Diabetes mellitus (DM) is not a single disease but it is a group of metabolic disorders affecting a huge number of populations in the world. It is mainly characterized by hyperglycemia, hyper aminoacidemia, hyperlipedemia, and hypoinsulinaemia. It leads to decrease in both insulin secretion and insulin action [1]. It is frequently associated with the development of micro and macro vascular diseases which include neuropathy, nephropathy, cardiovascular and cerebrovascular diseases [2]. The disease is associated with reduced quality of life and increased risk factors for mortality and morbidity. The long-term hyperglycemia is an important factor in the development and progression of micro- and macro vascular complications [3]. The worldwide prevalence of DM for all age groups was estimated to be 2.8% in 2000 and it is projected to be 5.4% in 2025. At present available therapies for the treatment of DM comprise insulin and various oral antihyperglycemic agents such as sulfonylurea’s, biguanides and glinides. In developing countries as products are expensive and not easily accessible. Currently, there is growing interest in herbal formulations due to its fewer side effects. So the traditional herbal medicines are mainly used which are obtained from plants, it plays important role in the management of DM [4]. In modern, herbal medicines have started to achieve importance as a source of hypoglycemic agents. Marles and Farnsworth expected that more than 1000 plant species are being used as folk medicine for diabetes [5]. Biological actions of the plant products used as alternative medicines to treat diabetes are related to their chemical composition. Natural formulations are rich in phenolic compounds, flavonoids, terpenoids and other constituents which show gradually diminution in blood glucose levels [6-8]. Several species of herbal drugs have been described in the scientific and popular literature as having antidiabetic activity [9]. Due to their perceived effectiveness, fewer side effects in clinical experience and relatively low costs, herbal drugs are prescribed [9]. Herbal formulations are traditionally used from long time in many countries for the treatment of DM. The aim of this review is to provide compile data about DM, its epidemiology, causes, pathophysiology, available treatment, diagnostic criteria, major available screening model system, herbal remedies to treat diabetes and pharmacologically tested herbal formulation. The review also face certain plant materials which were screened in alloxan and streptozotocin induced diabetic rat's model and the data information were collected from the available literature search published in last three year using alloxan induced diabetic rat model. Moreover, only sub acute and chronic diabetic study of the plant material was included in the present review. [10]

 

Scientific Name (Family)	Parts Used	Extraction solvent	Diabetic induced by	Active Ingredient’s	Probable Mechanism of action
Vernonia amygdalina (asteraceae)	Leaves	Hydroalcoholic, methanol, acetone and N-hexane	Alloxan	Anthraquinone, tannins, flavonoids, akaloids,  saponins, glycosides, terpenoids	Hypoglycemic activity by enhancing insulin secretion and insulin activity, lipid metabolism and antioxidant. [11]
Aegle marmelos (Rutaceae)	Leaves, juice	Methanol	Alloxan	Citral, cineole, citronellal, skimmianine, aegilin	Stimulates insulin secretion from beta cells inhibits insulin degradative process. [12]
Euonyrnus alatus (Celastraceae)	Leaves	Ethanol	STZ	Rutin,  β-sitosterol  and quercetin	Hypoglycemic activity by β-sitosterol, Stimulates insulin secretion from β cells inhibits insulin degradative process. [13]
Fructus Coini (Cornaceae)	Leaves, Seeds	Ether, benzene and chloroform	STZ	Bornyl acetate, camphor, borneol, beta-sitosterol, vanillic acid, stearic acid and palmitic acid	Increases gluconeogenesis and decreases Glycogenolysis. [14]
Tephrosia villosa (Leguminosae)	Whole plant	Alcohol/water	STZ	Flavones, flavanones, prenylated flavonoids, chalcones and rotenoids	Hypoglycemic, hypolipidemic and antioxidant property decreased influx of glucose in polyol pathway, increasing NADPH/NADP ratio and increased activity of glucose peroxidase. [15]
Zaleya decandra (Aizoaceae)	Whole  plant	Methanol	STZ	Terpenes and triterpenoids, sterols and steroids, phenolics, flavonoids, gums, resins, quinones, anthocyanidine,  saponins, antioxidants and fatty acids	Stimulates insulin secretion from beta cells inhibits insulin degradative process. [16]
Vernonia amygdalina (Asteraceae)	Leaves, flowers & Seed	Hydroalcoholic, methanol, acetone and N-hexane	STZ	Anthraquinones , tannins, flavonoids, alkaloids, saponins, glycosides, cyanogenic glycosides, terpenoids, tannins	Hypoglycemic activity by inhibiting oxidative Stress. [17]
Heinsia crinata (Rubiaceae)	Root, cortex	Methanol, hexane	Alloxan	Flavonoids, hydroxy-anthraquinones, saponins, steroids, tannins and glycoside	Hypoglycemic activity by lowering blood glucose and stimulating peripheral utilization of glucose. [18]
Barleria prionitis (Acanthaceae)	Rhyzomes	N-Hexane, ethyl acetate, methanol and water	Alloxan	Glycosides, methyl ester, 6-o-trans-p-coumaroyl-8-o-acetylshanzhiside methyl ester, barlerin, acetylbarlerin, 7-methoxydiderroside and lupulinoside	Increase in glucose uptake and glycogen deposition, inhibits activity of epinephrine on glucose metabolism resulting in utilization of peripheral glucose. does not alter cortisol concentration. [19]
Acacia Arabica (Leguminosae)	Seeds, leaves	Eyhanol, methanol	STZ	Kaempferol, quercetin, 3,4',7-trihydroxyl-3', 5-dimethoxyflavone, catechin, epicatechin, afzelechin, epiafzelechin, mesquitol, ophioglonin, aromadendrin  and phenol	Hypoglycemic effect in rat, through release of insulin. [20]
Nymphaea Pubescens (Nymphaeaceae)	Flower, leaves	Ethanolic extract	Alloxan	Alkaloids, carbohydrates, glycosides, sterols, phenolic compounds and tannins, amino acids, proteins and flavonoids	Increase the insulin secretion or inhibit the intestinal absorption of glucose. [21]
Paspalum scrobiculatum (Poaceae)	Stem juice, rhizomes, roots	Aqueous and ethanolic extract	Alloxan	Steroids, lipids, amino acids and carbohydrates	Reduce the blood glucose and lipid parameters. [22]
Adina cordifolia (Rubiaceae)	Leaves	Hydro-alcoholic	Alloxan	Tannins, saponins and flavonoids.	Increase the insulin secretion or inhibit the intestinal absorption of glucose. [23]
Afzelia africana (Fabaceae)	Stem bark	Aqueous	STZ	Flavonoids, proanthocyanidins, tannins, phenols and Flavonols.	Potentiating of insulin from β cells or by increasing peripheral glucose uptake. [24]
Acanthopanax senticosus (Araliaceae)	Whole plant	Hydroalcoholic	Alloxan	Polysaccharide.	Potent antioxidant activity leads to antidiabetic activity. [25]
Aralia elata (Araliaceae)	Root cortex	Ethanol	STZ	β-sitosterol, oleanolic acid, daucosterol, oleanolic acido-28-o-β-d-glucopyranoside, araloside a and sucrose. except oleanolic acid	The hypoglycemic activity of A. elata is mainly mediated through inhibition of aldose reductase activity. [26]
Grewia Asiatica (Malvaceae)	Fruit, Stem bark and leaves	Ethanol	Aloxan	Anthocyanin, cyanidin 3- glycoside 9, vitamin C	reduction in serum glucose level of alloxan induced diabetic rabbits. This anti- hyperglycemic may be mediated by its antioxidant and radical scavenging activity rather than by stimulating the release of insulin. [27]
Gymnema sylvestre (Asclepiadaceae)	Leaves	Ethanool	STZ	Gymnemic acid, gurmarin, and saponins	Causinga prominent suppression in bloodglucose, glycosylated hemoglobin and glycosylated plasma proteins together with restoring blood glucose homeostasis in type 2 diabetic patients. [28]
Lawsonia inermis (Lythraceae)	Whole plant	Ethanol as well as 95% methanol	Alloxan	Carbohydrates, flavonoids, proteins, phenolic compounds, tannins, terpenoids, alkaloids, quinones, xanthones, coumarins	Extracts of the whole plant exhibited potent hypoglycemic and hypolipidaemic activities in alloxan induced diabetic mice causing significant reduction in serum glucose, cholesterol and triglycerides level exceeding the effect of glibenclamide. [29]
Panax ginseng (Araliaceae)	Root and leaves	Methanol	STZ	Triterpene glycosides, ginsenoside, peptides, fatty acids and polyacetylene alcohol	aqueous extract showed a remarkable hypoglycemic activity, increasing insulin production, reducing pancreatic β-cells death and resistance to insulin, thus improving postprandial glycemia in diabetic patients. [30]

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Table 1: Important anti-diabetic potential herbal plants source and their active principles

Diabetes is a disorder of carbohydrate, fat and protein metabolism caused due to insufficient production of insulin or its inhibitory action, which can be considered as a major source of high economic loss which can in turn obstruct the development of nations [31]. Before there were drugs from drug companies, natural cures were used and they can still be used today. There are many herbs with strong antidiabetic properties. Herbal treatments for diabetes have been used in patients with insulin dependent and noninsulin dependent diabetes, diabetic retinopathy, diabetic neuropathy etc [32]. The families of plants with the most potent hypoglycaemic effects include Leguminoseae, Lamiaceae, Liliaceae, Cucurbitaceae, Asteraceae, Moraceae, Rosaceae, Euphorbiaceae and Araliaceae [33]. The most commonly studied species are: Opuntia streptacantha, Trigonella foenum graecum, Momordica charantia, Ficus bengalensis, Polygala senega and Gymnema sylvestre. In the experiments, oral glucose tolerance test, streptozotocin and alloxan induced diabetic mouse or rat were most commonly used model for the screening of antidiabetic drugs. Numerous mechanisms of actions have been proposed for plant extracts [34]. Some hypothesis relates to their effects on the activity of pancreatic beta cells, increase in the inhibitory effect against insulinase enzyme, increase of the insulin sensitivity or the insulin-like activity of the plant extracts [35]. Other mechanisms may also be involved such as increase of peripheral utilization of glucose, increase of synthesis of hepatic glycogen or decrease of glycogenolysis, inhibition of intestinal glucose absorption, reduction of glycaemic index of carbohydrates and reduction of the effect of glutathione [36]. In this review, natural products classified into terpenoids, alkaloids, flavonoids, phenolics, and some other categories have shown antidiabetic potential through the insulinomimetic activity of the plant extract. Roseoside, epigallocatechin gallate, beta-pyrazol-1-ylalanine, cinchonain, leucocyandin 3-O-beta-d-galactosyl cellobioside, leucopelargonidin-3-O-alpha-L rhamnoside, glycyrrhetinic acid, dehydrotrametenolic acid, strictinin, isostrictinin and pedunculagin, epicatechin and christinin-A isolated from the plant material have shown significant insulinomimetic activity along with significant antidiabetic potential. Additionally, some flavonoids and polyphenols, as well as sugar derivatives, are found to be effective due to some other extrapancreatic mechanisms. In this review 20 plants are included which have shown antidiabetic action through relese of insulin and some extra pancreatic mechanisms [37].

Present study has described a list of 20 antidiabetic plants used in the treatment of diabetes mellitus. Majority of plants are containing phytoconstituents such as flavonoids, terpenoids, coumarins and polyphenols.  Among of them flavonoids including flavan-3-ols, flavanones, flavonols, anthocyanidins, flavones and isoflavones. Terpenoids including Monoterpenoids, Diterpenoids, Triterpenoids and Polyterpenoids. Furthermore, phenolic compounds such as eugenol, eugenol acetate and gallic acid are present. These are capable to produce insulinomimetic action and also show that these plants have hypoglycemic effects and can be used to treat various types of secondary complications of diabetes mellitus.

1. Mukesh R, Namita P (2013) Medicinal plants with antidiabetic potential-a review. American-Eurasian J Agric Environ Sci 13: 81-94.

2. Vanessa FiorentinoT, Prioletta A, Zuo P, Folli F (2013) Hyperglycemia-induced oxidative stress and its role in diabetes mellitus related cardiovascular diseases. Current pharmaceutical design 19:5695-5703.

3. American Diabetes Association. Standards of medical care in diabetes (2015) abridged for primary care providers. Clinical diabetes: a publication of the American Diabetes Association 33: 97.

4. Akinmoladun AC, Farombi EO, Oguntibeju OO (2014) Antidiabetic botanicals and their potential benefits in the management of diabetes mellitus. In Antioxidant-Antidiabetic Agents and Human Health.

5. Martineau L.C, Adeyiwola-Spoor D.C, Vallerand.D, Afshar.A, Arnason J.T at et. al (2010) Enhancement of muscle cell glucose uptake by medicinal plant species of Canada's native populations is mediated by a common, Metformin-like mechanism. Journal of ethno pharmacology 127:396-406.

6. Sahib NG, Anwar F, Gilani AH, Hamid AA, Saari N et al. (2013) Coriander (Coriandrum sativum L.) A potential source of high value components for functional foods and nutraceuticals A review. Phytotherapy Research 27:1439-56.

7. Mazed MA, Mazed S (2011) Nutritional supplement for the prevention of cardiovascular disease, Alzheimer’s disease, diabetes, and regulation and reduction of blood sugar and insulin resistance.

8. Jia Q, Burnett B, Zhao Y (2014) inventors Unigen Inc, assignee. Formulation of a mixture of free-B-ring flavonoids and flavans for use in the prevention and treatment of cognitive decline and age-related memory impairments.

9. Rao MU, Sreenivasulu M, Chengaiah B, Reddy KJ, Chetty CM (2010) Herbal medicines for diabetes mellitus: a review. Int J PharmTech Res. 2:1883-1892.

10. Fisher C, Adams J, Frawley J, Hickman L, Sibbritt D (2017) Western herbal medicine consultations for common menstrual problems; practitioner experiences and perceptions of treatment. Phytotherapy Research.

11. Dégbé M, Debierre-Grockiego F, Tété-Bénissan A, Débare H, Aklikokou K et. al (2018) Extracts of Tectona grandis and Vernonia amygdalina have anti-Toxoplasma and pro-inflammatory properties in vitro. Parasite. 18: 25.

12. Aggarwal H, Nair J, Sharma P, Sehgal R, Naeem U et. al (2018) Aegle marmelos differentially affects hepatic markers of glycolysis, insulin signalling pathway, hypoxia, and inflammation in HepG2 cells grown in fructose versus glucose-rich environment. Molecular and cellular biochemistry 438:1-6.

13. Farzaneh V, Carvalho IS (2015) A review of the health benefit potentials of herbal plant infusions and their mechanism of actions. Industrial Crops and Products 65:247-58.

14. Farzaneh V, Carvalho IS (2015) A review of the health benefit potentials of herbal plant infusions and their mechanism of actions. Industrial Crops and Products 65:247-58.

15. Murti Y, Sharma S. FLAVONOID: A PHARMACOLOGICALLY SIGNIFICANT SCAFFOLD.

16. Malarvizhi D, Anusooriya P, Meenakshi P, Sundaram S, Oirere E et. al (2016) Isolation, Structural Characterization of Oleic Acid from Zaleya decandra Root Extract. Analytical Chemistry Letters 6: 669-677.

17. Onasanwo SA, Aitokhuehi GN, Ajayi OT, Faborode SO (2016) The Anxiolytic Properties of Vernonia Amygdalina (Asteraceae) in Laboratory Mice. African Journal of Biomedical Research 19:229-33.

18. Tshibangu PT, Kapepula PM, Kapinga MK, Mukuta AT, Kalenda DT et. al (2017) Antiplasmodial activity of Heinsia crinita (Rubiaceae) and identification of new iridoids. Journal of ethnopharmacology196:261-266.

19. Daniel M. (2016) Medicinal plants, chemistry and properties.

20. Khalid M, Hassani D, Bilal M, Butt ZA, Hamayun M et.al (2017) Identification of oral cavity biofilm forming bacteria and determination of their growth inhibition by Acacia arabica, Tamarix aphylla L. and Melia azedarach L. medicinal plants. Archives of oral biology 81:175-85.

21. Acharya J, De B (2016) Bioactivity-guided fractionation to identify β-glucuronidase inhibitors in Nymphaea pubescens flower extract. Cogent Food & Agriculture 2:113.

22. Da Silva Pinto L, de Souza FH, Nascimento IR, Lopes LM (2015) Phenylpropanoids from Paspalum atratum (POACEAE). Biochemical Systematics and Ecology. 63:68-71.

23. Harborne JB. C-glycosylflavonoids (2017) In the Flavonoids Advances in Research Since 19:69-106.

24. Mensah S, Houehanou TD, Sogbohossou EA, Assogbadjo AE et. al (2014) Effect of human disturbance and climatic variability on the population structure of Afzelia africana Sm. ex pers. (Fabaceae–Caesalpinioideae) at country broad-scale (Bénin, West Africa). South African Journal of Botany 95:165-173.

25. Zhai C, Wang M, Raman V, Rehman JU, Meng Y et.al (2017) Eleutherococcus senticosus (Araliaceae) Leaf Morpho-Anatomy, Essential Oil Composition, and Its Biological Activity Against Aedes aegypti (Diptera: Culicidae). Journal of medical entomology 54:658-669.

26. Sun Y, Li B, Lin X, Due J, Wang Z et.al (2017) Simultaneous Determination of Four Triterpenoid Saponins in Aralia elata Leaves by HPLCELSD Combined with Hierarchical Clustering Analysis. Phytochemical Analysis 28:202-209.

27. Wani TA, Pandith SA, Rana S, Bhat WW, Dhar N et.al (2015) Promiscuous breeding behaviour in relation to reproductive success in Grewia asiatica L.(Malvaceae). Flora-Morphology, Distribution, Functional Ecology of Plants 211:62-71.

28. Suman RK, Borde MK, Mohanty IR, Deshmukh YA (2015) Antidiabetic activity of Gymnema sylvestre leaves extract on streptozocin induced experimental diabetic rats. Indo American Journal of Pharm Research 5:2054-2060.

29. Moharana A, Das A, Subudhi E, Naik SK, Barik DP( 2018) Assessment of genetic fidelity using random amplified polymorphic DNA and inter simple sequence repeats markers of Lawsonia inermis L. plants regenerated by axillary shoot proliferation. Proceedings of the National Academy of Sciences, India Section B: Biological Sciences. 88:133-41.

30. Shin BK, Kwon SW, Park JH (2015) Chemical diversity of ginseng spooning from Panax ginseng. Journal of ginseng research 39:287-98.

31. World Health Organization (2016). Global report on diabetes.

32. Wang J, Li S, Fan Y, Chen Y, Liu D et.al (2010) Anti-fatigue activity of the water-soluble polysaccharides isolated from Panax ginseng CA Meyer. Journal of ethnopharmacology 130:421-430.

33. Patel DK, Prasad SK, Kumar R, Hemalatha S (2012) An overview on antidiabetic medicinal plants having insulin mimetic property. Asian Pacific journal of tropical biomedicine 2 : 320-330.

34. DAWOUD AD, SHAYOUB ME (2015) Effects of ethanolic leaf extract of Eucalyptus camaldulensis on oral glucose tolerance test in Type-2 Model diabetic rats. Journal of Network Communications and Emerging Technologies (JNCET).

35. Khan V, Najmi AK, Akhtar M, Aqil M, Mujeeb M et. al (2012) A pharmacological appraisal of medicinal plants with antidiabetic potential. Journal of pharmacy & bioallied sciences 4: 27.

36. Polakof S, Panserat S, Soengas JL, Moon TW (2012) Glucose metabolism in fish: a review. Journal of Comparative Physiology B 182:1015-1045.

37. Prabhakar PK, Doble M (2008) A target based therapeutic approach towards diabetes mellitus using medicinal plants. Current Diabetes Reviews 4:291-308.