bluuebunny/crossref_metadata_2025 huggingface dataset:
Kepemimpinan Bermutu: Konsep Pengembangan Lembaga Pendidikan Islam
Authors: Chairunnisa Ema , Najiyah Choirotun , Salsabila Hajar , Cendekia Dikara Wanadya Nirmalasari
Published: June 2020

The development of Islamic educational institutions in Indonesia seems increasingly complex in the current era. The management model requires a more modern order and relevant to the development of the times to be able to compete with other public institutions. Islamic educational institutions are often underestimated. Therefore, the concept of quality leadership is something that is important in advancing the management of Islamic education. The need for quality leadership that is able to manage various aspects, allows the achievement of the objectives of the institution to the fullest. This research will describe some important aspects of quality leadership in the management of Islamic educational institutions. This article uses the literature review method, which means collecting various writings, whether in the form of articles, journals, books, and in accordance with the theme to be discussed.
Diskursus Minoritas Melalui Kurikulum, Buku dan Kultur di Sekolah
Authors: Muaddab Hafis
Published: June 2020

This paper is concerned to explain minority discourse through the curriculum, books, and culture in schools. Conflicts between minorities and majorities can occur in Indonesia, whenever and wherever, whether motivated by differences in ethnicity, ethnicity, religion, or groups. The problem is whether the education sector has contributed to its prevention aspects. Moreover, the national education curriculum is still oriented on cognitive abilities, while aspects of social intelligence have not been touched. The various references available have also not opened students' awareness in accepting the existence of minority groups. School education still merely raises passive tolerance, has not yet fostered active tolerance. Educational orientation must be stressed on the importance of a transformative, dialogic approach and inclusive to diversity. Then, it also refers back to the achievement of Ki Hajar Dewantara's ideals of liberation and humanizing education.
¿Cómo se insertan los servicios médicos en el ámbito de la ley sobre protección de los derechos de los consumidores?
Authors: Barrientos Camus Francisca María
Published: June 2020

Se examina la posibilidad admitir la inserción de la responsabilidad médica dentro de las normas sobre protección de los derechos de los consumidores.
Company incorporation regimes in the UK, the US and Australia – In search of the golden mean
Authors: Alanazi Badar Mohammed Almeajel
Published: June 2020

The purpose of the law on incorporation has been heavily contested by academics. On one side of the debate are scholars who argue that company law should have an “enabling” role, in that it should empower business owners to arrange their affairs in a manner that best suits their purposes at the same time as minimising any interference from the state. On the other side of the debate are those who argue that company law should impose on the world of commerce strong regulatory measures to prevent such abuses. This conflict between the “enabling” and the “regulatory” role of company incorporation law is visible in many jurisdictions, with each of them achieving a different balance between the two approaches. Many scholarly studies have elaborated on how companies are incorporated and regulated. Some of them have been used in the current paper such as studies carried out by Bayern et al. (2017) and Reyes (2018). However, this paper examines the extent to which the incorporation regimes in the UK, the US, and Australia can be said to be “enabling” or “regulatory” in nature, through a detailed analysis of the law on company incorporation, ownership structure and the protection provided to the relevant stakeholders through the principles of separate legal personality.
100-OR: High-Affinity Islet Autoantibodies Predict Progression to Diabetes in Those Who Seroconvert after Age 10
Authors: FROHNERT BRIGITTE I. , DONG FRAN , WAUGH KATHLEEN , STECK ANDREA , NORRIS JILL M. , YU LIPING , REWERS MARIAN
Published: June 2020

The objective of this study was to determine if islet autoantibodies (IA) can develop de novo in youth ≥10 y. We also explored the risk of progression to T1D in youth seroconverting to IA after 10 y.

From the prospective DAISY birth cohort (n=2547), we excluded those who were ever previously IA positive, disenrolled prior to age 10, or had >24 month gap in annual IA testing, leaving 917 for analysis. Seroconversion was defined as IA+ by radiobinding assays for insulin, GAD, IA-2 or ZnT8 autoantibodies, confirmed within 3-6 months. The same autoantibodies were also measured by electrochemiluminescence (ECL) assays, to identify high-affinity IA.

IA developed after age 10 at a higher rate (p=0.049) in first-degree relatives than in general population youth with increased-risk HLA (Figure 1); there was no difference by sex or race/ethnicity. Of the 35 IA+ seroconverters, 6 progressed to T1D, during a median follow-up of 5.04 years (IQR: 3.56-8.45). This included 2 of 5 individuals who were multiple IA+ at seroconversion, with at least one IA confirmed as high-affinity by ECL. Among those with a single persistent IA+ at seroconversion, 4/9 youth with high-affinity IA (ECL+) progressed to T1D, compared to 0/21 of the youth with low-affinity IA (ECL-).

In conclusion, seroconversion continues after age 10. In our genetically at-risk cohort, all who progress to T1D had high-affinity IA confirmed by ECL.

Disclosure

B.I. Frohnert: None. F. Dong: None. K. Waugh: None. A. Steck: None. J.M. Norris: None. L. Yu: None. M. Rewers: None.

Funding

JDRF (5-ECR-2017-388-A-N); National Institutes of Health (R01DK32493)
1003-P: Estimating an Optimal Meal Bolus for Persons with Diabetes on Multiple Daily Injections Therapy without Carb Counting
Authors: JIANG BOYI , ZHONG YUXIANG , AGRAWAL PRATIK , CORDERO TONI L. , VIGERSKY ROBERT
Published: June 2020

Background: MDI therapy requiring carbohydrate (carb) counting can be burdensome for persons with diabetes (PWD). We conducted an in-silico feasibility study assessing the glycemic performance of a post-prandial rather than a carb-based bolus optimizer.

Methods: The data were collected from seven adults with T1D (Gender:M2/F5; Age:22-45) on MDI using the Guardian™ Connect continuous glucose monitoring system. All participants had three bolus events matched to three meals for ≥7 days. In the training stage, a glucose-insulin minimal model extracted the rate of glucose appearance in blood (Ra) for each meal. The Ra was taken as an input to adjust in-silico simulated bolus amounts until the greatest time in sensor glucose range (70-180 mg/dL, TIR) within 4hrs was reached. In the testing stage, two bolus strategies were tested: the average of the adjusted bolus from the training set (Uniform Bolus) and the average of the adjusted bolus from the training set associated with the time of day (TOD) of the meal announcement (TOD Bolus).

Results: We found increased TIR for TOD Bolus strategy compared to the User Bolus (baseline) strategy (See Table below).

Conclusion: The data suggested that the automated bolus optimizer without carb counting may allow for an increased time spent in the target range, without comprising time spent below range while reducing the burden of carb counting for PWD on MDI.

Disclosure

B. Jiang: Employee; Self; Medtronic. Y. Zhong: Employee; Self; Medtronic. P. Agrawal: None. T.L. Cordero: Employee; Self; Medtronic. R. Vigersky: Employee; Self; Medtronic.
1015-P: Insulin-Excipient–Induced Inflammation and Pharmacokinetic Variability
Authors: HIDAU MAHENDRA K. , KESSERWAN CHAFICA , QIAO YI , KREUTZER DON , KLUEH ULRIKE
Published: June 2020

Objective: To evaluate the impact of phenol-based insulin-excipient induced inflammation on insulin pharmacokinetic (PK) variability in diabetic mice and to evaluate effects of anti-inflammatory agents (dexamethasone and cromolyn) in minimizing excipient induced inflammation.

Methods: Using a modified murine air pouch model, saline or insulin excipients were continuously infused for durations of 1 and 3 days. Subsequently, a single subcutaneous insulin injection of 0.3U (1:100; Humalog) was placed into the air pouch. Blood samples were taken periodically. Bioanalysis was done by ELISA for PK evaluation. A separate analysis determined effects of anti-inflammatory agents co-infused with insulin on maintaining glycemia during infusion pump therapy while extending its lifespan. Tissue was analyzed by standard histopathology (H and E).

Results: Primary PK values Cmax, Tmax, AUC (0-120) for saline and excipient infused groups are depicted in Figure 1A and 1B. The excipient group demonstrated lower Tmax, AUC (0-120) and Cmax as compared to saline group. Figure 1C depicts a significantly greater degree of inflammation in all excipient treated groups. Usage of co-infusion with anti-inflammatory agents extends insulin infusion set lifespan.

Conclusion: Insulin excipients induce site specific inflammation that alters insulin PK and diminishes the in vivo insulin bioavailability. Confirmation in a porcine model is underway.

Disclosure

M.K. Hidau: None. C. Kesserwan: None. Y. Qiao: None. D. Kreutzer: Other Relationship; Self; Abbott Laboratories, cell and molecualar tissue enginnering (cmte). U. Klueh: Research Support; Self; Abbott. Other Relationship; Self; Cell and Molecular Tissue Engineering, LLC.

Funding

The Leona M. and Harry B. Helmsley Charitable Trust
102-OR: Detection of Diabetes from Whole-Body Magnetic Resonance Imaging Using Deep Learning
Authors: WAGNER ROBERT , DIETZ BENEDIKT , MACHANN JÜRGEN , SCHWAB PATRICK , DIENES JULIA K. , REICHERT STEFFEN , BIRKENFELD ANDREAS L. , HAERING HANS-ULRICH , SCHICK FRITZ , STEFAN NORBERT , HENI MARTIN , PREISSL HUBERT , SCHÖLKOPF BERNHARD , BAUER STEFAN , FRITSCHE ANDREAS
Published: June 2020

Obesity is one of the main drivers of the globally rising prevalence of type 2 diabetes (T2D). Yet, obesity is not uniformly associated with metabolic consequences. The location of fat accumulation is critical for metabolic health. Specific patterns of body fat distribution, such as an increased ratio of visceral to subcutaneous fat, are closely related to insulin resistance which is crucial in the pathogenesis of T2D. There might be further, hitherto unknown features of body fat distribution which could additionally contribute to the disease. We used a machine learning approach with dense convolutional neural networks (DCNN) to detect diabetes related variables from 2371 T1-weighted whole-body magnetic resonance image (MRI) data sets. Each single measurement was labelled by sex, age, BMI, insulin sensitivity, HbA1c and prediabetes or incident diabetes. The result was compared to conventional models using segmented body fat compartment volumes. Anatomical labels were assigned to locations in the DCNN gradient heatmaps that are critical for discrimination. The AUC-ROC was 0.87 for the discrimination of diabetes and 0.68 for prediabetes. Classification performance was superior to conventional models. Mean absolute regression errors were comparable to those of the conventional models. Heatmaps clearly showed that lower visceral abdominal regions were most critical in diabetes classification, while other significant areas comprised upper legs, arms and the neck region.Our results show that diabetes is detectable from whole-body MRI without any blood glucose measurement. Our technique of heatmap visualization unravels plausible anatomical regions and highlights the leading role of fat accumulation in the lower abdomen in the pathogenesis of T2D.

Disclosure

R. Wagner: Advisory Panel; Self; Novo Nordisk A/S. Speaker’s Bureau; Self; Novo Nordisk A/S. Other Relationship; Self; Eli Lilly and Company. B. Dietz: None. J. Machann: None. P. Schwab: Employee; Self; Roche Pharma. J.K. Dienes: Advisory Panel; Spouse/Partner; Novo Nordisk A/S. Speaker’s Bureau; Spouse/Partner; Novo Nordisk A/S. Other Relationship; Spouse/Partner; Eli Lilly and Company. S. Reichert: Other Relationship; Self; Lilly Diabetes. A.L. Birkenfeld: None. H. Haering: None. F. Schick: None. N. Stefan: None. M. Heni: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi. Speaker’s Bureau; Self; Novo Nordisk A/S. H. Preissl: None. B. Schölkopf: None. S. Bauer: None. A. Fritsche: None.

Funding

German Federal Ministry of Education and Research (01GI0925)
1025-P: Degludec-to-Glargine Transition: The First Real-World Study
Authors: CHAO JING , HIRSCH IRL B.
Published: June 2020

Switching from insulin degludec (iDeg) to another basal insulin is often needed upon admission. No study has reported glycemic data or how clinicians switch patients from iDeg to insulin glargine (iG100) during the acute transition period. We present the first real-world study of transitioning from iDeg to iG100 when patients with T1D or T2D are admitted to the hospital.

This is a retrospective chart review of 244 admissions to a tertiary care center between 2/1/16-10/31/19 to identify patients with T1D and T2D transitioning from iDeg to iG100 inpatient by hospitalists and surgeons. Inclusion criteria: using iDeg ≥ the 4 days prior to admission; documentation of the home dose of iDeg; and having ≥ 24 hours of BG data from the time of admission. Exclusion criteria: not using iDeg consistently within 4 days prior to admission; inability to verify home dose of iDeg; BG >250mg/dL on admission; and using corticosteroids or IV insulin within 4 days of admission. Thirty-one patients with T2D and 7 patients with T1D had analyses performed on their BG values, home iDeg doses, and inpatient iG100 doses between day 1-4 of the admission.

Clinicians gave iG100 at 0-100% of home iDeg dose anytime between 24-72 hours after the last iDeg dose. Patients with T2D used a median of 30U of iDeg at home (range 8-100U) and had a median/SD BG of 170 ± 40mg/dL. No patient with T2D had a BG<70mg/dL, 48% had BG of 250-300mg/dL, and 16% had BG>300mg/dL. Patients with T1D used a median of 13U of iDeg at home (range 3-55U) and had a median/SD BG of 177 ± 53mg/dL. Two patients of T1D had BG<70mg/dL, 86% had BG of 250-300mg/dL, 71% had a BG >300mg/dL, and 0% developed DKA during the transition.

Despite clinicians ordering arbitrary doses and timing of iG100 for this transition, patients with T2D maintained their BG in a safe range, but patients with T1D developed more glycemic variability with hypo- and overt hyperglycemia. Using evidence and knowledge of iDeg’s PK and PD, developing consensus guidelines emphasizing safety of patients with T1D undergoing iDeg to iG100 transition is possible.

Disclosure

J. Chao: None. I.B. Hirsch: Consultant; Self; Abbott, Bigfoot Biomedical, Roche Diabetes Care. Research Support; Self; Medtronic, Omnipod.
1027-P: Predicting Response to Bolus Insulin
Authors: EBY ELIZABETH L. , KELLY NEAL R. , BLODGETT MOIRA , STUBBINS CALLIE , MEADOWS ERIC , BENNEYWORTH BRIAN D. , FARIES DOUGLAS E.
Published: June 2020

Predicting success on a new step in therapy currently relies upon clinical expertise and heuristics. Even after the transition to bolus insulin, many people with diabetes fail to achieve glycemic control. Our objective was to develop a predictive model to classify patients into expected levels of success upon bolus insulin initiation. Machine learning methods were applied to a large nationally representative insurance claims database. Commercially insured adults with T2DM were identified at first observed use of bolus insulin injections. Those with ≥2 HbA1c values in the 15-month follow-up period (N=15,331) were included. HbA1c goal achievement was defined as <8% or at least a 1% reduction from baseline. We trained boosted decision tree ensembles (XGBoost) to assign people into Class 0 (never meeting goal), Class 1 (meeting but not maintaining goal), or Class 2 (meeting and maintaining goal) based on the demographic and clinical data available prior to initiating bolus insulin. Overall, the model’s ROC was 0.79 with greater performance on predicting those in Class 2 (ROC=0.92) than those in Classes 0 and 1 (ROC’s = 0.71 and 0.62, respectively). Among the patients with highest (top 10%) probability of being in each of the three categories, the model accurately separates Class 2 from the others but had difficulty distinguishing between Class 0 and 1 patients. Over 98% of patients predicted to be either Class 0 or Class 1 with high probability were true Class 0 or Class 1 patients. However, only 42% of those highly predicted as Class 0 were Class 0, with >50% being Class 1. Average HbA1c values in the year prior to starting bolus insulin was the most influential predictive factor. Results suggest that predictive modeling using routine healthcare data was reasonably accurate in classifying patients initiating bolus insulin who will achieve and maintain HbA1c goals. The model was less accurate differentiating between patients who never met and those who did not maintain goals. Incorporation of behavioral, psychosocial, or other factors could improve predictions.

Disclosure

E.L. Eby: Employee; Self; Eli Lilly and Company. N.R. Kelly: Consultant; Self; Eli Lilly and Company. Employee; Spouse/Partner; Optum, Inc. Employee; Self; Optum, Inc. Stock/Shareholder; Spouse/Partner; UnitedHealth Group. Stock/Shareholder; Self; UnitedHealth Group. M. Blodgett: None. C. Stubbins: None. E. Meadows: Employee; Self; Eli Lilly and Company. Employee; Spouse/Partner; Eli Lilly and Company. Stock/Shareholder; Spouse/Partner; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. B.D. Benneyworth: Employee; Self; Eli Lilly and Company. D.E. Faries: Employee; Self; Eli Lilly and Company.

Funding

Eli Lilly and Company
1032-P: Time-in-Range during Short-Term Intensive Insulin Therapy Is Associated with Clinical Outcomes in Patients with Newly Diagnosed Type 2 Diabetes
Authors: LIU LIEHUA , XU LIJUAN , KE WEIJIAN , ZHANG PEISHAN , XU CHANGLIU , ZANG DENG , LI YANBING
Published: June 2020

Background: Short-term intensive insulin therapy (SIIT) can reverse β cell dysfunction and induce glycemic remission in patients with newly diagnosed type 2 diabetes. Elimination of glucotoxicity to the maximum extent was considered the major mechanism. This study aimed to investigate the association of time in range (TIR) of predefined glycemic targets during SIIT with clinical outcomes after the therapy.

Methods: SIIT was given to 95 patients with newly diagnosed T2DM using insulin pump. Strict glycemic control (premeal, bedtime or 3am BG 3.9-6.0 mmol/L, 2hBG 3.9- 8.0 mmol/L) was achieved and maintained for 2 weeks. TIR was defined by calculating the percentage of daily eight-point blood glucose values (before and 2 hours after each meal, at bedtime and 3am) within the above-mentioned near-normoglycemic targets. Intravenous glucose tolerance tests were performed before and after SIIT with acute insulin response (AIR), HOMA IR and HOMA B calculated. Patients were followed for 1 year after withdrawal of insulin.

Results: Overall mean TIR was 68±11% during SIIT. After SIIT, both AIR and HOMA B increased while HOMA IR decreased. TIR during SIIT was significantly associated with improvement of AIR (r=0.36, P<0.001) but not with change of HOMA B (r=0.11, P=0.29) or HOMA IR (r=-0.17, P=0.11). One-year remission was observed in 59% (56/95) patients. Higher proportion of patients with TIR≥70% obtained glycemic remission for over 1 year compared with those with TIR<70% (71.4% vs. 49.1%, P=0.036) . In a logistic regression model, TIR≥70% was associated with higher 1- year glycemic remission after adjusting for Age, BMI and baseline A1c (OR 2.60, 95% CI 1.10-6. 13, P=0.03).

Conclusion: Higher TIR during SIIT indicates better recovery of βcell function and long-term glycemic outcomes.

Disclosure

L. Liu: None. L. Xu: None. W. Ke: None. P. Zhang: None. C. Xu: None. D. Zang: None. Y. Li: None.

Funding

National Key Research and Development Program of China (2018YFC1314100); Key Research and Development Program of Guangdong Province (2019B020230001); National Natural Science Foundation of China (81800716)
1038-P: Insulin Glargine 300 U/ml (Gla-300) vs. First-Generation Standard-of-Care Basal Insulin Analogs (SOC-BI) in Insulin-Naïve Patients with Type 2 Diabetes (T2D): Impact of Renal Function on the Outcomes of the Randomized Pragmatic Real-Life Achieve Control S
Authors: MENEGHINI LUIGI , CHENG ALICE , EVENOU PIERRE , GILL JASVINDER , MOHAMED AYAD , UMPIERREZ GUILLERMO E.
Published: June 2020

In the 12-month ACHIEVE Control study, significantly more insulin-naive patients with T2D treated with Gla-300 vs. SOC-BI (glargine 100 U/mL or detemir) achieved the primary composite endpoint of individualized HEDIS A1c target attainment at 6 months without documented symptomatic (≤70 mg/dL) or severe hypoglycemia. This post-hoc analysis explored outcomes in subgroups with estimated glomerular filtration rate (eGFR) of <60, 60 to <90, and ≥90 mL/min/1.73 m2. Patients with eGFR <60 mL/min/1.73 m2 were older and had longer T2D duration. Within each eGFR subgroup, baseline characteristics were generally balanced between treatment groups. Within subgroups, odds ratios for clinical outcomes generally showed trends favoring Gla-300 vs. SOC-BI, consistent with the overall study population (Figure). In patients with eGFR <60 mL/min/1.73 m2, the odds ratio point estimates for absence of documented symptomatic (≤70 mg/dL and <54 mg/dL) or severe hypoglycemia at 6 and 12 months strongly favored Gla-300 (>1.40). The results suggest a potential benefit of Gla-300 vs. SOC-BI for avoiding hypoglycemia in patients with compromised renal function that warrants further evaluation in prospective studies.

Disclosure

L. Meneghini: Advisory Panel; Self; Novo Nordisk Inc., Sanofi US. Consultant; Self; Applied Therapeutics, Sanofi US. A. Cheng: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Boehringer Ingelheim International GmbH, Eli Lilly and Company, HLS Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Medtronic, Merck & Co., Inc., Novo Nordisk A/S, Sanofi. Research Support; Self; Applied Therapeutics, Sanofi. Speaker’s Bureau; Self; Abbott, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Boehringer Ingelheim International GmbH, Eli Lilly and Company, Insulet Corporation, Janssen Pharmaceuticals, Inc., mdBriefCase, Medtronic, Merck & Co., Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. P. Evenou: Employee; Self; Sanofi. J. Gill: Other Relationship; Self; Sanofi US. A. Mohamed: None. G.E. Umpierrez: None.

Funding

Sanofi US
1039-P: Treatment Patterns and Outcomes before and after Human Regular U-500 Insulin Initiation in Patients with Type 2 Diabetes Previously on <200 Units/Day of Insulin
Authors: HOOD ROBERT C. , FAN LUDI , POLLOM ROY D. , BORRA SUJANA , HUANG AHONG , CHEN JIELING
Published: June 2020

Introduction: U-500 regular insulin (U-500R) was developed to help severely insulin-resistant patients meet high insulin requirements (>200 units/day). Here, we described in real-world setting a patient cohort using ≤200 units/day of standard concentration insulin or non-U500R concentrated insulin per pharmacy claims, who were then transitioned to U-500R with an average total daily dose (TDD) of >200 units/day.

Methods: Adults with ≥2 T2D claims who initiated U-500R (index) and had ≥1 HbA1c value in both 9-month pre- and 9-month post-index periods in the Veterans Health Administration database (01JAN2014-30JUN2017) were included. Treatment patterns and outcomes (observed TDDs for index claim, observed TDD, HbA1c, and hypoglycemia events per patient per year (PPPY) in pre and post-index periods) were assessed in both periods. Paired t-test or McNemar’s test was used for descriptives. Mixed linear model (MLM) and zero-inflated negative-binomial mixed model (ZINBM) were used to confirm the effect of U-500R exposure on HbA1c and hypoglycemia, respectively, adjusting for demographics, BMI, comorbidity index and TDD.

Results: Of 1,191 U-500R initiators, mean age was 63 years with 82% white, 96% male, and a mean BMI of 40. TDD for index U-500R claim was 354 units. Mean TDDs (147 units vs. 346 units), HbA1c (9.6% vs. 8.6%), and hypoglycemia (2.0 vs. 3.3) differ significantly pre- and post-index (p≤0.05), respectively. MLM confirmed HbA1c significantly dropped by 0.8% (p<0.01). ZINBM showed a 0.5 PPPY increase in hypoglycemia post-index (p<0.01).

Conclusions: Using insulin claims data, U-500R initiation resulted in a significant TDD increase of 199 units, which was accompanied by a significant drop in HbA1c and a slight increase in hypoglycemia. The low TDD and poor glucose control prior to U-500R initiation indicated poor patient compliance to the prescribers’ dosing intentions.

Disclosure

R.C. Hood: Advisory Panel; Self; Eli Lilly and Company, Insulet Corporation. Speaker’s Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Novo Nordisk Inc. L. Fan: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. R.D. Pollom: Employee; Self; Eli Lilly and Company. Employee; Spouse/Partner; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. Stock/Shareholder; Spouse/Partner; Eli Lilly and Company. S. Borra: Employee; Self; STATinMED. Other Relationship; Self; Eli Lilly and Company. A. Huang: Employee; Self; STATinMED. Other Relationship; Self; Eli Lilly and Company. J. Chen: None.
104-LB: Glucose-Insulin-Potassium (GIK) as a Proposed Treatment for Normoglycemic Diabetic Ketoacidosis: An Old Friend for a New Foe?
Authors: ESPINOZA-PERALTA DIEGO , MONJARDIN-ROCHIN JOSE ALFONSO , BÚRQUEZ-GONZÁLEZ MARIA E. , MIRELES-ZAVALA LEONOR G.
Published: June 2020

Introduction: Glucose, Insulin, and potassium (GIK) infusions were introduced into medical practice to reduce myocardial injury during a heart attack in 1962. Euglycemic diabetic ketoacidosis (EDKA) is a clinical triad comprising increased anion gap metabolic acidosis, ketonemia or ketonuria and blood glucose levels <250mg/dL. Based on common treatment delays due lack of hyperglycemia, we decided to start a new proposed protocol for patients with confirmed EDKA that included the use of GIK and compared them with historical controls before the protocol was established. GIK solution was prepared with Dextrose 5% solution 500 cc, 10 UI of short acting insulin al 10 mmol KCl. At al initial rate of 100 ml/hr.

Objectives: Describe general characteristics and compare time to remission, length of ICU stay and length of hospital time between patients with SGLT2i-associated EDKA in whom GIK was used compared to standard care.

Design: A Cohort study was designed to compare objectives between EDKA patients treated with a GIK-adapted protocol versus previous patients treated with standard of care of DKA. Patients and Methods: 4 Patients with EDKA treated with new protocol were compared with 7 previous patients treated with ADA recommendations for DKA.

Results: 41.66% of patients were male, type 2 diabetes was initially diagnosed in 66.66% of patients. No differences in ER characteristics between standard vs. GIK group. The use of GIK as an add-on treatment to standard care was associated with a significant lower time to resolution (1.5±0.5 vs. 3.57±1.61, p<0.01), fewer ICU days (2.5±0.57 vs. 5.57±1.98, p<0.01), in-hospital days (4.5±0.577 vs. 11.85±3.43, p<0.01). No differences in hypoglycemic or hipo/hyperkalemia were found.

Conclusions: With the wide use of SLGT2 inhibitors there has been a similar increase in the number of SGLT2i-associated EDKA. Were propose a different way of management of these patients. More research is needed in this field and entity.

Disclosure

D. Espinoza-Peralta: None. J. Monjardin-Rochin: None. M.E. Búrquez-González: None. L.G. Mireles-Zavala: None.
104-OR: Lifestyle Interventions in Persons with IGT Prolong the Time Free of Major Diabetes-Related Complications: 30-Year Results of the Da Qing Diabetes Prevention Outcome Study (DQDPOS)
Authors: GONG QIUHONG , ZHANG PING , WANG JINPING , CHEN YANYAN , AN YALI , FENG XINXING , CHENG YILING J. , MA JIXIANG , BENNETT PETER H. , LI GUANGWEI
Published: June 2020

Lifestyle interventions in persons with impaired glucose tolerance (IGT) delay the onset of diabetes, but freedom from complications is a major goal of diabetes prevention and management. The extent that lifestyle intervention can delay the onset of the common but serious complications of diabetes is ill-defined. We assessed freedom from any serious diabetes-related complication in the 30-year follow-up data from the Da Qing Diabetes Prevention study in which 576 adults with IGT, randomized to control or lifestyle intervention groups for six-years, were followed from the time of randomization to determine the onset of diabetes and occurrence of any serious diabetes-related complication defined as CVD events or death, severe retinopathy, nephropathy, neuropathy, or death due to acute diabetes complications or infection. We estimated differences between the intervention and control groups in the incidence and time free of serious complications. Lifestyle interventions significantly increased the time free of major serious diabetes-related complications (Table). The study provides yet further evidence supporting the value of implementing lifestyle interventions in persons with IGT.

Disclosure

Q. Gong: None. P. Zhang: None. J. Wang: None. Y. Chen: None. Y. An: None. X. Feng: None. Y.J. Cheng: None. J. Ma: None. P.H. Bennett: Advisory Panel; Self; World Health Organization. Stock/Shareholder; Self; Eli Lilly and Company, Pfizer Inc., Unilever, UnitedHealth Group. Other Relationship; Self; American Diabetes Association, European Association for the Study of Diabetes, European Diabetic Nephropathy Study Group, International Diabetes Federation, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. G. Li: None.
1057-P: Long-Term Testosterone Therapy Results in Remission of Type 2 Diabetes (T2DM) in 34.3% (61 of 178) Men with Hypogonadism and T2DM in a Real-World Registry Study
Authors: HAIDER KARIM S. , HAIDER AHMAD , SAAD FARID
Published: June 2020

Background: In 2018, ADA Standards of Medical Care in Diabetes added measurement of testosterone levels in men with T2DM as new recommendation.

Methods: A registry of men with hypogonadism (testosterone ≤12.1 nmol/L) was initiated in 2004 in a urological practice setting. 356 of 858 patients (41.5%) had T2DM diagnosed and treated in a diabetes center. Of these men, 178 received testosterone undecanoate (TU) injections 1000 mg/12 weeks (T-group) following an initial 6-week interval. Anthropometric and metabolic parameters were measured at least twice a year. Fasting insulin was used to calculate HOMA-IR.

Results: After a mean follow-up of 7.7±3.0 (minimum 2, maximum 11 years), 61 patients (34.3%) were in remission, defined as discontinuation of all diabetes medications and stable HbA1c <6.5%. In men who went into remission, HbA1c dropped from 8.7±1.0% at baseline to 5.4±0.1% at the last measurement, HOMA-IR from 10.2±2.5 to 1.7±0.5. In men who never received insulin, HOMA%S increased from 11.1±1.5 to 15.8±2.4. Anthropometric parameters: Body weight declined progressively from 113.6±13.8 to 90.9±8.4 kg by 22.6±8.0 kg, waist circumference from 111.1±7.5 to 98.3±4.6 cm by 12.6±4.3 cm. All patients were on metformin at baseline. 22 patients were on insulin. The average observation time was 130.7±25.9 months (10.9±2.2 years). The average time to discontinuation of diabetes medication was 8.6±2.9 years, average follow-up after achieving remission 2.5±2.3 years. Medication adherence to TU was 100% as all injections were administered in the office and documented. PSA and hematocrit stayed within normal range during the entire observation period.

Discussion: The effects of testosterone were likely mediated by sustained weight loss, increased lean body mass and a profound and sustained reduction of insulin resistance.

Conclusions: Long-term testosterone treatment in men with hypogonadism may result in remission of T2DM.

Disclosure

K.S. Haider: None. A. Haider: None. F. Saad: Consultant; Self; Bayer AG. Stock/Shareholder; Self; AbbVie Inc., Bayer AG.

Funding

Bayer AG
1088-P: Postprandial Dynamics of Glucagon Secretion in Type 2 Diabetic Patients: Changes Associated with Short-Term Improvements in Glycemic Control
Authors: KANAI RINA , MORI YUTAKA , NISHIMURA RIMEI
Published: June 2020

Objective: Type 2 diabetic patients were examined for their postprandial dynamics of glucagon secretion as well as for changes in these dynamics associated with short-term improvements in their glycemic control.

Methods: A total of 75 type 2 diabetic patients admitted for glycemic control who were not receiving incretin-related drugs (I) and SGLT2 inhibitors (S) at admission, 5 type 1 diabetic patients, 5 nondiabetic patients were subjected to meal tolerance tests (MTTs) during early morning fasting hours at admission. Blood samples were drawn from these patients preprandially, and 30, 60, and 120 minutes postprandially to measure their glucose, C-peptide and glucagon (Mercodia) values. Of the type 2 diabetic patients, those who improved glycemic control without both I and S (n = 10), were examined for changes in the postprandial dynamics of glucagon associated with improvements in glycemic control.

Results: The AUC C-peptide values was shown to be the lowest in type 1 diabetic patients, followed by type 2 diabetic patients and nondiabetic patients, and with AUC-glucose values and AUC-glucagon values were shown to be the highest in type 1 diabetic patients, followed by type 2 diabetic patients and nondiabetic patients. Of the type 2 diabetic patients, those with BMI ≥ 25 kg/m2 and BMI < 25 kg/m2 were not significantly different in their AUC glucose, while those with BMI ≥ 25 kg/m2 had significantly larger AUC C-peptide and AUC glucagon values than those with BMI < 25 kg/m2. MTTs performed after improving glycemic control showed significantly smaller AUC glucose, significantly elevated AUC C-peptide, and significantly smaller AUC glucagon values in those improving glycemic control without both I and S after admission.

Conclusions: Study results are in agreement with the conventional finding that decreased α-cell insulin action associated with decreased insulin secretion or insulin resistance leads to glucagon over-secretion secondarily.

Disclosure

R. Kanai: None. Y. Mori: None. R. Nishimura: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Speaker’s Bureau; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly Japan K.K., Medtronic, Merck & Co., Inc., Novo Nordisk Inc., Sanofi K.K., Takeda Pharmaceutical Company Limited.
1089-P: A Phase 1, Randomized, Double-Blind, Placebo-Controlled Multiple Ascending Dose Study of HD-6277, a Potent and Selective G-Protein-Coupled Receptor 40 (GPR40) Agonist, in Patients with Type 2 Diabetes Mellitus
Authors: KIM KI-HWAN , YANG HYE-JUNG , BAEK MYOUNGKI
Published: June 2020

Previously, HD-6277 was reported about its safety and tolerability in healthy volunteers both in single ascending doses (SAD) and multiple ascending doses (MAD) study over all doses under fasting conditions. Based on these results, two doses with 25mg and 100 mg were selected and administered for 28 days in T2DM patients. 20 subjects were randomized (7:3) in two cohort as an exploratory study. No serious adverse events (AEs) or discontinuations as a result of AEs occurred in T2DM patients. The geometric mean Cmax values at day 1 were 2236 and 9422 ng/mL and the geometric mean AUC24 values were 26160 h*ng/mL and 111100 h*ng/mL, respectively, for the 25 and 100 mg dose levels. Following daily oral doses for 14 days, the geometric mean Cmax,ss values were 3993 to 17400 ng/mL and the geometric mean AUC24,ss values were 59270 h*ng/mL and 261300 h*ng/mL with time to median maximum plasma concentration of 1.0 and 1.5 hours, respectively. Results for multiple dose administration of 100 mg in T2DM patients were comparable to those observed in healthy subjects in SAD and MAD study. The geometric mean CL,ss/F was consistent across the dose levels and approximately 0.4 L/h. The geometric mean accumulation ratio for AUC was 2.27 and 2.35 for the 25 and 100 mg dose levels, indicating modest accumulation of HD-6277 following multiple dose administration, which showed comparable profile with that of healthy subjects ranged from 2.14 to 2.34 across the dose levels in MAD study. Therefore, HD-6277 was safe, well tolerated and showed dose-related plasma exposure when the drug is administered at doses ranging from 25 to 100 mg in T2DM patients.

Disclosure

K. Kim: None. H. Yang: Employee; Self; Hyundai Pharm. Co,.Ltd. M. Baek: None.

Funding

Korean Ministry of Health and Welfare (HI17C2529)
109-OR: Genetic Discrepancy of HLA Class I Alleles in Chinese Patients with Type 1 Diabetes at Different Onset Ages
Authors: JIANG ZIYU , REN WENQIAN , XIAN YINGXIN , YAN JINHUA , YANG DAIZHI , LUO SIHUI , ZHENG XUEYING , XU WEN , BEI JIN-XIN , GROOP LEIF , WENG JIANPING
Published: June 2020

Association between HLA class I genes and onset ages of type 1 diabetes (T1D) has been reported in Europeans—risk A*2402 and B*3906 were associated with an earlier age at onset. However, there exists considerable heterogeneity in different populations and individuals of T1D. Its incidence varies dramatically by country and region, ranging from > 60 per 100000 persons years in Finland to 1.01 per 100000 persons years in China. With latter, as many as 65% of the newly diagnosed patients occurred among adults. Furthermore, little is known about the distribution of HLA class I alleles in Chinese patients with T1D at different onset ages. To clarify the contribution of HLA class I genes to T1D with different onset ages in Chinese, 376 patients with T1D and 500 healthy controls were enrolled in this study to analyze HLA-A, B, C alleles conditioning on DRB1-DQA1-DQB1 haplotypes. Among them, 159 patients with an onset age < 15 years were assigned into early-onset group (EG) while the rest 217 patients constituted the late-onset group (LG). After adjustment for linkage disequilibrium with HLA class II, A*24:02:01 (OR 2.7), B*54:01:01 (OR 4.1) and C*15:02:01 (OR 7.8) were associated with susceptibility in EG patients, while A*24:02:01 (OR 2.3), B*15:02:01 (OR 2.5), B*54:01:01 (OR 3.6) and C*08:01:01 (OR 2.0) were predisposing in LG patients when compared with control subjects. Besides, B*46:01:01 (OR 0.4) conferred protection against T1D in EG patients, while B*46:01:01 (OR 0.5) and A*02:07:01 (OR 0.6) were protective in LG patients. When comparing the distribution of HLA class I genes between EG and LG, the data showed that the frequency of A*11:01:01 was higher in LG than EG. When A*11:01:01 was analyzed in patients at all ages using linear regression, it showed a positive correlation between A*11:01:01 and T1D onset age.

In conclusion, the data showed that HLA class I alleles play a role in susceptibility to T1D with different onset ages among Chinese patients, which is independent from DR-DQ haplotypes.

Disclosure

Z. Jiang: None. W. Ren: None. Y. Xian: None. J. Yan: None. D. Yang: None. S. Luo: None. X. Zheng: None. W. Xu: None. J. Bei: None. L. Groop: None. J. Weng: None.

Funding

National Natural Science Foundation of China (81530025); National Key Research and Development Program of China (2017YFC1309603); Sun Yat-sen University (2007030)
1093-P: Association between First-Line Monotherapy with Metformin and the Risk of Atrial Fibrillation in Patients with Type 2 Diabetes Mellitus
Authors: TEKIN ZEHRA , MILINOVICH ALEX , JI XINGE , BAUMAN JANINE , KATTAN MICHAEL , PANTALONE KEVIN M. , ZIMMERMAN ROBERT S. , CHUNG MINA K. , KASHYAP SANGEETA
Published: June 2020

Background: Atrial fibrillation (AF) is the most frequent cardiac arrhythmia and is associated with an increased risk of thromboembolic events, heart failure, and frequent hospitalizations. Type 2 diabetes mellitus (T2DM) has one of the strongest associations with AF with an overall 35% increased risk. Metformin is the first-line medication for T2DM and it has been proposed to have anti-inflammatory, pro-metabolic and cardioprotective benefits, but its effect on AF is not well studied.

Our objective was to investigate whether the initial metformin monotherapy was associated with reduced AF rates compared to other non-insulin agents.

Methods: This retrospective cohort analysis involved adults with newly diagnosed T2DM between 2007 and 2017, without any history of arrhythmias or contraindications to metformin use including GFR less than 30 ml/min who initiated a single antidiabetes therapy (except insulin). A multivariate analysis was performed to control for other variables that may have impacted the association between initial therapy with metformin and the outcomes of interest.

Results: Out of 42384 cases with newly diagnosed diabetes, 5664 patients met the inclusion criteria. The majority of patients initiated monotherapy with metformin (81%), followed by sulfonylureas (13%) and thiazolidinediones (4%). The 10-year cumulative incidence of AF in the metformin group was 5.2% vs. 8.1% with others. Competing risk analysis did not demonstrate reduced rates of AF with metformin use (HR 0.92 95% CI 0.69 to 1.21; P = 0.55). Increased age and the presence of CHF were associated with significantly higher risk of AF (HR: 1.29, 95% CI: 1.21 to 1.37; P<0.001; HR: 2.73, 95% CI: 1.62 to 4.61; P<0.001, resp).

Conclusion: In this observational study following patients with newly diagnosed T2DM, first-line therapy with metformin, when compared to other non-insulin antidiabetes therapies, was not found to be associated with a decreased risk of developing AF.

Disclosure

Z. Tekin: None. A. Milinovich: Research Support; Self; Novartis AG, Novo Nordisk Inc. X. Ji: Research Support; Self; Merck & Co., Inc., Novo Nordisk Inc. J. Bauman: None. M. Kattan: Consultant; Self; GlaxoSmithKline plc. Research Support; Self; Boehringer Ingelheim (Canada) Ltd., Novo Nordisk Inc. K.M. Pantalone: Consultant; Self; Bayer Inc., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. Research Support; Self; Merck & Co., Inc., Novo Nordisk Inc. Speaker’s Bureau; Self; AstraZeneca, Merck & Co., Inc., Novo Nordisk Inc. R.S. Zimmerman: Research Support; Self; Bayer U.S., Merck & Co., Inc., Novo Nordisk A/S. Speaker’s Bureau; Self; LifeScan, Inc., Merck & Co., Inc. Stock/Shareholder; Self; Baxter, Bristol-Myers Squibb, Pfizer Inc., Procter & Gamble Company. M.K. Chung: None. S. Kashyap: Other Relationship; Self; GI Dynamics Inc.
1095-P: Exendin 4 Decreases Tumor Volume through Attenuation of psma-Induced Activation of NfκB Pathway in HPV-Induced Diabetes/Cancer Model
Authors: MAO DANDAN , CHAN JULIANA C.
Published: June 2020

Background: The diabetes-cancer link may be mediated by inflammation due to infection such as Human Papilloma Virus (HPV). Exendin 4, a Glucagon-like-peptide 1 agonist, has anti-hyperglycemic and anti- inflammatory effect and can attenuate certain cancer growth.

Methods: We used RNA microarray analysis to detect the gene expression after Exendin 4 treatment in the db/db mouse tumor, which was established by inoculation of mouse PV cancer cells (CUP-1). The latter originates from the kidney of baby C57BL/6J mice expressing HPV-16 E7 oncogene. We examined the effect of Exendin 4 on cell proliferation, apoptosis and gene expression along the inflammatory pathway in CUP-1 under different glucose environment. We developed CUP-1 cells with or without target gene overexpression (OE) or downregulation (DR) for inoculation into the db/db mouse. We compared RNA expression of the target gene in cervical cancer specimen from patients with or without diabetes.

Results: RNA expression of proteasome 20s (psma) was decreased after Exendin 4 treatment in the db/db mouse tumor. High glucose environment increased cell proliferation in CUP-1 cells, which was enhanced after OE of psma but attenuated after DR of psma. Exendin 4 suppressed NFκB P65 and IκB activation in CUP-1 cells under high glucose medium. After inoculation of CUP-1 cells with DR and OE of psma, the tumor size was decreased and increased in db/db mice respectively. Exendin 4 decreased the tumor volume in the db/db mice of psma OE group. In human cervical cancer specimen, RNA expression of psma was increased in patients with diabetes versus those without diabetes.

Conclusion: High glucose increased expression of psma, which activated NFκB inflammation pathway and promoted carcinogenesis. Exendin 4 suppressed the NFκB pathway activation and decreased tumor volume with corroborative evidence from human samples, suggesting that the anti-cancer effect of Exendin 4 might be mediated by the psma-NFκB pathway.

Disclosure

D. Mao: None. J.C. Chan: None.
110-OR: Type 2 Diabetes (T2D)–Associated TCF7L2 Genetic Variants and Indices of Insulin Secretion and Sensitivity in Individuals at Risk for Type 1 Diabetes (T1D)
Authors: REDONDO MARIA J. , WARNOCK MEGAN V. , BOCCHINO LAURA E. , GEYER SUSAN , PUGLIESE ALBERTO , STECK ANDREA , LIBMAN INGRID , EVANS-MOLINA CARMELLA , BECKER DOROTHY J. , SOSENKO JAY , BACHA FIDA ,   TYPE 1 DIABETES TRIALNET STUDY GROUP
Published: June 2020

In individuals with new onset T1D, T2D-associated TCF7L2 genetic variants are associated with lower area-under-the curve (AUC) glucose and higher AUC C-peptide responses to a mixed meal. We aimed to test whether TCF7L2 variants affect glucose metabolism in nondiabetic islet autoantibody-positive (AbPos) individuals. We studied 1065 TrialNet Pathway to Prevention Study participants (AbPos relatives of persons with T1D) with TCF7L2 SNPs who underwent oral glucose tolerance tests (OGTT) (mean age 16.3 yrs, 63% <18 years old, 91.1% non-Hispanic, 47.7% male; T2D-associated TCF7L2 SNP: 48.1% 0 alleles, 43.9% 1 allele, 8% 2 alleles). We assessed the contribution of TCF7L2 SNP variants on Fasting (FIIS) and OGTT Index of Insulin Sensitivity (OIIS), Insulin Secretion (OIISec), and Disposition Index (ODI) with univariate and multivariate analyses. Then we studied the interaction between TCF7L2 SNP and BMI. With Bonferroni correction for multiple comparisons, p-values <0.0086 were considered statistically significant. Insulin sensitivity and secretion indices were significantly associated with age (FIIS, OIIS, OIISec), BMI Z-score (FIIS, OIIS, OIISec, ODI) and Hispanic ethnicity (FIIS, OIIS) but not sex in univariate analyses. TCF7L2 SNP was not significantly associated with these indices in univariate or multivariate analyses adjusting for BMI, age, sex and race-ethnicity. There was a significant interaction between BMI and presence of 2 (vs. 0) TCF7L2 SNP alleles on insulin sensitivity (OIIS) in children (p=0.0079) but not adults (p=0.94). After adjusting for age, ethnicity and sex, the difference did not reach statistical significance (p=0.0135). Restricting to non-obese participants, the results were similar. In sum, in nondiabetic AbPos individuals, the TCF7L2 variant does not appear to impact insulin sensitivity or secretion indices after accounting for BMI, age, sex and race-ethnicity.

Disclosure

M.J. Redondo: None. M.V. Warnock: None. L.E. Bocchino: None. S. Geyer: None. A. Pugliese: None. A. Steck: None. I. Libman: Consultant; Self; Novo Nordisk A/S. C. Evans-Molina: Consultant; Self; Bristol-Myers Squibb. D.J. Becker: None. J. Sosenko: None. F. Bacha: Research Support; Self; AstraZeneca, Takeda Development Center Americas, Inc.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases