Clinical research
A systematic review of Iranian medicinal plants useful in diabetes mellitus

Introduction
The term diabetes mellitus describes several diseases of abnormal carbohydrate metabolism that are characterized by hyperglycaemia. It is associated with a relative or absolute impairment in insulin secretion, along with varying degrees of peripheral resistance to the action of insulin. Today about 2 565 500 people, equal to 6% of the population in the age group of 20-79 years, are suffering from diabetes mellitus in Iran; its prevalence is increasing as in other developing countries and is expected to reach 5 114 900 in 2025 [1]. For a very long time, plants have played an important role in the treatment of many diseases, especially in Eastern countries. The use of plants for treatment of diabetes has been common in the Iranian population too. These natural compounds are used by traditional herbalists for the management of diabetes in several parts of Iran [2]. There are enough reports on the positive effects of herbal medicines in the management of diabetes [3-45]. However, available herbal products have no clear statement of content or medically related information on the package labels, and they have not been validated or certified. For various reasons, in recent years the popularity of alternative medicine has increased. Surveys conducted in Australia and the U.S. indicate that almost 48.5 and 34% of respondents respectively had used at least one form of unconventional therapy, including herbal medicine. The WHO has also recommended evaluation of effective plants for conditions such as diabetes for which there are few safe modern drugs [46]. This leads to increasing demand for herbal products with anti-diabetic activity and fewer side effects. At the time being, some herbal preparations are used by diabetic patients in Iran, especially among unsuccessfully treated patients and those who are candidates for insulin therapy [2]. Most studies published in Iran have shown a statistically significant decrease in blood glucose but no there are no collective data and no systematic review has been performed yet. This is the first review that focuses on the efficacy and safety of Iranian medicinal plants in the management of diabetes.
Material and methods
The data sources EMBASE, Scopus, PubMed, Web of Science, Google Scholar, and IranMedex databases were searched up to 8th October 2007 for studies investigating medicinal plants in prevention and treatment of diabetes. The search terms were “diabetes” and “plant”, “herb”, “traditional”, and “natural” or “herbal medicine”, limited to Iran. The reference lists of articles were also reviewed for additional relevant studies.
Study selection

Inclusion criteria
All of the human studies with the key outcome of change in blood glucose or serum lipids in diabetic patients were included. Animal studies with the outcome of change in blood glucose, serum lipids, antioxidant parameters, hepatic enzymes, anti-inflammation, and vascular activity were also included.
Exclusion criteria
In vitro studies, review articles and letters to the editor were excluded. Unpublished data such as theses were not included. Studies published from countries other than Iran were excluded too. Two reviewers independently examined the title and abstract and references of each article to eliminate duplications, those published from countries other than Iran, and in vitro studies. The reviewers independently extracted data on the medicinal plant, dose, trial duration, sample size, outcome, results, and side effects.
Results

Human studies
Of publications identified in the initial database search, 12 trials on the efficacy of medicinal plants in diabetic patients were reviewed. Information from these clinical trials are summarized in Table I.
Blood glucose
The key outcome for anti-diabetic effects was reduction in blood glucose. These human studies showed a significant decrease in blood glucose after treatment with Citrullus colocynthus L., Silybum marianum, Psyllium, Teucrium polium, and Pomegranate [4, 6-12]. Securigera securidaca (1500 mg/day) had no benefit on improving glycaemic profile in type 2 diabetic patients [3]. Salvia leriifolia and Morus nigra had no hypoglycaemic effect but neuropathy and polyphagia became better during administration of the extracts [13, 14].
Serum lipids
Another key outcome in diabetes was reduction in serum lipids. In a before-after clinical trial, Garlic tablets significantly decreased total and LDL cholesterol levels in diabetic patients with hyperlipidaemia [5]. Improvement in lipid profile was shown by other medicinal plants including Silybum marianum, Psyllium, Teucrium polium, and Pomegranate [6-10, 12].
Side effects
The use of Securigera securidaca in the dose of 1500 mg in divided doses showed no gastrointestinal symptoms or liver and kidney abnormalities during two months of therapy [3]. Ten percent of patients treated with Citrullus colocynthis L. in the dose of 300 mg in three divided doses complained of mild diarrhoea [4]. No side effects were recorded with Psyllium (10 g/day) and an even better response to metformin was found [7, 9]. No adverse effects were reported for chronic use of Silybum marianum [6].
Animal studies
The details of the animal studies that investigated Iranian medicinal plants in animal diabetic models are summarized in Table II.
Blood glucose
The key outcome for anti-diabetic drugs in animal studies was reduction in blood glucose. These animal studies showed that Walnut leaf, coriander, Pomegranate, Garlic, Satureja khuzestanica, Phlomis anisodonta, Trigonella foenum graecum, olive (Olea europaea L.), Capsicum frutescens, Achillea santolina, Aloe vera, Salvia officinalis, Anathum graveolens, Teucrium polium, Urtica dioica, Morus nigra, Morus alba, Salvia lenifolia benth leaf, and Cynara scolymus improve blood glucose of diabetic animals.
Serum lipids
Improvement in lipid profile was shown by some medicinal plants including Satureja khuzestanica, Capsicum frutescens, Garlic, Aloe vera, Anathum graveolens, Persian Walnut, tarragon, and Cynara scolymus. In one study, Teucrium polium in a dose of 50 mg/kg increased blood lipid levels [39].
Discussion
In Iran, there are multiple plants that are unofficially taken by diabetic patients [2]. The present data show that some of these plants (Citrullus colocynthus L., Silybum marianum, Psyllium, Teucrium polium, and Pomegranate) are really effective in reducing blood glucose in diabetic patients [4, 6-12]. Animal studies have also shown that some natural plants are even more effective than currently used chemical drugs in diabetic animals [24, 27]. Special attention to these natural compounds seems necessary to search for novel therapeutic agents. Some of these plants have shown a significant hypoglycaemic effect in animals but not in humans (e.g. Garlic, Salvia leriifolia, Morus nigra, and Securigera securidaca) [3, 5, 13, 14, 17, 27, 35, 37, 41]. This controversy seems to be due to inappropriately designed clinical trials; it thus remains to be elucidated by further examinations in diabetic patients. It is notable that the hypoglycaemic effect of these herbal medicines can interfere with hypoglycaemic drugs and insulin, which are standard treatments for diabetic patients. Most physicians advise their patients to avoid herbal medicine, but in some cases the diabetic patients take it without informing their physicians [2]. This type of herbal therapy may lead to drug interaction or false and unstable blood glucose level monitoring [2]. Therefore, physicians should have adequate knowledge about herbal medicines effective in blood glucose to be prepared how to manage patients who are at risk. Any consumption of medicinal plants must be under the supervision of physicians. Some of these plants (Garlic, Silybum marianum, Psyllium, Teucrium polium, and Pomegranate) had anti-hyperlipidaemic properties and this reduction in serum lipids was statistically significant. Of course there were two controversial reports about Teucrium polium affecting blood lipid profile [12, 39], which needs to be proved by further studies. The medicinal plants with lipid-lowering potential can better be supplemented to standard therapy of diabetic patients. Investigation of other clinical trials in different parts of the world can help us to recommend a proper dose for diabetic patients. For some of these plants (Garlic and Pomegranate), proper randomized controlled trials are needed show their benefit in diabetic patients. Induction of insulin release is the mechanism of action for some medicinal plants, including Phlomis anisodonta, olive (Olea europaea L.), Garlic, Teucrium polium, and Urtica dioica [19, 24, 27, 34, 36]. In addition, density of islets in pancreatic tissue, percent of beta cells and islets size increased significantly in rats treated with Walnut leaf and Garlic [15, 17]. It has been suggested that enhanced production of free radicals and oxidative stress are central events to the development of diabetic complications. Use of antioxidants reduces oxidative stress and alleviates diabetic complications [47]. Most of the tested medicinal plants (e.g. Achillea santolina, Phlomis anisodonta, ginger) have shown antioxidant effects [19, 26, 29]. Further studies in diabetic animal models and also diabetic patients should be better focused on those Iranian herbal medicines that have been found to have adequate antioxidant effects in humans and some tested in disease models other than diabetes [48-60]. In conclusion, any consumption of medicinal plants must be under the supervision of physicians. Some natural plants are more effective than currently used chemical drugs in diabetic patients [24, 27]. Special attention to these natural compounds would open a new approach for novel therapeutic agents.
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