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Objectives: Epigenetic age acceleration (EAA) occurs when DNA methylation-predicted age is older than chronological age. EAA is associated with glucose intolerance in adults. In-utero exposure to gestational diabetes (GDM) is associated with glucose intolerance in offspring. It is not known if GDM predicts EAA in offspring or if offspring EAA is associated with insulin sensitivity and secretion. Methods: We examined the association between exposure to GDM in-utero and EAA, computed at average age 10.5 years, and EAA and measures of insulin sensitivity (HOMA-2S) and secretion (HOMA-2β) at average age 10.5 and 16.7 years in 209 girls and 209 boys in the Colorado EPOCH (Exploring Perinatal Outcomes Among Children) cohort. We calculated EAA using the Horvath, Hannum, and Levine calculators. Separate general linear mixed models adjusted associations for chronologic age and sex. Results: Exposure to GDM was associated with EAA using the Hannum (beta-coefficient 1.39, p=0.009) and Levine (1.92, p=0.024) but not the Horvath calculator (-0.01, p=0.69). EAA by the Hannum calculator predicted lower insulin sensitivity and higher insulin secretion (Table). Conclusions: We conclude that GDM predicts offspring EAA, and EAA is associated with decreased insulin sensitivity and increased insulin secretion. Associations are dependent upon the EAA calculator used. Disclosure C. Kim: None. K. K. Harrall: None. D. H. Glueck: None. B. Needham: None. D. Dabelea: None. Funding National Institutes of Health (R01DK076648, R01GM121081, R01DK068001307, M01RR00069, 5UG3OD023248)

Lifestyle changes may reduce the burdens of diabetes and cancer. We examined how changes in the 2018 WCRF/AICR Score, reflecting key cancer prevention recommendations, are associated with diabetes risk. The Diabetes Prevention Program (DPP) randomized adults with prediabetes to a lifestyle intervention (ILS), metformin (MET), or placebo (PLB) for a mean of 3.2 years, with follow-up in DPPOS for 11 years. The Score includes 7 components: weight, physical activity, plant-based diet, red/processed meat, sugar-sweetened drinks, fast foods, and alcohol (0-7 points, with 7 as the best total score). Scores were estimated at years 0, 1, 5, 6, 9, and 15 for participants with complete baseline data (N = 3,147). Covariates included sex, age, race/ethnicity, marital status, education, family history of diabetes, hormone therapy (females), and energy intake. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) stratified by treatment group estimated the association of Score changes with diabetes risk in DPP and DPPOS within and between groups. There were significant Score improvements within all groups over 15 years (p < 0.001); the differences between groups were only significant after 1 year (p < 0.001; 15 years: p = 0.137). For every 1-unit improvement in Score during DPP, there was a 29% and 16% lower diabetes risk in ILS (95% CI: 0.58 - 0.88) and PLB (95% CI: 0.72 - 0.99), respectively, and no significant association in MET. The time-dependent Score improvements in ILS and PLB were significantly associated with lower diabetes risk through year 15 (ILS HR: 0.86, 95% CI 0.77 - 0.96; PLB HR: 0.85, 95% CI 0.76 - 0.95). Changes in weight, physical activity, and plant-based diet appeared to be drivers of the Score’s effect. Findings suggest that Score improvements are associated with a long-term, lower risk for diabetes among adults with prediabetes. Future research can explore how this risk reduction impacts cancer risk. Disclosure M. M. M. Shams-white: None. B. M. Heckman-stoddard: None. D. Research group: None. A. H. Tjaden: None. S. Edelstein: None. S. Bassiouni: None. C. Kim: None. X. Pi-sunyer: None. K. A. Temple: None. E. M. Venditti: None. J. Reedy: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (U01DK048489)

OBJECTIVE: It is unclear how childhood adipose tissue deposition influences sex hormone profiles in later adolescence. DESIGN: Prospective cohort study PARTICIPANTS: Children (n=418) with a mean age of 10.5 (1.5) years at visit 1 and 16.7 (1.2) at visit 2 in the Exploring Perinatal Outcomes among Children (EPOCH) Study. MEASUREMENTS: We used reverse-scale Cox proportional hazard models to assess associations between pubertal dehydroepiandrosterone (DHEA), testosterone (T), and estradiol (E2) and childhood-to-puberty rate of change in visceral (VAT) and subcutaneous adipose tissue (SAT). Models stratified by sex and adjusted for childhood adiposity, maternal factors, birthweight, and pubertal onset, and then further adjusted for insulin, luteinizing hormone (LH), leptin and hepatic fat fraction. RESULTS: Among boys, more rapid accumulation of either VAT or SAT was associated with lower testosterone at visit 2 (HR 0.86, and 0.96, respectively, both p

The landscape of deprescribing, the planned process of dose reduction or stoppage for medications which are no longer of benefit, has been rapidly expanding with global efforts and the formation of regional and national deprescribing networks. The purpose of this qualitative study is to describe successes and challenges about deprescribing from thought-leaders across the world to inform future policy initiatives. We aim to conduct at least 15 key informant (KI) interviews; we have completed 13 to date. Codes were constructed to identify themes that depict the perspectives regarding deprescribing policy across the globe. The KIs primarily represent the fields of pharmacy and medicine from four global regions with years of deprescribing experience ranging from 5 to > 20. We identified two emerging overarching themes through our qualitative analysis: Regional Organization Support and Evidence & Knowledge gaps. Within these overarching themes, we further identified sub-themes and their representative quotes: Network Structure: “idea of the network was threefold: 1) To try and figure out what we need to activate healthcare providers to deprescribe; 2) To do work with community-dwelling seniors to motivate them and give them opportunities to deprescribe; 3) ...getting pharmacists to provide the education to the patients.” Cost-effectiveness: “If we can show that it is cost-effective to deprescribe, that there is actually a return here, not just in health terms but in monetary terms, I think that would really push it along.” This research will help to advance global efforts to optimize medication management.

Adverse drug reactions (ADRs) associated with drug-drug interactions (DDIs) represent a significant threat to public health. Unfortunately, most conventional methods for prediction of DDI-associated ADRs suffer from limited applicability and/or provide no mechanistic insight into DDIs. In this study, a hierarchical machine learning model was created to predict DDI-associated ADRs and pharmacological insight thereof for any drug pair. Briefly, the model takes drugs’ chemical structures as inputs to predict their target, enzyme, and transporter (TET) profiles, which are subsequently utilized to assess occurrences of ADRs, with an overall accuracy of ~91%. The robustness of the model for ADR classification was validated with DDIs involving three widely prescribed drugs. The model was then applied for interstitial lung disease (ILD) associated with DDIs involving atorvastatin, identifying the involvement of multiple targets, enzymes, and transporters in ILD. The model presented here is anticipated to serve as a versatile tool for enhancing drug safety.

Departing from traditional linguistic models, advances in deep learning have resulted in a new type of predictive (autoregressive) deep language models (DLMs). Using a self-supervised next-word prediction task, these models generate appropriate linguistic responses in a given context. In the current study, nine participants listened to a 30-min podcast while their brain responses were recorded using electrocorticography (ECoG). We provide empirical evidence that the human brain and autoregressive DLMs share three fundamental computational principles as they process the same natural narrative: (1) both are engaged in continuous next-word prediction before word onset; (2) both match their pre-onset predictions to the incoming word to calculate post-onset surprise; (3) both rely on contextual embeddings to represent words in natural contexts. Together, our findings suggest that autoregressive DLMs provide a new and biologically feasible computational framework for studying the neural basis of language.

Introduction: Cardiovascular disease (CVD) is the leading cause of death in women and early onset of menopause before the age of 40 years has been identified as a risk enhancer for future CVD events. Quantifying the magnitude of risk for premature CVD among women with early menopause may inform and guide the intensity of sex-specific preventive strategies. Methods: We included all women in the Coronary Artery Risk Development in Young Adults (CARDIA) study who attended a follow-up exam after the age of 40 years, had available data on menopausal status, and had not experienced premature CVD before 40 years. We performed multivariable Cox proportional hazards regression to examine the relationship between early onset of menopause defined as Results: Among 2136 women with mean age of 43.0 (SD 3.0), 9.1% reported premature menopause before the age of 40 years (4.5% in white and 13.9% in black women). Over a median follow-up of 14.0 (IQR 11.5, 16.9) years, 81 premature CVD events occurred. Incidence rate (95% CI) of CVD was 6.46 (2.43, 17.22) and 1.41 (0.92, 2.17) per 1,000 per person-years for white women with and without early onset menopause, respectively; 4.94 (2.66, 9.16) and 3.92 (2.94, 5.24) per 1,000 person-years for black women with and without early onset menopause (FIGURE). Conclusions: In a population-based sample, white women with early onset of menopause had a 3-fold higher rate of premature CVD events, independent of perimenopausal risk factor levels. Interventions to intensify CVD prevention in at-risk women are needed following early onset of menopause.

Introduction: Women who experience premature menopause are known to have higher rates of long-term atherosclerotic cardiovascular disease (ASCVD). Specifically, menopause prior to age of 40 years has been identified as a risk enhancer by the 2019 AHA/ACC Primary Prevention guidelines. Coronary artery calcium (CAC) may have clinical utility for refinement of risk stratification in this high-risk group of women for the primary prevention of ASCVD. Methods: We included women from the Coronary Artery Risk Development in Young Adults (CARDIA) study who completed a coronary-gated CT scan at a baseline age of 43-55 years. We excluded women who had a myocardial infarction prior to CAC assessment. Menopausal status was self-reported as before the age of 40 years, at 40 years or older, or pre-menopausal. No significant interaction by race was observed. We performed multinomial logistic regression analysis to examine the association between premature menopause and 3 categories of CAC (0, 1-99, and ≥100 Agatston units). In separate multivariable models, we adjusted for demographic and cardiovascular risk factors at the time of CAC measurement. Results: Of 1786 women, 167 (9.4%) experienced premature menopause, 1175 (65.8%) reached menopause after the age of 40 years, and 444 (24.9%) were pre-menopausal at the time of CT. Presence of any CAC in these 3 groups was 18.0%, 19.6%, and 11.3% for premature menopause, ≥40 menopausal, and the pre-menopausal groups, respectively (FIGURE). Premature menopause was not associated with higher odds of non-zero CAC in unadjusted or adjusted analyses. Conclusions: Premature menopause was not associated with prevalent CAC score in these women in mid-life. Consideration of alternative approaches or biomarkers for risk stratification for ASCVD should be evaluated in this high-risk group.

OBJECTIVE The aim of the study was to examine changes in kidney function during the menopausal transition (MT) and associations with levels of sex hormones (follicle stimulating hormone [FSH], sex hormone binding globulin [SHBG], estradiol, and testosterone). METHODS We used data from the Michigan site of Study of the Women's Health Across the Nation, a longitudinal study of the MT. For this analysis, we included women who had at least one creatinine measure before the final menstrual period (FMP) and at least one creatinine measure after the FMP (n = 101 women with 440 observations). To determine whether the declines in estimated glomerular filtration rate (eGFR) remained constant during the MT, we used local weighted regression curves to fit eGFR estimates. We examined the association between sex hormones and eGFR with longitudinal mixed models adjusting for baseline age, day of menstrual cycle, and time from FMP. RESULTS At baseline, women had a mean age of 45.4 ± 2.5 years; 54% were African-American and 46% were white. Although eGFR declined significantly over time, declines were linear, consistent with declines in eGFR due to age alone rather than the MT. Total testosterone, estradiol, ratio of testosterone:estradiol, and free androgen index were not significantly associated with eGFR, whereas lower FSH (-0.039, 95% confidence interval [CI] -0.067 to -0.012) and higher SHBG (0.050, 95% CI 0.004-0.096) were associated with higher eGFR. CONCLUSIONS Kidney function declines during the MT. Although associated with levels of FSH and SHBG, the rate of decline in eGFR is consistent with what would be expected of age alone.

Depolarized/damaged mitochondria aggregate at the perinuclear region prior to mitophagy in cells treated with mitochondrial stressors. However, the cellular mechanism(s) by which damaged mitochondria are transported and remain aggregated at the perinuclear region is unknown. Here, we demonstrate that mitofusins (Mfn1/2) are post-translationally modified by SUMO2 (Small Ubiquitin-related Modifier 2) in Human embryonic kidney 293 (Hek293) cells treated with protonophore CCCP and proteasome inhibitor MG132, both known mitochondrial stressors. SUMOylation of Mfn1/2 is not for their proteasomal degradation but facilitate mitochondrial congression at the perinuclear region in CCCP- and MG132-treated cells. Additionally, congressed mitochondria (mito-aggresomes) colocalize with LC3, ubiquitin, and SUMO2 in CCCP-treated cells. Knowing that SUMO functions as a “molecular glue” to facilitate protein-protein interactions, we propose that SUMOylation of Mfn1/2 may congress, glues, and confines damaged mitochondria to the perinuclear region thereby, protectively quarantining them from the heathy mitochondrial network until their removal via mitophagy in cells.

Among adults, higher T predicts lower VAT in men and higher VAT in women, and higher E2 predicts greater SAT in women. The degree to which the association between adiposity and sex steroids is bidirectional is controversial. Using data from a cohort of adolescents, we examined whether sex steroid levels in early puberty influenced VAT and SAT deposition in adolescents. EPOCH participants (n=418, 209 girls and 209 boys) underwent sex steroid measures at visit 1 (mean age 10 years) and magnetic resonance imaging (MRI) assessments of VAT and SAT at visit 1 and visit 2 (mean age 17 years). Using mixed models, we examined whether T and E2 at visit 1 were associated with overall VAT and SAT levels from visit 1 to visit 2. Models adjusted for maternal education and income as well as children’s race, pubertal status, caloric intake, physical activity levels, insulin, leptin, and MRI-measured hepatic fat fraction. Among girls, each unit increase in T was associated with a higher overall VAT (0.16, 95% confidence interval [CI] 0.04, 0.28) and SAT (0.33, 95% CI 0.33, 1.52) levels. Each unit increase in E2 was associated with overall higher SAT (0.56, 95% CI 0.28, 0.83) levels. Among boys, undetectable T was associated with higher VAT (5.12, 95% CI 1.90, 8.36) and lower SAT (-18.85, 95% CI -36.23, -1.46) levels. We conclude that endogenous T and E2 during the pubertal transition significantly influence adolescent adipose tissue deposition in both boys and girls. Future investigations should examine how the use of exogenous sex hormones impacts adipose tissue deposition during this critical period. Additional follow-up is needed to determine how adolescent fat deposition impacts subsequent glucose tolerance in early adulthood. Disclosure C. Kim: Research Support; Spouse/Partner; Apple. K.K. Harrall: None. D.H. Glueck: None. D. Dabelea: None. Funding National Institutes of Health (R01DK068001)

Background and Aims Lupus nephritis (LN) is a leading cause of morbidity and mortality in systemic lupus erythematosus (SLE) patients. T cells are believed to play a central role in the pathogenesis of both SLE and LN. CD6 is a co-stimulatory receptor, predominantly expressed on T cells, that binds to activated leukocyte cell adhesion molecule (ALCAM), a ligand expressed on antigen presenting cells and various epithelial and endothelial tissues. The CD6-ALCAM pathway plays an integral role in modulating T cell activation, proliferation, differentiation and trafficking, and is central to immune mediated inflammation. Itolizumab (EQ001) is a humanized IgG1 monoclonal antibody that binds CD6, blocks the interaction between CD6 and ALCAM, and inhibits both the activation and trafficking of T cells. Inhibiting the CD6-ALCAM pathway with itolizumab potentially represents a promising therapeutic approach for the treatment of LN. The aim of this study is to assess the safety and tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of subcutaneously administered itolizumab in patients with SLE with and without active proliferative lupus nephritis (apLN). Method This cohort-based dose escalation study includes two types of patients: The Type A cohort will enroll ∼24 patients with SLE without apLN (all treated with itolizumab) and the Type B cohort will randomize in a blinded manner ∼36 patients (3:1, itolizumab:placebo) with biopsy-proven ISN/RPS class III or IV (+ V) apLN who have had inadequate response to induction and/or post-induction maintenance treatment, exhibiting urine protein to creatinine ratio [UPCR] ≥1 g/g and active serology. Within both the Type A and Type B cohorts, up to 4 dose groups will be tested (Figure). Background treatments for SLE or LN are allowed. Following 4 weeks of treatment in a new higher dose Type A cohort and recommendation by an independent safety data review committee (DRC), the dose studied in the Type A cohort may then be studied in a Type B Cohort for a 12-week treatment duration (Figure). The primary endpoint is the safety and tolerability of itolizumab. Efficacy endpoints (in the Type B cohorts) include UPCR, estimated glomerular filtration rate, prednisone dose requirements, renal response, Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), FACIT Fatigue Scale, serologic markers, and other patient reported outcomes. In Type A cohort patients, clinical responses and pharmacologic activity will be assessed based on changes in serologic markers, SLEDAI-2K, FACIT Fatigue Scale. Pharmacodynamic markers, including markers that may allow future risk stratification, urinary ALCAM and CD6, will be examined in both cohort types. Results The study is ongoing. Six patients have been enrolled in Type A Cohort 1 (0.4 mg/kg dose) and completed both treatment and 4 weeks of post-treatment follow-up. The mean age was 59.5 (12.9) years, 100% were female; 67% were Hispanic/Latino; and 50% were White, and 50% were Black. Duration of SLE ranged from 3 years to 31 years. Concomitant medications for lupus included prednisone (83%, dose range 2.5 mg – 10 mg), methotrexate (33%), and anti-malarials (33%). Baseline SLEDAI-2K (mean 7.5 [2.2]) was based on findings of alopecia (83%); arthritis (67%); mucosal ulcers and rash (50% each); fever, increased dsDNA, and low complement (17% each). There were no adverse events. Additional data from this ongoing study will be presented. Conclusion Itolizumab, a monoclonal antibody blocking the CD6-ALCAM pathway, is a novel experimental treatment for LN. This is the first trial of itolizumab in patients with SLE and apLN. Data from the first cohort of patients suggest that the drug is safe and well-tolerated at a dose of 0.4 mg/kg over a 4-week treatment period. Additional cohorts of patients with SLE and apLN are currently being enrolled.

AIM: We investigated the association between acculturation strategies and cardiometabolic risk among South Asian(SA) immigrants in the US. METHODS: In this cross-sectional analysis of data from 849 SA participants in the Mediators of Atherosclerosis in SAs Living in America (MASALA), we performed multidimensional measures of acculturation to categorize the participants into three acculturation classes: separation(preference for SA culture), assimilation(preference for US culture), and integration(similar preference for both cultures). Differences in glycemic indices, blood pressure, lipid parameters and body composition by acculturation strategy were examined. RESULTS: Women in the integration class had the lowest prevalence of diabetes (16.4%), prediabetes (29.7%), fasting and 2-hr glucose compared to women in the separation class with the highest prevalence of diabetes (29.3%), prediabetes (31.5%), fasting and 2-hr glucose and 2-hr insulin (all p

Background and Aim: The Inflammatory Bowel Disease Disability Index (IBD-DI) is a measure of disability in inflammatory bowel disease (IBD). The IBD-DI is validated for use as a clinical interview but not for use as a self-report questionnaire. We aimed to validate the IBD-DI for self-report (IBD-DI-SR) and to reduce the number of items, using IBD patients from two centers. Methods: Between April and August 2017, ambulatory IBD patients were recruited from Christchurch Hospital, New Zealand and Concord Hospital, Australia. The IBD-DI clinical interview version was compared with a self-report version. Participants were randomized to do the clinical interview or self-report first. Validation of the IBD-DI-SR involved calculating the correlation coefficient between the clinician completed and self-reported version of the IBD-DI and Cronbach's α of internal consistency of the IBD-DI-SR. To create an item-reduced version, multiple linear regression was used. The R2 of the model described the overall association between the item-reduced IBD-DI-SR and the IBD-DI. Results: One hundred fourteen patients (57 from Christchurch and 57 from Sydney) completed the IBD-DI-SR validation phase, of whom 63 had Crohn's disease and 51 had ulcerative colitis. The Pearson correlation coefficient between the IBD-DI-SR and IBD-DI is 0.90 (P

Purpose To determine the application of various components of the Kidney Disease Improving Global Outcomes (KDIGO) bundle in managing patients at high-risk for AKI progression ([TIMP2]•[IGFBP7] >0.3) in the real-world setting. Methods Patients with a [TIMP2]•[IGFBP7] test ordered between 5/23/16–2/28/18 were evaluated. We reviewed the medical record for evidence of implementation of the KDIGO bundle in response to biomarker test results. Evidence including explicit documentation in physicians' note discussing [TIMP2]•[IGFBP7] results and implicit evidence from review of dose adjusted medications, discontinued nephrotoxins and therapeutic drug monitoring. Results 105 [TIMP2]•[IGFBP7] tests were conducted in 100 patients (54% female; mean age 55.4 ± 16.8; 89% in the ICU). Sixty-one patients had a value of >0.3 and 46 (75.4%) of these patients received at least one management strategy consistent with KDIGO. By contrast, nine patients (23.1%) with [TIMP2]•[IGFBP7] ≤0.3 received one or more components of the KDIGO bundle (p Conclusion In a real-world setting the use of urinary [TIMP2]•[IGFBP7] as an AKI risk screening tool resulted in differential application of various components of the KDIGO bundle for patient management for those with a positive test result.

Type 1 diabetes mellitus, which often originates during childhood, is a lifelong disease that requires intensive daily medical management. Because health care services are critical to patients with this disease, we investigated the frequency of interruptions in private health insurance, and the outcomes associated with them, for working-age adults with type 1 diabetes in the United States in the period 2001–15. We designed a longitudinal study with a nested self-controlled case series, using the Clinformatics(®) Data Mart Database. The study sample consisted of 168,612 adults ages 19–64 with type 1 diabetes who had 2.6 mean years of insurance coverage overall. Of these adults, 24.3 percent experienced an interruption in coverage. For each interruption, there was a 3.6 percent relative increase in glycated hemoglobin. The use of acute care services was fivefold greater after an interruption in health insurance compared to before the interruption and remained elevated when stratified by age, sex, or diabetic complications. An interruption was associated with lower perceived health status and lower satisfaction with life. We conclude that interruptions in private health insurance are common among adults with type 1 diabetes and have serious consequences for their well-being.

Background This study assessed the frequency of short-term oral corticosteroid use in adults with diabetes, examined the incidence of fractures, venous thromboembolism (VTE), and hospitalization for sepsis after corticosteroid use, and evaluated whether preventative medications mitigated adverse events. Methods A longitudinal study (2012–14) was conducted of 1 548 945 adults (aged 18–64 years) who received healthcare coverage through a large national health insurer. Incidence rate ratios (IRR) were calculated using conditional Poisson regression. Results Short-term oral corticosteroids were used by 23.9%, 20.8%, and 20.9% of adults with type 2 diabetes, type 1 diabetes, and no diabetes, respectively, during the 3-year period (P < 0.001). Baseline risks of fracture, VTE, and sepsis were greater for individuals with than without diabetes (P < 0.001). The combined effect of having diabetes and using corticosteroids was greater than the sum of the individual effects (synergy indices of 1.17, 1.23, 1.30 for fracture, VTE, and sepsis, respectively). The IRR for VTE in the 5–30 days after corticosteroid use was 3.62 (95% confidence interval [CI] 2.41–5.45). Fractures increased in the 5–30 days after corticosteroid use (IRR 2.06; 95% CI 1.52, 2.80), but concomitant use of ergocalciferol mitigated this risk (IRR 1.13; 95% CI 0.12, 11.07). The risk of hospitalization for sepsis was elevated with corticosteroid use (IRR 3.79; 95% CI 2.05, 7.01), but was mitigated by the concomitant use of statins. Conclusions Short-term oral corticosteroid use is common in adults with diabetes and is associated with an elevated, but low, risk of adverse events. The findings suggest that preventative medications may mitigate risk.

Mitophagy is defective in several neurodegenerative diseases, including Ataxia Telangiectasia (A-T). However, the molecular mechanism underlying defective mitophagy in A-T is unknown. Literature indicates that damaged mitochondria are transported to the perinuclear region prior to their removal via mitophagy. Our previous work has indicated that conjugation of SUMO2 (Small Ubiquitin-like Modifier 2) to mitofusins (Mfns) may be necessary for congression of mitochondria into SUMO2-/ubiquitin-/LC3-positive compact structures resembling mito-aggresomes at the perinuclear region in CCCP-treated HEK293 cells. Here, we demonstrate that Mfns are SUMOylated, and mitochondria are transported to the perinuclear region; however, mitochondria fail to congress into mito-aggresome-like structures in CCCP-treated A-T cells. Defect in mitochondrial congression is causally related to constitutively elevated ISG15 (Interferon-Stimulated Gene 15), an antagonist of the ubiquitin pathway, in A-T cells. Suppression of the ISG15 pathway restores mitochondrial congression, reduce oxidative stress, and level of unhealthy mitochondria, which is suggestive of restoration of mitophagy in A-T cells. ISG15 is also constitutively elevated and mitophagy is defective in Amytrophic Lateral Sclerosis (ALS). The constitutively elevated ISG15 pathway therefore appears to be a common unifying biochemical mechanism underlying defective mitophagy in neurodegenerative disorders thus, implying the broader significance of our findings, and suggest the potential role of ISG15 inhibitors in their treatment.

The objective of this study is to assess postmortem changes of the hepatic apparent diffusion coefficient (ADC) at multiple time points in the time interval of 16 hours postmortem in comparison to in vivo controls and to literature data. Hepatic diffusion-weighted imaging (DWI) was repeatedly performed at 1.5 Tesla (b values 50, 400, and 800 s/mm2) in 2-hourly steps within 16 hours postmortem in 19 cases (male to female 13:6, mean age 68.5 ± 12.2 years) and 5 in vivo controls. The core body temperature was measured rectally prior to every scan. Mean ADC values were calculated from regions of interest (ROIs) and compared to in vivo healthy controls and to literature data of normal liver parenchyma. Spearman rank correlation and Levenberg-Marquardt algorithm were used to assess a relationship between postmortem core body temperature and ADC values. Mean hepatic ADC values were significantly lower in postmortem cases than in in vivo controls (52.0 ± 15.0 · 10−5 mm2/s vs. 111.0 ± 15.7 · 10−5 mm2/s, p

To evaluate the ability of concentration of anti-Müllerian hormone (AMH), antral follicle count (AFC), and concentration of follicle stimulating hormone (FSH) to predict the onset of menopause.The Coronary Artery Risk Development in Young Adults Study (CARDIA) Women's Study was an ancillary study to CARDIA, a population-based study of adults aged 18-30 years followed for 3 decades. For this report, participants were women (n=426) who had attended the CARDIA year 15-16 (2000-2001) examination, had at least one ovary, were not pregnant, and underwent serum AMH and FSH measurement and transvaginal ultrasonography in 2002-2003.The probability of menopause in 5 years based upon AMH, FSH, and AFC.The mean age of the women at the time of AMH, FSH, and AFC assessment was 43 years. The cumulative incidence of menopause at 25 years (or follow-up) was 27% (n=426), and the incidence within 5 years was 13% (n=55). Among women aged 45-49 years, undetectable AMH concentrations were associated with a greater than 60% probability of menopause within 5 years, whereas approximately 1/3 of women with no or just one antral follicle experienced menopause within 5 years. Both low and high concentrations of FSH were associated with greater odds of menopause than intermediate concentrations. Models with multiple markers did not improve the prediction of menopause over that afforded by models with single markers.The ability to predict onset of menopause was improved with any of the three menopausal markers in addition to age. AMH concentrations were more closely associated with menopause than AFC or FSH.

Context The degree to which changes in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) relate to corresponding changes in plasma sex steroids is not known. Objective We examined whether changes in VAT and SAT areas assessed by computed tomography were associated with changes in sex hormones [dehydroepiandrosterone sulfate (DHEAS), testosterone, estradiol, estrone, and sex hormone binding globulin (SHBG)] among Diabetes Prevention Program participants. Design Secondary analysis of a randomized trial. Participants Overweight and glucose-intolerant men (n = 246) and women (n = 309). Interventions Intensive lifestyle change with goals of weight reduction and 150 min/wk of moderate intensity exercise or metformin administered 850 mg twice a day or placebo. Main outcome measures Associations between changes in VAT, SAT, and sex hormone changes over 1 year. Results Among men, reductions in VAT and SAT were both independently associated with significant increases in total testosterone and SHBG in fully adjusted models. Among women, reductions in VAT and SAT were both independently associated with increases in SHBG and associations with estrone differed by menopausal status. Associations were similar by race/ethnicity and by randomization arm. No significant associations were observed between change in fat depot with change in estradiol or DHEAS. Conclusions Among overweight adults with impaired glucose intolerance, reductions in either VAT and SAT were associated with increased total testosterone in men and higher SHBG in men and women. Weight loss may affect sex hormone profiles via reductions in visceral and subcutaneous fat.

Interferon-stimulated gene 15 (ISG15), an antagonist of the ubiquitin pathway, is elevated in cells and brain tissues obtained from ataxia telangiectasia (A-T) patients. Previous studies reveal that an elevated ISG15 pathway inhibits ubiquitin-dependent protein degradation, leading to activation of basal autophagy as a compensatory mechanism for protein turnover in A-T cells. Also, genotoxic stress (ultraviolet [UV] radiation) deregulates autophagy and induces aberrant degradation of ubiquitylated proteins in A-T cells. In the current study, we show that, as in A-T cells, ISG15 protein expression is elevated in cerebellums and various other tissues obtained from Atm-compromised mice in an Atm-allele-dependent manner (Atm+/+

Introduction Although current techniques for accelerated tooth movement often involve invasive surgical procedures, micro-osteoperforations (MOPs) using mini-implants may facilitate orthodontic tooth movement without raising flaps, reduce surgical risks, and increase patient acceptance. In this study, we evaluated the effectiveness of mini-implant–facilitated MOPs in inducing accelerated tooth movement and investigated the potential risks for root resorption. Methods Five MOPs were placed on the left side around the maxillary first molars in 6 rats using an automated mini-implant driver, whereas the right side received no MOPs as the control. Closed-coiled springs were secured from incisors to first molars for orthodontic tooth movement. Tooth movement was measured, and samples underwent radiologic and histologic analyses. Results The MOP side exhibited a 1.86-fold increase in the rate of tooth movement with decreased bone density and bone volume around the first molars compared with the control side. Hematoxylin and eosin and tartrate-resistant acid phosphatase analyses showed increased numbers of osteoclasts as well as new bone formation. Three-dimensional volumetric analysis of all 5 roots of the maxillary first molars demonstrated no statistically significant difference in root volumes. Conclusions Mini-implant–facilitated MOPs accelerated tooth movement without increased risk for root resorption and therefore may become a readily available and efficient treatment option to shorten orthodontic treatment time with improved patient acceptance.

We evaluated rotavirus vaccination rates in the United States by using records from a nationwide health database. From data on 519,697 infants, we found 68.6% received the entire rotavirus vaccine series. We noted pockets of undervaccination in many states, particularly in the Northeast and in some western states.

Objective. There have been few studies regarding the duration of insulin prescriptions and patient outcomes. This study evaluated whether A1C varied with the duration of insulin prescription in patients with type 1 diabetes. Methods. We conducted a longitudinal investigation (from 2001 to 2015) within a nationwide private health insurer. A cohort study was first used to compare A1C after 30-day only, 90-day only, and a combination (30-day and 90-day) of insulin prescriptions. Second, a self-controlled case series was used to compare A1C levels after 30-day versus 90-day prescriptions for the same person. Results. In the cohort study, there were 16,725 eligible patients. Mean A1C was 8.33% for patients with 30-day prescriptions compared to 7.69% for those with 90-day prescriptions and 8.05% for those who had a combination of 30- and 90-day prescriptions (P Conclusion. There was a statistically significant but clinically modest decrease in A1C with 90-day versus 30-day insulin prescriptions in adults. A mailed 90-day insulin prescription may be a reasonable choice for adults with type 1 diabetes.

Whether changes in visceral adipose tissue (VAT) in childhood predict adolescent androgens is not known. We examined the longitudinal relationship between MRI-assessed visceral adipose tissue (VAT) in childhood and future testosterone (T) among 418 EPOCH participants (209 girls and 209 boys) who were, on average 10.5 years at visit 1 and 16.7 years at visit 2. We used reverse Cox proportional hazards models in which hazard ratios less than 1 indicate greater risk for low (undetectable) sex hormones consistent with pre-puberty. Models explored the associations of baseline VAT, and change in VAT from visit 1 to visit 2, with risk of low sex hormone levels at visit 2, adjusted for covariates selected through backwards regression (race, self-reported Tanner stage, maternal income, insulin and leptin levels). All analyses were stratified by sex. In addition, due to different patterns of fat deposition in white and non-white adults, we tested for effect modification by race. In boys, the association between VAT at visit 1 and T at visit 2 differed by race; more VAT at visit 1 was associated with lower risk of low T at visit 2 among non-white boys (HR 1.02, 95% CI 1.007, 1.04) but not white boys (HR 1.00, 95% CI 0.98, 1.01). In contrast, greater fat accumulation between visits was associated with higher risk of low T at visit 2 (HR 0.90, 95% CI 0.83, 0.96), independent of race and other covariates. Among girls, neither baseline VAT levels, nor VAT accumulation between visits predicted risk of later low T concentrations. We conclude that greater VAT accumulation in childhood is associated with increased risk for low T levels, suggesting delayed puberty, in boys. These associations suggest that fat deposition may influence sex hormone profiles even in early childhood. Disclosure C. Kim: None. K.K. Harrall: None. D.H. Glueck: None. D. Dabelea: None. Funding National Institutes of Health

While type 2 diabetes is one of the most common chronic diseases in the United States, nationwide figures for incidence are difficult to obtain. We used data from a large national health insurer (Clinformatics Data Mart Database, years 2001-2017) to estimate the incidence of type 2 diabetes by state of residence at first diagnosis. Cases were adults, ages 20 years, with type 2 diabetes (ICD-CM codes with antidiabetic medication). Individuals with type 1 diabetes or secondary diabetes were excluded. The incidence rate per 100,000 person-years ranged from 450.9 in Texas to 164.1 in South Dakota (incidence rate ratio (IRR) 2.7; 95% CI: 2.5, 3.1). The states with the highest incidence were Texas, Mississippi and Alabama. States with the lowest incidence included South Dakota, North Dakota and Massachusetts. For men, the incidence rate of type 2 diabetes ranged from 524.9 in Mississippi to 212.8 in North Dakota (IRR 2.5; 95% CI: 2.2, 2.8). There was greater variation in the incidence for women; it ranged from 409.2 in Alabama to 109.8 in South Dakota (IRR 3.7; 3.1, 4.5). The median age at diagnosis was 54 years in men and 56 years in women. In conclusion, there is considerable interstate variability in the incidence of type 2 diabetes for the privately insured. Although many of the high incidence states were in the southern census region of the U.S., incidence rates were also high in Hawaii and Arizona. Disclosure M.A.M. Rogers: None. G. Imperatore: None. T. Basu: None. C. Kim: None. S.R. Benoit: None. D.B. Rolka: None. S. Saydah: None. Funding Centers for Disease Control and Prevention

CONTEXT: Despite sex differences in chronic kidney disease (CKD) onset and progression, it is unclear whether endogenous sex hormones are associated with kidney function in persons without CKD. DESIGN AND METHODS: We conducted a secondary analysis of the Diabetes Prevention Program (DPP) and its follow-up observational study, the DPP Outcomes Study, over 11 years. Participants included overweight and glucose-intolerant men (n = 889) and pre- and postmenopausal women (n = 1281) not using exogenous sex hormones and whose urine albumin-to-creatinine ratio (ACR) was

We evaluated whether rotavirus vaccination is associated with the incidence of type 1 diabetes among children. We designed a cohort study of 1,474,535 infants in the United States from 2001–2017, using data from a nationwide health insurer. There was a 33% reduction in the risk of type 1 diabetes with completion of the rotavirus vaccine series compared to the unvaccinated (95% CI: 17%, 46%). Completion of the pentavalent vaccine series was associated with 37% lower risk of type 1 diabetes (95% CI: 22%, 50%). Partial vaccination (incompletion of the series) was not associated with the incidence of type 1 diabetes. There was a 31% reduction in hospitalizations in the 60-day period after vaccination (95% CI: 27%, 35%) compared to unvaccinated children. Overall, there was a 3.4% decrease in incidence annually in children ages 0–4 in the United States from 2006–2017 which coincides with the vaccine introduction in 2006. We conclude that rotavirus vaccination is associated with a reduced incidence of type 1 diabetes. Rotavirus vaccination may be the first practical measure that could play a role in the prevention of this disease.

Objective To compare concentrations of antimullerian hormone (AMH) in women with and without type 1 diabetes. Design Cross-sectional analysis of longitudinal studies, adjusting for repeated measures. Setting Not applicable. Patient(s) Women aged 30–45 years who had not undergone oophorectomy, hysterectomy, or natural menopause at the time of AMH measurement were included (n = 376 in the Michigan Bone Health and Metabolism Study and n=321 in the Epidemiology of Interventions and Complications Study). Linear mixed regression was used to evaluate whether AMH concentrations differed by diabetes status, adjusting for repeated measurements of AMH within individual women, body mass index, smoking status, and oral contraceptive use. Intervention(s) None. Main Outcome Measure(s) Concentrations of AMH. Result(s) In unadjusted comparisons, women with and without diabetes had similar median AMH values before 35 years of age, although women with type 1 diabetes had a lower proportion of women with elevated AMH concentrations (≥5.0 ng/dL). After adjustment for covariates and multiple observations per woman, log AMH concentrations were significantly lower among women with type 1 diabetes compared with women without diabetes (β-coefficient −1.27, 95% confidence interval [−2.18, −0.36] in fully adjusted models) before 35 years of age. Conclusion(s) Before 35 years of age, women with type 1 diabetes have lower AMH levels than women without diabetes. Further investigation is needed to determine the etiologies of this difference and how it may contribute to reproductive disorders among women with type 1 diabetes.

We examined associations between intensive lifestyle intervention (ILS) and changes in testosterone and associations with mood among middle-aged men.Secondary analysis of men (n=886) participating in the Diabetes Prevention Program which randomized glucose-intolerant, overweight men to ILS, metformin, or placebo between 1996 and 1999.Changes in testosterone between baseline and 1-year follow-up asnd associations of these changes with mood measures (Beck Depression Inventory [BDI-II], Beck Anxiety Inventory [BAI]).Median baseline testosterone was 10.98nmol/l and 44% (n=385) had testosterone10.41nmol/l or 300ng/dl. Testosterone increases were greater among men randomized to ILS vs. metformin vs. placebo (1.15nmol/l vs. -0.12nmol/l vs. -0.27nmol/l, p0.001). The association between changes in testosterone and mood differed by study arm (p0.001 for interaction); there were no significant associations between changes in testosterone and mood changes among men in the ILS or placebo arms. Among men in the metformin arm, increases in testosterone were significantly associated with decreases in BDI-II (improved depressive symptoms) (β-coefficient -0.2336, p=0.0002) indicating a 0.23 decrease in BDI-II for every 1nmol/l increase in testosterone and decreases in BAI (improved anxiety symptoms) (β-coefficient -0.2147, p=0.0014). Similar patterns were observed for bioavailable testosterone.Among overweight middle-aged men with glucose-intolerance, ILS increased endogenous testosterone slightly but without significant improvements in mood. Metformin did not increase testosterone, but among metformin users, testosterone increases were associated with improvements in mood. Thus, interventions that increase endogenous testosterone may not also improve mood.

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.Secondary analysis of a prospective observational study.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).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.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.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.

Background: Immigration and the process of acculturation can lead to behavioral changes that exacerbate or reduce diabetes development. We investigated the association between acculturation strategies and cardiometabolic risk (CMR) factors among South Asian (SA) immigrants living in the U.S. Methods: Participants (n=849) in the Mediators of Atherosclerosis in SA Living in America (MASALA) study were categorized into 3 acculturation strategy classes based on self-reported questionnaire responses: separation (preference for SA culture), assimilation (preference for U.S. culture), and integration (similar preference for SA and U.S. cultures). Adjusted linear regression models examined associations of acculturation strategies with fasting and 2 hour glucose, lipids, blood pressure, waist circumference (WC), and body composition. Results: Overall, 22.4, 19.6, and 58% of men and 23.7, 26.2, and 50.1% of women were in separation, assimilation, and integration classes; respectively. Participants in the assimilation class had significantly lower levels of obesity, 2 hour glucose, insulin, HOMA-IR, triglycerides (TG), visceral fat, and higher HDL than those in the separation class (all p Conclusion: SA women who employed an assimilation strategy had a more favorable CMR profile compared to women using a separation strategy. Future research should investigate the behavioral pathways linking acculturation strategies with CMR and potential incorporation into prevention interventions. Disclosure M. Al-Sofiani: None. S.J. Langan: None. A.M. Kanaya: None. N.R. Kandula: None. B. Needham: None. C. Kim: None. D.M. Becker: None. D. Vaidya: None. S. Golden: None. C. Lee: None. R. Rastogi Kalyani: None.

Whether endogenous sex hormones are associated with chronic kidney disease (CKD) is not known. We conducted a secondary analysis of longitudinal data from the DPPOS, the follow-up study of the Diabetes Prevention Program (DPP), a randomized trial of diabetes prevention that assigned participants to placebo, metformin, or lifestyle intervention. This analysis included overweight and glucose-intolerant men (n=889) and women (n=1281) not using exogenous sex hormones who had urine albumin-to-creatinine ratio [ACR] < 30 mg/g and normal estimated glomerular filtration ratio [eGFR] ≥ 60 ml/min/1.73 m2. Sex hormones (dehydroepiandrosterone [DHEAS], dihydrotestosterone, testosterone, estradiol, estrone, and sex hormone binding globulin [SHBG]) were measured at baseline. CKD was defined as incident low eGFR and/or albuminuria ACR ≥ 30 mg/g. eGFR and ACR were measured annually over 11 years of DPPOS follow-up. Multivariable Cox regression models adjusted for eGFR and log-ACR, age, race/ethnicity, body mass index, blood pressure, insulin resistance, high-density lipoprotein, C-reactive protein, and use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and calcium channel blockers at baseline. At baseline, the mean (SD) of eGFR was 94 (15) ml/min/1.73 m2, and the median (IQR) of ACR was 4.5 (3.3-7.6) mg/g. During the follow-up period, 187 men (24.6%) and 263 women (24.2%) had incident albuminuria and 136 men (17.9%) and 123 women (11.3%) had incident low eGFR. Fifty-four (7.1%) of men and 43 (3.9%) of women had both abnormalities. Among men, higher SHBG was associated with lower risk of low eGFR (pooled hazard ratio [HR] per SD, 95% confidence interval [CI]: 0.73 [0.57, 0.9], p=0.01) and lower risk for CKD (pooled HR per SD 95% CI: 0.78 [0.64, 0.95], p=0.01). No significant associations were observed among women. We conclude that among overweight glucose-intolerant men, higher SHBG was associated with reduced risk of CKD. Disclosure C. Kim: None. A. Ricardo: None. E.J. Boyko: None. C.A. Christophi: None. M. Temprosa: Other Relationship; Self; Merck KGaA. K. Watson: None. X. Pi-Sunyer: None. R. Rastogi Kalyani: None. D. Research Group: None.

We evaluated whether the duration of insulin supply was associated with hemoglobin A1c. Data were obtained through the Clinformatics® Data Mart Database, from 2001-2015. Patients were grouped according to the duration of insulin supply: 30 days, 90 days, and a combination of both 30 day and 90 day prescriptions. Generalized estimating equations which account for repeated measures within patients were used, with robust estimates of variance. Prescription duration was regressed on HbA1c (dependent variable) with alpha=0.(2-tailed). There were 16,725 eligible patients (9362 with 30-day, 1280 with 90-day, and 6083 with both 30- and 90-day prescriptions). The mean number of HbA1c tests/patient was 3.1. Patients who used 30-day prescriptions had HbA1c values that were 0.65 greater than those with 90-day prescriptions (p Disclosure M.A.M. Rogers: None. C. Kim: None. R. Tipirneni: None. T. Banerjee: None. J. Lee: Consultant; Self; Unitio.

The Inflammatory Bowel Disease Disability Index (IBD-DI) is a measure of disability in inflammatory bowel disease (IBD). The IBD-DI is validated for use as a clinical interview but not for use as a self-report questionnaire. We aimed to validate the IBD-DI for self-report (IBD-DI-SR) and to reduce the number of items, using IBD patients from two centers.Between April and August 2017, ambulatory IBD patients were recruited from Christchurch Hospital, New Zealand and Concord Hospital, Australia. The IBD-DI clinical interview version was compared with a self-report version. Participants were randomized to do the clinical interview or self-report first. Validation of the IBD-DI-SR involved calculating the correlation coefficient between the clinician completed and self-reported version of the IBD-DI and Cronbach's α of internal consistency of the IBD-DI-SR. To create an item-reduced version, multiple linear regression was used. The ROne hundred fourteen patients (57 from Christchurch and 57 from Sydney) completed the IBD-DI-SR validation phase, of whom 63 had Crohn's disease and 51 had ulcerative colitis. The Pearson correlation coefficient between the IBD-DI-SR and IBD-DI is 0.90 (P 0.001), and Cronbach's α of the IBD-DI-SR was 0.86. The item-reduced version of the IBD-DI-SR consisted of eight questions instead of 28, explaining 77% of the variance.The IBD-DI-SR has demonstrated reliability and validity. The item-reduced IBD-DI-SR is a concise self-report instrument for measuring IBD disability, which makes the IBD-DI more widely usable.

It is unclear whether relative elevations in androgens or irregular menses (IM) are associated with greater cardiometabolic risk among women who are already overweight and glucose intolerant.We conducted a secondary analysis of the Diabetes Prevention Program (DPP) and the Diabetes Prevention Program Outcomes Study (DPPOS). Participants included women with sex hormone measurements who did not use exogenous estrogen (n = 1422). We examined whether free androgen index (FAI) or IM was associated with diabetes risk during the DPP/DPPOS or with coronary artery calcification (CAC) at DPPOS year 10. Models were adjusted for menopausal status, age, race or ethnicity, randomization arm, body mass index (BMI), and hemoglobin A1c.Women had an average age of 48.2 ± 9.9 years. Elevations in FAI and IM were associated with greater BMI, waist circumference, and blood pressure and lower adiponectin. FAI was not associated with diabetes risk during the DPP/DPPOS [hazard ratio (HR) 0.97; 95% confidence interval (CI), 0.93 to 1.02] or increased odds of CAC [odds ratio (OR) 1.06; 95% CI, 0.92 to 1.23]. IM was also not associated with diabetes risk during the DPP/DPPOS (HR 1.07; 95% CI, 0.87 to 1.31) or increased odds of CAC (OR 0.89; 95% CI, 0.53 to 1.49). Women who had both relative elevations in FAI and IM had similar diabetes risk and odds of CAC as women without these conditions. Differences by treatment arm and menopausal status were not observed.Among midlife women who were already glucose intolerant and overweight, androgen concentrations and IM did not additionally contribute to increased risk for diabetes or CAC.

OBJECTIVE Women with type 1 diabetes have increased risk of infertility compared to women without diabetes even after adjustment for irregular menses, but aetiologies are incompletely understood. Our aim was to examine the prevalence of abnormalities in ovarian markers consistent with polycystic ovary syndrome in women with type 1 diabetes and associations with irregular menses and diabetes-specific variables. DESIGN, PATIENTS AND MEASUREMENTS We conducted a secondary analysis of women in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC), a randomized trial and observational follow-up of intensive insulin therapy for type 1 diabetes. We included women with anti-Mullerian hormone (AMH) measurements among women not using oral contraceptives (n = 187). Initial AMH and testosterone measures were performed between EDIC years 1 and 4. History of irregular menses was assessed annually. RESULTS The median age of women was 35 (interquartile ratio 29, 40) years; 133 (35%) had elevated AMH and 62 (17%) reported irregular menses. Twelve per cent of women had relative elevations in total testosterone. In multivariable models, lower insulin dosages were associated with higher AMH concentrations (P = .0027), but not diabetes duration, glycemic control, body mass index or irregular menses. Neither irregular menses nor diabetes-specific variables were associated with testosterone concentrations. CONCLUSIONS Among women with type 1 diabetes in their thirties, abnormalities in ovarian markers are common and not associated with irregular menses and thus may partially account for decreased fecundity in women with type 1 diabetes.

Mitophagy is a cellular process by which dysfunctional mitochondria are degraded via autophagy. Increasing empirical evidence proposes that this mitochondrial quality-control mechanism is defective in neurons of patients with various neurodegenerative diseases such as Ataxia Telangiectasia, Alzheimer’s disease, Parkinson’s disease, and Amyotrophic Lateral Sclerosis. Accumulation of defective mitochondria and the production of reactive oxygen species due to defective mitophagy have been identified as causes underlying neurodegenerative disease pathogenesis. However, the reason mitophagy is defective in most neurodegenerative diseases is unclear. Like mitophagy, defects in the ubiquitin/26S proteasome pathway have been linked to neurodegeneration, resulting in the characteristic protein aggregates often seen in neurons of affected patients. Although initiation of mitophagy requires a functional ubiquitin pathway, whether defects in the ubiquitin pathway are causally responsible for defective mitophagy is not known. In this mini-review, we introduce mitophagy and ubiquitin pathways and provide a summary of our current understanding of the regulation of mitophagy by the ubiquitin pathway. We will then briefly review empirical evidence supporting mitophagy defects in neurodegenerative diseases. The review will conclude with a discussion of the constitutively elevated expression of ubiquitin-like protein Interferon-Stimulated Gene 15 (ISG15), an antagonist of the ubiquitin pathway, as a potential cause of defective mitophagy in neurodegenerative diseases. Impact statement Neurodegenerative diseases place an enormous burden on patients and caregivers globally. Over six million people in the United States alone suffer from neurodegenerative diseases, all of which are chronic, incurable, and with causes unknown. Identifying a common molecular mechanism underpinning neurodegenerative disease pathology is urgently needed to aid in the design of effective therapies to ease suffering, reduce economic cost, and improve the quality of life for these patients. Although the development of neurodegeneration may vary between neurodegenerative diseases, they have common cellular hallmarks, including defects in the ubiquitin-proteasome system and mitophagy. In this review, we will provide a summary of our current understanding of the regulation of mitophagy by the ubiquitin pathway and discuss the potential of targeting mitophagy and ubiquitin pathways for the treatment of neurodegeneration.

Context It is unclear whether relative elevations in androgens or irregular menses (IM) are associated with greater cardiometabolic risk among women who are already overweight and glucose intolerant. Research design and methods We conducted a secondary analysis of the Diabetes Prevention Program (DPP) and the Diabetes Prevention Program Outcomes Study (DPPOS). Participants included women with sex hormone measurements who did not use exogenous estrogen (n = 1422). We examined whether free androgen index (FAI) or IM was associated with diabetes risk during the DPP/DPPOS or with coronary artery calcification (CAC) at DPPOS year 10. Models were adjusted for menopausal status, age, race or ethnicity, randomization arm, body mass index (BMI), and hemoglobin A1c. Results Women had an average age of 48.2 ± 9.9 years. Elevations in FAI and IM were associated with greater BMI, waist circumference, and blood pressure and lower adiponectin. FAI was not associated with diabetes risk during the DPP/DPPOS [hazard ratio (HR) 0.97; 95% confidence interval (CI), 0.93 to 1.02] or increased odds of CAC [odds ratio (OR) 1.06; 95% CI, 0.92 to 1.23]. IM was also not associated with diabetes risk during the DPP/DPPOS (HR 1.07; 95% CI, 0.87 to 1.31) or increased odds of CAC (OR 0.89; 95% CI, 0.53 to 1.49). Women who had both relative elevations in FAI and IM had similar diabetes risk and odds of CAC as women without these conditions. Differences by treatment arm and menopausal status were not observed. Conclusions Among midlife women who were already glucose intolerant and overweight, androgen concentrations and IM did not additionally contribute to increased risk for diabetes or CAC.

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.

Copyright © 2015 by the Endocrine Society.Context: Steroid sex hormones and SHBG may modify metabolism and diabetes risk, with implications for sex-specific diabetes risk and effects of prevention interventions. Objective: This study aimed to evaluate the relationships of steroid sex hormones, SHBG and SHBG single-nucleotide polymorphisms (SNPs) with diabetes risk factors and with progression to diabetes in the Diabetes Prevention Program (DPP). Design and Setting: This was a secondary analysis of a multicenter randomized clinical trial involving 27 U.S. academic institutions. Participants: The study included 2898 DPP participants: 969 men, 948 premenopausal women not taking exogenous sex hormones, 550 postmenopausal women not taking exogenous sex hormones, and 431 postmenopausal women taking exogenous sex hormones. Interventions: Participantswererandomized to receive intensive lifestyle intervention, metformin, or placebo. Main Outcomes: Associations of steroid sex hormones, SHBG, and SHBG SNPs with glycemia and diabetes risk factors, and with incident diabetes over median 3.0 years (maximum, 5.0 y). Results: T and DHT were inversely associated with fasting glucose in men, and estrone sulfate was directly associated with 2-hour post-challenge glucose in men and premenopausal women. SHBG was associated with fasting glucose in premenopausal women not taking exogenous sex hormones, and in postmenopausal women taking exogenous sex hormones, but not in the other groups. Diabetes incidence was directly associated with estrone and estradiol and inversely with T inmen; the association with Twaslost after adjustment for waist circumference. Sex steroids were not associated with diabetes outcomes in women. SHBG and SHBG SNPs did not predict incident diabetes in the DPP population. Conclusions: Estrogens and T predicted diabetes risk in men but not in women. SHBG and its polymorphisms did not predict risk in men or women. Diabetes risk is more potently determined by obesity and glycemia than by sex hormones.

For decades, it has been recognized that men have a higher age-adjusted risk of ischemic cardiovascular (CVD) events compared to women, thus generating hypotheses that sex steroids contribute to CVD risk. Potential mechanisms include genomic and non-genomic effects of sex steroids as well as mediation through classic CVD risk factors and obesity. However, results from randomized studies suggest that sex steroid supplementation in men and women do not result in improved CVD outcomes and may increase CVD risk. In contrast, prospective observations from endogenous sex steroid studies, i.e. among participants not using sex steroids, have suggested the opposite relationship. We reviewed the findings of prospective observational studies in men (17 studies) and women (8 studies) that examined endogenous sex steroids and CVD risk. These studies suggested a lack of association or that lower levels of testosterone or dihydrotestosterone are associated with higher CVD risk in both men and women. Higher, rather than lower, estradiol levels were associated with higher CVD risk in women. There were several significant gaps in the literature. First, it is unclear whether more sensitive measures of sex steroid levels might detect significant differences. Second, there are few prospective studies in women. Similarly, no studies report outcomes for high-risk groups such as African-Americans and Hispanics. Finally, few studies report upon ischemic coronary disease as opposed to ischemic stroke separately, although relationships between sex steroids and CVD may vary by vascular bed. Future investigations need to examine high risk groups and to distinguish between subtypes of CVD.

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.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.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 (p0.0001) and with lower time-weighted hemoglobin A1c (p0.0001). Each 10% increase in hemoglobin A1c was accompanied by an 11% reduction in prostate specific antigen (p=0.0001).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.

We have shown that insulin-like growth factor I (IGF-1) infusion in Apoe(-/-) mice decreased atherosclerotic plaque size and plaque macrophage and lipid content suggesting that IGF-1 suppressed formation of macrophage-derived foam cells. Since 12/15-lipoxygenase (12/15-LOX) plays an important role in OxLDL and foam cell formation, we hypothesized that IGF-1 downregulates 12/15-LOX, thereby suppressing lipid oxidation and foam cell formation.We found that IGF-1 decreased 12/15-LOX plaque immunopositivity and serum OxLDL levels in Apoe(-/-) mice. IGF-1 reduced 12/15-LOX protein and mRNA levels in cultured THP-1 macrophages and IGF-1 also decreased expression of STAT6 transcription factor. IGF-1 reduction in macrophage 12/15-LOX was mediated in part via a PI3 kinase- and STAT6-dependent transcriptional mechanism. IGF-1 suppressed THP-1 macrophage ability to oxidize lipids and form foam cells. IGF-1 downregulated 12/15-LOX in human blood-derived primary macrophages and IGF-1 decreased LDL oxidation induced by these cells. IGF-1 reduced LDL oxidation and formation of foam cells by wild type murine peritoneal macrophages, however these effects were completely blocked in 12/15-LOX-null macrophages suggesting that the ability of IGF-1 to reduce LDL oxidation and foam cells formation is dependent on its ability to downregulate 12/15-LOX.Overall our data demonstrate that IGF-1 reduces lipid oxidation and foam cell formation via downregulation of 12/15-LOX and this mechanism may play a major role in the anti-atherosclerotic effects of IGF-1.