diabetes mellitus ( dm ) is a complex , chronic , and common disease . according to the international diabetes federation ( idf ) , approximately 415 million people suffer from dm worldwide , and the number is predicted to increase to nearly 642.6 million by 2040 . diabetes is prevalent in china , with 109.6 million people afflicted with the disease , ranking it first in the world . diabetes - related medical expenses in china were $ 51 billion in 2015 , which is a huge burden on the country 's health care system . diabetic microvascular complications commonly occur with dm , including diabetic nephropathy ( dn ) , diabetic peripheral neuropathy ( dpn ) , and diabetic retinopathy ( dr ) . due to the lack of early diagnostic markers , diabetic microvascular complications come to attention after the symptoms appear , and the prevention and the targeted therapeutic intervention of western medicine is very limited [ 4 , 5 ] . the multifactorial risk - reduction strategies of diabetic microvascular complications include addressing blood sugar and lipid control , weight management , and healthy lifestyle changes [ 68 ] . nevertheless , more than two - thirds of the patients still do not meet the targets for glycemic goal of hba1c < 7.0% in china , which can lead to the increased risk of microvascular complications . approximately 2040% of patients with type 2 diabetes ( t2 dm ) suffer from diabetic nephropathy , which is the leading cause of end - stage renal disease [ 10 , 11 ] . ace inhibitors   and arbs [ 13 , 14 ] have demonstrated the ability to protect renal function of dn but are not enough to retard the progression , and they are not recommended for the primary prevention of dn in patients who have normal blood pressure and normal uacr . laser photocoagulation therapy [ 16 , 17 ] and antivascular endothelial growth factor ( vegf ) therapy [ 18 , 19 ] are indicated for diabetic macular edema . both are beneficial in reducing the risk of further visual loss but generally not beneficial in reversing already diminished acuity . neuropathic pain is a typical clinical symptom , which can reduce the quality of life and limit patients ' mobility , and drugs have only been approved specifically for the relief the neuropathic pain [ 23 , 24 ] , not to reverse neuronal loss [ 25 , 26 ] . tcm has a 2,000-year history in treating dm and its complications in patients in china . in recent years , chinese medicine has made a breakthrough in the treatment theory of diabetes ; significant evidence exists which supports the thought that tcm interventions can independently treat diabetes [ 2830 ] , and numerous studies have demonstrated that traditional chinese blood circulation activating drugs have obvious advantages in the prevention and treatment of diabetic microvascular complications [ 3133 ] . , we introduced the relevant mechanisms of the traditional chinese blood circulation activating drugs on the treatment of diabetic microvascular complications based on the clinical and experimental studies . blood stasis is one of the important pathological concepts in traditional chinese medicine , which is generally a significant pathological product due to the disorder of blood circulation . the leading causes of blood stasis include qi deficiency , qi stagnation , and cold retention . the blood stasis syndrome is characterized by symptoms such as pain in a fixed position , nyctalgia , dark - purple coloring of the tongue or face , infraorbital darkness , sublingual varicosis , blood spots under the skin or tongue , or an astringent pulse that can manifest . researchers reported that high glucose environment causes the blood circulation obstacle and leads to blood stasis , and blood stasis is the core pathogenesis of microvascular complications [ 37 , 38 ] . promoting blood circulation to remove blood stasis is the main treatment principle . as many complications of diabetes usually take years to develop before becoming clinically apparent , experts believe that the blood stasis not only is in the end stage but also exists throughout the course of the disease . zhou et al .   proposed the luo disease (  ) theory and promoted the use of blood circulation activating drugs together with hypoglycemic agents at the beginning and through the duration of the treatment . blood stasis syndrome is similar to western medicine 's disturbance of microcirculation in which blood viscosity increases and causes blood coagulation . these pathological changes in the occurrence and development of the diabetes process have been confirmed . therefore , modern research provides a basis for the treatment of microvascular complications with the method of promoting blood circulation and removing blood stasis . the representative herbs and their application in microvascular complications , as well as proposed mechanisms of action and efficacy for treating diabetes , are described in table 1 . qi deficiency and blood stasis are the core pathogenesis of dn ; invigorating qi and promoting blood circulation herbs can reduce the diabetic nephropathy proteinuria , protect renal function , and delay the progress of dn . .   carried out a multicenter randomized , double - blind , placebo - controlled trial and reported that , based on conventional treatment with aceis or arbs , tangshen formula ( including notoginseng radix ) provided additional benefits in decreasing proteinuria and improving egfr in dn patients with macroalbuminuria . tian 's group retrospectively analyzed clinical outpatient medical records of dn and reported that didang formula ( including leeches and s. miltiorrhiza ) showed beneficial effects on the reduction of proteinuria and delaying the progression of dn . multiple clinical research teams [ 4749 ] confirmed that , in the routine treatment with western medicine , application of the kidney nourishing and blood activating formula ( including notoginseng radix , s. miltiorrhiza ) combined with enalapril   or irbesartan   to treat dn patients , had better efficacy in controlling blood glucose , blood lipid , urine albumin excretion rate ( uaer ) , serum creatinine ( scr ) , and 24-hour urinary protein quantity compared with the simple western medicine group . dr is caused by microangiopathy and capillary closure , which results in the breakdown of the blood - retinal barrier with retinal hemorrhage , exudate and edema formation , and macular edema . the improvement of ischemia and the protection of normal microvasculature in retinal tissue by blood circulation activating traditional chinese drugs , which can save the visual acuity and inhibit progression of dr patients , have been confirmed . lian et al .   reported that , compared with the placebo , compound danshen dripping pill ( cddp , consisting of salvia miltiorrhiza , panax pseudoginseng var . notoginseng , and dryobalanops aromatica gaertn.f . ) has definite efficacy in fluorescence fundus angiography ( ffa ) and funduscopic examination parameters for treating nonproliferative diabetic retinopathy ( npdr ) . luo et al .   reported that cddp has similar improvement and safety profiles to calcium dobesilate for npdr in 57 type 2 diabetes cases . in future dr treatments luo et al .   reported that qiming granule ( including typhae and leeches ) can reduce the retinal blood circulation time ( avct ) and arm - to - retinal circulation time ( arct ) , which may alleviate retinal hypoxia and ischemia by increasing retinal blood flow and improving blood circulation . the most common symptoms of dpn are induced by the extremity blood microcirculation disorder , including pain , dysesthesias ( unpleasant abnormal sensations of burning and tingling ) , and numbness . the main treatment principle of tcm is supplementing qi and activating blood circulation ; a number of interventions have been demonstrated to reduce the risk and slow the progression of dpn . reported a successful treatment case of dpn pain using a high dose of the traditional chinese medicine , huangqi guizhi wuwu tang ( including astragalus , cassia twig , and spatholobi ) in combination with aconitum . qi and yu   reported that the use of mudan granule ( containing ligusticum chuanxiong , salvia miltiorrhiza , hematoxylin , suberect spatholobus stem , and notoginseng radix ) combined with methylcobalamin can improve nerve conduction velocity and reduce the pain of pdpn . a clinical study found that danggui sini tang ( including angelica ) can help improve the conduction velocity of the common peroneal nerve in dpn treatment . observed that tangluoning ( tln ) can improve the nerve conductive velocity and clinical symptoms in dpn patients and the therapeutic mechanism may be induced by antioxidative effect . it is generally believed that hyperglycemia - induced oxidative stress is the important common mechanism , thus leading to further activation of the polyol pathway , nonenzymatic glycosylation , protein kinase c ( pkc ) , and the hexosamine pathway , which eventually lead to chronic microvascular complications . in addition , microvascular complications are associated with vascular endothelial dysfunction , blood coagulation , and abnormalities of fibrinolytic system activity . blood circulation activating drugs could be effective in these fields as natural supplementary medicines to complex , multilink , and multitarget drugs ( figure 1 ) . high glucose induces injury to vascular endothelial cells , which leads to progressive thickening of the basement membrane and obstruction of the involved microvascular , thus resulting in tissue hypoxia and increased lesions . patients with more vascular endothelial cells and a higher level of plasma endothelin have more incidences of getting microvascular diseases . blood circulation activating drugs can protect the function of vascular endothelial cells and the basement membrane so as to prevent and treat diabetic microvascular complications . some researchers used the diabetic injury of human umbilical vein endothelial cells ( huvecs ) as a model and found that jiawei taohe chengqi decoction ( including peach kernel ) through the regulation of dimensional protein plasminogen activator inhibitor-1 ( pai-1 ) improved vascular endothelial function . xuefu zhuyu decoction ( including carthamus tinctorius l. , angelica sinensis , peach kernel , and ligusticum wallichii ) can protect the endothelial function by improving the dpn 's ischemia and hypoxia state and regulating the microcirculation disturbance . ( including angelica sinensis , radix paeoniae rubra , ligusticum wallichii , carthamus tinctorius l. , and peach kernel ) can improve diabetic endothelial dysfunction and slow vascular cell proliferation at the systematic and local ocular level and improve microcirculation and the ability of tissue to be oxygen resistant [ 74 , 75 ] . microvascular hemodynamic changes are an early sign of diabetic microvascular disease . in the early stage of diabetes , there is an increase in blood flow and high perfusion in the kidney , retina , and other tissues . due to the increase in microvascular permeability , the protein can seep out and deposit in the vascular wall causing microvascular thrombosis and occlusion , which results in serious overall circulation damage . salvia miltiorrhiza can protect stz - induced diabetes rats from developing diabetic nephropathy , by suppressing the overexpressions of tgf-1 , ctgf , pai-1 , and fn in the renal cortex . leeches can improve renal hyperfiltration and high perfusion of dn rats in the first stage ; the mechanism may work through the downregulation of endothelial endothelin-1 ( et-1 ) expression . huang et al .   used ginkgo biloba extract ( egb761 ) to treat t2 dm patients for 3 months ; the results showed that diabetic patients ' blood coagulation degree was obviously decreased , erythrocyte binding capacity was enhanced , and retinal capillary blood flow velocity was significantly accelerated . red blood cell aggregation increased in patients with diabetes , showing a high coagulation state and abnormal release of oxygen . high platelet adhesion , abnormal anticoagulation , and blood viscosity increased , resulting in luminal stenosis and microcirculation , which work together to promote the occurrence of microvascular lesions . studies have shown that blood circulation activating drugs such as ligusticum chuanxiong and typhae pollen   and blood circulation activating formulas , including buyang huangwu formula , danggui sini formula , huangqi guizhi formula , and danhong injection , which can reduce blood viscosity , improve the high coagulation and high viscosity state . these prescriptions showed the effect of invigorating blood and hemostasis by ameliorating the abnormal hemorheological parameters and improving microcirculation , promoting oxygen and energy metabolism , and relieving clinical symptoms . oxidative stress is an imbalance between oxidation and antioxidation , an increase in ros and oxygen free radicals in vivo , which is considered to be an important factor leading to aging and disease [ 88 , 89 ] . ceriello and motz   proposed that oxidative stress is the common basis of insulin resistance , diabetes , and cardiovascular disease . according to the common mechanism of diabetic complications , it suggests that the damage to endothelial cells by oxidative stress is the common upstream mechanism of hyperglycemia - related vascular diseases . researches revealed that panax notoginseng [ 68 , 91 ] , curcumin , s. miltiorrhiza , tongluo formula   ( including ginseng , leech , scorpion , and centipede ) , huangqi guizhi formula , danzhi jiangtang capsule ( including leech ) [ 95 , 96 ] , and honghua injection   have antioxidative effects on the treatment of diabetic vascular complications . the main mechanisms reduce malondialdehyde content and increase superoxide dismutase activities to protect the vascular endothelial cells . these antioxidative effects improve microcirculation disturbance , thereby increasing blood flow to remove blood stasis . antioxidant therapy has become another new way to prevent and cure diabetes mellitus and its complications . sustained hyperglycemia could cause a variety of nonenzymatic glycation of proteins and ultimately form advanced glycation end products ( ages ) . the ages could bind to the specific receptors of mesangial cells , endothelial cells , and so forth via affecting the extracellular matrix , changing the intracellular signaling conduction , and then altering the structure and function of proteins in targeted organizations . studies showed that salvia miltiorrhiza , leech , rhizoma chuanxiong , radix notoginseng , and so forth can block the formation of ages and lead to the inhibition of the activation of pathways conducted by rage , thereby inhibiting activation of pathways , including erk1/2 , p38 , jak stat , and pi3k . these herb medicines can also downregulate the expression of ros by inhibiting the activation of nadh / nadph pathway , which result in the downregulation of vascular injury proteins and cytokines . according to the abovementioned multitarget mechanisms , the principle of promoting blood circulation by removing blood stasis became an important tool in the treatment of diabetic vascular complications . lipid toxicity is an independent risk factor for the onset of t2 dm   and lipid metabolic disorder plays an important role in diabetic microvascular complications . elevated free fatty acid ( ffa ) levels could lead to the damage of blood vessel endothelium [ 105 , 106 ] and also change the permeability basement membrane in endothelial cells , which result in the thickness of vascular intima . patients with t2 dm are sensitive to fatty acids metabolism and lipid peroxidation , which leads to the increased formation of free radicals and lipid peroxide and the damage of the normal structure of the subcellular membrane in the cell nucleus . blood circulation activating drugs showed an antihyperlipidemic effect on lowering the levels of total cholesterol ( cho ) , triglyceride ( tg ) , and ffa , improving the secretion function of  cells , which has been observed in both animals and humans [ 108 , 109 ] . clinical studies found that ginkgo biloba leaves extract tablets can regulate blood lipid metabolism and reduce lipid toxicity in patients with early t2 dm . mudan granules can improve blood glucose and blood lipids and reduce blood viscosity of dnp patients , which improves nerve conduction velocity and oxidative stress . impaired endothelium dependent vascular relaxation ( edvr ) plays an important role in the development of diabetic microvascular diseases . t2 dm and other metabolic abnormalities can enhance oxidative stress , induce nitric oxide inactivation , which results in reduced endothelial no production , and release a large number of oxygen free radicals and prostaglandin resulting in vascular diastolic dysfunction . studies showed that ligustrazine could improve the edvr of diabetic rats and rhubarb can reduce plasma endothelin-1 ( et-1 ) and increase the role of no in diabetic rats , which can protect the edvr , and inhibit icam-1 and vcam-1 expression in the thoracic aorta . the treatment of dm and its complications mainly depends on western drugs , but sometimes the clinical efficacy is far from satisfactory because of the failure to delay the progression of diabetic complications . tcm plays an important role in the treatment of dm and its complications in china via diverse ways . we confirm that the blood circulation activating drugs , both compound and formula , have a certain effect on the prevention and the treatment of dm - induced microvascular complications . more specifically , tcm herbs influenced not only blood glucose but also the microvascular environment and some signal pathways . further analysis of the blood circulation activating drugs salvia miltiorrhiza , p. notoginseng , typhae pollen , angelica sinensis , ligusticum wallichii , carthamus tinctorius l. , caulis spatholobi , leech , and so forth shows that certain kinds of tcm compounds , which have different roles in treating and preventing the microvascular complications , could have multiple effects in the treatment of the disease . treatment based on syndrome differentiation ( zheng ) is a basic rule of tcm treatment . according to the principle , the main syndrome patterns at the end stage of diabetic microvascular complications can be divided into qi deficiency with blood stasis (  ) , yin deficiency with blood stasis due to cold (  ) , and phlegm with blood stasis (  ) . these herbs need to be cataloged and cooperated with other drugs according to patients ' tcm zhengs . the tonified medicines radix codonopsis , radix ginseng , and astragali preparata are used to treat the qi deficiency zheng , while radix rehmanniae and radix trichosanthis relieve the yin deficiency zheng . significant evidences exist that support a range of tcm interventions to improve the diabetes outcomes . blood circulation activating drugs are critical to prevent acute complications and reduce the risk of long - term complications . however , most of the evidence - based researches were carried out in asian countries , and further studies should be performed in other continents so as to account for the population - dependent variation of efficacy and confirm the universality of the benefits of these drugs . above all , it is worth a further study to figure out the relationship and biochemical mechanism of different catalogs of tcm herbs in treating diabetic complications . with the rapid development of technology , tcm will play a more important role in complementary and alternative therapies for dm .
traditional chinese medicine ( tcm ) is an important complementary strategy for treating diabetes mellitus ( dm ) in china . 
 traditional chinese blood circulation activating drugs are intended to guide an overall approach to the prevention and treatment of microvascular complications of dm . 
 the core mechanism is related to the protection of the vascular endothelium and the basement membrane . here , we reviewed the scientific evidence underpinning the use of blood circulation activating drugs to prevent and treat dm - induced microvascular complications , including diabetic nephropathy ( dn ) , diabetic peripheral neuropathy ( dpn ) , and diabetic retinopathy ( dr ) 
 . furthermore , we summarized the effects and mechanism of tcm on improving blood rheology , inhibiting aggregation of platelet , forming advanced glycation end products ( ages ) , regulating oxidative stress , reducing blood fat , and improving lipid metabolism . 
 the paper provides a new theoretical basis for the clinical practice of tcm in the prevention and treatment of dm and its microvascular complications .