diabetes mellitus ( dm ) is a widespread metabolic disorder associated with increased risk of cardiovascular disease and other complications ( 1 - 4 ) . pathophysiological mechanisms underlying type 2 ( t2 dm ) and coronary artery outcomes include inflammation and oxidative stress ( 5 ) . the latter arises from an imbalance between the amount of oxidants produced and the antioxidant defense system . increased activity of the antioxidant enzymes superoxide dismutase ( sod ) and glutathione peroxidase ( gpx ) result in increased blood glucose and insulin levels , oxidative damage by free radicals , and the formation of highly toxic products such as malondialdehyde ( mda ) and lipid peroxidation products that can lead to insulin resistance ( 6 ) . some studies have shown that oxidative stress and insulin resistance are associated with higher levels of tumor necrosis factor ( tnf)- , interleukin ( il)-6 , c - reactive protein ( crp ) , and other markers of systemic inflammation ( 7 ) . inhibiting the expression of inflammatory and oxidative stress biomarkers as well as hyperlipidemia can contribute to the control of diabetes and related complications ( 8) . traditional chinese medicines are increasingly used as an adjunct to conventional treatments for t2 dm to improve diabetic symptoms and prevent complications . for example , jianyutangkang ( jytk ) is composed of zhimu ( rhizoma anemarrhenae ) , guijianyu ( euonymus alatus ) , and ciwujia ( acanthopanax senticosus ) . jytk extracts reduce postprandial blood glucose , lipid , and insulin concentrations in rats with diabetic and increase sod activity at high doses ( 12 , 13 ) . integrating traditional chinese and western approaches ( jytk plus metformin ) in patients with t2 dm may not only help to improve glycemia and insulin sensitivity , but may also alter diabetes - related lipid equilibrium to a greater extent than metformin alone ( 14 ) . jytk has antioxidant and anti - inflammatory characteristics ; however , these observations are limited to animal models and there have been no clinical trials carried out on patients with diabetes . in a pilot study at pla general hospital , jytk was used to treat t2 dm and its complications , and showed no adverse effects . the present clinical trial extended these findings and investigated the effects of jytk combined with metformin on the levels of sod , mda , and gpx as well as the inflammatory factors tnf- and il-6 in patients with t2 dm . the 500 mg jytk tablets ( science and technology center at pla general hospital , beijing , china ) contained 129 mg a. senticosus , 105 mg e. alatus , and 266 mg r. anemarrhenae , as determined by high performance liquid chromatography ( 15 - 17 ) . placebo tablets identical in appearance to jytk tablets were prepared at the academy of military medical sciences ( beijing , china ) . a total of 150 patients with t2 dm , recently diagnosed ( within the previous five years ) according to the world health organization ( who ) criteria ( 18 ) , were recruited from the pla general hospital outpatient service and chaoyang district shili baobeili and balitun community service stations in chaoyang district . of the 150 patients , 79 were assigned to the combined jytk / metformin treatment group and 71 to the metformin - only group ; 38 patients were lost to follow - up . patients with elevated glycosylated hemoglobin ( > 6.5% ) , taking metformin for treatment and had a diabetes duration  5 years were included in the study . exclusion criteria were patients taking other antihyperglycemic or antihyperlipidemic agents ; receiving insulin therapy ; with hematological diseases ; with cardiac , renal , or hepatic diseases or tachycardia , depression , or myocardial infarction ; the patients who consumed alcohol ; had hypothyroidism or experienced vertigo or seizures ; received treatment with estrogen , steroids , beta - blockers , or thiazide ; and females who were pregnant , planning pregnancy , or breast - feeding . treatment doses were prepared by an independent operator , not otherwise involved in the trial , and concealed in opaque , sealed envelopes that were sequentially numbered . the treatment group received metformin 1.5 g /day and jytk 4.5 g /day , and the control group received metformin 1.5 g /day and placebo 4.5 g /day . the investigators were blinded to the group assignment of patients using a coding system , with the codes known to an independent allocator and revealed only after completion of treatment and analyses . patients were instructed to follow a diet recommended for newly diagnosed patients with t2 dm and to walk 30 minutes a day at least three days a week during the trial . in the follow - up period , patients were phoned once a week to obtain their daily glucose levels and to supervise modifications to their lifestyle . the number of patients lost to follow - up due to lack of interest , contact , or time to return for an interview is shown in figure 1 using the flowchart model of the consolidated standards of reporting randomized clinical trials 2010 . patients were informed about the benefits and possible risks of the study and were free to withdraw at any time during the trial for any reason . the complete list of inclusion and exclusion criteria was approved by the pla general hospital ethics committee ( study identifier : nct00102589 ) . prior to intervention ( baseline , week 0 ) , at weeks 8 and 19 , and at the end of the trial ( 26 weeks ) , overnight fasting venous blood samples ( 8 ml ) were obtained from each patient between 07:00 and 09:00 hours . serum was separated by centrifugation at 2500 rpm for 10 minutes and immediately stored at -80c . mda , sod , and gpx levels were determined using commercially available kits ( nanjing jiancheng bio - company , nanjing , china ) . serum tnf- and il-6 concentrations were determined using specific human sandwich enzyme - linked immunosorbent assay kits from shanhai pulinsidun biological technology ( shanghai , china ) . body weight , body mass index ( bmi ) , waist and hip circumferences , blood pressure , and adverse effects were noted in medical records during the visits . an intent - to - treat analysis was carried out for all subjects and results are expressed as mean  sd . changes in biological parameters were examined by analysis of variance and the  test using graphpad prism software ( graphpad , la jolla , ca , usa ) . the dunnett test for multiple comparisons was used to analyze data from the same group before and after treatment . analysis of covariance ( ancova ) was used to identify differences between the two groups after intervention , with results adjusted according to baseline measurements and covariates . tests of treatment effects were carried out at a two - sided significance level of 0.05 , and 95% confidence intervals for differences between baseline and week 26 within - group changes were determined and considered as statistically significant for values other than zero . the 500 mg jytk tablets ( science and technology center at pla general hospital , beijing , china ) contained 129 mg a. senticosus , 105 mg e. alatus , and 266 mg r. anemarrhenae , as determined by high performance liquid chromatography ( 15 - 17 ) . placebo tablets identical in appearance to jytk tablets were prepared at the academy of military medical sciences ( beijing , china ) . a total of 150 patients with t2 dm , recently diagnosed ( within the previous five years ) according to the world health organization ( who ) criteria ( 18 ) , were recruited from the pla general hospital outpatient service and chaoyang district shili baobeili and balitun community service stations in chaoyang district . of the 150 patients , 79 were assigned to the combined jytk / metformin treatment group and 71 to the metformin - only group ; 38 patients were lost to follow - up . patients with elevated glycosylated hemoglobin ( > 6.5% ) , taking metformin for treatment and had a diabetes duration  5 years were included in the study . exclusion criteria were patients taking other antihyperglycemic or antihyperlipidemic agents ; receiving insulin therapy ; with hematological diseases ; with cardiac , renal , or hepatic diseases or tachycardia , depression , or myocardial infarction ; the patients who consumed alcohol ; had hypothyroidism or experienced vertigo or seizures ; received treatment with estrogen , steroids , beta - blockers , or thiazide ; and females who were pregnant , planning pregnancy , or breast - feeding . treatment doses were prepared by an independent operator , not otherwise involved in the trial , and concealed in opaque , sealed envelopes that were sequentially numbered . the treatment group received metformin 1.5 g /day and jytk 4.5 g /day , and the control group received metformin 1.5 g /day and placebo 4.5 g /day . the investigators were blinded to the group assignment of patients using a coding system , with the codes known to an independent allocator and revealed only after completion of treatment and analyses . patients were instructed to follow a diet recommended for newly diagnosed patients with t2 dm and to walk 30 minutes a day at least three days a week during the trial . in the follow - up period , patients were phoned once a week to obtain their daily glucose levels and to supervise modifications to their lifestyle . the number of patients lost to follow - up due to lack of interest , contact , or time to return for an interview is shown in figure 1 using the flowchart model of the consolidated standards of reporting randomized clinical trials 2010 . patients were informed about the benefits and possible risks of the study and were free to withdraw at any time during the trial for any reason . the complete list of inclusion and exclusion criteria was approved by the pla general hospital ethics committee ( study identifier : nct00102589 ) . prior to intervention ( baseline , week 0 ) , at weeks 8 and 19 , and at the end of the trial ( 26 weeks ) , overnight fasting venous blood samples ( 8 ml ) were obtained from each patient between 07:00 and 09:00 hours . serum was separated by centrifugation at 2500 rpm for 10 minutes and immediately stored at -80c . mda , sod , and gpx levels were determined using commercially available kits ( nanjing jiancheng bio - company , nanjing , china ) . serum tnf- and il-6 concentrations were determined using specific human sandwich enzyme - linked immunosorbent assay kits from shanhai pulinsidun biological technology ( shanghai , china ) . body weight , body mass index ( bmi ) , waist and hip circumferences , blood pressure , and adverse effects were noted in medical records during the visits . an intent - to - treat analysis was carried out for all subjects and results are expressed as mean  sd . changes in biological parameters were examined by analysis of variance and the  test using graphpad prism software ( graphpad , la jolla , ca , usa ) . the dunnett test for multiple comparisons analysis of covariance ( ancova ) was used to identify differences between the two groups after intervention , with results adjusted according to baseline measurements and covariates . tests of treatment effects were carried out at a two - sided significance level of 0.05 , and 95% confidence intervals for differences between baseline and week 26 within - group changes were determined and considered as statistically significant for values other than zero . all 112 subjects 59 in the jytk + metformin group and 52 in the metformin only group completed the 26-week clinical trial ; 38 were lost to follow - up due to lack of interest , contact , or time for a follow - up interview . all subjects who completed the study had acceptable compliance with the intervention , as determined by tablet counts , and did not report any adverse effects or symptoms associated with jytk supplementation . there were no significant differences between groups in terms of demographic characteristics , fasting plasma glucose , urinary albumin - to - creatinine ratio , or complete blood count ( p > 0.05 ) ( table 1 ) . bmi was unchanged after 26 weeks of treatment ( 26.6  6.9 to 26.7  2.0 kg / m in the control group ; 28.6  4.8 to 29.7  2.4 abbreviations : acr , urinary albumin - to - creatinine ratio ; bmi , body mass index ; cr , creatinine ; esr , sedimentation rate ; fpg , fasting plasma glucose ; hba1c , glycated hemoglobin ; hb , hemoglobin ; hdl - c , high density lipoprotein cholesterol ; ldl - c , low density lipoprotein - cholesterol ; neu , polymorphonuclear ; tc , total cholesterol ; tg , triglyceride ; wbc , white blood cell ; ua , urea nitrogen . no significant difference was detected between the groups using the sample t - test and  test in all items . sod , gpx , mda , high sensitivity crp , il-6 , and tnf- concentration before and after intervention are shown in table 2 . before starting study , there were no differences in these indices between the jytk / metformin combination treatment and metformin only groups ( p > 0.05 ) . after 18 weeks , serum tnf- and il-6 levels decreased by 15.56% and 22.45% , respectively , compared to the baseline values in patients treated with jytk . by the end of the study , tnf- , il-6 , and mda concentrations had decreased by 20.4% , 25.8% , and 20.8% , respectively in the treatment group , as compared to 3.4% , 7.8% , and 0% in the metformin only group ( figure 2 ) . on the other hand , sod level had increased by 15.27% compared to the control group . there were no differences between the two groups in terms of gxp and crp levels . abbreviations : gpx , glutathione peroxidase , hs - crp , high sensitivity c - reactive protein ; il-6 , interleukin 6 ; mda , malondialdehyde ; sod , superoxide dismutase ; tnf- , tumor necrosis factor-. values are expressed as mean  sd . p < 0.01 vs. mean pre - treatment mean value ( the dunnett test ) . variable change 95% ci , from baseline to week 26 within - group change , determined and considered as statistically significant for values other than zero . analysis of covariance ( ancova ) was used to identify differences between the two groups after intervention . * all 112 subjects 59 in the jytk + metformin group and 52 in the metformin only group completed the 26-week clinical trial ; 38 were lost to follow - up due to lack of interest , contact , or time for a follow - up interview . all subjects who completed the study had acceptable compliance with the intervention , as determined by tablet counts , and did not report any adverse effects or symptoms associated with jytk supplementation . there were no significant differences between groups in terms of demographic characteristics , fasting plasma glucose , urinary albumin - to - creatinine ratio , or complete blood count ( p > 0.05 ) ( table 1 ) . bmi was unchanged after 26 weeks of treatment ( 26.6  6.9 to 26.7  2.0 kg / m in the control group ; 28.6  4.8 to 29.7  2.4 abbreviations : acr , urinary albumin - to - creatinine ratio ; bmi , body mass index ; cr , creatinine ; esr , sedimentation rate ; fpg , fasting plasma glucose ; hba1c , glycated hemoglobin ; hb , hemoglobin ; hdl - c , high density lipoprotein cholesterol ; ldl - c , low density lipoprotein - cholesterol ; neu , polymorphonuclear ; tc , total cholesterol ; tg , triglyceride ; wbc , white blood cell ; ua , urea nitrogen . no significant difference was detected between the groups using the sample t - test and  test in all items . sod , gpx , mda , high sensitivity crp , il-6 , and tnf- concentration before and after intervention are shown in table 2 . before starting study , there were no differences in these indices between the jytk / metformin combination treatment and metformin only groups ( p > 0.05 ) . after 18 weeks , serum tnf- and il-6 levels decreased by 15.56% and 22.45% , respectively , compared to the baseline values in patients treated with jytk . by the end of the study , tnf- , il-6 , and mda concentrations had decreased by 20.4% , 25.8% , and 20.8% , respectively in the treatment group , as compared to 3.4% , 7.8% , and 0% in the metformin only group ( figure 2 ) . on the other hand , sod level had increased by 15.27% compared to the control group . there were no differences between the two groups in terms of gxp and crp levels . abbreviations : gpx , glutathione peroxidase , hs - crp , high sensitivity c - reactive protein ; il-6 , interleukin 6 ; mda , malondialdehyde ; sod , superoxide dismutase ; tnf- , tumor necrosis factor-. values are expressed as mean  sd . p < 0.01 vs. mean pre - treatment mean value ( the dunnett test ) . variable change 95% ci , from baseline to week 26 within - group change , determined and considered as statistically significant for values other than zero . analysis of covariance ( ancova ) was used to identify differences between the two groups after intervention . * jytk has antioxidant and anti - inflammatory properties ; hence , using it in combination with metformin may not only improve glycemia and insulin sensitivity in patients with t2 dm , but may also modulate lipid equilibrium . the present study investigated the effect of this combined treatment on serum oxidative stress and inflammation in patients with t2 dm . the results indicated that consuming 4.5 g jytk tablets daily for 26 weeks alters expression levels of oxidative stress and inflammation biomarkers ; sod level increased , while mda , il-6 , and tnf- levels decreased as compared to those of the patients treated with metformin alone . metformin along with pioglitazone , statins , glimepiride , voglibose , amlodipine , and telmisartan are widely used to treat diabetes . in the past several years , traditional chinese medicine , which involves combining different herbs into a single therapy , has improved diabetic symptoms and complications ( 18 - 21 ) , possibly through antioxidant and anti - inflammatory mechanisms ( 22 ) . the increase in free radical generation in patients with t2 dm can lead to vascular changes ( 23 , 24 ) ; panax ginseng , grape seed extract , and bitter melon all exhibit antioxidant capacities ( 23 , 25 - 26 ) , while diosgenin present in fenugreek improves glucose metabolism by promoting adipocyte differentiation and inhibiting inflammation in adipose tissues ( 27 ) . tangbikang , a traditional chinese medicine granule , prevents diabetic peripheral neuropathy - induced increases in serum il-6 and tnf- levels ( 28 ) . jytk tablets contain zhimu , guijianyu , and ciwujia as well as polysaccharides , flavonoids , mangiferin , anemaran , steroidal saponins , bis ( pyridine-2-yl ) ketone , and other active ingredients . polysaccharides and flavonoids in guijianyu demonstrate oxygen free radical - scavenging activity towards phenolic compounds ( 3 - 5 ) , while r. anemarrhenae has anti - diabetic effects , with mangiferin inhibiting the activity of -glucosidase . anemaran suppresses acute and chronic inflammation by inducing the secretion of adrenal glucocorticoid and inhibiting prostaglandin e synthesis or releasing in the inflammatory tissues ( 6 , 7 ) . thorn thistle saponins can reduce blood glucose levels in rats possibly by increasing antioxidative enzyme activity , which reduces cellular damages caused by free radicals and suppresses the immune response ( 8 , 9 ) . fasting plasma glucose ( fpg ) and glycosylated hemoglobin ( hba1c ) level , and a lipid profile were measured before , during , and after the combined jytk / metformin treatment . it was found out that the combination treatment not only helped to improve glycemia and insulin sensitivity , but it also helped to modify the diabetes related lipid equilibrium ( 14 ) . the results of this study suggest that combined jytk / metformin treatment may be effective to prevent diabetes complications resulted from increased inflammation , vasculogenesis , and oxidative stress . firstly , the levels of cat or other inflammatory factors such as il-1 were not measured . secondly , the sample size was relatively small and the intervention period was only 26 weeks , and it is therefore unclear whether jytk / metformin treatment can lead to long - term improvement in patients with t2 dm . in summary , this study provided evidence that jytk / metformin treatment can improve antioxidant indices and reduce inflammation in patients who are newly diagnosed with t2 dm . further investigations with larger sample sizes and longer intervention time are needed to confirm the beneficial combination effects of jytk in the management of diabetes complications .
backgrounddiabetes is a metabolic disorder caused by oxidative stress and inflammation . 
 jianyutangkang ( jytk ) , as a potential chinese integrative medicine , is an antioxidant used in chinese medicine with potential anti - inflammatory properties.objectivesthe present randomized clinical trial was carried out to evaluate the effects of jytk on oxidative stress and inflammation in patients with type 2 diabetes mellitus ( t2dm).patients and methodsthe parallel , randomized , double - blinded , placebo - controlled clinical trial included 150 newly diagnosed t2 dm patients receiving metformin treatment ( 1.5 g / day ) , some of whom also received jytk ( 4.5 g / day ) in tablet form . 
 the control group received 4.5 g / day placebo plus 1.5 g / day metformin . 
 body mass index ( bmi ) , fasting plasma glucose , urinary albumin - to - creatinine ratio , and complete blood count as well as antioxidant and inflammation indices such as tumor necrosis factor ( tnf)- , interleukin ( il)-6 , superoxide dismutase ( sod ) , malonaldehyde ( mda ) , glutathione peroxidase ( gpx ) , and high sensitivity c - reactive protein ( hs - crp ) levels were assessed at baseline and at different time points during the treatment.resultsall 112 patients , including 59 in the treatment group ( jytk + metformin ) and 52 controls ( metformin only ) completed the 26-week clinical trial . 
 jykt plus metformin treatment increased il-6 ( 36.4  11.5 ng / l ; p < 0.05 ) , tnf- ( 17.5  11.3 vs. 22.5  12.9 ng / l ; p < 0.05 ) , and mda ( 1.9  0.9 ; p < 0.05 ) levels compared to the control ( 2.2  0.6 mm / ml ) , whereas total sod level decreased ( 98.1  30.4 vs. 78.5  29.3 u / ml ; p < 0.05 ) . 
 there were no changes in gpx and hs - crp levels . 
 there were no adverse effects associated with jytk treatment.conclusionsjytk combined with metformin improves some antioxidant indices ( sod and mda ) , and decreases inflammation in patients with t2 dm , suggesting that it can reduce the risk of diabetic complications .