Complementary and alternative medicine for type 2 diabetes mellitus : Role of medicinal herbs

Complementary and alternative medicine (CAM) with glucose-lowering effect is increasingly being sought by patients and health care professionals. Its use is estimated at 17 to 80% among diabetic patients. Not only is this rarely reported to healthcare providers, but also that some CAM therapies have no empirical evidence. A review of commonly used CAM is therefore essential for safe and effective control of blood glucose level. A PubMed search was done using the following key terms: “natural products” “herbal medicine” “vitamins” “minerals” “herbs” “botanicals” “complementary and alternative medicine” “extract” “food” “diet” combined with the terms “diabetes” “diabetes mellitus” or “anti-diabetic”. Some papers were found through tracking citations from other publications. Commonly used glucose-lowering herbs include Ginseng species, Momordica charantia (Karela), Trigonella foenum graecum, Gymnema sylvestre, Allium cepa (onion), Allium sativum (garlic), Pterocarpus marsupium, Vaccinium myrtillus, Atriplex halimus and Aloe vera. Other alternative therapies were chromium, vanadium, magnesium, vitamin E, acupuncture and hot-tub therapy. In conclusion, research and use of CAM therapy is on the increase worldwide. Stringent regulatory policies and guidelines on CAM use are required to ensure that safe and appropriate CAM use is guided by empirical evidence.


INTRODUCTION
Diabetes mellitus (DM) is a metabolic disorder characterized by increased blood glucose levels.This disease is characterized by either lack of insulin production or deficient activity in the presence of normal or even elevated levels of insulin.Type 2 DM, which accounts for over 90% of the cases, is associated with disordered carbohydrate and fat metabolism.Chronically, the disease causes micro-vascular (retinopathy, nephropathy and neuropathy) and macro-vascular (hypertension, dyslipidemia, myocardial infarction and stroke) complications (Lucy et al., 2002).
Diabetes poses great challenge to the world's health care system.Its worldwide prevalence was estimated at 366 million in 2011.Of these, 183 million people were believed to be unaware of their condition.If no measures taken, the prevalence is projected to rise to 552 million people by 2030, representing around 10% of the global adult population (International Diabetes Federation, 2011a).In 2011, it was reported that one person died from diabetes related causes every seven seconds.Annual global health care spending on diabetes was up to US$465 billion in 2011 (International Diabetes Federation, 2011a).
In the management of type 2 DM, life style modification (exercise, weight control and nutrition) is crucial.A sedentary lifestyle was associated with the increased risk of impaired glucose tolerance and diabetes.Exercise and diet programs significantly reduce the risk for type 2 DM.A low-fat, vegetarian (vegan) diet has been reported to reverse the effects of DM.Oral glucose-lowering drugs and insulin injections are the conventional management modalities.They are however expensive and often associated with adverse effects, with the commonest being weight gain and hypoglycaemia (Sinha et al., 1996).Taking into consideration the aforementioned, the use of complementary and alternative medicine (CAM) has been on the increase.
Complementary and alternative medicine is defined as the practices, approaches, knowledge and beliefs that incorporate plant, animal and mineral-based medicines, spiritual therapies, manual techniques and exercise.UN National Institute of Health categorizes CAM into: alternative or whole medical systems, mind-body medicine, biologically based practices, manipulation and body-based therapies, and energy therapies.The prevalence of CAM use among people living with diabetes ranges from 17 to 80% (Chang et al., 2007).The frequency of CAM use is at 80% in Africa, 52 to 70% in Australia, 31% in Belgium, 40% in China, 49% in France, 60% in Japan, 46% in Switzerland, 24% in UK and 42% in USA (WHO Traditional Medicine Strategy, 2002).There is however a high rate of CAM use nondisclosure to physicians by patients (Khalaf and Whitford, 2010).This brings about the need for health care professionals to be aware of CAM use alongside conventional drugs.
The commonly used therapies among diabetic patients are herbal medicines, nutritional supplements, diet modifications, spiritual healing and relaxation techniques.The factors influencing CAM use include age, duration of diabetes, degree of complications and self-monitoring of blood glucose.Scientific literature on the efficacy of CAM in the management of DM is relatively sparse and heterogeneous.Moreover, there have not been comprehensive reviews incorporating diet, vitamins and mineral supplements in addition to herbal medicine, for glucose control among patients with diabetes.Our aim was therefore to explore the commonly used CAM products so as to inform clinical practice, education and research.This review is unique since it also explores various philosophies and underlying factors behind CAM use.

MATERIALS AND METHODS
A Medline search was performed using the following terms: "natural products" "herbal medicine" "vitamins" "minerals" "herbs" "botanicals" "complementary and alternative medicine" "extract" "food" "diet" combined with the terms "diabetes" "diabetes mellitus" or "anti-diabetic".Time filters were not applied during the search.Some papers were found through tracking citations from other publications.The plants identified were confirmed using http://www.ipni.orgfor spellings and family names.Botanical descriptions were checked using Medline and by referring to http://www.wikipedia.org.CAM therapies included were those supported by two or more publications and had insights on their mechanism of action.Expert judgement rather than a formal quality appraisal was used in determining the studies included.Publications without human trials and those in a language other than English were excluded.Some CAM therapies supported by limited trials but with proven glucose-lowering effect were included.Emphasis was made on herbs hence supplements from animal components (such as fish oil, among others) were not reviewed.

RESULTS
Of the 960 titles and abstracts retrieved, 72 (7.5%) were identified as potentially relevant to the review.These focused mainly on medicinal herbs (Table 1), vitamins, minerals, acupuncture and hot-tub therapy.

Momordica charantia
Momordica charantia (MC), also known as bitter melon, balsam pear or karela, is a plant commonly used in traditional medicine for its glucose-lowering effects (Shane, 2001;Chaturvedi et al., 2004;Sridhar et al., 2008).It is a climber of the family Cucurbitaceae, and is widely cultivated in Africa, Asia and South America both for food and for its medicinal use (Ooi et al., 2010).The parts used include the whole plant, fruit and seeds, which are bitter due to the presence of the chemical momordicin (Beloin et al., 2005).Preparations used include injectable extracts, juice extracts, and fried melon bits, among others (Welihinda et al., 1986;Shane, 2001).The glucose-lowering effect of its unripe fruit juice has been demonstrated in both experimental animal models (Welihinda et al., 1986) and human clinical trials (Srivastava et al., 1993).Active components of the fruit include charantin, vicine and insulin-like polypeptide (Lucy et al., 2002).Alcohol-extracted charantin from MC consists of mixed steroids and was reported to be more potent than tolbutamide (an oral glucose lowering drug) in an animal study (Sarkar et al., 1996).It has been shown to decrease blood glucose levels when injected subcutaneously into type 1 DM patients (Baldwa et al., 1977).Oral administration of bitter melon preparations also showed significant results when tried clinically in type 2 DM patients (Srivastava et al., 1993).Several mechanisms of action have been postulated including: enhanced insulin secretion, insulin-like action, tissue glucose uptake, liver muscle glycogen synthesis, glucose oxidation, and decreased hepatic gluconeogenesis (Akhtar et al., 1981;Bailey and Day, 1989).Hepatic portal inflammation and testicular lesions in dogs were reported in excessive administration of cerasee (a component of the wild variety of MC) (Dixit et al., 1978).It is furthermore contraindicated in pregnancy and when other glucose-lowering agents are being used (Basch et al., 2003).
Reported side effects include nervousness, immune-stimulant effects and excitation, which diminish with continued use or dosage reduction.Ginseng may exert an oestrogen-like effect in postmenopausal women, resulting in diffuse mammary nodularity and vaginal bleeding (Hammond and Whitworth, 1997).Ginseng may also inhibit the effects of warfarin (Janetzky and Morreale, 1997) and interact with the monoamine oxidase (MAO) inhibitor, phenelzine (Jones and Runikis, 1987).Massive overdose can bring about ginseng abuse syndrome, characterized by hypertension, insomnia, hypertonia and oedema (Punnonen and Lukola, 1984).It is contraindicated when using hypoglycaemic drugs, corticosteroids, oral contraceptives, anticoagulant drugs, digoxin, diuretics, MAO inhibitors and tricyclic depressants.

Trigonella foenum graecum (Fenugreek)
Fenugreek is a legume that grows in India, North Africa and Mediterranean regions.Its seeds are rich in alkaloid trigonelline, nicotinic acid and coumarin.Animal and human studies have reported that the legume lowers blood glucose and lipid levels, as well as increases HDL cholesterol levels (Ribes et al., 1984;Madar et al., 1988).Its seeds are rich in proteins, saponins and fibre.The high fibre content is a potential mechanism of the beneficial effect in DM patients (Madar et al., 1988).Purported mechanisms of action include delayed gastric emptying, slowed carbohydrate absorption and inhibition of glucose transport by the fibre content, as well as increased erythrocyte insulin receptors and modulation of peripheral glucose utilization.Urine may have a maple syrup smell after fenugreek consumption (Bartley et al., 1981).No other side effects have been reported, though, it is contraindicated in pregnancy, and when using glucose-lowering drugs, anticoagulants and MAO inhibitors.

Gymnema sylvestre (Gurmar)
This is a woody climber native to the tropical forests of central and southern India.It lowers glucose by increasing glucose uptake and utilization, and enhancing the production of endogenous insulin through cell permeability, increase in β-cell number and stimulation of β-cell function (Persaud et al., 1999;Shane, 2001).Side effects include reduction or loss of taste sensation of sweetness and bitterness if the plant is directly exposed to the tongue (Mozersky, 1999).

Allium cepa (Onion) and Allium Sativum (Garlic)
Allium cepa and Allium sativum are members of the lily family, having blood glucose lowering, anti-oxidant, antihypertensive and antihyperlipidemic effects (Sharma et al., 1977;Sheela and Augusti, 1992).Volatile oils in raw onion and garlic have been reported to lower fasting blood glucose level in both animal and human trials (Jain et al., 1973).The active compounds are believed to be Matheka and Alkizim 49 sulphur-containing compounds: allyl propyl disulfide (APDS) in onions and diallyl disulfide (allian) in garlic.These active compounds lower glucose levels by competing with insulin (a disulfide) for insulin-inactivating sites in the liver, resulting in increased levels of plasma insulin (Sheela and Augusti, 1992;Lucy et al., 2002).

Aloe vera
Aloe vera is a well-known species of aloe, a desert plant resembling cactus.The dried sap of Aloe vera is a traditional remedy used in DM management in the Arabian Peninsula.Aloe gel obtained from the inner portion of the leaves contains glucomannan, a hydrosoluble fibre which has a glucose-lowering effect (Shane, 2001).This has been investigated in both animal models and type 2 DM patients.Oral administration of the juice has also been reported to reduce fasting blood glucose and triglyceride levels in type 2 DM patients with or without combination of conventional anti-diabetic agents (Yongchaiyudha et al., 1996;Vogler and Ernst, 1999).No adverse effects have been reported.

Pterocarpus marsupium and epicatechin-containing plants
Pterocarpus marsupium has been used for DM management in India.The flavonoid, epicatechin, extracted from the bark of the plant has been shown to prevent β-cell damage in rats.In addition, both epicatechin and a crude alcohol extract of Pterocarpus marsupium have been shown to regenerate functional pancreatic β-cells in diabetic animals (Chakravarthy et al., 1982).They therefore have the potential to prevent induction and development of DM.On the other hand, epicatechin and catechin consist of glycosides and esters.They are flavan-3-ols, a group of flavanols with glucose-lowering properties (Subramanian et al., 1981).

Vaccinium myrtillus (Bilberry)
Bilberry (European blue berry) is a shrubby plant that grows in Europe.Its leaves were widely used in DM management before the availability of insulin (Bailey et al., 1989).Oral administration of bilberry leaf tea reduced blood glucose levels in normal and diabetic dogs, even when glucose was concurrently injected intravenously.Bilberry also has a beneficial role in preventing microvascular complications of DM, particularly, retinopathy (Caselli, 1985).The leaves are also useful against vascular complications, whereby anthocyanosides are Diabetes Endocrinol.
the most important constituents (Mills and Bone, 2000).

Atriplex halimus (Salt bush)
This plant is native to Israel, where much of the clinical data has been collected.Human trials have been used to report its glucose-lowering effect in type 2 DM (NYU Langone Medical Center).Sand rats develop type 2 DM when deprived of this plant (Collier et al., 1997).

Coccinia indica (Ivy gourd)
This creeping plant, used to treat "sugar urine", grows widely in India.Human and animal trials have widely been used to report its glucose-lowering effects (Kuppurajan et al., 1986;Kamble et al., 1998).Its mechanism of action is unknown, though insulin-like properties have been postulated (Kamble et al., 1998).
No adverse effects have been demonstrated.

Ocimum sanctum (holy basil)
This plant is commonly used in Ayurveda.Related species include Ocimum album and Ocimum basilicum.Its glucose-lowering effects have been demonstrated in animal model studies (Chattopadhyay, 1993).Its mechanism of action is unknown, though enhanced β-cell function and insulin secretion have been postulated.Although no adverse effects have been reported, further studies are warranted.

Ficus carica (fig leaf)
This plant is used in Spain and South Western Europe.Animal studies have shown its glucose-lowering effect.The mechanism of action is unknown, but some studies suggest facilitation of peripheral glucose uptake.No effect has been noted in c-peptide, thus, indicating noninsulin mediated effect.No adverse effects have been reported (Lucy et al., 2002).

Bauhinia forficata and Myrcia uniflora
Bauhinia forficata (Pata de vaca), indigenous to rainforests and tropical areas of South America, has been used in traditional management of DM.It has been referred to as "vegetable insulin" in Brazil.Myrcia uniflora, a South American herb, has also demonstrated glucoselowering effect.No adverse effects have been reported.The glucose-lowering roles of both herbs warrant further study (Russo et al., 1990).

Opuntia streptacantha (nopal)
Opuntia streptacantha (nopal) is found in the Western hemisphere, including the south-western US, and is commonly used for its glucose-lowering effect in Mexico.
It has a high-soluble fibre and pectin content, which may affect intestinal glucose uptake, partially, accounting for its glucose-lowering actions (Shapiro and Gong, 2002).
Trials have reported improvements in patients with type 2 DM with decreased insulin levels, suggesting enhanced insulin sensitivity and secretion (Yeh et al., 2003).No adverse effects were reported.

Eucalyptus globulus
This tree is widely found in tropical regions and is commonly used to control diabetes in India.The parts used include the bark and leaves.An aqueous extract (0.5 g/ml) of E. globulus increased peripheral glucose utilization in mice abdominal muscle, and stepwise enhanced insulin secretion from the clonal pancreatic βcells (Gray and Flatt, 1998a).Administration of E. globulus leaves to normal rats for 12 days however, did not result in hypoglycaemia.Streptozocin (STZ) administration to these pre-treated rats did not produce hyperglycaemia as severely as it was seen in the controls.In addition, pre-treated rats also showed less polydypsia and body weight loss (Swanston-Flatt et al., 1989).A study of the effects of the leaves on STZinduced damage in pancreatic islets on normal Wistar rats suggested that the plant ameliorates diabetic states by partial restoration of pancreatic β-cells and repair of the STZ-induced damage.This study suggests a beneficial effect of E. globulus in DM management (Mahmoudzadeh et al., 2010).No adverse effects have been reported.

Mangifera indica (mango)
This mango species is commonly found in tropical regions.It has been used as an anti-diabetic agent in Ayurvedic and Nigerian folk medicine.The glucoselowering effect of aqueous extract of the leaves has been reported in normal and diabetic rats (Aderibigbe et al., 1999b).The active component, 3β-taraxerol, enhances insulin induced glucose uptake through translocation of the glucose transporter, GLUT 4 (Sangeetha et al., 2010).

Syzygium cumini (Black berry, Jamun, Jambul)
This is an evergreen tree found in Sri Lanka, Nepal, Pakistan, India, America, Brazil and Caribbean islands.Alcohol extracts of the seeds were shown to significantly decrease blood glucose and urine sugar in alloxaninduced albino rats (Prince et al., 2004).Aqueous leaf extract (60 to 1000 µg/ml) administered to diabetic subjects, caused a dose dependent inhibition of adenosine deaminase (ADA) activity and a decrease in blood glucose level (Bopp et al., 2009).

Musa sapientum (banana)
This is a hybrid of wild seeded bananas (Musa balbasiana and Musa acuminata) found in tropical countries, especially Philippines.Aqueous and methanol root extracts have been reported to have anti-oxidant and glucose-lowering effects comparable to glibenclamide (Pari and Maheswari, 1999;Dhanabal et al., 2005;Adewoye et al., 2009).

Lantana camara
This flowering plant of the Verbena family is native to the American tropics: Mexico, Central America and Venezuela.It is also found in Africa, Australia and India.
A stearoyl glucoside of ursolic acid isolated from its leaves, showed significant blood glucose level reduction in STZ-induced diabetic rats (Kazmi et al., 2012).Once daily, administration of the leaves juice (1500 mg/kg) for 14 days showed significant glucose-lowering effect in rats (Garg et al., 1997).

Catharanthus roseus (Madagascar Periwinkle)
This plant, also known as Vinca rosea and Ammocallis rosea, is found in Madagascar.In Traditional Chinese Medicine, its extracts have been used to treat DM and malaria.Crude aqueous extracts of its leaves has been shown to reduce blood glucose level in normal and diabetic rats.It has however been shown to be cytotoxic (Nammi et al., 2003;Ahmed et al., 2007).

Chromium
Chromium is an essential micronutrient in humans.It serves as a cofactor in all insulin regulating activities, being a major determinant of insulin sensitivity (Offenbacher and Pi-Sunyer, 1990).Chromium facilitates insulin binding and subsequent uptake of glucose into the cell.Without chromium, insulin's action is blocked and glucose levels are elevated (Mooradian et al., 1994).Supplemental chromium has been shown to decrease fasting glucose levels, improve glucose tolerance, lower insulin levels and decrease total cholesterol and triglycerides, while increasing HDL cholesterol in normal, elderly and type 2 DM subjects (Mooradian et al., 1994).Foods rich in chromium include brewer's yeast, barley flour, broccoli, grape juice, whole wheat, potatoes, garlic, basil, orange juice and red wine (Castro et al., 1998;Miller, 1998).On the other hand, refined sugars, white flour products, and lack of exercise can deplete chromium levels.

Vanadium
Vanadium was used to control blood glucose levels prior to the discovery of insulin.Two studies confirmed the effectiveness of vandal sulphate at a dose of 100 mg/day in improving insulin sensitivity (Halberstam et al., 1996).

Magnesium
Magnesium deficiency is more common in type 2 diabetics than in the general population (Sjogren et al., 1988).It is essential in glucose metabolism and in the prevention of DM complications.Magnesium deficiency has been associated with complications of DM, especially, retinopathy.Magnesium is contraindicated when administering antibiotics, drugs to prevent osteoporosis, calcium channel blockers, muscle relaxants and diuretics.Increased magnesium intake can be achieved through diet without the use of supplements.Foods rich in magnesium include whole grains (brown rice, barley and oats), green vegetables (spinach and Swiss chard) and many bean varieties (Lucy et al., 2002).

Vitamin E
Diabetes produces a state of increased free radical activity.The purported effects of vitamin E on glucose control relate to the vitamin's potent lipophyllic antioxidant activity, with possible influences on protein glycation, lipid oxidation, and insulin sensitivity and secretion.Although its mechanism of action is unknown, it may also affect non-oxidative glucose metabolism (O'Connell, 2001).

Acupuncture
Acupuncture is a well known alternative therapy for chronic pain.In addition, experimental and clinical trials have reported its role in the management of DM and its complications (Hui, 1995;Huang, 1996).Acupuncture can act on the pancreas to enhance insulin synthesis, increase the number of receptors on target cells, and accelerate the utilization of glucose, resulting in blood glucose-lowering (Hui, 1995).Acupuncture also has an anti-obesity effect, the most modifiable risk factor for type 2 DM.Its precise mechanisms of action remain unclear.

Hydrotherapy (Hot-tub therapy)
Hot-tub therapy increases blood flow to skeletal muscles hence has been recommended to diabetic patients who are unable to exercise (Hooper, 1999).Hot-tub therapies also lead to decreased patient body weight, mean plasma glucose level and mean glycosylated haemoglobin (Hooper, 1999).Proper water sanitation and appropriate guidance should however be considered when administering hot-tub therapy for diabetic patients (Hooper, 2000).Caution must be taken to ensure that the water is not too hot, as neuropathy, a complication of diabetes, may prevent the patients from realizing that they are burning themselves, resulting in injury.

DISCUSSION
Thousands of plants are attributed with glucose-lowering effects.These herbs are used singly or in combination, to address various underlying factors contributing to hyperglycaemia (Sikha et al., 2012).This review summarizes the commonly used herbs in DM management, as well as explores some philosophies behind CAM use.
Though conventional practitioners pose great concern about CAM use, its use is widely gaining popularity (Yeh et al., 2003;Chang et al., 2007).The use of CAM is grounded on culture, knowledge, beliefs, experience and the advice of family and friends (Coulter and Willis, 2004).The people most likely to use CAM therapies thus include: people in poor health with chronic diseases, people committed to the environment, well-educated women (67%) interested in self-care, some cultural groups, those whose philosophies and values are congruent with CAM, those who think CAM is culturally relevant, on advice of family and friends, or after a traumatic event (International Diabetes Federation, 2011b).The World Health Organisation (WHO) encourages member states to integrate traditional and CAM therapy into national health care systems and ensure their rational use (WHO Traditional Medicine Strategy, 2002).China is one of the countries with a truly integrated system (International Diabetes Federation, 2011b).This integration entails collaboration between conventional and CAM practitioners through sharing of information and negotiating careful plans with achievable goals.Empowering CAM practitioners through appropriate education and skills is thus crucial (WHO Traditional Medicine Strategy, 2002).
Having more than one active ingredient, CAM is attributed with a range of actions (International Diabetes Federation, 2011b).It takes a while for an effect to show and may produce fewer side effects.Adverse effects associated with CAM include: ketoacidosis due to stoppage of insulin in type 1 DM, trauma and burns from moxibustion (TCM), cupping on neuropathic legs, hypoglycaemia, interaction with conventional medicines, hypertension, bruising from massage, allergy, inappropriate weight loss, renal and hepatic toxicity, and infections (WHO Traditional Medicine Strategy, 2002;Yeh et al., 2003).Some concerns regarding CAM use are justified; hence, legislation to govern CAM use is inevitable.Only CAM therapies with established empirical evidence should be used.Regulatory systems should ensure product quality, as well as report any herb/herb or herb/drug interactions.CAM products with no empirical evidence or with serious adverse effects should not be used.
This review is not without limitations.Thousands of herbs have demonstrated glucose-lowering effects, thus, they cannot all be included within the scope of this one review.Moreover, the review of CAM use is complicated by inconsistency of definition and research design.The number of subjects used in the trials, the methods of extracting the fruits, the parts of the plants used, and the amount of dose used, are different in the various trials.The various non-standardized forms of the drugs have been the basis for some trials hence results have been difficult to replicate.We thus recommend the preparation of standardized medicinal herbs for future studies and therapies.CAM safety and efficacy needs better evaluation by well-designed, controlled clinical studies.

Conclusion
Research and use of CAM therapy in DM is on the increase worldwide.Commonly used CAM products include herbal medicine, mineral and vitamin supplements, acupuncture and hot-tub therapy, among others.Of these, medicinal herbs have demonstrated better efficacy.However, exercise, weight control and nutrition remain key pillars in DM management, in addition to conventional therapy.Adverse effects have been reported in CAM; hence, empirical evidence should guide the safe and appropriate use of CAM.Stringent regulatory policies and guidelines of CAM use are required.