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1.  GLYCEMIC CONTROL AND URINARY TRACT INFECTIONS IN WOMEN WITH TYPE 1 DIABETES: RESULTS FROM THE DCCT/EDIC 
The Journal of urology  2016;196(4):1129-1135.
PURPOSE
We examined the relationship between glycemic control and urinary tract infections (UTI) in women with type 1 diabetes mellitus.
MATERIALS AND METHODS
Women enrolled in the Epidemiology of Diabetes Interventions and Complications (EDIC) study, the observational follow-up of the Diabetes Control and Complications Trial (DCCT) were surveyed to assess the rate of physician-diagnosed UTI in the preceding 12 months. The relationship between HbA1c levels and number of UTIs in the previous 12 months was assessed using a multivariable Poisson regression model.
RESULTS
At EDIC Year 17, 572 women were evaluated: mean age 50.7 ± 7.2 years, mean body mass index (BMI) 28.6 ± 5.9 kg/m2, type 1 diabetes duration 29.8 ± 5.0 years, and mean HbA1c 8.0 ± 0.9%. Of these, 86 (15.0%) reported at least one physician diagnosed UTI during the past 12 months. Higher HbA1c levels were significantly associated with number of UTIs, such that for every unit increase (1%) in recent HbA1c level, there was a 21% (p=0.02) increase in UTI frequency in the previous 12 months after adjusting for race, hysterectomy status, urinary incontinence (UI), sexual activity in the past 12 months, peripheral and autonomic neuropathy and nephropathy.
CONCLUSIONS
The frequency of UTI increases with poor glycemic control in women with type 1 diabetes. This relationship is independent of other well-described predictors of UTI and suggests that factors directly related to glycemic control may influence the risk of lower urinary tract infections.
doi:10.1016/j.juro.2016.04.071
PMCID: PMC5025347  PMID: 27131462
Urinary tract infection; Diabetes; Risk Factors
2.  Relationship of Urologic Complications With Health-Related Quality of Life and Perceived Value of Health in Men and Women With Type 1 Diabetes: The Diabetes Control and Complications Trial/Epidemiology of Interventions and Complications (DCCT/EDIC) Cohort 
Diabetes Care  2015;38(10):1904-1912.
OBJECTIVE
Limited information exists about the influence of urologic complications on health-related quality of life (HRQOL) in patients with type 1 diabetes.
RESEARCH DESIGN AND METHODS
We studied 664 men and 580 women from the Diabetes Control and Complications Trial/Epidemiology of Interventions and Complications Study: mean ages were 51.6 ± 6.6 and 50.6 ± 7.2 years and duration of diabetes was 29.5 ± 4.8 and 29.8 ± 5.1 years, respectively. We assessed associations of sexual dysfunction, lower urinary tract symptoms (LUTS), and, in women, urinary incontinence (UI) with general quality of life (SF-36), perceived value of health (EuroQol-5), diabetes-related quality of life (Diabetes Quality of Life Scale [DQOL]), and psychiatric symptoms (Symptom Checklist 90-R).
RESULTS
In both men and women, urologic complications adversely affected HRQOL and psychiatric symptoms, even after accounting for history of depression leading to treatment. Multivariable analyses accounting for the presence of diabetic retinopathy, neuropathy, and nephropathy also revealed substantial independent effects. In men, for example, the odds (95% CI) of a low DQOL score (≤25th percentile) were 3.01 (1.90–4.75) times greater with erectile dysfunction and 2.65 (1.68–4.18) times greater with LUTS and in women, 2.04 (1.25–3.35) times greater with sexual dysfunction and 2.71 (1.72–4.27) times greater with UI/LUTS combined compared with men and women without such complications. Similar effects were observed for the other measures.
CONCLUSIONS
Sexual dysfunction and urinary complications with type 1 diabetes are associated with decreased quality of life and perceived value of health and with higher levels of psychiatric symptoms, even after accounting for other diabetes complications and depression treatment.
doi:10.2337/dc15-0286
PMCID: PMC4580606  PMID: 26203062
3.  Lymphoblastoid Cell Lines as a Tool to Study Inter-Individual Differences in the Response to Glucose 
PLoS ONE  2016;11(8):e0160504.
Background
White blood cells have been shown in animal studies to play a central role in the pathogenesis of diabetic retinopathy. Lymphoblastoid cells are immortalized EBV-transformed primary B-cell leukocytes that have been extensively used as a model for conditions in which white blood cells play a primary role. The purpose of this study was to investigate whether lymphoblastoid cell lines, by retaining many of the key features of primary leukocytes, can be induced with glucose to demonstrate relevant biological responses to those found in diabetic retinopathy.
Methods
Lymphoblastoid cell lines were obtained from twenty-three human subjects. Differences between high and standard glucose conditions were assessed for expression, endothelial adhesion, and reactive oxygen species.
Results
Collectively, stimulation of the lymphoblastoid cell lines with high glucose demonstrated corresponding changes on molecular, cellular and functional levels. Lymphoblastoid cell lines up-regulated expression of a panel of genes associated with the leukocyte-mediated inflammation found in diabetic retinopathy that include: a cytokine (IL-1B fold change = 2.11, p-value = 0.02), an enzyme (PKCB fold change = 2.30, p-value = 0.01), transcription factors (NFKB-p50 fold change = 2.05, p-value = 0.01), (NFKB-p65 fold change = 2.82, p-value = 0.003), and an adhesion molecule (CD18 fold change = 2.59, 0.02). Protein expression of CD18 was also increased (p-value = 2.14x10-5). The lymphoblastoid cell lines demonstrated increased adhesiveness to endothelial cells (p = 1.28x10-5). Reactive oxygen species were increased (p = 2.56x10-6). Significant inter-individual variation among the lymphoblastoid cell lines in these responses was evident (F = 18.70, p < 0.0001).
Conclusions
Exposure of lymphoblastoid cell lines derived from different human subjects to high glucose demonstrated differential and heterogeneous gene expression, adhesion, and cellular effects that recapitulated features found in the diabetic state. Lymphoblastoid cells may represent a useful tool to guide an individualized understanding of the development and potential treatment of diabetic complications like retinopathy.
doi:10.1371/journal.pone.0160504
PMCID: PMC4979894  PMID: 27509144
4.  Delayed Gastric Emptying is Associated with Early and Long-Term Hyperglycemia in Type 1 Diabetes Mellitus 
Gastroenterology  2015;149(2):330-339.
Background and Aims
After the Diabetes Control and Complications Trial (DCCT), the Epidemiology of Diabetes Interventions and Complications (EDIC) study continued to demonstrate persistent benefit of prior intensive therapy on neuropathy, retinopathy, and nephropathy in type 1 diabetes mellitus (DM)., The relationship between control of glycemia and gastric emptying (GE) is unclear.
Methods
We assessed GE with a 13C-spirulina breath test and symptoms in 78 participants with type 1 diabetes at year 20 of EDIC. The relationship between delayed GE and HbA1c, complications of DM, and gastrointestinal symptoms were evaluated.
Results
GE was normal (37 participants, 50%), delayed (35 participants, 47%), or rapid (2 participants, 3%). The latest mean HbA1c was 7.7%. In univariate analyses, delayed GE was associated with greater DCCT baseline HbA1c and duration of DM prior to DCCT (P ≤ 0.04), greater mean HbA1c over an average of 27 years of follow up (during DCCT-EDIC, P = 0.01), lower R-R variability during deep breathing (P=0.03) and severe nephropathy (P=0.05) and a greater composite upper gastrointestinal symptom score (P<0.05). In multivariate models, retinopathy was the only complication of DM associated with delayed GE. Separately, DCCT baseline HbA1c (OR 1.6, 95% CI 1.1–2.3) and duration of DM (OR 1.2, 95%CI 1.01–1.3) prior to DCCT entry and mean HbA1c during DCCT-EDIC (OR 2.2, 95%CI 1.04–4.5) were independently associated with delayed GE.
Conclusions
In the DCCT/EDIC study, delayed GE was remarkably common and associated with gastrointestinal symptoms and with measures of early and long-term hyperglycemia. ClinicalTrials.gov numbers NCT00360815 and NCT00360893.
doi:10.1053/j.gastro.2015.05.007
PMCID: PMC4516593  PMID: 25980755
diabetic gastroparesis; HbA1c; glycemic control; neuropathy
5.  Significance of Epicardial and Intrathoracic Adipose Tissue Volume among Type 1 Diabetes Patients in the DCCT/EDIC: A Pilot Study 
PLoS ONE  2016;11(7):e0159958.
Introduction
Type 1 diabetes (T1DM) patients are at increased risk of coronary artery disease (CAD). This pilot study sought to evaluate the relationship between epicardial adipose tissue (EAT) and intra-thoracic adipose tissue (IAT) volumes and cardio-metabolic risk factors in T1DM.
Method
EAT/IAT volumes in 100 patients, underwent non-contrast cardiac computed tomography in the Diabetes Control and Complications Trial /Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study were measured by a certified reader. Fat was defined as pixels’ density of -30 to -190 Hounsfield Unit. The associations were assessed using–Pearson partial correlation and linear regression models adjusted for gender and age with inverse probability sample weighting.
Results
The weighted mean age was 43 years (range 32–57) and 53% were male. Adjusted for gender, Pearson correlation analysis showed a significant correlation between age and EAT/IAT volumes (both p<0.001). After adjusting for gender and age, participants with greater BMI, higher waist to hip ratio (WTH), higher weighted HbA1c, elevated triglyceride level, and a history of albumin excretion rate of equal or greater than 300 mg/d (AER≥300) or end stage renal disease (ESRD) had significantly larger EAT/IAT volumes.
Conclusion
T1DM patients with greater BMI, WTH ratio, weighted HbA1c level, triglyceride level and AER≥300/ESRD had significantly larger EAT/IAT volumes. Larger sample size studies are recommended to evaluate independency.
doi:10.1371/journal.pone.0159958
PMCID: PMC4961378  PMID: 27459689
6.  Longitudinal Association Between Endothelial Dysfunction, Inflammation, and Clotting Biomarkers With Subclinical Atherosclerosis in Type 1 Diabetes: An Evaluation of the DCCT/EDIC Cohort 
Diabetes Care  2015;38(7):1281-1289.
OBJECTIVE
There is considerable interest in identifying biomarkers that predict high risk for the development of macrovascular complications in patients with diabetes. Therefore, the longitudinal association between subclinical atherosclerosis as measured by internal carotid artery intima-media thickness (IMT) and acute-phase reactants, cytokines/adipokines, thrombosis, and adhesion molecules was examined.
RESEARCH DESIGN AND METHODS
Biomarkers were measured at four time points over 20 years in 886 DCCT/EDIC participants with type 1 diabetes. Four composite scores were created by combining z scores generated from within the data set of individual biomarkers: acute-phase reactants (fibrinogen, C-reactive protein), thrombosis (fibrinogen, active and total plasminogen activator inhibitor [PAI]-1), cytokines/adipokines (tumor necrosis factor receptor-1 and -2, active and total PAI-1, IL-6), and endothelial dysfunction (soluble intracellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, and soluble E-selectin). Internal carotid IMT was measured at EDIC years 1, 6, and 12, with elevated IMT defined at each time point as being in the upper quintile of its distribution.
RESULTS
Logistic regression models indicate that while individual biomarkers were not predictive of or associated with subclinical atherosclerosis, composite scores of acute-phase reactants (odds ratio [OR] 2.78 [95% CI 1.42, 5.42]), thrombolytic factors (OR 2.83 [95% CI 1.45, 5.52]), and cytokines/adipokines (OR 2.83 [95% CI 1.48, 5.41]) measured at our final time point EDIC years 8–11 were associated with higher levels of atherosclerosis at EDIC year 12, but findings were not consistent at early time points. The endothelial dysfunction score was not appreciably predictive of or associated with subclinical atherosclerosis at any of the time points measured.
CONCLUSIONS
The pathophysiologic relationship between higher biomarker levels and progression of subclinical atherosclerosis remains unclear.
doi:10.2337/dc14-2877
PMCID: PMC4477339  PMID: 25852210
7.  Testosterone and cardiac mass and function in men with type 1 diabetes in the Epidemiology of Diabetes Interventions and Complications Study (EDIC) 
Clinical endocrinology  2016;84(5):693-699.
Structured Summary
Objective
Low testosterone concentrations have been reported to be associated with increased risk of congestive heart failure, but the mechanisms are unclear. Our objectives was to examine the relationship between endogenous testosterone and measures of cardiac mass and function among men with type 1 diabetes.
Design
Secondary analysis of a prospective observational study.
Participants
Men (n=508) in the Epidemiology of Diabetes Interventions and Complications (EDIC) study, the observational follow-up of the Diabetes Control and Complications Trial.
Measurements
Testosterone assessed by liquid chromatography mass spectrometry at EDIC year 10 and cardiac magnetic resonance imaging (CMR) measures at EDIC years 14/15. Linear regression models were used to assess the relationship between testosterone, sex hormone binding globulin (SHBG) and left ventricular (LV) mass, volume, ejection fraction, and cardiac index before and after adjustment for age, randomization arm, alcohol and cigarette use, macroalbuminuria, hemoglobin A1c, insulin dose, body mass index, lipids, blood pressure, use of anti-hypertensive medications, and microvascular complications.
Results
In fully-adjusted models, total testosterone concentrations were significantly associated with LV mass (p=0.014), end-diastolic volume (p=0.002), end-systolic volume (p=0.012), and stroke volume (p=0.022) but not measures of LV function after adjustment for cardiac risk factors. Bioavailable testosterone was associated with LV mass but not volume or function, while SHBG was associated with volume but not mass or function.
Conclusions
Among men with type 1 diabetes, higher total testosterone was associated with higher LV mass and volume but not with function. The clinical significance of this association remains to be established.
doi:10.1111/cen.12990
PMCID: PMC4824167  PMID: 26641212
cardiac magnetic resonance imaging; testosterone; diabetes mellitus; sex hormones
8.  Effects of Prior Intensive Insulin Therapy and Risk Factors on Visual Quality-of-Life in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Cohort 
JAMA ophthalmology  2016;134(2):137-145.
Importance
Preservation of visual acuity in patients with diabetes is critical to preserve VQOL. Interventions to improve glycemic control through early intensive treatment of diabetes reduce rates of severe retinopathy and preserve VA.
Objective
To assess the effect of prior intensive treatment and risk factors on visual quality of life (VQOL) in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC) cohort.
Design
Randomized controlled clinical trial followed by an observational follow-up study.
Setting
28 institutions across the United States and Canada.
Participants
1184 DCCT/EDIC participants with type 1 diabetes completed the National Eye Institute (NEI) Visual Functioning Questionnaire (VFQ) during EDIC years 17-20, up to thirty years after the start of the DCCT.
Main Outcome Measures
The 25-item NEI-VFQ was administered. Visual acuity (VA) was measured by the Early Treatment of Diabetic Retinopathy Study (ETDRS) protocol and the presence and severity of retinopathy and macular edema were detected by masked grading of stereoscopic color fundus photographs using the ETDRS retinopathy severity scheme. The composite VQOL and subscales were scored on a scale of 0 to 100 corresponding to poor to excellent function, respectively. Quantile regression was used to assess the treatment/risk factor effect on median QOL score, owing to the ordinal scoring and a skewed distribution.
Results
The overall average VQOL for DCCT/EDIC participants with a 30 year duration of diabetes was high (median 91.7, interquartile (IQR), 89.7-96.9). After adjustment for gender, age, HbA1c, and retinopathy level at DCCT baseline, the former intensive (INT) treatment group had a significant, albeit modest, improvement in overall VQOL compared to the former conventional (CONV) diabetes treatment group (median difference −1.0 [−1.7, −0.3], p=0.0058). This beneficial treatment effect was fully attributed to the prior glycemic control in DCCT (explained treatment effect: 100%). Those with VA worse than 20/100 reported the lowest VQOL score.
Conclusions and Relevance
In the DCCT/EDIC cohort, VQOL remains high in both treatment groups. Intensive diabetes therapy modestly improved VQOL 30 years after the start of the DCCT. VA had the greatest impact on VQOL from among all risk factors.
doi:10.1001/jamaophthalmol.2015.4606
PMCID: PMC4825807  PMID: 26584339
9.  Endoplasmic reticulum stress-mediated induction of SESTRIN 2 potentiates cell survival 
Oncotarget  2016;7(11):12254-12266.
Upregulation of SESTRIN 2 (SESN2) has been reported in response to diverse cellular stresses. In this study we demonstrate SESTRIN 2 induction following endoplasmic reticulum (ER) stress. ER stress-induced increases in SESTRIN 2 expression were dependent on both PERK and IRE1/XBP1 arms of the unfolded protein response (UPR). SESTRIN 2 induction, post ER stress, was responsible for mTORC1 inactivation and contributed to autophagy induction. Conversely, knockdown of SESTRIN 2 prolonged mTORC1 signaling, repressed autophagy and increased ER stress-induced cell death. Unexpectedly, the increase in ER stress-induced cell death was not linked to autophagy inhibition. Analysis of UPR pathways identified prolonged eIF2α, ATF4 and CHOP signaling in SESTRIN 2 knockdown cells following ER stress. SESTRIN 2 regulation enables UPR derived signals to indirectly control mTORC1 activity shutting down protein translation thus preventing further exacerbation of ER stress.
doi:10.18632/oncotarget.7601
PMCID: PMC4914282  PMID: 26930721
SESTRIN 2; ER stress; UPR; cell death; autophagy
10.  Progression of Electrocardiographic Abnormalities in Type 1 Diabetes During 16 Years of Follow‐up: The Epidemiology of Diabetes Interventions and Complications (EDIC) Study 
Background
The electrocardiogram (ECG) is an objective tool for cardiovascular disease (CVD) risk assessment.
Methods and Results
We evaluated distribution of ECG abnormalities and risk factors for developing new abnormalities in 1314 patients with type 1 diabetes (T1D) from the Epidemiology of Diabetes Interventions and Complications (EDIC) study. Annual ECGs were centrally read. ECG abnormalities were classified as major and minor according to the Minnesota ECG Classification. At EDIC year 1 (baseline), 356 (27.1%) of the participants had at least 1 ECG abnormality (major or minor) whereas 26 (2%) had at least one major abnormality. During 16 years of follow‐up, 1016 (77.3%) participants developed at least 1 new ECG abnormality (major or minor), whereas 172 (13.1%) developed at least 1 new major abnormality. Independent risk factors for developing new major ECG abnormalities were: age, current smoking, increased systolic blood pressure, and higher glycosylated hemoglobin (hazard ratio [HR] [95% CI]: 1.04 [1.02–1.06] per 1‐year increase, 1.75 [1.22–2.53], 1.03 [1.01–1.05] per 1 mm Hg increase, and 1.16 [1.04–1.29] per 10% increase, respectively). Independent risk factors for developing any new ECG abnormalities (major or minor) were age and systolic blood pressure (HR [95% CI]: 1.02 [1.01–1.03] per 1‐year increase and 1.01 [1.00–1.02] per 1 mm Hg increase, respectively).
Conclusions
New ECG abnormalities commonly occur in the course of T1D, consistent with the recognized increasing risk for CVD as patients age. Advanced age, increased systolic blood pressure, smoking, and higher HbA1c are independent risk factor for developing major ECG abnormalities, which underscores the importance of tight glucose control in T1D in addition to management of common CVD risk factors.
doi:10.1161/JAHA.115.002882
PMCID: PMC4943265  PMID: 26976878
electrocardiogram; The Epidemiology of Diabetes Interventions and Complications Study; type 1 diabetes; Electrocardiology (ECG); Epidemiology
11.  Skin collagen fluorophore LW-1 versus skin fluorescence as markers for the long-term progression of subclinical macrovascular disease in type 1 diabetes 
Background
Skin collagen Long Wavelength Fluorescence (LWF) is widely used as a surrogate marker for accumulation of advanced glycation end-products. Here we determined the relationship of LWF with glycemia, skin fluorescence, and the progression of complications during EDIC in 216 participants from the DCCT.
Methods
LW-1 and collagen-linked fluorescence (CLF) were measured by either High Performance Liquid Chromatography (HPLC) with fluorescence detection (LW-1) or total fluorescence of collagenase digests (CLF) in insoluble skin collagen extracted from skin biopsies obtained at the end of the DCCT (1993). Skin intrinsic fluorescence (SIF) was noninvasively measured on volar forearm skin at EDIC year 16 by the SCOUT DS instrument.
Results
LW-1 levels significantly increased with age and diabetes duration (P < 0.0001) and significantly decreased by intensive vs. conventional glycemic therapy in both the primary (P < 0.0001) and secondary (P < 0.037) DCCT cohorts. Levels were associated with 13–16 year progression risk of retinopathy (>3 sustained microaneurysms, P = 0.0004) and albumin excretion rate (P = 0.0038), the latter despite adjustment for HbA1c. Comparative analysis for all three fluorescent measures for future risk of subclinical macrovascular disease revealed the following significant (P < 0.05) associations after adjusting for age, diabetes duration and HbA1c: coronary artery calcium with SIF and CLF; intima-media thickness with SIF and LW-1; and left ventricular mass with LW-1 and CLF.
Conclusions
LW-1 is a novel risk marker that is robustly and independently associated with the future progression of microvascular disease, intima-media thickness and left ventricular mass in type 1 diabetes.
Trial registration NCT00360815 and NCT00360893 at clinicaltrials.gov
Electronic supplementary material
The online version of this article (doi:10.1186/s12933-016-0343-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s12933-016-0343-3
PMCID: PMC4750185  PMID: 26864236
Glycation; Skin autofluorescence; HbA1c; Retinopathy; Nephropathy; Neuropathy
12.  Skin Advanced Glycation End Products Glucosepane and Methylglyoxal Hydroimidazolone Are Independently Associated With Long-term Microvascular Complication Progression of Type 1 Diabetes 
Diabetes  2014;64(1):266-278.
Six skin collagen advanced glycation end products (AGEs) originally measured near to the time of the Diabetes Control and Complications Trial (DCCT) closeout in 1993 may contribute to the “metabolic memory” phenomenon reported in the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study. We have now investigated whether the addition of four originally unavailable AGEs (i.e., glucosepane [GSPNE], hydroimidazolones of methylglyoxal [MG-H1] and glyoxal, and carboxyethyl-lysine) improves associations with incident retinopathy, nephropathy, and neuropathy events during 13–17 years after DCCT. The complete 10-AGE panel is associated with three-step Early Treatment of Diabetic Retinopathy Study scale worsening of retinopathy (P ≤ 0.002), independent of either mean DCCT or EDIC study A1C level. GSPNE and fructose-lysine (furosine [FUR]) correlate with retinopathy progression, independently of A1C level. The complete panel also correlates with microalbuminuria (P = 0.008) and FUR with nephropathy independently of A1C level (P ≤ 0.02). Neuropathy correlates with the complete panel despite adjustment for A1C level (P ≤ 0.005). MG-H1 and FUR are dominant, independent of A1C level (P < 0.0001), whereas A1C loses significance after adjustment for the AGEs. Overall, the added set of four AGEs enhances the association of the original panel with progression risk of retinopathy and neuropathy (P < 0.04) but not nephropathy, while GSPNE and MG-H1 emerge as the principal new risk factors. Skin AGEs are robust long-term markers of microvascular disease progression, emphasizing the importance of early and sustained implementation of intensive therapy.
doi:10.2337/db14-0215
PMCID: PMC4274803  PMID: 25187362
13.  The predictive role of markers of Inflammation and endothelial dysfunction on the course of diabetic retinopathy in Type 1 Diabetes 
Aims
This study was undertaken to determine whether levels of inflammation and endothelial dysfunction biomarkers in serum samples collected at baseline in the Diabetes Control and Complications Trial (DCCT) cohort could predict the development of retinopathy.
Methods
Levels of clotting/fibrinolysis, inflammation and endothelial dysfunction biomarkers were measured in 1391 subjects with type 1 diabetes to determine whether their levels predicted increased risk to develop or accelerated progression of retinopathy during 16 years of follow-up.
Results
Using regression models adjusted for DCCT treatment group, duration of diabetes, baseline retinopathy scores, HbA1c and albumin excretion rate, the baseline levels of sE-selectin and PAI-1 (active) were significantly associated with increased risk of a 3-step progression in retinopathy score in the Primary Prevention Cohort (PPC). After adjusting for additional covariates (e.g., ACE/ARB and statin therapy), this association persisted. Levels of active and total PAI-1 in the same group were also significantly associated, after similar adjustments, with the time to progress to severe non-proliferative retinopathy during the follow-up period (54% and 29%, respectively of increased risk). No associations were observed in the Secondary Intervention Cohort for any of the outcomes.
Conclusions
High levels of sE-selectin and PAI-1 are associated with the development of retinopathy in patients with uncomplicated type 1 diabetes.
doi:10.1016/j.jdiacomp.2014.08.004
PMCID: PMC4426877  PMID: 25441222
Type 1 diabetes; diabetes complications; retinopathy; biomarkers; E-selectin; Plasminogen activator inhibitor type 1
14.  Quality Control Measures over 30 Years in a Multicenter Clinical Study: Results from the Diabetes Control and Complications Trial / Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study 
PLoS ONE  2015;10(11):e0141286.
Implementation of multicenter and/or longitudinal studies requires an effective quality assurance program to identify trends, data inconsistencies and process variability of results over time. The Diabetes Control and Complications Trial (DCCT) and the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study represent over 30 years of data collection among a cohort of participants across 27 clinical centers. The quality assurance plan is overseen by the Data Coordinating Center and is implemented across the clinical centers and central reading units. Each central unit incorporates specific DCCT/EDIC quality monitoring activities into their routine quality assurance plan. The results are reviewed by a data quality assurance committee whose function is to identify variances in quality that may impact study results from the central units as well as within and across clinical centers, and to recommend implementation of corrective procedures when necessary. Over the 30-year period, changes to the methods, equipment, or clinical procedures have been required to keep procedures current and ensure continued collection of scientifically valid and clinically relevant results. Pilot testing to compare historic processes with contemporary alternatives is performed and comparability is validated prior to incorporation of new procedures into the study. Details of the quality assurance plan across and within the clinical and central reading units are described, and quality outcomes for core measures analyzed by the central reading units (e.g. biochemical samples, fundus photographs, ECGs) are presented.
doi:10.1371/journal.pone.0141286
PMCID: PMC4631458  PMID: 26529311
16.  Caffeine Consumption Contributes to Skin Intrinsic Fluorescence in Type 1 Diabetes 
Diabetes Technology & Therapeutics  2015;17(10):726-734.
Abstract
Background: A variant (rs1495741) in the gene for the N-acetyltransferase 2 (NAT2) protein is associated with skin intrinsic fluorescence (SIF), a noninvasive measure of advanced glycation end products and other fluorophores in the skin. Because NAT2 is involved in caffeine metabolism, we aimed to determine whether caffeine consumption is associated with SIF and whether rs1495741 is associated with SIF independently of caffeine.
Materials and Methods: SIF was measured in 1,181 participants with type 1 diabetes from the Epidemiology of Diabetes Interventions and Complications study. Two measures of SIF were used: SIF1, using a 375-nm excitation light-emitting diode (LED), and SIF14 (456-nm LED). Food frequency questionnaires were used to estimate mean caffeine intake. To establish replication, we examined a second type 1 diabetes cohort.
Results: Higher caffeine intake was significantly associated with higher SIF1LED 375 nm[0.6, 0.2] (P=2×10−32) and SIF14LED 456 nm[0.4, 0.8] (P=7×10−31) and accounted for 4% of the variance in each after adjusting for covariates. When analyzed together, caffeine intake and rs1495741 both remained highly significantly associated with SIF1LED 375 nm[0.6, 0.2] and SIF14LED 456 nm[0.4, 0.8]. Mean caffeinated coffee intake was also positively associated with SIF1LED 375 nm[0.6, 0.2] (P=9×10−12) and SIF14LED 456 nm[0.4, 0.8] (P=4×10−12), but no association was observed for decaffeinated coffee intake. Finally, caffeine was also positively associated with SIF1LED 375 nm[0.6, 0.2] and SIF14LED 456 nm[0.4, 0.8] (P<0.0001) in the replication cohort.
Conclusions: Caffeine contributes to SIF. The effect of rs1495741 on SIF appears to be partially independent of caffeine consumption. Because SIF and coffee intake are each associated with cardiovascular disease, our findings suggest that accounting for coffee and/or caffeine intake may improve risk prediction models for SIF and cardiovascular disease in individuals with diabetes.
doi:10.1089/dia.2015.0017
PMCID: PMC4575521  PMID: 26192006
17.  Skin collagen advanced glycation endproducts (AGEs) and the long-term progression of sub-clinical cardiovascular disease in type 1 diabetes 
Background
We recently reported strong associations between eight skin collagen AGEs and two solubility markers from skin biopsies obtained at DCCT study closeout and the long-term progression of microvascular disease in EDIC, despite adjustment for mean glycemia. Herein we investigated the hypothesis that some of these AGEs (fluorescence to be reported elsewhere) correlate with long-term subclinical cardiovascular disease (CVD) measurements, i.e. coronary artery calcium score (CAC) at EDIC year 7–9 (n = 187), change of carotid intima-media thickness (IMT) from EDIC year 1 to year 6 and 12 (n = 127), and cardiac MRI outcomes at EDIC year 15–16 (n = 142).
Methods
Skin collagen AGE measurements obtained from stored specimens were related to clinical data from the DCCT/EDIC using Spearman correlations and multivariable logistic regression analyses.
Results
Spearman correlations showed furosine (early glycation) was associated with future mean CAC (p < 0.05) and CAC >0 (p = 0.39), but not with CAC score <100 vs. >100. Glucosepane and pentosidine crosslinks, methylglyoxal hydroimidazolones (MG-H1) and pepsin solubility (inversely) correlated with IMT change from year 1 to 6(all P < 0.05). Left ventricular (LV) mass (cMRI) correlated with MG-H1, and inversely with pepsin solubility (both p < 0.05), while the ratio LV mass/end diastolic volume correlated with furosine and MG-H1 (both p < 0.05), and highly with CML (p < 0.01). In multivariate analysis only furosine (p = 0.01) was associated with CAC. In contrast IMT was inversely associated with lower collagen pepsin solubility and positively with glucosepane,
Conclusions
In type 1 diabetes, multiple AGEs are associated with IMT progression in spite of adjustment for A1c implying a likely participatory role of glycation and AGE mediated crosslinking on matrix accumulation in coronary arteries. This may also apply to functional cardiac MRI outcomes, especially left ventricular mass. In contrast, early glycation measured by furosine, but not AGEs, was associated with CAC score, implying hyperglycemia as a risk factor in calcium deposition perhaps via processes independent of glycation.
Trial registration: Registered at Clinical trial reg. nos. NCT00360815 and NCT00360893, http://www.clinicaltrials.gov
doi:10.1186/s12933-015-0266-4
PMCID: PMC4560872  PMID: 26341632
AGEs; A1c; DCCT/EDIC; Coronary artery calcium; Intima media thickening; Cardiac indices
18.  Musculoskeletal Complications in Type 1 Diabetes 
Diabetes Care  2014;37(7):1863-1869.
OBJECTIVE
The development of periarticular thickening of skin on the hands and limited joint mobility (cheiroarthropathy) is associated with diabetes and can lead to significant disability. The objective of this study was to describe the prevalence of cheiroarthropathy in the well-characterized Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort and examine associated risk factors, microvascular complications, and the effect of former DCCT therapy (intensive [INT] vs. conventional [CONV]) on its development.
RESEARCH DESIGN AND METHODS
This cross-sectional analysis was performed in 1,217 participants (95% of the active cohort) in EDIC years 18/19 after an average of 24 years of follow-up. Cheiroarthropathy—defined as the presence of any one of the following: adhesive capsulitis, carpal tunnel syndrome, flexor tenosynovitis, Dupuytren's contracture, or a positive prayer sign—was assessed using a targeted medical history and standardized physical examination. A self-administered questionnaire (Disabilities of the Arm, Shoulder and Hand [DASH]) assessed functional disability.
RESULTS
Cheiroarthropathy was present in 66% of subjects (64% of the INT group and 68% of the CONV group; P = 0.1640) and was associated with age, sex, diabetes duration, skin intrinsic fluorescence, HbA1c, neuropathy, and retinopathy (P < 0.005 for each). DASH functional disability scores were worse among subjects with cheiroarthropathy (P < 0.0001).
CONCLUSIONS
Cheiroarthropathy is common in people with type 1 diabetes of long duration (∼30 years) and is related to longer duration and higher levels of glycemia. Clinicians should include cheiroarthropathy in their routine history and physical examination of patients with type 1 diabetes because it causes clinically significant functional disability.
doi:10.2337/dc13-2361
PMCID: PMC4067398  PMID: 24722493
19.  Cardiovascular Autonomic Neuropathy, Erectile Dysfunction and Lower Urinary Tract Symptoms in Men with Type 1 Diabetes: Findings from the DCCT/EDIC 
The Journal of urology  2015;193(6):2045-2051.
PURPOSE
We evaluated the association between cardiovascular autonomic neuropathy (CAN), erectile dysfunction (ED) and lower urinary tract symptoms (LUTS) in men with type 1 diabetes (T1DM).
MATERIALS & METHODS
Male T1DM participants (n=635) in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Intervention and Complications Study (DCCT/EDIC) were studied. CAN was assessed by standardized cardiovascular reflex tests including changes in R-R variation with deep-breathing, Valsalva maneuver (Valsalva ratio), and changes in supine-to-standing diastolic blood pressure. ED was assessed by a proxy item from the International Index of Erectile Function (IIEF), and LUTS by the American Urological Association Symptom Index (AUASI). Multivariable logistic regression models estimated the association between CAN, ED and/or LUTS, adjusting for time-weighted glycemic control, blood pressure, age, and other covariates.
RESULTS
Men who developed ED and/or LUTS during EDIC had significantly lower R-R variation and Valsalva ratio at DCCT closeout and EDIC year 16/17 compared to those without ED or LUTS. In adjusted analysis, participants with CAN had 2.65 greater odds of ED and LUTS (95% CI=1·47,4·79).
CONCLUSIONS
These data suggest that CAN predicts the development of urological complications in men with long-standing T1DM. Studies evaluating the mechanisms contributing to these interactions are warranted for targeting effective prevention or treatment.
doi:10.1016/j.juro.2014.12.097
PMCID: PMC4439365  PMID: 25584994
Autonomic Neuropathy; Diabetes; Erectile Dysfunction; Lower Urinary Tract Symptoms
20.  Evaluating the Role of Epigenetic Histone Modifications in the Metabolic Memory of Type 1 Diabetes 
Diabetes  2014;63(5):1748-1762.
We assessed whether epigenetic histone posttranslational modifications are associated with the prolonged beneficial effects (metabolic memory) of intensive versus conventional therapy during the Diabetes Control and Complications Trial (DCCT) on the progression of microvascular outcomes in the long-term Epidemiology of Diabetes Interventions and Complications (EDIC) study. We performed chromatin immunoprecipitation linked to promoter tiling arrays to profile H3 lysine-9 acetylation (H3K9Ac), H3 lysine-4 trimethylation (H3K4Me3), and H3K9Me2 in blood monocytes and lymphocytes obtained from 30 DCCT conventional treatment group subjects (case subjects: mean DCCT HbA1c level >9.1% [76 mmol/mol] and progression of retinopathy or nephropathy by EDIC year 10 of follow-up) versus 30 DCCT intensive treatment subjects (control subjects: mean DCCT HbA1c level <7.3% [56 mmol/mol] and without progression of retinopathy or nephropathy). Monocytes from case subjects had statistically greater numbers of promoter regions with enrichment in H3K9Ac (active chromatin mark) compared with control subjects (P = 0.0096). Among the patients in the two groups combined, monocyte H3K9Ac was significantly associated with the mean HbA1c level during the DCCT and EDIC (each P < 2.2E-16). Of note, the top 38 case hyperacetylated promoters (P < 0.05) included >15 genes related to the nuclear factor-κB inflammatory pathway and were enriched in genes related to diabetes complications. These results suggest an association between HbA1c level and H3K9Ac, and a possible epigenetic explanation for metabolic memory in humans.
doi:10.2337/db13-1251
PMCID: PMC3994951  PMID: 24458354
22.  POOR GLYCEMIC CONTROL IS ASSOCIATED WITH REDUCED PROSTATE-SPECIFIC ANTIGEN CONCENTRATIONS IN MEN WITH TYPE 1 DIABETES 
The Journal of urology  2014;193(3):786-793.
PURPOSE
Previous studies have demonstrated lower prostate-specific antigen (PSA) concentrations in men with type 2 diabetes (T2DM), paralleling the reported lower prevalence of prostate cancer among diabetic men. Data on PSA in men with type 1 diabetes (T1DM), in whom insulin and obesity profiles differ from those in T2DM, are lacking. The objective of this study was to examine the relationship between long-term glycemic control and PSA in men with T1DM.
MATERIALS & METHODS
Total PSA was measured at one time in 639 men in the Epidemiology of Diabetes Interventions and Complications (EDIC) study, the observational follow up of participants in the Diabetes Control and Complications Trial (DCCT). The relationship between DCCT/EDIC weighted mean HbA1c and log PSA was assessed using linear regression modeling after adjusting for age, body mass index (BMI), total testosterone, statin and thiazide medication use, diabetes duration, and DCCT randomization arm and cohort.
RESULTS
The subjects had a median age of 52 years, BMI of 28.4 kg/m2 and DCCT/EDIC time weighted HbA1c of 7.9%. Total median (interquartile range) for PSA levels was 0.64 (0.43, 1.05). PSA levels increased significantly with age (p<0.0001) and with lower time weighted HbA1c (p<0.0001). Each 10% increase in HbA1c was accompanied by an 11% reduction in PSA (p=0.0001).
CONCLUSIONS
PSA levels decrease as HbA1c increases in men with T1DM. This relationship is independent of age, BMI, androgen levels, medication use and measures of diabetes severity, which suggest that factors related to glycemia may be directly affecting PSA levels.
doi:10.1016/j.juro.2014.08.115
PMCID: PMC4363040  PMID: 25218922
Glycemic Control; Diabetes; PSA
23.  Effect of Glycemic Treatment and Microvascular Complications on Menopause in Women With Type 1 Diabetes in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Cohort 
Diabetes Care  2014;37(3):701-708.
OBJECTIVE
We examined the impact of intensive versus conventional diabetes treatment upon menopause among women with type 1 diabetes in the Diabetes Control and Complications Trial (DCCT), a randomized controlled trial of intensive diabetes treatment, and its observational follow-up, the Epidemiology of Diabetes Interventions and Complications (EDIC) study.
RESEARCH DESIGN AND METHODS
In a secondary analysis of women in the DCCT/EDIC (n = 657), outcomes were the cumulative incidences of natural menopause and surgical menopause. Cox regression analyses were used to examine associations with treatment group, time-varying estimates of hemoglobin A1c (HbA1c), insulin dosage, BMI, and microvascular complications (retinopathy, nephropathy, and neuropathy).
RESULTS
By EDIC year 18, after an average of 28 years of follow-up, 240 (38%) women had experienced natural menopause and 115 (18%) women had experienced surgical menopause. Age at natural menopause was similar in the intensive versus conventional groups (49.9 vs. 49.0 years; P = 0.28), and age at surgical menopause was similar in the intensive versus conventional groups (40.8 vs. 42.0 years; P = 0.31). In multivariable models, treatment group, HbA1c, and microvascular complications were not associated with risk of natural or surgical menopause. Each 10 unit/day increase in insulin dosage decreased risk of natural menopause (hazard ratio [HR] 0.91, 95% CI 0.75–0.98) and each kg/m2 increase in BMI increased risk of surgical menopause (HR 1.08, 95% CI 1.00–1.16).
CONCLUSIONS
In the DCCT/EDIC, intensive versus conventional treatment group and HbA1c level were not associated with menopause risk. Greater insulin dose was associated with lower menopause risk.
doi:10.2337/dc13-1746
PMCID: PMC3931380  PMID: 24170751
24.  Association between seven years of intensive treatment of type 1 diabetes and long term mortality 
JAMA  2015;313(1):45-53.
Importance
Whether mortality in type 1 diabetes mellitus is affected following intensive glycemic therapy has not been established.
Objective
To determine whether mortality differed between the original intensive and conventional treatment groups in the long-term follow-up of the Diabetes Control and Complications Trial (DCCT) cohort.
Design, Setting, and Participants
After the DCCT (1983–1993) ended, participants were followed up in a multisite (27 US and Canadian academic clinical centers) observational study (Epidemiology of Diabetes Control and Complications [EDIC]) until December 31, 2012. Participants were 1441 healthy volunteers with diabetes mellitus who, at baseline, were 13 to 39 years of age with 1 to 15 years of diabetes duration and no or early microvascular complications, and without hypertension, preexisting cardiovascular disease, or other potentially life-threatening disease.
Intervention/Exposure
During the clinical trial, participants were randomly assigned to receive intensive therapy (n = 711) aimed at achieving glycemia as close to the nondiabetic range as safely possible, or conventional therapy (n = 730) with the goal of avoiding symptomatic hypoglycemia and hyperglycemia. At the end of the DCCT, after a mean of 6.5 years, intensive therapy was taught and recommended to all participants and diabetes care was returned to personal physicians.
Main Outcomes
Total and cause-specific mortality was assessed through annual contact with family and friends and through records over 27 years mean follow-up.
Results
Vital status was ascertained for 1429 (99.2%) participants. There were 107 deaths, 64 in the conventional and 43 in the intensive group. The absolute risk difference was −109 per 100 000 patient-years (95%CI, −218 to −1), with lower all-cause mortality risk in the intensive therapy group (hazard ratio [HR] = 0.67 [95%CI, 0.46–0.99]; P = .045). Primary causes of death were cardiovascular disease (24 deaths; 22.4%), cancer (21 deaths; 19.6%), acute diabetes complications (19 deaths; 17.8%), and accidents or suicide (18 deaths; 16.8%). Higher levels of glycated hemoglobin (HbA1c) were associated with all-cause mortality (HR = 1.56 [95%CI, 1.35–1.81 per 10% relative increase in HbA1c]; P < .001), as well as the development of albuminuria (HR = 2.20 [95%CI, 1.46–3.31]; P < .001).
Conclusions and Relevance
After a mean of 27 years’ follow-up of patients with type 1 diabetes, 6.5 years of initial intensive diabetes therapy was associated with a modestly lower all-cause mortality compared with conventional therapy.
doi:10.1001/jama.2014.16107
PMCID: PMC4306335  PMID: 25562265
25.  Validity of Self Report in Type 1 Diabetic Subjects for Laser Treatment of Retinopathy 
Ophthalmology  2013;120(12):10.1016/j.ophtha.2013.06.002.
Purpose
This study sought to determine the validity of self report of prior pan-retinal photocoagulation (PRP) and focal photocoagulation (FP) compared to fundus photography.
Design
Prospective cohort study.
Participants
1363 type 1 diabetic subjects from the Epidemiology of Diabetes Interventions and Complications (EDIC) Study, a subset of the 1441 subjects originally enrolled in the multi-center Diabetes Control and Complications Trial.
Methods
At each annual visit, subjects were asked by EDIC staff whether they had PRP and/or FP since the last completed annual clinic visit. Fundus photographs were collected in one quarter of the cohort each year and in the whole cohort at EDIC years 4 and 10. Photographs were graded for the presence and extent of PRP and FP. Seventeen years of subject reporting and photograph grading of PRP and FP were compared in EDIC subjects.
Main Outcome Measures
Kappa, sensitivity, specificity, and positive and negative predictive values were calculated for subject-reported PRP and FP. Factors influencing subject misreporting were investigated.
Results
For subject reporting, 1244 (96%) of 1296 subjects with gradable photographs accurately reported whether they had a history of PRP in one or both eyes, and 1259 (97.5%) of 1291 with valid photographs correctly reported their history of FP. Sensitivities for PRP and FP were 90.4 and 74.0%; specificities, 96.0 and 98.8%; positive predictive values, 75.9 and 80.3%; negative predictive values, 98.9 and 98.4%; and kappa 0.80 and 0.76. Risk factors associated with misreporting include prior laser for diabetic retinopathy and prior ocular surgery (each p <0.04).
Conclusions
For subjects with type 1 diabetes, in the absence of a clinical exam or fundus photographs, subject self report could be a reliable tool in a well-monitored study for assessing laser treatment type in diabetic retinopathy.
doi:10.1016/j.ophtha.2013.06.002
PMCID: PMC3818390  PMID: 23890420

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