bluuebunny/crossref_metadata_2025 huggingface dataset:
134-LB: Effectiveness and Safety of Empagliflozin in Routine Care Patients: Interim Results from the EMPagliflozin compaRative effectIveness and SafEty (EMPRISE) Study
Authors: PATORNO ELISABETTA , PAWAR AJINKYA , BESSETTE LILY G. , FRANKLIN JESSICA , NAJAFZADEH MEHDI , WEXLER DEBORAH J. , DERUAZ-LUYET ANOUK , BRODOVICZ KIMBERLY , SCHNEEWEISS SEBASTIAN
Published: June 2020

EMPRISE studies the effectiveness, safety and healthcare utilization of empagliflozin (EMPA), using data from Medicare and 2 U.S. commercial claims datasets (2014-2019). In an interim analysis on data from 2014-2017, we identified 39,169 pairs of 1:1 propensity score-matched patients ≥18 years with type 2 diabetes initiating EMPA or a DPP-4 inhibitor (DPP-4i). Effectiveness outcomes of interest were HHF [defined as a HF discharge diagnosis in the primary (HHF-Specific) or in any position (HHF-Broad)], a composite of MI and stroke, and all-cause mortality (Medicare only). Safety outcomes were lower-limb amputations (LLA), bone fractures, diabetic ketoacidosis (DKA), and acute kidney injury (AKI). We estimated pooled HR and 95% CI adjusting for >140 baseline covariates. Compared to DPP-4i, EMPA had a reduced risk of HHF [HHF-Specific: 0.46 (0.30-0.73); HHF-Broad: 0.63 (0.51-0.77)], a similar risk of MI or stroke [HR (95% CI) = 0.89 (0.73-1.09)], and a reduced risk of all-cause mortality [0.52 (0.36-0.76) in Medicare. Over a mean follow up of 178 days, EMPA was associated with a decreased risk of AKI [(0.64 (0.53-0.77)], an increased risk of DKA [1.56 (1.00-2.44)], and a similar risk of LLA and fractures (Table 1). In routine care, EMPA had an effectiveness profile consistent with RCT findings and safety outcomes in line with documented information.

Disclosure

E. Patorno: Other Relationship; Self; Boehringer Ingelheim International GmbH. A. Pawar: None. L.G. Bessette: None. J. Franklin: None. M. Najafzadeh: None. D.J. Wexler: Other Relationship; Self; Novo Nordisk A/S. A. Deruaz-Luyet: Employee; Self; Boehringer Ingelheim International GmbH. Employee; Spouse/Partner; Sanofi-Aventis Deutschland GmbH. K. Brodovicz: Employee; Self; Boehringer Ingelheim Pharmaceuticals, Inc. S. Schneeweiss: None.

Funding

Boehringer Ingelheim
1342-P: BMI from Birth to Age 10 Years by Types of Maternal Diabetes during Pregnancy
Authors: SIDELL MARGO A. , CHOW TING , MARTINEZ MAYRA P. , KOEBNICK CORINNA , PAGE KATHLEEN A. , BUCHANAN THOMAS A. , XIANG ANNY
Published: June 2020

Limited studies have assessed longitudinal growth among children exposed to different types of diabetes in-utero. We assessed BMI from birth to age 10 years in offspring of mothers who had pre-existing type 1 (T1D) or type 2 (T2D), gestational diabetes mellitus (GDM) or no diabetes during pregnancy. GDM was further divided into GDM managed with (GDM with meds) or without (GDM no meds) diabetes medication. More than 3.5 million BMI measurements were obtained from medical records of 218,227 singleton children born at 28-44 weeks gestation from 2008 to 2015. Relationships between BMI, age and diabetes exposure were modelled using random effects mixed models with quadratic B splines adjusted for maternal age, race/ethnicity, education, household income, pre-pregnancy BMI, gestational weight gain, maternal comorbidity, and child’s sex. At birth, the adjusted BMI had small differences among groups except for T1D which had the highest BMI [diff=0.4; 95%CI 0.2-0.6 kg/m2 relative to no diabetes]. After birth, the adjusted BMIs were comparable between T1D and T2D exposed. At about 48 months, the growth pattern started separating with highest BMI in T1D and T2D groups, followed by GDM with meds, GDM no meds and no diabetes groups (Figure). Thus, despite standard diabetes management, there exists a hierarchical BMI pattern in offspring exposed to different types of diabetes even after adjusting for important covariates, starting as early as age 4.

Disclosure

M.A. Sidell: None. T. Chow: None. M.P. Martinez: None. C. Koebnick: None. K.A. Page: None. T.A. Buchanan: None. A. Xiang: None.
1344-P: Metabolomics Reveals Broad Scale Metabolic Changes in Gestational Diabetes
Authors: LIU YU , KUANG ALAN , BAIN JAMES R. , GEORGE TABITHA , ILKAYEVA OLGA , MINCEY ADAM , MUEHLBAUER MICHAEL , LOWE LYNN P. , METZGER BOYD E. , NEWGARD CHRISTOPHER B. , SCHOLTENS DENISE , LOWE WILLIAM
Published: June 2020

Studies examining metabolites in GDM have been small with inconsistent results. To address this, we used targeted metabolomics to examine levels of 65 metabolites in a cohort of 3457 mothers from the Hyperglycemia and Adverse Pregnancy Outcome Study, of whom 547 were retrospectively diagnosed with GDM using IADPSG criteria. GDM was untreated. Metabolomics assays were performed on fasting and 1 hr serum samples collected during an oral glucose tolerance test (OGTT) at ∼28 weeks gestation. Differences in metabolite levels in women without and with GDM were determined using linear regression with adjustment for field center as well as maternal age, gestational age, height, mean arterial pressure, parity, smoking (yes/no), drinking (yes/no) and BMI at the OGTT and false discovery rate correction. Women with GDM had higher levels of a broad array of fasting metabolites, including branched chain amino acids (BCAA) and their metabolic byproducts, aromatic and other amino acids, triglycerides, non-esterified fatty acids and lipid byproducts, and medium- and long-chain acylcarnitines (ACs). Similar differences were seen 1 hr after a glucose load, except for higher levels of a broader array of ACs but lower levels of arachidonoyl carnitine in women with GDM. Prior studies categorizing women with GDM into those with normal and low insulin sensitivity demonstrated differences in maternal and newborn outcomes between groups. Compared to women with GDM and normal insulin sensitivity, women with GDM in the lowest quartile of insulin sensitivity had higher levels of BCAAs and their metabolic byproducts, aromatic amino acids, triglycerides, and lactate but lower levels of 3-hydroxybutyrate (3-HB) and multiple ACs. A generally a similar pattern was seen 1 hr after glucose except for no change in 3-HB. Together these data demonstrate broad scale perturbations in metabolites in women with GDM and differences across subgroups of women with GDM that may contribute to maternal and fetal complications related to GDM.

Disclosure

Y. Liu: None. A. Kuang: None. J.R. Bain: None. T. George: None. O. Ilkayeva: None. A. Mincey: None. M. Muehlbauer: None. L.P. Lowe: None. B.E. Metzger: None. C.B. Newgard: None. D. Scholtens: None. W. Lowe: None.
1355-P: Association between Glycated Hemoglobin and Glycemia during First Trimester of Pregnancy
Authors: FARO FERNANDA , RAMALHO RODRIGO F. , PRIETO WESLEY H. , PEREIRA MARIANA , SALLES JOAO E. , ROSA PEDRO S. , TELES MILENA G. , TAVARES RUSSO PEDRO DE SÁ
Published: June 2020

Background: first trimester glycemia ≥ 92 mg/dL is a valid criterion for diagnosis of gestational diabetes mellitus (GDM), excluding the requirement of Oral Glucose Tolerant Test (OGTT) later in pregnancy. Glycated Hemoglobin (A1C), is well stablished for diagnosis of diabetes mellitus, however its utility in the screening of GDM is not certain. The aim of this study was to associate A1C and glycemia values in the first trimester of pregnancy.

Methods: this was an observational retrospective study that included Brazilian women screened with A1C until 20 weeks of gestation between January 2009 and March 2019. Data were collected from a laboratory center. A1C was estimated by high-performance liquid chromatography. Exclusion criteria were hemoglobin < 11.0 and use of antidiabetic drugs or insulin. Women were divided into groups according to first trimester glycemia: <70; 70-85; 85-92; 92-126; ≥ 126 mg/dL. Primary outcome was association between A1C and glycemia values.

Results: a total of 17.764 women were included. The majority was in the 70-85 mg/dL group (9.689), followed by 85-92 mg/dL (5.420), 92-126 mg/dL (2.178), < 70 mg/dL (436) and ≥ 126 mg/dL (41). Means’ age were: 32.5 ± 4.79 (<70 mg/dL); 33.8 ± 4.14 (70-85 mg/dL); 34.2 ± 3.9 (85-92 mg/dL); 34.7 ± 4.03 (92-126 mg/dL) and 31.4 ± 3.46 years (≥ 126 mg/dL). Means’ Body Mass Index (BMI): 24.5 ± 2.68 (<70 mg/dL); 25.2 ± 3.88 (70-85 mg/dL); 25.8 ± 4.5 (85-92 mg/dL); 27.6 ± 4.83 (92-126 mg/dL) and 27.3 ± 2.59 years (≥ 126 mg/dL). A1C means were very similar in the first four groups: 4.92% ± 0.41 (<70 mg/dL); 5.01% ± 0.32 (70-85 mg/dL); 5.15% ± 0.32 (85-92 mg/dL) and 5.33% ± 0.42 (92-126 mg/dL). The group with glycemia ≥ 126 mg/dL presented A1C mean of 7.08% ± 1.49, significantly higher than all the other groups (p < 0.01 by Kruskal-Wallis test).

Conclusion: in this study, A1C values were not accurate to the screening of GDM in the first trimester of pregnancy. The main difference was in the group with glycemia ≥ 126 mg/dL, already defined as overt diabetes.

Disclosure

F. Faro: None. R.F. Ramalho: None. M. Pereira: None. J.E. Salles: Board Member; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Novo Nordisk Inc. P.S. Rosa: None. M.G. Teles: None. P. de Sá Tavares Russo: None.
1357-P: Gestational Diabetes Mellitus: Postpartum Metabolic Outcome and Risk Factors Involved
Authors: BARAN JESICA D. , ARANGUREN MARCELA I. , TAPPER MARIA X. , PAREDES MARIA S. , GENTILE MARIA BELEN , GRUD VALERIA , FERNANDEZ SANCHEZ MARY R. , NOGUEIRA JUAN PATRICIO , BOQUETE HUGO R.
Published: June 2020

Gestational diabetes mellitus (GDM) is a highly prevalent clinical entity that prospectively allows to identify a population of women with a high risk of developing type 2 diabetes mellitus (T2DM). The rate of persistent metabolic abnormalities after delivery and the evidence regarding risk factors related are limited and variable.

Objectives: 1) To describe the prevalence of carbohydrate metabolism (CHM) abnormalities after childbirth in Argentine women with GDM. 2) To categorize risk factors involved in such abnormalities.

Methods: During the last 5 years, 165 women with diagnosis of GDM (according to ADA criteria) were evaluated. Patients with diagnosed or suspected pregestational diabetes, clinical relevance comorbidities and those in treatment with hyperglycemic drugs were excluded. FPG and 2-hours plasma glucose during a 75-g OGTT were performed from 6 weeks postpartum.

Results: In the reassessment, 106 women (64.2%) had normal parameters (NP) and 59 (35.8%) showed impared glucemic metabolism (IGM): IGT in 18, IFG in 25, both abnormalities in 13 and 3 developed T2DM. In the IGM group, 74.6% were 30 yr or older while in the NP group only 52.8% (p=0.006). In women with pathologic reevaluation, 18.5% had a history of previous GDM compared to 4.8% in the other group (p=0.005). In patients with IGM, 62.5% showed pre-pregnancy BMI ≥ 27 vs. 44.3% in those with NP (p=0,039). A logistic regression analysis was performed to identify the pregnancy factors that independently predict IGM. As expected, age ≥ 30 yr (OR 4.05, 95%CI 1.01-15.08) and previous GDM (OR 11.35, 95%CI 1.22-104.86) were associated significantly (p=0.037).

Conclusions: In our population, the analysis showed a high prevalence of CHM abnormalities following GDM. We found a higher risk for IGM in patients who had a history of previous GDM, age ≥ 30 yr and BMI ≥ 27. We therefore believe it is important to categorize risk factors in order to establish preventive therapeutic actions, particularly in cases with greater vulnerability.

Disclosure

J.D. Baran: None. M.I. Aranguren: None. M.X. Tapper: None. M.S. Paredes: None. M. Gentile: None. V. Grud: None. M.R. Fernandez Sanchez: None. J. Nogueira: None. H.R. Boquete: None.
1360-P: Infertility Is Not Associated with Clinical Factors in Women with Type 1 Diabetes (T1D)
Authors: ERKIN-CAKMAK AYCA , BAILEY RYAN , CALHOUN PETER , CAKMAK HAKAN , WONG JENISE C.
Published: June 2020

Previous studies have shown adolescents with T1D diagnosed prior to menarche have an older age of menarche compared with those diagnosed after menarche and to the general population, and menstrual irregularity in women with T1D is more common than in those without T1D, suggesting that T1D may be associated with reproductive abnormalities. In this study, multiple regression models were used to explore the relationship between clinical factors and markers of reproductive health in 3528 women >18 years (mean age 39±17 years) in the T1D Exchange Clinic Registry who had a 5-year follow-up. Average age of menarche was 13±2 years, and 13% reported irregular menstrual periods unrelated to pregnancy or menopause. Younger age at T1D diagnosis was significantly associated with older age at menarche (p=0.001) after adjustment for race/ethnicity, current BMI, and report of severe hypoglycemia (SH). Having an evaluation for infertility was reported by 6% of participants and was associated with lower mean hemoglobin A1c (A1c; OR 0.79, 95% CI 0.67-0.91 for a 1% increase in A1c) and current use of continuous glucose monitoring (CGM, OR 1.58, 95% CI 1.16-2.16). Seeking an infertility evaluation was not significantly associated with age at T1D diagnosis, autoantibody status, or current menstrual regularity. Additionally, having an abnormal infertility evaluation was not associated with mean A1c (OR 0.85, 95% CI 0.62-1.17) or current use of CGM (OR 1.62, 95% CI 0.91-2.91). There were also no factors that were both clinically and statistically significantly associated with miscarriage or problems conceiving a child. These results suggest that women with T1D who are likely to seek infertility evaluations may be more determined to maintain optimal glycemic control with technology such as CGM, or that concern about fertility may drive the decision to use CGM and lower A1c. This study highlights the need for prospective studies to assess the impact of T1D on fertility in women.

Disclosure

A. Erkin-Cakmak: None. R. Bailey: None. P. Calhoun: Stock/Shareholder; Self; Dexcom, Inc. H. Cakmak: None. J.C. Wong: Consultant; Self; pH Pharma. Research Support; Self; Dexcom, Inc.

Funding

The Leona M. and Harry B. Helmsley Charitable Trust (G-2016PG-T1D053)
1362-P: Influence of Ethnicity on the Association between Body Mass Index and Prevalence of Gestational Diabetes
Authors: READ STEPHANIE , BERGER HOWARD , FEIG DENICE , FLEMING KAREN , RAY JOEL G. , SHAH BAIJU R. , LIPSCOMBE LORRAINE
Published: June 2020

Gestational diabetes (GDM) prevalence increases with increasing body mass index (BMI), and evidence suggests that the association may vary by ethnicity. Using a cross-sectional study, we examined the association between BMI and GDM by ethnicity. Data were obtained from administrative health datasets for all of Ontario, Canada. Using a validated algorithm, we identified Chinese and South Asian maternal ethnicity; all others were categorized as the general population. GDM was ascertained through hospital and claims records. The study population consisted of women without pre-existing diabetes who had a livebirth between April 2012 and March 2014. The relation between pre-pregnancy BMI and GDM was modeled using adjusted logistic regression, stratified by ethnicity. The study population consisted of 231,618 women, of whom 10,895 (4.7%) developed GDM. The prevalence of GDM was 9.9% among South Asians, 8.2% among Chinese and 4.3% of the general population of women. Compared to a normal BMI, having an overweight BMI (25-30 kg/m2) was associated with a higher aOR of GDM among Chinese (1.96, 95% CI: 1.50-2.56), South Asian (1.87, 1.47-2.36) and the general population of women (1.84, 1.69-2.01) (Figure). GDM prevalence is considerably higher across all levels of BMI in South Asian and Chinese women compared with the general population, suggesting the need for an ethnicity-specific screening approach for GDM.

Disclosure

S. Read: None. H. Berger: None. D. Feig: Advisory Panel; Self; Novo Nordisk A/S. Speaker’s Bureau; Self; Medtronic. K. Fleming: None. J.G. Ray: None. B.R. Shah: None. L. Lipscombe: None.

Funding

Diabetes Action Canada (PSI19-23)
1365-P: Type 2 Diabetes after Gestational Diabetes, a High-Risk Population
Authors: WOOD ANNA , BOYLE JACQUELINE , BARZI FEDERICA , BARR ELIZABETH L. , HARE MATTHEW J.I. , TITMUSS ANGELA , DEATH ELIZABETH , KIRKWOOD MARIE , SIMMONDS ALISON , MOORE ELIZABETH M. , OATS JEREMY , MCINTYRE DAVID , ZIMMET PAUL Z. ,   ESQ., BROWN ALEX D. , SHAW JONATHAN E. , MAPLE-BROWN LOUISE J.
Published: June 2020

Aboriginal and Torres Strait Islander women have high rates of gestational diabetes (GDM). The Pregnancy And Neonatal Diabetes Outcomes in Remote Australia (PANDORA) study is a prospective longitudinal cohort of women with type 2 diabetes (T2D), GDM or normoglycemia in pregnancy in the Northern Territory, Australia. In this analysis we report progression to prediabetes and T2D at 2.5 years [range 2.1, 3] postpartum in a subgroup of Aboriginal and Europid women with GDM and normoglycemia in pregnancy (n=337). Women with pre-existing T2D were excluded. Data were analysed using Fisher’s exact tests. Among Aboriginal women with GDM we assessed predictions for progression using multivariate logistic regression. Aboriginal women with GDM (n=111) were younger than Europid women with GDM (n=104) (29 years (SD 5.9) vs. 32 (5.6) p<0.01), with similar first trimester BMI (28.9 kg/m2 (SD 7.2) vs. 28.5 (6.7) p=0.64). Of Aboriginal women with GDM, 24 (22%) progressed to T2D and 12 (11%) to prediabetes. Of Aboriginal women with normoglycemia (n=60), 1 (2%) progressed to T2D and 1 (2%) to prediabetes (p<0.01 for combined outcome vs. GDM women). Of Europid women with GDM, none progressed to T2D and 4 (4%) to prediabetes and of those with normoglycemia (n=62) none progressed to diabetes or prediabetes (p=0.09 vs. GDM women). Among Aboriginal women with GDM, factors associated with postpartum diabetes or prediabetes were age (OR 1.11, 1.03-1.2) and, after adjusting for age: severity of GDM (higher fasting plasma glucose (per 1 mmol/L OR 2.11, 1.23-3.62), use of insulin (OR 3.20, 1.35-7.6)) and higher first trimester BMI (per 3 kg/m2 OR 1.22, 1.01-1.47). Not smoking was protective (OR 0.35, 0.14-0.90), although any breastfeeding at 6-months postpartum was not (OR 0.95, 0.36-2.47). To our knowledge this is the only prospective study of Aboriginal and Torres Strait Islander women with GDM. We report the highest rates in the world of T2D after GDM at 2.5 years postpartum, highlighting a need for targeted interventions in this high-risk population.

Disclosure

A. Wood: None. J. Boyle: None. F. Barzi: None. E.L. Barr: None. M.J.I. Hare: None. A. Titmuss: None. E. Death: None. M. Kirkwood: None. A. Simmonds: None. E.M. Moore: None. J. Oats: None. D. McIntyre: Other Relationship; Self; Novo Nordisk A/S. P.Z. Zimmet: None. A.D. Brown: None. J.E. Shaw: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Mylan, Sanofi. Research Support; Self; AstraZeneca. Speaker’s Bureau; Self; Eli Lilly and Company, Mylan. L.J. Maple-Brown: None.
1367-P: Risk and Indications for Cesarean Delivery among Women with Diabetes in the United States
Authors: GRASCH JENNIFER , MILLER KATHERINE , HAAS DAVID , TUULI METHODIUS , SCIFRES CHRISTINA M.
Published: June 2020

Women with diabetes are at increased risk for cesarean delivery, but there is a paucity of data examining practice patterns associated with indication for cesarean delivery among women with and without diabetes. We conducted a secondary analysis of the Consortium on Safe Labor data to evaluate cesarean delivery practices among women with gestational diabetes (GDM) and pregestational diabetes in a large U.S. cohort.

Of the 191,174 women, 9,791 (5.1%) had GDM and 2,792 (1.4%) had pregestational diabetes. The overall cohort cesarean delivery rate was 30%. After adjusting for covariates, cesarean delivery rates were higher for women with GDM (28 vs. 45%, aOR 1.44, 95% CI 1.36-1.54) and pregestational diabetes (28 vs. 59%, aOR 2.21, 95% CI 1.99-2.46). Women with GDM and pregestational diabetes were more likely to undergo pre-labor cesarean delivery. Because indications for cesarean delivery may differ by maternal parity, stratified analyses were performed in nulliparous and multiparous women by diabetes type. Elective cesarean delivery and cesarean delivery for macrosomia were more common among women with diabetes, while cesarean delivery for failure to progress was less likely (Table). These data suggest that encouraging an attempt of vaginal delivery in women with diabetes and no contraindications may be one strategy to reduce the risk for cesarean delivery in this high-risk population.

Disclosure

J. Grasch: None. K. Miller: None. D. Haas: None. M. Tuuli: None. C.M. Scifres: None.
1375-P: Gestational Diabetes–Associated Changes in the Circulating Exosomes in Fetal Circulation Revealed a Potential Role of These Nanovesicles in Fetal Growth and Metabolism
Authors: ORMAZABAL VALESKA , SCHOLZ-ROMERO KATHERIN , NAIR SOUMYALEKSHMI , GUANZON DOMINIC , ZUNIGA FELIPE , MCINTYRE DAVID , LAPPAS MARTHA , SALOMON CARLOS
Published: June 2020

The link between metabolic disorders during pregnancy and high risk of developing chronic noncommunicable diseases in later life has been well established. However, why the fetuses exposed to GDM have a higher risk of abnormal glucose homeostasis in later life, is still not fully understood. Exosomes have been well characterised in maternal circulation in normal and gestational diabetes pregnancies, however, the little is known about the profile of exosomes in fetal circulation. In this study, we isolated exosomes from cord-blood from women with normal tolerance glucose (NGT, n=35) and GDM (n=40) at the time of delivery. The miRNA content of exosomes was determined using a small RNA sequencing. The levels of circulating exosomes were significantly higher in GDM compared to NGT (p<0.05). Linear regression analysis identified a positive association between fetal length, maternal BMI and the levels of circulating exosomes in GDM, while no significant association was observed for NGT. Analysis of the miRNA within exosomes identified a range of miRNAs differentially expressed between NGT and GDM samples. Principal component analysis reveals a separation of the groups based on their miRNA profile. The miRNA contributing the most to this separation between normal and GDM conditions is miR-22-3p, thus this miRNA may be a key candidate for future GDM diagnostic strategies. Gene Ontology analysis shows that the miRNAs identified in exosomes regulate genes involved in insulin secretion in response to glucose stimulus, insulin receptor signalling, and glucose homeostasis. Thus, these data suggest that exosomes may alter gene expression and ultimately the cell phenotype by transferring specific miRNAs to target cells.

Disclosure

V. Ormazabal: None. S. Nair: None. D. Guanzon: None. F. Zuniga: None. D. McIntyre: Other Relationship; Self; Novo Nordisk A/S. M. Lappas: None. C. Salomon: None.

Funding

Diabetes Australia; Fondo Nacional de Desarrollo Científico y Tecnológico (1170809, 1190522)
138-LB: First-in-Human Study of YG1699, an SGLT1 and SGLT2 Dual Transporter Inhibitor
Authors: LI CHENGHAI , LI TONG , LEE FRANK , XU ROGER H. , WANG HELEN
Published: June 2020

YG1699 is an orally-delivered, small molecule drug candidate that inhibits both the sodium glucose transporter 1 (SGLT1, IC50 = 16.6 nM) and the sodium glucose transorter 2 (SGLT2, IC50 = 1.49 nM). In the preclinical studies, YG1699 could suppress plasma glucose increases following acute glucose challenges in rat oral glucose tolerance tests, and decrease plasma glucose levels in db/db mice in a dose dependent manner. YG1699 can suppress intestinal glucose absorbance and increase both urine and fecal glucose excretion. In addition, YG1699 could significantly increase plasma GLP-1 and PYY levels in animal models. In this upcoming conference, we would like to report our first-in-human clinical trial for YG1699. This clinical study was conducted in USA (Identifier: NCT03953092) with 64 healthy volunteers participated in this single ascending dose (SAD) and multiple ascending dose (MAD) as well as food effect studies. In this Phase 1 clinical trial, YG1699 was well tolerated at all dose levels and produced a dose-dependent increase in urinary glucose excretion in both SAD and MAD studies. YG1699 also demonstrated a very good pharmacokinetic profile with linear, and dose-dependent exposure. The data also show that YG1699 has adequate half-life that can support once daily dosing in Phase II clinical trials. Adverse events were low and generally mild and no SAEs were observed.

Disclosure

C. Li: None. T. Li: None. F. Lee: None. R.H. Xu: None. H. Wang: Board Member; Self; Youngene Therapeutics. Stock/Shareholder; Self; Youngene Therapeutics.
138-OR: Elevated Triglycerides as a Risk Factor for Postpartum Abnormal Glucose Metabolism in Chinese Women with Previous Gestational Diabetes
Authors: LAI MENGYU , FANG FANG , WANG YUFAN
Published: June 2020

Background: Whether elevated triglyceride (TG) levels during pregnancy can affect postpartum glucose metabolism in women with previous gestational diabetes mellitus (GDM) remained unknown. The aim of this study was to investigate the association between TG levels during the second trimester and postpartum abnormal glucose metabolism (AGM) in GDM women.

Methods: This was a retrospective cohort study including 513 GDM women. A 75 g oral glucose tolerance test (OGTT) was performed, and lipid levels were determined during pregnancy and the postpartum period. GDM patients were categorized into tertiles according to their TG levels at 24-28 weeks of gestation (TG<2.14 mmol/L, TG: 2.14-2.89 mmol/L and TG>2.89 mmol/L). A logistic regression model was used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs).

Results: During pregnancy, women in the high TG tertile showed higher HbA1c levels (5.47±0.58% versus 5.28±0.49%, p=0.006), higher total cholesterol (TC) levels (5.85±1.23 mmol/L versus 5.15±0.97 mmol/L, p=0.026) and higher HOMA-IR [2.36 (1.62-3.45) versus 1.49 (0.97-2.33), p<0.001] than the participants in the low TG tertile. After delivery, the prevalence rates of postpartum AGM based on above tertiles of TG levels during pregnancy were 26.90%, 33.33% and 43.27%, respectively (p=0.006). High TG tertile during the second trimester was associated with postpartum AGM (adjusted OR: 1.869, 95% CI: 1.104-3.165, p=0.020).

Conclusions: The elevated TG levels during pregnancy were not only accompanied by higher glucose and lipid levels and more severe insulin resistance at the time of the measurement, but were risk factors for postpartum AGM as well.

Disclosure

M. Lai: None. F. Fang: None. Y. Wang: None.

Funding

National Natural Science Foundation of China (81870610); Shanghai Science and Technology Commission Foundation (18411968800); Shanghai General Hospital (CTCCR-2018C13)
1384-P: Changes in OGTT-Based Measures of Insulin Secretory Response across Pregnancy
Authors: POWE CAMILLE E. , LOCASCIO JOSEPH J. , CATALANO PATRICK
Published: June 2020

Background: We previously showed that insulin response to an IV glucose load increases in early pregnancy, independent of changes in insulin sensitivity. It is unknown whether oral glucose tolerance test (OGTT)-based measures of insulin secretory response (ISR) capture the same phenomenon.

Methods: This is a secondary analysis of a longitudinal study. Participants (N=31) were studied pre-pregnancy and in early (12-14 wks) and late (34-36 wks) gestation. On separate days, after overnight fasts, an OGTT (75g pre-pregnancy/100g in pregnancy) and an hyperinsulinemic-euglycemic clamp were performed. We calculated Insulinogenic index (IGI), Corrected insulin response (CIR), insulin/glucose area under the curve (AUCins/AUCglu), and Stumvoll 1st Phase Estimate (Stumvoll) from OGTT insulin and glucose levels. Linear mixed effects models examined ISR in early as compared to pre- and late pregnancy; we adjusted p-values for 2 comparisons. Adjusted models included insulin sensitivity, measured with the clamp, as a time-dependent covariate.

Results: IGI (adjusted mean ± SEM) increased between pre- and early pregnancy (1.25 ± 0.13 vs. 1.52 ± 0.15, P<0.05) and remained stable between early and late pregnancy (1.41 ± 0.14, P=0.42). Findings did not change after adjustment for insulin sensitivity (pre:1.29 ± 0.13 vs. early: 1.59 ± 0.16, P=0.03; early vs. late: 1.31 ± 0.16, P=0.32). Changes in CIR were similar. AUCins/AUCglu increased from pre- to early pregnancy (0.47 ± 0.05 vs. 0.55 ± 0.05 P=0.03) and increased further from early to late pregnancy (0.79 ± 0.07, P<0.01). The increase in AUCins/AUCglu between pre- and early pregnancy was independent of changes in insulin sensitivity (0.50 ± 0.04 vs. 0.66 ± 0.05, P<0.01), but the increase between early and late pregnancy (0.65 ± 0.07) was not apparent after adjusting for insulin sensitivity (P>0.99). The results for Stumvoll were similar.

Conclusion: OGTT-based ISR indices capture an insulin sensitivity-independent augmentation of insulin secretion in early pregnancy.

Disclosure

C.E. Powe: None. J.J. Locascio: None. P. Catalano: None.

Funding

National Institutes of Health (K23DK113218); Robert Wood Johnson Foundation; Harold Amos Medical Faculty Development Award
1389-P: Low Muscle Mass and Risk of Development of Type 2 Diabetes in Korean Women with Previous Gestational Diabetes Mellitus
Authors: SHIN YUJIN , OH TAE JUNG , CHOI SUNGHEE , JANG HAK CHUL
Published: June 2020

Objective: The purpose of this study is to evaluate if low muscle mass increases risk of T2D in women with previous gestational diabetes mellitus (pGDM).

Methods: A total of 378 women with pGDM (mean age: 35.6 ± 3.9 years) was prospectively evaluated for incidence of T2D. GDM was diagnosed with 75g or 100g oral glucose tolerance test (OGTT) during 24-28 week gestational age. Reclassification of glycemic status was performed with 75g OGTT at 2 months after delivery and lean body mass (LBM) was assessed with bioelectrical impedance analysis (Inbody720, Seoul, Korea). LBM was divided by BMI and this index was divided into 3 tertiles: lowest ≤0.88 (N=107), middle 0.89-0.97 (N=111), highest ≥0.98 group (N=99). The primary outcome was incidence of T2D up to 1 year follow up.

Results: The lowest muscle group developed T2D (p=0.007) more than higher muscle groups. The trend for risk developing prediabetes and T2D was significantly increased according to LBM/BMI tertiles (p for trend=0.002). After adjusting family history of T2D, extent of gestational hyperglycemia and waist circumference, lowest group demonstrated HR for developing T2D 6.6 [CI 1.36 to 32.25], p=0.01, compared to the highest group.

Conclusion: Lower muscle mass is an independent risk factor for T2D in pGDM. Therefore, it is important to examine muscle mass during risk assessment for T2D in Korean non-obese women with pGDM.

Disclosure

Y. Shin: None. T. Oh: None. S. Choi: None. H. Jang: Speaker’s Bureau; Self; Daiichi Sankyo, Handok, Pfizer Inc., Takeda Pharmaceutical Company Limited.
140-LB: Effect of Vaginal Estrogen as Hormone Replacement Therapy for Menopause on SGLT2 Inhibitor–Associated Urinary Tract Infection: A Prospective Cohort Study
Authors: GAUTAM ASHISH , AGRAWAL PRABHAT K. , PURSNANI NIKHIL , RANI RUCHI
Published: June 2020

Introduction: Estrogen deficiency after menopause is an important predisposing factor for recurrent UTI (r UTI). Vaginal application of estrogen as “hormone replacement therapy (eHRT)” for prevention of menopause associated r UTI has moderate recommendation and evidence level grade B by AUA/CUA/SUFU guidelines 2019. Glycosuria with use of SGLT 2I among T2DM, increase risk of r UTI by 4-9%. SGLT2 I use among T2DM, post-menopausal females may further increase risk of r UTI.

Aim and Objective: This study was designed to observe (1) the Risk and frequency of UTI due to SGLT2 I among post-menopausal females with T2DM and (2) Preventive effect of vaginal e HRT for r UTI among them.

Methods: Forty-two, post-menopausal females having T2DM, using vaginal e HRT were selected as cases whereas controls were 38 matched females not using e HRT. Subjects in both groups were prescribed SGLT2 I considering eligibility and simultaneously adjusted the doses of other OHA’s or insulin to maintain the glycemic targets. They were targeted to follow for 12 months and evaluated periodically for symptomatic UTI and maintenance of glycemic targets. Diagnosis of symptomatic UTI was made using standard definition and guidelines.

Result: The 42 cases who were using vaginal e HRT (M = 2.5, SD = 1.5) compared to the 38 controls who were not using e HRT (M = 3.5, SD = 1.6) demonstrated significantly lesser frequency of UTI, t (78) = -2.56, p = .012. All the episodes of symptomatic UTI among cases were uncomplicated whereas 1 episode of UTI among 4 comparators forced for withdrawal of SGLT2 I and exclusion from observation period. The Fisher exact test statistic value is 0.0467. The result is significant at p < .05.

Conclusion: Estrogen HRT after menopause significantly reduces the frequency of UTI among T2DM females using SGLT2 I. Not using eHRT in these group of subjects may significantly increase risk of complicated UTI.

Disclosure

A. Gautam: None. P.K. Agrawal: None. N. Pursnani: None. R. Rani: None.
140-OR: Inhibition of Serotonin 2c Receptor Internalization Potentiates Lorcaserin Effect on Body Weight Loss
Authors: HE YANG , LIU HAILAN , XU YONG
Published: June 2020

As a body weight management medicine, lorcaserin, a selective agonist of serotonin 2C receptor (5-HT2CR) which is a G protein-coupled receptor, fails to maintain its effect on body weight loss after a long term administration. Thus, it is necessary to find a way to strengthen its effect on obesity treatment. It has been reported that the effect of lorcaserin on body weight loss is by activating Pro-opiomelanocortin (POMC) neurons in the arcuate nucleus (ARH). However, how POMCARH neuron activity changes after long term lorcaserin treatment remains unknown. In the present study, we found that POMCARH neurons cannot maintain its sensitivity to further lorcaserin stimulation after a long term lorcaserin treatment. By using in vitro electrophysiology recording and c-Fos immunostaining in the brain slice from control mice, we found that acute lorcaserin application significantly increased POMCARH neuron activity. However, this activation effect significantly decreased in mice with lorcaserin administration for consecutive 20 days. By in vivo fiber photometry calcium recording, we found that lorcaserin significantly increased POMCARH neuron activity in vivo at first day, but this activation effect decreased after 10 days lorcaserin treatment and almost disappeared after 20 days lorcaserin treatment. We further showed that this desensitization of POMCARH neurons to lorcaserin stimulation is mainly due to a beta-arrestin-mediated excessive internalization of 5-HT2C receptor in POMCARH neurons. Barbadin, a novel selective β-arrestin/adaptor protein 2 interaction inhibitor, maintains POMCARH neuron sensitivity to further lorcaserin stimulation by blocking prolonged lorcaserin-induced aberrant 5-HT2C receptor internalization. Co-treatment with barbadin also prolongs lorcaserin’s effect on body weight loss and food intake reduction in mice. Overall, our results may provide a potential strategy for facilitating obesity treatment by lorcaserin.

Disclosure

Y. He: None. H. Liu: None. Y. Xu: None.
1400-P: Rural/Urban Residence and Race/Ethnicity Differences in All-Cause Mortality Trends among Medicare Beneficiaries with Diabetes, 2001-2016
Authors: BULLARD KAI M. , ANDES LINDA J. , SAYDAH SHARON , ROLKA DEBORAH B. , MERCADO CARLA , IMPERATORE GIUSEPPINA , BENOIT STEPHEN R.
Published: June 2020

To examine rural/urban and racial/ethnic differences in all-cause mortality from 2001-2016 among older U.S. adults with diabetes, we used Medicare claims data linked to the National Death Index. We identified beneficiaries aged ≥67y who were enrolled in fee-for-service (FFS) plans with diabetes. Rural/urban residence was based on the 2016 Medicare core-based statistical area classification. Race/ethnicity was classified as: non-Hispanic white (NHW), non-Hispanic black (NHB), Asian/Pacific Islander (API), and Hispanic (HISP). Rates were age-/sex-standardized to the 2001 FFS population. From 2001 to 2016, there were absolute declines in mortality in all rural/urban and racial/ethnic subgroups (all p<0.001; Figure). By 2016, mortality rates were higher among rural residents (vs. urban) for all racial/ethnic groups (rate ratios: NHW [1.07 (1.06-1.08)]; NHB [1.05 (1.03-1.08)]; API [1.20 (1.09-1.32)], HISP [1.09 (1.05-1.13)]). Reductions in mortality were relatively consistent among rural HISP and API residents (p-trend<0.05); while rates plateaued after 2007 for NHW and after 2011 for NHB rural residents. Among urban residents, reductions in mortality slowed (NHB [2010]; API [2007]) or stalled (NHW [2009]; HISP [2010]) at varying times. Future research may be helpful in addressing mortality disparities in this diverse, aging population.

Disclosure

K.M. Bullard: None. L.J. Andes: None. S. Saydah: None. D.B. Rolka: None. C. Mercado: None. G. Imperatore: None. S.R. Benoit: None.
1403-P: Glycemic Control Levels Are Not Major Determinants of Accumulation of AGE
Authors: MIZUSHIRI SATORU , DAIMON MAKOTO , MURAKAMI HIROSHI , KAMBA AYA , MURABAYASHI MASAYA , NISHIYA YUKI
Published: June 2020

Objective: Chronic hyperglycemia increases glycation as well as oxidization, and, thus, facilitates production of advanced glycation end products (AGEs), whose accumulation is involved in the pathophysiology of diabetic complications. Although association between AGE and insulin resistance has been reported thoroughly, association between AGE and insulin secretion has not been well examined, especially in relation with age.

Research Design: Among participants of the population-based Iwaki study of Japanese held in 2014, those who attended the Iwaki study consecutively in 2014 and 2015 were enrolled in this study (n=518; model A), and we excluded fasting blood glucose levels <63 and >140 to calculate HOMA-β and IR (n=489; model B). We used skin autofluorescence as AGE, and also measured blood levels of Pentosidine and urine albumin-to-creatinine ratio.

Results: 1. AGE levels significantly increased from 1.93±0.52 to 1.97±0.44 (p=0.014) in the 1 year period.

2. Regression analysis showed correlations between ∆AGE (change in AGE in the 1 year period) and age, BUN, FPG and log10uACR in model A, and, age, log10uACR, and log10HOMA-ß in model B. However, these correlations became none-significant after adjustment for multiple factors mentioned above as well as factors representing glucose control levels such as HbA1c, except for age in models A and B, respectively.

3. Subjects were stratified into tertiles (mildly, moderately, rapidly progress) based on their ∆AGE, Logistic analysis revealed the aging is a significant risk for the accumulation of AGE (rapidly progress) (OR: 1.02. 95%CI: 1.01-1.03). ROC analysis showed the age of 60 as an optimal cut-off value for determining the risk subjects for the increase in AGE (OR: 1.74, 95%CI: 1.20-2.51).

Conclusions: The accumulation of AGEs may increase with increasing speed, which becomes rapid over the age of 60 independent of glycemic levels, uACR and HOMA-ß, indicating that not glycemic control levels but aging per se is a major contributor for AGE accumulation.

Disclosure

S. Mizushiri: None. M. Daimon: None. H. Murakami: None. A. Kamba: None. M. Murabayashi: None. Y. Nishiya: None.
1404-P: Association with Insulin Resistance and Sarcopenia: The Korean Frailty and Aging Cohort
Authors: CHOE HUN JEE , KIM KYUHO , OH TAE JUNG , CHOI SUNGHEE , PARK KYONG SOO , JANG HAK CHUL
Published: June 2020

Introduction: Previous studies demonstrated that older adults with diabetes had lower skeletal muscle mass, strength, and physical function compared with those without diabetes. The aim of this study is to evaluate the effect of hyperglycemia and insulin resistance in the progression of sarcopenia in older adults with diabetes.

Methods: The Korean Frailty and Aging Cohort Study is a multicenter prospective study with a baseline examination measured in 2016-2017. Longitudinal analysis was conducted with the 2018 follow up data. The difference of muscle related variables over the two years was evaluated for both genders and stratified by the presence of diabetes and insulin resistance.

Results: Among the 1,515 participants with baseline and two-year follow-up examination on skeletal muscle mass, strength, and function, 327 (21.6%) had diabetes mellitus at baseline. Participants showed decline in ASM, ASM/height2, ASM/body mass index (BMI), gait speed, and Timed Up and Go (TUG) test regardless of diabetes status over the two years (all p<0.001). In men with higher HOMA-IR (≥1.11), the decline of muscle mass indices (p<0.001), and TUG test (p=0.002) was significantly greater than men with lower HOMA-IR (<1.11). Women with higher HOMA-IR also showed greater decline in hand grip strength (p=0.040) gait speed (p=0.035), muscle mass indices (p<0.005), and TUG test (p=0.010) than women with lower HOMA-IR. None of the variables were significantly different when compared according to the baseline HbA1c level. In subjects without diabetes, the decline of muscle mass indices was significantly greater in subjects with higher HOMA-IR compared to those with lower HOMA-IR, but muscle strength and function were not affected by insulin resistance.

Conclusion: Insulin resistance shows preponderating influence over hyperglycemia in progression of sarcopenia in Korean older adults. This result suggests that insulin sensitizer might be beneficial in prevention of sarcopenia in older adults with diabetes.

Disclosure

H. Choe: None. K. Kim: None. T. Oh: None. S. Choi: None. K. Park: None. H. Jang: Speaker’s Bureau; Self; Daiichi Sankyo, Handok, Pfizer Inc., Takeda Pharmaceutical Company Limited.
1409-P: Diabetes Development in Adults with Cardiovascular Disease: Age Matters
Authors: CIGOLLE CHRISTINE , BLAUM CAROLINE , SZYMONIFKA JACKIE , KABETO MOHAMMED , HA JINKYUNG , ZHONG JUDY
Published: June 2020

The epidemiology of diabetes (DM) and subsequent development of cardiovascular disease (CVD) is well-studied. Less is known about the development/course of DM in adults with preexisting CVD. We hypothesized that incidence of DM in these adults varies by age. We analyzed waves 1993-2014 of the Health and Retirement Study, a nationally-representative health survey. Our study sample included adults ≥50 years (n=27,650) not having CVD or DM at entry. Age of CVD-onset was defined as age when respondent first reported CVD diagnosis. We classified adults who developed CVD into 3 age of CVD-onset groups (years): 50-59, 60-69, ≥70. For each group, we constructed a propensity-score-matched control group of respondents not having CVD. We compared risk of developing DM for each age of CVD-onset group and its matched control. Of all respondents, 683 developed CVD at 50-59 years, 1,609 at 60-69, and 3,253 at ≥70; 22,105 never developed CVD. Adults diagnosed with CVD at 50-59 years had substantial increased risk of DM: incidence risk ratio (IRR) 1.5 (1.1, 2.0). CVD diagnosis at 60-69 years also had increased risk of DM: IRR 1.2 (1.0, 1.5). CVD diagnosis at ≥70 years had no increased risk of DM: IRR 1.1 (0.9, 1.4). (Figure) Age of CVD diagnosis differentially impacts the risk of subsequent development of DM in middle-age and older adults. The relationship between DM and CVD is complex, with the role of prevalent CVD on DM incidence/course incompletely understood.

Disclosure

C. Cigolle: None. C. Blaum: None. J. Szymonifka: None. M. Kabeto: None. J. Ha: None. J. Zhong: None.

Funding

National Institutes of Health (AG054467-01)
1417-P: Lipoprotein(a)-Associated Residual Atherosclerotic Cardiovascular Disease Risk in Patients with Cardiovascular Disease on Statin Therapy by Diabetes Status
Authors: ZHAO YANGLU , SUNG JENNIFER C. , BROWNE AURIS , WONG NATHAN D.
Published: June 2020

Background: The relation between elevated lipoprotein(a) [Lp(a)] and future atherosclerotic cardiovascular disease (ASCVD) in those with vs. without diabetes mellitus (DM) but known cardiovascular disease (CVD) is not clear. We examined recurrent ASCVD event risk by DM status in persons with known CVD on statin therapy.

Methods: We studied 1,354 patients with and 2,005 patients without DM, all with prior CVD on statin therapy in the AIM-HIGH cohort. First and total recurrent ASCVD event rates were calculated by Lp(a) levels and the PWP model provided hazard ratios (HRs) for events over a mean follow-up of 3.3 years, adjusted for age, sex, trial treatment, LDL-C, and other risk factors.

Results: ASCVD event rates (per 1000 person years) increased with Lp(a) levels ranging from <15 mg/dl to ≥70 mg/dL in non-DM: 39.7 to 74.1 for first and 48.5 to 87.3 for total recurrent events and in DM: 51.1 to 79.5 for first and 69.8 to 100.3 for total recurrent events. The Table shows HRs by Lp(a) categories for first and total recurrent ASCVD events. A higher risk for first recurrent events is noted at lower Lp(a) levels in those with vs. without DM.

Conclusions: Higher Lp(a) levels predict residual ASCVD risk. However, ASCVD event risk may occur at lower levels of Lp(a) in those with vs. without DM. Future investigations in larger cohorts are needed to confirm these findings.

Disclosure

Y. Zhao: None. J.C. Sung: Employee; Self; Novartis Pharmaceuticals Corporation. A. Browne: Employee; Self; Novartis Pharmaceuticals Corporation. N.D. Wong: Advisory Panel; Self; Esperion Therapeutics, Inc. Research Support; Self; Amarin Corporation, Amgen, Boehringer Ingelheim Pharmaceuticals, Inc., Novartis AG, Novo Nordisk Inc. Speaker’s Bureau; Self; Amarin Corporation, Sanofi.
1422-P: Different Diagnostic Criteria for Diabetes and Risk of Cardiovascular Disease in the Greenland Inuit
Authors: BYBERG STINE , TVERMOSEGAARD MARIA , DÍAZ LARS , SENFTLEBER NINNA K. , LARSEN CHRISTINA V.L. , RØNN PERNILLE F. , BJERREGAARD PETER , PEDERSEN MICHAEL L. , JØRGENSEN MARIT E.
Published: June 2020

Introduction: Diabetes prevalence in Greenland is high and increasing. Diabetes can be diagnosed by different criteria; currently HbA1c levels ≥ 48 mmol/mol, fasting plasma glucose (FPG) ≥ 7.0 mmol/l and/or two-hour plasma glucose (2hPG) ≥ 11.1 mmol/l after an oral glucose tolerance test (OGTT). We compared the risk of cardiovascular disease (CVD) by different diagnostic criteria, in the Greenland Inuit. Methods: Participants included in the population-based Inuit Health in Transition (IHIT) study in Greenland (2005-2010), had HbA1c, FPG and 2hPG levels measured at entry. We followed participants in the Danish and Greenlandic health registers for a composite endpoint of non-fatal and fatal CVD until 31/12-2017. Participants with known diabetes (n=77) and previous CVD (n=140), were excluded. We compared incidence rates for different diagnostic criteria, adjusted for various clinical and sociodemographic confounders in separate Poisson regressions, using multiple imputations for missing data and split follow-up into 1-year age-bands to account for a non-constant effect of age.

Results: We included 2,898 adult participants, with 246 CVD events and 366 deaths during follow-up. In the crude analyses, incidence rate ratios (IRR) of CVD were highest among participants diagnosed by HbA1c (IRR:2.69; 95%CI (1.66-4.34)), followed by participants diagnosed by FPG (2.04 (1.27-3.27)), and both FPG and 2hPG (1.96 (1.31-2.94)), compared with normoglycemia. The IRR for all three diagnostic criteria were attenuated after confounder adjustment (HbA1c 1.14 (0.70-1.88); FPG: 0.81 (0.50-1.30); FPG and 2hPG: 0.78 (0.51-1.18)).

Conclusions: IRR of CVD were highest among participants diagnosed by HbA1c in the crude analyses. None of the diagnostic criteria were associated with CVD after adjustment, especially for age. Future studies will investigate other diabetes related complications, competing risks from death, and interactions with genetic variants in the Greenland population.

Disclosure

S. Byberg: None. M. Tvermosegaard: None. L. Díaz: None. N.K. Senftleber: None. C.V.L. Larsen: None. P.F. Rønn: Research Support; Self; Amgen, Danish Diabetes Academy. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. P. Bjerregaard: None. M.L. Pedersen: None. M.E. Jørgensen: Research Support; Self; Amgen, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi-Aventis. Stock/Shareholder; Self; Novo Nordisk A/S.