Weight gain trajectories and obesity rates in intensive and conventional treatments of type 1 diabetes from the DCCT compared with a control population without diabetes.

AIM: Obesity is a significant health issue for participants with type 1 diabetes undergoing intensive diabetes management. The temporal pattern and factors associated with weight gain after treatment initiation remain poorly understood including how weight gain in participants with and without type I diabetes compare. Our aim was to compare weight gain in those receiving intensive (INT) and conventional (CONV) type 1 diabetes treatment to a population without diabetes. METHODS: Participants included men and women of 18 years and older in the Diabetes Control and Complications Trial (DCCT) randomized to INT (n = 562) or CONV (n = 568) and a prospective, observational cohort without diabetes from the Coronary Artery Development in Young Adults (CARDIA, controls) study (n = 2446). Body mass index (BMI) trajectories and obesity prevalence were compared between groups and candidate metabolic and therapeutic moderators investigated. RESULTS: Annual weight gain with INT peaked 1.3 years after initiation and was greater than both CONV and controls before and after this peak. Obesity prevalence with INT was lower than controls at baseline, was similar to controls at 2 years and surpassed controls by 5 years. Obesity rates with CONV remained below controls at all time points. Greater annual weight gain in the DCCT was associated with lower haemoglobin A1c , higher insulin dose and family history of type 2 diabetes. CONCLUSIONS: Greater weight gain accompanying INT therapy occurs in two stages, leads to similar or greater obesity rates than controls after 2 years and is primarily modified by glucose control and family history, supportive of a therapeutic-genetic influence on weight trajectories.

Overview of the Lake Michigan Ozone Study 2017.

The Lake Michigan Ozone Study 2017 (LMOS 2017) was a collaborative multiagency field study targeting ozone chemistry, meteorology, and air quality observations in the southern Lake Michigan area. The primary objective of LMOS 2017 was to provide measurements to improve air quality modeling of the complex meteorological and chemical environment in the region. LMOS 2017 science questions included spatiotemporal assessment of nitrogen oxides (NO x = NO + NO2) and volatile organic compounds (VOC) emission sources and their influence on ozone episodes; the role of lake breezes; contribution of new remote sensing tools such as GeoTASO, Pandora, and TEMPO to air quality management; and evaluation of photochemical grid models. The observing strategy included GeoTASO on board the NASA UC-12 aircraft capturing NO2 and formaldehyde columns, an in situ profiling aircraft, two ground-based coastal enhanced monitoring locations, continuous NO2 columns from coastal Pandora instruments, and an instrumented research vessel. Local photochemical ozone production was observed on 2 June, 9-12 June, and 14-16 June, providing insights on the processes relevant to state and federal air quality management. The LMOS 2017 aircraft mapped significant spatial and temporal variation of NO2 emissions as well as polluted layers with rapid ozone formation occurring in a shallow layer near the Lake Michigan surface. Meteorological characteristics of the lake breeze were observed in detail and measurements of ozone, NOx, nitric acid, hydrogen peroxide, VOC, oxygenated VOC (OVOC), and fine particulate matter (PM2.5) composition were conducted. This article summarizes the study design, directs readers to the campaign data repository, and presents a summary of findings.

Impacts of lake breeze meteorology on ozone gradient observations along Lake Michigan Shorelines in Wisconsin.

Daytime onshore lake breezes are a critical factor controlling ozone abundance at coastal sites around Lake Michigan. Coastal counties along the western shore of Lake Michigan have historically observed high ozone episodes dating to the 1970s. We classified ozone episode days based on the extent or absence of the lake breeze (i.e., "inland", "near-shore" or "no" lake breeze) to establish a climatology of these events. This work demonstrated variable gradients in ozone abundances based on these different types of meteorology, with the sharpest ozone concentration gradients on days with a near-shore lake breeze. On 76-82% of days in which ozone reached 70 ppb for at least 1 hour, a lake breeze was present. Evidence of ozone gradients from multiple observation platforms during the 2017 Lake Michigan Ozone Study (LMOS 2017) are shown for two days with different depths of lake breezes.

The Course of Visual Recovery after Optic Neuritis: Experience of the Optic Neuritis Treatment Trial.

PURPOSE: To define the time course of visual recovery after optic neuritis and factors predictive of this course in the patients enrolled in the Optic Neuritis Treatment Trial. METHODS: The cohort for this study consisted of the 438 patients who completed the 6-month follow-up visit. Visual acuity was measured at baseline and at seven follow-up visits during the first 6 months. Factors predictive of recovery were evaluated with univariate and multivariate statistical tests. RESULTS: Visual recovery was rapid in all three treatment groups. In almost all patients, regardless of treatment group and initial severity of visual loss, improvement began within the first month. Among the 278 patients with baseline visual acuity of 20/ 50 or worse, all patients improved at least one line of visual acuity, and all except six improved at least three lines, during the 6-month follow-up period. Baseline visual acuity was the best predictor of the 6-month visual acuity outcome (P = 0.0001). Older age was statistically associated with a slightly worse outcome (P = 0.02), but this appeared to be of no clinical importance. CONCLUSIONS: In most patients with optic neuritis, visual recovery is rapid. The only factor of value in predicting the visual outcome is initial severity of visual loss. However, even when initial loss is severe, visual recovery is still good in most patients. Patients not following the usual course of visual recovery should be considered atypical. For such patients, further investigation in regard to etiology of the visual loss may be appropriate.

Impact of Excessive Weight Gain on Cardiovascular Outcomes in Type 1 Diabetes: Results From the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study.

OBJECTIVE: Intensive treatment (INT) of type 1 diabetes reduces the incidence of cardiovascular disease (CVD) events compared with conventional treatment (CONV), but it also results in more weight gain. Our objective was to examine whether excessive weight gain from INT of type 1 diabetes is independently associated with subsequent CVD events. RESEARCH DESIGN AND METHODS: Quartiles (Q) of weight gain in 1,213 participants aged 18 years and older at enrollment in the Diabetes Control and Complications Trial (DCCT) were determined within randomized treatment groups (INT vs. CONV) using change in BMI from baseline to the closeout DCCT visits. Effects of this weight gain on CVD risk factors and outcomes during an additional 20 years of observational follow-up were then determined. RESULTS: The Q4 INT group experienced greater proportional weight gain (median change in BMI, 6.08 kg/m2), increases in CVD risk factors, and need for medications for hypertension and lipids compared with the Q1-3 INT and comparable CONV groups. Over a mean of 26 years of follow-up, the numbers of major and total CVD events were not statistically different in Q4 compared with Q1-3 of either the INT or CONV group. By year 14, however, the incident CVD event curve became significantly higher in the Q4 INT group than in the Q1-3 INT groups (P = 0.024) and was similar to that for the CONV group. CONCLUSIONS: For the first 13 years after DCCT, INT for type 1 diabetes reduced macrovascular events compared with CONV, even when excessive weight gain occurred. After this, total CVD events significantly increased in the Q4 INT group, becoming equivalent to those in the CONV group. Longer follow-up is needed to determine whether this trend continues and results in more major CVD events.

Longitudinal Patterns of Occurrence and Remission of Erectile Dysfunction in Men With Type 1 Diabetes.

BACKGROUND: Men with diabetes are at greater risk of erectile dysfunction (ED). AIM: To describe the natural history of ED in men with type 1 diabetes. METHODS: We examined up to 30 years of prospectively collected annual ED status and demographic and clinical variables from 600 male participants in the Diabetes Control and Complications Trial (DCCT; 1983-1993) and its follow-up study, the Epidemiology of Diabetes Interventions and Complications (1994-present; data in this study are through 2012). OUTCOMES: Yes vs no response to whether the participant had experienced impotence in the past year and whether he had used ED medication. RESULTS: Sixty-one percent of men reported ED at least once during the study. For some men, the initial report of ED was permanent. For others, potency returned and was lost multiple times. Visual display of the data showed four longitudinal ED phenotypes: never (38.7%), isolated (6.7%), intermittent (41.8%), and persistent (12.8%). Men who never reported ED or in only 1 isolated year were younger, had lower body mass index, and better glycemic control than men in the intermittent and persistent groups at DCCT baseline. In a multivariable logistic model comparing men at their first year reporting ED, men who were older had lower odds of remission and men who were in the conventional DCCT treatment group had higher odds of remission. CLINICAL TRANSLATION: If validated in other cohorts, such findings could be used to guide individualized interventions for patients with ED. STRENGTHS AND LIMITATIONS: This is the first examination of ED with repeated measures at an annual resolution, with up to 30 years of responses for each participant. However, the yes vs no response is a limitation because the real phenotype is not binary and the question can be interpreted differently depending on the participant. CONCLUSIONS: Age, glycemic control, and BMI were important longitudinal predictors of ED. We have described a more complex ED phenotype, with variation in remission patterns, which could offer insight into different mechanisms or opportunities for intervention. If validated in other cohorts, such findings could be used to establish more accurate prognostication of outcomes for patients with ED to guide individualized interventions. Palmer MR, Holt SK, Sarma AV, et al. Longitudinal Patterns of Occurrence and Remission of Erectile Dysfunction in Men With Type 1 Diabetes. J Sex Med 2017;14:1187-1194.

Albuminuria Changes and Cardiovascular and Renal Outcomes in Type 1 Diabetes: The DCCT/EDIC Study.

BACKGROUND AND OBJECTIVES: In trials of people with type 2 diabetes, albuminuria reduction with renin-angiotensin system inhibitors is associated with lower risks of cardiovascular events and CKD progression. We tested whether progression or remission of microalbuminuria is associated with cardiovascular and renal risk in a well characterized cohort of type 1 diabetes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We studied 1441 participants in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study. Albumin excretion rate (AER) was quantified annually or biennially for up to 30 years. For each participant, albuminuria status was defined over time as normoalbuminuria (AER continuously <30 mg/d), sustained microalbuminuria (AER, 30-299 mg/d on two consecutive visits), macroalbuminuria (AER≥300 mg/d), or remitted microalbuminuria (transition from sustained microalbuminuria to AER<30 mg/d on two consecutive visits). We tested associations of time-updated albuminuria status with adjudicated clinical cardiovascular events, the development of reduced GFR (<60 ml/min per 1.73 m2 on two consecutive visits), and subclinical cardiovascular disease. RESULTS: At least one cardiovascular event occurred in 184 participants, and 98 participants developed reduced eGFR. Compared with normoalbuminuria, sustained microalbuminuria, remitted microalbuminuria, and macroalbuminuria were each associated with higher risk of cardiovascular events (adjusted hazard ratios [HRs] and 95% confidence intervals [95% CIs]: 1.79 [1.13 to 2.85], 2.62 [1.68 to 4.07], and 2.65 [1.68 to 4.19], respectively) and reduced eGFR (adjusted HRs [95% CIs], 5.26 [2.43 to 11.41], 4.36 [1.80 to 10.57], and 54.35 [30.79 to 95.94], respectively). Compared with sustained microalbuminuria, remission to normoalbuminuria was not associated with reduced risk of cardiovascular events (adjusted HR, 1.33; 95% CI, 0.68 to 2.59) or reduced eGFR (adjusted HR, 1.75; 95% CI, 0.56 to 5.49). Compared with normoalbuminuria, sustained microalbuminuria, remitted microalbuminuria, and macroalbuminuria were associated with greater carotid intima-media thickness, and macroalbuminuria was associated with a greater degree of coronary artery calcification. CONCLUSIONS: In type 1 diabetes, microalbuminuria and macroalbuminuria are associated with higher risks of cardiovascular disease and reduced eGFR, but achieving a remission of established microalbuminuria to normoalbuminuria does not appear to improve outcomes.

Lymphoblastoid Cell Lines as a Tool to Study Inter-Individual Differences in the Response to Glucose.

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.

Significance of Epicardial and Intrathoracic Adipose Tissue Volume among Type 1 Diabetes Patients in the DCCT/EDIC: A Pilot Study.

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.

Cardiovascular Autonomic Neuropathy, Sexual Dysfunction, and Urinary Incontinence in Women With Type 1 Diabetes.

OBJECTIVE: This study evaluated associations among cardiovascular autonomic neuropathy (CAN), female sexual dysfunction (FSD), and urinary incontinence (UI) in women with type I diabetes mellitus (T1DM). RESEARCH DESIGN AND METHODS: We studied 580 women with T1DM in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC). CAN was defined as: 1) R-R variation <15 with deep breathing or 2) R-R variation of 15-19.9 plus Valsalva ratio ≤1.5 or a supine-to-standing drop of 10 mmHg in diastolic blood pressure. A Sandvik Severity Index of 3-12 defined UI, and a Female Sexual Function Index (FSFI-R) score ≥22.75 defined FSD. Multivariable models estimated associations among CAN, FSD, and UI. RESULTS: At EDIC year 17, FSD was observed in 41% of women and UI in 30%. No statistically significant associations were observed between measures of CAN at DCCT closeout and subsequent report of FSD or UI. At EDIC year 16/17, there was a 53% increased odds of having UI with a Valsalva ratio ≤1.5. At both EDIC year 13/14 and EDIC year 16/17, a 5-unit increase in R-R variation was associated with a 1.11 greater odds of having FSD. CONCLUSIONS: In women with T1DM in the DCCT/EDIC, we found significant increased odds of FSD and UI with specific measures of CAN. In long-standing T1DM, CAN may predict development of FSD and may be a useful surrogate for generalized diabetic autonomic neuropathy.

Glycemic Control and Urinary Tract Infections in Women with Type 1 Diabetes: Results from the DCCT/EDIC.

PURPOSE: We examined the relationship between glycemic control and urinary tract infections in women with type 1 diabetes mellitus. MATERIALS AND METHODS: Women enrolled in the Epidemiology of Diabetes Interventions and Complications study, the observational followup of the Diabetes Control and Complications Trial, were surveyed to assess the rate of physician diagnosed urinary tract infections in the preceding 12 months. The relationship between glycated hemoglobin levels and number of urinary tract infections in the previous 12 months was assessed using a multivariable Poisson regression model. RESULTS: A total of 572 women were evaluated at year 17. Mean age was 50.7 ± 7.2 years, mean body mass index was 28.6 ± 5.9 kg/m(2), mean type 1 diabetes duration was 29.8 ± 5.0 years and mean glycated hemoglobin was 8.0% ± 0.9%. Of these women 86 (15.0%) reported at least 1 physician diagnosed urinary tract infection during the last 12 months. Higher glycated hemoglobin levels were significantly associated with number of urinary tract infections such that for every unit increase (1%) in recent glycated hemoglobin level, there was a 21% (p=0.02) increase in urinary tract infection frequency in the previous 12 months after adjusting for race, hysterectomy status, urinary incontinence, sexual activity in the last 12 months, peripheral and autonomic neuropathy, and nephropathy. CONCLUSIONS: The frequency of urinary tract infections increases with poor glycemic control in women with type 1 diabetes. This relationship is independent of other well described predictors of urinary tract infections and suggests that factors directly related to glycemic control may influence the risk of lower urinary tract infections.

New Locus for Skin Intrinsic Fluorescence in Type 1 Diabetes Also Associated With Blood and Skin Glycated Proteins.

Skin fluorescence (SF) noninvasively measures advanced glycation end products (AGEs) in the skin and is a risk indicator for diabetes complications. N-acetyltransferase 2 (NAT2) is the only known locus influencing SF. We aimed to identify additional genetic loci influencing SF in type 1 diabetes (T1D) through a meta-analysis of genome-wide association studies (N = 1,359) including Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) and Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR). A locus on chromosome 1, rs7533564 (P = 1.9 × 10(-9)), was associated with skin intrinsic fluorescence measured by SCOUT DS (excitation 375 nm, emission 435-655 nm), which remained significant after adjustment for time-weighted HbA1c (P = 1.7 × 10(-8)). rs7533564 was associated with mean HbA1c in meta-analysis (P = 0.0225), mean glycated albumin (P = 0.0029), and glyoxal hydroimidazolones (P = 0.049), an AGE measured in skin biopsy collagen, in DCCT. rs7533564 was not associated with diabetes complications in DCCT/EDIC or with SF in subjects without diabetes (nondiabetic [ND]) (N = 8,721). In conclusion, we identified a new locus associated with SF in T1D subjects that did not show similar effect in ND subjects, suggesting a diabetes-specific effect. This association needs to be investigated in type 2 diabetes.

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.

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.

Effects of Prior Intensive Insulin Therapy and Risk Factors on Patient-Reported Visual Function Outcomes in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Cohort.

IMPORTANCE: Preservation of vision in patients with diabetes mellitus is critical. Interventions to improve glycemic control through early intensive treatment of diabetes reduce rates of severe retinopathy and preserve visual acuity. OBJECTIVE: To assess the effects of prior intensive insulin treatment and risk factors on patient-reported visual function in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort. DESIGN, SETTING, AND PARTICIPANTS: Cohort study of 1184 participants with type 1 diabetes from the DCCT/EDIC study (randomized clinical trial followed by an observational follow-up study) who completed the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) during EDIC years 17 through 20 (September 1, 2009, through April 30, 2014) in 28 institutions across the United States and Canada. MAIN OUTCOMES AND MEASURES: The primary outcome was the composite NEI-VFQ-25 score. Secondary outcomes were visual acuity (measured by the Early Treatment Diabetic Retinopathy Study protocol), retinopathy level (determined by masked grading of stereoscopic color fundus photographs), and NEI-VFQ-25 subscale scores. The composite NEI-VFQ-25 scale and its subscales were scored 0 to 100, corresponding to poor to excellent function, respectively. RESULTS: The overall average NEI-VFQ-25 score for 1184 DCCT/EDIC participants (mean [SD] age, 52.3 [6.9] years; 48% female) with a 30-year duration of diabetes was high (all participants: median, 91.7; interquartile range [IQR], 89.7-96.9; intensive treatment [n = 605]: median, 94.7; IQR, 91.0-97.2; conventional treatment [n = 579]: median, 94.0; IQR, 88.4-96.1; P = .006 for intensive vs conventional). After adjustment for sex, age, hemoglobin A1c level, and retinopathy level at DCCT baseline, the former intensive treatment group had a significant, albeit modest, improvement in overall NEI-VFQ-25 score compared with the former conventional diabetes treatment group (median difference, -1.0; 95% CI, -1.7 to -0.3; P = .006). This beneficial treatment effect was fully attributed to the prior glycemic control in DCCT (explained treatment effect: 100%). Those with visual acuity worse than 20/100 reported the largest decline in visual function (median difference, -21.0; 95% CI, -40.5 to -1.6; P = .03). CONCLUSIONS AND RELEVANCE: In the DCCT/EDIC cohort, patient-reported visual function remains high in both treatment groups, comparable to previous reports of overall health-related quality of life. Intensive diabetes therapy modestly improved NEI-VFQ-25 score 30 years after the start of the DCCT, the benefit underestimated owing to more nonparticipants from the conventional treatment group. Visual acuity had the greatest effect on patient-reported visual function from among all risk factors. TRIAL REGISTRATION: clinicaltrials.gov Identifiers: NCT00360815 and NCT00360893.

Testosterone and cardiac mass and function in men with type 1 diabetes in the Epidemiology of Diabetes Interventions and Complications Study (EDIC).

OBJECTIVE: Low testosterone concentrations have been reported to be associated with increased risk of congestive heart failure, but the mechanisms are unclear. Our objective 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 (DCCT). 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, haemoglobin A1c, insulin dose, body mass index, lipids, blood pressure, use of antihypertensive 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.

Testosterone Concentrations and Cardiovascular Autonomic Neuropathy in Men with Type 1 Diabetes in the Epidemiology of Diabetes Interventions and Complications Study (EDIC).

INTRODUCTION: Previous studies have reported that lower testosterone concentrations are associated with cardiovascular autonomic neuropathy (CAN), a risk factor for cardiovascular events. However, no studies have examined this relationship in men with type 1 diabetes, who are at high risk for CAN. AIM: The aim of this study was to examine the associations between testosterone concentrations and measures of CAN in a large, well-characterized cohort of men with type 1 diabetes. METHODS: We conducted an analysis of men in the Diabetes Control and Complications Trial (DCCT), a randomized trial of intensive glucose control, and its observational follow-up the Epidemiology of Diabetes Intervention and Complications (EDIC) Study. Testosterone was measured by liquid chromatography mass spectrometry in stored samples from EDIC follow-up years 10 and 17. Regression models were used to assess the cross-sectional relationships between testosterone and CAN measures. MAIN OUTCOME MEASURES: The main CAN measure from EDIC follow-up year 17 was a standardized composite of R-R variation with paced breathing < 15, or R-R variation 15-20 combined with either a Valsalva ratio ≤ 1.5 or a decrease in diastolic blood pressure > 10 mm Hg upon standing. Continuous R-R variation and Valsalva ratio were secondary outcomes. RESULTS: Lower total and bioavailable testosterone concentrations at follow-up years 10 and 17 were not associated with the presence of CAN at year 17. In analyses using Valsalva ratio as a continuous measure, higher total (P = 0.01) and bioavailable testosterone concentrations (P = 0.005) were associated with a higher (more favorable) Valsalva ratio after adjustment for covariates including age, body mass index, smoking status, hypertension, and glycemia. CONCLUSIONS: Testosterone levels are not associated with CAN among men with type 1 diabetes. Although testosterone is associated with a higher Valsalva ratio, a more favorable indicator, the clinical significance of this association is not known.

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.

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.

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 = 0.039), [corrected] 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.