Continuous subcutaneous insulin infusion is more effective than multiple daily insulin injections in preventing albumin excretion rate increase in Type 1 diabetic patients

Aims To compare the effect of continuous subcutaneous insulin infusion (CSII) and multiple daily insulin injections (MDI) on albumin excretion rate (AER) in Type 1 diabetic patients. Methods In a 3‐year multicentre retrospective observational study, 110 Type 1 diabetic patients treated with CSII were compared with 110 patients treated with MDI matched at baseline for age, sex, diabetes duration and HbA_1c. At entry, 90 patients in each group had normal AER and 20 persistent microalbuminuria. AER, estimated glomerular filtration rate (eGFR), HbA_1c, lipids and blood pressure were assessed. Results HbA_1c was lower in the CSII than in the MDI group (8.1 ± 0.9 vs. 8.4 ± 1.3%; P < 0.005 after 3 years). Blood pressure and eGFR were similar during the study. AER [median (95% confidence interval)], similar at baseline [6.0 μg/min (9, 21) in the CSII group vs. 4.4 (8, 16) in the MDI group, NS] was significantly lower in the patients treated with CSII both at year 2 and at year 3 of follow‐up [4.7 μg/min (6, 12) vs. 6.4 (13, 29), P < 0.002]. This difference was observed even when normo‐ and microalbuminuric patients were analysed separately. Nine patients progressed to microalbuminuria in the MDI group and only one in the CSII group. Nine patients regressed to normoalbuminuria in the CSII group, whereas only two regressed to normoalbuminuria in the MDI group. Conclusions Despite a small benefit in terms of improved glycaemic control, CSII therapy may be useful in decreasing the progressive increase in AER in Type 1 diabetic patients.     

Comparison of Platelet Aggregability in Japanese Type 2 Diabetic Patients With and Without Microalbuminuria

Microalbuminuria is associated with higher cardiovascular morbidity and mortality in Type 2 (non-insulin-dependent) diabetic patients. This study was designed to assess whether Type 2 diabetic patients with microalbuminuria (urinary albumin excretion rate (AER) 20–200 μg min^?1) is associated with alterations in platelet aggregability as compared with those with normal urinary albumin excretion (AER < 20 μg min^?1). Platelet aggregability was compared between 21 Japanese Type 2 diabetic patients with microalbuminuria and 21 individually pair-matched (for age, sex, body mass index, treatment, and HbA_1c level) patients with normoalbuminuria. The in vitro platelet aggregation induced by 1.0 and 3.0 μmol I^?1 ADP and 0.5 and 1.0 mg I^?1 collagen was measured using platelet-rich plasma. No significant differences were observed between the two groups in the values for maximum percent platelet aggregation, percent aggregation at 3 min, and aggregation velocities after adding ADP or collagen. Microalbuminuric patients had significantly higher mean values for systolic (p < 0.004) and diastolic (p < 0.02) blood pressures and plasma fibrinogen level (p < 0.03) as compared with the respective mean values in normoalbuminuric patients. The results suggest that Japanese microalbuminuric Type 2 diabetic patients do not differ in the degree of platelet aggregability as compared with normoalbuminuric patients, despite an increase in certain other coronary risk factors.     

Regression of microalbuminuria in type 1 diabetic patients: results of a sequential intervention with improved metabolic control and ACE inhibitors

Abstract The objective was to evaluate the effect of improved metabolic control and ACE inhibition used sequentially in the treatment of type 1 diabetic patients with microalbuminuria. We studied 44 consecutive type 1 diabetic patients with microalbuminuria not previously treated with ACE inhibitors. Improved metabolic control (optimisation period) was attempted for 6–12 months and patients with persistent microalbuminuria were subsequently treated with ACE inhibitors. Stepwise logistic regression analysis included the variables age, age at diabetes onset, duration of diabetes, HbA1c, initial albumin excretion rate (AER) and mean blood pressure as predictors of final AER. Thirty per cent of patients regressed to normoalbuminuria after the optimisation period, and 58% of them maintained normal AER 4.5±1.3 years later (3–7 years). Patients achieving normoalbuminuria had lower baseline AER (53±22 vs. 94±63 mg/24 h, p=0.012). The initial AER level was the only factor associated with final AER (r=0.58, p=0.021). Thirty patients with persistent microalbuminuria were treated with ACE inhibitors for two years, 35.5% of whom regressed to normal AER. Patients achieving normoalbuminuria after ACE inhibitor treatment had lower baseline AER (55±24 vs. 132±75 mg/24 h, p=0.03). The initial AER was the sole predictor of final AER (r=0.51, p<0.013). Overall, the sequential use of improved metabolic control and ACE inhibitor therapy resulted in long-term normalisation of AER in 47.4% of patients. The sequential implementation of improved metabolic control and ACE inhibitor therapy had a long-term beneficial effect in type 1 diabetic patients with microalbuminuria. We propose that type 1 diabetic patients with microalbuminuria could benefit from a period of metabolic improvement before the initiation of ACE inhibitor therapy.     

Glomerular charge selectivity and the influence of improved blood glucose control in Type 1 (insulin-dependent) diabetic patients with microalbuminuria

Summary We first compared glomerular charge selectivity index in two matched groups of Type 1 (insulin-dependent) diabetic patients with micro and normoalbuminuria respectively, and secondly, investigated prospectively in a randomized clinical trial, the influence of improved metabolic control on selectivity index in diabetic patients with microalbuminuria. In Study 1, 27 patients with microalbuminuria (albumin excretion >-15 g/min in at least two out of three overnight urine samples) were matched (age, diabetes duration, mean 1-year HbA_1c, gender) with normoalbuminuria patients (n=24), and in Study 2, 23 microalbuminuric patients were randomly allocated to either intensive (continuous subcutaneous insulin infusion) or conventional treatment. Glomerular charge selectivity index was measured as IgG/IgG₄ selectivity index, i.e. total IgG/IgG₄ clearance ratio in timed overnight urine samples. The microalbuminuric patients had a significantly reduced selectivity index compared to the normoalbuminuric patients: 1.20 (0.92–1.40) vs 1.68 (1.22–2.21), median and 95% confidence interval (p<0.01). In Study 2, the HbA_1c improved in the intensive-treatment group compared to the conventional-treatment group: at 2, 6 and 12 months the difference in mean percentage HbA_1c between the groups was 1.1, 1.2 and 1.4, respectively (p<0.01). A sharp 50% increment in IgG/IgG₄ selectivity index was seen in the intensive-treatment group during the first 6 months (p<0.05 compared to the conventional group). We conclude that adolescents and young adults in an early stage of diabetic nephropathy have reduced glomerular charge selectivity, which may be improved by reducing the mean blood glucose level.     

Fibrinogen and AER are major independent predictors of 11-year cardiovascular mortality in type 2 diabetes: the Casale Monferrato Study

Aims/hypothesis Fibrinogen and elevated AER increase cardiovascular mortality, but few data are available in the type 2 diabetic population. We have conducted an 11-year follow-up study of the Casale Monferrato cohort to assess: (1) the long-term predictive role of AER independently of conventional risk factors; (2) the shape of its relationship with cardiovascular mortality; and (3) whether fibrinogen has a predictive effect independent of the increased cardiovascular risk associated with nephropathy.Methods During the follow-up period (1991–2001) a population-based cohort of 1,565 patients was regularly examined, and measurements of HbA₁c were centralised. Multivariate Cox proportional hazards modelling was employed to assess the role of fibrinogen and AER as predictors of all-cause and cardiovascular mortality, independently of baseline variables and individual cumulative average values of HbA₁c during follow-up.Results In 10,890.2 person-years of observations, 685 deaths were identified, giving an all-cause mortality rate of 63.4 per 1,000 person-years (95% CI 58.8–68.3). In Cox regression analyses, the strongest predictor of cardiovascular mortality was macroalbuminuria (relative risk 2.18, 95% CI 1.62–2.94), which was mainly associated with a high risk of short-term mortality. No increased risk was evident until the upper microalbuminuric range of AER values. Plasma fibrinogen was also a major independent predictor, and its role was not modified by AER, or by the exclusion of subjects developing chronic renal failure or diabetic nephropathy during follow-up.Conclusions/interpretation The results indicate that: (1) AER is the main independent predictor of 11-year cardiovascular mortality; (2) this effect is mainly evident in the upper range of microalbuminuria and in macroalbuminuria; and (3) fibrinogen has an independent effect on cardiovascular mortality, but no synergistic effect with AER, suggesting that both endothelial dysfunction and chronic inflammation are involved in the excess cardiovascular mortality of type 2 diabetic patients.     

Predictors of the development of microalbuminuria in patients with Type 1 diabetes mellitus: a seven-year prospective study

Aims To determine risk factors for the development of persistent microalbuminuria (albumin excretion rate (AER) ≥ 30 μg/min) in Type 1 diabetes mellitus. Methods One hundred and forty-eight initially normotensive Type 1 diabetic patients with normal albumin excretion (< 30 μg/min) were followed prospectively in hospital diabetes outpatient clinics for a median of 7 years. Main outcome measures were: progression to persistent microalbuminuria (albumin excretion rate ≥ 30 μg/min on at least two consecutive occasions); rate of change of albumin excretion rate; development of arterial hypertension (systolic blood pressure > 160 mmHg and/or diastolic blood pressure > 95 mmHg or commencement of antihypertensive therapy). Results In a median follow-up period of 7 years (range 6 months to 8 years), 14 patients progressed to persistent microalbuminuria, a cumulative incidence of 11% (95% confidence interval 6.36–16.94). AER remained persistently < 30 μg/min in 109 subjects and 25 developed intermittent microalbuminuria. In those who developed persistent microalbuminuria, baseline AER (16.2 (13.9–19.1) vs. 5.2 (3.8–9.2) μg/min, P < 0.01), blood pressure (136 (123–148)/80 (74–85) vs. 121 (118–124)/72 (70–73) mmHg, P < 0.05), and HbA₁ (10.2 (9.1–11.4) vs. 9.0 (8.7–9.4)%, P < 0.05) were higher than in those who continued to have persistent normoalbuminuria, retinopathy was more severe and height (1.64 (1.57–1.71) vs. 1.70 (1.69–1.72) m, P < 0.05) less. In multivariate analysis, baseline AER was the strongest predictor of the development of persistent microalbuminuria (P < 0.0001), followed by mean arterial pressure (P = 0.02) and HbA₁ (P = 0.05). Conclusions The level of AER, raised blood pressure and poor glycaemic control are the most important predictors of the development of microalbuminuria in Type 1 diabetes.     

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.     

Diabetic nephropathy is associated with low-grade inflammation in Type 1 diabetic patients

Aims/hypothesis Increased concentrations of C-reactive protein and interleukin-6, a finding suggestive of the presence of inflammation, have been observed in Type 2 diabetes. In such patients, C-reactive protein was predictive of diabetic nephropathy. Studies on low-grade inflammatory markers and nephropathy in Type 1 diabetic patients have shown conflicting results. Therefore we studied whether low-grade inflammation is associated with diabetic nephropathy in Type 1 diabetic patients.Methods We divided 194 Type 1 diabetic patients into three groups from the Finnish Diabetic Nephropathy Study based upon their albumin excretion rate. Patients with normoalbuminuria (n=67) had no antihypertensive medication or signs of cardiovascular disease, while patients with microalbuminuria (n=64) or macroalbuminuria (n=63) were all treated with an angiotensin-converting enzyme inhibitor, a drug that could attenuate low-grade inflammation. As a measure of insulin sensitivity we used estimated glucose disposal rate. C-reactive protein was measured by radioimmunoassay and interleukin-6 by high sensitivity enzyme immunoassay.Results C-reactive protein was higher in micro- and macroalbuminuric patients compared to normoalbuminuric patients (normoalbuminuria 2.0±1.7, microalbuminuria 2.6±1.7, macroalbuminuria 2.9±2.5 mg/l; p=0.016), while interleukin-6 increased in parallel with the severity of the renal disease (1.9±1.5, 2.9±3.3, 3.6±3.1 ng/l; p<0.0001). In multiple regression analysis albumin excretion rate was the only variable independently associated with C-reactive protein (p=0.03), whereas albumin excretion rate (p=0.0003), HDL-cholesterol (p=0.0135) and duration of diabetes (p=0.0176) were independently associated with interleukin-6.Conclusions/interpretation Low-grade inflammatory markers are associated with diabetic nephropathy in Type 1 diabetic patients. The predictive value needs to be assessed.Abbreviations DN diabetic nephropathy - CRP C-reactive protein - eGDR estimated glucose disposal rate - FinnDiane finnish diabetic nephropathy study - MDRD modification of diet in renal disease     

Indications of Low Sex Hormone Binding Globulin (SHBG) in Young Females with Type 1 Diabetes,and an Independent Association to Microalbuminuria

Sex hormone binding globulin (SHBG) is normally decreased during puberty and inversely related to insulin resistance. Microalbuminuria is rare before puberty in Type 1 diabetes implicating that sex hormones may contribute to its development. We investigated SHBG levels in young females with >5 years of Type 1 diabetes, and the association to microalbuminuria. Ten diabetic females with, and 15 without microalbuminuria, and 17 healthy controls in pubertal stage 4–5 were compared regarding anthropometric data, fasting serum levels of SHBG, testosterone, insulin, insulin-like growth factor-1 (IGF-1), lipids and lipoproteins. Multiple regression analyses were performed to study variables with independent influences on SHBG and albumin excretion rate (AER), respectively, in Type 1 diabetes. SHBG was lower and testosterone/SHBG ratio higher in normoalbuminuric females with diabetes than in controls. This was further emphasized in diabetic patients with microalbuminuria. IGF-1 was lower in Type 1 diabetes than in controls, and significantly decreased in microalbuminuric as compared to normoalbuminuric diabetic patients. IGF-1 was only correlated to SHBG in healthy controls. In Type 1 diabetes, applying stepwise multiple regression analysis, insulin dose, BMI, and HbA_1c had a significant and independent inverse influence on SHBG (r² = 0.77, p < 0.001). With log AER as the dependent variable, low SHBG, low IGF-1, HbA_1c, and age added to the regression (r² = 0.65, p = 0.004), whereas BMI, insulin dose and blood pressure did not. In conclusion, SHBG is decreased in young females with Type 1 diabetes, influenced by increased insulin requirements, BMI and HbA_1c. In turn, low SHBG seems to be independently associated to elevated AER in these patients. Prospective studies are necessary to confirm our results.     

Clustering of albumin excretion rate abnormalities in Caucasian patients with NIDDM

Summary Proteinuria and nephropathy have been found to cluster in families of non-insulin-dependent diabetic (NIDDM) Pima Indian, and in Caucasian insulin-dependent diabetic (IDDM) patients. No information is at present available for Caucasian NIDDM patients. The aim of the present study was to determine whether micro-macroalbuminuria (AER + ) is associated with albumin excretion rate abnormalities in diabetic and non-diabetic siblings of probands with NIDDM and AER + . We identified 169 Caucasian families with one NIDDM proband (the patient with longest known NIDDM duration) (101 families with only NIDDM siblings, 33 families with both NIDDM and non-NIDDM siblings and 35 families with only non-NIDDM siblings). Of the probands 56 had AER + [Prob-NIDDM-(AER + )], 78 had AER– [Prob-NIDDM-(AER–)], 74 siblings of Prob-NIDDM-(AER + ), and 113 siblings of Prob-NIDDM-(AER–) also had NIDDM. Data on albuminuria and retinopathy from multiple sibling pairs when the size of the sibship was more than two was adjusted according to a weighting factor. The odds ratio for AER + , in siblings of Prob-NIDDM-(AER + ) adjusted for age, hypertension, glycated haemoglobin A_{1 c} and other confounding variables was 3.94 (95 % confidence intervals: 1.93–9.01) as compared to siblings of Prob-NIDDM-(AER–). The 74 siblings of Prob-NIDDM-(AER + ) had higher prevalence of proliferative retinopathy than siblings of Prob-NIDDM-(AER–) (14 vs 2 %; p < 0.01). We also identified 66 non-diabetic siblings of 41 NIDDM probands with AER + and 36 non-diabetic siblings of 27 NIDDM probands with AER–. Albumin excretion was two times higher, although still within the normal range, in the non-diabetic siblings of Prob-NIDDM-(AER + ) than in siblings of Prob-NIDDM-(AER–) [median = 13.5 (range 0.5–148) vs 6.6 (range 1–17) μg/min (p < 0.05)]. In conclusion higher rates of albumin excretion aggregate in Caucasian families with NIDDM. Proliferative retinopathy is more frequently observed in families showing a clustering of AER + and NIDDM. These findings suggest that familial factors play a role in the pathogenesis of renal and retinal complications in NIDDM. [Diabetologia (1997) 40: 816–823] Received: 6 November 1996 and in revised form: 17 February 1997     

Prevalence of micro- and macroalbuminuria,arterial hypertension,retinopathy and large vessel disease in European Type 2 (non-insulin-dependent) diabetic patients

Summary The prevalence of micro- and macroalbuminuria was determined in Type 2 (non-insulin-dependent) diabetic patients, less than 76 years of age, attending a diabetic clinic during 1987. All eligible patients (n=557) were asked to collect a 24-h urine sample for quantitative albumin analysis. Urine collections were obtained in 296 males and 253 females (96%). Normoalbuminuria were defined as urinary albumin excretion30 mg/24 h (n=323), microalbuminuria as 31–299 mg/24 h (n=151), and macroalbuminuria as 300 mg/ 24 h (n=75). The prevalence of macroalbuminuria was significantly higher in males (20%) than in females (6%), while the prevalence of microalbuminuria was almost identical in males (26%) and females (29%). The prevalence of arterial hypertension increased with increased albuminuria, being 48%, 68%, and 85% in patients with normoalbuminuria, microalbuminuria, and macroalbuminuria respectively. Prevalence of proliferative retinopathy rose with increasing albuminuria, being 2%, 5% and 12% in patients with normoalbuminuria, microalbuminuria, and macroalbuminuria respectively. Prevalence of coronary heart disease, based on Minnesota coded electrocardiograms, was more frequent in patients with macroalbuminuria (46%) compared to patients with microalbuminuria (26%) and patients with normoalbuminuria (22%). Foot ulcers were more frequent in micro- and macroalbuminuric patients, being 13% and 25%, respectively, compared to 5% in patients with normoalbuminuria. This cross-sectional study has revealed a high prevalence of microalbuminuria (27%) and macroalbuminuria (14%) in Type 2 diabetic patients. Patients with raised urinary albumin excretion are characterized by obesity, elevated haemoglobin A_lc, increased frequency of arterial hypertension, proliferative retinopathy, coronary heart disease and foot ulcers. Thus, these findings suggest that urinary excretion of albumin should be monitored routinely in patients with Type 2 diabetes.     

Lipoprotein(a) in Type 1 Diabetic Patients with Renal Disease

Lp(a) was measured in 64 normoalbuminuric, 52 microalbuminuric, and 37 proteinuric Type 1 diabetic patients and 54 healthy subjects. Microalbuminuric and proteinuric Type 1 diabetic patients had higher median Lp(a) values (133 (16–1932) and 169 (17–1149) mg I^?1) than patients with normal AER (73 (15–1078) mg I^?1; p=0.048 and p=0.027). Lp(a) in healthy subjects (110 (15–1630)mg I^?1) did not differ from the diabetic subgroups. The frequency of Lp(a) values in the upper quarter of the normal distribution was similar in the diabetic groups and did not differ between diabetic and control subjects. The cumulative distribution of Lp(a) was similar in all groups. Lp(a) concentrations were not related to AER, age, gender, duration of diabetes, body mass index, glycaemic control, serum creatinine, free insulin or systolic blood pressure. Cholesterol, LDL-cholesterol, triglycerides, and apo B were higher in microalbuminuric and proteinuric than in normoalbuminuric Type 1 diabetic patients. Lp(a) was independently related to diastolic blood pressure, fibrinogen, and macroangiopathy. In conclusion, median Lp(a) concentrations tend to be higher in Type 1 diabetic patients with early and established renal disease, although the differences are small and the overlap between groups large. Lp(a) is related to diastolic blood pressure and fibrinogen, and this association of powerful risk factors suggests that Lp(a) may play a role in the pathogenesis of cardiovascular disease in Type 1 diabetic patients with proteinuria. Whether Lp(a) is an independent determinant of increased cardiovascular risk in these patients needs to be elucidated by prospective studies.     

Risk factors for mortality in Type II (non-insulin-dependent) diabetes: evidence of a role for neuropathy and a protective effect of HLA-DR4

Summary To test the hypothesis that interaction between genetic, immunological, clinical and metabolic risk factors influences the outcome of Type II (non-insulin-dependent) diabetes mellitus, we examined which of the above factors present at baseline were associated with mortality in 134 Type II diabetic patients followed for 9 years. Thirty-eight patients (29 %) died during the follow-up period; the majority of whom (68 %) died from cardiovascular disease. At baseline, the deceased patients had higher HbA_{1 c} values (p = 0.002), higher LDL-triglycerides (p = 0.007), lower HDL-cholesterol (p = 0.007), higher non-esterified fatty acid (NEFA) concentrations (p = 0.014), and higher albumin excretion rate (p < 0.0001) than the patients who survived. In addition, the frequency of HLA-DR4 (21 vs 39 %, p = 0.048) and of parietal cell antibodies (5 vs 14 %, p = 0.016) were decreased in the deceased as compared to the living patients. Patients who died during follow-up also had more retinopathy (42 vs 16 %, p = 0.002), neuropathy (57 vs 23 %, p < 0.001), microalbuminuria (45 vs 6 %, p < 0.0001), coronary heart disease (50 vs 13 %, p < 0.0001), and peripheral vascular disease (27 vs 9 %, p = 0.005) at baseline than patients who survived. In a multiple logistic regression analysis macroangiopathy (p = 0.004), neuropathy (p = 0.007), HbA_{1 c} (p = 0.018) and albumin excretion rate (p = 0.016) were independent risk factors for death. In patients free of cardiovascular disease at baseline, conventional risk factors such as LDL-cholesterol (p = 0.005) and age (p = 0.003) were associated with subsequent development of cardiovascular disease. In conclusion, in addition to coexisting macroangiopathy, increased albumin excretion rate, poor glycaemic control and neuropathy are risk factors for cardiovascular mortality in patients with Type II diabetes. The presence of HLA-DR4 and signs of autoimmunity may be associated with decreased risk of cardiovascular disease. [Diabetologia (1998) 41: 1253–1262] Received: 29 December 1997 and in revised form: 27 April 1998     

Pre-eclampsia but not pregnancy-induced hypertension is a risk factor for diabetic nephropathy in type 1 diabetic women

Aims/hypothesis Our aim was to study whether pre-eclampsia and pregnancy-induced hypertension are predictors of diabetic nephropathy in type 1 diabetic women. Materials and methods A total of 203 type 1 diabetic women, who were pregnant between 1988 and 1996 and followed at the Department of Obstetrics and Gynaecology in Helsinki, were re-assessed after an average of 11 years within the nationwide, multi-centre Finnish Diabetic Nephropathy Study. Diabetic nephropathy was defined as microalbuminuria, macroalbuminuria or end-stage renal disease. Results Patients with prior pre-eclampsia had diabetic nephropathy more often than patients with a normotensive pregnancy (diabetic nephropathy vs normal albumin excretion rate: 41.9% vs 8.9%; p<0.001), whereas patients with a history of pregnancy-induced hypertension did not (10.3% vs 8.9%; p=0.81). CHD was more prevalent in patients with a history of pre-eclampsia than in patients with a normotensive pregnancy (12.2% vs. 2.2%; p=0.03). Pre-eclampsia (odds ratio [OR] 7.7, 95% CI 1.6-36.1; p=0.01) and HbA_1c (OR 2.0, 95% CI 1.1-3.8; p<0.05) were associated with incident diabetic nephropathy even when adjusted for follow-up time, BMI, smoking, diabetes duration and age. Conclusions/interpretation These data suggest that a history of pre-eclamptic pregnancy but not pregnancy-induced hypertension is associated with an elevated risk of diabetic nephropathy. Electronic supplementary material Supplementary material is available in the online version of this article at and is accessible to authorised users.     

Association between plasma osteoprotegerin concentrations and urinary albumin excretion in Type 2 diabetes

Aims Osteoprotegerin (OPG) is a recently identified inhibitor of bone resorption. Recent studies indicate that OPG is also associated with endothelial dysfunction in Type 2 diabetes. The aim was to investigate the relationship between plasma OPG levels and urinary albumin excretion (UAE) in Type 2 diabetic patients. Methods This study included 154 newly diagnosed Type 2 diabetic patients and 46 healthy subjects. Plasma OPG and 24‐h UAE were measured. High‐resolution ultrasound was used to measure flow‐mediated (endothelium‐dependent arterial) dilation (FMD). Results Compared with the normoalbuminuric subgroup, OPG levels in the microalbuminuric subgroup were significantly higher, and OPG levels in macroalbuminuria subgroup were significantly higher than those in the normoalbuminuria and albuminuria subgroups. Multiple regression analysis showed that only FMD (r = ?0.26), C‐reactive protein (r = 0.23), fasting blood glucose (r = 0.25), 2‐h blood glucose (r = 0.21), HbA_1c (r = 0.28), UAE (r = 0.27) and retinopathy (r = 0.27) were significant factors associated with OPG. Pearson’s correlation analyses showed a positive correlation between OPG and logUAE (r = 0.440) and negative correlations between OPG and FMD (r = ?0.284), and between FMD and logUAE (r = ?0.602). Conclusions Plasma OPG levels are significantly associated with UAE in Type 2 diabetic patients.     

The relationship of urinary albumin excretion rate to ambulatory blood pressure and erythrocyte sodium-lithium countertransport in NIDDM

Summary Increased erythrocyte sodium-lithium countertransport rate is found in non-diabetic subjects with essential hypertension, and in insulin-dependent diabetic subjects with nephropathy. However, relationships between these variables in non-insulin-dependent diabetic subjects are ill-defined. In order to characterise the relationships between blood pressure, urinary albumin excretion, and erythrocyte sodium-lithium countertransport, 66 subjects with non-insulin-dependent diabetes were studied. Urinary albumin excretion rate correlated with mean 24-h ambulatory systolic blood pressure (r=0.57; p<0.001), but not with sodium-lithium countertransport (r=0.06; p=0.31). No significant relationship was observed between 24-h systolic blood pressure and erythrocyte sodium-lithium countertransport (r = 0.16; p=0.17). The principal differences between microalbuminuric and normoalbuminuric subjects (albumin excretion rate >15 g·min^–1 [n=20], and <15 g·min^–1, [n=46]) were: higher 24-h systolic blood pressure (145.9 [16.8] mm Hg vs 131.9 [16.8] mm Hg; p=0.006), nocturnal heart rate (72.4 [8.9] vs 67.4 [8.9] beats·min^–1; p=0.042), and HbA₁ (11.3 [1.5]% vs 10.1 [2.0]%; p=0.028), and a longer median duration of diabetes (10.0 vs 5.0 years; p = 0.02). In contrast, there was no significant difference in sodium-lithium countertransport rate between microalbuminuric (0.41 [0.18] mmol·l^–1·h^–1) and normoalbuminuric subjects (0.39 [0.15] mmol·l^–1· h^–1; p=0.687). In multiple regression analysis controlling for race, age, body mass index and HbA₁, the significant determinants of albumin excretion rate were 24-h systolic blood pressure (B [regression coefficient]=0.029, SE[B] [standard error of B]=0.009, t=2.95, p=0.005), duration of diabetes (B=0.430, SE[B]=0.169, t=2.54, p=0.016) and male gender (B=–1.170, SE[B]=0.457, t=–2.56, p=0.015). In conclusion, albumin excretion rates in non-insulin-dependent diabetic subjects are linked to hypertension and glycaemic exposure, but show no relationship to erythrocyte sodium-lithium countertransport.Abbreviations IDDM Insulin-dependent diabetes mellitus - NIDDM non-insulin dependent diabetes mellitus - SLC sodium lithium countertransport - AER albumin excretion rate - B regression - SE coefficient; standard error of B     

Albuminuria is a marker of increasing intracranial and extracranial vascular involvement in Type 2 diabetic Chinese patients

Aims/hypothesis Albuminuria has been reported to be a marker of cardiovascular risk factors and disease morbidity and mortality, but its relationship with intracerebral atherosclerotic disease is less clear. The aim of this study was to investigate the association between albuminuria and intracranial and extracranial vascular involvement in Chinese Type 2 diabetic patients.Methods The anthropometric and fasting biochemical measurements of 966 Type 2 diabetic patients with normoalbuminuria (55.6%), microalbuminuria (27.7%) or macroalbuminuria (16.7%) were compared. The prevalence of microvascular and macrovascular disease and middle cerebral artery (MCA) stenosis, measured by transcranial Doppler ultrasound, were also compared between the groups.Results Albuminuria was closely associated with a range of adverse parameters, including high BP, dyslipidaemia, smoking and adiposity (all p<0.01). The prevalence of microvascular disease (retinopathy p<0.001) and macrovascular disease (peripheral vascular disease p=0.012, myocardial infarction, p=0.004, MCA stenosis p<0.001) increased significantly with increasing levels of albuminuria. Albuminuria was also found to be an independent predictor of microvascular and macrovascular disease.Conclusions/interpretation Albuminuria was an independent predictor of increasing levels of vascular risk factors and microvascular and macrovascular disease in this group of Type 2 diabetic patients, and a possible role for albuminuria as a marker of intracranial cerebrovascular disease should be further investigated.     

A nationwide cross-sectional study of retinopathy and microalbuminuria in young Norwegian Type 1 (insulin-dependent) diabetic patients

Summary A nationwide cohort of Type 1 (insulin-dependent) diabetic patients was studied to determine the prevalence of retinopathy and microalbuminuria and to evaluate the association to various risk factors. Of 600 subjects with mean age of 19.8 years (range 8.0–30.3) and a mean duration of diabetes of 10.5 years (range 6.2–17.3),371 (60 %) volunteered for a clinical examination which included fundus photography, timed overnight urine samples for albumin excretion rate, measurement of arterial blood pressure and determination of HbA_1c, Retinopathy was found in 122 of 371 patients (32.8 %), in 3 of 41(7.3 %) patients aged less than 13 years. The youngest subject with retinopathy was 9.6 years old. Microalbuminuria was found in 44 of 351 patients (12.5 %), in 1 of 41(2.4 %) patients aged less than 13 years. The youngest subject with microalbuminuria was 11.5 years old. Mean HbA_1c was 8.6 % (normal range 4.5–6.1 %). Patients with retinopathy had significantly higher mean age (p = 0.0001), longer mean duration of diabetes (p = 0.0001), higher mean HbA_1c (p = 0.009), and higher mean arterial blood pressure (p = 0.0001) compared to patients without retinopathy. In microalbuminuric patients HbA_1c (p =0.0001) and mean arterial blood pressure (p = 0.01) were significantly higher compared to non-microal-buminuric patients, but there was no difference in age or diabetes duration. Ina multiple logistic regression model, age, HbA, duration of diabetes and mean arterial blood pressure were found to be significantly associated with retinopathy, while HbA_1c mean arterial blood pressure and onset before 13.0 years of age were found to be associated with microalbuminuria. The prevalence of retinopathy and microalbuminuria was relatively low. Both retinopathy and microalbuminuria were strongly associated with blood glucose control and developed at prepubertal age in some patients. The findings indicate that more intense optimization of blood glucose control in children and adolescents with Type 1 diabetes is warranted.     

Physiological inhibitors of blood coagulation and prothrombin fragment F 1+2 in type 2 diabetic patients with normoalbuminuria and incipient nephropathy

Microalbuminuria and haemostasis derangements have been considered as independent risk factors for cardiovascular death in type 2 (non-insulin-dependent) diabetic patients. Few studies have assessed coagulation inhibitors in type 2 diabetic patients with normoalbuminuria and microalbuminuria. Therefore, 32 type 2 diabetic patients with normoalbuminuria (albumin excretion rate, AER<20 mg/min, mean 7±1) and 28 type 2 diabetic patients with microalbuminuria (AER 20–200 mg/min, mean 84±11) were studied. The patients were matched for age, sex, disease duration and treatment, body mass index (BMI), blood pressure and glycohaemoglobin. Protein C and S activity, antithrombin III, thrombomodulin and prothrombin fragments 1+2 (F 1+2) were assessed together with fibrinogen, triglycerides, total and high density lipoprotein (HDL)-cholesterol concentrations. Fibrinogen, total and low density lipoprotein (LDL) concentrations were similar in the two groups, while a significant difference was observed for triglycerides (normoalbuminuric group: 128±10 mg/dl, microalbuminuric group: 184.1±17 mg/dl;P<0.007) and HDL-cholesterol (normoalbuminuric group: 45±2 mg/dl, microalbuminuric group: 39±2 mg/dl;P<0.05). The coagulation parameters were as follows: normoalbuminuric group: protein C activity 109%±5%, protein S 95.4%±5%, thrombomodulin 49.3±3 ng/ml, antithrombin III 93.3%±3%, F 1+2 1.05±0.04 nmol/l; microalbuminuric group: protein C activity 107%±4%, protein S 98.4%±4%, thrombomodulin 64.4±4 ng/ml, antithrombin III 93.3%±3%, F 1+2 1.03±0.05 nmol/l. The difference was significant for thrombomodulin (P<0.007). A significant direct correlation was observed in the microalbuminuric group between AER and thrombomodulin (r=0.38,P<0.05). In conclusion, our data do not support the hypothesis that a reduction in the activity of anticoagulant physiological inhibitors (protein C, protein S, antithrombin III) could contribute to explain the higher cardiovascular risk in type 2 diabetic patients with microalbuminuria. The elevation of plasma thrombomodulin concentration in type 2 diabetic patients could be the consequence of widespread vascular damage in diabetic patients with incipient nephropathy.     

Differences in HDL-cholesterol:apoA-I + apoA-II ratio and apoE phenotype with albuminuric status in Type I diabetic patients

Aims/hypothesis. To examine whether the HDL-cholesterol:apoA-I + apoA-II ratio and the ?2 allele are related to albuminuria at baseline and whether they are risk factors for progression of albuminuria in a cohort study of patients with Type I (insulin-dependent) diabetes mellitus.¶Methods. At baseline, the study cohort comprised 617 patients, aged 15–60 years, from seven European diabetic centres of the EURODIAB study. Albumin excretion rate, measured in a central laboratory, was categorised as normoalbuminuria at 20 μg/min or less, microalbuminuria between 20 and 200 μg/min or macroalbuminuria at 200 μg/min or over. Of the 250 patients who were normoalbuminuric at baseline and had follow-up albuminuria measurements, 34 patients were defined as early progressors.¶Results. At baseline, the mean HDL-cholesterol:apoA-I + apoA-II ratio was lower in macroalbuminuric patients (0.79, 95 % CI:0.74–0.83) compared with normoalbuminuric (0.88, 95 % CI:0.87–0.90) patients (p = 0.0002, adjusted for age and sex). At follow-up, 34 patients who progressed from normoalbuminuria to microalbuminuria or macroalbuminuria also had a slightly lower baseline ratio (0.85, 95 % CI:0.80–0.89) than those 216 who remained normoalbuminuric (0.89, 95 % CI:0.87–0.92) (adjusted p = 0.08). Neither of these relations were independent of LDL-cholesterol or fasting triglyceride. There was no association of the ?2 allele with albuminuria either at baseline (OR = 1.4, 95 % CI:0.7–2.8) or with progression of albuminuria (OR = 0.4, 95 % CI:0.1–3.5).¶Conclusion/interpretation. There is an inverse relation of HDL-cholesterol:apoA-I + apoA-II ratio with albuminuria at baseline. This lower ratio in microalbuminuric or macroalbuminuric patients could contribute to the increased risk of cardiovascular disease associated with nephropathy. There is weak evidence that HDL-composition is a risk factor for progression of albuminuria and no association of the ?2 allele with diabetic nephropathy. [Diabetologia 2000 43: 1353–1359]