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Aim: Angiotensin receptor blockers (ARBs) reduce vascular complications in diabetes independently of blood pressure. Experimental studies suggested that ARBs may restore the detoxifying enzyme glyoxalase 1, thereby lowering dicarbonyls such as methylglyoxal. Human data on the effects of ARBs on plasma dicarbonyl levels are lacking. We investigated, in individuals with type 2 diabetes, whether irbesartan lowered plasma levels of the dicarbonyls methylglyoxal, glyoxal, 3-deoxyglucosone and their derived advanced glycation end products (AGEs), and increased d-lactate, reflecting greater methylglyoxal flux. Methods: We analysed a subset of the Irbesartan in Patients with T2D and Microalbuminuria (IRMA2) study. We measured plasma dicarbonyls methylglyoxal, glyoxal and 3-deoxyglucosone, free AGEs and d-lactate using ultra-performance liquid chromatography tandem mass-spectrometry (UPLC-MS/MS) in the treatment arm receiving 300 mg irbesartan (n = 121) and a placebo group (n = 101) at baseline and after 1 and 2 years. Effect of treatment was analysed with repeated measurements ANOVA. Results: There was a slight, but significant difference in baseline median methylglyoxal levels [placebo 1119 (907–1509) nmol/l vs. irbesartan 300 mg 1053 (820–1427) nmol/l], but no significant changes were observed in any of the plasma dicarbonyls over time in either group and there was no effect of irbesartan treatment on plasma free AGEs or d-lactate levels at either 1 or 2 years. Conclusion: Irbesartan treatment does not change plasma levels of the dicarbonyls methylglyoxal, glyoxal and 3-deoxyglucosone, free AGEs or d-lactate in type 2 diabetes. This indicates that increased dicarbonyls in type 2 diabetes are not targetable by ARBs, and other approaches to lower systemic dicarbonyls are needed in type 2 diabetes. (Clinical Trial Registry No: #NCT00317915).

AIMS: To assess the difference between analogue and human insulin with regard to nocturnal glucose profiles and risk of hypoglycaemia in people with recurrent severe hypoglycaemia.METHODS: A total of 72 people [46 men, mean ± sd age 54 ± 12 years, mean ± sd HbA1c 65 ± 12 mmol/mol (8.1 ± 1.1%), mean ± sd duration of diabetes 30 ± 14 years], who participated in a 2-year randomized, crossover trial of basal-bolus therapy with insulin detemir/insulin aspart or human NPH insulin/human regular insulin (the HypoAna trial) were studied for 2 nights during each treatment. Venous blood was drawn hourly during sleep. Primary endpoints were nocturnal glucose profiles and occurrence of hypoglycaemia (blood glucose ≤ 3.9 mmol/l).RESULTS: During insulin analogue treatment, the mean nocturnal plasma glucose level was significantly higher than during treatment with human insulin (10.6 vs 8.1 mmol/l). The fasting plasma glucose level was similar between the treatments. Nocturnal hypoglycaemia was registered during 41/101 nights (41%) in the human insulin arm and 19/117 nights (16%) in the insulin analogue arm, corresponding to a hazard ratio of 0.26 (95% CI 0.14 to 0.45; PCONCLUSIONS: Treatment with insulin analogue reduces the occurrence of nocturnal hypoglycaemia assessed by nocturnal glucose profiles in people with Type 1 diabetes prone to severe hypoglycaemia. Nocturnal glucose profiles provide a more comprehensive assessment of clinical benefit of insulin regimens as compared to conventional recording of hypoglycaemia. This article is protected by copyright. All rights reserved.

Additional file 1. Additional figures and tables.

Hydrogen sulphide levels are reduced in many disease states, including diabetes and end-stage renal disease. We aimed to determine whether urinary sulphate excretion, as a proxy for hydrogen sulphide, was associated with progression of diabetic nephropathy.We conducted a post-hoc study of a prospective, randomized, controlled trial on the effect of a low vs. normal protein diet for 4 years, on decline of renal function in patients with Type 1 diabetes and diabetic nephropathy. We excluded patients with less than three measurements of glomerular filtration rate assessed by (51)Cr-EDTA plasma clearance (GFR) and less than 1 year of follow-up (n = 10), leaving 72 patients eligible for analyses. We studied both association of rate of decline in GFR and association of the combined endpoint of end-stage renal disease and death with baseline 24-h urinary sulphate excretion.Sulphate excretion was significantly associated with the slope of GFR (rs = -0.28, P = 0.02). In a multivariate regression model, sulphate excretion was a significant determinant of decline in GFR, independent of age, gender, blood pressure, HbA1c , smoking, albuminuria, baseline GFR and diet group (P0.01). In addition, adjusted r(2) increased from 5% in a model with the aforementioned risk factors to 22% when sulphate excretion was included in the model. Cox regression revealed a hazard ratio of 0.34 (95% CI 0.13-0.88, P = 0.026) for each natural log unit increase in urinary sulphate excretion.High urinary sulphate excretion was significantly associated with slower decline in (51)Cr-EDTA-assessed GFR in diabetic nephropathy, independent of known progression promoters.

INTRODUCTION: We recently developed and validated in existing trials a novel algorithm (PRE score) to predict long-term drug efficacy based on short-term (month-6) drug-induced changes in multiple risk markers. To show the value of the PRE score for ongoing and planned clinical trials, we here report the predicted long-term cardio-renal efficacy of aliskiren in type 2 diabetes, which was investigated in the ALTITUDE trial, but unknown at the time this study was conducted.METHODS: We established the relation between multiple risk markers and cardio-renal endpoints (as defined in ALTITUDE) using a background database from past clinical trials. The short-term effect of aliskiren on multiple risk markers was taken from the AVOID trial. A PRE score was developed by multivariate Cox analysis in the background population and was then applied to the baseline and month-6 measurements of the aliskiren treatment arm of the AVOID trial to predict cardio-renal risk. The net risk difference at these time-points, after correction for placebo effects, was taken to indicate the estimated long-term cardio-renal risk change.RESULTS: Based on the PRE score, we predicted that aliskiren treatment in ALTITUDE would confer a relative risk change of -7.9% (95% CI -2.5 to -13.4) for the cardio-renal endpoint, a risk change of -5.1% (-1.2 to -9.0) for the CV endpoint and a non-significant risk change of -19.9% (-42.1 to +2.1) for the renal endpoint.CONCLUSIONS: PRE score estimations suggested that aliskiren has only a marginal additive protective effect on cardio-renal endpoints. These predictions were validated by the results of the ALTITUDE trial, confirming the potential of the PRE score to prospectively predict drug efficacy on cardio-renal outcomes.

AIM: Insulin analogues reduce the risk of hypoglycaemia compared with human insulin in patients with type 1 diabetes (T1D) and minor hypoglycaemia problems. The HypoAna trial showed that, in patients with recurrent severe hypoglycaemia, treatment based on insulin analogues reduces the risk of severe hypoglycaemia. The present study aims to assess whether this also applies to non-severe hypoglycaemia events during the day and at night.METHODS: This 2-year investigator-initiated multicentre, prospective, randomized, open, blinded endpoint (PROBE) trial involved patients with T1D and at least two episodes of severe hypoglycaemia during the previous year. Using a balanced crossover design, patients were randomized to basal-bolus therapy based on analogue (detemir/aspart) or human (NPH/regular) insulins. A total of 114 participants were included. Endpoints were the number of severe hypoglycaemic events and non-severe events, including documented symptomatic and asymptomatic episodes occurring during the day and at night (ClinicalTrials.gov number: NCT00346996).RESULTS: Analogue-based treatment resulted in a 6% (2-10%; P=0.0025) overall relative risk reduction of non-severe hypoglycaemia. This was due to a 39% (32-46%; PCONCLUSION: In T1D patients prone to severe hypoglycaemia, treatment with analogue insulin reduced the risk of non-severe nocturnal hypoglycaemia compared with human insulin.

Diabet. Med. 29, 990–994 (2012) Abstract Aims To evaluate whether pulse pressure alone or with placental growth factor as estimates of arterial stiffness and endothelial dysfunction, predicts mortality, cardiovascular disease and progression to end-stage renal disease in patients with Type 1 diabetes. Methods Prospective, observational study, median (range) follow-up 8 (0–13) years, 900 patients with Type 1 diabetes, 458 with diabetic nephropathy, mean ± SD age 44 ± 11 years. Results During follow-up, we recorded 178 (20%) all-cause deaths, 109 (12%) cardiovascular deaths, 213 (24%) cardiovascular events and 73 (16%) progressed to end-stage renal disease. Elevated pulse pressure predicted all-cause and cardiovascular mortality and cardiovascular events [Hazard Ratio (HR) (95% CI) per 10 mmHg increase]: HR 1.2 (1.1–1.3), 1.3 (1.2–1.5) and 1.2 (1.1–1.3), P

Diabet. Med. 29, 337–344 (2012) Abstract Aims Placental growth factor is a vascular endothelial growth factor involved in angiogenesis, vascular inflammation and plaque formation. Soluble Fms-like tyrosine kinase 1 is a decoy receptor for placental growth factor, reducing its activity. The aim of this study is to evaluate the predictive value of placental growth factor and soluble Fms-like tyrosine kinase 1 in relation to all-cause and cardiovascular mortality and decline in kidney function in Type 1 diabetes. Methods This was a prospective, observational follow-up study with 8 (0–13) years [median (range)] of follow-up, including patients with Type 1 diabetes, of whom 458 had diabetic nephropathy [278 men; age 42 ± 11 years (mean ± sd), diabetes duration 28 ± 9 years, glomerular filtration rate 76 ± 33 ml min−1 1.73 m−2] and 442 had long-standing normoalbuminuria (234 men; age 45 ± 12 years, diabetes duration 28 ± 10 years). Results Placental growth factor and soluble Fms-like tyrosine kinase 1 levels measured at baseline were higher in patients with diabetic nephropathy compared with patients with long-standing normoalbuminuria [median (range)] 15 (4–131) vs. 11 (7–64) ng/l, (P

Parental type 2 diabetes mellitus increases the risk of diabetic nephropathy in offspring with type 1 diabetes mellitus. Several single nucleotide polymorphisms (SNPs) that predispose to type 2 diabetes mellitus have recently been identified. It is, however, not known whether such SNPs also confer susceptibility to diabetic nephropathy in patients with type 1 diabetes mellitus. We genotyped nine SNPs associated with type 2 diabetes mellitus in genome-wide association studies in the Finnish population, and tested for their association with diabetic nephropathy as well as with severe retinopathy and cardiovascular disease in 2,963 patients with type 1 diabetes mellitus. Replication of significant SNPs was sought in 2,980 patients from three other cohorts. In the discovery cohort, rs10811661 near gene CDKN2A/B was associated with diabetic nephropathy. The association remained after robust Bonferroni correction for the total number of tests performed in this study (OR 1.33 [95% CI 1.14, 1.56], p = 0.00045, p 36tests = 0.016). In the meta-analysis, the combined result for diabetic nephropathy was significant, with a fixed effects p value of 0.011 (OR 1.15 [95% CI 1.02, 1.29]). The association was particularly strong when patients with end-stage renal disease were compared with controls (OR 1.35 [95% CI 1.13, 1.60], p = 0.00038). The same SNP was also associated with severe retinopathy (OR 1.37 [95% CI 1.10, 1.69] p = 0.0040), but the association did not remain after Bonferroni correction (p 36tests = 0.14). None of the other selected SNPs was associated with nephropathy, severe retinopathy or cardiovascular disease. A SNP predisposing to type 2 diabetes mellitus, rs10811661 near CDKN2A/B, is associated with diabetic nephropathy in patients with type 1 diabetes mellitus.

Aims/hypothesis Homozygosity for a five leucine repeat (5L–5L) in the carnosinase gene (CNDP1) has been found to be cross-sectionally associated with a low frequency of diabetic nephropathy (DN), mainly in type 2 diabetes. We prospectively investigated in patients with type 1 diabetes whether: (1) 5L–5L is associated with mortality; (2) there is an interaction of 5L–5L with DN or sex for prediction of mortality; and (3) 5L–5L is associated with progression to end-stage renal disease (ESRD). Methods In this prospective study in white European patients with type 1 diabetes, individuals with DN were defined by persistent albuminuria ≥300 mg/24 h. Controls without nephropathy were defined by persistent (>15 years) normoalbuminuria

Diabet. Med. 27, 1144–1150 (2010) Abstract Aims Our aim was to evaluate the markers of tubulointerstitial damage, neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule 1 (KIM1) in Type 1 diabetic patients with different levels of albuminuria and in control subjects. In addition, the effect of renoprotective treatment on urinary NGAL was evaluated in diabetic nephropathy. Methods This was a cross-sectional study in 58 normoalbuminuric (u-albumin 300 mg/24 h) Type 1 diabetic patients and 55 non-diabetic control subjects. Furthermore, in a second study, urine-NGAL was measured in a randomized cross-over study of 56 Type 1 diabetic patients with diabetic nephropathy treated with lisinopril 20, 40 and 60 mg daily. Results Urine-NGAL levels were [geometric mean (95% CI)]: control subjects 74 (52–104) (pg/mmol creatinine), normoalbuminuric 146 (97–221), microalbuminuric 222 (158–312) and macroalbuminuric group 261 (175–390). Urine-NGAL increased significantly from the normo- to the micro- and further to the macroalbuminuric group (P

Background In addition to its glucose-lowering effect, metformin treatment has been suggested to improve lipidaemia in patients with type 2 diabetes. In contrast, in patients with type 1 diabetes (T1DM), information about the effect of metformin treatment on lipidaemia is limited. In this study, we report the effect of a 1-year treatment with metformin vs. placebo on plasma lipids in T1DM patients and persistent poor glycaemic control. Methods One hundred T1DM patients with haemoglobinA(1c) (HbA(1c)) >= 8.5% during the year before enrolment entered a 1-month run-in period on placebo treatment. Thereafter, patients were randomized (baseline) to treatment with either metformin (1000 mg twice daily) or placebo for 12 months (double masked). Patients continued ongoing insulin therapy and their usual outpatient clinical care. Outcomes were assessed at baseline and after 1 year. Results After 1 year, in those patients who did not start or stop statin therapy during the trial, metformin treatment significantly reduced total and LDL cholesterol by approximately 0.3 mmol/l compared with placebo (p = 0.021 and p = 0.018 respectively). Adjustment for statin use or known cardiovascular disease did not change conclusions. In statin users (metformin: n = 22, placebo: n = 13), metformin significantly lowered levels of LDL and non-HDL cholesterol by approximately 0.5 mmol/l compared with placebo (adjusted for changes in statin dose or agent: p = 0.048 and p = 0.033 respectively). HbA(1c) (previously reported) was not significant different between treatments. Conclusion In patients with poorly controlled T1DM, at similar glycaemic levels, adjunct metformin therapy during 1 year significantly lowered levels of proatherogenic cholesterolaemia independent of statin therapy. (Less)

In a series of 8 patients with recently discovered moderate essential hypertension the blood-retinal barrier permeability to fluorescein was determined by aid of quantitative vitreous fluorophotometry before and after normalization of the systemic blood pressure. The permeability before medical treatment was 1.69 X 10(-7) cm/sec (+/- SEM = 0.14) and after medical treatment and normalization of the blood pressure 1.27 X 10(-7) cm/sec (+/- SEM = 0.12), corresponding to the permeability in a normal population. Thus the blood-retinal barrier permeability is pathologically increased even in moderate degrees of essential hypertension, but this increase in permeability is reversible.

Creatinine clearance and daily urinary albumin and beta2-microglobulin excretion rates (radio-immunoassays) were measured several times in 14 patients with acromegaly. Eleven patients were treated with bromocriptine, 5 to 55 mg/day. The activity of the disease was assessed by measuring urinary growth hormone excretion (radio-immunoassay). In agreement with previous investigations we found the creatinine clearance elevated. However, no correlation was found between this variable and urinary growth hormone excretion. Urinary albumin and beta 2-microglobulin excretion rates were not significantly different from our previous results in 27 adults control subjects. There was no correlation between urinary growth hormone excretion and urinary albumin or beta 2-microglobulin excretion rates. Bromocriptine treatment reduced urinary growth hormone excretion from 220 to 91 ng/24 hours, p less than 0.01, but no significant alterations were induced in the above mentioned kidney function variables.

Background: Patients with diabetic nephropathy are at high risk for further progressive renal function loss. Treatments that decrease albuminuria have been linked with renal and cardiovascular protection. However, even when taking optimal treatment, residual renal and cardiovascular risk remains high which correlates with the magnitude of residual albuminuria. Use of vitamin D receptor activators, such as calcitriol and paricalcitol, is associated with improved sur- vival. A small study with paricalcitol showed reductions in albuminuria. The VITAL study tests the hypothesis whether paricalcitol persistently reduces albuminuria in diabetic subjects already receiving angiotensin-converting enzyme inhibitor (ACEI) and/or angiotensin receptor blocker (ARB) therapy. Methods: Randomization in this double-blind trial is equal allocation to paricalcitol 1 μ/day, 2 μg/day, or placebo. Inclusion criteria include: a diagnosis of type 2 diabetes, urinary albumin/creatinine ratio (UACR) between 100–3,000 mg/g, estimated glomerular filtration rate (eGFR) between 15–90 ml/min/1.73 m2, serum calcium Results: Baseline characteristics of the 281 subjects are: 69% men, mean age 64.9 ± 10.4 years, eGFR 40.7 ± 16.7 ml/min, median UACR (interquartile range) 612.3 mg/g (281–1,181 mg/g) and PTH 98.4 ± 63.8 pg/ml. Conclusion: This trial will be the first clinical test of the hypothesis that paricalcitol possesses pleiotropic effects and can modulate albuminuria in the setting of ACEI and/or ARB therapy. Results will have important clinical implications and are expected in November 2009.

The Pro12Ala polymorphism in the peroxisome proliferator-activated receptor-γ2 gene is suggested to associate with diabetic nephropathy and cardiovascular disease in type 2 diabetes. The aim of this study was to investigate the polymorphism in relation to diabetic nephropathy, end-stage renal disease (ESRD), mortality and cardiovascular (CVD) events in type 1 diabetic patients. This prospective observational follow-up study included 415 type 1 diabetic patients with overt diabetic nephropathy (252 men; age 42.2 ± 10.4 years [mean ± SD], duration of diabetes 28.3 ± 8.8 years, GFR 66 ± 8.8 ml/min) and 428 patients with longstanding type 1 diabetes and persistent normoalbuminuria (230 men; age 45.4 ± 11.6 years, duration of diabetes 27.8 ± 10.1 years). Follow-up: 8.1 (0.0–12.8) years (median [range]). There where no significant differences between cases and controls in genotype ( p = 0.51) or allele frequencies ( p = 0.25). Cox regression analysis revealed a covariate-adjusted hazard ratio (HR) for all-cause mortality in patients with the Ala/Ala genotype of 2.44 (1.23–4.84). The Pro12Ala polymorphism did not predict CVD events. However, the Ala/Ala genotype predicts ESRD (covariate-adjusted HR 2.60 (1.11–6.07)). Furthermore, Carriers of the Ala-allele had a higher rate of decline in GFR ( p = 0.040). In conclusion, the Pro12Ala polymorphism is not associated with type 1 diabetic nephropathy. The Ala-allele is associated with enhanced decline in GFR and predicts ESRD and all-cause mortality in patients with nephropathy.

In type 1 diabetic patients with microalbuminuria not receiving antihypertensive treatment, an increase in urinary AER (UAER) of 6-14%/year and a risk of developing diabetic nephropathy (DN) of 3-30%/year have been reported. We audited the long-term effect of blocking the renin-angiotensin-aldosterone system (RAAS) with an ACE inhibitor (ACEI) or angiotensin II receptor blocker (ARB) in microalbuminuric type 1 diabetic patients on progression of microalbuminuria and development of DN.All patients with type 1 diabetes and persistent microalbuminuria (30-300 mg/24 h) were identified (n=227) in 1995 at Steno Diabetes Center and followed for 11 years. Development of DN was defined as a UAER of300 mg/24 h in two of three consecutive urine samples.Age and duration of diabetes at baseline (mean+/-SD) were 46+/-15 and 28+/-13 years, respectively. During follow-up 14 patients emigrated and 58 (26%) died. Over the same period 79% were treated with an ACEI or ARB. There was a mean decline in UAER of 4%/year. Sixty-five patients (29%) progressed to overt DN, corresponding to 3.1%/year. However, 29 of them regressed to normo- or microalbuminuria on intensified antihypertensive treatment. Glycaemic control and blood pressure remained nearly unchanged.In our outpatient clinic, the implementation of RAAS-blocking treatment in type 1 diabetic patients with microalbuminuria successfully reduced long-term progression to overt DN to a rate similar to those previously reported in randomised, double-blind intervention trials of shorter duration using RAAS blockade.

Inhibition of renin with an active site inhibitor, aliskiren, lowers blood pressure (BP) in diabetic patients. Here, we studied the time course of the antihypertensive and antiproteinuric effect of renin inhibition in 15 patients with type 2 diabetes and elevated urinary albumin/ creatinine ratios (UACRs) to check whether aliskiren can decrease proteinuria. After a 4-week washout of previous medications, patients received aliskiren and furosemide daily for 28 days followed by a 4-week withdrawal period. Twenty-four-hour BPs were measured at baseline throughout treatment and withdrawal periods. The UACR was significantly reduced after 2 -4 days of treatment with another significant reduction after 28 days. Systolic blood pressure (SBP) was significantly lower after 7 days with no further reduction after 28 days. The BP returned toward baseline 3 days after withdrawal, whereas the UACR was still significantly reduced compared with baseline 12 days after withdrawal. Our study shows that aliskiren reduced 24 h SBP, and this was associated with a reduction in albuminuria in type 2 diabetic patients.

Aim Pregnancy-associated plasma protein A (PAPP-A) has been implicated in the aetiology of acute coronary syndromes and carotid and peripheral artherosclerosis. Diabetic nephropathy is characterized by increased cardiovascular risk. We investigated the prognostic value of PAPP-A in a large cohort of Type 1 diabetic patients. Methods In a prospective observational follow-up study, 197 Type 1 diabetic patients with diabetic nephropathy and a matched group of 178 patients with normoalbuminuria were followed for 10.1 (0–10.3) years. PAPP-A was determined at baseline. Results In patients with diabetic nephropathy, plasma PAPP-A was elevated 3.6 (0.4–51.1) mIU/l [median (range)] vs. 2.1 (0.4–46.6) mIU/l in normoalbuminuric patients, P

Aims: To study whether microalbuminuria, endothelial dysfunction and low-grade inflammation are associated with the presence and progression of diabetic retinopathy. Methods: Patients with Type 2 diabetes (n = 328) attending a diabetes clinic were followed for 10 years and examined annually during the last 7 years. Retinopathy was assessed after pupillary dilatation by direct ophthalmoscopy (baseline) and two-field 60°fundus photography (follow-up). Urinary albumin excretion, and markers of endothelial function (von Willebrand factor, tissue-type plasminogen activator, soluble E-selectin (sE-selectin), and soluble vascular cell adhesion molecule 1) and inflammatory activity (C-reactive protein and fibrinogen) were determined. Results: The prevalence of retinopathy was 33.8%. The median diabetes duration at baseline was 7 years (interquartile range 2-12 years). The highest tertiles of baseline urinary albumin excretion and glycated haemoglobin (HbA1c) were associated with prevalent retinopathy: odds ratio (OR) 95% confidence interval (CI) 2.80 (1.44-5.46) and 2.19 (1.11-4.32), respectively. Progression of retinopathy occurred in 188 patients. The second and third tertiles of baseline sE-selectin were associated with progression of retinopathy [1.44 (1.04-2.01) and 1.61 (1.19-2.18)] but not independently of HbA1c. None of the other markers was significantly associated with the presence or progression of retinopathy. High baseline HbA1c was significantly associated with progression of retinopathy: 1.65 (1.21-2.25). Conclusions: In this population of patients with Type 2 diabetes who attended a diabetes clinic, there was some evidence for a role of endothelial dysfunction in the progression of retinopathy. We could not demonstrate a role for low-grade inflammation. Our study emphasizes the importance of glycaemic control in the development and progression of retinopathy. © 2007 The Authors.

To develop and validate a model to simulate progression of diabetic kidney disease (DKD) from early onset until end-stage renal disease (ESRD), and to assess the effect of renin-angiotensin system (RAS) intervention in early, intermediate and advanced stages of DKD.We used data from the BENEDICT, IRMA-2, RENAAL and IDNT trials that assessed effects of RAS intervention in patients with type 2 diabetes. We built a model with discrete disease stages based on albuminuria and estimated glomerular filtration rate (eGFR). Using survival analyses, we assessed the effect of RAS intervention on delaying ESRD in early [eGFR60 ml/min/1.73 m(2) and albumin:creatinine ratio (ACR)30 mg/g], intermediate (eGFR 30-60 ml/min/1.73 m(2) or ACR 30-300 mg/g) and advanced (eGFR30 ml/min/1.73 m(2) or ACR300 mg/g) stages of DKD for patients in different age groups.For patients at early, intermediate and advanced stage of disease, whose mean age was 60 years and who received placebo, the median time to ESRD was 21.4, 10.8 and 4.7 years, respectively. RAS intervention delayed the predicted time to ESRD by 4.2, 3.6 and 1.4 years, respectively. The benefit of early RAS intervention was more pronounced in younger patients; for example, for patients with a mean age of 45 years, RAS intervention at early, intermediate or advanced stage delayed ESRD by 5.9, 4.0 and 1.1 years versus placebo.RAS intervention early in the course of proteinuric DKD is more beneficial than late intervention in delaying ESRD.

We described the characteristics in a referred cohort of type II diabetic patients in the Developing Education on Microalbuminuria for Awareness of renal and cardiovascular risk in Diabetes study evaluating the global prevalence and determinants of microalbuminuria (MA). A cross-sectional study evaluating 32,208 type II diabetic patients without known albuminuria from 33 countries was performed. Overall, 8057 patients were excluded, either because of prior known proteinuria or non-diabetic nephropathy (3670), or because of invalid urine collections (4387). One single random urinary albumin/creatinine ratio was obtained in 24,151 patients (75%). The overall global prevalence of normo-, micro-, and macroalbuminuria was 51, 39, and 10%, respectively. The Asian and Hispanic patients had the highest prevalence of a raised urinary albumin/creatinine ratio (55%) and Caucasians the lowest (40.6), P0.0001. HbA1c, systolic blood pressure (BP), ethnicity, retinopathy, duration of diabetes, kidney function, body height, and smoking were all independent risk factors of MA, P0.0001. Estimated glomerular filtration rate was below 60 ml/min/1.73 m(2) in 22% of the 11,573 patients with available data. Systolic BP below 130 mmHg was found in 33 and 43% had an HbA1c below 7%. The frequency of patients receiving aspirin was 32%, statins 29%, and BP-lowering therapy 63%. A high prevalence globally of MA and reduced kidney function, both conditions associated with enhanced renal and cardiovascular risk, was detected in type II diabetic patients without prior known nephropathy. Early detection, monitoring of vascular complications, and more aggressive multifactorial treatment aiming at renal and vascular protection are urgently needed.

Aims/hypothesis We examined whether plasma N-terminal probrain natriuretic peptide (NT-proBNP) predicts cardiovascular outcome in patients with type 2 diabetes.

It has been suggested that aldosterone plays a role in the initiation and progression of renal disease independently of arterial blood pressure and plasma angiotensin II levels. We evaluated the influence of plasma aldosterone levels on progression of diabetic nephropathy during long-term blockade of the renin–angiotensin–aldosterone system. A total of 63 hypertensive patients with type 1 diabetes and diabetic nephropathy were treated with losartan, 100 mg once daily, for a mean follow-up period of 35 months. Plasma aldosterone, GFR, albuminuria and 24-h blood pressure were determined at baseline and at regular intervals during the study. Patients were divided according to their increasing or decreasing levels of plasma aldosterone during long-term losartan treatment in an escape group (n=26) and a non-escape group (n=37). In the escape group, aldosterone levels increased from (geometric mean [95% CI]) 57 pg/ml (43–76 pg/ml) at 2 months, to 102 pg/ml (78–134 pg/ml) at the end of the study (p

Although hyperhomocysteinaemia and methylenetetrahydrofolate reductase gene polymorphism are accepted risk factors for cardiovascular disease, their association with micro angiopathy or blood pressure in diabetic patients is still being debated. This study explores the relation between plasma homocysteine concentrations, methylenetetrahydrofolate reductase gene polymorphism, hypertension, diabetic microvascular and macrovascular complications associated with kidney function.Vascular complications, hypertension, methylenetetrahydrofolate reductase genotype (RFLP with Hinf I digestion), and total plasma homocysteine (HPLC) were investigated in 389 well-characterized Type I (insulin-dependent) diabetic patients with normal (GFRor=75 ml x min(-1) x (1.73 m(2))(-1); n=273), or impaired renal function (GFR75 ml x min(-1) x (1.73 m(2))(-1); n=116).Patients with microvascular and macrovascular complications showed higher total plasma homocysteine concentrations than those without complications. However, after the data for GFR (main determinant for plasma homocysteine) was adjusted we observed that plasma homocysteine concentrations greater than 8.6 micro mol/l in patients with normal GFR are not related to vascular complications, but to hypertension (8.6-11.3 micro mol/l: OR 1.9;11.3 micro mol/l: OR 3.7). The risk for coronary heart disease (CHD) was also enhanced by a plasma homocysteine concentration greater than 11.3 micro mol/l (OR 5.9). Although the T allele was an independent determinant of plasma homocysteine, the methylenetetrahydrofolate reductase gene polymorphism was neither associated with diabetic vascular complications nor with hypertension.Increased plasma homocysteine concentrations but not the T allele per se, enhance the risk of hypertension and of CHD in Danish Type I diabetic patients with normal renal function.

Background Evidence links the lectin pathway of complement activation to diabetic kidney disease. Upon carbohydrate-recognition by pattern-recognition molecules, eg, mannan-binding lectin (MBL), the MBL-associated serine protease (MASP-2) is activated and initiates the complement cascade. The MASP2 gene encodes MASP-2 and the alternative splice product MBL-associated protein 19 (MAp19). Both MAp19 and MASP-2 circulate in complex with MBL. We tested the hypothesis that MAp19 and MASP-2 concentrations predict the risk of incident microalbuminuria. Methods Baseline MAp19 and MASP-2 were measured in 270 persons with newly diagnosed type 1 diabetes tracked for incidence of persistent microalbuminuria in a prospective observational 18-year-follow-up study. Results Seventy-five participants (28%) developed microalbuminuria during follow-up. MBL-associated protein 19 concentrations were higher in participants that later progressed to microalbuminuria as compared with those with persistent normoalbuminuria (268 ng/mL [95% CI, 243-293] vs 236 ng/mL [95% CI, 223-250], P = .02). Participants with MAp19 concentration within the highest quartile of the cohort had an increased risk of microalbuminuria as compared with participants with MAp19 concentration within the combined lower 3 quartiles in unadjusted Cox analysis, hazard ratio 1.86 ([95% CI, 1.17-2.96], P = .009). This remained significant in adjusted models, eg, adjusting for age, sex, HbA1c , systolic blood pressure, urinary albumin excretion, smoking, serum creatinine, and serum cholesterol. MBL-associated serine protease concentration was not associated with incidence of microalbuminuria. Conclusions In conclusion, the results show an association between baseline MAp19 concentration and the incidence of microalbuminuria in an 18-year-follow-up study on persons with newly diagnosed type 1 diabetes.

Angiotensin receptor blockers (ARBs) have multiple effects that may contribute to their efficacy on renal/cardiovascular outcomes. We developed and validated a risk score that incorporated short-term changes in multiple risk markers to predict the ARB effect on renal/cardiovascular outcomes. The score was used to predict renal/cardiovascular risk at baseline and at month 6 in the ARB treatment arm of the Reduction of Endpoints in NIDDM (noninsulin-dependent diabetes mellitus) with the Angiotensin II Antagonist Losartan (RENAAL) trial. The net risk difference at these time points indicated the estimated long-term renal/cardiovascular treatment effect. Predicted relative risk reductions (RRRs) based on multiple markers were close to observed RRRs for renal (RRR(predicted): 30.1% vs. RRR(observed): 21.8%; P = 0.44) and cardiovascular outcomes (RRR(predicted): 9.4% vs. RRR(observed): 9.2%; P = 0.98), in addition to being markedly more accurate than predicted RRRs based on changes in single markers. The score was validated in an independent ARB trial. Predictions of long-term renal/cardiovascular ARB effects are more accurate when considering short-term changes in multiple risk markers, challenging the use of single markers to establish drug efficacy.

Plasma clearance of 51Cr-EDTA is widely used to assess the glomerular filtration rate (GFR) in diabetic nephropathy. Originally, the ratio between the intravenously injected amount of tracer and the total area under the plasma concentration curve was used for the calculation of total 51Cr-EDTA plasma clearance (C(T)). Simplified methods, using the final mono-exponential part of the plasma curve, have been suggested, e.g. four samples, taken 180 to 240 min after injection (C(IV)), or using one sample taken at 240 min (C(I)). Our aim was to evaluate the agreement between measurements of GFR and rate of decline in GFR based upon these three methods. Bland & Altman plots were used to illustrate the range of agreement. We investigated 76 insulin-dependent diabetic (IDDM) patients with microalbuminuria or diabetic nephropathy. GFR was measured after a single intravenous injection of 3.7 MBq 51Cr-EDTA by determining the radioactivity in venous blood samples taken 5, 7, 10, 15, 30, 45, 60, 90, 120, 150, 180, 200, 220, and 240 min after the injection. Rate of decline in GFR was assessed using 12 (6-17) determinations of GFR over a period of time of 8 (4-10) years. Mean (SD) GFRT was 123 (21) ml x min(-1) compared to GFR(IV) 123 (21) ml x min(-1) (NS) and GFR(I) 115 (17) ml x min(-1) (p < 0.00001). The mean difference (95% limits of agreement) between GFR(T) and GFR(IV) was +0.6 (-16.6 to +17.7) ml x min(-1), and between GFR(T) and GFR(I) +8.0 (-6.0 to +22.2) ml x min(-1). The difference between GFR(T) and GFR(I) was significantly correlated with their mean value (r = 0.56, p < 0.00001), indicating increasing underestimation by GFR(I) with increasing GFR levels. The mean (SD) rate of decline in GFR(T) was 2.3 (3.9) ml x min(-1) x year(-1), compared to a mean rate of decline in GFR(IV) of 2.4 (3.6) ml x min(-1) x year(-1) (NS), and a mean rate of decline in GFR(I) of 2.2 (3.5) ml x min(-1) x year(-1) (NS). The mean difference (95% limits of agreement) between rate of decline in GFR(T) and rate of decline in GFR(IV) was +0.16 (-1.59 to +1.91) ml x min(-1) x year(-1), and between rate of decline in GFR(T) and rate of decline in GFR(I) -0.01 (-1.64 to +1.61) ml x min(-1) x year(-1), respectively. In conclusion, our cross-sectional study revealed a close agreement between GFR(T) and GFR(IV) with acceptable limits of agreement (precision), while GFR(I) lacked accuracy. However, a close agreement between rate of decline in GFR(T) and rate of decline in GFR(IV), and between rate of decline in GFR(T) and rate of decline in GFR(I), with acceptable limits of agreement (precision), suggests that both simplified methods are applicable for long-term follow-up.

AIMS/HYPOTHESIS: Methylglyoxal (MGO) is a major precursor for advanced glycation end-products (AGEs), which are thought to play a role in vascular complications in diabetes. Known MGO-arginine-derived AGEs are 5-hydro-5-methylimidazolone (MG-H1), argpyrimidine and tetrahydropyrimidine (THP). We studied THP in relation to type 1 diabetes, endothelial dysfunction, low-grade inflammation, vascular complications and atherosclerosis.METHODS: We raised and characterised a monoclonal antibody against MGO-derived THP. We measured plasma THP with a competitive ELISA in two cohort studies: study A (198 individuals with type 1 diabetes and 197 controls); study B (individuals with type 1 diabetes, 175 with normoalbuminuria and 198 with macroalbuminuria [>300 mg/24 h]). We measured plasma markers of endothelial dysfunction and low-grade inflammation, and evaluated the presence of THP and N (ε)-(carboxymethyl)lysine (CML) in atherosclerotic arteries.RESULTS: THP was higher in individuals with type 1 diabetes than in those without (median [interquartile range] 115.5 U/μl [102.4-133.2] and 109.8 U/μl [91.8-122.3], respectively; p = 0.03). THP was associated with plasma soluble vascular cell adhesion molecule 1 in both study A (standardised β = 0.48 [95% CI 0.38, 0.58]; p CONCLUSIONS/INTERPRETATION: Our results suggest that MGO-derived THP may reflect endothelial dysfunction among individuals with and without type 1 diabetes, and therefore may potentially play a role in the development of atherosclerosis and vascular disease.

To evaluate whether pulse pressure alone or with placental growth factor as estimates of arterial stiffness and endothelial dysfunction, predicts mortality, cardiovascular disease and progression to end-stage renal disease in patients with Type 1 diabetes.Prospective, observational study, median (range) follow-up 8 (0-13) years, 900 patients with Type 1 diabetes, 458 with diabetic nephropathy, mean ± SD age 44 ± 11 years.During follow-up, we recorded 178 (20%) all-cause deaths, 109 (12%) cardiovascular deaths, 213 (24%) cardiovascular events and 73 (16%) progressed to end-stage renal disease. Elevated pulse pressure predicted all-cause and cardiovascular mortality and cardiovascular events [Hazard Ratio (HR) (95% CI) per 10 mmHg increase]: HR 1.2 (1.1-1.3), 1.3 (1.2-1.5) and 1.2 (1.1-1.3), P0.001 (adjusted for sex, age, HbA(1c) , cholesterol, diastolic blood pressure, creatinine, smoking, previous cardiovascular disease and nephropathy status). Furthermore, pulse pressure predicted the development of end-stage renal disease in patients with diabetic nephropathy: HR 1.2 (1.1-1.4), P=0.011 (adjusted for sex, age, HbA(1c) , cholesterol, diastolic blood pressure, previous cardiovascular disease and glomerular filtration rate). In a two-hit model, patients with pulse pressure and placental growth factor levels above the median vs. below the median had increased risk of all-cause and cardiovascular mortality, cardiovascular events and progression to end-stage renal disease: adjusted HRs 2.3 (1.2-4.2), 4.2 (1.6-11.0), 2.3 (1.3-4.1) and 3.5 (1.0-11.8),P0.05.Elevated pulse pressure independently predicts mortality, cardiovascular events and progression to end-stage renal disease in patients with Type 1 diabetes. Placental growth factor adds to the predictive value of pulse pressure on cardiovascular and renal outcome.

Adding aldosterone receptor blockade to standard renoprotective treatment may provide additional renoprotection in patients with overt nephropathy. We expected an impact of spironolactone in early diabetic nephropathy, and for this hypothesis we studied the effect on markers of glomerular and tubular damage in patients with Type 1 diabetes and persistent microalbuminuria.A double-blind, randomized, placebo-controlled crossover study in 21 patients with Type 1 diabetes and microalbuminuria using spironolactone 25 mg or placebo once daily, for 60 days added to standard antihypertensive treatment. After each treatment period, the primary endpoint were evaluated: urinary(u)-albumin excretion/24 hour(h) and secondary endpoints; 24 h blood pressure, glomerular filtration rate (GFR) and markers of tubular damage: urinary liver-type fatty-acid binding protein (LFABP), neutrophil gelatinase associated lipocalin (NGAL) and kidney injury molecule 1 (KIM1).All patients completed the study. During spironolactone treatment, urinary albumin excretion rate was reduced by 60% (range 21-80%), from 90 mg/24 h to 35 mg/24 h (P=0.01). Blood pressure (24 h) did not change during spironolactone treatment (P0.2 for all comparisons). The GFR (SD) decreased from 78 (6) mL/min/1.73 m(2) to 72 (6) mL/min/1.73 m(2) (P=0.003). Urinary liver-type fatty-acid binding protein, neutrophil gelatinase-associated lipocalin and kidney injury molecule 1 did not change during treatment (P0.3 for all comparisons). Treatment was well-tolerated, but two patients had severe hyperkalaemia (plasma potassium = 5.7 mmol/l), which was sufficiently treated with diuretics and dietary intervention.Spironolactone treatment in addition to standard renoprotective treatment lowers urinary albumin excretion in microalbuminuric patients with Type 1 diabetes, and thus may offer additional renoprotection independent of blood pressure.

Introduction The effect of insulin analogues on glycaemic control is well-documented, whereas the effect on avoidance of severe hypoglycaemia remains tentative. We studied the frequency of severe hypoglycaemia in unselected patients with type 1 diabetes treated with insulin analogues, human insulin, or mixed regimens. Methods A questionnaire was posted from six Danish diabetes clinics to 6112 unselected patients with type 1 diabetes and filled in by 3861 patients (63.2%). Primary endpoint was number of episodes of severe hypoglycaemia in the preceding year. Mild hypoglycaemia was also reported. Results The frequency of severe hypoglycaemic episodes per patient-year in patients receiving long-acting insulin analogues was 1.47 ± 0.18 versus 1.09 ± 0.10 in patients on long-acting human insulin (p = 0.01). The frequency of severe hypoglycaemic episodes per patient-year was 1.09 ± 0.11 in patients on short-acting insulin analogues versus 1.26 ± 0.13 in patients on short-acting human insulin (p = 0.15), which was statistically significant in an adjusted analysis. Conclusions Severe hypoglycaemia is more frequent in patients with type 1 diabetes treated with long-acting insulin analogues. Confounding by indication may be involved. Clinical intervention trials using insulin analogues in patients prone to severe hypoglycaemia are highly needed.

Placental growth factor is a vascular endothelial growth factor involved in angiogenesis, vascular inflammation and plaque formation. Soluble Fms-like tyrosine kinase 1 is a decoy receptor for placental growth factor, reducing its activity. The aim of this study is to evaluate the predictive value of placental growth factor and soluble Fms-like tyrosine kinase 1 in relation to all-cause and cardiovascular mortality and decline in kidney function in Type 1 diabetes.This was a prospective, observational follow-up study with 8 (0-13) years [median (range)] of follow-up, including patients with Type 1 diabetes, of whom 458 had diabetic nephropathy [278 men; age 42 ± 11 years (mean ± sd), diabetes duration 28 ± 9 years, glomerular filtration rate 76 ± 33 ml min(-1) 1.73 m(-2) ] and 442 had long-standing normoalbuminuria (234 men; age 45 ± 12 years, diabetes duration 28 ± 10 years).Placental growth factor and soluble Fms-like tyrosine kinase 1 levels measured at baseline were higher in patients with diabetic nephropathy compared with patients with long-standing normoalbuminuria [median (range)] 15 (4-131) vs. 11 (7-64) ng/l, (P0.001) and 86 (42-3462) vs. 77 (43-1557) ng/l (P0.001), respectively. In patients with diabetic nephropathy, high levels of placental growth factor predicted all-cause and cardiovascular mortality [hazard ratio 1.94 (1.16-3.24) and hazard ratio 2.91 (1.45-5.85)] after adjustment for sex, age, smoking, systolic blood pressure, HbA(1c) , cholesterol, glomerular filtration rate and previous cardiovascular disease. High levels of placental growth factor predicted increased risk of end-stage renal disease [hazard ratio 2.77 (1.47-5.14)], but covariate adjustments attenuated the association [hazard ratio 1.89 (0.91-3.95)]. Among patients with long-standing normoalbuminuria, placental growth factor levels predicted fatal and non-fatal cardiovascular events [hazard ratio 1.97 (1.03-3.76)], but not all-cause mortality. Baseline soluble Fms-like tyrosine kinase 1 levels did not predict outcome in either group after adjustment.Placental growth factor is elevated in patients with Type 1 diabetes and diabetic nephropathy and predicts all-cause and cardiovascular mortality, but not deterioration of kidney function.

Diabet. Med. 28, 345–351 (2011) Abstract Objective To study the association between baseline retinal microaneurysm score and progression and regression of diabetic retinopathy, and response to treatment with candesartan in people with diabetes. Methods This was a multicenter randomized clinical trial. The progression analysis included 893 patients with Type 1 diabetes and 526 patients with Type 2 diabetes with retinal microaneurysms only at baseline. For regression, 438 with Type 1 and 216 with Type 2 diabetes qualified. Microaneurysms were scored from yearly retinal photographs according to the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Retinopathy progression and regression was defined as two or more step change on the ETDRS scale from baseline. Patients were normoalbuminuric, and normotensive with Type 1 and Type 2 diabetes or treated hypertensive with Type 2 diabetes. They were randomized to treatment with candesartan 32 mg daily or placebo and followed for 4.6 years. Results A higher microaneurysm score at baseline predicted an increased risk of retinopathy progression (HR per microaneurysm score 1.08, P

Our aim was to evaluate the markers of tubulointerstitial damage, neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule1 (KIM1) in Type 1 diabetic patients with different levels of albuminuria and in control subjects. In addition, the effect of renoprotective treatment on urinary NGAL was evaluated in diabetic nephropathy.This was a cross-sectional study in 58 normoalbuminuric (u-albumin30 mg/24 h), 45 microalbuminuric (30-300 mg/24 h) and 45 macroalbuminuric (300 mg/24 h) Type 1 diabetic patients and 55 non-diabetic control subjects. Furthermore, in a second study, urine-NGAL was measured in a randomized cross-over study of 56 Type 1 diabetic patients with diabetic nephropathy treated with lisinopril 20, 40 and 60 mg daily. Urine-NGAL levels were [geometric mean (95% CI)]: control subjects 74 (52-104) (pg/mmol creatinine), normoalbuminuric 146 (97-221), microalbuminuric 222 (158-312) and macroalbuminuric group 261 (175-390). Urine-NGAL increased significantly from the normo- to the micro- and further to the macroalbuminuric group (P0.05). Urine-NGAL was higher in normoalbuminuric vs. control subjects (P0.01). Plasma-NGAL was significantly higher in the normoalbuminuric and macroalbuminuric groups than in the control group. Urine-KIM1 was higher in all diabetic groups than in the control group (P0.001), with no difference between diabetic groups. During lisinopril treatment, urine-NGAL was reduced (95% CI) 17% (11-50) (not significant).Urine-NGAL and urine-KIM1 (u-KIM1) are elevated in Type1 diabetic patients, with or without albuminuria, indicating tubular damage at an early stage. Urine-NGAL increases significantly with increasing albuminuria. The ACE inhibitor lisinopril reduced urine-NGAL, but this was not statistically significant.

Carbon monoxide exposure of nine dogs for two to five hours giving an average carboxyhemoglobin concentration of 38 per cent caused an average increase in lymph flow via the thoracic duct of 70 per cent. Lymph flux of albumin (mw 69,000) and α₂-macroglobulin (mw 820,000) showed an average increase of 45 per cent and 90 per cent respectively. These results point to increased capillary permeability of fluid and protein in the splanchnic capillaries. Finally, the investigation suggests that diffusion of α₂-macroglobulin is restricted in the splanchnic capillaries, since a marked difference between the ratio of permeability coefficients for albumin and α₂-macroglobulin (P(alb)/Pα₂ -m=15.4) and the ratio between diffusion coefficients (D(alb)/Dα₂ -m=2.5) were found.

Endothelial progenitor cells (EPC) augment vascular repair and neovascularisation. Patients with type 2 diabetes have reduced EPC and increased risk of cardiovascular disease (CVD), which is reduced by multifactorial intervention. Our aim, therefore, was to evaluate in type 2 diabetic patients whether the numbers of EPC derived from peripheral blood mononuclear cells is influenced by a multifactorial treatment strategy. We enrolled 28 patients newly referred for initiation of multifactorial treatment, which consisted of improving glycaemic, lipid and blood pressure control, as well as antithrombotic therapy and lifestyle modification. EPC count was assessed by in vitro cultures at baseline and after 90 days of treatment. After 7 days in culture, we identified EPC by fluorescent staining of attached cells. Patients were treated with metformin, aspirin, statins and angiotensin II receptor blockers, and divided accordingly into groups of mono-, dual-, triple- or quadruple therapy. After 90 days of treatment, glycaemic control improved and total cholesterol decreased. Multifactorial intervention for 90 days significantly increased EPC count in cultures by 35% (from 105 [SE 8] to 140 [11] cells per field [p = 0.002]). The change in EPC among patients with quadruple therapy was higher (63%) than in untreated patients (−32%, p = 0.043). Numbers of EPC derived from peripheral blood mononuclear cells increased significantly after multifactorial intervention in type 2 diabetic patients. It remains to be shown whether these changes contribute to the beneficial effects of multifactorial intervention on diabetic micro- and macroangiopathy.

AIM: The optimal antiproteinuric dose of aliskiren is unknown. This study compared the effect of placebo and increasing doses of aliskiren on urinary albumin excretion rate (UAER). METHODS: The trial was a double-blind crossover design. Twenty-six patients with type 2 diabetes mellitus, hypertension and albuminuria were randomised to 2-month treatments with placebo or aliskiren 150 mg, 300 mg or 600 mg once daily, in random order. Primary endpoint was change in UAER; secondary endpoints included changes in 24-h BP, GFR, biomarkers and components of the renin-angiotensin-aldosterone system. RESULTS: Placebo geometric mean UAER was 350 mg/day, mean 24-h BP was 137/81 (SD 12/9) mmHg, GFR was 85 (SD 26) ml min(-1) 1.73 m(-2). Aliskiren 150, 300 and 600 mg daily reduced UAER significantly by 36% (95% CI 17-51), 48% (33-60) and 52% (38-63) respectively (p < 0.001) compared with placebo. UAER reduction during the 600 mg dose was not significantly different from the 300 mg dose. Twenty-four-hour systolic BP was reduced by 4.5, 8.0 and 9.2 mmHg versus placebo, significant for 300 and 600 mg (p

Insulin-dependent diabetic patients with diabetic nephropathy have a highly increased morbidity and mortality from cardiovascular diseases. To determine whether altered levels of apolipoprotein(a) (apo(a)), the glycoprotein of the potentially atherogenic lipoprotein(a) (Lp(a)), contribute to the increased risk of ischaemic heart disease, apo(a) was determined in 50 insulin-dependent diabetic patients with diabetic nephropathy (group 1), in 50 insulin-dependent diabetic patients with microalbuminuria (group 2), in 50 insulin-dependent diabetic patients with normoalbuminuria (group 3), and in 50 healthy subjects (group 4). The groups were matched with regard to sex, age and body mass index. The diabetic groups were also matched with regard to diabetes duration. The level of apo(a) was approximately the same in the four groups, being: 122 (x/ divided by 4.2) U l-1, 63 (x/ divided by 4.4) U l-1, 128 (x/ divided by 3.5) U l-1 and 126 (x/ divided by 3.7) U l-1 (geometric mean (x/ divided by antilog SD)) in group 1, 2, 3 and 4, respectively. 1 U l-1 apo(a) approximates 0.7 mg l-1 Lp(a).(ABSTRACT TRUNCATED AT 250 WORDS)

Purpose: To investigate, longitudinally, whether increases in markers of inflammation (CRP, sICAM-1) and endothelial dysfunction (sICAM-1, sVCAM-1) are associated with and precede the increase in pulse pressure (PP) in individuals with type-1 diabetes (DM1). Methods: Inception cohort of 277 DM1 patients (114 women; mean age at diagnosis: 27.5±13.8 yrs) who were consecutively admitted, upon diagnosis, between Sep’79–Aug’84 to an outpatient diabetic clinic (Gentofte, Denmark). Throughout a follow-up period of >20 yrs, patients’ PP, other risk factors, and CRP, sICAM-1 and sVCAM-1 were measured repeatedly (at 3–4 months intervals). Associations were analysed with generalized estimating equations (GEEs) and adjusted for sex, age at diagnosis, smoking, anti-hypertensive treatment and MAP. Results: PP increased by 0.53 mmHg/yr, CRP by 0.033mg/L/yr, sICAM-1 by 1.8 ng/ml/yr and sVCAM-1 by 1.8 ng/ml/yr over the 20-yr longitudinal period (all p

Long-term diabetes is associated with excess morbidity and mortality, and cardiovascular autonomic neuropathy and QTc interval abnormalities are both predictive of early cardiovascular death in diabetes. We aimed to investigate the effect of these risk factors in a large cohort of type 1 diabetic patients followed prospectively for 10 years.Three-hundred-and-ninety-one type 1 diabetic mellitus patients (240 M and 151 F, age 41.8 years +/- 9.9 (mean +/-SD), duration of DM 27.3 years +/- 8.2) were followed in an outpatient setting.Patients with decreased heart rate variability had an excess overall mortality that diminished after adjusting for conventional cardiovascular risk factors; hazard ratio 2.5 (0.9-6.8; p = 0.071) compared to patients with normal heart rate variability. Likewise, prolonged QTc interval was associated with premature death with an adjusted hazard ratio of 2.3 (1.3-4.0; p = 0.005). In a combined analysis, patients with abnormal values for heart rate variability and QTc had a poorer prognosis compared to patients with normal test values for both parameters (adjusted hazard ratio 6.7 (1.8-25; p = 0.005)). Of the 34 patients with both test values abnormal, 15 died and 14 of these from cardiovascular causes.We conclude that combined abnormality in heart rate variability and QTc is a strong predictor of mortality in type 1 diabetes independently of conventional risk factors. These results have implications for future screening and treatment programmes for cardiovascular disease in type 1 diabetes.

Udgivelsesdato: 2008-Nov AIMS/HYPOTHESIS: The bone-related peptide osteoprotegerin is produced by vascular cells and is involved in the process of vascular calcification. The aim of this study was to investigate the predictive value of plasma levels of osteoprotegerin in relation to mortality, cardiovascular events and deterioration in kidney function in patients with type 1 diabetes. METHODS: This prospective observational follow-up study included 397 type 1 diabetic patients with overt diabetic nephropathy (243 men; age [mean+/-SD] 42.1 +/- 10.6 years, duration of diabetes 28.3 +/- 9.9 years, GFR 67 +/- 28 ml min(-1) 1.73 m(2)) and a group of 176 patients with longstanding type 1 diabetes and persistent normoalbuminuria (105 men; age 42.6 +/- 9.7 years, duration of diabetes 27.6 +/- 8.3 years). RESULTS: The median (range) follow-up period was 11.3 (0.0-12.9) years. Among patients with diabetic nephropathy, individuals with high osteoprotegerin levels (fourth quartile) had significantly higher all-cause mortality than patients with low levels (first quartile) (covariate-adjusted hazard ratio [HR] 3.00 [1.24-7.27]). High osteoprotegerin levels also predicted cardiovascular mortality (covariate-adjusted HR 4.88 [1.57-15.14]). Furthermore, patients with high osteoprotegerin levels had significantly higher risk of progression to end-stage renal disease than patients with low levels (covariate-adjusted HR 4.32 [1.45-12.87]). In addition, patients with high levels of plasma osteoprotegerin had an elevated rate of decline in GFR. CONCLUSIONS/INTERPRETATION: High levels of osteoprotegerin predict all-cause and cardiovascular mortality in patients with diabetic nephropathy. Furthermore, high levels of osteoprotegerin predict deterioration of kidney function towards end-stage renal disease.

The cochlear and retrocochlear hearing function was evaluated in patients with long- and short-term insulin-dependent diabetes mellitus (IDDM) by means of psychoacoustic testing and auditory brain stem responses (ABR). Twenty patients with diabetic microangiopathy (median age 41 years, range 25-66 years) were examined. The median duration of their diabetes was 26 years (range 13-46 years). In addition, 19 patients without microangiopathy (median age 27 years, range 17-42 years) and with a median duration of the diabetes of 2 years (range 0-6 years) were examined. The metabolic control estimated by blood glucose concentration and glycosylated haemoglobin was identical in the two groups of IDDM patients. After correction for age and sex, no significant differences in hearing thresholds or discrimination scores were present between the two diabetic groups, or between the diabetic patients and an age- and sex-matched normal background population. In the patients with long-term IDDM, ABR produced abnormal responses in 40%, indicating the presence of diabetic encephalopathy, whereas ABR were abnormal in only 5% of the patients with short-term IDDM.