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The exchange of trace gases between the biosphere and the atmosphere is an important process that controls both chemical and physical properties of the atmosphere with implications for air quality and climate change. The terrestrial biosphere is a major source of reactive biogenic volatile organic compounds (BVOCs) that govern atmospheric concentrations of the hydroxy radical (OH) and ozone (O3) and control the formation and growth of secondary organic aerosol (SOA). Common simulations of BVOC surface–atmosphere exchange in chemical transport models use parameterizations derived from the growing season and do not consider potential changes in emissions during seasonal transitions. Here, we use observations of BVOCs over a mixed temperate forest in northern Wisconsin during broadleaf senescence to better understand the effects of the seasonal changes in canopy conditions (e.g., temperature, sunlight, leaf area, and leaf stage) on net BVOC exchange. The BVOCs investigated here include the terpenoids isoprene (C5H8), monoterpenes (MTs; C10H16), a monoterpene oxide (C10H16O), and sesquiterpenes (SQTs; C15H24), as well as a subset of other monoterpene oxides and dimethyl sulfide (DMS). During this period, MTs were primarily composed of α-pinene, β-pinene, and camphene, with α-pinene and camphene dominant during the first half of September and β-pinene thereafter. We observed enhanced MT and monoterpene oxide emissions following the onset of leaf senescence and suggest that senescence has the potential to be a significant control on late-season MT emissions in this ecosystem. We show that common parameterizations of BVOC emissions cannot reproduce the fluxes of MT, C10H16O, and SQT during the onset and continuation of senescence but can correctly simulate isoprene flux. We also describe the impact of the MT emission enhancement on the potential to form highly oxygenated organic molecules (HOMs). The calculated production rates of HOMs and H2SO4, constrained by terpene and DMS concentrations, suggest that biogenic aerosol formation and growth in this region should be dominated by secondary organics rather than sulfate. Further, we show that models using parameterized MT emissions likely underestimate HOM production, and thus aerosol growth and formation, during early autumn in this region. Further measurements of forest–atmosphere BVOC exchange during seasonal transitions as well as measurements of DMS in temperate regions are needed to effectively predict the effects of canopy changes on reactive carbon cycling and aerosol production.

OBJECTIVE: To evaluate the impact of former intensive versus conventional insulin treatment on neuropathy in Diabetes Control and Complications Trial (DCCT) intensive and conventional treatment subjects with type 1 diabetes 13-14 years after DCCT closeout, during which time the two groups had achieved similar A1C levels. RESEARCH DESIGN AND METHODS: Clinical and nerve conduction studies (NCSs) performed during the DCCT were repeated during the Epidemiology of Diabetes Interventions and Complications (EDIC) study by examiners masked to treatment status on 603 former intensive and 583 former conventional treatment subjects. Clinical neuropathy was defined by symptoms, sensory signs, or reflex changes consistent with distal polyneuropathy and confirmed with NCS abnormalities involving two or more nerves among the median, peroneal, and sural nerves. RESULTS: The prevalence of neuropathy increased 13-14 years after DCCT closeout from 9 to 25% in former intensive and from 17 to 35% in former conventional treatment groups, but the difference between groups remained significant (P < 0.001), and the incidence of neuropathy remained lower among former intensive (22%) than former conventional (28%) treatment subjects (P = 0.0125). Analytic models of incident neuropathy that adjusted for differences in NCS results at DCCT closeout showed no significant risk reduction associated with former intensive treatment during follow-up (odds ratio 1.17 [95% CI 0.84-1.63]). However, a significant persistent treatment group effect was observed for several NCS measures. Longitudinal analyses of overall glycemic control showed a significant association between mean A1C and measures of incident and prevalent neuropathy. CONCLUSIONS: The benefits of former intensive insulin treatment persisted for 13-14 years after DCCT closeout and provide evidence of a durable effect of prior intensive treatment on neuropathy.

The aim of this study was to examine differences between adolescents and adults in persistence of the benefits of intensive therapy 10 years after completion of the Diabetes Control and Complications Trial (DCCT). During the Epidemiology of Diabetes Interventions and Complications (EDIC) study, progression of retinopathy from DCCT closeout to EDIC year 10 was evaluated in 1,055 adults and 156 adolescents. During 10 years of follow-up, HbA(1c) (A1C) was similar between original intensive (INT) and conventional (CON) groups and between former adolescents and adults. At EDIC year 10, adults in the former INT group continued to show slower progression of diabetic retinopathy than those in the CON group (adjusted hazard reduction 56%, P < 0.0001), whereas in adolescents this beneficial effect had disappeared (32%, P = 0.13). Seventy-nine percent of observed differences in the prolonged treatment effect between adults and adolescents at year 10 were explained by differences in mean A1C during DCCT between adolescents and adults (8.9 vs. 8.1%), particularly between INT adolescents and adults (8.1 vs. 7.2%). Prior glycemic control during DCCT is vital for the persistence of the beneficial effects of INT therapy 10 years later. Lowering A1C to as close to normal as safely possible without severe hypoglycemia and starting as early as possible should be attempted for all subjects with type 1 diabetes. These results underscore the importance of maintaining A1C at target values for as long as possible because the benefits of former INT treatment wane over time if A1C levels rise.

This study investigated the long-term effects of intensive diabetic treatment on the progression of atherosclerosis, measured as common carotid artery intima-media thickness (IMT). A total of 1,116 participants (52% men) in the Epidemiology of Diabetes Interventions and Complications (EDIC) trial, a long-term follow-up of the Diabetes Control and Complications Trial (DCCT), had carotid IMT measurements at EDIC years 1, 6, and 12. Mean age was 46 years, with diabetes duration of 24.5 years at EDIC year 12. Differences in IMT progression between DCCT intensive and conventional treatment groups were examined, controlling for clinical characteristics, IMT reader, and imaging device. Common carotid IMT progression from EDIC years 1 to 6 was 0.019 mm less in intensive than in conventional (P < 0.0001), and from years 1 to 12 was 0.014 mm less (P = 0.048); but change from years 6 to 12 was similar (intensive - conventional = 0.005 mm, P = 0.379). Mean A1C levels during DCCT and DCCT/EDIC were strongly associated with progression of IMT, explaining most of the differences in IMT progression between DCCT treatment groups. Albuminuria, older age, male sex, smoking, and higher systolic blood pressure were significant predictors of IMT progression. Intensive treatment slowed IMT progression for 6 years after the end of DCCT but did not affect IMT progression thereafter (6-12 years). A beneficial effect of prior intensive treatment was still evident 13 years after DCCT ended. These differences were attenuated but not negated after adjusting for blood pressure. These results support the early initiation and continued maintenance of intensive diabetes management in type 1 diabetes to retard atherosclerosis.

The Effect of Intensive Glycemic Treatment on Coronary Artery Calcification in Type 1 Diabetic Participants of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Patricia A. Cleary 1 , Trevor J. Orchard 2 , Saul Genuth 3 , Nathan D. Wong 4 , Robert Detrano 5 , Jye-Yu C. Backlund 1 , Bernard Zinman 6 , Alan Jacobson 7 , Wanjie Sun 1 , John M. Lachin 1 , David M. Nathan 7 and for the DCCT/EDIC Research Group * 1 Biostatistics Center, George Washington University, Rockville, Maryland 2 University of Pittsburgh, Pittsburgh, Pennsylvania 3 Case Western Reserve University, Cleveland, Ohio 4 University of California, Irvine, California 5 Harbor UCLA (University of California, Los Angeles) Medical Center, Torrance, California 6 University of Toronto, Toronto, Canada 7 Harvard Medical School, Boston, Massachusetts Address correspondence to David M. Nathan MD, Diabetes Unit, Massachusetts General Hospital, 32 Fruit St., Boston, MA 02114-2698. E-mail: dnathan{at}partners.org . Reprint requests can be addressed to the DCCT/EDIC Research Group, Box NDIC/DCCT/EDIC, Bethesda, MD 20892 Abstract The Epidemiology of Diabetes Interventions and Complications (EDIC) study, an observational follow-up of the Diabetes Control and Complications Trial (DCCT) type 1 diabetes cohort, measured coronary artery calcification (CAC), an index of atherosclerosis, with computed tomography (CT) in 1,205 EDIC patients at ∼7–9 years after the end of the DCCT. We examined the influence of the 6.5 years of prior conventional versus intensive diabetes treatment during the DCCT, as well as the effects of cardiovascular disease risk factors, on CAC. The prevalences of CAC >0 and >200 Agatston units were 31.0 and 8.5%, respectively. Compared with the conventional treatment group, the intensive group had significantly lower geometric mean CAC scores and a lower prevalence of CAC >0 in the primary retinopathy prevention cohort, but not in the secondary intervention cohort, and a lower prevalence of CAC >200 in the combined cohorts. Waist-to-hip ratio, smoking, hypertension, and hypercholesterolemia, before or at the time of CT, were significantly associated with CAC in univariate and multivariate analyses. CAC was associated with mean HbA 1c (A1C) levels before enrollment, during the DCCT, and during the EDIC study. Prior intensive diabetes treatment during the DCCT was associated with less atherosclerosis, largely because of reduced levels of A1C during the DCCT. CAC, coronary artery calcification CT, computed tomography CVD, cardiovascular disease DCCT, Diabetes Control and Complications Trial EDIC, Epidemiology of Diabetes Interventions and Complications IMT, intima-media thickness ROC, receiver operating characteristics Footnotes * * A complete list of individuals and institutions participating in the DCCT/EDIC Research Group appears in the appendix . The Writing Group of the DCCT/EDIC Research Group takes responsibility for the contents of this article. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted August 23, 2006. Received May 11, 2006. 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), 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

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. 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. 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). 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.

OBJECTIVE:--The purpose of this study was to evaluate whether severe hypoglycemia or intensive therapy affects cognitive performance over time in a subgroup of patients who were aged 13-19 years at entry in the Diabetes Control and Complications Trial (DCCT). RESEARCH DESIGN AND METHODS--This was a longitudinal study involving 249 patients with type 1 diabetes who were between 13 and 19 years old when they were randomly assigned in the DCCT. Scores on a comprehensive battery of cognitive tests obtained during the Epidemiology of Diabetes Interventions and Complications follow-up study, ~18 years later, were compared with baseline performance. We assessed the effects of the original DCCT treatment group assignment, mean A1C values, and frequency of severe hypoglycemic events on eight domains of cognition. RESULTS:--There were a total of 294 reported episodes of coma or seizure. Neither frequency of hypoglycemia nor previous treatment group was associated with decline on any cognitive domain. As in a previous analysis of the entire study cohort, higher A1C values were associated with declines in the psychomotor and mental efficiency domain (P < 0.01); however, the previous finding of improved motor speed with lower A1C values was not replicated in this subgroup analysis. CONCLUSIONS:--Despite relatively high rates of severe hypoglycemia, cognitive function did not decline over an extended period of time in the youngest cohort of patients with type 1 diabetes.

A Genome-Wide Association Study Identifies a Novel Major Locus for Glycemic Control in Type 1 Diabetes, as Measured by Both A1C and Glucose Andrew D. Paterson 1 , 4 , Daryl Waggott 2 , Andrew P. Boright 3 , S. Mohsen Hosseini 1 , Enqing Shen 2 , Marie-Pierre Sylvestre 2 , Isidro Wong 1 , Bhupinder Bharaj 1 , Patricia A. Cleary 5 , John M. Lachin 5 , MAGIC (Meta-Analyses of Glucose and Insulin-related traits Consortium) * , Jennifer E. Below 8 , Dan Nicolae 8 , Nancy J. Cox 8 , Angelo J. Canty 6 , Lei Sun 4 , 7 , Shelley B. Bull 2 , 4 and the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group † 1 Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, Canada; 2 Samuel Lunenfeld Research Institute of Mount Sinai Hospital, Prosserman Centre for Health Research, Toronto, Canada; 3 Department of Medicine, University Health Network, University of Toronto, Toronto, Canada; 4 Dalla Lana School of Public Health, University of Toronto, Toronto, Canada; 5 The Biostatistics Center, The George Washington University, Rockville, Maryland; 6 Department of Mathematics and Statistics, McMaster University, Hamilton, Ontario, Canada; 7 Department of Statistics, University of Toronto, Canada; 8 Department of Medicine, Section of Genetic Medicine, The University of Chicago, Chicago, Illinois. Corresponding author: Andrew Paterson, andrew.paterson{at}utoronto.ca . Abstract OBJECTIVE Glycemia is a major risk factor for the development of long-term complications in type 1 diabetes; however, no specific genetic loci have been identified for glycemic control in individuals with type 1 diabetes. To identify such loci in type 1 diabetes, we analyzed longitudinal repeated measures of A1C from the Diabetes Control and Complications Trial. RESEARCH DESIGN AND METHODS We performed a genome-wide association study using the mean of quarterly A1C values measured over 6.5 years, separately in the conventional ( n = 667) and intensive ( n = 637) treatment groups of the DCCT. At loci of interest, linear mixed models were used to take advantage of all the repeated measures. We then assessed the association of these loci with capillary glucose and repeated measures of multiple complications of diabetes. RESULTS We identified a major locus for A1C levels in the conventional treatment group near SORCS1 (10q25.1, P = 7 × 10 −10 ), which was also associated with mean glucose ( P = 2 × 10 −5 ). This was confirmed using A1C in the intensive treatment group ( P = 0.01). Other loci achieved evidence close to genome-wide significance: 14q32.13 ( GSC ) and 9p22 ( BNC2 ) in the combined treatment groups and 15q21.3 ( WDR72 ) in the intensive group. Further, these loci gave evidence for association with diabetic complications, specifically SORCS1 with hypoglycemia and BNC2 with renal and retinal complications. We replicated the SORCS1 association in Genetics of Diabetes in Kidneys (GoKinD) study control subjects ( P = 0.01) and the BNC2 association with A1C in nondiabetic individuals. CONCLUSIONS A major locus for A1C and glucose in individuals with diabetes is near SORCS1 . This may influence the design and analysis of genetic studies attempting to identify risk factors for long-term diabetic complications. Footnotes *A complete list of investigators of MAGIC is provided in online appendix supplementary Table 10, available at http://diabetes.diabetesjournals.org/cgi/content/full/db09-0653/DC1 . †A complete list of investigators and members of the research group appears in N Engl J Med 2005;353:2643–2653. Clinical trial registry nos. NCT00360815 (DCCT) and NCT00360893 (EDIC), clinicaltrials.gov . The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Institute of Diabetes and Digestive and Kidney Diseases or the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. See accompanying commentary, p. 332 . . Received May 1, 2009. Accepted October 20, 2009. © 2010 by the American Diabetes Association.

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 HbA 1c . 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 HbA 1c : 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