bluuebunny/crossref_metadata_2025 huggingface dataset:
157-OR: People with Type 1 Diabetes and Impaired Awareness of Hypoglycemia Have a Delayed Reaction to Perform a Glucose Scan during Hypoglycemia: A Prospective Observational Study
Authors: MOSER OTHMAR , ZIKO HARIS , ELSAYED HESHAM , HOCHFELLNER DANIEL A. , POETTLER TINA , MUELLER ALEXANDER , ECKSTEIN MAX L. , KNOLL LISA , SOURIJ HARALD , MADER JULIA K.
Published: June 2020

Background: Considering that people with type 1 diabetes (T1D) and impaired awareness of hypoglycemia (IAH) have a delayed perception of hypoglycemia, the question arises if they perform scans later in case of hypoglycemia compared to those with normal hypoglycemia awareness (non-IAH). We assessed if the time until performing a scan after reaching hypoglycemia while using a flash glucose monitoring (Flash GM) system is different in people with T1D and IAH compared to people with T1D and non-IAH.

Material and Methods: 92 people with T1D (age of 42±14 years, BMI 25.1±4.0 kg/m2, HbA1c 57±9 mmol/mol (7.3±0.8%), 73 MDI/19 CSII) using a Flash GM system for 3 months were included. Flash GM data were downloaded and assessed for time until scan after reaching hypoglycemia level 1 (<70 mg/dL) and level 2 (<54 mg/dL) and compared for T1D with IAH versus non-IAH via unpaired t-test or Mann-Whitney-U test (p<0.05). IAH was routinely assessed by means of Gold, Clarke and Pedersen-Bjergaard Score.

Results: Significant differences were only found for the delay between reaching hypoglycemia and scan between IAH and non-IAH for both Gold Score (hypoglycemia level 1: IAH 78 min [51-105] vs. non-IAH 63 min [42-89], p=0.03; nighttime hypoglycemia level 2: IAH 140 min [107-227] vs. non-IAH 96 min [41-155], p=0.004) and Pedersen-Bjergaard Score (hypoglycemia level 1: IAH 76 min [52-97] vs. non-IAH 54 min [38-71], p=0.01; nighttime hypoglycemia level 1: IAH 132 min [79-209] vs. non-IAH 89 min [59-143], p=0.01; nighttime hypoglycemia level 2: IAH 134 min [66-212] vs. non-IAH 80 min [37-131], p=0.002).

Conclusion: These preliminary data suggest that the time until scan after reaching hypoglycemia may serve as an objective assessment tool for IAH in people with T1D.

Disclosure

O. Moser: Other Relationship; Self; Dexcom, Inc., Novo Nordisk A/S, Sanofi. H. Ziko: None. H. Elsayed: None. D.A. Hochfellner: None. T. Poettler: None. A. Mueller: None. M.L. Eckstein: Research Support; Self; Dexcom, Inc., Novo Nordisk A/S, Sanofi-Aventis. L. Knoll: None. H. Sourij: Advisory Panel; Self; Amgen, AstraZeneca, Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. Research Support; Self; Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. Speaker’s Bureau; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Sanofi. J.K. Mader: Advisory Panel; Self; Becton, Dickinson and Company, Eli Lilly and Company, Medtronic, Prediktor Medical, Sanofi-Aventis. Speaker’s Bureau; Self; Abbott, Eli Lilly and Company, Medtronic, Novo Nordisk A/S, Roche Diabetes Care, Sanofi-Aventis.
1576-P: Correlation Analysis between Insulin Sensitivity, Branched-Chain Acid, and Adiponectin Levels in Japanese Individuals with Varying Degrees of Glucose Tolerance
Authors: AMANO ERI , YOSHIMURA KUMIKO , FUNAKOSHI SHOGO , HIRANO SEIKI , OHMI SATOKO , TERADA YOSHIO , FUJIMOTO SHIMPEI
Published: June 2020

Recent researches have revealed an association between circulating branched-chain acid (BCAA) and obesity and insulin resistance. In addition, experiments using rodents have revealed that adiponectin (APN) regulates the systemic BCAA level by affecting its catabolism. However, the influence of glucose intolerance on the relationship between BCAA and insulin sensitivity (IS) and between APN and BCAA in humans is unknown. Hence, we aimed to investigate these associations in individuals with varying degrees of glucose tolerance. Based on the data of 75g OGTT in 75 Japanese individuals without diabetic medication [age:65±11 (mean±SD); BMI: 24.9±3.8], individuals were classified into the normal, impaired glucose tolerance, and diabetes (DM) group (n=25 in each group). Matsuda index (MI) was calculated as an index of IS. Normally-distributed loge-transformed (ln-) values were used for MI and APN. Fasting BCAA was assayed using an enzymatic method. In analysis of total individuals using stepwise regression analysis, BMI (β=-0.477, p<0.0001) and BCAA (β=-0.243, p=0.0195) are significant factors for predicting ln-MI. Furthermore, BMI, ln-APN, age, and sex are significant factors for predicting BCAA. In multiple regression analysis, using ln-MI as a dependent variable and BMI and BCAA as independent variables in each group, BCAA was negatively and significantly correlated with ln-MI only in the DM group, but not in the other groups [DM: β of BMI =-0.325, β of BCAA =-0.465 (p=0.02), R2=0.509]. In multiple regression analysis, using BCAA as a dependent variable and BMI and ln-APN as independent variables in each group, ln-APN was negatively and significantly correlated with BCAA in all the groups. In conclusion, BCAA was negatively correlated with IS independent of BMI, especially in individuals with DM. APN was negatively correlated with BCAA, independent of glucose tolerance.

Disclosure

E. Amano: None. K. Yoshimura: None. S. Funakoshi: None. S. Hirano: None. S. Ohmi: None. Y. Terada: None. S. Fujimoto: None.
1583-P: Decreased Serum 1,5-Anhydroglucitol Level Is Associated with Development of Abnormal Glucose Metabolism or Metabolic Syndrome in Male Japanese: Tokushima Cohort Study
Authors: HATA AKIKO , AKI NANAKO , ICHIHARA TAKAKO , TAMURA AYAKO , MINAGAWA TAKAKO , KUWAMURA YUMI , FUNAKI MAKOTO
Published: June 2020

Serum 1,5-anhydroglucitol (1,5-AG) is a useful clinical indicator for short-term glycemic control status, which exhibits a rapid decrease if blood glucose levels are poorly controlled in diabetic patients. Interestingly, some cross-sectional studies have suggested that serum 1,5-AG level decreases even before the onset of type 2 diabetes. Thus, the aim of the present study was to examine whether there is an association between a decrease in serum 1,5-AG level and the incidence of abnormal glucose metabolism (AbGM) or metabolic syndrome (MetS) in Japanese in a prospective cohort study. We here report a prospective occupational-based cohort study, which was conducted during 2010-2017 in Japan. Briefly, 1) 837 male workers without AbGM and 2) 843 male workers without MetS aged over 20 years were followed up prospectively. AbGM was defined as either: 1) fasting plasma glucose ≥ 110 mg/dl, 2) HbA1c ≥ 6.0% or 3) medication for hyperglycemia. In multivariate analysis after adjusting for age, BMI, smoking habit, alcohol intake, regular exercise and estimated glomerular filtration rate, the HR of developing MetS was 1.81 [95%CI: 1.12 to 2.92, P=0.01] in the lowest quartile of baseline serum 1,5-AG, compared with the highest quartile. In addition, the incidence and multivariate-adjusted HR of AbGM or MetS also increased with decreasing quartile of serum 1,5-AG (P for trend for both <0.05). Our findings suggest that a decrease in serum 1,5-AG level is a predictive marker for the future onset of AbGM or MetS in male Japanese.

Disclosure

A. Hata: None. N. Aki: None. T. Ichihara: None. A. Tamura: None. T. Minagawa: None. Y. Kuwamura: None. M. Funaki: None.

Funding

Tokushima Prefecture
1586-P: Five-Year Risk of Hepatobiliary Disease in Type 2 Diabetes: The Fremantle Diabetes Study Phase II
Authors: DAVIS WENDY A. , DAVIS TIMOTHY
Published: June 2020

Nonalcoholic fatty liver disease (NAFLD) is estimated to coexist in 30-64% of people with type 2 diabetes (T2D). Several risk scores use clinical/laboratory data to screen for NAFLD. Although not developed for diabetes, some include it as a binary variable. The prognostic value of a high score in T2D is unknown. We therefore aimed to i) identify prevalent/5-year incident hepatobiliary biliary disease (HBD) in community-based people with T2D, ii) evaluate available NAFLD risk scores to predict 5-year incident HBD, and iii) if none performed acceptably, develop a novel prognostic risk score. Detailed data from the Fremantle Diabetes Study Phase II (FDS2) cohort and validated linkages were used to identify ICD coded hospitalizations/cancer registrations for/with HBD and deaths from/with HBD. Of 1,499 FDS2 T2D participants recruited in 2008-2011, 204 (13.6%) had prevalent HBD and 94 (7.3%) of the remaining 1295 had a first HBD event during 5,979 person-years’ follow-up to the event, death from non-HBD causes (124 (9.6%)), or census at 5 years, whichever came first (incidence rate 16 (95% CI 13-19)/1,000 person-years). The discrimination of available NAFLD risk scores for prediction of 5-year incident HBD was weak (AUC 0.51 to 0.61). In a novel competing risk regression equation, Aboriginality, eGFR <30 and ≥90 ml/min/1.73m2, ln(AST/ALT), ln(GGT), ln(platelets), and ln(alpha-2-macroglobulin) independently predicted 5-year incident HBD. Discrimination (AUC (95% CI): 0.70 (0.64-0.76), calibration (Hosmer-Lemeshow test, P=0.07) and accuracy (Brier score 0.06 (range 0-0.96)) were acceptable. For a 10% risk cut-off, sensitivity was 38%, specificity 89%, PPV 20% and NPV 95%. This FDS2-derived prognostic risk equation for incident HBD may facilitate selection of people with T2D who would benefit from intensified management aimed at preventing the adverse outcomes of NAFLD.

Disclosure

W.A. Davis: Advisory Panel; Spouse/Partner; Lilly Diabetes, Merck Sharp & Dohme Corp., Novo Nordisk A/S. Speaker’s Bureau; Self; Boehringer Ingelheim International GmbH. Speaker’s Bureau; Spouse/Partner; Lilly Diabetes, Merck Sharp & Dohme Corp., Mylan, Novo Nordisk A/S, Sanofi-Aventis. Other Relationship; Self; Proteomics International. Other Relationship; Spouse/Partner; Proteomics International. T. Davis: Advisory Panel; Self; Lilly Diabetes, Merck Sharp & Dohme Corp., Novo Nordisk A/S. Speaker’s Bureau; Spouse/Partner; Boehringer Ingelheim International GmbH. Speaker’s Bureau; Self; Lilly Diabetes, Merck Sharp & Dohme Corp., Mylan, Novo Nordisk A/S, Sanofi-Aventis. Other Relationship; Self; Protemics International. Other Relationship; Spouse/Partner; Protemics International.

Funding

National Health and Medicine Research Council of Australia (513781, 1042231, 1126886)
159-OR: Vitamin E Treatment Reduces Severe Hypoglycemia-Induced Fatal Cardiac Arrhythmias in Type 1 Diabetic Rats
Authors: RENO CANDACE M. , OXSPRING MILAN B. , BAYLES JUSTIN , HOLIDAY IVANA , HUANG YIQING , FISHER SIMON J.
Published: June 2020

Severe hypoglycemia can lead to fatal cardiac arrhythmias. Our studies have shown that diabetes, per se, increases the risk of hypoglycemia-induced mortality in rats. It was hypothesized that excess oxidative stress, associated with diabetes, increases the heart’s susceptibility to hypoglycemia-induced fatal arrhythmias. To test this hypothesis, Sprague Dawley rats were made diabetic (streptozotocin 65 mg/kg) and randomized to two treatment groups: 1) antioxidant Vitamin E (400 mg/kg/day; n=18) or 2) control (vehicle, n=16) injected subcutaneously over 8 days. Then, rats underwent hyperinsulinemic (0.4 units/kg/min) severe hypoglycemic (10-15 mg/dl) clamps for 3 hours with continuous electrocardiogram recording. Confirming its antioxidant properties, Vitamin E treatment significantly reduced oxidative stress in the heart 3.3-fold versus controls (Figure). As compared to hypoglycemia-induced mortality of 38% in controls, Vitamin E treatment significantly reduced mortality to 6% (p<0.05; Figure). Additionally, Vitamin E treatment reduced 3rd degree heart block (6%) vs. control (46%; Figure). Overall, these results suggest that 1) oxidative stress in diabetes increases the heart’s susceptibility to hypoglycemia-induced arrhythmias, and 2) Vitamin E treatment reduces oxidative stress and reduces both cardiac arrhythmias and mortality to insulin-induced severe hypoglycemia.

Disclosure

C.M. Reno: None. M.B. Oxspring: None. J. Bayles: None. I. Holiday: None. Y. Huang: None. S.J. Fisher: None.

Funding

National Institutes of Health (5T32DK091317, R01NS070235); JDRF (3-APF-2017-407-A-N)
160-LB: T1D Technology Uptake in Massachusetts Schools: Preliminary Data Gathering
Authors: QUINN MARYANNE , PETTENGILL CAITLIN M. , AFZALI JEAN , TOULOUSE SHANYN , AFZALI JEAN , MELCHIONDA LAURIE A. , LINEHAN ANN , CONNOLLY JILL
Published: June 2020

As length of hospital stay at T1D diagnosis declines, clinicians must innovate to manage pediatric T1D care. Concurrently, insulin pump and continuous glucose monitor (CGM) use has increased in Massachusetts (MA) youth.

Objectives: To report school nurse assessments of: 1. time MA school nurses coordinate parent-student T1D care; 2. prevalence of IP and CGM use in MA schools.

Methods: Questionnaires were emailed to 1330 licensed school nurses in March 2019; 327 (25%) submitted data on 576 students, i.e., student/RN = 1.76.

Demographics: School Nurses: The School Health Unit in the Commonwealth of MA is divided into 5 regions: Western, Central, MetroWest/Boston, Northeast and Southeast. 93% of questionnaires were answered by public school nurses; 94% of nurses work in 1 school and 5% in 2 schools; 67% of schools have 1 FTE, 31% have 2 FTE and 3% have ≥3 FTE nurses;33% attended a T1D continuing education course in the past year.

Demographics: Students: ages 3 to 18 years, enrolled in pre-school-grade 12; 29% receive free, reduced or universal free school lunch; 4% speak English as a 2nd language; 67% have a 504 plan, 19% an Individualized Education Plan, and 79% an Individualized Health Care Plan. Attendance, Tardiness and Early Dismissal: School year 2018 - 2019: 12% of students were reported absent ≥10% of days; 8% were reported tardy ≥10% of days due to home T1D management; and 10% were dismissed early due to T1D

management concerns at school. No student was dismissed from school via ambulance.

Technology: 50% wear an insulin pump and 96% were reported to monitor glucose at school. Of those, 32% monitor interstitial and capillary glucose, 30% monitor only interstitial glucose and 37% monitor only capillary glucose. Four percent do not monitor glucose at school.

Communication: School nurse respondents spend 4.3 minutes/student/day communicating w a student’s parent/guardian. Massachusetts school nurses have ~7 hours/day to assist T1D-affected youth and the data supports most students see a school nurse daily.

Disclosure

M. Quinn: Advisory Panel; Self; Dexcom, Inc. C.M. Pettengill: None. J. Afzali: None. S. Toulouse: None. J. Afzali: None. L.A. Melchionda: None. A. Linehan: None. J. Connolly: None.
1603-P: Changes in Age- and Gender-Specific All-Cause Mortality Rates and Ratios in People with T2DM in Hungary between 2001-2016: A Nationwide Cohort Study
Authors: JERMENDY GYORGY , KISS ZOLTAN , ROKSZIN GYÖRGY , FÁBIÁN IBOLYA , WITTMANN ISTVAN , KEMPLER PETER
Published: June 2020

T2DM is associated with a higher risk of all-cause mortality; however, detailed analyses of age- and gender-specific subgroups are rare. The aim of the study was to analyze the changes of age- and gender-specific all-cause mortality rates and ratios (excess risk) in T2DM subjects (aged >40 years) in Hungary between 2001 and 2016. We used the central database of the National Institute of Health Insurance Fund. Annual all-cause mortality rates and ratios (T2DM/non-T2DM) were determined in males/females and in different age-groups (41-50, 51-60, 61-70, >71 years). Age-adjusted values were used for evaluating standardized mortality rates. Among pharmacologically treated T2DM subjects we found 117,700 and 329,845 males, 232,143 and 391,382 females in 2001 and 2016, respectively. Standardized all-cause mortality rate was higher in males than females in 2001 (4540/100,000 vs. 3365/100,000) which decreased to 4125/100,000 in males (change: -11.8%, p<0.0001) and to 2977/100,000 in females (change: -9.2%; p=0.0558) in 2016. The standardized all-cause mortality ratio was higher in females (1.39) than in males (1.13) in 2001. We found a significant increase (8.35%; p=0.0272) in standardized mortality ratios in our cohort between 2001 and 2016 which was higher in males (11.44%; p=0.0096) than females (2.78%; p=0.3288). We observed the most pronounced increase in all-cause mortality ratios between 2001 and 2016 in age-groups of 41-50 and 51-60 years in both genders (change varied from 54.2% to 101.8%; p<0.05) which was due to distinct tendencies in changes of mortality curves (more impressive decrease in non-T2DM subjects than in T2DM patients). Pharmacologically treated T2DM subjects in lower age-groups (41-60 years) had the highest increase in all-cause mortality ratios between 2001 and 2016 in Hungary. These data indicate that younger patients with T2DM need special attention for improving long-term outcomes.

Disclosure

G. Jermendy: None. Z. Kiss: None. G. Rokszin: None. I. Fábián: None. I. Wittmann: None. P. Kempler: None.

Funding

Hungarian Diabetes Association (2019)
1608-P: Life Years Lost Associated with Prediabetes in a 40-Year Follow-Up Study
Authors: RAPOPORT MICHA , CHETRIT ANGELA , NOVIKOV ILIA , CANTRELL DROR , DANKNER RACHEL
Published: June 2020

Background: The prevalence of prediabetes is gradually increasing and its association with life years lost (LYL) is yet to be determined.

Objective: to examine LYL associated with prediabetes as compared to normoglycemia, by age, sex, country of origin, smoking status, BMI, and blood pressure, using data of the Israel Study of Glucose Intolerance, Obesity and Hypertension (GOH) 40-year follow-up.

Methods: The population of the current study included 2,844 men and women (mean age 52±8.2 years) who underwent OGTT and anthropometric measurements, during 1976-1982, and were followed for mortality until May 2019. Normoglycemia, Prediabetes and diabetes were defined according to fasting plasma glucose, 2-hour post OGTT plasma glucose, reporting of having diabetes or use of antidiabetes medications. By the end of follow-up 27.7% remained alive and multiple imputation procedures were used for missing mortality dates.

Results: At baseline, 35.8%, 48.8% and 15.4% individuals were found with normoglycemia, prediabetes, and diabetes, respectively. Using multiple regression mixed models, the average difference in LYL associated with prediabetes as compared to normoglycemia was 4.3 years (95%CI 3.3-5.2; p<0.001). LYL were higher in prediabetic women than in prediabetic men 4.4 (95%CI 3.0-5.7) vs. 3.3 (95%CI 1.9-4.8). These differences persisted mainly in individuals younger than 60 years, with BMI<25 kg/m2, never smokers, and normotensives at baseline. Significant reductions of 9.9 years (95%CI 8.6-11.2) were observed for diabetes as compared to prediabetes and 14.2 years on average (95%CI 12.8-15.5) as compared to normoglycemic individuals.

Conclusions: This study reveals that life expectancy of middle-aged individuals with prediabetes is more than 4 years shorter than of normoglycemic individuals. As expected, diabetes was associated with the greatest LYL in this long-term cohort study.

Disclosure

M. Rapoport: None. A. Chetrit: None. I. Novikov: None. D. Cantrell: None. R. Dankner: None.
161-LB: Neurodevelopmental Outcomes of Infancy-Onset Diabetes
Authors: MCCAULEY MARY , DENSON ANNA M. , LETOURNEAU-FREIBERG LISA R. , SCOTT MEGAN N. , GREELEY SIRI ATMA W.
Published: June 2020

Background: Infancy-onset diabetes is largely monogenic before 6 months of age, whereas autoimmune type 1 diabetes is more likely from 6-12 months of age. As the most common neonatal diabetes, patients with KATP channel mutations exhibit a spectrum of neurodevelopmental disability that is largely related to brain expression of mutated channels. It is not known how glycemic dysregulation of any type of early-onset diabetes may affect brain development.

Methods: Subjects included from UChicago Monogenic Diabetes Registry with diabetes diagnosed under a year of age currently aged 4-20 years and unaffected sibling controls. Known KATP channel mutations or other rare causes affecting brain development were excluded. Measures of intellectual function (IF), executive function (EF), visual motor integration (VMI) and academic achievement (AA) were utilized (Table 1). A two-sample t-test was conducted comparing each group assuming unequal variance.

Results: Comprehensive testing was completed for those with infancy-onset diabetes and siblings (Table 1). There were no significant differences on any measure, though mean scores trended lower in the affected group.

Conclusion: Our findings show no difference in IF, EF, VMI, AA in children diagnosed with diabetes in infancy compared to their unaffected siblings. Our conclusions are limited due to a small sample size; differences may be subtle and require a larger sample size to be identified.

Disclosure

M. McCauley: None. A.M. Denson: None. L.R. Letourneau-Freiberg: None. M.N. Scott: None. S.W. Greeley: None.

Funding

American Diabetes Association (1-17-JDF-008 to S.A.W.G.); National Institute of Diabetes and Digestive and Kidney Diseases (R01DK104942, P30DK0205950); National Center for Advancing Translational Sciences (UL1TR002389)
1620-P: Metabolites Associated with Insulin Resistance in Women with and without Type 1 Diabetes
Authors: SNELL-BERGEON JANET K. , SCHAUER IRENE E. , BERGMAN BRYAN C. , NADEAU KRISTEN J. , CREE-GREEN MELANIE , KESHAWARZ AMENA , PYLE LAURA
Published: June 2020

Having type 1 diabetes (T1D) at least doubles insulin resistance (IR) compared to people without diabetes, but factors explaining this increased IR remain poorly understood. We analyzed untargeted plasma metabolomics in 30 premenopausal women aged 18-45 years (15 with and 15 without T1D) who underwent a hyperinsulinemic euglycemic clamp to measure insulin sensitivity. Sparse Partial Least Squares Discriminant Analysis (sPLS-DA) was used to identify metabolites that discriminated T1D status and diabetes-specific GIR tertile. Women with T1D had a significantly lower glucose infusion rate (GIR) than women without diabetes (5.5 ± 3.2 mg/kg/min vs. 12.8 ± 5.4 mg/kg/min, p=0.0001), indicating lower insulin sensitivity. Using sPLS-DA, we identified two components that discriminated T1D status (AUC=0.84) and two components that discriminated the lowest vs. highest group-specific GIR tertile (AUC= 0.91). Metabolite pathways discriminating T1D status and lowest vs. highest GIR tertile are shown in the Table. Common pathways discriminating both T1D and GIR tertile are in bold in the Table. Plasma metabolites mainly in the amino acid and lipid metabolism pathways differed by T1D status, and both overlapping and novel metabolites distinguished IR in premenopausal women. These data provide insight into common factors influencing IR regardless of diabetes status, as well as metabolic pathways affected by T1D.

Disclosure

J.K. Snell-Bergeon: Stock/Shareholder; Self; GlaxoSmithKline plc. I.E. Schauer: None. B.C. Bergman: Consultant; Spouse/Partner; Novo Nordisk Inc., Sanofi US. Research Support; Self; Eli Lilly and Company. Speaker’s Bureau; Spouse/Partner; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc. K.J. Nadeau: None. M. Cree-Green: Advisory Panel; Self; Novo Nordisk Inc. A. Keshawarz: None. L. Pyle: None.

Funding

American Diabetes Association (7-13-CD-10 to J.K.S-B.)
1635-P: Recurrent Mosaicism in Memory T-Cells from Newly Diagnosed Patients with Type 1 Diabetes
Authors: AL-RIYAMI MAHA , MARCHAND LUC , POLYCHRONAKOS CONSTANTIN
Published: June 2020

Type 1 diabetes (T1D) is an autoimmune disease resulting in destruction of pancreatic beta cells by infiltrating self-reactive T-cells into the islets. The concordance rate of T1D is far from 100% in monozygotic twins and in the inbred NOD mice, despite genetic identity and shared environment during the years of peak incidence. This suggests stochastic determinants such as, somatic mutations in the expanding autoantigen-specific T cell lineages, parallel to what is seen in the expanding tumor lineages in cancer.

Here, using comparative genomic hybridization (CGH), we found that ∼67% of our study subjects (newly diagnosed patients with T1D) carry somatic copy number aberrations (CNAs) in proinsulin- reactive CD3+ T cell clones. Some of the mutated genes reoccurred independently in cells from two or three different patients which is a substantial evidence for a pathogenic contribution. These include genes with T cell expression and a proliferation or regulatory function, such as IKZF1, CHD7 and SMARCA2. Moreover, we identified genes, such as SAMD1 and CASZ1 that were previously identified in T cells of diabetic NOD mice and also have a proliferative and a regulatory function. The level of TCR clonality of the tested lymphocytes shows that these somatic mutations can occur both pre- and post- to the thymic selection. CNAs in T cells involved in host defense (reaction to Tetanus Toxoid) obtained from the same patients were significantly smaller in size. Our data provide evidence of a potential role of somatic mutations in the pathogenesis of T1D and, potentially, other autoimmune diseases.

Disclosure

M. Al-Riyami: None. L. Marchand: None. C. Polychronakos: Employee; Self; MaiDa Gene Technology, Zhoushan, Zhejiang Province, China.

Funding

Canadian Institutes of Health Research (MOP-137050); Canadian Diabetes Association (OG-3-11-3429CP); Sultan Qaboos University (to M.A-R.)
1636-P: Transient Neonatal Diabetes: Clinical Differences between Patients Bearing KATP Mutations and 6q24 Defects May Guide Genetic Screening
Authors: BARBETTI FABRIZIO , BONFANTI RICCARDO , RABBONE IVANA , REINSTADLER PETRA , BIZZARRI CARLA , IAFUSCO DARIO
Published: June 2020

Transient neonatal diabetes mellitus (TNDM) is a subtype of neonatal diabetes (diagnosis: ≤ 180 days of life) characterized by remission within months from onset. TNDM is almost invariably associated with mutations in genes encoding the two subunits of ATP-dependent potassium channel (KATP), ABCC8 and KCNJ11, or with defects in chromosome 6. We reviewed genetic data, family history and clinical features including age at diabetes onset, mode of diabetes presentation, birth weight, type of diabetes treatment, time to remission, and diabetes therapy at relapse in 23 patients with TNDM of the Italian collection. Italian data set of TNDM patients included 8 cases with ABCC8 mutation, 8 cases with KCNJ11 mutation and 7 patients with 6q24 defects. Ten patients with KATP/TNDM (62%) had a parent with diabetes or IFG/IGT who carried the mutation. In contrast, none of the parents of patients with 6q24/TNDM showed glucose derangement. Age at diabetes onset did not exceed 5 weeks from birth in patients with 6q24 defects, and ranged from 1 to 34 weeks in patients with KATP mutations. Seven patients with KATP/TNDM presented with diabetic ketoacidosis (DKA); in contrast, three other patients entered into remission without any pharmacological treatment. No patients with 6q24/TNDM had DKA. Age at remission was higher for probands with KATP/TNDM than those with 6q24/TNDM (median 28.5 vs. 8 weeks, respectively, p=0.0023), along with time to remission (20.5 vs. 6 weeks, p=0.0056). Four patients with TNDM who had relapse of diabetes were treated with sulfonylureas (SU), and one with insulin (refusal of SU).

Conclusions: TNDM patients with positive family history for diabetes, onset of diabetes beyond 6 weeks from birth and long time to remission should be screened for mutations in KATP genes first. Remission without therapy observed in 3 cases with KATP/TNDM suggests that in parents with diabetes onset in adolescence, mild TNDM could have been overlooked.

Disclosure

F. Barbetti: Consultant; Self; Amring. R. Bonfanti: Advisory Panel; Self; Abbott, Medtronic, Roche Diabetes Care. I. Rabbone: None. P. Reinstadler: None. C. Bizzarri: None. D. Iafusco: None.
1655-P: Genetic Risk Factors for Incident Cardiovascular Disease in Type 2 Diabetes Patients
Authors: KWAK SOO HEON , MERCADER JOSEP M. , LEONG AARON , PORNEALA BIANCA , WU PEITAO , COLE JOANNE B. , MERINO JORDI , PARK KYONG SOO , CHO NAM H. , DUPUIS JOSEE , FLOREZ JOSE C. , MEIGS JAMES B.
Published: June 2020

Patients with type 2 diabetes (T2D) are at two-fold increased risk of cardiovascular disease (CVD). CVD is the leading cause of T2D morbidity and mortality. The aim of this study was to identify genetic risk factors associated with incident CVD in patients with T2D. We performed survival genome-wide association study (GWAS) with patients with T2D in the UK Biobank (UKBB), Partners HealthCare Biobank (PBB), and Korean Genome and Epidemiology (KoGES) studies. The primary outcome of the study was a composite of myocardial infarction and stroke that occurred at least one year after the diagnosis of T2D. We conducted survival GWAS using ’GWASTools’ R package adjusting for age, and sex. The results of the three cohorts were meta-analyzed using inverse variance weighted method. A total of 19,121 participants were included in the analyses (15,643 from UKBB, 1,161 from PBB and 2,317 from KoGES). The incidence rate of CVD was higher in the hospital-based study of PBB (33.5%) compared to population-based studies of UKBB (9.5%), and KoGES (8.0%). Although there was no genetic association reaching genome-wide significance, there were four genomic loci that had suggestive association evidence for incident CVD with P<1.0x10-6. These include distinct variants in rs113067014 (intergenic) on chromosome 1 (chr1), rs1367414 (intron in PAX3) on chr2, rs11762253 (intron in AC004160.1) on chr7, and rs2837174 (intron in IGSF5) on chr21. When we investigated 184 previously validated coronary artery disease loci, 17 reached nominal significance of P<0.05 with consistent direction of association. A polygenic score (PS) comprised of these 184 variants was significantly associated with risk of CVD in T2D patients (HR 1.20 per s.d. increase in PS, P=6.6x10-16).

In summary, we have implemented survival GWAS analysis to investigate genetic risk factors for incident CVD in patients with T2D. However, further increase in sample size is required to identify molecular features leading to increased CVD risk among individuals with T2D.

Disclosure

S. Kwak: None. J.M. Mercader: None. A. Leong: None. B. Porneala: None. P. Wu: None. J.B. Cole: None. J. Merino: None. K. Park: None. N.H. Cho: None. J. Dupuis: Consultant; Self; Merck Sharp & Dohme Corp. J.C. Florez: Advisory Panel; Self; Doris Duke Charitable Foundation. Other Relationship; Self; Novo Nordisk Inc., Park Street School. J.B. Meigs: Consultant; Self; Quest Diagnostics.
1664-P: Macrophage-Derived Lipid Signaling Contributes to Type 1 Diabetes Development
Authors: ALMUTAIRI ABDULAZIZ , GAI YING , LEI XIAOYONG Y. , PARK MARGARET A. , CHALFANT CHARLES , RAMANADHAM SASANKA , STEPHENSON DANIEL
Published: June 2020

Type 1 diabetes (T1D) is a consequence of autoimmune-mediated destruction of pancreatic β-cells and the leading causes for this process are incompletely understood. Our previous work suggests the involvement of lipid signaling from immune cells on T1D development. Relevant lipids were shown to be generated by the Ca2+-independent phospholipase A2β (iPLA2β), which is ubiquitously expressed and hydrolyzes membrane phospholipids at the sn-2 position to release bioactive lysophospholipids and free fatty acids such as arachidonic acid. Arachidonic acid can be metabolized to generate eicosanoids, many of which are pro-inflammatory. We found that iPLA2β activation promotes pro-inflammatory M1 macrophage phenotype and that selective inhibition of iPLA2β preserves β-cell mass and reduces T1D incidence and insulitis in the NOD mice. Herein, we report that NOD macrophages generate significantly higher pro-inflammatory lipids and reduced anti-inflammatory lipids than C57 macrophages during the prediabetic phase. Such changes in the lipidome are mitigated with reduced expression of iPLA2β. Specifically, lipidomics analyses revealed that NOD.iPLA2β+/- macrophage production of multiple pro-inflammatory lipids (PGE2, leukotrienes, 12-HETE, DHETs) is decreased, and of anti-inflammatory lipids increased, relative to NOD-derived macrophages. The mitigated inflammatory lipid signature during the prediabetic phase the NOD.iPLA2β+/- contributed to a reduced T1D incidence. These findings suggest a role for macrophage iPLA2β-derived lipids (iDLs) in T1D development. In support, adoptive transfer of NOD.iPLA2β+/- macrophages reduced T1D incidence and improved glucose tolerance; and conditional knockout of iPLA2β in macrophages reduced T1D incidence in the NOD mice. We hypothesize that iDLs produced by macrophages contribute to T1D development and that these could be targeted to prevent onset/progression of T1D.

Disclosure

A. Almutairi: None. Y. Gai: None. X.Y. Lei: None. M.A. Park: None. C. Chalfant: None. S. Ramanadham: None. D. Stephenson: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK110292); National Institute of Allergy and Infectious Diseases (R21AI146743)
168-LB: Prediction for Risk-Stratified Care for Women with Gestational Diabetes: The PeRSonal GDM Study
Authors: COORAY SHAMIL , BOYLE JACQUELINE , SOLDATOS GEORGIA , ZAMORA JAVIER , FERNANDEZ-FELIX BORJA M. , ALLOTEY JOHN , THANGARATINAM SHAKILA , TEEDE HELENA
Published: June 2020

Objective: To develop and validate a prediction model for adverse pregnancy outcomes at the time of gestational diabetes (GDM) diagnosis to stratify care.

Research Design and Methods: A prediction model development and validation study was conducted on data from a retrospective population-based study. The outcome to be predicted was a composite for adverse pregnancy outcome: hypertensive disorder of pregnancy, large-for-gestational (LGA) age neonate, neonatal hypoglycaemia requiring intravenous therapy, shoulder dystocia, perinatal death, neonatal bone fracture and nerve palsy.

Results: Predictors of the composite adverse pregnancy outcome were: fasting and 1 hour glucose from the diagnostic OGTT, gestational age of GDM diagnosis, previous macrosomia, previous pre-eclampsia or eclampsia, previous LGA, ethnicity, weight at GDM diagnosis and parity. The apparent performance of the model was reasonable: c-statistic was 0.691 (95% CI, 0.662 - 0.720) and the calibration plot showed near perfect agreement between predicted and observed risks (Figure 1).

Conclusions: A promising prediction model for adverse pregnancy outcomes in women with GDM was developed. Model estimation using the Least Absolute Shrinkage and Selection Operator method is currently underway to correct for over-optimism. External validation and decision curve analysis will determine suitability for clinical application.

Disclosure

S. Cooray: None. J. Boyle: None. G. Soldatos: None. J. Zamora: None. B.M. Fernandez-Felix: None. J. Allotey: None. S. Thangaratinam: None. H. Teede: Other Relationship; Self; Roche Diagnostics France.

Funding

National Health and Medical Research Council of Australia (APP1151242); Australian Academy of Science; Diabetes Australia Research Program; Medical Research Future Fund of Australia; Australian Government Department of Education and Training (7167_2019)
1683-P: Upregulation of Pancreatic Islet EGF Receptor Improves Beta-Cell Identity and In Vivo Vascularisation in a Directly Observed Transplant Model
Authors: SALEM VICTORIA , ALI USAMA , SUBA KINGA , BITSI STAVROULA , LOPES TATIANA , ALONSO ALDARA MARTIN , PATEL YATEEN S. , LECLERC ISABELLE , OWEN BRYN , RUTTER GUY A. , ROTHERY STEPHEN M. , TOMAS ALEJANDRA
Published: June 2020

Aims: Long-term outcomes for islet transplantation remain suboptimal. An important determinant of islet transplantation success is vascularisation of engrafted islets. The epidermal growth factor receptor (EGFR) is a key angiogenic and pro-survival factor. In an in vivo mouse model, we investigated if EGFR overexpression in pancreatic islets improves engraftment.

Methods: Donor islets from C57BL/6 mice were infected with adenoviruses generated to encoding human EGFR alongside a GFP reporter. To assess the effects of EGFR over-expression on beta-cell identity and function, qPCR was run to determine expression of angiogenesis, beta-cell enriched and beta-cell disallowed genes compared with islets infected with control (empty vector) virus. To assess the effects of EGFR-overexpression on implantation in vivo, EGFR-overexpressing or control (empty vector) islets were transplanted into the anterior chambers of the eyes of syngeneic recipients. Using confocal microscopy, islet volume (GFP signal) and blood vessel density (following IV administration of dextran conjugated Texas Red) were assessed regularly and longitudinally over 30 days.

Results: qPCR results showed that EGFR-overexpressing islets had greater gene expression of angiogenic factors. Consistent with preserved beta-cell identity, beta-cell enriched genes were upregulated in EGFR-overexpressing islets compared to control islets, whilst beta-cell disallowed genes were repressed. EGFR-overexpressing islets demonstrating greater density compared to control islets at all time points (n=5 animals per group, 1-5 islets per eye, p<0.05).

Conclusion: We are the first to demonstrate that EGFR overexpression can promote the vascularisation of transplanted islets in vivo. The transcriptional profiling of these islets suggests an improved potential for beta-cell regenerative capacity and function.

Disclosure

V. Salem: None. U. Ali: None. K. Suba: None. S. Bitsi: None. T. Lopes: None. A. Martin Alonso: None. Y.S. Patel: None. I. Leclerc: Consultant; Spouse/Partner; Sun Pharmaceutical Industries Ltd. Research Support; Spouse/Partner; Servier. B. Owen: None. G.A. Rutter: Consultant; Self; Sun Pharmaceutical Industries Ltd. Research Support; Self; Servier, Sun Pharmaceutical Industries Ltd. S.M. Rothery: None. A. Tomas: None.

Funding

Diabetes UK (15/0005317)
1702-P: PRDM1 Is a Novel Regulator of Angiogenesis in Adipose Tissue
Authors: LIU YAO , QU SHEN , LI JIN
Published: June 2020

Adipose tissue is highly vascularized, and angiogenesis is a key process involved in regulation of tissues homeostasis and remodeling. Studies in the past have shown the importance of adipose angiogenesis in glucose and lipid metabolism. Prdm1 is a transcription factor participating immune response. Recent studies suggest Prdm1 is regulated by VEGF and important for the heart development. To test the changes of Prdm1 in adipose tissue under different physiological conditions, we challenged the C57BL/6 mice with fasting, coldness or high fat diet (HFD). Our results showed that Prdm1 mRNA level of inguinal fat was downregulated by fasting, coldness and long-term HFD. But it was upregulated when the mice were exposed to a short-term HFD. Overexpression of Prdm1 in Human Umbilical Vein Endothelial Cells (HUVEC) leads to alteration of angiogenic capabilities in vitro.

In conclusion, we propose Prdm1 as a novel regulator of angiogenesis. Prdm1 may play important roles in glucose and lipid metabolism.

Disclosure

Y. Liu: None. S. Qu: None. J. Li: None.

Funding

National Key Research and Development Program of China (2018YFC1314100); National Natural Science Foundation of China (81970677); Shanghai Natural Science Foundation (18ZR1435800)
1703-P: Altered UCP1 Expression in ADSC-Derived Beige Adipocytes Determines Mitochondrial ROS Production in T2DM Patients
Authors: MICHURINA SVETLANA , STAFEEV IURII , SKLYANIK IGOR , SHESTAKOVA EKATERINA , YURASOV ANATOLIY , YAHYAEV KAMIL , RATNER ELIZAVETA , MENSHIKOV MIKHAIL , SHESTAKOVA MARINA V. , PARFYONOVA YELENA V.
Published: June 2020

Background: Under normal physiological conditions, adipose derived stem cells (ADSC) maintain adipose tissue homeostasis by responding to metabolic loading through proliferation and differentiation. Nevertheless, in T2DM their properties might be compromised. ADSC give rise to thermogenic beige adipocytes that make a significant contribution into excess energy utilization in obesity. We compared ADSC response to beiging inductors in obese patients with type 2 diabetes mellitus (T2DM) and with normal glucose tolerance (NGT).

Methods: We collected subcutaneous fat biopsies from 5 obese NGT (BMI>35kg/m2) and 5 obese T2DM patients during bariatric surgery. ADSC were enzymatically isolated and underwent white and beige adipogenic differentiation. UCP-1 level was evaluated by RT-PCR and Western blot. Expression of lipid metabolism and electron transport chain (ETC) genes were analyzed by RT-PCR. ROS production was evaluated by fluorescent microscopy.

Results: UCP-1 expression was decreased in beige adipocytes from T2DM patients in mRNA and protein levels. Nevertheless, expression and phosphorylation of lipolytic proteins were equal in beige adipocytes of NGT and T2DM groups. Expression analysis of ETC genes also has not shown any statistically significant differences. All the while, we revealed increased mitochondrial ROS production in T2DM beige adipocytes during beige differentiation.

Conclusions: These results indicate association of ADSC thermogenic potential and T2DM development. Decreased UCP1 level in complex with normal lipolysis and ETC activity in beige adipocytes from T2DM patients may be liable to elevated ROS level, known to initiate mitochondria damage and insulin resistance.

Disclosure

S. Michurina: None. I. Stafeev: None. I. Sklyanik: None. E. Shestakova: Employee; Spouse/Partner; AstraZeneca. Speaker’s Bureau; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novartis Pharma K.K., Novo Nordisk A/S, Sanofi-Aventis, Takeda Pharmaceutical Company Limited. A. Yurasov: None. K. Yahyaev: None. E. Ratner: None. M. Menshikov: None. M.V. Shestakova: None. Y.V. Parfyonova: None.

Funding

Russian Science Foundation (17-15-01435)
1706-P: Ginsenoside Rb2 Improves Insulin Resistance by Inhibiting Adipocyte Pyroptosis
Authors: GU XUEJIANG
Published: June 2020

Pyroptosis plays a critical role in the development of obesity-associated inflammation and insulin resistantance (IR). Ginsenoside Rb2 (Rb2), the main component of ginsenosides has drawn appreciable interest in the context of glucose metabolism. In the present study, we investigated Rb2-mediated protection against obesity-induced IR and the related mechanisms. Rb2 could significantly reduce high-fat diet (HFD)-induced body weight changes, fat accumulation and IR. In addition, Rb2 treatment inhibited pyroptosis-related genes and proteins,such as caspase-1, ASC, NLRP3, IL-1β and GSDMD in HFD-fed mice. The above results were recapitulated in 3T3-L1 adipocytes and demonstrated that Rb2 improved TNF-α induced IR and pyroptosis in 3T3-L1 adipocytes. Furthermore, Rb2 reduced the phosphorylation levels of p65 and IκBα both in vitro and in vivo. The present study showed that Rb2, which could serve as a promising agent for the treatment of IR and obesity, ameliorated IR by inhibiting pyroptosis in adipocytes in vivo and in vitro through the NF-κB pathway.

Disclosure

X. Gu: None.

Funding

Zhejiang Provincial Natural Science Foundation (LY20H070003, LQ12H07003); Wenzhou Science and Technology Bureau (Y20170047); National Key Research and Development Program of China (2016YFC1305202)
1710-P: Maternal Supplementation of Tetrahydrobiopterin Regulates Differentiation of Fetal Brown Adipose Tissue and Contributes to Offspring Metabolic Health
Authors: MINAMINO HIROTO , FUJITA YOSHIHITO , OGURI YASUO , GOTO TSUYOSHI , OHASHI AKIKO , FURUYA FUTOSHI , ISOMURA NOZOMI , KOHEI TAKESUE , LI YING , KAWARASAKI SATOKO , KAWADA TERUO , HASEGAWA HIROYUKI , INAGAKI NOBUYA
Published: June 2020

Brown adipose tissue (BAT) is a key organ that produces heat and dissipates energy, and may be clinically relevant to the treatment of obesity and diabetes. Tetrahydrobiopterin (BH4) is an essential co-factor of tyrosine hydroxylase, a rate-limiting enzyme of catecholamine biosynthesis including that of norepinephrine (NA) and nitric oxide (NO) synthase. Although both NA and NO are well-known factors in BAT differentiation, the role of BH4 in the differentiation of BAT is poorly understood. We investigated the role of BH4 in differentiation of BAT using a mouse model of BH4 deficiency, the Hph-1 mouse. Hph-1 neonatal mice exhibit dysplasia of BAT as well as attenuated thermogenesis-related gene expressions (UCP1, Dio2, Pgc1a) compared with control mice. As differentiation capacity is considered to be at maximum during late gestation, we administered BH4 to fetal Hph-1 mice via placental transfer using intraperitoneal injection to pregnant Hph-1 mice for 6 days just before birth. Maternal BH4 supplementation ameliorated dysplasia of neonatal BAT and restored thermogenesis-related genes expression. Intriguingly, offspring of the maternal BH4-supplementation group showed less weight gain, ameliorated glucose intolerance, and improved cold tolerance after growth under high fat chow diet. We then evaluated the direct effect of BH4 on brown adipocyte differentiation using brown pre-adipocytes isolated from control and Hph-1 mice. Compared with control mice, brown pre-adipocytes from Hph-1 mice showed reduced differentiation capacity, while BH4 supplementation in brown pre-adipocytes from Hph-1 mice ameliorated differentiation capacity nitric oxide-dependently. Taking these findings together, BH4 plays an integral role in the differentiation of BAT, especially in the fetal period, and may represent a novel target for prevention of metabolic disorders such as obesity and diabetes.

Disclosure

H. Minamino: None. Y. Fujita: None. Y. Oguri: None. T. Goto: None. A. Ohashi: None. F. Furuya: None. N. Isomura: None. T. Kohei: None. Y. Li: None. S. Kawarasaki: None. T. Kawada: None. H. Hasegawa: None. N. Inagaki: Research Support; Self; Astellas Pharma Inc., Drawbridge Health, Japan Tobacco Inc., Kissei Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Life Scan Japan, Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Novo Nordisk Pharma Ltd.,, Sanofi K.K., Sanwa Kagaku Kenkyusho, Terumo Medical Corporation. Speaker’s Bureau; Self; Astellas Pharma Inc., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited.
1715-P: Impaired Postprandial Adipose Tissue Microvascular Blood Flow in Healthy People with a Family History of Type 2 Diabetes
Authors: ROBERTS-THOMSON KATHERINE , RUSSELL RYAN D. , HU DONGHUA , GREENAWAY TIMOTHY M. , BETIK ANDREW C. , PARKER LEWAN , RICHARDS STEPHEN M. , PREMILOVAC DINO , KESKE MICHELLE
Published: June 2020

Microvascular blood flow (MBF) enables the delivery of key nutrients (e.g., lipids and glucose) and hormones (e.g., insulin) to adipose tissue. We have demonstrated that adipose tissue MBF is impaired in people with type 2 diabetes (T2D), postprandially. Whether this also occurs in people at risk of T2D (having a family history of T2D) is unknown. Eighteen healthy people with no family history of T2D for two generations (FH-), and sixteen healthy people with at least one parent with T2D (FH+) were recruited. Overnight-fasted participants had a blood sample taken for clinical chemistries, a DEXA scan performed for body composition and underwent a mixed meal challenge (MMC, 300kCal; 54% carbohydrate, 29% protein and 16% fat). Microvascular blood volume (MBV), velocity (β) and MBF in truncal subcutaneous adipose tissue was assessed by contrast-enhanced ultrasound before and 60 min post-MMC. Both groups were matched for age, BMI, clinical chemistries and post-MMC area under the glucose time curve (Table 1). FH+ had higher truncal fat (Table 1). Increases in adipose tissue MBF post-MMC were lower in FH+ which was mostly attributed to a lower MBV (Table 1). Despite having normal clinical chemistries and blood glucose regulation, FH+ have impaired post-prandial adipose tissue MBF coinciding with greater central obesity which might in part explain their heightened risk for developing T2D.

Disclosure

K. Roberts-Thomson: None. R.D. Russell: None. D. Hu: None. T.M. Greenaway: Advisory Panel; Self; Eli Lilly and Company. Speaker’s Bureau; Self; AstraZeneca, Sanofi-Aventis. A.C. Betik: None. L. Parker: None. S.M. Richards: None. D. Premilovac: None. M. Keske: None.