Traditional Chinese medicine Shenqi compound to improve lower extremity atherosclerosis of patients with type 2 diabetes by affecting blood glucose fluctuation: Study protocol for a randomized controlled multicenter trial.

BACKGROUND: Clinical and basic research supports that blood glucose fluctuation is an important predictor of diabetic vascular disease and an etiology of lower extremity atherosclerosis, which is an important pathological basis for lower extremity vascular diseases. Previous Chinese National Natural Science Foundation trials (No. 81503566) have reported that the traditional Chinese medicine Shenqi compound can reduce blood glucose fluctuation and low-grade inflammation, and protect blood vessels; however, there are no high-quality clinical evidences available to support the same. This multicenter randomized controlled trial aims to obtain more clinical evidence to confirm the efficacy and safety of Shenqi compound in type 2 diabetes with lower extremity atherosclerosis. METHODS: A multicenter RCT will be implemented in this study for a 32-week study period (8 weeks for intervention and 24 weeks for follow-up). Participants will be recruited from the Teaching Hospital of Chengdu University of TCM, Mianyang Hospital of TCM, and Shuangliu Hospital of TCM. Sixty participants will be randomly divided into a treatment group (basic treatment combined with traditional Chinese medicine Shenqi Compound) or a control group (basic treatment combined with Chinese medicine placebo) with 30 participants in each group. Patients will be selected considering the following inclusion criteria: age between 35 and 65 years, and a positive diagnosis for type 2 diabetes with lower extremity atherosclerosis and TCM syndromes. Primary outcome indicator is an arterial color Doppler ultrasound. Secondary outcome indicators include: blood glucose fluctuation indicators (MBG, SDBG, LAGE), islet ß-cell function evaluation indicators (Homa-IR, Homa-islet, SG, SCP), inflammation indicators (NLR, CRP, IL-6), blood lipids, and HbA1c. Safety index includes vital signs (T, P, R, BP), blood, urine, stool routine, liver and renal function, electrocardiogram, and adverse event records. The endpoint event is defined as the presence of gangrene in the lower limbs. DISCUSSION: Explore the clinical effect of traditional Chinese medicine "Shenqi Compound" to reduce blood glucose fluctuation and use HOMA-IR, the area under the glucose curve, and the area under the C-peptide curve to evaluate the effect of protecting islet ß cell function. TRIAL REGISTRATION: Chinese clinical trial registry (ChiCTR-1900027693). Registered on November 23, 2019. http://www.chictr.org.cn.

Effects of vitamin D supplementation on circulatory YKL-40 and MCP-1 biomarkers associated with vascular diabetic complications: A randomized, placebo-controlled, double-blind clinical trial.

AIM: Diabetic patients predispose to vascular diseases such as nephropathy, and retinopathy. Poor adherence to medical treatment and dietary recommendations in uncontrolled diabetes leads to vascular damages. Vitamin D has been extensively studied and found to be protective against diabetes mellitus. YKL-40 and Monocyte chemoattractant protein-1 (MCP-1) are considered to exert crucial role in diabetes and its complications. Therefore, this study was designed to investigate effects of vitamin D supplementation on serum levels of YKL-40 and MCP-1 involved in the development of diabetic complications. METHODS: For 12 weeks, 48 type 2 diabetic patients enrolled in the trial and randomly were divided into two groups (n = 24 per group), receiving one of the following: 100 µg (4000 IU) vitamin D or placebo. Before and after intervention, serumYKL-40, MCP-1, insulin, IL-6, TNF-α, 25- (OH) vitamin D and HbA1c were measured. RESULTS: Our results revealed that serum levels of 25 (OH) vitamin D significantly increased in vitamin D group (p < 0.001). Vitamin D supplementation also significantly reduced serum YKL-40 levels (-22.7 vs. -2.4 ng/ml; (p-value = 0.003)). There was a significant decline in MCP-1 concentration in intervention group at the end of the study (-45.7 vs. -0.9 pg/ml; (p = 0.001)). Furthermore, there was a significant decrease in IL-6, fasting insulin and HOMA-IR in intervention group after 3 months supplementation. CONCLUSIONS: Daily vitamin D supplementation effectively reduced circulatory YKL-40 and MCP-1 levels in patients with type-2 diabetes and vitamin D deficiency. Vitamin D might contribute in reducing diabetic complications via modulating YKL-40 and MCP-1 signaling pathways.

Vitamin D deficiency is associated with risk of developing peripheral arterial disease in type 2 diabetic patients.

BACKGROUND: The relationship between vitamin D levels and peripheral arterial disease (PAD) remains unclear. We assessed the association of serum 25-hydroxyvitamin D (25(OH)D) levels with the prevalence of PAD in patients with type 2 diabetes mellitus(T2DM). METHODS: A total of 1018 T2DM patients participated in this cross-sectional study. Serum 25(OH)D levels were measured and risk factors of PAD were recorded. PAD was diagnosed as an ankle-brachial index (ABI) < 0.9. RESULTS: The mean age of the diabetic patients was 58.59 ± 11.34 years. Of all the patients, only 20.1% had a 25(OH)D level ≥ 20 ng/mL. Compared to patients without PAD, serum 25(OH)D levels were significantly lower in those with PAD (14.81 ± 8.43 vs. 11.55 ± 5.65 ng/mL, P < 0.001). The overall prevalence of PAD was 7.7%. From the highest level (≥ 20 ng/mL) to the lowest level (< 10 ng/mL) of serum 25(OH)D, the prevalence of PAD was 2.8, 7.5 and 10.7% respectively. After adjustment for age, sex, body mass index (BMI), smoking status and season, compared to patients with serum 25(OH)D levels ≥20 ng/mL, the odds ratios of PAD in patients with a level of 10 to < 20 ng/mL and < 10 ng/mL was 3.587(95% CI: 1.314-9.790) and 5.540(95% CI: 2.004-15.320), respectively. When further considering the influence of coronary heart disease (CHD), hypertension and cerebral infarction, the ratios changed to 3.824(95% CI: 1.378-10.615) and 5.729(95% CI: 2.028-16.187), respectively. And after further adjustment for the duration of diabetes, glycated hemoglobin (HbA1c) and glomerular filtration rate (GFR), the ratios changed to 3.489(95% CI: 1.100-11.062) and 3.872(95% CI: 1.168-12.841), respectively. CONCLUSIONS: Reduced serum vitamin D levels were associated with an increased risk of PAD in T2DM patients. Randomized interventive clinical studies are required to verify the effects of vitamin D supplementation on PAD.

Altered bioavailability of epoxyeicosatrienoic acids is associated with conduit artery endothelial dysfunction in type 2 diabetic patients.

BACKGROUND: This pathophysiological study addressed the hypothesis that soluble epoxide hydrolase (sEH), which metabolizes the vasodilator and anti-inflammatory epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids (DHETs), contributes to conduit artery endothelial dysfunction in type 2 diabetes. METHODS AND RESULTS: Radial artery endothelium-dependent flow-mediated dilatation in response to hand skin heating was reduced in essential hypertensive patients (n = 9) and type 2 diabetic subjects with (n = 19) or without hypertension (n = 10) compared to healthy subjects (n = 36), taking into consideration cardiovascular risk factors, flow stimulus and endothelium-independent dilatation to glyceryl trinitrate. Diabetic patients but not non-diabetic hypertensive subjects displayed elevated whole blood reactive oxygen species levels and loss of NO release during heating, assessed by measuring local plasma nitrite variation. Moreover, plasma levels of EET regioisomers increased during heating in healthy subjects, did not change in hypertensive patients and decreased in diabetic patients. Correlation analysis showed in the overall population that the less NO and EETs bioavailability increases during heating, the more flow-mediated dilatation is reduced. The expression and activity of sEH, measured in isolated peripheral blood mononuclear cells, was elevated in diabetic but not hypertensive patients, leading to increased EETs conversion to DHETs. Finally, hyperglycemic and hyperinsulinemic euglycemic clamps induced a decrease in flow-mediated dilatation in healthy subjects and this was associated with an altered EETs release during heating. CONCLUSIONS: These results demonstrate that an increased EETs degradation by sEH and altered NO bioavailability are associated with conduit artery endothelial dysfunction in type 2 diabetic patients independently from their hypertensive status. The hyperinsulinemic and hyperglycemic state in these patients may contribute to these alterations. Trial registration NCT02311075. Registered December 8, 2014.

Involvement of RBP4 in Diabetic Atherosclerosis and the Role of Vitamin D Intervention.

The purposes of this study were to evaluate the expression of retinol-binding protein 4 (RBP4) in diabetic rats with atherosclerosis and to investigate the role of vitamin D intervention. Male Wistar rats were randomly divided into 4 groups, including the control group (NC), the diabetic rats (DM1), the untreated diabetic atherosclerosis rats (DM2), and the vitamin D-treated diabetic atherosclerosis rats (DM3). The levels of serum and adipose RBP4, fasting insulin (FINS), fasting plasma glucose (FPG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), triglycerides (TG), low-density lipoprotein cholesterol (LDL-c), 25-hydroxyvitamin D [25(OH)D], C-reactive protein (CRP), and systolic blood pressure (SBP) were measured. Homeostasis model assessment of insulin resistance (HOMA-IR), homeostasis model assessment ß-cell function index (HOMA-ß), and atherogenic indexes (AI) were calculated. Compared with group NC, the levels of RBP4, TG, LDL-c, FPG, FINS, CRP, AI1, AI2, SBP, and HOMA-IR increased, while the levels of HDL-c, 25(OH)D, and HOMA-ß decreased in groups DM1 and DM2. After 8 weeks of vitamin D supplementation in group DM3, the levels of 25(OH)D and HOMA-ß increased and the levels of LDL-c, TC, HOMA-IR, FINS, CRP, RBP4, AI1, AI2, and SBP decreased significantly when compared with group DM2 (P < 0.05); Pearson analysis showed that serum RBP4 was positively correlated with TG, FINS, HOMA-IR, SBP, CRP, and AI and negatively correlated with 25(OH)D. In addition, multivariable logistic regression analysis showed that serum RBP4, SBP, and HDL-c were predictors for the presence of diabetic atherosclerosis. These findings suggested that RBP4 could involve in the improvement of diabetic atherosclerosis; vitamin D had the ability to decrease the level of RBP4 and eventually played an important role in preventing atherosclerosis in diabetes.

Association of polyunsaturated/saturated fatty acids to metabolic syndrome cardiovascular risk factors and lipoprotein (a) in hypertensive type 2 diabetic patients.

The interactions between fatty acids (FA) classes: polyunsaturated (PUFA-ω6, PUFA-ω3), saturated (SFA), EPA (eicosapentaenoic acid-ω3), DHA (docosahexaenoic-ω3) and cardiometabolic syndrome (CMS) clusters, thrombosis development and vascular inflammation are subtle. This relationship is mediated by insulin resistance (IR), endothelial dysfunction, platelet aggregation disorder and atherosclerosis. OBJECTIVES: We investigated whether PUFA/SFA - PUFA-ω6/PUFA-ω3 ratios and EPA + DHA can be associated with predictive atherothrombogenic biomarkers status in type 2 diabetes (T2D) patients with or without hypertension (HT). The study was conducted on 507 adult subjects (men and women) cohort (36-54 years), divided into 3 groups: T2D, diabetic-hypertensive (DH) and healthy group. Patients were phenotyped regarding their CMS profile using the NCEP/ATPIII criteria. Hypertension was defined as systolic (SBP) and diastolic (DBP) blood pressure ≥140/90 mmHg, respectively. Insulin resistance was assessed by Homa-IR model. Metabolic, atherothrombogenic and inflammatory parameters (CRP) were analyzed by various automata; Non-esterified fatty acids (NEFA) by microfluorimetry; PUFA-ω6 and PUFA-ω3 by gas phase chromatography. CMS clusters and IR were found in T2D and DH groups. Dyslipidemia was correlated with accretion NEFA levels. The PUFA/SFA ratio and PUFA-ω3 level are decreased, concomitant with an increase ApoB100/ApoA1 ratio and very high lipoprotein (a) concentrations. Raising the PUFA-ω6/PUFA-ω3 ratio and PUFA-ω6 levels were associated with the drop HDL-c/LDL-c ratio and EPA+DHA drastic depletion. In conclusion, fatty acids nutritional quality may be associated with atherothrombogenic biomarkers, mainly Lp (a), to prevent the thrombosis and an accident vascular risk in diabetic-hypertensive subjects.

Longitudinal association between fasting blood glucose concentrations and first stroke in hypertensive adults in China: effect of folic acid intervention.

Background: Diabetes is a known risk factor for stroke, but data on its prospective association with first stroke are limited. Folic acid supplementation has been shown to protect against first stroke, but its role in preventing first stroke in diabetes is unknown.Objectives: This post hoc analysis of the China Stroke Primary Prevention Trial tested the hypotheses that the fasting blood glucose (FBG) concentration is positively associated with first stroke risk and that folic acid treatment can reduce stroke risk associated with elevated fasting glucose concentrations.Design: This analysis included 20,327 hypertensive adults without a history of stroke or myocardial infarction, who were randomly assigned to a double-blind daily treatment with 10 mg enalapril and 0.8 mg folic acid (n = 10,160) or 10 mg enalapril alone (n = 10,167). Kaplan-Meier survival analysis and Cox proportionate hazard models were used to test the hypotheses with adjustment for pertinent covariables.Results: During a median treatment duration of 4.5 y, 616 participants developed a first stroke (497 ischemic strokes). A high FBG concentration (≥7.0 mmol/L) or diabetes, compared with a low FBG concentration (<5.0 mmol/L), was associated with an increased risk of first stroke (6.0% compared with 2.6%, respectively; HR: 1.9; 95% CI: 1.3, 2.8; P < 0.001). Folic acid treatment reduced the risk of stroke across a wide range of FBG concentrations ≥5.0 mmol/L, but risk reduction was greatest in subjects with FBG concentrations ≥7.0 mmol/L or with diabetes (HR: 0.66; 95% CI: 0.46, 0.97; P < 0.05). There was a significant interactive effect of FBG and folic acid treatment on first stroke (P = 0.01).Conclusions: In Chinese hypertensive adults, an FBG concentration ≥7.0 mmol/L or diabetes is associated with an increased risk of first stroke; this increased risk is reduced by 34% with folic acid treatment. These findings warrant additional investigation. This trial was registered at clinicaltrials.gov as NCT00794885.

Exercise and Beta-Glucan Consumption (Saccharomyces cerevisiae) Improve the Metabolic Profile and Reduce the Atherogenic Index in Type 2 Diabetic Rats (HFD/STZ).

Physical activity and the ingestion of dietary fiber are non-drug alternatives commonly used as adjuvants to glycemic control in diabetic individuals. Among these fibers, we can highlight beta-glucans. However, few studies have compared isolated and synergic effects of physical exercise and beta-glucan ingestion, especially in type 2 diabetic rats. Therefore, we evaluated the effects beta-glucan (Saccharomyces cerevisiae) consumption, associated or not to exercise, on metabolic parameters of diabetic Wistar rats. The diabetes mellitus (DM) was induced by high-fat diet (HFD) associated with a low dose of streptozotocin (STZ-35 mg/kg). Trained groups were submitted to eight weeks of exercise in aquatic environment. In the last 28 days of experiment, animals received 30 mg/kg/day of beta-glucan by gavage. Isolated use of beta-glucan decreased glucose levels in fasting, Glycated hemoglobin (HbA1c), triglycerides (TAG), total cholesterol (TC), low-density lipoprotein (LDL-C), the atherogenic index of plasma. Exercise alone also decreased blood glucose levels, HbA1c, and renal lesions. An additive effect for reducing the atherogenic index of plasma and renal lesions was observed when both treatments were combined. It was concluded that both beta-glucan and exercise improved metabolic parameters in type 2 (HFD/STZ) diabetic rats.

The proportion of total C18:1 trans-fatty acids in red blood cell membranes relates to carotid plaque prevalence.

Consistent evidence supports the pro-atherogenic properties of dietary trans-fatty acids (TFAs). However, there are no clinical data on TFA intake and atheroma plaque. We cross sectionally investigated whether the proportion of total C18:1 TFA in red blood cells (RBCs), which mirrors dietary TFA intake, independently relates to carotid plaque prevalence in subjects with new-onset type 2 diabetes mellitus without prior cardiovascular disease (n=101, 56% men, mean age 61 years) and age- and sex-matched controls (n=96). RBC fatty acid composition was determined by gas chromatography. Plaque (defined as carotid intima-media thickness ≥1.5 mm) was sonographically assessed at three bilateral carotid segments. In multivariate models adjusting for group (diabetes or control) and classical cardiovascular risk factors, for each 0.1% increase in RBC total C18:1 TFA isomers, plaque prevalence increased by 53% (P=.002). In contrast, for each 0.1% increase in RBC alpha-linolenic acid, the vegetable omega-3 fatty acid, plaque prevalence decreased by 43% (P<.001). We conclude that the RBC membrane proportion of total C18:1 TFA, considered a proxy of intake, directly relates to the ultrasound feature that best predicts future cardiovascular events. Our findings support current recommendations to limit TFA intake for cardiovascular health promotion.

Low molecular weight fucoidan ameliorates streptozotocin-induced hyper-responsiveness of aortic smooth muscles in type 1 diabetes rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Low molecular weight fucoidan (LMWF) was prepared from Laminaria japonica Areschoug, a popular seafood and medicinal plant consumed in Asia. Chinese have long been using it as a traditional medicine for curing hypertension and edema. AIM OF THE STUDY: This study was intent to investigate the possible beneficial effect of LMWF on hyper-responsiveness of aortic smooth muscles instreptozotocin (STZ)-induced type 1 diabetic rats. MATERIALS AND METHODS: Sprague-Dawley rats were made diabetic by injection of STZ, followed by the administration of LMWF (50 or 100mg/kg/day) or probucol (100mg/kg/day) for 12 weeks. Body weight, blood glucose level, basal blood pressure, serum lipid profiles, oxidative stress, prostanoids production, and vasoconstriction response of endothelium-denuded aorta rings to phenylephrine were measured by Real time-PCR, Western blots, ELISA assay, and force myograph, respectively. RESULTS: LMWF (100mg/kg/day)-treated group showed robust improvements on STZ-induced body weight-loss, hypertension, and hyperlipidaemia as indicated by decreased serum level of total cholesterol, triglyceride, and low density lipoprotein cholesterol; while probucol, a lipid-modifying drug with antioxidant properties, displayed mild effects. In addition, LMWF appreciably ameliorated STZ-elicited hyper-responsiveness and oxidative stress in aortic smooth muscles as indicated by decreased superoxide level, increased glutathione content and higher superoxide dismutase activity. Furthermore, administration with LMWF dramatically prevented cyclooxygenase-2 stimulation and restored the up-regulation of thromboxane synthase and down-regulation of 6-keto-PGF1α (a stable metabolic product of prostaglandin I2) in the STZ-administered rats. CONCLUSION: This study demonstrates for the first time that LMWF can protect against hyperlipidaemia, hypertension, and hyper-responsiveness of aortic smooth muscles in type 1 diabetic rat via, at least in part, amelioration of oxidative stress and restoration of prostanoids levels in aortic smooth muscles. Therefore, LMWF can be a potential adjuvant treatment against cardiovascular complications in type 1 diabetes.

Effect of Vitamins C and E on Endothelial Function in Type 1 Diabetes Mellitus.

BACKGROUND/OBJECTIVES: Endothelial dysfunction due to hyperglycemia-induced oxidative damage is an important predictor of future cardiovascular risk in patients with type 1 diabetes mellitus (T1DM) and is present in adolescent T1DM. We hypothesized that combined treatment with the antioxidant vitamins C and E might improve endothelial function (EF) and other biochemical risk factors in adolescents with T1DM. SUBJECTS/METHODS: Open-label antioxidant supplementation was given for six weeks with endpoint measurements collected at baseline and study completion. Endpoints measured included EF and plasma measurements of biochemical endothelial risk. RESULTS: Two males and 7 females were studied. Mean age was 12.9 ± 0.9 yrs; mean T1DM duration was 5.5 ± 2.5 yrs; mean BMI was 22.1 ± 3.8 kg/m(2); and mean hemoglobin A1c was 9.3 ± 1.1%. No differences were found for EF, high sensitivity CRP, total antioxidant capacity, adiponectin, or endothelial progenitor cells (EPCs) between before and after combined vitamin C and E therapy. CONCLUSIONS: Our negative study results do not support previous findings of decreased oxidative damage, improved endothelial function, and increased vascular repair capacity with antioxidant therapy. Longer term studies may be needed to determine the effects, if any, of combined antioxidant therapy on EPCs, EF, and markers of micro- and macrovascular complications in T1DM.

In Vivo Effects of Quercetin in Association with Moderate Exercise Training in Improving Streptozotocin-Induced Aortic Tissue Injuries.

BACKGROUND: Diabetes mellitus (DM) is a chronic endocrine-metabolic disorder associated with endothelial dysfunction. Hyperglycemia, dyslipidemia and abnormal nitric oxide-mediated vasodilatation are the major causal factors in the development of endothelial dysfunction in DM. The prevention of endothelial dysfunction may be a first target against the appearance of atherosclerosis and cardiovascular diseases. We have investigated the synergistic protective effects of quercetin administration and moderate exercise training on thoracic aorta injuries induced by diabetes. METHODS: Diabetic rats that performed exercise training were subjected to a swimming training program (1 h/day, 5 days/week, 4 weeks). The diabetic rats received quercetin (30 mg/kg body weight/day) for 4 weeks. At the end of the study, the thoracic aorta was isolated and divided into two parts; one part was immersed in 10% formalin for histopathological evaluations and the other was frozen for the assessment of oxidative stress markers (malondialdehyde, MDA and protein carbonyls groups, PC), the activity of antioxidant enzymes (superoxide dismutase, SOD and catalase, CAT), nitrite plus nitrate (NOx) production and inducible nitric oxide synthase (iNOS) protein expression. RESULTS: Diabetic rats showed significantly increased MDA and PC levels, NOx production and iNOS expression and a reduction of SOD and CAT activity in aortic tissues. A decrease in the levels of oxidative stress markers, NOx production and iNOS expression associated with elevated activity of antioxidant enzymes in the aortic tissue were observed in quercetin-treated diabetic trained rats. CONCLUSIONS: These findings suggest that quercetin administration in association with moderate exercise training reduces vascular complications and tissue injuries induced by diabetes in rat aorta by decreasing oxidative stress and restoring NO bioavailability.

Microvascular oxygen partial pressure during hyperbaric oxygen in diabetic rat skeletal muscle.

Hyperbaric oxygen (HBO) is a major therapeutic treatment for ischemic ulcerations that perforate skin and underlying muscle in diabetic patients. These lesions do not heal effectively, in part, because of the hypoxic microvascular O2 partial pressures (PmvO2 ) resulting from diabetes-induced cardiovascular dysfunction, which alters the dynamic balance between O2 delivery (Q̇o2) and utilization (V̇o2) rates. We tested the hypothesis that HBO in diabetic muscle would exacerbate the hyperoxic PmvO2 dynamics due, in part, to a reduction or slowing of the cardiovascular, sympathetic nervous, and respiratory system responses to acute HBO exposure. Adult male Wistar rats were divided randomly into diabetic (DIA: streptozotocin ip) and healthy (control) groups. A small animal hyperbaric chamber was pressurized with oxygen (100% O2) to 3.0 atmospheres absolute (ATA) at 0.2 ATA/min. Phosphorescence quenching techniques were used to measure PmvO2 in tibialis anterior muscle of anesthetized rats during HBO. Lumbar sympathetic nerve activity (LSNA), heart rate (HR), and respiratory rate (RR) were measured electrophysiologically. During the normobaric hyperoxia and HBO, DIA tibialis anterior PmvO2 increased faster (mean response time, CONT 78 ± 8, DIA 55 ± 8 s, P < 0.05) than CONT. Subsequently, PmvO2 remained elevated at similar levels in CONT and DIA muscles until normobaric normoxic recovery where the DIA PmvO2 retained its hyperoxic level longer than CONT. Sympathetic nervous system and cardiac and respiratory responses to HBO were slower in DIA vs. CONT. Specifically the mean response times for RR (CONT: 6 ± 1 s, DIA: 29 ± 4 s, P < 0.05), HR (CONT: 16 ± 1 s, DIA: 45 ± 5 s, P < 0.05), and LSNA (CONT: 140 ± 16 s, DIA: 247 ± 34 s, P < 0.05) were greater following HBO onset in DIA than CONT. HBO treatment increases tibialis anterior muscle PmvO2 more rapidly and for a longer duration in DIA than CONT, but not to a greater level. Whereas respiratory, cardiovascular, and LSNA responses to HBO are profoundly slowed in DIA, only the cardiovascular arm (via HR) may contribute to the muscle vascular incompetence and these faster PmvO2 kinetics.

Ferulic acid combined with astragaloside IV protects against vascular endothelial dysfunction in diabetic rats.

Dysfunction of the endothelium is regarded as an important factor in the pathogenesis of vascular disease in diabetes mellitus (DM). Unfortunately, prevention of the progression of vascular complications of DM remains pessimistic. Ferulic acid and astragaloside IV, isolated from traditional Chinese medicine Angelica sinensis and Radix astragali respectively, exhibit potential cardio-protective and anti-hyperglycemic properties. In the present study, we investigated the protective effects and underlying mechanism of ferulic acid and astragaloside IV against vascular endothelial dysfunction in diabetic rats. After the diabetic rat model was established using streptozotocin, sixty rats were divided into 6 groups (control, model, ferulic acid, astragaloside IV, ferulic acid + astragaloside IV, and metformin) and treated for 10 weeks. Blood samples were collected to measure levels of hemoglobin A1c (HbAlc), triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), low density lipoproteins (Ox-LDL), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and creatinine (Cr), nitric oxide (NO) and endothelial nitric oxide synthase (eNOS), and abdominal aorta tissue samples were collected for observing histological morphology changes of endothelium and detecting gene and protein expression of nuclear factor-κB (NF-κB) P65, monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor α (TNF-α). We found that ferulic acid combined with astragaloside IV was capable of improving the structure of the aortic endothelium wall, attenuating the increase of HbAlc, TG, TC, LDL-C and Ox-LDL, promoting the release of NO and eNOS, and inhibiting over-activation of MCP-1, TNF-α, and NF-κB P65, without damage to liver and kidney function. In conclusion, ferulic acid combined with astragaloside IV exhibited significant protective effects against vascular endothelial dysfunction in diabetic rats through the NF-κB pathway involving decrease of Ox-LDL, increase of NO and eNOS, and activation of NF-κB P65, MCP-1 and TNF-α.

Effect of Semecaprus anacardium on diabetes-induced alterations in the activities of marker enzymes and antioxidant enzymes in type 2 diabetes induced cardiac vascular damage model in rats.

Semecarpus anacardium is a commonly used drug in the Siddha system of medicine for curing various metabolic disorders. The cardio protective effect of the drug in Type 2 diabetes-induced cardiovascular complications was studied in rats by feeding them with a high fat diet for 2 weeks followed by intra peritoneal injection of streptozotocin at a moderate dosage of 2*35 mg/kg/ b.wt 24 hr apart and leaving them for 8 weeks to develop cardiovascular complications. The effect of the drug was studied by analyzing levels of blood glucose, insulin, HbA1c, marker enzymes, the antioxidative enzymes and the levels of lipid peroxides in Type 2 diabetic rats. Diabetic rats were treated with SA at a dosage of 300 mg/kg/b.wt. for 8 weeks and the results were compared with diabetic rats treated with the combination therapy drugs metformin at a dosage of 100 mg/kg/b.wt and atorvastatin at a dosage of 10 mg/kg/b.wt for 8 weeks. The drug SA significantly decreased the blood glucose levels and also HbA1c levels while improving glucose tolerance at the same time. The levels of marker enzymes and lipid peroxides were significantly increased in diabetic rats when compared with control rats. On the other hand significant decreases in the levels of antioxidative enzymes were observed in diabetic rats. Upon treatment with the drug SA, all of these abnormalities were restored to near normalcy. The present study thereby establishes the protective effect of the drug against diabetes-induced cardiac damage.

Alpha-linolenic acid intake prevents endothelial dysfunction in high-fat diet-fed streptozotocin rats and underlying mechanisms.

BACKGROUND: Endothelial dysfunction is an important factor in the pathogenesis of diabetes related vascular complications, and acute alpha-linolenic acid (ALA) intake can increase flow-mediated dilation of the diabetic artery at 4 h postprandially. However, whether chronic ALA supplementation may prevent endothelial dysfunction in the process of diabetes and underlying mechanisms remains largely unknown. MATERIALS AND METHODS: The high-fat diet-fed streptozotocin (HFD-STZ) rats provided an animal model for T2DM. Age-matched normal and HFD-STZ rats randomly received normal diet or ALA (500 mg/kg per day). After 5 weeks of feeding, endothelial function was determined. RESULTS: Diabetes caused significant endothelial dysfunction (maximal vasorelaxation responses to ACh) in aortic segments, and ALA intake alleviated endothelial dysfunction. Superoxide production and peroxynitrite (ONOO-) formation were reduced with ALA supplement in diabetic vascular segments. Interestingly, ALA intake enhanced eNOS but inhibited iNOS activity in diabetic vessels. Moreover, ALA intake significantly increased eNOS phosphorylation. On the other hand, gp91phox and iNOS overexpression were reduced moderately with ALA intake in diabetic vessels. CONCLUSIONS: We concluded that ALA prevents diabetes-induced endothelial dysfunction by enhancing eNOS activity and attenuates oxidative/nitrative stress by inhibiting iNOS and NADPH oxidase expression and ONOO- production.

Impaired endothelium-dependent skin microvascular function during high-dose atorvastatin treatment in patients with type 1 diabetes.

AIMS: The present study investigated the effects of lipid-lowering therapy with atorvastatin on skin microvascular function in patients with type 1 diabetes and dyslipidaemia. METHODS: Twenty patients received daily treatment with atorvastatin 80 mg or placebo during 2 months in a randomised, double-blind, cross-over study. Forearm skin microcirculation was investigated with laser Doppler perfusion imaging during iontophoresis of acetylcholine and sodium nitroprusside to assess endothelium-dependent and endothelium-independent microvascular reactivity, respectively. Various biochemical markers of endothelial function were also investigated. RESULTS: Endothelium-dependent microvascular reactivity decreased during atorvastatin (p < 0.001), showing a significant treatment effect compared with placebo (p = 0.04). Atorvastatin treatment was also associated with increased haemoglobin A1C levels from 7.45% to 7.77% (p = 0.008). CONCLUSIONS: The present study shows impaired endothelium-dependent skin microvascular function during high-dose atorvastatin treatment in patients with type 1 diabetes, thus implicating a risk for deterioration of microvascular function during such therapy in these patients.

Effect of Danzhijiangtang capsule on monocyte chemoattractant protein-1 mRNA expression in newly diagnosed diabetes subclinical vascular lesions.

AIM: To investigate the effect of Danzhijiangtang capsule (DJC) on monocyte chemoattractant protein-1 (MCP-1) mRNA expression in newly diagnosed type 2 diabetes mellitus (T2DM) subclinical vascular lesions. METHODS: Sixty-two patients with newly diagnosed T2DM subclinical vascular lesions were randomly divided into a control group and treatment group of 31 cases each. Oral antidiabetic therapy with routine western medicine was conducted in both groups, and the treatment group was additionally treated with DJCs. The treatment course for both groups was 12 wk. Before and after treatment, the total efficiency and traditional Chinese medicine (TCM) syndrome score were calculated. The fasting plasma glucose (FPG), 2-h plasma glucose (2hPG), fasting insulin (FINS), insulin resistance index (IRI), hemoglobin (Hb)A1c, blood lipids, and hemorheology indices were determined. In addition, the levels of vascular endothelial growth factors including thrombomodulin (TM), von Willebrand factor (vWF), P-selectin and MCP-1 mRNA were determined. RESULTS: After 12 wk of treatment, the TCM syndrome score was significantly decreased compared to before treatment in both groups. After treatment, FPG, 2hPG, HbA1c, FINS, IRI, total cholesterol, triglycerides, low-density lipoprotein, high-density lipoprotein, whole blood low shear specific viscosity, plasma specific viscosity, TM, vWF, P-selectin and MCP-1 mRNA were significantly improved compared to before treatment in both groups. After treatment, the total efficiency and TCM syndrome score in the treatment group were better than in the control group. FINS, IRI, whole blood high shear specific viscosity, plasma specific viscosity, TM, vWF, P-selectin and MCP-1 mRNA level in the treatment group were significantly reduced after treatment compared with control group. CONCLUSION: DJCs are efficacious in supplementing qi, nourishing yin and invigorating blood circulation, and upregulate MCP-1 mRNA expression in patients with T2DM subclinical vascular lesions.

Effect of folic acid supplementation on plasma total homocysteine levels and glycemic control in patients with type 2 diabetes: a systematic review and meta-analysis.

AIM: The evidences illustrating the effects of folic acid supplementation (FAS) in individuals with type 2 diabetes on plasma total homocysteine (tHcy) levels and glycemic control have been contradictory. The aim of the study was to systematically search and quantitatively analyze the effect of FAS on tHcy levels and HbA1c compared with placebo. METHODS: We searched PubMed, Scopus, and Embase up to March 2012 without language restriction. Key words "folic acid" and "diabetes mellitus" with slight modifications based on the sources for search strategy were used. References of initially identified articles were examined to identify any other relevant studies. A random-effects model was used for estimation the pooled effect estimates (weighted mean different, WMD). RESULTS: Of 6185 studies identified, 4 studies with 183 patients were included. FAS had statistically significant effect on tHcy levels [WMD, -3.52; 95% confidence interval (CI), -4.44 to -2.60]. However, the effect on HbA1c levels [WMD, -0.37; 95% CI, -1.10 to 0.35] was not significant. CONCLUSIONS: Folic acid supplementation in patient with type 2 diabetes mellitus may reduce tHcy levels and have a trend to associate with better glycemic control compared with placebo. Further longitudinal studies on these intervention and outcomes are warranted.

Effect of vitamin D on aortic remodeling in streptozotocin-induced diabetes.

BACKGROUND: Diabetes mellitus is associated with micro- and macrovascular complications and increased cardiovascular risk. Elevated levels of serum asymmetric dimethylarginine (ADMA) may be responsible for endothelial dysfunction associated with diabetes-induced vascular impairment. Vitamin D may have potential protective effects against arterial stiffening. This study aimed to examine both the effects of diabetes on the functional/structural properties of the aorta and the endothelial function and the effects of vitamin D supplementation. METHODS: Male Wistar rats (n = 30) were randomly assigned to control untreated, diabetic untreated, and diabetic + cholecalciferol groups. Diabetes was induced by intraperitoneal injection of streptozotocin, followed by oral administration of cholecalciferol (500 IU/kg) for 10 weeks in the treatment group. Aortic pulse wave velocity (PWV) was recorded over a mean arterial pressure (MAP) range of 50 to 200 mmHg using a dual pressure sensor catheter. Intravenous infusion of phenylephrine and nitroglycerine was used to increase and decrease MAP, respectively. Serum 25-hydroxyvitamin D [25(OH)D] levels were measured using a radioimmune assay. ADMA levels in serum were measured by enzyme-linked immunoassay. Aortic samples were collected for histomorphometrical analysis. RESULTS: PWV up to MAP 170 mmHg did not reveal any significant differences between all groups, but in diabetic rats, PWV was significantly elevated across MAP range between 170 and 200 mmHg. Isobaric PWV was similar between the treated and untreated diabetic groups, despite significant differences in the levels of serum 25(OH)D (493 ± 125 nmol/L vs 108 ± 38 nmol/L, respectively). Serum levels of ADMA were similarly increased in the treated and untreated diabetic groups, compared to the control group. The concentration and integrity of the elastic lamellae in the medial layer of the aorta was impaired in untreated diabetic rats and improved by vitamin D supplementation. CONCLUSION: PWV profile determined under isobaric conditions demonstrated differential effects of uncontrolled diabetes on aortic stiffness. Diabetes was also associated with elevated serum levels of ADMA. Vitamin D supplementation did not improve the functional indices of aortic stiffness or endothelial function, but prevented the fragmentation of elastic fibers in the aortic media.