Long-term treatment with nifedipine reduces urinary albumin excretion and glomerular filtration rate in normotensive type 1 diabetic patients with microalbuminuria

The aim of the present study was to investigate the renal effects of long-term treatment with the calcium channel blocker nifedipine in normotensive type 1 diabetic patients with microalbuminuria. In a randomized, double-blind trial, 15 type 1 diabetic patients were treated with either nifedipine (n=8; dosage 30 mg/day) or placebo (n=7) for 12 months. At baseline and after 6 and 12 months of therapy, the albumin excretion rate (UAER, radioimmunoassay), glomerular filtration rate (GFR, chromium 51 ethylenediamine tetra-acetic acid clearance) and renal plasma flow (RPF, iodine 125 hippuran clearance) were determined. Nifedipine treatment caused a significant reduction of UAER after 6 and 12 months (median, Q₁/Q₃ in mg/24 h): baseline 84 (65/163); 6 months 35 (23/90),P<0.02; 12 months 39 (15/79),P<0.05. GFR was significantly decreased by nifedipine treatment (baseline 157±15, 6 months 122±8, 12 months 111±47 ml/min;P<0.05, mean ± SEM), whereas RPF remained constant. Nifedipine treatment did not influence systolic (baseline 121±7, 12 months 124±2 mmHg, mean ± SEM) or diastolic (baseline 72±2, 12 months 74±3 mmHg) arterial blood pressure. With placebo treatment no significant alterations of UAER, GFR, RPF and arterial blood pressure were observed. Metabolic control was constant throughout the whole study period. Thus, 1 year's treatment with nifedipine reduces the UAER and GFR in normotensive type 1 diabetic patients without influencing the systemic arterial blood pressure. The data, however, do not present a recommendation for the general use of nifedipine in these patients as the exact intrarenal mechanism of calcium channel blockers in humans remains to be established.     

Impaired autoregulation of glomerular filtration rate in Type 1 (insulin-dependent) diabetic patients with nephropathy

Summary The effect of acute lowering of arterial blood pressure upon kidney function in nephropathy was studied in 13 patients with long-term Type 1 (insulin-dependent) diabetes. Ten normal subjects (six normotensive and four hypertensive) and five short-term Type 1 diabetic patients without nephropathy served as controls. Renal function was assessed by glomerular filtration rate (single bolus ⁵¹Cr-EDTA technique) and urinary albumin excretion rate (radial immunodiffusion). The study was performed twice within 2 weeks, with the subjects receiving an intravenous injection of either clonidine (225 g) or saline (0.154 mmol/l). The arterial blood pressure was similar in the diabetic patients with nephropathy (mean 136±11 mmHg) and in the non-diabetic control subjects 88±5 (mean 140±25 mmHg). The clonidine injection induced sim- 92±15 ilar reductions in mean arterial blood pressure in all three groups (16–18 mmHg). While glomerular filtration rate and urinary albumin excretion rate remained unchanged in both control groups after clonidine injection, glomerular filtration rate dimished from 78 to 71 ml/min per 1.73 m² (p<0.01), and urinary albumin excretion declined from 1707 to 938 g/min (p<0.01) in the patients with diabetic nephropathy. Our results suggest that an intrinsic vascular (arteriolar) mechanism underlying the normal autoregulation of glomerular filtration rate, i. e. the relative constancy of glomerular filtration rate that occurs in response to rather wide variations in perfusion pressure, is defective in diabetic nephropathy.     

Plasma N-terminal pro-brain natriuretic peptide in Type 1 diabetic patients with and without diabetic nephropathy.

AIMS: Plasma N-terminal pro-brain natriuretic peptide (NT proBNP) is produced and released from cardiac ventricles; it is elevated in patients with heart failure, hypertension and chronic renal failure. This study aimed to examine the plasma levels of NT proBNP and their relationship in Type 1 diabetic patients with and without diabetic nephropathy. METHODS: We developed a non-competitive immunoluminometric assay with in-house antibodies to the N- and C-terminal domains of NT proBNP. We compared NT proBNP levels between 47 normoalbuminuric patients (group 1), 12 microalbuminuric patients (group 2) and 12 patients with macroalbuminuria (group 3). RESULTS: There were significant differences in 24-h systolic and diastolic blood pressure, diabetes duration, serum creatinine, LDL-cholesterol and HbA1c between the three groups; other parameters did not differ significantly. NT proBNP (median and range) levels were 5 (0.75-68), 22 (0.75-82) and 23 (0.75-374) fmol/ml for groups 1-3, respectively. Log-transformed data of NT proBNP were used to compare all three groups (P=0.016). The Pearson correlation between NT proBNP and albuminuria (R=0.27; P=0.02) was positive; HbA1c (R=0.25; P=0.03) and age (R=0.33; P=0.005) correlated significantly as well. On the basis of multiple regression analysis, the adjusted difference remained significant between the three groups. CONCLUSIONS: This is the first demonstration that NT proBNP levels are significantly higher in Type 1 diabetic patients with albuminuria. This may be caused by a down-regulation of A-type guanylate cyclase-coupled natriuretic peptide receptors in renal tubules or by elevated NT proBNP levels leading to higher glomerular hydraulic pressure or higher capillary permeability and possibly increased albumin excretion. Further studies are required to investigate the potential role of NT proBNP in patients with diabetic nephropathy and such other co-morbidities as cardiovascular disease.     

Segmental Tubular Sodium Reabsorption in Type 1 Diabetes

Segmental tubular sodium reabsorption in Type 1 (insulin-dependent) diabetes was measured in 36 patients in a cross-sectional study including one group (n = 13) without significant albuminuria (UalbV < 30 mg 24 h^?1), one group (n = 16) with albuminuria in the range from 30 to 300 mg 24 h^?1, and a group (n = 7) with nephropathy (UalbV > 300 mg 24 h^?1). Lithium clearance was used to measure end proximal delivery. From end proximal delivery, ⁵¹Cr-EDTA clearance (GFR) and sodium clearance, segmental tubular reabsorption was calculated. For all patients, GFR was directly correlated with end proximal delivery (r = 0.62, p<0.0005), while end proximal delivery was inversely correlated to fractional proximal reabsorption (r = ?0.71, p<0.0005). In the subgroup with UalbV less than 30 mg 24 h^?1, the direct correlation between GFR and end proximal delivery was also significant (r = 0.77, p<0.05). In the group with nephropathy (UalbV > 300 mg 24 h^?1), mean GFR and end proximal delivery were decreased and fractional proximal reabsorption was increased, but there was still a positive correlation between GFR and end proximal delivery (r = 0.75, p<0.05) and an inverse correlation between end proximal delivery and fractional proximal reabsorption (r = ?0.85, p<0.05). It is concluded that in these groups of diabetic patients the end proximal delivery is increased while GFR is increased. This finding is an argument against a recent hypothesis explaining intraglomerular hypertension, as well as increased glomerular filtration rate in some patients, as secondary to decreased end proximal delivery and reduced tubuloglomerular feedback activity. Nevertheless, the tubuloglomerular feedback activity may be reduced in Type 1 diabetes due to constant extracellular volume expansion.     

Low prevalence of cardiac autonomic neuropathy in Type 1 diabetic patients without nephropathy.

AIM: To assess the prevalence of cardiac autonomic neuropathy (CAN) in Type 1 diabetic patients with and without nephropathy. METHODS: Sixty-six consecutive patients without nephropathy (n = 24), with incipient (n = 26) or overt nephropathy (n = 16) and a diabetes duration between 21 and 31 years were examined. Heart rate variability (HRV) as measure for CAN was investigated with short-term spectral analysis in the low-frequency (LF) band (0.06-0.15 Hz), reflecting sympathetic and vagal activity, and high-frequency (HF) band (0.15-0.50 Hz), reflecting vagal activity. HRV was expressed as spectral power (ms2, log-transformed). Normal, age-corresponding reference values were established in 184 controls. QTc intervals and dispersion were measured. RESULTS: After adjustment for age, there was no significant difference between healthy controls and patients without nephropathy. After further adjustment for diabetes duration, HbA1c, hypertension and treatment with beta-blockers, HRV in both frequency bands decreased with evidence of nephropathy. LF band (supine): patients without nephropathy 5.56 (4.89-6.21) (least squares means and 95% confidence interval (CI)), incipient nephropathy 5.72 (5.15-6.29) and overt nephropathy 4.11 (3.27-4.96). HF band (supine): without nephropathy 5.93 (5.26-6.60), incipient nephropathy 5.99 (5.41-6.57) and overt nephropathy 4.84 (4.00-5.68). Significant differences were found for patients without and with incipient nephropathy compared with those with overt nephropathy in the LF band and between patients with incipient nephropathy compared with those with overt nephropathy in the HF band. QTc intervals and QTc dispersion increased significantly with increasing nephropathy. CONCLUSIONS: Long-term Type 1 diabetes without nephropathy was not associated with impaired cardiac autonomic function in our study. However, in those with nephropathy, a loss of both vagal and sympathetic activity was present, and the severity of CAN correlated positively with more advanced nephropathy.     

Glucose-induced changes in renal haemodynamics in proteinuric Type 1 (insulin-dependent) diabetic patients: inhibition by acetylsalicilic acid infusion

Summary The effect of hyperglycaemia on renal function in diabetic nephropathy remains poorly understood. We investigated the renal haemodynamic response to an acute plasma glucose rise from sustained euglycaemia to sustained hyperglycaemia in eight persistently proteinuric Type 1 (insulin-dependent) diabetic patients. Studies were performed in a double-blind cross-over manner after i.v. injection of 450 mg lysine acetylsalicilate (equivalent to 250 mg acetylsalicilic acid) or equal volume of 0.9% NaCl (isotonic saline). In the isotonic saline experiments hyperglycaemia produced a significant rise, by approximately 35%, in glomerular filtration rate in all patients from 41.5±5.2 to 55±6 ml·min^–1·1.73 m^–2 (p<0.005) and an increase in sodium paraminohippurate clearance from 178±22.7 to 220±20.0 ml·min^–1·1.73 m^–2 (p<0.05). These changes took place within the first 30 min of glucose infusion and were maintained for a 90 min hyperglycaemic period. Filtration fraction did not change significantly. Infusion of lysine acetylsalicilate lowered baseline glomerular filtration rate (isotonic saline vs lysine acetylsalicilate 41.5±5.2 vs 30.0±5.7 ml·min^–1·1.73 m^–2; p<0.05) and significantly blunted the rise in glomerular filtration rate during hyperglycaemia (glomerular filtration rate increment: saline vs lysine acetylsalicilate: 13.6±2.8 vs 5.3±1.8 ml·min^–1 ·1.73 m^–2; p<0.005). The effects on renal plasma flow were similarly blunted. In five additional patients, time- and volume-controlled isotonic saline experiments during sustained euglycaemia showed no significant changes in glomerular filtration rate and sodium paraminohippurate clearance. In Type 1 diabetic patients with advanced renal failure, acute hyperglycaemia induces a significant elevation in glomerular filtration rate and renal plasma flow which is likely to be mediated by renal prostaglandin production.     

Polymorphisms of human paraoxonase 1 gene (PON1) and susceptibility to diabetic nephropathy in Type I diabetes mellitus

Aims/hypothesis. Oxidative stress is a putative mechanism in the development of diabetic nephropathy. Paraoxonase gene 1 is an HDL-bound enzyme that protects tissues against oxidative damage. Three common polymorphisms of paraoxonase gene 1, T-107C in the promoter, Leu54Met and Gln192Arg, that modify paraoxonase activity have been associated with cardiovascular disease. This study aimed to find whether these polymorphisms also contribute to the development of diabetic nephropathy. Methods. The association between diabetic nephropathy and these three polymorphisms was examined in a case-control study. For this purpose, genomic DNA was collected from 188 patients with Type I (insulin-dependent) diabetes mellitus and diabetic nephropathy and from 179 unrelated patients with Type I diabetes but without diabetic nephropathy despite the duration of diabetes of 15 or more years. Results. The genotype and allele frequencies for each of the three polymorphisms (T-107C, Leu54Met and Gln192Arg) were similar in cases and control subjects. Conclusion/interpretation. The three polymorphisms in paraoxonase gene 1 that have been associated with serum levels of paraoxonase are not associated with diabetic nephropathy. We show that this genetically determined component of the antioxidant capacity of HDL does not play a critical part in the development of diabetic nephropathy. [Diabetologia (2000) 43: 1540–1543] Received: 14 July 2000 and in revised form: 21 August 2000     

The changing epidemiology of diabetic microangiopathy in type 1 diabetes

Diabetic microvascular complications in the kidney and the eye are a major burden for diabetic patients due to increased morbidity and mortality. Furthermore, diabetic nephropathy is the leading cause of end-stage renal disease and diabetic retinopathy is the leading cause of blindness in younger patients, representing a major public health concern. During the past two decades beneficial effects of, in particular, aggressive antihypertensive control and strict glycaemic control have been demonstrated in randomised controlled clinical trials. Technological improvements in diabetes care have made good metabolic control easier to achieve. Has this led to an improved prognosis? In observational studies from dedicated centres, a decrease from 47 to 13% has been reported in the incidence of proliferative diabetic retinopathy after 20–25 years of diabetes, and the incidence of overt diabetic nephropathy after 20 years has decreased from 28 to 5.8%. Even functional and morphological remission of diabetic nephropathy has been reported. Despite this, recent population-based studies have failed to demonstrate a decrease in the incidence of blindness caused by diabetes, and the incidence of end-stage renal disease has progressively increased. This may, in part, be the result of a combination of increasing numbers of diabetic patients and a lag phase between improvement in management and a decline in end-stage complications. It is of concern, however, that the results from specialised centres may not apply to routine diabetes care. It is, therefore, mandatory that the beneficial effects of pharmacological and non-pharmacological interventions demonstrated in clinical trials and recommended by treatment guidelines are translated into clinical practice to ensure a widespread improvement in prognosis.     

Erythrocyte sodium-lithium countertransport is not different in Type 1 (insulin-dependent) diabetic patients with and without diabetic nephropathy

Summary We studied erythrocyte sodium-lithium countertransport in 33 patients with Type 1 (insulin-dependent) diabetes mellitus with diabetic nephropathy, 18 patients with Type 1 diabetes without diabetic nephropathy and in 42 nondiabetic patients with various other renal diseases. No significant differences were found in sodium-lithium countertransport between these three groups (median (range) 322 (162–676) vs 321 (189–627) vs 300 (142–655) mol·1 cells^–1·h^–1). We conclude, that sodium-lithium countertransport cannot be used as a marker for diabetic nephropathy.     

Ophthalmological follow-up of Type 1 (insulin-dependent) diabetic patients after kidney and pancreas transplantation

We studied the effect of successful kidney and pancreas transplantation on visual function and diabetic retinopathy in 18 patients with long-term Type 1 (insulin-dependent) diabetes mellitus (17 to 38 years) and with advanced proliferative retinopathy. The average age of the patients was 42 years. Prior to transplantation, 5 eyes were in end-stage ophthalmic complication due to neovascular glaucoma. An ophthalmological follow-up was performed between 1–6 years post-surgery. Analysis of the results showed that the diabetic retinopathy had stabilized after transplantation in 12 cases (66 %) with a supplementary photocoagulation in the majority of cases. The proliferation continued in 4 patients (22 %) leading to blindness in 2 patients and recurrence of vitreous haemorrhages despite the photocoagulation in the other 2 cases. An improvement was observed on fluorescein angiography in a patient with pre-papillar glial proliferation without photocoagulation. Ten patients were reported to have a cataract and were operated on in two cases before transplantation; in one patient, the cataract increased following transplantation. In conclusion, the kidney and pancreas transplantation was not effective in our patients in reversing the clinical and angiographic signs of diabetic retinopathy. Moreover, a worsening of the lesions was observed in some cases; this was probably due to the irreversible microangiopathic lesions due to advanced evolution of diabetes.     

Increased plasma adiponectin concentrations are associated with microangiopathy in type 1 diabetic subjects

Aims/hypothesis Insulin resistance is related to an increased risk of diabetic retinopathy and nephropathy in type 1 diabetes. Patients with insulin resistance and/or macrovascular disease have abnormally low levels of adiponectin. The aim of this study was to investigate the relationships between adiponectin and renal and retinal diabetic complications in type 1 diabetic patients.Methods In this 6-year prospective follow-up observational study, we evaluated the severity of retinopathy at baseline and determined the incident risk of microalbuminuria in 126 normoalbuminuric patients with type 1 diabetes. Each patient was age- and sex-matched to two non-diabetic control subjects.Results Plasma adiponectin concentrations were significantly higher in diabetic subjects than in control subjects (p<0.0001). The adiponectin concentration was significantly higher in patients with severe diabetic retinopathy than in those without (39.1±14.0 vs 29.0±13.0 g/ml, p=0.0005). The 18 patients who developed persistent microalbuminuria had higher adiponectin concentrations than the other patients (35.8±14.5 vs 30.6±13.7 g/ml). Increased adiponectin concentrations were independently associated with the occurrence of microalbuminuria (p=0.0158) after adjustment for baseline urinary albumin concentration (p=0.004), sex (p=0.0054), blood pressure (NS) and metabolic control (NS).Conclusions/interpretation The elevated adiponectin concentrations observed in subjects with microvascular disease may indicate an altered regulation of this adipocytokine in patients with complications associated with type 1 diabetes.     

Association of aldose reductase gene Z+2 polymorphism with reduced susceptibility to diabetic nephropathy in Caucasian Type 1 diabetic patients.

AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.     

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

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

Relationship of progressively increasing albuminuria to apoprotein(a) and blood pressure in Type 2 (non-insulin-dependent) and Type 1 (insulin-dependent) diabetic patients

Summary This study has explored the temporal relationship between apoprotein(a), blood pressure and albuminuria over a mean interval of 11 years in a cohort of 107 diabetic patients of whom 26 (14 Type 2 (non-insulin-dependent), 12 Type 1 (insulin-dependent) had progressively increasing albuminuria (‘progressors’). In Type 2 diabetic patients, no significant differences were noted for HbA₁, blood pressure, creatinine clearance or serum lipids between progressors and non-progressors. In Type 1 diabetic patients, final systolic and diastolic blood pressures were higher in progressors compared with non-progressors and progressors showed impairment of renal function in association with a rise in blood pressure at the macroalbuminuric stage. Initial apoprotein(a) levels were similar in progressors and non-progressors of either diabetes type. Apoprotein(a) levels increased exponentially with time in 12 of 14 Type 2 progressors but only in 5 of 12 Type 1 progressors (p<0.01). In Type 2 diabetic patients, the annual increase in apoprotein(a) levels was 9.1±2.4%, which was significantly greater than in non-progressors, 2.0±1.2% (p<0.01) and also exceeded the rates of increase of apoprotein(a) in progressors with Type 1 diabetes, 4.0±1.4%, (p<0.05). Apoprotein(a) levels correlated significantly with albuminuria in 8 of 14 Type 2 progressors but only in 3 of 12 Type 1 progressors (p<0.05). The rate of increase of apoprotein(a) levels was not related to mean HbA₁, creatinine or creatinine clearance levels, or to albuminuria. The rate of rise of apoprotein(a) was not influenced by initial apoprotein(a) levels, suggesting that specific apoprotein(a) isoforms do not influence albuminuria-related increases in apoprotein(a). The data are consistent with the hypothesis that apoprotein(a) levels increase in response to albuminuria and may be part of a self-perpetuating process. This study also suggests that increases in apoprotein(a) levels commence during the microalbuminuria stage in diabetic patients, which is earlier than has been documented in non-diabetic proteinuria.     

Optimal dose of lisinopril for renoprotection in type 1 diabetic patients with diabetic nephropathy: a randomised crossover trial

Aims/hypothesis  The purpose of this study was to evaluate the optimal renoprotective effect of ultrahigh doses of lisinopril, as reflected by short-term changes in urinary albumin excretion rate (UAER), in type 1 diabetic patients with diabetic nephropathy. Methods  At the Steno Diabetes Center, 49 type 1 diabetic patients with diabetic nephropathy completed this double-masked randomised crossover trial consisting of an initial washout period followed by three treatment periods each lasting 2 months, where all patients received lisinopril 20, 40 and 60 mg once daily in randomised order in addition to slow-release furosemide. Allocation was concealed by sequentially numbered opaque sealed envelopes. UAER, 24 h ambulatory blood pressure (ABP) and estimated GFR were determined at baseline and after each treatment period. Results  All 49 patients completed all three treatment periods. Baseline values were: UAER (geometric mean [95% CI]) 362 (240–545) mg/24 h, 24 h ABP (mean [SD]) 142 (14)/74 (8) mmHg and estimated GFR 75 (29) ml min⁻¹ 1.73 m⁻². Reductions in UAER from baseline were 63%, 71% and 70%, respectively, with the increasing doses of lisinopril (p < 0.001). Compared with lisinopril 20 mg there was a further reduction in UAER of 23% with lisinopril 40 mg and 19% with 60 mg, p < 0.05. ABP was reduced from baseline by 10/5, 13/7 and 12/7 mmHg (p < 0.001 vs baseline, p < 0.05 for diastolic ABP 20 vs 40 mg, otherwise NS between doses). The difference in UAER between 20 and 40 mg lisinopril was significant after adjustment for changes in ABP (p < 0.01). Two patients were excluded from the study because of an increase in plasma creatinine and one because of high BP; otherwise the study medication was well tolerated with few, mild, dose-independent adverse effects. Conclusions/interpretation  Lisinopril 40 mg once daily is generally safe and offers additional reductions in BP and UAER in comparison with the currently recommended dose of 20 mg. Lisinopril 60 mg offers no further beneficial effect. Trial registration: ClinicalTrials.gov NCT00118976 Funding: This study was financed out of local funds and was not supported by the medical industry. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorised users.     

Analysis of the association between diabetic nephropathy and polymorphisms in the aldose reductase gene in Type 1 and Type 2 diabetes mellitus.

AIMS: To investigate the association between polymorphisms of the aldose reductase gene and diabetic nephropathy in both Type 1 and Type 2 diabetes mellitus, and to carry out a meta-analysis of published results. METHODS: We have investigated the role of two aldose reductase polymorphisms in four independent cohorts of cases and controls (two each with Type 1 and Type 2 diabetes) drawn from two ethnic populations, including 471 patients with nephropathy and 494 control diabetic patients without nephropathy. A C/T transition at position -106, and a (CA)n microsatellite marker 2.1 kb from the start site of the aldose reductase gene were genotyped in nephropathic patients and non-nephropathic controls from each cohort. RESULTS: Carriage of the -106 T allele was significantly associated with diabetic nephropathy in three of the four study groups. The Mantel-Haenszel combined odds ratio was 2.22 (95% CI 1.69, 2.94), P = 1.05 x 10(-8). We found no evidence for association of the microsatellite marker with nephropathy, despite moderate levels of disequilibrium between the two markers. Meta-analysis of published data yielded no evidence for association of the microsatellite marker with diabetic nephropathy in Type 2 diabetes, but varying degrees of association with diabetic nephropathy in Type 1 diabetes. CONCLUSIONS: Meta-analyses provide more convincing evidence of a role for the ALR2-106 marker than for the microsatellite marker in diabetic nephropathy (DN). More studies are now required to confirm these results and to establish whether the ALR2-106 polymorphism has a functional role in DN.     

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

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

2型糖尿病患者高敏C-反应蛋白与糖尿病肾病的关系

目的:探讨2型糖尿病肾病(DN)不同时期血清高敏C-反应蛋白(hs-CRP)的浓度变化与DN的关系。方法:采用速率散射比浊法测定144例2型糖尿病患者和49名正常对照的血清hs-CRP水平。根据尿白蛋白排泄率(UAER)将2型糖尿病患者分为3组:正常蛋白尿组53例、微量白蛋白尿组57例和临床蛋白尿组34例。结果:(1)2型糖尿病组的血清hs-CRP值较对照组显著升高(U=1458.5,P<0.001);(2)hs-CRP值随UAER的增加而增加(H=74.068,P<0.001);(3)hs-CRP值与空腹血糖、血尿酸、纤维蛋白原成正相关(r=0.26、0.33、0.30,P均<0.001),与高密度脂蛋白呈负相关(r=-0.14,P<0.05)。结论:C-反应蛋白可能参与了2型糖尿病和糖尿病肾病的发生发展。     

Factors Related to the Electric Taste Threshold in Type 1 Diabetic Patients

To specify the factors related to taste function in Type 1 diabetes mellitus, 50 diabetic out-patients and 50 control subjects paired for age and sex were screened for taste disorders. None of them consumed significant amounts of alcohol, smoked, or had disease or took drugs capable of altering taste. Taste was studied with electrogustometry, retinopathy was detected by fluorescein angiography, nephropathy by measurement of albuminuria and microalbuminuria, peripheral neuropathy by electroneurography and electromyography, and autonomic neuropathy by cardiovascular function tests. The electrogustometric threshold was, on average, significantly higher in the diabetic group (133 ± 30 μA) than in the control group (29 ± 9 μA; p < 0.001). Electric hypogeusia (electrogustometric threshold > 100 μA) was found among 54% of the diabetic patients vs 2% of the control subjects (p < 0.001). In the diabetic group, the electrogustometric threshold was associated with complications of diabetes, especially with peripheral neuropathy (210 ± 24 vs 90 ± 22 μA; p < 0.001) and microalbuminuria (185 ± 25 vs 86 ± 21 μA; p < 0.01). It was correlated with age (r = 0.37; p < 0.01) and duration of diabetes (r = 0.52; p < 0.001) but not with HbA_1c (r = ?0.04). Using multivariate analysis, duration of diabetes and peripheral neuropathy had the strongest association with taste impairment. These results support previous findings, suggesting that taste impairment is a degenerative complication of diabetes mellitus.