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Background: Sedentary behavior, such as excessive sitting, increases risk of cardiovascular disease and premature mortality in the general population, but this has not been assessed in type 1 diabetes. Occupational sitting is increasingly ubiquitous and often constitutes the largest portion of daily sitting time. Our aim was to identify clinical factors associated with excessive occupational sitting in type 1 diabetes and, in a prospective setting, to explore its association with cardiovascular events and all-cause mortality, independent of leisure-time physical activity., Methods: An observational follow-up study of 1,704 individuals (mean age 38.9 ± 10.1 years) from the Finnish Diabetic Nephropathy Study. Excessive occupational sitting, defined as ≥ 6 h of daily workplace sitting, was assessed using a validated self-report questionnaire. Data on cardiovascular events and mortality were retrieved from national registries. Multivariable logistic regression identified independently associated factors, while Kaplan-Meier curves and Cox proportional hazard models were used for prospective analyses., Results: Factors independently and positively associated with excessive occupational sitting included a high occupational category [OR 6.53, 95% CI (4.09‒10.40)] and older age [1.02 (1.00‒1.03)], whereas negatively associated factors included current smoking [0.68 (0.50‒0.92)], moderate albuminuria [0.55 (0.38‒0.80)], and high leisure-time physical activity [0.52 (0.36‒0.74)]. During a median follow-up of 12.5 (6.5-16.4) years, 163 individuals (9.6%) suffered cardiovascular events, and during a median follow-up of 13.7 (9.4-16.6) years, 108 (6.3%) deaths occurred. Excessive occupational sitting increased cardiovascular event risk (hazard ratio [HR] 1.55 [95% CI 1.10‒2.18]) after adjustment for confounders and other covariates. Furthermore, in a stratified multivariable analysis among current smokers, excessive occupational sitting increased the risk of all-cause mortality (2.06 [1.02‒4.20])., Conclusions: Excessive occupational sitting is associated with a higher risk of cardiovascular events and all-cause mortality in individuals with type 1 diabetes. This association persists regardless of leisure-time physical activity, after adjusting for independently associated variables identified in our cross-sectional analyses. These findings underscore the need to update physical activity guidelines to better address sedentary behavior and improve outcomes for individuals with type 1 diabetes. Targeting occupational sitting should be considered a key focus for interventions aimed at reducing overall sedentary time., (© 2024. The Author(s).)

Aims: We estimated overall refill adherence to all antihypertensive [AHT] and/or lipid-lowering drugs in the treatment regimen and its association with cardiovascular disease (CVD) in adults with type 1 diabetes, taking kidney disease into account., Methods: This Finnish Diabetic Nephropathy Study involved 1,558 adults with type 1 diabetes who had purchased AHT and/or lipid-lowering drugs within ± 0.5 year from baseline and were followed until their first CVD event, death, or end of 2015. Proportion of days covered (PDC) method was used to calculate adherence. The adherence was classified as good (≥80 %), intermediate (≥50 and <80%) or poor (<50%)., Results: Median adherence rate was 74% (IQR 63-84 %). Both good (OR 0.55 [95% CI 0.33, 0.92], P=0.02) and intermediate (0.47 [0.29, 0.77], P=0.003) adherence were associated with lower odds of CVD, compared to poor adherence. Moreover, the higher the adherence percentage point in those with moderate albuminuria, the lower was the odds for CVD (0.81 [0.67, 0.98], P=0.03, per 10 unit increase in adherence)., Conclusions: In adults with type 1 diabetes, refill adherence of 50% or more to cardio-protective medications is associated with lower odds of incident CVD. Our findings highlight the relevance of going beyond prescribing protective CVD drugs, ensuring, and improving medication adherence matters., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: P-H.G. has received lecture honoraria from Astellas, Astra Zeneca, Bayer, Boehringer Ingelheim, Eli Lilly, EloWater, Genzyme, Medscape, MSD, Mundipharma, Novartis, Novo Nordisk, Peer Voice, Sanofi and Sciarc. PHG is an advisory board member for AbbVie, Astellas, Astra Zeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Medscape, MSD, Mundipharma, Nestlé, Novartis, Novo Nordisk, and Sanofi. PHG has received investigator-initiated grants from Eli Lilly and Roche. EBPreports receiving lecture honorariums from Eli Lilly, Abbott, Astra Zeneca, Sanofi, and Boehringer Ingelheim. She was an advisory board member of Sanofi, and since February 2024 she has been a Boehringer-Ingelhiememployee. No other potential conflicts of interest relevant to this article were reported. The funding sources were not involved in the design or conduct of the study. All other authors declare that there is no duality of interest associated with this manuscript., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Despite improved glycemic treatment, the impact of glycation on pathological consequences may persist and contribute to adverse clinical outcomes in diabetes. In the present study we investigated the association between serum protein glycation products and progression of kidney disease as well as incident major adverse cardiovascular events (MACE) in type 1 diabetes., Methods: Fructosamine, advanced glycation end products (AGEs), and methylglyoxal-modified hydro-imidazolone (MG-H1) were measured from baseline serum samples in the FinnDiane study (n = 575). Kidney disease progression was defined as steep eGFR decline (> 3 mL/min/1.73 m 2 /year) or progression of albuminuria (from lower to higher stage of albuminuria). MACE was defined as acute myocardial infarction, coronary revascularization, cerebrovascular event (stroke), and cardiovascular death., Results: Fructosamine was independently associated with steep eGFR decline (OR 2.15 [95% CI 1.16-4.01], p = 0.016) in the fully adjusted model (age, sex, baseline eGFR). AGEs were associated with steep eGFR decline (OR 1.58 per 1 unit of SD [95% CI 1.07-2.32], p = 0.02), progression to end-stage kidney disease (ESKD) (HR 2.09 per 1 unit of SD [95% CI 1.43-3.05], p < 0.001), and pooled progression (to any stage of albuminuria) (HR 2.72 per 1 unit of SD [95% CI 2.04-3.62], p < 0.001). AGEs (HR 1.57 per 1 unit of SD [95% CI 1.23-2.00], p < 0.001) and MG-H1 (HR 4.99 [95% CI 0.98-25.55], p = 0.054) were associated with incident MACE. MG-H1 was also associated with pooled progression (HR 4.19 [95% CI 1.11-15.89], p = 0.035). Most AGEs and MG-H1 associations were no more significant after adjusting for baseline eGFR., Conclusions: Overall, these findings suggest that protein glycation products are an important risk factor for target organ damage in type 1 diabetes. The data provide further support to investigate a potential causal role of serum protein glycation in the progression of diabetes complications., (© 2024. The Author(s).)

Background: Dyslipidemia is a major risk factor for cardiovascular disease, and diabetes impacts the lipid metabolism through multiple pathways. In addition to the standard lipid measurements, apolipoprotein concentrations provide added awareness of the burden of circulating lipoproteins. While common genetic variants modestly affect the serum lipid concentrations, rare genetic mutations can cause monogenic forms of hypercholesterolemia and other genetic disorders of lipid metabolism. We aimed to identify low-frequency protein-altering variants (PAVs) affecting lipoprotein and lipid traits., Methods: We analyzed whole-exome (WES) and whole-genome sequencing (WGS) data of 481 and 474 individuals with type 1 diabetes, respectively. The phenotypic data consisted of 79 serum lipid and apolipoprotein phenotypes obtained with clinical laboratory measurements and nuclear magnetic resonance spectroscopy., Results: The single-variant analysis identified an association between the LIPC p.Thr405Met (rs113298164) and serum apolipoprotein A1 concentrations (p=7.8×10 -8 ). The burden of PAVs was significantly associated with lipid phenotypes in LIPC, RBM47, TRMT5, GTF3C5, MARCHF10, and RYR3 (p<2.9×10 -6 ). The RBM47 gene is required for apolipoprotein B post-translational modifications, and in our data, the association between RBM47 and apolipoprotein C-III concentrations was due to a rare 21 base pair p.Ala496-Ala502 deletion; in replication, the burden of rare deleterious variants in RBM47 was associated with lower triglyceride concentrations in WES of >170,000 individuals from multiple ancestries (p=0.0013). Two PAVs in GTF3C5 were highly enriched in the Finnish population and associated with cardiovascular phenotypes in the general population. In the previously known APOB gene, we identified novel associations at two protein-truncating variants resulting in lower serum non-HDL cholesterol (p=4.8×10 -4 ), apolipoprotein B (p=5.6×10 -4 ), and LDL cholesterol (p=9.5×10 -4 ) concentrations., Conclusions: We identified lipid and apolipoprotein-associated variants in the previously known LIPC and APOB genes, as well as PAVs in GTF3C5 associated with LDLC, and in RBM47 associated with apolipoprotein C-III concentrations, implicated as an independent CVD risk factor. Identification of rare loss-of-function variants has previously revealed genes that can be targeted to prevent CVD, such as the LDL cholesterol-lowering loss-of-function variants in the PCSK9 gene. Thus, this study suggests novel putative therapeutic targets for the prevention of CVD., (© 2022. The Author(s).)

Objectives: We studied apolipoprotein C-III (apoC-III) in relation to diabetic kidney disease (DKD), cardiovascular outcomes, and mortality in type 1 diabetes., Methods: The cohort comprised 3966 participants from the prospective observational Finnish Diabetic Nephropathy Study. Progression of DKD was determined from medical records. A major adverse cardiac event (MACE) was defined as acute myocardial infarction, coronary revascularization, stroke, or cardiovascular mortality through 2017. Cardiovascular and mortality data were retrieved from national registries., Results: ApoC-III predicted DKD progression independent of sex, diabetes duration, blood pressure, HbA 1c , smoking, LDL-cholesterol, lipid-lowering medication, DKD category, and remnant cholesterol (hazard ratio [HR] 1.43 [95% confidence interval 1.05-1.94], p = 0.02). ApoC-III also predicted the MACE in a multivariable regression analysis; however, it was not independent of remnant cholesterol (HR 1.05 [0.81-1.36, p = 0.71] with remnant cholesterol; 1.30 [1.03-1.64, p = 0.03] without). DKD-specific analyses revealed that the association was driven by individuals with albuminuria, as no link between apoC-III and the outcome was observed in the normal albumin excretion or kidney failure categories. The same was observed for mortality: Individuals with albuminuria had an adjusted HR of 1.49 (1.03-2.16, p = 0.03) for premature death, while no association was found in the other groups. The highest apoC-III quartile displayed a markedly higher risk of MACE and death than the lower quartiles; however, this nonlinear relationship flattened after adjustment., Conclusions: The impact of apoC-III on MACE risk and mortality is restricted to those with albuminuria among individuals with type 1 diabetes. This study also revealed that apoC-III predicts DKD progression, independent of the initial DKD category., (© 2021 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

This study assessed the association of CD5L and soluble CD36 (sCD36) with the risk of a cardiovascular event (CVE), including CV death and all-cause mortality in CKD. We evaluated the association of CD5L and sCD36 with a predefined composite CV endpoint (unstable angina, myocardial infarction, transient ischemic attack, cerebrovascular accident, congestive heart failure, arrhythmia, peripheral arterial disease [PAD] or amputation by PAD, aortic aneurysm, or death from CV causes) and all-cause mortality using Cox proportional hazards regression, adjusted for CV risk factors. The analysis included 1,516 participants free from pre-existing CV disease followed up for 4 years. The median age was 62 years, 38.8% were female, and 26.8% had diabetes. There were 98 (6.5%) CVEs and 72 (4.8%) deaths, of which 26 (36.1%) were of CV origin. Higher baseline CD5L concentration was associated with increased risk of CVE (HR, 95% CI, 1.17, 1.0-1.36), and all-cause mortality (1.22, 1.01-1.48) after adjusting for age, sex, diabetes, systolic blood pressure, dyslipidemia, waist circumference, smoking, and CKD stage. sCD36 showed no association with adverse CV outcomes or mortality. Our study showed for the first time that higher concentrations of CD5L are associated with future CVE and all-cause mortality in individuals with CKD.

Fatty acid binding protein 4 (FABP4) is implicated in the pathogenesis of cardiometabolic disorders. Pharmacological inhibition or genetic deletion of FABP4 improves cardiometabolic health and protects against atherosclerosis in preclinical models. As cardiovascular disease (CVD) is common in type 1 diabetes, we examined the role of FABP4 in the development of complications in type 1 diabetes, focusing on a functional, low-expression variant (rs77878271) in the promoter of the FABP4 gene. For this, we assessed the risk of CVD, stroke, coronary artery disease (CAD), end-stage kidney disease, and mortality using Cox proportional hazards models for the FABP4 rs77878271 in 5,077 Finnish individuals with type 1 diabetes. The low-expression G allele of rs77878271 increased the risk of CVD, independent of confounders. Findings were tested for replication in 852 Danish and 3,678 Finnish individuals with type 1 diabetes. In the meta-analysis, each G allele increased the risk of stroke by 26% ( P = 0.04), CAD by 26% ( P = 0.006), and CVD by 17% ( P = 0.003). In Mendelian randomization, a 1-SD unit decrease in FABP4 increased risk of CAD 2.4-fold. Hence, in contrast with the general population, among patients with type 1 diabetes the low-expression G allele of rs77878271 increased CVD risk, suggesting that genetically low FABP4 levels may be detrimental in the context of type 1 diabetes., (© 2021 by the American Diabetes Association.)

Background: Cardiovascular disease is the main determinant of premature mortality in patients with type 1 diabetes. However, time trends regarding different types of cardiovascular disease in childhood-onset type 1 diabetes with a long timespan from the diagnosis of diabetes are not well established. This study aimed to investigate the cumulative incidence of cardiovascular disease in individuals with type 1 diabetes in a population-based cohort in Finland, the country with the world's highest incidence of type 1 diabetes., Methods: In this retrospective, nationwide registry-based, cohort study, all patients who were diagnosed between Jan 1, 1965, and Dec 31, 1999 with type 1 diabetes when they were younger than 15 years old in Finland were followed up and monitored for the occurrence of cardiovascular disease (including coronary artery disease, stroke, peripheral artery disease, and heart failure) until the end of 2016 and for cardiovascular disease mortality until 2017. Cumulative incidences of cardiovascular disease were calculated by the Fine and Gray method according to the year of diabetes diagnosis using six diagnosis cohorts: 1965-69, 1970-74, 1975-1979, 1980-84, 1985-89, 1990-94, and 1990-95. Trends in cardiovascular disease event rates were analysed by Fine and Gray competing risks regression models using year of diabetes diagnosis as continuous variable. In addition, non-linearity in trends was assessed with restricted cubic splines. The excess risk of coronary artery disease and stroke was estimated by comparison with the risk in the Finnish general population by calculating standardised incidence ratios (SIRs) and their time trends. The data for Finnish general population were drawn from the Cardiovascular Disease Register of the National Institute of Health and Welfare. The SIRs were calculated as ratios of observed and expected number of events in individuals with type 1 diabetes during 1991-2014., Findings: 11 766 individuals were included in this study. During 361 033 person-years of follow-up and a median of 29·6 years (IQR 22·3-37·9) follow-up, a total of 1761 individuals had single or multiple types of cardiovascular disease events. 2686 events (864 [32·2%] coronary artery disease events, of which 663 were acute myocardial infarctions; 497 [18·5%] strokes; 854 [31·8%] peripheral artery diseases, of which 498 were lower extremity amputations; and 471 [17·5%] heart failure events) were reported until Dec 31, 2016, and 1467 deaths until Dec 31, 2017. Cardiovascular disease risk decreased linearly by 3·8% (hazard ratio [HR] 0·96 [95% CI 0·96-0·97]; p<0·0001) by later calendar year of diabetes diagnosis (p<0·0001). There was a decrease in the SIRs for both coronary artery disease and stroke within all 10-year age groups under 65 years, except for stroke in the oldest age group. However, the SIR was still 8·9 (95% CI 3·9-17·5) for coronary artery disease and 2·9 (1·3-5·7) for stroke in those diagnosed with type 1 diabetes in the 1990s. Finally, the cardiovascular disease death rate decreased constantly by diagnosis year., Interpretation: The risk of cardiovascular disease has decreased over time in Finland in individuals with childhood-onset type 1 diabetes. However, there is still considerable excess cardiovascular disease risk in individuals with type 1 diabetes compared with the general population. These results highlight the need for studies on the mechanisms of atherosclerosis from the time of diagnosis of type 1 diabetes to facilitate early and effective prevention of cardiovascular disease in these individuals., Funding: Folkhälsan Research Foundation, Academy of Finland, Wilhelm and Else Stockmann Foundation, Liv och Hälsa Society, Novo Nordisk Foundation, Finnish Foundation for Cardiovascular Research, Finnish Diabetes Research Foundation, Diabetes Research Foundation, Medical Society of Finland, Sigrid Jusélius Foundation, and Helsinki University Hospital Research Funds., Competing Interests: Declaration of interests P-HG reports honoraria from Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Elo Water, Genzyme, Medscape, Merck Sharpe & Dohme, Mundipharma, Novartis, Novo Nordisk, Peer Voice, and Sanofi; and is an advisory board member of AbbVie, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Janssen, Medscape, Merck Sharpe & Dohme, Novartis, Novo Nordisk, and Sanofi. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: The aim of this study was to determine the incidence of cardiovascular disease (CVD) and mortality as well as their risk factors in type 1 diabetes (T1D) of >50 years' duration., Research Design and Methods: From 5,396 individuals included in the Finnish Diabetic Nephropathy Study (FinnDiane), 729 diagnosed in 1967 or earlier survived with T1D for >50 years. In this FinnDiane 50-year cohort, cumulative incidence of CVD events was assessed from the diagnosis of diabetes, and the excess CVD risk, compared with 12,710 matched individuals without diabetes. In addition, risk factors for different types of CVD (both nonfatal and fatal) and mortality were analyzed, and cause-specific hazard ratios were estimated during a median follow-up of 16.6 years from the baseline visit (median duration of diabetes 39 years at baseline)., Results: In individuals with diabetes duration of >50 years, the 60-year cumulative incidence of CVD from the diagnosis of diabetes was 64.3% (95% CI 62.5-66.0). Compared with individuals without diabetes, the standardized incidence ratio for CVD was 7.4 (6.5-8.3); in those with normoalbuminuria, it was 4.9 (4.0-5.9). Mean HbA 1c and HbA 1c variability, dyslipidemia, BMI, kidney disease, age, and diabetes duration were the variables associated with incident CVD. In particular, HbA 1c was associated with peripheral artery disease (PAD). The standardized mortality ratio compared with the Finnish background population was 3.2 (2.8-3.7). The factors associated with mortality were diabetes duration, increased HbA 1c variability, inflammation, insulin resistance, kidney disease, and PAD., Conclusions: Individuals with T1D of very long duration are at a high risk of CVD. In addition, throughout the lifespan, optimal glycemic control remains central to CVD and excess mortality prevention., (© 2021 by the American Diabetes Association.)

H-ficolin recognizes patterns on microorganisms and stressed cells and can activate the lectin pathway of the complement system. We aimed to assess H-ficolin in relation to the progression of diabetic kidney disease (DKD), all-cause mortality, diabetes-related mortality, and cardiovascular events. Event rates per 10-unit H-ficolin-increase were compared in an observational follow-up of 2,410 individuals with type 1 diabetes from the FinnDiane Study. DKD progression occurred in 400 individuals. The unadjusted hazard ratio (HR) for progression was 1.29 (1.18-1.40) and 1.16 (1.05-1.29) after adjustment for diabetes duration, sex, HbA 1c , systolic blood pressure, and smoking status. After adding triglycerides to the model, the HR decreased to 1.07 (0.97-1.18). In all, 486 individuals died, including 268 deaths of cardiovascular causes and 192 deaths of complications to diabetes. HRs for all-cause mortality and cardiovascular mortality were 1.13 (1.04-1.22) and 1.05 (0.93-1.17), respectively, in unadjusted analyses. These estimates lost statistical significance in adjusted models. However, the unadjusted HR for diabetes-related mortality was 1.19 (1.05-1.35) and 1.18 (1.02-1.37) with the most stringent adjustment level. Our results, therefore, indicate that H-ficolin predicts diabetes-related mortality, but neither all-cause mortality nor fatal/non-fatal cardiovascular events. Furthermore, H-ficolin is associated with DKD progression, however, not independently of the fully adjusted model.

Background: ABO blood groups have previously been associated with cardiovascular disease (CVD) in the general population. This study aimed to investigate the potential relationship between ABO blood groups and CVD in individuals with type 1 diabetes according to diabetic nephropathy (DN) status., Methods: Adults with type 1 diabetes (4531 individuals) from the FinnDiane Study were evaluated. DN was determined by two out of three measurements of urinary albumin excretion rate. Albuminuria was defined as an excretion rate above 20 µg/min. CVD events were identified by linking the data with the Finnish Care Register for Health Care and the Finnish Cause of Death Register. Follow-up ranged from the baseline visit until a CVD event, death or the end of 2017. The impact of ABO blood groups on CVD risk was estimated by multivariable Cox-regression analyses adjusted for traditional risk factors., Results: At baseline, the median age was 38.5 (IQR 29.2-47.9) years, 47.5% were female and median duration of diabetes was 20.9 (11.4-30.7) years. There were 893 incident ischemic heart disease (IHD) events, 301 ischemic strokes (IS), and 415 peripheral artery disease (PAD) events during a median follow up of 16.5 (IQR 12.8-18.6) years. The A blood group showed the highest risk of IHD versus the O blood group, when microalbuminuria was present. Comparing the population with microalbuminuria with those with normoalbuminuria, only the A blood group elevated the risk of IHD. This increased risk was neither explained by the FUT2 secretor phenotype nor by the A-genotype distribution. The risk of IS or PAD was no different among the ABO blood groups regardless of diabetic nephropathy stage., Conclusion: The A blood group is a risk factor for IHD in individuals with type 1 diabetes and microalbuminuria.

Objective: It is well established that diabetic nephropathy increases the risk of cardiovascular disease (CVD), but how severe diabetic retinopathy (SDR) impacts this risk has yet to be determined., Research Design and Methods: The cumulative incidence of various CVD events, including coronary heart disease (CHD), peripheral artery disease (PAD), and stroke, retrieved from registries, was evaluated in 1,683 individuals with at least a 30-year duration of type 1 diabetes drawn from the Finnish Diabetic Nephropathy Study (FinnDiane). The individuals were divided into four groups according to the presence of diabetic kidney disease (DKD) and/or SDR (+DKD/+SDR, +DKD/-SDR, -DKD/+SDR, and -DKD/-SDR) at baseline visit. Furthermore, age-specific incidences were compared with 4,016 control subjects without diabetes. SDR was defined as laser photocoagulation and DKD as estimated glomerular filtration rate <60 mL/min/1.73 m 2 ., Results: During 12,872 person-years of follow-up, 416 incident CVD events occurred. Even in the absence of DKD, SDR increased the risk of any CVD (hazard ratio 1.46 [95% CI 1.11-1.92]; P < 0.01), after adjustment for diabetes duration, age at diabetes onset, sex, smoking, blood pressure, waist-to-hip ratio, history of hypoglycemia, and serum lipids. In particular, SDR alone was associated with the risk of PAD (1.90 [1.13-3.17]; P < 0.05) and CHD (1.50 [1.09-2.07; P < 0.05) but not with any stroke. Moreover, DKD increased the CVD risk further (2.85 [2.13-3.81]; P < 0.001). However, the risk was above that of the control subjects without diabetes also in patients without microvascular complications, until the patients reached their seventies., Conclusions: SDR alone, even without DKD, increases cardiovascular risk, particularly for PAD, independently of common cardiovascular risk factors in long-standing type 1 diabetes. More remains to be done to fully understand the link between SDR and CVD. This knowledge could help combat the enhanced cardiovascular risk beyond currently available regimens., (© 2018 by the American Diabetes Association.)

Diabetic kidney disease and other long-term complications are common in diabetes, and comprise the main cause of co-morbidity and premature mortality in individuals with diabetes. While familial clustering and heritability have been reported for all diabetic complications, the genetic background and the molecular mechanisms remain poorly understood. In recent years, genome-wide association studies have identified a few susceptibility loci for the renal complications as well as for diabetic retinopathy, diabetic cardiovascular disease and mortality. As for many complex diseases, the genetic factors increase the risk of complications in concert with the environment, and certain associations seem specific for particular conditions, for example, SP3-CDCA7 associated with end-stage renal disease only in women, or MGMT and variants on chromosome 5q13 associated with cardiovascular mortality only under tight glycaemic control. The characterization of the phenotypes is one of the main challenges for genetic research on diabetic complications, in addition to an urgent need to increase the number of individuals with diabetes with high quality phenotypic data to be included in future genetic studies., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

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.

Objective: Independent association of chronic kidney disease (CKD) and proliferative diabetic retinopathy (PDR) with cardiovascular disease (CVD) has not been established. In the Joslin 50-Year Medalist study, characterizing individuals with type 1 diabetes for 50 years or more, we examined the associations of CKD and PDR with CVD, which was validated by another cohort with type 1 diabetes from Finland., Research Design and Methods: This cross-sectional study characterized U.S. residents ( n = 762) with type 1 diabetes of 50 years or longer (Medalists) at a single site by questionnaire, clinical, ophthalmic, and laboratory studies. A replication cohort ( n = 675) from the longitudinal Finnish Diabetic Nephropathy Study (FinnDiane) was used. CKD and PDR were defined as estimated glomerular filtration rate <45 mL/min/1.73 m 2 (CKD stage 3b) and according to the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol, respectively. CVD was based on questionnaires and/or hospital discharge registers. Associations of CVD status with CKD and PDR were analyzed by multivariable logistic regression., Results: CVD prevalence in the Medalists with CKD and without PDR (+CKD/-PDR) ( n = 30) and CVD prevalence in the -CKD/+PDR group ( n = 339) were half the prevalence in the +CKD/+PDR group ( n = 66) (34.5% and 42.8% vs. 68.2%, P = 0.002). PDR status was independently associated with CVD (odds ratio 0.21 [95% CI 0.08-0.58], P = 0.003) in patients with CKD. Among the Finnish cohort, a trend toward a lower prevalence of CVD in the +CKD/-PDR group ( n = 21) compared with the +CKD/+PDR group ( n = 170) (19.1% vs. 37.1%, P = 0.10) was also observed., Conclusions: Absence of PDR in people with type 1 diabetes and CKD was associated with a decreased prevalence of CVD, suggesting that common protective factors for PDR and CVD may exist., (© 2018 by the American Diabetes Association.)

The increasing prevalence of chronic kidney disease (CKD) and diabetes over the last decade has resulted in increasing numbers of frail older patients with a combination of these conditions. Current treatment guidelines may not necessarily be relevant for such patients, who are mostly excluded from the trials upon which these recommendations are based. There is a paucity of data upon which to base the management of older patients with CKD. Nearly all current guidelines recommend less-tight glycaemic control for the older population, citing the lack of proven medium-term benefits and concerns about the high short-term risk of hypoglycaemia. However, reports from large landmark trials have shown potential benefits for both microvascular and macrovascular complications, though the relevance of these findings to this specific population is uncertain. The trials have also highlighted potential alternative explanations for the hazards of intensive glycaemic control. These include depression, low endogenous insulin reserve, low body mass index and side effects of the medication. Over the last few years, newer classes of hypoglycaemic drugs with a lower risk of hypoglycaemia have emerged. This article aims to present a balanced view of advantages and disadvantages of intense glycaemic control in this group of patients, which we hope will help the clinician and patient to come to an individualized management approach., (© The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

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

Controlling the blood glucose level is of outmost importance for the prevention of the micro- and macrovascular diabetic complications observed in patients with type 1 diabetes (T1D). Although the pathogenesis behind the complex cascade of complications is far from solved, one possible mechanism could be a negative effect of glucose on the arteries resulting in a stiffening of the arteries and ultimately in vascular complications. Intriguingly, patients with T1D have been shown to suffer from premature arterial aging compared to nondiabetic subjects-an association that is even more evident in the presence of diabetic complications such as diabetic nephropathy. Arterial stiffness has in several patient populations been shown to independently predict cardiovascular disease. However, interventional studies aimed at attenuating arterial stiffness to reduce cardiovascular disease in T1D are yet to come. Moreover, most of the data on pharmacological treatments of arterial stiffening are directed toward pathophysiological pathways other than hyperglycemia. Interestingly, the sodium-glucose transport-2 (SGLT2) inhibitor empagliflozin was recently shown to reduce both blood pressure and arterial stiffness in patients with type 2 diabetes. Whether, these effects can also be replicated in patients with T1D is an intriguing question. Tight metabolic and antihypertensive control are still of central importance for the prevention and the treatment of diabetic complications. However, the need for a noninvasive intermediate marker to identify at risk patients for aggressive treatment is evident. One such tool might be arterial stiffness linking diabetes to increased cardiovascular risk. Future research efforts exploring large-scale databases will play a key role in the identification of other clinically useful markers., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: PHG has received lecture fees from Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Genzyme, MSD, Novartis, Novo Nordisk, and Sanofi. He is an advisory board member of Abbvie, Astra Zeneca, Boehringer Ingelheim, Cebix, Eli Lilly, Janssen, MSD, and Novartis., (© 2016 Diabetes Technology Society.)

Aims: Cardiovascular autonomic dysfunction, evaluated as baroreflex sensitivity (BRS), could be acutely corrected by slow breathing or oxygen administration in patients with type 1 diabetes, thus suggesting a functional component of the disorder. We tested this hypothesis in patients with the type 2 diabetes with or without renal impairment., Methods: Twenty-six patients with type 2 diabetes (aged 61.0 ± 0.8 years, mean ± SEM; duration of diabetes 10.5 ± 2 years, BMI 29.9 ± 0.7 kg/m(2), GFR 68.1 ± 5.6 ml/min) and 24 healthy controls (aged 58.5 ± 1.0 years) were studied. BRS was obtained from recordings of RR interval and systolic blood pressure fluctuations during spontaneous and during slow, deep (6 breaths/min) controlled breathing in conditions of normoxia or hyperoxia (5 l/min oxygen)., Results: During spontaneous breathing, diabetic patients had lower RR interval and lower BRS compared with the control subjects (7.1 ± 1.2 vs. 12.6 ± 2.0 ms/mmHg, p < 0.025). Deep breathing and oxygen administration significantly increased arterial saturation, reduced RR interval and increased BRS in both groups (to 9.6 ± 1.8 and 15.4 ± 2.4 ms/mmHg, respectively, p < 0.05, hyperoxia vs. normoxia). Twelve diabetic patients affected by chronic diabetic kidney disease (DKD) presented a significant improvement in the BRS during slow breathing and hyperoxia (p < 0.025 vs. spontaneous breathing during normoxia)., Conclusions: Autonomic dysfunction present in patients with type 2 diabetes can be partially reversed by slow breathing, suggesting a functional role of hypoxia, also in patients with DKD. Interventions known to relieve tissue hypoxia and improve autonomic function, like physical activity, may be useful in the prevention and management of complications in patients with diabetes.

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 < 0.0001) for those without DN. In those with DN, the risk of CVD was higher if BP was not on target [hazard ratio (HR) 1.9 (1.1-3.3)], or none of the three targets [HR 2.2 (1.4-3.6)] were reached than if BP was on target. Although the risk of death without DN was higher in those who reached none of the targets (P = 0.003), after adjustment, no differences were observed between the groups. Failure to reach ADA treatment targets is associated with increased risk of mortality and CVD in patients with type 1 diabetes.

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.

Objective: Osteopontin (OPN) is a multifunctional protein suggested to be a player in the arterial disease of patients with type 2 diabetes. However, its role for complications in patients with type 1 diabetes (T1D) is unknown. We therefore investigated the associations between OPN and diabetic vascular complications and all-cause mortality in patients with T1D., Research Design and Methods: Serum OPN was measured in 2,145 adults with T1D without end-stage renal disease (ESRD; dialysis or transplantation) as part of the Finnish Diabetic Nephropathy (FinnDiane) Study. Data on renal status, cardiovascular disease (CVD), and all-cause mortality during follow-up were verified from medical files, hospital discharge registries, and the Finnish National Death Registry, respectively. The median follow-up time was 10.5 (interquartile range 8.9-11.8) years., Results: Serum OPN was higher at baseline in patients who developed incident microalbuminuria (16.0 ± 0.9 vs. 14.1 ± 0.2 µg/L; P = 0.04), progressed to ESRD (28.3 ± 1.7 vs. 15.4 ± 0.2 µg/L; P < 0.001), suffered an incident CVD event (20.2 ± 1.2 vs. 15.5 ± 0.2 µg/L; P < 0.001), or died (23.3 ± 1.4 vs. 15.8 ± 0.2 µg/L; P < 0.001) during follow-up. In multivariate Cox regression analysis, OPN was independently associated with the development of incident microalbuminuria, an incident CVD event, and death, after adjustments for associated risk factors. Even after calculating reclassification indexes, OPN was predictive of CVD and all-cause mortality beyond the Framingham risk score covariates and hs-CRP., Conclusions: Serum OPN is a strong predictor of incipient diabetic nephropathy, a first-ever CVD event, and all-cause mortality in patients with T1D. Serum OPN may be of clinical significance for the risk prediction of CVD events in patients with T1D., (© 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

A history of pre-eclampsia increases the risk of cardiovascular morbidity by mechanisms yet unknown. The aim of the present study was to assess whether plasma norepinephrine (NE) levels are increased 5-6 years after pre-eclamptic pregnancy and to investigate associations with pathophysiological mechanisms of cardiovascular disease: insulin sensitivity, vascular function and arterial pressure. A total of 28 women with previous pre-eclampsia and 20 controls were examined. Blood pressure (BP) and plasma levels of NE and endothelin-1 (ET-1) were measured at rest and after standing for 5 min. Insulin sensitivity was assessed with minimal model analysis and vascular function was assessed using venous occlusion plethysmography and pulse wave analysis. Twenty-four-hour BP measurements were carried out. Women with previous pre-eclampsia had higher levels of NE at rest (P=0.02), which did not associate significantly with insulin sensitivity or overall vasodilatory capacity. The 24-h mean of systolic and diastolic blood pressures (BPs) and heart rate did not differ between the groups (P=0.30, P=0.10 and P=0.46, respectively), and there was no significant association with NE levels. ET-1 levels were similar between the groups, but a positive correlation with systolic (P=0.04) and diastolic (P=0.03) BPs in the upright position was shown in the patient group. Increased levels of plasma NE are sustained in women with previous pre-eclampsia and may contribute to the increased risk for cardiovascular disease in these women.

Objective: Osteoprotegerin (OPG) is involved in the process of vascular calcification. We investigated whether OPG is associated with the development and progression of diabetes complications in adults with type 1 diabetes (T1D)., Research Design and Methods: Serum OPG was measured in 1,939 adults with T1D participating in the Finnish Diabetic Nephropathy (FinnDiane) Study. Patients with end-stage renal disease (dialysis or transplantation) at baseline were excluded from analysis. Data on cardiovascular (CV) events and mortality during follow-up were verified from hospital discharge registries (ICD codes) and the Finnish National Death Registry, respectively. The follow-up time was 10.4 ± 2.0 (mean ± SD) years., Results: Only patients with macroalbuminuria and/or renal impairment had elevated OPG concentrations, when compared with participants without overt kidney disease. Patients with retinopathy or CV disease also had higher OPG concentrations, but this was attributable to their higher frequency of chronic kidney disease. OPG predicted an incident CV event (hazard ratio 1.21 [95% CI 1.01-1.45]; P = 0.035) and peripheral vascular disease/amputation events (1.46 [1.13-1.88]; P = 0.004) during follow-up., Conclusions: We showed that serum OPG is an independent predictor of CV complications. OPG may be directly involved in extraosseous calcification, resulting in stiffening of the arteries and subsequent vascular insufficiency in patients with T1D.

Aims/hypothesis: Patients with type 1 diabetes and kidney disease have a higher risk of cardiovascular events. HLA class II genes are expressed on infiltrated inflammatory cells and smooth-muscle cells in atherosclerotic plaques. We hypothesised that HLA class II haplotypes or genotypes might influence the risk of cardiovascular complications and death in Finnish type 1 diabetic patients., Methods: We included 3,082 patients with type 1 diabetes from the Finnish Diabetic Nephropathy Study. We analysed the 12 and ten most common HLA II haplo- and genotypes, respectively, using χ (2) tests. The positive findings were analysed with three differently adjusted regression models with cardiovascular morbidity and death as endpoints. Different kidney status groups were analysed separately., Results: At baseline, the common (DR1/10)-DQB1*05:01 haplotype (20.4%) and the (DR1/10)-DQB1*05:01/DRB1*04:01-DQB1*03:02 genotype (8.7%) were independently associated with cardiovascular disease in all kidney status groups, except in patients with normal AER. At follow-up (9.45 years; range 0.1-16.1 years), the (DR1/10)-DQB1*05:01/DRB1*04:01-DQB1*03:02 genotype was associated with cardiovascular mortality rates in patients with normal AER and microalbuminuria., Conclusions/interpretation: The (DR1/10)-DQB1*05:01 haplotype and the (DR1/10)-DQB1*05:01/DRB1*04:01-DQB1*03:02 genotype are independently associated with cardiovascular events and death in Finnish type 1 diabetic patients.

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.

Background: Adiponectin is widely regarded as an anti-atherogenic, antioxidant and anti-inflammatory molecule. However, adiponectin concentration is paradoxically increased in individuals with type 1 diabetes, in whom it is positively associated with adverse clinical outcomes., Objective: To explore the association between serum adiponectin concentration and mortality outcomes in adults with type 1 diabetes., Design: Multicentre prospective cohort study., Setting: Primary and tertiary care., Subjects: Finnish adults with type 1 diabetes (n= 2034). Main outcome measures.  All-cause and cardiovascular mortality. Independent predictors of mortality were determined using the Cox and the Fine and Gray competing risks proportional hazards models., Results: During a median of 11 years of follow-up, there were 173 deaths (8.5%, 1.0 per hundred person-years). Adiponectin was linearly associated with all-cause mortality [Cox model: hazard ratio (HR) 1.02, 95% confidence interval (CI) 1.01-1.03, P<0.001] and cardiovascular mortality (Fine and Gray model: HR 1.02, 95% CI 1.00-1.04, P=0.035); patients with the highest adiponectin concentrations had the shortest survival. The mortality risk associated with adiponectin was independent of glycaemic and lipid control, pre-existing cardiovascular disease, markers of inflammation and the presence and severity of kidney disease., Conclusions: Although adiponectin is generally considered to be a protective molecule, increased concentrations of adiponectin in type 1 diabetes are independently associated with all-cause and cardiovascular mortality. Moreover, the fact that this association was observed for the first time in patients with normal urinary albumin levels, who have few comorbidities, suggests that adiponectin is specifically linked with vascular damage in type 1 diabetes., (© 2011 The Association for the Publication of the Journal of Internal Medicine.)

Purpose: To investigate whether variants in cardiovascular candidate genes, some of which have been previously associated with type 2 diabetes (T2D), diabetic retinopathy (DR), and diabetic nephropathy (DN), are associated with DR in the Candidate gene Association Resource (CARe)., Methods: Persons with T2D who were enrolled in the study (n = 2691) had fundus photography and genotyping of single nucleotide polymorphisms (SNPs) in 2000 candidate genes. Two case definitions were investigated: Early Treatment Diabetic Retinopathy Study (ETDRS) grades ≥ 14 and ≥ 30. The χ² analyses for each CARe cohort were combined by Cochran-Mantel-Haenszel (CMH) pooling of odds ratios (ORs) and corrected for multiple hypothesis testing. Logistic regression was performed with adjustment for other DR risk factors. Results from replication in independent cohorts were analyzed with CMH meta-analysis methods., Results: Among 39 genes previously associated with DR, DN, or T2D, three SNPs in P-selectin (SELP) were associated with DR. The strongest association was to rs6128 (OR = 0.43, P = 0.0001, after Bonferroni correction). These associations remained significant after adjustment for DR risk factors. Among other genes examined, several variants were associated with DR with significant P values, including rs6856425 tagging α-l-iduronidase (IDUA) (P = 2.1 × 10(-5), after Bonferroni correction). However, replication in independent cohorts did not reveal study-wide significant effects. The P values after replication were 0.55 and 0.10 for rs6128 and rs6856425, respectively., Conclusions: Genes associated with DN, T2D, and vascular diseases do not appear to be consistently associated with DR. A few genetic variants associated with DR, particularly those in SELP and near IDUA, should be investigated in additional DR cohorts.

Objective: Pulse pressure (PP), an estimate of arterial stiffness, has been shown to be associated with incident cardiovascular disease (CVD) in patients with type 1 diabetes (T1D). However, diabetic kidney disease, a strong predictor of CVD, was not previously taken into account. Furthermore, the role of PP as a predictor of diabetic nephropathy is not known. Therefore, we prospectively investigated the associations between PP and these diabetes complications in patients with T1D., Research Design and Methods: A total of 4,509 patients from the FinnDiane Study participated. Follow-up data on incident CVD events and renal status (median 5.3 years) were available in 69 and 76% of the patients, respectively. Altogether, 269 patients (8.6%) had an incident CVD event and 370 patients (10.8%) progressed to a higher level of albuminuria or to end-stage renal disease., Results: PP was higher at baseline in patients who experienced a CVD event (66 ± 18 vs. 52 ± 14 mmHg; P < 0.001) or progressed in their renal status (58 ± 18 vs. 54 ± 15 mmHg; P < 0.01) during follow-up. In a Cox regression model, PP was independently associated with a first ever CVD event (hazard ratio per 10 mmHg 1.22 [95% CI 1.10-1.34]) but not progression of renal disease (1.00 [0.89-1.12]) after adjustments for traditional risk factors., Conclusions: PP, a marker of arterial stiffness, is a risk factor for cardiovascular complications but not for diabetic nephropathy in patients with T1D.

Objective: Recent data from the Diabetes Control and Complications Trial (DCCT) indicated that A1C variability is associated with the risk of diabetes microvascular complications. However, these results might have been influenced by the interventional study design. Therefore, we investigated the longitudinal associations between A1C variability and diabetes complications in patients with type 1 diabetes in the observational Finnish Diabetic Nephropathy (FinnDiane) Study., Research Design and Methods: A total of 2,107 patients in the FinnDiane Study had complete data on renal status and serial measurements of A1C from baseline to follow-up (median 5.7 years), and 1,845 patients had similar data on cardiovascular disease (CVD) events. Intrapersonal SD of serially measured A1C was considered a measure of variability., Results: During follow-up, 10.2% progressed to a higher albuminuria level or to end-stage renal disease, whereas 8.6% had a CVD event. The SD of serial A1C was 1.01 versus 0.75 (P < 0.001) for renal status and 0.87 versus 0.79 (P = 0.023) for CVD in progressors versus nonprogressors, respectively. In a Cox regression model, SD of serial A1C was independently associated with progression of renal disease (hazard ratio 1.92 [95% CI 1.49-2.47]) and of a CVD event (1.98 [1.39-2.82]) even when adjusting for mean A1C and traditional risk factors. Interestingly for CVD, mean serial A1C itself was not predictive even though SD of A1C was., Conclusions: In patients with type 1 diabetes, A1C variability was not only predictive of incident microalbuminuria and progression of renal disease but also of incident CVD events.

Objective: To assess the predictive value of the metabolic syndrome in patients with type 1 diabetes., Research Design and Methods: Patients were from the prospective Finnish Diabetic Nephropathy (FinnDiane) Study (n = 3,783): mean age 37 +/- 12 years and diabetes duration 23 +/- 12 years. Metabolic syndrome was defined according to World Health Organization (WHO), National Cholesterol Education Program (NCEP), and International Diabetes Federation (IDF) definitions. Follow-up time was median 5.5 years (interquartile range 3.7-6.7). Mortality data were complete, whereas morbidity data were available in 69% of the patients., Results: The WHO definition was associated with a 2.1-fold increased risk of cardiovascular events and a 2.5-fold increased risk of cardiovascular- and diabetes-related mortality, after adjustment for traditional risk factors and diabetic nephropathy. The NCEP definition did not predict outcomes when adjusted for nephropathy but markedly added to the risk associated with elevated albuminuria alone (P < 0.001). The IDF definition did not predict outcomes., Conclusions: The metabolic syndrome is a risk factor, beyond albuminuria, for cardiovascular morbidity and diabetes-related mortality in type 1 diabetes.

Background: There is an unmet need for a straightforward and cost-effective assessment of multiple lipoprotein risk factors for vascular diseases., Aims: 1) To study the relation of various lipoprotein lipid and apolipoprotein (apo) measures on the Friedewald inputs, i.e. plasma triglycerides (TG), cholesterol (TC), and high-density lipoprotein cholesterol (HDL-C). 2) To build up regression models for the appropriate measures based solely on the Friedewald inputs., Methods: Data were available for 1,775 plasma samples, from which very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), and HDL were also isolated by ultracentrifugation. For HDL(2)-C and apolipoproteins, 343 and 247 samples were available, respectively., Results: Accurate models were obtained for VLDL-TG (cross-validation r=0.98), LDL-C (r=0.91), HDL(2)-C (r=0.92), apoA-I (r=0.92), and apoB (r=0.95). A semi-quantitative model was obtained for IDL-C (r=0.78). Due to the anticipated role of IDL-C in atherosclerosis, it was still kept within the accepted models and pursued further. The associations of the estimates with premature deaths were studied in 4,084 patients with type 1 diabetes. The associations of IDL-C and LDL-C were markedly different, the best predictors of mortality being apoB, apoB to apoA-I ratio, and IDL-C., Conclusions: The new models allow identification of clinically relevant lipoprotein profiles with no added cost to the conventional Friedewald formula.

Objective: Equol, a gut bacterial metabolite of isoflavone daidzein, may improve health through changes in vascular function and in estrogen metabolism. Tibolone, a synthetic steroid alternative for the treatment of postmenopausal symptoms, causes a different estrogenic milieu than estrogen and may affect vascular health. We studied the effects of equol production and soy supplementation on vascular function in postmenopausal women under long-term tibolone use., Methods: We screened 110 women using tibolone for 3-60 months for high equol production capacity with a one-week soy challenge. Twenty women with high equol production capacity (4-fold elevation in equol level) and 20 comparable control women without this capacity were treated in a randomized placebo-controlled cross-over trial with a soy drink (52 g of soy protein containing 112 mg of isoflavones) or placebo for 8 weeks. Arterial stiffness and endothelial function were assessed before and after soy and placebo supplementation with pulse-wave analysis., Results: Prior to soy supplementation arterial stiffness, expressed as augmentation index, was lower (p=0.01) in equol producers (25.9+/-1.1%) than non-equol producers (29.6+/-0.9%). Similarly, endothelial function index was better at baseline (p=0.009) in these women (72.3+/-5.3%) compared to women lacking equol production capacity (55.2+/-3.8%). Soy supplementation had no effect on arterial stiffness or endothelial function in either group., Conclusion: In postmenopausal tibolone users, endogenous equol production capability is associated with favorable vascular function. This phenomenon was not affected by soy and thus, equol producing capacity may be an independent vascular health marker, at least in postmenopausal women using tibolone.

The hyperglycemic milieu in diabetes results in the formation of advanced glycation end products (AGEs) that predominantly act through specific receptors, particularly the receptor for AGEs (RAGE). Two functional polymorphisms in the promoter of the RAGE gene (-429 T/C and -374 T/A) and one in the AGE binding domain in exon 3 (G82S) were studied in 996 Finnish type 1 diabetic patients. In patients with poor metabolic control (HbA(1c) >9.5%), the AA genotype of the -374 T/A polymorphism was more common in those with a normal albumin excretion rate than in those with proteinuria (30 vs. 10%, P = 0.01). We observed less coronary heart disease (6 vs. 14%, P < 0.05), acute myocardial infarction (2 vs. 14%, P = 0.01), and peripheral vascular disease (2 vs. 14%, P < 0.05) in patients with the AA genotype of the -374 T/A polymorphism than in those with the TT + TA genotype. Thus, the association between the RAGE -374 T/A homozygous AA genotype and cardiovascular disease as well as albumin excretion in type 1 diabetic patients with poor metabolic control suggests a gene-environment interaction in the development of diabetic nephropathy and cardiovascular complications.