Risk of Thyroid Cancer in People With Type 1 Diabetes by Autoimmune Thyroid Diseases and Tumor Histology.

Context: Thyroid cancer is the most common endocrine cancer, but little is known about it in type 1 diabetes (T1D) and its potential association with autoimmune diseases. Objective: This study aims to assess the risk of thyroid cancer in adults with long-term T1D compared to individuals without diabetes and the proposed association of thyroid autoimmune diseases with thyroid cancer. Methods: The study included 4758 individuals with T1D participating in the Finnish Diabetic Nephropathy Study and 12 710 controls. Thyroid cancers were obtained from the Finnish Care Registers for Health Care. Results: 27 (0.57%) individuals with T1D had thyroid cancer compared to 27 (0.21%) in the controls (standardized incidence ratio 2.43; 95% confidence interval 1.59-3.56). The absolute increase in incidence was modest, with a 0.36%-unit rise. This translates to 17 additional cases among 4710 individuals with T1D. Cancer type was papillary in 81.5% of individuals with T1D and 88.9% of the controls; the rest were follicular. In T1D the distribution of hypothyreosis was similar between those with (n = 5, 18.5%) and without (18.1%) cancer, but hyperthyreosis was diagnosed more often with thyroid cancer (n = 3, 11.1%) than without (2.3%, P = .003). None of the thyroid cancers were invasive or had metastatic characteristics. Conclusion: Although there is an excess risk of thyroid cancer, it is only marginally increased (0.36%-unit) in individuals with T1D compared to control individuals and was not associated with increased morbidity or mortality. An overdiagnosis effect due to regular health care contacts is the most likely explanation for the higher risk.

Stroke incidence increases with diabetic retinopathy severity and macular edema in type 1 diabetes.

BACKGROUND: As the retina is suggested to mirror the brain, we hypothesized that diabetic retinopathy and macular edema are indicative of stroke risk in type 1 diabetes and sought to assess this association in individuals with type 1 diabetes. METHODS: We included 1,268 adult FinnDiane Study participants with type 1 diabetes (age 38.7 ± 11.8 years, 51.7% men vs. 48.3% women, and 31.5% had diabetic kidney disease), data on baseline diabetic retinopathy severity, and first stroke during our observational follow-up. Retinopathy was graded by the Early Treatment Diabetic Retinopathy Study (ETDRS) scale, and macular edema as clinically significant (CSME) or not. Strokes identified from registries were confirmed from medical files. Adjusted hazard ratios (HR) for stroke by retinopathy severity and CSME were calculated by Cox models adjusted for clinical confounders, including diabetic kidney disease. RESULTS: During median 18.0 (14.1-19.3) follow-up years, 130 strokes (96 ischemic, 34 hemorrhagic) occurred. With no-very mild (ETDRS 10-20) retinopathy as reference, the adjusted HR for stroke was 1.79 (95%CI 1.02-3.15) in non-proliferative (ETDRS 35-53), and 1.69 (1.02-2.82) in proliferative (ETDRS 61-85) retinopathy. Corresponding adjusted HR for ischemic stroke was 1.68 (0.91-3.10) in non-proliferative and 1.35 (0.77-2.36) in proliferative retinopathy. The adjusted HR for hemorrhagic stroke was 2.84 (0.66-12.28) in non-proliferative and 4.31 (1.16-16.10) in proliferative retinopathy. CSME did not increase HR for any stroke type after adjustment for clinical confounders (data not shown). CONCLUSIONS: Stroke incidence increases with the severity of diabetic retinopathy independently of comorbid conditions, including diabetic kidney disease.

Incidence and risk factors for cancer in people with type 1 diabetes, stratified by stages of diabetic kidney disease: a nationwide Finnish cohort study.

Background: Individuals with type 1 diabetes (T1D) have been reported to have increased overall risk of cancer. In addition, individuals with a kidney transplant/transplantation (KT) have markedly increased cancer risk due to chronic use of immunosuppressive agents. However, it has not been elucidated whether the observed excess cancer risk is related to KT or whether diabetic kidney disease (DKD) per se is a risk factor for cancer in individuals with T1D. Methods: The study included 5035 individuals from the Finnish Diabetic Nephropathy Study (FinnDiane) and 14,061 control individuals without diabetes. We assessed the standardized incidence ratios (SIRs) for cancers in individuals with T1D compared to controls according to DKD status. Cox regression analyses were used to identify potential risk factors for cancer in individuals with type 1 diabetes. Findings: The SIR for overall cancer for all participants was 1.14 (1.05-1.24), for participants without KT 0.92 (0.83-1.01) and for participants with KT 4.78 (4.02-5.64). Participants without KT had in fact a reduced risk of prostate cancer with a SIR of 0.54 (0.37-0.76), cancer of urinary organs 0.41 (0.21-0.73) and respiratory and intrathoracic organs, 0.62 (0.38-0.97). Participants with KT had on the contrary an increased risk of non-melanoma skin cancer, SIR 14.50 (10.99-18.86), cancer in the lymphoid and hematopoietic tissue 5.38 (2.99-8.96), mouth or pharynx 5.13 (2.08-10.66), melanoma 5.12 [2.38-9.72]) and respiratory and intrathoracic organs 2.77 (1.21-5.49). The risk of thyroid cancer was increased both in participants without KT, SIR 2.14 (1.39-3.16) and with KT 5.30 (1.68-12.78). Interpretation: The excess overall cancer risk in individuals with type 1 diabetes is only seen in KT recipients and in thyroid cancer. The individuals without KT seem to have a decreased risk of some forms of cancer. Funding: Folkhälsan Research Foundation, Academy of Finland [316664], Wilhelm and Else Stockmann Foundation, Liv och Hälsa Society, Novo Nordisk Foundation [NNF OC0013659], Finnish Foundation for Cardiovascular Research, Finnish Diabetes Research Foundation, Medical Society of Finland, Sigrid Jusélius Foundation, and Helsinki University Hospital Research Funds [TYH2018207 and TYH 2020305].

Clustering of risk behaviours and associations between risk behaviours and cardio-metabolic risk factors in adult individuals with type 1 diabetes.

AIMS: To assess clustering of risk behaviours and their health determinants. METHODS: Cross-sectional health behaviour and health data were collected from individuals with type 1 diabetes, in the FinnDiane Study. Clustering of risk behaviours was assessed and associations between behaviours and health variables were investigated. RESULTS: Data were available from 956 participants (40 % men, mean age 46 years). Altogether, 4.3 % individuals reported no risk behaviours, while 25.7 %, 37.4 %, 24.7 %, 6.8 %, and 1.0 % reported 1, 2, 3, 4, and 5 risk behaviours, respectively. Reporting ≥4 risk behaviours occurred more frequently than expected by chance. Dietary non-adherence was most frequently reported (84.4 %), followed by low LTPA (54.4 %), poor sleep (41.9 %), high alcohol consumption (15.2 %), and smoking (11.2 %). Adjusted for confounders, relative to ≤1 risk behaviour, reporting ≥2 risk behaviours was associated with higher BMI, waist circumference, and diastolic blood pressure. Having ≥3 risk behaviours was associated with larger waist-hip ratio, and higher HbA1c and triglyceride concentration; ≥4 risk behaviours was associated with higher cholesterol concentration. Of the health behaviours, low LTPA had the highest number of deleterious health associations. CONCLUSIONS: Accumulation of risk behaviors increases negative health outcomes. Exhibiting ≥2 risk behaviours or low LTPA was associated with multiple adverse outcomes.

Medication profiling in women with type 1 diabetes highlights the importance of adequate, guideline-based treatment in low-risk groups.

Effective treatment may prevent kidney complications, but women might be underprescribed. Novel, data-driven insights into prescriptions and their relationship with kidney health in women with type 1 diabetes may help to optimize treatment. We identified six medication profiles in 1164 women from the FinnDiane Study with normal albumin excretion rate based on clusters of their baseline prescription data using a self-organizing map. Future rapid kidney function decline was defined as an annual estimated glomerular filtration rate (eGFR) loss > 3 ml/min/1.73 m2 after baseline. Two profiles were associated with future decline: Profile ARB with the highest proportion of angiotensin receptor blockers (odds ratio [OR] 2.75, P = 0.02) and highly medicated women in profile HighMed (OR 2.55, P = 0.03). Compared with profile LowMed (low purchases of all), profile HighMed had worse clinical characteristics, whereas in profile ARB only systolic blood pressure was elevated. Importantly, the younger women in profile ARB with fewer kidney protective treatments developed a rapid decline despite otherwise similar baseline characteristics to profile ACE & Lipids (the highest proportions of ACE inhibitors and lipid-modifying agents) without a future rapid decline. In conclusion, medication profiles identified different future eGFR trajectories in women with type 1 diabetes revealing potential treatment gaps for younger women.

The impact of diabetic nephropathy and severe diabetic retinopathy on chronic limb threatening ischemia risk in individuals with type 1 diabetes: a nationwide, population study.

Background: The prevalence, incidence and risk factors and especially the effect of diabetic nephropathy (DN) and diabetic retinopathy on the risk of chronic limb threatening ischemia (CLTI) have been sparsely studied in individuals with type 1 diabetes (T1D). Methods: The prospective cohort study consisted of 4697 individuals with T1D from the nationwide Finnish Diabetic Nephropathy (FinnDiane) Study. Medical records were thoroughly reviewed in order to ascertain all CLTI events. The key risk factors were DN and severe diabetic retinopathy (SDR). Findings: There were 319 events of confirmed CLTI, 102 prevalent events at baseline and 217 incident events during the follow-up of 11.9 (IQR 9.3-13.8) years. The 12-year cumulative incidence of CLTI was 4.6% (95% CI 4.0-5.3). Risk factors included presence of DN, SDR, age, duration of diabetes, HbA1c, systolic blood pressure, triglycerides and current smoking. Sub-hazard ratios (SHRs) according to combinations of DN status and presence (+) or absence (-) of SDR were 4.8 (2.0-11.7) for normoalbuminuria/SDR+, 3.2 (1.1-9.4) for microalbuminuria/SDR-, 11.9 (5.4-26.5) for microalbuminuria/SDR+, 8.7 (3.2-23.2) for macroalbuminuria/SDR-, 15.6 (7.4-33.0) for macroalbuminuria/SDR+ and 37.9 (17.2-78.9) for kidney failure compared with individuals with normal albumin excretion rate and without SDR. Interpretation: Diabetic nephropathy, especially kidney failure, is associated with high risk of limb threatening ischemia in individuals with T1D. The risk of CLTI increases gradually according to the severity of diabetic nephropathy. Also, diabetic retinopathy is independently and additively associated with high risk of CLTI. Funding: This research was funded by grants from Folkhälsan Research Foundation, Academy of Finland (316664), Wilhelm and Else Stockmann Foundation, Liv och Hälsa Society, Novo Nordisk Foundation (NNF OC0013659), Finnish Foundation for Cardiovascular Research, Finnish Diabetes Research Foundation, Medical Society of Finland, Sigrid Jusélius Foundation and Helsinki University Hospital Research Funds.

L-type calcium channel blocker increases VEGF concentrations in retinal cells and human serum.

OBJECTIVE: Vascular endothelial growth factor (VEGF) plays a key role in diabetic retinopathy (DR). Previously, we have reported an association between mutations in a gene coding for the L-type calcium channel subunit, VEGF and DR. L-type calcium channel blockers (LTCCBs) have been widely used as antihypertensive medication (AHM), but their association with VEGF and DR is still unclear. Therefore, we explored the effect of LTCCBs compared to other AHMs on VEGF concentrations in retinal cells and human serum. Furthermore, we evaluated the association between the use of LTCCBs and the risk of severe diabetic eye disease (SDED). RESEARCH DESIGN AND METHODS: Müller cells (MIO-M1) were cultured as per recommended protocol and treated with LTCCBs and other AHMs. VEGF secreted from cells were collected at 24 hours intervals. In an interventional study, 39 individuals received LTCCBs or other AHM for four weeks with a four-week wash-out placebo period between treatments. VEGF was measured during the medication and placebo periods. Finally, we evaluated the risk of SDED associated with LTCCB usage in 192 individuals from the FinnDiane Study in an observational setting. RESULTS: In the cell cultures, the medium VEGF concentration increased time-dependently after amlodipine (P<0.01) treatment, but not after losartan (P>0.01), or lisinopril (P>0.01). Amlodipine, but no other AHM, increased the serum VEGF concentration (P<0.05) during the interventional clinical study. The usage of LTCCB was not associated with the risk of SDED in the observational study. CONCLUSIONS: LTCCB increases VEGF concentrations in retinal cells and human serum. However, the usage of LTCCBs does not appear to be associated with SDED in adults with type 1 diabetes.

Apolipoprotein C-III predicts cardiovascular events and mortality in individuals with type 1 diabetes and albuminuria.

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, HbA1c , 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.

The pattern-recognition molecule H-ficolin in relation to diabetic kidney disease, mortality, and cardiovascular events in type 1 diabetes.

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, HbA1c, 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.

Every Fifth Individual With Type 1 Diabetes Suffers From an Additional Autoimmune Disease: A Finnish Nationwide Study.

OBJECTIVE: The aim of this study was to quantify the excess risk of autoimmune hypothyroidism and hyperthyroidism, Addison disease, celiac disease, and atrophic gastritis in adults with type 1 diabetes (T1D) compared with nondiabetic individuals in Finland. RESEARCH DESIGN AND METHODS: The study included 4,758 individuals with T1D from the Finnish Diabetic Nephropathy (FinnDiane) Study and 12,710 nondiabetic control individuals. The autoimmune diseases (ADs) were identified by linking the data with the Finnish nationwide health registries from 1970 to 2015. RESULTS: The median age of the FinnDiane individuals at the end of follow-up in 2015 was 51.4 (interquartile range 42.6-60.1) years, and the median duration of diabetes was 35.5 (26.5-44.0) years. Of individuals with T1D, 22.8% had at least one additional AD, which included 31.6% of women and 14.9% of men. The odds ratios for hypothyroidism, hyperthyroidism, celiac disease, Addison disease, and atrophic gastritis were 3.43 (95% CI 3.09-3.81), 2.98 (2.27-3.90), 4.64 (3.71-5.81), 24.13 (5.60-104.03), and 5.08 (3.15-8.18), respectively, in the individuals with T1D compared with the control individuals. The corresponding ORs for women compared with men were 2.96 (2.53-3.47), 2.83 (1.87-4.28), 1.52 (1.15-2.02), 2.22 (0.83-5.91), and 1.36 (0.77-2.39), respectively, in individuals with T1D. Late onset of T1D and aging increased the risk of hypothyroidism, whereas young age at onset of T1D increased the risk of celiac disease. CONCLUSIONS: This is one of the largest studies quantifying the risk of coexisting AD in adult individuals with T1D in the country with the highest incidence of T1D in the world. The results highlight the importance of continuous screening for other ADs in individuals with T1D.

The Long-Term Incidence of Hospitalization for Ketoacidosis in Adults with Established T1D-A Prospective Cohort Study.

CONTEXT: The long-term natural history of diabetic ketoacidosis (DKA) and its risk factors are poorly understood. OBJECTIVE: To determine the long-term incidence and predictors of DKA in adults with longstanding type 1 diabetes (T1D). DESIGN: All hospitalizations and deaths due to DKA between 1996 and 2016 were identified in 4758 adults with T1D from the Finnish Diabetic Nephropathy Study (FinnDiane), and a cohort of 16 224 adults with T1D from the Finnish general population. RESULTS: Between 1996 and 2015, there were 1228 DKA events in the FinnDiane participants (1.4/100 person-years) and 4914 DKA events (1.8/100 person-years) in adults with T1D from the general population. The majority were hospitalized only once. There was a modest increase in the frequency of DKA in the FinnDiane over the follow-up (~2.4%/year [95% CI, 0.3-4.5%]; P = 0.03). Predictors of DKA were glucose control, CSII, smoking and alcohol consumption, and raised high-density lipoprotein cholesterol and triacylglycerides. Diabetic nephropathy and renal impairment were associated with DKA; patients with end-stage renal disease, macroalbuminuria, and microalbuminuria had 2.09-fol (95% CI, 1.40-3.12), 1.65-fold (95% CI, 1.23-2.19), and 0.87-fold (95% CI, 0.61-1.24) risk of DKA compared with patients with normal albumin excretion rate, respectively. Patients with an estimated glomerular filtration rate <60 mL/min/1.73 m2 were also more likely to be hospitalized for DKA (HR 1.71 [95% CI, 1.26-2.67]). CONCLUSIONS: DKA remains a common cause of hospitalization in individuals with longstanding T1D. These data suggest that the goal to use SGLT2 inhibitors for their vasculo- and renoprotective actions may be problematic, as those most likely to benefit may also have the highest risk for DKA.

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

AIMS: 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. METHODS: Prospective 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). RESULTS: A 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. CONCLUSIONS: Frequent 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.

Variations in Risk of End-Stage Renal Disease and Risk of Mortality in an International Study of Patients With Type 1 Diabetes and Advanced Nephropathy.

OBJECTIVE: Patients with type 1 diabetes and diabetic nephropathy are targets for intervention to reduce high risk of end-stage renal disease (ESRD) and deaths. This study compares risks of these outcomes in four international cohorts. RESEARCH DESIGN AND METHODS: In the 1990s and early 2000s, Caucasian patients with type 1 diabetes with persistent macroalbuminuria in chronic kidney disease stages 1-3 were identified in the Joslin Clinic (U.S., 432), Finnish Diabetic Nephropathy Study (FinnDiane) (Finland, 486), Steno Diabetes Center Copenhagen (Denmark, 368), and INSERM (France, 232) and were followed for 3-18 years with annual creatinine measurements to ascertain ESRD and deaths unrelated to ESRD. RESULTS: During 15,685 patient-years, 505 ESRD cases (rate 32/1,000 patient-years) and 228 deaths unrelated to ESRD (rate 14/1,000 patient-years) occurred. Risk of ESRD was associated with male sex; younger age; lower estimated glomerular filtration rate (eGFR); higher albumin/creatinine ratio, HbA1c, and systolic blood pressure; and smoking. Risk of death unrelated to ESRD was associated with older age, smoking, and higher baseline eGFR. In adjusted analysis, ESRD risk was highest in Joslin versus reference FinnDiane (hazard ratio [HR] 1.44, P = 0.003) and lowest in Steno (HR 0.54, P < 0.001). Differences in eGFR slopes paralleled risk of ESRD. Mortality unrelated to ESRD was lowest in Joslin (HR 0.68, P = 0.003 vs. the other cohorts). Competing risk did not explain international differences in the outcomes. CONCLUSIONS: Despite almost universal renoprotective treatment, progression to ESRD and mortality in patients with type 1 diabetes with advanced nephropathy are still very high and differ among countries. Finding causes of these differences may help reduce risk of these outcomes.

The Association of Severe Diabetic Retinopathy With Cardiovascular Outcomes in Long-standing Type 1 Diabetes: A Longitudinal Follow-up.

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 m2. 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.

Dose-dependent effect of smoking on risk of coronary heart disease, heart failure and stroke in individuals with type 1 diabetes.

AIMS/HYPOTHESIS: The aim of this study was to assess the potential dose-dependent effects of smoking on the risk of CHD, heart failure and stroke in individuals with type 1 diabetes. METHODS: The study included 4506 individuals with type 1 diabetes who were participating in the Finnish Diabetic Nephropathy (FinnDiane) study. Intensity of smoking was estimated by packs per day and cumulative smoking by pack-years. Cox regression analyses were used to estimate the risk of incident CHD, heart failure or stroke during follow-up. RESULTS: One pack per day significantly increased the risk of incident CHD in current smokers compared with never smokers (HR 1.45 [95% CI 1.15, 1.84]), after adjustment for age, sex, HbA1c, hypertension, duration of diabetes and BMI. The risk of CHD in former smokers was similar to the risk in never smokers. The risk of incident heart failure was 1.43 (95% CI 1.03, 1.97) in current smokers per one pack per day and 1.37 (95% CI 1.05, 1.77) in former smokers, while the risk of incident stroke was 1.70 (95% CI 1.26, 2.29) and 1.49 (95% CI 1.14, 1.93), respectively. After further adjustments for lipids, however, the difference in the risk of heart failure in current and former smokers was no longer significant. Cumulative smoking data were similar to smoking intensity data. CONCLUSIONS/INTERPRETATION: There is a dose-dependent association between smoking and cardiovascular disease in individuals with type 1 diabetes. In men in particular, the risk of incident stroke remains high even after smoking cessation and is increased in current and former smokers independently of other risk factors.

The Genetic Landscape of Renal Complications in Type 1 Diabetes.

Diabetes is the leading cause of ESRD. Despite evidence for a substantial heritability of diabetic kidney disease, efforts to identify genetic susceptibility variants have had limited success. We extended previous efforts in three dimensions, examining a more comprehensive set of genetic variants in larger numbers of subjects with type 1 diabetes characterized for a wider range of cross-sectional diabetic kidney disease phenotypes. In 2843 subjects, we estimated that the heritability of diabetic kidney disease was 35% (P=6.4×10-3). Genome-wide association analysis and replication in 12,540 individuals identified no single variants reaching stringent levels of significance and, despite excellent power, provided little independent confirmation of previously published associated variants. Whole-exome sequencing in 997 subjects failed to identify any large-effect coding alleles of lower frequency influencing the risk of diabetic kidney disease. However, sets of alleles increasing body mass index (P=2.2×10-5) and the risk of type 2 diabetes (P=6.1×10-4) associated with the risk of diabetic kidney disease. We also found genome-wide genetic correlation between diabetic kidney disease and failure at smoking cessation (P=1.1×10-4). Pathway analysis implicated ascorbate and aldarate metabolism (P=9.0×10-6), and pentose and glucuronate interconversions (P=3.0×10-6) in pathogenesis of diabetic kidney disease. These data provide further evidence for the role of genetic factors influencing diabetic kidney disease in those with type 1 diabetes and highlight some key pathways that may be responsible. Altogether these results reveal important biology behind the major cause of kidney disease.

Smoking and progression of diabetic nephropathy in patients with type 1 diabetes.

AIMS: To evaluate the effect of cumulative smoking on the development of diabetic nephropathy. METHODS: Study included 3613 patients with type 1 diabetes, participating in the Finnish Diabetic Nephropathy Study. The 12-year cumulative risk of microalbuminuria, macroalbuminuria and end-stage renal disease (ESRD) was estimated for current, ex- and nonsmokers. Cox regression analyses, with multivariable adjustments for other risk factors for diabetic nephropathy, were used to evaluate the risk at different stages of diabetic nephropathy based on the cumulative amount of smoking in pack-years. RESULTS: The 12-year cumulative risk of microalbuminuria was 18.9 % (95 % CI 14.6-23.0, P < 0.0001) for current smokers and 15.1 % (10.3-19.6, P = 0.087) for ex-smokers, compared with 10.0 % (7.8-12.1) for nonsmokers. The corresponding risks of macroalbuminuria were 14.4 % (95 % CI 10.8-17.9, P < 0.0001), 6.1 % (3.5-8.6, P = 0.082) and 4.7 % (3.0-6.4), respectively. The 12-year cumulative risk of ESRD was 10.3 % (95 % CI 8.4-12.4, P < 0.0001) for current smokers and 10.0 % (7.9-12.3, P < 0.0001) for ex-smokers, compared with 5.6 % (4.6-6.7) for nonsmokers. In the current smokers, one pack-year increased the risk of macroalbuminuria with a HR of 1.025 (1.010-1.041) and the risk of ESRD with a HR of 1.014 (1.001-1.026) compared with nonsmokers, in the fully adjusted model. In the ex-smokers, the risk of macroalbuminuria and ESRD was no different from the risk in nonsmokers after multivariable adjustment. CONCLUSIONS: Current smoking is a risk factor for the progression of diabetic nephropathy and the risk increases with the increasing dose of smoking. Ex-smokers seem to carry a similar risk of progression of diabetic nephropathy as nonsmokers.

[Who will develop diabetic nephropathy?]. / Kuka sairastuu diabeettiseen nefropatiaan?

While the pathogenetic mechanisms of diabetic nephropathy are not fully known, the greatest risk factors include long duration of diabetes, prolonged poor glucose homeostasis, hypertension, lipid disorders, smoking and male gender. According to family studies, the development of diabetic nephropathy is also influenced by hereditary factors. Two gene loci associated with end-stage nephropathy have been identified in a genome-wide study. Diabetic nephropathy is a multifactorial disease, whereby elucidation of its pathogenetic of mechanisms requires extensive multidisciplinary studies. For the present it cannot be precisely predicted who will develop diabetic nephropathy.

Added value of soluble tumor necrosis factor-α receptor 1 as a biomarker of ESRD risk in patients with type 1 diabetes.

OBJECTIVE: Recent studies have suggested that circulating levels of the tumor necrosis factor-α receptor 1 (sTNFαR1) may be a useful predictor for the risk of end-stage renal disease (ESRD) in patients with diabetes. However, its potential utility as a biomarker has not been formally quantified. RESEARCH DESIGN AND METHODS: Circulating levels of sTNFαR1 were assessed in 429 patients with type 1 diabetes and overt nephropathy from the Finnish Diabetic Nephropathy (FinnDiane) cohort study. Predictors of incident ESRD over a median of 9.4 years of follow-up were determined by Cox regression and Fine-Gray competing risk analyses. The added value of sTNFαR1 was estimated via time-dependent receiver operating characteristic curves, net reclassification index (NRI), and integrated discrimination improvement (IDI) for survival data. RESULTS: A total of 130 individuals developed ESRD (28%; ESRD incidence rate of 3.4% per year). In cause-specific modeling, after adjusting for baseline renal status, predictors of increased incidence of ESRD in patients with overt nephropathy were an elevated HbA1c, shorter duration of diabetes, and circulating levels of sTNFαR1. Notably, sTNFαR1 outperformed estimated glomerular filtration rate in terms of R(2). Circulating levels of the sTNFαR1 also remained associated with ESRD after adjusting for the competing risk of death. A prediction model including sTNFαR1 (as a -0.5 fractional polynomial) was superior to a model without it, as demonstrated by better global fit, an increment of R(2), the C index, and area under the curve. Estimates of IDI and NRI(>0) were 0.22 (95% CI 0.16-0.28; P < 0.0001) and 0.98 (0.78-1.23; P < 0.0001), respectively. The median increment in the risk score after including sTNFαR1 in the prediction model was 0.18 (0.12-0.30; P < 0.0001). CONCLUSIONS: Circulating levels of sTNFαR1 are independently associated with the cumulative incidence of ESRD. This association is both significant and biologically plausible and appears to provide added value as a biomarker, based on the absolute values of NRI and IDI.

Epidemiology and risk factors for diabetic kidney disease.

Prevalence rates of diabetic kidney disease (DKD) are increasing in parallel with the incidence rates of diabetes mellitus. DKD has already become a significant health problem worldwide. Without radical improvements in prevention and treatment, DKD prevalence will continue to climb. The pathogenesis of DKD is complex and multifactorial, with genetic and environmental factors involved. Several nonmodifiable risk factors contribute to DKD, including genetics, sex, age, age at onset, and duration of diabetes. However, there are also several modifiable risk factors that have a strong effect on the risk of DKD. Traditional modifiable factors include glycemic control, blood pressure, lipids, and smoking. Other recently discovered modifiable risk factors include chronic low-grade inflammation, advanced glycation end products, and lack of physical activity. Efficient management of these modifiable risk factors may improve the prognosis of diabetic patients at risk of DKD.