Accepted Manuscript Title: Effects of Black Seed (Nigella Sativa) on Metabolic Parameters in Diabetes Mellitus: A Systematic Review Author: Javad Heshmati Nazli Namazi PII: DOI: Reference:
S0965-2299(15)00027-8 http://dx.doi.org/doi:10.1016/j.ctim.2015.01.013 YCTIM 1425
To appear in:
Complementary Therapies in Medicine
Received date: Revised date: Accepted date:
7-8-2014 22-1-2015 30-1-2015
Please cite this article as: Heshmati J, Namazi N, Effects of Black Seed (Nigella Sativa) on Metabolic Parameters in Diabetes Mellitus: A Systematic Review, Complementary Therapies in Medicine (2015), http://dx.doi.org/10.1016/j.ctim.2015.01.013 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Highlights Nigella sativa can improve glycemic status in diabetes models
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Nigella sativa can improve lipid profiles in diabetes models
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Nigella sativa can be used as a complementary therapies in diabetes mellitus
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Effects of Black Seed (Nigella Sativa) on Metabolic Parameters in Diabetes Mellitus: A
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Systematic Review
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Javad Heshmati a, Nazli Namazi*b
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a
Health Care Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
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b
Nutrition Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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*Corresponding Author: Nutrition Research Center, Tabriz University of Medical
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Sciences, Tabriz, Iran; E-mail:[email protected]
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Abstract
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Background: Current evidence indicated beneficial effects of some medicinal herbs on
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metabolic parameters. Nigella sativa is an example of herbs which can ameliorate
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metabolic factors in diabetes mellitus. Despite several narrative review studies on medicinal
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properties of NS, it seems that there is no systematic review to summarize effects of NS on
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glucose homoeostasis and lipid profile in diabetes mellitus. Therefore, the aim of present
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study was to review effects of Nigella sativa on metabolic parameters in diabetes mellitus.
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Methods: Pubmed, Science Direct, Google scholar and Springer databases were searched
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from 1995 till January 2014. Key words were included: Nigella Sativa, black Seed,
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diabetes, glucose level, lipid and Insulin. Searching was limited to articles with English
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language. Review articles, case reports, abstract in symposium and congress, studies on
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Nigella sativa mixed with other plants were excluded. Based on critically appraise,
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eligibility of included articles were evaluated.
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Results: Finally 19 eligible articles (2 human trials, 14 animal models and 3 in vivo/in vitro
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studies) were selected. They indicated that Nigella sativa can modulate hyperglycemia and
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lipid profile dysfunction with various potential mechanisms including its antioxidant
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characteristics and effects on insulin secretion, glucose absorption, gluconeogenesis and
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gene expression. Some studies compared effects of various types (extract, oil, powdered) of
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Nigella sativa with each other and they reported different characteristics with various types
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of black seed.
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Conclusion: Nigella sativa can improve glycemic status and lipid profile in diabetes
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models. However, more clinical trials are necessary to clarify beneficial effects of Nigella
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sativa, its effective type and dosage for diabetes management and its complications.
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Introduction
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Diabetes mellitus (DM) is a global health concern characterized by impairment in insulin
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secretion or insulin action. According to an International Diabetes Federation (IDF) report,
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the prevalence of diabetes was 171 million in 2001 and it is expected to increase to 366
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million by 2030 (1). Following the metabolic dysfunction in DM, the risk of developing
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cardiovascular diseases, dyslipidemia, infection, morbidity and mortality can increase (2,
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3). For controlling diabetes, various treatments including diet, life style changes,
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biochemical and herbal medicine in combine or alone have been used (4, 5). Many
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populations consume complementary and alternative medicine and there is high tendency to
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use medicinal herbs for diabetes treatment in worldwide (6). Due to side effects of some
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chemical drugs and high tendency of people to consume medicinal herbs, World Health
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Organization (WHO) persuades researchers to study efficacy and side effects of herbs with
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potential therapeutic properties (7).
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Current evidence demonstrated beneficial effects of some medicinal herbs such as Urtica
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dioica, Trigonella foenum, Silybum marianum and Nigella sativa (NS) for controlling
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glucose level and lipid profile in diabetes models (8-10). NS or Black seed is one of the
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medicinal plants with anti-hyperglycemia and anti-hyperlipidemia characteristics (11). It is
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a plant of Ranunculaceae family which grows widely in many Middle Eastern countries. Its
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seed colored black and taste bitter (12). NS has many different chemical ingredients
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including Thymocinon (TQ), essential fatty acids particularly linoleic and oleic acid, trans-
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anethole, p-cymene, alpha pinene, limonene, and carvone. It is used in traditional medicine
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in different forms such as powder, oil and extract (12, 13). Previous studies indicated many
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medical characteristics of black seed including antimicrobial, anti-inflammatory and
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antioxidative effects (14, 15) . Also anti-diabetic effects of black seed have been reported
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in several studies (16-18). Despite several narrative review studies on medicinal properties
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of NS, it seems that there is no systematic review to summarize glucose homoeostasis and
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lipid profile effects of NS in diabetes mellitus. Therefore, the aim of present study was to
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evaluate effects of Nigella sativa on glycemic status and lipid profile in DM.
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Article selection
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We searched databases of Pubmed, Science Direct, Google scholar and Springer from 1995
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till January 2014. Key words were selected based on Mesh terms. They were included:
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“Nigella sativa” or “black Seed” or “black cumin” and “diabetes”, “glucose level”, “lipid”,
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and “Insulin”. Also we hand searched references of articles. Two reviewers extracted data
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independently, and then titles and abstracts of each article were assessed to delete
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duplication data. Any irrelevant papers were excluded. The remaining articles were
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reviewed to determine compatibility with the inclusion criteria. Searching was limited to
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articles with English language. Review articles, case reports, abstract in symposium and
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congress, articles about effects of NS mixed with other plants were excluded. After
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critically appraise of articles, 19 articles were selected (Fig 1). Characteristic of studies
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have been summarized in Table 1.
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Summary of studies and potential mechanisms
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Studies were classified into three groups: human, animal and in vivo/in vitro studies. 1. Human studies
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Based on the criteria, two human studies were found (16, 17). Kaatabi et al evaluated
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different dosage of powdered NS (1, 2 and 3 gr/day) in patients with type 2 diabetes. They
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indicated that 1 g/day NS increased high-density lipoprotein cholesterol (HDL-c) levels
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after 12 weeks. Two and 3g/day of black seed significantly decreased total cholesterol
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(TC), triglyceride (TG) and low-density lipoprotein cholesterol (LDL-c) levels and
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increased HDL-C concentration. Increasing dosage from 2 to 3gr/day did not indicate
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higher improvement in lipid profile (16). Also Bamosa et al demostrated that only 2g/day
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NS seed decreased fasting blood sugar (FBS), 2 hours postprandially glucose (2-hPG),
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glycosylated hemoglobin (HbA1c) and insulin resistance without any renal or hepatic side
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effects in patients with type 2 diabetes after 3 months (17).
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2. Animal studies
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Of 19 selected articles, 14 studies evaluated effects of NS in animal models. Meral et al
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indicated that 20 ml/kg aqueous extract of NS orally decreased glucose level and
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improved antioxidant status in diabetic rabbits after two months (19). In Saleh Mansi et
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al study, oral treatment with 20 ml/kg aqueous extract of NS elevated insulin levels in
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diabetic rats after 15 days (15). It also affect glucose metabolism through the inhibition
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of hypothalamus-pituitary-adernal axis. Based on Kaleem et al study, oral
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administration of 300 mg/kg ethanol extract of NS decreased lipid peroxidation and
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antioxidant enzymes levels in diabetic rats after 30 days (20). In Houcher et al study,
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intra peritoneal 810 mg/kg/day crude methanol extract and 2.5 ml/kg/day NS oil
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decreased glucose and increased total antioxidant capacity (TAC) concentrations in
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diabetic rats after 25 days (21). Kanter et al demonstrated that 50 mg/kg thymoquinone
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orally in diabetic rats increased activities of mitochondria in leukocytes, energy
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metabolism and insulin levels after 20 days intervention (14, 22-24). Also Salama et al
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concluded that oral treatment with 500 mg/kg NS oil in diabetic rat model decreased
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glucose level and increased insulin, C-peptide pyruvate dehydrogenase and TAC
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concentrations (25). Based on Alimohamadi et al study, only injection low dose
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(5mg/kg) of hydroalcoholic extract of NS showed positive effects on regeneration of
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pancreatic beta cells, therefore in diabetic rats insulin secretion increased and FBS
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levels decreased (26). Also Sultan et al reported that added 4% fixed oil and 0.3%
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essential oil of NS to the diet reduced glucose and Malondialdehyde (MDA) levels,
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improved lipid profile and enhanced body antioxidant capacity in diabetic rats. They
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reported that essential oils were more effective than fixed oils to reduce oxidative
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damages after 56 days in rats (18).
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3. In vivo/In vitro studies
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According to the criteria, finally 4 in vivo/ in vitro studies were evaluated. They
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indicated that NS can play anti-hyperglycemic roles and improve glucose metabolism
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and lipid profile with various mechanisms. In Rchid et al trial, effects of subfractions of
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NS with different dosages (0.01, 0.1, 1 and 5 mg/ml) on pancreatic cells of rats were
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studied. They reported that stimulating effect of NS extract on insulin secretion is
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stronger in whole extract or basic subfractions, and acidic subfractions only indicated
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stimulating effects in higher dosage (27). Meddah et al indicated that aqueous extract
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of NS (0.1 pg/ml t0 100 ng/ml for in vitro) could inhibit glucose absorption directly and
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in vivo study showed that 2 g/kg aqueous extract of NS improved glucose tolerance in
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diabetic rats after 6 weeks. They compared NS effects with 300 mg/kg/day and no
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significant differences were observed between two groups (28). Based on Andaloussi et
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al study, ethanol extract of NS can act as an agonist PPAR-gamma and induce insulin-
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like effects on skeletal muscle cells and adiposities (29). Also Abdelmeguid et al
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reported that single intraperitoneal of aqueous extract and NS oil act as a protective
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factor against oxidative stress in vivo and in vitro studies and they decreased glucose
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levels in diabetic rats (13). Besides mentioned mechanisms, Alimohammadi et al
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demonstrated that 20 mg/kg NS extract had no significant effects on glucose levels, but
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5 mg/kg of hydroalcoholic NS extract showed therapeutic effects on blood sugar in
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diabetic rats by ameliorating beta cells and increasing insulin secretion (26).
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In the present study, we reviewed effects of NS on glycemic status and lipid profile in DM.
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It seems only two studies evaluated effects of NS in patients with diabetes. But these two
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clinical studies were open label trials without placebo-control group.
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Animal and in vivo/in vitro studies evaluated effects of various forms of NS (extract, oil,
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powered) in diabetes models. Although, they indicated beneficial effects of NS on glycemic
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status and lipid profile in diabetes models, but efficacy of NS on various indicators of
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glycemic status and lipid profile were different. Differences in the chemical composition of
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NS in different regions and preparation are related to the pharmacological activity.
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Potential mechanisms of ameliorating glycemic indices and lipid profile are discussed as
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follow:
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I.
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Antioxidant characteristics In most studies, possible anti-hyperglycemia and anti-hyperlipidemia effects of NS
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were attributed to its antioxidants components. TQ and dithymoquinone are the main
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antioxidant components in NS (30). Black seed in all forms of usage, such as ingestion
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and injection can improve body antioxidant defense. Some studies indicated that NS
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can elevate TAC and antioxidant enzymes and decrease lipid peroxidation (13, 18-21,
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25). Reduction in oxidative stress help to regeneration of pancreatic beta cells (22),
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preserving integrity of pancreatic beta-cells, increasing numbers of islets and their
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diameters (26), reduction in insulin resistance (17), increasing in insulin secretion (15,
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26) ,(27) and inhibition of advanced glycation end product (31). Reduction in free
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radicals directly and indirectly can trigger lipid metabolism. Antioxidant components
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can prevent lipid peroxidatinon and improve enzyme function which participates in
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lipid metabolism (32). Besides, glycemic improvement can modulate lipid dysfunction
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particularly in patients with diabetes (33).
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Insulin secretion: TQ and other antioxidant components of NS can increase insulin secretion by improving energy metabolism in mitochondria and it can reduce
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liver damages in diabetic rats. Also, NS can improve the intracellular pathways
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of insulin receptors. It can participate in rising insulin concentration and
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inhibition hypothalamus-pituitary adrenal axis (15).
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Gluconeogenesis: NS can decrease gluconeogenesis which contributes to
III.
hyperglycemia in diabetes models (26), (13). TQ can decrease expression of
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gluconeogenic enzymes (glucose-6-phosphtse and fructose 1,6 bisphosphatase)
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and hepatic glucose production (21). IV.
Gene expression: It has been indicated that ethanol extract of NS is an agonist of
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PPAR-gamma gene and NS can increase PPAR-gamma activity more than 50%
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at dose of 200 μg/ml (29). Also, TQ can increase uptake of LDL-c by up-
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regulation of hepatic receptors of LDL-c. It can inhibit 3-hydroxy-3-
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methylglutaryl- coenzyme A (HMG-CO-A) reductase gene and suppress
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synthesis of cholesterol (30). Glucose absorption
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Meddah et al indicated that ingestion of aqueous extract of NS reduced glucose
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absorption in diabetic rats. It seems that NS can inhibit sodium-glucose co-transporter.
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Second potential mechanism may be suppressive effects of polyphenol ingredients on
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transporter of glucose absorption (28).
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VI.
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Le et al indicated that a 4-week intragastric gavage with petroleum ether extract of NS
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caused a 25% reduction in food intake. Also it improved lipid profile and insulin sensivity
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in rats. They concluded that petroleum ether extract of NS has a slight anorexic effect
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which cause reduction in food intake and body weight. Also it can activate Mitogen-
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activated protein kinases (MAPK) and Protein kinase B (PKB) pathways which are
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involved in insulin-sensitizing action (34). Also Kaleem et al reported that 300 mg/day
Reduction in body weight
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ethanolic extract of NS decreased body weight in streptozocin-induced diabetic rats after 30
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days (20). Based on Haque et al study, 5ml NS oil decreased body weight and body mass
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index (BMI) after 6 weeks in subjects with metabolic syndrome (35). Based on Najmi et al
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study, 500mg/day NS for 2 months decreased body weight in subjects with metabolic
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syndrome (36). Constituents of NS mainly TQ and lipase enzyme in NS can involve in anti-
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obesity effects of NS (37). Moreover, Bamosa et al indicated that NS can decrease insulin
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resistance in subjects with T2DM. Reduction in insulin resistance can involve in faster
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losing weight (17). Losing weight can be a potential mechanism for improving glucose
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status and lipid profile in DM. However, more studies are needed to clarify weight-
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lowering effects of NS in DM.
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Future prospects
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Despite positive effects of NS on metabolic parameters in diabetes models, limited clinical
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trials with no placebo group evaluated anti-hyperglycemia and anti-hyperlipidemia effects
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of NS. For future studies, double-blind placebo-controlled randomized clinical trials were
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suggested to evaluate NS on glucose homeostasis and lipid concentrations in DM.
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Conclusion
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Nigella Sativa can improve glucose homeostasis and lipid profiles in diabetes models with
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various potential mechanisms. Modulation of metabolic parameters in DM can prevent
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diabetes complications including atherosclerosis and cardiovascular diseases. Therefore,
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NS can be used as a complementary therapies in DM. But due to differences in models,
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chemical compositions of difference sources of NS, dosage, and duration of intervention, it
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is difficult to determine effective type and dosage of NS in diabetes management. More
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studies are suggested to clarify effective type and dosage of NS in patients with diabetes.
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Conflict of Interest
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Authors declared no conflict of interest
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References
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[1]. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes estimates for the year 2000 and projections for 2030. Diabetes Care 2004; 27(5):1047-53. [2]. Zoungas S, Chalmers J, Ninomiya T, Li Q, Cooper ME, Colagiuri S, et al. Association of HbA1c levels with vascular complications and death in patients with type 2 diabetes: evidence of glycaemic thresholds. Diabetologia 2012; 55(3):636-43. [3]. Nathan DM. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study at 30 years: overview. Diabetes Care 2014; 37(1):9-16. [4]. Bharti SK, Srivastava A, Singh R. Review on effect of combination drug therapy on diabetes mellitus and its management. Population 2014; 5(10):90. [5]. Mumu SJ, Saleh F, Ara F, Afnan F, Ali L. Non-adherence to life-style modification and its factors among type 2 diabetic patients. Indian J Public Health 2014; 58(1):40. [6]. Mirhoseini M, Baradaran A, Rafieian-Kopaei M. Medicinal plants, diabetes mellitus and urgent needs. J Herb Med Pharma 2014; 2(2):1-10. [7]. World Health Organization. WHO traditional medicine strategy 2002-2005. Available at: http://apps.who.int/medicinedocs/en/d/Js2297e/. [8]. Grover JK, Yadav S, Vats V. Medicinal plants of India with anti-diabetic potential. J Ethnopharm 2002; 81(1):81-100. [9]. Maobe M, Gatebe E, Gitu L, Rotich H. Preliminary phytochemical screening of eight selected medicinal herbs used for the treatment of diabetes, malaria and pneumonia in Kisii region, southwest Kenya. Eur J Applied Scie 2013; 5(10):01-6. [10]. Patel DK, Prasad SK, Kumar R, Hemalatha S. An overview on antidiabetic medicinal plants having insulin mimetic property. Asian Pacific J Tropic Biomed 2012; 2(4):320-30. [11]. Mathur ML, Gaur J, Sharma R, Haldiya KR. Antidiabetic properties of a spice plant Nigella sativa. J Endocrino & Metabolism 2011;1 (1):1-8. [12]. Shrivastava R. M, Agrawal R. C, Parveen Z. A Review on Therapeutic Applications of Nigella Sativa. J Chem & Cheml Sci 2011; 4:241-8. [13]. Abdelmeguid NE, Fakhoury R, Kamal SM, Al Wafai RJ. Effects of Nigella sativa and thymoquinone on biochemical and subcellular changes in pancreatic β‐cells of streptozotocin‐induced diabetic rats. J Diabetes 2010; 2(4):256-66.
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[14]. Kanter M, Akpolat M, Aktas C. Protective effects of the volatile oil of Nigella sativa seeds on β-cell damage in streptozotocin-induced diabetic rats: a light and electron microscopic study. J Molecular Histol 2009; 40(5-6):379-85. [15]. Mansi KMS. Effects of oral administration of water extract of nigella sativa on serum concentrations of insulin and testosterone in alloxan-induced diabetic rats. Pak J Biolo Scie 2005; 8(8):1152-56. [16]. Kaatabi H, Bamosa AO, Lebda FM, Al Elq AH, Al-Sultan AI. Favorable impact of Nigella sativa seeds on lipid profile in type 2 diabetic patients. J Family & Community Med 2012; 19(3):155. [17]. Bamosa AO, Kaatabi H, Lebdaa FM, Elq AM, Al-Sultanb A. Effect of Nigella sativa seeds on the glycemic control of patients with type 2 diabetes mellitus. Indian J Physiol Pharmacol 2010; 54(4):344-54. [18]. Sultan MT, Butt MS, Karim R, Zia-Ul-Haq M, Batool R, Ahmad S, et al. Nigella sativa Fixed and Essential Oil Supplementation Modulates Hyperglycemia and Allied Complications in Streptozotocin-Induced Diabetes Mellitus. Evidence-Based Complement & Alter Med 2014; 2:1-10. [19]. Meral I, Yener Z, Kahraman T, Mert N. Effect of Nigella sativa on Glucose Concentration, Lipid Peroxidation, Anti-Oxidant Defence System and Liver Damage in Experimentally-Induced Diabetic Rabbits. J Vet Medicine Series 2001; 48(10):593-9. [20]. Kaleem M, Kirmani D, Asif M, Ahmed Q, Bano B. Biochemical effects of Nigella sativa L seeds in diabetic rats. Indian J Expe Biol 2006; 44(9):745. [21]. Houcher Z, Boudiaf K, Benboubetra M, Houche B. Effects of Methanolic Extract and Commercial Oil of Nigella sativa L. on Blood Glucose and Antioxidant Capacity in Alloxan-Induced Diabetic Rats. Pteridines 2007;18:8-18. [22]. Kanter M. Effects of Nigella sativa and its major constituent, thymoquinone on sciatic nerves in experimental diabetic neuropathy. Neurochem Res. 2008 Jan;33(1):87-96.
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[23]. Kanter M, Coskun O, Korkmaz A, Oter S. Effects of Nigella sativa on oxidative stress and beta-cell damage in streptozotocin-induced diabetic rats. Anat Rec A Discov Mol Cell Evol Biol 2004; 279(1):685-91. [24]. Kanter M, Meral I, Yener Z, Ozbek H, Demir H. Partial regeneration/proliferation of the beta-cells in the islets of Langerhans by Nigella sativa L. in streptozotocin-induced diabetic rats. Tohoku J Exp Med 2003; 201 (4):213-9. [25]. Salama RHM. Hypoglycemic effect of lipoic acid, carnitine and Nigella sativa in diabetic rat model. Inter J Health Scie 2011; 5 (2):126. [26]. Alimohammadi S, Tavakoli M, Hobbenaghi R, Khadivar F, Javanbakht J, Akbari H. Protective and antidiabetic effects of extract from Nigella sativa on blood glucose concentrations against streptozotocin (STZ)-induced diabetic in rats: an experimental study with histopathological evaluation. Diagnostic Pathol 2013; 8:137-44. [27]. Rchid H, Chevassus H, Nmila R, Guiral C, Petit P, Chokaırid M, et al. Nigella sativa seed extracts enhance glucose-induced insulin release from rat-isolated Langerhans islets. Fundam Clin Pharmacol 2004; 18:525–9
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[28]. Meddah B, Ducroc R, El Abbes Faouzi M, Eto B, Mahraoui L, BenhaddouAndaloussi A, et al. Nigella sativa inhibits intestinal glucose absorption and improves glucose tolerance in rats. J Ethnopharma 2009; 121(3):419-24. [29]. Benhaddou‐Andaloussi A, Martineau L, Vallerand D, Haddad Y, Afshar A, Settaf A, et al. Multiple molecular targets underlie the antidiabetic effect of Nigella sativa seed extract in skeletal muscle, adipocyte and liver cells. Diabetes Obes Metab 2010; 12(2):14857. [30]. Fararh KM, Ibrahim AK, Elsonosy YA. Thymoquinone enhances the activities of enzymes related to energy metabolism in peripheral leukocytes of diabetic rats. Res Vet Scie 2010; 88(3):400-4. [31]. Jack N. Losso, Hiba A. Bawadi, Madhavi Chintalapati. Inhibition of the formation of advanced glycation end products by thymoquinone. Food Chemistry 2011; 128:55-61. [32]. Yin H, Xu L, Porter NA. Free radical lipid peroxidation: mechanisms and analysis. Chem Reviews 2011;111 (10):5944-72. [33]. Kendall DM, Rubin CJ, Mohideen P, Ledeine J-M, Belder R, Gross J, et al. Improvement of Glycemic Control, Triglycerides, and HDL Cholesterol Levels With Muraglitazar, a Dual Peroxisome Proliferator-Activated Receptor Activator, in Patients With Type 2 Diabetes Inadequately Controlled With Metformin Monotherapy A doubleblind, randomized, pioglitazone-comparative study. Diabetes Care 2006; 29(5):1016-23. [34]. Le P.M, Benhaddou-Andaloussi A, Elimadi A, Settaf A, Cherrah Y, Haddad P.S. The petroleum ether extracts of Nigella sativa seeds exert insulin sensitizing and lipid lowering action in rats. J Ethnopharmacol 2004; 94(2-3): 251-259. [35]. Haque S. F, Najmi M.N.A. Indigenous herbal product Nigella sativa proved effective as an anti-obesity therapy in metabolic syndrome. Int J Med Res 2011; 1(3), 173176. [36]. Najmi A, Haque S. F, Naseeruddin M, Khan R. A. Effect of Nigella Sativa oil on various clinical and biochemical parameters of metabolic syndrome. Int J Dia Dev Ctries 2008; 16: 85-87. [37]. Akova A, Ustun G. Activity and adsorption of lipase from Nigella sativa seeds, Biotechnol Lett 2000; 22(5):355-359
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Fig 1: Trend of screening and choosing articles
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Additional records identified through other sources (n =6)
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Screening
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Records after duplicates removed (n =40)
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Records screened (n = 29)
Records excluded (n = 11)
Full-text articles excluded (n =10)
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Full-text articles assessed for eligibility (n = 29)
Included
Eligibility
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Identification
Records identified through database searching (n =61)
Studies included in qualitative synthesis (n = 19)
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Author/date
Subject
Source
Sultan et al, diabetic rats
Malaysia
2014
Dosage 4.0% fixed oil
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Table 1- Summary table of Nigella sativa actions and its pharmacological effects.
Intervention
Fixed and essential NS oil
Duration
Results
56 days
Hypoglycemic effects ↑HDL-C level
0.3% essential oil
ed
↑Total antioxidant capacity and glutathione
ce pt
↓MDA , TC, TG and LDL-c levels
Alimohamma diabetic rats
Iran
5, 10, and 20 Hydroalcholic NS extract
32 days
↑ Insulin secretion
mg/kg
Ac
di et al, 2013
Kaatabi et al,
diabetic man
2012
& woman
Saudi Arabia
1, 2 and 3 gr /day
5mg/kg: ↓ FBS
↑Pancreatic islets, cells and their diameter Powdered NS
12 wk
1 gr/day: - TC, LDL-C, TG; ↑HDL-C 2 gr/ day: ↓TC, TG and LDL-C; ↑ HDL 3 gr/ day: ↓ TC, TG and LDL-C; ↑HDL;
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Saudi Arabia
500 mg/kg
2011
Fararh et al, diabetic rats
Egypt
subjects
Abdelmeguid , et al, 2010
diabetic rats
ce pt
diabetes
2 Saudi Arabia
Ac
Bamosa et al, Type 2010
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Thymoquinone
30 days
Egypt
1,2,3gr/day
Not more effective than 2gr/day ↓Glucose concentration ↑ Insulin and C-peptide ↑ TAC
20 days
↓ Plasma glucose, TC, TG ↑ Insulin concentration , malate
ed
2010
50 mg/kg/day
NS Oil
M an
Salama, et al, diabetic rats
us
cr
15
dehydrogenase in leukocytes NS Seeds
3 months
2gr/day: ↓ FBS, HbA1C ↓ 2 hPG ↓Insulin resistance ↑ beta-cell function
2mL⁄kg and 5%
Aqueous
aqueous extract;
oil
0.2 mL⁄ kg oil, 3
extract and NS 30 days
↓ Serum glucose after 10 days ↑ Insulin concentration after 20 days ↑ SOD level with extract and thymoquinone
Page 17 of 20
ip t cr
16
us
mg⁄mL
Meddah
et rat jejunum
Morocco
al, 2009
In
vitro:
M an
thymoquinone
0.1 Aqueous extract of NS
6 wk
In vivo: glucose tolerance and body weight
pg/ml-100 ng/ml
improvement
muscle cells and 3T3-L1 adiposities
Ethanol extract of NS
18 hr
↑Glucose uptake in skeletal cells and adiposities
ce pt
skeletal
-
Ac
al , 2009
Morocco
ed
In vivo: 2 gr/kg Andaloussi et C2C12
In vitro: Inhibition of glucose absorption and
Page 18 of 20
diabetic rats
Turkey
0.2 ml/kg/day
Volatile oil of NS
ip t
us
Kanter et
cr
17
2008, 2005,
et diabetic rats
al, 2007
ce pt
Houcher
Algeria
810mg/kg/day
Ac
2006
India
300 mg/kg/day
proliferation
of
↓GSH, glucose level and serum nitric oxide ↑Insulin level, SOD and Catalase levels
↓Lipid peroxidation and GSH Methanol extract of NS
25days
↓ Glucose level
NS Oil ↑ TAC
2.5ml/kg/day
Kaleem et al, wister rats
regeneration/
60 days
ed
2003
Partial
pancreatic beta-cells,
M an
al,2009,
30 days
Ethanol extract of NS
30 days
↑ Catalase, SOD and insulin levels ↓Lipid peroxidation, GPX and glutathione, ↓Body weight
Page 19 of 20
et Male rats
Jordan
20 mL/kg
ip t
Aqueous extract of NS
us
Mansi
cr
18
Saleh et al, diabetic rats
Jordan
20 ml/ kg/day
2005
cells Meral 2001
et al, Male rabbits
mg/mL
ce pt
pancreatic
0.01, 0.1, 1 and 5 Whole, basic and acidic
Turkey
20 ml/kg
↑Insulin level ↓ Adrenocorticotropic hormone (ACTH)
15 days
↑Insulin level ↓ Glucose level
30min
Whole and basic extract: ↑insulin release
2 months
↑GSH and ceruloplasmin concentrations
subfractions of NS
Aqueous extract of NS
↓ MDA and glucose levels
Ac
2004
-
Aqueous extract of NS
ed
Rchid, et al, Rat
M an
al,2006
3wk
Page 20 of 20
S0965-2299(15)00027-8 http://dx.doi.org/doi:10.1016/j.ctim.2015.01.013 YCTIM 1425
To appear in:
Complementary Therapies in Medicine
Received date: Revised date: Accepted date:
7-8-2014 22-1-2015 30-1-2015
Please cite this article as: Heshmati J, Namazi N, Effects of Black Seed (Nigella Sativa) on Metabolic Parameters in Diabetes Mellitus: A Systematic Review, Complementary Therapies in Medicine (2015), http://dx.doi.org/10.1016/j.ctim.2015.01.013 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
1
Highlights Nigella sativa can improve glycemic status in diabetes models
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Nigella sativa can improve lipid profiles in diabetes models
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Nigella sativa can be used as a complementary therapies in diabetes mellitus
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Effects of Black Seed (Nigella Sativa) on Metabolic Parameters in Diabetes Mellitus: A
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Systematic Review
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Javad Heshmati a, Nazli Namazi*b
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a
Health Care Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
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b
Nutrition Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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*Corresponding Author: Nutrition Research Center, Tabriz University of Medical
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Sciences, Tabriz, Iran; E-mail:[email protected]
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Abstract
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Background: Current evidence indicated beneficial effects of some medicinal herbs on
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metabolic parameters. Nigella sativa is an example of herbs which can ameliorate
26
metabolic factors in diabetes mellitus. Despite several narrative review studies on medicinal
27
properties of NS, it seems that there is no systematic review to summarize effects of NS on
28
glucose homoeostasis and lipid profile in diabetes mellitus. Therefore, the aim of present
29
study was to review effects of Nigella sativa on metabolic parameters in diabetes mellitus.
30
Methods: Pubmed, Science Direct, Google scholar and Springer databases were searched
31
from 1995 till January 2014. Key words were included: Nigella Sativa, black Seed,
32
diabetes, glucose level, lipid and Insulin. Searching was limited to articles with English
33
language. Review articles, case reports, abstract in symposium and congress, studies on
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Nigella sativa mixed with other plants were excluded. Based on critically appraise,
35
eligibility of included articles were evaluated.
36
Results: Finally 19 eligible articles (2 human trials, 14 animal models and 3 in vivo/in vitro
37
studies) were selected. They indicated that Nigella sativa can modulate hyperglycemia and
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lipid profile dysfunction with various potential mechanisms including its antioxidant
39
characteristics and effects on insulin secretion, glucose absorption, gluconeogenesis and
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gene expression. Some studies compared effects of various types (extract, oil, powdered) of
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Nigella sativa with each other and they reported different characteristics with various types
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of black seed.
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Conclusion: Nigella sativa can improve glycemic status and lipid profile in diabetes
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models. However, more clinical trials are necessary to clarify beneficial effects of Nigella
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sativa, its effective type and dosage for diabetes management and its complications.
46
Introduction
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Diabetes mellitus (DM) is a global health concern characterized by impairment in insulin
48
secretion or insulin action. According to an International Diabetes Federation (IDF) report,
49
the prevalence of diabetes was 171 million in 2001 and it is expected to increase to 366
50
million by 2030 (1). Following the metabolic dysfunction in DM, the risk of developing
51
cardiovascular diseases, dyslipidemia, infection, morbidity and mortality can increase (2,
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3). For controlling diabetes, various treatments including diet, life style changes,
53
biochemical and herbal medicine in combine or alone have been used (4, 5). Many
54
populations consume complementary and alternative medicine and there is high tendency to
55
use medicinal herbs for diabetes treatment in worldwide (6). Due to side effects of some
56
chemical drugs and high tendency of people to consume medicinal herbs, World Health
57
Organization (WHO) persuades researchers to study efficacy and side effects of herbs with
58
potential therapeutic properties (7).
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Current evidence demonstrated beneficial effects of some medicinal herbs such as Urtica
60
dioica, Trigonella foenum, Silybum marianum and Nigella sativa (NS) for controlling
61
glucose level and lipid profile in diabetes models (8-10). NS or Black seed is one of the
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medicinal plants with anti-hyperglycemia and anti-hyperlipidemia characteristics (11). It is
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a plant of Ranunculaceae family which grows widely in many Middle Eastern countries. Its
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seed colored black and taste bitter (12). NS has many different chemical ingredients
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including Thymocinon (TQ), essential fatty acids particularly linoleic and oleic acid, trans-
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anethole, p-cymene, alpha pinene, limonene, and carvone. It is used in traditional medicine
67
in different forms such as powder, oil and extract (12, 13). Previous studies indicated many
68
medical characteristics of black seed including antimicrobial, anti-inflammatory and
69
antioxidative effects (14, 15) . Also anti-diabetic effects of black seed have been reported
70
in several studies (16-18). Despite several narrative review studies on medicinal properties
71
of NS, it seems that there is no systematic review to summarize glucose homoeostasis and
72
lipid profile effects of NS in diabetes mellitus. Therefore, the aim of present study was to
73
evaluate effects of Nigella sativa on glycemic status and lipid profile in DM.
74
Article selection
75
We searched databases of Pubmed, Science Direct, Google scholar and Springer from 1995
76
till January 2014. Key words were selected based on Mesh terms. They were included:
77
“Nigella sativa” or “black Seed” or “black cumin” and “diabetes”, “glucose level”, “lipid”,
78
and “Insulin”. Also we hand searched references of articles. Two reviewers extracted data
79
independently, and then titles and abstracts of each article were assessed to delete
80
duplication data. Any irrelevant papers were excluded. The remaining articles were
81
reviewed to determine compatibility with the inclusion criteria. Searching was limited to
82
articles with English language. Review articles, case reports, abstract in symposium and
83
congress, articles about effects of NS mixed with other plants were excluded. After
84
critically appraise of articles, 19 articles were selected (Fig 1). Characteristic of studies
85
have been summarized in Table 1.
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86
Summary of studies and potential mechanisms
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Studies were classified into three groups: human, animal and in vivo/in vitro studies. 1. Human studies
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Based on the criteria, two human studies were found (16, 17). Kaatabi et al evaluated
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different dosage of powdered NS (1, 2 and 3 gr/day) in patients with type 2 diabetes. They
91
indicated that 1 g/day NS increased high-density lipoprotein cholesterol (HDL-c) levels
92
after 12 weeks. Two and 3g/day of black seed significantly decreased total cholesterol
93
(TC), triglyceride (TG) and low-density lipoprotein cholesterol (LDL-c) levels and
94
increased HDL-C concentration. Increasing dosage from 2 to 3gr/day did not indicate
95
higher improvement in lipid profile (16). Also Bamosa et al demostrated that only 2g/day
96
NS seed decreased fasting blood sugar (FBS), 2 hours postprandially glucose (2-hPG),
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glycosylated hemoglobin (HbA1c) and insulin resistance without any renal or hepatic side
98
effects in patients with type 2 diabetes after 3 months (17).
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2. Animal studies
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Of 19 selected articles, 14 studies evaluated effects of NS in animal models. Meral et al
101
indicated that 20 ml/kg aqueous extract of NS orally decreased glucose level and
102
improved antioxidant status in diabetic rabbits after two months (19). In Saleh Mansi et
103
al study, oral treatment with 20 ml/kg aqueous extract of NS elevated insulin levels in
104
diabetic rats after 15 days (15). It also affect glucose metabolism through the inhibition
105
of hypothalamus-pituitary-adernal axis. Based on Kaleem et al study, oral
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administration of 300 mg/kg ethanol extract of NS decreased lipid peroxidation and
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antioxidant enzymes levels in diabetic rats after 30 days (20). In Houcher et al study,
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intra peritoneal 810 mg/kg/day crude methanol extract and 2.5 ml/kg/day NS oil
109
decreased glucose and increased total antioxidant capacity (TAC) concentrations in
110
diabetic rats after 25 days (21). Kanter et al demonstrated that 50 mg/kg thymoquinone
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orally in diabetic rats increased activities of mitochondria in leukocytes, energy
112
metabolism and insulin levels after 20 days intervention (14, 22-24). Also Salama et al
113
concluded that oral treatment with 500 mg/kg NS oil in diabetic rat model decreased
114
glucose level and increased insulin, C-peptide pyruvate dehydrogenase and TAC
115
concentrations (25). Based on Alimohamadi et al study, only injection low dose
116
(5mg/kg) of hydroalcoholic extract of NS showed positive effects on regeneration of
117
pancreatic beta cells, therefore in diabetic rats insulin secretion increased and FBS
118
levels decreased (26). Also Sultan et al reported that added 4% fixed oil and 0.3%
119
essential oil of NS to the diet reduced glucose and Malondialdehyde (MDA) levels,
120
improved lipid profile and enhanced body antioxidant capacity in diabetic rats. They
121
reported that essential oils were more effective than fixed oils to reduce oxidative
122
damages after 56 days in rats (18).
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3. In vivo/In vitro studies
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According to the criteria, finally 4 in vivo/ in vitro studies were evaluated. They
125
indicated that NS can play anti-hyperglycemic roles and improve glucose metabolism
126
and lipid profile with various mechanisms. In Rchid et al trial, effects of subfractions of
127
NS with different dosages (0.01, 0.1, 1 and 5 mg/ml) on pancreatic cells of rats were
128
studied. They reported that stimulating effect of NS extract on insulin secretion is
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stronger in whole extract or basic subfractions, and acidic subfractions only indicated
130
stimulating effects in higher dosage (27). Meddah et al indicated that aqueous extract
131
of NS (0.1 pg/ml t0 100 ng/ml for in vitro) could inhibit glucose absorption directly and
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in vivo study showed that 2 g/kg aqueous extract of NS improved glucose tolerance in
133
diabetic rats after 6 weeks. They compared NS effects with 300 mg/kg/day and no
134
significant differences were observed between two groups (28). Based on Andaloussi et
135
al study, ethanol extract of NS can act as an agonist PPAR-gamma and induce insulin-
136
like effects on skeletal muscle cells and adiposities (29). Also Abdelmeguid et al
137
reported that single intraperitoneal of aqueous extract and NS oil act as a protective
138
factor against oxidative stress in vivo and in vitro studies and they decreased glucose
139
levels in diabetic rats (13). Besides mentioned mechanisms, Alimohammadi et al
140
demonstrated that 20 mg/kg NS extract had no significant effects on glucose levels, but
141
5 mg/kg of hydroalcoholic NS extract showed therapeutic effects on blood sugar in
142
diabetic rats by ameliorating beta cells and increasing insulin secretion (26).
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143
In the present study, we reviewed effects of NS on glycemic status and lipid profile in DM.
144
It seems only two studies evaluated effects of NS in patients with diabetes. But these two
145
clinical studies were open label trials without placebo-control group.
146
Animal and in vivo/in vitro studies evaluated effects of various forms of NS (extract, oil,
147
powered) in diabetes models. Although, they indicated beneficial effects of NS on glycemic
148
status and lipid profile in diabetes models, but efficacy of NS on various indicators of
149
glycemic status and lipid profile were different. Differences in the chemical composition of
150
NS in different regions and preparation are related to the pharmacological activity.
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151
Potential mechanisms of ameliorating glycemic indices and lipid profile are discussed as
152
follow:
153
I.
ip t
Antioxidant characteristics In most studies, possible anti-hyperglycemia and anti-hyperlipidemia effects of NS
155
were attributed to its antioxidants components. TQ and dithymoquinone are the main
156
antioxidant components in NS (30). Black seed in all forms of usage, such as ingestion
157
and injection can improve body antioxidant defense. Some studies indicated that NS
158
can elevate TAC and antioxidant enzymes and decrease lipid peroxidation (13, 18-21,
159
25). Reduction in oxidative stress help to regeneration of pancreatic beta cells (22),
160
preserving integrity of pancreatic beta-cells, increasing numbers of islets and their
161
diameters (26), reduction in insulin resistance (17), increasing in insulin secretion (15,
162
26) ,(27) and inhibition of advanced glycation end product (31). Reduction in free
163
radicals directly and indirectly can trigger lipid metabolism. Antioxidant components
164
can prevent lipid peroxidatinon and improve enzyme function which participates in
165
lipid metabolism (32). Besides, glycemic improvement can modulate lipid dysfunction
166
particularly in patients with diabetes (33).
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Insulin secretion: TQ and other antioxidant components of NS can increase insulin secretion by improving energy metabolism in mitochondria and it can reduce
169
liver damages in diabetic rats. Also, NS can improve the intracellular pathways
170
of insulin receptors. It can participate in rising insulin concentration and
171
inhibition hypothalamus-pituitary adrenal axis (15).
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172
Gluconeogenesis: NS can decrease gluconeogenesis which contributes to
III.
hyperglycemia in diabetes models (26), (13). TQ can decrease expression of
174
gluconeogenic enzymes (glucose-6-phosphtse and fructose 1,6 bisphosphatase)
175
and hepatic glucose production (21). IV.
Gene expression: It has been indicated that ethanol extract of NS is an agonist of
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176
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PPAR-gamma gene and NS can increase PPAR-gamma activity more than 50%
178
at dose of 200 μg/ml (29). Also, TQ can increase uptake of LDL-c by up-
179
regulation of hepatic receptors of LDL-c. It can inhibit 3-hydroxy-3-
180
methylglutaryl- coenzyme A (HMG-CO-A) reductase gene and suppress
181
synthesis of cholesterol (30). Glucose absorption
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Meddah et al indicated that ingestion of aqueous extract of NS reduced glucose
184
absorption in diabetic rats. It seems that NS can inhibit sodium-glucose co-transporter.
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Second potential mechanism may be suppressive effects of polyphenol ingredients on
186
transporter of glucose absorption (28).
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VI.
188
Le et al indicated that a 4-week intragastric gavage with petroleum ether extract of NS
189
caused a 25% reduction in food intake. Also it improved lipid profile and insulin sensivity
190
in rats. They concluded that petroleum ether extract of NS has a slight anorexic effect
191
which cause reduction in food intake and body weight. Also it can activate Mitogen-
192
activated protein kinases (MAPK) and Protein kinase B (PKB) pathways which are
193
involved in insulin-sensitizing action (34). Also Kaleem et al reported that 300 mg/day
Reduction in body weight
Page 10 of 20
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ethanolic extract of NS decreased body weight in streptozocin-induced diabetic rats after 30
195
days (20). Based on Haque et al study, 5ml NS oil decreased body weight and body mass
196
index (BMI) after 6 weeks in subjects with metabolic syndrome (35). Based on Najmi et al
197
study, 500mg/day NS for 2 months decreased body weight in subjects with metabolic
198
syndrome (36). Constituents of NS mainly TQ and lipase enzyme in NS can involve in anti-
199
obesity effects of NS (37). Moreover, Bamosa et al indicated that NS can decrease insulin
200
resistance in subjects with T2DM. Reduction in insulin resistance can involve in faster
201
losing weight (17). Losing weight can be a potential mechanism for improving glucose
202
status and lipid profile in DM. However, more studies are needed to clarify weight-
203
lowering effects of NS in DM.
204
Future prospects
205
Despite positive effects of NS on metabolic parameters in diabetes models, limited clinical
206
trials with no placebo group evaluated anti-hyperglycemia and anti-hyperlipidemia effects
207
of NS. For future studies, double-blind placebo-controlled randomized clinical trials were
208
suggested to evaluate NS on glucose homeostasis and lipid concentrations in DM.
209
Conclusion
210
Nigella Sativa can improve glucose homeostasis and lipid profiles in diabetes models with
211
various potential mechanisms. Modulation of metabolic parameters in DM can prevent
212
diabetes complications including atherosclerosis and cardiovascular diseases. Therefore,
213
NS can be used as a complementary therapies in DM. But due to differences in models,
214
chemical compositions of difference sources of NS, dosage, and duration of intervention, it
215
is difficult to determine effective type and dosage of NS in diabetes management. More
216
studies are suggested to clarify effective type and dosage of NS in patients with diabetes.
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Conflict of Interest
219
Authors declared no conflict of interest
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[28]. Meddah B, Ducroc R, El Abbes Faouzi M, Eto B, Mahraoui L, BenhaddouAndaloussi A, et al. Nigella sativa inhibits intestinal glucose absorption and improves glucose tolerance in rats. J Ethnopharma 2009; 121(3):419-24. [29]. Benhaddou‐Andaloussi A, Martineau L, Vallerand D, Haddad Y, Afshar A, Settaf A, et al. Multiple molecular targets underlie the antidiabetic effect of Nigella sativa seed extract in skeletal muscle, adipocyte and liver cells. Diabetes Obes Metab 2010; 12(2):14857. [30]. Fararh KM, Ibrahim AK, Elsonosy YA. Thymoquinone enhances the activities of enzymes related to energy metabolism in peripheral leukocytes of diabetic rats. Res Vet Scie 2010; 88(3):400-4. [31]. Jack N. Losso, Hiba A. Bawadi, Madhavi Chintalapati. Inhibition of the formation of advanced glycation end products by thymoquinone. Food Chemistry 2011; 128:55-61. [32]. Yin H, Xu L, Porter NA. Free radical lipid peroxidation: mechanisms and analysis. Chem Reviews 2011;111 (10):5944-72. [33]. Kendall DM, Rubin CJ, Mohideen P, Ledeine J-M, Belder R, Gross J, et al. Improvement of Glycemic Control, Triglycerides, and HDL Cholesterol Levels With Muraglitazar, a Dual Peroxisome Proliferator-Activated Receptor Activator, in Patients With Type 2 Diabetes Inadequately Controlled With Metformin Monotherapy A doubleblind, randomized, pioglitazone-comparative study. Diabetes Care 2006; 29(5):1016-23. [34]. Le P.M, Benhaddou-Andaloussi A, Elimadi A, Settaf A, Cherrah Y, Haddad P.S. The petroleum ether extracts of Nigella sativa seeds exert insulin sensitizing and lipid lowering action in rats. J Ethnopharmacol 2004; 94(2-3): 251-259. [35]. Haque S. F, Najmi M.N.A. Indigenous herbal product Nigella sativa proved effective as an anti-obesity therapy in metabolic syndrome. Int J Med Res 2011; 1(3), 173176. [36]. Najmi A, Haque S. F, Naseeruddin M, Khan R. A. Effect of Nigella Sativa oil on various clinical and biochemical parameters of metabolic syndrome. Int J Dia Dev Ctries 2008; 16: 85-87. [37]. Akova A, Ustun G. Activity and adsorption of lipase from Nigella sativa seeds, Biotechnol Lett 2000; 22(5):355-359
Ac ce p
296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327
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17
Fig 1: Trend of screening and choosing articles
ip t
Additional records identified through other sources (n =6)
an
Screening
us
Records after duplicates removed (n =40)
M
Records screened (n = 29)
Records excluded (n = 11)
Full-text articles excluded (n =10)
Ac ce p
te
d
Full-text articles assessed for eligibility (n = 29)
Included
Eligibility
cr
Identification
Records identified through database searching (n =61)
Studies included in qualitative synthesis (n = 19)
Page 15 of 20
ip t cr
14
Author/date
Subject
Source
Sultan et al, diabetic rats
Malaysia
2014
Dosage 4.0% fixed oil
M an
us
Table 1- Summary table of Nigella sativa actions and its pharmacological effects.
Intervention
Fixed and essential NS oil
Duration
Results
56 days
Hypoglycemic effects ↑HDL-C level
0.3% essential oil
ed
↑Total antioxidant capacity and glutathione
ce pt
↓MDA , TC, TG and LDL-c levels
Alimohamma diabetic rats
Iran
5, 10, and 20 Hydroalcholic NS extract
32 days
↑ Insulin secretion
mg/kg
Ac
di et al, 2013
Kaatabi et al,
diabetic man
2012
& woman
Saudi Arabia
1, 2 and 3 gr /day
5mg/kg: ↓ FBS
↑Pancreatic islets, cells and their diameter Powdered NS
12 wk
1 gr/day: - TC, LDL-C, TG; ↑HDL-C 2 gr/ day: ↓TC, TG and LDL-C; ↑ HDL 3 gr/ day: ↓ TC, TG and LDL-C; ↑HDL;
Page 16 of 20
Saudi Arabia
500 mg/kg
2011
Fararh et al, diabetic rats
Egypt
subjects
Abdelmeguid , et al, 2010
diabetic rats
ce pt
diabetes
2 Saudi Arabia
Ac
Bamosa et al, Type 2010
ip t
Thymoquinone
30 days
Egypt
1,2,3gr/day
Not more effective than 2gr/day ↓Glucose concentration ↑ Insulin and C-peptide ↑ TAC
20 days
↓ Plasma glucose, TC, TG ↑ Insulin concentration , malate
ed
2010
50 mg/kg/day
NS Oil
M an
Salama, et al, diabetic rats
us
cr
15
dehydrogenase in leukocytes NS Seeds
3 months
2gr/day: ↓ FBS, HbA1C ↓ 2 hPG ↓Insulin resistance ↑ beta-cell function
2mL⁄kg and 5%
Aqueous
aqueous extract;
oil
0.2 mL⁄ kg oil, 3
extract and NS 30 days
↓ Serum glucose after 10 days ↑ Insulin concentration after 20 days ↑ SOD level with extract and thymoquinone
Page 17 of 20
ip t cr
16
us
mg⁄mL
Meddah
et rat jejunum
Morocco
al, 2009
In
vitro:
M an
thymoquinone
0.1 Aqueous extract of NS
6 wk
In vivo: glucose tolerance and body weight
pg/ml-100 ng/ml
improvement
muscle cells and 3T3-L1 adiposities
Ethanol extract of NS
18 hr
↑Glucose uptake in skeletal cells and adiposities
ce pt
skeletal
-
Ac
al , 2009
Morocco
ed
In vivo: 2 gr/kg Andaloussi et C2C12
In vitro: Inhibition of glucose absorption and
Page 18 of 20
diabetic rats
Turkey
0.2 ml/kg/day
Volatile oil of NS
ip t
us
Kanter et
cr
17
2008, 2005,
et diabetic rats
al, 2007
ce pt
Houcher
Algeria
810mg/kg/day
Ac
2006
India
300 mg/kg/day
proliferation
of
↓GSH, glucose level and serum nitric oxide ↑Insulin level, SOD and Catalase levels
↓Lipid peroxidation and GSH Methanol extract of NS
25days
↓ Glucose level
NS Oil ↑ TAC
2.5ml/kg/day
Kaleem et al, wister rats
regeneration/
60 days
ed
2003
Partial
pancreatic beta-cells,
M an
al,2009,
30 days
Ethanol extract of NS
30 days
↑ Catalase, SOD and insulin levels ↓Lipid peroxidation, GPX and glutathione, ↓Body weight
Page 19 of 20
et Male rats
Jordan
20 mL/kg
ip t
Aqueous extract of NS
us
Mansi
cr
18
Saleh et al, diabetic rats
Jordan
20 ml/ kg/day
2005
cells Meral 2001
et al, Male rabbits
mg/mL
ce pt
pancreatic
0.01, 0.1, 1 and 5 Whole, basic and acidic
Turkey
20 ml/kg
↑Insulin level ↓ Adrenocorticotropic hormone (ACTH)
15 days
↑Insulin level ↓ Glucose level
30min
Whole and basic extract: ↑insulin release
2 months
↑GSH and ceruloplasmin concentrations
subfractions of NS
Aqueous extract of NS
↓ MDA and glucose levels
Ac
2004
-
Aqueous extract of NS
ed
Rchid, et al, Rat
M an
al,2006
3wk
Page 20 of 20
