Per-henrik Groop | University of Helsinki (original) (raw)

Papers by Per-henrik Groop

Research paper thumbnail of Oxygen-induced impairment in arterial function is corrected by slow breathing in patients with type 1 diabetes

Scientific Reports, 2017

Hyperoxia and slow breathing acutely improve autonomic function in type-1 diabetes. However, thei... more Hyperoxia and slow breathing acutely improve autonomic function in type-1 diabetes. However, their effects on arterial function may reveal different mechanisms, perhaps potentially useful. To test the effects of oxygen and slow breathing we measured arterial function (augmentation index, pulse wave velocity), baroreflex sensitivity (BRS) and oxygen saturation (SAT), during spontaneous and slow breathing (6 breaths/min), in normoxia and hyperoxia (5 L/min oxygen) in 91 type-1 diabetic and 40 age-matched control participants. During normoxic spontaneous breathing diabetic subjects had lower BRS and SAT, and worse arterial function. Hyperoxia and slow breathing increased BRS and SAT. Hyperoxia increased blood pressure and worsened arterial function. Slow breathing improved arterial function and diastolic blood pressure. Combined administration prevented the hyperoxia-induced arterial pressure and function worsening. Control subjects showed a similar pattern, but with lesser or no stati...

Research paper thumbnail of Endotoxins are associated with visceral fat mass in type 1 diabetes

Scientific Reports, 2016

Bacterial lipopolysaccharides (LPS), potent inducers of inflammation, have been associated with c... more Bacterial lipopolysaccharides (LPS), potent inducers of inflammation, have been associated with chronic metabolic disturbances. Obesity is linked to dyslipidemia, increased body adiposity, and endotoxemia. We investigated the cross-sectional relationships between serum LPS activity and body adiposity as well as inflammation in 242 subjects with type 1 diabetes. Body fat distribution was measured by DXA and serum LPS activity by the limulus amebocyte lysate end-point assay. Since no interaction between visceral fat mass and sex was observed, data were pooled for the subsequent analyses. LPS was independently associated with visceral fat mass, when adjusted for traditional risk factors (age, sex, kidney status, hsCRP, insulin sensitivity). In the multivariate analysis, serum LPS activity and triglyceride concentrations had a joint effect on visceral fat mass, independent of these factors alone. A combination of high LPS and high hsCRP concentrations was also observed in those with the...

Research paper thumbnail of Age at menarche and the risk of diabetic microvascular complications in patients with type 1 diabetes

Diabetologia, Jan 25, 2015

The aim of this study was to evaluate the relationship among age at onset of diabetes, age at ons... more The aim of this study was to evaluate the relationship among age at onset of diabetes, age at onset of menarche and risk of diabetic nephropathy and laser-treated retinopathy in type 1 diabetes. Data related to age at menarche were collected through questionnaires and were available for 1,304 women who participated in the Finnish Diabetic Nephropathy Study (FinnDiane). A possible association between age at menarche and diabetic nephropathy and retinopathy was investigated. There was an inverse relationship between the age at onset of diabetes and age at menarche: the younger the age at onset of diabetes, the higher the age at menarche (p < 0.0001). A non-linear relationship between the age of menarche and risk of diabetic microvascular complications was found in patients with diabetes onset before menarche, but there was no such association in patients with diabetes onset after menarche. Women with delayed menarche (> mean age + 2 years) had a 2.30 (95% CI 1.27, 4.17; p < 0...

Research paper thumbnail of Genetic Evidence for a Causal Role of Obesity in Diabetic Kidney Disease

Diabetes, 2015

Obesity has been posited as an independent risk factor for diabetic kidney disease (DKD), but est... more Obesity has been posited as an independent risk factor for diabetic kidney disease (DKD), but establishing causality from observational data is problematic. We aimed to test whether obesity is causally related to DKD using Mendelian randomization, which exploits the random assortment of genes during meiosis. In 6,049 subjects with type 1 diabetes, we used a weighted genetic risk score (GRS) comprised of 32 validated BMI loci as an instrument to test the relationship of BMI with macroalbuminuria, end-stage renal disease (ESRD), or DKD defined as presence of macroalbuminuria or ESRD. We compared these results with cross-sectional and longitudinal observational associations. Longitudinal analysis demonstrated a U-shaped relationship of BMI with development of macroalbuminuria, ESRD, or DKD over time. Cross-sectional observational analysis showed no association with overall DKD, higher odds of macroalbuminuria (for every 1 kg/m2 higher BMI, odds ratio [OR] 1.05, 95% CI 1.03–1.07, P <...

Research paper thumbnail of Oxygen deteriorates arterial function in type 1 diabetes

Acta Diabetologica, 2015

Aims Although oxygen is commonly used to treat various medical conditions, it has recently been s... more Aims Although oxygen is commonly used to treat various medical conditions, it has recently been shown to worsen vascular function (arterial stiffness) in healthy volunteers and even more in patients in whom vascular function might already be impaired. The effects of oxygen on arterial function in patients with type 1 diabetes (T1D) are unknown, although such patients display disturbed vascular function already at rest. Therefore, we tested whether short-term oxygen administration may alter the arterial function in patients with T1D. Methods We estimated arterial stiffness by augmentation index (AIx) and the pulse wave velocity equivalent (SI-DVP) in 98 patients with T1D and 49 age-and sex-matched controls at baseline and during hyperoxia by obtaining continuous noninvasive finger pressure waveforms using a recently validated method. Results AIx and SI-DVP increased in patients (P \ 0.05) but not in controls in response to hyperoxia. The increase in AIx (P = 0.05), systolic (P \ 0.05), and diastolic (P \ 0.05) blood pressure was higher in the patients than in the controls. Conclusions Short-term oxygen administration deteriorates arterial function in patients with T1D compared to non-diabetic control subjects. Since disturbed arterial function plays a major role in the development of diabetic complications, these findings may be of clinical relevance. Keywords Augmentation index Á Blood pressure Á Hyperoxia Á Oxygen Á Pulse wave velocity Á Type 1 diabetes Abbreviations SBP Systolic blood pressure DBP Diastolic blood pressure PP Pulse pressure MAP Mean arterial pressure AIx Augmentation index AIx HR Heart rate-adjusted augmentation index AER Albumin excretion rate T1D Type 1 diabetes SI-DVP An index of large artery stiffness (SIDVP) derived from the digital volume pulse (DVP) Managed by Antonio Secchi.

Research paper thumbnail of The consequences of failure to achieve targets of guidelines for prevention and treatment of diabetic complications in patients with type 1 diabetes

Acta diabetologica, 2015

To study how the targets of glycemic, blood pressure (BP) and lipid control based on the American... more To study how the targets of glycemic, blood pressure (BP) and lipid control based on the American Diabetes Association (ADA) guidelines have been implemented, and to assess the risk of cardiovascular events (CVD) and mortality in patients with type 1 diabetes stratified by nephropathy (DN) status. A nationally representative cohort of patients with type 1 diabetes (N = 3,151) from the FinnDiane Study were included. CVD and deaths were identified from the national registers. The treatment targets were HbA1C <7 %, BP <140/80 mmHg and LDL cholesterol <2.6 mmol/l. About 63 % of the patients with DN and 34 % of the patients without DN reached none of the targets. With DN, the 10-year cumulative risk of CVD was 17.4 % (95 % CI 11.1-23.2) if BP was on target, 29.9 % (23.0-36.2, P = 0.03) if BP was not on target and 28.4 % (24.9-31.8, P = 0.009) in those who reached none of the targets. The corresponding figures were 3.8 % (2.7-4.8), 4.4 % (2.7-6.2, P = 0.3) and 8.1 % (6.4-9.8, P &...

Research paper thumbnail of The cross-sectional associations between sense of coherence and diabetic microvascular complications, glycaemic control, and patients' conceptions of type 1 diabetes

Health and quality of life outcomes, 2010

Sense of coherence (SOC) has been associated with various self-care behaviours in the general pop... more Sense of coherence (SOC) has been associated with various self-care behaviours in the general population. As the management of type 1 diabetes heavily relies on self-management, the SOC concept could also prove important in this population. This paper is a report of a study conducted among patients with type 1 diabetes to assess the associations between SOC and glycaemic control, microvascular complications, and patients' conceptions of their disease. Altogether 1,264 adult patients (45% men, age range 18-82 years) with type 1 diabetes participated in this cross-sectional study. SOC was evaluated using a 13-item SOC questionnaire. Standardized assays were used to determine HbA1c. Nephropathy status was based on albumin excretion rate and retinal laser-treatment was used as an indication of severe retinopathy. Patients' subjective conceptions of diabetes were studied using a questionnaire. Higher SOC scores, reflecting stronger SOC, were associated with lower HbA1c values. St...

Research paper thumbnail of Risk factors of hypertensive pregnancies in women with diabetes and the influence on their future life

Annals of Medicine, 2014

Diabetic women carry a 2-4 times increased risk of a hypertensive pregnancy compared to non-diabe... more Diabetic women carry a 2-4 times increased risk of a hypertensive pregnancy compared to non-diabetic people. This risk is related to presence of diabetic nephropathy, but also poor glycaemic control. Efforts to improve glycaemic control have decreased perinatal morbidity and mortality related to diabetic nephropathy. Despite good glycaemic control, overt nephropathy is associated with a variety of pregnancy complications, such as fetal growth restriction and pre-eclampsia. General population studies show that women with a history of pre-eclampsia are more prone to develop cardiovascular disease later in life than women with a history of normotensive pregnancy. Furthermore, recent data regarding the long-term effects of hypertensive pregnancies on late diabetic complications indicate that these women should be followed and treatment should be started early. In this review we summarize data on risk factors and long-term effects of hypertensive pregnancies on late diabetic complications that may be of clinical relevance in the prevention of these complications.

Research paper thumbnail of Predicting major outcomes in type 1 diabetes: a model development and validation study

Diabetologia, 2014

Aims/hypothesis Type 1 diabetes is associated with a higher risk of major vascular complications ... more Aims/hypothesis Type 1 diabetes is associated with a higher risk of major vascular complications and death. A reliable method that predicted these outcomes early in the disease process would help in risk classification. We therefore developed such a prognostic model and quantified its performance in independent cohorts. Methods Data were analysed from 1,973 participants with type 1 diabetes followed for 7 years in the EURODIAB Prospective Complications Study. Strong prognostic factors for major outcomes were combined in a Weibull regression model. The performance of the model was tested in three different prospective cohorts: the Pittsburgh Epidemiology of Diabetes Complications study (EDC, n=554), the Finnish Diabetic Nephropathy study (FinnDiane, n=2,999) and the Coronary Artery Calcification in Type 1 Diabetes study (CACTI, n=580). Major outcomes included major CHD, stroke, end-stage renal failure, amputations, blindness and all-cause death. Results A total of 95 EURODIAB patients with type 1 diabetes developed major outcomes during follow-up. Prognostic factors were age, HbA 1c , WHR, albumin/creatinine ratio and HDL-cholesterol level. The discriminative ability of the model was adequate, with a concordance statistic (C-statistic) of Electronic supplementary material The online version of this article

Research paper thumbnail of Novel genetic susceptibility loci for diabetic end-stage renal disease identified through robust naive Bayes classification

Diabetologia, 2014

Aims/hypothesis Diabetic nephropathy is a major diabetic complication, and diabetes is the leadin... more 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.

Research paper thumbnail of Novel Susceptibility Locus at 22q11 for Diabetic Nephropathy in Type 1 Diabetes

PLoS ONE, 2011

Background: Diabetic nephropathy (DN) affects about 30% of patients with type 1 diabetes (T1D) an... more Background: Diabetic nephropathy (DN) affects about 30% of patients with type 1 diabetes (T1D) and contributes to serious morbidity and mortality. So far only the 3q21-q25 region has repeatedly been indicated as a susceptibility region for DN. The aim of this study was to search for new DN susceptibility loci in Finnish, Danish and French T1D families. Methods and Results: We performed a genome-wide linkage study using 384 microsatellite markers. A total of 175 T1D families were studied, of which 94 originated from Finland, 46 from Denmark and 35 from France. The whole sample set consisted of 556 individuals including 42 sib-pairs concordant and 84 sib-pairs discordant for DN. Two-point and multi-point non-parametric linkage analyses were performed using the Analyze package and the MERLIN software. A novel DN locus on 22q11 was identified in the joint analysis of the Finnish, Danish and French families by genome-wide multipoint nonparametric linkage analysis using the Kong and Cox linear model (NPL pairs LOD score 3.58). Nominal or suggestive evidence of linkage to this locus was also detected when the three populations were analyzed separately. Suggestive evidence of linkage was found to six additional loci in the Finnish and French sample sets. Conclusions: This study identified a novel DN locus at chromosome 22q11 with significant evidence of linkage to DN. Our results suggest that this locus may be of importance in European populations. In addition, this study supports previously indicated DN loci on 3q21-q25 and 19q13.

Research paper thumbnail of Polymorphisms in the nephrin gene and diabetic nephropathy in type 1 diabetic patients

Kidney International, 2003

Polymorphisms in the nephrin gene and diabetic nephropathy of specific gene loci or susceptibilit... more Polymorphisms in the nephrin gene and diabetic nephropathy of specific gene loci or susceptibility genes [2]. Most of in type 1 diabetic patients. the genes investigated so far have been involved in blood Background. Several mutations in the nephrin gene are repressure, cardiovascular disease, glucose metabolism, or sponsible for the lack of slit membrane of the glomeruli leading glomerular basement membrane. With the discovery of to massive proteinuria present already in utero. Variations in nephrin, the glomerular podocyte layer, which is one of the nephrin gene may also affect the degree of proteinuria in acquired kidney diseases. We tested the hypothesis of whether the barriers separating the glomerular capillary from the any of the polymorphisms identified in the coding region of urinary space, has drawn a great deal of attention. This the nephrin gene were associated with diabetic nephropathy. transmembrane protein has been shown to be located Methods. In a case-control, cross-sectional study, 996 Finnspecifically at the slit diaphragm separating the podocyte ish type 1 diabetic patients from the FinnDiane Study were genotyped by standard polymerase chain reaction protocol. foot processes [3]. Results. The frequencies of the rare alleles in the E117K, At least 60 mutations in the nephrin gene (NPHS1) R408Q, and N1077S polymorphisms in the entire cohort were have been identified [4]. Most of these mutations are 34%, 8%, and 12%, respectively. When comparing patients disease-causing, resulting in the lack of the nephrin prowith a mutant allele with the wild genotype there was no differtein with consequent congenital nephrosis (CNF), charence between the patients with end-stage renal disease, proteinuria, microalbuminuria, and those with a normal albumin excreacterized by massive proteinuria already in utero [5]. tion rate (df ϭ3, 2 ϭ1.62, 1.31 and 0.77). Neither were the However, several sequence variants were also found in polymorphisms associated with the progression of kidney disa healthy control population, suggesting that they are ease, nor with creatinine clearance and albumin excretion rate. common polymorphisms. The functional implication of Conclusion. This study does not support an involvement of the coding region of the nephrin gene in the pathogenesis of these polymorphisms is not known but they might infludiabetic nephropathy in type 1 diabetic patients. Furthermore, the amount of proteinuria is diminished by ACE inhibitors [9] as well as by AT2 inhibitors [10].

Research paper thumbnail of Competing-Risk Analysis of ESRD and Death among Patients with Type 1 Diabetes and Macroalbuminuria

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.

Research paper thumbnail of Birth Weight Is Inversely Correlated to Adult Systolic Blood Pressure and Pulse Pressure in Type 1 Diabetes

Hypertension, 2004

In the general population, there is an inverse relationship between birth weight and adult systol... more In the general population, there is an inverse relationship between birth weight and adult systolic blood pressure. Because blood pressure in diabetic patients at least in part seems to be regulated by different mechanisms than in nondiabetic subjects, it is not known whether a similar correlation exists in diabetic individuals. Therefore, we obtained data on birth weight from original birth certificates in 1543 type 1 diabetic patients. Blood pressure was measured auscultatorily on a single occasion. In the 1225 patients born at term (after 37 weeks of gestation), the age-and sex-adjusted regression coefficients between systolic blood pressure and birth weight was Ϫ1.90 mm Hg/kg (95% confidence interval [CI], Ϫ3.71 to Ϫ0.09). The finding remained unchanged after adjustment for body mass index, current smoking, duration of diabetes, social class, antihypertensive therapy, glomerular filtration rate, glycemic control, and elevated albuminuria. The regression coefficient between birth weight and pulse pressure was of a similar magnitude. The age-adjusted regression coefficient between systolic blood pressure and birth weight seemed stronger in females (Ϫ3.34 mm Hg/kg; 95% CI, Ϫ6.06 to Ϫ0.62) than in males (Ϫ0.42 mm Hg/kg; 95% CI, Ϫ2.80 to 1.95), although this difference was not statistically significant. As a new finding, we report an inverse relationship between weight at birth and systolic blood pressure and pulse pressure in adult type 1 diabetic patients. Given the deleterious effects of elevated arterial blood pressure in diabetes, the impact of intrauterine growth retardation on the development of end-organ damage needs to be clarified. (Hypertension. 2004;44:832-837.

Research paper thumbnail of Lipid abnormalities predict progression of renal disease in patients with 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.

Research paper thumbnail of Early autonomic dysfunction in type 1 diabetes: a reversible disorder?

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. Methods We compared 116 type 1 diabetic patients with 36 matched healthy control participants and 12 hearttransplanted participants with surgically denervated hearts. Autonomic function tests and spectral analysis of heart rate and blood pressure variability were performed. BRS was estimated by four methods during controlled (15 breaths per minute) and slow deep-breathing (six breaths per minute), and in supine and standing positions. Results Conventional autonomic function tests were normal, but resting spectral variables and BRS were reduced during normal controlled breathing in patients with type 1 diabetes. However, slow deep-breathing improved BRS in patients with type 1 diabetes, but not in patients with surgically denervated hearts. Standing induced similar reductions in BRS in diabetic and control participants. Conclusions/interpretation Although we found signs of increased sympathetic activity in patients with type 1 diabetes, we also observed a near normalisation of BRS with a simple functional test, indicating that early autonomic derangements are to a large extent functional and potentially correctable by appropriate interventions.

Research paper thumbnail of Association between mannose-binding lectin, high-sensitivity C-reactive protein and the progression of diabetic nephropathy in type 1 diabetes

Diabetologia, 2010

Aims/hypothesis Diabetic nephropathy has been associated with low-grade inflammation and activati... more Aims/hypothesis Diabetic nephropathy has been associated with low-grade inflammation and activation of the complement system in cross-sectional studies. Data from prospective studies are sparse. We investigated the associations of the complement activator mannose-binding lectin (MBL) and the inflammatory marker high-sensitivity C-reactive protein (hsCRP) with the development of nephropathy in a large prospective study of patients with type 1 diabetes from the Finnish Diabetic Nephropathy (FinnDiane) Study. Methods Baseline MBL and hsCRP were measured in 1,564 type 1 diabetes patients from the FinnDiane study, of whom 1,010 had a normal albumin excretion rate, 236 had microalbuminuria and 318 had macroalbuminuria. The main outcome was progression in renal disease during follow-up. Results Both baseline MBL (p=0.038) and hsCRP (p<0.001) increased with increasing level of albuminuria. During 5.8± 2.2 years of follow-up, progression to a higher albuminuria level or end-stage renal disease (ESRD) occurred in 201 patients. MBL levels were higher in progressors compared with non-progressors at all steps of progression, and in a covariate adjusted multivariate Cox-regression analysis MBL levels above the median were significantly associated with progression from macroalbuminuria to ESRD (hazard ratio 1.88, 95% CI 1.06-3.32, p=0.030). In a univariate analysis, hsCRP levels above the median were significantly associated with progression from normal albumin excretion rate to microalbuminuria, but the association was only borderline significant after adjustment for covariates (hazard ratio 1.56, 95% CI 0.97-2.51, p=0.068). Conclusions/interpretation This study demonstrates that concentrations of both MBL and hsCRP are associated with the progression of renal disease in type 1 diabetes.

Research paper thumbnail of Purchase of antidepressant agents by patients with type 1 diabetes is associated with increased mortality rates in women but not in men

Diabetologia, 2011

Aims/hypothesis Individuals with diabetes have increased mortality rates compared with the genera... more Aims/hypothesis Individuals with diabetes have increased mortality rates compared with the general population. In patients with type 2 diabetes depression further contributes to the increased mortality. Depression and mortality rates in patients with type 1 diabetes are an understudied phenomenon. We therefore studied their association in a prospective setting. Methods We followed 4,174 participants (51% men, age 39±12 years, diabetes duration 22±12 years [mean± SD]) in the Finnish Diabetic Nephropathy Study (FinnDiane) for an average of 9 years. Depression was defined as purchase of antidepressant agents at baseline and during follow-up. These data were obtained from the Finnish Drug Prescription Register. Data on allcause mortality and cause of death were obtained from the Finnish Cause of Death Register. Results At baseline, 313 (7.5%) patients had purchased antidepressant agents. During follow-up 758 (18.2%) additional cases were observed. Purchasers of antidepressant agents at baseline had the highest 10-year cumulative mortality rate (22.5% [95% CI 18.1, 26.6]), followed by those with such purchases during follow-up (18.0% [15.4, 20.5]) and those with no purchases (10.1% [9.0, 11.2], p<0.001). In the adjusted Cox regression models (age, diabetes duration, diastolic blood pressure, smoking, HbA 1c and nephropathy), the purchase of antidepressant agents at baseline was associated with mortality in women, but not in men. Cardiovascular diseases were the major cause of death in non-purchasers of antidepressant agents. In antidepressant purchasers, chronic diabetic complications were the most frequent underlying cause of death. Conclusions/interpretation In a population of patients with type 1 diabetes, purchase of antidepressant agents was associated with increased mortality rates in women, but not in men.

Research paper thumbnail of Soluble receptor for AGE (RAGE) is a novel independent predictor of all-cause and cardiovascular mortality in type 1 diabetes

Diabetologia, 2011

Aims/hypothesis Activation of the receptor for AGE (RAGE) is implicated in the development and pr... more Aims/hypothesis Activation of the receptor for AGE (RAGE) is implicated in the development and progression of vascular complications of diabetes. In this study, we explore factors and mortality outcomes associated with soluble RAGE (sRAGE) in a multicentre nationwide cohort of Finnish adults with type 1 diabetes. Methods Baseline sRAGE concentrations were estimated in 3,100 adults with type 1 diabetes. Clinical and biological variables independently associated with sRAGE were identified using multivariate regression analysis. Independent predictors of mortality were determined using Cox and Fine-Gray proportional-hazards models. Results The main independent determinants of sRAGE concentrations were estimated glomerular filtration rate, albuminuria, body mass index, age, duration of diabetes, HbA 1c and insulin dose (all p<0.05). During a median of 9.1 years of follow-up there were 202 deaths (7.4 per 1,000 patient years). sRAGE was independently associated with all-cause (Cox model: HR 1.03) and cardiovascular mortality (Fine-Gray competing risks model: HR 1.06) such that patients with the highest sRAGE concentrations had the greatest risk of mortality, after adjusting for age, sex, macrovascular disease, HDL-cholesterol, HbA 1c , triacylglycerol, high-sensitivity C-reactive protein (hsCRP) and the presence and severity of chronic kidney disease. Although polymorphisms in the gene coding for RAGE were significantly associated with sRAGE concentrations, none were associated with mortality outcomes. Conclusions/interpretation Increased concentrations of sRAGE are associated with increased all-cause and cardiovascular mortality in type 1 diabetes, potentially reflecting the activation and production of RAGE in the context of accelerated vascular disease. These novel findings highlight the importance of the RAGE activation in the prevention and management of diabetic complications. Keywords Advanced glycation end-products. AGE. Mortality. RAGE. Type 1 diabetes Abbreviations AIC Akaike's information criteria BIC Bayesian information criteria CKD Chronic kidney disease M. C. Thomas and J. Söderlund contributed equally to this study.

Research paper thumbnail of Serum Concentration of Cystatin C and Risk of End-Stage Renal Disease in Diabetes

Diabetes Care, 2012

OBJECTIVE Patients with diabetes have a high risk of end-stage renal disease (ESRD). We examined ... more OBJECTIVE Patients with diabetes have a high risk of end-stage renal disease (ESRD). We examined whether prediction of this outcome, according to chronic kidney disease (CKD) staging by creatinine-based estimates of the glomerular filtration rate (eGFRcreat), is improved by further staging with serum cystatin C–based estimates (eGFRcyst). RESEARCH DESIGN AND METHODS Patients with diabetes in CKD stages 1–3 were selected from three cohorts: two from Joslin Diabetes Center, one with type 1 diabetes (N = 364) and one with type 2 diabetes (N = 402), and the third from the Finnish Diabetic Nephropathy (FinnDiane) Study of type 1 (N = 399). Baseline serum concentrations of creatinine and cystatin C were measured in all patients. Follow-up averaged 8–10 years and onsets of ESRD (n = 246) and death unrelated to ESRD (n = 159) were ascertained. RESULTS Although CKD staging by eGFRcyst was concordant with that by eGFRcreat for 62% of Joslin patients and 73% of FinnDiane patients, those given ...

Research paper thumbnail of Oxygen-induced impairment in arterial function is corrected by slow breathing in patients with type 1 diabetes

Scientific Reports, 2017

Hyperoxia and slow breathing acutely improve autonomic function in type-1 diabetes. However, thei... more Hyperoxia and slow breathing acutely improve autonomic function in type-1 diabetes. However, their effects on arterial function may reveal different mechanisms, perhaps potentially useful. To test the effects of oxygen and slow breathing we measured arterial function (augmentation index, pulse wave velocity), baroreflex sensitivity (BRS) and oxygen saturation (SAT), during spontaneous and slow breathing (6 breaths/min), in normoxia and hyperoxia (5 L/min oxygen) in 91 type-1 diabetic and 40 age-matched control participants. During normoxic spontaneous breathing diabetic subjects had lower BRS and SAT, and worse arterial function. Hyperoxia and slow breathing increased BRS and SAT. Hyperoxia increased blood pressure and worsened arterial function. Slow breathing improved arterial function and diastolic blood pressure. Combined administration prevented the hyperoxia-induced arterial pressure and function worsening. Control subjects showed a similar pattern, but with lesser or no stati...

Research paper thumbnail of Endotoxins are associated with visceral fat mass in type 1 diabetes

Scientific Reports, 2016

Bacterial lipopolysaccharides (LPS), potent inducers of inflammation, have been associated with c... more Bacterial lipopolysaccharides (LPS), potent inducers of inflammation, have been associated with chronic metabolic disturbances. Obesity is linked to dyslipidemia, increased body adiposity, and endotoxemia. We investigated the cross-sectional relationships between serum LPS activity and body adiposity as well as inflammation in 242 subjects with type 1 diabetes. Body fat distribution was measured by DXA and serum LPS activity by the limulus amebocyte lysate end-point assay. Since no interaction between visceral fat mass and sex was observed, data were pooled for the subsequent analyses. LPS was independently associated with visceral fat mass, when adjusted for traditional risk factors (age, sex, kidney status, hsCRP, insulin sensitivity). In the multivariate analysis, serum LPS activity and triglyceride concentrations had a joint effect on visceral fat mass, independent of these factors alone. A combination of high LPS and high hsCRP concentrations was also observed in those with the...

Research paper thumbnail of Age at menarche and the risk of diabetic microvascular complications in patients with type 1 diabetes

Diabetologia, Jan 25, 2015

The aim of this study was to evaluate the relationship among age at onset of diabetes, age at ons... more The aim of this study was to evaluate the relationship among age at onset of diabetes, age at onset of menarche and risk of diabetic nephropathy and laser-treated retinopathy in type 1 diabetes. Data related to age at menarche were collected through questionnaires and were available for 1,304 women who participated in the Finnish Diabetic Nephropathy Study (FinnDiane). A possible association between age at menarche and diabetic nephropathy and retinopathy was investigated. There was an inverse relationship between the age at onset of diabetes and age at menarche: the younger the age at onset of diabetes, the higher the age at menarche (p < 0.0001). A non-linear relationship between the age of menarche and risk of diabetic microvascular complications was found in patients with diabetes onset before menarche, but there was no such association in patients with diabetes onset after menarche. Women with delayed menarche (> mean age + 2 years) had a 2.30 (95% CI 1.27, 4.17; p < 0...

Research paper thumbnail of Genetic Evidence for a Causal Role of Obesity in Diabetic Kidney Disease

Diabetes, 2015

Obesity has been posited as an independent risk factor for diabetic kidney disease (DKD), but est... more Obesity has been posited as an independent risk factor for diabetic kidney disease (DKD), but establishing causality from observational data is problematic. We aimed to test whether obesity is causally related to DKD using Mendelian randomization, which exploits the random assortment of genes during meiosis. In 6,049 subjects with type 1 diabetes, we used a weighted genetic risk score (GRS) comprised of 32 validated BMI loci as an instrument to test the relationship of BMI with macroalbuminuria, end-stage renal disease (ESRD), or DKD defined as presence of macroalbuminuria or ESRD. We compared these results with cross-sectional and longitudinal observational associations. Longitudinal analysis demonstrated a U-shaped relationship of BMI with development of macroalbuminuria, ESRD, or DKD over time. Cross-sectional observational analysis showed no association with overall DKD, higher odds of macroalbuminuria (for every 1 kg/m2 higher BMI, odds ratio [OR] 1.05, 95% CI 1.03–1.07, P <...

Research paper thumbnail of Oxygen deteriorates arterial function in type 1 diabetes

Acta Diabetologica, 2015

Aims Although oxygen is commonly used to treat various medical conditions, it has recently been s... more Aims Although oxygen is commonly used to treat various medical conditions, it has recently been shown to worsen vascular function (arterial stiffness) in healthy volunteers and even more in patients in whom vascular function might already be impaired. The effects of oxygen on arterial function in patients with type 1 diabetes (T1D) are unknown, although such patients display disturbed vascular function already at rest. Therefore, we tested whether short-term oxygen administration may alter the arterial function in patients with T1D. Methods We estimated arterial stiffness by augmentation index (AIx) and the pulse wave velocity equivalent (SI-DVP) in 98 patients with T1D and 49 age-and sex-matched controls at baseline and during hyperoxia by obtaining continuous noninvasive finger pressure waveforms using a recently validated method. Results AIx and SI-DVP increased in patients (P \ 0.05) but not in controls in response to hyperoxia. The increase in AIx (P = 0.05), systolic (P \ 0.05), and diastolic (P \ 0.05) blood pressure was higher in the patients than in the controls. Conclusions Short-term oxygen administration deteriorates arterial function in patients with T1D compared to non-diabetic control subjects. Since disturbed arterial function plays a major role in the development of diabetic complications, these findings may be of clinical relevance. Keywords Augmentation index Á Blood pressure Á Hyperoxia Á Oxygen Á Pulse wave velocity Á Type 1 diabetes Abbreviations SBP Systolic blood pressure DBP Diastolic blood pressure PP Pulse pressure MAP Mean arterial pressure AIx Augmentation index AIx HR Heart rate-adjusted augmentation index AER Albumin excretion rate T1D Type 1 diabetes SI-DVP An index of large artery stiffness (SIDVP) derived from the digital volume pulse (DVP) Managed by Antonio Secchi.

Research paper thumbnail of The consequences of failure to achieve targets of guidelines for prevention and treatment of diabetic complications in patients with type 1 diabetes

Acta diabetologica, 2015

To study how the targets of glycemic, blood pressure (BP) and lipid control based on the American... more To study how the targets of glycemic, blood pressure (BP) and lipid control based on the American Diabetes Association (ADA) guidelines have been implemented, and to assess the risk of cardiovascular events (CVD) and mortality in patients with type 1 diabetes stratified by nephropathy (DN) status. A nationally representative cohort of patients with type 1 diabetes (N = 3,151) from the FinnDiane Study were included. CVD and deaths were identified from the national registers. The treatment targets were HbA1C <7 %, BP <140/80 mmHg and LDL cholesterol <2.6 mmol/l. About 63 % of the patients with DN and 34 % of the patients without DN reached none of the targets. With DN, the 10-year cumulative risk of CVD was 17.4 % (95 % CI 11.1-23.2) if BP was on target, 29.9 % (23.0-36.2, P = 0.03) if BP was not on target and 28.4 % (24.9-31.8, P = 0.009) in those who reached none of the targets. The corresponding figures were 3.8 % (2.7-4.8), 4.4 % (2.7-6.2, P = 0.3) and 8.1 % (6.4-9.8, P &...

Research paper thumbnail of The cross-sectional associations between sense of coherence and diabetic microvascular complications, glycaemic control, and patients' conceptions of type 1 diabetes

Health and quality of life outcomes, 2010

Sense of coherence (SOC) has been associated with various self-care behaviours in the general pop... more Sense of coherence (SOC) has been associated with various self-care behaviours in the general population. As the management of type 1 diabetes heavily relies on self-management, the SOC concept could also prove important in this population. This paper is a report of a study conducted among patients with type 1 diabetes to assess the associations between SOC and glycaemic control, microvascular complications, and patients' conceptions of their disease. Altogether 1,264 adult patients (45% men, age range 18-82 years) with type 1 diabetes participated in this cross-sectional study. SOC was evaluated using a 13-item SOC questionnaire. Standardized assays were used to determine HbA1c. Nephropathy status was based on albumin excretion rate and retinal laser-treatment was used as an indication of severe retinopathy. Patients' subjective conceptions of diabetes were studied using a questionnaire. Higher SOC scores, reflecting stronger SOC, were associated with lower HbA1c values. St...

Research paper thumbnail of Risk factors of hypertensive pregnancies in women with diabetes and the influence on their future life

Annals of Medicine, 2014

Diabetic women carry a 2-4 times increased risk of a hypertensive pregnancy compared to non-diabe... more Diabetic women carry a 2-4 times increased risk of a hypertensive pregnancy compared to non-diabetic people. This risk is related to presence of diabetic nephropathy, but also poor glycaemic control. Efforts to improve glycaemic control have decreased perinatal morbidity and mortality related to diabetic nephropathy. Despite good glycaemic control, overt nephropathy is associated with a variety of pregnancy complications, such as fetal growth restriction and pre-eclampsia. General population studies show that women with a history of pre-eclampsia are more prone to develop cardiovascular disease later in life than women with a history of normotensive pregnancy. Furthermore, recent data regarding the long-term effects of hypertensive pregnancies on late diabetic complications indicate that these women should be followed and treatment should be started early. In this review we summarize data on risk factors and long-term effects of hypertensive pregnancies on late diabetic complications that may be of clinical relevance in the prevention of these complications.

Research paper thumbnail of Predicting major outcomes in type 1 diabetes: a model development and validation study

Diabetologia, 2014

Aims/hypothesis Type 1 diabetes is associated with a higher risk of major vascular complications ... more Aims/hypothesis Type 1 diabetes is associated with a higher risk of major vascular complications and death. A reliable method that predicted these outcomes early in the disease process would help in risk classification. We therefore developed such a prognostic model and quantified its performance in independent cohorts. Methods Data were analysed from 1,973 participants with type 1 diabetes followed for 7 years in the EURODIAB Prospective Complications Study. Strong prognostic factors for major outcomes were combined in a Weibull regression model. The performance of the model was tested in three different prospective cohorts: the Pittsburgh Epidemiology of Diabetes Complications study (EDC, n=554), the Finnish Diabetic Nephropathy study (FinnDiane, n=2,999) and the Coronary Artery Calcification in Type 1 Diabetes study (CACTI, n=580). Major outcomes included major CHD, stroke, end-stage renal failure, amputations, blindness and all-cause death. Results A total of 95 EURODIAB patients with type 1 diabetes developed major outcomes during follow-up. Prognostic factors were age, HbA 1c , WHR, albumin/creatinine ratio and HDL-cholesterol level. The discriminative ability of the model was adequate, with a concordance statistic (C-statistic) of Electronic supplementary material The online version of this article

Research paper thumbnail of Novel genetic susceptibility loci for diabetic end-stage renal disease identified through robust naive Bayes classification

Diabetologia, 2014

Aims/hypothesis Diabetic nephropathy is a major diabetic complication, and diabetes is the leadin... more 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.

Research paper thumbnail of Novel Susceptibility Locus at 22q11 for Diabetic Nephropathy in Type 1 Diabetes

PLoS ONE, 2011

Background: Diabetic nephropathy (DN) affects about 30% of patients with type 1 diabetes (T1D) an... more Background: Diabetic nephropathy (DN) affects about 30% of patients with type 1 diabetes (T1D) and contributes to serious morbidity and mortality. So far only the 3q21-q25 region has repeatedly been indicated as a susceptibility region for DN. The aim of this study was to search for new DN susceptibility loci in Finnish, Danish and French T1D families. Methods and Results: We performed a genome-wide linkage study using 384 microsatellite markers. A total of 175 T1D families were studied, of which 94 originated from Finland, 46 from Denmark and 35 from France. The whole sample set consisted of 556 individuals including 42 sib-pairs concordant and 84 sib-pairs discordant for DN. Two-point and multi-point non-parametric linkage analyses were performed using the Analyze package and the MERLIN software. A novel DN locus on 22q11 was identified in the joint analysis of the Finnish, Danish and French families by genome-wide multipoint nonparametric linkage analysis using the Kong and Cox linear model (NPL pairs LOD score 3.58). Nominal or suggestive evidence of linkage to this locus was also detected when the three populations were analyzed separately. Suggestive evidence of linkage was found to six additional loci in the Finnish and French sample sets. Conclusions: This study identified a novel DN locus at chromosome 22q11 with significant evidence of linkage to DN. Our results suggest that this locus may be of importance in European populations. In addition, this study supports previously indicated DN loci on 3q21-q25 and 19q13.

Research paper thumbnail of Polymorphisms in the nephrin gene and diabetic nephropathy in type 1 diabetic patients

Kidney International, 2003

Polymorphisms in the nephrin gene and diabetic nephropathy of specific gene loci or susceptibilit... more Polymorphisms in the nephrin gene and diabetic nephropathy of specific gene loci or susceptibility genes [2]. Most of in type 1 diabetic patients. the genes investigated so far have been involved in blood Background. Several mutations in the nephrin gene are repressure, cardiovascular disease, glucose metabolism, or sponsible for the lack of slit membrane of the glomeruli leading glomerular basement membrane. With the discovery of to massive proteinuria present already in utero. Variations in nephrin, the glomerular podocyte layer, which is one of the nephrin gene may also affect the degree of proteinuria in acquired kidney diseases. We tested the hypothesis of whether the barriers separating the glomerular capillary from the any of the polymorphisms identified in the coding region of urinary space, has drawn a great deal of attention. This the nephrin gene were associated with diabetic nephropathy. transmembrane protein has been shown to be located Methods. In a case-control, cross-sectional study, 996 Finnspecifically at the slit diaphragm separating the podocyte ish type 1 diabetic patients from the FinnDiane Study were genotyped by standard polymerase chain reaction protocol. foot processes [3]. Results. The frequencies of the rare alleles in the E117K, At least 60 mutations in the nephrin gene (NPHS1) R408Q, and N1077S polymorphisms in the entire cohort were have been identified [4]. Most of these mutations are 34%, 8%, and 12%, respectively. When comparing patients disease-causing, resulting in the lack of the nephrin prowith a mutant allele with the wild genotype there was no differtein with consequent congenital nephrosis (CNF), charence between the patients with end-stage renal disease, proteinuria, microalbuminuria, and those with a normal albumin excreacterized by massive proteinuria already in utero [5]. tion rate (df ϭ3, 2 ϭ1.62, 1.31 and 0.77). Neither were the However, several sequence variants were also found in polymorphisms associated with the progression of kidney disa healthy control population, suggesting that they are ease, nor with creatinine clearance and albumin excretion rate. common polymorphisms. The functional implication of Conclusion. This study does not support an involvement of the coding region of the nephrin gene in the pathogenesis of these polymorphisms is not known but they might infludiabetic nephropathy in type 1 diabetic patients. Furthermore, the amount of proteinuria is diminished by ACE inhibitors [9] as well as by AT2 inhibitors [10].

Research paper thumbnail of Competing-Risk Analysis of ESRD and Death among Patients with Type 1 Diabetes and Macroalbuminuria

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.

Research paper thumbnail of Birth Weight Is Inversely Correlated to Adult Systolic Blood Pressure and Pulse Pressure in Type 1 Diabetes

Hypertension, 2004

In the general population, there is an inverse relationship between birth weight and adult systol... more In the general population, there is an inverse relationship between birth weight and adult systolic blood pressure. Because blood pressure in diabetic patients at least in part seems to be regulated by different mechanisms than in nondiabetic subjects, it is not known whether a similar correlation exists in diabetic individuals. Therefore, we obtained data on birth weight from original birth certificates in 1543 type 1 diabetic patients. Blood pressure was measured auscultatorily on a single occasion. In the 1225 patients born at term (after 37 weeks of gestation), the age-and sex-adjusted regression coefficients between systolic blood pressure and birth weight was Ϫ1.90 mm Hg/kg (95% confidence interval [CI], Ϫ3.71 to Ϫ0.09). The finding remained unchanged after adjustment for body mass index, current smoking, duration of diabetes, social class, antihypertensive therapy, glomerular filtration rate, glycemic control, and elevated albuminuria. The regression coefficient between birth weight and pulse pressure was of a similar magnitude. The age-adjusted regression coefficient between systolic blood pressure and birth weight seemed stronger in females (Ϫ3.34 mm Hg/kg; 95% CI, Ϫ6.06 to Ϫ0.62) than in males (Ϫ0.42 mm Hg/kg; 95% CI, Ϫ2.80 to 1.95), although this difference was not statistically significant. As a new finding, we report an inverse relationship between weight at birth and systolic blood pressure and pulse pressure in adult type 1 diabetic patients. Given the deleterious effects of elevated arterial blood pressure in diabetes, the impact of intrauterine growth retardation on the development of end-organ damage needs to be clarified. (Hypertension. 2004;44:832-837.

Research paper thumbnail of Lipid abnormalities predict progression of renal disease in patients with 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.

Research paper thumbnail of Early autonomic dysfunction in type 1 diabetes: a reversible disorder?

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. Methods We compared 116 type 1 diabetic patients with 36 matched healthy control participants and 12 hearttransplanted participants with surgically denervated hearts. Autonomic function tests and spectral analysis of heart rate and blood pressure variability were performed. BRS was estimated by four methods during controlled (15 breaths per minute) and slow deep-breathing (six breaths per minute), and in supine and standing positions. Results Conventional autonomic function tests were normal, but resting spectral variables and BRS were reduced during normal controlled breathing in patients with type 1 diabetes. However, slow deep-breathing improved BRS in patients with type 1 diabetes, but not in patients with surgically denervated hearts. Standing induced similar reductions in BRS in diabetic and control participants. Conclusions/interpretation Although we found signs of increased sympathetic activity in patients with type 1 diabetes, we also observed a near normalisation of BRS with a simple functional test, indicating that early autonomic derangements are to a large extent functional and potentially correctable by appropriate interventions.

Research paper thumbnail of Association between mannose-binding lectin, high-sensitivity C-reactive protein and the progression of diabetic nephropathy in type 1 diabetes

Diabetologia, 2010

Aims/hypothesis Diabetic nephropathy has been associated with low-grade inflammation and activati... more Aims/hypothesis Diabetic nephropathy has been associated with low-grade inflammation and activation of the complement system in cross-sectional studies. Data from prospective studies are sparse. We investigated the associations of the complement activator mannose-binding lectin (MBL) and the inflammatory marker high-sensitivity C-reactive protein (hsCRP) with the development of nephropathy in a large prospective study of patients with type 1 diabetes from the Finnish Diabetic Nephropathy (FinnDiane) Study. Methods Baseline MBL and hsCRP were measured in 1,564 type 1 diabetes patients from the FinnDiane study, of whom 1,010 had a normal albumin excretion rate, 236 had microalbuminuria and 318 had macroalbuminuria. The main outcome was progression in renal disease during follow-up. Results Both baseline MBL (p=0.038) and hsCRP (p<0.001) increased with increasing level of albuminuria. During 5.8± 2.2 years of follow-up, progression to a higher albuminuria level or end-stage renal disease (ESRD) occurred in 201 patients. MBL levels were higher in progressors compared with non-progressors at all steps of progression, and in a covariate adjusted multivariate Cox-regression analysis MBL levels above the median were significantly associated with progression from macroalbuminuria to ESRD (hazard ratio 1.88, 95% CI 1.06-3.32, p=0.030). In a univariate analysis, hsCRP levels above the median were significantly associated with progression from normal albumin excretion rate to microalbuminuria, but the association was only borderline significant after adjustment for covariates (hazard ratio 1.56, 95% CI 0.97-2.51, p=0.068). Conclusions/interpretation This study demonstrates that concentrations of both MBL and hsCRP are associated with the progression of renal disease in type 1 diabetes.

Research paper thumbnail of Purchase of antidepressant agents by patients with type 1 diabetes is associated with increased mortality rates in women but not in men

Diabetologia, 2011

Aims/hypothesis Individuals with diabetes have increased mortality rates compared with the genera... more Aims/hypothesis Individuals with diabetes have increased mortality rates compared with the general population. In patients with type 2 diabetes depression further contributes to the increased mortality. Depression and mortality rates in patients with type 1 diabetes are an understudied phenomenon. We therefore studied their association in a prospective setting. Methods We followed 4,174 participants (51% men, age 39±12 years, diabetes duration 22±12 years [mean± SD]) in the Finnish Diabetic Nephropathy Study (FinnDiane) for an average of 9 years. Depression was defined as purchase of antidepressant agents at baseline and during follow-up. These data were obtained from the Finnish Drug Prescription Register. Data on allcause mortality and cause of death were obtained from the Finnish Cause of Death Register. Results At baseline, 313 (7.5%) patients had purchased antidepressant agents. During follow-up 758 (18.2%) additional cases were observed. Purchasers of antidepressant agents at baseline had the highest 10-year cumulative mortality rate (22.5% [95% CI 18.1, 26.6]), followed by those with such purchases during follow-up (18.0% [15.4, 20.5]) and those with no purchases (10.1% [9.0, 11.2], p<0.001). In the adjusted Cox regression models (age, diabetes duration, diastolic blood pressure, smoking, HbA 1c and nephropathy), the purchase of antidepressant agents at baseline was associated with mortality in women, but not in men. Cardiovascular diseases were the major cause of death in non-purchasers of antidepressant agents. In antidepressant purchasers, chronic diabetic complications were the most frequent underlying cause of death. Conclusions/interpretation In a population of patients with type 1 diabetes, purchase of antidepressant agents was associated with increased mortality rates in women, but not in men.

Research paper thumbnail of Soluble receptor for AGE (RAGE) is a novel independent predictor of all-cause and cardiovascular mortality in type 1 diabetes

Diabetologia, 2011

Aims/hypothesis Activation of the receptor for AGE (RAGE) is implicated in the development and pr... more Aims/hypothesis Activation of the receptor for AGE (RAGE) is implicated in the development and progression of vascular complications of diabetes. In this study, we explore factors and mortality outcomes associated with soluble RAGE (sRAGE) in a multicentre nationwide cohort of Finnish adults with type 1 diabetes. Methods Baseline sRAGE concentrations were estimated in 3,100 adults with type 1 diabetes. Clinical and biological variables independently associated with sRAGE were identified using multivariate regression analysis. Independent predictors of mortality were determined using Cox and Fine-Gray proportional-hazards models. Results The main independent determinants of sRAGE concentrations were estimated glomerular filtration rate, albuminuria, body mass index, age, duration of diabetes, HbA 1c and insulin dose (all p<0.05). During a median of 9.1 years of follow-up there were 202 deaths (7.4 per 1,000 patient years). sRAGE was independently associated with all-cause (Cox model: HR 1.03) and cardiovascular mortality (Fine-Gray competing risks model: HR 1.06) such that patients with the highest sRAGE concentrations had the greatest risk of mortality, after adjusting for age, sex, macrovascular disease, HDL-cholesterol, HbA 1c , triacylglycerol, high-sensitivity C-reactive protein (hsCRP) and the presence and severity of chronic kidney disease. Although polymorphisms in the gene coding for RAGE were significantly associated with sRAGE concentrations, none were associated with mortality outcomes. Conclusions/interpretation Increased concentrations of sRAGE are associated with increased all-cause and cardiovascular mortality in type 1 diabetes, potentially reflecting the activation and production of RAGE in the context of accelerated vascular disease. These novel findings highlight the importance of the RAGE activation in the prevention and management of diabetic complications. Keywords Advanced glycation end-products. AGE. Mortality. RAGE. Type 1 diabetes Abbreviations AIC Akaike's information criteria BIC Bayesian information criteria CKD Chronic kidney disease M. C. Thomas and J. Söderlund contributed equally to this study.

Research paper thumbnail of Serum Concentration of Cystatin C and Risk of End-Stage Renal Disease in Diabetes

Diabetes Care, 2012

OBJECTIVE Patients with diabetes have a high risk of end-stage renal disease (ESRD). We examined ... more OBJECTIVE Patients with diabetes have a high risk of end-stage renal disease (ESRD). We examined whether prediction of this outcome, according to chronic kidney disease (CKD) staging by creatinine-based estimates of the glomerular filtration rate (eGFRcreat), is improved by further staging with serum cystatin C–based estimates (eGFRcyst). RESEARCH DESIGN AND METHODS Patients with diabetes in CKD stages 1–3 were selected from three cohorts: two from Joslin Diabetes Center, one with type 1 diabetes (N = 364) and one with type 2 diabetes (N = 402), and the third from the Finnish Diabetic Nephropathy (FinnDiane) Study of type 1 (N = 399). Baseline serum concentrations of creatinine and cystatin C were measured in all patients. Follow-up averaged 8–10 years and onsets of ESRD (n = 246) and death unrelated to ESRD (n = 159) were ascertained. RESULTS Although CKD staging by eGFRcyst was concordant with that by eGFRcreat for 62% of Joslin patients and 73% of FinnDiane patients, those given ...