Frequent physical activity is associated with reduced risk of severe diabetic retinopathy in type 1 diabetes.

AIMS: The aim of this study was to investigate whether leisure-time physical activity (LTPA) is associated with the development of severe diabetic retinopathy in individuals with type 1 diabetes. METHODS: Prospective observational analysis as part of the Finnish diabetic nephropathy (FinnDiane) Study with a mean follow-up time of 10.7 years was performed. A total of 1612 individuals with type 1 diabetes were recruited, and LTPA was assessed at baseline using a validated self-report questionnaire. Severe diabetic retinopathy was defined as the initiation of laser treatment due to severe nonproliferative, proliferative retinopathy or diabetic maculopathy (identified from the Care Register for Health Care). RESULTS: A total of 261 patients received laser treatment during the follow-up. Higher frequency of LTPA was associated with a lower incidence of severe diabetic retinopathy (p = 0.024), a finding that remained significant after adjustment for gender, duration, age at onset of diabetes, kidney function, BMI, triglycerides and systolic blood pressure. However, when HbA1c and smoking were added to the Cox regression model the association was no more significant. CONCLUSIONS: Frequent LTPA is associated with a lower incidence of severe diabetic retinopathy during the follow-up. The total amount or the other components of LTPA (intensity or duration of a single session) were not associated with severe diabetic retinopathy.

Soluble receptor for AGE in diabetic nephropathy and its progression in Finnish individuals with type 1 diabetes.

AIMS/HYPOTHESIS: Activation of the receptor for AGE (RAGE) has been shown to be associated with diabetic nephropathy. The soluble isoform of RAGE (sRAGE) is considered to function as a decoy receptor for RAGE ligands and thereby protects against diabetic complications. A possible association between sRAGE and diabetic nephropathy is still, however, controversial and a more comprehensive analysis of sRAGE with respect to diabetic nephropathy in type 1 diabetes is therefore warranted. METHODS: sRAGE was measured in baseline serum samples from 3647 participants with type 1 diabetes from the nationwide multicentre Finnish Diabetic Nephropathy (FinnDiane) Study. Associations between sRAGE and diabetic nephropathy, as well as sRAGE and diabetic nephropathy progression, were evaluated by regression, competing risks and receiver operating characteristic curve analyses. The non-synonymous SNP rs2070600 (G82S) was used to test causality in the Mendelian randomisation analysis. RESULTS: Baseline sRAGE concentrations were highest in participants with diabetic nephropathy, compared with participants with a normal AER or those with microalbuminuria. Baseline sRAGE was associated with progression from macroalbuminuria to end-stage renal disease (ESRD) in the competing risks analyses, but this association disappeared when eGFR was entered into the model. The SNP rs2070600 was strongly associated with sRAGE concentrations and with progression from macroalbuminuria to ESRD. However, Mendelian randomisation analysis did not support a causal role for sRAGE in progression to ESRD. CONCLUSIONS/INTERPRETATION: sRAGE is associated with progression from macroalbuminuria to ESRD, but does not add predictive value on top of conventional risk factors. Although sRAGE is a biomarker of diabetic nephropathy, in light of the Mendelian randomisation analysis it does not seem to be causally related to progression from macroalbuminuria to ESRD.

Regression of albuminuria and its association with incident cardiovascular outcomes and mortality in type 1 diabetes: the FinnDiane Study.

AIMS/HYPOTHESIS: Our aim was to assess regression of albuminuria and its clinical consequences in type 1 diabetes. METHODS: The analysis included 3642 participants from the Finnish Diabetic Nephropathy (FinnDiane) Study with a 24 h urine sample and a history of albuminuria available at baseline. A total of 2729 individuals had normal AER, 438 a history of microalbuminuria and 475 a history of macroalbuminuria. Regression was defined as a change from a higher category of albuminuria pre-baseline to a lower category in two out of the three most recent urine samples at baseline. The impact of regression on cardiovascular events (myocardial infarction, stroke, coronary procedure) and mortality was analysed over a follow-up of 14.0 years (interquartile range 11.9-15.9). RESULTS: In total, 102 (23.3%) individuals with prior microalbuminuria and 111 (23.4%) with prior macroalbuminuria had regressed at baseline. For individuals with normal AER as a reference, the age-adjusted HRs (95% CI) for cardiovascular events were 1.42 (0.75, 2.68) in individuals with regression from microalbuminuria, 2.62 (1.95, 3.54) in individuals with sustained microalbuminuria, 3.15 (2.02, 4.92) in individuals with regression from macroalbuminuria and 5.49 (4.31, 7.00) in individuals with sustained macroalbuminuria. Furthermore, for all-cause and cardiovascular mortality rates, HRs in regressed individuals were comparable with those with sustained renal status at the achieved level (i.e. those who did not regress but remained at the most advanced level of albuminuria noted pre-baseline). CONCLUSIONS/INTERPRETATION: Progression of diabetic nephropathy confers an increased risk for cardiovascular disease and premature death. Notably, regression reduces the risk to the same level as for those who did not progress.

Physical Activity Reduces Risk of Premature Mortality in Patients With Type 1 Diabetes With and Without Kidney Disease.

OBJECTIVE: The aims of the study were to assess how baseline leisure-time physical activity (LTPA) and its exercise components intensity, duration, and frequency are associated with all-cause and cardiovascular mortality in patients with type 1 diabetes 1) overall, 2) stratified by presence or absence of chronic kidney disease (CKD), and 3) stratified by sex. RESEARCH DESIGN AND METHODS: The study design was prospective and observational and included 2,639 patients with type 1 diabetes from the ongoing nationwide multicenter Finnish Diabetic Nephropathy (FinnDiane) Study. Mean follow-up time was 11.4 ± 3.5 years. LTPA was assessed by using a validated self-report questionnaire. Three hundred ten patients (11.7%) had CKD defined as an estimated glomerular filtration rate of ≤60 mL/min/1.73 m2. RESULTS: During follow-up, 270 deaths occurred. LTPA and all its components were associated with all-cause mortality, even after adjustment for the potential confounders sex, diabetic nephropathy, duration of diabetes, age at onset of diabetes, systolic blood pressure, triglycerides, BMI, and HbA1c. Only exercise intensity was associated with cardiovascular mortality after adjustment for the confounders. Of the patients with CKD, 127 died during follow-up. The total amount of LTPA and exercise frequency were independently associated with lower risk of all-cause mortality when adjusted for covariates. CONCLUSIONS: Exercise is associated with a lower risk of premature all-cause and cardiovascular mortality in patients with type 1 diabetes. This study also demonstrates that physical activity is associated with a lower risk of mortality in patients with type 1 diabetes and CKD.

Frequent and intensive physical activity reduces risk of cardiovascular events in type 1 diabetes.

AIMS/HYPOTHESIS: Cardiovascular disease (CVD) is the most common cause of premature death and disability among patients with type 1 diabetes. Diabetic nephropathy accounts for the increased cardiovascular morbidity and mortality of these patients. We recently showed that the intensity of exercise predicts the incidence and progression of diabetic nephropathy in patients with type 1 diabetes. Little is known about the relationship between physical activity and CVD. Therefore, we studied how physical activity affects the risk of CVD events in patients with type 1 diabetes. METHODS: A 10 year follow-up study including 2180 type 1 diabetes patients from the nationwide multicentre Finnish Diabetic Nephropathy Study (FinnDiane). Leisure time physical activity (LTPA) was assessed by a previously validated self-report questionnaire. A CVD event was defined as a verified myocardial infarction, coronary procedure or stroke. Patients were analysed separately for the risk of developing a first ever CVD event and for the risk of a recurrent CVD event following a baseline event. RESULTS: A total of 206 patients had an incident CVD event during follow-up. A higher total LTPA and higher intensity, frequency and duration of activity were associated with a lower risk of incident CVD events. The observed association between exercise frequency and incident CVD remained significant when adjusted for classic risk factors. Exercise intensity also had a borderline effect on the recurrence-free time in patients with a major CVD event at baseline. CONCLUSIONS/INTERPRETATION: This study suggests that exercise, particularly high frequency and high intensity exercise, may reduce the risk of CVD events in patients with type 1 diabetes.

Smoking and progression of diabetic nephropathy in patients with type 1 diabetes.

AIMS: To evaluate the effect of cumulative smoking on the development of diabetic nephropathy. METHODS: Study included 3613 patients with type 1 diabetes, participating in the Finnish Diabetic Nephropathy Study. The 12-year cumulative risk of microalbuminuria, macroalbuminuria and end-stage renal disease (ESRD) was estimated for current, ex- and nonsmokers. Cox regression analyses, with multivariable adjustments for other risk factors for diabetic nephropathy, were used to evaluate the risk at different stages of diabetic nephropathy based on the cumulative amount of smoking in pack-years. RESULTS: The 12-year cumulative risk of microalbuminuria was 18.9 % (95 % CI 14.6-23.0, P < 0.0001) for current smokers and 15.1 % (10.3-19.6, P = 0.087) for ex-smokers, compared with 10.0 % (7.8-12.1) for nonsmokers. The corresponding risks of macroalbuminuria were 14.4 % (95 % CI 10.8-17.9, P < 0.0001), 6.1 % (3.5-8.6, P = 0.082) and 4.7 % (3.0-6.4), respectively. The 12-year cumulative risk of ESRD was 10.3 % (95 % CI 8.4-12.4, P < 0.0001) for current smokers and 10.0 % (7.9-12.3, P < 0.0001) for ex-smokers, compared with 5.6 % (4.6-6.7) for nonsmokers. In the current smokers, one pack-year increased the risk of macroalbuminuria with a HR of 1.025 (1.010-1.041) and the risk of ESRD with a HR of 1.014 (1.001-1.026) compared with nonsmokers, in the fully adjusted model. In the ex-smokers, the risk of macroalbuminuria and ESRD was no different from the risk in nonsmokers after multivariable adjustment. CONCLUSIONS: Current smoking is a risk factor for the progression of diabetic nephropathy and the risk increases with the increasing dose of smoking. Ex-smokers seem to carry a similar risk of progression of diabetic nephropathy as nonsmokers.

The Presence and Consequence of Nonalbuminuric Chronic Kidney Disease in Patients With Type 1 Diabetes.

OBJECTIVE: This study investigated the prevalence of nonalbuminuric chronic kidney disease in type 1 diabetes to assess whether it increases the risk of cardiovascular and renal outcomes as well as all-cause mortality. RESEARCH DESIGN AND METHODS: This was an observational follow-up of 3,809 patients with type 1 diabetes from the Finnish Diabetic Nephropathy Study. All patients were Caucasians and thoroughly examined at baseline. Their mean age was 37.6 ± 11.8 years and duration of diabetes 21.2 ± 12.1 years. Follow-up data on cardiovascular and renal outcomes and mortality were retrieved from registers. During 13 years of median follow-up, 378 developed end-stage renal disease, 415 suffered an incident cardiovascular event, and 406 died. RESULTS: At baseline, 78 (2.0%) had nonalbuminuric chronic kidney disease. This was associated with older age, female sex, history of retinal laser treatment, cardiovascular events, and the number of antihypertensive drugs in use, but not with blood pressure levels or specific antihypertensive agents. Nonalbuminuric chronic kidney disease did not increase the risk of albuminuria (hazard ratio [HR] 2.0 [95% CI 0.9-4.4]) or end-stage renal disease (HR 6.4 [0.8-53.0]) but did increase the risk of cardiovascular events (HR 2.0 [1.4-3.5]) and all-cause mortality (HR 2.4 [1.4-3.9]). The highest risk of cardiovascular and renal end points was observed in the patients with albuminuria. CONCLUSIONS: Nonalbuminuric chronic kidney disease is not a frequent finding in patients with type 1 diabetes, but when present, it is associated with an increased risk of cardiovascular morbidity and all-cause mortality but not with renal outcomes.

Kidney injury molecule-1 and the loss of kidney function in diabetic nephropathy: a likely causal link in patients with type 1 diabetes.

OBJECTIVE: We evaluated the predictive value and clinical benefit of urinary kidney injury molecule (KIM)-1 for progression of diabetic nephropathy (DN) in type 1 diabetes. We also investigated its causal role for the decrease of estimated glomerular filtration rate (eGFR) by a Mendelian randomization (MR) approach. RESEARCH DESIGN AND METHODS: We followed 1,573 patients with type 1 diabetes for 6 years. KIM-1 was measured at baseline and normalized with urinary creatinine. KIM-1 predictive value was evaluated by Cox regression, while its added predictive benefit was evaluated using a panel of statistical indexes. The causality for the loss of renal function was evaluated with MR, utilizing the top signal from our genome-wide association study (GWAS) as the instrumental variable. RESULTS: KIM-1 was not an independent predictor of progression of DN when adjusted for albumin excretion rate (AER) and added no prognostic benefit to AER or eGFR. In multiple regressions, KIM-1 was associated with lower eGFR independently of diabetes duration (ß = -4.066; P < 0.0001) but not of AER. In our GWAS, rs2036402 in the KIM1 gene was strongly associated with KIM-1 (ß = -0.51; P = 6.5 × 10(-38)). In the MR, KIM-1 was associated with lower eGFR, independently of diabetes duration and AER (ß = -5.044; P = 0.040), suggesting a causal relationship. CONCLUSIONS: KIM-1 did not predict progression to end-stage renal disease independently of AER and added no prognostic benefit to current biomarkers. Nevertheless, the MR showed that the inverse association of increased KIM-1 levels with lower eGFR is likely to represent a causal link.

Urinary adiponectin is an independent predictor of progression to end-stage renal disease in patients with type 1 diabetes and diabetic nephropathy.

OBJECTIVE: We investigated the predictive value of urinary adiponectin (uADP) for the progression of diabetic nephropathy (DN) as well as for the principal determinants of uADP concentrations. RESEARCH DESIGN AND METHODS: uADP was measured in 2,090 patients with type 1 diabetes followed for a median of 5.8 (4.4-6.9) years and in 111 subjects without diabetes. Progression was defined as a change in albuminuria (albumin excretion rate [AER]) to a higher stage or development of end-stage renal disease (ESRD). Various Cox regression and competing risk models were used to evaluate the predictive value of uADP for DN progression. The added predictive benefit to AER or estimated glomerular filtration rate (eGFR) was estimated by the area under the receiver operating characteristic curve, integrated discrimination improvement (IDI), continuous net reclassification improvement (NRI), and other statistical indexes. The determinants of uADP were investigated by multiple regression analyses. RESULTS: uADP was an independent predictor of progression to ESRD (hazard ratio 1.60, P < 0.001) and was an even better predictor than AER (P = 0.04) or as good as eGFR (P = 0.79). Furthermore, uADP added a significant benefit when used together with AER (NRI 0.794, P = 0.03; IDI 0.115, P < 0.0001) or eGFR (NRI 0.637, P < 0.001; IDI 0.087, P < 0.0001). The common determinants of uADP were glycemic control, tubular injury, and AER. CONCLUSIONS: uADP is a strong independent predictor of DN progression from macroalbuminuria to ESRD and adds a significant predictive benefit to current biomarkers in patients with type 1 diabetes.

Leisure-time physical activity and development and progression of diabetic nephropathy in type 1 diabetes: the FinnDiane Study.

AIMS/HYPOTHESIS: The aim of this study was to assess how physical activity predicts the development and progression of diabetic nephropathy in patients with type 1 diabetes. METHODS: This prospective study (follow-up time 6.4 ± 3.1 years) included 1,390 patients (48.5% men, mean age 37.0 ± 12.4 years, duration of diabetes 20.4 ± 12.3 years) participating in the nationwide multicentre Finnish Diabetic Nephropathy (FinnDiane) Study. Leisure-time physical activity (LTPA) was assessed using a validated self-report questionnaire. Renal status was defined according to standard clinical cut-off values for urinary AER. RESULTS: The total amount of LTPA was not associated with progression in renal status. For the intensity of LTPA, however, the 10 year cumulative progression rate was 24.0% (95% CI 18.8, 28.8), 13.5% (95% CI 10.3, 16.6) or 13.1% (95% CI 10.3%, 16.6%; p = 0.01) of the patients with low, moderate or high intensity LTPA. This pattern was similar to that for the development of de novo microalbuminuria. Corresponding progression rates for LTPA frequency of <1, 1-2 or >2 sessions/week was 24.7% (95% CI 18.3, 30.7), 14.7% (95% CI 10.2, 19.0) or 12.6% (95% CI 9.4, 15.7), respectively (p = 0.003). CONCLUSIONS/INTERPRETATION: This study demonstrates for the first time in a prospective setting the relationship between physical activity and the risk of diabetic nephropathy in patients with type 1 diabetes. The data suggest that physical activity, and in particular its intensity, may have an impact on the initiation and progression of diabetic nephropathy in type 1 diabetes.

Different risk factor profiles for ischemic and hemorrhagic stroke in type 1 diabetes mellitus.

BACKGROUND AND PURPOSE: Despite the fact that patients with type 1 diabetes mellitus have a markedly increased risk of experiencing a stroke, independent risk factors for stroke and its subtypes in these patients have remained unclear. METHODS: A total of 4083 patients with type 1 diabetes mellitus from the Finnish Diabetic Nephropathy (FinnDiane) Study, without a history of stroke at baseline, were included. Strokes were classified based on medical files and brain imaging. At baseline, mean age was 37.4±11.8 years, duration of diabetes mellitus was 20.0 (11.0-30.0) years, and 51% were men. During 9.0±2.7 years (36 680 patient-years) of follow-up, 105 patients experienced an ischemic stroke and 44 a hemorrhagic stroke. Cox proportional hazards analyses were performed to determine independent risk factors. RESULTS: Independent risk factors for ischemic stroke were duration of diabetes mellitus, presence of diabetic nephropathy, higher hemoglobin A1c, higher systolic blood pressure, insulin resistance, and history of smoking, whereas sex, lipids, high-sensitivity C-reactive protein, and the metabolic syndrome were not associated with an increased risk. Diabetic nephropathy, severe diabetic retinopathy, higher systolic blood pressure, and lower body mass index were independently associated with hemorrhagic stroke. CONCLUSIONS: The risk factor profile for ischemic stroke seems partly different from that of hemorrhagic stroke in patients with type 1 diabetes mellitus.

Added value of soluble tumor necrosis factor-α receptor 1 as a biomarker of ESRD risk in patients with type 1 diabetes.

OBJECTIVE: Recent studies have suggested that circulating levels of the tumor necrosis factor-α receptor 1 (sTNFαR1) may be a useful predictor for the risk of end-stage renal disease (ESRD) in patients with diabetes. However, its potential utility as a biomarker has not been formally quantified. RESEARCH DESIGN AND METHODS: Circulating levels of sTNFαR1 were assessed in 429 patients with type 1 diabetes and overt nephropathy from the Finnish Diabetic Nephropathy (FinnDiane) cohort study. Predictors of incident ESRD over a median of 9.4 years of follow-up were determined by Cox regression and Fine-Gray competing risk analyses. The added value of sTNFαR1 was estimated via time-dependent receiver operating characteristic curves, net reclassification index (NRI), and integrated discrimination improvement (IDI) for survival data. RESULTS: A total of 130 individuals developed ESRD (28%; ESRD incidence rate of 3.4% per year). In cause-specific modeling, after adjusting for baseline renal status, predictors of increased incidence of ESRD in patients with overt nephropathy were an elevated HbA1c, shorter duration of diabetes, and circulating levels of sTNFαR1. Notably, sTNFαR1 outperformed estimated glomerular filtration rate in terms of R(2). Circulating levels of the sTNFαR1 also remained associated with ESRD after adjusting for the competing risk of death. A prediction model including sTNFαR1 (as a -0.5 fractional polynomial) was superior to a model without it, as demonstrated by better global fit, an increment of R(2), the C index, and area under the curve. Estimates of IDI and NRI(>0) were 0.22 (95% CI 0.16-0.28; P < 0.0001) and 0.98 (0.78-1.23; P < 0.0001), respectively. The median increment in the risk score after including sTNFαR1 in the prediction model was 0.18 (0.12-0.30; P < 0.0001). CONCLUSIONS: Circulating levels of sTNFαR1 are independently associated with the cumulative incidence of ESRD. This association is both significant and biologically plausible and appears to provide added value as a biomarker, based on the absolute values of NRI and IDI.

Different lipid variables predict incident coronary artery disease in patients with type 1 diabetes with or without diabetic nephropathy: the FinnDiane study.

OBJECTIVE: To study the ability of lipid variables to predict incident coronary artery disease (CAD) events in patients with type 1 diabetes at different stages of nephropathy. RESEARCH DESIGN AND METHODS: Patients (n = 3,520) with type 1 diabetes and available lipid profiles participating in the Finnish Diabetic Nephropathy Study (FinnDiane) were included in the study. During a follow-up period of 10.2 years (8.6-12.0), 310 patients suffered an incident CAD event. RESULTS: Apolipoprotein B (ApoB)/ApoA-I ratio was the strongest predictor of CAD in normoalbuminuric patients (hazard ratio 1.43 [95% CI 1.17-1.76] per one SD increase), and ApoB was the strongest in macroalbuminuric patients (1.47 [1.19-1.81]). Similar results were seen when patients were stratified by sex or glycemic control. LDL cholesterol was a poor predictor of CAD in women, normoalbuminuric patients, and patients with HbA1c below the median (8.3%, 67 mmol/L). The current recommended triglyceride cutoff of 1.7 mmol/L failed to predict CAD in normoalbuminuric patients, whereas the cohort median 0.94 mmol/L predicted incident CAD events. CONCLUSIONS: In patients with type 1 diabetes, the predictive ability of the lipid variables differed substantially depending on the patient's sex, renal status, and glycemic control. In normoalbuminuric patients, the ratios of atherogenic and antiatherogenic lipoproteins and lipids were the strongest predictors of an incident CAD event, whereas in macroalbuminuric patients, no added benefit was gained from the ratios. Current treatment recommendations may need to be revised to capture residual CAD risk in patients with type 1 diabetes.

Novel genetic susceptibility loci for diabetic end-stage renal disease identified through robust naive Bayes classification.

AIMS/HYPOTHESIS: Diabetic nephropathy is a major diabetic complication, and diabetes is the leading cause of end-stage renal disease (ESRD). Family studies suggest a hereditary component for diabetic nephropathy. However, only a few genes have been associated with diabetic nephropathy or ESRD in diabetic patients. Our aim was to detect novel genetic variants associated with diabetic nephropathy and ESRD. METHODS: We exploited a novel algorithm, 'Bag of Naive Bayes', whose marker selection strategy is complementary to that of conventional genome-wide association models based on univariate association tests. The analysis was performed on a genome-wide association study of 3,464 patients with type 1 diabetes from the Finnish Diabetic Nephropathy (FinnDiane) Study and subsequently replicated with 4,263 type 1 diabetes patients from the Steno Diabetes Centre, the All Ireland-Warren 3-Genetics of Kidneys in Diabetes UK collection (UK-Republic of Ireland) and the Genetics of Kidneys in Diabetes US Study (GoKinD US). RESULTS: Five genetic loci (WNT4/ZBTB40-rs12137135, RGMA/MCTP2-rs17709344, MAPRE1P2-rs1670754, SEMA6D/SLC24A5-rs12917114 and SIK1-rs2838302) were associated with ESRD in the FinnDiane study. An association between ESRD and rs17709344, tagging the previously identified rs12437854 and located between the RGMA and MCTP2 genes, was replicated in independent case-control cohorts. rs12917114 near SEMA6D was associated with ESRD in the replication cohorts under the genotypic model (p < 0.05), and rs12137135 upstream of WNT4 was associated with ESRD in Steno. CONCLUSIONS/INTERPRETATION: This study supports the previously identified findings on the RGMA/MCTP2 region and suggests novel susceptibility loci for ESRD. This highlights the importance of applying complementary statistical methods to detect novel genetic variants in diabetic nephropathy and, in general, in complex diseases.

Genome-wide association study of urinary albumin excretion rate in patients with type 1 diabetes.

AIMS/HYPOTHESIS: An abnormal urinary albumin excretion rate (AER) is often the first clinically detectable manifestation of diabetic nephropathy. Our aim was to estimate the heritability and to detect genetic variation associated with elevated AER in patients with type 1 diabetes. METHODS: The discovery phase genome-wide association study (GWAS) included 1,925 patients with type 1 diabetes and with data on 24 h AER. AER was analysed as a continuous trait and the analysis was stratified by the use of antihypertensive medication. Signals with a p value <10(-4) were followed up in 3,750 additional patients with type 1 diabetes from seven studies. RESULTS: The narrow-sense heritability, captured with our genotyping platform, was estimated to explain 27.3% of the total AER variability, and 37.6% after adjustment for covariates. In the discovery stage, five single nucleotide polymorphisms in the GLRA3 gene were strongly associated with albuminuria (p < 5 × 10(-8)). In the replication group, a nominally significant association (p = 0.035) was observed between albuminuria and rs1564939 in GLRA3, but this was in the opposite direction. Sequencing of the surrounding genetic region in 48 Finnish and 48 UK individuals supported the possibility that population-specific rare variants contribute to the synthetic association observed at the common variants in GLRA3. The strongest replication (p = 0.026) was obtained for rs2410601 between the PSD3 and SH2D4A genes. Pathway analysis highlighted natural killer cell mediated immunity processes. CONCLUSIONS/INTERPRETATION: This study suggests novel pathways and molecular mechanisms for the pathogenesis of albuminuria in type 1 diabetes.

Association of dietary sodium intake with atherogenesis in experimental diabetes and with cardiovascular disease in patients with Type 1 diabetes.

It is recommended that individuals with diabetes restrict their dietary sodium intake. However, although salt intake is correlated with BP (blood pressure), it also partly determines the activation state of the RAAS (renin-angiotensin-aldosterone system), a key mediator of diabetes-associated atherosclerosis. apoE KO (apolipoprotein E knockout) mice were allocated for the induction of diabetes with streptozotocin or citrate buffer (controls) and further randomized to isocaloric diets containing 0.05%, 0.3% or 3.1% sodium with or without the ACEi [ACE (angiotensin-converting enzyme) inhibitor] perindopril. After 6 weeks of study, plaque accumulation was quantified and markers of atherogenesis were assessed using RT-PCR (reverse transcription-PCR) and ELISA. The association of sodium intake and adverse cardiovascular and mortality outcomes were explored in 2648 adults with Type 1 diabetes without prior CVD (cardiovascular disease) from the FinnDiane study. A 0.05% sodium diet was associated with increased plaque accumulation in diabetic apoE KO mice, associated with activation of the RAAS. By contrast, a diet containing 3.1% sodium suppressed atherogenesis associated with suppression of the RAAS, with an efficacy comparable with ACE inhibition. In adults with Type 1 diabetes, low sodium intake was also associated with an increased risk of all-cause mortality and new-onset cardiovascular events. However, high sodium intake was also associated with adverse outcomes, leading to a J-shaped relationship overall. Although BP lowering is an important goal for the management of diabetes, off-target actions to activate the RAAS may contribute to an observed lack of protection from cardiovascular complications in patients with Type 1 diabetes with low sodium intake.

Sense of coherence, food selection and leisure time physical activity in type 1 diabetes.

BACKGROUND: Successful management of type 1 diabetes depends on the self-care practices. Sense of coherence has been associated with various measures of lifestyle choices. We aimed to study the associations between sense of coherence and self-care practices in patients with type 1 diabetes. We hypothesized that patients with weak sense of coherence have less prudent food choices and lower physical activity. METHODS: Cross-sectional data from 1104 patients (44% men, mean age 45±12 years) from the FinnDiane Study were available. Sense of coherence, dietary intake, and leisure time physical activity were evaluated using self-reported questionnaires. Diet score was calculated based on the degree to which food choices complied with dietary guidelines. Weekly metabolic equivalent hours were calculated by multiplying the activity duration by the activity- and intensity-specific metabolic equivalent. RESULTS: The sense of coherence score correlated positively both with the diet score and the weekly metabolic equivalent hours. Those in the lowest sense of coherence tertile had both the lowest diet scores and the lowest weekly metabolic equivalent hours values. Among women, the sense of coherence score was associated with the diet score when adjusted for age, socioeconomic status, received dietary guidance, and nephropathy status. The sense of coherence score independently predicted the metabolic equivalent hours value in men. CONCLUSIONS: A higher sense of coherence score predicted more prudent food choices in women and higher physical activity in men. In the future, the health consequences associated with a weak sense of coherence should be studied prospectively. Also, the possibility to use the sense of coherence questionnaire as a screening instrument to identify patients who could benefit from intensified counseling should be investigated.

New susceptibility loci associated with kidney disease in type 1 diabetes.

Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genome-wide association studies (GWAS) of T1D DN comprising ~2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2 × 10(-8)) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0 × 10(-9)). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-ß1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1 × 10(-7)), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN.

Association testing of previously reported variants in a large case-control meta-analysis of diabetic nephropathy.

We formed the GEnetics of Nephropathy-an International Effort (GENIE) consortium to examine previously reported genetic associations with diabetic nephropathy (DN) in type 1 diabetes. GENIE consists of 6,366 similarly ascertained participants of European ancestry with type 1 diabetes, with and without DN, from the All Ireland-Warren 3-Genetics of Kidneys in Diabetes U.K. and Republic of Ireland (U.K.-R.O.I.) collection and the Finnish Diabetic Nephropathy Study (FinnDiane), combined with reanalyzed data from the Genetics of Kidneys in Diabetes U.S. Study (U.S. GoKinD). We found little evidence for the association of the EPO promoter polymorphism, rs161740, with the combined phenotype of proliferative retinopathy and end-stage renal disease in U.K.-R.O.I. (odds ratio [OR] 1.14, P = 0.19) or FinnDiane (OR 1.06, P = 0.60). However, a fixed-effects meta-analysis that included the previously reported cohorts retained a genome-wide significant association with that phenotype (OR 1.31, P = 2 × 10(-9)). An expanded investigation of the ELMO1 locus and genetic regions reported to be associated with DN in the U.S. GoKinD yielded only nominal statistical significance for these loci. Finally, top candidates identified in a recent meta-analysis failed to reach genome-wide significance. In conclusion, we were unable to replicate most of the previously reported genetic associations for DN, and significance for the EPO promoter association was attenuated.

Circulating ACE2 activity is increased in patients with type 1 diabetes and vascular complications.

OBJECTIVE: Angiotensin-converting enzyme 2 (ACE2) is a homolog of ACE that counterbalances the actions of angiotensin (AT)II and promotes vasodilatation. Circulating ACE2 activity is increased in diabetes in experimental models. The role of ACE2 in human pathophysiology is unknown. We examined whether ACE2 activity is altered in patients with type 1 diabetes (T1D), with and without diabetic nephropathy. METHODS: Quantitative ACE2 activity in serum was measured by a fluorometric assay in 859 patients with T1D in the Finnish Diabetic Nephropathy (FinnDiane) study and in 204 healthy controls. Pulse-wave analysis with augmentation index (AIx) measurement was performed in 319 patients with T1D and 114 controls. RESULTS: ACE2 activity was increased in men with T1D and microalbuminuria (30.2 ±â€Š1.5 ngE/ml) when compared to patients without albuminuria (27.0 ±â€Š0.5 ngE/ml, P < 0.05) or controls (25.6 ±â€Š0.8 ngE/ml, P < 0.05). ACE2 activity was increased in male and female patients who were on ACE inhibitor (ACEi) treatment, also independently of albuminuria. Male and female patients with coronary heart disease (CHD) had significantly increased ACE2 activity (35.5 ±â€Š2.5 vs. 27.0 ±â€Š0.5 ngE/ml, P < 0.001 among male T1D patients vs. male controls). ACE2 activity correlated positively with systolic blood pressure (rs = 0.175, P < 0.001), AIx (rs = 0.191, P = 0.010) and diabetes duration (rs = 0.198, P < 0.001), and negatively with estimated glomerular filtration rate (rs = -0.109, P = 0.016) among male T1D patients. CONCLUSIONS: ACE2 activity increases with increasing vascular tone and when the patient with T1D has microvascular or macrovascular disease, indicating that ACE2 may participate as a compensatory mechanism in the regulation of vascular and renal function in patients with T1D.