A Critical Review on Traditional Herbal Drugs : An Emerging Alternative Drug for Diabetes

Diabetes is a chronic metabolic disease reaching an epidemic proportion in many parts of the world. By the year 2025 it is expected that 333 million people of the world will have diabetes as their main ailment. As today, India assumes the position of the diabetic capital of the world with the highest percentage of its population suffering from diabetes. It is pathetic to mention that in proportion to its people suffering from diabetes, this country has very weak spending power for treatment because of wide spread poverty. Therefore, this review is aimed at opening up new vistas in realizing the therapeutic potential of Ayurveda in treatment of diabetes and other chronic diseases. All drugs which we have discussed in this review have a significant role in therapy of diabetes mellitus.


Introduction
The word diabetes was coined by the Greek physician Aretaeus in the first century AD Diabetes mellitus has been known since ages and sweetness of urine has been mentioned in Ayurveda by Sushruta.Its pharmacotherapy is 80 year old.The presence of sugar in the urine of diabetics was demonstrated by Dobson in 1755 [1].Yet, as we have spent one decade of new millennium, our knowledge of the nature and treatment of diabetes is still incomplete.Diabetes mellitus is most serious; chronic metabolic and characterized by high blood glucose level [2].Hyperglycemia is caused by relative or absolute deficiency of insulin or by a resistance to the action of insulin at the cellular level.It is most common endocrine disorder, affecting 41 million individuals in India and as many as 200 million world-wide.The worldwide prevalence of diabetes for all age groups was estimated to be 2.8% in 2000 and it is projected to be 5.4% in 2025.Currently available therapies for diabetes include insulin and oral antidiabetic agents such as sulfonylurea, biguanides, α-glucosidase inhibitors and glinides, in develpoping countries as products are expensive and not easily accessible [3].DM (diabetes mellitus) has been become a clinical model for general model for general medicine.The primary defect in fuel metabolism results in widespread, multi-organ complications that ultimately encompass virtually every system of the body.Although from a clinical standpoint, this may be true, our increasing knowledge of patho-physiology of the syndrome, together with the mechanisms of long term complication, has placed diabetes researched at the frontier of immunology and molecular biology [1].

Etiology of Diabetes, Cure and Strategy
Diabetic patients are diagnosed by blood or urinary glucose measurement through different techniques.On the basis of etiology DM (Diabetes mellitus) are categories mainly two types viz: 1) Primary Diabetes (Type I or Insulin Dependent Diabetes Mellitus).
2) Secondary Diabetes (Type II or Non Iinsulin Dependent Diabetes Mellitus).
Primary DM (Diabetes mellitus) clinically dependent on insulin due to there is decrease in the number of β-cells in the islets of langerhans and thus there is absolute deficiency of insulin hence this is known as Insulin Dependent Diabetes Mellitus (IDDM) or Type I.The main treatment for this Type I of DM (Diabetes mellitus) is insulin.
Secondary DM (Diabetes mellitus) is referred as Type II or Non Insulin Dependent Diabetes Mellitus (NIDDM) because these types of patients are insulin resistances as well as loss of insulin secretion contributes to the onset of disease.The patients are usually obese and the treatment is usually dietary, through supplementary oral Hypoglycemic drugs.
As the complications induced by diabetes mellitus are very serious and goes to worst day by day hence, there is potent need of medicine to cure the diabetes mellitus.In this review we will go through the all the possible cure available to preventing the complications and its limitation also, to finding out the alternatives of these synthetic drugs, having no or few side effects with low price and ease to reach the common people.

Strategy for Treatment of Diabetes
Basic therapeutic approach to treat diabetes may be to inhibit the absorption of glucose by retarding the action of gastro-intestinal enzymes such as α-glucosidase and α-amylase.Because the complication of disease is mainly due to the higher glucose level in blood which dysfunction the other organs of body.Thus we can say that the effective α-glucosidase inhibitors may serves as chemotherapeutic agents for clinic use in the treatment of diabetes and obesity [4,5].

Insulin
Insulin increases glucose uptake in cells by stimulating the translocation of the glucose transporter GLUT4 from intracellular sites to the cell surface [6,7].Insulin circulates in blood as the free monomer and its half life in plasma is about 5 -6 min in normal subjects.Although glucose is the principal stimulus to insulin secretion in human beings, this process is tightly regulated by the coordinated of nutrients, gastrointestinal and pancreatic hormones and autonomic neurotransmitters [8].The main draw back of insulin is taken through injection.

Oral Hypoglycemic Drugs
Oral Hypoglycemic drugs are those drugs that lower blood glucose level and taken orally.These drugs are synthetic and complex organic substances.Hence the search for oral active drugs is in demand.3) Others a) Acarbose; b) Guar Gum.These drugs are effective in diabetes but having some limitations such as hypoglycemia occurs with regular use of sulfonylurea compounds but occurrences are much fewer than with insulin therapy.It is prescribed by doctors that biguanids should not use in patients with renal diseases.On the other hand the main side effect of Acarbose is flatulence [1].

Metallotherapy
The current literature also shows that metallopharmaceuticals is an area of growing interest as is evident through the clinical trials that are being conducted worldwide for the usages of metals in therapeutics.Metallotherapy is a new therapeutic strategy to treat diabetes with metal complexes.It is first studied by Coulson and Dandona in 1980 that ZnCl 2 stimulate lipogenesis in rat adipocytes similarly to the action of Insulin.In three decades there are many researchers reported insulin-mimetic activity, α-glucosidase and α-amylase inhibition with different coordination of different ligand with transition metals.However the strategies to treat the diabetes mellitus through metal complexes are in early stage hence there are no side effects reported at all.Some metal complexes are in trial stage for treating diabetes.

Herbal Drugs
There are many herbal products/herbal extracts are reported to treat the diabetes mellitus, we can classify these drugs according to their mode of action as: 3.1.4.1.Extracts/Drugs Act as α-Glucisidase or α-Amylase Inhibitor These types of drugs/extracts are able to reduce the blood glucose level by inhibiting the gastric enzymes which is obligatory for the break the polysaccharides in to the simple sugar.
The aqueous and methanolic extract of Syzgium cumini (seed) and Pisidium guajava (leaves) shows α-amylase inhibition [9]; while Rhus verniciflua stem screened for α-glucosidase inhibition effect mixture of methanol and ethanol extract shows the potent inhibition of α-glucosedase enzyme [10].There are large number of plants which have the capability to inhibit the α-glucosidase and α-amylase activity and may be used as treatment of diabetes Type I and Type II.

Extracts/Drugs Increases Insulin Secretion or
β-Cell Regeneration These types of drugs are directly concern with the Type I or IDDM diabetes which are disable to secreting the less or few amount of insulin.
Radix of Acorus calamus is used as in the therapy of diabetes in traditional folk medicine of America and Indonesia, this sensitize the insulin activity of its ethyl acetate extract [11].On the other hand Ginsenoside Rh2 an active compound found in Panax ginseng root increased plasma insulin level parallel with lowering the plasma glucose level [12].Moreover aqueous extract of Syzgium cumini bark stimulate β-cell regeneration by proliferation of its precursor or cells in the pancreatic duct [13].
3.1.4.3.Extracts/Drugs Act as Hypoglycemic, Antihyperglycemic or Antidiabetic Effect These classes of herbal drugs reduce the blood glucose level directly, this may be also used to treat the both type of diabetes mellitus (IDDM and NIDDM).
Mangifera indica Linn.(Locally known as mango tree) has antidiabetic property, ethanolic and water extract of leaves and stem bark of Mangifera indica shows significant antihyperglycemic effect [14].Extract of Hedychium spicatum rhizomes also show the antihyperglycemic effect [15].Ficus bengalensis bark extract show antidiabetic and ameliorative activity [16].While alcoholic aqueous extract of Coccinia indica (C.cordifolia) aerial part exhibit the hypoglycemic effect and fruit of Ficus glomerata shows hypoglycemic activity [17,18].
3.1.4.4.Extracts/Drugs Dealing with the Complications of Diabetes Mellitus Diabetes mellitus is metabolic syndrome characterized by deregulation in carbohydrate metabolism associated with defect in insulin secretion or action by which glucose level of blood increases, the different type of complication occurred.To treat these type of problem many herbal drugs/extract may play a key role.
The aqueous extract of bark of Ficus religiosa Linn reduces oxidative stress in Type II diabetes mice model [19].Extract of fruit of Benincasa gispida decrease gastric ulcer index in diabetic rat model [20].Hexane extract of Derris scanders show potent α-glucosidase inhibition effect and moderate free radical scavenging activity [21].Pongamia pinnata flower shows antihyperglycemic and antilipid-peroxidative effect with reference drugs glibenclamide [22].Oral administrations of Coccinia indica leaf extract (200 mg/kg body weight) for 45 days significantly reduce the thiobarbituric acid reactive substances and hydroperoxides.The extract also causes a significant increase in reduced glutathione, superoxide dismutase, catalase, glutathione peroxidase and glutathione-S-transferase in liver and kidney of streptozoto-cin diabetic rats, which clearly shows the antioxidant property [23].Some plants are listed in Table 1 which has the antidiabetic properties.

Plants Used for Curing Diabetes Mellitus in Ayurveda
India has a great ancient heritage of traditional medicine.
The material medica of Indian provides much information on ethnic folklore practices and traditional aspects of therapeutically important natural products [26,27].Indian traditional medicine is based on various systems, including Ayurveda, Siddha and Unani (ASU).With the emerging interest of the world in adopting and studied traditional systems and in exploiting their potential from different healthcare perspectives, it is necessary to listing some of plants which are used to curing the diabetes from ancient time are listed in [28][29][30][31] Table 2.

Trials of Traditional Medicines
There are several herbal drugs are formulated according to traditional and modern knowledge of ethanobotany.Bio-active molecules have been cross checked on diabetic models and several are in trail courses.Some of trails are as: Wendell D. Winters (2003) et al. [32] studied inhibittion of the progression of Type II diabetes in the C57BL/ 6J mouse model by an anti-diabetes herbal formula prepare from Chinese herbs which was activated and mixed according to proprietary formula ingredients through standard method.The herbal formula had eight major herbals, Ginseng Radix (17%), Rehmannia Radix (17%), Astragali Radix (10%), Trichosanthis Radix (10%), Ophiopogous Radix (10%), Puerariae Radix (10%), Lycii fructus (10%), Discoreae Rizoma (10%) and found that 4% -8% of regular feeding with ADHF shows significant reduction in blood glucose level and increase in insulin level further they suggested ADHF should be used as diet supplement.
Ikuko Kimura (1999) et al. [33] studied the antihyperglycemic blend effect of traditional Chinese medicine byakko-ka-ninjin-to on alloxan and diabetic KK-CA y Mice and concluded that the water extract of Byakko-Kaninjin-to (BN) which have Ginseng root, licorice root, Anemarrhena asphodeloides (rhizome), Fibrosum gypsum and rice with blend of Ca ++ shows the antihyperglycemic effect.
In the management of diabetes Type II a trail of Vijayasar (Pterocarpus marsupium) had done in different location in India by ICMR group to check the efficacy of Vijayasar in contrast of synthetic drug Tolbutamide.Study shows that Vijayasar is an effective blood glucose lowering traditional Indian plant agent, its glycemic effect being comparable to that of Tolbutamide in treatment  patient with Type II diabetes and free from any significant side effect [34].

Herbal Drugs and Its Organic Compounds for Treatment of Diabetes Mellitus
Mordern treatments (synthetic drugs) of diabetes mellitus are focused on lowering the glucose level to normal level into blood while traditional medicines/drugs/extracts are complex in nature as well as their mechanism of action.Ayurvedic formulations, often complex with several herbal-mineral ingredients, are governed by well-described pharmacological principles of preparation, compatibility and administration.Classic texts contain descriptions of classic formulations, traditional Ayurvedic practitioners often modify them to suit the individual constitution (prakriti), which confers genetic predisposition toward disease and therapy response, and is vital to ensure medication safety [183].It is very hard or laborious work to isolate and identify each and every compound found in plant extracts.However researchers find out some compounds from extract of plants and their actions are also studied.List of some plants, their isolated compounds and mechanism of action are tabled in Table 3.

Need and Importance of Herbal Medicine
As we mention above the cure of diabetes mellitus is mentioned in Ayurveda.Ayurvedic researches undertaken during the last 50 years have not been very rewarding, except for the extremely useful exercise of literary research.Further the age of synthetic drugs comes but unfortunately, after the introduction of sulfonylurea and metformin about 50 years no major lead has been obtained in the direction of proper treatment of diabetes.This is the big question mark on synthetic drugs for anwering the diabetes mellitus.s      Plant extract or different folk plants preparations are being prescribed by the traditional practitioners and also accepted by the users for diabetes and other diseases in many countries especially in third world countries.Therefore, a proper scientific evaluation and searching plants by pharmacological test followed by chemical investigation is potentially necessary.
The plants drugs or extract have the marvelous efficacy to curing the diabetes and its complication without having any side effects.At present there are several Chinese traditional formulated drugs available in market but the right answer for diabetes mellitus is awaited.
According to the WHO about 65% -80% of world population in developing counties depends on all intents and purposes on plant for their primary health care due to scarcity and lack of access to modern medicine [35].Historically all medicinal preparation were derive from plants, whether in the simple form of plant parts or in the more complex form of crude extract mixture etc.The primary benefits of using plant-derived medicines are that they are relatively safer than synthetic alternative drug [36].Use of ethanobotanical information in medicinal plant research has gain considerable attention in segment of the scientific community [37].
As we know that India has ancient heritage of traditional medicine.In India where 75% population belong from the remote area and more than 50% of people survives below the poverty line enthusiastically use plants for the treating the diseases.During the last few decease there has been an increasing interest in the study of medicinal plant and their traditional use in different part of India.
In the recent years numbers of reports on the use of plants in traditional healing by either tribal people or indigenous communities of India is increasing [38].Muniappan Ayyanar et al. 2011 [39] conducted a study in Tirunelveli hills of Western Ghats in India and found that Costus speciosus smith (Costaceae), Gymnema sylvestre Linn (Apocynaceae) are used for treating diabetes mellitus.In this review we have concluded that plants are best sources for developing the alternative drug to curing diabetes mellitus, which has no side effects and low cost by which it is simple to a common man to be treated.There is a need of searching our traditional medicines.Some of ethanobotanical plants are listed here in Tables 1 and 2 which has antidiabetic properties.

Conclusion
All drugs which we have discussed in this review have a significant in their mode of action and therapy of diabetes mellitus, in contrast of plants bioactive phyto-molecules are less known about their mode of action but there is no doubt about the role of plants to treating diabetes.
It is also important to screening the world's plant diversity extensively for more and specific bioactive phytomolecules which are helpful in treating diabetes mellitus.On the other hand the traditional formulation of antidiabetic drugs must be researched and re-standardized by using new techniques and methods for managing the diabetes mellitus.Furthermore these drugs will be accessible to the people who are unable to purchase the costly synthetic drugs.Hence herbal drugs may be an emerging alternative of synthetic drugs to curing diabetes mellitus.