up-regulation of insulin receptors in the presence of GHP 700. The rate at which insulin binds to the receptors from hepatocytes is greater than the rate at which insulin binds to skeletal muscle receptors. These results indicate that GHP 700 may enhance the expression of insulin receptors.

2) Effect of GHP 700 on insulin secretion in pancreatic P cells In addition to the measurement of insulin receptors of hepatocytes and skeletal muscle, the level of insulin secretion in the pancreas was measured. 40 g of GHP 700 was mixed with 200 ml of water and slowly boiled for 6 to 12 hours until 100 ml of the extract remained. 2.5 ml (lg/rat:5g/kg body weight) of the extracted solution was intubated daily at 10:a.m. for 7 months.
Briefly, PBS-treated or GHP 700-treated GK rats were anesthetized with phenobarbital. The pancreas was isolated and perfused as descibed in the references below. The perfusate (Krebs-Ringer bicarbonate buffer: 118 mM NaCI, 4 mM Kcl, 2.5 mM CaC12, 1.2 mM MgSO4, 1.2 mM
KH2PO4 25 mM NaHCO311.2 g/L bovine serum albumin, and 40 g/L dextran) containing 16 mM

glucose was used. The effluent was collected from the cannula in the portal vein at 2 minute intervals and stored at -20 C. Insulin secretion was measured and calculated as described in Portha et al (1991) and Giriox et al (1983).

The results, as shown in figure 2 demonstrate that the secretion of insulin from GHP 700-treated GK rats increased when compared to PBS-treated control GK rats.
Without wishing to be bound by theory, this data indicates that GHP 700 may enhance the secretion of insulin from pancreatic (3 cells as a result of an increase in the synthesis of insulin in the pancreatic (3 cells, and/or an acceleration of insulin secretion.

In lean, normal, non-diabetic persons, glucose levels are maintained by a balance between insulin secretion from pancreatic (3 cells and insulin action in the splanchnic (liver and gut) and peripheral (muscle and adipose) tissues. NIDDM develops when this balance is upset and impaired P cell function (decrease of insulin secretion), and/or abnormal insulin action (insulin resistance) occurs (Leahy et al 1990; Porte 1991; Reaven 1988). Therefore, the decrease of insulin secretion from the pancreatic P cells is one of the mechanisms involved in the development of NIDDM.

3) Effect of GHP 700 on the inhibition of a-glucohydrolase Complex carbohydrates present in the diet must be degraded to monosaccharides by a-glucohydrolase before they are absorbed in the gastrointestinal tract. In NIDDM patients there is less biologically active insulin which utilizes absorbable glucose. Therefore, if the degradation of complex carbohydrates into monosaccharides is inhibited, the amount of absorbable glucose is significantly less, resulting in the requirement for insulin to decrease.
Thus, the control of NIDDM in GHP 700-treated animals was determined by analysing the inhibition of the degradation of complex carbohydrates into monosaccharides by a-glucohydrolase catalysed enzymatic reactions. PBS-treated and GHP 700-treated WF rats were fasted overnight and heat-hydrolyzed starch (2g/kg) suspended in water (2g/20m1) was intubated. Fifty minutes later, blood samples were collected and blood glucose levels were determined.

Figure 3 represents the blood glucose levels of WF rats administered PBS, PBS
and starch, or GHP 700 and starch. WF rats administered PBS exhibited the lowest blood glucose levels. WF rats administered PBS and starch exhibited the highest blood glucose levels. WF rats administered GHP 700 and starch exhibited blood glucose levels that were lower than the levels found in WF rats administered PBS and starch, but higher than the levels found in WF rats administered PBS.

These results suggest that the degradation of complex carbohydrates is inhibited because the blood glucose levels of WF rats loaded with carbohydrates (starch) and treated with GHP 700 were lower than WF rats treated with PBS and loaded with carbohydrates.
Because both insulin secretion and insulin action are normal in WF rats, the lower blood glucose level of GHP 700-treated rats must result from a lower rate of degradation of complex carbohydrates to monosaccharides, resulting in a decrease of absorbable glucose. Since a-glucohydrolase is required for the degradation of complex carbohydrates to monosaccharides, this enzyme must be decreased in GHP 700-treated WF rats.

The degradation of starch was inhibited in GHP 700-treated WF rats, suggesting that intestinal a-glucohydrolase significantly decreased in GHP 700-treated WF rats when compared to PBS-treated WF rats.

Some components in GHP 700 have the ability to lower blood glucose. Without wishing to be bound by theory, this ability may be a result of the inhibition of the degradation of complex carbohydrates into monosaccharides by the inhibition of a-glucohydrolase catalysed enzymatic reactions.

4) Effect of GHP 700 on the glucose transporter Glucose enters the P cells through a membrane-bound facilitated transporter that is designated GLUT2, or the liver P cell transporter. It has been proposed that impaired glucose entry into P cells causes a loss of glucose-induced insulin secretion in NIDDM
patients (see attached). This hypothesis is based on the observation that every hyperglycaemic rodent model exhibits a marked reduction of GLUT2 protein in their P cells. To determine whether the level of GLUT2 protein in the pancreatic P cells increases in GHP 700-treated animals, a Western blot was performed with pancreatic islet homogenates from GHP 700-treated GK rats and PBS-treated control GK rats. The preliminary experimental data reveals that GHP
700-treated GK rats show an increased level of GLUT2 protein in the pancreatic (3 cells when compared to PBS-treated control GK rats (data not shown). Without wishing to be bound by theory, this result suggests that GHP 700 may improve glucose transport by increasing the level of transporter protein.

Example 5: Toxicity test of GHP 700 in rats WF rats or SJL/J mice were administered the GHP 700 extract (50 mg/gm body weight i.e., l Ox's the regular dose) every day for seven months. Each animal was sacrificed by CO2 asphyxiation. The esophagus, stomach, intestine, lung, heart, kidney, liver, brain and 5 pancreas of each animal was removed. A small piece of each organ was fixed with formalin and stained with hematoxylin and eosin as described elsewhere (Baek, H.S., and Yoon, J.W. (1990).
The stained sections were examined under a microscope (Figure 4).

Esophagus, Stomach, and Intestine: The esophagus (Figure 4A), stomach (Figure 4B) 10 and intestine (Figure 4C) showed intact mucosae and lacked inflammatory cell infiltrates or other features of cellular injury or necrosis.

Liver: The liver (Figure 4D) showed well-defined lobules and cords of hepatocytes separated by anastomosing sinuses and central vein, with no mononuclear cell infiltration, 15 necrosis, or intranuclear glycogen infiltration.

Kidney: The kidney (Figure 4E) showed intact glomeruli, tubules and vessels.
Glomerular changes, tubular strophy, interstitial lymphocytic infiltration and necrosis were not observed.

Lung: A few dispersed macrophages and normal appearing alveoli, bronchioles, bronchi and vessels were present in the lungs (Figure 4F).

Heart: The endocardium and myocardium of the heart (Figure 4G) were normal.
Brain: Nerve and glial cells of the cerebral cortex (Figure 4H) exhibited no evidence of necrosis, haemorrhage or infarction.

Pancreas: Endocrine and exocrine cells exhibited intact morphology. No necrosis or lymphocytic infiltration was evident (data not shown).

These data indicate that high doses of GHP 700 did not have any deleterious effects on these organs.

Example 6: Effect of GHP 700 on the Control of blood glucose in NIDDM Patients 1) Treatment of NIDDM

To prevent, treat, or cure NIDDM the defects found in patients with NIDDM need to be addressed so that up-regulation of insulin receptors, enhancement of insulin secretion from pancreatic P cells and improvement of the synthesis of GLUT2 protein in pancreatic (3 cells results. In addition, inhibiting the degradation of complex carbohydrates into monosaccharides also relieves symptoms associated with NIDDM.

In order to examine the effect of GHP 700 on NIDDM patients, 1 l Og (0.
aristatus 40%, 0. japonicus 13%, C. officinalis 10%, T. kirilowii 17%, and M. folium 20%) of GHP 700 was mixed with 900 ml of water and slowly boiled for 6 to 12 hours until 450 ml of the extract remained. The supernatant of the boiled material was filtered to remove the precipitate and the extract supernatant was divided into three portions, each aliquot contained 150 ml of the GHP

700 extract. 150 ml of the GHP 700 extract was administered orally between meals (10 a.m. and 3 p.m.) to NIDDM patients. The duration of treatment varied from 3 to 8 months.

The results of these experiments are presented in Table 6. GHP 700 positively affects over 70%
of NIDDM patients, based on blood glucose levels. Patients also reported a general improvement in overall health.

Table 6. Effect of GHP on the Control of Blood Glucose in NIDDM Patients Patient Duration of Duration of BGL* BGL after Treatment initials disease treatment before treatment with insulin (years) (months) treatment (mg/dl) after GHP
(mg/dl) K.D. 5 4 320 128 No B.H. 11 3 380 132 No Y.S. 7 6 398 180 No K.T. 10 6 429 173 No P.T. 15 6 469 210 Yes O.P. 9 6 425 168 No T.Y. 12 7 406 162 Yes J.S. 13 8 417 132 No H.G. 14 4 425 187 Yes L.H. 12 4 396 178 No *BGL = Blood glucose level The blood glucose level of 3 out of 10 patients decreased to 140 mg/dl, and lower, after administration of GHP 700 for approximately four months. The blood glucose level of 4 out of 10 of these patients decreased from approximately 400 mg/dl to 170 mg/dl. The blood glucose level of the remaining 3 patients ranged from 170 mg/dl to 240 mg/dl from 400 mg/dl.

In general, the blood glucose level of all NIDDM patients administered GHP 700 lowered over the course of the treatment period. However, great variation exists in blood glucose levels among these patients. For example, some patients (-30%) exhibited close to normal blood glucose levels (non-fasting blood glucose level of 120-140 mg/dl). Other patients (-40%) exhibited slightly higher than normal blood glucose levels (non-fasting blood glucose level of 146-178 mg/dl). The remaining patients (-30%) exhibited slightly higher blood glucose levels than all of the other patients (non-fasting blood glucose level of 187-240 mg/dl). Diet, exercise, and stress, as well as genetic, environmental, and psychological factors may offer possible explanations for the variation that exists among NIDDM patients. Differences in the genetic make-up among these patients results in different physiological conditions at the cellular and molecular level, such as different rates of insulin/receptor up-regulation and different levels of insulin secretion, insulin synthesis, and GLUT2 protein synthesis.
Environmental factors, diet, exercise, and stress may be different among NIDDM patients. The psychological make-up of the patient (e.g. an individual's ability to deal with stress) is another important factor when examining the varied responses of NIDDM patients to GHP 700.

Regardless of the variation among NIDDM patients in response to GHP 700, the general symptoms associated with NIDDM are substantially improved in all patients treated with GHP
700. These improvements are as follows:

1) An increased amount of urine and reduced frequency of urination.

2) Kidney discomfort, as a result of poor kidney function, is improved, resulting in greater comfort.

3) Interrupted sleep becomes relatively sound.

4) Almost complete relief of pain and stiffness in joints.

5) General weakness and fatigue is replaced with an energetic physical condition.
6) Rough skin becomes smooth and soft.

Even though GHP 700 refers to a specific composition comprising 40%
Orthosiphon aristatus, 10% Cornus officinalis, 17% Trichosanthes kirilowii maxim, 13%
Ophiopogon japanicus, and 20% Morusfolium, as was used in this Example, the ratios (on a weight /weight basis) of each plant extract will vary in accordance with the requirement of the patient. For example, hypoglyceamic patients typically require elevated levels of Morusfolium, in the range of 30-40%. Similarly, patients that over-eat also require higher amount of Morusfolium. Higher levels of Morusfolium are also used if a patient is hypoglyceamic and over-eats. Other variations may also be included for other patient requirements, for example, in obese patients, the amount of Orthosiphon aristatus is increased to about 60%. When the amounts of these plant extracts are varied, the proportions of the other plant extracts within the composition would be adjusted accordingly. Therefore, the percent composition on a weight/weight basis of the plant extracts will vary depending upon the need at the time of treatment. It is to be understood that the percent composition of "GHP 700" is one example of a "typical" composition of these plant extracts, however, the actual amounts of each extract varies in accordance to the specific requirements of the treatment at hand.

2) Cure of NIDDM

Three months after termination of treatment with GHP 700, the blood glucose levels of six out of seven patients did not change dramatically (Table 7). The blood glucose levels of one out of seven patients increased slightly (168 mg/dl to 186 mg/dl).

5 Table 7 Blood Glucose Levels of NIDDM Patients After Termination of GHP 700 Treatment Patient Initials BGL* at BGL at 3 Months Termination After Termination (mg/dl) of Treatment (mg/dl) Y.S. 180 183 10 K.T. 173 170 K.D. 128 134 O.P. 168 186 B.H. 132 134 J.S. 132 137 15 L.H. 178 175 *BGL = Blood Glucose Level Note: Patients who did not receive insulin were selected The present invention has been described with regard to preferred embodiments.
However, it will be obvious to persons skilled in the art that a number of variations and modifications can be made without departing from the scope of the invention as described in the following claims.

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Claims (23)

1. A composition comprising Cornus officinalis, Trichosanthes kirilowii maxim, phiopogon japanicus, and Morus folium.

2. The composition of claim 1, further comprising Orthosiphon aristatus.

3. The composition of claim 2, comprising from about:

1-96% Orthosiphon aristatus, 1-96% Cornus officinalis, 1-96% Trichosanthes kirilowii maxim, 1-96% Ophiopogon japanicus, and 1-96% Morus folium.

4. The composition of claim 3, comprising from about:
20-80% Orthosiphon aristatus, 2-40% Cornus officinalis, 2-40% Trichosanthes kirilowii maxim, 2-40% Ophiopogon japanicus, and 2-60% Morus folium.

5. The composition of claim 4 comprising about:
40% Orthosiphon aristatus 10% Cornus officinalis 17% Trichosanthes kirilowii maxim 13% Ophiopogon japanicus 20% Morus folium.

6. A composition effective in the treatment of non-insulin-dependent diabetes mellitus comprising a water extract obtained from at least three of the following plants:

Orthosiphon aristatus, Cornus officinalis, Trichosanthes kirilowii maxim, Ophiopogon japanicus, and Morus folium.

7. The composition of claim 6 comprising an extract obtained from Morus folium and at least two other extract obtained from the group consisting of Orthosiphon aristatus, Cornus officinalis, Trichosanthes kirilowii maxim and Ophiopogon japanicus in the presence of a suitable carrier.

8. A composition effective in the treatment of non-insulin-dependent diabetes mellitus comprising the composition of any one of claims 1, 2, and 4 in the presence of a suitable carrier.

9. A composition effective in the prevention of non-insulin-dependent diabetes mellitus comprising the composition of claim 2 or 4 in the presence of a suitable carrier.

10. A composition effective in curing non-insulin-dependent diabetes mellitus comprising the composition of claim 2 or 4 in the presence of a suitable carrier.

11. A use of a suitable amount of the composition of any one of claims 1, 2, 4, 6, and 7, for the treatment of non-insulin-dependent diabetes mellitus in a mammal.

12. A use of a suitable amount of the composition of any one of claims 1, 2, 4, 6, and 7, for the preparation of a medicament for the treatment of non-insulin-dependent diabetes mellitus in a mammal.

13. A use of a suitable amount of the composition of claim 2 or 4, for the prevention of non-insulin-dependent diabetes mellitus (NIDDM) in a mammal susceptible to developing NIDDM.

14. A use of a suitable amount of the composition of claim 2 or 4, for the preparation of a medicament for the prevention of non-insulin-dependent diabetes mellitus (NIDDM) in a mammal susceptible to developing NIDDM.

15. A use of a suitable amount of the composition of claim 2 or 4, for curing non-insulin-dependent diabetes mellitus (NIDDM) in a mammal, wherein the use is for a period of time effective in treating NIDDM followed by discontinuation of said use.

16. A use of a suitable amount of the composition of claim 2 or 4, for the preparation of a medicament for curing non-insulin-dependent diabetes mellitus (NIDDM) in a mammal.

17. The use of claim 11, wherein the composition is the composition of claim 4, and the suitable amount is in a range from about 1 mg/g body weight to about 50 mg/g body weight.

18. The use of claim 17, wherein the suitable amount is in the range of about 1 mg/g body weight to about 10 mg/g body weight.

19. The use of claim 13, wherein the composition the composition of claim 4, and the suitable amount is in a range from about 1 mg/g body weight to about 50 mg/g body weight.

20. The use of claim 19, wherein the suitable amount is in the range of about 1 mg/g body weight to about 10 mg/g body weight.

21. The use of claim 15, wherein the composition is the composition of claim 4, and the suitable amount is in a range from about 1 mg/g body weight to about 50 mg/g body weight.

22. The use of claim 21, wherein the suitable amount is in the range of about 1 mg/g body weight to about 10 mg/g body weight.

23. A method for the preparation of the extract in the composition of claim 6 comprising, extracting the plants in boiling water and filtering prior to use.