The search for new hypoglycemic agents from plants

Diabetes mellitus is a serious endocrine disorder that causes millions of deaths worldwide. The conventional drugs are associated with a number of adverse effects and limitations. In the search for better alternatives, many medicinal plants have been investigated and a variety of compounds have also been isolated. In the present review, medicinal plants selected from those that have been investigated for their antidiabetic potential between the year 2000 and 2013 are presented. The most common families of plants presented are the Asteraceae, Euphorbiaceae and Gentianaecae. The structures of some previously isolated compounds with antidiabetic potential are presented. Most of the isolated antidiabetic principles are alkaloids, flavonoids, amino acid, steroids and organic acids. It was however discovered that most of the investigations are preliminary in nature. More detailed investigations into the efficacy, mode of action and safety profile of these plants and the isolated compounds in preclinical and clinical studies are recommended.


INTRODUCTION
Diabetes mellitus is a chronic disorder characterized by elevated blood glucose levels and disturbance in carbohydrate, fat and protein metabolism (Aguwa, 2004).Diabetic patients experience various vascular complications such as, atherosclerosis, diabetic nephropathy, retinopathy and neuropathy (Sheetz, 2002).The 2012 report by the International Diabetes Federation (IDF) showed that more than 371 million people (8.3% of the world's population) had diabetes and the number of people with diabetes was increasing in every country, while 4.8 million people died and 471 billion USD were spent due to diabetes in 2012 (IDF, 2012).
The currently available therapy for diabetes includes insulin and various oral anti-diabetic agents such as the sulfonylureas, biguanides, thiazolidinediones and αglucosidase inhibitors.These drugs are used as monotherapy or in combination to achieve better glycemic control.Each of the oral antidiabetic agents is however, associated with a number of serious adverse effects (Moller, 2001;Nwaegerue et al., 2007).Plantbased drugs have been known to be safe and cheaper.Before the discovery of insulin by Banting and Best (1922), the only options were those based on traditional practices (Ribnicky et al., 2009).Thus the search for safer and easily available antidiabetic agents among medicinal plants continues.According to world ethnobotanical information reports, almost 800 plants possess antidiabetic potential (Alarcon-Aguilara et al., 1998).
Recently, an ethnobotanical survey of the plants used in the treatment of diabetes mellitus was conducted in some areas of South-Western Nigeria.The survey revealed the use of about 132 different plants species belonging to 56 families in the treatment of diabetes mellitus (Soladoye et al., 2012).Though these plants are claimed to possess hypoglycemic properties, most claims are anecdotal and few have received adequate medical or scientific evaluation (Bailey and Day, 1989).Several reviews on the plants used in the management of diabetes have been reported in the past (Bnouham et al., 2006;Kavishankar et al., 2011;Akah et al., 2002).However, information on the nature and source of the putative hypoglycemic active agents of some of the plants are scattered.Plant products are known to be rich in phenolic compounds, flavonoids, terpenoids, coumarins and other constituents which reduce blood glucose levels (He et al., 2005;Jung et al., 2006).There is need therefore to update the current knowledge as more plants are being investigated and to highlight the molecular structures and nature of some of the isolated hypoglycemic agents from plants.Here we present a list of selected plants which have been investigated for their hypoglycemic potentials between years 2000 to 2013.Also presented are the molecular structures and sources of some of the potential hypoglycemic compounds which have been isolated from medicinal plants.

Some plants investigated for antidiabetic activity
The first part of the present review work was conducted by searching the PubMed, Medline and Google scholar for medicinal plants that have been investigated between 2000 and 2013.Only some of the plants were selected based on their ethno-botanical importance and the depth of research on them.The second part of the work involves the hypoglycemic or antidiabetic plants with their active principles isolated.Unlike the first part of the work, the compounds were not necessarily identified in the period 2000 to 2013.The botanical, family and the common names of the medicinal plants that have been investigated for their antidiabetic potential are presented in Table 1.The most commonly occurring family of plants listed include Asteraceae (6), Euphorbiaceae (5), Gentianeacea (5), Brassicaceae (3), Caesalpiniaceae (3), Lamiaceae (3), Myrtaceae (3), Asclepiadaceae (2), Convolvulaceae (2), Cucurbitaceae (2), Oxalidaceae (2) and Papillionaceae (2).The investigations carried out on the plants have employed several plant extracts (aqueous, other solvents) in various models such as in vitro techniques involving enzyme inhibition or isolated cells, in vivo techniques involving administration (through oral or parenteral route, in various doses) in normal, chemical (alloxan, streptozotocin)-induced or in genetically modified diabetic animals (mice, rabbits, rats and dogs) and oral glucose tolerance test (OGTT).The experiments in animals were of acute (within 24 h) or chronic (a few days to few months) duration.Few of the studies have been carried out in humans.Toxicity studies and investigations on the mode of action of the plants are limited.

Chemical structures of isolated compounds from antidiabetic plants
The active compounds from the antidiabetic medicinal plants with their sources are shown in Figure 1.Twenty eight (28) compounds from different medicinal plants are shown.They have varied structures but most of them are alkaloids (11) or flavonoids (10) in nature.Others are amino acids (2), steroids and organic acid.

DISCUSSION
In this review, selected plants which have been investigated for antidiabetic potentials between year 2000 and 2013 are presented.The present work and earlier reviews on this subject show that a lot of research work has been performed in recent times in the search for antidiabetic agents from plants.However, not all the listed plants from ethnobotanical surveys are fully explored and most of the investigations have been preliminary studies.More detailed researches are therefore advocated in the search for more efficacious and safer hypoglycemic agents from plants.In addition, their long-term benefits in diabetic complications need to be evaluated in controlled studies.
The variety of phytoconstituent classes and the wide differences in the molecular structure of the isolated compounds suggest the possibility of different mechanisms of action in lowering blood glucose.Some have been shown to inhibit α-amylase with others potentiating the action or enhancing the release of insulin.Alkaloids inhibit α-glucosidase and decrease glucose transport through the intestinal epithelium.Polysaccharides increase the level of serum insulin, reduce the blood glucose level and enhance tolerance to glucose.Flavonoids suppress the glucose level, reduce plasma cholesterol and triglycerides significantly and increase hepatic glucokinase activity probably by enhancing the insulin release from pancreatic islets.Saponins stimulate the release of insulin and block the formation of glucose in the bloodstream (Patel et al., 2012;Bhushan et al., 2010).The detailed investigation into the actual mechanism of action of many of the plants and the isolated compounds is however, lacking.Further investigations to establish the actual mode of action of these plants and the isolated compounds are needed.
Besides efficacy and mode of action, the majority of the plants extracts and isolated compounds have not been subjected to thorough toxicological studies in animal models The aqueous extract at a dosage of 200 mg/kg is found to possess significant antidiabetic activity (Nabi et al., 2013) Table 1.Cont'd.Psidium guajava L. Myrtaceae Leaf extract inhibit the increase of plasma sugar level in alloxan-induced diabetic rats during OGTT; leaf extracts also shows significant inhibitory effect on glucose diffusion in vitro (Mukhtar et al., 2004;Basha and Kumari, 2012) Punica granatum L. (pomegranate) Lythraceae Hypoglycemia (aqueous-ethanolic extract of flowers in normal and hyperglycaemic rats (400 mg/kg) (Jafri et al., 2000) Retama raetam (RR) (Forssk) Webb.
Urticaceae Hypoglycemic (Kavalali et al., 2003) Vernonia amygdalina Del.Astereaceae Extract improves biochemical and heamatological parameters in diabetic rats; combination of extract with metformin at various ratios shows that the ratio of 1:2 (extract: metformin) causes the most significant (p<0.05)reduction in blood sugar (66.07%) compared to control (Akah et al., 2009;Adikwu et al., 2010) Withania soimifera (L) Dunal Solanaceae Hypoglycemic, antioxidant, diuretic and hypocholesterolemic (Adallus and Radhika, 2000) Zygophyllum gaetulum Emb and Maire Zygophyllaceae Hypoglycemic, increases plasma insulin levels (Jaouhari et al., 2000) let alone in clinical settings.Isolating the compounds is a necessary step in the search for a new hypoglycemic agent.The safety of the isolated compounds is also of importance as it is possible that the isolated compound could be more toxic than when present in the plant in association with other agents.For instance, Galega officinals which is rich in guanidine was traditionally used in the management of diabetes in Europe.However, guanidine proved too toxic to be used in clinical practice.Metformin, a biguanide and the current drug of choice in the management of type 2 diabetes was later developed from the guanidines (Sterne, 1969;Bailey, 1988).Those plants with promising antidiabetic potential as well as the isolated compounds therefore need to be subjected to detailed toxicological evaluation.

Conclusion
The present review has indicated that there is currently great interest in the search for antidiabetic agents from plants and many potential compounds have been isolated.However, most of the investigations have been preliminary in nature.
There is urgent need therefore to fully explore these promising plants by carrying out further  Handa et al., 1989;Atta-ur-Rahman, 1989)   research geared towards identifying and exhaustively evaluating the putative phytochemicals with more emphasis on their pharmacological and toxicological profile.
The list of plants in this review is not exhaustive of all the plants investigated for hypoglycemic effects.However, it is hoped that the list of medicinal plants presented here will further broaden the knowledge base on the various medicinal plants available for the management of diabetes mellitus.The studies already performed and highlighted the need for more studies in this direction.

Table 1 .
Medicinal plants with investigated antidiabetic potentials.