Orosomucoid in urine is a powerful predictor of cardiovascular mortality in normoalbuminuric patients with type 2 diabetes at five years of follow-up

Aims/hypothesis To study whether urinary orosomucoid excretion rate (UOER) predicts mortality in normoalbuminuric patients with diabetes at 5 years of follow-up, and to investigate the relationship between orosomucoid in serum and urine.Methods A cohort of 578 patients with diabetes (430 type 2, 148 type 1) was followed prospectively for an average of 5 years. UOER was measured in timed overnight urine samples.Results Eighty-two patients with type 2 diabetes and 17 patients with type 1 diabetes died. Among patients with type 2 diabetes, 251 (58%) had normoalbuminuria; increased UOER independently predicted cardiovascular mortality (OR 4.94, 95% CI 1.60–15.22; p<0.006) in those with normoalbuminuria and in the entire cohort of patients with type 2 diabetes (odds ratio 3.63, 95% CI 1.50–8.81; p<0.005). Patients with increased UOER had a higher all-cause mortality than those with normal UOER (log-rank test, p<0.001 for type 2 patients; p<0.04 for type 1 patients). In patients with type 1 diabetes, there were five cardiovascular deaths and no significant predictive value of UOER. Patients with increased UOER had a subclinical increase in serum orosomucoid.Conclusion/interpretation Increased UOER was an independent, powerful predictor of cardiovascular mortality in normoalbuminuric patients with type 2 diabetes and in the entire cohort of patients with type 2 diabetes. There were indications of UOER as being a valuable marker in type 1 diabetes that showed differences in survival between patients with normal versus increased UOER. Serum orosomucoid was associated with UOER; UOER may be a marker of low-grade inflammation in patients with diabetes.     

Microalbuminuria in patients with Type 2 diabetes mellitus from general practice: course and predictive value.

AIMS: To assess the course of microalbuminuria in patients with Type 2 diabetes mellitus in general practice and the predictive value of urinary albumin concentration on all-cause mortality, cardiovascular mortality and cardiovascular morbidity. METHODS: Cohort study in Type 2 diabetic patients tested for microalbuminuria in 1992, and re-tested in 1998. During follow-up all cardiovascular morbidity and mortality were recorded. RESULTS: Of the original sample of 317 patients, 163 patients were re-tested. The mean change in urinary albumin concentration was +16.2 mg/l (range -122.0 to +602 mg/l). Seventy-five per cent of the patients without microalbuminuria in 1992 still had no microalbuminuria in 1998 and 40% of those with microalbuminuria in 1992 reverted to normoalbuminuria in 1998. Cox survival analysis, stratified for age, showed that microalbuminuria at baseline resulted in a risk ratio of all-cause mortality of 1.4 (95% confidence interval 0.8-2.7), of cardiovascular mortality of 1.2 (0.5-2.8) and of new cardiovascular events (including cardiovascular mortality) of 1.4 (0.8-2.3). CONCLUSIONS: In the majority of patients the change of urinary albumin excretion was small, but the range was wide. A weak non-significant relationship between microalbuminuria and all-cause mortality and cardiovascular morbidity was observed.     

Plasma N-terminal pro-B-type natriuretic peptide and mortality in type 2 diabetes

Aims/hypothesis Raised N-terminal pro-B-type natriuretic peptide (NT-proBNP) is associated with a poor cardiac outcome in non-diabetic populations. Elevated NT-proBNP predicts excess morbidity and mortality in diabetic patients with an elevated urinary albumin excretion rate. This study investigated the prognostic value of NT-proBNP in a cohort of type 2 diabetic patients. Subjects, materials and methods In a prospective observational follow-up study, 315 type 2 diabetic patients with normoalbuminuria (n=188), microalbuminuria (n=80) and macroalbuminuria (n=47) at baseline were followed for a median (range) of 15.5 (0.2–17.0) years. Plasma NT-proBNP concentrations were determined by immunoassay at baseline. Endpoints were overall and cardiovascular mortality. Results Of the patients, 162 died (51%), 119 of them (74%) due to cardiovascular causes. All-cause mortality was increased in patients with NT-proBNP in the second and third tertiles (hazard ratios [95% CI] compared with the first tertile, 1.70 [1.08–2.67] and 5.19 [3.43–7.88], p<0.001). These associations persisted after adjustment for urinary albumin excretion rate, glomerular filtration rate and conventional cardiovascular risk factors (covariate adjusted hazard ratios 1.46 [0.91–2.33] and 2.54 [1.56–4.14], p<0.001). This increased mortality was attributable to more cardiovascular deaths in the second and third NT-proBNP tertile (unadjusted hazard ratios 1.63 [0.96–2.77] and 4.88 [3.01–7.91], p<0.001; covariate adjusted 1.37 [0.79–2.37] and 2.26 [1.27–4.02], p=0.01). When patients with normo-, micro- and macroalbuminuria were analysed separately, NT-proBNP levels above the median (62 ng/l) were consistently associated with increased overall and cardiovascular mortality in all three groups (p<0.001). Conclusions/interpretation In patients with type 2 diabetes, elevated circulating NT-proBNP is a strong predictor of the excess overall and cardiovascular mortality, this predictor status being independent of urinary albumin excretion rate and conventional cardiovascular risk factors.     

Haemostatic Measures in Type 2 Diabetic Patients with Microalbuminuria

The major cause of disability and early mortality in Type 2 diabetes is cardiovascular disease. An enhanced urinary albumin excretion is strongly predictive of increased mortality, but the causal relationship behind this association is unclear. Abnormalities in the haemostatic system may be involved in the vascular pathology. We therefore studied the level of von Willebrand factor (vWf:Ag), factor VIII (VIII:Ag), fibrinogen, and fibronectin in male diabetic patients 50–70 years of age, with normal albumin excretion (n = 14), microalbuminuria (n = 14), and frank albuminuria (n = 7). Fourteen healthy age-matched males served as a reference group. There were no significant differences between normo-and micro-albuminuric patients but vWf:Ag (p < 0.01), VIII:Ag (p < 0.01), and fibrinogen (p < 0.05) were increased in those with frank albuminuria. Urinary albumin excretion rate was significantly correlated to vWf:Ag (r = 0.46, p = 0.005), VIII:Ag (r = 0.45, p = 0.007), and fibrinogen (r = 0.49, p = 0.003). The known duration of diabetes was correlated to vWf and F VIII. The increased level of vWf:Ag in Type 2 diabetes and the significant association to the urinary albumin excretion rate may suggest a linkage between albuminuria and cardiovascular disease. However, the present study demonstrated no increase in haemostatic variables in patients with microalbuminuria as compared with those with normal albumin excretion.     

Urinary orosomucoid excretion rate in patients with non-insulin-dependent diabetes mellitus

Urinary excretion rate and clearance of alpha 1-acid glycoprotein (orosomucoid), a major serum glycoprotein which is more anionic (pI 2.7) than albumin (pI 4.7) were measured by RIA in timed overnight urine samples from non-insulin-dependent diabetic patients with different urinary albumin excretion rate and from healthy controls. The 50th percentiles of urinary orosomucoid excretion rate in patients with normo-, micro-, and macroalbuminuria were larger than those in healthy controls. Urinary excretion rate and clearance of orosomucoid increased in parallel with increase in albumin excretion rate in diabetic patients with an albumin excretion rate of more than 10 micrograms/min. On the basis of their levels of urinary orosomucoid excretion, patients with normoalbuminuria of less than 10 micrograms/min could be divided into two groups, one with a normal and the other with an elevated urinary orosomucoid excretion rate. The findings suggest that kidneys of diabetic patients with an albumin excretion rate of more than 10 micrograms/min are unable to distinguish the difference in pI between albumin and orosomucoid, and that a subgroup with an elevated orosomucoid excretion rate may be present among diabetics with normoalbuminuria.     

Heritability of albumin excretion rate in families of patients with Type II diabetes

Abstract Aims/hypothesis. To study whether albumin excretion rate is an inherited trait in families of patients with Type II (non-insulin-dependent) diabetes mellitus. Methods. We used three different approaches. Heritability of albumin excretion rate was studied in 267 nuclear families from the Botnia Study in Western Finland using parent-offspring regression. Albumin excretion rate was also measured in 206 non-diabetic offspring of 119 Type II diabetic parents with or without albuminuria (albumin excretion rate > 20 μg/min). Finally, albumin excretion rate was measured in altogether 652 siblings of 74 microalbuminuric and 320 normoalbuminuric probands. To study the potential confounding effect of blood pressure, the heritability of blood pressure was estimated in 718 nuclear families. Results. Using parent-offspring regression, the heritability of albumin excretion rate was about 30 %, being the strongest from mothers to sons (35–39 % resemblance). The heritability for systolic blood pressure ranged from 10 to 20 % and for diastolic blood pressure from 10 to 27 %. Offspring of albuminuric Type II diabetic parents had higher albumin excretion rates (median 5.4 [range 1.0–195] vs 4.0 [1.0–23] μg/min, p = 0.0001) and a higher frequency of microalbuminuria (11 vs 2 %, p = 0.012) than offspring of normoalbuminuric parents. Further, siblings of microalbuminuric probands had higher albumin excretion rates than siblings of normoalbuminuric probands (4.1 [0.6–14.5] vs 3.6 [0.2–14.4] μg/min, p < 0.01). Conclusion/interpretation. The data suggest that albumin excretion rate is an inherited trait in families of patients with Type II diabetes. [Diabetologia (1999) 42: 1359–1366] Received: 10 February 1999 and in revised form: 18 June 1999     

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     

Ten-year cardiovascular mortality in relation to risk factors and abnormalities in lipoprotein composition in Type 2 (non-insulin-dependent) diabetic and non-diabetic subjects

Summary The purpose of the present study was to examine 10-year cardiovascular morbidity and mortality in patients with newly-diagnosed Type 2 (non-insulin-dependent) diabetes mellitus and non-diabetic control subjects and to evaluate the effects of general risk factors, plasma insulin, urinary albumin excretion, lipoprotein abnormalities characteristic of Type 2 diabetes and the degree of hyperglycaemia in diabetic patients on cardiovascular mortality. Furthermore, the extent to which the above-mentioned factors could contribute to the excessive cardiovascular mortality observed in diabetic patients was examined. In the years 1979–1981, altogether 133 (70 men, 63 women) newly-diagnosed patients with Type 2 diabetes and 144 (62 men, 82 women) non-diabetic control subjects aged 45–64 years were studied. Both groups were re-examined in the years 1985–1986 and 1991–1992. The impact of different factors on cardiovascular mortality was examined by univariate analyses after adjustment for age and sex and by multiple logistic regression analyses. The age-standardized total and cardiovascular mortality rates were substantially higher in diabetic men (17.8 and 15.0%, total and cardiovascular mortality, respectively p = 0.06 and NS) and women (18.5 and 16.6%, p<0.01 for both) than in non-diabetic control men (5.2 % both total and cardiovascular mortality) and women (4.2 and 2.2 %). Cardiovascular mortality was not related to the treatment modality (diet, oral drugs, insulin) at 5 years from diagnosis. Use of diuretics, beta-blocking agents or their combination at baseline did not make a significant contribution to cardiovascular mortality either. In multiple logistic regression analysis on diabetic patients, age, LDL triglycerides, smoking, blood glucose and ischaemic ECG at baseline had independent associations with cardiovascular mortality. Interestingly, urinary albumin excretion rate measured at 5-year examination also predicted 10-year cardiovascular mortality after adjustment for the effects of major risk factors including lipoprotein abnormalities, but its predictive power reduced to a nonsignificant level when the effect of plasma glucose was taken into account. The relative risk of cardiovascular mortality associated with diabetes was 8.2 after allowing for age alone, but it declined to 3.7 when all contributing factors from the baseline examination (except blood glucose) were taken into account. In conclusion, the present results indicate that LDL triglycerides and/or other changes in lipoprotein composition characteristic of Type 2 diabetes and manifesting as elevated serum triglycerides are atherogenic and they strongly predict increased cardiovascular mortality. Furthermore, it is hypothesized that the consequences of long-term hyperglycaemia could explain a large proportion of the remaining excessive cardiovascular mortality risk among Type 2 diabetic patients.     

Increased urinary orosomucoid excretion is not related to impaired renal function in patients with type 2 diabetes

ObjectivesIncreased urinary orosomucoid excretion rate (UOER) independently predicted cardiovascular mortality in patients with type 2 diabetes at 5-years of follow-up. To further explore UOER in relation to local renal physiological phenomena, we studied renal glomerular and tubular functions in patients with type 2 diabetes and normal or increased UOER.MethodsWe performed a cross-sectional study of 40 patients with type 2 diabetes (normal UOER, n=16; increased UOER, n=24) who displayed no signs of cardiovascular disease and 21 healthy control persons. The renal clearance values of [⁵¹Cr]ethylenediaminetetraacetic acid ([⁵¹Cr]EDTA), lithium, orosomucoid, albumin, and sodium were measured.ResultsPatients with type 2 diabetes had normal glomerular filtration rate (GFR) measured by [⁵¹Cr]EDTA clearance. The clearance value of orosomucoid was highly increased in patients with increased UOER. The clearance values of albumin were similar in patients with increased UOER and in healthy controls. Investigations of renal tubular function revealed normal and similar levels of lithium clearance and proximal and distal reabsorption of sodium and water. Serum values of orosomucoid were higher in patients with increased UOER than in healthy controls (P<.001), but were still within reference limits, suggesting chronic low-grade inflammation. UOER was associated with increasing values of orosomucoid clearance (P<.0001) independently of serum orosomucoid.ConclusionsPatients with type 2 diabetes and increased UOER had normal GFR and showed no signs of renal glomerular or tubular dysfunction. We therefore hypothesize that increased levels of UOER may be caused by local renal production of orosomucoid due to chronic low-grade inflammation.     

Absolute level and rate of change of albuminuria over 1 year independently predict mortality and cardiovascular events in patients with diabetic nephropathy.

AIMS: To determine the nature of the association between baseline albuminuria and risk of all-cause mortality and cardiovascular disease, and to determine if the rate of change of albuminuria from baseline over 1 year predicts these endpoints in patients with diabetic nephropathy. METHODS: Cohort study of 427 patients (161 Type 1 and 266 Type 2) with diabetic nephropathy defined as urinary albumin excretion (UAE) > or = 30 mg/24 h at baseline (mean age 53.4 years). Patients were recruited at the time of referral to a diabetic nephropathy clinic and followed up annually for an average of 5 years. UAE rate was re-measured at 1 year and the rate of change from baseline calculated. RESULTS: All-cause mortality and cardiovascular disease increased significantly and continuously across quintiles of baseline UAE (P for linear trend < 0.001 in both outcomes). The rate of change of albuminuria over 1 year (log10) independently predicted all-cause mortality (hazard ratio (95% confidence interval) 1.76 (1.39, 3.11)) and cardiovascular mortality (1.57 (1.13, 5.22)). Taken as a categorical variable, a rate of change of albuminuria > or = 30% independently predicted mortality and cardiovascular events (2.07 (1.5, 4.30) and 1.89 (1.33, 4.06), respectively). CONCLUSIONS: The rate of change of albuminuria over 1 year independently predicts mortality and cardiovascular disease in diabetic nephropathy and may have clinical utility as a risk marker in identifying a subgroup of patients at particular risk. The risk of these outcomes is continuous across the range of baseline albuminuria in patients with diabetic nephropathy.     

Prolonged QTc interval predicts mortality in patients with Type 1 diabetes mellitus.

AIMS: To evaluate prolonged QTc interval and QT dispersion as predictors of all-cause and cardiovascular mortality after adjustment for well-established risk factors in Type 1 diabetic patients. METHODS: From a cohort of all adult Type 1 diabetic patients, duration of diabetes >or= 5 years, attending the clinic in 1984 and followed in an observational study for 10 years (n = 939), all subjects with resting baseline electrocardiograms were identified (n = 697, 360 males). The QT length was measured and corrected for heart rate (QTc). Maximal QTc length (QTc max) and QT dispersion were determined. RESULTS: At baseline, 431 had normoalbuminuria (< 30 mg/24 h), 138 had microalbuminuria (30-299 mg/24 h) and 128 had macroalbuminuria (>or= 300 mg/24 h) of whom 66 (15%), 35 (25%) and 61 (48%) died during follow-up, respectively (26 (6%), 14 (10%), 21 (16%) from cardiovascular disease). QTc max. was 442 (1.2) ms (mean (SEM)) for survivors and 457 (3.7) in patients who died (P < 0.001). In a Cox proportional hazards model including baseline values of putative risk factors, independent predictors of death were QTc max (P = 0.03), age (P < 0.001), presence of hypertension (P = 0.001), male sex (P < 0.001), log urinary albumin excretion (P < 0.001), smoking (P = 0.04), log serum-creatinine (P < 0.001), height (P < 0.001), low social class (P = 0.04), whereas QT dispersion, heart rate, and HbA1c were not included. In the subgroup with macroalbuminuria, but not for all patients, QTc max was an independent risk factor for cardiovascular mortality. CONCLUSION: QTc prolongation, but not increased QT dispersion, is an independent marker of increased mortality in patients with Type 1 diabetes mellitus.     

Comparison of renal resistive index among patients with Type 2 diabetes with different levels of creatinine clearance and urinary albumin excretion

Diabet. Med. 29, 1043–1046 (2012) Aim To evaluate the prevalence of increased renal resistive index and related factors among patients with Type 2 diabetes with different levels of creatinine clearance and urinary albumin excretion. Methods Laboratory analyses, including calculation of 24‐h urinary albumin excretion and 24‐h creatinine clearance, and renal doppler ultrasonography to measure renal resistive index, were carried out for patients newly diagnosed with Type 2 diabetes mellitus. Results Participants were classified into four groups according to 24‐h creatinine clearance and 24‐h urinary albumin excretion levels. Group 1 was composed of 73 patients (54.1%) with normal 24‐h creatinine clearance and 24‐h urinary albumin excretion. Group 2 was composed of 34 (25.2%) patients with normal 24‐h creatinine clearance and increased 24‐h urinary albumin excretion. Group 3 was composed of 14 (10.4%) patients with decreased 24‐h creatinine clearance and normal 24‐h urinary albumin excretion. Group 4 was composed of 14 (10.4%) patients with both decreased 24‐h creatinine clearance and increased 24‐h urinary albumin excretion . In total, 41 patients (30.4%) had increased renal resistive index levels. Comparison of the four groups with respect to increased renal resistive index revealed: among group 1 patients, 10 (13.7%) had increased renal resistive index levels; among group 2 patients, 14 (41.2%) had increased renal resistive index levels; among group 3 patients, eight (57.1%) had increased renal resistive index levels; among group 4 patients, nine (64.3%) had increased renal resistive index levels (P < 0.0001 for trend). In multivariate regression, 24‐h creatinine clearance (P < 0.0001), but not 24‐h urinary albumin excretion, was related to increased renal resistive index levels. Conclusion Renal resistive index levels were highest in patients with Type 2 diabetes with both decreased 24‐h creatinine clearance and increased 24‐h urinary albumin excretion, whereas they were lowest in patients with normal creatinine clearance and normal urinary albumin excretion.     

Cardiovascular Risk Factors in Type I (Insulin-dependent) Diabetic Patients with and without Proteinuria

ABSTRACT. In diabetes mellitus cardiovascular mortality among patients with increased urinary albumin excretion seems to be higher than in patients with normal urinary albumin excretion. Therefore we investigated blood pressure, total cholesterol, fibrinogen and in vivo platelet adhesion in 61 patients with type I (insulin-dependent) diabetes, 39 without complications, such as retinopathy or proteinuria and 22 with proteinuria and slightly elevated serum creatinine. The two groups had similar age, sex, diabetes duration and glucose control. Blood pressure, total cholesterol, fibrinogen and in vivo platelet adhesion were all significantly elevated in patients with proteinuria (p<0.01), whereas these parameters were normal in the uncomplicated diabetic patients, independent of diabetes duration. The mortality of cardiovascular disease during 20 years' follow-up was significantly higher among patients with proteinuria compared with patients without proteinuria (p<0.001), indicating that these risk factors contribute to the increased cardiovascular mortality in patients with clinical nephropathy.     

Urinary transferrin excretion in type 1 (insulin-dependent) diabetes mellitus.

Urinary excretion of transferrin and albumin was studied by radioimmunoassay in 47 adult patients with Type 1 diabetes and 28 control subjects. Median (range) urinary transferrin excretion rate was significantly elevated in the diabetic group 0.58 (0.02-2663.3) micrograms min-1 compared with the control group 0.04 (0.01-0.28) micrograms min-1, p less than 0.001. Urinary transferrin:creatinine ratios (x 10(2)) were different in diabetic 47 (0.6-958.0) micrograms mmol-1 and control groups 0.7 (0.06-2.3) micrograms mmol-1, p less than 0.001). There were correlations between urinary transferrin and albumin excretion rates in diabetic (r = 0.78, p less than 0.001) and control groups (r = 0.81, p less than 0.05). Forty (85%) diabetic patients had elevated transferrin excretion rates, 18 (38.3%) had elevated albumin excretion rates. All diabetic patients with elevated albumin excretion rates had elevated transferrin excretion rates. Twenty-one (77.8%) of the patients with normal albumin excretion rates had elevated transferrin excretion rates. Urinary excretion of N-acetyl-beta-D-glucosaminidase was greater in diabetic patients than control subjects (142 vs 58 mumol h-1 l-1, p less than 0.001). There were correlation between transferrin and N-acetyl-beta-D-glucosaminidase excretion (r = 0.67, p less than 0.01) and albumin and N-acetyl-beta-D-glucosaminidase excretion (r = 0.63, p less than 0.01) in the diabetic group. Elevated urinary transferrin excretion rate may be a marker for renal dysfunction in diabetes mellitus.     

Increased mortality in Type II diabetic patients using sulphonylurea and metformin in combination: a population-based observational study

Aims/hypothesis. This study analysed cause-specific mortality in Type II (non-insulin-dependent) diabetic patients using either sulphonylurea alone or in combination with metformin. Methods. Patients were followed from the first day they were taking either the combination or sulphonylurea alone. Odds ratios by Cox regression analyses were adjusted for age, sex, duration of diabetes, study area, year of inclusion and fasting blood glucose at inclusion. Results. We included 169 patients taking sulphonylurea and metformin in combination and 741 patients taking only sulphonylurea. Mean (range) follow-up time was 6.1 (0.1–13.0) years. The adjusted odds ratio for overall mortality was 1.63 (95 % confidence interval 1.27–2.09) in patients taking sulphonylurea and metformin combination vs those using sulphonylurea alone. For mortality from ischaemic heart disease and stroke the adjusted odds ratios were 1.73 (95 % confidence interval 1.17–2.55) and 2.33 (95 % confidence interval 1.17–4.63), respectively. Conclusion/interpretation. There was a higher cardiovascular mortality in Type II diabetic patients taking sulphonylurea and metformin in combination than in those taking only sulphonylurea. Hence, it cannot be excluded that this kind of combination therapy possibly increases cardiovascular mortality. It is feasible that the increased mortality was secondary to a more aggressive type of diabetes in the patients using sulphonylurea and metformin in combination. Combination therapy is known to promote additional blood glucose reduction but there is as yet no evidence that a sulphonylurea and metformin combination is more beneficial on micro- or macrovascular disease than sulphonylurea or metformin alone. [Diabetologia (2000) 43: 558–560] Received: 6 December 1999 and in revised form: 7 February 2000     

Undiagnosed diabetes mellitus among patients with prior myocardial infarction

Objective To determine the prevalence of undiagnosed diabetic subjects in a group of long-term myocardial infarction (MI) survivors and to investigate their cardiovascular risk factors and medical care. Methods Glucose tolerance (OGTT WHO 1985), cardiovascular risk factors (blood pressure, lipids, urinary albumin), and primary medical care during the previous year were assessed among 244 patients without previously known diabetes (mean age±SD: 70.5±6.9 yrs; 75% males; time since incident infarction: 6.5 years (median), inter-quartile range: 4–9 years) from the population-based MONICA myocardial infarction registry in Augsburg (Germany). Results Proportion of undiagnosed diabetes among MI registry patients was 29/244, 12% (95%CI: 8–17%); impaired glucose tolerance was found in 27% (22–34%). Using fasting glucose according to ADA 1997 criteria, 11% (7–16%) had diabetes and 17% (12–22%) impaired fasting glucose. MI registry patients with newly detected diabetes (WHO or ADA) showed a more adverse risk factor profile (higher triglycerides, lower HDL-cholesterol, increased urinary albumin) than subjects with normal glucose tolerance after controlling for possible confounders (age, sex, time since MI, antihypertensive and lipid-lowering medication). No significant differences were observed for self-reported medical care during the previous year among diabetic compared to non-diabetic subjects (number of physician visits and basic investigations). Conclusions There was a high prevalence of undiagnosed diabetes mellitus among the selected elderly long-term MI survivors. Because mortality rate after MI has been previously shown to be increased in diabetic patients, screening for glucose intolerance appears to be as essential as for standard cardiovascular risk factors.     

Evidence of changes in renal charge selectivity in patients with Type 1 (insulin-dependent) diabetes mellitus

Summary Altered filtration of macromolecules due to decreased electrical charge of the glomerular basement membrane might be the initial step in the development of albuminuria in patients with Type 1 (insulin-dependent) diabetes mellitus. We therefore investigated the selectivity index, i. e. renal clearance of non-glycated plasma albumin/clearance of glycated plasma albumin in 38 patients with Type 1 diabetes mellitus. The two albumin molecules differed slightly in charge, non-enzymatic glycated albumin being more anionic at physiological pH compared with unmodified plasma albumin. Glycated albumin in plasma and urine was determined by a specific, sensitive and highly reproducible chromatographic procedure. In diabetic patients with normal urinary albumin excretion, the selectivity index was increased threefold compared with that of non-diabetic subjects (2p< 0.01). A significant correlation (r=0.53, 2p < 0.01) between haemoglobin A_1c and selectivity index was demonstrated in these patients, indicating a change in charge-dependent renal filtration could possibly be attributed to non-enzymatic glycation of components in the glomerular basement membrane and tubuli. Diabetic patients with increased albumin excretion rate had a significantly lower selectivity index compared with patients with normal albumin excretion (2p < 0.01). A significant negative correlation (r=0.85, 2p <0.001, exponential curve fit) was seen between urinary albumin excretion and selectivity index in the diabetic patients, indicating that the capability of differentiating between macromolecules of different charges is again lost with increasing urinary albumin excretion.In conclusion, the selectivity index is significantly increased in Type 1 diabetic patients with normal urinary albumin excretion, possibly due to non-enzymatic glycation of structural glomerular proteins. The selectivity index is again reduced with increasing urinary albumin excretion, possibly due to structural changes different from non-enzymatic glycation. This observation is in accordance with the hypothesis that loss of anionic charges due to reduced heparan sulphate content in glomerular basement membranes plays an important role in the early stages of diabetic renal disease.     

Early glomerular hyperfiltration and the development of late nephropathy in Type 1 (insulin-dependent) diabetes mellitus

Summary We performed a follow-up study of the glomerular function in a series of 29 Type 1 (insulin-dependent) diabetic patients who had been studied 18 years previously. Initial median duration of diabetes was 2 years (range 0–9) and at follow-up 21 (17–27) years. At follow-up, 8 diabetic patients exhibited increased urinary albumin excretion rate 515 (32-3234) g/min with glomerular filtration rates significantly lower than 21 diabetic patients with normal urinary albumin excretion (85 vs 126ml/min/1.73 m²; p<0.01). The patients with increased urinary albumin excretion rate also had higher arterial blood pressure (145/90 vs 120/80) mm Hg; p<0.02) and increased frequency of proliferative retinopathy (7 out of 8 vs 2 out of 21; p = 0.0001) as compared to the group with normal urinary albumin excretion. However, we found no association of increased urinary albumin excretion rate (incipient or overt nephropathy) to early glomerular hyperfiltration as median initial glomerular filtration rate was 142 ml/min/1.73 m² in the diabetic patients with increased urinary albumin excretion and 147 ml/min/1.73 m² in the patients with normal excretion rate (p>0.05)     

Abnormalities in plasmas concentrations of lipoproteins and fibrinogen in Type 1 (insulin-dependent) diabetic patients with increased urinary albumin excretion

Summary Type 1 (insulin-dependent) diabetic patients with clinical nephropathy have a more than ten-fold increase in mortality of cardiovascular diseases compared with diabetic patients without nephropathy. The risk factors for cardiovascular disease, plasma concentrations of lipoproteins and fibrinogen, were investigated in 74 long-term diabetic patients: 37 with normal urinary albumin excretion, 20 with incipient nephropathy and 17 with overt clinical nephropathy based on urinary albumin excretion. The groups were matched according to sex, age and diabetes duration. The concentration of plasma cholesterol, very low density lipoprotein cholesterol, low density lipoprotein cholesterol, triglyceride and fibrinogen rose with increasing urinary albumin excretion. The plasma concentrations of these lipoproteins and fibrinogen were 11–14% higher in the patients with incipient nephropathy and 26–87% higher in the patients with overt clinical ne phropathy compared with the patients without nephropathy. The plasma concentration of high density lipoprotein cholesterol was unaffected by albuminuria. Patients with normal urinary albumin excretion and HbA_1c>8.0% had significantly higher very low density lipoprotein- and lower high density lipoprotein cholesterol concentrations compared with patients with HbA_1c<8.0%. Simple addition of the described risk factors can only account for a minor part of the greatly increased cardiovascular mortality in patients with diabetic nephropathy. An additional and possibly more decisive factor might be a change in the arterial wall, a change which promotes lipid accumulation and/or facilitates thrombus formation.     

Plasma lipids and urinary albumin excretion rate in Type 1 diabetes mellitus: the EURODIAB IDDM Complications Study.

AIMS: To examine the relationship between increased urinary albumin excretion rate and fasting plasma lipids among male and female respondents to the EURODIAB IDDM Complications Study, and attempt to explain inconsistencies in previous reports. METHODS: A cross-sectional study of 3250 randomly selected Type 1 diabetic patients from 31 diabetes clinics in 16 European countries was carried out between 1989 and 1990. Plasma lipids and urinary albumin were measured centrally. The present analysis was confined to the subgroup of 2205 patients attending after a 10-12 h overnight fast. Mean age was 33 years (SD 10) and mean duration of Type 1 diabetes mellitus was 15 years (SD 9). RESULTS: The prevalence of microalbuminuria (24-h urinary albumin excretion rate 20-200 microg/min) was 21.7% (95% confidence interval 19.9-23.5) and macroalbuminuria (24-h urinary albumin excretion rate > 200 microg/min) 7.8% (6.6-9.0). In comparison to patients with normal urinary albumin excretion rate (< 20 microg/min), and after controlling for age, sex, glycaemic control, duration of diabetes and current smoking, macroalbuminuria was associated with significantly (P<0.01) increased fasting plasma triglycerides, cholesterol, LDL-cholesterol, cholesterol:HDL-cholesterol ratio and, in women, reduced HDL-cholesterol. In men and women with microalbuminuria, the only significant association was with increased plasma triglycerides. CONCLUSIONS: These data confirm that there is an association between fasting plasma lipids and increasing urinary albumin excretion rate in European Type 1 diabetic patients. In microalbuminuric patients, however, the association was weaker than previously reported and partly explained by confounding factors.