bluuebunny/crossref_metadata_2025_split huggingface dataset:
113-OR: ADA Presidents' Select Abstract: Dishabituation with High Intensity Exercise Improves Epinephrine Response and Symptomatic Awareness to Hypoglycemia in People with Type 1 Diabetes and Impaired Awareness of Hypoglycemia
Authors: FARRELL CATRIONA M. , WEST DANIEL J. , HAPCA SIMONA M. , JONES TIMOTHY , MCNEILLY ALISON D. , MCCRIMMON RORY J. 
Published: June 2019

Impaired awareness of hypoglycemia (IAH) affects approx. 20-25% of all people with type 1 diabetes (T1D) and is a major risk factor for severe hypoglycemia. We recently proposed that IAH may develop as a form of adaptive memory to repeated hypoglycemia; referred to as Habituation. Consistent with this hypothesis, we demonstrated restoration of defective counterregulatory (CRR) responses to hypoglycemia in a rodent model of IAH following introduction of a novel stress stimulus [high intensity exercise (HIT)]; referred to as Dishabituation. In this study we sought to further test our hypothesis by examining whether a single episode of HIT would amplify counterregulatory response to subsequent hypoglycemia in people with T1D who had IAH (assessed by Gold score ≥4, Modified Clark score≥4 or DAFNE hypoglycaemia awareness rating 2 or 3). We recruited 12 participants to a single-centre, randomized, cross-over study. Individuals were randomized to one episode of HIT (4 x 30 s cycle sprints [2 min recovery] at 150% of max Watts achieved during VO2peak assessment) or rest. The following day they underwent a 90-minute hyperinsulinaemic hypoglycemic clamp study at 2.5 mmol/l with measurement of hormonal CRR and symptom scores. Each clamp study was separated by at least 2-weeks. We found that a single episode of HIT led to a 30% increase in the epinephrine response [mean (SEM) 418.8 +/- 62.84 vs. 541.1 +/- 70.5 pg/ml; p&lt;0.05] accompanied by a significant increase in total symptom scores (Edinburgh Hypoglycemia scale: 24.25 +/- 2.96 vs. 27.5 +/- 3.9, p&lt;0.05) during equivalent hypoglycemia induced the following day. These findings are consistent with the hypothesis that IAH develops in people with T1D as a habituated response and that introduction of a novel stressor can restore, at least partially, the CRR response to hypoglycemia. HIT may represent a novel therapeutic intervention for people with IAH.

Disclosure
C.M. Farrell: None. D.J. West: Research Support; Self; Arla Foods Ingredients, Dexcom, Inc. S.M. Hapca: None. T. Jones: Research Support; Self; Dexcom, Inc., Medtronic MiniMed, Inc. Speaker's Bureau; Self; Eli Lilly and Company, Roche Diabetes Care. A.D. McNeilly: None. R.J. McCrimmon: Advisory Panel; Self; Eli Lilly and Company, Novo Nordisk A/S, Sanofi-Aventis. Research Support; Self; The Leona M. and Harry B. Helmsley Charitable Trust.

Funding
JDRF; Diabetes UK
1133-P: Four Days of Hyperoxia Exposure Confers Sustained Improvement in Glucose Homeostasis
Authors: JAIN SHALINI , HARRISON ALEXANDRIA V. , LORENZO FELIPE , MCCLAIN DON 
Published: June 2019

Obesity and type 2 diabetes are co-morbidities, and their prevalence is continually growing. In obesity, in the face of lipid accumulation, adipose tissue become hypoxic with reduced blood flow, accompanied by low grade inflammation and insulin resistance. We therefore hypothesized that exposure to high oxygen (hyperoxia) could improve glucose homeostasis in obesity. We treated normal and fast-food diet (40% fat)-induced obese mice (10 months old) with hyperoxia (95%) for 4 days and quantified the effects on glucose homeostasis and insulin sensitivity. We found that immediately after the hyperoxic treatment, glycemia was modestly higher compared to pretreatment levels. However, both fasting and post-challenge blood glucose levels were significantly decreased after 6 days of hyperoxia treatment in both normal (28±8%; p=0.01) and obese mice (36±4%; p=0.007)). Plasma insulin levels decreased by 41% in both normal (p=0.0026) and obese (p=0.0033) mice and Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) values were also significantly decreased (63±4%; p=0.0009 in normal and 55±13%; p=0.0049 in obese mice)after hyperoxia treatment, indicating that the improvements in glucose homeostasis were associated with improved insulin sensitivity. Surprisingly, these metabolic improvements were maintained more than one month after hyperoxia treatment, and occurred without significant effects on weight. These results demonstrate that exposure to hyperoxia improves fasting blood glucose levels, glucose tolerance and insulin sensitivity, suggesting that the hyperoxia treatment may provide a new approach for supportive treatment of diabetes and obesity.

Disclosure
S. Jain: None. A.V. Harrison: None. F. Lorenzo: None. D. McClain: None.

Funding
U.S. Department of Veterans Affairs; National Institute of Diabetes and Digestive and Kidney Diseases
1142-P: Efficacy and Safety of Antidiabetes Treatment in Adjunct to Insulin in Type 1 Diabetes
Authors: CAI XIAOLING , YANG WENJIA , ZHANG SIMIN , JI LINONG 
Published: June 2019

Aims: To evaluate the efficacy and safety of antidiabetes treatment in adjunct to insulin in type 1 diabetes.
Methods: A systematic search of MEDLINE, Embase and Cochrane Central Register of Controlled Trials was made from the beginning date to June 2018.
Results: A total of 48 studies were included in the meta-analysis. Compared with placebo, treatment with metformin, treatment with a-glucosidase inhibitor (AGI), treatment with GLP-1 receptor agonist, treatment with SGLT2 inhibitor, treatment with pramlintide all showed significant decrease in HbA1c from baseline (Table 1). Compared with placebo, treatment with metformin, treatment with GLP-1 receptor agonist, treatment with SGLT2 inhibitor, treatment with pramlintide all resulted in significant decrease in insulin dosage from baseline (Table 1).
Conclusion: Compared with placebo, in type 1 diabetes patients, in adjunctive to insulin treatment, treatment with metformin, treatment with GLP-1 receptor agonist, treatment with SGLT2 inhibitor, treatment with pramlintide all resulted in significant decrease in HbA1c and insulin dosage from baseline.

Disclosure
X. Cai: None. W. Yang: None. S. Zhang: None. L. Ji: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Eli Lilly and Company, Merck KGaA, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk A/S, Roche Pharma, Sanofi, Takeda Pharmaceutical Company Limited. Research Support; Self; AstraZeneca, Bristol-Myers Squibb Company, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis AG, Roche Pharma, Sanofi.
1157-P: Two-Year Results of Multicenter, Prospective Study of Metabolic Surgery in Obese Type 2 Diabetes Mellitus Subjects in China
Authors: BAO YUQIAN , LIANG HUI , ZHANG PIN , WANG CUNCHUAN , JIANG TAO , ZHANG NENGWEI , ZHU JIANGFAN , YU HAOYONG , HAN JUNFENG , LIN SHIBO , YANG JINGGE , YANG WAH , CHEN SHU , DU DEXIAO , MA YINGZHANG , FEGELMAN ELLIOTT J. , SCHWIERS MICHAEL , WAGGONER JASON , YANG TENGFEI , ZHANG RONGRONG , JIA WEIPING 
Published: June 2019

Introduction: Metabolic surgery, including Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG), is the only proven means of sustained weight loss and type diabetes mellitus (T2DM) remission/control but data are limited in China.
Method: Patients underwent laparoscopic RYGB or SG at 6 Chinese sites from Aug 2014 to Jan 2016 and returned for follow-up regularly after surgery. We evaluated the impact on a composite measure of glycemic control, which was defined as Complete Remission: HbA1c &lt; 6% and FPG &lt; 5.6 mmol/L for 1 year absent antidiabetic medications; Partial Remission: HbA1c 6 - 6.4% and FPG 5.6 - 6.9 mmol/L for 1 year absent antidiabetic medications; Improvement: Reduction in HbA1c (&gt; 1%) or FPG (&gt;1.4 mmol/L) or reduction accompanied by a decrease in antidiabetic medication for at least 1 year; Unchanged: Absence of remission or improvement; Recurrence: HbA1c or FPG in the diabetic range or need for antidiabetic medication after initial remission.
Results: There were 101 procedures completed. The mean (±SD) age of the patients was 37.1±9.7 years, and 52% were women. The mean BMI was 35.0±5.0 and mean HbA1c was 8.1±1.7% at baseline. Outcomes at 2-year follow-up were available for 80 patients (63 RYGB and 17 SG) and showed substantial improvements. Complete or partial remission at 2 years was achieved in at least 83% of patients in two groups (33 [53.2%] and19 [30.6%] in RYGB; 12 [70.6%] and 3 [17.6%] in SG), less than 5% were unchanged and recurrence was not seen in either group. There was a significant reduction in HbA1c from baseline in both RYGB and SG (-2.4 ± 1.8% [P&gt;0.001] and -2.1 ± 1.8% [P&gt;0.001]). Concurrent significant improvements in cardiometabolic parameters such as triglycerides and blood pressure, and reductions in antidiabetic medication usage were also observed.
Conclusion: The 2 years data demonstrate a clinically meaningful impact on a composite measure of glycemic control with a majority of patients demonstrating complete remission of T2DM in both groups.

Disclosure
Y. Bao: None. H. Liang: None. P. Zhang: None. C. Wang: None. T. Jiang: None. N. Zhang: None. J. Zhu: None. H. Yu: None. J. Han: None. S. Lin: None. J. Yang: None. W. Yang: None. S. Chen: None. D. Du: None. Y. Ma: None. E.J. Fegelman: Employee; Self; Ethicon US, LLC. M. Schwiers: Employee; Self; Ethicon, Inc. J. Waggoner: Employee; Self; Ethicon, Inc. T. Yang: Employee; Self; Johnson & Johnson Medical Devices Companies. R. Zhang: None. W. Jia: None.

Funding
Ethicon Inc.
1173-P: Therapeutic Response to Metformin Monotherapy in Type 2 Diabetes Is Associated with Butyrate-Producing Gut Microbiota
Authors: HUNG WEI-WEN , HUNG WEI CHUN 
Published: June 2019

Type 2 diabetes is the fifth leading cause of death in Taiwan. The metabolic derangements in type 2 diabetes have been attributed to the compositional changes of the gut microbiota. Metformin, as the first-line treatment for type 2 diabetes, has been found to exert its antidiabetic actions through modulations of the gut microbiota. However, to our knowledge, no literature reported the associations between the therapeutic response to metformin monotherapy and the compositions of the gut microbiota. Thus, we hypothesized that the compositions of gut microbiota differ in type 2 diabetes with failure and success of metformin monotherapy. We had recruited 381 type 2 diabetes diagnosed for more than two years in a university hospital. Then based on medical records, we identified 12 subjects as the metformin-failure group and 14 as the metformin-success group, who maintained HbA1C&gt;7% with not only metformin or with metformin monotherapy, respectively. We collected the biochemical data and analyzed the gut microbiota by Illumina sequencing of 16S rRNA gene. The result showed that while the two groups having similar clinical characteristics, the gut microbiota were significantly different by principal coordinates analysis. In addition, the metformin-success group had decreased richness and evenness. Furthermore, butyrate-producing gut microbiota including Butyrivibrio and Blautia producta increased in the metformin-success group. The short-chain fatty acids (SCFAs), including acetate, butyrate, and propionate, are produced by gut microbiota. The imbalance in the ratio of the SCFAs, such as decrease in butyrate and increase in acetate, leads to metabolic derangements in type 2 diabetes. Our finding showed that the metformin-success group were associated with butyrate-producing gut microbiota.
In conclusion, the gut microbiota that can reverse the imbalance of SCFAs might be the key for diabetes to have sustained metabolic benefits with metformin monotherapy.

Disclosure
W. Hung: None. W. Hung: None.

Funding
Kaohsiung Medical University
1176-P: Synthetic Immunomodulatory Peptoids to Control Autoimmunity in Type 1 Diabetes
Authors: RAMAKRISHNAN PARAMESWARAN , POKORSKI JON , DE JESUS TRISTAN J. , CENTORE JOSHUA 
Published: June 2019

Type 1 diabetes is an autoimmune disease associated with hyperglycemia. Increased glucose flux enhances the hexosamine biosynthetic pathway and intracellular posttranslational modification of proteins by the sugar N-acetyl glucosamine (GlcNAc) in a process called O-GlcNAcylation. We discovered that hyperglycemia increases the O-GlcNAcylation of the transcription factor, nuclear factor kappaB (NF-κB) c-Rel at serine 350. O-GlcNAcylation of c-Rel activates c-Rel-dependent transcription of proautoimmune cytokines in T cells and inhibits the expression of T regulatory cell specific transcription factor FOXP3. These reciprocal effects caused by c-Rel O-GlcNAcylation may act as positive feedback accelerator of autoimmunity under hyperglycemia. Hence, blocking the function of O-GlcNAcylated c-Rel will have dual benefits in controlling autoimmune diabetes by diminishing the T cell-mediated autoimmunity and enhancing the T regulatory cell function to suppress autoimmunity. We developed a novel peptoid, called peptoid3 that specifically blocks the function of O-GlcNAcylated c-Rel. We found that peptoid3 treatment significantly decreased T cell receptor-induced, O-GlcNAcylation-dependent expression of proautoimmune cytokines and enhanced FOXP3 expression in T cells. Peptoid3 treatment selectively affected autoimmunity-associated genes and did not exhibit toxicity on survival or proliferation of T cells. Broad inhibition of hexosamine biosynthetic pathway or NF-κB will cause many side effects due to their ubiquitous importance in multiple biological functions. Therefore, inhibitors of O-GlcNAcylated NF-κB c-Rel function may prove long-sought-after specific molecular therapeutic to diminish autoimmunity in type 1 diabetes.

Disclosure
P. Ramakrishnan: None. J. Pokorski: None. T.J. de Jesus: None. J. Centore: None.

Funding
National Institute of Allergy and Infectious Diseases (R01AI116730-01A1)
1178-P: MSDC-0602 Directly Inhibits Mitochondrial Pyruvate Transport
Authors: RAUCKHORST ADAM J. , OONTHONPAN LALITA , TAYLOR ERIC B. 
Published: June 2019

The mitochondrial pyruvate carrier (MPC) occupies a carbohydrate metabolism nexus and is a potential target of thiazolidinediones (TZDs) prescribed to treat the metabolic syndrome. MSDC-0602, a TZD-like, PPARγ sparing molecule, is currently in phase 2B clinical for NASH treatment following positive results in animal studies. Previous research demonstrates that MSDC-0602 inhibits mitochondrial pyruvate oxidation and physically interacts with the MPC. However, the extent to which MSDC-0602 directly inhibits mitochondrial pyruvate uptake has not been fully resolved. Here, we aimed to comprehensively test the action of MSDC-0206 as a specific MPC inhibitor. We examined MSDC-0602 treatment effects on pyruvate oxidation and pyruvate transport by isolated liver mitochondria from normal chow (NCD)- and high fat diet (HFD)-fed mice. MSDC-0602 inhibited pyruvate-driven State III and State IV+Uncoupled respiration in a dose dependent manner. MSDC-0602 reduced pyruvate-driven respiration to levels observed for liver mitochondria isolated from MPC liver knockout (MPC LivKO) mice. NCD and HFD mice showed similar response to MSDC-0602. These data confirm that MSDC-0602 inhibits pyruvate-driven respiration. However, pyruvate oxidation is an indirect measure of MPC activity because it depends upon pyruvate-oxidizing enzymes and electron transport. To directly test the action of MSDC-0602 on mitochondrial pyruvate transport, we performed isolated mitochondria 14C-pyruvate uptake assays. Pyruvate uptake was significantly decreased by MSDC-0602 to rates observed for MPC LivKO mouse liver mitochondria. Finally, we examined effects of MSDC-0602 metabolites and found them to also inhibit isolated liver mitochondria pyruvate oxidation. Together, these data demonstrate that MSDC-0602 directly and specifically inhibits MPC activity as a mechanism for impairing downstream pyruvate utilization. The therapeutic effects of MSDC-0602 may be conferred by MPC inhibition and resulting metabolic adaptations.

Disclosure
A.J. Rauckhorst: None. L. Oonthonpan: None. E.B. Taylor: Research Support; Self; Cirius Therapeutics.

Funding
American Diabetes Association (1-18-PDF-060 to A.J.R.); National Institutes of Health (DK104998); Cirius Therapeutics
1185-P: Predictive Model for Hyperglycemic Events after High Dose Corticosteroid Administration
Authors: SIMONS MORGAN G. , FUTOMA JOSEPH D. , GAO MICHAEL , COREY KRISTIN , SENDAK MARK , WHALEN KRISTA B. , DOSHI-VELEZ FINALE , MCGEE ANN S. , SETJI TRACY 
Published: June 2019

Background: Patients who receive high dose corticosteroids and thereafter become hyperglycemic are at increased risk of inpatient mortality and developing diabetes. However, it is difficult to predict which patients will become hyperglycemic.
Methods: A cohort of 19882 patients with 28845 inpatient encounters between Oct 2014 and Aug 2018 was selected to create a model to predict incident hyperglycemia. Patients in this cohort were 18 years old and had received high dose corticosteroids (20mg/day of prednisone equivalents). Patients who died during admission or were discharged to hospice were excluded. Model features included creatinine, bicarbonate, AST, ALT, and albumin results and total steroid administration dose in the prior 24 hours as continuous variables and the presence of a lactate result in this period as a binary indicator variable. The outcome of hyperglycemic events was defined as patients having a blood glucose value above 180 within 12 hours of steroid administration. A logistic regression analysis was used as the predictive method.
Results: A subset of 71837 steroid administrations were used to create the predictive model and 8278 were used to test the model’s performance (AUC of 0.737).
Conclusion: Several labs in the 24 hours prior to receipt of high dose steroids are associated with hyperglycemia. The presence of a lactate result was the most significant predictor of future hyperglycemia.

Disclosure
M.G. Simons: None. J.D. Futoma: None. M. Gao: None. K. Corey: None. M. Sendak: None. K.B. Whalen: None. F. Doshi-velez: None. A.S. McGee: None. T. Setji: None.
119-LB: Bolus Dosing Accuracy of Two Recent Insulin Pumps
Authors: ZIEGLER RALPH , WALDENMAIER DELIA , MENDE JOCHEN , HAUG CORNELIA , FRECKMANN GUIDO 
Published: June 2019

In continuous subcutaneous insulin infusion (CSII) therapy, bolus doses are delivered to cover meals and to correct high blood glucose values. Data for bolus dosing accuracy were already presented for different insulin pump systems. In this study, two lately released insulin pumps were tested accordingly.
Two new insulin pumps (MiniMed® 670G and mylife™ YpsoPump®) with soft cannula were tested. In an experimental setting following EN 60601-2-24, both pumps were installed with the tip of the cannula in a water-filled beaker placed on an electronic balance. To avoid evaporation an oil film was applied. After a run-in period, 25 successive 1.0 U and 0.1 U boluses and 12 successive 10 U boluses were delivered and weighed individually. In addition, time for a bolus delivery of 10 U was recorded. Each insulin pump was tested 9 times.
While for 10 U and 1 U boluses 100% of deliveries of both pumps were within ±15% of target, only 85% (670G) and 88% (YpsoPump), respectively, of 0.1 U boluses were within these limits. Delivery time of a 10 U bolus was different between the two pumps, 6.7 min (standard speed) and 43 sec (quick) for 670G vs. 19 sec for YpsoPump, but complied with the respective manufacturer’s labeling.
These results fit to the previously tested durable insulin pumps for which similar percentages of deliveries within ±15% of target (100% for 10 and 1 U and 71% to 96% for 0.1 U) were observed. As delivery accuracy decreases with smaller bolus doses, care should be given especially when treating small children with CSII.

Disclosure
R. Ziegler: Advisory Panel; Self; Abbott, Lilly Diabetes, Novo Nordisk A/S, Roche Diabetes Care. D. Waldenmaier: None. J. Mende: None. C. Haug: None. G. Freckmann: Advisory Panel; Self; Abbott, Novo Nordisk Pharma GmbH, Sensile Medical AG. Consultant; Self; Metronom Health Europe, Roche Diabetes Care, Sanofi. Speaker’s Bureau; Self; Ascensia Diabetes Care, Dexcom, Inc., Ypsomed AG.

Funding
Roche Diabetes Care GmbH
1191-P: Sotagliflozin Reduces Glucose Variability and Risk for Hyperglycemia in Adults with Type 1 Diabetes
Authors: KOVATCHEV BORIS , WANG STELLA , OLIVEIRA JULIANA H. , STEWART JOHN A. , LAPUERTA PABLO , CASTRO RITA 
Published: June 2019

Individuals with type 1 diabetes (T1D) face daily challenges in achieving optimal glycemic control by reducing hyperglycemia while avoiding hypoglycemia. Optimization is reflected by the High/Low Blood Glucose Indices (HBGI/LBGI) - established metrics using self-monitored blood glucose, or continuous glucose monitoring (CGM) data, to assess glycemic variability (GV) and predict the risks of hyper- and hypoglycemia with intensification of therapy.
In the phase 3 inTandem1 and 2 studies, sotagliflozin (SOTA), a dual SGLT1 and 2 inhibitor used as adjunct to optimized insulin therapy in adults with T1D, reduced HbA1c vs. placebo. Significant improvement of glucose time in range (70-180 mg/dL) without increasing time &lt;70 mg/dL was previously reported in the pooled CGM substudy. In this analysis (N=265), we evaluated hyper- and hypoglycemic risks with SOTA 200 mg and 400 mg, both taken once daily, using LBGI and HBGI computed from CGM data.
Compared with placebo, HBGI values were lower with SOTA 400 mg at study weeks 4, 12, and 24, and SOTA 200 mg at weeks 4 and 12 (p&lt;0.0001) (Figure).
The percentage of adults in moderate (4.5-9) or high-risk (&gt;9) HBGI categories was reduced with SOTA throughout the study for both dosages, and minimal changes were seen in LBGI values and risk categories.
The CGM profile showed that SOTA reduced GV through a favorable impact on HBGI without changing LBGI.

Disclosure
B. Kovatchev: Advisory Panel; Self; Sanofi. Board Member; Self; TypeZero Technologies, Inc. Consultant; Self; Sanofi, Tandem Diabetes Care. Research Support; Self; Dexcom, Inc., Roche Diabetes Care, Tandem Diabetes Care. Speaker's Bureau; Self; Dexcom, Inc. Stock/Shareholder; Self; TypeZero Technologies, Inc. Other Relationship; Self; Johnson & Johnson, Sanofi. S. Wang: Employee; Self; Sanofi US. J.H. Oliveira: Employee; Self; Sanofi. Employee; Spouse/Partner; Sanofi. J.A. Stewart: Employee; Self; Sanofi. Stock/Shareholder; Self; Sanofi. P. Lapuerta: Employee; Self; Lexicon Pharmaceuticals, Inc. Stock/Shareholder; Self; Lexicon Pharmaceuticals, Inc. R. Castro: Employee; Self; Sanofi US.

Funding
Lexicon Pharmaceuticals, Inc.; Sanofi