bluuebunny/crossref_metadata_2025 huggingface dataset:
Study of Urea Embed Mesoporous Nano Silica on Yield and Yield Attributing Characters of Rice Grown in Mollisols
Authors: SINGH1 KHARAG , SINGH VIJAY KANT , RAM SHRI , SINGH KRISHNA  PAL
Published: June 2019

Rice (Oryza sativa L.) is a stable food more than two billion people are getting 60-70 per cent their energy requirement from rice and its derived products. Present research investigated effect of urea embed mNS (embed in the mesoporousnano silica by simple immersion loading using aqueous solution and this formulation of nanofertilizer) on rice crop in pot experiment under polyhouse condition. Nine treatments consisted (T1: Control, T2:N30P60K40,T3:N60P60K40, T4:N90P60K40, T5:N120P60K40, T6:N30(mNS)P60K40,T7:N60(mNS)P60K40, T8:N90(mNS)P60K40 and T9:N120 (mNS)P60K40.) in three replications. In this study, the results revealed that the growth parameter, grain and straw yields as well as yield attributes (effective tillers, panicle length, grains per panicle and 1000-grain weight) were significantly affected by urea embed nano silica application. The highest grain and straw yields were recorded in treatment T9 giving 323.02 and 124.05 per cent more over control, due to exposure of urea embed mNS as compared to ordinary urea dose of chemical fertilizers. The sustained release of urea embedded mNSaccurs 7-8 days after exposure which is extraordinarily slow as compared to ordinary urea. These results are preliminary but promising and open the doors to use nanomaterials as an efficient nanofertilizer.
Effects of the geometry of residential buildings with a sunspace on their energy performance
Authors: Vukadinovic Ana , Radosavljevic Jasmina , Djordjevic Amelija , Petrovic Nemanja
Published: June 2019

The increase in energy consumption in building design and construction and
the issues related to environmental protection have steered many current
researchers toward examining the ways to reduce total CO2 emissions, which
resulted in the development of various measures to increase energy
efficiency. One measure for more cost-efficient and rational use of energy
resources in individual residential buildings is the application of passive
solar systems with a sunspace. This paper presents the effects of the shape
factor of a residential building with a passive sunspace on the total
consumption of heating and cooling energy. The total amount of energy
required for building heating and cooling was calculated by means of dynamic
modelling using EnergyPlus software. The simulations were run according to
the meteorological parameters for the city of Nis. For simulation purposes,
models of residential buildings with a passive sunspace and square- and
rectangle-shaped floors were designed. The variations between the models
include different building shape factor, floor geometry, surface area of the
southern fa?ade, and glazing percentage, i.e. window-to-wall ratio (WWR).
Examination of the models with WWR=20%, WWR=40%, and WWR=60% revealed that
the elongated shape of a building with the aspect ratio of 2.25:1, with the
longer side of the fa?ade facing south, is the most favourable in terms of
heating energy consumption. For the same WWRs, the elongated shape of a
building with the aspect ratio of 1.56:1, with the longer side of the fa?ade
facing south, is the most favourable in terms of cooling energy consumption.
As WWR increases, so does the amount of energy required to cool the
building. The biggest increase in heating energy consumption was observed in
buildings with the aspect ratio 1:2.25, with the shorter side facing south.
The unsteady liquid film flow of the carbon nanotubes engine oil nanofluid over a non-linear radially extending surface
Authors: Alzahrani Abdullah , Ullah Malik , Gul Taza , Baleanu Dumitru
Published: June 2019

The enhancement of heat transfer through carbon material is the objective of this study. The renowned class of carbon identified as single walled carbon nanotubes and multi walled carbon nanotubes, nanofluid-flow over a non-linear and unstable surface has been explored. The thermophysical properties of the two sorts of carbon nanotube have been implemented from the experimental outputs in the existent literature using engine oil as a base fluid. The viscous dissipation term has also been included in the energy equation improve the heat transfer rate. The thickness of the nanofluid thin layer is kept variable under the influence of the unstable and non-linear stretching of the disk. The elementary governing equations have been transformed into coupled non-linear differential equations. The problem solution is achieved through BVP 2.0 package of the optimal homotopy analysis method. The square residual error for the momentum and thermal boundary-layers up to the 20th order approximations have been obtained. The numerical ND-solve method has been used to validate the he optimal homotopy analysis method results. The impact of the model parameters vs. velocity field and temperature distribution have been shown through graphs and tables. The impact of the physical parameters on the temperature profile and velocity, pitch for both multi wall carbon nanotubes and single walled carbon nanotubes is gained in the range of 0 ? ? ? 4%. From the obtained results it is observed that the single walled carbon nanotubes nanofluids are more efficient to improve the heat transfer phenomena as compared to the multi wall carbon nanotubes.
Hybrid Insulin Peptides Are Autoantigens in Type 1 Diabetes
Authors: Baker Rocky L. , Rihanek Marynette , Hohenstein Anita C. , Nakayama Maki , Michels Aaron , Gottlieb Peter A. , Haskins Kathryn , Delong Thomas
Published: June 2019

We recently established that hybrid insulin peptides (HIPs) are present in human islets and that T cells reactive to HIPs are found in the residual islets of organ donors with type 1 diabetes (T1D). Here, we investigate whether HIP-reactive T cells are indicative of ongoing autoimmunity in patients with T1D. We used interferon-γ enzyme-linked immune absorbent spot analyses on peripheral blood mononuclear cells (PBMCs) to determine whether patients with new-onset T1D or control subjects displayed T-cell reactivity to a panel of 16 HIPs. We observed that nearly one-half of the patients responded to one or more HIPs. Responses to four HIPs were significantly elevated in patients with T1D but not in control subjects. To characterize the T cells reactive to HIPs, we used a carboxyfluorescein succinimidyl ester–based assay to clone T cells from PBMCs. We isolated six nonredundant, antigen-specific T-cell clones, most of which reacting to their target HIPs in the low nanomolar range. One T-cell clone was isolated from the same patient on two different blood draws, indicating persistence of this T-cell clone in the peripheral blood. This work suggests that HIPs are important target antigens in human subjects with T1D and may play a critical role in disease.
106-OR: Geminin Expression in Human Fetal Pancreas
Authors: BAEYENS LUC , SCHEEL DAVID W. , YANG KATHERINE , GERMAN MICHAEL
Published: June 2019

Geminin (Gmnn) is a coiled-coil nuclear protein originally identified as a DNA replication inhibitor. In addition, nuclear Gmnn regulates gene expression by interacting (through a domain distinct from the Cdt1-interacting domain) with Brg1, the catalytic subunit of the SWI/SNF chromatin remodeling complex. In this context, Gmnn regulates expression of key transcription factors involved in differentiation. The dual role of Gmnn in the cell cycle and differentiation has been viewed as a critical mechanism for linking replication and differentiation. We wanted to test its role in human pancreas development. We found a robust Gmnn expression in the human fetal pancreas but its expression slightly decreased with age. Remarkably the fraction of cells expressing both Gmnn and Ki67 declined much faster with age. We isolated 13WD human fetal pancreas and studied the proportion of replicating Sox9+cells. We compared control human fetal explants with fetal explants transduced with a shRNA lentivirus directed against Gmnn (Gmnnsh) and discovered that Gmnnshexplants display a decrease in proliferation compared to controls after 2 days in culture. RNA sequencing comparing Gmnnshexplants to controls revealed a marked decrease in transcripts associated with endocrine differentiation. To evaluate the effects on endocrine differentiation, human fetal pancreases were isolated at 13WD and treated for 5 days with lentiviruses or casein kinase inhibitors. We detected a significant reduction in the number of insulin+cells after treatment with the casein kinase inhibitor TBB and a significant reduction in the number of glucagon+cells after treatment with TBB or after siCsnk2a1. Overexpression of Gmnn significantly increased the proportion of Neurog3+cells compared to the control explants.

Finally, we found that inhibition of Gmnn or casein kinase 2 was capable of significantly reducing expression of Nkx6.1 compared to controls. We conclude that Gmnn may play a critical role pancreas cell replication and endocrine specification in human development.

Disclosure

L. Baeyens: None. D.W. Scheel: None. K. Yang: None. M. German: Advisory Panel; Self; Encellin. Stock/Shareholder; Self; Encellin, Viacyte, Inc.

Funding

JDRF
1060-P: Effect of Dulaglutide and Long-Acting Insulin Combination Therapy in Patients with Type 2 Diabetes
Authors: ITO KOHEI , SATOH SHINOBU , KONDO YOSHINOBU , TERAUCHI YASUO
Published: June 2019

Objective: Glucagon-like peptide-1 receptor agonists (GLP-1-RA) are assumed to decrease the number of injections and improve blood glucose control in patients with type 2 diabetes (T2D). We aimed to evaluate the effects of switching from multiple daily insulin injection therapy (MDI) to combination therapy involving a long-acting GLP-1-RA, dulaglutide, and long-acting insulin on glycemic control.

Methods: We examined patients with T2D who admitted to our department and underwent blood glucose management with MDI, followed by flash glucose monitoring. The treatment was subsequently switched to dulaglutide + long-acting insulin combination therapy. We evaluated the blood glucose excursion after MDI and 1 and 24 weeks after dulaglutide + long-acting insulin combination therapy. Furthermore, we evaluated hemoglobin A1c (HbA1c) after 12 and 24 weeks of dulaglutide + long-acting insulin combination therapy.

Results: We enrolled 20 patients (mean age: 68.6 ± 11.7 years; HbA1c value: 10.1% ± 2.8%; previous MDI: n = 4). Mean blood glucose levels after MDI and 1 and 24 weeks after dulaglutide + long-acting insulin combination therapy were 124.8 ± 35.6, 122.5 ± 30.4, and 119 ± 21.3 mg/dl, respectively. Blood glucose level was significantly lower 24 weeks after dulaglutide + long-acting insulin combination therapy than shortly after MDI (P = 0.0048). Furthermore, blood glucose excursion tended to decrease after switching to dulaglutide + long-acting insulin combination therapy. After 12 and 24 weeks of the switch, HbA1c value significantly decreased (−3.6% ± 0.78%, P = 0.0003 and −3.7% ± 0.78%, P = 0.0002, respectively).

Conclusions: The switch from MDI to dulaglutide + long-acting insulin combination therapy resulted in better blood glucose control, with reductions in blood glucose excursion and the number of self-injections; moreover, the effects continued for 24 weeks.

Disclosure

K. Ito: None. S. Satoh: None. Y. Kondo: None. Y. Terauchi: Advisory Panel; Self; AstraZeneca, Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Sanofi. Research Support; Self; Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Shionogi & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd. Speaker's Bureau; Self; Astellas Pharma Inc., AstraZeneca, Bayer Yakuhin, Ltd., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Shionogi & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd.
110-LB: The Comparison of Glycemic Remission and Nonremission Patients after Sitagliptin Combination with Short-Term Intensive Insulin Therapy
Authors: KE WEIJIAN , LIU LIEHUA , HE XIAOYING , LI YANBING
Published: June 2019

Short-term intensive insulin therapy (IIT) could induce long-term glycemic remission. Sitagliptin increased endogenous GLP-1 content to achieved glucose control. The combination of sitagliptin with IIT might enhance the effect of improving alpha cell and beta cell function. 72 newly diagnosed type 2 diabetes patients with hypoglycemic therapy naïve were enrolled, with 47.6±9.0 years in age, with BMI of 25.2±2.7 kg/m2, FPG of 11.1±3.4mmol/L, and HbA1c of 10.6±2.3%. Continuous subcutaneous insulin infusion (CSII) were used as IIT, which were maintained for 14 days after patients achieving euglycemia. The treatment course of sitagliptin was 90 days. After cessation of sitagliptin, 45.8% of patients (33/72) achieved 1-year glycemic remission without any hypoglycemic medications. Compared the baseline of remission and non-remission groups, the baseline fasting plasma glucose (FPG) of remission group was lower (10.0±3.0 vs. 12.0±3.5mmol/L, p=0.012), but the levels of HbA1c, acute insulin response (AIR), HOMA-B and HOMA IR were not different between groups. After CSII cessation, FPG of remission group was still lower than non-remission group (5.8±0.8 vs. 6.9±1.1mmol/L, p<0.001), beta cell function and insulin resistance were improved significantly(HOMA-B: 62.96(25.94) vs. 40.67(41.79), p=0.026; HOMA-IR: 1.56(0.54) vs. 1.74(0.99), p=0.003). Analyzed insulin dosage of the 14th day after achieving glycemic target, basal insulin dosage was lower in remission group (9.6±5.6IU/d, vs. 14.4±7.1IU/d, p=0.002).

In conclusion, lower levels of FPG at baseline and after IIT, less basal insulin usage during IIT, and better improvement of beta-cell function and insulin resistance suggested the possibility of glycemic remission after combination of IIT and sitagliptin therapy.

Disclosure

W. Ke: None. L. Liu: None. X. He: None. Y. Li: None.
1138-P: Dipeptidyl Peptidase-4 Inhibitors Attenuate Thyroid-Stimulating Hormone Levels
Authors: SHIMODA YOKO , OKADA JUNICHI , YAMADA EIJIRO , SAITO TSUGUMICHI , OKADA SHUICHI , YAMADA MASANOBU
Published: June 2019

We have reported that a patient with painless thyroiditis induced by the cessation of dipeptidyl peptidase-4 inhibitor was accompanied with type 2 diabetes mellitus (T2DM). Given the lack of clarity regarding the possibility whether dipeptidyl peptidase-4 inhibitors (DPP-4is) attenuates thyroid hormone levels, we compared thyroid-stimulating hormone (TSH) and free thyroxine (FT4) levels between patients with T2DM who were not prescribed DPP-4is and patients with T2DM who were prescribed DPP-4is. 12 patients were prescribed DPP-4is (DPP-4is group) and 33 patients were not prescribed DPP-4is (w/o DPP-4is group). TSH and FT4 levels were measured in all of these patients and TSH and FT4 levels were annually measured in all of patients in the current population for more than three years. The TSH levels in the DPP-4is group was significantly higher than those of w/o DPP-4is group (2.11 ±0.67 vs1.58 ±0.64 μIU/mL, mean ±standard deviation, reference range: 0.33~4.05, p= 0.0189). The FT4 levels in the DPP-4is group was not significantly different from those of w/o DPP-4is group (1.06 ±0.086 vs1.01 ±0.12 ng/dL, mean ±standard deviation, reference range: 0.97~1.69, p= 0.0189). The measured TSH and FT4 levels were normal range in all of subjects in this clinical study. Nevertheless, TSH levels in patients with T2DM prescribed DPP-4is was significantly higher than those of the patients with T2DM not prescribed DPP-4is although we did not see the difference in FT4 levels between two groups. Despite of the small sample size, this clinical study provides important information. One strength of the current study is that the TSH and FT4 levels were annually measured in all patients with T2DM in the current population for more than three years. DPP-4is might modulate TSH levels in the absence of Metformin and further investigates with large population were necessary whether we need to monitor thyroid function regularly when we prescribe DPP-4is for the patients with T2DM.

Disclosure

Y. Shimoda: None. J. Okada: None. E. Yamada: None. T. Saito: None. S. Okada: None. M. Yamada: None.
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 <0.01) and pregenual anterior cingulate cortex (ACC, NAH p <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<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 > 6 months) and to reduce HbA1c levels in both the overall population and patients with HbA1c > 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 > 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 > 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<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<0.01), while TCF7L2 did not affect DId (p=0.22). Glucose time to peak>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<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<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<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 >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
167-OR: Activation of Myocardial Mitochondria Akt1 Improved Diabetic Cardiomyopathy and Body Composition—The Heart as a Metabolic Organ
Authors: CHEN YU-HAN , TA ALBERT , LEE HSIAOCHEN , YOU-HSIEN LIN HUGO , CHEN YUMAY , WANG PING H.
Published: June 2019

Insulin acutely stimulates Akt1 translocation into cardiac mitochondria, which is blunted in T2DM due to insulin resistance. To study the role of mitochondrial Akt (mito-Akt) in diabetic cardiomyopathy and its implication on whole body metabolism, we generated two transgenic mice lines with heart-specific Cre-lox, using inducible mitochondria-targeting dominant negative Akt (CAMDAKT) or constitutively active Akt (CAMCAKT). CAMDAKT mice developed cardiomyopathy and heart failure after Tamoxifen (T) induction when compared to corn oil (CO) injected CAMDAKT mice. To study whether activation of myocardial mito-Akt can reverse diabetic cardiomyopathy, two models of diabetic cardiomyopathy resembling different phases of T2DM were used in this study. First, after 5-months high fat/fructose diet (HFF), mice developed LV dysfunction, obesity, glucose intolerance, and hyperinsulinemia. In this model, T-CAMCAKT mice restored LV function and averted cardiomyopathy. A second metabolic model was induced with a 12-weeks HFF diet and low-dose streptozotocin injections, which led to overweight, hyperglycemia, and reduced insulin secretion. CO mice showed higher heart failure markers (ANF, BNP, MYH7) and increased expression of cardiac PDK4, CPT1, CPT2 and CD36. In the T-CAMCAKT mice, cardiomyopathy was reversed. Thus, activation of mito-Akt reversed diabetic cardiomyopathy. While T-CAMCAKT showed similar improvement of cardiomyopathy in these two metabolic models, body composition was different. In the first HFF model, mito-Akt activation did not alter body composition or glucose homeostasis, but fatty liver was improved. In the second metabolic model with reduced insulin secretion, T-CAMCAKT mice had better OGTT, lower fat mass (16.6% vs. 26.5%, p<0.001) and higher lean mass (77.1% vs. 68.1%, p<0.001).

Summary: myocardial mito-Akt locally modulated cardiac metabolism and LV function, and remotely modulated whole body metabolism.

Disclosure

Y. Chen: None. A. Ta: None. H. Lee: None. H.Y. Lin: None. Y. Chen: None. P.H. Wang: None.
1676-P: Racial and Ethnic Disparities in Type 1 (T1D) and Type 2 (T2D) Diabetes Incidence in Young Adults: The Diabetes in Young Adults (DiYA) Study
Authors: FERRARA ASSIAMIRA , ALEXANDER JANET G. , SRIDHAR SNEHA B. , RITCHIE JENNA , SLEZAK JEFF , TAKHAR HARPREET S. , VEGA-DAILY LETICIA I. , SAYDAH SHARON , IMPERATORE GIUSEPPINA , QUESENBERRY CHARLES , LAWRENCE JEAN M.
Published: June 2019

Data on the incidence of T1D and T2D among racially and ethnically diverse young adults are sparse. To fill this gap, we conducted surveillance in a diverse population of 2.3 million members (15.3% Asian, 7.0% black, 34.6% Hispanic, 33.2% white, 9.9% other) of Kaiser Permanente California, in 2017, aged 20-45 years without recognized diabetes as of 12/31/2016. Incident cases were identified through electronic health records based on the following criteria: a) ≥2 ICD-10 diagnosis codes for diabetes, b) 1 ICD-10 diagnosis for diabetes plus ≥1 prescription for diabetes medication, or c) 1 ICD-10 diagnosis plus ≥2 glucose or HbA1c values diagnostic of diabetes according to the ADA criteria. T1D was defined based on >50% of ICD-10 codes indicating T1D.

We identified 7,862 incident diabetes cases in 2017: 122 (1.6%) T1D and 7,713 (98.1%) T2D. Age- and sex-standardized T1D and T2D incidence rates per 100,000 person-years are reported in the Table. The incidence of T1D was highest in white and black, followed by Hispanic and Asian individuals. The incidence of T2D was highest among Hispanic followed by black, Asian and white individuals.

In young adults, there are large racial and ethnic disparities in the incidence of T1D and T2D. Targeted disease management strategies are needed. Further research into possible etiological factors may identify targeted prevention strategies.

Disclosure

A. Ferrara: None. J.G. Alexander: None. S.B. Sridhar: None. J. Ritchie: None. J. Slezak: None. H.S. Takhar: None. L.I. Vega-Daily: None. S. Saydah: None. G. Imperatore: None. C. Quesenberry: None. J.M. Lawrence: None.

Funding

Centers for Disease Control and Prevention (1U18DP006289)
1678-P: Comparisons of Combined C-Peptide and Glucose Intermediate Endpoints for Identifying Individuals at Very High Risk for Type 1 Diabetes
Authors: JACOBSEN LAURA M. , CLEMENTS MARK A. , REDONDO MARIA JOSE , NATHAN BRANDON M. , SCHATZ DESMOND , SOSENKO JAY M.
Published: June 2019

Type 1 diabetes (T1D) prevention trials can be shortened if intermediate endpoints indicative of a very high risk of progression are reached before diagnosis. Since Index60, a composite C-peptide and glucose measure, has been shown to have potential use as such an endpoint, we evaluated additional combinations of C-peptide and glucose as endpoints. Diabetes Prevention Trial-type 1 participants (n=702) with baseline values below threshold (set arbitrarily at 95th percentile for each endpoint) were followed at 0.5-1.0 year intervals with 2-hour OGTTs for the first (incident) OGTT that thresholds were exceeded. Participants were then followed for T1D. All endpoints were reached, on average, over 1 year prior to the diagnosis of T1D. Risks for subsequent T1D after the incident OGTT were substantial, but variable (3-year risk=0.66-0.81). There was also appreciable variation in numbers reaching endpoints (n=55-117) and positive predictive values for T1D (PPV=62-77%). Ages were lowest for Glucose/C-peptide measures at incident OGTTs. Index60 performed best regarding key endpoint criteria: number reaching endpoint, 3-year risk, and PPV.

In conclusion, individuals highly likely to ultimately develop T1D can be identified over 1 year before diagnosis by combined C-peptide and glucose endpoints. It appears that such endpoints should be considered for T1D prevention trials.

Disclosure

L.M. Jacobsen: None. M.A. Clements: Advisory Panel; Self; Glooko, Inc. Consultant; Self; Eli Lilly and Company. Speaker's Bureau; Self; Medtronic. M.J. Redondo: None. B.M. Nathan: None. D. Schatz: None. J.M. Sosenko: None.

Funding

National Institutes of Health; JDRF