Flipped C-Terminal Ends of APOA1 Promote ABCA1-Dependent Cholesterol Efflux by Small HDLs.

BACKGROUND: Cholesterol efflux capacity (CEC) predicts cardiovascular disease independently of high-density lipoprotein (HDL) cholesterol levels. Isolated small HDL particles are potent promoters of macrophage CEC by the ABCA1 (ATP-binding cassette transporter A1) pathway, but the underlying mechanisms are unclear. METHODS: We used model system studies of reconstituted HDL and plasma from control and lecithin-cholesterol acyltransferase (LCAT)-deficient subjects to investigate the relationships among the sizes of HDL particles, the structure of APOA1 (apolipoprotein A1) in the different particles, and the CECs of plasma and isolated HDLs. RESULTS: We quantified macrophage and ABCA1 CEC of 4 distinct sizes of reconstituted HDL. CEC increased as particle size decreased. Tandem mass spectrometric analysis of chemically cross-linked peptides and molecular dynamics simulations of APOA1, the major protein of HDL, indicated that the mobility of C-terminus of that protein was markedly higher and flipped off the surface in the smallest particles. To explore the physiological relevance of the model system studies, we isolated HDL from LCAT-deficient subjects, whose small HDLs (like reconstituted HDLs) are discoidal and composed of APOA1, cholesterol, and phospholipid. Despite their very low plasma levels of HDL particles, these subjects had normal CEC. In both the LCAT-deficient subjects and control subjects, the CEC of isolated extra-small HDL (a mixture of extra-small and small HDL by calibrated ion mobility analysis) was 3- to 5-fold greater than that of the larger sizes of isolated HDL. Incubating LCAT-deficient plasma and control plasma with human LCAT converted extra-small and small HDL particles into larger particles, and it markedly inhibited CEC. CONCLUSIONS: We present a mechanism for the enhanced CEC of small HDLs. In smaller particles, the C-termini of the 2 antiparallel molecules of APOA1 are "flipped" off the lipid surface of HDL. This extended conformation allows them to engage with ABCA1. In contrast, the C-termini of larger HDLs are unable to interact productively with ABCA1 because they form a helical bundle that strongly adheres to the lipid on the particle. Enhanced CEC, as seen with the smaller particles, predicts decreased cardiovascular disease risk. Thus, extra-small and small HDLs may be key mediators and indicators of the cardioprotective effects of HDL.

Perceived and calculated diet quality improvements in a randomized mHealth weight loss trial.

The diet quality of US adults is poor and cross-sectional analyses suggest self-perception of healthful dietary intake may be overestimated. This analysis assessed the concordance between calculated and perceived diet quality and changes in diet quality among adults seeking weight loss and enrolled in a 12-month randomized behavioral trial. Healthy Eating Index-2015 diet quality (HEI) was calculated from self-administered 24-hour recalls. Perceived diet quality (PDQ) was measured on a 100-point scale. Higher scores indicate better diet quality. Concordance was assessed using the concordance correlation coefficient and Bland-Altman plots. The one hundred and five participants with complete dietary data were mostly female and white. There was good agreement between HEI and PDQ scores at 12 months for less than a third of participants. Most of the disagreement arose from PDQ scores being higher than HEI scores. Even fewer participants had good agreement between HEI changes and PDQ changes. Participants perceived greater improvement in diet quality than indicated by HEI score changes. Concordance was low at 12 months and for change in diet quality. Despite the diet quality of adults seeking weight loss being suboptimal and not improving, many perceived their diet quality and diet quality improvements as better than calculated. Future studies might explore the effect of misperceptions on weight loss outcomes.

Effect of an mHealth weight loss intervention on Healthy Eating Index diet quality: the SMARTER randomised controlled trial.

In the few weight loss studies assessing diet quality, improvements have been minimal and recommended calculation methods have not been used. This secondary analysis of a parallel group randomised trial (regsitered: https://clinicaltrials.gov/ct2/show/NCT03367936) assessed whether self-monitoring with feedback (SM + FB) v. self-monitoring alone (SM) improved diet quality. Adults with overweight/obesity (randomised: SM n 251, SM + FB n 251; analysed SM n 170, SM + FB n 186) self-monitored diet, physical activity and weight. Real-time, personalised feedback, delivered via a study-specific app up to three times daily, was based on reported energy, fat and added sugar intake. Healthy Eating Index 2015 (HEI-2015) scores were calculated from 24-hour recalls. Higher scores represent better diet quality. Data were collected August 2018 to March 2021 and analysed spring 2022. The sample was mostly female (78·9 %) and white (85·4 %). At baseline, HEI-2015 total scores and bootstrapped 95 % CI were similar by treatment group (SM + FB: 63·11 (60·41, 65·24); SM: 61·02 (58·72, 62·81)) with similar minimal improvement observed at 6 months (SM + FB: 65·42 (63·30, 67·20); SM: 63·19 (61·22, 64·97)) and 12 months (SM + FB: 63·94 (61·40, 66·29); SM: 63·56 (60·81, 65·42)). Among those who lost ≥ 5 % of baseline weight, HEI-2015 scores improved (baseline: 62·00 (58·94, 64·12); 6 months: 68·02 (65·41, 71·23); 12 months: 65·93 (63·40, 68·61)). There was no effect of the intervention on diet quality change. Clinically meaningful weight loss was related to diet quality improvement. Feedback may need to incorporate more targeted nutritional content.

Risk of longer-term neurological conditions in the Deepwater Horizon Oil Spill Coast Guard Cohort Study - Five years of follow-up.

BACKGROUND: Long-term neurological health risks associated with oil spill cleanup exposures are largely unknown. We aimed to investigate risks of longer-term neurological conditions among U.S. Coast Guard (USCG) responders to the 2010 Deepwater Horizon (DWH) oil spill. METHODS: We used data from active duty members of the DWH Oil Spill Coast Guard Cohort Study (N=45224). Self-reported oil spill exposures were ascertained from post-deployment surveys. Incident neurological outcomes were classified using International Classification of Diseases, 9th Revision, codes from military health encounter records up to 5.5 years post-DWH. We used Cox Proportional Hazards regression to calculate adjusted hazard ratios (aHR) and 95% confidence intervals (CI) for various incident neurological diagnoses (2010-2015). Oil spill responder (n=5964) vs. non-responder (n= 39260) comparisons were adjusted for age, sex, and race, while within-responder comparisons were additionally adjusted for smoking. RESULTS: Compared to those not responding to the spill, spill responders had reduced risks for headache (aHR=0.84, 95% CI: 0.74-0.96), syncope and collapse (aHR=0.74, 95% CI: 0.56-0.97), and disturbance of skin sensation (aHR=0.81, 95% CI: 0.68-0.96). Responders reporting ever (n=1068) vs. never (n=2424) crude oil inhalation exposure were at increased risk for several individual and grouped outcomes related to headaches and migraines (aHR range: 1.39-1.83). Crude oil inhalation exposure was also associated with elevated risks for an inflammatory nerve condition, mononeuritis of upper limb and mononeuritis multiplex (aHR=1.71, 95% CI: 1.04-2.83), and tinnitus (aHR=1.91, 95% CI: 1.23-2.96), a condition defined by ringing in one or both ears. Risk estimates for those neurological conditions were higher in magnitude among responders reporting exposure to both crude oil and oil dispersants than among those reporting crude oil only. CONCLUSION: In this large study of active duty USCG responders to the DWH disaster, self-reported spill cleanup exposures were associated with elevated risks for longer-term neurological conditions.

The role of endoscopic endonasal surgery in the management of prolactinomas based on their invasiveness into the cavernous sinus.

PURPOSE: To review our institutional experience with the surgical management of prolactinomas through the endoscopic endonasal approach with specific focus on cavernous sinus invasion. METHODS: Clinical and radiographic data were collected retrospectively from the electronic medical record of 78 consecutive patients with prolactinomas undergoing endoscopic endonasal resection from 2002 to 2019. Immediate and late post-operative remission were defined as prolactin < 20 ng/mL within 14 days and 1-year of surgery without adjuvant therapy, respectively. Cavernous sinus invasion was quantified by Knosp score. RESULTS: A total of 78 patients with prolactinoma, 59% being male, underwent surgical resection with a mean age of 37 ± 13 years. Indications for surgery were medication resistance in 38 patients (48.7%), medication intolerance in 11 (14.1%), and patient preference in 29 (37.2%). Patients with Knosp 0-2 achieved higher immediate remission rates (83.8%) compared to patients with Knosp 3 (58.8%) and Knosp 4 (41.7%) patients (p = 0.003). Long-term remission rates were 48.7% and increased to 71.8% when combined with adjuvant treatments. Knosp 4 prolactinomas had significantly higher tumor volumes, higher preoperative prolactin levels, higher recurrence rates, higher rates of adjuvant therapy utilization, and were more likely to have failed dopamine agonist therapy compared to other tumor grades (p < 0.05). We encountered 18 complications in our series, and no cerebrospinal fluid leaks. CONCLUSION: The endoscopic endonasal approach is a safe and effective modality that can be employed in properly selected patients with invasive prolactinomas. It is associated with improved control and remission rates despite cavernous sinus invasion, though at a lower rate than without invasion.

Cardiovascular Disease in Adults with Type 1 Diabetes: Looking Beyond Glycemic Control.

PURPOSE OF REVIEW: Despite improvements in treatment, people with type 1 diabetes continue to have increased cardiovascular disease (CVD) risk. Glycemic control does not fully explain this excess CVD risk, so a greater understanding of other risk factors is needed. RECENT FINDINGS: The authors review the relationship between glycemia and CVD risk in adults with type 1 diabetes and summarize evidence regarding other factors that may explain risk beyond glycemia. Insulin resistance, weight gain, sex differences, genetics, inflammation, emerging markers of risk, including lipid subclasses and epigenetic modifications, and future directions are discussed. As glycemic control improves, an increased focus on other CVD risk factors is warranted in type 1 diabetes. Novel markers and precision medicine approaches may improve CVD prediction, but a lack of type 1 diabetes-specific guidelines for lipids, blood pressure, and physical activity are likely impediments to optimal CVD prevention in this high-risk population.

Association of Coding Variants in Hydroxysteroid 17-beta Dehydrogenase 14 (HSD17B14) with Reduced Progression to End Stage Kidney Disease in Type 1 Diabetes.

BACKGROUND: Rare variants in gene coding regions likely have a greater impact on disease-related phenotypes than common variants through disruption of their encoded protein. We searched for rare variants associated with onset of ESKD in individuals with type 1 diabetes at advanced kidney disease stage. METHODS: Gene-based exome array analyses of 15,449 genes in five large incidence cohorts of individuals with type 1 diabetes and proteinuria were analyzed for survival time to ESKD, testing the top gene in a sixth cohort (n=2372/1115 events all cohorts) and replicating in two retrospective case-control studies (n=1072 cases, 752 controls). Deep resequencing of the top associated gene in five cohorts confirmed the findings. We performed immunohistochemistry and gene expression experiments in human control and diseased cells, and in mouse ischemia reperfusion and aristolochic acid nephropathy models. RESULTS: Protein coding variants in the hydroxysteroid 17-ß dehydrogenase 14 gene (HSD17B14), predicted to affect protein structure, had a net protective effect against development of ESKD at exome-wide significance (n=4196; P value=3.3 × 10-7). The HSD17B14 gene and encoded enzyme were robustly expressed in healthy human kidney, maximally in proximal tubular cells. Paradoxically, gene and protein expression were attenuated in human diabetic proximal tubules and in mouse kidney injury models. Expressed HSD17B14 gene and protein levels remained low without recovery after 21 days in a murine ischemic reperfusion injury model. Decreased gene expression was found in other CKD-associated renal pathologies. CONCLUSIONS: HSD17B14 gene is mechanistically involved in diabetic kidney disease. The encoded sex steroid enzyme is a druggable target, potentially opening a new avenue for therapeutic development.

Cardiovascular health in early adulthood predicts the development of coronary heart disease in individuals with type 1 diabetes: 25 year follow-up from the Pittsburgh Epidemiology of Diabetes Complications study.

AIMS/HYPOTHESIS: Type 1 diabetes increases CHD risk. We examined the use of the American Heart Association's cardiovascular health metrics (blood pressure, total cholesterol, glucose/HbA1c, BMI, physical activity, diet, smoking) to predict incidence of CHD among individuals with type 1 diabetes, with the hypothesis that a better American Heart Association health metric profile would be associated with lower incident CHD. METHODS: Prevalence of the seven cardiovascular health metrics was determined using first and second visits from adult participants (mean age 28.6 years) in the Epidemiology of Diabetes Complications prospective cohort study of childhood-onset type 1 diabetes. An ideal metric score (0-7) was defined as the sum of all metrics within the ideal range, and a total metric score (0-14) was calculated based on poor, intermediate and ideal categories for each metric. Incident CHD development (medical record-confirmed CHD death, myocardial infarction, revascularisation, ischaemic electrocardiogram changes or Epidemiology of Diabetes Complications physician-determined angina) over 25 years of follow-up was examined by metric scores. RESULTS: Among 435 participants, BMI, blood pressure, total cholesterol and smoking demonstrated the highest prevalence within the ideal range, while diet and HbA1c demonstrated the lowest. During 25 years of follow-up, 177 participants developed CHD. In Cox models, each additional metric within the ideal range was associated with a 19% lower risk (p = 0.01), and each unit increase in total metric score was associated with a 17% lower risk (p < 0.01) of CHD, adjusting for diabetes duration, estimated glomerular filtration rate, albumin excretion rate, triacylglycerols, depression and white blood cell count. CONCLUSIONS/INTERPRETATION: Among individuals with type 1 diabetes, higher cardiovascular health metric scores were associated with lower risk of incident CHD. The American Heart Association-defined cardiovascular health metrics provide straightforward goals for health promotion that may reduce CHD risk in the type 1 diabetes population. Graphical abstract.

Heterogeneous long-term trajectories of glycaemic control in type 1 diabetes.

AIMS: We aimed to identify long-term HbA1c trajectories and examine associated characteristics in an observational, childhood-onset (<17 years) type 1 diabetes cohort. METHODS: Data are from the Epidemiology of Diabetes Complications study, comprising 405 participants with ≥2 of seven possible HbA1c measurements over follow-up (1988-2013) and available DNA (baseline mean diabetes duration 21 years, 53% men). HbA1c trajectories were estimated using latent class growth models. Baseline and change in participant characteristics were compared across trajectories. RESULTS: Five HbA1c trajectories were identified: low (51%), intermediate stable (22%), improved (19%), high stable (6%), and worsened (2%; not included in analyses). Age, diabetes duration, diabetes onset age, and sex did not differ across trajectories. Characteristics did not differ significantly between intermediate stable and low trajectories at baseline, though albumin excretion rate (AER, p = 0.0002) and estimated glomerular filtration rate (eGFR, p = 0.001) worsened slightly more in intermediate stable over time. Improved and high stable trajectories had higher baseline LDL-c (p = 0.002 and 0.003, respectively). Improved trajectory increased median self-monitoring of blood glucose from <1 to 3.5 times/day (p < 0.0001) and had larger LDL-c improvement (p = 0.004) but greater worsening of AER (p < 0.0001) and eGFR (p < 0.0001) than low. The A allele of rs12970134 (near MC4R) was associated with improved (p = 0.0003) or high stable (p = 0.001) HbA1c trajectory, both patterns with high baseline HbA1c. CONCLUSIONS: Long-term HbA1c trajectories were primarily associated with modifiable factors in this type 1 diabetes cohort. The intermediate stable pattern had a risk factor profile that suggests some protection against adverse metabolic effects of chronic hyperglycaemia, warranting further study.

Persistent polypharmacy and fall injury risk: the Health, Aging and Body Composition Study.

BACKGROUND: Older adults receive treatment for fall injuries in both inpatient and outpatient settings. The effect of persistent polypharmacy (i.e. using multiple medications over a long period) on fall injuries is understudied, particularly for outpatient injuries. We examined the association between persistent polypharmacy and treated fall injury risk from inpatient and outpatient settings in community-dwelling older adults. METHODS: The Health, Aging and Body Composition Study included 1764 community-dwelling adults (age 73.6 ± 2.9 years; 52% women; 38% black) with Medicare Fee-For-Service (FFS) claims at or within 6 months after 1998/99 clinic visit. Incident fall injuries (N = 545 in 4.6 ± 2.9 years) were defined as the initial claim with an ICD-9 fall E-code and non-fracture injury, or fracture code with/without a fall code from 1998/99 clinic visit to 12/31/08. Those without fall injury (N = 1219) were followed for 8.1 ± 2.6 years. Stepwise Cox models of fall injury risk with a time-varying variable for persistent polypharmacy (defined as ≥6 prescription medications at the two most recent consecutive clinic visits) were adjusted for demographics, lifestyle characteristics, chronic conditions, and functional ability. Sensitivity analyses explored if persistent polypharmacy both with and without fall risk increasing drugs (FRID) use were similarly associated with fall injury risk. RESULTS: Among 1764 participants, 636 (36%) had persistent polypharmacy over the follow-up period, and 1128 (64%) did not. Fall injury incidence was 38 per 1000 person-years. Persistent polypharmacy increased fall injury risk (hazard ratio [HR]: 1.31 [1.06, 1.63]) after adjusting for covariates. Persistent polypharmacy with FRID use was associated with a 48% increase in fall injury risk (95%CI: 1.10, 2.00) vs. those who had non-persistent polypharmacy without FRID use. Risks for persistent polypharmacy without FRID use (HR: 1.22 [0.93, 1.60]) and non-persistent polypharmacy with FRID use (HR: 1.08 [0.77, 1.51]) did not significantly increase compared to non-persistent polypharmacy without FRID use. CONCLUSIONS: Persistent polypharmacy, particularly combined with FRID use, was associated with increased risk for treated fall injuries from inpatient and outpatient settings. Clinicians may need to consider medication management for FRID and other fall prevention strategies in community-dwelling older adults with persistent polypharmacy to reduce fall injury risk.

A Targeted Multiomics Approach to Identify Biomarkers Associated with Rapid eGFR Decline in Type 1 Diabetes.

BACKGROUND: Individuals with type 1 diabetes (T1D) demonstrate varied trajectories of estimated glomerular filtration rate (eGFR) decline. The molecular pathways underlying rapid eGFR decline in T1D are poorly understood, and individual-level risk of rapid eGFR decline is difficult to predict. METHODS: We designed a case-control study with multiple exposure measurements nested within 4 well-characterized T1D cohorts (FinnDiane, Steno, EDC, and CACTI) to identify biomarkers associated with rapid eGFR decline. Here, we report the rationale for and design of these studies as well as results of models testing associations of clinical characteristics with rapid eGFR decline in the study population, upon which "omics" studies will be built. Cases (n = 535) and controls (n = 895) were defined as having an annual eGFR decline of ≥3 and <1 mL/min/1.73 m2, respectively. Associations of demographic and clinical variables with rapid eGFR decline were tested using logistic regression, and prediction was evaluated using area under the curve (AUC) statistics. Targeted metabolomics, lipidomics, and proteomics are being performed using high-resolution mass-spectrometry techniques. RESULTS: At baseline, the mean age was 43 years, diabetes duration was 27 years, eGFR was 94 mL/min/1.73 m2, and 62% of participants were normoalbuminuric. Over 7.6-year median follow-up, the mean annual change in eGFR in cases and controls was -5.7 and 0.6 mL/min/1.73 m2, respectively. Younger age, longer diabetes duration, and higher baseline HbA1c, urine albumin-creatinine ratio, and eGFR were significantly associated with rapid eGFR decline. The cross-validated AUC for the predictive model incorporating these variables plus sex and mean arterial blood pressure was 0.74 (95% CI: 0.68-0.79; p < 0.001). CONCLUSION: Known risk factors provide moderate discrimination of rapid eGFR decline. Identification of blood and urine biomarkers associated with rapid eGFR decline in T1D using targeted omics strategies may provide insight into disease mechanisms and improve upon clinical predictive models using traditional risk factors.

The role of coronary artery calcification testing in incident coronary artery disease risk prediction in type 1 diabetes.

AIMS/HYPOTHESIS: We sought to assess the role of coronary artery calcification (CAC) and its progression in predicting incident coronary artery disease (CAD) in individuals with type 1 diabetes using data from the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study. METHODS: The present study examined 292 participants who had at least one CAC measure and were free from CAD at baseline; 181 (62%) had repeat CAC assessments 4-8 years later and did not develop CAD between the two CAC measures. The HRs of incident CAD events were estimated using Cox models in categorised or in appropriately transformed CAC scores. C statistics and net reclassification improvement (NRI) were used to assess the added predictive value of CAC for incident CAD. RESULTS: At baseline, the mean age of participants was 39.4 years and the mean diabetes duration was 29.5 years. There were 76 participants who experienced a first incident CAD event over an average follow-up of 10.7 years. At baseline, compared with those without CAC (Agatston score = 0), the adjusted HR (95% CI) in groups of 1-99, 100-399 and ≥400 was 3.1 (1.6, 6.1), 4.4 (2.0, 9.5) and 4.8 (1.9, 12.0), respectively. CAC density was inversely associated with incident CAD in those with CAC volume ≥100 (HR 0.3 [95% CI 0.1, 0.9]) after adjusting for volume score. Among participants with repeated CAC measures, annual CAC progression was positively associated with incident CAD after controlling for baseline CAC. The HR (95% CI) for above vs below the median annual CAC volume progression was 3.2 (1.2, 8.5). When compared with a model that only included established risk factors, the addition of CAC improved the predictive ability for incident CAD events in the whole group. CONCLUSIONS/INTERPRETATION: CAC is strongly associated with incident CAD events in individuals with type 1 diabetes; its inclusion in CAD risk models may lead to improvement in prediction over established risk factors.

Glucose Management and the Sex Difference in Excess Cardiovascular Disease Risk in Long-Duration Type 1 Diabetes.

PURPOSE OF REVIEW: The protection against CVD observed in women compared to men in the general population is essentially erased in type 1 diabetes. This review will discuss evidence regarding the role of glucose management on CVD risk by sex, with a particular focus on studies of long-duration type 1 diabetes of > 20 years. RECENT FINDINGS: Across studies, women with type 1 diabetes have similar or worse glycemic control compared to men, despite higher rates of intensive insulin therapy. The association between HbA1c and CVD risk does not seem to differ by sex, but few studies have reported on sex-specific analyses. Beyond HbA1c, there is a lack of published data regarding the relationship between other aspects of glucose management and CVD risk by sex in type 1 diabetes. Glucose management factors do not seem to directly account for the increased CVD risk in women with type 1 diabetes, but may influence other risk factors that play a more direct role.

Meta-genome-wide association studies identify a locus on chromosome 1 and multiple variants in the MHC region for serum C-peptide in type 1 diabetes.

AIMS/HYPOTHESIS: The aim of this study was to identify genetic variants associated with beta cell function in type 1 diabetes, as measured by serum C-peptide levels, through meta-genome-wide association studies (meta-GWAS). METHODS: We performed a meta-GWAS to combine the results from five studies in type 1 diabetes with cross-sectionally measured stimulated, fasting or random C-peptide levels, including 3479 European participants. The p values across studies were combined, taking into account sample size and direction of effect. We also performed separate meta-GWAS for stimulated (n = 1303), fasting (n = 2019) and random (n = 1497) C-peptide levels. RESULTS: In the meta-GWAS for stimulated/fasting/random C-peptide levels, a SNP on chromosome 1, rs559047 (Chr1:238753916, T>A, minor allele frequency [MAF] 0.24-0.26), was associated with C-peptide (p = 4.13 × 10-8), meeting the genome-wide significance threshold (p < 5 × 10-8). In the same meta-GWAS, a locus in the MHC region (rs9260151) was close to the genome-wide significance threshold (Chr6:29911030, C>T, MAF 0.07-0.10, p = 8.43 × 10-8). In the stimulated C-peptide meta-GWAS, rs61211515 (Chr6:30100975, T/-, MAF 0.17-0.19) in the MHC region was associated with stimulated C-peptide (ß [SE] = - 0.39 [0.07], p = 9.72 × 10-8). rs61211515 was also associated with the rate of stimulated C-peptide decline over time in a subset of individuals (n = 258) with annual repeated measures for up to 6 years (p = 0.02). In the meta-GWAS of random C-peptide, another MHC region, SNP rs3135002 (Chr6:32668439, C>A, MAF 0.02-0.06), was associated with C-peptide (p = 3.49 × 10-8). Conditional analyses suggested that the three identified variants in the MHC region were independent of each other. rs9260151 and rs3135002 have been associated with type 1 diabetes, whereas rs559047 and rs61211515 have not been associated with a risk of developing type 1 diabetes. CONCLUSIONS/INTERPRETATION: We identified a locus on chromosome 1 and multiple variants in the MHC region, at least some of which were distinct from type 1 diabetes risk loci, that were associated with C-peptide, suggesting partly non-overlapping mechanisms for the development and progression of type 1 diabetes. These associations need to be validated in independent populations. Further investigations could provide insights into mechanisms of beta cell loss and opportunities to preserve beta cell function.

Hemoglobin A1c Level and Cardiovascular Disease Incidence in Persons With Type 1 Diabetes: An Application of Joint Modeling of Longitudinal and Time-to-Event Data in the Pittsburgh Epidemiology of Diabetes Complications Study.

Type 1 diabetes (T1D) is associated with increased risk of cardiovascular disease (CVD), but hyperglycemia (measured by hemoglobin A1c (HbA1c) level), which characterizes T1D, has itself been an inconsistent predictor of CVD incidence. However, only baseline HbA1c or a summary measure (e.g., mean level over follow-up) is usually analyzed. Joint models allow simultaneous modeling of repeatedly measured longitudinal covariates, using random effects, and time-to-event data. We evaluated data from the Pittsburgh Epidemiology of Diabetes Complications Study, an ongoing prospective cohort study of childhood-onset T1D that has followed participants since 1986-1988 and has repeatedly found little association between baseline HbA1c or mean follow-up HbA1c and coronary artery disease incidence. Of 561 participants without CVD at baseline, 263 (46.9%) developed CVD over a period of 25 years (1986-2014). In joint models, each 1% unit increase in HbA1c trajectory was associated with a 1.26-fold increased risk of CVD (95% confidence interval: 1.07, 1.45), after adjustment for baseline levels of other CVD risk factors, and a 1.13-fold increased risk (95% confidence interval: 0.99, 1.32) after adjustment for updated mean levels of other CVD risk factors. These findings, which support the need for good glycemic control to prevent CVD in persons with T1D, underscore the importance of utilizing methods incorporating within-subject variation over time when analyzing and interpreting longitudinal cohort study data.

Gestational diabetes diagnostic methods (GD2M) pilot randomized trial.

To test the feasibility of conducting a pragmatic randomized controlled trial (RCT) comparing the International Association of Diabetes in Pregnancy Study Groups (IADPSG) versus Carpenter-Coustan diagnostic criteria for gestational diabetes (GDM), and to examine patient and provider views on GDM screening. A single-blinded pragmatic pilot RCT. Participants with a singleton pregnancy between 24 and 28 weeks gestation received a 50 g oral glucose challenge test and if the value was <200 mg/dL were randomized to either the 2 h 75 g OGTT using the IADPSG criteria or the 3 h 100 g OGTT using the Carpenter-Coustan criteria. Primary outcome was the feasibility of randomization and screening. Secondary outcomes included patient and provider views (or preferences) on GDM testing. Sixty-eight women were recruited, 48 (71 %) enrolled and 47 (69 %) were randomized. Participants in both study arms identified the main challenges to GDM testing to be: drinking the glucola, fasting prior to testing, waiting to have blood drawn, and multiple venipuntures. Women in both study arms would prefer the 2 h 75 g OGTT or whichever test is recommended by their doctor in a future pregnancy. Physicians and nurse midwives endorsed screening and were comfortable with being blinded to the GDM testing strategy and results values. Both pregnant women and providers value GDM screening, and pregnant women can be recruited to a blinded, randomized GDM screening trial with minimal attrition and missing data.

Predicting major outcomes in type 1 diabetes: a model development and validation study.

AIMS/HYPOTHESIS: Type 1 diabetes is associated with a higher risk of major vascular complications and death. A reliable method that predicted these outcomes early in the disease process would help in risk classification. We therefore developed such a prognostic model and quantified its performance in independent cohorts. METHODS: Data were analysed from 1,973 participants with type 1 diabetes followed for 7 years in the EURODIAB Prospective Complications Study. Strong prognostic factors for major outcomes were combined in a Weibull regression model. The performance of the model was tested in three different prospective cohorts: the Pittsburgh Epidemiology of Diabetes Complications study (EDC, n = 554), the Finnish Diabetic Nephropathy study (FinnDiane, n = 2,999) and the Coronary Artery Calcification in Type 1 Diabetes study (CACTI, n = 580). Major outcomes included major CHD, stroke, end-stage renal failure, amputations, blindness and all-cause death. RESULTS: A total of 95 EURODIAB patients with type 1 diabetes developed major outcomes during follow-up. Prognostic factors were age, HbA1c, WHR, albumin/creatinine ratio and HDL-cholesterol level. The discriminative ability of the model was adequate, with a concordance statistic (C-statistic) of 0.74. Discrimination was similar or even better in the independent cohorts, the C-statistics being: EDC, 0.79; FinnDiane, 0.82; and CACTI, 0.73. CONCLUSIONS/INTERPRETATION: Our prognostic model, which uses easily accessible clinical features can discriminate between type 1 diabetes patients who have a good or a poor prognosis. Such a prognostic model may be helpful in clinical practice and for risk stratification in clinical trials.

An Epigenome-Wide Association Study of DNA Methylation and Proliferative Retinopathy over 28 Years in Type 1 Diabetes.

Purpose: To perform a prospective epigenome-wide association study of DNA methylation (DNAm) and 28-year proliferative diabetic retinopathy (PDR) incidence in type 1 diabetes (T1D). Design: Prospective observational cohort study. Participants: The Pittsburgh Epidemiology of Diabetes Complications (EDC) study of childhood-onset (< 17 years) T1D. Methods: Stereoscopic fundus photographs were taken in fields 1, 2, and 4 at baseline, 2, 4, 6, 8, 16, 23, and 28 years after DNAm measurements. The photos were graded using the modified Airlie House System. In those free of PDR at baseline (n = 265; mean T1D duration of 18 years at baseline), whole blood DNAm (EPIC array) at 683 597 CpGs was analyzed in Cox models for time to event. Associations between significant CpGs and clinical risk factors were assessed; genetic variants associated with DNAm were identified (methylation quantitative trait loci [meQTLs]). Mendelian randomization was used to examine evidence of causal associations between DNAm and PDR. Post hoc regional and functional analyses were performed. Main Outcome Measures: Proliferative diabetic retinopathy was defined as the first instance of a grade of ≥ 60 in at least 1 eye or pan-retinal photocoagulation for PDR. Follow-up time was calculated from the study visit at which DNAm data were available (baseline) until PDR incidence or censoring (December 31, 2018 or last follow-up). Results: PDR incidence was 53% over 28-years' follow-up. Greater DNAm of cg27512687 (KIF16B) was associated with reduced PDR incidence (P = 6.3 × 10-9; false discovery rate [FDR]: < 0.01); 113 cis-meQTLs (P < 5 × 10-8) were identified. Mendelian randomization analysis using the sentinel meQTL as the instrumental variable supported a potentially causal association between cg27512687 and PDR. Cg27512687 was also associated with lower pulse rate and albumin excretion rate and higher estimated glomerular filtration rate, but its association with PDR remained independently significant after adjustment for those factors. In regional analyses, DNAm of FUT4, FKBP1A, and RIN2 was also associated with PDR incidence. Conclusions: DNA methylation of KIF16B, FUT4, FKBP1A, and RIN2 was associated with PDR incidence, supporting roles for epigenetic regulation of iron clearance, developmental pathways, and autophagy in PDR pathogenesis. Further study of those loci may provide insight into novel targets for interventions to prevent or delay PDR in T1D. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Sex differences in the associations of HDL particle concentration and cholesterol efflux capacity with incident coronary artery disease in type 1 diabetes: The RETRO HDLc cohort study.

BACKGROUND: In type 1 diabetes, women lose their relative protection (compared to men) against coronary artery disease (CAD), while high-density lipoprotein cholesterol (HDL-C) is less strongly associated with lower CAD risk in women. OBJECTIVE: We aimed to assess whether sex differences in the HDL particle concentration (HDL-P) and cholesterol efflux capacity (CEC) association with CAD may explain these findings. METHODS: HDL-P (calibrated differential ion mobility analysis) and total and ATP binding cassette transporter A1 (ABCA1)-specific CEC were quantified among 279 men and 271 women with type 1 diabetes (baseline mean age 27·8 years; diabetes duration, 19·6 years). Clinical CAD was defined as CAD death, myocardial infarction and/or coronary revascularization. RESULTS: Women had higher large HDL-P levels and marginally lower concentrations of small HDL-P and ABCA1-specific CEC than men. No sex differences were observed in extra-small HDL-P, medium HDL-P and total CEC. During a median follow-up of 26 years, 37·6 % of men and 35·8 % of women developed CAD (p = 0·72). In multivariable Cox models stratified by sex (pTotal HDL-P x sex interaction=0·01), HDL-P was negatively associated with CAD incidence in both sexes. However, associations were stronger in men, particularly for extra-small HDL-P (hazard ratio (HR)men=0·11, 95 % confidence interval (CI): 0·04-0·30; HRwomen=0·68, 95 % CI: 0·28-1·66; pinteraction=0·001). CEC did not independently predict CAD in either sex. CONCLUSION: Despite few absolute differences in HDL-P concentrations by sex, the HDL-P - CAD association was weaker in women, particularly for extra-small HDL-P, suggesting that HDL-P may be less efficient in providing atheroprotection in women and perhaps explaining the lack of a sex difference in CAD in type 1 diabetes.