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Objective: Microalbuminuria and metabolic syndrome are both associated with cardiovascular disease (CVD). The aim of this study was to determine the potential association between numbers of components in the metabolic syndrome, different levels of microalbuminuria and renal function. We also aimed to determine the risk of death and CVD at different levels of microalbuminuria and renal function and numbers of components in the metabolic syndrome. Design: Population-based observational follow-up study Setting: Epidemiological research unit (Copenhagen City Heart Study). Subjects: A total of 2696 men and women, 30–70 years of age. Baseline measures: Urinary albumin excretion (UAE), creatinine clearance and metabolic risk factors were measured in 1992–1994. Main outcome measurements: The participants were followed prospectively by registers until 1999–2000 with respect to CVD, and until 2004 with respect to death. Results: We found a strong association between microalbuminuria and the metabolic syndrome: 2% with none and 18% with five metabolic risk factors had microalbuminuria ( P < 0.001). No association between impaired renal function defined as creatinine clearance <60 mL min−1 and the metabolic syndrome was found. Microalbuminuria was associated with increased risk of death and CVD to a similar extend as the metabolic syndrome, irrespective of concomitant presence of metabolic syndrome (RR≈2; P < 0.001). Impaired renal function was not associated with increased risk of death and CVD in subjects with the metabolic syndrome. Conclusions: Microalbuminuria (UAE >5 μg min−1) confers increased risk of death and CVD to a similar extent as the metabolic syndrome. [ABSTRACT FROM AUTHOR]

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), P<0.0001. HbA1c, systolic blood pressure (BP), ethnicity, retinopathy, duration of diabetes, kidney function, body height, and smoking were all independent risk factors of MA, P<0.0001. Estimated glomerular filtration rate was below 60 ml/min/1.73 m2 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.Kidney International (2006) 69, 2057–2063. doi:10.1038/sj.ki.5000377; published online 12 April 2006 [ABSTRACT FROM AUTHOR]

Recent trials have linked calcium antagonists with adverse cardiovascular events in hypertensive patients with diabetes. A closer examination of these trials (in particular the Appropriate Blood Pressure Control in Diabetes [ABCD] trial and the Fosinopril Versus Amlodipine Cardiovascular Events Trial [FACET]) reveals a lack of data from which to draw conclusions of harm. In fact, based on the results of these trials and the recent Hypertension Optimal Treatment (HOT) Trial, one may conclude that the combination of a calcium antagonist with an ACE inhibitor is a rational therapeutic choice in patients with coexisting hypertension and diabetes. [ABSTRACT FROM AUTHOR]

Objective . 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. Material and methods . 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. Results . 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. Conclusions . 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. [ABSTRACT FROM AUTHOR]

Abstract Aims Elevated levels of urinary albumin excretion rate (AER) predict high risk for progressing to end-stage renal disease. In streptozotocin-induced diabetes, supplementation with vitamin C or E reduces albuminuria and glomerular hypertrophy. We tested the hypothesis that supplementation of both vitamin C and E in pharmacological doses lowers AER in Type 2 diabetic patients with persistent micro/macroalbuminuria. Methods Thirty Type 2 diabetic patients with AER 30–300 mg/24 h were included in a double-blind randomised, cross-over trial. Patients received vitamin C (1250 mg) and vitamin E (680 IU) per day or matching placebo for 4 weeks with a 3-week wash-out period between treatment periods in random order. Results Combined treatment with vitamin C and E reduced AER by 19% (95% CI 6–34%) (p = 0.04), geometric mean 197 mg/24 h (95% CI 114–341 mg/24 h) vs. 243 mg/24 h (146–404 mg/24 h). No changes were seen in serum creatinine, haemoglobin A1C or blood pressure. Fasting plasma concentrations of vitamin C and E increased in all patients during active treatment (mean vitamin C 79.4 μmol/L (SD 27.8) vs. 41.9 μmol/L (18.4) and vitamin E 47.0 μmol/L (19.8) vs. 29.5 μmol/L (15.3), P < 0.000001). Except for two patients that started additional blood pressure lowering treatment during the run-in period, no changes in medication, food and exercise habits or in the number of smokers occurred during the study. Conclusion Short-term treatment with vitamin C and E in pharmacological doses lowers AER in Type 2 diabetic patients with micro/macroalbuminuria. Further long-term, large-scale studies of this albuminuria reducing treatment modality are warranted. Diabet. Med. 18, 756–760 (2001). [ABSTRACT FROM AUTHOR]

Unlabelled: The ability of the kidney to maintain constancy of glomerular filtration rate (GFR) over a wide range of renal perfusion pressures is termed autoregulation. Defective autoregulation of GFR has been demonstrated in patients with diabetic and non-diabetic nephropathy and in streptozotocin diabetic rats during hyperglycaemia. Information on the potential impact of acute changes in glycaemic control on autoregulation of GFR in diabetic patients is lacking. Therefore the aim of our study was to evaluate the effect of acute lowering of blood pressure (BP) on GFR during normoglycaemia and hyperglycaemia. We investigated 14 (12m/2f) normoalbuminuric patients with non-insulin dependent diabetes (NIDDM). The patients were examined in random order on two separate days with blood glucose (BG)<10 mmol/L or with BG>15 mmol/L. GFR (single shot [51Cr] EDTA plasma clearance technique) was measured twice each day; first without clonidine (baseline) followed by intravenous injection of clonidine 100-150 microg. We measured BG (One Touch 2), and BP (Takeda TM2420) several times during each GFR measurement. Clonidine reduced mean arterial blood pressure with 20 (1.4) vs. 16 (1.2) mmHg (mean (SE)) with BG<10mmol/L and with BG>15 mmol/L, respectively (p=0.053). GFR diminished in average from 92 (3.1) to 86 (3.7) ml/min/1.73m2 with BG<10 mmol/L (p<0.05), and from 102 (4.1) to 98 (4.2) ml/min/1.73 m2 with BG> 15 mmol/L, NS. Mean difference between changes in GFR (95% confidence interval) between the examination with BG<10 mmol/L and with BG>15 mmol/L were 2.3 (-1.3 to 5.9) ml/min/1.73 m2 (NS). The mean BG during normoglycaemia was 6.9 (0.3) vs.16.9 (0.4) during hyperglycaemia.Conclusion: Our study suggests that acute changes in glycaemic control have no detectable effect on autoregulation of GFR in NIDDM patients. Hyperglycaemia enhances GFR. [ABSTRACT FROM AUTHOR]

Focuses on a study which assessed whether angiotensin-converting enzyme inhibitors prevents cardiovascular events in hypertensive type 2 diabetics. Comparison with conventional antihypertensive treatments; Results; Recommendations.

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). [ABSTRACT FROM AUTHOR]

One reason for the inadequacy of current renoprotective therapy and the persistent poor renal prognosis in diabetic nephropathy is the large interindividual variation in response to treatment. Genetic as well as non-genetic factors are known to influence treatment efficacy. This Commentary summarizes the impact of the angiotensin-converting enzyme (ACE) insertion/deletion polymorphism in the ACE gene on initiation and progression of diabetic nephropathy.Kidney International (2006) 69, 1293–1295. doi:10.1038/sj.ki.5000283 [ABSTRACT FROM AUTHOR]

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; P < 0.0001) with insulin analogue. Conclusions 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. [ABSTRACT FROM AUTHOR]

Background: Altered regulation of extracellular matrix remodeling by matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase (TIMP) may contribute to vascular complications in type 1 diabetes. We investigated associations between plasma MMP-1, -2, -3, -9, -10 and TIMP-1, and cardiovascular events and all-cause mortality in type 1 diabetic patients. Methods: We prospectively followed 337 type 1 diabetic patients [mean age 41.4 years (9.6), 39% female], 170 with and 167 without diabetic nephropathy, with median follow-up of 12.3 years. Survival analyses were applied to investigate differences in plasma MMP-1, -2, -3, -9, -10, and TIMP-1-levels in patients with and without a cardiovascular event and in those who died vs survivors. All analyses were adjusted for age, sex, duration of diabetes, HbA1c, nephropathy and for other conventional cardiovascular risk factors. Results: After adjustment for potential confounders, higher MMP-2 plasma levels were significantly associated with higher incidence of cardiovascular events [HR 1.49 (95% CI 1.11; 1.99)], and higher plasma levels of MMP-1 [1.38 (1.07; 1.78)], MMP-2 [1.60 (1.19; 2.15)] and MMP-3 [1.39 (1.05; 1.85)] were associated with all-cause mortality. All associations were independent of low-grade inflammation and endothelial dysfunction as estimated by plasma markers. Associations between MMP-2 and cardiovascular events and between MMP-3 and mortality were attenuated after further adjustment for eGFR and changes in eGFR. Conclusions: Higher levels of MMP-2 are associated with CVD and higher MMP-1, -2 and -3 with all-cause mortality. In addition, associations between MMP-2 and CVD, and MMP-3 and mortality were attenuated after adjustment for eGFR while both MMPs were associated with eGFR decline, indicating a possible mediating role of eGFR. [ABSTRACT FROM AUTHOR]

Aims To investigate whether the degree of albuminuria reduction observed in the ALTITUDE trial is associated with renal and cardiovascular protection, and secondly, whether the reduction in albuminuria was too small to afford clinical benefit. Methods In a post hoc analysis of the ALTITUDE trial in 8561 patients with type 2 diabetes and chronic kidney disease or cardiovascular disease we examined the effect of albuminuria changes at 6 months on renal and cardiovascular outcomes using Cox proportional hazard regression. Results The median change in albuminuria in the first 6 months in the aliskiren arm of the trial was −12% (25th to 75th percentile: −48.7_to_ +41.9%) and 0.0% (25th to 75th percentile: −40.2_to_55%) in the placebo arm. Changes in albuminuria in the first 6 months were linearly associated with renal and cardiovascular endpoints: a >30% reduction in albuminuria in the first 6 months was associated with a 62% reduction in renal risk and a 25% reduction in cardiovascular risk compared with an increase in albuminuria. The association between changes at 6 months in albuminuria and renal or cardiovascular endpoints was similar in the two treatment groups (p for interaction >0.1 for both endpoints). Conclusions The addition of aliskiren to angiotensin-converting enzyme inhibitor/angiotensin receptor blocker therapy resulted in albuminuria changes that were associated with renal and cardiovascular risk changes. This did not translate into renal or cardiovascular protection because the overall reduction in albuminuria in the aliskiren arm was too small and nearly similar to that in the placebo arm. [ABSTRACT FROM AUTHOR]

Aims: 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. Methods: 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 [eGFR>60 ml/min/1.73m2 and albumin:creatinine ratio (ACR) <30 mg/g], intermediate (eGFR 30-60 ml/min/1.73m2 or ACR 30-300 mg/g) and advanced (eGFR <30 ml/min/1.73m2 or ACR >300 mg/g) stages of DKD for patients in different age groups. Results: 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. Conclusions: RAS intervention early in the course of proteinuric DKD is more beneficial than late intervention in delaying ESRD. [ABSTRACT FROM AUTHOR]

Aims 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. Methods 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 51Cr- 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. Results 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 ( P < 0.01). In addition, adjusted r2 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. Conclusion High urinary sulphate excretion was significantly associated with slower decline in 51Cr- EDTA-assessed GFR in diabetic nephropathy, independent of known progression promoters. [ABSTRACT FROM AUTHOR]

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 < 0.001 (adjusted for sex, age, HbA1c, 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, HbA1c, 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), P < 0.05. Conclusions 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. [ABSTRACT FROM AUTHOR]

Diabet. Med. 29, e184-e190 (2012) Abstract Aims 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. Methods 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). Results 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 ( P > 0.2 for all comparisons). The GFR (SD) decreased from 78 (6) mL/min/1.73 m2 to 72 (6) mL/min/1.73 m2 ( P = 0.003). Urinary liver-type fatty-acid binding protein, neutrophil gelatinase-associated lipocalin and kidney injury molecule 1 did not change during treatment ( P > 0.3 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. Conclusions 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. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

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 < 0.001) and 86 (42-3462) vs. 77 (43-1557) ng/l ( P < 0.001), 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, HbA1c, 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. Conclusion 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. [ABSTRACT FROM AUTHOR]

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 normoal buminuric, 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 < 0.0001 in Type 1 diabetes; HR 1.07,P = 0.0174 in Type 2 diabetes) and reduced the likelihood of regression (HR 0.79, P < 0.0001 in Type 1 diabetes; HR 0.85, P = 0.0009 in Type 2 diabetes), all adjusted for baseline variables and treatment. Candesartan reduced the risk of microaneurysm score progression. Conclusions Microaneurysm counts are important prognostic indicators for worsening of retinopathy, thus microaneurysms are not benign. Treatment with renin-angiotensin system inhibitors is effective in the early stages and may improve mild diabetic retinopathy. Microaneurysm scores may be useful surrogate endpoints in clinical trials. [ABSTRACT FROM AUTHOR]

Diabet. Med. 27, 1144–1150 (2010) 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 < 30mg/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. 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 < 0.05). Urine-NGAL was higher in normoalbuminuric vs. control subjects ( P < 0.01). 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 ( P < 0.001), with no difference between diabetic groups. During lisinopril treatment, urine-NGAL was reduced (95% CI) 17% (11–50) (not significant). Conclusions Urine-NGAL and urine-KIM1 (u-KIM1) are elevated in Type 1 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. [ABSTRACT FROM AUTHOR]

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 haemoglobinA1c (HbA1c) ≥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). HbA1c (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. [ABSTRACT FROM AUTHOR]

Objective . Low density lipoprotein cholesterol (LDL-C) is an independent and modifiable risk factor for development of cardiovascular disease (CVD). Postprandial lipid metabolism has been linked to CVD, but little is known about the postprandial LDL-C profile in patients with type-2 diabetes (T2DM). We aimed to study the postprandial levels of LDL-C in T2DM patients. Material and methods . After an overnight fast, 74 T2DM patients, mean age approximately 60 years, were served a standard fat-rich meal of 3,515 kJ containing 54 % fat, 13 % protein and 33 % carbohydrates. Only drinking water was allowed postprandially. Blood samples were drawn at times 0 (fasting), 1.5, 3.0, 4.5 and 6.0 h (postprandial). In all samples, LDL-C was measured with modified beta quantification (separation by ultracentrifugation followed by measurement of infranate high density lipoprotein cholesterol (HLD-C) using a homogeneous assay). Results . At all postprandial times, levels of LDL-C showed highly significant (p<0.005) decreases compared to time 0 (mean [95 % CI] maximum change in LDL-C levels at 3.0 h: -0.16 mmol/L [-0.12; -0.20]; p<0.001). Independently of fasting LDL-C levels and ongoing statin therapy, LDL-C decreased significantly more in female compared to male patients postprandially (mean [95 % CI] maximum unadjusted change versus time 0 in LDL-C for men [n = 56] at 3.0 h: -0.14 mmol/L [-0.19; -0.10], p<0.001; for women [n = 18] at 4.5 h: -0.26 mmol/L [-0.35; -0.18], p<0.001; -0.14 mmol/L [-0.24; -0.05], p = 0.005 between genders for the mean [95 % CI] fasting adjusted difference at 4.5 h in the change versus time 0 in LDL-C; gender by time interaction: p = 0.007 (repeated measures mixed model)). Conclusions . In T2DM patients served a fat-rich meal, levels of LDL-C decreased significantly more in women compared to men postprandially, irrespective of fasting levels or ongoing statin therapy. This might have implications in the atherosclerotic process and on any difference in the risk of CVD between genders. [ABSTRACT FROM AUTHOR]

Abstract: 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±8.8ml/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. [Copyright &y& Elsevier]

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.Kidney International (2008) 73, 1419–1425; doi:10.1038/ki.2008.68; published online 12 March 2008 [ABSTRACT FROM AUTHOR]

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 < 0.0001. For acute coronary syndromes, a PAPP-A threshold of 10 mIU/l has been suggested. Thirty-seven patients were above the threshold and of these 13 patients (35%) died, compared with 60 of 338 patients (18%) below the threshold; log rank test P = 0.007. PAPP-A significantly predicted mortality after adjustment for presence of nephropathy; hazard ratio for dying when PAPP-A was above the threshold 2.1 (95% CI 1.13–3.9); P = 0.019. After adjusting for traditional risk factors, the results were attenuated. When only patients with nephropathy were analysed, PAPP-A was significantly predictive of all-cause mortality [ P = 0.008; 2.43 (1.26–4.67)] in unadjusted analysis. After adjustment, the predictive value of PAPP-A for all-cause mortality was attenuated ( P = 0.064). Conclusion We find PAPP-A to be associated with increased mortality in Type 1 diabetic patients with nephropathy in unadjusted analysis. After adjustment for traditional risk factors, the prognostic value of PAPP-A was no longer significant. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aim: Metformin is the ‘drug-of-first-choice’ in obese patients with type 2 diabetes mellitus (T2DM) due to its antihyperglycaemic and cardiovascular protective potentials. In non-obese patients with T2DM, insulin secretagogues are empirically used as first choice. In this investigator-initiated trial, we evaluated the effect of metformin vs. an insulin secretagogue, repaglinide on glycaemic regulation and markers of inflammation and insulin sensitivity in non-obese patients with T2DM. Methods: A single-centre, double-masked, double-dummy, crossover study during 2 × 4 months involved 96 non-obese (body mass index ≤ 27 kg/m2) insulin-naïve patients with T2DM. At enrolment, previous oral hypoglycaemic agents (OHA) were stopped and patients entered a 1-month run-in on diet-only treatment. Hereafter, patients were randomized to either repaglinide 2 mg thrice daily followed by metformin 1 g twice daily or vice versa each during 4 months with 1-month washout between interventions. Results: End-of-treatment levels of haemoglobin A1c (HbA1c), fasting plasma glucose, mean of seven-point home-monitored plasma glucose and fasting levels of high-sensitivity C-reactive protein and adiponectin were not significantly different between treatments. However, body weight, waist circumference, fasting serum levels of insulin and C-peptide were lower and less number of patients experienced hypoglycaemia during treatment with metformin vs. repaglinide. Both drugs were well tolerated. Conclusions: In non-obese patients with T2DM, overall glycaemic regulation was equivalent with less hypoglycaemia during metformin vs. repaglinide treatment for 2 × 4 months. Metformin was more effective targeting non-glycaemic cardiovascular risk markers related to total and abdominal body fat stores as well as fasting insulinaemia. These findings may suggest the use of metformin as the preferred OHA also in non-obese patients with T2DM. [ABSTRACT FROM AUTHOR]

Reduction of nephrotic range albuminuria is associated with markedly improved renal and cardiovascular outcome in patients with diabetic nephropathy. Aldosterone has been suggested to play a role in the progression of diabetic nephropathy. We therefore aimed to evaluate the short-term effect of aldosterone antagonism with spironolactone on nephrotic range albuminuria and blood pressure in diabetic nephropathy. Twenty Caucasian patients with diabetic nephropathy and nephrotic range albuminuria (>2500 mg/24 h) despite recommended antihypertensive treatment completed this double-masked, randomized crossover trial. Patients were treated in random order with spironolactone 25 mg once daily and matched placebo for 2 months, on top of ongoing antihypertensive treatment, including an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker in maximally recommended doses. Median (range) number of antihypertensive drugs was 3 (2–5). After each treatment period, albuminuria, 24-h ambulatory blood pressure, and glomerular filtration rate (GFR) were determined. Spironolactone on top of recommended renoprotective treatment induced a 32% (95% confidence interval (CI): 21–42%) reduction in albuminuria from (geometric mean (95% CI)) 3718 (2910–4749) mg/24 h on placebo treatment (P<0.001). There was a significant reduction in 24-h blood pressure of 6 (2–10)/4 (2–6) mm Hg and day blood pressure of 7 (3–12)/5 (3–7) mm Hg (P<0.01), whereas night blood pressure remained unchanged. Spironolactone induced an insignificant reversible reduction in GFR of 3 ml/min/1.73 m2 from 64 (27) ml/min/1.73 m2. No patients were excluded due to adverse events. Our results suggest that spironolactone treatment on top of recommended renoprotective treatment including maximal renin–angiotensin system blockade may offer additional renoprotection in patients with diabetic nephropathy and nephrotic range albuminuria.Kidney International (2006) 70, 536–542. doi:10.1038/sj.ki.5001580; published online 14 June 2006 [ABSTRACT FROM AUTHOR]

Aims Aldosterone is one of the main effectors of the renin–angiotensin–aldosterone system regulating blood pressure. Previous studies have shown that the aldosterone synthase promoter polymorphism −344T/C influences aldosterone levels and is associated with hypertension, a risk factor for the initiation and progression of diabetic nephropathy. Therefore, we investigated whether the −344T/C polymorphism is associated with the development and progression of diabetic nephropathy in Type 1 diabetes mellitus. Methods The −344T/C polymorphism was determined using standard PCR techniques in 422 Type 1 diabetic patients with overt diabetic nephropathy [mean age 43 years (sd 11)], and in 479 patients with persistent normoalbuminuria and long-standing Type 1 diabetes [age 47 years (sd 12), duration of diabetes 27 years (sd 10)]. Furthermore, we genotyped 163 Type 1 diabetic patients with overt diabetic nephropathy treated with angiotensis-converting enzyme inhibitors (ACE-I). These patients were followed for a median of 6 years (range 3–14), with nine measurements (range 3–29) of glomerular filtration rate (GFR), and had a decline in GFR of 3.1 (−3.2; 23.7) ml/min per year. Results There was no significant difference between cases and controls in either genotype distributions (cases TT 0.33, TC 0.48, CC 0.19; controls TT 0.32, TC 0.48, CC 0.20) or allele frequencies (cases T/C 0.57/0.43; controls T/C 0.56/0.44). Furthermore, a genotype–phenotype interaction analysis in the normoalbuminuric patients revealed no differences in sex distribution, age, duration of diabetes, blood pressure, HbA1c, or urinary albumin excretion rate across genotypes. In the observational follow-up study, the rate of decline in GFR did not differ between groups of patients with different −344T/C genotype ( P = 0.41). However, the T-allele made a statistically significant contribution to both systolic and diastolic pressure during follow-up ( P = 0.006 and 0.032, respectively). Conclusions The −344T/C polymorphism of the aldosterone synthase gene is not associated with initiation or progression of diabetic nephropathy in Caucasian Type 1 diabetic patients, but modulates blood pressure variation. [ABSTRACT FROM AUTHOR]

Objective . It has been suggested that an aldosterone synthase gene polymorphism (CYP11B2 ­344T/C) is predictive of the blood pressure lowering effect of angiotensin II receptor blockers in essential hypertension. We investigated whether this polymorphism is predictive of reductions in blood pressure and albuminuria and preservation of glomerular filtration rate (GFR) during short‐term and long‐term treatment with losartan in 57 hypertensive type‐1 diabetic patients with diabetic nephropathy. Material and methods . After a 4‐week washout period, patients received losartan (100 mg o.d.) and were followed for a mean follow‐up of 36 months. At baseline, after 2 and 4 months, and every 6 months thereafter, GFR ( 51 Cr‐EDTA‐clearance), albuminuria and 24‐h blood pressure were determined. The CYP11B2 ­344T/C polymorphism was determined by standard polymerase chain reaction (PCR). Results . The TT, CT and CC genotypes were found in 28 %, 58 % and 14 % of patients, respectively. At baseline albuminuria and blood pressure did not differ between genotype groups. Plasma aldosterone levels (geometric mean (95 % CI)) were similar at baseline: 87 (60–125), 77 (53–112), and 89 (49–161) pg mL -1 and during follow‐up (not significant). After initiation of losartan treatment, comparable mean (SE) reductions in blood pressure and albuminuria were seen in patients with TT, CT and CC genotypes ( p >0.6 between groups). After long‐term follow‐up, there was a tendency towards a difference in systolic blood pressure reduction ( p = 0.07, one‐way ANOVA), suggesting a poorer response in patients with the CC genotype. No significant difference in rate of decline in GFR (median (range)) was seen between groups (TT, CT, CC): 4.2 (-1.0 to 16.0), 3.2 (-1.6 to 13.8) and 2.6 (-0.1 to 11.0) mL min -1 year -1 , respectively ( p = 0.5). Conclusions . Compared to a previous smaller study of angiotensin II receptor blockade in essential hypertension, we could not confirm that CYP11B2 ­344T/C genotypes contribute towards explaining the observed variability in response to treatment with angiotensin II receptor blockers, which could be due to lack of power. [ABSTRACT FROM AUTHOR]

The Z−2 allele of the (AC)n polymorphism in the aldose reductase gene ( ALR2) confers increased risk of microvascular diabetic complications, whereas the Z+2 allele has been proposed to be a marker of protection. However data are conflicting. Therefore, we investigated whether this polymorphism is associated with diabetic nephropathy and retinopathy in Type 1 diabetes mellitus in a large case–control study and a family-based analysis. A total of 431 Type 1 diabetic patients with diabetic nephropathy and 468 patients with longstanding Type 1 diabetes and persistent normoalbuminuria were genotyped for the case–control study. In addition, 102 case trios and 98 control trios were genotyped for a family-based study. Thirteen different alleles were identified. In the case–control study, the Z+2 allele frequency was significantly higher in the normoalbuminuric diabetic than in patients with diabetic nephropathy (0.17 vs. 0.11, P = 0.008), suggesting a protective function of the Z+2 allele. No significant increase in the frequency of the putative risk allele Z−2 was found in patients with diabetic nephropathy vs. controls (0.39 vs. 0.36). No association with diabetic retinopathy was found. Although the results of the transmission of the Z−2 and Z+2 alleles in the independent family-based study were consistent with the association study, the number of informative families was limited and thus differences were not statistically significant. The Z+2 allele of the ALR2 promoter polymorphism is associated with a reduced susceptibility to diabetic nephropathy in Danish Type 1 diabetic patients, suggesting a minor role for the polyol pathway in the pathogenesis of diabetic kidney disease. No association of the ALR2 polymorphism with diabetic retinopathy was found. Diabet. Med. (2004) [ABSTRACT FROM AUTHOR]

Jacobsen P, Rossing K, Hansen BV, Bie P, Vaag A, Parving H-H (Steno Diabetes Center, Gentofte; University of Aarhus, Aarhus; and University of Southern Denmark, Odense, Denmark). Effect of short-term hyperglycaemia on haemodynamics in type 1 diabetic patients. J Intern Med 2003; 254: 464–471. Mechanisms underlying glucose-mediated development and progression of diabetic complications are incompletely understood. We tested the impact of short-term hyperglycaemia on systemic blood pressure and regulatory hormones in type 1 diabetic patients. We included 18 patients [13 men, mean (SEM) diabetes duration 10 (1) years] without signs of autonomic neuropathy or renal complications in a randomized single-blinded cross-over trial using insulin–glucose clamp technique. Patients were clamped for 90 min to blood glucose of 5 mmol L−1 (euglycaemia) and 15 mmol L−1 (hyperglycaemia) in random order. Blood pressure was measured noninvasively every 5 min (Takeda TM2421 device). Regulatory hormones were determined at the end of each clamp period. Systolic blood pressure increased [mean (95% CI)] 3 (1, 5) mmHg during hyperglycaemia from 123 (SEM 2) during euglycaemia, P = 0.01. Diastolic blood pressure remained unchanged at 78 (2) mmHg. Hyperglycaemia reduced plasma concentrations of: renin [14 (4, 23)%, P = 0.02], angiotensin II [17 (8, 25)%, P < 0.01] and adrenaline [20 (10, 29)%, P < 0.01]. Plasma concentration of atrial natriuretic peptide increased by 11 (6, 17) pg mL−1 ( P < 0.01) from 43 (2) pg mL−1. We calculated a median (range) increase in extracellular volume and plasma volume (PV) of 2.6 (0.7–5.3)% and 5.0 (−4.7 to 8.6)%, respectively. In type 1 diabetic patients without signs of autonomic neuropathy short-term hyperglycaemia induced a modest increase in systolic blood pressure and suppression of the renin–angiotensin system, possibly caused by PV expansion because of fluid shift from intra- to extracellular compartment. [ABSTRACT FROM AUTHOR]

Objectives: Intrauterine growth retardation, as seen in individuals with low weight at birth, may give rise to a reduction in nephron number. Oligonephropathy has been linked to hypertension and renal disease in adult life. We tested the concept that low weight at birth acts as a risk factor for progression of diabetic nephropathy.Design and Subjects: We performed an observational follow-up study of 161 (97 men) type 1 diabetic patients with diabetic nephropathy [mean age (SD): 35 (11) years, mean duration of diabetes: 22 (8) years]. All patients had been followed for at least 3 years [median (range): 8 (3-20)] with at least three measurements [9 (3-31)] of glomerular filtration rate (GFR) (51Cr-EDTA). Information about birth size was obtained from midwife registrations.Settings: Steno Diabetes Center, a tertiary referral centre.Main Outcome Measures: Loss of kidney function according to birth weight and weight/length ratio at birth.Results: There was no correlation in univariate analysis between birth weight or weight/length ratio and rate of decline in GFR, neither in men nor in women. Furthermore, the 27 patients with birth weights below the 20th centile had a rate of decline in GFR [median (range)] similar to the 134 patients above: 2.6 (-4.7; 9.6) vs. 3.4 (-2.3; 19.3) mL min(-1) year(-1), respectively (NS). A multiple regression analysis revealed that albuminuria, arterial blood pressure, and haemoglobin A1C during follow-up showed a significant correlation with the decline in GFR [R2 (adjusted) = 0.34], whereas birth weight and birth weight/length ratio did not.Conclusions: Our study does not suggest that weight at birth is associated with progression of established diabetic nephropathy in type 1 diabetic patients, whilst several other potential modifiable risk factors were identified. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the cumulative incidence of nephrotic-range albuminuria (NRA), the frequency of remission, and the impact on progression, we analyzed data from a prospective cohort study of type 1 diabetic patients with diabetic nephropathy.Research Design and Methods: All of the albuminuric type 1 diabetic patients (n = 321, 121 women), who had at least yearly measurements of glomerular filtration rate (GFR) with a (51)Cr-EDTA plasma clearance technique and were followed for at least 3 years, were evaluated. NRA, defined as persistent albuminuria >2,500 mg/24 h, occurred in 126 patients (35 women) aged (mean +/- SD) 34 +/- 8 years, with duration of diabetes 22 +/- 8 years and follow-up time from onset of NRA (median [range]) 8.7 (3.0-20.9) years. Remission of NRA was defined as sustained albuminuria <600 mg/24 h for at least 1 year.Results: The cumulative incidence of NRA was 39%. Remission was induced in 28 of 126 (22%) patients; 21 were predominantly treated with ACE inhibitors, 7 with non-ACE inhibitor medications. Remission lasted 3.6 (1.0-18.1) years. More women (37%) than men (16%) obtained remission (P = 0.01). In the remission group compared with the no-remission group, mean arterial blood pressure (mean +/- SEM) was reduced (102 +/- 1 vs. 106 +/- 1 mmHg, P < 0.01), the rate of decline in GFR was diminished (3.8 +/- 0.6 vs. 7.5 +/- 0.5 ml x min(-1) x year(-1), P < 0.001), and serum cholesterol was lower (5.3 +/- 0.2 vs. 6.1 +/- 0.1 mmol/l, P < 0.01) during the whole follow-up period. No difference in glycemic control was found between groups (HbA(1c) 9.2 vs. 9.4%, NS).Conclusions: In contrast to observations made before the use of antihypertensive treatment, our prospective observational study suggests that aggressive antihypertensive treatment with and without ACE inhibitors can induce long-lasting remission in a sizeable fraction of type 1 diabetic patients with NRA. The group of patients obtaining remission is characterized by slow progression of diabetic nephropathy and improved cardiovascular risk profile. [ABSTRACT FROM AUTHOR]

Background: Microalbuminuria and hypertension are risk factors for diabetic nephropathy. Blockade of the renin-angiotensin system slows the progression to diabetic nephropathy in patients with type 1 diabetes, but similar data are lacking for hypertensive patients with type 2 diabetes. We evaluated the renoprotective effect of the angiotensin-II-receptor antagonist irbesartan in hypertensive patients with type 2 diabetes and microalbuminuria.Methods: A total of 590 hypertensive patients with type 2 diabetes and microalbuminuria were enrolled in this multinational, randomized, double-blind, placebo-controlled study of irbesartan, at a dose of either 150 mg daily or 300 mg daily, and were followed for two years. The primary outcome was the time to the onset of diabetic nephropathy, defined by persistent albuminuria in overnight specimens, with a urinary albumin excretion rate that was greater than 200 microg per minute and at least 30 percent higher than the base-line level.Results: The base-line characteristics in the three groups were similar. Ten of the 194 patients in the 300-mg group (5.2 percent) and 19 of the 195 patients in the 150-mg group (9.7 percent) reached the primary end point, as compared with 30 of the 201 patients in the placebo group (14.9 percent) (hazard ratios, 0.30 [95 percent confidence interval, 0.14 to 0.61; P< 0.001] and 0.61 [95 percent confidence interval, 0.34 to 1.08; P=0.081 for the two irbesartan groups, respectively). The average blood pressure during the course of the study was 144/83 mm Hg in the placebo group, 143/83 mm Hg in the 150-mg group, and 141/83 mm Hg in the 300-mg group (P=0.004 for the comparison of systolic blood pressure between the placebo group and the combined irbesartan groups). Serious adverse events were less frequent among the patients treated with irbesartan (P=0.02).Conclusions: Irbesartan is renoprotective independently of its blood-pressure-lowering effect in patients with type 2 diabetes and microalbuminuria. [ABSTRACT FROM AUTHOR]

Background: Diabetic nephropathy is the leading cause of end-stage renal disease. Interruption of the renin-angiotensin system slows the progression of renal disease in patients with type 1 diabetes, but similar data are not available for patients with type 2, the most common form of diabetes. We assessed the role of the angiotensin-II-receptor antagonist losartan in patients with type 2 diabetes and nephropathy.Methods: A total of 1513 patients were enrolled in this randomized, double-blind study comparing losartan (50 to 100 mg once daily) with placebo, both taken in addition to conventional antihypertensive treatment (calcium-channel antagonists, diuretics, alpha-blockers, beta-blockers, and centrally acting agents), for a mean of 3.4 years. The primary outcome was the composite of a doubling of the base-line serum creatinine concentration, end-stage renal disease, or death. Secondary end points included a composite of morbidity and mortality from cardiovascular causes, proteinuria, and the rate of progression of renal disease.Results: A total of 327 patients in the losartan group reached the primary end point, as compared with 359 in the placebo group (risk reduction, 16 percent; P=0.02). Losartan reduced the incidence of a doubling of the serum creatinine concentration (risk reduction, 25 percent; P=0.006) and end-stage renal disease (risk reduction, 28 percent; P=0.002) but had no effect on the rate of death. The benefit exceeded that attributable to changes in blood pressure. The composite of morbidity and mortality from cardiovascular causes was similar in the two groups, although the rate of first hospitalization for heart failure was significantly lower with losartan (risk reduction, 32 percent; P=0.005). The level of proteinuria declined by 35 percent with losartan (P<0.001 for the comparison with placebo).Conclusions: Losartan conferred significant renal benefits in patients with type 2 diabetes and nephropathy, and it was generally well tolerated. [ABSTRACT FROM AUTHOR]

In type 1 diabetic patients with microalbuminuria not receiving antihypertensive treatment, an increase in urinary albumin excretion rate (AER) of 6% to 14%/year and a risk for the development of diabetic nephropathy of 3% to 30%/year have previously been reported. The aim of the present study was to audit the effect of angiotensin converting enzyme (ACE) inhibition on the progression of microalbuminuria and development of diabetic nephropathy. We consecutively identified 227 type 1 diabetic patients with persistent microalbuminuria (urinary AER between 30 and 300mg/24h, ELISA). According to the level (> or = 100 or < 100mg/24 h) and/or rate of progression in urinary AER (>6% or < or =6%/year), patients were divided into a high-risk group (n= 177) and a low-risk group (n= 50) for development of diabetic nephropathy. According to international guidelines, all patients at high-risk were recommended ACE-inhibitor treatment. Throughout the study, 67% of the patients were treated with an ACE inhibitor. Urinary AER significantly declined by 8.3%/year (95% CI: 2.8 to 13.9) in the whole group of patients, and the risk for the development of diabetic nephropathy during follow-up was 3.5%/year. Glycaemic control and blood pressure remained unchanged during the study. The implementation of modified international guidelines regarding the use of ACE inhibition in the treatment of microalbuminuric type 1 diabetic patients reduced progression to diabetic nephropathy comparable to what has previously been reported in intervention trials. [ABSTRACT FROM AUTHOR]

Objective: We studied the effect of a diet supplementation with fish oil in insulin-dependent diabetic patients with nephropathy in order to evaluate whether abnormal transcapillary escape rate of albumin and procoagulant activity in these patients could be modified.Methods: A double-blind, randomized, controlled study was carried out at a tertiary referral centre. The subjects were 29 insulin-dependent diabetic patients with nephropathy. One year of fish oil supplementation (4.6 g n-3 fatty acids/day) was compared with placebo (olive oil). The main outcome measures were N-3 fatty acid proportions of platelet lipids, transcapillary escape rate of albumin, prothrombin fragment 1 + 2, thrombin-antithrombin complexes, markers of fibrinolysis, fibrinogen, factor VII antigen and activity, thrombomodulin, von Willebrand factor, platelet factor 4 and beta-thromboglobulin. These were measured every 6 months.Results: Neither transcapillary escape rate of albumin (7.4 (median) (5.0-9.8) (range) % vs. 7.0 (4.6-10.6) %) nor prothrombin fragment 1 + 2 (0.97 (0.72-2.40) nmol/L vs. 1.01 (0.59-3.11) nmol/L) changed after 12 months of fish oil supplementation.Conclusion: Increased transcapillary escape rate of albumin and activity could not be modified during diet supplementation with fish oil in insulin-dependent diabetic patients with nephropathy. [ABSTRACT FROM AUTHOR]

Advanced glycation end-products (AGEs) may play an important role in the pathogenesis and progression of cardiovascular and renal complications of diabetes. Four putative AGE receptors (RAGEs), AGE-R1, AGE-R2, and AGE-R3 have been described. In this study, we scanned the sequence of the genes encoding these AGE receptors in 48 patients with type 1 diabetes and investigated the identified polymorphisms (n = 19) in 199 type 1 diabetic patients with nephropathy and 193 type 1 diabetic patients without nephropathy. Overall, none of the polymorphisms was strongly associated with nephropathy. The minor allele of a polymorphism located in the promoter region of the RAGE gene (C-1152A) conferred a weak protective effect (P < 0.05) and was associated with a longer duration of nephropathy-free diabetes (P = 0.08). [ABSTRACT FROM AUTHOR]

Evaluates prolonged QTc interval and QT dispersion in predicting mortality of patients with Type I diabetes mellitus in Caucasus. Risk factors in cardiovascular mortality rate; Use of Analysis of variance in the study; Increase mortality in patients.

Objective: High-dose treatment with cyclooxygenase inhibitors reduces urinary albumin excretion rate (AER) in type 1 diabetic patients with microalbuminuria and macroalbuminuria. This effect may lead to an incorrect classification of albuminuria (normo-, micro-, and macroalbuminuria) and jeopardize the monitoring of antiproteinuric treatment (e.g., ACE inhibition). Whether similar difficulties exist using low-dose acetylsalicylic acid (ASA), now widely recommended for primary and secondary prevention of cardiovascular events in type 1 diabetic patients with micro- and macroalbuminuria, remains to be elucidated.Research Design and Methods: We performed a randomized double-blind crossover trial in 17 type 1 diabetic patients with microalbuminuria (urinary AER 30-300 mg/24 h). Patients were given ASA (150 mg/daily) for 4 weeks followed by placebo for 4 weeks with at least a 2-week washout period in random order. At the end of each treatment period, AER (enzyme-linked immunosorbent assay), glomerular filtration rate (GFR) (plasma clearance of 51Cr-EDTA), blood pressure (BP) (Hawksley), and HbA1c (by high-performance liquid chromatography) were measured. Patients were advised to follow a normal diabetes diet without sodium restriction and received their usual antihypertensive treatment during the investigation.Results: During the study (ASA vs. placebo), urinary AER (geometric mean 64 [95% CI 39-105] vs. 59 [40-87] mg/24 h), GFR (mean 106 [93-118] vs. 104 [90-117] ml x min(-1) x 1.73 m(-2)), systolic BP (mean 130 [119-141] vs. 130 [119-142] mmHg), diastolic BP (mean 71 [65-78] vs. 71 [64-78] mmHg), and HbA1c (mean 8.4% [8.0-9.0] vs. 8.5% [8.1-9.0]) remained unchanged.Conclusions: Treatment with 150 mg ASA daily does not have any impact on AER or GFR in type 1 diabetic patients with microalbuminuria. Consequently, primary and secondary prevention of cardiovascular events with low-dose ASA does not interfere with the classification of AER or monitoring of antiproteinuric treatment in such patients. [ABSTRACT FROM AUTHOR]

Objective: To compare the long-term effect on kidney function of a long-acting calcium antagonist (nisoldipine) versus a long-acting ACE inhibitor (lisinopril) in hypertensive type 1 diabetic patients with diabetic nephropathy.Research Design and Methods: We performed a 4-year prospective, randomized, double-dummy controlled study comparing nisoldipine (20-40 mg once a day) with lisinopril (10-20 mg once a day). The study was double-blinded for the first year and single-blinded thereafter. The study included 51 hypertensive type 1 diabetic patients with diabetic nephropathy. Three patients dropped out during the first month; results for the remaining 48 patients are presented.Results: At baseline, the two groups were comparable: glomerular filtration rate (GFR) was 85 +/- 5 and 85 +/- 6 ml x min(-1) x [1.73 m](-2); mean 24-h ambulatory blood pressure was 108 +/- 3 and 105 +/- 2 mmHg, and albuminuria was 1,554 mg/24 h (95% CI 980-2,465) and 1,033 mg/24 h (760-1,406) in the lisinopril and nisoldipine groups, respectively. Mean 24-h arterial blood pressure during the study did not differ between the lisinopril and nisoldipine groups (100 +/- 2 and 103 +/- 1 mmHg, respectively). The time-course of albuminuria differed between groups (P < 0.001). Whereas initiation of treatment with lisinopril resulted in a reduction from baseline albuminuria by 52% (95% CI 14-73), albuminuria in the nisoldipine group did not change throughout the study GFR declined in a biphasic manner with an initial (0-6 months) reduction of 1.3 +/- 0.3 ml x min(-1) x month(-1) in the lisinopril group compared with 0.2 +/- 0.4 ml x min(-1) x month(-1) in the nisoldipine group (P < 0.01). The subsequent sustained decline (6 to 48 months or the end of treatment) was identical in the two groups: 0.5 +/- 0.1 ml min(-1) x month(-1) (NS). Two patients in the lisinopril group and three patients in the nisoldipine group entered therapy for end-stage renal failure.Conclusions: Long-term treatment with lisinopril or nisoldipine has similar beneficial effects on progression of diabetic nephropathy in hypertensive type 1 diabetic patients. [ABSTRACT FROM AUTHOR]

SUMMARY Aims Elevated urinary albumin excretion is associated with macrovascular atherosclerotic complications in Type 1 diabetes mellitus. Adhesion molecules mediate leucocyte adhesion to the endothelium early in the atherosclerotic process. The present study tests the hypothesis that microalbuminuria and diabetic nephropathy are associated with elevated plasma concentrations of soluble vascular adhesion molecule (sVCAM)-1, soluble intercellular adhesion molecule (sICAM)-1, and soluble E-selectin (sE-selectin) aiming to illustrate factors of potential pathogenetic relevance for the excess cardiovascular disease in diabetic patients with renal complications. Methods Soluble adhesion molecule concentrations were measured by enzyme-linked immunosorbent assays (ELISA) in healthy controls (n = 16) and in 59 Type 1 diabetic patients: group 1 – patients with normoalbuminuria (n = 16); group 2 – patients with microalbuminuria (n = 15); group 3 – patients with macroalbuminuria and normal serum creatinine (n = 15), group 4 – patients with macroalbuminuria and moderately elevated serum creatinine (n = 13). Results Plasma concentrations of sVCAM-1 and sICAM-1 were similar in healthy controls and normoalbuminuric Type 1 diabetic patients, but the concentrations were increased by the presence of microalbuminuria and overt nephropathy (P < 0.001 and P < 0.0001, anova). Concentrations of sE-selectin did not differ between diabetic patients and controls. Conclusions Plasma concentration of sICAM-1 is elevated in Type 1 diabetic patients with microalbuminuria and the concentrations of sICAM-1 as well as sVCAM-1 are elevated in patients with macroalbuminuria and normal s-creatinine. The elevated plasma concentrations of these soluble adhesion molecule concentrations in patients with renal complication can be of pathogenetic importance for the development of atherosclerosis and plasma soluble adhesion molecule concentrations may provide additional... [ABSTRACT FROM AUTHOR]

Patients with non-insulin-dependent diabetes (NIDDM) are at independent risk of cardiovascular death. The reason is only partially understood. The aim of our study was therefore to evaluate the impact of corrected QT interval length (QTc) and QT dispersion (QT-disp) on mortality in a cohort of 324 Caucasian NIDDM patients. A resting 12-lead ECG was recorded at baseline. Maximum (QT-max) and minimum QT (QT-min) intervals were measured, and QT-max was corrected for heart rate (QTc-max). QT-disp was defined as the difference between QT-max and QT-min. QTc-max was 454 (376-671) ms½ (median (range)) and QT-disp 61 (0-240) ms. Prolonged QTc interval (PQTc), defined as QTc-max>440 ms½, was present in 67% of the patients and prolonged QT-disp (PQT-disp), defined as QT-disp>50 ms, was present in 51%. During the 9-year follow-up period, 100 patients died (52 from cardiovascular diseases). Thirty-seven percent of the patients with PQTc died compared with 17% with normal QTc interval (p<0.001). The Cox proportional hazard model, including putative risk factors at baseline, revealed the following independent predictors of all cause mortality; QTc-max (p<0.05), age (p<0.0001), albuminuria (p<0.01), retinopathy (p<0.01), HbA1c (p<0.05), insulin treatment (p<0.01), total cholesterol (p<0.01), serum creatinine (p<0.05) and presence of cardiac heart disease based on Minnesota coded ECG (p<0.001). Whereas QT-disp was not a predictor. QTc-max interval was an independent predictor of cardiovascular mortality. Our study showed a high prevalence of QTc and QT-disp abnormalities and indicated that QTc-max but not QT-disp is an independent predictor of all cause and cardiovascular mortality in NIDDM patients. [ABSTRACT FROM AUTHOR]

Objective: A familial predisposition was proposed to be a determinant of the increased morbidity and mortality from cardiovascular disease in type 1 diabetic patients with diabetic nephropathy. The insertion allele of an insertion/deletion polymorphism in the ACE (ACE/ID) gene seems to protect against coronary heart disease in nondiabetic and diabetic subjects. The aim of the present study was to evaluate these hypotheses in parents of a large group of type 1 diabetic patients with and without diabetic nephropathy.Research Design and Methods: We investigated cardiovascular morbidity and mortality of parents of 163 type 1 diabetic patients with nephropathy and parents of 163 sex- and age-matched normoalbuminuric patients with type 1 diabetes.Results: Kaplan-Meier curves showed that total parental mortality was significantly increased in parents of type 1 diabetic patients with nephropathy (121 of 244 [ approximately 50%] ) as compared with parents of normoalbuminuric type 1 diabetic patients (119 of 269 [approximately 44%]) (P = 0.008 [log-rank test]) partially due to an increase in cardiovascular deaths (48 of 244 [approximately 20%] vs. 42 of 269 [approximately 16%], P<0.05). In addition, more patients with nephropathy, as compared with the normoalbuminuric group, had at least one parent with fatal/nonfatal cardiovascular disease (46% [95% CI 38-54] vs. 36% [28-44], P = 0.05). Fathers of patients homozygous for the I-allele of the ACE/ID polymorphism had significantly less myocardial infarction as compared with other genotypes (P = 0.03), regardless of the nephropathic state of the offspring.Conclusions: Cardiovascular morbidity and early mortality clusters in parents of type 1 diabetic patients with diabetic nephropathy The ACE/ID polymorphism helps explain the increased morbidity from cardiovascular disease. [ABSTRACT FROM AUTHOR]

SummaryAims To elucidate the putative factors involved in the blunted nocturnal blood pressure reduction in hypertensive Type 2 diabetic patients with diabetic nephropathy. Methods Extracellular fluid volume and fluid shift from interstitial to plasma volume (haematocrit), sympathetic nervous activity (plasma noradrenaline and adrenaline) and the internal ‘body clock’ (serum melatonin) were investigated in 31 hypertensive Type 2 diabetes mellitus (DM) patients with diabetic nephropathy (24 males, age 60 (45–73) years). All variables, except extracellular volume, were measured repeatedly with the patients lying awake in bed from 21:30 to 23:00 h (baseline) and during sleep from 23:00 to 07:00 h. Using the median nocturnal blood pressure reduction (8.4%) as a guide, the patients were divided into groups; group 1 with the highest and group 2 with the lowest nocturnal blood pressure reduction. Results Haematocrit decreased from baseline to the sleep period in group 1 by a mean (95% confidence interval (CI)) of 1.7 (0.3–3.1)%, but it increased by 0.5 (–1.0–1.9)% in group 2, mean difference (95% CI), –2.1 (–4.0 to –0.2)% (P = 0.029). Noradrenaline decreased from baseline to the sleep period, mean (95% CI), by 13.3 (0.0–25.0)% in group 1 but rose by 7.7 (–9.7–28.4)% in group 2, mean difference (95% CI), –19.6 (–35–0.0)% (P = 0.049). The nocturnal blood pressure change correlated to the nocturnal change in both noradrenaline (r = 0.51, P = 0.004) and haematocrit (r = 0.42, P = 0.018). Adrenaline remained constant in both groups. Extracellular fluid volume and plasma melatonin levels were comparable in the two groups. Conclusion Sustained adrenergic activity during sleep is associated with blunted nocturnal blood pressure reduction in hypertensive Type 2 DM patients with diabetic nephropathy, probably mediated through a lack of peripheral vasodilatation whereas... [ABSTRACT FROM AUTHOR]

SummaryAims To determine the natural course of kidney function and to evaluate the impact of putative progression promoters in Caucasian Type 2 diabetes mellitus (DM) patients with diabetic nephropathy who had never received any antihypertensive treatment. Methods A long-term observational study of 13 normotensive to borderline hypertensive Type 2 DM patients with diabetic nephropathy. Glomerular filtration rate (GFR) was measured approximately every year (51Cr-EDTA plasma clearance technique). Albuminuria, blood pressure (BP) and haemoglobin A1c (HbA1c) was determined 2–4 times per year and serum cholesterol every second year. Results The patients (12 males/one female), age 56 ± 9 (mean ± sd) years, with a known duration of diabetes of 10 ± 6 years, were followed for 55 (24–105) (median (range)) months. GFR decreased from 104 (50–126) to 80 (39–112) ml.min–1.1.73 m–2 (P = 0.002) with a median rate of decline of 4.5 (– 0.4 to 12) ml.min–1.year–1. During follow-up, albuminuria rose from 494 (301–1868) to 908 (108–2169) mg/24 h (P = 0.25), while BP, HbA1c and serum cholesterol remained essentially unchanged. In univariate analysis the rate of decline in GFR did not correlate significantly with neither baseline nor mean values during follow-up of BP, albuminuria, HbA1c and serum cholesterol. Conclusions Our study suggests that normotensive to borderline hypertensive Type 2 DM patients with diabetic nephropathy have a rather slow decline in kidney function, but we did not unravel the putative progression promoters responsible for the variation in rate of decline in GFR. Diabet. Med. 16, 388–394 (1999). [ABSTRACT FROM AUTHOR]

Background: The ability of the kidney to maintain constancy of the glomerular filtration rate (GFR) over a wide range of renal perfusion pressures is termed autoregulation. Defective autoregulation of GFR has been demonstrated in diabetic nephropathy. Whether this is also the case in patients with nondiabetic nephropathies is not known. Methods: We investigated the effect of acute lowering of blood pressure (BP) on GFR in 16 (8 males and 8 females) albuminuric subjects suffering from different nondiabetic nephropathies and in 14 (7 males and 7 females) controls matched with respect to sex, age, BP, and baseline GFR. The subjects received in random order an intravenous injection of either clonidine (150 to 225 microg) or saline (0.154 mmol/liter) within two weeks. We measured GFR ([51Cr]-EDTA), albuminuria (enzyme-linked immunosorbent assay; ELISA), and BP (Takeda TM-2420). Results: Clonidine induced similar reductions in mean arterial BP 17 (2) versus 19 (2) mm Hg [mean (SE)] in patients with nephropathy and in controls, respectively. GFR diminished in average from 89 (6) to 82 (5) ml/min/1.73 m2 (P < 0.05), and albuminuria declined from a geometric mean of 1218 (antilog SE 1.3) microg/min to 925 (1.3) in the patients with nondiabetic nephropathies (P < 0.05), whereas these variables remained unchanged in the control group. The mean difference between changes in GFR (95% confidence interval) between the nondiabetic macroalbuminuric and control subjects was 6.1 (-0.03 to 12.21) ml/min/1.73 m2 (P = 0.051). Conclusion: Our study suggests that albuminuric patients with nondiabetic nephropathies frequently suffer from impaired autoregulation of GFR. [ABSTRACT FROM AUTHOR]

Nonenzymatic glycation is increased in diabetes. Most studies so far have focused on the role of advanced glycation end products (AGEs) in vascular complications, whereas the role of early glycation Amadori-modified proteins, which is the predominant form of glycated proteins, has not been systemically investigated in humans. We developed an antiserum against glycated human serum albumin (HSA) and used this to study the role of early glycation products in vascular complications in type 1 diabetic patients. Amadori albumin was determined to be the recognition epitope of the antiserum. The antibody recognized a specific glucose adduct and a conformational component specific for human albumin in Amadori albumin, with no recognition of AGEs. Plasma Amadori albumin levels were significantly higher in type 1 diabetic patients (n = 55) than in healthy control subjects (n = 60) (39.2+/-9.9 vs. 20.9+/-4.0 U/ml, P < 0.0005). Amadori albumin correlated with levels of plasma markers of endothelial function von Willebrand factor (r = 0.29, P < 0.05) and vascular cell adhesion molecule-1 (r = 0.41, P < 0.005), but not soluble E-selectin. In addition, Amadori albumin immunoreactivity was detected in the capillaries of retinas of diabetic patients. Plasma levels of Amadori albumin were determined in a second group of type 1 diabetic patients with long-standing diabetes with (n = 199) or without (n = 192) diabetic nephropathy. Patients with nephropathy had higher Amadori albumin levels than did those without it (50.9+/-9.5 vs. 45.1+/-6.3 U/ml, P < 0.0005). Age-, sex-, and diabetes duration-adjusted analyses showed that nephropathy was significantly associated with Amadori albumin with an odds ratio (OR [95% CI]) of 1.11 [1.08-1.15] per U/ml increase. After additional adjustment for levels of creatinine, glycated hemoglobin, cholesterol, triglycerides, blood pressure, preexistent retinopathy, and cardiovascular disease, Amadori albumin continued to be significantly associated with nephropathy (OR 1.06 [1.01-1.11]) per U/ml increase. Our results are consistent with a proposed pathophysiological role of Amadori albumin in microvascular complications of type 1 diabetic patients. [ABSTRACT FROM AUTHOR]

BACKGROUND: Due to the high satiating effect of protein, a high-protein diet may be desirable in the treatment of obesity. However the long-term effect of different levels of protein intake on renal function is unclear. OBJECTIVE: To assess the renal effects of high vs Iow protein contents in fat-reduced diets. DESIGN: Randomized 6 months dietary intervention study comparing two controlled adlibitum diets with 30 energy (E%) fat content: high-protein (HP; 25 E%) or Iow-protein, (LP, 12 E% protein). All food was provided by self-selection in a shop at the department, and high compliance to the diet composition was confirmed by measurements of urinary nitrogen excretion. SUBJECTS: 65 healthy, overweight and obese (25 < body mass index (BMI) < 34 kg/m²). RESULTS: Dietary protein intake changed from 91.1 g/d to a 6 months intervention average of 70.4 g/d (P < 0.05) in the LP group and from 91.4 g/d to 107.8 g/d (P < 0.05) in the HP group, producing changes in glomular filtration rate (GFR) of - 7.1 ml/min in the LP group and + 5.2 ml/min in the HP group (group effect: P < 0.05). Kidney volume decreased by - 6.2cm³ in the LP group and increased by Jr 9.1 cm³ in the HP group (P < 0.05), whereas albuminuria remained unchanged in all groups. CONCLUSION: Moderate changes in dietary protein intake cause adaptive alterations in renal size and function without indications of adverse effects. [ABSTRACT FROM AUTHOR]