Effects of ginger (Zingiber officinale) on plasma

http://informahealthcare.com/ijf ISSN: 0963-7486 (print), 1465-3478 (electronic) Int J Food Sci Nutr, Early Online: 1–5 ! 2013 Informa UK Ltd. DOI: 10.3109/09637486.2013.775223

RESEARCH ARTICLE

Effects of ginger (Zingiber officinale) on plasma glucose level, HbA1c and insulin sensitivity in type 2 diabetic patients Sepide Mahluji1, Vahide Ebrahimzade Attari1, Majid Mobasseri2, Laleh Payahoo1, and Alireza Ostadrahimi3 Students’ Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran, 2Endocrinology and Metabolism Section, Department of Medicine, Imam Reza Hospital, Tabriz, Iran, and 3Nutrition Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

Abstract

Keywords

The present study was aimed to evaluate the effects of Zingiber officinale on some biochemical parameters in type 2 diabetic (DM2) patients. In a randomized double-blind placebo controlled trial, 64 patients with DM2 were assigned to ginger or placebo groups (receiving 2 g/d of each). A 3 d diet record, anthropometric measurements and concentrations of fasting blood glucose (FPG), HbA1c, lipid profile (including total cholesterol, triglyceride, low density lipoprotein and high density lipoprotein) and also the homeostasis model assessment (HOMA) and quantitative insulin-sensitivity check index (QUICKI) were determined before and after 2 months of intervention. Ginger supplementation significantly lowered the levels of insulin (11.0 2.3 versus 12.1 3.3; p ¼ 0.001), LDL-C (67.8 27.2 versus 89.2 24.9; p ¼ 0.04), TG (127.7 43.7 versus 128.2 37.7; p ¼ 0.03) and the HOMA index (3.9 1.09 versus 4.5 1.8; p ¼ 0.002) and increased the QUICKI index (0.313 0.012 versus 0.308 0.012; p ¼ 0.005) in comparison to the control group; while, there were no significant changes in FPG, TC, HDL-C and HbA1c (p40.05). In summary, ginger supplementation improved insulin sensitivity and some fractions of lipid profile in DM2 patients. Therefore it may be considered as a useful remedy to reduce the secondary complications of DM2.

Blood glucose, diabetes, ginger, insulin sensitivity

Introduction Type 2 diabetes mellitus (DM2), a growing public health concern, is mostly associated with remarkably increased morbidity and mortality rates. Some secondary complications of DM2 including kidney, nervous system, infectious and microvascular disorders are believed to be limited by tight glycemic control (Turner et al., 1998). Moreover, some studies have shown that insulin sensitization can improve both glycemic control and endothelial function, resulting in less incidence of atherosclerosis (Kamenova, 2006; Pei et al., 2007; Pistrosch et al., 2004). In spite of the availability of the conventional pharmaceutical treatments, it is often difficult to achieve and maintain proper glycemic control (Vuksan et al., 2007). In some cases, pharmaceutical products are associated with serious side effects such as hypoglycemic coma and hepatorenal disturbances (Shanmugam et al., 2011). Therefore, replacing these pharmaceutical products with herbal medicines and dietary supplements is of great interest. A large number of medicinal plants have been used in the traditional systems of medicine worldwide. Recently, researchers have investigated hypoglycemic effects of these plants confirming the benefits of several plants and spices. Further attempts to find more effective anti-diabetic drugs continue according to the recommendation of World Health Organization (WHO).

Correspondence: Alireza Ostadrahimi, Associate Professor in Nutrition, Nutrition Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. E-mail: [email protected]

History Received 23 June 2012 Revised 30 January 2013 Accepted 5 February 2013 Published online 15 March 2013

Considering the cost-effectiveness of medicinal plants, effective anti-diabetic plants or their components could be commercially formulated as modern medicines (Kavishankar et al., 2011). Zingiber officinale, a perennial plant commonly known as ginger, belongs to the family of Zingibeaceae. For centuries, the rhizome of the plant has been used for culinary aims and curing a wide range of ailments such as arthritis, rheumatism, muscular aches, constipation, indigestion, vomiting, hypertension, dementia and fever (Ali et al., 2008). In addition, recent studies have mentioned the therapeutic effects of ginger on osteoarthritis (Altman & Marcussen, 2001), musculoskeletal disorder (Srivastava & Mustafa, 1992), nausea and vomiting (Bryer, 2005), motion sickness (Lien et al., 2003), migraine (Mustafa & Srivastava, 1990), cancer (Shukla & Singh, 2007), hyperlipidemia and hyperglycemia (Ali et al., 2008; White, 2007). The main constituents of ginger are categorized in essential volatile oils (1–5%) – sesquiterpenoids and monoterpenoids – and non-volatile pungent compounds including gingerols, shogaols, paradols and zingerones. Most therapeutic activities of ginger such as anti-inflammatory, hypotensive and analgesic effects are related to gingerols and shogaols mostly found in fresh and dried ginger rhizomes, respectively (Shukla & Singh, 2007). There are some scientific evidences on the effects of ginger on the blood levels of glucose and lipids (Bhandari & Pillai, 2005; Elshater et al., 2009). Al-Amin et al. (2006) reported hypoglycaemic and hypolipidemic potentials of ginger at a dose of 500 mg/kg in the streptozotocin-induced diabetic rats. Ozougwu & Eyo (2011) also suggested a significant blood glucose lowering effect by ginger in diabetic rats in a dose-dependent manner. In contrast, a dietary dose of 30% ginger powder has been

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reported to increase blood glucose levels in normal rats (Singhal & Joshi, 1983). The only relevant human clinical trial is a survey on coronary artery disease patients, results of which demonstrated that supplementation with 4 g/d ginger for 3 months failed to alter blood glucose levels significantly (Bordia et al., 1997). The results obtained from a few studies have also mentioned that ginger has effects on insulin sensitivity (Goyal & Kadnur, 2006; Kato et al., 2006; Sekiya et al., 2004). According to some evidences, ginger powder consumption at doses up to 6 g/d is not associated with any serious side effects except for mild gastrointestinal complications such as slight heart burn, diarrhea and irritation of the mouth (Desai et al., 1990; White, 2007). So far, little attention has been paid to evaluate the effect of Z. officinale on blood biochemical parameters in diabetic patients. Therefore, the present study was aimed to investigate the effects of daily ginger intake on the levels of fasting plasma glucose, glycozilated hemoglobin (HbA1c), lipid profile and insulin sensitivity in DM2 patients over a 2-month period.

Materials and methods Study design This study was a randomized, double blind, placebo-controlled trial performed on patients with DM2 aged between 38 and 65 years of either sex and an average body mass index (BMI) of 29.5 kg/m2. The subjects with type 2 diabetes for at least 2 years and without blood pressure abnormality were recruited for this study from the Tabriz Association of Diabetes, Tabriz, northwest Iran. Recruitment was performed via telephone. All participants in the two groups were matched based on hypoglycemic and hypolipidemic drug consumption and diabetes duration. Moreover, in ginger and control groups, 11 (42.3%) and 10 (35.7%) patients consumed hypolipidemic drugs, respectively. The study was approved by Medical Ethics Committee of the Tabriz University of Medical Sciences and also recorded by the identification code of IRCT201202232017N7 in clinical trials registry of Iran. Prior to the study, informed written consents were obtained from all of the participants. Exclusion criteria were insulin therapy at baseline or throughout the study, smoking, pregnancy and breastfeeding, taking any herbal plants as a home remedy or as a supplement within the previous 3 weeks or throughout the study, any acute illnesses or having kidney, liver, gallbladder or thyroid disorders, inflammatory intestinal diseases and immunodeficiency diseases. Sample size was determined based on data from a previous study (Alizadeh-Navaei et al., 2008) considering ¼ 0.05 with power of 80% using total cholesterol as primary outcome and aiming to detect changes 3.3%. Accordingly, the sample size was computed as 25 per group. Regarding a possible loss to follow-up, a safety margin of 30% was determined and consequently 32 patients were allocated in each group. Treatment Sixty-four eligible patients were randomly assigned to the two groups of 32 subjects. Each subject received one tablet of ginger or placebo twice a day immediately after lunch and dinner for 8 weeks. The subjects were instructed to maintain their diet and physical activity during the intervention. All subjects were permitted to consume their usual medications according to their physicians’ recommendation. Three-day food records were taken from all patients at the beginning and end of the intervention to be confident of constant dietary intake.

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Tablet preparation Fresh rhizomes of Z. officinale were purchased from local market, dried and ground into fine particles. The powder was delivered to a pharmaceutical laboratory (Tabriz University of Medical Sciences, Tabriz, Iran) to prepare tablets containing 1 g ginger in each. Corn starch was used as the placebo. The tablet’s solidity was measured by hardness tester (Erweka, Heusenstamm, Germany), and maintained at approximately 7–8 Strong Cobb. Opening time was determined by disintegrating tester apparatus based on the United States Pharmacopeia Methods, allowing them to open in stomach approximately within 10 min. The tablets were placed in identical bottles by a third person not directly involved in this study. This person labeled the bottles with two codes which remained unknown to the researchers until the end of intervention. Color of ginger and placebo tablets was similar and a slight amount of ginger powder was added to the placebo tablets to give ginger odor to all placebo tablet containers. To evaluate the compliance, the patients were followed and were asked to give back the bottle of tablets to the researchers and the remainder of tablets we checked. People having consumed at least 90% of the tablets were included in the statistical analysis. Anthropometric and biochemical assessments Anthropometric parameters including height and weight were measured at the beginning and end of the intervention to calculate the BMI. Body weight was measured with light clothing and without shoes using Seca scale (Seca, Hamburg, Germany). Height was also measured without shoes using a statiometer (Seca). Blood samples (5 ml) were taken in a 12–14 h fasting state (water permitted) at the beginning and after 2 months of intervention. Sera were obtained by high-speed centrifugation and stored at 70 C until the analysis of fasting serum glucose and insulin. Fasting serum glucose, TG, TC, LDL-C, HDL and HbA1c were determined by the enzymatic colorimetric method with commercial kits (Pars Azmun Co., Tehran, Iran) on an automatic analyzer (Abbott, model Alcyon 300, Abbott Park, IL). Plasma insulin concentration was determined by radioimmunoassay kit (Monobind Inc., Lake Forest, CA) using the ELISA method (ELISA reader of Shimadzu Co., Duisburg, Germany). Insulin resistance was estimated according to the homeostasis model assessment (HOMA) calculated as follows: HOMAIR ¼ fasting concentrations of glucose (mg/dl) insulin (mU/ml)/ 405 (Matthews et al., 1985). Moreover insulin-sensitivity was determined using quantitative insulin-sensitivity check index (QUICKI) by the following formula: QUICKI ¼ 1/[log insulin (mU/ml) þ log glucose (mg/dl)], many investigators believe that QUICKI is superior to HOMA in terms of determining insulin sensitivity (Borai et al., 2007). Statistical analysis The data were analyzed by SPSS software (version 17; SPSS Inc., Chicago, IL) and the results were expressed as mean standard deviation (SD) except for mean percentage differences and nutrient intake. The normality of the distribution of variables was determined by the Kolmogorov–Smirnov test. The background characteristics, nutrient intake and baseline experimental data in the two groups were compared using independent chisquared and sample t-tests. Analysis of covariance (ANCOVA) was used to identify any differences in anthropometric parameters, levels of FBG, TC, TG, LDL-C, HDL-C, HbA1c, insulin, QUICKI and HOMA indexes between the two groups after intervention. Changes in anthropometric measurements, blood glucose, lipid profile, HbA1c, insulin, QUICKI and HOMA for

Effects of ginger

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64 patients

Randomization

Placebo (2 g/d)

Ginger (2 g/d)

Treatment failure: 1

Treatment failure: 2

Follow up

Travel: 1

8 weeks

Medication changing: 1


Travel: 1

Completed:

Analysis

Medication changing: 0

Completed: 30 patients

28 patients

Figure 1. Study participant flow diagram. Table 1. Baseline characteristics of study participants.a Item

Intervention (ginger)

Placebo

49.2 5.1 14:12 79.3 11.8 29.2 4.0 142 34 7.0 1.3 12.7 2.9

53.1 7.9 16:12 76.8 14.5 29.8 5.0 153 47 6.9 1.4 11.5 3.0

Age (year) Sexb (M:F) Weight (kg) BMI (kg/m2) Fasting blood glucose (mg/dl) HbA1c (%) Insulin (mU/ml) a

Data are presented as means SD. Frequency.

b

all participants between the beginning and end of the trial were compared by paired sample t-tests. Differences with p50.05 were considered to be statistically significant (Zar, 1999).

Results Among 64 patients recruited to the study, six were excluded during the study, as shown in Figure 1. Participants showing good compliance with the ginger consumption and no serious side effects or symptoms were reported except for two patients with slight heart burn in the beginning of the intervention. Despite the diversity of the consumed hypoglycemic drugs, they remained constant for all participants throughout the study. Table 1 presents baseline characteristics of the participants in two groups. No statistically significant differences regarding the body wWight, BMI, age, blood glucose, insulin and HbA1c existed between the ginger and placebo groups at the baseline (p40.05). The dietary intakes of participants throughout the study are shown in Table 2. No significant differences in energy and other nutrient intakes were observed between the two groups at baseline. No significant changes from baseline were observed within the two groups. At the end of the study, no statistically significant differences in dietary intakes were observed between the two groups (p40.05). Table 3 shows anthropometric characteristics, fasting plasma glucose concentrations, lipid profile (TG, TC, LDL-C and

HDL-C), HbA1c, insulin, HOMA and QUICKI before and after intervention in both the groups. There were no statistically significant differences in weight, BMI, HbA1c and fasting plasma glucose in the ginger group compared to baseline. While at the end of study, the fasting plasma insulin (p50.001) and HOMA (p ¼ 0.01) significantly decreased and QUICKI (p ¼ 0.02) significantly increased after two months of intervention in the ginger group in comparison to the baseline phase. These parameters remained unchanged in the placebo group throughout the study. The mean percentage differences of fasting plasma glucose (6.1%), HbA1c (3.5%), insulin (13%), HOMA (8.1%) and QUICKI (1.4%) were also calculated and are presented in Table 3. The results of analysis of covariance (ANCOVA) revealed significant differences between two groups in insulin (p ¼ 0.001), HOMA (p ¼ 0.002) and QUICKI (p ¼ 0.005). Although, as shown in Table 2, the concentrations of glucose and HbA1c altered, they were not statistically significant. No statistically significant differences existed in blood lipid parameters between the ginger and control groups at baseline. Results of ANCOVA, showed statistically significant differences between the two groups in TG (p ¼ 0.039) and LDL-C (p ¼ 0.04) at the end of the study. As shown in Table 3, ginger consumption caused an 11.7% decrease in TG and a 13.7% decrease in LDL-C compared with the baseline. Serum TC and HDL-C remained unchanged in the ginger group throughout the study.

Discussion To the best of our knowledge, this is the first study investigating the effects of ginger supplementation on fasting plasma glucose, HbA1c, insulin, lipid profile and insulin resistance in type 2 diabetic patients. The results of the present study indicate that short-term supplementation with ginger for 8 weeks in diabetic patients could change insulin levels and sensitivity, with no significant changes in the concentrations of glucose and HbA1c. Furthermore, ginger consumption decreases the levels of TG and LDL-C significantly. Similar to our study, Bordia et al. (1997) indicated that oral supplementation of 4 g of ginger per day for a period of 3 months in coronary artery disease patients failed to reduce blood glucose levels; while, this finding is not in agreement with the results of

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Table 2. Dietary intake of subjects throughout the study.

a

Intervention (ginger) Item Energy (kCal) Carbohydrate (g) Protein (g) Total fat (g) Saturated fat (g) Monounsaturated fat (g) Polyunsaturated fat (g) Manganese (mg) Chromium (mg)

Placebo

Before

After

Before

After

p

1940 553.2 284.8 84 65.8 25.6 62.3 21.9 20.8 6.4 19.8 5.0 15.6 3.5 4.8 1.8 1.57 0.17

1811.5 424.7 255.3 46.4 59.4 13.5 63.1 29.3 21.9 5.7 20.8 5.6 15.3 3.3 4.5 1.7 1.63 0.2

1788 488.5 250.1 46.4 66.7 16 58.9 20.4 18.9 4.9 18.5 5.1 16.6 4.5 4.4 1.8 1.56 0.23

1880.9 452.3 258.5 65.1 66.4 17.4 60 22.4 19.6 5.3 19.3 3.5 17.0 3.6 4.3 1.5 1.55 0.26

0.58 0.84 0.13 0.67 0.37 0.14 0.10 0.65 0.26

a

Data are presented as means SEM.

Table 3. Effects of ginger or placebo consumption on some parameters in diabetic patients.a


Intervention Variables Weight (kg) BMI (kg/m2) Fasting blood glucose (mg/dl) HbA1c (% total Hb) Insulin (mU/ml) HOMA QUICKI Triglyceride Total cholesterol LDL-Cc HDL-Cd

Control b

Before

After

Changes (%)

79.3 11.8 29.1 3.1 142 34 7.0 1.3 12.7 2.9 4.4 1.3 0.309 .011 152.3 58.4 146.7 35.1 79.6 20.2 44.5 8.5

79.1 11.4 29.2 4 147 23 6.7 1.4 11.0 2.3* 3.9 1.0* 0.313 .012* 127.7 43.7* 143 35.2 67.8 27.2* 40.6 6.4

0.19 0.08 0.21 0.1 6.1 3.9 3.5 2.9 13.0 1.8 8.1 3.8 1.4 0.59 11.7 4.8 3.7 1.6 13.7 5.5 4.8 2.1

Before

After

Changes (%)b

p ANCOVA

76.8 14.5 29.6 4.8 153 47 6.9 1.4 11.5 3.0 4.2 1.4 0.312 .014 129.1 52.1 156.1 34.3 91.7 20.8 46.4 7.4

76.9 14.1 29.8 5 159 42 6.8 1.5 12.1 3.3 4.5 1.8 0.308 .012 128.2 37.7 149 43.5 89.2 24.9 43.9 7.1

0.21 0.10 0.01 0.03 5.5 2.7 1.7 2.6 6.8 4.0 11.3 5.1 1.1 0.62 4.6 2.2 3.9 1.9 1.5 1.4 3.9 1.3

0.51 0.63 0.424 0.664 0.001 0.002 0.005 0.039 0.2 0.04 0.28

a

Data are presented as means SD. Mean percentage differences are presented as mean SEM. c High-density lipoprotein cholesterol. d Low-density lipoprotein cholesterol. *p50.05 significantly different from baseline. b

some previous studies on diabetic animals. Al-Amin et al. (2006) reported that ginger extract decreased the plasma level of glucose (52%), in streptozotocin-induced diabetic rats. In another study, intraperitoneal administration of aqueous extracts of ginger at three different doses was associated with hypoglycemic effects in diabetic rats in a dose-dependant manner (Ozougwu & Eyo, 2011). Elshater et al. (2009) also demonstrated that post-treatment and pre-treatment with the ginger extract reduced plasma glucose levels in type one diabetic rats. Moreover, hypolipidemic effect of ginger was mentioned in this study. Reduction in TG and LDL-C levels was in agreement with the present study while increased levels of HDL-C and reduced concentrations of TC were in contrast with the findings of our study. Insulin resistance, as a common metabolic abnormality in type 2 diabetes, is an underlying trait for many cardiovascular and metabolic disorders such as hypertension and dyslipidemia provoking a widespread interest in developing new insulin sensitization agents. In the present study, HOMA and QUICKI indexes were determined as the predictors of insulin resistance and insulin sensitivity, respectively. According to our results, fasting plasma insulin levels (p50.001) and HOMA (p ¼ 0.01) significantly decreased and QUICKI (p ¼ 0.02) significantly increased after 2 months of intervention in the ginger group. Similar to our study, Goyal & Kadnur (2006) reported that methanol and ethyl acetate extracts of ginger in obese mice reduced both insulin and glucose levels enhancing insulin sensitivity. An in vitro study on preadipocytes showed that ginger and particularly gingerol improved adipocyte differentiation and insulin-sensitivity (Sekiya et al., 2004). In contrast

to our study, treatment with Z. officinale caused a significant decrease in fasting glucose and increase in insulin percentages in streptozotocin-induced non-insulin-dependent diabetic rats (Akhani et al., 2005). As mentioned previously, given the lack of a clinical trial on the effects of ginger powder in diabetic patients, the inconsistency with some experimental studies may be attributable to the pharmacological form of ginger as an extract or type of diabetes. There are some evidence that one potential factor in the etiology of insulin resistance is limited cellular antioxidant defenses against oxidative stress. Numerous studies have indicated that treatment with antioxidants could improve glucose transport activity and whole-body glucose tolerance in type 2 diabetic humans and insulin-resistant animals. Ginger contains so many ingredients including gingerols, shogaols, paradols and zigerons with antioxidant effects. Although the exact mechanisms of the action of these compounds are not well-understood, they might result from the increased protein content of GLUT-4, insulin receptors and enhanced b-cell functions (Henriksen, 2006). In spite of improvement in insulin resistance, fasting plasma glucose did not change in the present study. The possible explanation for this controversy may be interpreted as an improvement in postprandial glucose disposal. Some investigations have mentioned that insulin resistance may have different effects on fasting and post-prandial glucose concentrations as fasting plasma glucose could be normal during insulin resistance, whereas severe hyperglycemia occurs after a glucose load test (O’Rahilly et al., 1994). Therefore, one of the limitations of our

DOI: 10.3109/09637486.2013.775223

study seems to be the absence of measurement of 2 h postprandial glucose concentration.

Conclusion In conclusion, in this study oral ginger supplementation decreased the levels of insulin, TG and LDL-C in subjects with type 2 diabetes mellitus without a significant effect on fasting plasma glucose and HbA1c. Moreover, insulin sensitivity, as a major factor of chronic complications of type 2 diabetes, improved in the present study. Regarding to the novelty and preliminary nature of this study, further studies with large doses of ginger and longer duration of intervention are required to evaluate the effects of ginger supplementation on blood glucose control and insulin sensitivity.


Acknowledgements The authors offer their special thanks to the Tabriz association of diabetes for helping with recruiting patients. This is a report of a database from thesis entitled ‘‘The effect of ginger (Zingiber officinale) on blood sugar, HbA1c and insulin sensitivity in type 2 diabetic patients’’.

Declaration of interest The authors have no conflict of interest. This study was supported by a grant from The Research ViceChancellor of Tabriz University of Medical Sciences (Tabriz, Iran).

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