Nitric oxide system is involved in glomerular hyperfiltration in Japanese normo- and micro-albuminuric patients with type 2 diabetes

Glomerular hyperfiltration plays a pathogenic role in the early stages of diabetic nephropathy. Experimental studies in laboratory animals suggest that nitric oxide (NO) might be involved in the pathogenesis of glomerular hyperfiltration. We performed a cross-sectional study to determine the relationship between diabetic glomerular hyperfiltration and the NO system. Normoalbuminuric (n=41), microalbuminuric (n=25), and macroalbuminuric (n=16) patients with type 2 diabetes were recruited in this study and compared with age-matched 84 non-diabetic control subjects. Creatinine clearance and urinary NO(2)(-)/NO(3)(-) excretion (urinary NOx) were measured, and the expression of endothelial cell nitric oxide synthase (ecNOS) was evaluated in human renal tissues. Glomerular hyperfiltration was present in 19 (37.5%) and nine (36.6%) of normoalbuminuric and microalbuminuric type 2 diabetic patients, respectively. The urinary NOx was significantly higher in normoalbuminuric patients compared with normal subjects. Creatinine clearance correlated significantly with urinary NOx in normoalbuminuric and microalbuminuric patients. Immunohistochemical staining intensities for ecNOS were significantly increased in glomerular endothelial cells of microalbuminuric type 2 diabetic patients as compared with the control subjects. These results suggest that NO may contribute to the pathogenesis of glomerular hyperfiltration in Japanese type 2 diabetic patients.     

URINARY EXCRETION OF HUMAN EPIDERMAL GROWTH FACTOR IN THE VARIOUS STAGES OF DIABETIC NEPHROPATHY

Epidermal growth factor (EGF) is a polypeptide mitogen first isolated from mouse submaxillary glands and later from human urine. We have examined the pattern of urinary excretion of human EGF (hEGF) in normal subjects and in diabetic patients with varying degrees of nephropathy. hEGF was measured by homologous radioimmunoassay and expressed in terms of urinary creatinine excretion. On the basis of their albumin excretion rate, the diabetic patients were divided into those with normoalbuminuria (albumin excretion rate 3.5 (1.4-9.8) micrograms/min; mean (range)), microalbuminuria (albumin excretion rate 75 (30-128) micrograms/min) and macroalbuminuria (289 (169-879) micrograms/min). The albumin excretion rate for the normal subjects was 3.7 (1.6-9.7) micrograms/min. The mean (range) hEGF excretion (nmol hEGF/mmol creatinine) was 0.69 (0.47-1.29) for 19 healthy subjects, 0.60 (0.16-1.36) for the normoalbuminuric group (n = 18; NS), 0.47 (0.10-0.83) for the microalbuminuric patients (n = 19; P less than 0.001 vs controls and normoalbuminuric diabetics) and 0.38 (0.10-0.63) for the macroalbuminuric group (n = 18; P less than 0.001 vs controls and normoalbuminuric diabetics). There was an inverse correlation between albumin excretion rate and hEGF: creatinine ratio (r = -0.49; P = 0.02). These results show a progressive decline in hEGF excretion in diabetic patients with varying degrees of nephropathy and do not support the hypothesis that increased kidney size seen in early nephropathy is due to excessive amounts of EGF in the urine.     

Activity of the unstimulated renin-angiotensin-aldosterone system in type 1 diabetic patients with and without proteinuria

There have been conflicting reports of the activity of the renin-angiotensin-aldosterone system in diabetes. We studied the activity of the unstimulated renin-angiotensin-aldosterone system in 73 consecutive Type 1 diabetic patients with varying degrees of albuminuria. Patients with elevated albumin excretion rates had elevated median plasma renin activity (macroalbuminuric 2.2, range 0.5-8.2, p less than 0.05; microalbuminuric 2.3, 0.7-7.1, p less than 0.001; vs normoalbuminuric 1.0, 0.2-4.5 nmol l-1 h-1) and higher systolic blood pressure (macroalbuminuric 141 +/- 27 vs normoalbuminuric 116 +/- 13 mmHg, mean +/- SD, p less than 0.01) compared with those with normal albumin excretion rates. Aldosterone secretion and function were normal in all patients studied.     

Asymmetrical dimethylarginine is related to renal function, chronic inflammation and macroangiopathy in patients with Type 2 diabetes and albuminuria.

AIMS: Patients with Type 2 diabetes mellitus (T2DM) and micro- and macroalbuminuria are at increased cardiovascular risk. The endogenous nitric oxide synthase inhibitor asymmetrical dimethylarginine (ADMA) is increased in renal failure and could promote atherosclerosis. To determine the relationship between ADMA, renal albumin excretion rate (AER) and cardiovascular risk, we studied 103 T2DM patients. METHODS: ADMA, symmetrical dimethylarginine (SDMA) and L-arginine were determined by high-performance liquid chromatography in plasma from 36 normo-, 40 micro- and 27 macroalbuminuric patients with T2DM (age 64 +/- 11 years; 38 women) who had comparable age, sex and metabolic parameters. Forty-six patients had macrovascular disease (MVD). RESULTS: ADMA was significantly increased in patients with micro- and macroalbuminuria [median 0.61 (interquartile range 0.55-0.70) micromol/l and 0.62 (0.50-0.79) micromol/l, respectively] compared with those with normoalbuminuria [0.55 (0.48-0.63) micromol/l; both P < 0.05]. SDMA was elevated in micro- and macroalbuminuria [0.57 (0.42-0.80) micromol/l and 0.64 (0.50-0.96) micromol/l] compared with normoalbuminuric subjects [0.44 (0.37-0.53) micromol/l; both P < 0.01]. Patients with increased AER and MVD had higher ADMA and SDMA compared with those without MVD (both P < 0.001). L-arginine was comparable between all groups. ADMA correlated significantly with high-sensitivity C-reactive protein (hsCRP) and glomerular filtration rate (GFR) but not with the extent of albumin excretion, body mass index, fasting glucose, HbA(1c) or plasma lipids. CONCLUSIONS: Increased ADMA in T2DM patients with albuminuria is linked to cardiovascular disease and is associated with renal dysfunction and subclinical inflammation.     

Angiotensin-converting enzyme activity is involved in the mechanism of increased endogenous nitric oxide synthase inhibitor in patients with type 2 diabetes mellitus.

The renin-angiotensin system plays an important role in the elevation of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, in hypertensive patients, so the present study was designed to examine whether angiotensin-converting enzyme (ACE) activity is also involved in the mechanism of ADMA elevation in type 2 diabetes mellitus (NIDDM). A crossover study was performed to determine if ACE inhibition with perindopril (4 mg/day) for 4 weeks decreases serum ADMA concentration and plasma von Willebrand factor (vWF) level (a marker of endothelial injury) in 11 patients with NIDDM. None of the patients was treated with insulin or oral hypoglycemic drugs, and none had major diabetic complications. Before the protocol began, serum ADMA and plasma vWF were significantly higher in the 11 NIDDM patients, when compared with 8 control subjects without diabetes. Perindopril did not affect blood pressure or glucose metabolism, but did significantly decrease serum ADMA and plasma vWF. These results suggest that endothelial injury associated with ADMA elevation may be present even in patients with non-complicated NIDDM, and that increased activity of ACE may be involved in such endothelial dysfunction.     

Lipid hydroperoxide and markers of renal disease susceptibility in African-Caribbean and Caucasian patients with Type 2 diabetes mellitus.

AIMS: The reasons for the increased incidence of diabetic nephropathy in African-Caribbean compared with Caucasian subjects are poorly understood. Increased oxidative stress is linked to the development of endothelial dysfunction and histological abnormalities associated with diabetic renal disease. Therefore, it was assessed whether a marker of oxidative stress, lipid hydroperoxide (LOOH) and endothelial damage, von Willebrand factor (vWF) varied according to ethnic origin in the presence or absence of early diabetic nephropathy. METHODS: Eighty-eight patients with Type 2 diabetes mellitus of African-Caribbean or Caucasian origin without a history of cardiovascular disease or clinical proteinuria were studied. Patients were classified as having microalbuminuria or normal albumin excretion. Fasting plasma vWF and LOOH were measured by an inhouse enzyme-linked immunoassay and ferrous oxidation with xylenol orange (FOX) assay, respectively. The relationship of LOOH to urinary albumin status, the metabolic disturbances of diabetes, blood pressure and ethnic origin were assessed using multivariate analysis. RESULTS: Compared with Caucasian patients those of African-Caribbean origin had higher systolic blood pressure and HDL-cholesterol (157.8 +/- 17.0 vs. 147.8 +/- 24.4, P = 0.041 and 1.6 +/- 0.4 vs. 1.3 +/- 0.5, P = 0.018) but lower total triglycerides (1.3 +/- 0.8 vs. 1.9 +/- 1.1, P = 0.008). LOOH was significantly higher in the African-Caribbean patients compared with Caucasians (5.98 +/- 2.49 vs. 4.49 +/- 2.19, P = 0.006). vWF tended to be higher in microalbuminuric patients but showed no variation with ethnicity. In logistic regression analysis, LOOH was the only independent predictor of a raised albumin excretion rate (P = 0.008). In multiple regression analysis, African-Caribbean ethnicity (P = 0.020) HDL-cholesterol (P = 0.036), total triglycerides (P = 0.002) and a raised albumin excretion rate (P = 0.002) were independent predictors of LOOH. CONCLUSIONS: In this group of Type 2 diabetic patients an increase in LOOH is associated with abnormal urinary albumin excretion. African-Caribbean origin was a determinant of LOOH independently of microalbuminuria. It is postulated that increased oxidative stress is of pathophysiological significance in accelerating the development of renal disease in African-Caribbean patients.     

Endothelium-dependent and independent vasodilation studied at normoglycaemia in Type I diabetes mellitus with and without microalbuminuria

Aims/hypothesis. We examined whether endothelial function is impaired in patients with Type I (insulin-dependent) diabetes mellitus under conditions of near-normoglycaemia compared with age-matched healthy control subjects. Our aim was to determine whether microalbuminuria is associated with endothelial dysfunction in Type I diabetes. Methods. Endothelial function, measured as post-ischaemic flow-mediated dilatation of the brachial artery using ultrasound, was compared among 17 microalbuminuric and 17 normoalbuminuric diabetic patients, and 17 control subjects. Glyceryl trinitrate-mediated dilatation of the brachial artery was used to measure endothelium-independent function. All diabetic patients were studied at near-normoglycaemia, using insulin and 5 % dextrose infusions to maintain blood glucose between 3.5 and 8.0 mmol/l. Results. Flow-mediated dilatation was significantly lower in microalbuminuric diabetic patients (3.2 ± 0.3 %) compared with normoalbuminuric diabetic patients (5.4 ± 0.6 %) and control subjects (7.9 ± 0.6 %, p < 0.001). Normoalbuminuric diabetic patients also had significantly lower flow-mediated dilatation than control subjects (p = 0.01). Glyceryl trinitrate mediated dilatation was significantly lower in the microalbuminuric patients compared with the control subjects (11.9 ± 1.1 % vs 20.0 ± 1.2 %, p = 0.001). Albumin excretion rate and glycated haemoglobin showed a significant negative independent correlation with flow-mediated dilatation (both p < 0.05). Conclusion/interpretation. Type I diabetic patients show endothelial dysfunction at near-normoglycaemia compared with the control subjects, and this abnormality is more marked in diabetic patients with microalbuminuria. Endothelial dysfunction in Type I diabetes is related to the albumin excretion rate and glycaemic control. The presence of endothelial dysfunction in normoalbuminuric diabetic patients suggests it could precede microalbuminuria as an early risk marker for cardiovascular disease. [Diabetologia (2001) 44: 593–601] Received: 6 November 2000 and in revised form: 11 January 2001     

The prevalence of hypercholesterolaemia and its relationship with albuminuria in insulin-dependent diabetic patients: an epidemiological study.

To assess the prevalence of hypercholesterolaemia and its relationship with metabolic control and urinary albumin excretion in Type 1 diabetic patients, all 1577 insulin-dependent patients attending the outpatient clinic at the Steno Memorial Hospital were studied. None had previously received lipid-lowering drugs. Hypercholesterolaemia, defined as plasma concentration of cholesterol above 6.4 mmol l-1 was found in 156 patients (10%) (95%) confidence intervals (CI) 8.4-11.5%) compared with 11% in the Danish background population. Compared with the normolipidaemic diabetic patients, the hyperlipidaemic patients were older (42 vs 37 years: p less than 0.001, 95% CI for difference in means 3-7 years), they had a higher glycosylated HbA1C (9.2 vs 8.6%, p less than 0.001, 95% CI for difference in means 0.4-1.3%) and their urinary albumin excretion was 32 vs 12 mg 24 h-1, p less than 0.001. Of the 1577 diabetic patients, 1084 patients (73%) had normal urinary albumin excretion (UAE less than 30 mg 24 h-1), 255 (17%) had microalbuminuria (UAE 30-300 mg 24 h-1) and 136 (9%) had overt clinical nephropathy (UAE greater than 300 mg 24 h-1). The plasma concentration of cholesterol rose significantly with increasing urinary albumin excretion; normoalbuminuric 4.78 mmol l-1 +/- 1.06 (mean +/- SD); microalbuminuric: 5.12 mmol l-1 +/- 1.23 and macroalbuminuric: 4.89 mmol l-1 +/- 1.38 (p less than 0.001). The influence of metabolic control on the plasma level of cholesterol was of only minor clinical importance.(ABSTRACT TRUNCATED AT 250 WORDS)     

Alterations in serum lipids and apolipoproteins in male Type 1 (insulin-dependent) diabetic patients with microalbuminuria

Summary The relationships between serum lipid, apolipoprotein levels and urinary albumin excretion were investigated in 20 male Type 1 (insulin-dependent) diabetic patients with microalbuminuria (overnight urinary albumin excretion between 10 and 200 g/min), in 18 male Type 1 diabetic patients without microalbuminuria and in 18 male control subjects. In the microalbuminuric patients low density lipoprotein cholesterol was higher than in the control subjects (p<0.05); the high density lipoprotein/low density lipoprotein cholesterol ratio was lower than in the normoalbuminuric diabetic patients (p<0.05), and in the control subjects (p<0.01); apolipoprotein B was higher than in the normoalbuminuric patients (p<0.05); the apolipoprotein A₁/B ratio was lower than in the normoalbuminuric diabetic patients (p<0.05). Serum triglyceride was higher in the microalbuminuric diabetic patients and in the control subjects than in the normoalbuminuric diabetic patients (p<0.05, for both), but was not different between the microalbuminuric diabetic patients and the control subjects. No significant differences between the 3 groups were present with respect to serum cholesterol, high density lipoprotein cholesterol and apolipoprotein A₁. In the 2 combined Type 1 diabetic groups there were significant correlations between urinary albumin excretion and the high density lipoprotein/low density lipoprotein cholesterol ratio (R -0.40, p<0.02), apolipoprotein B (R0.35, p<0.05) and the apolipoprotein A₁/B ratio (R -0.44, p<0.01). These results indicate microalbuminuria related differences in lipid and apolipoprotein levels in male Type 1 diabetic patients, which may contribute to an increased risk of cardiovascular disease.     

Serum and urinary nitric oxide in Type 2 diabetes with or without microalbuminuria: relation to glomerular hyperfiltration

BACKGROUND: Glomerular hyperfiltration is considered as one of the pathophysiological mechanisms for the development of diabetic nephropathy. Oxidative stress is enhanced in patients with diabetes mellitus. Reportedly, nitric oxide (NO) might be involved in the pathogenesis of hyperfiltration. We investigated the relationship between hyperfiltration and NO system, and malondialdehyde (MDA) levels in Type 2 diabetics with/without microalbuminuria. METHODS: In 39 microalbuminuric, 29 normoalbuminuric Type 2 diabetic patients and 32 healthy controls, serum creatinine, nitrite, nitrate, urinary microalbumin, nitrite, nitrate, plasma MDA and estimated glomerular filtration rate (EGFR) values, calculated according to the Cockcroft and Gault formula, were recorded. RESULTS: Serum and urine NO levels were higher in both microalbuminurics and normoalbuminurics than controls. There were no significant differences in EGFR between groups. However, hyperfiltration was determined in 31% of normoalbuminurics and 20% of microalbuminurics. Serum and urine NO levels were higher in patients with hyperfiltration. Plasma MDA levels were significantly elevated in both microalbuminurics and normoalbuminurics when compared with controls. Serum glucose and microalbuminuria were positively correlated in microalbuminuric diabetics. Serum NO levels were also positively correlated with EGFR in both normoalbuminurics and microalbuminurics. HbA1c levels were positively correlated with both urinary albumin excretion and plasma MDA levels in normoalbuminuric diabetics. CONCLUSIONS: Hyperglycemia is associated with an increased NO biosynthesis and lipid peroxidation. Increased oxidative stress may contribute to the high NO levels in Type 2 diabetes. Furthermore, the high NO levels may lead to hyperfiltration and hyperperfusion, which in turn leads to an increase in urinary albumin excretion and thus causes progression of nephropathy in early Type 2 diabetes.     

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.     

Microalbuminuria,insulin sensitivity and haemostatic factors in non-diabetic treated hypertensive men

Abstract. Objective . To examine whether microalbuminuria in non-diabetic, treated hypertensive men is associated with insulin resistance and measures of endothelial function, thrombogenesis and fibrinolysis. Design . Cross-sectional study. Setting . Outpatient clinic in city hospital. Patients . Ninety-two treated hypertensive men, aged 57–77 years, either with a serum cholesterol of ≥ 6.5 mmol L^?1 or smokers, or both. Patients with diabetes mellitus or overnight urinary albumin excretion of > 100 mg 12 h^?1 were excluded. Main outcome measures . Overnight urinary albumin excretion, insulin-mediated glucose disposal (hyper-insulinaemic euglycaemic clamp), blood glucose and plasma insulin during oral glucose tolerance test, fibrinogen, von Willebrand factor and plasminogen activator inhibitor activity. Results . Microalbuminuric patients had increased blood glucose concentrations during the oral glucose tolerance test and higher plasma fibrinogen levels compared with the normoalbuminuric patients. In a randomly selected subgroup (n = 36), insulin-mediated glucose disposal was lower in microalbuminuric than in normoalbuminuric patients, and an inverse relationship between insulin sensitivity and albuminuria (r = –0.37; P = 0.028) was found. This relationship was not significant after adjustment for body-mass index (P = 0.098). In the univariate analyses including all patients, albuminuria was associated with blood glucose, serum creatinine, body-mass index, systolic blood pressure, fibrinogen, von Willebrand factor and cholesterol (negatively). In a multiple regression analysis, only the body-mass index was independently related to urinary albumin excretion. Conclusions . Microalbuminuria was associated with insulin resistance but obesity was a confounding factor. Relationships between microalbuminuria and fibrinogen as well as von Willebrand factor were found, but only in univariate analysis.     

Preperitoneal fat deposition estimated by ultrasonography in patients with non-insulin-dependent diabetes mellitus

Preperitoneal fat is an indicator of visceral fat deposition, which is closely related to atherosclerosis and coronary heart disease in obese patients. We assessed the relationship of preperitoneal fat deposition and various clinical characteristics in 90 patients with non-insulin-dependent diabetes mellitus (NIDDM). Preperitoneal and subcutaneous fat deposition were measured by ultrasonography. In both the male and female diabetics, preperitoneal fat levels were significantly higher than in age-matched healthy subjects. We also determined blood pressures, fasting plasma glucose, glycosylated hemoglobin A1c, serum lipids, fasting immunoreactive insulin (FIRI), daily urinary C-peptide (CPR), serum leptin, urinary albumin excretion and body mass index (BMI). Of these parameters, BMI, FIRI, leptin and daily urinary CPR were positively correlated with preperitoneal fat deposition. Patients with diet therapy alone showed significantly higher preperitoneal fat levels than those receiving insulin therapy. In female, patients with increased preperitoneal fat showed higher prevalence of hypertension than those with decreased fat. Macroalbuminuric patients had a lower preperitoneal fat than microalbuminuric and normoalbuminuric patients. Patients with proliferative retinopathy exhibited lower preperitoneal fat than did those without retinopathy. Preperitoneal fat levels were positively correlated with motor or sensory nerve conduction velocity. Conclusion: The present findings suggest that in NIDDM patients, increased preperitoneal fat deposition is closely associated with obesity, hypertension and hyperinsulinemia, and negatively modulates diabetic microangiopathy including nephropathy, retinopathy and neuropathy.     

Thrombomodulin Levels in Insulin-dependent Diabetic Patients with Microalbuminuria

Thrombomodulin (TM) plays an important role in the regulation of blood coagulation at the endothelial surface. TM is also present in plasma, where an increase of its level seems to reflect endothelial damage. Since microalbuminuria is associated with an increased atherothrombotic risk and is considered an expression of widespread vascular damage, we evaluated plasma thrombomodulin levels, blood pressure, and plasma lipid values in Type 1 diabetic patients with micro- and normoalbuminuria. Thrombomodulin was measured in 12 microalbuminuric (albumin excretion rate 20–200 μg min^?1 in 2 of 3 overnight urine collections) and in 12 normoalbuminuric (albumin excretion rate < 20 μg min^?1) Type 1 diabetic patients matched for age, sex, body mass index, smoking habits, diabetes duration, and glycated haemoglobin. Mean thrombomodulin was significantly higher in micro- than in normalbuminuric group (59.34 ± 3.58 vs 43.56 ± 3.52 ng ml^?1 p < 0.01). Systolic and diastolic blood pressure were significantly higher in micro- than in normoalbuminuric group (p < 0.05). There was a positive correlation between plasma thrombomodulin and albumin excretion rate (p = 0.013, r = 0.49), and between thrombomodulin and diastolic blood pressure (p = 0.023, r = 0.46) in diabetic patients as a whole but not in the individual groups. These findings suggest the presence of an endothelial injury in microalbuminuric patients.     

Abnormal increases in urinary albumin excretion during pregnancy in IDDM women with pre-existing microalbuminuria

Summary We compared urinary albumin excretion during and after pregnancy in 30 insulin-dependent diabetic (IDDM) women with normoalbuminuria and in 12 IDDM women with microalbuminuria (>15 g·min^–1) prior to conception. There was a 6.7-fold increase in the urinary albumin excretion up until the third trimester in the women with pre-existing microalbuminuria, compared with a 3.8-fold increase in the normoalbuminuric women. In both groups of patients the urinary albumin excretion reached a peak during the third trimester with 492±404 g·min^–1 in the microalbuminuric women vs 43±36g·min^–1 in the normoalbuminuric women (p<0.0005). Two women from each of the groups developed eclampsia with diastolic blood pressure over 90 mm Hg, mild or moderate oedema and macroproteinuria. Four of the pregnant women with pre-existing microalbuminuria showed a transient nephrotic syndrome (33.3%) with protein excretion over 3 g in 24-h urine samples during the third trimester. In contrast, this was not observed in any of the normoalbuminuric women (p<0.05). Within 12 weeks after delivery the urinary albumin excretion rates dropped to the pre-conception values in both patient groups. Renal function remained normal during pregnancy in both of the groups, with a physiological increase in creatinine clearance up until the third trimester (26% increase in the normoalbuminuric women vs 22% in the microalbuminuric women). In conclusion, the effect of pregnancy on the urinary albumin excretion in diabetic women with preexisting microalbuminuria is an exaggeration of the increase of albuminuria in diabetic women with normoalbuminuria; normalization occurs within 12 weeks after delivery in all cases. This enhancement of the albumin excretion in the microalbuminuric women cannot be explained by a larger increase in the hyperfiltration during pregnancy.Abbreviations IDDM Insulin-dependent diabetes mellitus - NIDDM non-insulin-dependent diabetes mellitus     

Prothrombin Fragment 1 + 2 and Antithrombin III-Thrombin Complex in Microalbuminuric Type 2 Diabetic Patients

In microalbuminuria there is an increased cardiovascular risk not fully explained by the excess of conventional risk factors. To investigate whether or not microalbuminuria is associated with haemostatic abnormalities in Type 2 diabetic patients, we measured the prothrombin fragment 1 + 2, a marker of thrombin generation, and the thrombin-antithrombin complex, a marker of thrombin neutralization. Plasma levels of prothrombin fragment 1 + 2 and thrombin-antithrombin complex were assayed in 17 microalbuminuric patients (albumin excretion rate, AER 20–200 μg min^?1) and in 17 comparable normoalbuminuric (AER < 20 μg min^?1) Type 2 diabetic patients. Plasma prothrombin fragment 1 + 2 was significantly higher in microalbuminuric than in normoalbuminuric patients (1.09 ± 0.06 vs 0.86 ± 0.04 nM, p = 0.003). Individual values of F1 + 2 were above the upper limit of the normal range in 8/17 microalbuminuric and in none of the normoalbuminuric Type 2 diabetic patients. Plasma thrombin-antithrombin complex values were not significantly different in the two groups and were not correlated with AER. These results suggest that microalbuminuria is associated with a prethrombotic state and a relatively defective thrombin neutralization. Coagulation abnormalities might be part of the cardiovascular risk in microalbuminuric patients.     

Characteristic of Ambulatory Blood Pressure in Normotensive Subjects With Type 2 Diabetes Mellitus

INTRODUCTIONAmbulatory blood pressure monitoring (ABPM) isa wide-used method for BP measurement and known asmore effective than clinic readings, especially inevaluation of circadian variation and identification ofthe so-called "white-coat hypertension". Reduction inthe nocturnal BP fall in ABPM may be associated withan increased risk of end-organ damage including renaland cardiovascular complications in patients withessential hypertension. In diabetic patients,microalbuminuria is a ke…     

Low prevalence of microalbuminuria in normotensive patients with insulin-dependent diabetes mellitus

We studied the prevalence of microalbuminuria (urinary albumin excretion rate [UAER] greater than 20 micrograms/min less than or equal to 200 micrograms/min) as determined in a single, timed, overnight urine collection in 156 normotensive (BP less than 140/90), Albustix negative subjects with type 1 diabetes and its association with arterial blood pressure, the duration of diabetes, levels of glycosylated hemoglobin, body mass index, daily insulin dose and serum cholesterol. Nineteen subjects (12.2%) had a UAER in the microalbuminuric range. The microalbuminuric patients had a significantly longer duration of diabetes, 21 +/- 2 vs 15 +/- 1 years (P less than 0.01), higher diastolic blood pressure, 80 +/- 2 vs 76 +/- 1 mmHg (P less than 0.05) and serum cholesterol concentration, 206 +/- 11 vs 186 +/- 3 mg/dl (P less than 0.05) than did the normoalbuminuric subjects. There were no differences between the normoalbuminuric and microalbuminuric subjects in terms of age, systolic blood pressure, body mass index, daily insulin dose or glycosylated hemoglobin levels. These data indicate that the prevalence of microalbuminuria in type 1 diabetes has probably been overestimated in previous studies due to the inclusion of patients with hypertension. Thus, microalbuminuria, rather than being a predictor of the development of diabetic renal disease, may indicate the presence of diabetic nephropathy with rising blood pressure levels. Further investigation is needed to clarify the relationship between microalbuminuria and coronary risk factors such as serum cholesterol and diastolic blood pressure levels.     

Clinical significance of microalbuminuria in Japanese subjects with non-insulin-dependent diabetes

In order to elucidate the clinical significance of microalbuminuria in non-insulin-dependent diabetes mellitus (NIDDM), 62 Japanese subjects with NIDDM and without proteinuria were followed for three years. After the three-year follow up, four (19%) of 21 microalbuminuric patients—albumin excretion rates (AER) greater than 15 μg/min—developed overt proteinuria, while none of the 42 normoalbuminuric patients did. Among these normoalbuminuric patients, eight patients (19.5%) developed microalbuminuria. The microalbuminuric patients who developed overt proteinuria had higher AER at the beginning of the study than the patients who stayed microalbuminuric. The patients who developed microalbuminuria showed a significantly higher systolic blood pressure in the final year than the patients who stayed normoalbuminuric. These results indicate that microalbuminuria precedes overt proteinuria in Japanese NIDDM, and progression of diabetic nephropathy is rapid and associated with a rise in blood pressure.     

QT dispersion in type 2 diabetic patients with altered diurnal blood pressure rhythm

BACKGROUND: QT dispersion (QTd) is a good prognostic marker in type 2 diabetic patients without previous cardiovascular disease. Diabetic patients with an attenuated decline in nocturnal blood pressure (non-dippers) have been shown to have increased risk of diabetic complications, vascular events and mortality. AIM: The aim of this study was to evaluate the relationship between diurnal blood pressure rhythm, QTd and microvascular complications in type 2 diabetic patients. METHODS: Cardiovascular autonomic function tests, 24-h ambulatory blood pressure monitoring and urinary albumin excretion measurements were performed in healthy controls (n = 25), normoalbuminuric (n = 34) and microalbuminuric (n = 23) type 2 diabetic patients. QTd was assessed manually from 12-lead surface electrocardiograms. RESULTS: Compared with the controls, both normoalbuminuric and microalbuminuric diabetic patients had increased QTd (59.11 +/- 15.86; 60.27 +/- 17.95 vs. 40.48 +/- 10.92, p < 0.001 and p < 0.001, respectively). Similarly, diabetic patients had increased QTd regardless of the presence of autonomic neuropathy. On the other hand, non-dipper diabetic patients had increased QTd compared with the controls and dipper diabetic patients (69.73 +/- 14.50 vs. 40.48 +/- 10.92; 47.84 +/- 9.62 ms, p < 0.001). There was a negative correlation between QTd and diurnal diastolic blood pressure change (r = -0.48, p < 0.0005). CONCLUSION: Patients with type 2 diabetes mellitus were found to have increased QT dispersion irrespective of the presence of diabetic autonomic neuropathy. However, QT dispersion in dipper diabetic patients was similar to the controls. This finding might point out that attenuated decline of nocturnal blood pressure could be a more sensitive marker for autonomic neuropathy.