依那普利对糖尿病者肾血流动力学及尿白蛋白的影响

本文比较了２８例老年糖尿病合并微白蛋白尿患者服依那普利（ｅｎａｌｐｒｉｌ）４周前后尿微量白蛋白、血及尿β２－微球蛋白、肾小球滤过率（以内生肌酐清除率表示）等变化。结果显示服药后尿微白蛋白排泄减少、内生肌酐清除率下降；将２８例分成正常（尿白蛋白＜２５ｍｇ／２４ｈ）及亚临床微白蛋白尿组（２５～１００ｍｇ／２４ｈ），发现前组服药后尿白蛋白排泄率无变化，而后组明显减少；按内生肌酐清除率将２８例分成正常组（＜１２０ｍｌ／ｍｉｎ）和升高组（＞１２０ｍｌ／ｍｉｎ），发现前组服药后内生肌酐清除率无改变，而后组明显降低。因此依那普利对老年糖尿病伴有尿微白蛋白和（或）内生肌酐清除率升高患者的肾脏有更明显的保护作用。     

Effects of low-dose losartan treatment on persistent microalbuminuria in normotensive type 1 diabetic subjects.

To examine the effect of low-dose losartan, an angiotensin II antagonist, on persistent microalbuminuria in normotensive Type 1 diabetes mellitus, 16 subjects with Type 1 diabetes were randomly assigned to two 2-month treatment periods, with either losartan (25 mg/day) or enalapril (5 mg/day) in a single-blind cross-over design. Urinary albumin excretion (UAE), blood pressures, lipids, glycemia, HbA1C, serum potassium and creatinine clearance were measured before and after each treatment period. The UAEs were similarly reduced after both treatments. The median UAE decreased by 27.8%, from 162 (range 65-250) to 117 (34-190) mg/day (p<0.01) after enalapril, and decreased by 25%, from 160 (60-246) to 120 (36-184) mg/day (p<0.01) after losartan. The systolic and diastolic blood pressures also decreased significantly (p<0.05), whereas serum levels of potassium increased (p<0.01) after both treatments. The levels of serum HbA1c, mean fasting glucose, total cholesterol, triglycerides, LDL cholesterol, HDL cholesterol and creatinine clearances were not significantly (p>0.05 in all) changed by either the enalapril or losartan treatment. No significant differences were found between the effects of enalapril and losartan. In conclusion, losartan treatment reduces microalbuminuria as effectively as enalapril in normotensive Type 1 diabetic patients.     

2型糖尿病患者微量白蛋白尿与缺血性心脏病的关系

目的 :探讨 2型糖尿病患者微量白蛋白尿与缺血性心脏病 (IHD)的关系。方法 :6 1例 2型糖尿病患者 ,依有无并发 IHD分为糖尿病并 IHD组 (17例 )和糖尿病不并 IHD组 (44例 ) ,分析比较两组心血管疾病危险因素。再依微量白蛋白尿含量分为微量白蛋白尿组 (2 2例 )和非白蛋白尿组 (39例 ) ,比较两组 IHD的发生率。结果 :糖尿病并 IHD微量白蛋白尿含量明显高于不并 IHD组〔(98.5 1± 48.97) m g/L∶ (9.87± 5 .84) mg/L ,P <0 .0 1〕;微量白蛋白尿组并发 IHD的发生率显著高于非白蛋白尿组 (45 .45 %∶ 17.95 % ,P<0 .0 5 )。结论 :检测微量白蛋白尿是预测 2型糖尿病患者 IHD发病率的有意义的指标。     

The response to antihypertensive therapy is dependent on renal structural changes. A 5-year prospective study of renal biopsy in type 2 diabetic patients with micro-macroalbuminuria

A substantial fraction of patients with diabetes mellitus develop end-stage renal disease. We wanted to study the influence of renal structural changes on the response to treatment of the systemic blood pressure (BP) in type 2 diabetic patients with micro- or macroalbuminuria.MethodsA 5-year observational prospective study of 40 type 2 diabetic patients. Renal biopsy was performed on the indication micro-macroalbuminuria. Twenty-four-hour ambulatory BP and urine sampling were performed yearly. The goal for treatment was a nightly systolic BP below 140 mmHg. Glomerular filtration rate was examined early with plasma clearance of iohexol.ResultsThe nightly systolic BP goal <140 mmHg was achieved in 23 of 40 patients. The nightly systolic BP at start of study was correlated to the mean level of nightly systolic BP during the observation period. The glomerular basement membrane (GBM) thickness (BMT) was of prognostic significance for achieving the goal for antihypertensive treatment. Of the 12 patients with BMT below the median of 478 nm, 9 (75%) achieved the goal, while only 5 of 12 (42%) with BMT above 478 nm achieved a nightly systolic BP <140 mmHg. Also, the degree of interstitial fibrosis correlated to the nightly systolic BP.ConclusionA thick basement membrane and the degree of interstitial fibrosis were associated with a lower number of patients achieving the goal of a nightly systolic BP <140 mmHg.     

Long-term treatment with nifedipine reduces urinary albumin excretion and glomerular filtration rate in normotensive type 1 diabetic patients with microalbuminuria

The aim of the present study was to investigate the renal effects of long-term treatment with the calcium channel blocker nifedipine in normotensive type 1 diabetic patients with microalbuminuria. In a randomized, double-blind trial, 15 type 1 diabetic patients were treated with either nifedipine (n=8; dosage 30 mg/day) or placebo (n=7) for 12 months. At baseline and after 6 and 12 months of therapy, the albumin excretion rate (UAER, radioimmunoassay), glomerular filtration rate (GFR, chromium 51 ethylenediamine tetra-acetic acid clearance) and renal plasma flow (RPF, iodine 125 hippuran clearance) were determined. Nifedipine treatment caused a significant reduction of UAER after 6 and 12 months (median, Q₁/Q₃ in mg/24 h): baseline 84 (65/163); 6 months 35 (23/90),P<0.02; 12 months 39 (15/79),P<0.05. GFR was significantly decreased by nifedipine treatment (baseline 157±15, 6 months 122±8, 12 months 111±47 ml/min;P<0.05, mean ± SEM), whereas RPF remained constant. Nifedipine treatment did not influence systolic (baseline 121±7, 12 months 124±2 mmHg, mean ± SEM) or diastolic (baseline 72±2, 12 months 74±3 mmHg) arterial blood pressure. With placebo treatment no significant alterations of UAER, GFR, RPF and arterial blood pressure were observed. Metabolic control was constant throughout the whole study period. Thus, 1 year's treatment with nifedipine reduces the UAER and GFR in normotensive type 1 diabetic patients without influencing the systemic arterial blood pressure. The data, however, do not present a recommendation for the general use of nifedipine in these patients as the exact intrarenal mechanism of calcium channel blockers in humans remains to be established.     

Circadian changes in blood pressure and their relationships to the development of microalbuminuria in type 1 diabetic patients

Diabetic nephropathy in type 1 diabetic patients, as it is currently understood, progresses in a stepwise fashion from normoalbuminuria to microalbuminuria, then to overt proteinuria and progression to chronic renal failure, and ultimately to end-stage renal disease. The role of early blood pressure changes in relation to diabetic nephropathy is now better understood in light of recent data using ambulatory blood pressure monitoring as a means to monitor blood pressure changes noninvasively throughout the day. Cross-sectional studies with type 1 diabetic patients with microalbuminuria have shown that the normal nocturnal blood pressure often fails to fall normally during sleep. The question of which comes first, microalbuminuria or a rise in blood pressure in patients with type 1 diabetes, was recently addressed in a prospective study. An increase in systolic blood pressure during sleep precedes the development of microalbuminuria and may play a causative role in its development.     

Effect of vitamin E therapy on progression of diabetic nephropathy

Pathogenesis of diabetic nephropathy, which belongs to most serious microangiopathic complications of diabetes, is still not completely clear. Thromboxan A2 and increased oxidation stress are new factors apparently associated with pathogenesis of diabetic nephropathy. It was the aim of the contribution to verify the participation of thromboxan A2 and oxidation stress in the pathogenesis of diabetic nephropathy, as well as to follow the effects of treatment with vitamin E on its progression. In 19 diabetic subjects with microalbuminemia (MA) (age 55.2 +/- 7.6 years), 10 diabetic subjects with normoalbuminemia (NA) (age 54.4 +/- 6.1 years) and in 10 healthy subjects (age 53.6 +/- 9.4) the authors examined the level of malondialdehyde (MLDA) in serum, metabolites of thromboxan A2 (thromboxan B2-TXB2) and prostacyclin PGI2 (6-keto-PGF1 alpha) in urine by means of an RIA method (Isotop, Hungary). The diabetic patients with microalbuminemia were subsequently administered natural vitamin E (EVIT, Rodisna, FRG) at the daily dose of 1200 IU for the period of four months. After two and four months, respectively, MA, MLDA, TXB2 and 6-keto-PGF1 alpha) were examined. The age of the subjects in the two groups was not significantly different. In diabetic subjects with MA, the authors observed significantly higher MLDA levels in serum than in the control individuals (0.55 +/- 0.26 vs. 0.22 +/- 0.02 mumol/l, P < 0.001) and a significant difference occurred also in TBX2 in urine (134.7 +/- 113.8 vs. 27.7 +/- 10.1 ng/12 h, P < 0.001). Increased levels of TXB2 in urine were already present in diabetic subjects with NA as compared with healthy individuals (69.1 +/- 38.8 vs. 27.7 +/- 10.1 ng/12 h, P < 0.05). The treatment with vitamin E caused a significant decrease of MA (93.8 +/- 45.6 vs. 67.95 +/- 28.4 micrograms/min, P < 0.05), MLDA in serum (0.55 +/- 0.26 vs. 0.32 +/- 0.16 mumol/l, P < 0.001). On the basis of our results it is possible to suppose the role of oxidation stress and increased level of thromboxan A2 in the pathogenesis of diabetic nephropathy. The authors also confirmed that the treatment with vitamin E favorably decreases microalbuminemia, while the nephroprotective effect is apparently mediated not only by the antioxidant action, but also the decrease of thromboxan A2 production.     

Risk factors for the progression of microalbuminuria in Japanese type 2 diabetic patients--a 10 year follow-up study

To clarify risk factors for the progression of microalbuminuria in Japanese type 2 diabetic patients, the longitudinal study for 10 years was conducted on 67 outpatients with type 2 diabetes, who had shown no overt proteinuria at baseline. The urinary albumin index (UAI) has been determined based on the mean of at least two random urine samples each year. Categories were defined as normoalbuminuria (UAI < 30.0 mg/g x Cr.), microalbuminuria (30.0 < or = UAI < 300.0), and macroalbuminuria (UAI > or = 300.0). Progression was defined as worsening of the category and/or more than doubling of the baseline UAI value. Multiple logistic regression analysis was performed using age, duration of diabetes, HbA1c, blood pressure, BMI, serum lipids, smoking habits, and alcohol consumption as independent variables and the progression of microalbuminuria as a dependent variable. Age and HbA1c were estimated as significant and independent variables. Furthermore, genetic polymorphisms of angiotensin I-converting enzyme (ACE) and angiotensinogen were analyzed to evaluate the genetic contribution. The D/D genotype of ACE was significantly more common in progressors than in non-progressors. These results suggest that glycemic control and age are important risk factors and the D/D genotype of ACE acts as a risk factor for the progression of microalbuminuria in Japanese type 2 diabetic patients.     

依那普利和伊贝沙坦对糖尿病合并动脉粥样硬化患者血管内皮功能的影响

目的比较血管紧张素转换酶抑制剂（ACEI）依那普利5mg和血管紧张素受体拮抗剂（ARB）伊贝沙坦150mg治疗2型糖尿病合并动脉粥样硬化（AS）患者肱动脉内皮功能的变化。方法确诊的2型糖尿病合并AS患者用完全随机设计，将患者分为ACEI组47例，依那普利开始剂量2．5mg／d，逐渐加至5mg／d；ARB组49例，用伊贝沙坦逐渐加量至150mg／d；对照组48例，不用以上药物。疗程3个月以上。血管B超检查患者治疗前、后肱动脉内皮功能的变化。随访3个月。结果ACEI组患者治疗后肱动脉内皮依赖性舒张功能（EDV）从（3.3±2．7）％提高至（5．6±4．2）％（P=0．001），肱动脉非内皮依赖性舒张功能（EIV）从（12．6±7．4）％提高至（12．8±7．1）％（P=0．835）；ARB组患者治疗后EDV从（4．4±2．9）％提高到（6．2±3．2）％（P=0．038），EIV从（10．6±5．8）％下降到（9．5±4．7）％（P=0．230）；而对照组患者治疗前、后EDV、EIV改变差异元统计学意义（P〉0．05）。治疗前、后EDV、EIV变化值比较，ACEI组和ARB组相比差异元统计学意义（P〉0．05）。结论依那普利和伊贝沙坦均可改善2型糖尿病合并动脉粥样硬化患者的肱动脉内皮功能。     

Intraventricular septal hypertrophy in type 1 diabetic patients with microalbuminuria or early proteinuria

To investigate whether the slightly increased blood pressure that occurs in early diabetic renal disease is associated with hypertensive left ventricular hypertrophy, M-mode echocardiograms were recorded in 11 non-diabetic control subjects and four groups of Type 1 diabetic patients. These were 15 patients without microvascular complications, 10 with microalbuminuria, 12 with early persistent proteinuria, and 8 with established renal impairment. Mean blood pressure was 133/80 mmHg (uncomplicated patients), 143/85 mmHg (microalbuminuria), 147/92 mmHg (early proteinuria) and 158/85 mmHg (renal impairment). Mean intraventricular septal width in the uncomplicated diabetic patients was 9.8 (SE 1.2) mm which did not differ from non-diabetic control subjects. Mean septal width was significantly greater in the other groups (microalbuminuria, 12.7 (1.1) mm, p less than 0.02; proteinuria, 12.0 (0.7) mm, p less than 0.05; renal impairment, 15.5 (1.8) mm, p less than 0.001). Left ventricular mass increased progressively between groups and was significantly increased in those with renal impairment (140 (21) vs 103 (5) g m-2 in uncomplicated patients, p less than 0.05). Septal width in the diabetic population not receiving antihypertensives (n = 37) was significantly correlated with systolic blood pressure (r = 0.45, p less than 0.005) which was the only variable independently related to septal width and ventricular mass. It appears that the slight increase in blood pressure that occurs in microalbuminuria and early proteinuria is frequently associated with hypertensive left ventricular hypertrophy.     

Elevated serum angiotensin I converting enzyme activity in type I,insulin-dependent diabetic subjects with persistent microalbuminuria

Angiotensin I-converting enzyme (ACE), which is synthesized by vascular endothelial cells, is sometimes elevated in diabetic subjects. To determine whether serum ACE is elevated in subjects at high risk of malignant microangiopathy, serum ACE activity in 34 normotensive, type 1 insulin-dependent diabetic subjects with persistent microalbuminuria (30–300 mg/24 h) was compared with that in 30 normotensive, normoalbuminuric type 1 diabetic subjects of the same age [37±15 (mean ±SD) vs 38±14 years], sex (21 M/13 F vs 15 M/15 F), stage of retinopathy (14 vs 16 nil/11 vs 7 background/6 vs 4 preproliferative/3 vs 3 proliferative) and HbA_1c (7.7±1.9 vs 8.2±1.0%). Serum ACE activity of diabetic subjects was also compared with 120 age and sex related healthy controls. Serum ACE activity was higher in subjects with microalbuminuria than in those with normoalbuminuria (406±114 vs 359±97 IU/l;P=0.03), or in controls (307±95 IU/l;P=0.0001). Normoalbuminuric subjects also had higher ACE activity than controls (P=0.02). Serum ACE activity was not related to diabetes duration (r=0.01; NS), HbA_1c (r=0.05; NS), or stage of retinopathy in diabetic subjects (r=0.06; NS), while stage of retinopathy was related to age (r=0.42;P=0.003) and to diabetes duration (r=0.74;P=0.0001) in these subjects. Elevated ACE activity occurs in type 1 diabetic subjects, especially in those with microalbuminuria. This may give early indication of lesions in vascular endothelial cells.This work was presented at the 27th meeting of the European Association for the Study of Diabetes in Dublin, Ireland, 10–14 September 1991, and published in an abstract form: Diabetologia (1991) 34: A17     

Silent myocardial ischemia is associated with autonomic neuropathy and other cardiovascular risk factors in type 1 and type 2 diabetic subjects, especially in those with microalbuminuria

The prevalence of silent myocardial ischemia (SMI) seems to be above average in diabetic subjects. As routine screening is costly, identifying high-risk populations is mandatory. This study aimed to estimate the prevalence of SMI in diabetic subjects and in controls and to define the diabetic population at risk. We studied 353 asymptomatic caucasian subjects (217 with diabetes and 136 controls matched by age, sex, and cardiovascular risk factors) with normal resting ECG. The diabetic group included 39 type 1 and 178 type 2 diabetics (age 57±11 yr, 162 males/55 females). Subjects performed the Treadmill Test (TT) and, when abnormal, underwent single-photon emission computed tomography (SPECT) with exercise testing or dipyridamole injection. Coronary angiography was performed if the SPECT was suggestive of ischemia. TT was positive in 16 (8.5%) diabetics: 3 with type 1 and 13 with type 2. No controls had positive TT. SPECT was performed in 13 subjects and was positive in 10; angiography was performed in 7 and identified significant lesions in all cases. Patients with SMI were older and had a higher prevalence of autonomic neuropathy, hypertension, and dyslipidemia than those without. Microalbuminuria was also higher in the SMI group (613±211 vs 72±245 mg/d; p<0.05). We conclude that diabetic patients aged over 60 with autonomic neuropathy and other cardiovascular risk factors should be screened for the presence of SMI especially if they have increased microalbuminuria.     

Effect of the nurse-led program on blood glucose control and microalbuminuria development in type 2 diabetic populations

Current study was to evaluate whether the nurse-led program can improve glycated hemoglobin (HbA1c) control and reduce the incidence of microalbuminuria in type 2 diabetic mellitus (DM2) populations. A total of 150 DM2 subjects were randomly assigned to the usual-care group and nurse-led program group. Study endpoints included the HbA1c value, the percentage of subjects with HbA1c < 7.0%, the incidence of microalbuminuria, and the rate of adhering to antidiabetic drug at 6 months’ follow-up. At baseline, there was no difference in fasting plasma glucose, HbA1c, proportion of subjects with HbA1c < 7.0%, the use of antidiabetic drug, and urinary albumin-creatinine ratio between these two groups. After 6 months’ follow-up, the mean fasting plasma glucose and HbA1c were lower in the nurse-led program group, as was the proportion of subjects with HbA1c < 7.0%. The median urinary albumin-creatinine ratio and rate of incident microalbuminuria were also lower in the nurse-led program. The nurse-led program was associated with higher odds of achieving HbA1c < 7.0% and a lower incidence of microalbuminuria. After adjusted for covariates, the nurse-led program was still associated with 32% higher odds of achieving HbA1c < 7.0% and 11% lower incidence of microalbuminuria. These benefits were consistent by sex and age, while greater in those with obesity or hypertension (P interaction < .05). The nurse-led program is beneficial for blood glucose control and prevention of microalbuminuria.     

Endothelial dysfunction in Type 2 diabetic subjects with and without microalbuminuria.

AIMS: The primary aim of this study was to determine whether microalbuminuria is associated with endothelial dysfunction in Type 1 diabetes mellitus. The secondary aim was to determine whether any reported biochemical markers of cardiovascular risk are associated with endothelial dysfunction in this group. METHODS: Measurements were made of the vasodilatory responses of the brachial artery to post-ischaemic hyperaemia and to sublingual glyceryl trinitrate (GTN) (causing endothelium-dependent and endothelium-independent dilation, respectively) using a high-resolution ultrasound technique in 18 Type 1 diabetic patients with microalbuminuria, 18 age and sex-matched normoalbuminuric Type 1 diabetic patients and 18 non-diabetic control subjects. RESULTS: There was a significant reduction in flow-mediated dilation (FMD) in microalbuminuric and normoalbuminuric diabetic patients compared with control subjects (2.4% (95% confidence interval (CI) 1.0-3.8%) and 2.3% (95% CI 0.7-3.9%) respectively vs. 6.3% (95% CI 5.1-7.5%), P<0.0001) but no difference in GTN-mediated dilation (14.7% (95% CI 10.7-18.7%) and 15.2% (95% CI 11.2-19.2%) vs. 18.7% (95% CI 16.1-21.3%), P = 0.09). There was no significant difference in FMD, however, between the microalbuminuric group and normoalbuminuric group (P=0.45). FMD was not significantly associated with urinary albumin-creatinine ratio, glycosylated haemoglobin, plasma glucose, lipid or lipoprotein concentrations in diabetic patients. There was a positive correlation between active transforming growth factor (TGF)-beta concentration, a novel biochemical marker of macrovascular disease, and FMD in diabetic patients (r=0.36, P<0.05). GTN-mediated dilation was positively associated with HDL-cholesterol concentration (r = 0.49, P = 0.002) but not with other biochemical variables (including active TGF-beta concentration). Active TGF-beta concentration was not associated with degree of microalbuminuria or other biochemical parameters. CONCLUSIONS: These data suggest that endothelial dysfunction occurs in Type 1 diabetic patients regardless of urine albumin status. Endothelial dysfunction appears therefore to predate the development of microalbuminuria as a marker for the development of coronary artery disease. It is also concluded that low plasma levels of active TGF-beta are associated with an impaired endothelial response and this may provide a useful tool for identifying Type 1 diabetic patients at a greater risk of coronary artery disease.