[Enzymological Studies on the Mechanisms of Pathogenesis of Diabetic Complications].

　Aldose reductase (AR) is involved in the pathogenesis of complications in diabetes. In this study, the enzymatic properties of AR isolated from various sources and a recombinant human AR (rh-AR) were analyzed in detail. The sensitivity of different forms of AR to several AR inhibitors (ARIs) was compared. Our findings enabled us to propose that human AR should be used as the target enzyme in the development of ARIs. An enzyme-linked immunosorbent assay (ELISA) for human AR which employed monoclonal antibodies against rh-AR was created, and this method was used to demonstrate the distribution of AR in human tissues. AR was widely distributed in various organs and blood cell components. The levels of erythrocyte AR (e-AR) were 10.1±1.9 ng/mg Hb and 10.5±3.0 ng/mg Hb in healthy volunteers and diabetic patients, respectively, and thus there was no significant difference between them. The e-AR levels of diabetic patients were assayed using the ELISA developed to investigate the potential correlation between AR levels and the onset of diabetic complications. There were significant correlations between the incidence of diabetic neuropathy and e-AR levels in patients with disease duration of less than 10 years, and between the incidence of diabetic retinopathy and e-AR levels in patients with disease duration of 10-20 years. Our results suggest that measurement of e-AR levels in patients could help optimize drug therapy with ARIs and be a useful method to predict the onset of complications due to the upregulation of the polyol pathway.

The effect of care intervention for obese patients with type II diabetes.

The incidence of type II diabetes mellitus (T2DM) is increasing worldwide and affecting the quality of people's life. This study was designed to evaluate the effect of care intervention on body weight and glycemic parameters in obese T2DM patients.One hundred twenty-six obese T2DM cases were randomly divided into 2 groups. Patients in control group received conventional care, while patients in the intervention group received dietary, exercise, and psychology interventions on the basis of conventional care. Twelve months follow-up was performed to compare the changes of body weight and glycemic parameters in the 2 groups.There were 119 patients completing the research, 60 in the intervention group and 59 in control group. The levels of fasting plasma glucose (FPG), 2 hours postprandial blood glucose (PBG2 h), hemoglobin A1c (HbA1c), and aldose reductase (AR) were all significantly decreased (all, P < .05) in intervention group compared with the control group after 12 months follow-up. Moreover, the body weight and BMI (body mass index) were also significantly reduced in intervention group, and the weight loss was significantly higher in intervention group than that in control group during the follow-up.To implement care intervention for obese T2DM patients could strengthen the management of blood glucose, reduce body weight and complications.

Effects of S-Allylcysteine on Biomarkers of the Polyol Pathway in Rats with Type 2 Diabetes.

OBJECTIVES: We evaluated the effects of S-allylcysteine (SAC) on biomarkers of the polyol pathway in streptozotocin-nicotinamide (STZ-NA)-induced diabetes in rats. METHODS: Diabetes was induced in male albino Wistar rats by intraperitoneal administration of STZ (55 mg kg-1 bw-1) and NA (110 mg kg-1 bw-1). SAC (150 mg kg-1 bw-1) was orally administered to the rats with diabetes for 45 days to assess its effects on blood glucose, insulin, insulin resistance, glycated hemoglobin, aldose reductase (AR), sorbitol dehydrogenase (SDH), sorbitol, fructose, thiobarbituric acid-reactive substances (TBARS), hydroperoxide, hemoglobin and glutathione (GSH). RESULTS: On SAC administration in the rats with diabetes, the levels of blood glucose, insulin resistance, glycated hemoglobin, AR, SDH, sorbitol, fructose, TBARS and hydroperoxide increased significantly (p<0.05), whereas those of insulin, hemoglobin and GSH decreased. SAC showed therapeutic effects similar to those of gliclazide in decreasing blood glucose, AR, SDH, sorbitol, fructose, glycosylated hemoglobin, TBARS and hydroperoxides levels and significant increases in insulin, hemoglobin and GSH activity in rats with diabetes. Moreover, histopathologic studies also revealed the protective effect of SAC on pancreatic beta cells. CONCLUSIONS: The results indicate that SAC prevents complications of diabetes by reducing the influx of glucose in the polyol pathway, thereby elevating the GSH level and reducing the activities of AR and SDH. Therefore, SAC may have imperative implications for the deterrence and early treatment of type 2 diabetes.

Age-Specific Peculiarities of Modulation of Blood Aldo-Keto Reductase Isoenzyme Spectrum.

The aldo-keto reductase spectrum of the blood was studied at different stages of ontogeny to elucidate the role of reduction pathway in utilization of the carbonyl products of free radical oxidation in modulation of organism sensitivity to the damaging effect of stress during ontogeny. The studies revealed the age-specific changes in aldo-keto reductase spectrum in the blood. An analogy of the aldo-keto reductase spectrum structure in animals of early maturity and in old rats was found. The appearance of age specificity of the aldo-keto reductase spectrum in the blood creates metabolic prerequisites for changes in the efficiency of utilization of carbonyl products of free radical oxidation via their reductive transformation.

Detection of AKR1B10 in Peripheral Blood by Anti-AKR1B10-Conjugated CdTe/CdS Quantum Dots.

BACKGROUND: Aldo-ketoreductase family 1 member B10 (AKR1B10) is a novel prognostic predictor and therapeutic target for colorectal cancer (CRC), and enzyme-linked immunosorbent assays (ELISAs) and electrochemiluminescence (ELC) assays are sample-consuming and high-cost methods. Therefore, it is very necessary to develop a new, simple, and fast yet highly sensitive and specific method for the detection of AKR1B10 in serum. Semiconducting quantum dots (QDs) possess a high fluorescence quantum yield, stability against photobleaching, and size-controlled luminescence properties; thus, they are suitable for photoelectrochemical tumor marker detection, especially in complex biological samples. However, CdTe/CdS QDs have not been applied for the detection of AKR1B10 in serum. METHODS: AKR1B10 in peripheral blood has been established using anti-AKR1B10-conjugated CdTe/CdS QDs and measurements. The assay sensitivity was determined by measuring the quenched fluorescence intensity of AKR1B10 at 0.5, 1, 2, 5, or 10 ng/mL in phosphate-buffered solution (PBS) or 0.25%, 0.5%, 1.0%, 2.0%, or 5% human serum diluted in PBS. The assay was optimized under different pH values (7.00 - 7.40) for different reaction durations (10 - 60 minutes). The specificity of anti-AKR1B10-QDs was determined by testing the inhibition of AKR1B10 activity with carcinoembryonic antigen (CEA), immunoglobulin G (IgG), or alpha-fetoprotein (AFP), each at 1 ng/mL. RESULTS: Under the optimized incubation time (30 minutes) at room temperature and optimal pH (7.1 - 7.2), a correlation between the decreased fluorescence intensity of anti-AKR1B10-conjugated CdTe/CdS QDs and the concentration of AKR1B10 in the range from 0.05 to 100 ng/mL was established. The assay was sensitive for the detection of AKR1B10 in the range from 0.05 to 100 ng/mL, and the detection limit was 0.02 ng/mL. The assay presented a high specificity because the anti-AKR1B10-conjugated CdTe/CdS QDs only reacted with AKR1B10 in the sera in the presence of CEA, IgG, or AFP. CONCLUSIONS: In conclusion, the immunofluorescence assay to detect AKR1B10 in serum using anti-AKR1B10-conjugated CdTe/CdS QDs was simple and fast yet presented high sensitivity and specificity. Our findings provide a promising tool for the early prediction of CRC.

Association of diabetic autonomic neuropathy with red blood cell aldose reductase activity.

OBJECTIVE: Activation of polyol pathway based on increased activity of aldose reductase (AR) has been implicated in the development of diabetic complications including diabetic autonomic neuropathy (DAN). The relationship between DAN and hyperglycemia-induced activation of polyol pathway is still uncertain. In the present study, we investigate the association between aldose reductase activity and diabetic autonomic neuropathy by measuring AR level in red blood cells (RBC). METHOD: In this study, 145 subjects with diabetes with or without DAN and 32 subjects without diabetes have been included. All subjects have been investigated for autonomic function tests and RBC aldose reductase activity. DAN was defined if results of any 2 of the tests of parasympathetic function were abnormal. RBC aldose reductase level was determined spectrophotometrically and expressed as unit/g of hemoglobin. The values were expressed as mean ± standard deviation, and ANOVA test has been applied for comparison between groups. RESULTS: RBC aldose reductase activity was found to be significantly higher in people with diabetes with autonomic neuropathy in comparison to people with diabetes without autonomic neuropathy and healthy individuals without diabetes. Aldose reductase (AR) level ranges from 0.8 units/g Hb to 14.2 units/g Hb. The mean AR level was 8.6±2.95 units in subjects of DM with autonomic neuropathy, while mean AR level was 4.1±1.78 units and 2.0±0.89 units in people with diabetes without neuropathy and normal healthy individuals, respectively (p<0.001). CONCLUSIONS: High aldose reductase activity is associated with the presence of autonomic neuropathy in subjects of type 2 DM.

LC-MS/MS method for the quantification of aldose reductase inhibitor-epalrestat and application to pharmacokinetic study.

A simple and rapid LC-MS/MS method was developed and validated for the quantification of epalrestat, an aldose reductase inhibitor for the treatment of diabetic neuropathy. Following protein precipitation epalrestat and IS were eluted with 10mM ammonium acetate and acetonitrile using a rapid gradient program on reverse phase column. Multiple reaction monitoring mode was used to monitor the transitions of m/z 318→58 for epalrestat and m/z 410→348 for the IS. The assay exhibited a linear dynamic range of 2-5,000 ng/mL for epalrestat in rat plasma. Acceptable precision and accuracy were obtained for concentrations over the standard curve range. The within batch accuracy was in the range of 101.3-108.0% with precision in the range of 3.0-12.3%. All the other validation parameters were within the acceptable limits. Validated method was applied to analyze rat plasma samples obtained from a pharmacokinetic study. After oral administration of epalrestat at 10mg/kg to wistar rats (n=3) mean C(max), AUC(0-24) (ngh/mL) and t(1/2) were found to be 4077 ± 1327 ng/mL, 8989 ± 1590 ngh/mL and 2.9 ± 1.4h, respectively. Bioavailability was found to be 90 ± 14% for epalrestat in male wistar rats.

AKR1B10 overexpression in breast cancer: association with tumor size, lymph node metastasis and patient survival and its potential as a novel serum marker.

Aldo-keto reductase 1B10 (AKR1B10) is a secretory protein that is upregulated with tumorigenic transformation of human mammary epithelial cells. This study demonstrated that AKR1B10 was overexpressed in 20 (71.4%) of 28 ductal carcinomas in situ, 184 (83.6%) of 220 infiltrating carcinomas and 28 (87.5%) of 32 recurrent tumors. AKR1B10 expression in breast cancer was correlated positively with tumor size (p = 0.0012) and lymph node metastasis (p = 0.0123) but inversely with disease-related survival (p = 0.0120). Univariate (p = 0.0077) and multivariate (p = 0.0192) analyses both suggested that AKR1B10, alone or together with tumor size and node status, is a significant prognostic factor for breast cancer. Silencing of AKR1B10 in BT-20 human breast cancer cells inhibited cell growth in culture and tumorigenesis in female nude mice. Importantly, AKR1B10 in the serum of breast cancer patients was significantly increased to 15.18 ± 9.08 ng/ml [n = 50; 95% confidence interval (CI), 12.60-17.76], with a high level up to 58.4 ng/ml, compared to 3.34 ± 2.27 ng/ml in healthy donors (n = 60; 95% CI, 2.78-3.90). In these patients, AKR1B10 levels in serum were correlated with its expression in tumors (r = 0.8066; p < 0.0001). Together our data suggests that AKR1B10 is overexpressed in breast cancer and may be a novel prognostic factor and serum marker for this deadly disease.

[Aldehyde reductase activity and blood aldo-keto reductase spectrum in adolescents with neuroendocrine obesity].

Investigation of aldehyde-reductase activity and blood aldo-keto reductase spectrum has been performed in 13-15 and 16-18-years old adolescents with obesity to clear up the mechanisms of neuroendocrine obesity at the age of puberty. It has been established that basal aldehyde reductase activity and blood aldo-keto reductase spectrum of healthy adolescents in early puberty do not differ from those of healthy adolescents in late puberty. A decreased aldehyde reductase activity and some alterations in blood aldo-keto reductase spectrum have been observed in late puberty in adolescents with neuroendocrine obesity. In adolescents with obesity there have been registered some changes in blood aldo-keto reductase spectrum which are not accompanied by any alterations in its aldehyde reductase activity. The results obtained suggest that certain prerequisites are formed in late puberty to complicate the course of neuroendocrine obesity.

Comparative study of peripheral neuropathy and nerve regeneration in NOD and ICR diabetic mice.

The non-obese diabetic (NOD) mouse was suggested as an adequate model for diabetic autonomic neuropathy. We evaluated sensory-motor neuropathy and nerve regeneration following sciatic nerve crush in NOD males rendered diabetic by multiple low doses of streptozotocin, in comparison with similarly treated Institute for Cancer Research (ICR) mice, a widely used model for type I diabetes. Neurophysiological values for both strains showed a decline in motor and sensory nerve conduction velocity at 7 and 8 weeks after induction of diabetes in the intact hindlimb. However, amplitudes of compound muscle and sensory action potentials (CMAPs and CNAPs) were significantly reduced in NOD but not in ICR diabetic mice. Morphometrical analysis showed myelinated fiber loss in highly hyperglycemic NOD mice, but no significant changes in fiber size. There was a reduction of intraepidermal nerve fibers, more pronounced in NOD than in ICR diabetic mice. Interestingly, aldose reductase and poly(ADP-ribose) polymerase (PARP) activities were increased already at 1 week of hyperglycemia, persisting until the end of the experiment in both strains. Muscle and nerve reinnervation was delayed in diabetic mice following sciatic nerve crush, being more marked in NOD mice. Thus, diabetes of mid-duration induces more severe peripheral neuropathy and slower nerve regeneration in NOD than in ICR mice.

Glucose and collagen regulate human platelet activity through aldose reductase induction of thromboxane.

Diabetes mellitus is associated with platelet hyperactivity, which leads to increased morbidity and mortality from cardiovascular disease. This is coupled with enhanced levels of thromboxane (TX), an eicosanoid that facilitates platelet aggregation. Although intensely studied, the mechanism underlying the relationship among hyperglycemia, TX generation, and platelet hyperactivity remains unclear. We sought to identify key signaling components that connect high levels of glucose to TX generation and to examine their clinical relevance. In human platelets, aldose reductase synergistically modulated platelet response to both hyperglycemia and collagen exposure through a pathway involving ROS/PLCγ2/PKC/p38α MAPK. In clinical patients with platelet activation (deep vein thrombosis; saphenous vein graft occlusion after coronary bypass surgery), and particularly those with diabetes, urinary levels of a major enzymatic metabolite of TX (11-dehydro-TXB2 [TX-M]) were substantially increased. Elevated TX-M persisted in diabetic patients taking low-dose aspirin (acetylsalicylic acid, ASA), suggesting that such patients may have underlying endothelial damage, collagen exposure, and thrombovascular disease. Thus, our study has identified multiple potential signaling targets for designing combination chemotherapies that could inhibit the synergistic activation of platelets by hyperglycemia and collagen exposure.

Evaluation of antidiabetic potential of selected traditional Chinese medicines in STZ-induced diabetic mice.

AIMS: Traditional Chinese medicine (TCM) has been used for treating complex chronic diseases owing to their fewer side-effects, better patient tolerance and relatively less cost. The present work was carried out to study the anti-diabetic efficacy and mechanisms of 34 TCMs. MATERIALS AND METHODS: Streptozotocin (STZ)-diabetic mice were orally administrated with corresponding herbal solution once a day for 4 weeks. At the end of experiment, the level of plasma glucose, malondialdehyde (MDA), the activity of superoxide dismutase (SOD) and the serum aldose reductase (AR) were determined, the effects of TCM extract on α-glucosidase and angiotensin-converting enzyme (ACE) in vitro were also evaluated. RESULTS: 13 out of the 34 herbs showed a statistically significant plasma glucose lowering action compared with the diabetic control group. Biochemical analysis revealed that Atractylodes macrocephala, Codonopsis pilosula, Dioscorea opposite, Flos lonicerae and Pueraria lobata may retard the progression of diabetes via reduce the blood glucose level and prevent the increase of AR activity. Other tested herbs, such as Ramulus cinnamomi, Cinnamomum cassia, and Eucommia ulmoides, showed the antidiabetic ability by either prevent the decrease in SOD activity or suppress the increase of MDA. Zymologic assay reveals that Pueraria lobata and Anemarrhena asphodeloides showed the highest inhibition against α-glucosidase and ACE respectively. Interestingly, the post-treatment glucose levels and AR activity were positively correlated with kidney/body weight of 34 herbs treated diabetic mice (p = 0.02, 0.04 respectively). CONCLUSIONS: Several potential antidiabetic herbs derived from Chinese traditional pharmacopeia such as Dioscorea opposite, Pueraria lobata, Codonopsis pilosula and Ramulus cinnamomi, have been found to exert a beneficial action on diabetes and diabetic complications via multi-mechanisms.

Erythrocyte aldose reductase activity and sorbitol levels in diabetic retinopathy.

PURPOSE: Activation of polyol pathway due to increased aldose reductase (ALR2) activity has been implicated in the development of diabetic complications including diabetic retinopathy (DR), a leading cause of blindness. However, the relationship between hyperglycemia-induced activation of polyol pathway in retina and DR is still uncertain. We investigated the relationship between ALR2 levels and human DR by measuring ALR2 activity and its product, sorbitol, in erythrocytes. METHODS: We enrolled 362 type 2 diabetic subjects (T2D) with and without DR and 66 normal subjects in this clinical case-control study. Clinical evaluation of DR in T2D patients was done by fundus examination. ALR2 activity and sorbitol levels along with glucose and glycosylated hemoglobin (HbA1C) levels in erythrocytes were determined. RESULTS: T2D patients with DR showed significantly higher specific activity of ALR2 as compared to T2D patients without DR. Elevated levels of sorbitol in T2D patients with DR, as compared to T2D patients without DR, corroborated the increased ALR2 activity in erythrocytes of DR patients. However, the increased ALR2 activity was not significantly associated with diabetes duration, age, and HbA1C in both the DR group and total T2D subjects. CONCLUSIONS: Levels of ALR2 activity as well as sorbitol in erythrocytes may have value as a quantitative trait to be included among other markers to establish a risk profile for development of DR.

Epithelial cell density in cataractous lenses of patients with diabetes: association with erythrocyte aldose reductase.

In the present study we evaluated the cell density of lens epithelium and its relation to the degree of erythrocyte aldose reductase (AR) in patients with type 2 diabetes. This prospective clinical study included 46 eyes of patients with type 2 diabetes and 48 eyes of patients without diabetes mellitus (DM). Flat preparations of lens epithelial cells (LECs) attached to the anterior capsule were studied. Multiple regression analysis was performed to evaluate the association between lens cell density and age, gender, type of cataract, duration of diabetes, diabetic retinopathy (DR), the levels of glycosylated hemoglobin (HbA1c) and erythrocyte AR. The mean density of LECs of patients with type 2 diabetes was 4,141+/-508cells/mm(2), which was significantly lower than that of patients without DM (4,560+/-458cells/mm(2); p<0.0001). Multiple regression analysis revealed that the level of erythrocyte AR was correlated with the reduction of LECs in the eyes of patients with type 2 diabetes. The correlation between the density of LECs and the amount of erythrocyte AR was significant in the diabetic group with a high value of HbA1c (>6.5%) or with DR. These results suggest that the polyol pathway via AR may be associated with the reduction of epithelial cell density in the eyes of patients with DM.

Inhibitory effects of astragaloside IV on diabetic peripheral neuropathy in rats.

Astragaloside IV (AGS-IV), a new glycoside of cycloartane-type triterpene isolated from the root of Astragalus membranaceus (Fisch.) Bunge, has been used experimentally for its potent immune-stimulating, anti-inflammatory, and antioxidative actions. A recent study has shown AGS-IV to be an aldose-reductase inhibitor and a free-radical scavenger. This study examined the effects of AGS-IV on motor nerve conduction velocity (MNCV), tailflick threshold temperature, biochemical indexes, and the histology of the sural nerve after diabetes was induced in rats with 75 mg/kg streptozotocin (STZ). AGS-IV (3, 6, 12 mg/kg, twice a day) was administered by oral gavage for 12 weeks after diabetes was induced. Compared with control (nondiabetic) rats, obvious changes in physiological behaviors and a significant reduction in sciatic MNCV in diabetic rats were observed after 12 weeks of STZ administration. Morphological analysis showed that AGS-IV suppressed a decrease in myelinated fiber area, an increase in myelinated fiber density, and an increase in segmental demyelination in diabetic rats. The protective mechanism of AGS-IV involved a decrease in declining blood glucose concentration and HbA1C levels, and an increase in plasma insulin levels. AGS-IV increased the activity of glutathione peroxidase in nerves, depressed the activation of aldose reductase in erythrocytes, and decreased the accumulation of advanced glycation end products in both nerves and erythrocytes. Moreover, AGS-IV elevated Na+,K+-ATPase activity in both the nerves and erythrocytes of diabetic rats. These results indicate that AGS-IV exerts protective effects against the progression of peripheral neuropathy in STZ-induced diabetes in rats through several interrelated mechanisms.

Effects of melatonin on plasma oxidative stress in rats with streptozotocin induced diabetes.

The aim of this study was to evaluate the effect of single melatonin injection on plasma oxidative stress in rats with streptozotocin induced diabetes. Diabetes was induced after a single intraperitoneal dose of streptozotocin (60 mg/kg), while hyperglycemia was determined 10 days upon injection. Diabetic rats were divided into two groups. In the first group the injection of melatonin was applied intraperitoneally (20 mg/kg), while the second group received physiological solution. Twenty-four hours later the rats were killed and their blood was centrifuged. In the rat plasma the following parameters were evaluated: the glucose level, superoxide radical, lipid peroxidation, reduced glutathione, total antioxidant capacity, antioxidant enzymes and the aldose reductase activity. The injected melatonin decreased the superoxide radical in the rat plasma. Moreover, melatonin increased the total antioxidative capacity and the activity of antioxidative enzymes superoxide dismutase and glutathione peroxidase. These results indicate that melatonin is a strong scavenger, which may diminish negative effects of oxidative stress in diabetic rats 24 hours after its application The findings suggest that melatonin is also a strong antioxidant. It increases the antioxidant enzymes activity, inhibiting the release of superoxide radicals. A high total antioxidative capacity and the lower activity of aldose reductase enlarge melatonin scavenger capacity against reactive oxygen species in diabetic rats.

[Analysis of correlative factors affecting IIEF-5 scores of type 2 diabetic patients].

OBJECTIVE: To investigate the correlative factors affecting the IIEF-5 scores of the patient with type 2 diabetic mellitus (T2DM). METHODS: A total of 149 T2DM patients were investigated for the relationships between their IIEF-5 score and such factors as age, body mass index (BMI), fasting plasma glucose (FPG), 2hPG, insulin (INS), GHbA1c, C-peptide, nitric oxide (NO), testosterone (T), estradiol (E2), the ratio of testosterone to estradiol (T/E), erythrocyte aldose reductase (AR), drinking, smoking, concomitant diseases, complications and medication. RESULTS: The scores of the groups of smoking, complication, medication and concomitant disease were significantly lower than those of the controls. There was significant negative correlation between IIEF-5 scores and age, BMI, FPG, 2hPG, INS, GHbA1c and AR (P < 0.05), and significant positive correlation between IIEF-5 scores and NO (P < 0.05). But there was no correlation between drinking, T, E2 and T/E2 (P > 0.05). CONCLUSION: Many factors may affect the IIEF-5 scores of T2DM patients.

Preventing and treating actions of compound lian zhu capsule on micrangium lesions in diabetic rats.

Tissue culture, biochemical techniques and radioimmunoassay were used to study the effects of Compound Lian Zhu Capsule on micrangium lesions in diabetic rats. The results indicated that blood sugar, glycosylated hemoglobin (GHb), urinary protein and malondialdehyde (MDA) contents, aldose reductase (AR) activity and 3H-TdR incorporation rate in the vascular smooth muscle cell (VSMC) were significantly higher, and plasma NO content in the diabetes mellitus (DM) group were significantly lower than those in the normal control group (both P < 0.05). The above indexes in the Chinese medicine (TCM) treatment group were improved significantly as compared with the DM group, with no significantly differences, except urine volume and urinary protein, as compared with the normal control group. It is suggested that Compound Lian Zhu Capsules cansignificantly alleviate the complicated lesions of the micrangium in diabetic rats.

Protective effects of bendazac lysine on early experimental diabetic nephropathy in rats.

AIM: To investigate the preventive and protective effects of bendazac lysine (BDL) on experimental early diabetic nephropathy (DN) rats. METHODS: After an early DN model was induced by streptozotocin, rats were administered BDL at doses of 100, 200, and 400 mg/kg for 8 weeks. Blood glucose, microalbuminuria, kidney index, total antioxidative capacity, laminin, advanced glycation end products (AGE), aldose reductase (AR) activity, and the relative quantity of transforming growth factor beta1 (TGF- beta1) mRNA were measured by different methods. The ultrastructural morphology was observed by transmission electron microscope. RESULTS: The physical behaviors of early DN rats were hypopraxia, cachexia, and polyuria, while those treated with high doses of BDL were vibrant and vigorous. For BDL-treated DN rats, when compared with vehicle-treated DN rats, the blood glucose level and the intensity of oxidative stress were ameliorated. Also, the microalbuminuria level, AGE either in serum or in renal, and AR activity were significantly reduced. Furthermore, the expression of TGF-beta1 mRNA in the kidney cortex was declined and the thickness of glomerular base membrane was decreased significantly. The ultrastructure of glomerulus and mesangial matrix of BDL-treated DN rats were ameliorated. CONCLUSION: BDL has protective effects on several pharmacological targets in the progress of DN and is a potential drug for the prevention of early DN.