bluuebunny/crossref_metadata_2025_split huggingface dataset:
344-OR: Persistent Treatment Gaps and Disparities in U.S. Diabetes Mellitus Care in 2005-2016
Authors: KAZEMIAN POOYAN , SHEBL FATMA M. , MCCANN NICOLE , WALENSKY ROCHELLE , WEXLER DEBORAH J. 
Published: June 2019

We sought to evaluate whether diabetes mellitus (DM) diagnosis, linkage to care, and meeting individual and combined treatment targets improved over time and to investigate potential disparities in U.S. DM care.
To do so, we derived percentages of diagnoses, linkage, and treatment goal achievement from NHANES in 2005-08, 2009-12, and 2013-16, and developed a logistic regression model adjusting for period, demographics, education, and health insurance.
In 2013-16, 74% of U.S. adults with DM were aware of their diagnoses; 70% were linked to DM care, 70% met HbA1c, 70% met blood pressure, 51% met cholesterol target, and 84% did not smoke. Twenty-one percent of patients achieved all treatment goals (Figure).
None of the individual and combined outcomes improved over the 3 study periods (p=0.08-0.98). Compared to middle-aged adults with DM (45-64y), older adults (≥65y) were more likely (OR 1.64, 95% CI 1.20-2.24) and younger adults (18-44y) were less likely (OR 0.50, 95% CI 0.28-0.90) to meet the combined goals. Women achieved the combined goals less often (OR 0.59, 95% CI 0.46-0.76). Reporting non-Hispanic black race (vs. non-Hispanic white race) was associated with reduced likelihood of achieving the combined goals (OR 0.59, 95% CI 0.42-0.82).
Despite major advances in DM medications and new care models, U.S. DM care has not significantly improved between 2005 and 2016.

Disclosure
P. Kazemian: None. F.M. Shebl: None. N. McCann: None. R. Walensky: Other Relationship; Spouse/Partner; Aileron. D.J. Wexler: Other Relationship; Spouse/Partner; APOLO1BIO.

Funding
Boston Area Diabetes Endocrinology Research Center; Steve and Deborah Gorlin MGH Research Scholar Award
350-OR: Disparities in Uptake of Guideline-Recommended Postpartum Diabetes Screening after GDM
Authors: BROWN SUSAN D. , TSAI AI-LIN , HEDDERSON MONIQUE M. , QUESENBERRY CHARLES , FERRARA ASSIAMIRA 
Published: June 2019

For women with GDM, ADA guidelines urge screening at 4-12 weeks postpartum via OGTT, given its superior sensitivity to detect diabetes. Yet data on screening uptake according to these guidelines is scarce. In a large California integrated health system, we evaluated uptake and predictors of guideline-recommended screening among 2,207 women (77% racial/ethnic minorities) diagnosed with GDM in 2011-2012. Overall screening uptake was 47.9% but varied by race/ethnicity (Figure). In a multivariable adjusted model, black race/ethnicity (odds ratio [OR], [95% CI]: 0.64 [0.44-0.95]) vs. white; having less than a college degree (0.67 [0.56-0.81]) vs. having at least a college degree; parity ≥2 (0.58 [0.45-0.74]) vs. 0; and higher pre-pregnancy BMI (0.97 [0.95-0.98] per unit increase) were associated with lower odds of screening uptake. In the same model, attending a postpartum medical visit (7.96 [4.36-14.5]); Chinese race/ethnicity (2.03 [1.41-2.92]) vs. white; greater years of age (1.04 [1.02-1.06] per unit increase); and greater gestational weeks at delivery (1.06 [1.02-1.10] per unit increase) were associated with higher odds of screening uptake. Postpartum screening uptake varies by patient characteristics in an integrated health system setting. Strategies to reduce barriers, especially among black and non-college educated women, present an opportunity to reduce downstream diabetes health disparities.

Disclosure
S.D. Brown: None. A. Tsai: None. M.M. Hedderson: None. C. Quesenberry: None. A. Ferrara: None.

Funding
Kaiser Permanente Northern California
352-OR: Maternal Triglycerides in Gestational Diabetes Are Strongly Associated with Increased Newborn Hepatic Fat Independent of Subcutaneous Fat
Authors: HERNANDEZ TERI L. , FARABI SARAH S. , HIRSCH NICOLE , DUNN EMILY Z. , HAUGEN ELIZABETH A. , BRUMBAUGH DAVID , BROWN MARK S. , FRIEDMAN JACOB E. , BARBOUR LINDA (LYNN) A. 
Published: June 2019

The incidence of childhood obesity continues to rise and alarmingly, 40% are already estimated to have nonalcoholic fatty liver disease (NAFLD), the leading cause of liver transplantation. An early origin exposure that contributes to NAFLD may be maternal obesity, diet, triglycerides (TG) and free fatty acids (FFA) in-utero, particularly in offspring of mothers with diabetes or gestational diabetes (GDM) who are at high risk for childhood metabolic disorders. In this pilot study, we explored the hypothesis that maternal TG in diet-controlled GDM (A1GDM) is associated with offspring intrahepatic lipid (IHL) accumulation. We randomized newly diagnosed A1GDM women (n=13, BMI 32±2 [mean±SEM]) to eucaloric diets at 32 weeks. Fasting and postprandial (PP) glucose, insulin, TG, FFA, and glycerol were measured in a breakfast test meal study (hourly x5) at baseline and 37 weeks. Newborn IHL content (Magnetic Resonance Spectroscopy; MRS) and body composition (%fat, PEAPOD) were measured at ~10 days. At 32 weeks, but not at 37 weeks, maternal fasting TG (199±17 mg/dL) and the 5-hour TG area-under-the-curve (AUC) were strongly associated with newborn IHL (r=0.69, p=0.01; r=0.75, p=0.003, respectively). The 1-hour and 2-hour PPTG (205-206±19-20 mg/dL) were highly associated with IHL (r=0.69-0.73; p≤0.01) as was the 5-hour glycerol AUC (r=0.65, p=0.01). There was no relationship between IHL and subcutaneous %fat by PEAPOD. We found no associations between maternal pre-pregnancy BMI, gestational weight gain (11±1.6 kg), glucose, insulin, or FFA and IHL. These data are the first in humans to support that maternal TG exposure at the time of GDM diagnosis, when fetal subcutaneous fat depots are early in development, may result in increased liver lipid deposition. If confirmed, MRS newborn liver fat measures and early interventions targeting maternal TG may be indicated to lower fetal liver fat deposition that could potentially be a developmental risk for pediatric NAFLD.

Disclosure
T.L. Hernandez: None. S.S. Farabi: None. N. Hirsch: None. E.Z. Dunn: None. E.A. Haugen: None. D. Brumbaugh: None. M.S. Brown: None. J.E. Friedman: Consultant; Self; Janssen Research & Development. L.A. Barbour: None.

Funding
National Institutes of Health
353-OR: Comparison of Methods for Classifying Heterogeneity in Gestational Diabetes (GDM) and Association with Outcomes
Authors: MCINTYRE DAVID , MADSEN LENE R. , GIBBONS KRISTEN S. , SACKS DAVID A. , MA RONALD C. , TAM WING H. , CATALANO PATRICK 
Published: June 2019

An underlying principle of the IADPSG GDM classification is that women at similar risk of adverse pregnancy outcomes related to hyperglycemia should be classified similarly. Powe et al have described heterogeneous GDM phenotypes related to impaired insulin secretion and/or insulin sensitivity and reported that pregnancy complications relate primarily to impaired insulin sensitivity. However, their Gen3G cohort was largely Caucasian and GDM women received treatment. Our study was designed to further examine this hypothesis in a diverse population of 6128 untreated women from 5 centers in the blinded epidemiologic HAPO study. Following similar methodology (Impairment = parameter value &lt;25th centile for non GDMs), women with IADPSG GDM were classified as (1) GDMsecr - impaired insulin secretion - using either HOMA β (Hβ) or Insulinogenic index (II); (2) GDMsens - impaired insulin sensitivity - using Matsuda index; (3) Both 1 and 2; (4) GDMND - No Defect. Analyses compared neonatal outcome frequencies (LGA, excess neonatal (NN) adiposity, NN hypoglycemia, NN hyperinsulinemia) with non GDM women and between GDM groups using χ2 tests and logistic regression analyses adjusted for multiple confounders including maternal age, height, smoking, FH of diabetes, BMI at the OGTT visit, ethnicity and HAPO study center. Hβ and II gave divergent results for GDMsecr, with only 25% concordance. GDMND women (10% of all GDM by Hβ, 6% by II) showed outcome frequencies similar to non GDM women. NN hypoglycemia was unrelated to GDM group. In all adjusted analyses, using either Hβ or II, Groups 1-3 showed higher odds (aORs 1.6-3.1; p &lt; 0.01 vs. non GDM) for LGA, NN adiposity and NN hyperinsulinemia. Although Hβ and II identify different women as having defects in insulin secretion, both may contribute to detection of a lower risk group of GDMND women. Beyond this, the division of women according to insulin secretion and insulin sensitivity status did not permit additional risk stratification.

Disclosure
D. McIntyre: None. L.R. Madsen: None. K.S. Gibbons: None. D.A. Sacks: None. R.C. Ma: Advisory Panel; Self; Boehringer Ingelheim International GmbH. Research Support; Self; AstraZeneca, Bayer AG, Pfizer Inc. Stock/Shareholder; Self; GemVCare. Other Relationship; Self; AstraZeneca. W.H. Tam: None. P. Catalano: None.
358-OR: Adiponectin, Leptin, and FGF-21 Levels in Adolescents Exposed and Not Exposed to Gestational Diabetes—Results from the Danish National Birth Cohort
Authors: KAMPMANN FREJA BACH , BAUN THUESEN ANNE CATHRINE , HJORT LINE , BJERRE METTE , FRYSTYK JAN , TETENS INGE , BJERREGAARD ANNE AHRENDT , CHAVARRO JORGE E. , OLSEN SJURDUR F. , DAMM PETER , VAAG ALLAN A. , GRUNNET LOUISE 
Published: June 2019

Background: Offspring of mothers with gestational diabetes mellitus (GDM) are at increased risk of developing metabolic diseases. Adipokines such as adiponectin and leptin may be involved in the underlying mechanisms. Fibroblast growth factor 21 (FGF-21) has recently been identified as a potent metabolic regulator. Therefore, we investigated the impact of fetal exposure to GDM on adiponectin, leptin and FGF-21 levels and their associations with metabolic and adiposity traits during adolescence.
Methods: A prospective study comparing 502 offspring of GDM exposed mothers and 535 offspring of non-exposed mothers. During a clinical exam of offspring, aged 9-16 years old, metabolic traits were measured and fasting blood samples collected and assayed for serum concentrations of leptin, adiponectin and FGF-21.
Results: GDM exposed offspring had 34% (95% CI: 18-51%) higher leptin levels, and 34% (95% CI: -48, -15%) lower FGF-21 concentrations than non-exposed offspring (p&lt;0.05), but no significant differences in adiponectin concentrations were found. These differences remained significant after adjusting for major confounders, including maternal pre-pregnancy BMI. Offspring leptin concentrations correlated positively with insulin and HOMA-IR, whereas adiponectin concentrations were inversely correlated (p&lt;0.05). Elevated leptin and decreased adiponectin concentrations correlated with all measures of adiposity, whereas FGF-21 correlated with total fat percentage only. In analyses stratified by offspring BMI z-score categories, GDM exposure had no significant effect on leptin and adiponectin concentrations.
Conclusion: GDM exposed offspring had higher leptin and lower FGF-21 concentrations than non-exposed controls, but this was driven by higher prevalence of adiposity among GDM offspring. The differential adipokine concentration does not seem to be the major driver behind the dysmetabolic phenotype among GDM offspring.

Disclosure
F.B. Kampmann: None. A. Thuesen: None. L. Hjort: None. M. Bjerre: None. J. Frystyk: None. I. Tetens: None. A.A. Bjerregaard: None. J.E. Chavarro: None. S.F. Olsen: None. P. Damm: Advisory Panel; Self; Novo Nordisk A/S. Other Relationship; Self; Novo Nordisk A/S. A.A. Vaag: Employee; Self; AstraZeneca. L. Grunnet: None.

Funding
Danish Council for Strategic Research; Innovation Fund, Denmark (09-067124, 11-115923); Novo Nordisk Foundation (NNF160C0022518); Danish Diabetes Academy
362-OR: Deletion of METTL14 in Beta Cells in Adult Mice Induces Diabetes Related to Increased ER Stress
Authors: MEN LILI , SUN JUAN , REN DECHENG 
Published: June 2019

N6-methyladenosine (m6A) is the most abundant mRNA modification. However, the role of m6A in regulating β-cell function is unknown. To address the functional role of METTL14, a key component of the m6A methyltransferase complex, in β-cells, we generated an METTL14 β-cell specific knockout mouse in adult MIP-CreERT transgenic mice. 4 weeks after tamoxifen treatment (100 mg/kg for 3 times every other day), the feeding glucose of βKO mice were 55.1% higher in βKO mice. βKO mice are also glucose intolerant. The AUC was increased by 54.7% in βKO mice (P&lt;0.01). The fasting glucose were 307.5 ± 24.3 mg/dl in βKO mice and 219.0 ± 7.8 mg/dl in control mice (P&lt;0.001). The response to insulin was similar between βKO and control mice. The feeding insulin levels in βKO mice were significantly decreased by 58.9% (P&lt;0.01). The serum insulin levels from βKO mice were significantly lower at 0, 15 and 30 minutes after glucose challenge. In addition, the insulin secretion from βKO islets was less than 50% of control islets after incubated at 16.7 mM glucose. Surprisingly, β-cell mass in βKO mice was 55.9% higher than that in control mice (P&lt;0.05). In addition, we did not detect β-cell death in βKO islets. However, β-cell proliferation in βKO islets was increased by 1.3-fold. To understand the molecular mechanism, we performed RNA-seq to detect the gene expression in βKO and control islets from male mice 8 weeks after tamoxifen treatment. Among 106 altered genes in βKO islets, 104 genes were upregulated (P&lt;0.001) and 2 genes were downregulated. The genes response to ER stress such as Pdia4, Itpr1, Thbs1, Ire1α and Igfbp5 were among the top up-regulated genes. We applied m6A-seq in MIN6 cells and confirmed that Ire1α was modified by m6A in its last exon and 3' UTR region. We further showed that both mRNA and protein of Ire1α and spliced XBP-1 were significantly increased in βKO islets.
In conclusion, METTL14 plays an important role in regulating insulin secretion, and METTL14 deficiency in β-cells induces diabetes by increasing ER stress.

Disclosure
L. Men: None. J. Sun: None. D. Ren: None.

Funding
National Institutes of Health (P30DK020595)
365-OR: The NLRP3 Inflammasome Mediates Early Beta-Cell Dysfunction Triggered by Islet Amyloid
Authors: DENROCHE HEATHER C. , KIM NAHAE , YAU KIANA , NACKIEWICZ DOMINIKA , ORBAN PAUL C. , SUEN IMELDA , VERCHERE CAMERON B. 
Published: June 2019

Islet amyloid, formed by islet amyloid polypeptide (IAPP) aggregates, may be a trigger of islet inflammation in T2D. In vitro studies using bone marrow-derived macrophages suggest roles for Toll-like receptor 2 (TLR2), and the NLRP3 inflammasome in mediating IAPP aggregate-induced inflammatory gene expression. To assess the impact of amyloid on islet macrophages in vivo, we performed single cell RNA sequencing on sorted islet immune cells from mice which develop islet amyloid via expression of human IAPP (hIAPP-Tg mice); this uncovered robust changes in islet macrophage populations, including upregulation of TLR2 (∼3.0 fold, p=0.002) and NLRP3 (∼2.8 fold, p=0.006) in proinflammatory macrophages. To test whether these receptors mediate IAPP aggregate-induced inflammation and beta cell dysfunction in vivo, we examined if TLR2 or NLRP3 deletion attenuated islet amyloid-induced beta cell dysfunction by crossing hIAPP-Tg mice to Tlr2-/- or Nlrp3-/- mice. Loss of TLR2 did not impact beta cell dysfunction in hIAPP-Tg Tlr2-/- male or female mice compared to hIAPP-Tg Tlr2+/+ littermates, revealing that TLR2 is not necessary for islet-amyloid driven beta cell pathology. In contrast, NLRP3 knockout improved glucose tolerance in young hIAPP-Tg male mice and delayed diabetes onset on high fat diet (HFD) (10.9 vs. 4.9 weeks; p=0.02) compared to hIAPP-Tg littermates with intact NLRP3. However, hIAPP-Tg Nlrp3-/- males eventually developed diabetes and glucose intolerance on long-term HFD. In female hIAPP-Tg mice, in which islet amyloid forms more slowly, NLRP3 deletion markedly improved glucose tolerance after 18 weeks of HFD relative to hIAPP-Tg Nlrp3+/+ controls (AUC: 886 ± 207 vs. 1854 ± 296, p&lt;0.0001). The glycemic benefit of NLRP3 knockout was not due to altered insulin sensitivity, and was absent in non-hIAPP expressing mice, which do not form amyloid. Thus, NLRP3, but not TLR2, mediates early islet amyloid-induced beta cell dysfunction, and may be a therapeutic target for islet inflammation in T2D.

Disclosure
H.C. Denroche: Advisory Panel; Self; Integrated Nanotherapeutics. N. Kim: Employee; Self; Integrated Nanotherapeutics. K. Yau: None. D. Nackiewicz: None. P.C. Orban: None. I. Suen: None. C.B. Verchere: Advisory Panel; Self; Sirona Biochem. Board Member; Self; Integrated Nanotherapeutics.

Funding
JDRF; Canadian Institutes of Health Research
371-P: Hypoglycemia in the Brain Is Required to Augment Counterregulatory Responses to Hypoglycemia when Liver Glycogen Levels Are Enhanced
Authors: WARNER SHANA O. , SMITH MARTA S. , FARMER BEN , WINNICK JASON J. 
Published: June 2019

In a previous study, we showed that elevated hepatic glycogen levels can generate a signal in the liver during insulin (INS)-induced hypoglycemia that is relayed to the brain, resulting in enhanced counterregulatory (CR) hormone secretion and net hepatic glucose output (NHGO). The purpose of this study was to determine whether hypoglycemia in the brain is required for this augmentation to occur. Fasted (18 hour) dogs were studied and each experiment began with a 4h glycogen deposition period in which each animal received somatostatin and basal intraportal infusions of both INS and glucagon (GGN). Plasma glucose (PG) was doubled by an intravenous (IV) glucose infusion and liver glycogen content was enhanced in all animals (76 ± 6 and 68 ± 4 mg/g in Brain EU and HYPO, respectively) by an intraportal infusion of fructose. A 2h control period followed, during which hyperglycemia and basal replacement of hormones were continued but fructose infusion was stopped. In the final 2h hypoglycemic period, somatostatin and GGN infusions were stopped and the plasma INS level was increased 16-fold by an IV infusion of INS. During the final period, whole body PG was clamped at 52 ± 1 mg/dL in one group (HYPO; n=6). In a second group, PG in the head was clamped at 92 ± 3 mg/dL by infusing glucose into the carotid and vertebral arteries (Brain EU; n=8) while the glucose level in the rest of the body remained at 51 ± 1 mg/dL. During the final hour of the hypoglycemic period, NHGO was lower in Brain EU compared to HYPO (0.8 ± 0.2 vs. 2.2 ± 0.4 mg/kg/minute, p&lt;0.01). This decrease in NHGO was associated with a decrease in CR hormone secretion, as GGN (27 ± 6 vs. 53 ± 8 pg/mL, p&lt;0.01) and epinephrine (451 ± 103 vs. 1106 ± 143 pg/mL, p&lt;0.01) were lower when the brain was euglycemic (Brain EU vs. HYPO, respectively). These data suggest that the augmented CR responses that occur during INS-induced hypoglycemia when liver glycogen content is enhanced, require hypoglycemia in the brain.

Disclosure
S.O. Warner: None. M.S. Smith: None. B. Farmer: None. J.J. Winnick: None.

Funding
National Institutes of Health
38-OR: Beta-Arrestin-1 Regulates Pancreatic Beta-Cell Function and Plays a Key Role in Maintaining Whole Body Glucose Homeostasis
Authors: BARELLA LUIZ F. , ROSSI MARIO , PYDI SAI PRASAD , JAIN SHANU , ZHU LU , CHEN WEI , WESS JÜRGEN 
Published: June 2019

Beta-arrestin-1 and -2 (barr1 and barr2, respectively) are major GPCR-associated signaling molecules that are widely expressed throughout the body. Studies with whole body barr1 and barr2 KO mice have shown that beta-arrestins play important roles in key metabolic functions. In this study, we inactivated the barr1 gene in a conditional fashion specifically in beta-cells of adult mice (beta-barr1-KO mice). In vivo studies showed that beta-barr1-KO mice exhibited a pronounced impairment in glucose tolerance and glucose-stimulated insulin secretion (GSIS), when mice were maintained on high-fat diet (HFD). Studies with isolated perifused pancreatic islets prepared from HFD beta-barr1-KO mice confirmed that barr1 deletion in beta-cells led to a significant decrease in GSIS. Interestingly, HFD beta-barr1-KO mice displayed pronounced reductions in beta-cell mass and the rate of beta-cell proliferation, suggesting that barr1 is required for the expansion of beta-cell mass that occurs during HFD feeding. To test whether enhanced barr1 signaling in beta-cells might ameliorate the metabolic deficits associated with the consumption of a HFD, we also generated transgenic mice over-expressing barr1 in beta-cells (RIPII-barr1 mice). These transgenic mice displayed metabolic phenotypes that were opposite to those observed with the beta-barr1-KO mice, including improved glucose tolerance and GSIS in vivo as well as increased beta-cell mass. This is the first study demonstrating that barr1 is critical for the proper function of pancreatic beta-cells and for maintaining whole body glucose homeostasis. Identification of the cellular mechanisms through which barr1 signaling promotes beta-cell function and proliferation may lead to the development of novel drugs useful for the treatment of type 2 diabetes.

Disclosure
L.F. Barella: None. M. Rossi: None. S. Pydi: None. S. Jain: None. L. Zhu: None. W. Chen: None. J. Wess: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases
380-P: Online CME Improves Clinical Knowledge/Competence Related to Managing T2D in Older Patients with Hypoglycemic Risk
Authors: LARKIN AMY , LACOUTURE MICHAEL , LE ANNE 
Published: June 2019

We sought to determine if online continuing medical education (CME) activities could improve the clinical knowledge/competence of primary care physicians (PCPs), diabetologists/endocrinologists (D/Es), and nurses/nurse practitioners (N/NPs) regarding the management type 2 diabetes (T2D) in older patients with hypoglycemia risk. The effect of two online, video-based CME activities were evaluated using knowledge/competence linked pre-/post-assessment questions. McNemar’s chi-squared test (P &lt;.05 indicates statistical significance) assessed educational effect. The activities launched between August 23, 2018 and November 1, 2018, and data were collected for 8 weeks each. In total, 202 D/Es, 1,192 PCPs and 5,480 N/NPs answered all pre-/post-assessment questions for at least 1 activity. Improvements were demonstrated among D/Es, PCPs, and N/NPs: Knowledge: 35% of D/Es (N=139, P&lt;.0001), 40% of PCPs (N=729, P&lt;.0001), and 42% of N/NPs (n=4119, P&lt; .0001) improved regarding insulin dosing when switching between insulin therapies Competence: 27% of D/Es (N=63, P=.0023), 33% of PCPs (N=463, P&lt;.0001), and 18% of N/NPs (n=1361, P&lt; .0001) improved related to selection of antihyperglycemic agent for an older T2D patient at risk of hypoglycemia 63% of D/Es (N=139, P&lt;.0001), 56% of PCPs (N=729, P&lt;.0001), and 43% of N/NPs (n=4119, P&lt; .0001) improved related to the most appropriate insulin dose for a given patient Continued educational gaps: • 32% of D/Es (N=63), 44% of PCPs (N=463), and 63% of N/NPs (n=1361) failed to select the most appropriate insulin for a patient at risk of hypoglycemia • 33% of D/Es (N=63), 37% of PCPs (N=463), and 43% of N/NPs (n=1361) failed to recognize the impact on hypoglycemia of switching basal insulin therapies This study demonstrates the success of online video-based CME on improving knowledge/competence in D/Es, PCP, and N/NPs related to managing T2D in older patients. Continued knowledge gaps were identified for future educational targets.

Disclosure
A. Larkin: None. M. LaCouture: None. A. Le: None.

Funding
Sanofi