Impaired left-ventricular function in insulin-dependent diabetic patients with increased urinary albumin excretion

Cardiac function was studied in 30 patients with insulin-dependent diabetes mellitus. Three groups, matched for age and diabetes duration, were defined as: group I (n = 10), normal urinary albumin excretion less than 30 mg 24 h-1; group II (n = 10), incipient diabetic nephropathy (urinary albumin excretion in the range of 30-300 mg 24 h-1); and group III (n = 10), clinical diabetic nephropathy (urinary albumin excretion greater than 300 mg 24 h-1). Ten non-diabetic subjects matched for sex and age served as controls. The left-ventricular end-diastolic volume measured by radionuclide cardiography was, at rest and during exercise, lower in group II and III compared with controls (p less than 0.05), while intermediate values were found in group I. The cardiac output was similar in the control group and group I; it was reduced, but not significantly so (p = 0.10), in group III and was significantly lower in group II (p less than 0.05). Stroke volume was also lower in group II and III than in controls (p less than 0.05), but not so in group I. These differences could not be explained by differences in metabolic control, blood pressure, blood volume status, degree of autonomic neuropathy or frequency of coronary heart disease. Our results might suggest that insulin-dependent diabetic patients with slightly but persistently elevated urinary albumin excretion have reduced diastolic compliance of the left-ventricle leading to impaired cardiac performance.(ABSTRACT TRUNCATED AT 250 WORDS)     

Severity of glomerulopathy predicts long-term urinary albumin excretion rate in patients with type 1 diabetes and microalbuminuria.

OBJECTIVE: To investigate whether the degree of glomerular structural lesions in young patients with type 1 diabetes and microalbuminuria was associated with urinary albumin excretion rate (AER) 6 years later and whether the AER level was influenced by blood glucose control, blood pressure, or glomerular filtration rate (GFR). RESEARCH DESIGN AND METHODS: There were 17 young adults with type 1 diabetes and microalbuminuria, 8 men and 9 women with mean age 20 years (95% CI: 18-22) and duration of diabetes of 11 years (10-13), who participated in a 6-year prospective study. Kidney biopsies (measurements of basement membrane thickness [BMT] and mesangial and matrix volume fractions) and GFR were performed at baseline. AER and HbA1c were measured at least three times a year and blood pressure once a year. RESULTS: In a multivariate analysis, baseline BMT and mean 6-year HbA1c contributed significantly to AER at the end of the study (R2 = 0.69, P < 0.01). When mesangial volume fraction replaced BMT as the independent variable, this parameter and AER at baseline predicted the AER at 6 years (R2 = 0.55, P < 0.55). Mesangial volume fraction and BMT (in separate analysis) contributed significantly to change in AER during the study. During the study, neither AER (30 micrograms/min [19-40] to 16 micrograms/min [7-90]) nor blood pressure (96 mmHg [92-102] to 95 mmHg [91-98]) changed significantly in the group. However, HbA1c was reduced from 10.3 (9.6-11.0) to 8.4% (7.8-9.1) (P < 0.01). CONCLUSIONS: In young patients with microalbuminuria, the long-term urinary AER was predicted by the degree of glomerular structural changes and associated with blood glucose control, but not with blood pressure or GFR.     

Urinary albumin excretion rate is associated with increased ambulatory blood pressure in normoalbuminuric type 2 diabetic patients

OBJECTIVE: To evaluate the 24-h blood pressure profile in normoalbuminuric type 2 diabetic patients. RESEARCH DESIGN AND METHODS: A cross-sectional study was conducted in 90 type 2 diabetic patients with a urinary albumin excretion rate (UAER) <20 microg/min on two occasions, 6 months apart (immunoturbidimetry). Patients underwent clinical and laboratory evaluations. Ambulatory blood pressure monitoring and echocardiograms were also performed. RESULTS: UAER was found to correlate positively with systolic doctor's office blood pressure measurements (r = 0.243, P = 0.021) and ambulatory blood pressure (24 h: r = 0.280, P = 0.008) and left ventricular posterior wall thickness (r = 0.359, P = 0.010). Patients were divided into four groups according to UAER (<5, > or =5-10, > or =10-15, and > or =15-20 microg/min). Systolic blood pressure parameters for the 1st, 2nd, 3rd, and 4th groups, respectively, were 123.0 +/- 10.6, 132.5 +/- 15.0, 139.0 +/- 23.4, and 130.7 +/- 8.0 mmHg for 24-h blood pressure (ANOVA P = 0.004) and 48.4 +/- 6.0, 54.5 +/- 11.2, 58.8 +/- 15.6, and 57.6 +/- 8.0 mmHg for 24-h pulse pressure (ANOVA P = 0.003). A progressive increase in the prevalence of diabetic retinopathy was observed from the 1st to the 4th UAER group: 27.3, 43.8, 45.5, and 66.7% (P = 0.029 for trend). CONCLUSIONS: In type 2 diabetic patients, UAER in the normoalbuminuric range is positively associated with systolic ambulatory blood pressure indexes, left ventricular posterior wall thickness, and diabetic retinopathy, suggesting that intensive blood pressure treatment may prevent diabetes complications in these patients.     

Assessment of small and large fiber function in long-term type 1 (insulin-dependent) diabetic patients with and without painful neuropathy

Twelve neural function tests (thermal discrimination thresholds, pain perception thresholds to heat and cold stimuli, vibration perception thresholds, and motor and sensory nerve conduction velocities) were assessed in the lower and upper extremities of 60 long-term type 1 diabetic patients. Thirty patients were asymptomatic (group 1) and 30 patients had painful neuropathy (group 2), predominantly originating in the distal lower limbs (group 2a; n = 20) or in the distal upper limbs (group 2b; n = 10). There were no significant differences between the groups with regard to age, duration of diabetes or glycemic control. Eleven of the 12 functions tested (6 in lower and upper limbs, respectively) were significantly diminished in both groups of diabetics as compared to age-matched control subjects. Group 2a had significant impairment in 5 of 6 parameters of the lower limbs, while in group 2b only 1 of 6 functions of the upper limbs was diminished. In the whole diabetic group, the most frequent abnormality was an elevated threshold for thermal sensation in the foot. Significant correlations between small and large fiber abnormalities were observed predominantly in the foot. Selective affection of small or large fiber functions showed different patterns in the arms and in the legs. In the upper extremities selective impairment in nerve conduction was predominant, while in the lower extremities it was thermal sensation. These findings suggest that both generalized and selective small or large fiber affection may occur in long-term type 1 diabetic patients. Dysfunction of both modalities is more severe in the lower limbs, when painful symptoms have developed in this region.     

Increased urinary excretion of digoxin-like immunoreactive substance by insulin-dependent diabetic patients: a linkage with hypertension?

Excretion of digoxin-like immunoreactivity (DLIS) was measured by RIA in timed overnight urine collections from 91 normotensive nondiabetic subjects and 104 normotensive insulin-dependent diabetic (IDDM) patients. The mean +/- SD DLIS excretion rate for the diabetic patients significantly exceeded that for the controls (73 +/- 41 vs 63 +/- 36 pg/min, P = 0.024). In both groups, the mean DLIS excretion rates for men were significantly higher (P = 0.0014, P = 0.006) than for women. In the controls, the DLIS excretion rate significantly correlated with the urinary excretion rate of creatinine (P less than 0.01), Na+ (P less than 0.05), and K+(P less than 0.05), and with the subjects' body weight (P less than 0.01), body mass index (P less than 0.05), and systolic blood pressure (P less than 0.05). In the diabetics, the DLIS excretion rate was significantly correlated with body weight (P less than 0.05) and with urinary excretion rates for albumin (P less than 0.01), creatinine (P less than 0.01), Na+ (P less than 0.05), and K+(P less than 0.05). Our data indicate that: (a) increased amounts of a cardiac glycoside-like substance (or a group of substances) are excreted in the urine of IDDM patients; (b) the urinary excretion of DLIS seems to depend on glomerular filtration rate and physiocochemical properties of glomerular membrane, as well as on subjects' body mass; and (c) because cardiac glycoside-like substances may increase peripheral vascular resistance, increased urinary excretion of DLIS by IDDM patients may indicate a tendency to develop hypertension.     

Autonomic dysfunction and urinary albumin excretion rate are associated with an abnormal blood pressure pattern in normotensive normoalbuminuric type 1 diabetic patients

OBJECTIVE: To analyze the role of autonomic function and other possible factors associated with a blunted fall in nocturnal blood pressure. RESEARCH DESIGN AND METHODS: A total of 39 normotensive normnoalbuminuric type 1 diabetic patients were studied. Glomerular filtration rate (51Cr-EDTA technique), extracellular volume (51Cr-EDTA distribution volume), and urinary albumin excretion rate (UAER) (by radioimmunoassay) were measured. The subjects' 24-h ambulatory blood pressure and a 24-h electrocardiogram were recorded simultaneously Heart rate variability was calculated in the time domain for 24 h, in the frequency domain at night, at rest in the supine position, and during tilt. Patients were classified according to diastolic blood pressure (dBP) night/day ratio as dipper patients (< or =0.9) and nondipper patients (>0.9). RESULTS: Nondipper patients presented a higher low-frequency (LF) component (a sympathetic index) and higher LF/high-frequency (HF) ratio during sleep than dipper patients (0.29 +/- 0.12 vs. 0.19 +/- 0.10 normalized units [n.u.], P = 0.008; and 0.98 +/- 0.53 vs. 0.55 +/- 0.45 n.u., P = 0.007, respectively). At rest, the LF component in nondipper patients (0.38 +/- 0.13 n.u.) was higher than in dipper patients (0.27 +/- 0.12 n.u., P = 0.04). After the tilt, nondipper patients did not show an increase in the LF component (P = 0.32), but in dipper patients, the increase was significant (P = 0.001). In both groups, tilting promoted a decrease in the HF component (a parasympathetic index). In a stepwise multiple linear regression analysis, the LF component during sleep and the UAER accounted for 24% of the variability in the dBP night/day ratio. CONCLUSIONS: The predominance of sympathetic activity and increased levels of UAER, although within the normal range, are associated with a blunted fall in nocturnal dBP in normoalbuminuric normotensive type 1 diabetic patients.     

Vitamin D levels and asymptomatic coronary artery disease in type 2 diabetic patients with elevated urinary albumin excretion rate

OBJECTIVE

Coronary artery disease (CAD) is the major cause of morbidity and mortality in type 2 diabetic patients. Severe vitamin D deficiency has been shown to predict cardiovascular mortality in type 2 diabetic patients.

RESEARCH DESIGN AND METHODS

We investigated the association among severe vitamin D deficiency, coronary calcium score (CCS), and asymptomatic CAD in type 2 diabetic patients with elevated urinary albumin excretion rate (UAER) >30 mg/24 h. This was a cross-sectional study including 200 type 2 diabetic patients without a history of CAD. Severe vitamin D deficiency was defined as plasma 25-hydroxyvitamin D (p-25[OH]D3) <12.5 nmol/L. Patients with plasma N-terminal pro-brain natriuretic peptide >45.2 ng/L or CCS ≥400 were stratified as being high risk for CAD (n= 133). High-risk patients were examined by myocardial perfusion imaging (MPI; n = 109), computed tomography angiography (n = 20), or coronary angiography (CAG; n = 86). Patients’ p-25(OH)D3 levels were determined by high-performance liquid chromatography/tandem mass spectrometry.

RESULTS

The median (range) vitamin D level was 36.9 (3.8–118.6) nmol/L. The prevalence of severe vitamin D deficiency was 9.5% (19/200). MPI or CAG demonstrated significant CAD in 70 patients (35%). The prevalence of CCS ≥400 was 34% (68/200). Severe vitamin D deficiency was associated with CCS ≥400 (odds ratio [OR] 4.3, 95% CI [1.5–12.1], P = 0.005). This association persisted after adjusting for risk factors (4.6, 1.5–13.9, P = 0.007). Furthermore, severe vitamin D deficiency was associated with asymptomatic CAD (adjusted OR 2.9, 1.02–7.66, P = 0.047).

CONCLUSIONS

In high-risk type 2 diabetic patients with elevated UAER, low levels of vitamin D are associated with asymptomatic CAD.Coronary artery disease (CAD) is the major cause of morbidity and mortality in patients with type 2 diabetes. Diabetic patients have been shown to have an increased prevalence of subclinical CAD (1). Coronary calcium score (CCS), a noninvasive screening method quantifying the extent of coronary artery calcification (CAC), is generally accepted as a marker of increased cardiovascular risk. CCS has been shown to correlate strongly with histopathologic CAD (2,3) and the development of adverse coronary events (4,5).Results from cross-sectional studies examining the relation between low vitamin D levels and presence of CAD in the general population are conflicting (6,7). In type 1 diabetic patients, vitamin D deficiency has been shown to independently predict both prevalence and development of CAC (8). However, a study in type 2 diabetic patients with a history of cardiovascular disease (CVD) found a strong inverse association between low vitamin D levels and prevalent coronary, cerebrovascular, or peripheral CVD (9). Furthermore, low vitamin D levels have been associated with increased cardiovascular morbidity and mortality in the general population (10) and in patients with type 1 (8) and 2 (11) diabetes.To expand our knowledge on the increased all-cause and cardiovascular mortality seen in type 2 diabetic patients with low vitamin D levels, the current study investigated the association between severe vitamin D (plasma 25-hydroxyvitamin D [p-25(OH)D3]) deficiency and the presence of elevated CAC and asymptomatic CAD in type 2 diabetic patients with elevated urinary albumin excretion rate (UAER) >30 mg/24 h.     

2型糖尿病微血管病变患者血小板平均体积与尿清蛋白排泄率的关系

目的探讨血小板平均体积(MPV)及尿清蛋白排泄率(UAER)在糖尿病微血管病变患者中测定的意义及关系。方法对67例糖尿病微血管病变患者分别采用全自动血细胞分析仪和免疫散射比浊法测定血小板平均体积及UAER,并与20例糖尿病无血管并发症组和30例正常对照组比较。结果糖尿病微血管病变组血小板平均体积(11．43±2．00)及UAER(2．07±0．62)均显著高于正常对照组8．69±1．85(P＜0．01)、0．97±0．18(P＜0．01)和糖尿病无血管并发症组9．02±1．91(P＜0．01)、1．05±0．23(P＜0．01);而糖尿病无血管并发症组与正常对照组间血小板平均体积及UAER差异无统计学意义(P＞0．05);糖尿病微血管病变患者大量清蛋白尿组MPV(12．29±2．11)显著高于正常清蛋白尿组10．02±0．90(P＜0．01)和微量清蛋白尿组11．08±1．82(P＜0．05),微量清蛋白尿组显著高于正常清蛋白尿组(P＜0．05)。结论MPV及UAER的检测,对糖尿病微血管病变的发生、发展及早期诊断和治疗具有重要意义,是反映糖尿病徽血管病变范围及病变程度的指标。     

A longitudinal evaluation of urinary glycosaminoglycan excretion in normoalbuminuric type 1 diabetic patients.

BACKGROUND: Previously, we found high urinary glycosaminoglycan (GAG) concentration, together with an altered electrophoretic pattern, in normoalbuminuric type 1 diabetic subjects with hemoglobin A(1c) (HbA(1c)) > or =8.0%. The purpose of this study was long-term evaluation of GAG excretion variations in these patients compared to those with HbA(1c) < 8.0% at baseline who maintained better metabolic control over time. METHODS: We enrolled 26 normotensive, normoalbuminuric type 1 diabetic patients and divided them into two groups according to mean HbA(1c) levels during the follow-up period. GAGs were isolated from 24-h urine samples on two separate occasions, at baseline and after a mean (+/-SD) follow-up of 6.8+/-1.1 years. RESULTS: All patients remained normoalbuminuric at follow-up, and had normal urinary alpha(1)-microglobulin levels. In patients with HbA(1c) <8.0%, total GAG levels and low sulfated chondroitin sulfate-proteoglycan/chondroitin sulfate ratio were almost unchanged during the follow-up period. In contrast, these increased in patients with HbA(1c) > or =8.0% and were significantly related to both HbA(1c) levels and the duration of poor glycemic control. CONCLUSIONS: Our results show a strong influence of hyperglycemic environment on GAG metabolism in diabetes and indicate that the distribution pattern of urinary GAGs, besides their total concentration, may be predictive of altered GAG metabolism in type 1 diabetes.     

Decreased distensibility of resistance vessels of the skin in type 1 (insulin-dependent) diabetic patients with microangiopathy

The distensibility of the resistance vessels of the skin at the dorsum of the foot was determined in 11 long-term type 1 (insulin-dependent) diabetic patients with nephropathy and retinopathy, nine short-term type 1 diabetic patients without clinical microangiopathy and in nine healthy non-diabetic subjects. Blood flow was measured by the local 133Xe-xenon washout technique in a vascular bed locally paralysed by the injection of histamine. Blood flow was measured before, during and after a 40 mmHg increase of the vascular transmural pressure, induced by head-up tilt. The mean increase in blood flow during head-up tilt was only 24% in diabetic subjects with and 48% in diabetic patients without clinical microangiopathy, compared with 79% in normal non-diabetic subjects (P less than 0.0005 and P less than 0.05, respectively). An inverse correlation between microvascular distensibility and degree of hyalinosis of the terminal arterioles in biopsies from the skin was demonstrated (r = - 0.57, P less than 0.001). Our results suggest that terminal arteriolar hyalinosis reduces the microvascular distensibility and probably increases the minimal vascular resistance, thereby impeding hyperaemic responses.     

Collagen binding activity in sera of patients with insulin-dependent (type 1) and non insulin-dependent (type 2) diabetes mellitus

An increase in the capacity of serum IgG to bind to native type IV collagen was observed in patients with both insulin-dependent and non insulin-dependent diabetes mellitus. This increased binding seems to be due to circulating immune complexes in the majority of the cases and to autoantibodies in some. The increased collagen binding activity was associated in postpubertal patients with the presence of diabetic microangiopathy, suggesting a pathogenetic role.     

2型糖尿病患者尿白蛋白排泄率与血脂的关系

目的探讨2型糖尿病患者尿白蛋白排泄率与血脂的关系。方法无尿路感染及原发性肾脏疾病病史的2型糖尿病患者68例,按尿白蛋白排泄率分为正常白蛋白尿组、微量白蛋白尿组和大量白蛋白尿组。检测所有患者的空腹血糖、糖化血红蛋白、血清甘油三酯、总胆固醇、低密度脂蛋白胆固醇、高密度脂蛋白胆固醇。结果微量白蛋白尿组和大量白蛋白尿组空腹血糖、糖化血红蛋白、收缩压和舒张压均高于正常白蛋白尿组;大量白蛋白尿组的空腹血糖、糖化血红蛋白、收缩压和舒张压均较微量白蛋白尿组高。微量白蛋白尿组和大量白蛋白尿组血清甘油三酯、总胆固醇和低密度脂蛋白胆固醇水平均高于正常白蛋白尿组;大量白蛋白尿组血清甘油三酯、总胆固醇和低密度脂蛋白胆固醇较微量白蛋白尿组高。3组血清高密度脂蛋白胆固醇水平无统计学意义(P>0.05)。结论2型糖尿病患者尿白蛋白排泄率不仅与糖代谢指标和血压有关,与血脂也存在相关性,提示脂质代谢紊乱在糖尿病肾病的发生、发展中可能起一定的作用。     

LDL-apheresis in patients with nephrotic syndrome: effects on serum albumin and urinary albumin excretion

BACKGROUND: Hyperlipidemia is a common feature of the nephrotic syndrome (NS). From retrospective studies, it has been suggested that aggressive lipid-lowering with low-density lipoprotein apheresis (LDL-A) may not only improve dyslipidemia but also decrease urinary albumin excretion and increase serum levels of albumin in patients with focal segmental sclerosis. METHODS: Seven patients (6 males) aged 44 +/-7 years (SEM) with NS (duration 29+/-11 months) of diverse etiologies were investigated in a prospective study. A fixed protocol of LDL-A was designed for treatment twice-a-week for 3 weeks and then once a week for 7 weeks. The effects of LDL-A on lipid parameters (cholesterol, triglycerides, HDL, Lp(a), apo A-I, apo B) and renal parameters (iohexol clearance, serum albumin and 24-h urinary albumin excretion) were evaluated. RESULTS: Following treatment by LDL-A a remission in the severity of the NS was observed in two patients whereas a clear improvement was observed in four of the patients. A small, but significant (P<0.05), increase in serum albumin levels from 20+/-2 to 24+/-2 g L(-1) was noted after LDL-A. As expected, serum lipid parameters improved during LDL-A, and significant decreases in serum cholesterol, apo B and plasma Lp(a) were observed at different time-points of LDL-A. Conversely, no significant changes in either triglyceride, HDL or apo A-I levels were observed during LDL-A. CONCLUSIONS: The present uncontrolled prospective study shows that LDL-A causes a rapid 30-40% decrease in serum cholesterol and plasma Lp(a) levels in patients with NS. The present prospective study also suggests that short-term LDL-A treatment may increase serum albumin levels in nephrotic patients.     

Effects of losartan and amlodipine on urinary albumin excretion and ambulatory blood pressure in hypertensive type 2 diabetic patients with overt nephropathy

OBJECTIVE: Few studies have assessed whether 24-h blood pressure control induced by antihypertensive agents improves macroalbuminuria in hypertensive type 2 diabetic patients with overt nephropathy. We evaluated the effects of losartan and amlodipine on 24-h blood pressure, autonomic nervous activity, and albuminuria in these patients. RESEARCH DESIGN AND METHODS: In this open-label, parallel-prospective, randomized study, 44 patients were treated with losartan and 43 with amlodipine for a 12-week titration phase and a maintenance phase for a maximum of 12 weeks. Twenty-four-hour blood pressure and urinary albumin excretion were measured before and during treatment. Simultaneously, power spectral analysis of heart rate was performed to evaluate low frequency (LF) and high frequency (HF) components and LF-to-HF ratios as an index of sympathovagal balance. RESULTS: Losartan decreased (P < 0.001) mean blood pressure from 162/91 to 150/82 mmHg during daytime and from 146/82 to 137/74 mmHg during nighttime (systolic/diastolic). Amlodipine also decreased (P < 0.001) blood pressure from 159/90 to 147/82 mmHg during daytime and from 143/81 to 131/72 mmHg during nighttime. LF and HF components and nighttime-to-daytime ratios for the LF-to-HF ratios did not differ during treatment in two groups, showing no changes in the diurnal autonomic nervous rhythm. Losartan decreased (P < 0.001) 24-h urinary albumin excretion from 810 mg/day (95% CI 780-1,140) to 570 (510-910). Amlodipine, however, did not decrease (P = 0.893) albuminuria (790 mg/day [780-1,170] vs.790 [710-1,260]). CONCLUSIONS: These results suggest that in type 2 diabetes with overt nephropathy, 24-h blood pressure regulation alone is inadequate to reduce macroalbuminuria and additional effects of losartan are crucial for antiproteinuric action.