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Background. Obstructive sleep apnoea (OSA) is related to type 2 diabetes (T2DM), and it may be associated with reduced inspiratory muscle strength (IMS). The aim of this study was to investigate the IMS in patients with T2DM, with or without OSA. Methods. Patients with T2DM with OSA (n=33) and without OSA (n=28) were included. The maximum IMS was tested using the POWERbreathe KH2 device. Reference IMS values were data calculated using an algorithm based on general populations and adjusted for age and gender. Results. There was no difference in IMS between the OSA group (median (range) 77 (35–124) cmH2O) and the non-OSA group (84 (33–122) cmH2O) (p=0.97). The IMS values were reduced in the OSA group compared with the reference values (92.9 (62.3–100.0) cmH2O) (p=0.030), whereas the non-OSA group did not have reduced IMS. When the IMS values of all T2DM patients were compared with reference values, the IMS values were 79 (33–124) cmH2O and 93.8 (62.3–102.4) cmH2O, respectively (p=0.017). Conclusion. No difference in IMS between patients with T2DM with or without OSA was found. However, patients with T2DM and OSA had reduced IMS compared with age- and gender-matched references whereas the non-OSA group did not have reduced IMS. [ABSTRACT FROM AUTHOR]

Hypoglycemia is associated with increased activity in the low-frequency bands in the electroencephalogram (EEG). We investigated whether hypoglycemia awareness and unawareness are associated with different hypoglycemia-associated EEG changes in patients with type 1 diabetes. Twenty-four patients participated in the study: 10 with normal hypoglycemia awareness and 14 with hypoglycemia unawareness. The patients were studied at normoglycemia (5-6 mmol/L) and hypoglycemia (2.0-2.5 mmol/L), and during recovery (5-6 mmol/L) by hyperinsulinemic glucose clamp. During each 1-h period, EEG, cognitive function, and hypoglycemia symptom scores were recorded, and the counterregulatory hormonal response was measured. Quantitative EEG analysis showed that the absolute amplitude of the ϑ band and α-ϑ band up to doubled during hypoglycemia with no difference between the two groups. In the recovery period, the ϑ amplitude remained increased. Cognitive function declined equally during hypoglycemia in both groups and during recovery reaction time was still prolonged in a subset of tests. The aware group reported higher hypoglycemia symptom scores and had higher epinephrine and cortisol responses compared with the unaware group. In patients with type 1 diabetes, EEG changes and cognitive performance during hypoglycemia are not affected by awareness status during a single insulin-induced episode with hypoglycemia. [ABSTRACT FROM AUTHOR]

In this study we estimate the subcutaneous tissue counter pressure during drug infusion from a series of injections of insulin in type 2 diabetic patients using a non-invasive method. We construct a model for the pressure evolution in subcutaneous tissue based on mass continuity and the flow laws of a porous medium. For equivalent injection forces we measure the change in the infusion rate between injections in air at atmospheric pressure and in tissue. From a best fit with our model, we then determine the flow permeability as well as the bulk modulus of the tissue, estimated to be of the order 10−11–10−10 m2 and 105 Pa, respectively. The permeability is in good agreement with reported values for adipose porcine tissue. We suggest our model as a general way to estimate the pressure build-up in tissue during subcutaneous injection. [ABSTRACT FROM AUTHOR]

Aim: To investigate whether Roux-en-Y gastric bypass surgery (RYGB) - an in vivo model for normalisation of hyperglycaemia - improves carotid intima-media thickness (IMT) in patients with type 2 diabetes (T2D)/ impaired glucose tolerance (IGT) and normal glucose tolerance (NGT). Methods: Observational prospective study, 34 obese patients (T2D (n = 14)/IGT (n = 4), and NGT (n = 16)) were investigated before and six and 12 months after RYGB. Results: Mean carotid IMT was significantly reduced 12 months after RYGB in patients with T2D/IGT (–0.041 mm (95% CI–0.069;–0.012, p = 0.005)) but not in patientswithNGT (–0.010 mm(–0.039; 0.020, p = 0.52)). The between-group difference was not significant (p = 0.13). Twelve months after RYGB, patients with respectively T2D/IGT and NGT demonstrated changes in weight: –29.9 kg, p < 0.001/–30.6 kg, p < 0.001, HbA1c: –0.7%, p < 0.001/–0.1%, p = 0.33, systolic blood pressure: –2 mmHg, p = 0.68/–10 mmHg, p = 0.01 and diastolic blood pressure: –8 mmHg, p=0.003/–11 mmHg, p b 0.001. 80% of T2D patients terminated antihyperglycaemic medication. Conclusion: Mean carotid IMT was significantly reduced 12 months after RYGB in patients with T2D/IGT which provides evidence to support that the earliest atherosclerotic changes in the arterial wall are reversible. Although numerically different from the changes observed in patients with NGT, the between-group difference was not statistically significant. [ABSTRACT FROM AUTHOR]

CD2-associated protein (CD2AP) is essential for podocyte function. CD2AP mutations have been found in patients with focal segmental glomerulosclerosis, a disease histologically resembling diabetic nephropathy and often progressing to end-stage renal disease (ESRD). We hypothesised that variations in the CD2AP gene may contribute to susceptibility to glomerular injury in diabetes and investigated if single-nucleotide polymorphisms (SNPs) in CD2AP are associated with diabetic nephropathy in patients with type 1 diabetes. The discovery cohort consisted of 2,251 Finnish patients with type 1 diabetes. SNPs were selected from the HapMap database to cover the CD2AP gene. The associations between genotyped SNPs and diabetic nephropathy or ESRD were analysed with the chi-squared test and logistic regression. Three SNPs were selected for replication in cohorts from Denmark, Italy, the United Kingdom and Ireland. None of the 15 successfully genotyped SNPs were associated with diabetic nephropathy when compared to patients with normal albumin excretion rate. However, when genotype frequencies in patients with ESRD were compared with all other patients, two CD2AP SNPs, rs9369717 and rs9349417, were found to be associated with ESRD. The meta-analysis of the original and two additional European cohorts resulted in significant p values <0.01 for these SNPs. A third SNP, rs6936632, was suggestively associated with ESRD in the Finnish patients and in the meta-analysis of four cohorts. CD2AP gene variants may contribute to susceptibility to ESRD in patients with type 1 diabetes. [ABSTRACT FROM AUTHOR]

The aim of this study was to assess the effect of the angiotensin II receptor blocker Irbesartan on protein damage by glycation, oxidation and nitration in patients with type 2 diabetes and microalbuminuria. In a double-masked randomised crossover trial of 52 hypertensive type 2 diabetic patients, antihypertensive treatment was replaced with bendroflumethiazide. After 2-months wash-out, patients were treated randomly with Irbesartan 300, 600, and 900 mg o.d., each dose for 2 months in a three-way crossover study. Glycation, oxidation and nitration adduct residues in plasma protein and related urinary free adducts were determined by stable isotopic dilution analysis liquid chromatography-tandem mass spectrometry . Treatment with Irbesartan decreased urinary excretion of advanced glycation endproducts (AGEs)-methylglyoxal- and glyoxal-derived hydroimidazolones, MG-H1 and G-H1. Urinary AGEs were decreased by 30-32%. In plasma protein, treatment with Irbesartan increased content of glycation adducts N-fructosyl-lysine, AGEs N-carboxymethyl-lysine, N-carboxyethyl-lysine and pentosidine, and also increased content of oxidation markers N-formylkynurenine and dityrosine. This was attributed to decreased clearance of plasma protein modified by N-fructosyl-lysine and oxidative markers through the glomerular filter tightened by Irbesartan treatment. Treatment of patients with type 2 diabetes with Irbesartan decreased urinary excretion of MG-H1, G-H1 and 3-NT, which may result from decreased exposure to these AGEs. This is likely achieved by blocking angiotensin II signalling and related down-regulation of glyoxalase 1 and may contribute to health benefits of Irbesartan therapy. [ABSTRACT FROM AUTHOR]

Background/aims: Sporadic reports on immediate and delayed cutaneous reactions to insulin detemir, a modern insulin analogue, have raised unsupported claims of allergy of type I, III and IV. The purpose of this experimental study using a provocative design was to elucidate the potential mechanisms behind such skin reactions. Material and methods: A total of 40 patients with type 1 diabetes or insulin-requiring type 2 diabetes, all naïve to insulin detemir, were injected on the thigh with 0.l mL of insulin detemir (Levemir®) administered with an 8 mm needle at three different depths, i.e. intradermal, subdermal and subcutaneously. Saline was injected as control. Any cutaneous reactions were assessed after 10 and 30 min, after 24 and 48 h and after 7 days. Histopathology of positive reactions on day 7 was obtained. The study was randomized, controlled, double-blinded, and conducted in accordance with ICH-GCP guidelines. Blood flow was recorded with the Periflux PF5010, and skin colour ( a*) with the DSMII colorimeter. Results: Clinical reading, flowmetry and colorimetry consistently showed delayed reactions after intradermal insulin injection (35 of 40 patients reacted with mainly weak reactions, P<0.05), peaking after 48 h, contrasting no special reaction immediately after injection, except for reactions attributed to needle trauma. A total of 22 patients reacted on subdermal injection and 21 on subcutaneous injection. Histopathology on day 7 from 22 reactions in 15 patients showed a consistent pattern of inflammation with eosinophilia as typically observed in adverse skin reactions to a variety of medicines. Reactions were interpreted as non-specific biologic responses to the insulin different from direct toxic actions and classical allergic reaction patterns. Only one person registered itch/discomfort. A prick test vs. histamine reference excluded insulin detemir to be a pharmacological histamine releaser. Thus, provocative testing with insulin detemir produced delayed skin reaction but no immediate reaction. Measurement of circulating insulin detemir-specific antibodies by RIA before and after 3 months showed no increase. Conclusion: Non-allergic delayed skin reactions from intradermal and, to a minor degree, subdermal and subcutaneous injections of insulin detemir were frequent in this experimental study and showed a consistent histology pattern of inflammation with eosinophilia. Immediate reactions were not produced. The reactions are unlikely to be specific for insulin detemir, and other insulins should be studied in a similar provocative design. [ABSTRACT FROM AUTHOR]

A decrease in the number and dysfunction of endothelial progenitor cells (EPC) may increase the risk for progression of cardiovascular disease (CVD) in type 1 diabetic patients with diabetic nephropathy (DN). Our aim was to evaluate EPC numbers in asymptomatic CVD type 1 diabetic patients with or without DN and to study the effect of CVD and medication on EPC numbers. Methods: We examined EPC numbers in 37 type 1 diabetic patients with DN and 35 type 1 diabetic patients with long-standing normoalbuminuria. Patients were without symptoms of CVD and the prevalence of CVD was previously shown to be very low. EPC number was assessed in in vitro cultures by fluorescent staining of attached cells. Results: There was no difference in EPC numbers between patients with DN (mean ± SD 120 ± 49 cells/field) and normoalbuminuria (108 ± 41 cells/field; p = 0.25). Furthermore, EPC number was not associated with CVD (p > 0.05). Conventional risk factors were significantly higher in patients with DN and they received more CVD-preventive treatment. All patients receiving simvastatin or calcium-channel blockers had higher numbers of EPC compared to patients not treated with these drugs. Conclusions: Asymptomatic patients with DN had EPC numbers similar to normoalbuminuric patients, which was related to aggressive CVD intervention therapy. This may have contributed to the low prevalence of CVD. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

OBJECTIVE -- To evaluate vitamin D as a predictor of all-cause and cardiovascular mortality and risk of progression to micro- or macroalbuminuria in type 2 diabetic patients. RESEARCH DESIGN AND METHODS-- In a longitudinal observational follow-up study, 289 type 2 diabetic patients with normoalbuminuria (n = 172), microalbuminuria (n = 73), and macroalbuminuria (n = 44) at baseline were followed for a median (range) of 15.0 (0.2-23) years. Mean ± SD age was 54 ± 9 years. Plasma 25-hydroxyvitamin D3 levels were determined by high-performance liquid chromatography/tandem mass spectrometry on baseline samples. Severe vitamin D deficiency was defined as the lower 10th percentile (<13.9 nmol/1). RESULTS-- Median (range) vitamin D level was 35.7 (5-136.7) nmol/1. Vitamin D levels were not associated with age, sex, estimated glomerular filtration rate, urinary albumin excretion rate (UAER), or A1C at baseline, but low levels were weakly associated with elevated systolic blood pressure (R = 0.13, P = 0.03). During follow-up, 196 (68%) patients died. All-cause mortality was increased in patients with severe vitamin D deficiency (hazard ratio 1.96 [95% CI 1.29-2.98]). The association persisted after adjustment for UAER, A1C, diabetes duration, and conventional cardiovascular risk factors (2.03 [1.31-3.13]). Severe vitamin D deficiency was associated with increased cardiovascular mortality (1.95 [1.11-3.44]), and the association persisted after adjustment (1.90 [1.15-3.10]). Severe vitamin D deficiency at baseline did not predict progression to micro- or macroalbuminuria. CONCLUSIONS -- In type 2 diabetic patients, severe vitamin D deficiency predicts increased risk of all-cause and cardiovascular mortality, independent of UAER and conventional cardiovascular risk factors. Whether vitamin D substitution improves prognosis remains to be investigated. [ABSTRACT FROM AUTHOR]

It has been suggested that genetic susceptibility plays an important role in the pathogenesis of diabetic nephropathy. A large-scale genotyping analysis of gene-based single nucleotide polymorphisms (SNPs) in Japanese patients with type 2 diabetes identified the gene encoding acetyl-coenzyme A carboxylase beta (ACACB) as a candidate for a susceptibility to diabetic nephropathy; the landmark SNP was found in the intron 18 of ACACB (rs2268388: intron 18 +4139 C . T, p = 1.4x10-6, odds ratio = 1.61, 95% confidence interval [CI]: 1.33-1.96). The association of this SNP with diabetic nephropathy was examined in 9 independent studies (4 from Japan including the original study, one Singaporean, one Korean, and two European) with type 2 diabetes. One case-control study involving European patients with type 1 diabetes was included. The frequency of the T allele for SNP rs2268388 was consistently higher among patients with type 2 diabetes and proteinuria. A meta-analysis revealed that rs2268388 was significantly associated with proteinuria in Japanese patients with type 2 diabetes (p = 5.35x10-8, odds ratio = 1.61, 95% Cl: 1.35-1.91). Rs2268388 was also associated with type 2 diabetes-associated end-stage renal disease (ESRD) in European Americans (p = 6x10-4, odds ratio = 1.61, 95% Cl: 1.22- 2.13). Significant association was not detected between this SNP and nephropathy in those with type 1 diabetes. A subsequent in vitro functional analysis revealed that a 29-bp DNA fragment, including rs2268388, had significant enhancer activity in cultured human renal proximal tubular epithelial cells. Fragments corresponding to the disease susceptibility allele (T) had higher enhancer activity than those of the major allele. These results suggest that ACACB is a strong candidate for conferring susceptibility for proteinuria in patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Background: As part of a clinical proteomics program focused on diabetes and its complications we are looking for new and better protein biomarkers for diabetic nephropathy. The search for new and better biomarkers for diabetic nephropathy has, with a few exceptions, previously focused on either hypothesis-driven studies or urinary based investigations. To date only two studies have investigated the proteome of blood in search for new biomarkers, and these studies were conducted in sera from patients with type 2 diabetes. This is the first reported in depth proteomic study where plasma from type 1 diabetic patients was investigated with the goal of finding improved candidate biomarkers to predict diabetic nephropathy. In order to reach lower concentration proteins in plasma a pre-fractionation step, either hexapeptide bead-based libraries or anion exchange chromatography, was performed prior to surface enhanced laser desorption/ionization time-of-flight mass spectrometry analysis. Results: Proteomic analysis of plasma from a cross-sectional cohort of 123 type 1 diabetic patients previously diagnosed as normoalbuminuric, microalbuminuric or macroalbuminuric, gave rise to 290 peaks clusters of which 16 were selected as the most promising biomarker candidates based on statistical performance, including independent component analysis. Four of the peaks that were discovered have been identified as transthyretin, apolipoprotein A1, apolipoprotein C1 and cystatin C. Several yet unidentified proteins discovered by this novel approach appear to have more potential as biomarkers for diabetic nephropathy. Conclusion: These results demonstrate the capacity of proteomic analysis of plasma, by confirming the presence of known biomarkers as well as revealing new biomarkers for diabetic nephropathy in plasma in type 1 diabetic patients. [ABSTRACT FROM AUTHOR]

OBJECTIVE -- The inflammation marker YKL-40 is elevated in patients with type 2 diabetes and is associated with atherosclerosis and increased cardiovascular mortality. In the present study, YKL-40 levels were examined in patients with type 1 diabetes with increasing levels of albuminuria, known to be associated with an increased risk of cardiovascular disease. RESEARCH DESIGN AND METHODS--A total of 149 patients with type 1 diabetes attending Steno Diabetes Center were examined: 58 had normoalbumimuria (urinary albumin excretion rate <30 mg/24 h) 46 had persistent microalbummuria (urinary albumin excretion rate 30-300 mg/24 h), and 45 had persistent macroalbuminuria/diabetic nephropathy (urinary albumin excretion rate >300 mg/24 h). The control group consisted of 55 healthy individuals. Groups were matched according to sex and duration of diabetes (> 30 years). RESULTS -- Median levels [interquartile range] of serum YKL-40 were significantly higher in normoalbuminuria versus control (37 129-521 vs. 53 [32-105] ng/ml, P < 0.01) and were increasing with increasing levels of albuminuria (microalbuminuria 74 [45-160] ng/ml and diabetic nephropathy 117 [68-215] ng/ml; P < 0.001 for all comparisons). YKL-40 levels correlated with the urinary albumin-to-creatinine ratio in the total group of participants (r² = 0.25, P < 0.001.). Significant but weak intercorrelations of YKL-40 were found with age, diastolic blood pressure, AlC, and serum creatinine. After adjustment for significant covariates, albuminuria was significantly associated with YKL-40 levels (P < 0.001). CONCLUSIONS--YKL-40 levels are elevated in patients with type 1 diabetes with an independent association between increasing YKL-40 levels arid increasing levels of albuminuria. The present study is the first to suggest a role of YKL-40 in the gradually progressing vascular complications in patients with type 1 diabetes. [ABSTRACT FROM AUTHOR]

Objective . To evaluate risk factors for progression from persistent microalbuminuria to diabetic nephropathy in the Irbesartan in Patients with Type 2 diabetes and Microalbuminuria (IRMA 2) study, including biomarkers of endothelial dysfunction, chronic low-grade inflammation, growth factors and advanced glycation end products (AGE peptides). Methods . IRMA 2 was a 2-year multicentre, randomized, double-blind trial comparing irbesartan (150 and 300 mg once daily) versus placebo. The primary end-point was time to onset of diabetic nephropathy. Samples from a subgroup from the placebo and the 300 mg irbesartan treatment group were used in this post-hoc analysis (n = 269, 68 %). Nine biomarkers were analysed: high sensitivity C-reactive protein (hs-CRP), interleukin 6 (IL-6), fibrinogen, von Willebrand Factor (vWf), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular cell adhesion molecule-1 (sICAM-1), sE-selectin, transforming growth factor-beta (TGF-β) and AGE peptides. Mean standard deviation scores (Z-scores) were used to combine biomarker information. Results . In a Cox enter model with combined Z-scores for biomarkers of endothelial dysfunction (vWf, sVCAM-1, sICAM-1, sE-selectin) and for biomarkers of inflammation (hs-CRP, IL-6, fibrinogen), endothelial dysfunction (hazard ratio for a 28 % increase ( = 1 SD) in Z-score) 3.20 (1.56 to 6.56), p = 0.001) and UAER (HR for a 75 % increase ( = 1 SD) in UAER) 2.61 (1.30 to 5.23), p = 0.007) were found as independent predictors. Independently, IL-6 and vWf predicted the end-point. In addition, endothelial Z-score was associated with progression of albuminuria (p = 0.038). Conclusion . Endothelial dysfunction and possibly inflammation are novel predictors of progression to diabetic nephropathy in patients with type 2 diabetes and microalbuminuria independently of traditional risk factors. ClinicalTrials.gov ID: NCT00317915. [ABSTRACT FROM AUTHOR]

Background: Despite intensive insulin treatment, many patients with type-1 diabetes (T1DM) have longstanding inadequate glycaemic control. Metformin is an oral hypoglycaemic agent that improves insulin action in patients with type-2 diabetes. We investigated the effect of a one-year treatment with metformin versus placebo in patients with T1DM and persistent poor glycaemic control. Methodology/Principal Findings: One hundred patients with T1DM, preserved hypoglycaemic awareness and HaemoglobinA1c (HbA1c) ≥8.5% during the year before enrolment entered a one-month run-in on placebo treatment. Thereafter, patients were randomized (baseline) to treatment with either metformin (1 g twice daily) or placebo for 12 months (double-masked). Patients continued ongoing insulin therapy and their usual outpatient clinical care. The primary outcome measure was change in HbA1c after one year of treatment. At enrolment, mean (standard deviation) HbA1c was 9.48% (0.99) for the metformin group (n = 49) and 9.60% (0.86) for the placebo group (n = 51). Mean (95% confidence interval) baseline-adjusted differences after 12 months with metformin (n = 48) versus placebo (n = 50) were: HbA1c, 0.13% (-0.19; 0.44), p = 0.422; Total daily insulin dose, -5.7 U/day (-8.6; -2.9), p<0.001; body weight, -1.74 kg (-3.32; -0.17), p = 0.030. Minor and overall major hypoglycaemia was not significantly different between treatments. Treatments were well tolerated. Conclusions/Significance: In patients with poorly controlled T1DM, adjunct metformin therapy did not provide any improvement of glycaemic control after one year. Nevertheless, adjunct metformin treatment was associated with sustained reductions of insulin dose and body weight. Further investigations into the potential cardiovascular-protective effects of metformin therapy in patients with T1DM are warranted. [ABSTRACT FROM AUTHOR]

Adiponectin levels are increased in patients with type I diabetes especially in the presence of microangiopathy. Here we determined the predictive value of serum adiponectin levels and 8 adiponectin gene polymorphisms for mortality, cardiovascular events and end-stage renal disease in type I diabetic patients. This prospective, observational follow-up study of type I diabetics consisted of 438 patients with overt diabetic nephropathy that were compared to 440 type I patients with normal albumin excretion. These two groups were followed an average of 8 years and generally matched for gender, age and duration of diabetes. Cox regression analysis of 373 patients showed a covariate-adjusted hazard ratio for all-cause mortality of 1.46 for a change of one standard deviation in log10 of serum adiponectin. There was no association with cardiovascular events; however, serum adiponectin levels predicted end stage renal disease in a covariate-adjusted analysis. Two of eight gene polymorphisms, found in the 878 patients, were associated with increased serum adiponectin levels but none of the polymorphisms were associated with a renal or cardiovascular outcome. These studies show that high serum adiponectin levels predict mortality and progression to end stage renal disease in type I diabetic patients.Kidney International (2008) 74, 649–654; doi:10.1038/ki.2008.201; published online 21 May 2008 [ABSTRACT FROM AUTHOR]

OBJECTIVE -- We evaluated the association of biomarkers of endothelial dysfunction and inflammation with all-cause mortality and cardiovascular mortality and morbidity and decline in glomerular filtration rate (GFR) in type 1 diabetic patients. RESEARCH DESIGN AND METHODS -- We prospectively followed 199 type 1 diabetic patients with diabetic nephropathy and 192 patients with persistent normoalbuminuria. Biomarkers were measured at baseline. RESULTS -- We constructed two Z scores: the mean inflammatory Z score combined C-reactive protein, interleukin-6, soluble intercellular adhesion molecule (sICAM-1), and secreted phospholipase A2 and the mean Z score for endothelial dysfunction combined soluble vascular cell adhesion molecule 1, plasminogen activator inhibitor-1, and sICAM-1. The mean Z score of inflammatory biomarkers was associated with mortality and the combined end point in patients with diabetic nephropathy after multivariate adjustment (hazard ratio 1.7 [95% CI 1.1-2.6]; P = 0.025 and 1.5 [1.1-2.21; P = 0.017). The mean Z score for endothelial dysfunction biomarkers was associated with mortality in a model adjusting for age and sex in patients with diabetic nephropathy (1.6 [1.0-2.3]; P = 0.031). The mean Z score for endothelial dysfunction correlated with decline in GFR (r = -0.243; P = 0.001); the correlation persisted after multivariate adjustment (coefficient -1.38 [95% CI -2.27 to -0.50]; P = 0.002). CONCLUSIONS -- Mean Z scores of inflammatory biomarkers are significantly associated with all-cause mortality and cardiovascular morbidity and mortality in patients with nephropathy after multivariate adjustment. These data suggest that the high risk of cardiovascular disease in type 1 diabetes may be explained in part by inflammatory activity. Mean Z score of endothelial dysfunction correlated after multivariate adjustment with the rate of decline in GFR. [ABSTRACT FROM AUTHOR]

The impact of irbesartan treatment on biomarkers of low-grade inflammation, endothelial dysfunction, growth factors, and advanced glycation end products (AGEs) during the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IRMA 2) study was evaluated. IRMA 2 was a 2-year multicenter, randomized, double-blind trial in patients comparing irbesartan (150 or 300 mg once daily) versus placebo. The primary end point was onset of overt nephropathy. A subgroup (n = 269, 68%) was analyzed for biomarkers at baseline and after 1 and 2 years. High-sensitivity C-reactive protein (hs-CRP), interleukin (IL)-6, fibrinogen, adhesion molecules, transforming growth factor-β and AGE peptides were assessed. Irbesartan treatment yielded significant changes in hs-CRP (based on generalized estimating equation regression coefficient) with a 5.4% decrease per year versus a 10% increase per year in the placebo group (P < 0.001). Fibrinogen decreased 0.059 g/l per year from baseline versus placebo's 0.059 g/l increase per year (P = 0.027). IL-6 showed a 1.8% increase per year compared with placebo's 6.5% increase per year (P = 0.005). Changes in IL-6 were associated with changes in albumin excretion (P = 0.04). There was no treatment effect on the other biomarkers. Irbesartan (300 mg once daily) reduces low-grade inflammation in this high-risk population, and this may reduce the risk of micro-and macrovascular disease. Diabetes 55:3550-3555, 2006 [ABSTRACT FROM AUTHOR]

Linkage studies have mapped loci for diabetic nephropathy and associated phenotypes on chromosome 3q. We studied 14 plausible candidate genes in the linkage region because of their potential role in vascular complications. In a large-scale study of patients from Denmark, Finland, and France who have type 1 diabetes, 1,057 case and 1,127 control subjects, as well as 532 trios, were investigated for association with diabetic nephropathy. We analyzed 69 haplotype-tagging single nucleotide polymorphisms and nonsynonymous variants that were identified by sequencing. Polymorphisms in three genes, glucose transporter 2 (SLC2A2), kininogen (KNG1), and adiponectin (ADIPOQ), showed nominal association with diabetic nephropathy in single-point analysis. The T-allele of SLC2A2_16459CT was associated with a decreased risk of diabetic nephropathy (odds ratio 0.79 [95% CI 0.66-0.96], P = 0.016), whereas the T-allele of KNG_7965CT and the A-allele of ADIPOQ_prom2GA were associated with increased risk of nephropathy (1.17 [1.03-1.32], P = 0.016; 1.46 [1.11-1.93], P = 0.006, respectively). Analyses of the transmission disequilibrium test showed similar trends only for ADIPOQ_prom2GA with the overtransmission of the A-allele to patients with diabetic nephropathy (1.52 [0.86 2.66], P = NS) and of the G-allele to patients without diabetic nephropathy (0.50 [0.27-0.92], P = 0.026). The overall significance for this variant (nominal P = 0.011) suggests that ADIPOQ might be involved in the development of diabetic nephropathy. Diabetes 55:3166-3174, 2006 [ABSTRACT FROM AUTHOR]

OBJECTIVE -- Xylosyltransferase I (XT-I) is the chain-initiating enzyme in the biosynthesis of proteoglycans in basement membranes. It catalyzes the transfer of xylose to selected serine residues in the core protein. The XYLT-II gene codes for a protein highly homologous to XT-I. Proteoglycans are important components of basement membranes and are responsible for their permeability properties. Type 1 diabetic patients have an altered proteoglycan metabolism, which results in microvascular complications. Thus, genetic variations in the xylosyltransferase genes might be implicated in the initiation and progression of these complications. RESEARCH DESIGN AND METHODS -- Genotyping of four genetic variations in the genes XYLT-I and XYLT-II was performed in 912 type 1 diabetic patients (453 with and 459 without diabetic nephropathy) using restriction fragment-length polymorphism. RESULTS -- The distribution of the c.343G>T polymorphism in XYLT-I is significantly different between patients with and without diabetic nephropathy (P = 0.03). T-alleles were more frequent in patients with diabetic nephropathy (odds ratio 2.47 [95% CI 1.04-5.83]). The allelic frequencies of the other investigated XYLT-I and XYLT-II variations (XYLT-I: c. 1989T>C in exon 9; XYLT-II: IVS6-9T>C and IVS6-14_IVS6-13insG in intron 5; and c.2402C>G: p.T801R in exon 11) were not different between patients with and without diabetic nephropathy. CONCLUSIONS -- The XYLT-I c.343G>T polymorphism contributes to the genetic susceptibility to development of diabetic nephropathy in type 1 diabetic patients. [ABSTRACT FROM AUTHOR]

Improved prognosis in type 1 diabetic patients with nephropathy: A prospective follow-up study. Background. In early studies, a median survival time of 5 to 7 years from onset of diabetic nephropathy was observed. Furthermore, end-stage renal disease (ESRD) was the main cause of death. We prospectively assessed the impact of reno- and cardiovascular protective treatment on prognosis in type 1 diabetic patients with diabetic nephropathy. Methods. We prospectively followed 199 type 1 diabetic patients with diabetic nephropathy and 192 patients with normoalbuminuria for 10 years. Aggressive antihypertensive treatment was initiated in patients with diabetic nephropathy in mid 1980s, whereas statins and aspirin were not prescribed routinely until April 2002. The primary end point was cardiovascular mortality and morbidity. Secondary end points were all-cause mortality and ESRD. Results. During follow-up, 79 patients (40%) with nephropathy reached the primary end point versus 19 (10%) of normoalbuminuric patients, log rank test P < 0.0001. Predictors of the primary end point were: nephropathy (hazard ratio 3.26; 95% confidence interval 1.89 to 5.62), previous event (3.19; 2.04 to 4.97), age (1.27; 1.04 to 1.55), and systolic blood pressure (1.13; 1.03 to 1.24). In the nephropathy group, 60 patients (30%) died; hereof, 25 deaths (42%) were ascribed to cardiovascular causes while 30 patients (50%) with nephropathy died with ESRD. The estimate of median survival time from onset of diabetic nephropathy was 21.7 years, SE 3.3 years. Conclusion. The survival of patients with diabetic nephropathy has improved most likely due to aggressive antihypertensive treatment and improved glycaemic control. [ABSTRACT FROM AUTHOR]

Objective To evaluate baseline predictors for the development of persistent microalbuminuria and macroalbuminuria prospectively in patients with type 1 diabetes. Design Prospective observational study of an inception cohort. Setting Outpatient diabetic clinic in a tertiary referral center, Gentofte, Denmark. Participants 286 patients (216 adults) newly diagnosed with type 1 diabetes consecutively admitted to the clinic between 1 September 1979 and 31 August 1984. Main outcome measures Persistent microalbuminuria and persistent macroalbuminuria. Results During the median follow up of 18.0 years (range 1.0-21.5 years), total of 4706 patient years of follow up, 79 of 277 patients developed persistent microalbuminuria. 27 progressed further to persistent macroalbuminuria. The cumulative incidence of persistent microalbuminuria and persistent macroalbuminuria was 33.6% (95% confidence interval 27.2% to 40.0%) and 14.6% (8.9% to 20.3%), respectively. Significant predictors (95% confidence intervals) for the development of persistent microalbuminuria were a 10-fold increase in urinary albumin excretion rate (relative risk 3.78, 1.57 to 9.13), being male (2.41, 1.43 to 4.06), a 10 mm Hg increase in mean arterial blood pressure (1.38, 1.20 to 1.57), a 1% increase in hemoglobin A1c (1.18, 1.04 to 1.32), and a 1cm increase in height (0.96, 0.95 to 0.98). 28 patients with microalbuminuria (35%) regressed to normoalbuminuria either transiently (n =15) or permanently (n =13). Conclusions Around one third of patients newly diagnosed with type 1 diabetes develop persistent microalbuminuria within the first 20 years of diabetes. Several potentially modifiable risk factors predict the development of persistent microalbuminuria and persistent macroalbuminuria. [ABSTRACT FROM AUTHOR]

Objective: Increased plasma concentration of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, has been associated with endothelial dysfunction, insulin resistance, and atherosclerosis in nondiabetic populations. In end-stage renal failure, circulating ADMA is elevated and a strong predictor of cardiovascular outcome. This study investigated the relation between ADMA and diabetic micro- and macrovascular complications in a large cohort of type 1 diabetic patients with and without early diabetic nephropathy.Research Design and Methods: ADMA concentrations in plasma were determined by a high-performance liquid chromatography method in 408 type 1 diabetic patients with overt diabetic nephropathy (252 men; mean age 42.7 years [SD 11.0], mean duration of diabetes 28 years [SD 9], median serum creatinine level 102 micromol/l [range 52-684]). A group of 192 patients with longstanding type 1 diabetes and persistent normoalbuminuria served as control subjects (118 men; mean age 42.6 years [SD 10.2], mean duration of diabetes 27 years [SD 9]).Results: In patients with diabetic nephropathy, mean +/- SD plasma ADMA concentration was elevated 0.46 +/- 0.08 vs. 0.40 +/- 0.08 micromol/l in normoalbuminuric patients (P<0.001). An increase in plasma ADMA of 0.1 micromol/l increased the odds ratio of nephropathy to 2.77 (95% CI 1.89-4.05) (P<0.001). Circulating ADMA increased in nephropathy patients with declining kidney function, as indicated by elevated values in the lower quartiles of glomerular filtration rate (<76 ml.min(-1).1.73 m(-2)) (P<0.001 ANOVA). Mean ADMA levels were similar in patients with or without diabetic retinopathy (P>0.2). However, in 44 patients with nephropathy and history of myocardial infarction and/or stroke, ADMA was significantly elevated at 0.48 +/- 0.08 micromol/l compared with 0.46 +/- 0.08 micromol/l in patients without major cardiovascular events (P=0.05).Conclusions: Elevated circulating ADMA may contribute to the excess cardiovascular morbidity and mortality in early diabetic nephropathy. [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]

Elevated vascular endothelial growth factor in type 1 diabetic patients with diabetic nephropathy. Background. Growth factors have been suggested to play a role in the development and progression of diabetic nephropathy. Vascular endothelial growth factor (VEGF) is a potent cytokine family that induces angiogenesis and markedly increases endothelial permeability. The aim of the present study was to investigate plasma levels of VEGF in a large cohort of type 1 diabetic patients with diabetic nephropathy and in long-standing type 1 diabetic patients with persistent normoalbuminuria, and to evaluate VEGF as a predictor of nephropathy progression. Methods. We measured VEGF with an enzyme-linked immunosorbent assay (ELISA) technique in 199 type 1 diabetic patients with diabetic nephropathy (122 males, age 41 ± 10 years, diabetes duration 28 ± 8 years), glomerular filtration rate (GFR) (median [range]) 75 [10–143] mL/min/1.73 m2, and in 188 long-standing type 1 diabetic patients with persistent normoalbuminuria (115 males, age 43 ± 10 years, diabetes duration 27 ± 9 years). One hundred fifty-five of the proteinuric patients were followed for at least 3 years after baseline examination with yearly GFR measurements. Results. Plasma levels of VEGF were significantly increased in patients with nephropathy as compared to the normoalbuminuric group; (median [range]): 45.7 [22.0–410] versus 27.1 [22.0–355] ng/L, respectively, P < 0.001. This difference was ascribed to elevated VEGF levels in nephropathic men: 51.8 [22.0–410] versus 22.0 [22.0–308] ng/L, P < 0.001. No differences were found between women with and without nephropathy: 37.8 [22.0–325] versus 36.6 [22.0–335] ng/L, NS. In proteinuric patients with GFR above and below the median value, there was no difference in the level of VEGF, NS. Plasma VEGF was below the detection limit (22.0 ng/L) in 60 patients with nephropathy and 93 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]

Presents a study which compared the effects of the calcium channel blocker, nisoldipine, and the ACE inhibitor, lisinopril, on left ventricular mass and systolic function in type 1 diabetic patients with diabetic nephropathy. Research design and methods; Results; Conclusions.

OBJECTIVES -- To measure left ventricular mass (LVM), left ventricular volumes, and left ventricular function (LVF) in a cohort of type 1 diabetic patients and to correlate measures of imaging to NH2-terminal pro-brain natriuretic peptide (NT-proBNP). RESEARCH DESIGN AND METHODS -- In a cross-sectional study, all patients with type 1 diabetes underwent cardiovascular magnetic resonance imaging. We included 63 patients with diabetic nephropathy and 73 patients with normoalbuminuria. RESULTS -- All patients had normal global LVF. LVM was increased in patients with diabetic nephropathy compared with patients with persistent normoalbuminuria. Patients with nephropathy had smaller left ventricular volumes and increased levels of NT-proBNP. Linear regression analysis in patients with diabetic nephropathy showed that NT-proBNP and creatinine were associated with LVM. CONCLUSIONS -- Increased LVM is identified in asymptomatic type 1 diabetic patients with nephropathy compared with normoalbuminuric patients. Elevated levels of NT-proBNP were associated with increased LVM, which are both markers of increased cardiovascular risk. [ABSTRACT FROM AUTHOR]

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A correction to the article "Glycemic Variability Is Associated With Reduced Cardiac Autonomic Modulation in Women With Type 2 Diabetes" that appeared in the 2015 issue of "Diabetes Care" is presented. [ABSTRACT FROM AUTHOR]

Aim: Urinary adiponectin (u-adiponectin) excretion has been suggested to reflect early glomerular damage. Inspired by this, we studied the levels of u-adiponectin in type 1 diabetic patients with different levels of urinary albumin excretion (UAE). Methods: U-adiponectin was analysed by ELISA in type 1 diabetic patients: Fifty-eight with normoalbuminuria (<30 mg albumin/24 h), 43 with persistent microalbuminuria (30–300 mg/24 h) and 44 with persistent macroalbuminuria (>300 mg/24 h). For comparison, a control group of 55 healthy individuals was included. Results: U-adiponectin increased with increasing levels of UAE (p < 0.01). U-adiponectin median (interquartile range): Normoalbuminuria 0.38 (0.14–1.31), microalbuminuria 1.12 (0.20–2.68), macroalbuminuria 9.20 (1.10–23.35) and controls 0.09 (0.06–0.24) μg/g creatinine. Levels were unrelated to sex, age, cholesterol, diastolic BP and BMI. U-adiponectin was weakly associated with increasing systolic BP and HbA1c (r2 b 0.1, p < 0.05), but strongly related to increasing UAE (r2 = 0.57, p < 0.001) and decreasing eGFR (r2 = 0.26, p < 0.001). The relationship between UAE and u-adiponectin was significant in all groups and independent of eGFR, BMI, BP and HbA1c. Furthermore, u-adiponectin was associated with markers of tubular damage (p < 0.01). Conclusion: U-adiponectin rises with increasing levels of UAE in patients with type 1 diabetes. This is in accordance with the hypothesis that loss of adiponectin may reflect glomerular and/or tubular damage. [ABSTRACT FROM AUTHOR]

Abstract: Background: We have previously found that acute intravenous infusion of an ACE inhibitor normalized the reduced coronary vasomotor function in type 2 diabetes. The aim of the present study was to extend this investigation to an angiotensin II receptor blocker (ARB) administered orally in normotensive, asymptomatic type 2 diabetes patients without albuminuria. Results: Fourteen type 2 diabetes patients were included. Each patient had myocardial perfusion measured by PET at three occasions: at baseline, following 3 weeks of treatment with 50mg/d and following another 3 weeks of treatment with 100mg/d of losartan. Baseline myocardial perfusion was similar at all three sessions (0.89±0.05, 0.90±0.08 and 0.84±0.05mL/(ming) tissue, respectively). Likewise, maximal hyperaemic perfusion after i.v. dipyridamole (0.56mg/kg bwt) was low but similar at the three sessions (2.01±0.14, 2.05±0.17 and 1.90±0.20mL/(ming) tissue, respectively). Myocardial perfusion reserve, i.e. maximal hyperaemic flow relative to baseline flow, was also low, but similar before and after treatment with losartan (2.36±0.24, 2.44±0.24 and 2.62±0.42mL/(ming) tissue, respectively). Conclusions: Oral treatment with an ARB did not normalize coronary vasomotor function in type 2 diabetes patients without cardiovascular disease. [Copyright &y& Elsevier]

Remission and regression in the nephropathy of type 1 diabetes when blood pressure is controlled aggressively. Background. Diabetic nephropathy is a chronic, progressive kidney disease with a mean rate of decline of in glomerular filtration rate (GFR) of 10 to 12 mL/min/year (natural history). The introduction of aggressive antihypertensive treatment has improved the renal prognosis during the last decades. To examine whether remission and regression of diabetic nephropathy are possible in type 1 diabetic patients, we analyzed data from a prospective observational cohort study that was started in 1983. Methods. We measured GFR with a 51Cr-EDTA plasma clearance technique every year for seven years (range 3 to 14 years) in 301 consecutive type 1 diabetic patients with diabetic nephropathy. Diabetic nephropathy was diagnosed clinically if the following criteria were fulfilled: persistent albuminuria> 200 μg/min, presence of diabetic retinopathy, and no evidence of other kidney or renal tract disease. Blood pressure, albuminuria, glycosylated hemoglobin A1c, and serum cholesterol were measured every three to four months during the study. In total, 271 patients received antihypertensive treatment, 179 patients predominantly with angiotensin-converting enzyme inhibitors. Remission was defined as albuminuria <200 μg/min sustained for at least one year and a decrease of at least 30% from preremission levels (surrogate endpoint), and regression as a rate of decline in GFR (ΔGFR) equal to the natural aging process: ≤1 mL/min/year during the entire observation period (principal end point). Results. The total number of patients who obtained remission was 92 (31%), with a duration of remission of [median (range)] 3.4 (1.0 to 14.1) years, and regression 67 (22%). The patients were stratified in quintiles by the average value of office mean arterial blood pressure (mean ± SE): 93 ± 0.5, 99 ± 0.2, 103 ± 0.1, 107 ± 0.2, and 113 ± 0.4 mm Hg. The prevalence of patients obtaining remission/regression was 58/42, 33/32, 25/11, 20/20, and 17/7% in each quintile, respectively. Spontaneous remission and regression occurred in 10 and 14 patients from the persistent normotensive group (N = 30), none of whom had ever received antihypertensive treatment. In all 301 consecutive patients, the (mean ± SE) ΔGFR was 4.0 ± 0.2 mL/min/year during the investigation period. Conclusions. Our study suggests that aggressive antihypertensive treatment in type 1 diabetic patients can induce remission and regression in a sizable fraction of patients with diabetic nephropathy. Lower arterial blood pressure, reduced albuminuria, and better glycemic control were predictors of regression of diabetic nephropathy. [ABSTRACT FROM AUTHOR]

Assesses the glomerular filtration rate to diagnose the progression of diabetic nephropathy in diabetic patients. Etiology of diabetic nephropathy; Assessment of the risk factors of filtration power; Distinction of progression parameters in the prognosis of diabetic nephropathy.

Progression of diabetic nephropathy in normotensive type 1 diabetic patients Background The first aim of our long-term study was to describe the natural history of diabetic nephropathy in 59 normotensive type 1 diabetic patients. Secondly, we evaluated genetic and nongenetic progression promoters. Methods The following progression promoters were determined: the insertion/deletion polymorphism in the angiotensin converting enzyme (ACE) gene, blood pressure, albuminuria, hemoglobin A 1c , cholesterol, smoking, height, and gender. We studied the natural history by measuring 51 Cr-EDTA plasma clearance at yearly intervals at least three times during [median (range)] 5.5 (2.2 to 18.3) years. Results At baseline the three groups (II, N = 11; ID, N = 25, and DD, N = 23) had comparable GFR (103 ± 16; 99 ± 19; 113 ± 22 ml/min/1.73 m 2 , respectively; mean ± SD ), arterial blood pressure, albuminuria, and hemoglobin A 1c . During the follow-up there was a median rate of decline in GFR in all 59 patients of 1.2 (range 12.9 to –4.4) ml/min/year. During the study period no significant differences were observed in: the rate of decline in glomerular filtration rate [median (range) 0.9 (10.6 to –1.9); 2.5 (12.9 to –4.4); 1.4 (10.8 to –1.9 ml/min/year)], arterial blood pressure, albuminuria, hemoglobin A 1c or cholesterol between the three groups (II, ID and DD), respectively. At baseline, multiple linear regression analysis including the above-mentioned putative risk factors revealed that albuminuria, short stature, and male gender independently predict an enhanced decline in GFR [R 2 (adjusted) = 0.33; P < 0.002]. During the follow-up period, only albuminuria acted as an independent progression promoter [R 2 (adjusted) = 0.37; P < 0.0001]. Conclusions Our study revealed a rather slow progression of kidney disease in normotensive type 1 diabetic patients with diabetic nephropathy. Albuminuria, short stature, and male gender act as progression promoters in such patients. [ABSTRACT FROM AUTHOR]