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.

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.

Intensive diabetes therapy and ocular surgery in type 1 diabetes.

BACKGROUND: The Diabetes Control and Complications Trial (DCCT) showed a beneficial effect of 6.5 years of intensive glycemic control on retinopathy in patients with type 1 diabetes. METHODS: Between 1983 and 1989, a total of 1441 patients with type 1 diabetes in the DCCT were randomly assigned to receive either intensive diabetes therapy or conventional therapy aimed at preventing hyperglycemic symptoms. They were treated and followed until 1993. Subsequently, 1375 of these patients were followed in the observational Epidemiology of Diabetes Interventions and Complications (EDIC) study. The self-reported history of ocular surgical procedures was obtained annually. We evaluated the effect of intensive therapy as compared with conventional therapy on the incidence and cost of ocular surgery during these two studies. RESULTS: Over a median follow-up of 23 years, 130 ocular operations were performed in 63 of 711 patients assigned to intensive therapy (8.9%) and 189 ocular operations in 98 of 730 patients assigned to conventional therapy (13.4%) (P<0.001). After adjustment for DCCT baseline factors, intensive therapy was associated with a reduction in the risk of any diabetes-related ocular surgery by 48% (95% confidence interval [CI], 29 to 63; P<0.001) and a reduction in the risk of all such ocular procedures by 37% (95% CI, 12 to 55; P=0.01). Forty-two patients who received intensive therapy and 61 who received conventional therapy underwent cataract extraction (adjusted risk reduction with intensive therapy, 48%; 95% CI, 23 to 65; P=0.002); 29 patients who received intensive therapy and 50 who received conventional therapy underwent vitrectomy, retinal-detachment surgery, or both (adjusted risk reduction, 45%; 95% CI, 12 to 66; P=0.01). The costs of surgery were 32% lower in the intensive-therapy group. The beneficial effects of intensive therapy were fully attenuated after adjustment for mean glycated hemoglobin levels over the entire follow-up. CONCLUSIONS: Intensive therapy in patients with type 1 diabetes was associated with a substantial reduction in the long-term risk of ocular surgery. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; DCCT/EDIC ClinicalTrials.gov numbers, NCT00360893 and NCT00360815.).

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.

Delayed Gastric Emptying Is Associated With Early and Long-term Hyperglycemia in Type 1 Diabetes Mellitus.

BACKGROUND & AIMS: After the Diabetes Control and Complications Trial (DCCT), the Epidemiology of Diabetes Interventions and Complications (EDIC) study continued to show 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 (13)C-spirulina breath test and symptoms in 78 participants with type 1 diabetes at year 20 of EDIC. The relationship between delayed GE and glycated hemoglobin (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 before DCCT (P ≤ .04), greater mean HbA1c over an average of 27 years of follow-up evaluation (during DCCT-EDIC, P = .01), lower R-R variability during deep breathing (P = .03) and severe nephropathy (P = .05), and a greater composite upper gastrointestinal symptom score (P < .05). In multivariate models, retinopathy was the only complication of DM associated with delayed GE. Separately, DCCT baseline HbA1c (odds ratio [OR], 1.6; 95% confidence interval [CI], 1.1-2.3) and duration of DM (OR, 1.2; 95% CI, 1.01-1.3) before DCCT entry and mean HbA1c during DCCT-EDIC (OR, 2.2; 95% CI, 1.04-4.5) were associated independently 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.

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.

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.

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.

Cardiovascular autonomic neuropathy, erectile dysfunction and lower urinary tract symptoms in men with type 1 diabetes: findings from the DCCT/EDIC.

PURPOSE: We evaluated the association between cardiovascular autonomic neuropathy, and erectile dysfunction and lower urinary tract symptoms in men with type 1 diabetes. MATERIALS AND METHODS: Male type 1 diabetes participants (635) in the DCCT/EDIC were studied. Cardiovascular autonomic neuropathy was assessed by standardized cardiovascular reflex tests including changes in respiratory rate variation with deep breathing, Valsalva maneuver (Valsalva ratio) and changes in supine to standing diastolic blood pressure. Erectile dysfunction was assessed by a proxy item from the International Index of Erectile Function, and lower urinary tract symptoms were assessed with the AUASI (American Urological Association Symptom Index). Multivariable logistic regression models estimated the association between cardiovascular autonomic neuropathy and erectile dysfunction and/or lower urinary tract symptoms, adjusting for time weighted glycemic control, blood pressure, age and other covariates. RESULTS: Men in whom erectile dysfunction and/or lower urinary tract symptoms developed during EDIC had a significantly lower respiratory rate variation and Valsalva ratio at DCCT closeout and EDIC year 16/17 compared to those without erectile dysfunction or lower urinary tract symptoms. In adjusted analysis, participants with cardiovascular autonomic neuropathy had 2.65 greater odds of erectile dysfunction and lower urinary tract symptoms (95% CI 1.47-4.79). CONCLUSIONS: These data suggest that cardiovascular autonomic neuropathy predicts the development of urological complications in men with long-standing type 1 diabetes. Studies evaluating the mechanisms contributing to these interactions are warranted for targeting effective prevention or treatment.

Poor glycemic control is associated with reduced prostate specific antigen concentrations in men with type 1 diabetes.

PURPOSE: Previous studies have revealed lower prostate specific antigen concentrations in men with type 2 diabetes, paralleling the reported lower prevalence of prostate cancer in diabetic men. Data are lacking on prostate specific antigen in men with type 1 diabetes whose insulin and obesity profiles differ from those with type 2 diabetes mellitus. In this study we examined the relationship between long-term glycemic control and prostate specific antigen in men with type 1 diabetes mellitus. MATERIALS AND METHODS: Total prostate specific antigen was measured at one time in 639 men in the EDIC, the observational followup of participants in the DCCT. The relationship between DCCT/EDIC weighted mean hemoglobin A1c and log prostate specific antigen was assessed using linear regression modeling after adjusting for age, body mass index, total testosterone, statin and thiazide medication use, diabetes duration, and DCCT randomization arm and cohort. RESULTS: Median subject age was 52 years, body mass index was 28.4 kg/m(2) and DCCT/EDIC time-weighted hemoglobin A1c was 7.9%. Median prostate specific antigen was 0.64 ng/ml (IQR 0.43, 1.05). Prostate specific antigen increased significantly with age (p <0.0001) and with lower time-weighted hemoglobin A1c (p <0.0001). Each 10% increase in hemoglobin A1c was accompanied by an 11% reduction in prostate specific antigen (p=0.0001). CONCLUSIONS: Prostate specific antigen decreases as hemoglobin A1c increases in men with type 1 diabetes mellitus. This relationship is independent of age, body mass index, androgen levels, medication use and measures of diabetes severity, which suggests that factors related to glycemia may directly affect prostate specific antigen levels.

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.

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.

Longitudinal changes in estimated and measured GFR in type 1 diabetes.

Estimation of GFR from serum concentrations of creatinine and cystatin C has been refined using cross-sectional data from large numbers of people. However, the ability of the improved estimating equations to identify changes in GFR within individuals over time has not been rigorously evaluated, particularly within the normal range of GFR. In cross-sectional and longitudinal analyses of 1441 participants in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study with type 1 diabetes, we compared GFR estimated from creatinine (eGFR(Cr)), cystatin C (eGFR(Cys)), or both (eGFR(Cr+Cys)) with iothalamate GFR (iGFR), including changes in each over time. Mean (SD) iGFR was 122.7 (21.0) ml/min per 1.73 m(2). In cross-sectional analyses, eGFR(Cr+Cys) estimated iGFR with the highest correlation (r=0.48 versus 0.39-0.42), precision, and accuracy. In longitudinal analyses, change in eGFR(Cr+Cys) best estimated change in iGFR; however, differences between estimates were small, and no estimate accurately classified change in iGFR. Over a median 23 years of follow-up, mean rate of change in eGFR was similar across estimates of eGFR(Cr), eGFR(Cys), and eGFR(Cr+Cys) (-1.37, -1.11, and -1.29 ml/min per 1.73 m(2) per year, respectively). Associations of BP and hemoglobin A1c with change in eGFR were strongest for eGFR(Cys) and eGFR(Cr+Cys). Together, these results suggest that the addition of cystatin C to creatinine to estimate GFR may improve identification of the causes and consequences of GFR loss in type 1 diabetes, but may not meaningfully improve the tracking of GFR in clinical care.

Renal outcomes in patients with type 1 diabetes and macroalbuminuria.

Macroalbuminuria, defined as urine albumin excretion rate (AER)≥300 mg/d, has long been considered a stage of irreversible kidney damage that leads reliably to GFR loss. We examined the long-term renal outcomes of persons with type 1 diabetes who developed incident macroalbuminuria during the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study. One hundred fifty-nine participants developed incident macroalbuminuria and were subsequently followed for a median duration of 9 years (maximum of 25 years). At the time of macroalbuminuria diagnosis, mean (SD) age was 37 (9) years, mean (SD) duration of diabetes was 17 (5) years, median AER was 524 mg/d, and mean (SD) eGFR was 108 (20) ml/min per 1.73 m(2). Ten years after macroalbuminuria diagnosis, the cumulative incidence of a sustained reduction in AER to <300 mg/d was 52%, mostly but not entirely under treatment with renin-angiotensin system inhibitors. The cumulative incidence of impaired GFR (sustained eGFR<60 ml/min per 1.73 m(2)) 10 years after macroalbuminuria diagnosis was 32%, including 16% who developed ESRD. Lower hemoglobin A1c and BP and regression to AER<300 mg/d were associated with reduced risk of developing impaired GFR. In conclusion, people with type 1 diabetes who develop macroalbuminuria are at high risk of progressive kidney disease. However, through at least 10 years of follow-up, AER could often be controlled, and GFR frequently remained in the normal range.

Association between 7 years of intensive treatment of type 1 diabetes and long-term mortality.

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. INTERVENTIONS AND EXPOSURES: 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 AND MEASURES: 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 rate when compared with conventional therapy. TRIAL REGISTRATION: clinicaltrials.gov Identifiers: NCT00360815 and NCT00360893.

GWAS identifies an NAT2 acetylator status tag single nucleotide polymorphism to be a major locus for skin fluorescence.

AIMS/HYPOTHESIS: Skin fluorescence (SF) is a non-invasive marker of AGEs and is associated with the long-term complications of diabetes. SF increases with age and is also greater among individuals with diabetes. A familial correlation of SF suggests that genetics may play a role. We therefore performed parallel genome-wide association studies of SF in two cohorts. METHODS: Cohort 1 included 1,082 participants, 35-67 years of age with type 1 diabetes. Cohort 2 included 8,721 participants without diabetes, aged 18-90 years. RESULTS: rs1495741 was significantly associated with SF in Cohort 1 (p < 6 × 10(-10)), which is known to tag the NAT2 acetylator phenotype. The fast acetylator genotype was associated with lower SF, explaining up to 15% of the variance. In Cohort 2, the top signal associated with SF (p = 8.3 × 10(-42)) was rs4921914, also in NAT2, 440 bases upstream of rs1495741 (linkage disequilibrium r (2) = 1.0 for rs4921914 with rs1495741). We replicated these results in two additional cohorts, one with and one without type 1 diabetes. Finally, to understand which compounds are contributing to the NAT2-SF signal, we examined 11 compounds assayed from skin biopsies (n = 198): the fast acetylator genotype was associated with lower levels of the AGEs hydroimidazolones of glyoxal (p = 0.017). CONCLUSIONS/INTERPRETATION: We identified a robust association between NAT2 and SF in people with and without diabetes. Our findings provide proof of principle that genetic variation contributes to interindividual SF and that NAT2 acetylation status plays a major role.

Intensive diabetes therapy and glomerular filtration rate in type 1 diabetes.

BACKGROUND: An impaired glomerular filtration rate (GFR) leads to end-stage renal disease and increases the risks of cardiovascular disease and death. Persons with type 1 diabetes are at high risk for kidney disease, but there are no interventions that have been proved to prevent impairment of the GFR in this population. METHODS: In the Diabetes Control and Complications Trial (DCCT), 1441 persons with type 1 diabetes were randomly assigned to 6.5 years of intensive diabetes therapy aimed at achieving near-normal glucose concentrations or to conventional diabetes therapy aimed at preventing hyperglycemic symptoms. Subsequently, 1375 participants were followed in the observational Epidemiology of Diabetes Interventions and Complications (EDIC) study. Serum creatinine levels were measured annually throughout the course of the two studies. The GFR was estimated with the use of the Chronic Kidney Disease Epidemiology Collaboration formula. We analyzed data from the two studies to determine the long-term effects of intensive diabetes therapy on the risk of impairment of the GFR, which was defined as an incident estimated GFR of less than 60 ml per minute per 1.73 m(2) of body-surface area at two consecutive study visits. RESULTS: Over a median follow-up period of 22 years in the combined studies, impairment of the GFR developed in 24 participants assigned to intensive therapy and in 46 assigned to conventional therapy (risk reduction with intensive therapy, 50%; 95% confidence interval, 18 to 69; P=0.006). Among these participants, end-stage renal disease developed in 8 participants in the intensive-therapy group and in 16 in the conventional-therapy group. As compared with conventional therapy, intensive therapy was associated with a reduction in the mean estimated GFR of 1.7 ml per minute per 1.73 m(2) during the DCCT study but during the EDIC study was associated with a slower rate of reduction in the GFR and an increase in the mean estimated GFR of 2.5 ml per minute per 1.73 m(2) (P<0.001 for both comparisons). The beneficial effect of intensive therapy on the risk of an impaired GFR was fully attenuated after adjustment for glycated hemoglobin levels or albumin excretion rates. CONCLUSIONS: The long-term risk of an impaired GFR was significantly lower among persons treated early in the course of type 1 diabetes with intensive diabetes therapy than among those treated with conventional diabetes therapy. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; DCCT/EDIC ClinicalTrials.gov numbers, NCT00360815 and NCT00360893.).

New directions in ER stress-induced cell death.

Endoplasmic reticulum (ER) stress has been implicated in the pathophysiology of many diseases including heart disease, cancer and neurodegenerative diseases such as Alzheimer's and Huntington's. Prolonged or excessive ER stress results in the initiation of signaling pathways resulting in cell death. Over the past decade much research investigating the onset and progression of ER stress-induced cell death has been carried out. Owing to this we now have a better understanding of the signaling pathways leading to ER stress-mediated cell death and have begun to appreciate the importance of ER localized stress sensors, IRE1α, ATF6 and PERK in this process. In this article we provide an overview of the current thinking and concepts concerning the various stages of ER stress-induced cell death, focusing on the role of ER localized proteins in sensing and triggering ER stress-induced death signals with particular emphasis on the contribution of calcium signaling and Bcl-2 family members to the execution phase of this process. We also highlight new and emerging directions in ER stress-induced cell death research particularly the role of microRNAs, ER-mitochondria cross talk and the prospect of mitochondria-independent death signals in ER stress-induced cell death.

Validity of self-report in type 1 diabetic subjects for laser treatment of retinopathy.

PURPOSE: This study sought to determine the validity of self-report of prior panretinal photocoagulation (PRP) and focal photocoagulation (FP) compared with fundus photography. DESIGN: Prospective cohort study. PARTICIPANTS: One thousand three hundred sixty-three type 1 diabetic subjects from the Epidemiology of Diabetes Interventions and Complications (EDIC) study, a subset of the 1441 subjects originally enrolled in the multicenter Diabetes Control and Complications Trial. METHODS: At each annual visit, subjects were asked by EDIC staff whether they had undergone PRP, FP, or both since the last completed annual clinic visit. Fundus photographs were collected from one quarter of the cohort each year and from the entire 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: The κ, 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. For PRP and FP, sensitivities were 90.4% and 74.0%, respectively; specificities were 96.0% and 98.8%, respectively; positive predictive values were 75.9% and 80.3%, respectively; negative predictive values were 98.9% and 98.4%, respectively; and κ values were 0.80 and 0.76, respectively. Risk factors associated with misreporting included 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 examination or fundus photographs, subject self-report could be a reliable tool in a well-monitored study for assessing laser treatment type in diabetic retinopathy.