The effects of atorvastatin on endothelial function in diabetic patients and subjects at risk for type 2 diabetes

We have investigated the effect of atorvastatin on the endothelial function of patients with diabetes and subjects at risk for type 2 diabetes in a 12-wk, prospective, randomized, placebo-controlled, double-blind clinical trial. The flow- mediated dilation (FMD; endothelium dependent) and nitroglycerin-induced dilation (endothelium independent) in the brachial artery and the vascular reactivity at the forearm skin were measured. FMD improved in the atorvastatin-treated, at-risk subjects [median (25-75 percentile), 7.2% (2.9-9.6%) at exit visit vs. 6.6% (2.9-9.5%) at baseline; P < 0.05]. A similar improvement of FMD was found in atorvastatin-treated diabetic patients [median (25-75 percentile), 5.6 (3.9-7.9) at exit visit vs. 4.2 (3.2-7.2) at baseline; P = 0.07]. No changes were observed in nitroglycerin-induced dilation and the microcirculation reactivity measurements in either group. In the at-risk group, there was a decrease in the C-reactive protein [median (25-75 percentile), 0.12 mg/dl (0.07-0.27 mg/dl) at exit visit vs. 0.24 mg/dl (0.07-0.35 mg/dl) at baseline; P < 0.05] and TNF alpha [median (25-75 percentile), 2.6 pg/ml (1.8-4.1 pg/ml) at exit visit vs. 4.4 pg/ml (3.6-6.0 pg/ml) at baseline; P < 0.05] in the atorvastatin-treated patients, whereas in the diabetes group, a decrease in endothelin-1 (mean +/- SD, 0.97 +/- 0.29 pg/ml at exit visit vs. 1.19 +/- 0.42 pg/ml at baseline; P < 0.05) and plasminogen activator inhibitor-1 [median (25-75 percentile), 18 ng/ml (9-24 ng/ml) at exit visit vs. 27 ng/ml (7-41 ng/ml) at baseline; P < 0.05] were observed. We conclude that atorvastatin improves endothelial function and decreases levels of markers of endothelial activation and inflammation.     

通心络对改善2型糖尿病患者血管内皮功能的临床观察

目的 探讨通心络胶囊对2型糖尿病患者血管内皮依赖性舒张功能的影响及相关机理.方法 80例2型糖尿病患者,随机分为对照组和通心络组,利用高分辨率超声观察治疗前后肱动脉舒张功能,以及血清一氧化氮(NO)、内皮素(ET)、6-酮-前列腺素F1α(6-keto-PGF1α)和血栓素B2(TXB2)浓度的变化.结果 经4周的治疗,通心络组血流介导的血管舒张(FMD)由治疗前的(8.19±0.71)%,上升为(12.47±0.98)%(P＜0.05).血清NO浓度也较治疗前显著升高[(47.65±4.38)pg/ml对(52.91±4.83)pg/ml,P＜0.001].ET浓度较治疗前显著降低[(31.23±2.46)pg/ml对(24.34±2.46)pg/ml;P＜0.001],而非内皮依赖性的血管舒张反应治疗前后无明显改变(P＞0.05).对照组上述参数治疗前后均无明显变化.结论 在4周的疗程中通心络可以调控NO/ET的平衡,改善2型糖尿病患者血管内皮依赖性的舒张功能,未发现明显的不良反应.     

Kidney function and retinol status in type 2 diabetes mellitus patients

Kidneys play an important role in retinol turnover. We postulated that retinol homeostasis is disturbed in diabetic nephropathy. The aim of this research was to study the effect of kidney impairment on urinary excretion and on serum concentrations of retinol in type 2 diabetes mellitus patients. For this purpose, 41 type 2 diabetes patients and 9 sex -and age-matched healthy subjects were enrolled. Serum and urinary retinol and retinol-binding protein (RBP) were assessed by high-pressure liquid chromatography and enzyme-linked immunosorbent assay, respectively. The study showed that 17 out of 41 diabetic patients (41.5%) and none of the controls excreted retinol in urine (P < 0.02). Retinol excretion in the urine in these patients was 1.5-fold more prevalent than hypercreatininemia. Urinary retinol significantly correlated with clinically diagnosed nephropathy (P = 0.02). All but one of the patients with hypercreatininemia excreted retinol in the urine. Serum retinol and RBP in patients with hypercreatininemia were higher than in controls (P < 0.002). Values of urinary retinol, unlike urinary RBP, albumin and total protein, did not overlap between patients and controls. Our results indicate that (i) urinary retinol is a specific sign of tubular damage in type 2 diabetic patients and (ii) urinary retinol enables a more clear-cut identification of proximal tubule dysfunction in type 2 diabetes patients than urinary RBP or albumin.     

Pioglitazone restores endothelial function in patients with type 2 diabetes treated with insulin

The primary aim of this study was to evaluate the effect of pioglitazone on endothelial function, as assessed by flow-mediated dilatation (FMD) nitroglycerine-induced dilatation (NID) in patients with type 2 diabetes mellitus treated with insulin. A randomized double-blind placebo-controlled trial involved 20 patients with insulin-treated type 2 diabetes. Patients received either pioglitazone 30 mg or placebo for 4 months. FMD, NID, and HbA1c were measured before and after 4 months of treatment. HbA1c decreased from 10.0 (+/- 2.3) to 8.4 (+/- 2.0) in the pioglitazone group, a statistically significant improvement in glycemic control (p = 0.018). HbA1c was unchanged in the placebo group (p = 0.477). Endothelial function as assessed by FMD significantly improved from 10.1 (+/- 4.0)% to 14.6 (+/- 6.2)% in the pioglitazone group (p = 0.036) as compared to the placebo group (p = 0.705). There was a trend towards improvement in the NID in the pioglitazone group (from 13.3 +/- 8.0% to 18.9 +/- 5.4%; p = 0.056). In insulin-treated patients with type 2 diabetes, the addition of pioglitazone improves endothelial function, as measured by FMD. Addition of pioglitazone to insulin in type 2 diabetes patients may favorably impact vascular function in diabetes, even after many years of insulin resistance and hyperglycemia.     

Thiazolidinediones-improving endothelial function and potential long-term benefits on cardiovascular disease in subjects with type 2 diabetes

Endothelial dysfunction, which leads to impaired vasodilation, is an early event in the development of atherosclerosis. A number of mechanisms involving, for example, cell adhesion molecules, chemokines, and cytokines, contribute to this inflammatory disease, and insulin resistance plays a cardinal role in accelerating these processes. Hyperglycemia and other metabolic abnormalities that are commonly associated with insulin resistance also contribute to impaired endothelial function. In addition, the important role of the endothelium in damage repair following a cardiovascular event is emerging. The combination of proatherogenic factors in patients with type 2 diabetes results in blunted endothelial function and an increased risk of cardiovascular disease. Insulin-sensitizing agents such as thiazolidinediones have demonstrated a number of clinical benefits, including anti-inflammatory and antithrombotic properties, which may impact on the course of atherosclerosis. Recent studies have demonstrated that thiazolidinediones improve endothelial function in subjects with and without type 2 diabetes.     

瑞舒伐他汀对2型糖尿病患者血管内皮功能的影响

目的观察瑞舒伐他汀对2型糖尿病患者血管内皮功能的影响。方法选择2型糖尿病（T2DM）患者并根据血脂水平分为血脂正常组21例和高脂血症组28例,两组均给予瑞舒伐他汀10mg/d口服,连续12周。测定治疗前、后患者的体重指数（BMI）、总胆固醇（TC）、甘油三酯（TG）、低密度脂蛋白-胆固醇（LDL-C）、高密度脂蛋白-胆固醇（HDL-C）、空腹血糖、空腹胰岛素、2h血糖、2h胰岛素、糖化血红蛋白（HbA1C）、高敏C反应蛋白（hs-CRP）、血管性血友病因子（vWF）,以及肱动脉内皮依赖性舒张功能（EDD）。结果①瑞舒伐他汀治疗可明显改善高脂血症组的血脂代谢;②血脂正常组及高脂血症组患者治疗后血清hs-CRP较治疗前均明显下降,分别为[（5.27±1.26）mg/Lvs.（6.66±1.37）mg/L,P〈0.01],[（5.31±1.34）mg/Lvs.（6.72±1.39）mg/L,P〈0.01];高脂血症组患者的vWF水平由（188.73±20.74）%降至（169.53±21.01）%,P〈0.05;③高脂血症组患者的肱动脉EDD治疗后较治疗前有明显改善[（6.12±1.02）%vs.（7.58±0.97）%,P〈0.01]。结论瑞舒伐他汀可改善2型糖尿病伴高脂血症患者的血管内皮功能,其机制与其调节血脂,减轻炎症反应有关。     

Improved endothelial function with metformin in type 2 diabetes mellitus

OBJECTIVES: This study was designed to assess the effect of metformin on impaired endothelial function in type 2 diabetes mellitus. BACKGROUND: Abnormalities in vascular endothelial function are well recognized among patients with type 2 (insulin-resistant) diabetes mellitus. Insulin resistance itself may be central to the pathogenesis of endothelial dysfunction. The effects of metformin, an antidiabetic agent that improves insulin sensitivity, on endothelial function have not been reported. METHODS: Subjects with diet-treated type 2 diabetes but without the confounding collection of cardiovascular risk factors seen in the metabolic syndrome were treated with metformin 500 mg twice daily (n = 29) or placebo (n = 15) for 12 weeks. Before and after treatment, blood flow responses to intraarterial administration of endothelium-dependent (acetylcholine), endothelium-independent (sodium nitroprusside) and nitrate-independent (verapamil) vasodilators were measured using forearm plethysmography. Whole-body insulin resistance was assessed on both occasions using the homeostasis model (HOMA-IR). RESULTS: Subjects who received metformin demonstrated statistically significant improvement in acetylcholine-stimulated flows compared with those treated with placebo (p = 0.0027 by 2-way analysis of variance), whereas no significant effect was seen on nitroprusside-stimulated (p = 0.27) or verapamil-stimulated (p = 0.40) flows. There was a significant improvement in insulin resistance with metformin (32.5% reduction in HOMA-IR, p = 0.01), and by stepwise multivariate analysis insulin resistance was the sole predictor of endothelium-dependent blood flow following treatment (r = -0.659, p = 0.0012). CONCLUSIONS: Metformin treatment improved both insulin resistance and endothelial function, with a strong statistical link between these variables. This supports the concept of the central role of insulin resistance in the pathogenesis of endothelial dysfunction in type 2 diabetes mellitus. This has important implications for the investigation and treatment of vascular disease in patients with type 2 diabetes mellitus.     

Lowering serum urate does not improve endothelial function in patients with type 2 diabetes

Aims/hypothesis Endothelial dysfunction contributes to excess cardiovascular risk in patients with type 2 diabetes. There is strong evidence of an association between high serum uric acid concentrations and endothelial dysfunction, and uric acid has been proposed as an independent cardiovascular risk factor in type 2 diabetes. We hypothesised that lowering of uric acid concentrations might allow restoration of endothelial function in this high-risk group. Methods Intravenous urate oxidase (1.5 mg) was administered to ten patients with type 2 diabetes and ten healthy participants in a two-way, randomised, placebo-controlled, crossover study. Forearm blood flow responses to intra-brachial acetylcholine, sodium nitroprusside and N ^G-monomethyl-l-arginine (L-NMMA) were measured using venous occlusion plethysmography. The augmentation index (AIx) was determined by pulse wave analysis as a measure of large arterial stiffness. Results Acetylcholine and L-NMMA evoked lesser responses in patients with type 2 diabetes than in healthy participants. Baseline AIx was higher in patients with type 2 diabetes (mean ± SD: 13.1 ± 6.9%) than in healthy participants (2.0 ± 5.1%; p = 0.006). Urate oxidase lowered serum uric acid concentrations by 64 ± 11% (p < 0.001), but this had no effect on forearm blood flow responses or AIx in either group. Conclusions/interpretation Substantial short-term lowering of uric acid did not have a direct vascular effect, suggesting that, on its own, this might not be an effective strategy for restoring endothelial function in patients with type 2 diabetes.     

Association between plasma visfatin and vascular endothelial function in patients with type 2 diabetes mellitus

Visfatin is a newly identified adipocytokine that mimics insulin action. However, the pathophysiological role of visfatin in diabetic patients is not fully understood. The main purpose of this study was to investigate the association of plasma visfatin with endothelial function in patients with type 2 diabetes mellitus. In addition, the relationships of visfatin with oxidative stress, low-grade inflammation, atherosclerosis, adiponectin, plasma renin activity, and aldosterone were also explored, and the effect of pioglitazone on visfatin was examined. Visfatin levels were measured in 80 patients with type 2 diabetes mellitus and in 28 age-matched healthy subjects. Endothelial function was evaluated by using flow-mediated vasodilatation (FMD), oxidative stress was assessed by the level of urinary 8-iso-prostaglandin F2alpha, and atherosclerosis and inflammation were measured by using the intimal-medial complex thickness and the levels of high-sensitivity C-reactive protein and fibrinogen. Pioglitazone was administered for 12 weeks at a dose of 30 mg/d in a further 20 patients with type 2 diabetes mellitus. There was a significant negative correlation between the log10-transformed (log) plasma visfatin concentration and FMD or creatinine clearance (R=-0.2672, P=.0167; R=-0.2750, P=.0136). Log visfatin was also positively correlated with log urinary albumin excretion (R=0.2305, P=.0397). In addition, it was also found that visfatin had a significant negative correlation with plasma aldosterone (R=-0.2432, P=.0297). In stepwise regression analysis, creatinine clearance, log aldosterone, FMD, and sex showed a significant association with log visfatin (P=.0040, P=.0069, P=.0444, and P=.0487, respectively), and log 8-iso-prostaglandin F2alpha showed a tendency for an association (P=.0515). Pioglitazone therapy did not affect the visfatin concentration in the 20 pioglitazone-treated patients with diabetes, although a significant elevation of visfatin was obtained in a subgroup of 11 female patients (P=.0381). In conclusion, the current study showed that visfatin is negatively associated with vascular endothelial function evaluated by FMD and creatinine clearance, and positively associated with log urinary albumin excretion. Visfatin was also negatively correlated with circulating aldosterone. Pioglitazone therapy for 12 weeks did not affect the plasma visfatin concentration significantly in all diabetic patients, but a significant elevation in visfatin was obtained in women only.     

Effects of improved glycaemic control on endothelial function in patients with type 2 diabetes

Background: Patients with type 2 diabetes have abnormal endothelial function but it is not certain whether improvements in glycaemic control will improve endothelial function. Aims: To examine the effects of short‐term improved glycaemic control on endothelial function in patients with inadequately regulated type 2 diabetes mellitus. Methods: Forty‐three patients with type 2 diabetes and glycosylated haemoglobin (HbA_1c) > 8.9% were randomized to either improved glycaemic control (IC) n = 21 or usual glycaemic control (UC) n = 22 for 20 weeks. Using high‐resolution B‐mode ultrasound, brachial artery flow‐mediated dilatation (FMD) and glyceryl trinitrate‐mediated dilatation (GTN‐D) were measured at baseline and 20 weeks later. Results: After 20 weeks, HbA_1c was significantly lower in IC versus UC (IC 8.02 ± 0.25% versus UC 10.23 ± 0.23%, P < 0.0001) but changes in FMD and GTN‐D were not different between the groups (FMD at baseline and week 20 IC 5.1 ± 0.56% versus 4.9 ± 0.56% and UC 4.2 ± 0.51% versus 3.1 ± 0.51%; P = 0.23: GTN‐D IC 12.8 ± 1.34% versus 10.4 ± 1.32% and UC 13.7 ± 1.2% versus 12.7 ± 1.23%; P = 0.39). In the IC group weight increased by 3.2 ± 0.8 kg after 20 weeks compared to 0.02 ± 0.70 kg in UC (P = 0.003). Blood pressure and serum lipid concentrations did not change in either group. Conclusions: Short‐term reduction of HbA_1c levels did not appear to affect endothelial function in patients with type 2 diabetes and previously poorly regulated glycaemic control. (Intern Med J 2001; 31: 322–328)     

Autonomic, endothelial function and the analysis of gait in patients with type 1 and type 2 diabetes

Abstract Ten control subjects and 20 subjects with type 1 and type 2 diabetes were examined to compare autonomic, endothelial function and gait characteristics while walking in a linear path and during turns. To measure deviations in gait, timing was recorded from foot sensors worn in the shoes and from accelerometers (2 axis) mounted on the head, shoulder, hips, knees and ankles, bilaterally. The results of the experiments showed that subjects with diabetes took additional steps when walking in a linear path and during turns. They also took significantly more time to walk a given distance (greater than 30%) than control subjects. Accelerometry data also revealed that there was an increase in flexion/extension and lateral movement at the major joints in the body. Joint movements at the hip, knee, ankle and shoulders showed a 50 and 100% increase in movement at the joints during gait for subjects with diabetes compared to control subjects. These findings suggest that individuals with type 1 and type 2 diabetes can have significant problems in both the timing and quality of gait. These impairments are likely secondary to dysfunction of the vestibular, somatosensory and autonomic system in diabetics. Data here showed at least a 50% impairment in local tissue blood flow and autonomic function in subjects in both type 1 and type 2 diabetes compared to control subjects.     

A simplified indication of metabolic syndrome to recognize subjects with a moderate risk to develop type 2 diabetes mellitus in a large Italian sample

To propose a simplified tool to recognize subjects with a moderate risk to develop type 2 diabetes mellitus (Type 2 DM): this method would take into account only variables from metabolic syndrome definitions which are cheaply assessable. A total of 3,003 employees without diabetes in Italy who attended one annual health examination between 2009 and 2012 were enrolled in this cross-sectional study. A questionnaire was administered along with the annual health examination to record personal and familiar anamnesis. To identify Type 2 DM-prone individuals, the diabetes predictive model by Stern MP et al. was used. Then a multiple logistic regression model was developed using the predicted probability 20 %+ of developing Type 2 DM as the outcome variable and a panel of easily measurable continuous baseline characteristics as explanatory variables (waist circumference, WC; body mass index, BMI; and systolic blood pressure, SBP). The optimism-adjusted area under the curve of the proposed model receiver-operating characteristic (ROC) is 0.90. The effects of the explanatory variables on the presumed Type 2 DM risk are summarized by the following adjusted odds ratio values: 2.65 for SBP (P < 0.001), 2.01 for WC (P = 0.04) and 4.64 for BMI (P < 0.001). The satisfactory ROC of the proposed model suggests the importance of simple assessments in the prognostic information on Type 2 DM risk. Such ease of use may be particularly relevant in populations facing the transition from traditional to industrial food who do not have a sophisticated health service yet.     

Cost-utility of empagliflozin in patients with type 2 diabetes at high cardiovascular risk

Aims

In the Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes (EMPA-REG) trial, empagliflozin reduced cardiovascular and all-cause mortality in type 2 diabetes (T2D) patients at high cardiovascular risk. We sought to estimate the cost-effectiveness of empagliflozin versus standard treatment for the prevention of cardiovascular morbidity and mortality in patients with T2D.