A Systematic Review of Efficacy and Safety of Urtica dioica in the Treatment of Diabetes

This review focuses on the efficacy and safety of Urtica dioica which has been utilized in traditional medicine for management of diabetes. All relevant databases including Pubmed, Google Scholar, Web of Science, Scopus, Iranmedex and MD Consult were searched for the terms diabetes mellitus and Urtica dioica without limitation up to 15th September 2010. All the animal studies with the outcome of change in blood glucose or other relevant complications of diabetes and all available abstracts were included. Review articles and letters to the editor were excluded. Search of databases resulted in 724 articles which 87 were potentially relevant studies on Urtica dioica and diabetes. On the basis of inclusion/exclusion criteria, 21 studies were finally included. One human and 20 animal studies were reviewed for the efficacy of Urtica dioica. Most of these studies showed significant decrease in blood glucose and complications of diabetes by use of Urtica dioica. Urtica dioica can affect both pancreatic and extra pancreatic pathways. Available evidences suggest that Urtica dioica can be used to treat diabetes and its long-term complications. Of course, further experiments would help determine exact mechanisms of action, effects and side effects of this herbal medicine.

INTRODUCTION

Diabetes is one of the most common chronic diseases in the world. The number of people with diabetes is increasing dramatically due to population growth, aging, urbanization, and increasing prevalence of obesity and physical inactivity that is finally associated with major health and socio-economic problems. The extent and severity of these problems are reflected in extra mortality and at-risk people. For example, according to the last International Diabetes Federation (IDF) report, about 2566000 people (6% total population) are suffering from diabetes in Iran and its prevalence is increasing like other developing countries expecting to reach 5114900 in 2025 (Sicree et al., 2007). Current estimates demonstrate that the world prevalence of diabetes will increase to 7.7% (439 million) adults by 2030. Between 2010 and 2030, there will be a 69% increase in number of diabetic patients in developing countries and 20% in developed countries (Shaw et al., 2010). So, with regard to the issue of socioeconomic burden of diabetes, discovery of more effective and less side effect therapies are necessary. In the recent years good data have been obtained from traditional medicines indicating usefulness of many herbal medicines (Hasani-Ranjbar et al., 2008, 2009). For a very long time, plants have been an important role part of treatment of many diseases. The use of plants to treat diabetes is a centuries-old practice. More than 400 traditional plant treatments for diabetes have been recorded, but only a small number of these have received scientific and medical evaluation to assess their efficacy. Hypoglycemic action from some treatments has been confirmed in animal models, and various hypoglycemic compounds have been identified. Traditional treatments may provide valuable clues for the development of new oral hypoglycemic agents and simple dietary adjuncts. Urtica dioica (Stinging Nettle) has been used for centuries for food and medical purposes. The genus name Urtica comes from the Latin verb urere, meaning to burn because of stinging hairs of the herb. The species name dioica means two houses because the plant usually contains either male or female flowers. It is abundant in North America, Northern Europe and most of Asia, usually found in the rural area. It contains flavonoides (0.7-1.8%), silicic acid (1-4%), potassium-ions (0.6%), nitrates (1.5-3%), volatile oil, histamine, serotonin, acetylcholine, formic acid and leukotrienes (LTB4, LTC4, LTD4). The blood sugar lowering effect of Urtica dioica has been mentioned in old script such as those written by Avicenna. There have been other reports indicating the benefits of using the infusion or the extract of the leaves or other parts of this plant for the use in diabetes (Ramos et al., 1992; Swanston-Flatt et al., 1989). Moreover, it is used internally and externally as supportive therapy for prostatic hyperplasia (Hirano et al., 1994; Krzeski et al., 1993; Kayser et al., 1995), inflammation (Obertreis et al., 1996), rheumatoid arthritis, hypertension and allergic rhinitis (Mittman, 1990).

The present systematic review aimed to evaluate the efficacy and safety of Urtica dioica in diabetes by reviewing all animal and human studies.

MATERIALS AND METHODS

Databases of Pubmed, Google Scholar, Web of Science, Scopus, Iranmedex, and MD Consult were searched up to 15th September 2010, for studies examined Urtica dioica in prevention or treatment of diabetes. The search terms were diabetes and Urtica dioica without limiting search elements. A Flow diagram of the search process has been shown in Fig. 1. Among the studies, there were only one human study and the rest of them were animal ones. All of animal studies with the outcome of change in blood glucose and other relevant complications of diabetes with available abstracts were included.

Fig. 1:	Flow diagram of the search process.*There was one study which had both in vivo and in vitro sections. **There was one study which had both animal and human parts

Review articles and letters to the editor were examined to ensure inclusion of all relevant studies. Unpublished data such as dissertations were not included. Two reviewers independently examined the title, abstract and references of each article to eliminate duplication. The reference lists of articles were also reviewed for additional relevant studies. The reviewers summarized data on Urtica dioica for dose, treatment duration, grouping, main outcome, probable mechanism and side effects (Table 1).

RESULTS

The electronic database search identified 724 articles which 87 were potentially relevant studies on Urtica dioica and diabetes. Finally, based on our inclusion and exclusion criteria, 21 studies were included (Table 1) (Ramos et al., 1992; Swanston-Flatt et al., 1989; Said et al., 2008; Bnouham et al., 2010; Bnouham et al., 2003; Bijan et al., 2003; Petlevski et al., 2001; Shahraki et al., 2009; Fathi-Azad et al., 2005; Khouri and Golalipour, 2006; Golalipour et al., 2009a; Golalipour et al., 2010; Gunes et al., 1999; Neef et al., 1995; Jahanshahi et al., 2009; Fazeli et al., 2008; Fazeli et al., 2010; Golalipour et al., 2007a; Golalipour and Khouri, 2007b; Petlevski et al., 2003; Golalipour et al., 2009b). Only one human study was found which applied Urtica dioica in combination with Juglans regia L. Olea europea L. and Atriplex halimus L. in the form of Glucolevel tablets. This study revealed that acceptable glucose level was achieved in patients treated with Glucolevel (Said et al., 2008). Besides, animal studies showed significant decrease in blood glucose after treatment with Urtica dioica (Said et al., 2008; Bnouham et al., 2010; Bnouham et al., 2003; Bijan et al., 2003; Petlevski et al., 2001; Shahraki et al., 2009; Fathi-Azad et al., 2005; Golalipour et al., 2009a; Golalipour and Khouri, 2007b). One animal study showed ineffectiveness of Urtica dioica in treated animals (Khouri and Golalipour, 2006) and another study showed that Urtica dioica can aggravate diabetes (Swanston-Flatt et al., 1989). One animal study showed that the active component of Urticadioica can increase insulin content of blood in normal and streptozotocin-induced diabetes (Bijan et al., 2003). A suggested mechanism for action of Urtica dioica in reducing hyperglycemia is illustrated in Fig. 2. There were reports investigated intracellular changes in animals receiving Urtica dioica. Two studies showed that hydroalcoholic extract of Urtca Dioica reduces density of astrocytes in dentate gyrus in the diabetic rats (Jahanshahi et al., 2009; Fazeli et al., 2008 ). Another study demonstrated that this extract has no significant neuroprotective benefit in diabetes-induced loss of pyramidal cells in the CA3 hippocampal subfields of young diabetic rats (Fazeli et al., 2010).

STZ: Streptozotocin, i.v: Intravenous, i.p: Intraperitoneal, NOD: Non-obese diabetic

Fig. 2:	Suggested mechanisms of action of Urtica dioica in reducing hyperglycemia

Three studies pointed the effect of Urtica dioica on renal complications of diabetes. In another study, the protective effect of Urtica dioica on morphometric and histological alterations in streptozotocin diabetic rats were reported (Golalipour et al., 2009a). Another study showed that Urtica dioica has no protection on renal complication of diabetes and even causes nephrotoxicity (Gunes et al., 1999). Another research revealed that Urtica has no effect on morphometric indices in diabetic rats (Golalipour et al., 2007a). One study noticed that Urtica dioica can modulate the main morphometric indices of liver such as area of hepatocytes, nuclei and nucleolus in periportal and perivenous zones (Golalipour et al., 2009b). Another study showed that Urtica dioica has antioxidant effect in diabetes which influences lipid peroxidation and antioxidative activity of glutathione S-transferases in the liver of diabetic NOD mice (Petlevski et al., 2003). Scientists in 2007 showed protective activity of Urtica dioica in beta-cells of Langerhans in hyperglycemic rats (Golalipour and Khouri, 2007b).

DISCUSSION

Looking back demonstrates that natural remedies have played an important role in people's daily life in most parts of the world. Some herbs are traditionally used in treatment of type 2 diabetes. Urtica dioica has been used traditionally in Morocco, Turkey, Brazil, Jordan, Iran and many other countries. The present study reviewed the effects of Urtica dioica on diabetes. Most of the included studies concluded that Urtica dioica can significantly reduce blood sugar. Researchers have proposed several mechanisms for this process. Possible effects of Urtica dioica could be categorized into two groups of pancreatic and extrapancreatic. Regarding to pancreatic effects, they have been suggested that Urtica dioica enhances the secretagogue function of islets of Langerhance and it is a potent stimulator of insulin release from β-cells (Bijan et al., 2003). Urtica has shown protective effect on β-cells in hyperglycemic rats (Fazeli et al., 2008).

Extra-pancreatic mechanisms that Urtica dioica affects glucose homeostasis include inhibition of intestinal absorption of glucose (Bnouham et al., 2003), inhibitory effects on the alpha amylase activity in a dose dependent-manner (Nickavar and Yousefian, 2010) and forming unique glucose permeable pores to facilitate glucose uptake (Domola et al., 2010).

On the other hand, investigators found that Urtica dioica has benefits on complications of diabetes and can cause a delay in development of late complications associated with hyperglycemia. They showed that Urtica can compensate granul cells in dentate gyrus after diabetes-induced cell loss, so it can ameliorate cognitive impairment in diabetes (Jahanshahi et al., 2009; Fazeli et al., 2008). A further effect of Urtica dioica is in the liver. Urtica has shown antioxidant effect in the liver, which can influence lipid peroxidation and increase the antioxidative activity of glutathione S-transferases in the liver (Petlevski et al., 2003) and can cause a little modulation in the main morphometric indices of live (Golalipour et al., 2009b). Meanwhile, platelet hyperaggregability is one of the pathogenesis of diabetes which Urtica can reduce and thus prevents cardiovascular complications of diabetes (El-Haouari et al., 2007). Its effects on kidney have been controversial. Among studies conducted in this field, only one showed protective effects of Urtica dioica on renal morphometric and histological alterations of diabetes (Golalipour et al., 2009a).

Besides in some in vivo and in vitro studies, Urtica dioica had no effects on diabetes or vice versa showed toxic effects on kidney and liver (Ramos et al., 1992; Swanston-Flatt et al., 1989; Gunes et al., 1999). And its mechanism of action is still controversial (Mobaseri et al., 2010).

In conclusion, considering all available evidences, the integration of chemical drugs with Urtica dioica may be possible and recommendable for management of diabetes. As a matter of fact, antioxidant composition of Urtica dioica should be noted as an excellent influencing element in management of diabetes and its complications (Rahimi et al., 2005; Momtaz and Abdollahi, 2010; Sarkhail et al., 2007; Mohseni-Salehi-Monfared et al., 2009; Milani et al., 2005; Malihi et al., 2009). In the recent years, Urtica dioica in combination with Rosa canina, Tanacetum vulgare and selenium and electromagnetic processing (named and patented as IMOD) has been tested in rat diabetes 1 model and found to improve oxidative and immunological distresses of type-1 immunogenic diabetes but could not normalize blood glucose (Mohseni-Salehi-Monfared et al., 2010). Of course evidence-based supports on the efficacy and safety of Urtica in diabetes are too few and needs further well-designed clinical trials. IMOD containing Urtica dioica is a good example of this hypothesis that has been found useful in experimental colitis (Baghaei et al., 2010), in human sever sepsis (Mahmoodpoor et al., 2010) and as an immunomodulator (Khairandish et al., 2009).

Meanwhile better experimental studies should be conducted to elucidate exact mechanism of action of Urtica dioica in diabetes.

ACKNOWLEDGMENT

This study is the outcome of an in-house non-financially supported study.