Clinical study on Ayurvedic herbal drug (Mustadi Kwatha Ghanavti) therapy in patients with Type 2 Diabetes
Vibhukant Kushwaha* & Anjana Kar
*Department of Kaya chikitsa, Government Ayurvedic College, Atarra-210201, District Banda, UP E-mail:vibhu.kant2009@gmail.com
Received 14 July 2016, revised 12 September 2016
Mustadi kwatha ghanavati (MKG) consists of 9 medicinal herbs with anti-hyperglycemic, antihyperlipidemic and antihypertensive potential. The aim of this study was to examine the effect of treatment with MKG on metabolic profile and symptomatic distress related parameters in patients with Type 2 diabetes (T2D). A total of 100 patients with T2D were recruited from outpatient diabetes clinic (50 men and 50 women; aged 35-60 yrs). They were randomly and equally divided into a control group and a treatment group. People in the treatment group were given 500 mg twice/day of MKG before meal for 60 days, whereas the control group had received placebo (Godanti bhasma, 2 pills 125 mg/day, before meal for 60 days. For management of symptomatic distress, patients were assigned to practice yoga, vedic meditation and received cinnamon oil body massage in addition to diet restrictions. Symptomatic distress related parameters and treatment satisfaction of the patients were evaluated with the help of visual analog scale and diabetes treatment satisfaction questionnaires. Assessment of all these parameters were done at the baseline (day 0) and at endline (day 60) treatment. Efficacy of treatment was measured on the basis of relief in observed symptoms of diabetes and clinical parameters. Data was analyzed with t-test, ANCOVA and chi-square test. We observed a statistically significant reducing effect (p < 0.001) of MKG interventions on fasting blood glucose, post prandial blood glucose, urine glucose, total-cholesterol, systolic blood pressure and diastolic blood pressure levels than placebo treatment. Overall, Mustadi kwatha ghanavati demonstrated several beneficial effects on metabolic profile, provides relief in levels of symptomatic distress related parameters and treatment satisfaction, thus showing therapeutic potential for T2D patients.
Keywords: Mustadi Kwatha Ghanavati, Metabolic profile, Symptomatic distress, Yoga, Diet IPC Int. Cl.8: A61K 36/00, A01 16/02, A23L 33/00, A61H 1/00, A63B 1/00-A63B 26/00
Ayurvedic treatment strategy for diabetes management includes methods like herbal suppliments, Panchakarma, dietetics, yoga and meditation1,2,3. Early stage diabetes is manifested by the presence of clinical parameters alteration, pancreatic β cell dysfunction, impaired Agni (metabolic activity) and depleted Ojas (immune strength)1,4. The main causes of Madhumeha (diabetes mellitus) are aggravation of tridoshas (kapha, pitta, vata) due to dhatukshya (body constitution damage), increase in medo dhatu (adipocyte), increase in free radicals, low physical activity and over nutrition1. In addition to these, recent evidence suggests that diabetes is strongly associated with stress, fatigue, inflammation, mild cognitive impairment, frequent urination and decline in physical activity5,6,7,8,9. Therefore, it is essential to reduce all of these factors that contribute to the symptomatic distress in diabetic patients for glycemic management. As treatments are most effective when diabetes is found at the early
stages, it is essential to track markers of vascular complications. Therefore, in various studies the importance of identifying pericytes loss, stress markers, inflammatory markers, and oxidative stress markers for early diagnosis of diabetes complications were proposed8. Several efforts have been made to evaluate anti-hyperglycemic herbs or special combinations of herbs in single medicinal formulation, such as Saptarangyadi, Nyagrodhadi and Asanadi Ghanavati reported in Indian Ayurvedic medicine1. However, there is limited evidence for the treatment effects of Mustadi kwatha ghanavati (MKG) which has been described in ‘Charaka Samhita’ for the management of diabetes. Further, understanding diabetes treatment specific satisfaction has important implication for patient care and evaluating the therapeutic outcome.
Therefore, the aim of the present study was to evaluate the effectiveness of treatment with MKG, in people with type 2 diabetes (T2D). This study also intended to examine specific other approaches used in
—————
*Corresponding author
complementary Ayurvedic therapies by interventions of yoga, vedic meditation, body massage and diet restriction in these patients for symptomatic distress related parameters management.
Methodology
Study population
In this open randomised controlled trial study, a total of 100 patients with T2D (50 men and 50 women; age 35-60 yrs; mean body mass index was 25.40 ± 11 kg/m², average duration of diabetes was 8.9 ± 1.20 yrs) were recruited from diabetic outpatient clinic of Govt. Ayurvedic Medical College, Attara, Banda, UP, India. Patients with T2D (diagnosed as per WHO criteria) not suffering from late stage complications of diabetes (microvascular/
macrovascular) and other major disease were only included in this study. Written consent was obtained from all participants. Ethical committee clearance certificate was obtained from the Institution.
Experimental design
Patients with T2D were randomly divided into two equal groups of treatment and control. In each group, baseline (0 day) and endline (after 60 day) treatment evaluation studies were conducted to collect information on a variety of clinical parameters namely, fasting and postprandial blood glucose (FBG, PPBG), urine glucose (UG), total cholesterol (TC), systolic and diastolic blood pressure (SBP/DBP), physical strength loss (PL), inflammation (I), fatigue (F), stress (S), frequent urination (FU), body pain (BP) and cognitive impairment (CI).
Drug source
Mustadi kwatha ghanavati (MKG) was prepared in the laboratory by following classical method described in ‘Ayurvedic Formulary of India’. In addition, its main ingredients include 9 traditional medicinal herbs. All the ingredients of MKG were procured from the local market of Lucknow, India.
Table 1 presents the details of MKG ingredients with their characteristics.
Treatment procedures
The treatment group patients (N = 50) had been treated with MKG (2 pills 500 mg/day, before meal) orally for 60 days; the control group patients (N = 50) had been treated with placebo (Godanti bhasma, 2 pills 125 mg/day, before meal) for 60 days. Anupan
(Adjuvant) of MKG and Godanti bhasma is lukewarm water. In addition, both groups were assigned to yoga, Vedic meditation and body massage therapies with diet restriction. In this study period of 60 days, patients consumed mostly Ayurveda kapha diet for balancing kapha dosha. They practiced simple yogasanas namely, pranayams, setubandhasana, balasana, vajrasana and sarvangasana for 20 min in the morning. They also practiced vedic meditation with Om chanting for 15 minutes. Besides, patients received 10 min of body massage therapy with cinnamon oil (Oil constituents: 2-3 drops of cinnamon essential oil added to olive oil).
Metabolic profile parameters study technique
An Accu-Chek Active glucometer was used for the FBG and PPBG levels assessment in capillary samples. Additionally, urine test strips (Uristix, Bayer) were utilized for testing UG in urine samples.
In order to evaluate TC, venous blood was sampled after a 12 hrs fasting and taken for laboratory diagnosis by a specific cholesterol colorimetric quatitation kit (Sigma-Aldrich Corporation, India).
SBP and DBP were measured in the sitting position with an oscillometric device (OMRON M8 Comfort).
Symptomatic distress related parameters study technique
Symptomatic distress related parameters, such as PL, I, F, S, FU, BP and CI were measured by the visual analog scale (VAS). This scale ranges from 0 (represent the best health status) to 10 (represent the worst health status). The patients were asked to indicate their experience level for each parameter on the scale. Responses were scored as (i) Never (ii) Low (iii) Modest (iv) Severe.
Treatment satisfaction study technique
Patients were asked to complete a diabetes treatment satisfaction questionnaire (DTSQ) at baseline and after study completion. DTSQ consists of 8 items (Satisfied, hyperglycemia, hypoglycemia, convenience, flexibility, understanding, recommend and continue). Each item is scored on a scale of 0 (extremely dissatisfied) to 6 (extremely satisfied). The total score (48) is an addition of the 6 individual item scores.
Statistical analysis
Data analysis was performed by Microsoft excel 2010 (USA) with ANCOVA, t-test and χ2test.
Results
Table 2 presents comparisons of baseline and endline treatment evaluation of metabolic profile parameters between and within the control and the treatment group. In treatment group, after intervention of MKG treatment, there was a satistically significantly (t-test, p < 0.01) decrease in all parameters (FBG, PPBG, UG, TC, SBP and DBP) as compared with baseline evaluation levels. However, in control group no significant change was observed for any of the parameter after placebo treatment intervention. Further, although there were significant differences in a number of parameters (FBG, PPBG, TC and DBP) between the two groups before treatment (p < 0.05), however, endline evaluation results have shown significant
differences for all parameters (p < 0.001). The results indicate that MKG appears to be more effective in improving metabolic profile as compared to placebo treatment.
The distribution of the patients according to VAS score categories (never, low, moderate, severe) for symptomatic distress related parameters (PL, I, F, S, FU, BP and CI) during baseline and endline evaluation is described for both the groups in Table 3. The frequency of patients in the control group of VAS categories was similar during baseline and endline evaluations for F, FU, BP and CI. However, compared with baseline, a significantly greater frequency of the control patients had scores in the lower level of severity for PL, I and S (p < 0.05) after the placebo
Table 1―List of ingredients used in preparation of Mustadi kwatha ghanavati (MKG) formulation with their properties and bioactive chemical constituents
Herbs Plant parts (wt.) Balances Bioactive chemical compounds
Terminalia bellirica (Gaertn.) Roxb. Fruit rind (6gm) Kapha, Pitta Flavonoids, alkaloids, Saponin, phenolic compounds, steroids, carboxylic acid, tannin and glycoside
Citrullus colocynthis (L.) Schrad. Root (3gm) Kapha, Pitta Glycosides, flavonoids, alkaloids, fatty acids and essential oils Marsdenia tenacissima R.Br. Root bark (6gm) Kapha, Pitta Polyoxypregnane: 11α,12β-Di-O-tigloyl-tenacigenin B Cedrus deodara (Roxb.) G.Don Inner wood & oil
(6gm+40 drops) Kapha, Vata Quesrcetin, essential oil
Terminalia chebula Retz. Fruit (6gm) All three Polyphenols, terpenes, anthocyanins, flavonoids, alkaloids and glycosides.
Curcuma longa L. Rhizome (3gm) Kapha, Vata Curcumin, flavonoids, phenols, terpinoids, essential oil, sesquiterpenes, curcuminoids
Symplocos racemosa Jacq. Stem bark (6gm) Kapha, Pitta Beta-sitosterol, phloretin 2'glucoside, oleanolic acid Emblica officinalis Gaertn. Fruit (6gm) All three Gallic acid, gallotanin, ellagic acid and corilagin
Cyperus rotundus L. Tuber (6gm) Kapha, Pitta Essential oils, phenolic acids, ascorbic acids, and flavonoids Vata (air and ether), Pitta (water and fire) and Kapha (water and earth)
Table 2—Changes in metabolic profile parameters following treatment with MKG
Parameters Group Baseline Endline T- test t-value
(p-value)
ANCOVA f value (p value)
Mean ± Standard Error
Fasting blood glucose (mg/dl) Control 187.02 ± 4.20** 178.42 ± 3.40*** 1.59 (0.06) 347.19 (<0.001) Treatment
174.50 ± 2.06 122.12 ± 0.54 24.59 (<0.001) Postprandial blood glucose
(mg/dl) Control 270.60 ± 2.09*** 266.84 ± 2.09*** 1.27 (0.10) 1344.65 (<0.01) Treatment 246.00 ± 4.71 165.44 ± 1.76 16.01 (<0.001)
Urine Glucose (mmol/L) Control 0.93 ± 0.05 0.91 ± 0.04*** 0.29 (0.39) 67.00 (<0.001) Treatment 0.90 ± 0.06 0.62 ± 0.04 4.13 (<0.001)
Total cholesterol (mg/dl) Control 128.70 ± 3.50* 127.88 ± 3.07*** 0.18 (0.43) 255.58 (<0.001) Treatment 135.48 ± 2.06 111.20 ± 1.31 9.95 (<0.001)
Systolic blood pressure (mm Hg) Control 136.32 ± 1.11 133.24 ± 1.12*** 1.05 (0.45) 255.58 (<0.001) Treatment 132.32 ± 1.11 118.70 ± 1.50 7.30 (<0.001)
Diastolic blood pressure (mm Hg) Control 74.50 ± 0.88** 72.88 ± 0.75*** 1.39 (0.08) 106.61 (<0.001) Treatment 77.86 ± 1.07 75.22 ± 0.46 2.27 (<0.01)
*p<0.05, **p<0.01, ***p<0.001, Statistical significance of differences between treatment and control groups at baseline and at endline evaluations (based on t-test). Ancova: Group × Time effect
intervention. Furthermore, the frequency of patients in the treatment group of VAS category was improved significantly (Chi-square, p < 0.005) from baseline to endline evaluation for all parameters. Baseline and endline evaluation VAS score values for symptomatic distress related parameters were also compared between and within control and treatment groups using the t-test (Table 4). Compared to baseline score, statistically significant (p < 0.05) mean decrease in
VAS score was observed in control group for I, S and CI levels at the endline evaluations. Conversely, we observed a significant decrease (p < 0.05) in mean VAS score for each parameter (PL, I, F, S, FU, BP and CI) when comparing baseline and endline evaluations in treatment group.
Further, ANCOVA was applied to examine the group (treatment and control) × evaluation time effect (baseline and endline) interactions. The results showed
Table 3—Frequency distribution of control and treatment group patients in different response category (Never, low, modest and severe) of symptoms distress related parameters
Parameters Baseline responses Endline responses Chi-square test
1 2 3 4 1 2 3 4 χ2value, df (p-value)
Treatment Group (N=50) Treatment Group (N=50)
Physical strength loss 5 24 17 4 20 28 0 2 26.97, 3 (<0.001)
Inflammation 11 9 25 5 11 27 9 3 17.02, 3 (<0.001)
Fatigue 0 9 14 27 2 16 25 7 18.82, 3 (<0.001)
Stress 5 12 29 4 15 7 28 0 10.33, 3 (<0.05)
Frequent urination 6 5 27 12 5 29 16 0 31.84, 3 (<0.001)
Body pain 9 13 25 3 11 28 8 3 14.44, 3 (<0.01)
Cognitive impairment 11 8 16 15 30 10 7 3 20.54, 3 (<0.001)
Control Group (N=50) Control Group (N=50)
Physical strength loss 21 14 10 5 21 23 6 0 8.19, 3 (<0.05)
Inflammation 21 15 7 7 31 14 5 0 9.29, 3 (<0.05)
Fatigue 9 23 15 3 15 13 18 4 4.69, 3 (0.19)
Stress 6 18 12 14 16 24 10 0 19.58, 3 (<0.001)
Frequent urination 6 30 9 5 15 26 8 1 6.86, 3 (0.07)
Body pain 4 30 14 2 9 29 8 4 4.24, 3 (0.23)
Cognitive impairment 23 15 8 4 25 18 6 1 2.42, 3 (0.48)
1= Never, 2= Low, 3= Modest, 4= Severe
Table 4—Changes in symptoms distress related parameters following treatment with MKG
Parameters Group Baseline Endline t-Test ANCOVA
Mean ± Standard Error t-value (p value) f-value (p value) Physical strength loss (PL) Control 4.84 ± 0.41 4.1 ± 0.29*** -1.49 (0.07)
58.41 (<0.001) Treatment 4.3 ± 0.31 2.04 ± 0.29 -5.33 (<0.01)
Inflammation (I) Control 4.86 ± 0.42 3.44 ± 0.29 -2.80 (<0.01)
1.69 (0.20) Treatment 5.02 ± 0.42 3.24 ± 0.34 -3.27 (<0.01)
Fatigue (F) Control 5.66 ± 0.33** 5.58 ± 0.39 -0.16 (0.44)
30.63 (<0.001) Treatment 7.08 ± 0.33 5.22 ± 0.32 -4.06 (<0.01)
Stress (S) Control 6.44 ± 0.34** 4.64 ± 0.30* -3.92 (<0.01)
1.01 (0.32) Treatment 5.1 ± 0.31 3.78 ± 0.38 -2.68 (<0.01)
Frequent urination (FU) Control 4.1 ± 0.34*** 4.68 ± 0.30** 1.26 (0.10)
70.99 (<0.001) Treatment 5.88 ± 0.35 3.68 ± 0.26 -5.08 (<0.01)
Body pain (BP) Control 4.7 ± 0.27 5.34 ± 0.32*** 1.54 (0.06)
54.50 (<0.001) Treatment 4.54 ± 0.32 3.2 ± 0.33 -2.92 (<0.01)
Cognitive impairment (CI) Control 4.50 ± 0.39 2.96 ± 0.45 -2.60 (<0.05)
2.05 (0.16) Treatment 5.10 ± 0.48 3.92 ± 0.38 -1.93 (<0.05)
*p<0.05, **p<0.01, ***p<0.001, statistical significance of differences between treatment and control group at baseline and at endline evaluations (based on t-test). Ancova: Group × Time effect
significant differences in all metabolic profile parameters (FBG, PPBG, UG, TC, SBP and DBP) and most of the symptomatic distress related parameters (PL, F, FU and BP) between control and treatment group (Tables 2&4). Overall the treatment group reported a significant improvement in all metabolic profile parameters, as well as in symptomatic distress related parameters, such as PL, F, FU and BP after treatment intervention when compared to the control group. However, there were no group × time effect interactions for 3 parameters, such as I, S and CI.
These data suggest that both groups showed a similar improvement after treatment intervention for I, S and CI.
Further, most DTSQ scale total scores were lower at baseline evaluation among control (11.67 ± 0.15) and treatment (11.46 ± 0.24) groups. Following treatment the overall average DTSQ scale score was 12.02 ± 0.16 and 20.55 ± 0.29 for control and treatment groups, respectively. In general, treatment group patients reported a better satisfaction with the therapy as compared to control group. Fig. 1, dipicts that average DTSQ scale score was statistically significantlly different between baseline and endline scale scores in treatment group (t-test value - 24.27;
p < 0.001). However, comparison of endline with baseline DTSQ scale scores among control group showed no change (t-test value -1.58; p = 0.06).
Discussion
Overall the results revealed that the formulation of Mustadi Kwatha Ghanavati (MKG) has antidiabetic properties and produced a multiple favorable effects.
It has proved to be potentially capable of reducing blood glucose level, urine glucose level, cholesterol level and may improve blood pressure level in patients with type 2 diabetes. Hence, this formulation can be used as a natural source of antidiabetic medicine. These findings are consistent with results of previous studies, in which there is robust
experimental evidence supporting the hypoglycemic activity of T. bellirica (Gaertn.) Roxb., C. colocynthis (L.) Schrad., T. chebula Retz., C. longa L., S. racemosa Jacq., E. officinalis Gaertn., C. deodara (Roxb.) G.Don. and C. rotundus L. in diabetic patients10-16. However, these studies have examined efficacy of individual herb and confirmed their potential antidiabetic outcome. Further, only few scientific literatures are available to support the antidiabetic activity of M. tenacissima R.Br., which was also included in the present formulation of MKG.
According to 'Charaka Samhita' most of these herbs are characterised by astringent, bitter and pungent in Rasa (taste); light, digestible and dry in Guna (characteristics); hot and ionized in Virya (potency);
pungent in Vipaka (post digestion effect).
Diabetes is characterised by various metabolic pathogenesis, for that reason individual plant’s bioactive secondary metabolites are not enough to accomplish the desirable therapeutic effects. In consequence, MKG formulation is an Ayurvedic polyherbal combination of 9 medicinal herbs with varying properties for achieving a better therapeutic effect. These herbs are most cited plants in traditional Indian medicine and Ayurvedic materia medica due to their high content of numerous biologically active secondary plant metabolites for the treatment of diabetes and other diseases. From the earlier studies, it was suggested that the biologically active secondary plant metabolites reported from these herbs belong to all 3 diverse groups, such as terpenes, phenolics and nitrogen containing compounds14,17,20. These bioactive secondary metabolites control cellular function by acting as an antioxidants, enzyme inhibitors or inducers, signaling molecule inhibitors or inducers and up regulation or down regulation of gene expression21. Based on these informations, many studies have suggested mechanisms by which herbal ingredients of MKG formulation bring about their antidiabetic activities. The anti-hyperglycemic functions of E. officinalis Gaertn., T. bellirica (Gaertn.) Roxb. and C. longa L. may be attributed to their antioxidant potential and reduction in inflammation18,19,10. Pharmacological studies have revealed that C. rotundus L. and S. racemosa Jacq. exhibit α-amylase and α-glucosidase inhibitory effects thus are effective antihyperglycemic herbs20. Earlier preclinical study confirms that treatment with T. chebula Retz. causes amplification of the expression of GLUT gene mRNA
Fig. 1―DTSQ scale average score responses at baseline and at endline treatment sessions among treatment and control group
and increases adiponectin secretion11. It has been shown that C. colocynthis (L.) Schrad. stimulates the release of insulin from β-cells21. Besides, C. deodara (Roxb.) G.Don. is able to influence the cellular regeneration of islet of langerhans in the pancreas and restores its normal size15. But, to a great extent of this information are based on lab studies and animal model.
Further studies on more human subjects with improved experimental design are required to explain the effects and mechanism of action for these herbs. In addition, there is no adequate evidence to suggest that the MKG formulation is toxic. In the present study, we did not observe any incidence of side effect throughout the study period in the treatment group. Still, more studies are needed to confirm these findings. Among diabetic patients PL, I, F, S, FU, BP and CI are persistent and distressing complaint due to elevated glycemic level7,8,9,22,23,24. The results of this study indicate that at baseline, patients reported high levels of symptomatic distress. Completion of therapy was associated with clinically significant improvements in the severity of PL, I, F, S, FU, BP and CI levels in most patients of both the groups. This could be attributed due to the intervention of MKG, massage with cinnamon oil, yoga, vedic meditation and diet restriction. Studies of these aspects of MKG effect on symptomatic distress related parameters are limited. Nonetheless, the results corroborate earlier studies wherein it was found that Ayurvedic herbs, yoga, meditation and diet have improved health related quality of life in diabetic patients without causing adverse effects3,25. Body massage therapy can reduce muscle tension, nociceptive pain and biochemical mediators of inflammation26. The beneficial effects of massage using cinnamon essential oil can be attributed to its anti-inflammatory, antimicrobial, antidiabetic and vasodilator activities as well as it can improve cognitive function27. Further, there have been many studies on diet control showing that formula diets, carb counting and dietary high- polyphenols extra-virgin olive oil might help to improve inflammatory adipokines and metabolic rate in overweight diabetic patients28,29. Besides, yoga and meditation can benefit diabetic patients by reducing hyperglycemia, hyperlipidemia and hypertension2. In addition, this study examined the effect of MKG treatment on patient treatment satisfaction. We observed that treatment group patients perceived their medication to be effective and expressed certain amount of symptomatic distress relief after treatment. MKG promotes food absorption, relieves constipation and
prevents bloating. Additionally, it is an undeniable fact that diabetes is not completely curable it is a controllable disease till now. On the basis of these findings, it is suggested that MKG may be an effective natural medicine for type 2 diabetes disease control and can be included in diet of patients.
Conclusion
This study represents an effective approach to management of type 2 diabetes, wherein comprehensive Ayurvedic treatment methods (intake of Mustadi kwatha ghanavati, yoga, meditation, diet and herbal oil massage) might improve the health quality of patients.
Acknowledgment
Authors are thankful to all the participants for their necessary support during this work.
References
1 Das B, Mitra A & Hazra J, Management of madhumeha (diabetes mellitus) with current evidence and interventions with Ayurvedic rasausadhis, Indian J Tradit Knowle, 10 (4) (2011) 624-628.
2 Gainey A, Himathongkam T, Tanaka H & Suksom D, Effects of Buddhist walking meditation on glycemic control and vascular function in patients with type 2 diabetes, Comple Ther Med, 26 (6) (2016) 92-97.
3 Sharma R, Amin H & Prajapati PK, Yoga: As an adjunct therapy to trim down the Ayurvedic drug requirement in non insulin-dependent diabetes mellitus, Anc Sci Life, 33 (4) (2014) 229-235.
4 Dixit AK, Dey R, Suresh A, Chaudhuri S, Panda AK, et al., The prevalence of dyslipidemia in patients with diabetes mellitus of ayurveda Hospital, J Diabetes Metab Disord, 13 (2014) 58.
5 Glover CM, Wang Y, Fogelfeld L & Lynch EB, Stress and other determinants of diabetes-specific quality of life in low-income African Americans with uncontrolled type 2 diabetes mellitus, J Health Care Poor Underserved, 27 (3) (2016) 1345-1356.
6 Koley M, Saha S, Arya JS, Choubey G, Ghosh S, et al., Knowledge, attitude, and practice related to diabetes mellitus among diabetics and nondiabetics visiting homeopathic hospitals in West Bengal, India, J Evid Based Comple Altern Med, 21 (1) (2016) 39-47.
7 Jain A, Sharma R, Choudhary PK, Yadav N, Jain G, et al., Study of fatigue, depression, and associated factors in type 2 diabetes mellitus in industrial workers, Ind Psychiatr J, 24 (2) (2015) 179-184.
8 Hojs R, Ekart R, Bevc S & Hojs N, Markers of inflammation and oxidative stress in the development and progression of renal disease in Diabetic patients, Nephron, 25 (6) (2016) In press.
9 Ucok K, Yalcinkaya H, Acay A, Coban NF, Aslanalp S, et al., Do patients with newly diagnosed type 2 diabetes have
impaired physical fitness, and energy expenditures?, Neth J Med, 73 (6) (2015) 276-283.
10 Sabu MC & Kuttan R, Antidiabetic and antioxidant activity of Terminalia bellirica Roxb, Indian J Exp Biol, 60 (2009) 270-275.
11 Shyni GL, Kavitha S, Indu S, Arya AD, Anusree SS, et al., Chebulagic acid from Terminalia chebula enhances insulin mediated glucose uptake in 3T3-L1 adipocytes via PPARγ signaling pathway, Biofactors, 40 (6) (2014) 646-657.
12 Nabavi SF, Thiagarajan R, Rastrelli L, Daglia M, Sobarzo- Sánchez E, et al., Curcumin: a natural product for diabetes and its complications, Curr Top Med Chem, 15 (23) (2015) 2445-2455.
13 Antu KA, Riya MP, Mishra A, Anilkumar KS, Chandrakanth CK, et al., Antidiabetic property of Symplocos cochinchinensis is mediated by inhibition of alpha glucosidase and enhanced insulin sensitivity, PLOS One, 9 (9) (2014) e105829.
14 D'souza JJ, D'souza PP, Fazal F, Kumar A, Bhat HP, et al., Anti-diabetic effects of the Indian indigenous fruit Emblica officinalis Gaertn: active constituents and modes of action, Food Funct, 5 (4) (2014) 635-644.
15 Singh P, Khosa RL & Mishra G, Evaluation of antidiabetic activity of ethanolic extract of Cedrus deodara (Pinaceae) stem bark in streptozotocin induced diabetes in mice, Nigerian J Expt Clin Biosci, 1 (1) (2013) 33-38.
16 Nadkarni MA, Vyas SN, Baghel MS & Ravishankar B, Randomized placebo-controlled trial of mustadi ghanavati in hyperlipidemia, Ayurveda, 31 (3) (2010) 287-293.
17 Hussain AI, Rathore HA, Sattar MZ, Chatha SA, Sarker SD, et al., Citrullus colocynthis (L.) Schrad (bitter apple fruit): a review of its phytochemistry, pharmacology, traditional uses and nutritional potential, J Ethnopharmacol, 155 (1) (2014) 54-66.
18 Kaur G, Invally M & Chintamaneni M, Influence of piperine and quercetin on antidiabetic potential of curcumin, J Comple Integr Med, 25 (6) (2016) In press.
19 Nain P, Saini V, Sharma S & Nain J, Antidiabetic and antioxidant potential of Emblica officinalis Gaertn. leaves extract in streptozotocin-induced type-2 diabetes mellitus (T2DM) rats, J Ethnopharmacol, 142 (1) (2012) 65-71.
20 Tran HH, Nguyen MC, Le HT, Nguyen TL, Pham TB, et al., Inhibitors of α-glucosidase and α-amylase from Cyperus rotundus, Pharm Biol, 52 (1) (2014) 74-77.
21 Singh LW, Traditional medicinal plants of Manipur as anti- diabetics, J Med Plant Res, 5 (5) (2011) 677–687.
22 Sun J, Xia W, Cai R, Wang P, Huang R, et al., Serum insulin degrading enzyme level and other factors in type 2 diabetic patients with mild cognitive impairment, Curr Alzheimer Res, 14 (6) (2016).
23 Drivsholm T, de Fine Olivarius N, Nielsen AB & Siersma V, Symptoms, signs and complications in newly diagnosed type 2 diabetic patients, and their relationship to glycaemia, blood pressure and weight, Diabetologia, 48 (2) (2005) 210-214.
24 Krein SL, Heisler M, Piette JD, Makki F & Kerr EA, The Effect of chronic pain on diabetes patients’ self- management, Diabetes Care, 28 (1) (2005) 65-70.
25 Pandey A, Tripathi P, Pandey R, Srivatava R & Goswami S, Alternative therapies useful in the management of diabetes: A systematic review, J Pharm Bioallied Sci, 3 (4) (2011) 504–512.
26 Sejari N, Kamaruddin K, Ramasamy K, Lim SM, Neoh CF, et al., The immediate effect of traditional Malay massage on substance P, inflammatory mediators, pain scale and functional outcome among patients with low back pain:
study protocol of a randomised controlled trial, BMC Comple Altern Med, 15 (1) (2016) 16-16.
27 Ranasinghe P, Perera S, Gunatilake M, Abeywardene E, Gunapala N, et al., Effects of Cinnamomum zeylanicum (Ceylon cinnamon) on blood glucose and lipids in a diabetic and healthy rat model, Pharmacogn Res, 4 (2) (2012) 73–79.
28 Gökşen D, Atik Altınok Y, Ozen S, Demir G, et al., Effects of carbohydrate counting method on metabolic control in children with type 1 diabetes mellitus, J Clin Res Pediatr Endocrinol,6 (2) (2014) 74-78.
29 Santangelo C, Filesi C, Varì R, Scazzocchio B, Filardi T, et al., Consumption of extra-virgin olive oil rich in phenolic compounds improves metabolic control in patients with type 2 diabetes mellitus: a possible involvement of reduced levels of circulating visfatin, J Endocrinol Invest, 25 (6) (2016) In press.