Medicinal Components in Edible Mushrooms on Diabetes Mellitus Treatment

Mushrooms belong to the family “Fungi” and became famous for their medicinal properties and easy accessibility all over the world. Because of its pharmaceutical properties, including anti-diabetic, anti-inflammatory, anti-cancer, and antioxidant properties, it became a hot topic among scientists. However, depending on species and varieties, most of the medicinal properties became indistinct. With this interest, an attempt has been made to scrutinize the role of edible mushrooms (EM) in diabetes mellitus treatment. A systematic contemporary literature review has been carried out from all records such as Science Direct, PubMed, Embase, and Google Scholar with an aim to represents the work has performed on mushrooms focuses on diabetes, insulin resistance (IR), and preventive mechanism of IR, using different kinds of mushroom extracts. The final review represents that EM plays an important role in anticipation of insulin resistance with the help of active compounds, i.e., polysaccharide, vitamin D, and signifies α-glucosidase or α-amylase preventive activities. Although most of the mechanism is not clear yet, many varieties of mushrooms’ medicinal properties have not been studied properly. So, in the future, further investigation is needed on edible medicinal mushrooms to overcome the research gap to use its clinical potential to prevent non-communicable diseases.

The term "diabetes mellitus" or "DM" is derived from the Greek word "diabetes", which means siphon, to pass through, and the Latin word "mellitus", which means sweet. Diabetes mellitus is a group of non-communicable metabolic diseases characterized by prolonged hyperglycemia resulting from defects in insulin secretion, insulin action, or both [20]. According to American Diabetes Association, 1997 (ADA), diabetes mellitus is classified as type 1 diabetes mellitus (T1DM) (insulin-dependent or juvenile-onset; accounting for 3-10% cases), type 2 diabetes mellitus (T2DM) (non-insulin-dependent or adult-onset; accounting 85-90% cases), and gestational diabetes mellitus (hyperglycemia occurs during the second or third trimester of pregnancy and generally resolves after delivery; accounting 2-5% cases) [21,22]. According to the International Diabetes Federation Data in 2015, 415 million people (80% from middle-and low-income family) was suffering from diabetes, and if it continues to grow will reach 642 million people by 2040 [23]. T1DM is generally accompanied by an autoimmune disorder that triggers the destruction of pancreatic beta cells, alterations in lipid metabolism, enhanced hyperglycemia-mediated oxidative stress, endothelial cell dysfunction, and apoptosis [24,25]. Whereas T2DM causes glucotoxicity, lipotoxicity, endoplasmic reticulum-induced stress, and apoptosis, which finally leads to progressive loss of beta cells [26]. Specific symptom includes polydipsia, polyphagia, polyuria, and nocturia, whereas complication comprises microvascular (retinopathy, nephropathy, and neuropathy) and macrovascular (ischemic heart disease, peripheral vascular disease, and cerebrovascular disease) abnormalities. Several studies have proven that insulin resistance (IR) is the main factor to be concerned about in complications of DM [26][27][28]. Besides IR, some of the common risk factors for insulin resistance are oxidative stress, hydrolytic enzymatic inhibition, inflammation, genetic habitual, environmental, dyslipidemia, obesity, and epigenetic modulations [29,30]. Thus, many pathological factors use to contribute to insulin resistance, although the exact mechanism is not clear yet.
By considering the following factors, the main aim of this review is to elucidate the role of edible mushroom (EM) in diabetes mellitus (DM) treatment by monitoring bioactive compounds of mushrooms, pathophysiology of insulin resistance (IR), and the preventive mechanism of IR using EMs. The data were retrieved by searching scientific publications (research and/or review papers) from databases including Science Direct, PubMed, Embase, and Google Scholar with keywords such as "diabetes", "insulin resistance", "mushroom extracts", "in vivo and in vitro studies", etc. A total of 100 publications were collected, including in vivo and in vitro studies (Figure 1), in which 23 common edible mushroom varieties have been identified (Table 1), and further discussion has been carried out based on scientific literature availability on DM.

Calocybe indica
Milky white mushroom

Lenzites betulina
Wood-rooting fungi [47] [47] 18 Pholiota microspora Slippery mushroom 23 Termitomyces robustus Termitomyces mushrooms [53] We further investigated different species of edible mushrooms and presented the data based on hypoglycemic compounds. After considering the potential bioactive compounds, in vivo and in vitro research analysis was carried out, and the information is represented in Table 2. [51] 22 Agrocybe aegerita 23 Termitomyces robustus Termitomyces mushrooms [53] We further investigated different species of edible mushrooms and presented the data based on hypoglycemic compounds. After considering the potential bioactive compounds, in vivo and in vitro research analysis was carried out, and the information is represented in Table 2. [52] 23 Termitomyces robustus Termitomyces mushrooms 20 Lentinula edodes Shiitake mushroom [50] 21 Hypsizygus tessellatus Buna shimeji [51] 22 Agrocybe aegerita Poplar mushroom, Chestnut mushroom, Velvet pioppini [52] 23 Termitomyces robustus Termitomyces mushrooms [53] We further investigated different species of edible mushrooms and presented the data based on hypoglycemic compounds. After considering the potential bioactive compounds, in vivo and in vitro research analysis was carried out, and the information is represented in Table 2.

Diabetes Mellitus and Insulin Resistance
Nowadays, the global incidence of diabetes is escalating in both developed and developing countries. Generally, obesity is directly involved in the pathogenesis of T2DM along with insulin resistance (IR), and the incidence of IR in T1DM is also increasing frequently. Therefore, it is crucial to understand the mechanism of glucose homeostasis and insulin resistance.
Pancreatic cell plays an important role in glucose homeostasis. T2DM reduces insulin secretion by 50% and also lessens the sensitivity of peripheral tissue to insulin up to 70%. So, the study on IR has a great clinical significance in medical interventions. Basically, insulin exerts its effect through phosphorylation of phosphoinositide 3-kinase (PI3K) and protein kinase B (PkB, Akt) [72,73]. Next, through PI3k phosphorylation, it activates glucose transporter 4 (GLUT4). Other factors involved in insulin action and carbohydrate metabolism are serine/threonine kinase Akt phosphorylates GSk3 ß, FOXOs, IRS (insulinregulated sequence), and SREBP-1c (sterol-regulated element-binding protein transcription factors) (Figure 2) [74].
Insulin sensitivity can be defined as a pathological condition in which normal plasma insulin level in targeted tissues fails to maintain normal blood glucose levels via enhancement of endogenous glucose production, lipogenesis, and glycolysis [75]. Thereby, IR refers to a state that exhibits the reduced biological effect of a given insulin concentration. So, IR increases insulin secretion and thus enhances fasting plasma insulin level, which is finally considered IR [76]. Moreover, IR is not only associated with DM but also several pathological conditions such as cardiovascular disease, non-alcoholic fatty liver disease, and cancer as well [77]. Relationship between liver insulin resistance and macronutrients. ChREBP-carbohydrate response element-binding protein, INSR-insulin receptor, SREBP-1c-sterol-regulated elementbinding protein, mTORC1-mammalian target of rapamycin complex 1 or mechanistic target of rapamycin complex 1.

Diabetes Mellitus and Insulin Resistance Preventive Mechanism by Edible Mushroom
Mushrooms possess medicinal components due to the presence of different types of secondary metabolites such as polysaccharides, lectins, lactones, terpenoids, alkaloids, antibiotics, and metal-chelating agents [78]. Mechanism of insulin resistance using mushroom is as follows.

Blood Glucose-Lowering Effect of Polysaccharide
Polysaccharides are ubiquitous biopolymers made up of simple sugar or monosaccharides linked together by glycosidic linkage. Based on structure, polysaccharides are divided into two groups-homopolysaccharides (linear or highly branched, composed of the same monosaccharide molecules) and heteropolysaccharides (made up of different monosaccharide units) [79]. Earlier studies show that mushrooms are rich in ß-D-glucans, ß-glucan, a type of dietary fiber that shows promising health benefits against T2DM [80]. Mushroom extracts from Pleurotus species [56], Boletu [58], Grifola frondosa [81], Agaricus bisporus [38], Hericium erinaceus [63], and Ganoderma lucidum [82] regulate the synthesis of glycogen and lowers blood glucose levels by regulating gene expression of glycogen synthase kinase (GSK-3 ß), glycogen synthase (GS) and glucose transporter 4 (GLUT4) in liver and muscle. Therefore GSK-3 ß could be identified as an insulin-mediated GSregulated negative regulator [83]. Other mechanisms by which polysaccharides prevent insulin resistance are by reducing α-amylase activity, α-glucosidase activities, and finally facilitating PI3K/AKT pathways, which are directly involved in glucose homeostasis [78].
Other mechanisms by which polysaccharides lowers blood glucose level is as follows-

Maintains Pancreatic ß Cells Activity
Mushrooms polysaccharides (ß-D-glucan) act as a potent immune modulator and prevent activations of pro-inflammatory cytokines by reducing the activity of NF-kB, and it also outlawed oxidative damage. Bioactive compounds from mushrooms, especially polysaccharides, prevent pancreatic ß-cell apoptosis and hinder glucotoxicity [80]. Studies also showed that mushroom extracts from Pleurotus spp., Boletus, Agaricus bisporus, and Hericium erinaceus have a significant effect on ß-cell functionality and thus maintain ß-cell growth [63].

Role of Vitamin D in Blood Glucose Regulations
Mushroom resides from the fungal kingdom, and unlike a plant, it has a high concentration of ergosterol in the cell wall. In the presence of sunlight, ergosterol in the mushroom cell wall is transformed to pre-vitamin D2 and thermally isomerized to ergocalciferol, commonly known as vitamin D2 [90]. 1, 5 (OH) 2D or 1,25-dihydroxy vitamin D plays an important role in glucose homeostasis. It also protects ß-cells from harmful immune attacks by its direct action on ß-cells, and indirect action on different immune cells, including inflammatory macrophages, dendritic cells, and a variety of T cells [91]. Molecular mechanisms by which vitamin D maintains insulin secretion is by regulating intracellular calcium concentration. Vitamin D, with the help of calbindin, facilitates Ca+ absorption, PKA activation, and PLC synthesis, which facilitates calcium secretion that, in consequence, leads to insulin secretion [92] (Figure 4). Subsequently, the genomic mechanism of vitamin D action is mediated by the vitamin D receptor (VDR). The active form of vitamin D 1,25 (OH)2 D3 binds to VDR and forms a heterodimer with the retinoid receptors (RXR). The complex of 1,25 (OH)2 D3-VDR-RXR is translocated to the nucleus and binds to vitamin D-responsive elements (VDRE), thereby facilitating epigenetic modulations and preventing insulin resistance [93].
In short, vitamin D shows its function in different ways, such as inherited gene polymorphism, immune-regulatory functions, proliferation preventive actions, anti-inflammatory activities (decreases the functions of pro-inflammatory cytokines, TNF-α, IL-8b, and IL-6), and finally regulates the production of adipokines and thereby prevents insulin resistance (via IRS, AKT, PPARy, and VDRE gene regulations) [94] (Table 3). The bioavailability of vitamin D in diabetic treatment is still controversial, and based on the available data, it is not yet transparent among scientists [95]. However, recent findings from randomized placebo trial data by Urbain et al., 2011 shows that button mushroom treated with UV-B can improve vitamin D2 bioavailability among human subjects, and the significant value does not differ with vitamin D2 supplements [96].  [97][98][99][100]. Therefore, the question remains the exact mechanism and dose-dependent action of vitamin D on diabetes mellitus treatment.

Conclusions
In the present review, a total of 23 edible mushrooms have been scrutinized to review the medicinal components and diabetes mellitus preventive activities. Among all the varieties, 13 varieties have anti-diabetic properties. Mushrooms' anti-diabetic activity is generally dependent on their polysaccharide (ß-D-glucan) and vitamin D contents. Therefore, in vivo and in vitro studies show that among 13 varieties, only 11 verities demonstrated anti-diabetic activities. Additionally, the most widely studied variations are Pleurotus, Grifola, and Ganoderma species. Thus, based on the available data, it can be concluded that mushrooms are beneficial fungi that have a great potential to treat non-communicable diseases, especially diabetes. However, future research work is necessary for the clinical field such as animal study (in vivo and in vitro), enzyme inhibition assay (α-amylase, αglucosidase, pancreatic lipase, and DPP4-dipeptidyl peptidase 4), human trial, pilot study, as well as prospective and retrospective studies to use the possible therapeutic applications of mushrooms. Special focus must be given to the link between vitamin D and insulin resistance along with enzymatic assay by considering its potential effect. Furthermore, without adequate investigation, the conclusion is relatively challenging. So, further revelation is recommended in the clinical probe.

Data Availability Statement:
The data that support the findings of this study are available from the corresponding author upon reasonable request.