Helichrysum Genus and Compound Activities in the Management of Diabetes Mellitus

The global management of diabetes mellitus (DM) involves the administration of recommended anti-diabetic drugs in addition to a non-sedentary lifestyle upon diagnosis. Despite the success recorded from these synthetic drugs, the traditional method of treatment using medicinal plants is increasingly accepted by the locals due to its low cost and the perceived no side effects. Helichrysum species are used in folk medicine and are documented for the treatment of DM in different regions of the world. This study reviews Helichrysum species and its compounds’ activities in the management of DM. An extensive literature search was carried out, utilizing several scientific databases, ethnobotanical books, theses, and dissertations. About twenty-two Helichrysum species were reported for the treatment of diabetes in different regions of the world. Among these Helichrysum species, only fifteen have been scientifically investigated for their antidiabetic activities, and twelve compounds were identified as bioactive constituents for diabetes. This present review study will be a useful tool for scientists and health professionals working in the field of pharmacology and therapeutics to develop potent antidiabetic drugs that are devoid of side effects.


Introduction
Diabetes mellitus is a very prevalent disease affecting both developed and developing countries. Concerted efforts by the International Diabetes Federation (IDF) and the American Diabetes Association (ADA) to reduce the spike in global diabetes cases and mortality have witnessed different advocacies over the past years. The IDF [1] report shows that 463 million (9.3%) adults worldwide are suffering from diabetes, and this number is projected to increase by 51% in 2030 (578 million) and 2045 (700 million). The prevalence of diabetes varies according to geographical region, with more than 80% of diabetic patients living in low-to-middle-income countries, which poses additional challenges with ineffective treatment [2]. Diabetes mellitus is caused by increased blood glucose levels (hyperglycemia) due to defects in insulin action, insulin secretion, or both [3].
The two common types of diabetes (insulin-dependent (type 1) and non-insulindependent (type 2)) occur when the body cannot properly store and use glucose. Type 1 is reported to be common in children and is controlled by an autoimmune disorder resulting in a lack of insulin production. Type 2 diabetes is prevalent among adults, characterized by insufficient insulin production and or sensitivity to glucose uptake [4]. Both types of diabetes can lead to life-threatening complications such as neurological conditions, cardiovascular disease, damage to blood vessels, kidney disease, and vision loss [5]. In general, the common symptoms of diabetes mellitus include increased hunger, numbness in hands and feet, frequent urination, excessive thirst, tiredness and fatigue, blurred vision, that take long to heal, and sexual dysfunction in men [6]. To date, there is no cure for diabetes; however, several efforts including the use of medicinal plants such as Helichrysum species are continuously targeted to find a permanent treatment for diabetes.

Conventional Treatment of Diabetes
The conventional treatment of diabetes requires oral administration of synthetic hypoglycemic agents. These synthetic hypoglycemic agents include alpha-glucosidase inhibitors (acarbose and miglitol), insulin secretagogues (meglitinides and sulfonylureas), and insulin sensitizers (thiazolidinediones, biguanides, and metformin), among others that ultimately suppress increasing plasma glucose levels ( Figure 1). These drugs are known to function in two distinct ways: (1) during glucose synthesis via enzyme inhibition of glycopolymers breakdown and, (2) insulin bioavailability via the repair of β-cells of the pancreas, thereby improving insulin release and sensitivity for glucose uptake [7]. However, despite the use of these glucose-lowering drugs for the treatment of diabetes, most of these drugs have been reported with negative side effects, such as abdominal pain, headache, dizziness, diarrhea, flatulence, and digestive discomfort [8,9]. In addition, the high cost of these drugs also limits their usage. Hence, there is a need for a cheaper and more efficient drug through the application of natural products from medicinal plants with near-zero side effects [10].

Medicinal Plants as Alternative Therapies for Diabetes
In line with some drawbacks linked with the use of current glucose-lowering (antidiabetic) drugs, medicinal plants have been reported to play a significant role and serve as alternative therapies for the treatment of diabetes mellitus [11][12][13]. This is mostly due to the presence of several antidiabetic compounds (alkaloid, phenolic, flavonoid, and tannin), thereby improving the ability of pancreatic tissues to enhance insulin secretion or reducing the intestinal absorption of glucose [14]. In addition, the least side effects, ease of availability, and lower cost also make medicinal plants the main key players in the treatment of diabetes. Recently, the number of people with diabetes cases has been growing steadily and causing increasing concerns in most developing countries. Despite the presence of several antidiabetic drugs in the pharmaceutical market, the treatment of diabetes using medicinal plants has been recommended and often successful [15]. In the

Medicinal Plants as Alternative Therapies for Diabetes
In line with some drawbacks linked with the use of current glucose-lowering (antidiabetic) drugs, medicinal plants have been reported to play a significant role and serve as alternative therapies for the treatment of diabetes mellitus [11][12][13]. This is mostly due to the presence of several antidiabetic compounds (alkaloid, phenolic, flavonoid, and tannin), thereby improving the ability of pancreatic tissues to enhance insulin secretion or reducing the intestinal absorption of glucose [14]. In addition, the least side effects, ease of availability, and lower cost also make medicinal plants the main key players in the treatment of diabetes. Recently, the number of people with diabetes cases has been growing steadily and causing increasing concerns in most developing countries. Despite the presence of several antidiabetic drugs in the pharmaceutical market, the treatment of diabetes using medicinal plants has been recommended and often successful [15]. In the literature, various research areas have reported the use of medicinal plants and their active components as alternative sources for the treatment of diabetes [16,17]. For example, Salehi et al. [18] reported the antidiabetic of medicinal plants and their active compounds. In the study, the authors described several medicinal plants with anti-diabetic potential. Duarte et al. [19] also reported naturally occurring compounds from different plant extracts exhibiting inhibition of alpha-amylase, alpha-glucosidase, and related enzymes in the management of type II diabetes. Another study by IfedibaluChukwu et al. [20] reported in vivo antidiabetic properties of isolated compounds from the methanol stem bark extract of Vernonia amygdalina using streptozotocin-induced diabetes rats. In the study, it was revealed that the isolated compound (6β, 10β, 14β-trimethylheptadecan-15α-olyl-15-O-β-D-glucopyranosyl-1,5β-olide) demonstrated a significant reduction in the blood glucose as compared to standard metformin. Studies conducted by Hasan et al. [21] reviewed a list of medicinal plants and their compounds with proven antidiabetic activities in vivo and in vitro. The antidiabetic properties of these reported plants are often attributed to their different phytochemical constituents [22]. Interestingly, these phytochemicals are well distributed in many species, including the Helichrysum species used in folk medicine for the management of diabetes. However, there are inadequate studies reporting on Helichrysum species and their compounds used for the treatment of diabetes. Considering the traditional use of Helichrysum species in many parts of the world for the treatment of diabetes, the current study was undertaken to review the Helichrysum genus on species used in the management of diabetes and identify the bioactive constituents with reported antidiabetic activities. This review study is expected to identify the present knowledge gap and provide an important baseline for future studies.

An Overview of Ethnobotanical and Pharmacological Relevance of Helichrysum Genus
The Helichrysum genus encompasses typically aromatic herbs and shrubs with dense leaves that belong to the family of Asteraceae. The genus is widely distributed worldwide but is mostly found in Africa, with its highest diversity in South Africa, where about 500 known species occur. The plants belonging to this genus are well-known as everlasting flowers with leaves oblong to lanceolate. They have been in use for more than 3000 years for various folkloric purposes [23]. In traditional medicine, some Helichrysum plant parts are either drunk as teas or prepared as "burnt offering" smoke to appeal for blessings from the ancestors and are used to purify the home of the sick patients [24]. In addition, the plant from the Helichrysum genus has also been reported in traditional medicine for the treatment of several ailments, including stomach pain, gall bladder problems, jaundice, colds, wound healing, diabetes mellitus, skin infections, and asthma [25][26][27]. Nevertheless, with the emergence of scientific data on the use of Helichrysum species in the last few decades, some of the reported traditional claims have been scientifically supported. To mention a few, Tirillini et al. [28] reported the antioxidant activity of methanol extract of Helichrysum foetidum from east Africa. Additionally, research conducted by Matić et al. [29] revealed the antitumor potential of Helichrysum zivojinii extract. Another study conducted by Süzgeç-Selçuk and Birteksöz [30] reported the antimicrobial actions of flavonoids isolated from Helichrysum chasmolycicum. Ranaivoarisoa et al. [31] also reported the anti-plasmodial effect of Helichrysum gymnocephalum from Southern Africa. The anti-inflammatory activity of Helichrysum stoechas extracts from north Africa has also been reported [32] among others. It is imperative to note that several plants belonging to the Helichrysum genus have been more extensively researched for various bioactivities than their role as antidiabetic agents.

Antidiabetic Potentials of Helichrysum Species and Metabolites in Folk Medicine
Several Helichrysum species used for the treatment of diabetes have been identified in the literature (Table 1). Despite this, not all have been scientifically investigated for their antidiabetic activity (Table 2). In addition, only a few compounds obtained from these Helichrysum species have been shown to exhibit antidiabetic activity ( Figure 2). Thus, in this section, a comprehensive description of plant species belonging to the genus Helichrysum used in the management of diabetes along with the compounds displaying antidiabetic activity will be elaborated. antidiabetic activity (Table 2). In addition, only a few compounds obtained from th Helichrysum species have been shown to exhibit antidiabetic activity ( Figure 2). Thus, this section, a comprehensive description of plant species belonging to the genus Helich sum used in the management of diabetes along with the compounds displaying antid betic activity will be elaborated.

Description and Ethnobotanical Usage
Helichrysum arenarium ( Figure 3) is a perennial herb that grows up to 50 cm in heig with a robust and short rhizome [33]. The stem of the plant is generally branched at upper part and carries alternate leaves of about 2 to 5 cm in length. H. arenarium is wid dispersed in Europe, Central Asia, and China [33]. The plant is well known in traditio medicine. The decoction from the aerial parts of H. arenarium is used for the treatment diabetes [33]. The flowers are also reported to contain constituents and bitter substan used to promote gastric and pancreatic secretion. In addition, the infusions of the H. a narium inflorescence are also used in the treatment of gallbladder disorders (rheumatis cystitis, gout, arthritis) [34].  Table 2.

Helichrysum arenarium Description and Ethnobotanical Usage
Helichrysum arenarium ( Figure 3) is a perennial herb that grows up to 50 cm in height with a robust and short rhizome [33]. The stem of the plant is generally branched at the upper part and carries alternate leaves of about 2 to 5 cm in length. H. arenarium is widely dispersed in Europe, Central Asia, and China [33]. The plant is well known in traditional medicine. The decoction from the aerial parts of H. arenarium is used for the treatment of diabetes [33]. The flowers are also reported to contain constituents and bitter substances used to promote gastric and pancreatic secretion. In addition, the infusions of the H. arenarium inflorescence are also used in the treatment of gallbladder disorders (rheumatism, cystitis, gout, arthritis) [34].

Toxicity
Kramberger et al. [36] documented the toxicity of H. arenariu thors revealed that the aqueous extract was only toxic at the hig v/v) against lymphoma (U937) cells, while the same extract displa (v/v) concentration in both the human colorectal adenocarcinom colon fibroblast (CCD112CoN) cell lines.

In Vitro Antidiabetic Study
Research conducted by Morikawa et al. [37] showed that th arenarium inhibited the dipeptidyl peptidase-IV (DPP4) activity w µg/mL.

In Vivo Antidiabetic Study
The in vivo antidiabetic studies conducted by Morikawa et a the extract showed significant inhibition against the increase in sucrose-loaded mice at a concentration of 500 mg/kg.

Toxicity
Kramberger et al. [36] documented the toxicity of H. arenarium. In the study, the authors revealed that the aqueous extract was only toxic at the highest concentration (5%, v/v) against lymphoma (U937) cells, while the same extract displayed toxicity even at 1% (v/v) concentration in both the human colorectal adenocarcinoma (Caco-2) and primary colon fibroblast (CCD112CoN) cell lines.

In Vitro Antidiabetic Study
Research conducted by Morikawa et al. [37] showed that the methanol extract of H. arenarium inhibited the dipeptidyl peptidase-IV (DPP4) activity with an IC 50 value of 41.2 µg/mL.

In Vivo Antidiabetic Study
The in vivo antidiabetic studies conducted by Morikawa et al. [37] also revealed that the extract showed significant inhibition against the increase in blood glucose levels in sucrose-loaded mice at a concentration of 500 mg/kg.

Helichrysum aureum Description and Ethnobotanical Usage
Helichrysum aureum ( Figure 4) is a perennial plant with a woody rootstock and rosette of radical leaves. It has flowering stems of 0.1-0.6 m in height with small leaves. H. aureum is native to Swaziland, Zimbabwe, Angola, South Africa, and Mozambique. In South Africa, it is broadly dispersed in the Cape provinces, KwaZulu-Natal, and Free State. Traditionally, H. aureum is used by the people of Basotho for the treatment of diabetes [38].

In Vitro Antidiabetic Study
The literature surveys revealed no reported scientific validation of the in vitro antidiabetic activity of H. aureum.

In Vivo Antidiabetic Study
To date, there are no reported in vivo studies of any extracts from H. aureum.

Antidiabetic Activity of Isolated Compounds
Literature survey revealed no reports on the antidiabetic activity of compounds from H. aureum.

Description and Ethnobotanical Usage
Helichrysum caespititium ( Figure 5) is a perennial creeping plant of 10 to 20 cm in height. The leaves of the plant are linear, clutching at the base and hairy on both sides, while its flowers are white to yellow [41]. H. caespititium is broadly distributed in Lesotho, Zimbabwe, South Africa, and Swaziland [42]. In South Africa, the whole plant of H. caespititium is cooked and then used to alleviate diabetes mellitus [43]. Additionally, the plant is also used for the treatment of some medical conditions such as wounds, ulceration, skin infection diseases, nausea, tuberculosis, bronco-pneumonia, and sexually transmitted infections [27]

In Vitro Antidiabetic Study
The literature surveys revealed no reported scientific validation of the in vitro antidiabetic activity of H. aureum.

In Vivo Antidiabetic Study
To date, there are no reported in vivo studies of any extracts from H. aureum.

Antidiabetic Activity of Isolated Compounds
Literature survey revealed no reports on the antidiabetic activity of compounds from H. aureum.

Helichrysum caespititium Description and Ethnobotanical Usage
Helichrysum caespititium ( Figure 5) is a perennial creeping plant of 10 to 20 cm in height. The leaves of the plant are linear, clutching at the base and hairy on both sides, while its flowers are white to yellow [41]. H. caespititium is broadly distributed in Lesotho, Zimbabwe, South Africa, and Swaziland [42]. In South Africa, the whole plant of H. caespititium is cooked and then used to alleviate diabetes mellitus [43]. Additionally, the plant is also used for the treatment of some medical conditions such as wounds, ulceration, skin infection diseases, nausea, tuberculosis, bronco-pneumonia, and sexually transmitted infections [27].

In Vitro Antidiabetic Study
The literature surveys revealed no reported scientific validation of the in vitro antidiabetic activity of H. aureum.

In Vivo Antidiabetic Study
To date, there are no reported in vivo studies of any extracts from H. aureum.

Antidiabetic Activity of Isolated Compounds
Literature survey revealed no reports on the antidiabetic activity of compounds from H. aureum.

Description and Ethnobotanical Usage
Helichrysum caespititium ( Figure 5) is a perennial creeping plant of 10 to 20 cm in height. The leaves of the plant are linear, clutching at the base and hairy on both sides, while its flowers are white to yellow [41]. H. caespititium is broadly distributed in Lesotho, Zimbabwe, South Africa, and Swaziland [42]. In South Africa, the whole plant of H. caespititium is cooked and then used to alleviate diabetes mellitus [43]. Additionally, the plant is also used for the treatment of some medical conditions such as wounds, ulceration, skin infection diseases, nausea, tuberculosis, bronco-pneumonia, and sexually transmitted infections [27]  Research conducted by Mamabolo et al. [45] reported the toxicity of H. caespititium. The findings of the study showed that the whole plant extracts (hexane, dichloromethane, methanol, and aqueous extracts) of H. caespititium had low-to-high toxic effects in rat hepatoma (H411E) cell lines. In the study, the highest toxicity was reported for the dichloromethane whole plant extract of H. caespititium with a lethal concentration 50 (LC 50 ) value of 82.86 µg/mL compared to the standard control, doxorubicin (LC 50 = 10.80 µg/mL).

In Vitro Antidiabetic Study
It is imperative to note that the in vitro antidiabetic activity of H. caespititium has not been scientifically investigated.

In Vivo Antidiabetic Study
To date, there has been no report on the in vivo antidiabetic activity of H. caespititium in the literature.

Antidiabetic Activity of Isolated Compounds
Presently, information on the antidiabetic activity of isolated compound from H. caespititium is very scanty in the literature.

Helichrysum graveolens Description and Ethnobotanical Usage
Helichrysum graveolens ( Figure 6) is an herbaceous plant belonging to the Helichrysum genus, with grey-bushy foliage and thin everlasting flower-heads. The plant is native to Eastern Europe, Caucasus, Turkey, Iran, and South Africa [46]. Traditionally, the decoction from H. graveolens has been reported to be active in the treatment of diabetes mellitus in several regions of South Africa, Anatolia, and Turkey [46]. The capitulums of the plant are also reported to be consumed for the treatment of jaundice, diuretic, and wound healing in the rural districts of Anatolia [46].

Toxicity
Research conducted by Mamabolo et al. [45] reported the toxicity of H. caespititium. The findings of the study showed that the whole plant extracts (hexane, dichloromethane, methanol, and aqueous extracts) of H. caespititium had low-to-high toxic effects in rat hepatoma (H411E) cell lines. In the study, the highest toxicity was reported for the dichloromethane whole plant extract of H. caespititium with a lethal concentration 50 (LC50) value of 82.86 µg/mL compared to the standard control, doxorubicin (LC50 = 10.80 µg/mL).

In Vitro Antidiabetic Study
It is imperative to note that the in vitro antidiabetic activity of H. caespititium has not been scientifically investigated.

In Vivo Antidiabetic Study
To date, there has been no report on the in vivo antidiabetic activity of H. caespititium in the literature.

Antidiabetic Activity of Isolated Compounds
Presently, information on the antidiabetic activity of isolated compound from H. caespititium is very scanty in the literature.

Description and Ethnobotanical Usage
Helichrysum graveolens ( Figure 6) is an herbaceous plant belonging to the Helichrysum genus, with grey-bushy foliage and thin everlasting flower-heads. The plant is native to Eastern Europe, Caucasus, Turkey, Iran, and South Africa [46]. Traditionally, the decoction from H. graveolens has been reported to be active in the treatment of diabetes mellitus in several regions of South Africa, Anatolia, and Turkey [46]. The capitulums of the plant are also reported to be consumed for the treatment of jaundice, diuretic, and wound healing in the rural districts of Anatolia [46].

Toxicity
Studies on the toxicity of H. graveolens revealed no toxicity activity displayed by the plant against the tested cells [48,49]. Kutluk et al. [48] investigated and reported that the whole plant aqueous and ethanol extracts were not toxic to Vero African green monkey kidney cell lines, even at the highest tested concentration of 64 µg/mL. Yazdi et al. [49] supported these results, whereby they reported no toxicity effects of the aerial parts aqueous extract of H. graveolens in C26 colon carcinoma cells up to 5.0 µg/mL concentration.

Toxicity
Studies on the toxicity of H. graveolens revealed no toxicity activity displayed by the plant against the tested cells [48,49]. Kutluk et al. [48] investigated and reported that the whole plant aqueous and ethanol extracts were not toxic to Vero African green monkey kidney cell lines, even at the highest tested concentration of 64 µg/mL. Yazdi et al. [49] supported these results, whereby they reported no toxicity effects of the aerial parts aqueous extract of H. graveolens in C26 colon carcinoma cells up to 5.0 µg/mL concentration.

In Vitro Antidiabetic Study
Several reports have confirmed the antidiabetic activities of H. graveolens. Orhan et al. [50] revealed that the hydroethanolic extract from H. graveolens exhibited 55.7% inhibition at a concentration of 3000 µg/mL against alpha-amylase enzyme. In the same study, the authors also showed that the same extract demonstrated significant inhibition against the alpha-glucosidase enzyme with IC 50 values of 0.7129 mg/mL.

In Vivo Antidiabetic Study
A study by Aslan et al. [46] showed that the aqueous and ethanol extracts of H. graveolens significantly reduced blood glucose levels in streptozotocin-induced diabetic rats at a 500 mg/kg dose concentration.

Antidiabetic Activity of Isolated Compounds
A literature search revealed no report of antidiabetic compounds from H. graveolens.

Helichrysum gymnocomum Description and Ethnobotanical Usage
Helichrysum gymnocomum (Figure 7) is a straggling aromatic perennial herb with pleasantly scented flowers. The stems of the plant are often decumbent and rooting at the base while the leaves are very variable and pleasantly scented [24]. H. gymnocomum grows abundantly in the Eastern Cape and KwaZulu-Natal provinces of South Africa [51]. In addition, the plant is also native to Lesotho. Traditionally, the decoction of the fresh leaves of the plant is taken orally for the treatment of diabetes [52]. In Vitro Antidiabetic Study Several reports have confirmed the antidiabetic activities of H. graveolens. Orhan et al. [50] revealed that the hydroethanolic extract from H. graveolens exhibited 55.7% inhibition at a concentration of 3000 µg/mL against alpha-amylase enzyme. In the same study, the authors also showed that the same extract demonstrated significant inhibition against the alpha-glucosidase enzyme with IC50 values of 0.7129 mg/mL.

In Vivo Antidiabetic Study
A study by Aslan et al. [46] showed that the aqueous and ethanol extracts of H. graveolens significantly reduced blood glucose levels in streptozotocin-induced diabetic rats at a 500 mg/kg dose concentration.

Antidiabetic Activity of Isolated Compounds
A literature search revealed no report of antidiabetic compounds from H. graveolens.

Description and Ethnobotanical Usage
Helichrysum gymnocomum (Figure 7) is a straggling aromatic perennial herb with pleasantly scented flowers. The stems of the plant are often decumbent and rooting at the base while the leaves are very variable and pleasantly scented [24]. H. gymnocomum grows abundantly in the Eastern Cape and KwaZulu-Natal provinces of South Africa [51]. In addition, the plant is also native to Lesotho. Traditionally, the decoction of the fresh leaves of the plant is taken orally for the treatment of diabetes [52]

In Vitro Antidiabetic Study
No reported in vitro studies were found in the literature.

In vivo antidiabetic study
No reported in vivo studies were found in the literature.

Antidiabetic activity of isolated compounds
Bioactive constituents in diabetes from H. gymnocomum are yet to be reported.

In Vitro Antidiabetic Study
No reported in vitro studies were found in the literature.

In vivo antidiabetic study
No reported in vivo studies were found in the literature.

Antidiabetic activity of isolated compounds
Bioactive constituents in diabetes from H. gymnocomum are yet to be reported.

Helichrysum italicum Description and Ethnobotanical Usage
Helichrysum italicum (Figure 8) is a small evergreen shrub that grows on dry, rocky, and sandy ground. It has small leaves with a revolute margin and woody stems at the base and is 60 cm or more in height. H. italicum is native to Mediterranean countries such as Turkey, Portugal, Italy, and Greece [54]. The infusion or decoction of the plant is traditionally used for the treatment of diabetes [55]. In addition, infusion and decoction are also used to treat dermatologic, digestive, and respiratory disorders.

Description and Ethnobotanical Usage
Helichrysum italicum (Figure 8) is a small evergreen shrub that grows on dry, rocky, and sandy ground. It has small leaves with a revolute margin and woody stems at the base and is 60 cm or more in height. H. italicum is native to Mediterranean countries such as Turkey, Portugal, Italy, and Greece [54]. The infusion or decoction of the plant is traditionally used for the treatment of diabetes [55]. In addition, infusion and decoction are also used to treat dermatologic, digestive, and respiratory disorders. The study reported that the infusion was not toxic up to 5% v/v concentration in U937 cells, whereas for Caco-2 it was toxic at 1% v/v. A higher concentration (2% v/v) was toxic for CCD112CoN cells than for cancerous cell line Caco-2. Staver et al. [58] and Gismondi et al. [59] independently showed that H. italicum essential oil exhibited toxicity effects against HeLa human cervix adenocarcinoma (IC50 = 0.075 mg/mL) and MCF-7 human breast cancer (IC50 = 0.057 mg/mL) cells, as well as B16F10 murine melanoma, respectively, in a dose-dependent manner. Nostro et al. [60], in their research study assessing the genotoxicity of H. italicum, found that the diethyl ether extract of the plant exhibited no DNA damaging activity, even at the highest concentration (2000 g/disc).

In Vitro Antidiabetic Study
Research on the in vitro antidiabetic activity of H. italicum has been investigated [55,61,62]. The study conducted by Pereira et al. [55] revealed that the water-based preparation (infusion and decoction) from H. italicum flowers exhibited moderate inhibition of alpha-glucosidase activity compared to the control at 10 mg/mL. In the research study by de la Garza et al. [61], the methanol:water (1:1) extract of H. italicum was reported to exhibit significant inhibitory activity against both alpha-glucosidase and alpha-amylase enzymes, with IC50 values of 0.19 and 0.83 mg/mL, respectively. Aćimović et al. [62], in their research study, showed that H. italicum essential oil had strong inhibitory activity on alpha-glucosidase enzyme (62.02%) at the tested concentration (250 mg/mL).

In Vivo Antidiabetic Study
The in vivo study reported by de la Garza et al. [61] demonstrated that H. italicum methanol:water (1:1) extract reduced blood glucose levels, thereby improving postprandial glycemic control in rats. In a separate study [63], it was shown by the authors that the methanol:water (3:1) extract of H. italicum ameliorated hyperglycaemia in db/db mice. Another research study [64] revealed that the methanol:water (3:1) extract of H. italicum

Toxicity
Toxicity studies involving H. italicum have mainly been concerted in vitro [57]. Kramberger et al. [36] evaluated cell viability on lymphoma cell line (U937), adenocarcinoma cell line (Caco-2), and primary colon fibroblasts (CCD112CoN) after exposure to the aerial parts infusion of H. italicum. The study reported that the infusion was not toxic up to 5% v/v concentration in U937 cells, whereas for Caco-2 it was toxic at 1% v/v. A higher concentration (2% v/v) was toxic for CCD112CoN cells than for cancerous cell line Caco-2. Staver et al. [58] and Gismondi et al. [59] independently showed that H. italicum essential oil exhibited toxicity effects against HeLa human cervix adenocarcinoma (IC 50 = 0.075 mg/mL) and MCF-7 human breast cancer (IC 50 = 0.057 mg/mL) cells, as well as B16F10 murine melanoma, respectively, in a dose-dependent manner. Nostro et al. [60], in their research study assessing the genotoxicity of H. italicum, found that the diethyl ether extract of the plant exhibited no DNA damaging activity, even at the highest concentration (2000 g/disc).

In Vitro Antidiabetic Study
Research on the in vitro antidiabetic activity of H. italicum has been investigated [55,61,62]. The study conducted by Pereira et al. [55] revealed that the water-based preparation (infusion and decoction) from H. italicum flowers exhibited moderate inhibition of alphaglucosidase activity compared to the control at 10 mg/mL. In the research study by de la Garza et al. [61], the methanol:water (1:1) extract of H. italicum was reported to exhibit significant inhibitory activity against both alpha-glucosidase and alpha-amylase enzymes, with IC 50 values of 0.19 and 0.83 mg/mL, respectively. Aćimović et al. [62], in their research study, showed that H. italicum essential oil had strong inhibitory activity on alpha-glucosidase enzyme (62.02%) at the tested concentration (250 mg/mL).

In Vivo Antidiabetic Study
The in vivo study reported by de la Garza et al. [61] demonstrated that H. italicum methanol:water (1:1) extract reduced blood glucose levels, thereby improving postprandial glycemic control in rats. In a separate study [63], it was shown by the authors that the methanol:water (3:1) extract of H. italicum ameliorated hyperglycaemia in db/db mice. Another research study [64] revealed that the methanol:water (3:1) extract of H. italicum markedly reduced hyperinsulinemia and insulin resistance induced by high-fat sucrose (HFS) diet in insulin-resistant rats (at 2 g/kg concentration).

Antidiabetic Activity of Isolated Compounds
Presently, no studies have been reported on the antidiabetic activity of isolated compounds from H. italicum.

Helichrysum nudifolium Description and Ethnobotanical Usage
Helichrysum nudifolium (Figure 9) is a fast-growing plant with a light-yellow inflorescence and shiny green leaves. The plant's flowering stalks can reach 1.5 m in height. It is very easy to grow in the garden and is widely found in South Africa. In South Africa, it is one of the most important species culturally, medicinally, and historically [65]. Traditionally, the fresh leaves or roots of H. nudifolium are boiled and taken orally for the treatment of diabetes [66]. Additionally, the leaves and roots are also used as traditional medicine for wound dressing, internal sores, and chest complaints [65].

Antidiabetic Activity of Isolated Compounds
Presently, no studies have been reported on the antidiabetic activity of isolat pounds from H. italicum.

Description and Ethnobotanical Usage
Helichrysum nudifolium (Figure 9) is a fast-growing plant with a light-yello rescence and shiny green leaves. The plant's flowering stalks can reach 1.5 m in h is very easy to grow in the garden and is widely found in South Africa. In South A is one of the most important species culturally, medicinally, and historically [65 tionally, the fresh leaves or roots of H. nudifolium are boiled and taken orally for t ment of diabetes [66]. Additionally, the leaves and roots are also used as tradition icine for wound dressing, internal sores, and chest complaints [65].

In Vitro Antidiabetic Study
The literature search revealed no reported in vitro antidiabetic activity of H lium.

In Vivo Antidiabetic Study
To date, there are no reported in vivo antidiabetic activities of H. nudifolium.

Antidiabetic activity of isolated compounds
Regrettably, there are no reports on the antidiabetic activity of the isolat pounds from H. nudifolium.

In Vitro Antidiabetic Study
The literature search revealed no reported in vitro antidiabetic activity of H. nudifolium.

In Vivo Antidiabetic Study
To date, there are no reported in vivo antidiabetic activities of H. nudifolium.

Antidiabetic activity of isolated compounds
Regrettably, there are no reports on the antidiabetic activity of the isolated compounds from H. nudifolium.

Helichrysum odoratissimum Description and Ethnobotanical Usage
Helichrysum odoratissimum (Figure 10) is an aromatic, branched perennial plant with small grey leaves [69]. The leaves of the H. odoratissimum vary from linear-oblong, lingulate, to lanceolate. This plant has a yellow flowerhead borne in clusters at the tips of the twigs. H. odoratissimum is broadly found in South Africa, Mozambique, Zimbabwe, Lesotho, and Malawi [69]. In South Africa, it is found in the Eastern Cape across the mountains and coastal areas. In traditional medicine, the infusion from the whole plant is taken orally to treat diabetes [66]. In Lesotho, the whole plant part is mixed with other plants as herbal medicine to treat backache [69].

Description and Ethnobotanical Usage
Helichrysum odoratissimum (Figure 10) is an aromatic, branched perennial pl small grey leaves [69]. The leaves of the H. odoratissimum vary from linear-oblon late, to lanceolate. This plant has a yellow flowerhead borne in clusters at the tip twigs. H. odoratissimum is broadly found in South Africa, Mozambique, Zimbabw tho, and Malawi [69]. In South Africa, it is found in the Eastern Cape across the mo and coastal areas. In traditional medicine, the infusion from the whole plant is take to treat diabetes [66]. In Lesotho, the whole plant part is mixed with other plants a medicine to treat backache [69].

In Vivo Antidiabetic Study
The in vivo antidiabetic activity of the aqueous leaf extract of H. odoratiss alloxan-induced rats was demonstrated by Ngagi et al. [72]. The results indicated H. odoratissimum extract substantially lowered blood glucose levels in diabetic non-dose-dependent manner (between 50 to 150 mg/kg body weight).

Antidiabetic Activity of Isolated Compounds
To date, there are no reported studies involving the antidiabetic activity of t pounds from H. odoratissimum.

Description and Ethnobotanical Usage
Helichrysum plicatum (Figure 11) is a species belonging to the Helichrysum gen simple and broad leaves. It is an herbaceous perennial plant that grows up to 0

In Vivo Antidiabetic Study
The in vivo antidiabetic activity of the aqueous leaf extract of H. odoratissimum in alloxan-induced rats was demonstrated by Ngagi et al. [72]. The results indicated that the H. odoratissimum extract substantially lowered blood glucose levels in diabetic rats in a non-dose-dependent manner (between 50 to 150 mg/kg body weight).

Antidiabetic Activity of Isolated Compounds
To date, there are no reported studies involving the antidiabetic activity of the compounds from H. odoratissimum.

Helichrysum platicum Description and Ethnobotanical Usage
Helichrysum plicatum ( Figure 11) is a species belonging to the Helichrysum genus with simple and broad leaves. It is an herbaceous perennial plant that grows up to 0.24 m in height. H. platicum is widely found in Balkan, Iran, and Anatolian Peninsulas [73]. The infusion prepared from the plant is used to suppress diabetes symptoms [74].
Plants 2022, 11, x height. H. platicum is widely found in Balkan, Iran, and Anatolian Peninsulas [ infusion prepared from the plant is used to suppress diabetes symptoms [74].

In Vitro Antidiabetic Study
To the best of our knowledge, there are no reported of in vitro antidiabetic st H. plicatum.

In Vivo Antidiabetic Study
A research study indicated by Aslan et al. [78] revealed the in vivo antidiabet ity of H. plicatum aqueous and ethanol extracts in normal and streptozotocin-ind abetic rats. In the study, the results showed that the aqueous and ethanol extracts strated significant antihyperglycemic activity at a concentration of 500 mg/kg body as compared with tolbutamide used as a positive control.

Description and Ethnobotanical Usage
Helichrysum petiolare ( Figure 12) is a vigorous shrub with silver-gray hair c the aromatic round-shaped leaf [80]. It is one of the well-known and most used m of the Helichrysum genus. The plant grows to about 0.5 to 1 m in height with it whitish-cream in color. H. petiolare is found in the drier inland parts of South Afric inces, such as the Eastern Cape and KwaZulu-Natal [81]. In South African tradition icine, the infusion of the whole plant is taken orally to treat diabetes [66]. In addi decoction of the leaves of H. petiolare is used to improve skin texture and for wou ing [82].

In Vitro Antidiabetic Study
To the best of our knowledge, there are no reported of in vitro antidiabetic studies of H. plicatum.

In Vivo Antidiabetic Study
A research study indicated by Aslan et al. [78] revealed the in vivo antidiabetic activity of H. plicatum aqueous and ethanol extracts in normal and streptozotocin-induced diabetic rats. In the study, the results showed that the aqueous and ethanol extracts demonstrated significant antihyperglycemic activity at a concentration of 500 mg/kg body weight as compared with tolbutamide used as a positive control.

Helichrysum petiolare Description and Ethnobotanical Usage
Helichrysum petiolare ( Figure 12) is a vigorous shrub with silver-gray hair covering the aromatic round-shaped leaf [80]. It is one of the well-known and most used members of the Helichrysum genus. The plant grows to about 0.5 to 1 m in height with its flower whitish-cream in color. H. petiolare is found in the drier inland parts of South African provinces, such as the Eastern Cape and KwaZulu-Natal [81]. In South African traditional medicine, the infusion of the whole plant is taken orally to treat diabetes [66]. In addition, the decoction of the leaves of H. petiolare is used to improve skin texture and for wound healing [82].

Toxicity
An extensive search of the literature revealed at least three documen vestigating the toxicity of H. petiolare [40,84,85]. Lourens et al. [40] reported roform:methanol (1:1) extract of H. petiolare had toxic effects on glioblas transformed human kidney epithelial (Graham), and breast adenocarcin cells at 0.1 mg/mL, showing 76%, 59%, and 33% activity, respectively. Aladejana et al. [84] revealed that the whole plant ethanol extract of H. pe strated significant toxicity in L6 myocytes cells and HepG2 (C3A) hepa µg/mL concentration. Sagbo and Otang-Mbeng [85] in their toxicity asse methanol extract of H petiolare also reported that the extract was toxic a mouse melanoma cells and MeWo human melanoma cells in a dose-depen The same group [85] also reported the genotoxicity of the plant extract (met the Vero cell line at the highest three concentrations tested (50, 100, and 20 In Vitro Antidiabetic Study The in vitro antidiabetic potential of H. petiolare using hum (HepG2/C3A) and rat skeletal (L6) myoblast cell lines has been shown [84] the study indicated that the whole plant boiled and cold aqueous extracts significantly increased glucose uptake in L6 and HepG2/C3A cell lines at 50 µg/mL, respectively. In the same study, it was also indicated that the ext alpha-amylase and alpha-glucosidase activities in a dose-dependent manne to the respective positive controls. In another study [86], the aqueous aceton petiolare was shown to display an increased glucose uptake in HepG2 cells tion-dependent manner and had moderate inhibitory effects against alph alpha-glucosidase activity compared to the acarbose, the positive contr study.

In Vivo Antidiabetic Study
To the best of our knowledge, there are no antidiabetic studies reporte

Toxicity
An extensive search of the literature revealed at least three documented studies investigating the toxicity of H. petiolare [40,84,85]. Lourens et al. [40] reported that the chloroform:methanol (1:1) extract of H. petiolare had toxic effects on glioblastoma (SF-268), transformed human kidney epithelial (Graham), and breast adenocarcinoma (MCF-7) cells at 0.1 mg/mL, showing 76%, 59%, and 33% activity, respectively. The work of Aladejana et al. [84] revealed that the whole plant ethanol extract of H. petiolare demonstrated significant toxicity in L6 myocytes cells and HepG2 (C3A) hepatocytes at 100 µg/mL concentration. Sagbo and Otang-Mbeng [85] in their toxicity assessment of the methanol extract of H petiolare also reported that the extract was toxic against B16F10 mouse melanoma cells and MeWo human melanoma cells in a dose-dependent manner. The same group [85] also reported the genotoxicity of the plant extract (methanol) against the Vero cell line at the highest three concentrations tested (50, 100, and 200 µg/mL).

In Vitro Antidiabetic Study
The in vitro antidiabetic potential of H. petiolare using human hepatoma (HepG2/C3A) and rat skeletal (L6) myoblast cell lines has been shown [84]. The results of the study indicated that the whole plant boiled and cold aqueous extracts of H. petiolare significantly increased glucose uptake in L6 and HepG2/C3A cell lines at 25 µg/mL and 50 µg/mL, respectively. In the same study, it was also indicated that the extracts inhibited alphaamylase and alpha-glucosidase activities in a dose-dependent manner as compared to the respective positive controls. In another study [86], the aqueous acetone extract of H. petiolare was shown to display an increased glucose uptake in HepG2 cells in a concentrationdependent manner and had moderate inhibitory effects against alpha-amylase and alphaglucosidase activity compared to the acarbose, the positive control used in the study.

In Vivo Antidiabetic Study
To the best of our knowledge, there are no antidiabetic studies reported in vivo.

Material and Methods
A comprehensive literature survey was carefully conducted from August 2021 to February 2022. A report about the Helichrysum genus used traditionally in the management of diabetes was retrieved from various scientific databases such as Science Direct, Medline, Scopus, Web of Science, PubMed, Google Scholar, and Medline. In addition, ethnobotanical books, theses, and dissertations were also retrieved from various university libraries. The keywords and terms used during the search to obtain relevant articles or research papers were "Helichrysum species", "diabetes", "traditional medicine", and "ethnopharmacology".

Conclusions and Recommendations
The present study reviews the Helichrysum genus and its compounds' activities in the management of diabetes mellitus. Out of the twenty-two Helichrysum species reported for the management of diabetes, only fifteen species have been scientifically evaluated, and many of these reported species exhibited their antidiabetic through inhibition of carbohydrate hydrolyzing enzymes (alpha-amylase and alpha-glucosidase) and reduction of blood glucose levels in streptozotocin-induced diabetic rats. The antidiabetic effects of these plants are attributed to several antidiabetic compounds, and only a few bioactive compounds have been identified in some species. However, it is worth noting that effort should be made to isolate more antidiabetic compounds from these species. In addition, an effort also needs to be devoted to the mechanism of antidiabetic action (in vitro and in vivo studies) of many previously explored and unexplored Helichrysum species.