bluuebunny/crossref_metadata_2025_split huggingface dataset:
114-OR: Evidence for Alterations in Salience Processing in People with Type 1 Diabetes and Impaired Awareness of Hypoglycemia
Authors: JACOB PETER , OSBORNE CONSTANCE E. , ZELAYA FERNANDO , AMIEL STEPHANIE A. , CHOUDHARY PRATIK 
Published: June 2019

Resting state networks are functionally connected neurons that show similar low-frequency blood oxygen-level dependent (BOLD) signal oscillations. The salience network (SN) is crucial for switching between two other networks: the default mode network (DMN) and the central executive network (CEN). The DMN is active when the brain is not cognitively engaged; the CEN is active when the brain is engaged in a specific task. We hypothesized that impaired awareness of hypoglycemia (IAH) in people with type 1 diabetes (T1D) would be associated with disruption of the integrity of the salience network at hypoglycemia.
Methods: Fourteen nondiabetic (ND), 15 T1D with normal awareness of hypoglycemia (NAH) and 22 T1D with IAH participants, matched for age and T1D duration, underwent a two-step hypoglycemic clamp. Resting state BOLD functional magnetic resonance image (fMRI) time series were obtained, one at 90 mg/dL, one at 47 mg/dL. Images were analyzed using the CONN toolbox in SPM12. We used the right anterior insula (AI) as a seed region for the SN in a seed to voxel analysis.
Results: The SN was identified in all three groups at euglycemia. At hypoglycemia ND and NAH had brisk symptom response and altered coupling between SN and regions associated with the DMN: precuneus (ND p &lt;0.01) and pregenual anterior cingulate cortex (ACC, NAH p &lt;0.01), IAH had lower symptoms and no change in SN coupling. Mean symptom increase at hypoglycemia was 15.3 (ND and NAH) and 1.5 (IAH, p&lt;0.00001). A 2x2 mixed ANOVA interaction between aware groups (HC and NAH n=29) and IAH (n=22) showed differences in connectivity reduction between the ACC and AI at hypoglycemia (pFEW-Corr=0.04).
Conclusions: During hypoglycemia, reduced connectivity between SN and DMN, seen in ND and NAH, may be an important switch for hypoglycemia recognition, facilitating protective behavioral responses. Lack of SN connectivity change may underpin impaired awareness and failure of appropriate responses to hypoglycemia seen in IAH.

Disclosure
P. Jacob: None. C.E. Osborne: None. F. Zelaya: None. S.A. Amiel: None. P. Choudhary: Advisory Panel; Self; AstraZeneca, Insulet Corporation, Medtronic, Roche Diabetes Care, Sanofi. Speaker's Bureau; Self; Eli Lilly and Company, Novartis AG, Novo Nordisk Inc., WebMD.
1165-P: In Vitro Actions of a Novel Biguanide (BIG), NT1195, That Support Its Use in T2D
Authors: LIVINGSTON JAMES N. , COBB JEFFERY E. , BROWN KATHLEEN K. , KAVANAGH KYLIE , BATCHELOR KENNETH W. 
Published: June 2019

Metformin, a frontline treatment for T2D, is a BIG drug with low potency and limiting side effects. To overcome these limitations, we examined a compound library of 265 novel BIGs by screening these agents against five organic cationic transporters (OCTs) (OCTs 1, 2 and 3, PMATE and MATE1), an approach based on the need of OCTs for BIG cell entry and action. mRNA expression data from vervet monkey liver, fat and muscle showed OCT1, OCT3, PMAT and MATE1 were the predominate transporters and were used to guide our search for more potent and selective BIGs. BIG transport activity was measured by a decrease in oxygen consumption rate (OCR) in HEK 293 cells that express a single OCT and the results reported as EC50 values. Following the screening, we identified NT1195 from its EC50 transport values of 25, 5, 12, 3 and 57 uM respectively for OCT1, 2 and 3, PMAT and MATE1 when compared to those for metformin of 409, 320, 133, 288 and 5,993 uM. Other cellular effects of NT1195 were then examined in human adipocytes and myotubes, and in H4-lle liver cells. AMPK activation, a basic feature of BIG action, was increased by 6-fold over basal by NT1195 in fat cells versus a 3-fold increase by metformin; the EC50 values were respectively 78 uM and 4,928 uM. NT1195 stimulated AMPK in myotubes by 3-fold with an EC50 of 1,994 uM; metformin stimulation AMPK by 1.8-fold with an EC50 of 7,817 uM. Both agents produced a 2-fold activation of AMPK in H4-II e cells but with different EC50 values of 641 uM for NT1195 and 5,576 uM for metformin. Glucose production by H4-IIe cells was inhibited 90% by both BIGs, whereas the EC50 values were 32 nM for NT1195 and 285 uM for metformin. NT1195 inhibited lipolysis in human fat cells stimulated by isoproterenol by 90% with an EC50 of 286 uM while metformin inhibited lipolysis by 66% with an EC50 of 4,360 uM. Therefore overall, these findings demonstrate the much greater potency of NT1195 over metformin and supports its potential as an improved therapeutic for T2D.

Disclosure
J.N. Livingston: Consultant; Self; CohBar, Inc. Employee; Self; NovoTarg Therapeutics. J.E. Cobb: Consultant; Self; NovaTarg Therapeutics. K.K. Brown: None. K. Kavanagh: Research Support; Self; Takeda Development Centre Europe Ltd. K.W. Batchelor: None.

Funding
National Institutes of Health
1266-P: Diabetes INSIDE: Improving Population HbA1c Testing and Targets in Primary Care with QI
Authors: FURMAN ROY E. , HARLAN TIMOTHY S. , LEBLANC LESLEY , FURMAN ELISE , FONSECA VIVIAN 
Published: June 2019

As a participant in the ADA’s Diabetes INSIDE program, a 19-member multidisciplinary QI team identified care quality gaps after reviewing 6 years (1/2010 to 5/2016) of EHR data on 3,136 T2DM outpatients seen by 190 PCPs in an urban academic medical center. The team set goals to increase HbA1c testing frequency (reduce 45% of patients with HbA1c intervals &gt; 6 months) and to reduce HbA1c levels in both the overall population and patients with HbA1c &gt; 9%. Implemented strategies included 1) a provider outreach program of departmental and individualized actionable data reports of HbA1c testing intervals and outcomes, 2) a patient outreach program to address individual timely follow-up care, 3) a patient awareness campaign to improve understanding of following and improving clinical outcomes, 4) improving structured EHR data capture to improve population monitoring, and 5) standardizing workflow across clinics for pre-visit planning, patient outreach, patient education, checking completion of appointment goals, and post-visit follow-up.
Eight-years of EHR follow-up data (1/2010 to 5/2018) on 7,798 patients (mean age 61 years, 57% female, 62% black, 97% insured) with 136,004 visits showed target improvements. Population characteristics were stable over time. A department-stratified Cox proportional hazards model controlling for age, gender, race, and HbA1c level showed a statistically signification 20% reduction in HbA1c testing intervals &gt; 6 months (HR = 1.20±0.07). Statistical process control charts (6 years pre- and 2 years post-intervention) showed statistically significant 15.5% relative improvement in the patient proportion with HbA1c &gt; 9% from 13% to 11% following QI interventions and a significant 2.1% improvement of population mean HbA1c from 7.4% to 7.2%.

Disclosure
R.E. Furman: None. T.S. Harlan: None. L. LeBlanc: None. E. Furman: None. V. Fonseca: Board Member; Self; American Association of Clinical Endocrinologists. Consultant; Self; Abbott, Asahi Kasei Corporation, Novo Nordisk Inc., Sanofi US, Takeda Pharmaceutical Company Limited. Research Support; Self; Bayer US. Stock/Shareholder; Self; Amgen Inc., BRAVO4HEALTH, Mellitus Health.

Funding
Eli Lilly and Company; Novo Nordisk; Sanofi
1307-P: Real-World Health-Care Costs Impacted by Diabetes Mellitus (DM) among Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis (NAFLD/NASH) Patients with Advanced Liver Diseases (AdvLD)
Authors: WONG ROBERT , KACHRU NANDITA , MARTINEZ DIANE , MOYNIHAN MEGHAN , OZBAY A. BURAK , GORDON STUART 
Published: June 2019

Objective: Comorbidities such as DM accelerate the progression of NAFLD/NASH to AdvLD [compensated cirrhosis (CC)/decompensated cirrhosis (DCC)/liver transplant (LT)/hepatocellular carcinoma (HCC)]. This study examined the impact of DM on healthcare costs among NAFLD/NASH patients with AdvLD in the U.S.
Methods: Adult NAFLD/NASH patients identified from IBM Watson Health MarketScan claims database (2006-2016) were followed from initial NAFLD/NASH diagnosis to identify development of AdvLD (first diagnosis as index date), stratified by presence of DM (ICD codes/medications). Mean annual healthcare costs for each stage was obtained from per patient per month values (2016 USD). Results: Overall 468,017 NAFLD/NASH patients were identified with 24% having DM (mean age 51 years, 58% females, high comorbidity burden - 56% hypertension, 55% hyperlipidemia). Mean annual costs were higher (p&lt;0.05) for DM vs. non-DM patients (Figure) among NAFLD/NASH, CC, and DCC patients.
Conclusions: Comorbid DM is associated with significantly higher (23-31%) healthcare costs in patients with NAFLD/NASH, CC, and DCC, which represents the majority clinical burden of NAFLD in the U.S. Novel treatment options are needed among NAFLD/NASH patients with DM to prevent progression and subsequent healthcare costs.

Disclosure
R. Wong: Advisory Panel; Self; Gilead Sciences, Inc. Consultant; Self; Gilead Sciences, Inc. Research Support; Self; Gilead Sciences, Inc. Speaker's Bureau; Self; Gilead Sciences, Inc. N. Kachru: Employee; Self; Gilead Sciences, Inc. Stock/Shareholder; Self; Gilead Sciences, Inc. D. Martinez: None. M. Moynihan: Employee; Self; IBM. A. Ozbay: Employee; Self; Gilead Sciences, Inc. Stock/Shareholder; Self; Gilead Sciences, Inc. S. Gordon: Consultant; Self; Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc.
1317-P: Static, but Nondynamic, ß-Cell Responsiveness to Glucose Is Affected by the Risk Variant rs7903146 of TCF7L2 and Associated with a Delayed Time-to-Glucose-Peak in Obese Youths
Authors: GALDERISI ALFONSO , TRICO DOMENICO , MAN CHIARA DALLA , SIEBEL STEPHAN , SANTORO NICOLA , PIERPONT BRIDGET , COBELLI CLAUDIO , CAPRIO SONIA 
Published: June 2019

Background: Beta-cell function can be dissected into a dynamic component, estimating the immediate secretion after glucose change, and a static component representing the insulin secreted at any given glucose level. We evaluated their clinical and genetic determinants as well as their effect on glucose time to peak in obese youths.
Methods: A 3hOGTT was performed in 630 obese youths (374F, 13.6±3.1y, 33.3±7.5kg/m2); dynamic (DId) and static (DIs) components of beta-cell function were estimated by the oral minimal model. Participants were genotyped for the rs7903146 of TCF7L2 and grouped into 3 tertiles for DId and DIs. Effect of sex, BMI, age, ethnicity and TCF7L2 on DIs/DId was estimated by multivariate regression model.
Results: Lower DId, as well as DIs, were associated with higher BMI and 2h-glucose, while fasting glucose was increased in the lower DIs tertile. The risk genotype (TT) for the TCF7L2 and the BMI, were both associated to a lower DIs (p&lt;0.01), while TCF7L2 did not affect DId (p=0.22). Glucose time to peak&gt;30min was more likely in the lower DIs, without a difference among the DId tertiles (Figure).
Conclusion: The risk variant of TCF7L2 is associated with a blunted DIs, in the absence of an effect on the DId, and accompanied by a delayed glucose time to peak. The role of TCF7L2 in the incretin response might be responsible for this effect.

Disclosure
A. Galderisi: None. D. Trico: None. C. Dalla Man: None. S. Siebel: None. N. Santoro: None. B. Pierpont: None. C. Cobelli: None. S. Caprio: None.

Funding
National Institutes of Health (R01DK085577-01, R01HD40787, R01HD28016, P30DK045735, K12DK094714-02, R01DK111038-01A1); Robert E. Leet and Clara Guthrie Patterson Trust; European Medical International Framework (EMIF115372)
143-OR: Illuminating Ldb1 as a Novel Transcriptional Regulator of Brown Adipose Function
Authors: KEPPLE JESSICA , LIU YANPING , HUNTER CHAD S. 
Published: June 2019

Brown adipose tissue (BAT) is critical for thermogenesis and glucose/lipid homeostasis. BAT utilizes fatty acids and glucose for heat production via mitochondrial uncoupling, and is thus an attractive therapeutic target for combatting obesity. Expanding the energy uncoupling capacity of this tissue requires a greater understanding of underlying BAT transcriptional mechanisms. We recently reported on a transcriptional co-regulator, LIM domain binding protein 1 (Ldb1), which appears to have novel roles in BAT biology. Ldb1 acts as a dimerized scaffold allowing for the assembly of transcriptional complexes and is important for the development and function of many metabolic tissues, including the brain and pancreatic islets. However, roles for BAT-expressed Ldb1 have not been elucidated. We set out to test the hypothesis that Ldb1 directly impacts BAT development and function. Our in vitro studies have shown that primary brown adipocytes lacking Ldb1 have reductions in BAT-selective genes including Ucp1 and Elovl3 and are unable to induce Ucp1 expression upon agonist treatment, a result similarly observed in the X9 Ucp1-expressing cell line. To test Ldb1 roles in vivo, we developed a mouse model, termed Ldb1ΔBAT, in which Ldb1 was reduced in thermogenic adipocytes using a Ucp1-driven Cre recombinase. The Ldb1ΔBAT mice were cold intolerant during a cold challenge, which is supportive of thermogenic defects in the Ldb1-deficient tissue. The knockout mice were also glucose intolerant via intraperitoneal glucose challenge and preliminary data suggest insulin insensitivity, via intraperitoneal insulin tolerance test. Histological analyses of Ldb1ΔBAT BAT depots indicated an alteration in brown adipocyte morphology and potentially intercellular lipid content, suggesting cellular dysfunction. Overall, this work indicates that Ldb1 has a direct role in maintaining thermogenic and metabolic function in BAT.

Disclosure
J. Kepple: None. Y. Liu: None. C.S. Hunter: None.
1450-P: High Risk of Mortality and Disease Progression Associated with Diabetes Mellitus (DM) and Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis (NAFLD/NASH) in Medicare Patients
Authors: LOOMBA ROHIT , FRAYSSE JEREMY , LI SUYING , OZBAY A. BURAK , HARRISON STEPHEN A. 
Published: June 2019

Background: DM patients have a 7-8 times higher risk of development of NASH with advanced fibrosis or cirrhosis than non-DM, which are predictors of mortality in NASH patients. This study evaluated mortality in NAFLD/NASH patients by liver disease severity and DM status.
Methods: This was a retrospective study from 2007-2015 of a 20% sample of U.S. Medicare beneficiaries and included NAFLD/NASH-DM patients (ICD codes/medications). Survival analyses performed via Kaplan-Meier curves for incidences of all-cause mortality and disease progression.
Results: This study identified NAFLD/NASH-DM patients: 100,098 with NAFLD/NASH only, 2,520 compensated cirrhosis (CC), 45,881 decompensated cirrhosis (DCC), 408 liver transplant (LT), and 384 hepatocellular carcinoma (HCC). Rates of comorbidities were high (at least 71% with cardiovascular disease). In 1 year, mortality was higher in DCC patients (18.1%) than in CC (4.3%) and NAFLD/NASH only (2.1%) (Figure). This trend continued over the study period. Liver disease progression was higher in CC patients with DM compared to no DM (20% vs. 17%).
Conclusions: NAFLD/NASH-DM patients overall mortality rate of 25.1% was 2-times higher than the expected rate for similarly aged general population of 12.7% (Social Security life table) over 8-year the study period.

Disclosure
R. Loomba: Consultant; Self; Eli Lilly and Company, Novo Nordisk Inc. J. Fraysse: Employee; Self; Gilead Sciences, Inc. S. Li: Consultant; Self; Gilead Sciences, Inc. A. Ozbay: Employee; Self; Gilead Sciences, Inc. Stock/Shareholder; Self; Gilead Sciences, Inc. S.A. Harrison: Advisory Panel; Self; Gilead Sciences, Inc.
1473-P: Circulating Epoxyeicosatrienoic Acids, Diabetes, and Cardiovascular Disease
Authors: LEMAITRE ROZENN N. , JENSEN PAUL N. , ZEIGLER MAXWELL B. , FRETTS AMANDA M. , SITLANI COLLEEN , KING IRENA B. , SOTOODEHNIA NONA , MCKNIGHT BARBARA , TOTAH RHEEM A. 
Published: June 2019

Epoxyeicosatrienoic Acids (EETs) are cytochrome P450 derivatives of arachidonic acid that have multiple biological activities, including anti-inflammatory, vasodilatory and platelet anti-aggregation. Additionally, manipulation of EET levels in animal studies suggests a protective role in diabetes. Whether EET levels are related to risk of diabetes and cardiovascular complications of diabetes in humans is largely unknown. We measured 4 species of EET in fasting plasma samples from the Cardiovascular Health Study, a cohort of older adults. Using Cox regression models, we examined the associations of baseline EET levels with 1) risk of incident diabetes and 2) risk of incident myocardial infarction and stroke among participants with diabetes. Among 3222 participants without diabetes, increased levels of each plasma EET were associated with greater risk of diabetes (Table). Among participants with diabetes, increased EETs levels were associated with reduced risk of myocardial infarction but increased risk of stroke (Table). The study findings suggest that circulating EETs are not protective of diabetes in humans, and higher levels in the context of diabetes, may have mixed consequences on cardiovascular complications.

Disclosure
R.N. Lemaitre: None. P.N. Jensen: None. M.B. Zeigler: None. A.M. Fretts: None. C. Sitlani: None. I.B. King: None. N. Sotoodehnia: None. B. McKnight: None. R.A. Totah: None.

Funding
National Institutes of Health
1502-P: Novel Subgroups of Type 2 Diabetes at Diagnosis in a Southern European Cohort
Authors: BONADONNA RICCARDO C. , TROMBETTA MADDALENA , ZUSI CHIARA , DAURIZ MARCO , BOSELLI MARIA LINDA , BONORA ENZO 
Published: June 2019

In 739 GADA-negative patients of the Verona Newly Diagnosed Type 2 Diabetes Study (VNDS) we investigated whether the 4 (severe insulin deficient: SIDD; severe insulin resistant: SIRD; mild obese: MOD; mild age related: MARD) novel subgroups (1) of type 2 diabetes (T2D) were identifiable at diagnosis. Data-driven 4-means cluster analysis of 4 variables [age, BMI, HOMA2 beta cell function (BCF) and insulin resistance] was run as in (1). Two clusters were consistent with SIDD and MARD; the others were labeled obese insulin resistant (OIRD), likely encompassing MOD and SIRD, and early onset diabetes (EOD) (Table). Among 8 diabetes risk alleles tested in (1), HHEX/IDE (rs1111875) and TSPAN8 (rs7961581) had highest prevalence in OIRD (p&lt;0.05). Clamp measured insulin sensitivity (IS), but not modeled BCF (glucose sensitivity) of 5-hour OGTT, was different in all comparisons (Table). OIRD and MARD had lower eGFR than EOD and SIDD (Table). Prevalence of cardiovascular disease (ischemic ECG; plaques at US scans of carotid and peripheral arteries) was higher in MARD (p&lt;0.01), while retinopathy and albuminuric nephropathy were similar in the 4 clusters. At a 14-month follow-up (n=419), SIDD held the highest HbA1c (p&lt;0.01). Thus, in the VNDS, novel subgrouping of T2D is largely confirmed and is associated to significant heterogeneity of genetics, pathophysiology, organ damage and evolution of glucose control.
References
1. PMID 29503172

Disclosure
R.C. Bonadonna: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck Sharp & Dohme Corp., Sanofi-Aventis. Speaker's Bureau; Self; Eli Lilly and Company, Sanofi-Aventis. M. Trombetta: None. C. Zusi: None. M. Dauriz: None. M. Boselli: None. E. Bonora: None.

Funding
Italian Ministry of Education, Universities and Research; Italian Scientific Research Programs of Relevant National Interest (2015373Z39_004)
1568-P: Discontinuation of Metformin among Patients with Reduced Renal Function
Authors: CHU PATRICIA , GRIFFIN MARIE R. , MIN JEA YOUNG , HACKSTADT AMBER J. , CHIPMAN JONATHAN J. , GREEVY ROBERT A. , HUNG ADRIANA M. , GRIJALVA CARLOS G. , ROUMIE CHRISTIANNE 
Published: June 2019

Background: In 2008, the American Diabetes Association (ADA) suggested metformin be used in patients with diabetes and reduced renal function. We evaluated time trends in metformin discontinuation for patients who reached reduced renal threshold.
Methods: Using National Veterans Administration and Medicare databases, we assembled a cohort of metformin and glipizide users who reached serum creatinine &gt;1.5/1.4 mg/dL for males/females. Odds ratio (OR) of medication discontinuation within 180 days of renal threshold over time was modeled using multivariable logistic regression, with metformin discontinuation in 2008 as reference.
Results: There were 18,025 metformin patients and 22,595 glipizide who met renal threshold. In 2008, 55.3% metformin patients discontinued within 180 days of renal threshold. Figure 1 depicts probability of metformin and glipizide discontinuation annually. The odds of metformin discontinuation was 1.25 (1.23, 1.35) vs. glipizide. In a fitted regression of discontinuation probability, there was no statistical difference in slopes between the two treatments (p=0.125).
Conclusions: Probability of discontinuing metformin with reduced renal function decreased over time but was more likely than glipizide discontinuation. The decrease in discontinuation over time was similar in both treatments.

Disclosure
P. Chu: None. M.R. Griffin: None. J. Min: None. A.J. Hackstadt: None. J.J. Chipman: None. R.A. Greevy: None. A.M. Hung: None. C.G. Grijalva: None. C. Roumie: None.

Funding
U.S. Department of Veterans Affairs (CX000570-07 to C.R.)
1606-P: Lifetime Risk of Developing Diabetes and Years of Life Lost Due to Diabetes in Brazil: Estimates for the Year 2016
Authors: BRACCO PAULA , SCHMIDT MARIA I. , LOTUFO PAULO A. , BARRETO SANDHI MARIA , DUNCAN BRUCE B. 
Published: June 2019

Background: Lifetime risk (LR) of developing diabetes and the years of life lost (YLLs) due to the disease are intuitive ways to characterize the diabetes burden.
Methods: We applied the illness-death model. For LR, we inputted age- and sex-specific diabetes incidence rates and the nondiabetic population mortality rate. For YLLs, which compares the life expectancy of people with and without diabetes, we additionally input diabetes mortality rates. We estimated incidence and prevalence rates based on the Brazilian risk factor surveillance system. We calculated mortality rates combining diabetes prevalence, all-cause mortality obtained from national statistics, and diabetes mortality rate ratios from ELSA-Brasil, an ongoing cohort study.
Results: The risk of developing diabetes from age 35 to the age shown in the Table (column “Lifetime Risk”) was higher in women; YLLs due to developing diabetes at the age indicated were higher in men. In 2016, for women aged 35 without diabetes, the LR up to age 80 was 41.3%; for men, 28.0%. Considering a life expectancy of 80 years for those without diabetes, a man diagnosed with diabetes at age 40 would lose 6.1 years of life; a woman, 3.1 years.
Conclusion: This approach generates estimates of easy comprehension, which may be of use in health education and decision-making. The large risks and losses we found emphasize the importance of effective prevention policies.

Disclosure
P. Bracco: None. M.I. Schmidt: Research Support; Self; Eli Lilly and Company. Research Support; Spouse/Partner; Eli Lilly and Company. P.A. Lotufo: None. S. Barreto: None. B.B. Duncan: Research Support; Self; Eli Lilly and Company. Research Support; Spouse/Partner; Eli Lilly and Company.

Funding
Brazilian Ministry of Health