Johan Wadén | University of Helsinki (original) (raw)

Papers by Johan Wadén

Diabetologia, 2011

Aims/hypothesis This study examined sex-related differences in the cumulative risk of proliferati... more Aims/hypothesis This study examined sex-related differences in the cumulative risk of proliferative retinopathy (PR) and end-stage renal disease (ESRD) over 40 years of duration of type 1 diabetes according to age at diabetes onset. Methods We assessed 4,416 patients from the Finnish Diabetic Nephropathy Study population. Kaplan-Meier analysis was used to provide cumulative incidence rates and Cox regression analyses for HRs. Results There were no sex-related differences in the cumulative incidence of ESRD in patients diagnosed with type 1 diabetes between 0 to 4 and 5 to 9 years. Thereafter the risk started to diverge. The cumulative incidence of ESRD in patients diagnosed between 10 to 14 and ≥15 years was 17.4% (95% CI 13.4-21.2) and 13.0% (9.6-16.2) respectively in women, while in men it was 32.2% (28.0-36.1) and 24.6% (20.8-28.1) respectively. The respective HRs were (onset at 10 to 14 years) 1.9 (p<0.0001) and (onset at ≥15 years) 1.8 (p<0.001), respectively. There was no difference in the risk of PR between men and women diagnosed between 0 and 4 years of age, but progressive sex-related differences in the cumulative incidence of PR were observed with increasing age at onset. The HRs for men in the age-at-onset groups 5 to 9, 10 to 14 and ≥15 years of age were 1.3 (95% CI 1.0-1.6), 1.3 (1.1-1.6) and 2.1 (1.6-2.6) compared with women in these groups, respectively. Conclusions/interpretation The difference between the sexes with regard to risk of diabetic microvascular complications is highly dependent on the age at onset of diabetes. The risk of ESRD and PR risk doubled in men compared with women when age at onset was ≥15 years.

Diabetes care, 2005

The aim of this study was to estimate the prevalence of the metabolic syndrome in Finnish type 1 ... more The aim of this study was to estimate the prevalence of the metabolic syndrome in Finnish type 1 diabetic patients and to assess whether it is associated with diabetic nephropathy or poor glycemic control. In all, 2,415 type 1 diabetic patients (51% men, mean age 37 years, duration of diabetes 22 years) participating in the nationwide, multicenter Finnish Diabetic Nephropathy (FinnDiane) study were included. Metabolic syndrome was defined according to the National Cholesterol Education Program diagnostic criteria. Patients were classified as having normal albumin excretion rate (AER) (n = 1,261), microalbuminuria (n = 326), macroalbuminuria (n = 383), or end-stage renal disease (ESRD) (n = 164). Glycemic control was classified as good (HbA1c <7.5%), intermediate (7.5-9.0%), or poor (>9.0%). Creatinine clearance was estimated with the Cockcroft-Gault formula. The overall prevalence of metabolic syndrome was 38% in men and 40% in women. The prevalence was 28% in those with norma...

Diabetes Care, 2015

We evaluated the predictive value and clinical benefit of urinary kidney injury molecule (KIM)-1 ... more 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. 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. 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 (β = -4.066; P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001) but not of AER. In our GWAS, rs2036402 in the KIM1 gene was strongly associated with KIM-1 (β = -0.51; P = 6.5 × 10(-38)). In the MR, KIM-1 was associated with lower eGFR, independently of diabetes duration and AER (β = -5.044; P = 0.040), suggesting a causal relationship. 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.

Diabetes Care, 2015

We investigated the predictive value of urinary adiponectin (uADP) for the progression of diabeti... more 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. 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. uADP was an independent predictor of progression to ESRD (hazard ratio 1.60, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 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 &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001) or eGFR (NRI 0.637, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001; IDI 0.087, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001). The common determinants of uADP were glycemic control, tubular injury, and AER. 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.

Diabetes Care, 2014

Recent studies have suggested that circulating levels of the tumor necrosis factora receptor 1 (s... more Recent studies have suggested that circulating levels of the tumor necrosis factora receptor 1 (sTNFaR 1 ) 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.

Diabetes Care, 2014

To study the ability of lipid variables to predict incident coronary artery disease (CAD) events ... more 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. 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. 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. In patients with type 1 diabetes, the predictive ability of the lipid variables differed substantially depending on the patient&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;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.

Stroke, 2014

Background and Purpose-Despite the fact that patients with type 1 diabetes mellitus have a marked... more 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 A 1c , 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. (Stroke. 2014;45:2558-2562.) The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/

Diabetologia, Jan 30, 2015

The aim of this study was to assess how physical activity predicts the development and progressio... more 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. 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. 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. Correspondi...

Medicine & Science in Sports & Exercise, 2009

Journal of the American Society of Nephrology, 2011

Patients with both type 1 diabetes and CKD have an increased risk of adverse outcomes. The compet... more Patients with both type 1 diabetes and CKD have an increased risk of adverse outcomes. The competing risks of death and ESRD may confound the estimates of risk for each outcome. Here, we sought to determine the major predictors of the cumulative incidence of ESRD and pre-ESRD mortality in patients with type 1 diabetes and macroalbuminuria while incorporating the competing risk for the alternate outcome into a Fine-Gray competing-risks analysis. We followed 592 patients with macroalbuminuria for a median of 9.9 years. During this time, 56 (9.5%) patients died and 210 (35.5%) patients developed ESRD. Predictors of incident ESRD, taking baseline renal function and the competing risk for death into account, included an elevated HbA 1c , elevated LDL cholesterol, male sex, weight-adjusted insulin dose, and a shorter duration of diabetes. By contrast, predictors of pre-ESRD death, taking baseline renal function and the competing risk for ESRD into account, included only age, the presence of established macrovascular disease, and elevated cholesterol levels. This competing-risks approach has potential to highlight the appropriate targets and strategies for preventing premature mortality in patients with type 1 diabetes.

Journal of Hypertension, 2012

Angiotensin-converting enzyme 2 (ACE2) is a homolog of ACE that counterbalances the actions of an... more 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. 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. ACE2 activity was increased in men with T1D and microalbuminuria (30.2 ± 1.5 ngE/ml) when compared to patients without albuminuria (27.0 ± 0.5 ngE/ml, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05) or controls (25.6 ± 0.8 ngE/ml, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 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 ± 2.5 vs. 27.0 ± 0.5 ngE/ml, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001 among male T1D patients vs. male controls). ACE2 activity correlated positively with systolic blood pressure (rs = 0.175, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001), AIx (rs = 0.191, P = 0.010) and diabetes duration (rs = 0.198, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001), and negatively with estimated glomerular filtration rate (rs = -0.109, P = 0.016) among male T1D patients. 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.

Diabetologia, 2014

An abnormal urinary albumin excretion rate (AER) is often the first clinically detectable manifes... more 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. 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 &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;10(-4) were followed up in 3,750 additional patients with type 1 diabetes from seven studies. 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 &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 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. This study suggests novel pathways and molecular mechanisms for the pathogenesis of albuminuria in type 1 diabetes.

Diabetologia, 2009

Aims/hypothesis We studied the impact of baseline lipid variables on the progression of renal dis... more Aims/hypothesis We studied the impact of baseline lipid variables on the progression of renal disease in a large nationwide prospective cohort of patients with type 1 diabetes. Methods A total of 2,304 adult patients with type 1 diabetes and available lipid profiles participating in the Finnish Diabetic Nephropathy Study (FinnDiane) were evaluated. Data on progression of renal disease were verified from medical files and patients were followed for 5.4±2.0 (mean ± SD) years. Results High triacylglycerol, apolipoprotein (Apo) B, ApoA-II and HDL 3 -cholesterol concentrations predicted incident microalbuminuria. Progression to macroalbuminuria was predicted by high triacylglycerol and ApoB. When AER was entered into the model, triacylglycerol was no longer an independent predictor, but when patients with normal AER and microalbuminuria at baseline were pooled, triacylglycerol, HbA 1c , male sex and AER were all independent predictors of renal disease. High total cholesterol, LDLcholesterol, non-HDL-cholesterol and triacylglycerol as well as low HDL-cholesterol, HDL 2 -cholesterol, ApoA-I and ApoA-II concentrations were predictive of progression to end-stage renal disease. However, when estimated GFR was entered into the model, only total cholesterol remained an independent predictor of progression. Conclusions/interpretation Lipid abnormalities, particularly high triacylglycerol concentrations, increase the risk of progression of renal disease.

Diabetologia, 2007

Aims/hypothesis We studied the relationship between the lipid profile, estimated GFR (eGFR) and A... more Aims/hypothesis We studied the relationship between the lipid profile, estimated GFR (eGFR) and AER in patients with type 1 diabetes. We also assessed the association between the lipid profile and glycaemic control, obesity and hypertension in an environment free of manifest renal disease, as well as exploring how well the patients would have achieved the targets set in international guidelines. Methods A total of 2,927 adult patients who had type 1 diabetes and for whom lipid profiles were available were included from people participating in the nationwide, multicentre Finnish Diabetic Nephropathy Study (FinnDiane). eGFR was determined using the Cockcroft-Gault formula adjusted for body surface area. Results Patients with impaired renal function (eGFR <60 ml min −1 1.73 m −2 ) had higher total cholesterol, triacylglycerol and apolipoprotein B, and lower HDLcholesterol concentrations than patients with normal renal function (eGFR >90 ml min −1 1.73 m −2 ) or mildly impaired renal function (eGFR 60-90 ml min −1

Diabetologia, 2009

Aims/hypothesis Cardiac autonomic neuropathy is associated with increased morbidity and mortality... more Aims/hypothesis Cardiac autonomic neuropathy is associated with increased morbidity and mortality rates in patients with type 1 diabetes. The prevalence of early autonomic abnormalities is relatively high compared with the frequency of manifest clinical abnormalities. Thus, early autonomic dysfunction could to some extent be functional and might lead to an organic disease in a subgroup of patients only. If this is true, manoeuvres such as slow deep-breathing, which can improve baroreflex sensitivity (BRS) in normal but not in denervated hearts, could also modify autonomic modulation in patients with type 1 diabetes, despite autonomic dysfunction.

Diabetologia, 2013

Aims/hypothesis This study aimed to investigate whether variation in long-term glycaemia in type ... more Aims/hypothesis This study aimed to investigate whether variation in long-term glycaemia in type 1 diabetes as measured by HbA 1c variability is associated with the cumulative incidence and risk of retinopathy requiring laser treatment. Methods The effect of HbA 1c variability was assessed in 2,019 Finnish Diabetic Nephropathy (FinnDiane) study patients. The patients were studied in two partially overlapping subcohorts with either verified first laser treatment (n=1,459) or retinopathy severity graded from ophthalmic records with the Early Treatment of Diabetic Retinopathy Study (ETDRS) scale (n=1,346). The ratio of intrapersonal SD and mean of serially measured HbA 1c was considered an estimate of HbA 1c variability.

Diabetologia, 2010

Aims/hypothesis We studied the impact of a family history of type 2 diabetes on physical fitness,... more Aims/hypothesis We studied the impact of a family history of type 2 diabetes on physical fitness, lifestyle factors and diabetes-related metabolic factors. Methods The Prevalence, Prediction and Prevention of Diabetes (PPP)-Botnia study is a population-based study in Western Finland, which includes a random sample of 5,208 individuals aged 18 to 75 years identified through the national Finnish Population Registry. Physical activity, dietary habits and family history of type 2 diabetes were assessed by questionnaires and physical fitness by a validated 2 km walking test. Insulin secretion and action were assessed based upon OGTT measurements of insulin and glucose. Results A family history of type 2 diabetes was associated with a 2.4-fold risk of diabetes and lower physical fitness (maximal aerobic capacity 29.2±7.2 vs 32.1±7.0, p=0.01) despite having similar reported physical activity to that of individuals with no family history. The same individuals also had reduced insulin secretion adjusted for insulin resistance, i.e. disposition index (p<0.001) despite having higher BMI (27.4±4.6 vs 26.0±4.3 kg/m 2 , p<0.001).

Diabetes Care, 2008

The purpose of this study was to elucidate whether serum adiponectin is associated with progressi... more The purpose of this study was to elucidate whether serum adiponectin is associated with progression of diabetic nephropathy in type 1 diabetic patients. This was a prospective follow-up study as a part of the nationwide Finnish Diabetic Nephropathy Study; 1,330 type 1 diabetic patients were followed for 5.0 +/- 2.2 years. Patients were divided at baseline into three groups according to their urinary albumin excretion rate (AER) in three consecutive overnight or 24-h urine collections: 818 patients with normoalbuminuria (AER &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;20 microg/min), 216 patients with microalbuminuria (20 microg/min &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;or= AER &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 200 microg/min), and 296 patients with macroalbuminuria (AER &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;or=200 microg/min). Progression of albuminuria was the main outcome. Adiponectin was measured by a time-resolved immunofluorometric assay, and the values were log-transformed and adjusted for age, BMI, and sex before analysis. Progression either to the next albuminuria level or to end-stage renal disease (ESRD) occurred in 193 patients. No difference in adiponectin concentrations was observed between progressors and nonprogressors in patients with normoalbuminuria or microalbuminuria. In the patients with macroalbuminuria, progression to ESRD was associated with higher adiponectin in the entire group (23.4 +/- 17.1 vs. 16.0 +/- 8.5 mg/l, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001) and in men (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001) and women (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001) separately. Progression to ESRD was also associated with systolic blood pressure, insulin dose, A1C, serum cholesterol, serum triglycerides, AER, and estimated glomerular filtration rate (eGFR). When these covariates were inserted in a Cox regression analysis, A1C, triglycerides, eGFR, and adiponectin were significantly associated with progression from macroalbuminuria. Increased serum adiponectin levels predict the progression from macroalbuminuria to ESRD in type 1 diabetic patients.

Diabetes Care, 2009

OBJECTIVE -The purpose of this study was to study the association between a parental history of t... more OBJECTIVE -The purpose of this study was to study the association between a parental history of type 2 diabetes and the metabolic profile as well as the presence of the metabolic syndrome and diabetes complications in patients with type 1 diabetes.

Diabetes Care, 2011

OBJECTIVE-Many guidelines recommend reduced consumption of salt in patients with type 1 diabetes,... more OBJECTIVE-Many guidelines recommend reduced consumption of salt in patients with type 1 diabetes, but it is unclear whether dietary sodium intake is associated with mortality and endstage renal disease (ESRD).

Diabetologia, 2011

Aims/hypothesis This study examined sex-related differences in the cumulative risk of proliferati... more Aims/hypothesis This study examined sex-related differences in the cumulative risk of proliferative retinopathy (PR) and end-stage renal disease (ESRD) over 40 years of duration of type 1 diabetes according to age at diabetes onset. Methods We assessed 4,416 patients from the Finnish Diabetic Nephropathy Study population. Kaplan-Meier analysis was used to provide cumulative incidence rates and Cox regression analyses for HRs. Results There were no sex-related differences in the cumulative incidence of ESRD in patients diagnosed with type 1 diabetes between 0 to 4 and 5 to 9 years. Thereafter the risk started to diverge. The cumulative incidence of ESRD in patients diagnosed between 10 to 14 and ≥15 years was 17.4% (95% CI 13.4-21.2) and 13.0% (9.6-16.2) respectively in women, while in men it was 32.2% (28.0-36.1) and 24.6% (20.8-28.1) respectively. The respective HRs were (onset at 10 to 14 years) 1.9 (p<0.0001) and (onset at ≥15 years) 1.8 (p<0.001), respectively. There was no difference in the risk of PR between men and women diagnosed between 0 and 4 years of age, but progressive sex-related differences in the cumulative incidence of PR were observed with increasing age at onset. The HRs for men in the age-at-onset groups 5 to 9, 10 to 14 and ≥15 years of age were 1.3 (95% CI 1.0-1.6), 1.3 (1.1-1.6) and 2.1 (1.6-2.6) compared with women in these groups, respectively. Conclusions/interpretation The difference between the sexes with regard to risk of diabetic microvascular complications is highly dependent on the age at onset of diabetes. The risk of ESRD and PR risk doubled in men compared with women when age at onset was ≥15 years.

Diabetes care, 2005

The aim of this study was to estimate the prevalence of the metabolic syndrome in Finnish type 1 ... more The aim of this study was to estimate the prevalence of the metabolic syndrome in Finnish type 1 diabetic patients and to assess whether it is associated with diabetic nephropathy or poor glycemic control. In all, 2,415 type 1 diabetic patients (51% men, mean age 37 years, duration of diabetes 22 years) participating in the nationwide, multicenter Finnish Diabetic Nephropathy (FinnDiane) study were included. Metabolic syndrome was defined according to the National Cholesterol Education Program diagnostic criteria. Patients were classified as having normal albumin excretion rate (AER) (n = 1,261), microalbuminuria (n = 326), macroalbuminuria (n = 383), or end-stage renal disease (ESRD) (n = 164). Glycemic control was classified as good (HbA1c <7.5%), intermediate (7.5-9.0%), or poor (>9.0%). Creatinine clearance was estimated with the Cockcroft-Gault formula. The overall prevalence of metabolic syndrome was 38% in men and 40% in women. The prevalence was 28% in those with norma...

Diabetes Care, 2015

We evaluated the predictive value and clinical benefit of urinary kidney injury molecule (KIM)-1 ... more 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. 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. 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 (β = -4.066; P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001) but not of AER. In our GWAS, rs2036402 in the KIM1 gene was strongly associated with KIM-1 (β = -0.51; P = 6.5 × 10(-38)). In the MR, KIM-1 was associated with lower eGFR, independently of diabetes duration and AER (β = -5.044; P = 0.040), suggesting a causal relationship. 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.

Diabetes Care, 2015

We investigated the predictive value of urinary adiponectin (uADP) for the progression of diabeti... more 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. 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. uADP was an independent predictor of progression to ESRD (hazard ratio 1.60, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 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 &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001) or eGFR (NRI 0.637, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001; IDI 0.087, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001). The common determinants of uADP were glycemic control, tubular injury, and AER. 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.

Diabetes Care, 2014

Recent studies have suggested that circulating levels of the tumor necrosis factora receptor 1 (s... more Recent studies have suggested that circulating levels of the tumor necrosis factora receptor 1 (sTNFaR 1 ) 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.

Diabetes Care, 2014

To study the ability of lipid variables to predict incident coronary artery disease (CAD) events ... more 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. 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. 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. In patients with type 1 diabetes, the predictive ability of the lipid variables differed substantially depending on the patient&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;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.

Stroke, 2014

Background and Purpose-Despite the fact that patients with type 1 diabetes mellitus have a marked... more 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 A 1c , 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. (Stroke. 2014;45:2558-2562.) The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/

Diabetologia, Jan 30, 2015

The aim of this study was to assess how physical activity predicts the development and progressio... more 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. 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. 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. Correspondi...

Medicine & Science in Sports & Exercise, 2009

Journal of the American Society of Nephrology, 2011

Patients with both type 1 diabetes and CKD have an increased risk of adverse outcomes. The compet... more Patients with both type 1 diabetes and CKD have an increased risk of adverse outcomes. The competing risks of death and ESRD may confound the estimates of risk for each outcome. Here, we sought to determine the major predictors of the cumulative incidence of ESRD and pre-ESRD mortality in patients with type 1 diabetes and macroalbuminuria while incorporating the competing risk for the alternate outcome into a Fine-Gray competing-risks analysis. We followed 592 patients with macroalbuminuria for a median of 9.9 years. During this time, 56 (9.5%) patients died and 210 (35.5%) patients developed ESRD. Predictors of incident ESRD, taking baseline renal function and the competing risk for death into account, included an elevated HbA 1c , elevated LDL cholesterol, male sex, weight-adjusted insulin dose, and a shorter duration of diabetes. By contrast, predictors of pre-ESRD death, taking baseline renal function and the competing risk for ESRD into account, included only age, the presence of established macrovascular disease, and elevated cholesterol levels. This competing-risks approach has potential to highlight the appropriate targets and strategies for preventing premature mortality in patients with type 1 diabetes.

Journal of Hypertension, 2012

Angiotensin-converting enzyme 2 (ACE2) is a homolog of ACE that counterbalances the actions of an... more 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. 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. ACE2 activity was increased in men with T1D and microalbuminuria (30.2 ± 1.5 ngE/ml) when compared to patients without albuminuria (27.0 ± 0.5 ngE/ml, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05) or controls (25.6 ± 0.8 ngE/ml, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 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 ± 2.5 vs. 27.0 ± 0.5 ngE/ml, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001 among male T1D patients vs. male controls). ACE2 activity correlated positively with systolic blood pressure (rs = 0.175, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001), AIx (rs = 0.191, P = 0.010) and diabetes duration (rs = 0.198, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001), and negatively with estimated glomerular filtration rate (rs = -0.109, P = 0.016) among male T1D patients. 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.

Diabetologia, 2014

An abnormal urinary albumin excretion rate (AER) is often the first clinically detectable manifes... more 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. 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 &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;10(-4) were followed up in 3,750 additional patients with type 1 diabetes from seven studies. 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 &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 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. This study suggests novel pathways and molecular mechanisms for the pathogenesis of albuminuria in type 1 diabetes.

Diabetologia, 2009

Aims/hypothesis We studied the impact of baseline lipid variables on the progression of renal dis... more Aims/hypothesis We studied the impact of baseline lipid variables on the progression of renal disease in a large nationwide prospective cohort of patients with type 1 diabetes. Methods A total of 2,304 adult patients with type 1 diabetes and available lipid profiles participating in the Finnish Diabetic Nephropathy Study (FinnDiane) were evaluated. Data on progression of renal disease were verified from medical files and patients were followed for 5.4±2.0 (mean ± SD) years. Results High triacylglycerol, apolipoprotein (Apo) B, ApoA-II and HDL 3 -cholesterol concentrations predicted incident microalbuminuria. Progression to macroalbuminuria was predicted by high triacylglycerol and ApoB. When AER was entered into the model, triacylglycerol was no longer an independent predictor, but when patients with normal AER and microalbuminuria at baseline were pooled, triacylglycerol, HbA 1c , male sex and AER were all independent predictors of renal disease. High total cholesterol, LDLcholesterol, non-HDL-cholesterol and triacylglycerol as well as low HDL-cholesterol, HDL 2 -cholesterol, ApoA-I and ApoA-II concentrations were predictive of progression to end-stage renal disease. However, when estimated GFR was entered into the model, only total cholesterol remained an independent predictor of progression. Conclusions/interpretation Lipid abnormalities, particularly high triacylglycerol concentrations, increase the risk of progression of renal disease.

Diabetologia, 2007

Aims/hypothesis We studied the relationship between the lipid profile, estimated GFR (eGFR) and A... more Aims/hypothesis We studied the relationship between the lipid profile, estimated GFR (eGFR) and AER in patients with type 1 diabetes. We also assessed the association between the lipid profile and glycaemic control, obesity and hypertension in an environment free of manifest renal disease, as well as exploring how well the patients would have achieved the targets set in international guidelines. Methods A total of 2,927 adult patients who had type 1 diabetes and for whom lipid profiles were available were included from people participating in the nationwide, multicentre Finnish Diabetic Nephropathy Study (FinnDiane). eGFR was determined using the Cockcroft-Gault formula adjusted for body surface area. Results Patients with impaired renal function (eGFR <60 ml min −1 1.73 m −2 ) had higher total cholesterol, triacylglycerol and apolipoprotein B, and lower HDLcholesterol concentrations than patients with normal renal function (eGFR >90 ml min −1 1.73 m −2 ) or mildly impaired renal function (eGFR 60-90 ml min −1

Diabetologia, 2009

Aims/hypothesis Cardiac autonomic neuropathy is associated with increased morbidity and mortality... more Aims/hypothesis Cardiac autonomic neuropathy is associated with increased morbidity and mortality rates in patients with type 1 diabetes. The prevalence of early autonomic abnormalities is relatively high compared with the frequency of manifest clinical abnormalities. Thus, early autonomic dysfunction could to some extent be functional and might lead to an organic disease in a subgroup of patients only. If this is true, manoeuvres such as slow deep-breathing, which can improve baroreflex sensitivity (BRS) in normal but not in denervated hearts, could also modify autonomic modulation in patients with type 1 diabetes, despite autonomic dysfunction.

Diabetologia, 2013

Aims/hypothesis This study aimed to investigate whether variation in long-term glycaemia in type ... more Aims/hypothesis This study aimed to investigate whether variation in long-term glycaemia in type 1 diabetes as measured by HbA 1c variability is associated with the cumulative incidence and risk of retinopathy requiring laser treatment. Methods The effect of HbA 1c variability was assessed in 2,019 Finnish Diabetic Nephropathy (FinnDiane) study patients. The patients were studied in two partially overlapping subcohorts with either verified first laser treatment (n=1,459) or retinopathy severity graded from ophthalmic records with the Early Treatment of Diabetic Retinopathy Study (ETDRS) scale (n=1,346). The ratio of intrapersonal SD and mean of serially measured HbA 1c was considered an estimate of HbA 1c variability.

Diabetologia, 2010

Aims/hypothesis We studied the impact of a family history of type 2 diabetes on physical fitness,... more Aims/hypothesis We studied the impact of a family history of type 2 diabetes on physical fitness, lifestyle factors and diabetes-related metabolic factors. Methods The Prevalence, Prediction and Prevention of Diabetes (PPP)-Botnia study is a population-based study in Western Finland, which includes a random sample of 5,208 individuals aged 18 to 75 years identified through the national Finnish Population Registry. Physical activity, dietary habits and family history of type 2 diabetes were assessed by questionnaires and physical fitness by a validated 2 km walking test. Insulin secretion and action were assessed based upon OGTT measurements of insulin and glucose. Results A family history of type 2 diabetes was associated with a 2.4-fold risk of diabetes and lower physical fitness (maximal aerobic capacity 29.2±7.2 vs 32.1±7.0, p=0.01) despite having similar reported physical activity to that of individuals with no family history. The same individuals also had reduced insulin secretion adjusted for insulin resistance, i.e. disposition index (p<0.001) despite having higher BMI (27.4±4.6 vs 26.0±4.3 kg/m 2 , p<0.001).

Diabetes Care, 2008

The purpose of this study was to elucidate whether serum adiponectin is associated with progressi... more The purpose of this study was to elucidate whether serum adiponectin is associated with progression of diabetic nephropathy in type 1 diabetic patients. This was a prospective follow-up study as a part of the nationwide Finnish Diabetic Nephropathy Study; 1,330 type 1 diabetic patients were followed for 5.0 +/- 2.2 years. Patients were divided at baseline into three groups according to their urinary albumin excretion rate (AER) in three consecutive overnight or 24-h urine collections: 818 patients with normoalbuminuria (AER &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;20 microg/min), 216 patients with microalbuminuria (20 microg/min &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;or= AER &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 200 microg/min), and 296 patients with macroalbuminuria (AER &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;or=200 microg/min). Progression of albuminuria was the main outcome. Adiponectin was measured by a time-resolved immunofluorometric assay, and the values were log-transformed and adjusted for age, BMI, and sex before analysis. Progression either to the next albuminuria level or to end-stage renal disease (ESRD) occurred in 193 patients. No difference in adiponectin concentrations was observed between progressors and nonprogressors in patients with normoalbuminuria or microalbuminuria. In the patients with macroalbuminuria, progression to ESRD was associated with higher adiponectin in the entire group (23.4 +/- 17.1 vs. 16.0 +/- 8.5 mg/l, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001) and in men (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001) and women (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001) separately. Progression to ESRD was also associated with systolic blood pressure, insulin dose, A1C, serum cholesterol, serum triglycerides, AER, and estimated glomerular filtration rate (eGFR). When these covariates were inserted in a Cox regression analysis, A1C, triglycerides, eGFR, and adiponectin were significantly associated with progression from macroalbuminuria. Increased serum adiponectin levels predict the progression from macroalbuminuria to ESRD in type 1 diabetic patients.

Diabetes Care, 2009

OBJECTIVE -The purpose of this study was to study the association between a parental history of t... more OBJECTIVE -The purpose of this study was to study the association between a parental history of type 2 diabetes and the metabolic profile as well as the presence of the metabolic syndrome and diabetes complications in patients with type 1 diabetes.

Diabetes Care, 2011

OBJECTIVE-Many guidelines recommend reduced consumption of salt in patients with type 1 diabetes,... more OBJECTIVE-Many guidelines recommend reduced consumption of salt in patients with type 1 diabetes, but it is unclear whether dietary sodium intake is associated with mortality and endstage renal disease (ESRD).