Current approaches toward a potential cure for T1D have focused on three main targets: Ablation of the β-cell-specific autoimmune response; β-cell replacement therapy using islet transplantation; and potentiation of β-cell mass and function using pharmacologic agents capable of promoting β-cell proliferation, regeneration, and/or repair. In the first method recombinant antigens that trigger an immune response of β-cell destruction are used. In this way, the tolerance of immune cells to auto-antigens is trying to be developed. However, this approach is quite new and not enough research has been conducted. The quickest and most promising approach that afforded patients complete independence from exogenous insulin is islet or β-cells’ transplantation. However, it should be noted that this method is accompanied with intake of immunosuppressants to reduce the possibility of transplant rejection. Therefore, at this stage of the fight against DM, most attention is paid to the study and research of drugs which are able to potentiate the effect of residual β-cells and/or induce their regeneration.
Several approaches were made to reduce the hyperglycemia, the hallmark of DM, with treatments such as sulfonylureas, which stimulate pancreatic islet cells to secrete insulin; meteoric, which acts to reduce hepatic glucose production; alpha-glucosidase inhibitors, which interfere with glucose adsorption and insulin itself, which suppresses glucose production and augments glucose utilization. These therapies have limited efficacy, limited tolerability, and significant mechanism-based side effects (Table 1). Of particular danger is the use of some medicines that can promote weight gain, hypoglycemia, and insulin resistance. Another problem particular to some medicines (e.g., sulphonylureas) is the development of resistance to the treatment. Therefore, the search for new preparations is extremely important. The growing public interest and awareness of natural medicines have led the pharmaceutical industry and academic researchers to pay more attention to medicinal plants and mushrooms. The apparent reversal of the trend from western to herbal medicine is partly due to the fact that synthetic drugs have always shown adverse reactions and other undesirable side effects. This has led to the belief that natural products are safer because they are more harmonious with biological systems[66,67]. In addition, the cost of administering modern antidiabetic drugs is beyond the reach of people in low-income groups and for those living in rural areas.
Medicinal mushrooms and their use
Mushrooms comprise an extremely abundant and diverse world. The number of mushroom species on Earth is currently estimated at 150000-160000; yet, perhaps only 10% are known to science. Mushrooms are currently evaluated for their nutritional value and acceptability, as well as for their pharmacological properties. They make up a vast and yet largely untapped source of new powerful pharmaceutical products. The majority of higher Basidiomycetes mushrooms contain many types of biologically active high-molecular weight and low-molecular weight compounds in fruit bodies, cultured mycelia, and cultured broth which has different properties[71,72].
Medicinal mushrooms have an established history of use in traditional oriental therapies. Contemporary research has validated and documented much of the ancient knowledge. Ancient oriental medicine has stressed the importance of several mushroom species, mostly Ganoderma lucidum (W. Curt.: Fr.) P. Karst. (Ling zhi or Reishi) and Lentinus edodes (Berk.) Singer (Shiitake). Mushrooms have also played an important role as a cure for ailments affecting the rural populations of Russia and other Slavic European countries. The most important species in these areas were Inonotus obliquus (Pers.: Fr.) Pilat (Chaga), Fomitopsis officinalis (Vill.: Fr.) Bond. et Singer, and Fomes fomentarius Fr.: Fr. These species were used in the treatment of gastrointestinal disorders, various forms of cancers, bronchial asthma, night sweats, etc. There is also a long history of traditional use of mushrooms as curatives in Mesoamerica (especially species of the genus Psilocybe), Africa (Yoruba populations in Nigeria and Benin), Algeria, and Egypt. A very special role of fly agaric [Amanita muscaria (L.:Fr.) Pers.] is found in Siberia and Tibetan shamanism, Buddhism, and Celtic myths[71,74,75].
Nowadays, medicinal mushrooms are used as dietary food, dietary supplemental products, pharmaceuticals, natural bio-control agents in plant protection with insecticidal, fungicidal, bactericidal, herbicidal, nematicidal, and antiphytoviral activities, and cosmeceuticals.
Medicinal mushrooms are comparable to “medicinal plants” and can be defined as macroscopic fungi, mostly higher Basidiomycetes and some Ascomycetes, which are used in the form of extracts or powder for prevention, alleviation, or healing of diseases, and/or in providing a balanced healthy diet.
Modern clinical practice in Taiwan, Japan, China, South Korea, and other Asian countries rely on mushroom-derived preparations. These preparations have many active compounds, which identify their importance as food and as medicines. This includes mainly high-molecular weight compounds such as polysaccharides (e.g., β-D-glucans, glucuronoxylomannan), proteins, polysaccharide-protein complexes, lipopolysaccharides, glucoproteins, and lectins. Low-molecular weight metabolites include lactones, terpenoids, alkaloids, sterols, phenolic substances, and antibiotics with different active groups, metal chelating agents, etc. Also, medicinal mushrooms have enzymes - laccase, superoxide dismutase, glucose oxidase, peroxidase[72,77]. As dietary supplement products, mushrooms contain a small amount of lipids and cholesterol, and low levels of carbohydrates. At the same time, they are rich in fiber, protein, minerals, and vitamins. The wide range of bioactive compounds determines antitumor, immunomodulating, antioxidant, radical scavenging, cardiovascular, antihypercholesterolemic, antiviral, antibacterial, antiparasitic, hepatoprotective, and antidiabetic properties of medicinal mushrooms[79,80].
Antidiabetic properties of Agaricus brasiliensis and Ganoderma lucidum
Research has shown that some mushrooms may have the potential to lower elevated blood sugar levels. But the explanation for this effect is limited, except for some mushrooms. Therefore, it would be necessary to carry out more research on mushrooms with a focus to identify the active compounds in specific mushrooms for the treatment of DM and its complications.
Agaricus brasiliensis (A. brasiliensis, Royal Sun Agaricus) is native to Brazil and widely grown in Japan. This mushroom is used in the treatment of atherosclerosis, hepatitis, hyperlipidemia, dermatitis, and cancer, and its polysaccharides, α-glucan and β-glucan, have been shown to have immunomodulating and antimutagenic effects both in vivo and in vitro[75,81]. The possible mechanisms of natural polysaccharides to DM might base on six directions: (1) the elevation of plasma insulin, and the decline of pancreatic glucagon; (2) the increase of insulin sensitivity, and the improvement of insulin resistance; (3) the restraint of α-glycosidase enzymes in bowel, and the reduction of carbohydrates decomposition and absorption; (4) the increase of hepatic glycogen, and the inhibition of sugar dysplasia; (5) the increased glucose use of peripheral tissue; (6) the scavenging free radicals and lipid peroxidation. Also, hypoglycemic and antidiabetic properties of A. brasiliensis have been reported. Di Naso et al showed that A. brasiliensis extract exhibited a significant antioxidant activity in streptozotocin (STZ)-induced diabetic rats decreasing lipoperoxidation and iNOS expression in the lungs. These results suggest that A. brasiliensis treatment effectively reduced the oxidative stress and contributes to tissue recovery in diabetes. Another study demonstrated that A. brasiliensis extracts derived from submerged-culture broth significantly reduced blood glucose levels in an oral glucose-tolerant test in STZ-induced diabetic rats. There is also clinical evidence that A. brasiliensis combined with antidiabetic drugs can improve insulin resistance in T2D patients. It is shown that β-glucans and oligosaccharides of A. brasiliensis have antihyperglycemic, antihypertriglyceridemic, antihypercholesterolemic, and anti-arteriosclerotic activity in diabetic rats. One group has suggested that the A. brasiliensis antidiabetic effect in diabetic rats is due to its suppression of OS and proinflammatory cytokine production, which then results in improvement of the mass of pancreatic β-cells. But, nevertheless, additional pharmacological studies are needed to elucidate the mechanism of A. brasiliensis action as well as to assess the use of these species for the treatment of human DM.
Ganoderma lucidum (G. lucidum, Ling zhi, Reishi), has a leading place in present-day medicinal mushroom development. G. lucidum has been utilized for centuries in East Asia to prevent or treat various diseases and was used in traditional Chinese medicine as a tonic in promoting good health, perpetual youth, vitality, and longevity. It is widely grown on a commercial scale and is commonly purchased for its medicinal and spiritual properties. Worldwide, more than 250 Ganoderma species have been described. Recent studies on G. lucidum have shown many interesting biological activities including antitumor, antiinflammatory, antioxidant, and antidiabetic effects[75,77].
Antihyperglycemic effects of G. lucidum have been extensively studied and have shown potential therapeutic activities. It has been shown that oral administration of water extracts of G. lucidum significantly reduced the increase in blood glucose and insulin levels in rats following the oral glucose tolerant test. Prevention of the progression of diabetic renal complications as well as a lowering of the increased serum glucose and triglyceride levels was reported in STZ-induced diabetic rats. Another study demonstrated that polysaccharides isolated from G. lucidum significantly increased nonenzymatic and enzymatic antioxidants and serum insulin levels, and reduced lipid peroxidation and blood glucose levels in STZ-diabetic rats[88,89]. In alloxan-induced diabetic rats, the aqueous extract of G. lucidum normalized blood glucose levels.
It was shown that G. lucidum consumption can provide beneficial effects in treating T2D by lowering the serum glucose levels through the suppression of the hepatic enzyme gene expression involved in gluconeogenesis in a clinical study showed that Ganopoly (polysaccharide fractions extracted from G. lucidum by a patented technique) efficaciously lowered blood glucose concentration in patients with confirmed T2D. It was shown that G. lucidum polysaccharides attenuated myocardial collagen cross-linking in diabetic rats, which was related to the decreased level of AGEs and augmented activities of antioxidant enzymes. Also, it was shown that ganoderol B (bioactive sterol from G. lucidum fruit body) has a strong inhibitory activity on α-glucosidase and can be proposed as a treatment for T2D. Orally administered proteoglycan extract, Fudan-Yueyang-G. lucidum, to STZ-induced diabetic rats showed a significant decrease in plasma glucose levels. It appears that there are a number of biologically active compounds to be explored in the mycelium, and future research should focus in that direction.