Systematic review on urine albumin testing for early detection of diabetic complications.

OBJECTIVES: To determine whether microalbuminuria is an independent prognostic factor for the development of diabetic complications and whether improved glycaemic or blood pressure control has a greater influence on the development of diabetic complications in those with microalbuminuria than in those with normoalbuminuria. DATA SOURCES: Electronic databases up until January 2002. REVIEW METHODS: A protocol for peer review by an external expert panel was prepared that included selection criteria for data extraction and required two independent reviewers to undertake article selection and review. Completeness was assessed using hand-searching of major journals. Random effects meta-analysis was used to obtain combined estimates of relative risk (RR). Funnel plots, trim and fill methods and meta-regression were used to assess publication bias and sources of heterogeneity. RESULTS: In patients with type 1 or type 2 DM and microalbuminuria there is a RR of all-cause mortality of 1.8 [95% confidence interval (CI) 1.5 to 2.1] and 1.9 (95% CI 1.7 to 2.1) respectively. Similar RRs were found for other mortality end-points, with age of cohort being inversely related to the RR in type 2 DM. In patients with type 1 DM, there is evidence that microalbuminuria or raised albumin excretion rate has only weak, if any, independent prognostic significance for the incidence of retinopathy and no evidence that it predicts progression of retinopathy, although strong evidence exists for the independent prognostic significance of microalbuminuria or raised albumin excretion rate for the development of proliferative retinopathy (crude RR of 4.1, 95% CI 1.8 to 9.4). For type 2 DM, there is no evidence of any independent prognostic significance for the incidence of retinopathy and little, if any, prognostic relationship between microalbuminuria and the progression of retinopathy or development of proliferative retinopathy. In patients with type 1 DM and microalbuminuria there is an RR of developing end-stage renal disease (ESRD) of 4.8 (95% CI 3.0 to 7.5) and a higher RR (7.5, 95% CI 5.4 to 10.5) of developing clinical proteinuria, with a significantly greater fall in glomerular filtration rate (GFR) in patients with microalbuminuria. In patients with type 2 DM, similar RRs were observed: 3.6 (95% CI 1.6 to 8.4) for developing ESRD and 7.5 (95% CI 5.2 to 10.9) for developing clinical proteinuria, with a significantly greater decline in GFR in the microalbuminuria group of 1.7 (95% CI 0.1 to 3.2) ml per minute per year compared with those who were normoalbuminuric. In adults with type 1 or type 2 DM and microalbuminuria at baseline, the numbers progressing to clinical proteinuria (19% and 24%, respectively) and those regressing to normoalbuminuria (26% and 18%, respectively) did not differ significantly. In children with type 1 DM, regression (44%) was significantly more frequent than progression (15%). In patients with type 1 or type 2 DM and microalbuminuria, there is scarce evidence as to whether improved glycaemic control has any effect on the incidence of cardiovascular disease (CVD), the incidence or progression of retinopathy, or the development of renal complications. However, among patients not stratified by albuminuria, improved glycaemic control benefits retinal and renal complications and may benefit CVD. In the effects of angiotensin-converting enzyme (ACE) inhibitors on GFR in normotensive microalbuminuric patients with type 1 DM, there was no evidence of a consistent treatment effect. There is strong evidence from 11 trials in normotensive type 1 patients with microalbuminuria of a beneficial effect of ACE inhibitor treatment on the risk of developing clinical proteinuria and on the risk of regression to normoalbuminuria. Patients with type 2 DM and microalbuminuria, whether hypertensive or not, may obtain additional cardiovascular benefit from an ACE inhibitor and there may be a beneficial effect on the development of retinopathy in normotensive patients irrespective of albuminuria. There is limited evidence that treatment of hypertensive microalbuminuric type 2 diabetic patients with blockers of the renin--angiotensin system is associated with preserved GFR, but also evidence of no differences in GFR in comparisons with other antihypertensive agents. The data on GFR in normotensive cohorts are inconclusive. In normotensive type 2 patients with microalbuminuria there is evidence from three trials (all enalapril) of a reduction in risk of developing clinical proteinuria; in hypertensive patients there is evidence from one placebo-controlled trial (irbesartan) of a reduction in this risk. Intensive compared with moderate blood pressure control did not affect the rate of progression of microalbuminuria to clinical proteinuria in the one available study. There is inconclusive evidence from four trials of any difference in the proportions of hypertensive patients progressing from microalbuminuria to clinical proteinuria when ACE inhibitors are compared with other antihypertensive agents, and in one trial regression was two-fold higher with lisinopril than with nifedipine. CONCLUSIONS: The most pronounced benefits of glycaemic control identified in this review are on retinal and renal complications in both normoalbuminuric and microalbuminuric patients considered together, with little or no evidence of any greater benefit in those with microalbuminuria. Hence, microalbuminuric status may be a false boundary when considering the benefits of glycaemic control. Classification of a person as normoalbuminuric must not serve to suggest that they will derive less benefit from optimal glycaemic control than a person who is microalbuminuric. All hypertensive patients benefit from blood pressure lowering and there is little evidence of additional benefit in those with microalbuminuria. Antihypertensive therapy with an ACE inhibitor in normotensive patients with microalbuminuria is beneficial. Monitoring microalbuminuria does not have a proven role in modulating antihypertensive therapy while the patient remains hypertensive. Recommendations for microalbuminuria research include: determining rate and predictors of development and factors involved in regression; carrying out economic evaluations of different screening strategies; investigating the effects of screening on patients; standardising screening tests to enable use of common reference ranges; evaluating the effects of lipid-lowering therapy; and using to modulate antihypertensive therapy.

Activation of the innate immune system as a predictor of cardiovascular mortality in Type 2 diabetes mellitus.

AIMS: Activation of innate immunity may play a major role in the development and pathophysiology of Type 2 diabetes; we therefore investigated whether a marker of innate immunity (serum sialic acid) predicts cardiovascular disease (CVD) and all-cause mortality in Type 2 diabetes. METHODS: Type 2 diabetic subjects (n=128, age 31-64 years at outset) participating in the Lewisham Diabetes Survey were followed up for a mean of 12.8 years. Baseline measurements were made of serum sialic acid and known or putative risk factors for CVD. Cause of death was coded from death certificates, post mortem examination and hospital records. RESULTS: Fifty-six (43%) subjects had died after 12.8 years. The major cause of death was CVD (71.4%), predominantly coronary heart disease (62.5%). Baseline variables significantly associated with CVD mortality were sialic acid and CVD (borderline significance smoking and cholesterol). In multivariate analysis, significant independent predictors of CVD mortality were sialic acid [standardized relative risk (95% confidence interval) 1.53 (1.12, 2.10)], age, male sex and existing CVD. CONCLUSIONS: Activated innate immunity (low-grade inflammation) is a risk factor for CVD mortality in Type 2 diabetes, independently of other known risk factors, including existing CVD. Since activation of the innate immune system predicts Type 2 diabetes, it may be a common antecedent of both Type 2 diabetes and CVD.

Factors associated with plasma lipids and lipoproteins in type 1 diabetes mellitus: the EURODIAB IDDM Complications Study.

AIM: To assess the determinants and prevalence of hyperlipidaemia in Type 1 diabetic patients in the EURODIAB IDDM Complications Study. METHODS: Standardized questionnaire data were obtained and anthropometric and biochemical measurements performed on 3159 Type 1 diabetic patients, randomly selected from 31 diabetes clinics. Plasma lipid levels were determined centrally, using enzymatic methods RESULTS: Plasma total cholesterol, high-density lipoprotein cholesterol (HDL-C), and HDL subfractions were higher in women than in men, while plasma triglycerides were higher in men (P < 0.001). Total cholesterol, low-density lipoprotein cholesterol (LDL-C) and HDL-C and HDL-C subfractions were, as expected, significantly associated with age and HbA1c in both sexes. Age and HbA1c adjusted values of triglyceride, total cholesterol, LDL-C, HDL-C and HDL3-C in men and triglyceride and HDL2-C in women showed significant associations with central obesity, measured as the waist to hip ratio (WHR). Current smokers had lipid profiles characteristic of insulin resistance in comparison to nonsmokers. Significant positive associations were observed between hypertension and plasma triglycerides, total cholesterol and LDL-C in men and women. In men, degree of physical activity was negatively associated with triglyceride and positively related to HDL-C and HDL3-C. The prevalence of LDL-hypercholesterolaemia (LDL-C > 3.35 mmol/L) was 45% in men and in women, while plasma triglyceride levels > 1.7 mmol/L were observed in 12% of men and 8% of women. CONCLUSION: The results of this study indicate that lipid levels in Type 1 diabetic patients are strongly influenced by smoking habit and central obesity in a way that is characteristic of the insulin resistance syndrome.

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.

The innate immune response and type 2 diabetes: evidence that leptin is associated with a stress-related (acute-phase) reaction.

OBJECTIVE: Leptin is produced by adipose tissue and controls food intake and body weight. Although blood levels of leptin reflect energy stores, cytokines also stimulate leptin production from fat. Because we have proposed that type 2 diabetes mellitus is associated with a cytokine-mediated acute-phase or stress response, part of the innate immune system, we sought evidence that leptin is increased in type 2 diabetes partly as a stress response, independently of obesity and sex. DESIGN: We selected two groups of type 2 diabetic patients with either a low acute-phase response (< 2.30 mmol/l serum concentration of the acute-phase marker sialic acid) or high response (> 2.30 mmol/l sialic acid), but pair-matched for body mass index (BMI) and sex. PATIENTS: Twenty type 2 diabetic subjects (11 male, 9 female) in each group, whose body mass index (BMI) and age were comparable (mean +/- SD: 28.8 +/- 3.8 vs. 28.9 +/- 3.8 kg/m2, and 60.7 +/- 8.9 vs. 61.9 +/- 12.3 years, low vs. high acute-phase responders, respectively). The glycaemic control was also similar in each group (glycated haemoglobin: 9.1 +/- 2.2 vs. 8.9 +/- 1.9%). MEASUREMENTS: Serum concentrations of sialic acid, leptin, interleukin-6 (IL-6) (the major cytokine mediator of the acute-phase response) and cortisol were assayed in fasting venous blood samples from patients and the results compared. RESULTS: Serum leptin concentration was increased in the high compared to the low acute-phase group (median 13.2 (range 3.6-55) vs. 8.1 (2.0-22.5) microg/l, P = 0.004). IL-6 and cortisol concentrations were also higher in the high-stress group (1.9 (1.0-6.4) vs. 1.4 (0.4-7.5) ng/l, P = 0.02; and 409 (180-875) vs. 290 (157-705) nmol/l, P = 0.02, respectively). Leptin was strongly correlated with BMI (r = 0.61, P < 0.001), but also with sialic acid (r = 0.40, P = 0.01) and IL-6 (r = 0.38, P = 0.04). CONCLUSIONS: Serum leptin concentrations in type 2 diabetes are partly related to an acute-phase or stress response, independent of BMI and sex. The association of hyperleptinaemia with elevated serum cortisol provides a mechanism for leptin resistance in type 2 diabetes (glucocorticoids inhibit the central action of leptin). This study provides further support for the theory that type 2 diabetes is asociated with chronic innate immune activation.

Microalbuminuria and coronary heart disease in NIDDM: an incidence study.

In most survival studies in NIDDM, microalbuminuria (urinary albumin excretion rate 20-200 microg/min) predicts early mortality; in cross-sectional studies, it is associated with coronary heart disease (CHD) morbidity. It is unclear, however, whether microalbuminuria is a risk factor for the development of CHD or the result of it, and little is known of the factors that predispose to the development of microalbuminuria in NIDDM. We examined these issues in a 7-year prospective study of a hospital-based cohort comprising 146 white NIDDM patients without clinical albuminuria. Microalbuminuria was a significant risk factor for both all-cause mortality (relative risk 3.94, 95% CI 2.04-7.62) and CHD mortality (relative risk 7.40, 95% CI 2.94-18.7) when adjusted for age only. Its independent predictive power did not persist, however, in age-adjusted multivariable survival analysis that allowed for the other significant risk factors: male sex, preexisting CHD, high levels of glycated hemoglobin, and high serum cholesterol. Among men free of CHD at baseline, the independent risk factors for CHD morbidity and mortality were microalbuminuria, current smoking, high diastolic blood pressure, and high serum cholesterol (all P < 0.05). For the 100 NIDDM patients with normoalbuminuria at baseline, the incidence of microalbuminuria was 29% over the 7-year period. In that group, fasting plasma glucose, current smoking, preexisting CHD, and high initial urinary albumin excretion rate were risk factors for the development of microalbuminuria (all P < 0.05). When men and women were analyzed separately, preexisting CHD was a significant risk factor in men only. These results demonstrate that microalbuminuria predicts incident clinical CHD in men with NIDDM. Preexisting CHD is also a risk factor for incident microalbuminuria in men, however, suggesting that microalbuminuria and CHD are not causally related but rather reflect common determinants.

Ethnic differences in correlates of microalbuminuria in NIDDM. The role of the acute-phase response.

OBJECTIVE: To investigate whether microalbuminuria is associated with markers of the acute-phase response in NIDDM and whether there are ethnic differences in this association among the three main racial groups in Malaysia. RESEARCH DESIGN AND METHODS: NIDDM patients of Chinese, Indian, and Malay origin attending a diabetic clinic in Kuala Lumpur, Malaysia, were matched for age, sex, diabetes duration, and glycemic control (n = 34 in each group). Urinary albumin-to-creatinine ratio was measured in an early morning urine sample. Biochemical measurements included markers of the acute-phase response: serum sialic acid, triglyceride, and (lowered) HDL cholesterol. RESULTS: The frequency of microalbuminuria did not differ among the Chinese, Indian, and Malay patients (44, 41, and 47%, respectively). In Chinese patients, those with microalbuminuria had evidence of an augmented acute-phase response, with higher serum sialic acid and triglyceride and lower HDL cholesterol levels; and urinary albumin-to-creatinine ratio was correlated with serum sialic acid and triglyceride. The acute-phase response markers were not different in Indians, with microalbuminuria being high in even the normoalbuminuric Indians; only the mean arterial blood pressure was correlated with urinary albumin-to-creatinine ratio in the Indians. Malay NIDDM subjects had an association of microalbuminuria with acute-phase markers, but this was weaker than in the Chinese subjects. CONCLUSIONS: Microalbuminuria is associated with an acute-phase response in Chinese NIDDM patients in Malaysia, as previously found in Caucasian NIDDM subjects. Elevated urinary albumin excretion has different correlates in other racial groups, such as those originating from the Indian subcontinent. The acute-phase response may have an etiological role in microalbuminuria.

NIDDM as a disease of the innate immune system: association of acute-phase reactants and interleukin-6 with metabolic syndrome X.

Non-insulin-dependent diabetes mellitus (NIDDM) is commonly associated with hypertriglyceridaemia, low serum HDL-cholesterol concentrations, hypertension, obesity and accelerated atherosclerosis (metabolic syndrome X). Since a similar dyslipidaemia occurs with the acute-phase response, we investigated whether elevated acute-phase/stress reactants (the innate immune system's response to environmental stress) and their major cytokine mediator (interleukin-6, IL-6) are associated with NIDDM and syndrome X, and may thus provide a unifying pathophysiological mechanism for these conditions. Two groups of Caucasian subjects with NIDDM were studied. Those with any 4 or 5 features of syndrome X (n = 19) were compared with a group with 0 or 1 feature of syndrome X (n = 25) but similar age, sex distribution, diabetes duration, glycaemic control and diabetes treatment. Healthy non-diabetic subjects of comparable age and sex acted as controls. Overnight urinary albumin excretion rate, a risk factor for cardiovascular disease, was also assayed in subjects to assess its relationship to the acute-phase response. Serum sialic acid was confirmed as a marker of the acute-phase response since serum concentrations were significantly related to established acute-phase proteins such as alpha-1 acid glycoprotein (r = 0.82, p < 0.0001). There was a significant graded increase of serum sialic acid, alpha-1 acid glycoprotein, IL-6 and urinary albumin excretion rate amongst the three groups, with the lowest levels in non-diabetic subjects, intermediate levels in NIDDM patients without syndrome X and highest levels in NIDDM patients with syndrome X. C-reactive protein and cortisol levels were also higher in syndrome X-positive compared to X-negative patients and serum amyloid A was higher in both diabetic groups than in the control group. We conclude that NIDDM is associated with an elevated acute-phase response, particularly in those with features of syndrome X. Abnormalities of the innate immune system may be a contributor to the hypertriglyceridaemia, low HDL cholesterol, hypertension, glucose intolerance, insulin resistance and accelerated atherosclerosis of NIDDM. Microalbuminuria may be a component of the acute-phase response.

Serum sialic acid concentration and coronary heart disease in NIDDM.

OBJECTIVE--To examine the association between serum sialic acid concentrations and coronary heart disease (CHD) in a cross-sectional study of non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS--NIDDM patients (n = 145) attending a diabetic clinic were studied. CHD status was assessed by questionnaire and electrocardiogram coding, and potential risk factor assessment included measurement of fasting serum lipid and lipoprotein concentrations, blood pressure, and urinary albumin excretion rate (AER). RESULTS--Male NIDDM patients with CHD had a higher serum sialic acid level than those without CHD: 2.56 (2.24, 2.72) mmol/l vs. 2.24 (2.18, 2.30) mmol/l, P = 0.01, mean (95% confidence interval). They were also older, had a longer duration of diabetes, had a higher AER, had higher total triglyceride, very-low-density lipoprotein triglyceride and cholesterol, and lipoprotein(a) concentrations, and had a lower apolipoprotein A1 concentration. In an age adjusted multiple lipoprotein(a), hypercholesterolemia, and hypertension were associated with CHD. In women, only hypertension treatment was associated with CHD. CONCLUSIONS--There is a strong univariate association between elevated serum sialic acid and CHD in men (but not women) with NIDDM.

Insulin resistance in insulin-dependent diabetic patients with microalbuminuria.

In insulin-dependent diabetes, microalbuminuria increases the risk of cardiovascular and renal disease. By means of a euglycaemic hyperinsulinaemic clamp method, we measured total-body glucose utilisation rate and studied the interaction of this measure of insulin sensitivity with known risk factors for cardiovascular disease in 14 diabetic patients with microalbuminuria and 14 with normal albumin excretion (median albumin excretion rate [AER] 56.2 [range 39.2-80.6] vs 8.8 [7.4-10.7] micrograms per min). The two groups were of similar age, duration of diabetes, and body-mass index. Total-body glucose disposal rate was significantly lower in the patients with microalbuminuria than in those without (mean 7.86 [SD 1.40] vs 9.04 [0.90] mg/kg per min; p < 0.05). There were also significant differences between the groups in the daily insulin dose needed for equivalent glucose control (0.76 [0.20] vs 0.65 [0.10] U/kg, p < 0.05), mean systolic blood pressure over 24 h ambulatory monitoring (134 [7] vs 127 [7] mm Hg; p < 0.05), and various plasma lipid concentrations, contributing to a more atherogenic profile in the microalbuminuric group. Total-body glucose disposal rate was inversely correlated with body-mass index and log10 AER. The insulin sensitivity of the microalbuminuric group remained impaired after adjustment for blood pressure and body-mass index. Impaired insulin sensitivity is a feature of insulin-dependent diabetic patients with microalbuminuria, which adds, with other factors, to the increased risks of renal and cardiovascular disease in these patients.

Effect of beta-blocker therapy on serum lipoprotein profiles in patients on renal dialysis and in diabetic nephropathy.

We determined whether the serum lipoprotein levels in insulin-dependent diabetic patients (IDDM) with nephropathy and in patients on haemodialysis or continuous ambulatory peritoneal dialysis were affected by beta-blocker therapy. A case control study was performed in 18 IDDM patients with diabetic nephropathy, in 18 patients receiving chronic haemodialysis (HD) and 16 patients undergoing continuous ambulatory peritoneal dialysis (CAPD). In IDDM patients with diabetic nephropathy very low density lipoprotein-cholesterol (VLDL-CHOL) (0.680 +/- 0.17 vs 0.197 +/- 0.04 mmol/l, p = 0.004), total triglycerides (1.71 +/- 0.23 vs 0.808 +/- 0.14 mmol/l, p = 0.004) and very low density lipoprotein triglyceride (VLD-TG) were higher in the beta-blocker therapy group. In haemodialysis patients, beta-blocker therapy caused no significant changes in the serum lipoprotein profiles compared to the control group. In patients receiving continuous ambulatory peritoneal dialysis VLDL-CHOL was significantly higher (1.47 +/- 0.24 vs 1.08 +/- 0.21 mmol/l, p = 0.042) and cholesterol-high density lipoprotein (HDL-CHOL) was lower in the beta-blocker therapy group. The elevated VLDL-CHOL level (0.96 +/- 0.12 vs 1.24 +/- 0.14 mmol/l, p = 0.021) was correlated with the duration of CAPD in patients receiving beta-blocker therapy. Antihypertensive therapy with beta-blockers in IDDM patients with persistent proteinuria and in patients on continuous ambulatory peritoneal dialysis appears to adversely effect serum lipoproteins which may add to their cardiovascular risk.

Prospective study of microalbuminuria as predictor of mortality in NIDDM.

Retrospective studies of patients with non-insulin-dependent diabetes mellitus (NIDDM) have suggested that microalbuminuria predicts early all-cause (mainly cardiovascular) mortality independently of arterial blood pressure. These findings have not been confirmed in prospective studies, and it is not known whether the predictive power of microalbuminuria is independent of other major cardiovascular risk factors. During 1985-1987, we examined a representative group of 141 nonproteinuric patients with NIDDM for the prevalence of coronary heart disease and several of its established and putative risk factors, including raised urinary albumin excretion (UAE) rate. Thirty-six patients had microalbuminuria (UAE 20-200 micrograms/min), and 105 had normal UAE (less than 20 micrograms/min). At follow-up, an average of 3.4 yr later, 14 patients had died. There was a highly significant excess mortality (chiefly from cardiovascular disease) among those with microalbuminuria (28%) compared to those without microalbuminuria (4%, P less than 0.001). In univariate survival analysis, significant predictors of all-cause mortality included microalbuminuria (P less than 0.001), hypercholesterolemia (P less than 0.01), hypertriglyceridemia (P less than 0.05), and preexisting coronary heart disease (P less than 0.05). The predictive power of microalbuminuria persisted after adjustment for the effects of other major risk factors (P less than 0.05). We conclude that microalbuminuria is a significant risk marker for mortality in NIDDM, independent of the other risk factors examined. Its presence can be regarded as an index of increased cardiovascular vulnerability and a signal for vigorous efforts at correction of known risk factors.

Sodium-lithium countertransport activity and insulin resistance in normotensive IDDM patients.

In insulin-dependent diabetes (IDDM), an overactivity of sodium-lithium countertransport (Na+/Li+ CT) has been associated with the risk of nephropathy and hypertension, two conditions of insulin resistance. We investigated the sensitivity to insulin with a hyperinsulinemic (approximately 719 pM [approximately 100 microU/ml]) euglycemic clamp in two groups of normotensive nonproteinuric IDDM patients; 12 (10 men, 2 women) had high Na+/Li+ CT activity (mean 0.47, range 0.42-0.68 mmol/L red blood cells [RBC]/h, group 1) and 12 (9 men, 3 women) had normal Na+/Li+ CT activity (mean 0.24, range 0.12-0.31 mmol/L RBC/h, group 2). The two groups were similar in age (mean +/- SE 36 +/- 2 vs. 33 +/- 1 yr), duration of diabetes (19 +/- 3 vs. 18 +/- 2 yr), body mass index (26 +/- 0.8 vs. 24 +/- 0.6 kg/m2), arterial blood pressure (systolic/diastolic 121 +/- 4/79 +/- 2 vs. 122 +/- 3/77 +/- 2 mmHg), and glycemic control (HbA1 8.5 +/- 0.4 vs. 8.0 +/- 0.4%). Albumin excretion rate (AER) ranged between 4.7 and 148 (geometric mean 14) micrograms/min in group 1 and between 2.7 and 93 (geometric mean 11) micrograms/min in group 2. There were four microalbuminuric patients (AER greater than 30 micrograms/min) in each group. Whole-body glucose uptake was significantly reduced on average in group 1 compared with group 2 (41.6 +/- 2.2 mumol.kg-1.min-1 [7.48 +/- 0.4 mg.kg-1.min-1] vs. 49.6 +/- 2.2 mumol.kg-1.min-1 [8.93 +/- 0.4 mg.kg-1.min-1, P = 0.03), but some overlap existed between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Restriction of dietary protein and progression of renal failure in diabetic nephropathy.

In a study of the effect of a low-protein diet on the progression of renal disease 19 insulin-dependent diabetic patients with persistent clinical proteinuria were observed for 12-39 (mean 29) months while they were on a normal-protein diet (1.13 [0.06] g/kg per day), then for 12-49 (mean 33) months on a low-protein diet (0.67 [0.03] g/kg per day). The low-protein diet had no adverse effect on nutrition or glycosylated haemoglobin concentration. Mean supine blood pressure (BP) fell slightly on the low-protein diet and was probably due to the start or modification of antihypertensive medication in 9 patients. The mean rate of decline in glomerular filtration rate fell from 0.61 (SEM 0.14) ml/min per month with the normal-protein diet to 0.14 (0.08) with the low-protein diet, and this effect remained highly significant after adjustment for blood pressure, energy intake, and glycosylated haemoglobin. The rise in the fractional clearance of albumin during a normal-protein diet stopped with the low-protein diet, and there was a significant fall in albumin excretion from 467 (95% CI 234-895) micrograms/24 h on the normal-protein to 340 (138-719) on the low-protein diet. Thus, a low-protein diet, with its reduction in protein and possibly other dietary components such as phosphate or fat, seems to retard the rate of decline of glomerular filtration rate in diabetic nephropathy independently of blood pressure changes and glycaemic control.

Plasma lipid and coagulation factor concentrations in insulin dependent diabetics with microalbuminuria.

OBJECTIVE: To determine whether insulin dependent diabetics with microalbuminuria have significant abnormalities in concentrations of lipoproteins, apolipoproteins AI and B, fibrinogen, and clotting factor VII which could result in increased cardiovascular risk. DESIGN: Case-control study. SETTING: Outpatient department of a metabolic ward. PATIENTS: Group of 20 insulin dependent diabetics with urinary albumin excretion rates greater than 30 micrograms/min (microalbuminuria) and 20 individually matched insulin dependent diabetics with normal urinary albumin excretion rates (below 30 micrograms/min) matched for age, sex, and duration of diabetes. INTERVENTIONS: Fasting venous blood samples were taken for determination of concentrations of glucose, glycated haemoglobin, lipoproteins, apolipoproteins AI and B, fibrinogen, and factor VII. Height, weight, arterial pressure, and usual insulin dose were recorded, and each patient was given a dietary questionnaire to be completed at home. END POINT: Comparison of blood pressure and concentrations of lipoproteins, apolipoproteins AI and B, and fibrinogen in the diabetics with microalbuminuria and the controls. MEASUREMENTS AND MAIN RESULTS: Patients with microalbuminuria had significantly higher concentrations of low density lipoprotein cholesterol (mean 3.33 (SE 0.20) v 2.84 (0.12) mmol/l) and very low density lipoprotein cholesterol (0.30 (0.05) v 0.17 (0.03) mmol/l) than controls but significantly lower concentrations of high density lipoprotein 2 subfraction cholesterol (0.32 (0.04) v 0.54 (0.04) mmol/l). Concentrations of total triglyceride (1.11 (0.14) v 0.68 (0.08) mmol/l), very low density lipoprotein triglyceride (0.56 (0.10) v 0.30 (0.05) mmol/l), apolipoprotein B (0.88 (0.06) v 0.67 (0.03) g/l) and fibrinogen (2.2 (0.1) v 1.9 (0.1) g/l), and diastolic arterial pressure (80 (2) v 74 (2) mm Hg), were also higher in patients with microalbuminuria. CONCLUSIONS: Cardiovascular risk factors--namely, disturbances in lipoprotein and apolipoprotein concentrations, increased fibrinogen concentration, and increased arterial pressure--are already present in insulin dependent diabetics with microalbuminuria. The increased risk of coronary heart disease in patients with clinical proteinuria may result from prolonged exposure to these risk factors, which are present before any impairment of renal function.

The relationship of high density lipoprotein subfractions to alcohol consumption, other lifestyle factors, and coronary heart disease.

Serum high density lipoprotein (HDL) levels are inversely related to the risk of coronary heart disease. Controversy exists regarding the relative importance of HDL subfractions, and few studies have related subfraction levels to lifestyle factors associated with coronary risk. We examined the relationship of the major subfractions, HDL2 and HDL3, to alcohol consumption, cigarette smoking, physical exercise, body mass index, and socioeconomic status in 88 men and 49 women aged 35-64 years. Body mass index was inversely related to HDL2-cholesterol (C), particularly in men, but had no significant relationship with HDL3-C. Cigarette smoking and degree of physical exercise were not significantly related to either HDL subfraction. Alcohol consumption had a strong positive correlation with HDL3-C in both sexes; this association was statistically significant after controlling for cigarette smoking, body mass index, and serum triglyceride. Minnesota-coded ECG abnormalities and positive responses to the WHO chest pain questionnaire were associated with lower levels of HDL-C and HDL2-C in both sexes, and significantly lowered levels of HDL3-C in men but not women. These findings suggest that HDL3-C, as well as HDL2-C, may be related to coronary risk, and indicate that the protective effects of alcohol consumption may be mediated via this subfraction.