Innate immune system and adiponectin in diabetic nephropathy in type 1 diabetes

Introduction: The pathogenesis of diabetic nephropathy remains a matter of debate, although strong evidence suggests that it results from the interaction between susceptibility genes and the diabetic milieu. The true pathogenetic mechanism remains unknown, but a common denominator of micro- and macrovascular complications may exist. Some have suggested that low-grade inflammation and activation of the innate immune system might play a synergistic role in the pathogenesis of diabetic nephropathy. Aims of the study: The present studies were undertaken to investigate whether low-grade inflammation, mannan-binding lectin (MBL) and α-defensin play a role, together with adiponectin, in patients with type 1 diabetes and diabetic nephropathy. Subjects and methods: This study is part of the ongoing Finnish Diabetic Nephropathy Study (FinnDiane). The first four cross-sectional substudies of this thesis comprised 194 patients with type 1 diabetes divided into three groups (normo-, micro-, and macroalbuminuria) according to their albumin excretion rate (AER). The fifth substudy aimed to determine whether baseline serum adiponectin plays a role in the development and progression of diabetic nephropathy. This follow-up study included 1330 patients with type 1 diabetes and a mean follow-up period of five years. The patients were divided into three groups depending on their AER at baseline. As a measure of low-grade inflammation, highly sensitive CRP (hsCRP) and α-defensin were measured with radio-immunoassay, and interleukin-6 (IL-6) with high- sensitivity enzyme immuno-assay. Mannan-binding lectin and adiponectin were determined with time-resolved immunofluorometric assays. The progression of albuminuria from one stage to the other served as a measure of the progression of diabetic nephropathy. Results: Low-grade inflammatory markers, MBL, adiponectin, and α-defensin were all associated with diabetic nephropathy, whereas MBL, adiponectin, and α-defensin per se were unassociated with low-grade inflammatory markers. AER was the only clinical variable independently associated with hsCRP. AER, HDL-cholesterol and the duration of diabetes were independently associated with IL-6. HbA1c was the only variable independently associated with MBL. The estimated glomerular filtration rate (eGFR), AER, and waist-to-hip ratio were independently associated with adiponectin. Systolic blood pressure, HDL-cholesterol, total cholesterol, age, and eGFR were all independently associated with α-defensin. In patients with macroalbuminuria, progression to end-stage renal disease (ESRD) was associated with higher baseline adiponectin concentrations. Discussion and conclusions: Low-grade inflammation, MBL, adiponectin, and defensin were all associated with diabetic nephropathy in these cross-sectional studies. In contrast however, MBL, adiponectin, and defensin were not associated with low-grade inflammatory markers per se. Nor was defensin associated with MBL, which may suggest that these different players function in a coordinated fashion during the deleterious process of diabetic nephropathy. The question of what causes low-grade inflammation in patients with type 1 diabetes and diabetic nephropathy, however, remains unanswered. We could observe in our study that glycemic control, an atherosclerotic lipid profile, and waist-to-hip ratio (WHR) were associated with low-grade inflammation in the univariate analysis, although in the multivariate analysis, only AER, HDL-cholesterol, and the duration of diabetes, as a measure of glycemic load, proved to be independently associated with inflammation. Notably, all these factors are modifiable with changes in lifestyle and/or with a targeted medication. In the follow-up study, elevated serum adiponectin levels at baseline predicted the progression from macroalbuminuria to ESRD independently of renal function at baseline. This observation does not preclude adiponectin as a favorable factor during the process of diabetic nephropathy, since the rise in serum adiponectin concentrations may remain a mechanism by which the body compensates for the demands created by the diabetic milieu.Tausta:Diabeettinen munuaistauti on edelleen loppuvaiheen munuaisten vajaatoiminnan tärkein syy. Diabeettisen munuaistaudin synty ja taudin eteneminen ovat liitetyt perimän ja diabeettisen ympäristön yhteisvaikutukseen, jonka seurauksena n 15-40% tyypin 1 diabeetikoista kehittyy tämä elinmuutos. Diabeettinen munuaistauti liittyy vahvasti sydän- ja verisuonitauteihin ja samalla ennenaikaiseen kuolleisuuteen myös sydäntautien kautta, jonka havainnon myötä on ehdotettu pienten ja suurten verisuonten ongelmien selittyvän yhteisen tekijän kautta ilmaantuviksi. Näitä mahdollisia yhteisiä tekijöitä ovat matala-asteinen tulehdusprosessi ja myötäsyntyisen immuunijärjestelmän aktivoituminen. Tutkimusaineisto ja metodit: Tutkimus on osa FinnDiane (Finnish Diabetic Nephropathy Study) tutkimusta. Tutkimuksen tarkoituksena oli viiden eri osatyön kautta selvittää tyypin 1 diabeetikoilla matala-asteisen tulehduksen, mannaania sitovan lektiinin (MBL), adiponektiinin ja α-defensiinin mahdollista osuutta diabeettisen munuaistaudin synnylle ja taudin etenemiselle. Neljä ensimmäistä osatyötä olivat poikkileikkaustutkimuksia, joissa 194 potilaan joukko oli jaettu munuaisten kautta virtsaan erittyvän albumiinin (AER) perusteella ensin kolmeen ryhmään: normo-, mikro- ja makroalbuminuria. Potilasryhmät kaltaistettiin sukupuolen ja sairastamisajan perusteella. Lyhyin sairastamisaika oli 13 vuotta, joka tarkoittaa normoalbuminuristen kohdalla samalla jo vähäistä todennäköisyyttä sairastua diabeettiseen munuaistautiin jatkossa. Mikroalbuminuriaa tai makroalbuminuriaa edustavat potilaat olivat kaikki ACE-hoidolla, joka hoito noudatti täten verenpainelääkityksen osalta Suomen Käypä-Hoito suositusta. Viidennessä osatyössä selvitettiin adiponektiinin mahdollista osuutta diabeettisen nefropatian synnylle ja etenemiselle. Potilaat jaettiin myös tässä tutkimuksessa lähtötilanteen albuminurian perusteella alussa kolmeen ryhmään. Seurantaan osallistui 1330 tyypin 1 diabeetikkoa seuranta-ajan ollessa 5 vuotta. Herkkä CRP ja α-defensiini määritettiin radio-immunologisella, interleukin-6(IL-6) herkällä entsyymi-immunomenetelmällä ja MBL sekä adiponektiini immunofluorometrisellä menetelmällä. Tulokset: CRP ja IL-6 ovat koholla tyypin 1 diabeetikoilla, joilla on diabeettinen munuaistauti.MBL-, adiponektiini- ja α-defensiinin pitoisuudet ovat suurentuneet diabeettisessa munuaistaudissa, mutta keskinäistä yhteyttä ei ollut todettavissa näiden muutosten ja CRP:n tai IL-6 välillä. Seurantatutkimuksessa oli todettavissa merkittävästi korkeammat alkutilanteen adiponektiinipitoisuudet makroalbuminuriasta loppuvaiheen munuaisten vajaatoimintaan edenneiden diabeetikoiden kohdalla. Keskustelu ja loppupäätelmä: Matala-asteinen tulehdus, MLB, adiponektiini ja α-defensiini liittyvät diabeettiseen munuaistautiin poikkileikkaustutkimustemme valossa. MBL, adiponektiini ja α-defensiini eivät kuitenkaan liittyneet matala-asteiseen tulehdukseen, eikä α-defensiini MBL:iin, jotka havainnot viittaavat näiden eri tekijöiden mahdolliseen koordinoituun toimintaan diabeettisessa munuaistaudissa. Emme kuitenkaan pysty toistaiseksi vastaamaan kysymykseen, mikä tuottaa matala-asteisen tulehduksen tyypin 1 diabeetikoille, joilla on diabeettinen munuaistauti. Mahdollisiin aiheuttajiin saattaa kuulua perimä, ylipaino, korkea verensokeri, poikkeavat veren rasva-arvot, tupakointi ja vähäinen liikunta. Tähän sopien sokeritasapaino, veren rasva-arvot ja korkea vyötärö-lantio-suhde liittyivät matala-asteiseen tulehdukseen alkuanalyysin perusteella, vaikka jatkoanalyysissä vain AER, HDL-kolesteroli ja diabeteksen kesto (=vuosikausien sokeristuminen) liittyivät matala-asteiseen tulehdukseen toisista tekijöistä riippumattomina tekijöinä. On huomattava, että perimää lukuunottamatta em. tekijät ovat muutettavissa joko elämäntavan muutoksilla ja/tai oikein kohdistetulla lääkityksellä. Seurantatutkimuksen alun korkea adiponektiini ennusti diabeetikoiden etenemistä makroalbuminuriasta loppuvaiheen munuaisten vajaatoimintaan riippumatta munuaisten vajaatoiminnan asteesta alussa. Adiponektiinin nousu saattaa kuitenkin myös tässä tilassa toimia yhtenä elimistön mekanismeista, jolla yritetään vähentää diabeettiseen nefropatiaan liittyvän häiriötilan vahingollisuutta munuaisille ja muulle verisuonistolle

Association between adherence to dietary recommendations and high-sensitivity C-reactive protein level in type 1 diabetes

Aims: Inflammation plays an important role in the pathogenesis of cardiovascular diseases. Diet, as a modifiable risk factor, may in turn impact systemic inflammation. We therefore assessed whether adherence to the dietary recommendations is associated with high-sensitivity C-reactive protein (hs-CRP) concentrations in type 1 diabetes. Methods: Cross-sectional data from 677 FinnDiane study participants (48% men, mean +/- standard deviation age 46 +/- 13 years) were included. Dietary intake was assessed with a self-administered questionnaire. A diet score, with higher values denoting better adherence to the recommendations, was calculated. Serum hs-CRP concentration was measured, and individuals with hs-CRP 3.0 but <10.0 mg/l were compared. Results: Men and women with high hs-CRP had higher BMI, waist circumference, and triglyceride concentration, but lower HDL-cholesterol concentration. Adjusted for BMI, mean diet score was higher in the low hs-CRP group, both in men (10.8 +/- 3.6 vs. 9.9 +/- 3.8, p = 0.023) and women (12.7 +/- 3.4 vs. 11.6 +/- 3.5, p = 0.021). After further adjustments with potential confounding factors, the difference remained significant only in men. Conclusions: A diet that more closely adheres to the dietary recommendations is associated with lower hs-CRP in men. A prudent diet may help reduce systemic inflammation in type 1 diabetes. (C) 2017 Elsevier B.V. All rights reserved.Peer reviewe

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

Fear of hypoglycaemia and self-management in type 1 diabetes

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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

Insulin exposure mitigates the increase of arterial stiffness in patients with type 2 diabetes and albuminuria: an exploratory analysis

Aims Insulin possesses both vasodilatory and sympathomimetic activities. The aim was to examine the relationship between changes in insulin exposure and arterial stiffness in type 2 diabetes (T2D). Methods Patients with T2D with (n = 22) or without (n = 24) albuminuria, and non-diabetic controls (n = 25) were randomized to a crossover study having a breakfast with or without pre-meal rapid-acting insulin. Pulse wave velocity (PWV) was measured at 30 min before and at 60-min intervals up to 240 min after the breakfast. Results At baseline, both postprandial aortic (p = 0.022) and brachial (p = 0.011) PWV were higher in individuals with T2D than in healthy controls irrespective of the presence of albuminuria. In patients with albuminuria, weight-adjusted insulin dose correlated inversely with the excursion of the aortic (r = - 0.412, p = 0.006) and brachial (r = - 0.372; p = 0.014) PWV. Similarly, circulating endogenous insulin concentrations correlated inversely with the aortic (r = - 0.347, p = 0.026) and brachial (r = - 0.622, p =Peer reviewe

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

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