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Appendix A - Selected scientific references on the hypoglycemic effects of substances found in LEVOLAR from Cordyceps, Coprinus and Grifola mushrooms.

Hypoglycemic activity of a polysaccharide (CS-F30) from the cultural mycelium of Cordyceps sinensis and its effect on glucose metabolism in mouse liver.


Biol Pharm Bull 1996 Feb;19(2):294-6u
Kiho T, Yamane A, Hui J, Usui S, Ukai S.
Gifu Pharmaceutical University, Japan.

A polysaccharide (CS-F30) obtained from the cultural mycelium of Cordyceps sinensis showed potent hypoglycemic activity in genetic diabetic mice after intraperitoneal administration, and the plasma glucose level was quickly reduced in normal and streptozotocin-induced diabetic mice after intravenous administration. Administration of CS-F-30 to normal mice significantly increased the activities of hepatic glucokinase, hexokinase and glucose-6-phosphate dehydrogenase, although the glycogen content in the liver was reduced. Furthermore, CS-F30 lowered the plasma triglyceride level and cholesterol level in mice.

Hypoglycemic activity and chemical properties of a polysaccharide from the
cultural mycelium of Cordyceps sinensis.

Biol Pharm Bull 1993 Dec;16(12):1291-3

Kiho T, Hui J, Yamane A, Ukai S.
Gifu Pharmaceutical University, Japan.

Crude polysaccharides were obtained from a hot-water extract and alkaline extracts of the cultural mycelium of Cordyceps sinensis. They showed significant activity in normal mice and streptozotocin-induced diabetic mice as a result of intraperitoneal (i.p.) injection. A crude polysaccharide (CS-OHEP) obtained from 5% sodium hydroxide extract slightly lowered the plasma glucose level in normal mice by oral (p.o.) administration. A neutral polysaccharide (CS-F30) exhibited higher hypoglycemic activity than its crude polysaccharide (CS-OHEP), exhibited by i.p. injection, and it significantly lowered the glucose level by p.o. administration (50 mg/kg). However, it hardly affected the plasma insulin level in normal mice. CS-F30 ([alpha]D + 21 degrees in water) is composed of galactose, glucose and mannose (molar percent, 62:28:10), and its molecular weight is about 45000.

Structural features and hypoglycemic activity of a polysaccharide (CS-F10) from the cultured mycelium of Cordyceps sinensis.

Biol Pharm Bull 1999 Sep;22(9):966-70

Kiho T, Ookubo K, Usui S, Ukai S, Hirano K.
Department of Pharmaceutics, Gifu Pharmaceutical University, Japan.

A polysaccharide (CS-F10) purified from a hot water extract of the cultured mycelium of Cordyceps sinensis was composed of galactose, glucose and mannose in a molar ratio of 43:33:24; its molecular weight was estimated to be about 15000. The results of chemical and spectroscopic investigations suggest that CS-F10 has a comb-type structure, and has alpha-D-glucopyranosyl residues on the terminal of the side-chains and characteristic sugar residues of C. sinensis i.e., 1,5-linked beta-D-galactofuranosyl residues. CS-F10 significantly lowered the plasma glucose level in normal, streptozotocin (STZ)-induced diabetic and epinephrine-induced hyperglycemic mice after intraperitoneal administration (50 mg/kg). Administration of CS-F10 to STZ-induced diabetic mice significantly increased the activity of hepatic glucokinase. A significant reduction in the hepatic glucose output was observed following the infusion of CS-F10 using the perfused rat liver. CS-F10 also significantly decreased protein content of facilitative glucose transporter isoform 2 (GLUT2) from rat liver following i.p. administration. These effects presumably contribute to the hypoglycemic activity.

Antihypertensive and metabolic effects of whole Maitake mushroom powder and its fractions in two rat strains.

Mol Cell Biochem 2002 Aug;237(1-2):129-36

Talpur NA, Echard BW, Fan AY, Jaffari O, Bagchi D, Preuss HG.
Department of Physiology and Biophysics, Georgetown University Medical Center, Washington, DC 20007, USA.

Maitake mushroom has been reported to favorably influence hypertension and diabetes mellitus. The purpose of this study was to compare the effects of whole Maitake mushroom powder and two extracts designated as ether soluble (ES) and water soluble (WS) on Zucker fatty rats (ZFR), a model of insulin resistance, and on spontaneously hypertensive rats (SHR), a model of genetic hypertension. In the initial study, we followed four groups of eight ZFR and SHR receiving special diets: a baseline diet (BD), BD + whole Maitake mushroom powder (20% w/w), BD + fraction ES (0.10% w/w), and BD + WS (0.22% w/w). Different effects of these dietary regimens on the 2 rat strains were found. At 35 days, only consumption of the ES diet significantly decreased systolic BP (SBP) in SHR (average 197 vs. 176 mm Hg, p < 0.001), while in ZFR only the groups consuming the whole Maitake and WS diets showed significantly decreased SBP (138 vs. 120-125 mm Hg, p < 0.001). A challenge test with losartan (an angiotensin II receptor blocker) indicates that angiotensin II does not play a major role in SBP regulation of ZFR, but does in SHR where consumption of ES relative to other groups significantly lowered activity of this system. In SHR, glucose, cholesterol, circulating insulin and HbA1C were virtually similar among all dietary groups; but whole Maitake (-22%), ES (-120%) and WS (-80%) diets were associated with decreased triglycerides, and the ES diet with lowered serum creatinine (-29%). In ZFR, circulating insulin and HbA1C were significantly decreased in the whole Maitake powder and ES groups, and tended to be lower in the WS group compared to control. In the ensuing studies, we gavaged ZFR once daily with water (control), 44 mg fraction WS, or 44 mg fraction WS plus 100 microg niacin-bound chromium (NBC). Oral gavage of WS clearly lowered SBP and circulating glucose concentrations, more so with the addition of chromium. We conclude that the examined forms of Maitake mushroom have antihypertensive and antidiabetic potential which differ among rat strains. The ES fraction may decrease SBP in SHR via alteration in the renin-angiotensin system.

Maitake (Grifola frondosa) improve glucose tolerance of experimental diabetic rats.


J Nutr Sci Vitaminol (Tokyo) 2001 Feb;47(1):57-63

Horio H, Ohtsuru M.
Department of Food Science and Nutrition, Faculty of Home Economics, Nishikyushu University, Saga, Japan.

We have previously reported that rats with diabetes induced by injecting streptozotocin into neonates showed remarkably lower blood glucose, urine volume, and glucosuria after administration of Maitake (Grifola frondosa). In the present study, we investigated the effects of Maitake on insulin concentration, organ weight, serum composition, and islets of Langerhans in streptozotocin-induced diabetic rats using the same method. The diabetic rats were produced by injecting 80 mg/kg B.W. streptozotocin into 2-d-old neonates. From the age of 9 wk, the rats were given experimental diets for 100 d. The diabetes and control groups were given either diets containing 20% Maitake (DM and CM groups) or control diets (D and C groups). During administration of the experimental diets, we measured body weight, food intake, amount of feces, and serum insulin concentration at glucose loading. The glucose tolerance test was performed at the 10th week after the start of the experimental diets. The D group had an initial fasting blood glucose of 225+/-49 mg/dL, and a maximum blood glucose of 419+/-55 mg/dL at 60 min. In the DM group, however, the initial fasting blood glucose was 170+/-23 mg/dL, and the maximum blood glucose was 250+/-41 mg/dL at 15 min. Both values were markedly lower than those in the D group (p<0.05). The insulin concentration at 15 min. after glucose loading in the DM group was 41+/-16 microU/mL, which was significantly higher than that in the D group (15+/-7 microU/mL) (p<0.05). After the 100-d experimental period, blood samples were collected. The fructosamine level was significantly lower in the DM group (152+/-21 mmol/L) than in the D group (185+/-13 mmol/L). The concentration of 1.5-A.G. (1.5-anhydro glucitol) was significantly higher in the DM group (9.33+/-2.42 microg/mL) than in the D group (1.33+/-0.52 microg/mL). Observation of insulin antibody stain in the Langerhans cells of the pancreas using ABC method showed a decrease insulin antibody stain in the D group. The cells of the DM group were stained more darkly than those of the D group. From these results, we postulated that the bioactive substances present in Maitake can ameliorate the symptoms of diabetes.

Anti-diabetic activity present in the fruit body of Grifola frondosa (Maitake).

Biol Pharm Bull 1994 Aug;17(8):1106-10

Kubo K, Aoki H, Nanba H.
Yukiguni Maitake Co., Ltd. Niigata, Japan.

The fruit body of Grifola frondosa (maitake), Basidiomycetes was confirmed to contain substances with anti-diabetic activity. When 1 g/d of powdered fruit body of maitake was given orally to a genetically diabetic mouse (KK-Ay), blood glucose reduction was observed, in contrast to the control group in which the blood glucose increased with ageing. Moreover, levels of insulin and triglyceride in plasma demonstrated a change similar to blood glucose with feeding of maitake. Ether-ethanol-soluble (ES) and hot water-soluble (WS) fractions were prepared from the fruit body and their hypoglycemic activity was examined. Blood glucose-lowering activity was found when ES-fraction or WS-50% ethanol float (X) fraction was administered orally, but other WS-fractions were inactive. These results suggest that the anti-diabetic activity was present not only in the ES-fraction consisting of lipid but also in the X-fraction of peptidoglycan (sugar:protein = 65:35).


Possible hypoglycemic effect of Maitake mushroom on
Type 2 diabetic patients.

Diabetic Medicine Volume 18 Issue 12 Page 1010 - December 2001

S. Konno, D. G. Tortorelis, S. A. Fullerton, A. A. Samadi, J. Hettiarachchi and H. Tazaki

The efficacy of sulphonylureas is often disappointing because they are believed to act primarily upon pancreatic -cells for insulin secretion. A secondary action on peripheral insulin sensitization has also been postulated We investigated a possible hypoglycaemic effect of maitake (Grifola frondosa) mushroom polysaccharides (MMP). MMP has been shown to have a blood glucose-lowering effect on diabetic mice (KK-Ay) suggesting their potential antidiabetic activity. This hypoglycaemic action of MMP is presumed to be associated with activation of insulin receptors in insulin-targeted cells. Safety of MMP has been granted by the US Food and Drug Administration (FDA) and has also been approved for an Investigational New Drug (IND) application for patients with advanced cancers. Accordingly, two volunteers with Type 2 diabetes on glibenclamide therapy gave their informed consent and agreed to participate in this pilot trial. MMP is commercially available in a caplet form prepared from the fruit bodies of maitake mushrooms (Maitake Products, Ridgefield Park, NJ, USA). MMP was taken orally and the fasting blood glucose (FBG) and glycosylated haemoglobin (HbA1c) monitored throughout.

A 44-year-old Asian male with newly diagnosed Type 2 diabetes had a FBG value of 13.8mmol/l and HbA1c of 11.5%. No retinopathy/neuropathy or other diabetes-related complications were present. He was immediately started on daily 2.5mg glibenclamide therapy and his FBG levels fell to approx. 10mmol/l in the next 2days. He also started on 500-mg caplet of MMP three times a day with glibenclamide and his FBG declined to approx. 5.6mmol/l in 10days. Afterwards, his FBG levels remained 4.4-5.0mmol/l for the next 3months and HbA1c was also down to 5.2%. Glibenclamide was then reduced to 1.25mg with two MMP caplets daily, and his FBG levels remained 4.4-5.0mmol/l for the next 2months. Consequently, glibenclamide was completely withdrawn but he was kept on daily two MMP caplets, and his FBG levels retained approx. 5.0mmol/l with HbA1c of 5.6% over 6months. During this glibenclamide-free period, MMP caplets were also stopped for 2weeks. In this wash-out interval, FBG rose to 6.7mmol/l but returned to 4.4mmol/l when daily MMP intake was resumed. It is important to note that he also lost 7kg in weight during this trial as he improved his physical fitness. Although it has been over 1.5years since his initial diagnosis, he is currently free of any medications except for daily two MMP caplets with the normoglycaemic state.

A 75-year-old Caucasian female diagnosed with Type 2 diabetes for 6 years was also subjected to a MMP regimen. Her average FBG had been approx. 11.0 mmol/l with HbA1c of approx. 9.1% under daily glibenclamide (5mg) therapy. No retinopathy/neuropathy or other diabetes-related complications was noted. When she was recently placed on daily three MMP caplets with glibenclamide (5mg), her FBG values declined to 7.2mmol/l in 2weeks and remained around 6.0-7.2mmol/l over the next 2.5months. She also experienced a mild weight loss of around 2kg. Glibenclamide was then reduced to 2.5mg with MMP, and her FBG remained below7.2mmol/l.

In this brief report, two Type 2 diabetic patients showed a good response to MMP for their glycaemic control. A newly diagnosed diabetic patient under glibenclamide therapy has consequently become free of glibenclamide in 5months and his FBG currently remains in a normoglycaemic (approx. 5.0mmol/l) range with daily intake of two MMP caplets. Despite partial and complete improvements of the glycaemic control in our patients with MMP, the exact mechanism of MMP-mediated hypoglycaemic activity is not fully elucidated. MMP is postulated to have a stimulatory effect on the insulin receptor to overcome insulin resistance [4]. However, due to the unavailability of insulin (C-peptide) measurements in this study, a potential insulin-sensitizing effect of MMP cannot be properly assessed. Furthermore, the accompanying weight loss may also have contributed to the improvement in glycaemic control. More volunteer patients are now recruited in controlled MMP trials to obtain sufficient subject numbers and additional insulin data. A primary effect of MMP on the insulin receptor activity is also being investigated using an in vitro experimental model (cell cultures). In conclusion, polysaccharides of maitake mushroom may have a possible hypoglycaemic effect on Type 2 diabetic patients.

Effects of a water-soluble extract of Maitake mushroom on circulating glucose/insulin concentrations in KK mice.

Diabetes Obes Metab 2002 Jan;4(1):43-8

Manohar V, Talpur NA, Echard BW, Lieberman S, Preuss HG.
Department of Physiology, Georgetown University Medical Center, Washington, DC 20007, USA.

AIM: We examined benefits of a water-soluble extract of maitake mushroom designated as Fraction X (FXM) on the glucose/insulin metabolism of insulin-resistant KK mice, and compared the results of FXM with those of a sulphonylurea, Glipizide.

DESIGN: In several acute studies, insulin-resistant KK mice were gavaged with a single dose of varying concentrations of FXM, or a single dose of one concentration of the oral hypoglycaemic drug, Glipizide. In the one chronic study, KK mice were gavaged with FXM, Glipizide, or an equal volume of isotonic saline (baseline control) twice daily. Retro-orbital blood was drawn on the morning of the 4th and 7th days before the early gavage. Blood glucose was measured by routine laboratory procedures, and serum insulin was estimated by a radioimmunoassay (RIA) assay developed specifically for rodents.

RESULTS: At a dose of FXM (140 mg/mouse), a statistically significant lowering of circulating glucose concentrations was again seen at 8-12 h and 16-18 h after oral gavage. The lowering approximated 25% of the original concentration. Oral gavage of Glipizide resulted in statistically significantly lower values of circulating glucose (25-37% lower compared with baseline) at 8-24 h post dosing. In the chronic study, the circulating concentrations of glucose and insulin of mice taking 140 mg FXM per day were decreased significantly at days 4 and 7.

CONCLUSIONS: FXM, a natural extract obtained from maitake mushroom, favourably influences glucose/insulin metabolism in insulin-resistant KK mice. The lowering of both circulating glucose and insulin concentrations suggests that FXM works primarily by enhancing peripheral insulin sensitiveity.

Effect of Coprinus comatus on plasma
glucose concentrations in mice.

Planta Med 1984 Dec;50(6):525-6

Bailey CJ, Turner SL, Jakeman KJ, Hayes WA.

Abstract: To investigate anecdotal evidence that Coprinus comatus can lower blood glucose, normal mice were fed a diet containing powered dried fruit bodies of C. comatus (33.3%w/w). Plasma glucose concentrations were reduced after 11 days, and intraperitoneal glucose tolerance was improved. However, body weight gain was not substantially reduced. Plasma glucose was marginally lowered 10 hours after intragastric administration of dried C. comatus (3.6 g/kg body weight). The results suggest a slowly generated, mild hypoglycaemic effect of C. comatus in normal mice, accompanied by metabolic effects capable of interrupting body weight gain.

 

 

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