Progress in diabetes research in China

Authors

  • Guang NING,

    1. Shanghai Clinical Center for Endocrine and Metabolic Diseases and Division of Endocrine and Metabolic Diseases of E-Institutes of Shanghai Universities, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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  • Jie HONG,

    1. Shanghai Clinical Center for Endocrine and Metabolic Diseases and Division of Endocrine and Metabolic Diseases of E-Institutes of Shanghai Universities, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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  • Yufang BI,

    1. Shanghai Clinical Center for Endocrine and Metabolic Diseases and Division of Endocrine and Metabolic Diseases of E-Institutes of Shanghai Universities, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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  • Weiqiong GU,

    1. Shanghai Clinical Center for Endocrine and Metabolic Diseases and Division of Endocrine and Metabolic Diseases of E-Institutes of Shanghai Universities, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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  • Yifei ZHANG,

    1. Shanghai Clinical Center for Endocrine and Metabolic Diseases and Division of Endocrine and Metabolic Diseases of E-Institutes of Shanghai Universities, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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  • Zhiguo ZHANG,

    1. Shanghai Clinical Center for Endocrine and Metabolic Diseases and Division of Endocrine and Metabolic Diseases of E-Institutes of Shanghai Universities, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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  • Yun HUANG,

    1. Shanghai Clinical Center for Endocrine and Metabolic Diseases and Division of Endocrine and Metabolic Diseases of E-Institutes of Shanghai Universities, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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  • Weiqing WANG,

    1. Shanghai Clinical Center for Endocrine and Metabolic Diseases and Division of Endocrine and Metabolic Diseases of E-Institutes of Shanghai Universities, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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  • Xiaoying LI

    1. Shanghai Clinical Center for Endocrine and Metabolic Diseases and Division of Endocrine and Metabolic Diseases of E-Institutes of Shanghai Universities, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Guang Ning, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 RuiJin 2nd Road, Shanghai 200025, China.
Tel: +86 21 64370045, ext. 665344
Fax: +86 21 64373514
Email: guangning@medmail.com.cn

Abstract

The prevalence of diabetes, especially Type 2 diabetes mellitus (T2DM), is increasing markedly throughout the world, including in China. Because T2DM and its complications are associated with considerable socioeconomic burden and mortality, there is increasing interest in developing strategies to prevent or delay progression of the disease. In recent decades, many researchers have focused on the mechanism of onset of diabetes, as well as examining the benefits of various interventions in subjects with different glucose tolerance status to prevent or delay development of the disease. In the present article, we focus on five areas (epidemiology, early intervention, insulin sensitivity and β-cell function, adipocytokines, and traditional Chinese medicine) to review the progress of research into diabetes in China today. The prevalence of diabetes in China is one of the highest in the world. However, with lifestyle interventions and appropriate pharmacological therapies (including traditional Chinese medicine), T2DM may be prevented, well controlled, or even put into remission. Accurate estimation of insulin secretion and insulin sensitivity, as well as better characterization of the physiological function of adipocytokines, could give us a better understanding of the basic mechanisms underlying the onset of diabetes and could lead to better interventions in people with impaired glucose tolerance and T2DM.

Introduction

With social and cultural changes, the prevalence of diabetes in China is estimated to increase markedly from a prevalence of 4.3% among 20–79-year-old people in 2007 to increase to 5.6% in 2025.1 There is a long history of the treatment of Type 2 diabetes mellitus (T2DM) in China. In ancient China, T2DM was recognized as xiaokezheng (disease with symptomatic polydipsia) or xiaodanzheng (disease with symptomatic polydipsia and polyphagia). Because T2DM is associated with considerable socioeconomic burden and mortality, many studies have proposed strategies to prevent, delay, or cause remission of the disease and its associated cardiovascular complications. Furthermore, because both β-cell dysfunction and insulin resistance have proven to be potential mechanisms in the development of T2DM and can be demonstrated long before overt diabetes is diagnosed, the accurate estimation of insulin secretion, insulin sensitivity, and defining the physiological functions of adipocytokines could provide us with a better understanding of the basic mechanisms underlying the onset of the disease. In the present article, we focus on several areas to review the progress of research into diabetes in China today. Our aim is to provide a comprehensive review of the status of current research and to contribute to further progress in the determining appropriate treatment, as well as the underlying mechanisms, T2DM.

Epidemiology of diabetes in China

Following India, China has the highest number of people suffering from diabetes.2 It is well known that diabetes is a lifestyle-related disease. Rapid urbanization has occurred in China over the past two decades. Urbanization is associated with changes in a number of lifestyle factors, such as physical inactivity, an unhealthy diet, and obesity, all of which are implicated in the etiology of diabetes. In 1980, a study in 14 provinces throughout China indicated a prevalence of diabetes of 0.67%.3 The 1994 China National Diabetes Survey examination of 224 251 men and women aged 25–64 years yielded estimates of 2.5% for the prevalence of diabetes, almost fourfold higher figures reported in 1980.4 In 2002, the InterASIA study revealed that 5.2% of men and 5.8% of women in China aged between 35 and 74 years had diabetes.5 The age-standardized prevalence of diabetes was higher in northern China compared with southern China (7.4% vs 5.4%; P < 0.001; Fig. 1). Another example of the increase in the prevalence of diabetes in China is the industrial city of DaQing. A study comparing the prevalence of diabetes in 1986 and 1994 reported that the standardized prevalence rates of diabetes were 1.04% and 3.51%, respectively, a 3.4-fold increase over a period of 8 years.6

Figure 1.

 Prevalence of diabetes among Chinese men (bsl00001) and women (□) aged 35–74 years in (a) urban and (c) rural areas, as well as (b) northern and (d) southern China. Reproduced with permission from Gu et al.5

Compared with the reported prevalence of diabetes throughout China in these early studies, rates in Western populations were higher. For example, based on data from the National Health and Nutrition Examination Survey (NHANES) 1988–94,7 the prevalence of diabetes in the US in people aged ≥20 years was found to be 7.8%. Another large epidemiological study8 performed in Canada found that the prevalence of diabetes was 5.2%, almost twofold higher than that in China at the same time. Rapid increases in the prevalence of diabetes have also been detected in Western populations over the past two decades. Data from NHANES 1999–20029 revealed that 9.3% of the population in the US had diabetes. Meanwhile, Lipscombe et al.8 reported that in 2005 the prevalence of diabetes in Canada had increased to 8.8%.

A study of 31 Chinese provinces in 2000–1 reported that the age-standardized prevalence of diabetes was 1.5-fold higher among the urban population compared with the rural population (7.8% vs 5.1%, respectively).5 Another survey of the prevalence of diabetes conducted in 2002 in urban and rural Chinese populations in Qingdao indicated a higher prevalence of diabetes in urban versus rural areas (6.9% vs 5.6%, respectively).10 More specifically, a study of 9925 subjects aged 60 years and over found that the prevalence of diabetes in elderly subjects in metropolitan areas, middle cities, and what was termed 1st, 2nd, 3rd, and 4th country areas (defined on the basis of economic criteria, with 1st areas being the most affluent and 4th areas the least) was 17.0%, 11.4%, 4.9%, 4.7%, and 1.9%, respectively.11 In metropolitan areas, such as Shanghai, lifestyles have changed remarkably, with decreased physical activity and a greater intake of fats and rapidly absorbed carbohydrates. A study of 11 589 residents aged 15–74 years in urban and rural areas of Shanghai indicated that the prevalence of diabetes in these areas was 11.2% and 5.3%, respectively.12 An intermediate prevalence rate of 7.2% was found for people aged >15 years living in an urbanizing area, namely the Qingpu district in west Shanghai (Fig. 2),13 suggesting an important role for urbanization in the development of diabetes.

Figure 2.

 Prevalence of diabetes in urban, rural and urbanizing rural areas around Shanghai.

Several clinical studies in China have provided important information on the progression of diabetes. Previous studies have shown that the progression rate to diabetes among patients with impaired glucose tolerance (IGT) is approximately 7% per year.14 Jia et al.14 followed a group of 5628 randomly selected adults, aged 20–94 years, living in the Huayang and Caoyang communities in Shanghai from 1998–2001 to 2002–4. In 2002–4, 2666 adults underwent anthropometric measurements, blood biochemical analyses, and a 75 g oral glucose tolerance test (OGTT). The annual incidence of diabetes in subjects with normal glucose tolerance (NGT) and impaired glucose regulation (IGR) was 0.66% and 7.81%, respectively, with the latter group having a significantly higher likelihood of developing diabetes (P < 0.001). After 3 years, the cumulative incidence of diabetes and IGR was 4.96% and 11.10%, respectively. The cumulative incidence of developing isolated impaired fasting glucose (IFG), isolated IGT, and combined IGT in this population after 3 years was 1.46%, 8.76%, and 0.88%, respectively. In another study, Pan et al.15 collected data from 49 primary healthcare centers across five regions of China. Clinical information pertaining to 2248 diabetic patients was obtained. Mean glycosylated hemoglobin (HbA1c) was found to be 7.7 ± 1.7%, with only 25.9% of patients attaining optimal glycemic control (HbA1c <6.5%). The most frequent complication reported was neuropathy (36.2%), followed by cataracts (32.2%) and background retinopathy (23.2%). Most (62.0%) people with T2DM were overweight (BMI ≥23 kg/m2). Thus, there appears to be a general need for patients to undergo more intensive therapy to prevent the onset of late complications.

In addition to the important contribution of environmental factors, including changes in dietary patterns and lifestyle, genetic determinants also play a major role in susceptibility to T2DM. Over the past decade, considerable efforts have been made to identify genes that increase a person’s susceptibility to T2DM, but progress has been slower than anticipated. Although common variants have been replicated in a few genes, including PPARG, KCNJ11, and TCF7L2, in individuals of European ancestry,16–18 relatively few studies have been conducted in Chinese populations. In one such study, Xiang et al.19 found two regions on chromosomes 6q21-q23 and 1q21-q24 showing significant linkage to T2DM/impaired glucose homeostasis in a Chinese population, although these T2DM susceptibility loci have not been validated in other ethnic groups.

Recently, advances in genome-wide association studies have accelerated the discovery of diabetes susceptibility genes. Lin et al.,20 from the Institute for Nutritional Sciences, examined the associations between common variants in CDKAL1, CDKN2A/B, IGF2BP2, SLC30A8, HHEX/IDE, EXT2 and LOC387761 loci identified in genome-wide association studies with T2DM and diabetes-related phenotypes in 3210 unrelated Chinese Hans, including 424 subjects with T2DM, 878 with IFG, and 1908 with normal fasting glucose (NFG). The results indicated that in Chinese Hans, common variants in CDKAL1, CDKN2A/B, IGF2BP2, and SLC30A8 loci independently or additively contribute to the risk of T2DM, likely mediated through β-cell dysfunction.

Li et al.21 investigated associations between SLC30A8 and T2DM in a Chinese population and identified a significant association for the single nucleotide polymorphism (SNP) rs13266634 in combined T2DM/IGR and NGT subjects. The association was also observed separately for patients with T2DM and NGT controls. These results provided evidence that SLC30A8 is a susceptible locus for T2DM in the Chinese population and that variations in this gene can influence insulin secretion. Retinol-binding protein (RBP) 4 is a newly discovered adipokine that has a role in insulin resistance and obesity.22 In their study, Jia et al.22 suggested that genetic variants in the RBP4 gene may be associated with circulating RBP4 concentrations and phenotypes related to glucose metabolism. Hepatocyte nuclear factor (HNF) 1β is a transcription factor that is critical for pancreatic cell formation and glucose homeostasis and Jia et al.23 reported that variations in the HNF1β region were associated with T2DM in Chinese. In another study, Jia et al.24 identified a novel risk-conferring G6PC2 SNP for T2DM in a Chinese population and confirmed previous findings that G6PC2 variants are associated with fasting plasma glucose concentration.25 It is believed that G6PC2 may be involved in the glucose phosphorylation pathway.25 Finally, two genome-wide association studies in east Asian populations added KCNQ1 to the list of T2DM susceptibility genes.26,27 The association between KCNQ1 and T2DM susceptibility in Chinese populations was validated by He et al.28 and Jia et al.29 In addition, Jia et al.29 also found that KCNQ1 had an effect on β-cell function. These T2DM susceptibility loci need to be confirmed in populations from other ethnic groups.

Early intervention in IGT or newly diagnosed T2DM

Some studies have demonstrated that the contribution of postprandial hyperglycemia to HbA1c levels is greatest in individuals in the early stages of hyperglycemia or when diabetes is relatively well controlled. A potential explanation for this is that postprandial hyperglycemia may be dominant in prediabetic individuals.30,31

Thus, several prospective studies in China have focused on comparing the effects of different interventions on the prevention of T2DM in people with IGT or the recovery of β-cell function in newly diagnosed T2DM patients (Table 1).32–37 The Chinese DaQing diabetes prevention study,32,33 a 20-year follow-up study, demonstrated the effects of diet and exercise in preventing T2DM in people with IGT, with the combined lifestyle interventions (diet only, exercise only, and diet plus exercise) leading to a 51% lower incidence of T2DM during the 6 year intervention and a 43% lower incidence of T2DM over the 20 year period compared with the control group. These results demonstrate that a group-based lifestyle intervention over 6 years produces a long-lasting reduction in the incidence of T2DM for up to 14 years after the intervention. During the entire study period, there were 145 strokes, 66 myocardial infarctions, and 142 deaths, of which 68 were attributed to cardiovascular disease. There was a trend for a reduction in cardiovascular events and all-cause mortality in the study that did not reach statistical significance, perhaps due to the relatively low statistical power of the trial in addressing these endpoints.

Table 1.   Efficacy of different interventions in Chinese subjects with impaired glucose tolerance or newly diagnosed Type 2 diabetes mellitus
ReferenceStudy designPurposeStudy subjectsInterventionDurationResultsConclusions
  1. IGT, impaired glucose tolerance; T2DM, Type 2 diabetes mellitus; FBG, fasting blood glucose; PBG, postprandial blood glucose; R, randomized; DB, double blind; PC, placebo controlled; PMS, post-marketing surveillance; CDQDPS, China Da Qing Diabetes Prevention study; MDI, multiple daily insulin injection; CSII, continuous subcutaneous insulin infusion; OHA, oral hypoglycemic agent.

Wang et al.23n = 321; open-label, prospective studyTo assess the effects of different interventions in Chinese subjects with IGTIGTFour arm: Group I, control; Group II, lifestyle intervention; Group III, acarbose 50 mg, t.i.d. p.o.; Group IV, metformin 0.25 g, t.i.d. p.o.3 yearsAnnual diabetes incidence 11.6% in the control group cf. 8.2% in the lifestyle group (P = 0.0928), 2% in the acarbose group (P = 0.0001), and 4.1% in metformin group (P = 0.0002)Pharmacological intervention with acarbose or metformin significantly decreased the incidence of diabetes in an IGT population
Hu et al.24n = 261; R, DB, PC studyTo assess the effects of acarbose in Chinese subjects with IGTIGTTwo arms (1:1 ratio): Group I, acarbose 50 mg, t.i.d. p.o; Group II, placebo16 weeksAcarbose reduced 2-h PBG concentrations by 12% (P = 0.0001) and insulin concentrations by 26% (P < 0.01)
The number of patients who developed T2DM was assessed as a secondary parameter, but there was a non-significant trend in favor of acarbose (n = 7 in the acarbose group and n = 12 in the placebo group)
Acarbose is efficacious in improving glucose status in individuals with IGT
Yasuda et al.26n = 2548; open-label prospective PMS studyTo assess the efficacy, safety, and acceptance of acarbose in Chinese subjects with T2DM or IGT in daily clinical practiceIGT (11.8%) and T2DM (88.2%)One arm: acarbose 50–100 mg, t.i.d. p.o. (150–300 mg/day; mean dose 159.4 mg/day)Mean 13.9 weeksIn T2DM patients, HbA1c was reduced by 1.4%, FBG by 42.1 mg/dL, and 2-h PBG by 98.9 mg/dL
In IGT patients, HbA1c was reduced by 0.9%, FBG by 11.8 mg/dL, and 2-h PBG by 42.9 mg/dL
Acarbose was efficacious and safe in Chinese patients with T2DM and IGT under day-to-day treatment conditions
Hu et al.22n = 577; open-label, R, prospective study, with a 20-year follow-up study of the CDQDPS To assess whether intensive lifestyle intervention (for 6 years) has a long-term (14 years after the intervention) effect on the risk of diabetes, diabetes-related complications and mortality in Chinese subjects with IGTIGTFour arms: Group I, control; Group II, diet intervention; Group III, exercise intervention; Group IV, diet plus exercise intervention20 years (active intervention took place over 6 years; the follow-up study took place 14 years after the intervention)When Groups I, II, and III were considered as whole, combined lifestyle intervention resulted in a 51% lower incidence of T2DM during the 6-year intervention and a 43% lower incidence of T2DM over the 20-year period compared with the control group
No significance was found between the intervention and control groups in the rate of first CVD events and all-cause mortality
Group-based lifestyle intervention over 6 years produced a lon-lasting reduction in the incidence of T2DM for up to 14 years after the intervention Whether lifestyle intervention leads to a reduction of CVD and mortality remains unknown
Unoki et al.27n = 382; open, R, prospective studyTo assess the efficacy of short-term intensive insulin therapy (MDI and CSII) compared with OHAs on glycaemic control, remission rate, and β-cell function in patients with newly diagnosed T2DMNewly diagnosed T2DMThree arms: Group I, MDI; Group II, CSII; Group III, OHAShort intensive therapy was stopped after normoglycemia was maintained for 2 weeks
Patients were then followed-up on diet and exercise alone for 1 year
Remission rates after 1 year were significantly higher in the CSII (51.1%) and MDI (44.9%) groups than in the OHA group (26.7%; P = 0.0012)
Among the remission groups, the increase in the acute insulin response was maintained after 1 year in the CSII (P = 0.235) and MDI (P = 0.063) groups, but declined significantly in the OHA group (P < 0.0001)
Early intensive insulin intervention in newly diagnosed T2DM patients has favorable outcomes with regard to the recovery and maintenance of β-cell function and prolonged glycemic remission compared with treatment with OHAs

Although lifestyle modifications such as diet and exercise have been recommended as first-line interventions in IGT subjects, pharmacological therapies may also be considered for those who fail to obtain ideal glucose levels through lifestyle modification. Yang et al.34 performed an open-label prospective study at five centers throughout China to assess the effects of different interventions (control, lifestyle intervention, acarbose, and metformin) in subjects with IGT. After a 3-year intervention, the annual incidence of diabetes was 11.6% in the control group, 8.2% in the lifestyle group (P = 0.0928), 2% in the acarbose group (P = 0.0001), and 4.1% in the metformin group (P = 0.0002). Pan et al.35 also performed a randomized double-blind placebo-controlled study in 261 IGT subjects confirming that intervention with acarbose in people with IGT could significantly reduce 2-h postprandial blood glucose (PBG) and insulin concentrations. Their results were also confirmed by a post-marketing surveillance (PMS) study of 2548 subjects with IGT or T2DM.36 Thus, pharmacological intervention with acarbose is efficacious in improving the glycemic status of individuals with IGT.

Early intensive insulin therapy in patients with newly diagnosed T2DM may improve β-cell function and result in extended glycemic remissions. Weng et al.37 performed a multicenter randomized trial to compare the effects of transient intensive insulin therapy with those of oral hypoglycemic agents (OHA) on β-cell function and diabetes remission rate. The study randomized 382 patients newly diagnosed with T2DM to continuous subcutaneous insulin infusion (CSII), multiple daily insulin (MDI), or OHA. Immediately after the treatment period, the acute insulin response was partly restored, β-cell function was significantly increased, and insulin resistance was significantly decreased in all patients (P < 0.0001). A year after stopping therapy, the remission rate was 42% among those who reached normal blood glucose levels during the treatment period. Remission rates were 51.1% among those treated with CSII, 44.9% among those treated with MDI, and only 26.7% in the group treated with OHA.37 The risk of relapse was reduced by 44% with CSII and by 31% with MDI compared with the risk of relapse associated with the use of OHAs, reductions that were significant at P = 0.001 and P = 0.032, respectively. These data suggest that the use of intensive insulin therapy early in the course of the disease warrants further clinical investigation.

Treatment of T2DM with traditional Chinese medicine

In the traditional Chinese medicine (TCM) system, according to its clinical symptoms, T2DM is classified as xiaokezheng (disease with symptomatic polydipsia) or xiaodanzheng (disease with symptomatic polydipsia and polyphagia), both of which mean diabetes.38 TCM has a long history in treatment of Xiaoke (polydipsia). Many Chinese herbal medicines are prescribed by physicians to treat diabetes. Some classical prescriptions and folk remedies with outstanding curative effect have been in use for hundreds of years and some have been developed into modern medicinal preparations for the treatment of diabetes with evidence of therapeutic effects. A large body of research has evaluated the effects of these medicines and their chemical constituents, including experimental and clinical investigations.

Compound formulae (Fufang)

Most remedies in TCM are used preferentially as combinations. Fufang is comprised of many different herbs. The selection of the compound formulae, or fufang, is based on the holistic philosophy of TCM and follows the rule of drug synergism and compatibility.39 The key to Chinese herbal medicine is to choose a combination of plant species based on the particular symptoms and characteristics of the patient and guided by the various theories of TCM.40

β-Cell dysfunction has an important role in the pathological progress of diabetes, especially in T2DM. Many Chinese herbs contain ingredients such as polysaccharides and saponins, which may improve impaired immune system function or have antioxidant properties. Perhaps for this reason, some tradition herbal medicines and their combinations have been reported to protect the pancreatic islets and β-cells.41,42

Shen-qi Jiangtang granules are comprised of ginseng, milkvetch root, common yam rhizome coptis root, and a number of other substances. Of these, ginseng and milkvetch root are rich in polysaccharides and ginseng further contains a number of saponins. A clinical study of the hypoglycemic efficacy of Shen-qi Jiangtang granula was performed at the Zaozhuang Fourth Hospital. Sixty diabetic patients treated with Shen-qi exhibited significant lowering of plasma glucose concentrations in a 3-h OGTT, whereas plasma insulin and C peptide levels increased markedly.41 In a 14-day study of streptozotocin (STZ)-induced diabetic Sprague-Dawley rats, Shen-qi significantly increased plasma malondialdehyde levels and superoxide dismutase levels in pancreatic homogenates, as well as reducing blood glucose concentrations.42

Insulin resistance is central to metabolic syndrome and can lead to T2DM. Many TCM reduce insulin resistance. For example, Jin-qi, a combination of honeysuckle flower, milkvetch root, and coptis root, was evaluated by Li et al.43 in a clinical investigation in 2003 in Beijing Fengtai Hospital, in which a total of 100 patients with T2DM participated. The clinical dose was seven tablets of Jin-qi per dose, administered three times daily. The sulfonylurea glipizide was administered to the control group and a combination treatment group was also evaluated. After treatment, 2-h PBG was significantly decreased in both the Jin-qi and glipizide groups, and insulin sensitivity was also improved with Jin-qi.43

Traditional Chinese herbal medicines and their compound recipes, although appearing less effective than existing drugs, tend to have fewer side-effects and may significantly postpone or alleviate diabetic complications. Some TCMs appear to be effective for both controlling hyperglycemia and improving diabetic complications. For example, Tang-shen ning reduces levels both of HbA1c and urinary albumin in patients with diabetic nephropathy.44 Another compound recipe, Jin-Mai-Tong, has been shown to significantly improve diabetic peripheral neuropathy by Liang et al.,45 who treated STZ-diabetic rats with 22.5 g/kg per day Jin-Mai-Tong intragastrically for 8 weeks. Compared with a group receiving amino guanidine, sciatic nerve conduction velocity (NCV) increased in the Jin-Mai-Tong-treated group, whereas sorbitol and aldose reductase concentrations in the sciatic nerve decreased significantly. The improvement in NCV was closely associated with the decreased accumulation of sorbitol.

Although a number of traditional Chinese herbal medicines have been reported to have antidiabetic effects, the molecular targets of these compounds have not been elucidated and a careful analysis of their mode of action has not been undertaken. These may offer considerable promise as lead compounds that may improve diabetes and obesity.

Ginseng

Panax ginseng C. A. Meyer shows promising results in the treatment of diabetes.46,47 Ginseng has been used in China as a tonic for hundreds of years. In the Chinese traditional medical treatment of diabetes, ginseng is incorporated in many prescriptions. The main active agents in P. ginseng are ginsenosides, which are triterpene saponins.48

Shang et al.49 found that with standard differentiation inducers, ginsenoside Rb1, the most abundant ginsenoside in ginseng root, facilitated adipogenesis of 3T3-L1 preadipocytes. After treatment of differentiating adipocytes with Rb1, basal and insulin-mediated glucose uptake was significantly augmented, accompanied by upregulation of mRNA and protein levels of the glucose transporter GLUT4.49 These data indicate that the antidiabetic and insulin-sensitizing activities of the ginsenoside Rb1 are involved, at least in part, in the enhancing effect on peroxisome proliferator-activated receptor (PPAR) γ2 and CCAAT box enhancer binding protein (C/EBP) α expression, hence promoting adipogenesis.

Previous studies have demonstrated that ginsenoside Re, one of the active compounds in ginseng, has a significant antihyperglycemic effect.50,51 Zhang et al.52 investigated the mechanism by which Re reduced insulin resistance in 3T3-L1 adipocytes, as well as in rats fed a high-fat diet (HFD) to determine its antihyperglycemic mechanism of action. It was found that Re increased glucose uptake in 3T3-L1 cells and the glucose infusion rate, determined by clamp, in HFD rats. Activation of insulin signaling by Re is initiated at insulin receptor substrate (IRS)-1 and further passes on through phosphatidylinositol 3-kinase and downstream signaling cascades. Moreover, Re markedly suppressed c-Jun N-terminal kinase (JNK) and nuclear factor-κB activation.52

Berberine

Berberine (BBR), derived from the Chinese herb Coptis, has been reported to have beneficial effects in T2DM and hyperlipidemia.53–56 Lee et al.54 showed that in vivo administration of BBR has a insulin sensitizing effect, as well as weight- and lipid-lowering actions, in both db/db mice and HFD rats. Of note, BBR acutely stimulated AMP-activated protein kinase (AMPK) activity as its target in both myotubes and adipocytes in vitro, contributing to enhanced GLUT4 translocation in myotubes and reducing adipocyte lipid mass.54

Kong et al.55 administered BBR to hypercholesterolemic patients, as well to hyperlipidemic hamsters. These authors demonstrated a reduction in total and low-density lipoprotein (LDL)–cholesterol, with increased hepatic LDL receptor mRNA and protein levels independent of sterol regulatory element binding protein, that was dependent on extracellular signal-regulated kinase (ERK) activation, suggesting that the mechanism of action of BBR may be complementary to that of statin drugs.

Recently Zhang et al.56 evaluated the efficacy and safety of BBR in the treatment of hyperglycemia and dyslipidemia in 116 newly diagnosed patients with T2DM and dyslipidemia randomly allocated to BBR 1.0 g daily versus placebo for 3 months. In that study, BBR showed a robust glucose-lowering effect, reducing fasting and postprandial plasma glucose by 1.4 and 3.1 mmol/L, respectively, at 3 months. In addition, HbA1c decreased from 7.5% to 6.6%. Total cholesterol, LDL–cholesterol, and triglyceride levels decreased by 18%, 21%, and 36%, respectively. A euglycemic hyperinsulinemic clamp test was performed in 54 randomly selected patients for assessment of insulin sensitivity and indicated a significant increase in insulin action.56

Conclusions

In recent decades, considerable progress has been made in the epidemiology and treatment of diabetes in China. The prevalence of diabetes in China is one of the highest in the world. However, with lifestyle interventions and appropriate pharmacological therapies, T2DM may be prevented, controlled, and put into remission. There are considerable advantages in the use of TCM in the treatment of T2DM, although the mechanisms of action need to be clarified, as do the interactions between various active compounds. More accurate clinical trials are also needed to confirm the efficacy of these agents in patients with T2DM.

Acknowledgments

The authors’ work reported herein was was supported by grants from the Shanghai Municipal Science and Technical Commission (No. 07JC14042), National Natural Science Foundation of China (No. 30700383 and 30725037) and the Shanghai Municipal Education Commission (No. 24119054).

Disclosure

The authors declare that they have no conflicts of interest.

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