Phytotherapy for diabetes mellitus; A review of Middle Eastern and North African folk medicinal plants

Introduction Diabetes mellitus (DM) is a chronic metabolic disorder affecting people worldwide. According to the World Health Organization, there are currently 220 million people with type 2 DM, with expectations to increase to more than 365 million by 2030. The highest increase in disease incidence is currently in undeveloped countries in Africa and Asia and herbal medicines are mostly investigated and used for this problem in these regions (1-4). Type 1 diabetes is insulin-dependent, while type 2 or noninsulin dependent DM is treated with oral anti-diabetic medications (4,5). Drugs used to treat type 2 diabetes are not without limitations (6); for example, Metformin and Glucagon-like peptide-1 agonists are associated with gastrointestinal distress (6). Sulfonylureas usually cause hypoglycemia and weight gain, while Pioglitazone may increase the possibility of developing bladder cancer and other disorders, such as edema, heart failure, weight gain, and distal bone fractures in postmenopausal women (6), in addition to the high cost of these medications. Therefore, patients seek other methods of treatment. In lowand middle-income countries, patients rely on folk medicine as a cheaper alternative to modern pharmaceuticals. Phytomedicines or plant-based remedies are used worldwide to treat diabetes and other diseases. Many locally grown herbs have shown significant anti-diabetic effects in many countries (7,8). Their main advantages are the low cost and lower levels of adverse effects and their ability to control blood glucose levels. Therefore, delaying the development of diabetic complications. Many of these herbs enhance insulin release, boost glucose uptake by muscle or adipose tissues, http://www.herbmedpharmacol.com doi: 10.34172/jhp.2021.01


Introduction
Diabetes mellitus (DM) is a chronic metabolic disorder affecting people worldwide. According to the World Health Organization, there are currently 220 million people with type 2 DM, with expectations to increase to more than 365 million by 2030. The highest increase in disease incidence is currently in undeveloped countries in Africa and Asia and herbal medicines are mostly investigated and used for this problem in these regions (1)(2)(3)(4).
Type 1 diabetes is insulin-dependent, while type 2 or noninsulin dependent DM is treated with oral anti-diabetic medications (4,5). Drugs used to treat type 2 diabetes are not without limitations (6); for example, Metformin and Glucagon-like peptide-1 agonists are associated with gastrointestinal distress (6). Sulfonylureas usually cause hypoglycemia and weight gain, while Pioglitazone may increase the possibility of developing bladder cancer and other disorders, such as edema, heart failure, weight gain, and distal bone fractures in postmenopausal women (6), in addition to the high cost of these medications. Therefore, patients seek other methods of treatment.
In low-and middle-income countries, patients rely on folk medicine as a cheaper alternative to modern pharmaceuticals. Phytomedicines or plant-based remedies are used worldwide to treat diabetes and other diseases. Many locally grown herbs have shown significant anti-diabetic effects in many countries (7,8). Their main advantages are the low cost and lower levels of adverse effects and their ability to control blood glucose levels. Therefore, delaying the development of diabetic complications. Many of these herbs enhance insulin release, boost glucose uptake by muscle or adipose tissues, and reduce glucose absorption from the intestine and glucose yielding from the liver (7,8).
Historically, plant extracts were prepared and used either orally, topically, or by vapor inhalation for managing diseases (7,8). The Ancient Egyptians were the first to investigate the medicinal uses of castor oil, wine, opium, mints, and beer (7). In recent years, there has been an increasing interest in investigating the anti-diabetic effects of many medicinal plants, due to their wealth of biologically active material. This review aims to highlight the anti-diabetic effects of traditional plants cultivated in the Middle East and North Africa (MENA) region that has been recently used in research.

Methods
A comprehensive search using terms; Diabetes, phytotherapy, herbal medicine, folk medicine, in vivo, in vitro, and clinical trials yielded close to 20000 results spanning the period 1990 to 2020. The majority of the data available used plant extracts either in vitro or in vivo, with a minimal number (<1%) of clinical trials using plant-based therapy present in the literature. We selected mainly plants cultivated in the MENA as the primary focus for our review.

Phytoconstituents and their mechanisms of action
Plant extracts exert their function due to the presence of a wide range of phytoconstituents or chemical compounds, each with a specific mechanism in reducing blood glucose or restoring it to normal levels (9). These compounds range from alkaloids, carbohydrates, anthranoids, flavonoids, saponins, amino acids, peptidoglycans, polyphenols, glycosides to vitamins, minerals, and inorganic compounds. Each constituent works on a specific metabolic pathway (9).
Among the most common phytoconstituents in plants are alkaloids, which are nitrogen-containing chemical compounds with a wide range of therapeutic potential. Many alkaloids exert their hypoglycemic activity as a result of having alpha-glucosidase (GLA) inhibiting activity (10). GLA catalyzes the cleavage of glucose from disaccharides and oligosaccharides. This inhibition will delay the absorption time of glucose by slowing the breakdown of starch in the small intestine so that glucose can slowly enter the bloodstream. Another alkaloid, allyl propyl disulfide from Allium sativum exerts its hypoglycemic effect through affecting glycogen synthesis (11). Mostly, this happens as a result of inhibiting lactate dehydrogenase enzyme. The enzyme catalyzes the conversion of pyruvate into lactate. Carbohydrates like pectin, pectin fibers, mucilaginous fibers and guar gum from Trigonella foenum graecum, as well as glucomannan, caryophyllene, cellulose, and mannose from Aloe vera, affect insulin secretion, absorption, and digestion of carbohydrates (12). Anthranoid compounds such as chrysophanic acid and cinnamic acid from Aloe vera possibly enhance insulin secretion and synthesis. C-glycosides from Trigonella foenum graecum lower glucose levels by targeting carbohydrate metabolism and glucose transport (13).
Flavonoids are present in a wide range of plants and are considered poly-hydroxy polyphenolic compounds (14). Flavonoids such as apigenin, quercitrin, quercetin, rutin, 7-O-glucoside, and naringenin from Camellia sinensis aid the restoration of pancreatic β-cells and enhance the secretion of insulin (14). Epigallocatechin gallate, epigallocatechin, epicatechin, catechin and quercetin from Camellia sinensis and Punica granatum have free radical scavenging and insulinemic activity (14,15). Also, citrus bioflavonoids like hesperidin and naringin from Camellia sinensis target glycolysis, glycogen synthesis, and gluconeogenesis. Some peptidoglycans like Fenugreekine from Trigonella foenum graecum and glucosamines from Aloe vera are involved in glucose transport, carbohydrate digestion, and absorption (16). Sotolon and trigonelline extracted from Trigonella foenum graecum restore β cells of the pancreas and enhance insulin secretion (16). Curcumin, turmerone, zingiberene, and germacrone from Curcuma longa also improve the metabolism of glucose.
Vitamins like A and E present in a range of plants might help in controlling glucose concentration (17). Minerals such as zinc from many plants like, for example, Aloe vera improves insulin sensitivity when present in high serum levels (18). Amino acids and carboxylic acid derivatives are among the phytoconstituents of medicinal value in diabetes. For example, leucine, isoleucine, and alanine from Aloe vera stimulate insulin secretion. Also, ferulic acid extracted from Curcuma longa boosts free radical scavenging activity and the secretion of insulin (19).

MENA region anti-diabetic medicinal plants
A map of the plants cultivated in the MENA region is shown in Figure 1. A distinction between the geographic locations is shown on the map. Below we summarize the most common anti-diabetic medicinal plants cultivated and used in the region together with the most recent reported data on in vitro and in vivo experimental models of DM in  Table 3.

Limitations of using anti-diabetic Middle Eastern and North African plants
Despite the presence of previous research about many medicinal plants from both regions supporting their anti-diabetic effectiveness, some limitations might prevent the proper exploitation of these plants. Lack of standardization might be on the top of the main challenges that hinder the progress of utilizing the regions' medicinal plants. Variations in doses, anti-diabetic parameters, and duration of therapy make it challenging to determine the medicinal plant with the best reported anti-diabetic effect (20). Moreover, previous reports demonstrated that lack of data exchange among traditional herbal practitioners and between practitioners and researches might represent a threat in utilizing these plants (7). Another challenge facing the utilization of anti-diabetic plants is the continuous destruction of the plants' natural habitat as a result of climate as well as environmental changes leaving many endangered species facing the possibility of extinction in the coming few years (7) .

Discussion and future perspectives
Plant-derived products in the global market are provided mainly from either Chinese, Indian, and Western plants.
In comparison to plants from other regions, like China or India, medicinal plants from the MENA region have never been adequately investigated, explored, evaluated, or exploited. Extensive research is needed to fill the gap in information concerning safety, toxicity, contamination, possible interaction with other synthetic drugs, and proper dosage (8,20,21). Chinese traditional medicine is successfully promoted via a science-based approach. The great effort and financial support that has been put by China was evident by 3563 extracts, 64 715 compositions, and 130 kinds of Chinese herbs-derived drugs under development. Other countries and or regions could adopt this successful approach in utilizing and promoting traditional medicine to take advantage of their herbal heritage.
This review provides a summary of the anti-diabetic role of some typical Middle Eastern and North African medicinal plants through previous experiments done in vitro, in vivo, and clinical trials. From the collected data, medicinal plants from both regions not only hold a remarkable hypoglycemic potential but also help to delay the development and progression of complications through their antioxidant, hepatoprotective, renalprotective, and anti-hyperlipidemic effects.
Most In vitro studies investigated the effects of plants on the enzymes; Alpha-amylase (ALA) and GLA. The inhibition of ALA activity, together with GLA, is considered to be a successful strategy for the management of diabetes. Both ALA, which breaks down long-chain carbohydrates and GLA, which catalyzes glucose cleavage from disaccharide, is effective in delaying glucose absorption (22). In our review, in vitro GLA and ALA inhibition were consistent with exhibiting hypoglycemic effects in vivo in almost all plants included. However, plants like A. santolina and T. polium, did not inhibit GLA and ALA in vitro, although showing an anti-diabetic effect in vivo. It can be suggested that they exert their hypoglycemic effect by mechanisms other than lowering these enzymes. Time and money-saving computational chemistry tools like molecular modeling and molecular docking allow for the prediction of molecule's inhibition actions of enzymes. For example, molecules from Rosemary and Salvia can inhibit the dipeptidyl peptidase 4 (DDP4) enzyme, which is involved in the treatment of type 2 DM (23).
Animal studies in this review investigated an array of parameters to address the anti-diabetic potential of medicinal plants. Improving these parameters is essential to demonstrate efficacy. Together with fasting blood glucose (FBG) and serum insulin levels, liver parameters like alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma glutamyl transferase (γGT) were used to estimate hepatocyte injury. It is suggested that hyperglycemia promotes the accumulation    ↓: decrease, ↑: increase, X: no effect, >: more effective.

In vitro
Ethyl acetate extract of the root -↓ ALA and GLA (82) In vivo (Alloxan-induced diabetic rats) Aqueous extract of the root 500 mg/kg/d PO for 6 weeks ↓ FBG In vitro Ethyl acetate extract of the rhizomes -↓ LDL oxidation; ↑ Glucose uptake   ↓: decrease, ↑: increase, X: no effect of reactive oxygen species, accelerates cell damage, and contributes to the development and worsening of diabetic complications. Blood urea, creatinine (CRTN), and uric acid levels are indications of the kidney damage associated with hyperglycemia-caused oxidative stress. Among the investigated parameters is homeostatic model assessment of insulin resistance (HOMA-IR), which is used for the assessment of insulin resistance (24). It is suggested that hyperglycemia leads to insulin resistance in peripheral tissues as a result of the impairment of insulin secretion and sensitivity (24). Antioxidant parameters like super oxide dismutase (SOD) and glutathione peroxidase (GPx) were used to assess the antioxidant potential. Interestingly, anti-diabetic plants may contribute to protection against developing DM, as shown in some clinical trials. For example, A. vera delayed the onset of the disease in prediabetic patients (Table 3).
In conclusion, more investigations are needed to utilize medicinal plants from these regions as a source of future drugs that contribute to managing the disease more efficiently than current medications. For example, T. polium, which is grown in the Mediterranean region, showed potent glucose-lowering activity similar to insulin in one study. However, the exact hypoglycemic agents and their mechanisms of action are yet to be identified (25). That is why more research should be directed towards understanding the mechanisms responsible for the anti-diabetic activity of many plants. Finding ways to circumvent the limitations of utilizing medicinal plants is essential. A database of medicinal plants in both regions showing critical data such as usage parameters, safety, toxicity, contamination, and drug interactions might help face limitations. Pharmaceutical companies, together with government authorities, should help to provide more research and start initiatives to spread awareness among traditional practitioners and to protect endangered medicinal plant species from extinction, which will eventually pave the way for using the regions' medicinal plants commercially.
Authors' contribution SA, MB, NE contributed in designing the study, performed data collection and manuscript preparation. AA supervised and edited the manuscript. Final version of the manuscript was confirmed by all authors. SA, MB, NE contributed equally

Conflict of interests
The authors declare no conflict of interest.

Ethical considerations
No ethical approval was required for this review article

Funding/Support
This work was partially supported by a research support grant (SSE-BIOL-A.A-FY17-RG-2018) from the American university in Cairo.