Physical activity and diabetic complications in patients with type 1 diabetes

Type 1 diabetes is associated with the risk for late diabetic complications which are divided into microvascular (retinopathy, nephropathy, and neuropathy) and macrovascular (cardiovascular disease, CVD) diseases. The risk for diabetic complication can be reduced by effective treatment, most importantly the glycaemic control. Glycaemia in type 1 diabetes is influenced by the interplay between insulin injections and lifestyle factors such as physical activity and diet. The effect of physical activity in patients with type 1 diabetes is not well known, however. The aim of this thesis was to investigate the physical activity and the physical fitness of patients with type 1 diabetes with special emphasis on glycaemic control and the diabetic complications. The patients included in the study were all part of the nationwide, multicenter Finnish Diabetic Nephropathy (FinnDiane) Study which aims to characterise genetic, clinical, and environmental factors that predispose to diabetic complications in patients with type 1 diabetes. In addition, subjects from the IDentification of EArly mechanisms in the pathogenesis of diabetic Late complications (IDEAL) Study were studied. Physical activity was assessed in the FinnDiane Study in 1945 patients by a validated questionnaire. Physical fitness was measured in the IDEAL Study by spiroergometry (cycle test with measurement of respiratory gases) in 86 young adults with type 1 diabetes and in 27 healthy controls. All patients underwent thorough clinical characterisation of their diabetic complication status. Four substudies were cross-sectional using baseline data and one study additionally used follow-up data. Physical activity, especially the intensity of activities, was reduced in patients affected by diabetic nephropathy, retinopathy, and CVD. Low physical activity was associated with poor glycaemic control, a finding most clear in women and evident also in patients with no signs of diabetic complications. Furthermore, low physical activity was associated with a higher HbA1c variability, which in turn was associated with the progression of renal disease and CVD during follow-up. A higher level of physical activity was also associated with better insulin sensitivity. The prevalence of the metabolic syndrome in type 1 diabetes was also lower the higher the physical activity. The aerobic physical fitness level of young adults with type 1 diabetes was reduced compared with healthy peers and in men an association between higher fitness level and lower HbA1c was observed. In patients with type 1 diabetes, a higher physical activity was associated with better glycaemic control and may thus be beneficial with respect to the prevention of diabetic complications.Tyypin 1 diabetekseen liittyy riski diabeettisiin liitännäissairauksiin, tai komplikaatioihin, kuten nefropatiaan eli munuaistautiin, retinopatiaan eli silmätautiin, neuropatiaan eli hermotautiin (yhteisnimellä mikrovaskulaariset komplikaatiot) sekä sydän- ja verisuonisairauksiin (makrovaskulaariset komplikaatiot). Liitännäissairauksien synnyn riskiä voidaan vähentää tehokkaalla diabeteksen hoidolla painottaen erityisesti verensokeritasapainoon. Tyypin 1 diabetesta sairastavilla verensokeritasapainoon liittyy insuliinipistosten sekä elämäntavan, kuten liikunnan ja ruokavalion, välinen yhteysvaikutus. Liikunnan merkitystä verensokeritasapainoon on kuitenkin tutkittu niukasti tyypin 1 diabeteksessa. Tämän väitöskirjan päämääränä oli tarkastella tyypin 1 diabetesta sairastavien potilaiden liikuntatottumusten ja fyysisen kuntotason yhteyttä verensokeritasapainoon ja diabeettisiin liitännäissairauksiin. Väitöskirjaosatöissä tutkitut potilaat ovat osallistuneet maankattavaan suomalaiseen monikeskustutkimukseen FinnDiane (Finnish Diabetic Nephropathy Study), jonka päämääränä on tutkia diabeettisille liitännäissairauksille altistavia niin perinnöllisiä, kliinisiä kuin ympäristötekijöitäkin tyypin 1 diabetesta sairastavilla. Lisäksi tutkittiin potilaita IDEAL- tutkimuksesta (IDentification of EArly mechanisms in the pathogenesis of diabetic Late complications), joka on FinnDiane:n alatutkimus. FinnDiane:ssa 1945 potilaan liikuntatottumukset kartoitettiin kyselylomakkeen avulla. IDEAL-tutkimuksessa mitattiin 86 nuoren aikuisen tyypin 1 diabetesta sairastavan fyysinen kunto spiroergometrialla (eli polkupyöräkoe hengityskaasumittauksineen) ja tuloksia vertailtiin 27 terveeseen verrokkiin. Potilaat tutkittiin erityisen tarkasti diabeettisten liitännäissairauksien suhteen. Väitöskirjan viidestä osatyöstä neljä käsittelee poikkileikkaustuloksia ja yhdessä lisäksi käytettiin potilaiden seurantatietoja. Liikunta, ja varsinkin sen intensiteetti, oli alhaisempi niillä potilailla joilla oli joko diabeettinen nefropatia, retinopatia tai sydän- ja verisuonisairauksia. Alhainen liikunnan taso oli yhteydessä huonompaan verensokeritasapainoon tyypin 1 diabetesta sairastavilla naisilla ja tämä yhteys havaittiin myös niillä naisilla, joilla ei ollut lainkaan diabeettisia liitännäissairauksia. Vähäinen liikunta oli yhteydessä myös suurempaan verensokeritasapainon (HbA1c) vaihteluun ja tämä vaihtelu oli potilaiden seurannassa osaltaan yhteydessä diabeettisen munuaistaudin etenemiseen sekä sydän- ja verisuonisairauksien ilmaantumiseen. Potilailla, jotka liikkuivat enemmän, oli keskimäärin myös parempi insuliiniherkkyys. Metabolisen oireyhtymän esiintyvyys tyypin 1 diabetesta sairastavilla oli myös suurempi mitä matalampi liikunnan taso oli. Aerobinen kuntotaso (kestävyyskunto, maksimaalinen hapenottokyky) oli nuorilla aikuisilla tyypin 1 diabetesta sairastavilla matalampi verrattuna terveisiin verrokkeihin, joiden ikä-, sukupuoli- ja painoindeksijakauma oli diabetespotilaita vastaava. Lisäksi havaittiin, että korkeampi kuntotaso oli miehillä yhteydessä parempaan verensokeritasapainoon. Näin ollen, korkeampi liikunnan taso tyypin 1 diabetesta sairastavilla potilailla oli yhteydessä parempaan verensokeritasapainoon, mikä lienee edullista ajatellen diabeettisten liitännäissairauksien ehkäisyä

Network of vascular diseases, death and biochemical characteristics in a set of 4,197 patients with type 1 diabetes (The FinnDiane Study)

<p/> <p>Background</p> <p>Cardiovascular disease is the main cause of premature death in patients with type 1 diabetes. Patients with diabetic kidney disease have an increased risk of heart attack or stroke. Accurate knowledge of the complex inter-dependencies between the risk factors is critical for pinpointing the best targets for research and treatment. Therefore, the aim of this study was to describe the association patterns between clinical and biochemical features of diabetic complications.</p> <p>Methods</p> <p>Medical records and serum and urine samples of 4,197 patients with type 1 diabetes were collected from health care centers in Finland. At baseline, the mean diabetes duration was 22 years, 52% were male, 23% had kidney disease (urine albumin excretion over 300 mg/24 h or end-stage renal disease) and 8% had a history of macrovascular events. All-cause mortality was evaluated after an average of 6.5 years of follow-up (25,714 patient years). The dataset comprised 28 clinical and 25 biochemical variables that were regarded as the nodes of a network to assess their mutual relationships.</p> <p>Results</p> <p>The networks contained cliques that were densely inter-connected (<it>r </it>> 0.6), including cliques for high-density lipoprotein (HDL) markers, for triglycerides and cholesterol, for urinary excretion and for indices of body mass. The links between the cliques showed biologically relevant interactions: an inverse relationship between HDL cholesterol and the triglyceride clique (<it>r </it>< -0.3, <it>P </it>< 10^-16), a connection between triglycerides and body mass via C-reactive protein (<it>r </it>> 0.3, <it>P </it>< 10^-16) and intermediate-density cholesterol as the connector between lipoprotein metabolism and albuminuria (<it>r </it>> 0.3, <it>P </it>< 10^-16). Aging and macrovascular disease were linked to death via working ability and retinopathy. Diabetic kidney disease, serum creatinine and potassium, retinopathy and blood pressure were inter-connected. Blood pressure correlations indicated accelerated vascular aging in individuals with kidney disease (<it>P </it>< 0.001).</p> <p>Conclusion</p> <p>The complex pattern of links between diverse characteristics and the lack of a single dominant factor suggests a need for multifactorial and multidisciplinary paradigms for the research, treatment and prevention of diabetic complications.</p

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

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

The Association Between Dietary Sodium Intake, ESRD, and All-Cause Mortality in Patients With Type 1 Diabetes

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 end-stage renal disease (ESRD). RESEARCH DESIGN AND METHODS: In a nationwide multicenter study (the FinnDiane Study) between 1998 and 2002, 2,807 enrolled adults with type 1 diabetes without ESRD were prospectively followed. Baseline urinary sodium excretion was estimated on a 24-h urine collection. The predictors of all-cause mortality and ESRD were determined by Cox regression and competing risk modeling, respectively. RESULTS: The median follow-up for survival analyses was 10 years, during which 217 deaths were recorded (7.7%). Urinary sodium excretion was nonlinearly associated with all-cause mortality, such that individuals with the highest daily urinary sodium excretion, as well as the lowest excretion, had reduced survival. This association was independent age, sex, duration of diabetes, the presence and severity of chronic kidney disease (CKD) (estimated glomerular filtration rate [eGFR] and log albumin excretion rate), the presence of established cardiovascular disease, and systolic blood pressure. During follow-up, 126 patients developed ESRD (4.5%). Urinary sodium excretion was inversely associated with the cumulative incidence of ESRD, such that individuals with the lowest sodium excretion had the highest cumulative incidence of ESRD. CONCLUSIONS: In patients with type 1 diabetes, sodium was independently associated with all-cause mortality and ESRD. Although we have not demonstrated causality, these findings support the calls for caution before applying salt restriction universally. Clinical trials must be performed in diabetic patients to formally test the utility/risk of sodium restriction in this setting

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

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

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

The aim of this study was to investigate whether leisure-time physical activity (LTPA) is associated with the development of severe diabetic retinopathy in individuals with type 1 diabetes.Peer reviewe

Arterial stiffness and vascular complications in patients with type 1 diabetes: The finnish diabetic nephropathy (FinnDiane) study

While patients with type 1 diabetes (T1D) are known to suffer from early cardiovascular disease (CVD), we examined associations between arterial stiffness and diabetic complications in a large patient group with T1D.This study included 807 subjects (622 T1D and 185 healthy volunteers (age 40.6 ± 0.7 versus 41.6 ± 1.2 years; P = NS)). Arterial stiffness was measured by pulse wave analysis from each participant. Furthermore, information on diabetic retinopathy, nephropathy, and CVD was collected. The renal status was verified from at least two out of three urine collections.Patients with T1D without signs of diabetic nephropathy had stiffer arteries measured as the augmentation index (AIx) than age-matched control subjects (17.3% ± 0.6% versus 10.0% ± 1.2%; P0.001). Moreover, AIx (OR 1.08; 95% CI 1.03-1.13; P = 0.002) was associated with diabetic laser-treated retinopathy in patients with normoalbuminuria in a multivariate logistic regression analysis. The same was true for AIx and diabetic nephropathy (1.04 (1.01-1.08); P = 0.004) as well as AIx and CVD (1.06 (1.00-1.12); P = 0.01) in patients with T1D.Arterial stiffness was associated with microvascular and macrovascular complications in patients with T1D

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

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

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

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