Anti-Diabetogenic Properties

Compiled by Initiative Team Member Glenn Cardwell APD

There is great interest in the ability of fresh produce to reduce the risk of disease, such as diabetes. The World Health Organisation states that more than 220 million in the world have diabetes and in 2005 about 1.1 million Diabetesdeaths from diabetes occur in the poorer countries. The number with diabetes worldwide is expected to rise to 366 million people in 2030 ( /).

According to the International Diabetes Federation, in 2010 the proportion of population aged 20-79 years with diabetes ranged from less than 4% in central Africa to 12% in North America and 14% in Saudi Arabia. ( It is estimated that diabetes killed over 630,000 Europeans, 310,000 North Americans and 1.15 million from South East Asia in 2010.

The estimated economic burden of diabetes worldwide was $US376 billion in 2010 and expected to be $US490 billion by 2030 ( Nearly 12% of the total global healthcare budget is spent on diabetes.

People with diabetes usually have a pancreas that does not produce adequate insulin or a body that does not respond adequately to circulating insulin, both leading to high blood glucose. Elevated blood glucose levels cause long-term damage to cells in the kidneys and eyes and increase the risk of heart disease. It is widely agreed that prevention of diabetes can be achieved in many cases by being active, being a healthy weight and eating a healthy diet.

This part of the report also suggests that mushrooms also assist in normalising blood glucose levels. Mushrooms are very low in kilojoules/calories and help to control the appetite (Cheskin et al. 2008), therefore helping to maintain a healthy body weight. Mushrooms may provide a range of unique compounds that can influence both insulin release and sensitivity, and blood glucose levels. This is more likely to be the case with type 2 diabetes (commonly a lifestyle disease) than with type 1 diabetes where additional insulin is required, often given through daily injections.

Anti-Diabetogenic Effects: A small human trial has suggested a positive effect of mushrooms on insulin resistance and therefore potentially a positive affect in the treatment of type 2 diabetes. A large number of animal studies, in both normal and diabetic animal models, have confirmed the hypoglycaemic effects of mushrooms and mushroom components. The hypoglycaemic effects appear to be mediated via mushroom polysaccharides (possibly both alpha- and beta-glucans) via a direct interaction with insulin receptors on target tissues, although this mechanism remains to be confirmed.

Anti-Diabetogenic Properties

Studies in humans

A randomized, double-blind, and placebo-controlled clinical trial (72 patients) has evaluated the effects of Agaricus blazei Murill in combination with metformin and gliclazide on insulin resistance in type 2 diabetes. Supplementation of Agaricus blazei Murill extract improved insulin resistance among subjects with type 2 diabetes. The increase in adiponectin concentration after taking Agaricus blazei Murill extract for 12 weeks may be the mechanism that resulted in the observed effect (Hsu et al., 2007).

Animal model (mouse) studies

An aqueous extract of Ganoderma lucidum (0.03 and 0.3g/kg) has been shown to lower the serum glucose level in obese/diabetic (+db/+db) mice after one week of treatment whereas a reduction was observed in lean (+db/+m) mice only fed with 0.3g/kg of G. lucidum at the fourth week. A higher hepatic PEPCK gene expression was found in +db/+db mice. G. lucidum (0.03 and 0.3g/kg) markedly reduced PEPCK gene expression in +db/+db mice whereas the expression of PEPCK was attenuated in +db/+m mice (0.3g/kg G. lucidum). These data demonstrate that G. lucidum consumption can provide beneficial effects in treating type 2 diabetes mellitus in mice by lowering the serum glucose levels through the suppression of hepatic PEPCK gene expression (Seto et al., 2009).

Hypoglycaemic activity of an aqueous extract of Pleurotus pulmonarius in alloxan-induced diabetic mice has been reported. Pleurotus pulmonarius extract was administrated orally at doses of 250, 500, and 1,000mg/kg to separate groups of mice (normal and alloxan-treated mice), and serum glucose and body weight were measured. In the separate group of mice, an oral glucose tolerance test was carried out. Acute oral toxicity data showed no mortality in the normal mice up to 5,000mg/kg, while oral administration of extracts reduced the serum glucose level in alloxan-treated diabetic mice at all the doses tested after acute and chronic (28 days) administration. The extract also showed increased glucose tolerance in both normal and diabetic mice. The data suggest that the extract possesses hypoglycaemic activity (Badole et al., 2006).

In a subsequent study by the same group, the interaction of an aqueous extract of Pleurotus pulmonarius with acarbose on serum glucose levels, and on an oral glucose-tolerance test in alloxan induced diabetic mice was studied. The anti-hyperglycaemic effects of aqueous extract and acarbose alone were similar but combination treatment of the Pleurotus pulmonarius extract with acarbose produced a more synergistic anti-hyperglycaemic effect than either agent alone (Badole and Bodhankar, 2007).

The structure and anti-tumour activity of polysaccharide fractions of the fruit body of Agaricus brasiliensis have been studied in cold and hot water extracts (CWE and HWE) on a mouse diabetic model (C57BL Ksj-db/db). Compared to the water administered control group, the body weight, urinary glucose exclusion, urinary pH, blood glucose level, and organs weight were comparable. The splenocytes of CWE administered mice produced a higher concentration of interleukin-6. By megascopic and microscopic examinations of renal sections, the number of the mice having abnormal kidney was 3/5 (control), 2/5 (HWE), and 0/5 (CWE) suggested the activity of the renal protection in the cold water extract. The results suggested that the pharmacological action of the cold water extract of A. brasiliensis is significantly stronger than that of the hot water extract (Furukawa et al., 2006).

The anti-diabetic effect of an alpha-glucan (MT-alpha-glucan) from the fruit body of Maitake mushrooms (Grifola frondosa) on KK-Ay mice (a type 2 diabetes animal model) has been evaluated. Treatment with MT-alpha-glucan significantly decreased the body weight, level of fasting plasma glucose, glycosylated serum protein, serum insulin, triglycerides, cholesterol, free fatty acid and malondialdehyde content in liver. Treatment with MT-alpha-glucan significantly increased the content of hepatic glycogen, reduced glutathione and the activity of liver superoxide dismutase and glutathione peroxidase. Moreover, the insulin binding capacity to liver crude plasma membranes increased and histopathological changes in the pancreas were ameliorated in the treatment group. The data suggested that MT-alpha-glucan has an anti-diabetic effect on KK-Ay mice, which may be related to its effect on insulin receptors by increasing insulin sensitivity and ameliorating insulin resistance of peripheral target tissues (Lei et al., 2007).

The hypoglycaemic activity of fermented mushroom of Grifola frondosa rich in vanadium(GFRV) has been demonstrated in alloxan- and adrenalin-induced hyperglycaemic mice. After the mice were administered with GFRV, the blood glucose and the HbA1c of alloxan-induced hyperglycaemic mice decreased and an increase of blood glucose induced by adrenalin was inhibited (Cui et al., 2009).

In a similar study, alloxan- and adrenalin-induced hyperglycaemic mice were administered with Coprinus comatus rich in vanadium, the blood glucose of alloxan-induced hyperglycaemic mice decreased, an increase of blood glucose induced by adrenalin was inhibited and the sugar tolerance of the normal mice was improved. However, the same result was not observed with Ganoderma lucidum and Grifola frondosa (Han and Liu, 2009).

Extracellular polysaccharides (EPS) from Laetiporus sulphureus var. miniatus have been shown to have stimulatory effects on insulinoma cell (RINm5F) proliferation and insulin secretion, in a dose-dependent manner. In addition, EPS also reduced the STZ-induced apoptosis in RINm5F cells indicating the mode of the cytoprotective role of EPS on RINm5F cells (Hwang et al., 2008). Hypoglycaemic effects of exopolysaccharides (EPS) produced by mycelial cultures of the mushrooms Tremella fuciformis and Phellinus baumii have been reported in genetically obese (ob/ob) mice. The data suggested that both EPS exhibited a considerable hypoglycaemic effect and improved insulin sensitivity possibly via regulation of lipid metabolism (Cho et al., 2007).

A polysaccharide isolated from Phellinus linteus has also recently been reported to inhibit the development of autoimmune diabetes in non-obese diabetic (NOD) mice (Kim et al., 2010). In this study, 80% of the NOD mice had developed diabetes by 24 weeks of age, but none of the polysaccharide-Phellinus linteus -treated NOD mice developed diabetes. Histological examination of the pancreatic islets revealed that most of the islets isolated from treated mice were less infiltrated with lymphocytes compared with those of control mice. The polysaccharide inhibited the expression of inflammatory cytokines, including IFN-gamma, IL-2, and TNF-alpha by Th1 cells and macrophages, but up-regulated IL-4 expression by Th2 cells in NOD mice. The polysaccharide did not prevent streptozotocin-induced diabetic development in ICR mice. These data suggest that this polysaccharide isolated from Phellinus linteus inhibits the development of autoimmune diabetes by regulating cytokine expression.

Animal model (rat) studies

Agaricus bisporus has been shown to lower blood glucose and cholesterol levels in streptozotocin (STZ)-induced diabetic and rats fed a hypercholesterolemic diet (Jeong et al., 2010). The STZ-induced diabetic male Sprague-Dawley rats fed Agaricus bisporus powder (200 mg/kg of body weight) for 3 weeks had significantly reduced plasma glucose and triglyceride concentrations (24.7% and 39.1%, respectively), liver enzyme activities, alanine aminotransferase and aspartate aminotransferase (11.7% and 15.7%, respectively), and liver weight gain. In hypercholesterolemic rats, oral feeding of the Agaricus bisporus powder for 4 weeks resulted in a significant decrease in plasma total cholesterol and low-density lipoprotein (22.8% and 33.1%, respectively). A similar significant decrease in hepatic cholesterol and triglyceride concentrations was observed (36.2% and 20.8%, respectively). The decreases in total cholesterol, low-density lipoprotein, and triglyceride concentrations were accompanied by a significant increase in plasma high-density lipoprotein concentrations demonstrating significant hypoglycemic and hypolipidemic activity in rats.

Lectins from Agaricus bisporus and Agaricus campestris have been shown to stimulate insulin and glucagon release from isolated rat islets in the presence of 2 mM glucose. Maximal stimulation of insulin release was reported at lectin concentrations above 58 mg/mL (approximately 1 mM). The lectin did not alter islet glucose oxidation to CO2 or incorporation of [3H] leucine into trichloracetic acid-precipitable material, nor did it modify rates of insulin secretion induced by 20 mM glucose. None of nine other lectins tested stimulated insulin release, whereas stimulation of fat cell glucose oxidation was a general property of the lectins. The data also suggested that lectin binding is essential for the expression of insulin-releasing activity. The authors proposed that the specific interaction between mushroom lectin and its receptors may lead to conformational changes in the structure of the membranes of the islet A2- and B-cells that facilitate exocytosis (Ewart et al., 1975).

The hypoglycaemic effect of exo-polymers (EPs) produced from submerged mycelial cultures of several varieties of mushrooms on streptozotocin (STZ)-induced diabetic rats have been investigated. The five experimental groups were fed with EPs (50mg/kg body weight) for 7 days. Significant reductions in plasma glucose, total cholesterol, and triglyceride levels were observed in rats fed with Lentinus edodes and Cordyceps militaris EPs. Plasma glucose and total cholesterol were also reduced by administration of Phellinus linteus EPs, but the triglyceride level was not changed significantly. The EPs of the three mushroom species also demonstrated a marked reduction in the level of plasma glutamate-pyruvate transaminase (GPT). The result demonstrates the hypoglycaemic activity of EPs of three mushroom varieties in STZ-induced diabetic rats and suggests some potential in the control of diabetes mellitus (Kim et al., 2001).

Similarly, a hypoglycaemic effect of exo- and endo-biopolymers produced by a submerged mycelial culture of Ganoderma lucidum in streptozotocin-induced diabetic rats has also been reported (Yang et al., 2004).

The hypolipidemic effect of exo-polymers produced in submerged mycelial cultures of Hericium erinaceus (HE), Auricularia auricula judae (AA), Flammulina velutipes (FV), Phellinus pini (PP), and Grifola frondosa (GF) has been investigated in dietary-induced hyperlipidemic rats. The animals were administered with exo-polymers at the level of 100mg/kg body weight daily for four weeks. A hypolipidemic effect was achieved in all the experimental groups, however, HE exo­polymer proved to be the most potent, significantly reducing plasma triglyceride (28.9%), total cholesterol (29.7%), low-density lipoprotein (LDL) cholesterol (39.6%), phospholipid (16.0%), and liver total cholesterol (28.9%) levels, compared to the saline administered (control) group. The results demonstrate the potential of HE exo-polymer in treating hyperlipidemia in dietary-induced hyperlipidemic rats (Yang et al., 2002a).

A subsequent study by the same group, using higher concentrations (200mg/kg body weight in streptozotocin-induced diabetic rats) of exo-polymers from a submerged mycelial culture of Lentinus edodes has shown that the administration of the exo-polymer reduced the plasma glucose level by as much as 21.5%, and increased plasma insulin by 22.1% compared to the control group. It was also shown to lower the plasma total cholesterol and triglyceride levels by 25.1 and 44.5%, respectively (Yang et al., 2002c).

Beta-glucans and their enzymatically hydrolyzed oligosaccharides from Agaricus blazei have anti­hyperglycemic, anti-hypertriglyceridemic, anti-hypercholesterolemic, and anti-arteriosclerotic activity indicating overall anti-diabetic activity in diabetic rats. However, the enzymatically hydrolyzed oligosaccharides have been shown to have around twice the activity of beta-glucans with respect to anti-diabetogenic activity (Kim et al., 2005). Semipurified fractions of a submerged-culture broth of Agaricus blazei Murill have also been reported to reduce blood glucose levels in streptozotocin-induced diabetic rats (Oh et al., 2010).

Oral administration of Maitake mushroom fractions has been shown to lower blood pressure and fasting blood glucose of Zucker fatty rats, a model of insulin resistance and type 2 diabetes mellitus. The authors concluded that specific fractions of Maitake mushroom, alone or combined with other natural products such as bitter melon and niacin-bound chromium, may be useful in the treatment of insulin resistance (Talpur et al., 2002).

Enhanced insulin-hypoglycaemic activity (improvement in insulin sensitivity) has also been reported in spontaneously hypertensive rats consuming a glycoprotein extracted from Maitake mushrooms (Preuss et al., 2007).

The effects of fermented Chaga mushroom (Inonotus obliquus) powder on the lipid concentrations and the activities of liver marker enzymes of serum in genetically diabetic Otsuka Long-Evans Tokushima fatty (OLETF) rats have been studied. Rats were fed a semi-synthetic diet supplemented with 50g/kg Chaga mushroom powder (CM) or 50g/kg fermented Chaga mushroom powder (FCM) for 8 weeks (26 to 34 weeks of age). Nondiabetic Long-Evans Tokushima Otsuka (LETO) rats were used as age-matched non-diabetic control animals. Water consumption was significantly higher in the OLETF control than the LETO rats. Water consumption in the FCM-fed OLETF rats tended to be less than in both the OLETF control and CM-fed OLETF rats. Serum concentrations of triglycerides and total cholesterol were significantly higher in the OLETF control rats than in the LETO rats while within the OLETF rat groups, the consumption of FCM resulted in a significantly lower serum triglyceride concentration and slightly lowered serum total cholesterol concentration when compared to the OLETF control and CM-fed rats. The livers of the OLETF CM-fed rats showed less fatty changes compared to the OLETF control rats and fat deposition in the hepatocytes was nearly absent. The data suggested that orally ingested fermented Chaga mushroom has a possible beneficial effect on the complications known to occur in obesity-related non-insulin dependent diabetes mellitus (NIDDM) OLETF rat (Cha et al., 2006).

An improvement of insulin resistance and insulin secretion by water extracts of Cordyceps militaris, Phellinus linteus, and Paecilomyces tenuipes in 90% pancreatectomized rats has also been reported (Choi et al., 2004b), while the presence of anti-hyperglycaemic, insulin-releasing and insulin-like activity in Agaricus campestris in streptozotocin (STZ)-induced diabetic mice has also been demonstrated (Gray and Flatt, 1998)(Gray and Flatt, 1998).

A hypoglycaemic effect of extracellular fungal polysaccharides (EPS) in STZ-induced diabetic rats has been reported. The differential expression patterns of rat kidney proteins from normal, STZ-induced diabetic, and EPS-treated diabetic rats, were analysed. A histopathological examination showed that EPS administration restored the impaired kidney in STZ-induced rats to almost normal architecture (Hye-Jin et al.  2007). Following oral administration of exopolysaccharide produced from submerged mycelial culture of Lentinus strigosus (Schwein.) Fr. (Family Polyporaceae) in STZ-induced diabetic rats, their serum glucose levels were reduced by up to 21.1% at the dose of 150 mg/kg of body weight. Plasma insulin levels of STZ-induced diabetic rats decreased compared to control rats. The hypoglycaemic potential of the EPS was further supported by histological observations of pancreatic islets of Langerhans (Yamac et al., 2008).

Submerged-culture mycelia and broth of Grifola frondosa have been shown to contain bioactive components for improving glycaemic responses, such as decreases in serum triglyceride, fructosamine, and blood glucose concentrations in male Wistar rats injected with nicotinamide plus STZ (diabetic rats) (Lo et al., 2008). A similar study with Ganoderma lucidum has reported both hypoglycaemic and anti-hyperglycaemic effects in Wistar rats (Mohammed et al., 2007). Ganoderma lucidum polysaccharides have also been shown to significantly and dose-dependently increase nonenzymic and enzymic antioxidants, serum insulin level and reduce lipid peroxidation and blood glucose levels in STZ-diabetic rats (Jia et al., 2009).