bluuebunny/crossref_metadata_2025_split huggingface dataset:
281-OR: Directness and Sustainability of rtCGM Effects on Hypoglycemia: A Secondary Analysis of the Hypode Study
Authors: EHRMANN DOMINIC , HEINEMANN LUTZ , FRECKMANN GUIDO , WALDENMAIER DELIA , HERMANNS NORBERT 
Published: June 2019

The HypoDE study demonstrated that real-time continuous glucose monitoring (rtCGM) can reduce biochemical as well as clinical hypoglycemia in people with hypoglycemia problems. However, it is not clear how quick a reduction of low glucose values via rtCGM occurs and how sustainable this is. We analyzed the rtCGM group of the HypoDE study and compared the 4-week baseline phase with masked rtCGM to three 4-week intervals within the therapy/outcome phase (T/O phase) with open rtCGM (Dexcom G5). Only participants with no recent experience with CGM were included. At baseline, 6.5±6.2% of the glucose values of the 75 participants were below 70 mg/dl and 2.5±3.3% were below 54 mg/dl. In the first week, these percentages dropped significantly to 2.9±0.4%, respectively 0.7±1.3%. For the remainder of the T/O phase, these percentages stayed stable (not crossing the lower 95% CI interval of the baseline values; see Figure). Time-in-Range (TIR) improved significantly in the first 12 weeks and then started to drop to baseline level. rtCGM results in an immediate and significant reduction of level 1 (&lt; 70 mg/dl) and level 2 (&lt; 54 mg/dl) hypoglycemic values. This initial effect can be sustained throughout the entire study period without wear off. The avoidance of hypoglycemia was not associated with a deterioration of TIR.

Disclosure
D. Ehrmann: Advisory Panel; Self; Medtronic. Speaker's Bureau; Self; Abbott, Berlin-Chemie AG, Dexcom, Inc. L. Heinemann: Consultant; Self; Roche Diabetes Care. Research Support; Self; Dexcom, Inc. Stock/Shareholder; Self; Profil Institute for Metabolic Research, ProSciento. 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. D. Waldenmaier: None. N. Hermanns: Advisory Panel; Self; Abbott. Board Member; Self; Eli Lilly and Company. Research Support; Self; Abbott, Berlin-Chemie AG, Dexcom, Inc., Roche Diabetes Care. Speaker's Bureau; Self; Berlin-Chemie AG, Dexcom, Inc., Novo Nordisk A/S.

Funding
Dexcom, Inc.
284-LB: Quantifying and Localizing the Mitochondrial Proteome
Authors: WU YIBO 
Published: June 2019

Mitochondria are essential organelles that regulate a wide range of cellular functions. Here, we have developed data-independent acquisition mass spectrometry (DIA-MS) strategy and have quantified 3648 proteins in 114 proteomes collected from the BXD genetic reference populations in five tissues: liver, heart, brain, brown adipose tissue (BAT) and quadriceps. Protein expression varied more significantly across tissues than across genetic backgrounds. Although we observed broad correlation between transcript and protein expression, genes in the same pathway may have striking difference in regulation on transcript and protein levels, for example the genes in the electron transport chain. We compared two fractions from each tissue, mitochondria and total tissue. By comparing these two fractions, we identified several dozen proteins as mitochondrial proteins, which have not been reported in the literature. Among them, we validated three proteins in mitochondria (MTAP, SOAT2 and IMPDH2), and one protein in the mitochondria-associated membrane (ABCC6). Our results have revealed the disrupted protein composition of complex V of the electron transport chain on protein level, but not on the transcript level. Furthermore, we confirmed UCP1 protein level as a better predictor for cold test response compared with its transcript level. These findings demonstrate the synergy of proteomics and genomics to study complex metabolic processes, and they provide a resource for further discovery and analysis of proteoforms and protein localization.

Disclosure
Y. Wu: None.
286-LB: The Difference in Metabolic Profiles between Liver Cirrhosis Patients and Healthy Control before Liver Cirrhosis Development: A Prospective, Korean Cancer Prevention Study-II Cohort Study
Authors: YOO HYE JIN , KIM MINJOO , HAN YOUNGMIN , YOONJEONG CHOI , LEE JONG HO 
Published: June 2019

Objectives: In the prospective Korean Cancer Prevention Study-II (KCPS-II), we investigated the application of metabolomics to differentiate subjects with incident liver cirrhosis (LC group) from subjects who remained free of LC (control group) during a mean follow-up period of 7 years, with the aim of identifying valuable biomarkers for LC.
Methods: Metabolic alterations were investigated using baseline serum samples from 94 subjects with incident LC and 180 age- and sex-matched LC-free subjects via ultra-performance liquid chromatography (UPLC)-linear-trap quardrupole (LTQ)-Orbitrap mass spectrometry (MS).
Results: A total of 46 metabolites were identified through the metabolic analysis. Among them, 11 metabolite levels were significantly higher, and 18 metabolite levels were significantly lower in the LC group than in the control group. 9 metabolic pathways, including glyoxylate and dicarboxylate metabolism, amino acid metabolism, fatty acid metabolism, linoleic acid metabolism, α-linolenic acid metabolism, and arachidonic acid metabolism, showed significant differences between the two groups. Logistic regression revealed that the incidence of LC was independently affected by serum levels of myristic acid, palmitic acid, linoleic acid, eicosapentaenoic acid (EPA), lysophosphatidic acid (LPA) (18:1), glycolic acid, lysophosphatidylcholine (lysoPC) (22:6), and succinylacetone (R2=0.837, P&lt;0.001).
Conclusions: This prospective study showed the clinical relevance of dysregulation of various metabolisms on the incidence of LC. Additionally, myristic acid, palmitic acid, linoleic acid, EPA, LPA (18:1), glycolic acid, lysoPC (22:6), and succinylacetone were identified as independent variables affecting the incidence of LC.

Disclosure
H. Yoo: None. M. Kim: None. Y. Han: None. C. Yoonjeong: None. J. Lee: None.

Funding
Korean Ministry of Health and Welfare (HI14C2686); Korean National Research Foundation (NRF-2012M3A9C4048762, NRF-2017R1C1B2007195)
286-OR: Phase 3 Results for Dasiglucagon as a Fast and Effective Treatment for Severe Hypoglycemia
Authors: PIEBER THOMAS R. , HOEVELMANN ULRIKE , WILLARD JULIE , PLUM-MOERSCHEL LEONA , MOURITZEN ULRIK , TEHRANCHI RAMIN , ARONSON RONNIE 
Published: June 2019

Introduction: Severe hypoglycemia is one of the most feared adverse outcomes of insulin therapy and requires urgent assistance. The use of currently available glucagon products for rescue treatment of severe hypoglycemia is limited by complex reconstitution steps required before injection, as these products are not stable in solution. As a result, there is compelling evidence that glucagon products are under-prescribed and underused. Dasiglucagon is a stable peptide analog of human glucagon, to be administered via a ready-to-use auto-injector, in development for treatment of severe hypoglycemia.
Methods: In this pivotal Phase 3 trial, the clinical efficacy and safety of 0.6 mg dasiglucagon was compared to placebo and with reference to GlucaGen®. In total, 168 patients with T1D were randomized (2:1:1) and dosed following induced hypoglycemia to reach the glucose target of 55 mg/dL. The primary endpoint was time to PG recovery, defined as first PG increase ≥20 mg/dL after treatment initiation without rescue glucose.
Results: The primary endpoint, time to plasma glucose recovery, was found to be faster for dasiglucagon than placebo. The median time to recovery was 10 min for dasiglucagon vs. 12 and 40 min for GlucaGen® and placebo, respectively (Dasiglucagon vs. Placebo: p&lt;0.001). In the dasiglucagon arm, 65% of patients had recovered within 10 min vs. 49% of patients receiving GlucaGen®. Similarly after 15 min, 99% of patients treated with dasiglucagon had recovered vs. 95% of patients treated with GlucaGen®. There were no serious adverse events in any groups. Nausea and vomiting were reported with similar frequencies for dasiglucagon and GlucaGen® (nausea: 55% and 53%, vomiting: 23% and 19%, respectively).
Conclusion: Dasiglucagon 0.6mg was demonstrated to be a safe, fast and effective treatment option for severe hypoglycemia.

Disclosure
T.R. Pieber: Advisory Panel; Self; ADOCIA, Arecor Limited, AstraZeneca, Novo Nordisk A/S, Sanofi. Speaker's Bureau; Self; Novo Nordisk A/S. U. Hoevelmann: None. J. Willard: None. L. Plum-Moerschel: None. U. Mouritzen: Employee; Self; Zealand Pharma A/S. R. Tehranchi: Employee; Self; Zealand Pharma A/S. R. Aronson: Research Support; Self; AstraZeneca, Becton, Dickinson and Company, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Medtronic, Merck & Co., Inc., Novo Nordisk Inc., Sanofi, Senseonics.
288-OR: Novel Epigenetic Mechanism for Maternal Exercise Effects on Offspring Metabolic Health
Authors: KUSUYAMA JOJI , WAGNER ANA B. , HIRSHMAN MICHAEL F. , GOODYEAR LAURIE J. 
Published: June 2019

Obesity and type 2 diabetes in mothers can initiate a vicious cycle of multi-generational metabolic dysfunction. Conversely, maternal exercise (MatEx) in mice improves offspring metabolic health. We previously found that the mechanism for this critical benefit of MatEx involves multiple epigenetic changes inducing increased expression of TCA and fatty acid oxidation (FAO) genes in offspring liver, leading to enhanced liver function. Here, we hypothesize that maternal high fat diet (MatHFD) and MatEx result in histone modifications, an important means of epigenetic regulation. C57BL/6 female mice were fed chow or HFD, housed with (trained) or without (sedentary) running wheels for 2 weeks before breeding and through gestation. Offspring were chow fed and sedentary and livers studied up to age 52 weeks. Trimethylation of lysine 4 on histone H3 (H3K4me3), a hallmark of active transcription, was decreased in promoters of TCA and FAO genes in offspring livers from MatHFD. Importantly, this decrease was fully reversed in offspring livers from MatEx. In fact, offspring livers from MatEx had increased H3K4me3 in these genes as early as embryonic day 13.5 and at all times after birth. Altered H3K4me3 was associated with changes in H3K4 methyltransferase (HKMT) activity, as MatHFD decreased, and MatEx increased HKMT activity in offspring livers. MatHFD induced protein carbonylation in offspring liver, and MatEx prevented this harmful effect on protein function. LC-MS/MS showed that WDR82, a regulatory component of HKMT, was robustly carbonylated in offspring liver of MatHFD, an effect reversed by MatEx. Overexpression of WDR82 in offspring hepatoblasts from MatHFD recovered H3K4me3 levels and hepatic gene expression. In sum, these data demonstrate that maternal exercise reverses the detrimental effects of maternal HFD on H3K4me3 function, likely via protection of WDR82 from carbonylation. We have identified a novel epigenetic mechanism by which maternal exercise improves offspring metabolic health.

Disclosure
J. Kusuyama: None. A.B. Wagner: None. M.F. Hirshman: Stock/Shareholder; Self; Abbott Laboratories, AbbVie Inc., Amgen Inc., Colgate-Palmolive Company, Medtronic. L.J. Goodyear: None.

Funding
National Institutes of Health (to L.J.G.); Sunstar Foundation (to J.K.)
292-LB: The Exercise-Like Impacts of Conditioned Media Harvested from Cultured Dental Pulp Stem Cells on Myokine Expressions in Skeletal Muscles
Authors: KANADA SAKI , MAKINO ERIKO , NAKAMURA NOBUHISA , MIYABE MEGUMI , ITO MIZUHO , HATA MASAKI , SAIKI TOMOKAZU , MINATO TOMOMI , MIYAZAWA KEN , GOTO SHIGEMI , MATSUBARA TATSUAKI , NARUSE KEIKO 
Published: June 2019

Exercise improves not only glycemic control, but also other metabolic disorders in diabetic patients. Furthermore, exercise also stimulate muscle-derived secreted factors, myokines, via muscle contraction. The receptors of myokines expressed in the whole body and myokines affect autocrine, paracrine, and systemic functions for all people and patients with diabetes. In this study, we have demonstrated that there are exercise-like impacts of conditioned media from cultured dental pulp stem cells (DPSCs) on myokine expressions in skeletal muscles. DPSCs were isolated and cultured from the mandibular incisors of 6-week-old male Sprague-Dawley (SD) rats. Conditioned media from DPSCs (DPSC-CM) was collected after 24-hour culture of DPSCs in the serum-free medium and concentrated by a factor of 10. We firstly investigated the effects of DPSC-CM on exercise-induced myokines, follistatin-like 1 (Fstl1), Fractalkine, and fibroblast growth factor 21 (FGF-21) in C2C12 myotubes. DPSC-CM significantly increased the gene expressions of Fstl1 (209±16%, P&lt;0.01), Fractalkine(182±41%, P&lt;0.05), and FGF-21 (1021±39%, P&lt;0.01) in C2C12 myotubes. To confirm these effects in vivo, we administered DPSC-CM (1.0 ml/rat) into 10 sites of unilateral hindlimb skeletal muscles of male SD rats, and examined the effects on myokine gene and protein expression. DPSC-CM significantly increased Fstl1 gene expression in the gastrocnemius muscles (477±140%, P&lt;0.05). Immunohistochemical staining revealed that the expression of Fstl1 was increased in the DPSC-CM-injected gastrocnemius muscles. These results suggest that there is a novel exercise-like impact of DPSC-CM on skeletal muscles.

Disclosure
S. Kanada: None. E. Makino: None. N. Nakamura: None. M. Miyabe: None. M. Ito: None. M. Hata: None. T. Saiki: None. T. Minato: None. K. Miyazawa: None. S. Goto: None. T. Matsubara: None. K. Naruse: None.
293-OR: Flexible Insulin Therapy: Untethered Insulin Regimen Using Insulin Degludec and Continuous Subcutaneous Insulin Infusion (CSII) in Avidly Exercising Patients with T1D: FIT Untethered Study
Authors: ARONSON RONNIE , LI AIHUA , BROWN RUTH E. , MCGAUGH SARAH , YAVELBERG LOREN , RIDDELL MICHAEL 
Published: June 2019

Athletes with T1D using CSII routinely remove their pump for prolonged periods, predisposing to hyperglycemia and ketosis. We examined the safety and efficacy of an “Untethered” approach - evenly splitting basal insulin between adjusted CSII and a daily injection of insulin degludec. This randomized cross-over study explored glycemic outcomes following in-clinic, fasted exercise (90-minute moderate- and 30-minute high-intensity). After a 1-week run-in, subjects were randomized to Usual CSII or Untethered CSII, for 5-week periods including a week of optimization, and then crossed over. Nineteen patients (age 34 ± 10 (mean ± SD), T1D duration 16 ± 11 years; mean A1C 7.1 ± 0.5) have completed both periods. In the 6 hours following moderate exercise, the Untethered arm showed improved mean glucose and spent 61% more time in range relative to the Usual arm (p&lt;0.001) (Table). Similar trend was seen following high intensity exercise. There were no differences in pre-exercise glucose or total daily insulin dose (TDD). Both regimens were well-tolerated with no serious adverse events. An “Untethered” regimen of injected basal insulin and adjusted-rate CSII is safe and effective in avidly exercising subjects with T1D using CSII and may offer improved glycemic control in the immediate period following moderate-intensity exercise.

Disclosure
R. Aronson: Research Support; Self; AstraZeneca, Becton, Dickinson and Company, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Medtronic, Merck & Co., Inc., Novo Nordisk Inc., Sanofi, Senseonics. A. Li: None. R.E. Brown: None. S. McGaugh: None. L. Yavelberg: None. M. Riddell: Advisory Panel; Self; Xeris Pharmaceuticals, Inc. Research Support; Self; Dexcom, Inc. Speaker's Bureau; Self; Insulet Corporation, Medtronic MiniMed, Inc. Stock/Shareholder; Self; Zucara Therapeutics Inc.

Funding
Novo Nordisk
294-OR: Type 1 Diabetes Patients with Residual Beta-Cell Function Display Improved Time in Euglycemia and Less Glycaemic Fluctuation after Exercise
Authors: TAYLOR GUY S. , SMITH KIERAN , SCRAGG JADINE , BASHIR AYAT , ORAM RICHARD A. , MCDONALD TIMOTHY J. , STEVENSON EMMA J. , SHAW JAMES A. , WEST DANIEL J. 
Published: June 2019

Aims: Exercise can disrupt glycemia in individuals with type 1 diabetes (T1D). A large inter-individual variability in the glucose responses to exercise exists. It is not known how residual beta-cell function in long duration T1D influences glycaemia around exercise.
Methods: Individuals with T1D completed a postprandial urine C-peptide creatinine ratio test (UCPCR), and 25 participants (M/F 14/11, 39.4±12.4 years, HbA1c 58.8±9.3 mmol/mol-1, BMI 25.6±4.0 kg/m2, diabetes duration 21.4±13.7 years) with a range of UCPCR were recruited. Participants were split into undetectable, microsecretors and clinically significant C-peptide groups (&lt;0.001, 0.001-0.2 and &gt;0.2 nmol/mmol, respectively). After a maximum exercise test, participants attended the second visit whereby they completed 45 minutes of walking at 60%VO2peak. Participants then left the laboratory, with the remainder of the trial under free-living control. Blinded continuous glucose monitoring (CGM) was captured for 12 hours before exercise and for 3 days afterwards. Data (mean±SD) were analysed by one way ANOVA with significance accepted at p ≤0.05.
Results: CGM data were successfully captured for 22/25 participants. In the 12 hours prior to exercise, there was no significant differences in CGM between groups. In the first 12 hours post-exercise, the clinical C-peptide group spent significantly more time (83.7±23.2%) in time in euglycemia (3.9-10 mmol/l) compared to the microsecretors (38.8±16.9%, p =0.002) and undetectable participants (40.5±23.3%, p =0.005). The clinical group had lower post exercise SD (1.95±1.26) than the microsecretors (3.56±1.09 p =0.045) and tended to be lower than the undetectable (3.54±1.10 p =0.07).
Conclusion: Residual beta-cell function may offer protection against exercise induced dysglycemia. C-peptide could potentially be a method of stratifying the amount of exercise related support patients need to manage glucose around exercise.

Disclosure
G.S. Taylor: None. K. Smith: None. J. Scragg: None. A. Bashir: None. R.A. Oram: Other Relationship; Self; Randox Laboratories Ltd. T.J. McDonald: None. E.J. Stevenson: None. J.A. Shaw: Advisory Panel; Self; Sanofi. Other Relationship; Self; Novo Nordisk A/S. D.J. West: Research Support; Self; Arla Foods Ingredients, Dexcom, Inc.

Funding
Diabetes Research & Wellness Foundation
296-LB: Novel Analogs of the Mitochondrially Encoded Peptide CB5064 Improve Body Weight and Glucose Tolerance in Dio Mice, and Demonstrate Selective Agonism at the Apelin Receptor
Authors: GRINDSTAFF KENT , STENGER EMILY , SHANG ROBIN , YU TRACY , LUO WENDY C. , KIM VIRNA V. , PEREZ-TILVE DIEGO , CUNDY KENNETH C. 
Published: June 2019

Metabolic dysregulation is integral to the development and pathogenesis of many age-related diseases, including type 2 diabetes and obesity. Several mitochondrially encoded peptides have previously been shown to be secreted from cells and to act as regulatory signals for metabolic homeostasis, including MOTS-c, SHLP2, and humanin. Novel modified analogs of a newly identified mitochondrially encoded peptide, CB5064, have been synthesized and evaluated for plasma stability, activity in a broad screen of G protein-coupled receptor (GPCR) target engagement, and for potential biological activity in diet-induced obese (DIO) mice. In vitro evaluation demonstrated that CB5064 analogs interact with and activate the apelin receptor (APJ/AGTRL1/APLNR). The observed EC50 values of several novel CB5064 analogs at the apelin receptor were in the low µM range, in some cases achieving maximum responses similar to the natural substrate, Apelin-13. In DIO mice, once daily administration of the same series of CB5064 analogs demonstrated a range of effects on metabolic regulation, including significant reduction in body weight, selective fat mass loss, and improved glucose tolerance. The apelin receptor is widely expressed in tissues and appears to play a critical role in energy metabolism, cardiovascular function, fluid homeostasis, angiogenesis, and in diabetic complications. These mitochondria-based peptide analogs therefore represent an entirely new class of molecules with agonist activity at the apelin receptor and potential for use as a source of novel therapeutics for type 2 diabetes, cardiovascular disease, and other age-related disorders. Additional evaluation of the therapeutic potential of these peptides is ongoing.

Disclosure
K. Grindstaff: Employee; Self; CohBar, Inc. E. Stenger: None. R. Shang: Other Relationship; Self; CohBar Inc. T. Yu: None. W.C. Luo: None. V.V. Kim: None. D. Perez-Tilve: Research Support; Self; CohBar, Inc., Novo Nordisk A/S. K.C. Cundy: Employee; Self; CohBar, Inc. Stock/Shareholder; Self; CohBar, Inc.
297-OR: Usefulness of Coefficient of Variation (CV) to Assess Hypoglycemia in Older Adults with Type 1 Diabetes (T1D)
Authors: TOSCHI ELENA , SLYNE CHRISTINE , DUFOUR ALYSSA B. , ATAKOV-CASTILLO ASTRID , CARL SAM , SIFRE KAYLA , GREENBERG JORDAN , MUNSHI MEDHA 
Published: June 2019

Background: New metrics generated by Continuous Glucose Monitoring (CGM) have highlighted the importance of glucose variability, measured as coefficient of variation. It is also suggested that CV may be a more accurate measure to assess time spent in hypoglycemia, as opposed to A1c. This association in older adults is not well studied.
Methods: Older adults (age ≥65 years) with T1D underwent 2 weeks of CGM. Based on the international consensus, CV was calculated by dividing standard deviation of glucose by mean glucose from CGM. The participants were stratified by CV ≤ 36%, or &gt;36%. Duration of clinically significant hypoglycemia (glucose level ≤ 54 mg/dl) and A1c were measured.
Results: We evaluated 76 older adults (mean age 71 years, duration of T1D 39 years, 62% on insulin pump, and 38% on multiple daily injections (MDI)). In participants with CV ≤36% (n=19, 25%), A1c was 6.8±0.8%, and they spent 9.6 min/day in hypoglycemia, while in those with CV&gt;36% (n=57, 75%), A1c was 7.5±0.8%, and they spent 43 min/day in hypoglycemia (p=0.003 and p&lt;0.0001, respectively). In participants with CV&gt;36%, those using MDI had longer duration of hypoglycemia compared to those using insulin pump (61 minutes/day vs. 33 minutes/day, p=0.03), despite similar A1c (7.5% in both groups).
Conclusion: In our cohort of older adults with T1D, CV&gt;36% is associated with higher duration of hypoglycemia despite higher A1c. Keeping CV value &lt;36% in a vulnerable population may help mitigate risk of hypoglycemia independent of A1c value.

Disclosure
E. Toschi: Advisory Panel; Self; Lexicon Pharmaceuticals, Inc. C. Slyne: None. A.B. Dufour: None. A. Atakov-Castillo: None. S. Carl: None. K. Sifre: None. J. Greenberg: None. M. Munshi: Consultant; Self; Lilly Diabetes, Sanofi.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases