Iranian Medicinal Plants in Diabetes Management: A Narrative Review of Traditional Herbal Remedies and Their Hypoglycemic Effects
Abstract
Diabetes mellitus is a significant global health concern, especially in Iran. Currently, numerous oral antihyperglycemic agents and insulin are prescribed to manage diabetes. Historically, in Middle Eastern countries, medicinal herbals were used to manage diabetes in patients. Furthermore, the adverse effects of some diabetes management drugs provide an eager potential for researchers to find novel alternative treatments that reduce the side effects and also increase their efficacy. In addition, the rich history of Iranian traditional medicine reveals the vital role of traditional herbals and their compounds in treating and mitigating diabetes mellitus and its associated complications. Several studies conducted to investigate the hypoglycemic properties related to these plant species. In this narrative review, we aimed at a comprehensive study of Iranian plant species with antidiabetic properties through experimental evidence. Our review illustrated that the traditional herbal active ingredients are not well-defined, limiting their standardization. Current efforts focus on identifying these components to improve their therapeutic efficacy.
1. Introduction
1.1. An Overview of Diabetes Mellitus
Diabetes is the global health concern and prevalence challenge in the 21st century led to more efforts to found the new agents to manage it much more effective [1, 2]. Diabetes mellitus is a serious, chronic, and complex metabolic disorder of multiple etiologies with serious acute and chronic consequences [3]. Diabetes mellitus affects developing and developed countries and leads to a major socioeconomic challenge. It is estimated that 25% of the world’s population is affected by diabetes [4, 5].
A condition characterized by a malfunction in the metabolic processes, the cells within the body encounter challenges in effectively metabolizing sugar. This impairment is from an inadequate presence of insulin, a pivotal blood glucose-regulating peptide hormone, in the target tissues, either due to insulin insensitivity or an insufficient insulin supply. The inefficiency of insulin to facilitate sugar metabolism arises from the inability of the pancreas to produce an adequate quantity of insulin or when the body exhibits diminished responsiveness to the insulin it produces. Consequently, the organism resorted to breaking its fat, protein, and glycogen sources to synthesize sugar, resulting in elevated blood sugar levels. This elevation is exacerbated by the liver’s production of excess byproducts known as ketones [5–11]. Diabetes mellitus is characterized by chronic hyperglycemia with abnormalities in macromolecule metabolism due to impaired insulin secretion, insulin function, or both. Diabetes causes long-term damage, dysfunction, and failure of various organ systems (heart, blood vessels, eyes, kidneys, and nerves), leading to disability and premature death [10]. The severity of damage caused by hyperglycemia on the relevant organ systems may depend on the duration of the disease and the degree of control. Numerous symptoms such as thirst, polyuria, blurred vision, and weight loss are also associated with diabetes [10, 12].
1.2. Global and Iranian Prevalence of Diabetes Mellitus
In 2011, the worldwide prevalence of diabetes among adults aged 20 to 69 was recorded at 7.7%. Projections indicated that this figure would rise to 9% by the year 2030. The prevalence of diabetes exhibits significant variation across different regions and countries. For example, projections indicate that by 2030, the prevalence in Africa will be approximately 4.1%, whereas in Europe, North America and the Caribbean, South and Central America, and Southeast Asia, the estimated prevalence rates are 8%, 11.8%, 9.4%, and 10%, respectively, among individuals aged 20–79 years. This translates to approximately 28 million, 64.6 million, 51.2 million, 39.9 million, and 120.9 million people in these regions by 2030, contributing to a global total of 551.8 million individuals with diabetes [13, 14]. Research conducted in 2017 revealed that 415 million people were affected by this condition, with projections suggesting an increase to 642 million by 2045 [13, 15]. Furthermore, data from 2011 indicated that 11.4% (with a 95% confidence interval) of Iranian adults aged 25 to 70 were diagnosed with diabetes. Notably, the prevalence was higher among women (12.86%) compared to men (9.90%), and urban residents (12.69%) exhibited a greater prevalence than their rural counterparts (7.62%) [13]. Additional studies have estimated the annual incidence of diabetes in the Iranian population to be around 1% of the total population [16–18].
1.3. Antidiabetic Medications and Associated Complications
The major antidiabetic effects observed in the literature were hypoglycemia, hyperlipidemia, and regulation of insulin secretion. Several oral hypoglycemic drugs exert antidiabetic effects through various mechanisms, namely, sulfonylureas, biguanides, α-glucosidase inhibitors, thiazolidinediones (TZDs), and nonsulfonylurea secretions. Oral sulfonylureas, such as glimepiride and glyburide, are mainly used to lower blood sugar by stimulating insulin release from the islets of Langerhans. This is achieved by binding sulfonylurea receptors on cell membrane receptors, resulting in the closure of adenosine triphosphate-dependent potassium channels. As a result, the cell membrane depolarizes and causes calcium release. Invasion occurs by release of stored insulin from secretory granules in cells. This mechanism acts only in the presence of insulin [19, 20].
Oral hypoglycemic drugs, biguanides, act to reduce hepatic gluconeogenesis and compensate for peripheral tissue sensitivity to insulin, actions that increase insulin uptake and utilization of sugar. However, biguanides are ineffective in the absence of insulin. The best example for this class is metformin [21]. Organic cation carriers absorb metformin (with a half-life of approximately 5 h) and is not metabolized in the body and is widely distributed in various tissues such as the intestine, liver, and kidneys. The main way of elimination is through the kidneys. Metformin is contraindicated in patients with advanced renal failure, characterized by a glomerular filtration rate (GFR) of less than 30 mL/min/1.73 m2 [22]. When using metformin, a significant decrease in GFR requires dose adjustment. Patients are advised to discontinue the drug if nausea, vomiting, or dehydration occurs for any reason, as this can help prevent ketoacidosis. Before starting treatment with metformin, it is necessary to evaluate renal function [23]. Metformin may cause gastrointestinal disturbances, such as diarrhea, nausea, and dyspepsia, in approximately 30% of patients. Initiating metformin therapy at low doses usually increases tolerance. Additionally, extended-release formulations of metformin are less likely to induce gastrointestinal issues. Metformin could potentially lead to lactic acidosis, particularly in individuals with severe renal impairment. Additionally, the efficacy of metformin may diminish as diabetes progresses. While metformin is highly effective when insulin production is adequate, its effectiveness decreases after β-cell failure occurs, which leads to a Type 1 diabetes phenotype [24, 25].
Other notable oral hypoglycemic agents include TZDs, such as pioglitazone and rosiglitazone. These factors primarily increase insulin sensitivity in muscle and fat tissues and reduce hepatic glucose production a little more. TZDs function as potent and selective agonists of the peroxisome proliferator-activated receptor gamma (PPAR-γ), which is located in the liver, skeletal muscle, and adipose tissue. Activation of PPARs regulates the transcription of insulin-responsive genes that are crucial for the control of glucose transport, production, and utilization. TZDs have also been reported to enhance cellular function by reducing levels of free fatty acids, which may ultimately lead to cell death [26, 27]. Briefly, the oral antidiabetic mechanism of actions is demonstrated in Figure 1.
1.4. Iranian Medicinal Plants as an Alternative Source of Antidiabetic Drugs
Medicinal plants have the potential to be used more effectively in the treatment of diabetes and its complications. Plant-derived substances represent a significant resource for the discovery of potential lead compounds and are expected to play a crucial role in the advancement of drug development initiatives in the future. The accessibility, cost-effectiveness, and low incidence of adverse effects render herbal medicines crucial in targeted therapies, particularly in rural communities [28, 29]. Many plants serve as abundant sources of bioactive compounds, which are esteemed for their significant medicinal properties and minimal side effects. Historically, herbs have provided numerous medicinal examples, from which a substantial number of contemporary pharmaceuticals are either directly or indirectly derived [30–32].
The rising incidence of diabetes has generated considerable apprehension among healthcare professionals and the general populace. While traditional antidiabetic pharmaceuticals are accessible, herbal remedies have consistently demonstrated significant efficacy in the management of this condition [33]. Medicinal plants and herbal components, recognized for their minimal toxicity and lack of negative side effects, offer promising therapeutic alternatives for the management of diabetes [34, 35]. Numerous studies have demonstrated the advantages of utilizing herbs with hypoglycemic properties in the treatment of diabetes [36]. Table 1 presents information on a variety of plant species indigenous to Iran, encompassing a total of 39 plants classified into 30 unique genera. Notably, certain genera contain multiple species with documented antidiabetic properties. In this comprehensive narrative review, we focus on Iranian medicinal plants that have undergone validation through laboratory animal models and clinical trials for their efficacy in addressing diabetes. Moreover, Figure 2 illustrates the Iranian medicinal herbals.
| Genus | Species | Iran and other countries | Function | Reference | |
|---|---|---|---|---|---|
| 1 | Allium | Ampeloprasum | Central Asia and northern Europe | Antidiabetic | [37] |
| Sativum | China | α-Amylase inhibitor, hypoglycemic, α-glucosidase inhibitor, antihyperglycemic | [38–41] | ||
| Stipitatum | Turkey and Central Asia | Hypoglycemic, α-glucosidase inhibitor | [42] | ||
| 2 | Aloe | Vera | Africa, Mediterranean region | α-Amylase inhibitor, hypoglycemic | [43–48] |
| 3 | Berberis | Vulgaris | Moderate and semitropical regions of Asia, Europe, Africa, North America, and South America | Antidiabetic | [49] |
| 4 | Cucurbita | Ficifolia | Asia, Africa, and South America | Hypoglycemic | [50–52] |
| 5 | Cynomorium | Coccineum | Western Mediterranean, northern Africa, Arabian Peninsula, western China | Antidiabetic | |
| Songaricum | Northwestern China and Central Asia | Antidiabetic | [53] | ||
| 5 | Eucalyptus | Globulus | Tasmania and southeastern Australia | Antihyperglycemic | [54, 55] |
| 6 | Ferula | Assafoetida | Afghanistan | Antidiabetic | [56, 57] |
| 7 | Morus | Alba | China, India | Antidiabetic, hypoglycemic, α-glucosidase, and α-amylase inhibition | [58–61] |
| Nigra | Asia (Korea, Japan, China, India), North America, and Africa | Antidiabetic | [58, 62, 63] | ||
| 8 | Otostegia | Persica | India, Pakistan | Antidiabetic | [64] |
| 9 | Rheum | Ribes | Turkey, Iraq, Pakistan, Afghanistan, Russia | Hypoglycemic | [65–67] |
| Turkestanicum | Central Asia | Antidiabetic | [68] | ||
| 10 | Rhus | Coriaria | Lebanon, Syria, Jordan, Turkey | Antidiabetic | [69] |
| Canina | Europe, North Africa, West Asia | Antidiabetic | [70, 71] | ||
| 11 | Salvia | Hypoleuca | — | Antidiabetic | [72] |
| Officinalis | Europe, Central and South America, Mediterranean, and Southeast Asia | Hypoglycemic, α-glucosidase inhibitor | [42] | ||
| 12 | Terminalia | Chebula | Southeast Asia and India | α-Amylase inhibitor | [73–78] |
| 13 | Teucrium | Polium | Europe, North Africa, and southwestern Asia | Hypoglycemic | [79–81] |
| Caramanicus | — | Antidiabetic | [82] | ||
| 14 | Urtica | Dioica | Eurasia | α-Amylase inhibitor | [83–86] |
| 15 | Vaccinium | Arctostaphylos | Turkey (Black Sea region) and Bulgaria | α-Amylase inhibitor | [87] |
| 16 | Amygdalus | Lycioides | South Anatolia | Antidiabetic | [88] |
| 17 | Anethum | Graveolens | Mediterranean countries, Southeastern Europe, Southern Asia | Antidiabetic | [89, 90] |
| 18 | Camellia | Sinensis | China, South, and Southeast Asia | α-Amylase inhibitor | [91] |
| 19 | Carthamus | Tinctorius | China, India, Egypt | α-Glucosidase inhibitor | [92, 93] |
| 20 | Citrullus | Colocynthis | Algeria, Southeast Asia | Hypoglycemic | [94–96] |
| 21 | Dorema | Aucheri | — | Hypoglycemic | [97] |
| 22 | Eremurus | Persicus | — | Antidiabetic | [98] |
| 23 | Foeniculum | Vulgare | Sudan, Portugal | Antidiabetic | [99–101] |
| 24 | Hordeum | Vulgare | Scotland | Antidiabetic | [102] |
| 25 | Juglans | Regia | Algeria, Turkey, Austria, Iran | Hypoglycemic | [103–106] |
| 26 | Pimpinella | Tirupatiensis | Turkey, China, Korea, Egypt, Palestine, Lebanon, Europe | Antidiabetic | [107, 108] |
| 27 | Portulaca | Oleracea | Trinidad and Tobago, India (Ayurveda), Algeria, China (TCM), Mexico | Hypoglycemic | [109–113] |
| 28 | Raphanus | Sativus | China | Antidiabetic | [114, 115] |
| 29 | Securigera | Securidaca | Western Asia, Europe, Australia | Antidiabetic | [116, 117] |
| 30 | Trigonella | Foenum-graecum | Turkey, Algeria, Bangladesh, Pakistan, Morocco, Algeria, Mediterranean, China, India | Hypoglycemic | [118–133] |
1.4.1. Abelmoschus esculentus
Abelmoschus esculentus, commonly known as okra, is a remarkable crop of the Malvaceae family, originating in India and several northeastern African countries, including Sudan and Ethiopia [31]. Both traditional medicine and modern scientific research have emphasized the potential of okra to positively influence blood glucose and insulin levels [31, 32]. Deepasakthi et al. explored the antioxidant and antidiabetic properties of Abelmoschus esculentus (okra), a widely recognized plant with various health benefits. The plant was soaked in water overnight, and the aqueous extract was then subjected to phytochemical screening. The extract demonstrated notable antioxidant activity with an IC50 value of 280 μg/mL, comparable to vitamin C. It also showed inhibitory effects on the starch-hydrolyzing enzymes alpha-amylase and alpha-glucosidase, with IC50 values of 380 μg/mL and 320 μg/mL, respectively, similar to the standard antidiabetic drug acarbose. These findings suggest that soaking okra overnight enhances its therapeutic potential [134]. Lu et al. demonstrated that proanthocyanidins in unripe seeds of okra were relatively responsible for the α-glucosidase and α-amylase inhibitory activity [135]. Wu et al. investigated the phenolic profiles and bioactivities of five okra cultivars in China and found significant variations in their phenolic content and bioactivities. The total flavonoid content (TFC) ranged from 1.75 to 3.39 mg RE/g DW, with Shuiguo having the highest TFC. High-performance liquid chromatography identified five phenolic compounds, including isoquercitrin and quercetin-3-O-gentiobioside as the main components. All cultivars showed strong antioxidant activity and inhibitory effects on lipase, α-glucosidase, and α-amylase. Notably, Shuiguo had superior bioactivity, suggesting its potential use as a natural antioxidant and enzyme inhibitor for managing hyperlipidemia and hyperglycemia [136]. Furthermore, quercetin exhibits a potential protective effect on pancreatic beta cells against apoptosis and enhancing insulin secretion. A previous study by Erfani Majd et al. revealed that supplementing streptozotocin (STZ)-induced diabetic rats with 200 mg/kg of green okra powder had the potential to ameliorate islet structure and downregulate the expression of the PPAR-ꝩ gene, a pivotal regulator of glucose homeostasis and cellular proliferation [137]. Furthermore, Uadia et al. showed that okra improves hyperglycemia and repairs β-cell damage induced by STZ in adult Wistar rats. The treatment group exhibited a noteworthy increase in high-density lipoprotein cholesterol (HDL-C) levels and catalase activity, coupled with a significant decrease in blood glucose, total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C), and malondialdehyde levels, along with enhanced superoxide dismutase activity, when compared to the diabetic control group [138]. In a randomized double-blinded trial, Moradi et al. reported that 8 weeks of okra administration led to a notable reduction in blood glucose levels, homeostasis model assessment-insulin resistance (HOMA-IR), TG, TC, LDL-C, and LDL-C/HDL-C ratio in Type 2 diabetic (T2DM) patients. There was no considerable difference among intervention and control groups in HbA1c, HDL-C, and fasting insulin levels [139].
1.4.2. Allium ampeloprasum
Allium genus includes nearly 800 species, such as Allium cepa (onion), Allium sativum (garlic), Allium hirtifolium (shallots), and Allium ampeloprasum (leeks) [140]. It is an important genus of the Amaryllidaceae family, broadly spread in Central Asia and northern Europe. Researchers have introduced a range of secondary metabolites isolated from Allium species, including flavonoids, polyphenols, and tannins. Accumulated evidence has disclosed that Allium and its bioactive constituents contain a variety of health functions, including antioxidant, antihyperlipidemic, antimicrobial, and antidiabetic activities [141]. Notably, Allium ampeloprasum, an indigenous Iranian dietary and medicinal plant commonly referred to as Persian Leek, holds a prominent position. It ranks among the most widely cultivated vegetable products throughout Iran [142]. This vegetable is extensively consumed as food or folk remedy. Results from previous studies have underscored the efficacy of Persian Leek in the management of diabetes mellitus when administered over the course of a month. Onion and garlic are other traditional and popular plant-based foods in the Iranian food basket [143]. Numerous research endeavors have been undertaken to elucidate the glucose-lowering potential inherent in garlic and onion. These investigations have unveiled the robust antidiabetic properties of the phytochemical compounds present in these vegetables through a series of comprehensive studies, spanning in vitro, animal, and human trials. Elevated evidence suggests that onion exhibits the capacity to regulate glucose levels by inhibiting the activities of α-amylase and α-glucosidase enzymes, as substantiated by various studies [144–146]. Besides, many animal and human studies evaluated the antidiabetic activity of garlic. They reported that garlic extract reduces blood cholesterol and glucose levels by promoting insulin secretion from pancreatic cells [143, 147].
1.4.3. Aloe vera
Aloe vera belongs to the Liliaceae family and is native to tropical regions, including the southern Mediterranean region and the north of Africa [148, 149]. In Iran, Aloe vera thrives predominantly in the southern regions and is extensively utilized for both medicinal and cosmetic purposes [150]. Numerous pharmaceutical applications of Aloe vera have been documented, including antiulcer, anticancer, immunomodulatory, hypoglycemic, anti-inflammatory, antioxidant, and antidiabetic properties. Aloe vera have the numerous pharmaceutical applications such as antiulcer, anticancer, immunomodulatory, hypoglycemic, anti-inflammatory, antioxidant, and antidiabetic properties [151, 152]. Several investigations revealed the potential effect of Aloe vera on blood sugar control in T2DM patients, but the findings have been contradictory. For example, the Zarintan et al. double-blind randomized clinical trial suggested that daily administration of 1000 mg of Aloe vera for 2 months did not produce significant changes in TC, LDL, HDL, HbA1c, or FBS levels in patients with T2DM [153]. In contrast, in a comprehensive systematic review and meta-analysis including eight trials, Suksomboon et al. described Aloe vera significantly improved blood glucose and HbA1c in T2DM [154].
1.4.4. Berberis vulgaris
Berberis vulgaris, commonly referred to as Zereshk in Persian, holds a prominent place in the Iranian culinary tradition and belongs to the Berberidaceae family [155]. The various parts of Berberis vulgaris have been used in traditional medicine for more than 2500 years [156]. Iran stands as one of the world’s largest producers of Berberis vulgaris, with a production of more than 10,000 tons of dried Berberis vulgaris fruit, particularly in Southern Khorasan [155]. The alkaloid compound berberine, derived from Berberis vulgaris, plays a pivotal role. This compound exhibits a range of beneficial properties, including hypoglycemic, hypolipidemic, hypotensive, anti-inflammatory, and antioxidant activities [157]. In a randomized clinical trial, Tahmasebi et al. examined the hypoglycemics and hypolipidemic activities of the root extract of Berberis vulgaris in T2DM patients. The Berberis vulgaris extract alone at a concentration of 1000 mg per day significantly reduced blood glucose levels, fasting insulin, fructosamine, HOMA-IR, TC, and LDL-C. It increased HDL-C [158]. Furthermore, in a systematic review and meta-analysis, Safari et al. reported that Berberis vulgaris supplementation decreases the elevation of blood insulin levels in adults. They also said that Berberis vulgaris did not considerably affect other glycemic indices, including blood glucose, HOMA-IR, and glycosylated hemoglobin (HbA1c) [159].
1.4.5. Cucurbita ficifolia
Cucurbita ficifolia, commonly called pumpkin, is a member of Cucurbitaceae family and has a traditional role as a valuable culinary ingredient and a remedy in Iran. Previous findings suggested that Cucurbita ficifolia may lower blood glucose and improve insulin sensitivity and glucose tolerance [160]. The relation between the consumption of pumpkins and diabetes was investigated in different studies. In Askari et al. study, they indicated that consumption of pumpkin for 8 weeks significantly reduced TC, TG, LDL-C, blood glucose, and glycosylated hemoglobin in 80 diabetic participants [50]. Nevertheless, the precise mechanisms responsible for pumpkin’s antidiabetic activity have yet to be fully elucidated.
1.4.6. Cynomorium coccineum
Cynomorium coccineum, belonging to the Cynomorium genus within the Cynomoriaceae family, is recognized by various names, such as Maltese mushroom, fungus melitensis, champignon, and truth. This medicinal plant has a long history of traditional use to treat a wide range of ailments such as premature ejaculation, colic, and digestive disorders [161]. Besides, its primary compounds include triterpenes, flavonoids, and steroids. Pharmacological research has identify several remarkable biological properties of Cynomorium coccineum such as its antidiabetic and antioxidant characteristics [162]. Remarkably, aqueous extracts of Cynomorium coccineum have exhibited robust antioxidant activity along with inhibitory effects on α-glucosidase and α-amylase enzymes [163].
1.4.7. Eucalyptus globulus
Eucalyptus globulus (eucalyptus) is a tall, fast-growing, and evergreen tree, belongs to the Myrtaceae family, and it is originated from Tasmania and southeastern Australia [164]. In Iran, eucalyptus is broadly distributed particularly in the Sistan–Baluchestan Province. Eucalyptus globulus has been extensively used to treat and manage diabetes mellitus in Iranian traditional medicine. Its oil and leaves are employed to manage different complaints of diabetes mellitus. The therapeutic features of Eucalyptus include antiseptic, antimigraines, antirheumatism, antiparasitic, antiulcer burns, and antidiabetic [164, 165]. The antidiabetic effects of Eucalyptus were verified in STZ-diabetic rat models. Several in vivo studies revealed the oral administration of eucalyptus extract illustrated the dose-dependent glucose-lowering effect in STZ-induced diabetic rats. The hypoglycemic effects of eucalyptus are believed to be associated with its antioxidant properties [166, 167].
1.4.8. Morus
Mulberry, a member of the Morus genus within the Moraceae family, has a rich history of as both a nourishing dietary component and a therapeutic agent, particularly in the management of diabetes mellitus, in Iran and various other countries [168]. Numerous scientific investigations have provided significant evidence to support the hypoglycemic properties exhibited by Morus species. An earlier in vitro study by Nickavar and Mousazadeh highlighted the α-amylase inhibitory activity present in three distinct mulberry varieties such as Morus nigra (black mulberry), Morus rubra (red mulberry), and Morus alba (white mulberry) [169]. Recently, studies have illustrated the potent α-glucosidase inhibitory activity exhibited by certain compounds, including 1-deoxynojirimycin and its metabolites found in mulberry leaves. Researchers have discovered that some compounds, such as 1-deoxynojirimycin and its metabolites in mulberry leaves, possess strong α-glucosidases inhibitory activity [170]. Furthermore, in Europe, black mulberry leaves have historically been employed to stimulate insulin production and manage diabetes [171].
1.4.9. Otostegia persica
The genus Otostegia persica Boiss belongs to the lamiaceae family and grows in Iran, India, and Pakistan and is traditionally used to treat arthritis, hypertension, gastric discomfort, hyperlipidemia, and diabetes [172]. Several types of flavonoids have been extracted from the Otostegia persica Boiss, consisting of alpha-pinene, morin, kaempferol, and quercetin [173]. The unique properties of this plant include antioxidant, antimicrobial, antidiabetic, anti-inflammatory, antiblood pressure, and liver protection [174]. In the study of Manzari-Tavakoli et al., the properties of improving insulin secretion, reducing blood sugar, and antifat were revealed in diabetic rats of Otostegia persica Boiss extract [175]. One of the most effective mechanisms of Otostegia persica Boiss to reduce high blood glucose is to inhibit the conversion of polysaccharides into monosaccharides [174].
1.4.10. Rheum
The genus Rheum, a member of the family Polygonaceae, contains approximately 103 species and is distributed worldwide, with primary populations in China, Afghanistan, Pakistan, Turkey, Russia, and Iran [176]. In Iran, the dominant species is Rheum ribes, which is a perennial and resistant plant, commonly known as rhubarb, and is found in mountainous areas.
The root of genus Rheum has significant antioxidant properties and is traditionally used in folk medicine to treat various diseases such as ulcers, hemorrhoids, high blood pressure, obesity, diarrhea, diabetes, high cholesterol, constipation, and psoriasis [177]. Furthermore, the hypoglycemic effects of the aqueous extract of Rheum ribes have been elucidated through a series of in vivo and in vitro investigations. Notably, Ghafouri et al. conducted a double-blind randomized controlled trial to evaluate the effects of Rheum ribes supplementation on glycemic indices and apolipoproteins in patients with T2DM. 60 patients were divided into three groups for 6 weeks, who received 450 mg of aqueous extract, ethanolic extract, or placebo. Both extracts significantly decreased insulin levels, HOMA-IR, HOMA-B, ApoB, and ApoB/ApoA1 ratio, while increasing ApoA1. In addition, no significant changes were observed in blood glucose. The placebo group showed no significant changes. These results show that Rheum ribes may improve insulin resistance and apolipoprotein profile in patients with T2DM [176]. Moreover, Ghafouri et al. evaluated the impact of Rheum ribes supplementation on glycemic indices and apolipoproteins in patients with T2DM. In this randomized controlled trial, 450 mg of Rheum ribes aqueous extract and 450 mg of Rheum ribes ethanolic extract resulted in a significant reduction in serum levels of insulin, HOMA-IR, ApoB, and ApoB/ApoA1 ratio, without no substantial change in glucose levels [178].
Rheum turkestanicum is another member of the genus Rheum, which is recommended as a natural antidiabetic medicine in traditional Iranian medicine. In a study conducted by Hosseini et al., using STZ-induced diabetic rats, oral administration of hydroalcoholic extract derived from Rheum turkestanicum root (at doses of 200 and 300 mg/kg) during four weeks showed a significant effect in reducing diabetic dyslipidemia. Rheum turkestanicum revealed its antidiabetic effects by improving serum TG, TC, and LDL-C levels [179]. The potential antidiabetic properties of Rheum species are attributed to the significant presence of flavonoids and anthraquinones. Studies illustrated that these bioactive compounds activate the PPAR-γ and modulate the expression of various genes involved in lipid and glucose metabolism. Furthermore, chrysophanol, chrysophanol-8-O-β-D-glucopyranoside, and flavonoids have been found to enhance the effect of insulin on glucose internalization by stimulating GlUT4 transcription and increasing insulin receptor phosphorylation [66, 180].
1.4.11. Rhus
Rosaceae or rose family, divided into approximately 90 genera and 2500 species, is a group of plants with hypoglycemic properties, which mainly exists in Europe, North Africa, and West Asia. Among the family members, the Rosa canina species has been widely utilized as an approved natural remedy for the treatment of diabetes mellitus in Iranian traditional medicine [181]. Clinical trial studies revealed the effect of oral administration of aqueous extract of rose fruit on T2DM patients, which showed a decrease in fasting blood sugar and serum total/HDL-C without any adverse effects in the participants [182]. Also, in the in vitro study by Fattahi et al. in 2017, the antidiabetic effects of Rosa canina fruits were investigated. The researchers assessed the extract’s protective role in pancreatic β-cells and its influence on glucose metabolism in the HepG2 cell line. Findings suggested that R. canina may act as a growth factor for β-cells, indicating a novel mechanism for its antidiabetic properties. Further research is necessary to clarify its mechanisms in diabetes management [183]. Moreover, the hypoglycemic effects of Rosa canina have been confirmed in diabetic rodent models, in particular, treated with Rosa canina, a significant reduction in blood glucose levels was observed, underscoring its effectiveness in improving hyperglycemia [184]. Moreover, in an in vivo study, intraperitoneal administration of hydroalcoholic extract of Rosa canina fruit significantly reduced serum glucose, LDL-C, total, and TG concentrations in alloxan-induced diabetic rats [185].
1.4.12. Terminalia chebula
Terminalia chebula, also known as myrobalan, belongs to the genus Terminalia and the family Combretaceae and is native to South and Southeast Asia, including India, Nepal, China, Sri Lanka, and Malaysia. In Iran, myrobalan is hailed and has a long history of usage in Iranian traditional medicine to treat and manage some illnesses, including dementia, constipation, and diabetes [73]. Additionally, the combination therapy with Commiphora mukul, Commiphora myrrha, and Terminalia chebula extracts significantly improved blood glucose, lipid profiles, insulin levels, and antioxidant activity in diabetic rats, showing effects comparable to metformin. This herbal mix may offer potential as a beneficial antidiabetic and hypolipidemic treatment [75]. Myrobalan was extensively employed as an antidiabetic agent due to its antioxidant, hypoglycemic, and hypolipidemic properties [186]. At the molecular level, polyphenols emerge as the principal constituents within myrobalan, characterized by their robust antioxidant capacity, which is attributed to their proficiency in inhibiting lipid peroxidation. These properties have been validated through a multitude of both animal and human studies, which have consistently demonstrated the favorable lipid and glucose-lowering effects associated with Terminalia chebula extract [73, 74, 187, 188].
1.4.13. Teucrium
Teucrium polium, a member of the Lamiaceae family, display a wide range of biological activities, such as antioxidant, anti-inflammatory, antihyperglycemic, and hypolipidemic properties. Comprehensive investigations using in vitro and in vivo have been conducted to delineate the antihyperglycemic effects exhibited by Teucrium polium and its bioactive constituents. Teucrium polium demonstrates distinct antidiabetic attributes through a multifaceted approach, involving several key mechanisms. These mechanisms include the stimulation of insulin secretion, the attenuation of oxidative stress, the restoration of pancreatic β-cells, the facilitation of GLUT-4 translocation and subsequent glucose uptake, and the inhibition of α-amylase activity. These findings collectively underscore the comprehensive nature of its antidiabetic properties [189–192]. Moreover, in vivo study by Agrawal and Kulkarni investigated the effects of aqueous extract from Terminalia chebula fruits on T2DM rats induced by STZ. Treatment with 500 and 1000 mg/kg of the extract for six weeks significantly reduced increased plasma glucose levels and improved lipid profiles. The extract also lowered liver enzymes, enhanced insulin sensitivity, and increased antioxidant levels (glutathione and catalase). Histopathological analysis showed protective effects on pancreatic tissue, with increased SIRT1 expression. These findings suggest that Terminalia chebula extract is effective in managing T2DM [193].
1.4.14. Urtica dioica
Urtica dioica, known as nettle, is the best-known member of the genus Urtica and the family Urticaceae, native to Eurasia. Urtica dioica is very popular in folk medicine due to its hypoglycemic effect to better manage diabetes. Also, nettle extract is a traditional Iranian drink that is widely consumed as a nonalcoholic drink among Iranian diabetic patients [194]. It is hypothesized that Urtica dioica distillate may influence protein and lipid metabolisms and alter their function. Additionally, a variety of medicinal functions have been confirmed for nettle leaves, such as induction of insulin secretion and improvement of pancreatic β-cell function. Some studies also suggested that nettle extract has appreciable α-amylase and α-glucosidase inhibitory activity [195–197].
1.4.15. Vaccinium arctostaphylos
The genus Vaccinium, which consists of more than 450 species, is from the family Ericaceae and is native to the tropical mountain areas of America and Asia. The species of Vaccinium arctostaphylos, locally known as Iranian Vaccinium (Qare-Qat), is the only member of the Vaccinium genus present in Iran, which is mainly distributed in Hyrcanian forests [198]. Numerous scientific studies have decipher several biological and therapeutic activities of Qare-Qat that have made it an attractive medical and industrial plant [199]. Furthermore, in vivo study by Saliani, Montasser Kouhsari, and Izad explored the antidiabetic effects of ethanolic extract from Vaccinium arctostaphylos in diabetic rats. Results indicated that the extract significantly increased insulin and adiponectin levels while reducing free fatty acids, TNF-α, and reactive oxygen species. It enhanced activities of key hepatic enzymes related to glucose metabolism, increased glycogen content, and positively influenced gene expression linked to insulin signaling. The treatment also normalized histological abnormalities in the liver. Their findings support the hypoglycemic and hypolipidemic properties of Vaccinium arctostaphylos [200]. It has been distinguished that Qare-Qat contains several secondary metabolites such as anthocyanins, procyanidins, and flavanols, which are responsible for several biological functions, including lowering serum glucose levels and improving lipid profile and antioxidant defense system [201].
1.4.16. Amygdalus lycioides
Amygdalus lycioides Spach, a species belonging to the Amygdalus genus and Rosaceae family, is native to South Anatolia [202]. However, in Iranian traditional medicine, this plant is often known as “Badam Talkh kuhi” and has been applied as an anti-inflammatory and antimicrobial herbal relief since ancient times. Different parts of this plant are also used to cure diabetes in Iranian traditional medicine [203]. Up to this point, these compounds include flavonoids, terpenoids, phenolic compounds, and alkaloids [202]. Investigation has shown that certain flavonoids, such as quercetin, have a significant ability to significantly reduce plasma glucose concentrations. These flavonoid compounds have the potential to modulate intestinal glucose absorption by targeting GLUT2 expression or function. An additional plausible mechanism for the glucose-lowering activity of “bitter almond” extract involves the induction of insulin secretion or regeneration of pancreatic beta cells [204].
1.4.17. Anethum graveolens
Anethum graveolens, also named Dill, is a member of the Umbelliferae family (Apiaceae) and is indigenous to regions such as the Mediterranean, Southeastern Europe, Southern Asian countries, and the southeastern area of Iran [205]. Previously, various pharmacological and medicinal effects of Dill such as anticancer, anti-inflammatory, antidiabetic, antioxidant, antisecretory, diuretic, antihyperlipidemic, and antihypercholesterolemia activity have been reported [206]. A randomized clinical trial illustrated that consumption of Dill extract significantly reduced TC and LDL-C serum levels but did not change TG or HDL-C levels in T2DM patients [207]. Haidari et al. also reported that Dill extract could have beneficial effects on serum levels of insulin, glucose, HOMA-IR index, LDL-C, TC, and malondialdehyde [208].
Furthermore, Anethum graveolens plant potentially elevated the serum levels of HDL-C and total antioxidant capacity in T2DM patients [208]. In a comprehensive systematic review and meta-analysis conducted by Mousavi et al., the effect of Dill supplementation on the lipid profile and glycemic control of adult participants was fully investigated. The results of this investigation revealed a significant reduction in LDL-C levels, as well as a notable decrease in serum insulin and the HOMA-IR index. However, it is noteworthy that no significant effects were observed regarding serum TC, TGs, HDL-C, or glucose levels [209].
2. Discussion and Conclusion
This narrative review highlights the wide range of plant species with antidiabetic properties. These findings reflect long-standing studies emphasizing utilizing botanical remedies to control glucose levels and improve metabolic health. The investigated plants, such as Abelmoschus esculentus (okra) [138] and Anethum graveolens (wash) [208], demonstrated a wide range of bioactive chemicals and processes that contribute to their medicinal properties. Inhibition of the main enzymes involved in carbohydrate digestion by Abelmoschus esculentus shows a significant antidiabetic potential that significantly reduces blood glucose levels and improves lipid profile.
In addition, Berberis vulgaris revealed strong hypoglycemic and lipid-lowering effects, while its effect on some blood sugar indices needs further research. Extensive data support the glucose-lowering and insulin-sensitizing actions of Berberis vulgaris and Cucurbita ficifolia (pumpkin), but more mechanical research is needed to fully understand their mechanisms of action [158]. Besides, Cynomorium coccineum shows significant antioxidant and enzyme inhibitory properties that make it suitable for controlling diabetes by oxidative stress reduction and enzyme activity regulation [210].
Moreover, Eucalyptus globulus and some species of mulberry show a wide range of processes, such as stimulation of insulin production, reduction of oxidative stress, and facilitation of glucose absorption. Their promise in diabetes control is underscored by these findings, which also emphasize the diverse properties of their therapeutic actions [165, 171].
This review also emphasizes the role of traditional herbs such as Urtica dioica [177] (nettle) and Vaccinium arctostaphylos (Qare-Qat) which significantly help in blood sugar control and lipid management. Antioxidant and antidiabetic properties of Terminalia chebula and Teucrium polium confirm their therapeutic potential through lipid and glucose modulation [198].
Furthermore, Rheum [211], Rosa canina [212], and Amygdalus lycioides species [213] illustrated the effectiveness of plant-derived flavonoids and other bioactive compounds in increasing insulin action and regulating glucose metabolism. Also, Anethum graveolens (wash) [213] is attracting research attention with its effects on LDL-C and antioxidant status while showing variable effects on other glycemic and lipid parameters.
Overall, this review emphasizes the significant potential of these plant species in the development of natural antidiabetic treatments. The diverse mechanisms and compounds identified point to a promising future for incorporating these plants into comprehensive diabetes management strategies. Several research types, such as clinical trials and mechanistic studies, are necessary to optimize their therapeutic use and fully utilize their benefits for diabetes care [178].
Conclusively, many medicinal plants have been utilized individually or in formulations to prevent and management diabetes and/or its complications in traditional medicine. Many diabetic subjects use traditional herbal remedies in Iran despite modern medicinal drugs. To address this limitation, with these herbal formulations is that their active ingredients are not well specified. Therefore, that is important to identify the active component and molecular interactions, which will help to determine the therapeutic efficacy and standardization of the product. At present, efforts are being made to peruse the mechanism of action of some of these plants. Therefore, this documented information on the medicinal plants used in Iran may be employed as useful data for future studies.
Ethics Statement
This narrative review does not include original data collection or involve human participants as it synthesizes existing literature. Due to this, there is no need for ethical approval. Nonetheless, we confirm that all information sources used in this review are from reliable and ethical research and have been accurately presented and properly cited.
Disclosure
We declare that this narrative review was collected from existing literature and provided a comprehensive insight according to recent studies.
Conflicts of Interest
The authors declare no conflicts of interest.
Author Contributions
Mohammad Reza Afsharmanesh and Zeinab Mohammadi are co-first authors and contributed equally to this work. The final version of the article was reviewed and approved by all authors.
Funding
This narrative review was supported by the Golestan University of Medical Sciences (GOUMS) (Grant number: 114622).
Acknowledgments
I would like to express my deep appreciation to Golestan University of Medical Sciences for their support and resources.
Open Research
Data Availability Statement
This article is a narrative review based on publicly available studies and sources. All data supporting the findings of this study are sourced from published literature, as cited in the reference section. No new data were generated or analyzed specifically for this review. Therefore, data sharing is not applicable to this article.
