Potential Application of Some Lamiaceae Species in the Management of Diabetes

Diabetes is one of the most dangerous metabolic disorders, with high rates of mortality worldwide. Since ancient times, medicinal plants have been used in traditional medicine to treat many diseases, including diabetes and its related complications. Plants are widely accepted, affordable, and perceived to have minimal adverse side effects. The Lamiaceae family is a potential source of therapeutic agents for the management of metabolic disorders, including diabetes. Hence, this review paper summarizes the antidiabetic use of Lamiaceae species in folk medicine globally. Furthermore, we present the antidiabetic activities and phytochemical constituents of twenty-three (23) Lamiaceae species and the antidiabetic activity of some notable chemical constituents isolated from some of these Lamiaceae species.


Introduction
Diabetes mellitus (DM) is one of the most dangerous metabolic disorders, causing high mortality rates worldwide [1]. It is well known that insulin plays a crucial role in glucose homeostasis, as it activates the transport of blood glucose inside the skeletal muscle [2]. However, insulin resistance in target tissues and the shortage of insulin production from pancreatic β-cells are the principal attributes of type 2 diabetes. Additionally, type 2 DM characterization also encompasses a decrease in peripheral glucose uptake within the muscle, adipose, or liver cells and an increase in endogenous glucose secretion, causing increased blood glucose concentration [3][4][5]. Therefore, agents with the ability to activate glucose uptake in these tissues can ameliorate insulin resistance and treat diabetes [6]. Many synthetic antidiabetic drugs such as acarbose, sulfonylurea, miglitol, metformin, and thiazolidinedione are already present in the market. However, their effectiveness is restricted because of their high cost and adverse side effects [7,8], which incentivize the development of powerful natural antidiabetic products/drugs with minimal adverse side effects.
The family possesses significant economic value, as it contains some horticultural species and culinary herbs, such as rosemary, salvia, ocimum, and leonotis. They are well reputed because of the high level of aromatic compounds within their leaves, flowers, and essential oils. These compounds are pharmacologically active terpenoids that play vital roles in developing new bioactive products within the cosmeceuticals, nutraceuticals, 3.2. Ballota nigra L.

Traditional Uses
Ballota nigra is native to the Mediterranean region and predominantly found in Europe and Asia [21].
People in many parts of Turkey use the aerial parts of B. nigra traditionally to treat haemorrhoids, wounds, ulcers, animal bites, sores, flu, colds, and flatulence, and as an antiseptic for inflamed skin, wounds, burns, and diabetes mellitus [21,22].

Antidiabetic Activity
A 70% ethanol extract of Ballota nigra has been reported to possess hypoglycaemic, insulin-releasing, and cholesterol-lowering effects in rats [22].

Traditional Uses
Becium grandiflorum is endemic to Ethiopia and Eretria. It occurs in Kenya and Tanzania [23].
The fresh leaves of B. grandiflorum are traditionally used to treat many ailments such as malaria, bacterial infections, diabetes mellitus, wound healing, influenza, respiratory depression, and inflammatory disorders [24].

Phytochemical Constituents
The predominant vacuolar flavonoid of B. grandiflorum is the 8-O-glucoside of isothymusin, while the significant external flavonoids are isothymusin and cirsimaritin [23].

Antidiabetic Activity
The hydroalcoholic extract of B. grandiflorum has been reported to exhibit significant antihyperglycemic activity (p 0.05) in STZ-induced diabetic mice. It also showed a considerable amelioration in oral glucose tolerance and body weight, which justified this species' potential usage in managing diabetes mellitus complications in Ethiopian folk medicine [25].

Traditional Uses
Calamintha officinalis is native to the northern part of Iran [26]. It is widely distributed in Southern and Central Europe, Western Asia, and North Africa [27].
Different parts of C. officinalis (stem, leaves, and seeds) are used to treat different diseases, including lowering the blood glucose level in diabetic patients [28,29].

Phytochemical Constituents
The phytochemical studies of the aerial part of C. officinalis revealed the presence of polyphenolic compounds, such as chlorogenic, caffeic, hydroxycinnamic, and rosmarinic acids [30].

Antidiabetic Activity
The bio-evaluation of the aqueous extract of C. officinalis showed significant hypoglycaemic activity in normal and streptozotocin-induced diabetic rats without modifying the concentrations of basal plasma insulin [31]. Additionally, the aqueous extract of C. officinalis demonstrated remarkable hypoglycaemic activity in normal and STZ diabetic rats without influencing the basal plasma insulin concentrations [30]. The antidiabetic and antioxidant activities of the crude extract and its isolates (rosmarinic and caffeic acids) from the aerial parts of C. officinalis revealed that both rosmarinic and caffeic acids are prominent natural agents for controlling diabetes [30].

Traditional Uses
Coleus forskohlii is native to India. It is widely distributed in Nepal, Thailand, and Sri Lanka [32].

Phytochemical Constituents
Forskolin was the first labdane diterpene isolated from the root of Coleus in 1974 [32]. Additionally, forskolin derivatives such as forskolin E, F, G, and H were isolated from the same source [37]. The phytochemistry of Coleus is mainly composed of diterpenes [35]. Approximately 20 constituents have been found in different parts of the plant, whereas forskolin and coleonols are the most predominant phytochemicals of the root [34]. Other minor diterpenes such as 9-deoxyforskolin, deactylforskolin, 9-dideoxy-7-deacetylforskolin, and 1,9-dideoxy-7-deacetylforskolin have been isolated from the root extract. Additionally, 1,6-diacetoxy-9-deoxyforskolin, forskolin I, forskolin J, and forskolin L were isolated from Chinese Coleus [37]. Two more diterpenoids, such as 6-acetyl-1,9-dideoxy forskolin and 6-acetyl-1-deoxyforskolin, were also reported. Another three new minor labdane diterpene glycosides, forskoditerpenoside C-E, and a novel labdane diterpene forskoditerpene A were isolated from the ethanolic extract of the whole plant [37]. Coleonol E and F were reported from Indian Coleus. Coleol and coleosol were isolated from the roots. Coleon O and S and plectrin were reported from the leaves of Kenyan Coleus [35]. The presence of 3-hydroxyisoforskolin and 3-hydroxy forskolin was also mentioned in the same source [37].

Antidiabetic Activity
The leaves of Coleus have been reported to have a wide range of pharmaceutical applications, including in diabetes and weight loss [34]. The extract of Coleus has been reported to attenuate/reduce the hypoglycaemic action of tolbutamide via a hepatic CYP2Cmediated mechanism [38]. Forskolin, the main predominant constituent of C. forskohlii, has been reported to stimulate glucose-induced insulin secretion in the in vitro model [37,39].  [40].

Antidiabetic Activity
The 50% aqueous ethanolic extract of H. suaveolens has been reported to possess significant antihyperglycemic activity in streptozotocin-induced diabetic rats and decrease the cholesterol and triglyceride levels in a significant manner [43]. The aerial part of H. suaveolens has been reported to possess antidiabetic and antioxidant properties [41].

Traditional Uses
Lavandula angustifolia is native to the northern region of Jordan and the Mediterranean region (France, Spain, and Italy) [44].
L. angustifolia has been used in Jordanian folk medicine since ancient times in the management of diabetes [45][46][47].

Antidiabetic Activity
A bio-evaluation of the methanolic extract of L. angustifolia regarding the management of diabetic dyslipidaemia demonstrated that L. angustifolia can inhibit HSL and PL activities in a dose-dependent manner, with IC 50 values of 175.5 and 56.5 µg/mL, respectively. The inhibitory activity demonstrated by L. angustifolia could be attributed to the presence of rosmarinic acid with IC 50 values of 125.2 and 51.5 µg/mL for PL and HSL, respectively, and gallic acid with IC 50 values of 10.1 and 14.5 µg/mL for PL and HSL, respectively, which are the major compounds of L. angustifolia [45].

Traditional Uses
Lavandula dentata occurs in the Mediterranean and Saharan regions [50]. L. dentata is traditionally used in various parts of the world to treat gastrointestinal, diabetes mellitus, nervous, and rheumatic ailments [51].

Phytochemical Constituents
Phytochemical studies showed that triterpenoids (ursolic acid), flavonoids (luteolin), and coumarins (umbelliferone) were the main phytochemical constituents of the aerial parts of L. dentata [52]. Additionally, three classes of secondary metabolites, such as phenolic compounds, terpenes, and alkaloids, are predominantly found in L. dentata [53]. L. dentata has been reported to exhibit hypolipidemic, antioxidant, and hypoglycaemic activities. It has also been reported to reduce blood sugar levels (p 0.05) [54].

Traditional Uses
Lavandula multifida is native to south-western Europe, the Mediterranean, and North Africa (from Morocco to Egypt) [55].

Antidiabetic Activity
L. multifida has been reported to possess antioxidant and antihypolipidemic activities [58]. Additionally, it has been also reported for its potent hypoglycaemic activity [55].

Traditional Uses
Lavandula stoechas is widely distributed in Morocco, Tunisia, Algeria, Spain, France, Greece, Italy, Turkey, Iran, and Saudi Arabia and around the Mediterranean basin [59].
L. stoechas is used in traditional Tunisian medicine to treat depression, headaches, and diabetes [60].

Antidiabetic Activity
L. stoechas has been reported to reduce blood sugar levels [60,62]. The aerial parts of L. stoechas effectively protect against increases in the blood glucose level, and a decrease in the antioxidant activities was observed [60].
3.11. Leonotis leonurus (L.) R.Br 3.11.1. Traditional Uses Leonotis leonurus is native to Southern Africa. It is widely distributed in the Eastern and Western Cape, Kwazulu-Natal, and Mpumalanga provinces [63].
L. leonurus (leaves and stems) is traditionally used in South Africa to treat diabetes, coughs, colds, influenza, chest infections, hypertension, eczema, epilepsy, menstruation delayed, intestinal worms, and constipation [63,64]. The tea prepared from the whole plant is utilized for piles, arthritis, bladder and kidney diseases, cancer, obesity, and rheumatism [65].

Antidiabetic Activity
L. leonurus has been reported to lower the blood glucose level in streptozotocininduced diabetic rats. Additionally, L. leonurus' aqueous extract has antihyperglycaemic and antilipidemic activities. Its aqueous leaf extract induced a significant (p 0.05-0.001) hypoglycaemic effect in rats, which was ascribed to different diterpenoids, polyphenolics, flavonoids, and other phytochemical constituents of the plant extract [66].

Traditional Uses
Leonotis nepetifolia is native to tropical and subtropical Africa and has been naturalized worldwide [67].
L. nepetifolia is traditionally used to treat kidney diseases, rheumatism, dysmenorrhea, bronchial asthma, diarrhoea, fever, influenza, colds, and coughs as well as adult-onset type-2 diabetes mellitus [68]. In India, the plant is used for skin problems, malaria, and rheumatism. The plant is also used to treat asthma and epilepsy in South Africa [69].

Antidiabetic Activity
The bio-evaluation of the ethanolic extract of the whole plant of L. nepetifolia exhibited a potent antidiabetic activity in diabetic rats [72].

Traditional Uses
Marrubium vulgare is native to the Mediterranean Sea region and widely distributed in many temperate regions of North Africa, Asia, and Europe [73].
M. vulgare is used in Morocco, Mexico, and Algeria in the treatment of diabetes mellitus [74,75].

Antidiabetic Activity
Scientific studies on M. vulgare have demonstrated through in vivo research the hypoglycaemic effect of M. vulgare, which supports its traditional use in controlling diabetes mellitus [80]. M. vulgare has been reported to possess hypoglycaemic and antioxidant activities. The 80% ethanolic extract of M. vulgare showed a moderate alpha-glucosidase inhibitory activity, with an IC 50 value of 12.66 µg/mL [78,81]. The methanolic extract exhibited a considerable decrease in blood glucose and a significant increase in plasma insulin and tissue glycogen contents [82]. The administration of an infusion from the aerial parts of M. vulgare significantly decreased the blood glucose level in a dose-dependent manner in alloxan-induced diabetic rats [83]. The ethanolic extract from the root considerably suppressed the increase in the plasma glucose level in healthy rats [83]. Moreover, M. vulgare shows an antidiabetic effect by suppressing the carbohydrate absorption from the intestine and thereby reducing the postprandial increase in the blood glucose level [74]. The oral administration of the aqueous extract induced significant antidiabetic and antihyperlipidemic dose-dependent effects in treated animals [75]. M. vulgare significantly lessen the blood glucose level, pancreatic levels of interferon-gamma and nitric oxide, total cholesterol, low-density lipoprotein (LDL), and very LDL cholesterol and triglycerides compared with diabetic mice [79]. The methanolic extract was found to have PPARγ agonist activity in a luciferase reporter assay. PPARγ adjusts the glucose and lipid metabolism and its synthetic agonists such as pioglitazone ameliorate insulin resistance, thus it is clinically employed for diabetes therapy [84].

Traditional Uses
Ocimum gratissimum is native to Asia and South Africa [85]. O. gratissimum is widely used in Africa and Asia for treating diabetic symptoms. It is traditionally utilized in Western Africa and Nigeria as a febrifuge, antimalarial, anticonvulsant, antimicrobial, and antioxidant agent and for the treatment of high fever, epilepsy, diarrhoea, mental illness, and diabetes mellitus [86]. The plant is also used in Africa to treat bacterial and fungal infections, fever, colds, stomach upset, haemorrhoids, catarrh, and diabetes [87][88][89][90].

Antidiabetic Activity
The methanolic and aqueous extracts of the leaves showed hypoglycaemic activity. Additionally, the aqueous extract at the dose of 500 mg/kg significantly decreased the blood glucose level (p 0.05) of diabetic rats by 81.3% after 24 h of extract administration [93]. The leaf extract was reported to have antidiabetic activity in streptozocin-induced diabetic rats [88]. O. gratissimum decreased the baseline blood glucose levels in normal and alloxaninduced rats [94]. The leaf extract showed a potential plasma glucose lowering effect [95].
The aqueous extract showed anti-hyperglycaemic and antioxidant potentials. The hypoglycaemic effect of the methanolic extracts showed a decrease in the blood glucose level of 69% and 56% for alloxan-induced diabetic and normal rats, respectively [96].

Traditional Uses
Ocimum sanctum is native to India and is widely distributed in Australia, Malaysia, West Africa, and Arab countries [97].
O. sanctum is used worldwide to reduce the risk factors associated with several disorders, including hypoglycaemia [98].

Antidiabetic Activity
The aqueous suspension considerably decreases the blood glucose level (P 0.0001) and oxidative stress with a significant increase in glycogen and protein in diabetic rats [96,98]. A 70% ethanol extract of the leaves of O. sanctum has been reported to significantly decrease the blood glucose level in both normal and streptozotocin-induced diabetic rats [96]. In vivo studies of the ethanolic extract have also shown a decrease in the blood glucose level and an increase in the plasma insulin activity in type 2 diabetes mellitus. Another study showed a significant decrease in diabetic symptoms (polyphagia, polydipsia, and tiredness) in type 2 diabetic patients who consumed the leaf powders of O. sanctum [96]. Additionally, the ethanol extract activates insulin production from the perfused pancreas, isolated islets, and clonal pancreatic cells [100]. The leaf extracts of O. sanctum have been shown to have anti-hyperglycaemic effects by increasing the insulin secretion from isolated islets, the perfused pancreas, and clonal pancreatic β-cells [96,101].

Traditional Uses
Ocimum basilicum is native to Africa and Asia [96,102]. Basil improves digestion and is also suitable for curing epistaxis when mixed with camphor. The infusion of O. basilicum is useful in cephalagia, fever, coughs, gouty joints, otitis, snake bites, stomach problems, and gout and is given internally to treat cystitis, nephritis, and internal piles. The infusion of basil seed is used to treat gonorrhoea, chronic dysentery, diarrhoea, and diabetes mellitus [103,104].

Phytochemical Constituents
The phytochemical analysis of the aqueous extract of O. basilicum showed the presence of tannins, saponins, and cardiac glycosides [103]. Phenolic acids, caffeic acid derivatives, and flavonol-glycosides are the main constituents found in O. basilicum [103].

Antidiabetic Activity
The aqueous extract significantly lowered both plasma triglycerides (TG) and cholesterol in acute hyperlipidaemia induced by Triton WR-1339 in rats [105]. The aqueous extract of the whole plant exhibited a hypoglycaemic effect in normal and streptozotocin diabetic rats [106]. Furthermore, the methanol-dichloromethane extract of the leaves has anti-hyperglycaemic effects [96]. The extracts have been reported to possess different pharmacological effects, including blood glucose-lowering and hepatoprotective properties [107]. The extract of the aerial parts possessed antidiabetic effects, which might be mediated by limiting glucose absorption through the inhibition of carbohydrate metabolizing enzymes and the enhancement of hepatic glucose mobilization [107].
The extract demonstrated significant dose-dependent inhibition against rat intestinal sucrose, maltose, and porcine pancreatic alpha-amylase [108]. The ethanolic extract of the leaves exhibited hepatoprotective effects against H 2 O 2 -and CCl 4 -induced liver damage [108].

Traditional Uses
O. canum is native to tropical Africa [109]. O. canum is used for the treatment of various types of diseases, including lowering blood glucose [107]. The leaves of O. canum are used for the treatment of diabetes in Ghana [110,111].

Antidiabetic Activity
O. canum has been reported to inhibit the growth of cataracts in diabetic patients. Aqueous extracts of the leaves showed anti-hyperglycaemic activity [111].
The total extract demonstrated a significant (p 0.01) decrease in blood glucose levels and ameliorated other altered biochemical parameters which were related to diabetes. Moreover, histopathological modifications of the pancreas were also observed in streptozotocin-induced diabetic rats [96].

Traditional Uses
Rosmarinus officinalis is native to the Mediterranean region, and it is one of the most popular evergreen culinary herbs cultivated worldwide, including in South America [112].

Antidiabetic Activity
Rosemary extract and its polyphenols (carnosic and rosmarinic acids) have been reported to possess significant antidiabetic effects in different in vivo models of type 2 diabetes and insulin-like effects in insulin target cells in in vitro models [117].
The aqueous extract has been reported to potentially reduce the oxidative stress induced by streptozotocin and blood glucose levels [118]. Rosemary was found to demonstrate significant alpha-glucosidase inhibitory activity (60% decreases) [114].

Traditional Uses
Salvia lavandulifolia is native to the Iberian Peninsula. It is widely distributed in the Mediterranean area, mainly from the east of Spain to the Western Mediterranean, south east France, and north west Africa (Morocco and Algeria) [119].

Phytochemical Constituents
The main phytochemical constituents of the aerial parts of S. lavandulifolia are flavonoids and terpenoids. Diterpenoids are the main compounds found in the roots. The herb presents phenolic monoterpenoids, flavones, and rosmarinic acid [119]. Numerous compounds, such as ursolic acid and galdosol, were reported from the same source [120].

Antidiabetic Activity
The bio-evaluation of the hypoglycaemic activity of S. lavandulifolia demonstrated that this plant significantly decreases the blood glucose levels in alloxan-diabetic rabbits [121].

Traditional Uses
Salvia officinalis is native to the Southern Europe and Mediterranean areas; it is a perennial round shrub widely naturalized throughout the world [122].
S. officinalis is used against diabetes mellitus in many countries [123]. S. officinalis is used in Asia and Latin America's folk medicine to treat different kinds of diseases, such as seizure, gout, ulcers, rheumatism, dizziness, inflammation, tremor, diarrhoea, paralysis, obesity, and diabetes [124].

Antidiabetic Activity
S. officinalis has been reported to have a wide range of pharmaceutical applications, including hypoglycaemic and hypolipidemic effects. Additionally, S. officinalis has been reported to have a hypoglycaemic effect on diabetic animals and be beneficial for type 2 diabetic patients due to its ability to reduce liver glucose production [123,126]. The methanolic extracts of S. officinalis have considerably decreased serum glucose levels in type 1 diabetic rats. The aqueous extract of S. officinalis has been found to possess insulinlike effects [123].
Infusions (tea) of S. officinalis have been reported to reduce liver glucose production and increase insulin action. S. officinalis has been demonstrated to be as powerful as metformin, a well-known oral antidiabetic drug utilized for the treatment of type 2 diabetes [123].

Traditional Uses
Salvia fruticosa is native to the Eastern Mediterranean area and Jordan [15]. S. fruticosa has also been utilized for improving memory and as a hypoglycaemic agent [127].

Phytochemical Constituents
Three flavonoids named luteolin, apigenin, and rutin, in addition to three phenolic acids named ferulic, gallic, and rosmarinic acids, were identified from the aerial parts. Moreover, dehydro-abietic acid and carnosol were isolated from the root [128].

Antidiabetic Activity
S. fruticosa has been reported to possess hypoglycaemic activity by reducing the intestinal absorption of glucose [129]. This plant is well known for its antidiabetic activities in Jordan. The oral administration of a 10% leaf infusion of 0.25 g/kg BW caused a significant reduction in blood glucose levels in alloxanized rabbits without exerting any effect on normal ones [15].

Traditional Uses
Teucrium polium is native to Southwest Asia and the Mediterranean region. It widely distributed in nearly all the Mediterranean countries, Europe, south-western Asia, and North Africa [130].
T. polium is traditionally used for the treatment of different kinds of pathological conditions, such as diabetes, inflammations, gastrointestinal disorders, and rheumatism [131]. It is also used by Iranians for its anti-inflammatory, antipyretic, diuretic, diaphoretic, tonic, antispasmodic, antihypertensive, analgesic, antibacterial, and antidiabetic effects [132]. In southern Iran, many type 2 diabetic patients use the aqueous extract made from the dried aerial parts of T. polium as an antidiabetic drug [130].

Phytochemical Constituents
Phytochemical investigations of T. polium have revealed that various classes of compounds such as terpenoids, flavonoids, iridoids, and sterols are present in its aerial part and root. Numerous flavonoids such as salvigenin, luteolin, apigenin, cirsiliol, rutin, cirsimaritin, and eupatorin have been reported from the roots and aerial parts. Additionally, two iridoid glycosides, teuhircoside and teucardoside, have been isolated from a hydrophilic fraction [130]. Several steroidal compounds, such as stigmasterol, β-sitosterol, campesterol, clerosterol, and brassicasterol, have also been isolated from the same source [133].

Antidiabetic Activity
T. polium and its isolates have been reported to have a broad spectrum of pharmacological applications, including hypoglycaemic and hypolipidemic effects. T. polium enhanced insulin secretion by nearly 135% after a single dose of the plant extract (equivalent to 0.1 mg plant leaf powder per mL of the culture medium) at a high glucose concentration (16 mmol/L). Its aqueous extract (50 mg/kg) significantly (p 0.05) decreased the serum glucose levels of diabetic Sprague-Dawley male rats from 283.622.1 to 96.211.9 mg/dL [130].
T. polium extract has been reported to reverse the symptoms of streptozotocin-induced diabetes in rats by adjusting the pancreatic transcription factor pancreas/duodenum homeobox gene-1 (Pdx1) and forkhead transcription factor (FoxO1) expressions [134].
T. polium showed a considerable decrease in the blood glucose level of STZ-diabetic rats and demonstrated protective effects on pancreatic tissue in STZ-induced oxidative stress based on its strong oxidative capacity. Furthermore, T. polium showed weak alphaamylase inhibitory activity (5%) [15].

Traditional Uses
Teucrium cubense is native to northern and tropical Africa, and it is widely distributed in Coastal Germander, sandy clay, Padre, and the Matagorda Islands [135].
T. cubense is considerably employed in the Mexican folklore to treat type 2 diabetes. It is used as an oral hypoglycaemic agent in Saudi Arabia and North Africa [15].

Antidiabetic Activity
The aqueous extract of T. cubense has been reported to decrease plasma glucose levels in healthy rabbits. Additionally, 70 µg/mL of T. cubense extract activated glucose uptake by 112% (murine) and 54% (human) in insulin-sensitive cells. At the same time, it induced the incorporation of glucose by 69% (murine) and 31% (human) in insulin-resistant adipocytes [135].
According to the scientific databases consulted for this review, twenty-three plant species of the Lamiaceae family, belonging to twelve (12) genera, are used for managing and treating diabetes mellitus worldwide (Table 1). Table 1 also provides relevant information regarding the plant species, part of the plant used, mode of preparation, and geographic locations of their traditional uses for diabetes. Teucrium cubense Jacq. Mexican, Saudi Arabia, and North Africa Hypoglycaemic activity [15,135]

Compounds Plant Source Biological Activity/Mode of Action References
Rosmarinic acid

C. officinalis Rosemary S. lavandulifolia O. canum
Hypoglycaemic effect Significant antidiabetic effects in different in in vivo models and insulin-like effects in insulin target cells in in vitro models of type 2 diabetes [30,63] Caffeic acid C. officinalis S. officinalis Hypoglycaemic effect [30] Forskolin

Compounds Plant Source Biological Activity/Mode of Action References
Rosmarinic acid

C. officinalis Rosemary S. lavandulifolia O. canum
Hypoglycaemic effect Significant antidiabetic effects in different in in vivo models and insulin-like effects in insulin target cells in in vitro models of type 2 diabetes [30,63] Caffeic acid C. officinalis S. officinalis Hypoglycaemic effect [30] Forskolin

C. forskohlii
Glucose-induced insulin secretion Decreases fasting blood glucose levels Enhances the glucose-mediated stimulus Induces cells to release insulin Decreases basal glucose in healthy rats Attenuates the severity of hyperglycaemia in diabetic Rats [33] Marrubiin L. leonurus Increases the level of insulin and glucose transporter-2 gene expressions in INS-1 cells [137] S. officinalis Stimulates insulin secretion and decreases glucose intolerance [138] Forskolin C. forskohlii

Compounds Plant Source Biological Activity/Mode of Action References
Forskolin Attenuates the severity of hyperglycaemia in diabetic Rats

L. leonurus
Increases the level of insulin and glucose transporter-2 gene expressions in INS-1 cells [137] Ellagic acid

T. polium
Reduces blood glucose The hypoglycaemic effect in diabetic rats Stimulate the synthesis of glycogen in muscles Antihyperglycemic and Insulinmimetic activities [143] T. polium Improves diabetes through decreasing blood glucose, lipid profile, HbA1c. Increased insulin secretion [144] Quercetin S. officinalis Stimulate β-cells to release more insulin [139] Plants 2021, 10, x FOR PEER REVIEW 16 of 24

T. polium
Reduces blood glucose The hypoglycaemic effect in diabetic rats Stimulate the synthesis of glycogen in muscles Antihyperglycemic and Insulinmimetic activities [143] Salvigenin

T. polium
Reduces blood glucose The hypoglycaemic effect in diabetic rats Stimulate the synthesis of glycogen in muscles Antihyperglycemic and Insulinmimetic activities [143] T. polium Improves diabetes through decreasing blood glucose, lipid profile, HbA1c. Increased insulin secretion [144] Ursolic acid

T. polium
Reduces blood glucose The hypoglycaemic effect in diabetic rats Stimulate the synthesis of glycogen in muscles Antihyperglycemic and Insulinmimetic activities [143] T. polium Improves diabetes through decreasing blood glucose, lipid profile, HbA1c. Increased insulin secretion [144] Luteolin T. polium Antidiabetic effects and hypoglycaemic effect [142] Plants 2021, 10, x FOR PEER REVIEW 16 of 24

T. polium
Reduces blood glucose The hypoglycaemic effect in diabetic rats Stimulate the synthesis of glycogen in muscles Antihyperglycemic and Insulinmimetic activities [143] T. polium Improves diabetes through decreasing blood glucose, lipid profile, HbA1c. Increased insu- [144] Apigenin T. polium

Reduces blood glucose The hypoglycaemic effect in diabetic rats
Stimulate the synthesis of glycogen in muscles Antihyperglycemic and Insulinmimetic activities [143]

Conclusions
This comprehensive review shows that the Lamiaceae species is used traditionally to treat diabetes by peoples of different regions and continents, including Africa, Asia, South and Central America, the Middle East, and Europe ( Figure 1). Remarkably, four of the twenty-three species presented in this paper are used to manage diabetes in Morocco; meanwhile, most of the species-nine of twenty-three species-used for the management of diabetes belong to only two genera, Lanvandula and Ocimum. Additionally, this review highlights the antidiabetic capabilities and pharmacological mechanisms of action of each plant extract and some notable chemical constituents isolated from some of these Lamiaceae species. The scientific validation of the traditional use of Lamiaceae species in managing and preventing diabetes and related complications is presented.

Conclusions
This comprehensive review shows that the Lamiaceae species is used traditionally to treat diabetes by peoples of different regions and continents, including Africa, Asia, South and Central America, the Middle East, and Europe ( Figure 1). Remarkably, four of the twenty-three species presented in this paper are used to manage diabetes in Morocco; meanwhile, most of the species-nine of twenty-three species-used for the management of diabetes belong to only two genera, Lanvandula and Ocimum. Additionally, this review highlights the antidiabetic capabilities and pharmacological mechanisms of action of each plant extract and some notable chemical constituents isolated from some of these Lamiaceae species. The scientific validation of the traditional use of Lamiaceae species in managing and preventing diabetes and related complications is presented. 16

Conclusions
This comprehensive review shows that the Lamiaceae species is used traditionally to treat diabetes by peoples of different regions and continents, including Africa, Asia, South and Central America, the Middle East, and Europe ( Figure 1). Remarkably, four of the twenty-three species presented in this paper are used to manage diabetes in Morocco; meanwhile, most of the species-nine of twenty-three species-used for the management of diabetes belong to only two genera, Lanvandula and Ocimum. Additionally, this review highlights the antidiabetic capabilities and pharmacological mechanisms of action of each plant extract and some notable chemical constituents isolated from some of these Lamiaceae species. The scientific validation of the traditional use of Lamiaceae species in managing and preventing diabetes and related complications is presented.

O. gratissimum
Significant decrease in the glycemic levels in diabetic mice [93] Plants 2021, 10, x FOR PEER REVIEW 17 of 24 Oleanolic acid

Conclusions
This comprehensive review shows that the Lamiaceae species is used traditionally to treat diabetes by peoples of different regions and continents, including Africa, Asia, South and Central America, the Middle East, and Europe ( Figure 1). Remarkably, four of the twenty-three species presented in this paper are used to manage diabetes in Morocco; meanwhile, most of the species-nine of twenty-three species-used for the management of diabetes belong to only two genera, Lanvandula and Ocimum. Additionally, this review highlights the antidiabetic capabilities and pharmacological mechanisms of action of each plant extract and some notable chemical constituents isolated from some of these Lamiaceae species. The scientific validation of the traditional use of Lamiaceae species in managing and preventing diabetes and related complications is presented.

Conclusions
This comprehensive review shows that the Lamiaceae species is used traditionally to treat diabetes by peoples of different regions and continents, including Africa, Asia, South and Central America, the Middle East, and Europe ( Figure 1). Remarkably, four of the twenty-three species presented in this paper are used to manage diabetes in Morocco; meanwhile, most of the species-nine of twenty-three species-used for the management of diabetes belong to only two genera, Lanvandula and Ocimum. Additionally, this review highlights the antidiabetic capabilities and pharmacological mechanisms of action of each plant extract and some notable chemical constituents isolated from some of these Lamiaceae species. The scientific validation of the traditional use of Lamiaceae species in managing and preventing diabetes and related complications is presented. Based on the literature reviewed, the Lamiaceae species is a potential source of an diabetic agents. However, further research studies based on preclinical and clinical stu ies are required to clarify the use of the Lamiaceae species in the management of diabete emphasizing its potential therapeutic application in the prevention of diabetes and relat complications. Moreover, ethnobotanical, preclinical, and clinical investigations will co tribute towards developing, promoting, and managing indigenous knowledge systems   Based on the literature reviewed, the Lamiaceae species is a potential source of antidiabetic agents. However, further research studies based on preclinical and clinical studies are required to clarify the use of the Lamiaceae species in the management of diabetes, emphasizing its potential therapeutic application in the prevention of diabetes and related complications. Moreover, ethnobotanical, preclinical, and clinical investigations will contribute towards developing, promoting, and managing indigenous knowledge systems.