Medicinal Mushrooms: Natural Supplement for Diabetics
Diabetes Mellitus (DM) is a metabolic disease where the body has increased blood sugar levels due to two reasons, in the majority of cases: the regulatory anabolic hormone, the insulin production (type 1 DM) or the end organ/cellular response (type 2 DM) due to it being inefficient. The classic symptoms are polyuria, polydipsia and polyphagia. Whilst DM can lead to acute complications like diabetic ketoacidosis or a nonketotic hyperosmolar coma, long term the cardiovascular, renal and retinal damages are more likely.
The insulin regulates the glucose, the most important source of cellular energy from carbohydrate levels within the blood stream. Physiologically, the increased levels of insulin promotes cellular growth, protein synthesis and also allows fat and glycogen stores (in the liver and muscle) to build up. Opposed to when the level is low initially releasing glucagon stores and then later, fat burning becomes more dominant over the longer term.
Epidemiological data shows that 3.8 million UK citizens have been diagnosed with DM, from which around 90% belong to type 2 with not exclusively, the remaining 10% accounting for the type 1 DM population.
Medicinal mushrooms have traditionally been used for different purposes mostly in the Orient culture. The interest towards these extracts is largely increasing, although it is also well known that as non-patentable molecules are present and the identification of these active molecules is challenging, the interest of the commercial pharmaceutical industry is obviously low.
The aim of this article is to review the more recent and relevant (only highly cited peer-reviewed with a strong impact) literature and available evidence for probably the most often referred medicinal mushrooms for diabetes: the Ganoderma Lucidum, Grifola Frondosa, Agaricus Blazei Murill and the Cordyceps species.
Ganoderma Lucidum (Reishi)
Ganoderma Lucidum is one of the oldest, traditionally used medicinal mushrooms, known for over 2000 years with a special esteem in East Asia.
The reported active ingredients are the triterpenoids - also called ganodermic acids, which have similar molecules to steroid hormones - polysaccharides (β-d-glucans), coumarin, mannitol and alkaloids. Ganoderma triterpenoids have been found to have anti-hypertensive, hypocholesterolemic, hepatoprotective, and anti-histaminic effects, anti-tumour and anti-engiogenic activity; they also inhibit platelet aggregation and complement inhibition. Polysaccharides via immunomodulation and anti-angiogenesis shows anti-tumour activity with free radicals scavenging, reducing cellular mutagenetic damage.[3
Zhang et al (2004) used normal fasted mice and concluded that Ganoderma polysaccharides via pancreatic islet cell Ca2+ influx, release insulin, having hypoglycaemic effects without modifying the islet cell insulin content.
BS Teng et al. (2012)  studied the effects of the proteoglycan, an extract of the Ganoderma, alongside two conventional antidiabetic (insulin sensitizer) drugs, both of which decrease the amount of glucose produced by the liver and also increase the sensitivity of the insulin on the muscle tissue only (biguanide: Metformin) or on both the muscle and fat tissue (glitazones -thiazolidinediones, Rosiglitazone). Previously, PTP1B gene knockout mice proven to be obesity resistant with an increased insulin sensitivity. The protein tyrosine phosphatase 1B (PTP1B) - which is an insulin receptor regulator and effectively decreases the insulin sensitivity of the tissues - is inhibited by the Ganoderma extract. The reduction in the glucose levels were significant with a consecutive decrease (on day 10, 20 and 30), with an increased insulin level. The improvement in the blood lipid profile and FFA was considerably better than the two insulin sensitizer medications.
Grienke et al (2011) set out to identify the Farnesoid X receptor ligands among 25 Ganoderma Lucidum constituents (FXR, which belongs to the nuclear hormone family). The FXR is activated, as monomer stimulates the expression of the GLUT4, which is the main insulin-dependent glucose transporter and also responsible for reducing the production of cholesterol. Five lanostane identified as FXR agonist with two independent mechanisms: promoter-reporter study and mRNA level analysis of gen CYP7A1 (regulated by FXR). Also the inhibition of TNF or LPS induced expression of IL8 and E-selectin as anti-inflammatory effects were observed. The most potent lanostane-type triterpenes were the ergosterol peroxide and the ganodermanontriol.
Ganoderma not only improve the diabetic, glucose / insulin profile but also are indicated to be highly beneficial in compromised wound healing, regenerative angiogenesis and potentially other long term consequences of DM by suppressing mitochondrial oxidative stress.
Grifola Frondosa (Maitake)
Grifola frondosa is a polypore mushroom (lacking a stalk) found growing in clusters at the base of trees. Populated under the name of Maitake, they lower blood sugar as they naturally contain an alpha glucosidase inhibitor, prolonging the rapid absorption of carbohydrates from the bowel content.
Laboratory standardized animals studied (insulin resistant KK fed by gavage) performed to document the short (acute, or after a single dose) and long term (chronic) effects of various concentrations of G. frondosa water extracts (called FXM, containing proteoglucans with beta-1,6 main chain with alpha-1,4 branching) compared to control and oral hypoglcaemic drugs, Glipizide. Glipizide is a standard second generation suphonyurea acting by increasing the insulin release after meals from its pancreatic origin and sensitizing peripheral tissue. Statistically significant lower glucose concentration were recorded up to18 h after oral gavage of G. frondosa extract (lowering effect approximated to 25 % compared to controls) while Glipizide resulted in 25-37 % beneficial decrease over the period of 24 h after singe administration (as acute effect). Although, it is important to note that for statistical analysis the recording periods were split into 8-12, 16-18 and 20-24h hours of observation. Based on the shorter, but significant effects of the G frondosa, instead of a single intake over a period of 24h the single highly effective doses were split into two over the same period. The long term effects were observed on day 0, 4 and day 7. While the extract seemingly showed on plotted results a higher significant decrease of blood glucose at all points of observations not only against the negative control (normal saline) but even against the positive control Glipizide, adding a good scientific method of validation. The consistent decrease of the circulatory insulin level over the long term experiment suggest that the G. frondosa extract is operating primarily by enhancing peripheral insulin sensitivity having only a few points of observation, this is not necessarily the pure way of action.
Beta-glucans, may be through slowing the absorption of sugars mitigating the bolus effect of rapid glucose release into the blood stream, albeit causing early satiety and/or effects on various intestinal hormones, could be as important.[12-15]
Alpha-glucosidase is a common target of inhibitor drugs (Acarbose, Miglitol and Voglibose) for diabetes, which block the breakdown of starches and some other sugars in the intestine lowering the glucose absorption and availability postprandially (after meals).
An active principle against alpha-glucosidase of the gastrointestinal tract, identified as D-(+)-trehalose (by Field Desorption Mass Spectra, FDMS, Nuclear Magnetic Resonance, 1H-, 13C- NMR and Distortion-less Enhancement by Polarization Transfer, DEPT). A 100mg water extract of G. frondosa exhibits 93 % inhibition on alpha-glucosidase. Trehalose, the proposed active agent in G frondosa, is inhibitory with 45 % (at a concentration of 2x10-3), while 1-deoxynojirimycin inhibitory activity was 52 % with a lower concentration. The 1-deoxynojirimycin is an amino sugar (a well known bioactive dietary ingredient) which exhibits a high level of adherence to the alpha-glucosidase, with a competitive inhibitory action, found to occupy almost entirely the active site of the enzyme (quantified by inhibition assays and isotherm titration calorimetry).
Trehalose, a non-reducing disaccharide (present in large amounts within many yeasts, plants, bacteria and invertebrate animals serving as signaling molecules to control growth and metabolism) is shown to be able to protect proteins and cellular membranes from deactivation and denaturation by various stress such as desiccation, dehydration, heat, cold and oxidation. This molecule normally does not occur within mammalian cells, while trehalose (a digestive enzyme) in the intestinal tract (and also in the kidney) is present.
Agaricus Blazei Murill
Agaricus Blazei Murill also known as mushroom of the sun or Almond mushroom is known to stimulate the immune system and is used in oncology therapy in Japan and Brazil[19, 20] This mushroom contains high levels of beta glucans.
High fat (HF) diets induce weight gain, obesity and increase fat mass which can result in hyperleptinaemia and hyperinsulinaemia with the development of inflammatory biomarkers expressing visceral fat tissue. Vincent et al (2012) tested Agaricus Blazei Murill (ABM) extract on a Wistar rat, animal model, on a HF diet. The ABM extract without changing the bowel flora with the very same dietary and calorie intake was found to be protective against weight gain over the study period of 20 weeks, and all other study induced disorders when compared to the control group without the ABM supplementation. Interestingly, this was potentially due to increased energy expenditure and increased locomotor activity with decreased pancreatic lipase activity within the jejunum.
A randomized, double-blind, placebo-controlled trial was performed by Chung-Hua et al. (2007) on a population of 536 registered diabetic patients, who had DM, diagnosed (type 2) for over 1 year, and had been taking gliclazide and metformin for over a 6 month period of time. The insulin resistance was assessed (by homeostasis model), recorded and confirmed that ABM improved insulin resistance compared to the control group taking the combination of gliclazide and metformin. ABM supplementary treatment increased by 20%, the adiponectin after 12 weeks, while a 12% decrease was observed in the control group. Adiponectin is an adipocyte-derived hormone which decreases insulin resistance and is indicated to be a potential treatment for DM type 2 and in other insulin resistant conditions.
Cordyceps is a genus of fungi acting as endoparasitoids on insects, arthropods and on other fungi. The best known species is C sinensis referred as ’caterpillar fungus’ first recorded in the 15th century in Tibet. Two Cordyceps species: the C. sinensis and C. militaris are considered more recently as having medical potential.
Depression has a higher prevalence among the diabetic population and only 1 out of 3 get diagnosed and treated. Patients with DM and major depression affect each other negatively with decreased adherence to the prescribed regimen.
The Cordyceps sinensis in animal studies (streptozotocin induced diabetes, a model of type 2 DM) is shown to decrease serum glucose and increase significantly the level of insulin. Depression which is quantified by physical activity has also significantly improved - with certain modalities even above the level of non-diabetic activity - when compared to the DM affected population without other treatment.[24, 25] Moreover, unfavourable diabetes induced weight changes and also polydipsia improved.[26, 27]
The Cordyceps militaris lowers the glucose level by inducing insulin secretion in animal studies without being affected by DM.
The active agents of the Cordyceps species is not well published, however cordycepsin from a different C. species provided the source of ciclosporin immunosupressing drug.
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Mr Péter Bujtár (MD, MSc bio.eng., DMD)