bluuebunny/crossref_metadata_2025_split huggingface dataset:
1993-P: Deconstruction of the Role of the Amylin and Calcitonin Receptors in the Regulation of Body Weight and Glucose Tolerance
Authors: LARSEN ANNA T. , SONNE NINA , ANDREASSEN KIM V. , KARSDAL MORTEN ASSER , HENRIKSEN KIM 
Published: June 2019

Dual amylin and calcitonin receptor agonists (DACRAs) are novel candidates for treatment of T2D and obesity due to their beneficial effects on body weight, blood glucose and insulin sensitivity, effects that are superior to those of amylin. However, it is unknown how dual receptor activation by DACRAs compare to activation of either the amylin or the calcitonin receptor in vivo, and to what extent the calcitonin receptor is involved in the beneficial metabolic effects of DACRAs. In this study, we compared the effects of a highly potent DACRA, KBP, rat amylin (rAMY), rat calcitonin (rCT) and the combination of rAMY and rCT on long term efficacy on body weight, food intake and glucose tolerance. High fat fed Sprague Dawley rats were treated 4 weeks with KBP (5 µg/kg/day), rAMY (300 µg/kg/day), rCT, (300 µg/kg/day) and the combination of rAMY and rCT (300+300 µg/kg/day). To compensate for the different activity profiles, peptides were delivered by continuous subcutaneous infusion. Chronic treatment with KBP, rAMY and the combination of rAMY and rCT resulted in a 17%, 11% and 8% vehicle-corrected weight loss, respectively, while rCT alone had no effect. All treatments significantly reduced food intake in the initial phase of the study, while KBP and rAMY resulted in a prolonged reduced food intake. Interestingly, KBP was superior in terms of body weight loss (p&lt;0.001) even though rAMY and KBP reduced the accumulated food intake equally. Moreover, KBP and rAMY improved oral glucose tolerance with significantly reduced insulin levels. Again, KBP was superior to the other treatments (p&lt;0.001).
In conclusion, dual activation of amylin and calcitonin receptors by KBP has beneficial effects on body weight and glucose tolerance superior to that of activating either receptor alone. This was despite correcting for the different activity of the peptides. Understanding of the dual or single receptor activation mechanisms is high pharmaceutical interest.

Disclosure
A.T. Larsen: None. N. Sonne: None. K.V. Andreassen: Employee; Self; Nordic Bioscience. M.A. Karsdal: Employee; Self; Nordic Bioscience. K. Henriksen: Employee; Self; Nordic Bioscience. Employee; Spouse/Partner; Novo Nordisk A/S. Stock/Shareholder; Self; Nordic Bioscience. Other Relationship; Self; Nordic Bioscience.
2009-P: Molecular Mechanisms of Obesity-Associated Vascular Vulnerability via Signals of Appetite Regulation
Authors: MORI KENTARO , TSUCHIYA KYOICHIRO , NAKAMURA SUGURU , SHIBA KUMIKO , MIYACHI YASUTAKA , OGAWA YOSHIHIRO , KITAMURA KENICHIRO 
Published: June 2019

Background: Obesity is a risk factor of hypertension and abdominal aortic aneurysm (AAA). Melanocortin 4 receptor (MC4R) is activated by α-melanocyte-stimulating hormone (α-MSH) to mediate most of the anorectic effects of leptin. In humans, deficiency or mutation of MC4R is the most common monogenic form of obesity. However, it remains unknown whether MC4R signaling affects the development of obesity-associated hypertension, vascular vulnerability and aortic aneurysm.
Methods and Results: MC4R-knockout (KO) mice fed a high-fat/high-sucrose diet (HF/HS) for 20 weeks displayed obesity associated with hyperleptinemia compared to HF/HS-fed wild type (WT) mice. MC4R-KO mice exhibited hypertension, increase of medial thickness and elastic lamina destruction, and elevation of inflammatory and fibrosis-related genes including TGF-β and osteopontin (OPN) in aortae. MC4R-KO mice showed higher incidence of angiotensin II (Ang II, 500 ng/kg/min)-induced AAA (73%) than WT mice (8%). MC4R-KO mice with ob/ob background exhibited lower incidence of Ang II-induced AAA (50%) than MC4R-KO mice, but higher than ob/ob mice (12.5%). Treatment of OPN-blocking antibody decreased Ang II-induced AAA incidence in HF/HS-fed MC4R-KO mice. In vascular smooth muscle cells (VSMCs), leptin (100 ng/ml) significantly upregulated OPN gene expression. α-MSH suppressed AngII-induced TGF-β gene expression in VSMCs, and LPS/IFN-γ-induced iNOS gene expression in peritoneal macrophages. However, these effects of α-MSH were abolished in primary macrophages from MC4R-KO mice and RAW264.7 cells pretreated with MC4R antagonist HS024.
Conclusion: Our observation indicates that deficiency of MC4R promotes the vascular vulnerability in mice. It suggests that, not only hyperleptinemia, but also impairment of α-MSH-MC4R signaling in VSMCs and macrophages, may also promote the vascular vulnerability.

Disclosure
K. Mori: None. K. Tsuchiya: None. S. Nakamura: None. K. Shiba: None. Y. Miyachi: None. Y. Ogawa: None. K. Kitamura: None.
2080-P: Endobarrier (EB) in Diabetes/Prediabetes with Obstructive Sleep Apnea (OSA) Study—Maintenance of Improvement after EB Removal
Authors: YADAGIRI MAHENDER , KINNEY FIONA Y. , ASHMAN NATALIE , SHARRATT EMMA S. , GREENWOOD CHERYL , ADAMS JESSICA , WYRES MELANIE C. , LANG MICHAEL H. , BLEASDALE JOHN , FOGDEN EDWARD , ANDERSON MARK , WALTON CHRISTOPHER , GREENSTONE MICHAEL A. , RYDER ROBERT E. 
Published: June 2019

EB, a 60cm endoscopically implanted proximal intestinal liner is implanted for up to one year and then removed. We assessed Apnoea Hypopnoea Index (AHI), weight and HbA1c before and during EB treatment and following its removal in the 10 patients with moderate OSA requiring continuous positive airway pressure ventilation (CPAP) {80% female, 6/10 (60%) type 2 diabetes, 4/10 (40%) prediabetes, mean ± SD age 53.5±10.3 years, BMI 38.01±2.9 kg/m2} who have attended at least on follow-up after removal. During EB implant, mean ± SD HbA1c fell by 1.2±1.8% from 7.7 ± 1.7 to 6.6 ± 1.1% (p=0.069), weight by 11.1±4.1 kg from 104.9± 14.6 to 93.8±14.7 kg (p&lt;0.001). Prior to EB, all patients had AHI in the National Institute for Health and Care Excellence (NICE) moderate OSA range (15-29.9 events/hour). During EB treatment, AHI of all patients fell below 15 events/hour, such that they no longer required CPAP, according to NICE guidelines. At follow-up at median (range) 9.65 (3-17.6) months after EB removal latest AHI was below 15 in all patients such that they remained off CPAP. Improvements in other metabolic parameters were also sustained (Table). These results confirm previously demonstrated metabolic improvements from EB in diabesity and demonstrate major benefit in the moderate OSA co-morbidity, allowing patients to discontinue CPAP with maintenance of improvement at follow-up.

Disclosure
M. Yadagiri: None. F.Y. Kinney: None. N. Ashman: None. E.S. Sharratt: None. C. Greenwood: None. J. Adams: None. M.C. Wyres: None. M.H. Lang: None. J. Bleasdale: None. E. Fogden: None. M. Anderson: None. C. Walton: Advisory Panel; Spouse/Partner; Celgene Corporation. Speaker's Bureau; Spouse/Partner; Leo Pharma, Novartis Pharmaceuticals Corporation. M.A. Greenstone: None. R.E. Ryder: Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Bioquest.

Funding
Association of British Clinical Diabetologists
2117-P: Biomarkers Isolated from Extracellular Vesicles Prior to Bariatric Surgery May Be Associated with Postoperative Resolution of Type 2 Diabetes
Authors: HILLYER REBECCA , SULLIVAN TRAVIS , CHRIST KIMBERLY , HODARKAR AMEYA , HODGE MARY BETH 
Published: June 2019

Introduction: Bariatric surgery has been shown to lead to resolution of type 2 diabetes mellitus (T2DM) in 78.1% of patients (Buchwald, Am J Med 2009), however, it also confers significant risk for potential complications. It is unclear in the preoperative setting which patients will have resolution of T2DM following bariatric surgery. The objective of this study is to identify if patients who have resolution of T2DM following bariatric surgery express different biomarkers preoperatively from their counterparts who do not have resolution of T2DM.
Methods: Blood samples were obtained from patients who presented to the Center for Surgical Weight Loss with T2DM and either BMI ≥ 40 or BMI ≥ 35 with weight-related comorbidities. All 20 patients studied then underwent gastric bypass or gastric sleeve surgery. At 6 to 12 months postoperatively the patients were evaluated for resolution of T2DM; defined as a hemoglobin A1c less than 6.5 and off all diabetic medications. Extracellular vesicles were isolated from patient serum and analyzed to identify and quantify microRNA and protein biomarkers. The biomarkers in patients who had resolution of T2DM were compared to the biomarkers in patients who had persistent T2DM.
Results: Out of the 395 microRNA detected, there were 10 that were significantly differentially expressed between patients who had resolution of T2DM after bariatric surgery and those who did not. Out of the 71 proteins detected, there were 5 identified that differed significantly between the two groups.
Conclusion: Preoperatively, patients with T2DM who undergo bariatric surgery with subsequent resolution of T2DM may have a different biomarker profile than patients whose T2DM does not resolve following bariatric surgery. If these biomarkers are validated in a larger population of patients, they could be used to help clinicians select patients in the preoperative setting who would benefit most from bariatric surgery.

Disclosure
R. Hillyer: None. T. Sullivan: None. K. Christ: None. A. Hodarkar: None. M. Hodge: None.

Funding
Ellison Foundation; Cancer Prevention and Research Institute of Texas
2134-P: Protection of Beta-Cell Mass from Diabetogenic Condition-Induced Apoptosis by the Inhibition of Mammalian STE20-Like Protein Kinase 1 (MST1)
Authors: SAMEERMAHMOOD ZAHEERBASHA , SIVANANDHAN DHANALAKSHMI , KALITA BISWAJIT , RAMAIAH SOWMYA , SIDDIQUI AMIR , ZOPE BHARAT R. , KADNUR SANJAY V. , KANAVALLI MADHURI , KRISHNAKUMAR V. , SWAMINATHAN SRINIVASAN , RUDRESH G. , MOHIRE SUNIL , BURRI RAGHUNADHA R. , KRISTAM RAJENDRA , JEYARAJ D.A , RAJAGOPAL SRIRAM , DHAKSHINAMOORTHY SARAVANAKUMAR 
Published: June 2019

Impaired insulin secretion, a characteristic of type 2 diabetes (T2D) is partly attributed to decreased β-cell mass due to apoptotic cell death under diabetogenic conditions. Current therapies for diabetes do not address apoptotic cell death mediated β-cell deterioration. Mammalian STE20-like protein kinase 1 (MST1) is reported as one of the critical regulators of β-cell apoptosis under diabetogenic conditions, and therefore, inhibition of MST1 in β-cells may offer β-cell protection and preserve β-cell mass under diabetogenic conditions. We carried out an investigation of MST1 modulation, apoptotic signaling in islet samples from healthy controls, T2D patients and in pancreatic cell lines using MST1 specific siRNAs, and a small molecule inhibitor of MST1 (XMU-MP-1, IC50 ∼100 nM) under diabetogenic conditions. Elevated levels of phospho-MST1, cleaved MST1, and pro-apoptotic markers such as cleaved caspase-3 and BIM were observed in islet samples from T2D patients as compared to healthy control, suggesting the activation of MST1 mediated apoptotic pathway under diabetogenic conditions. Similar findings were observed when pancreatic samples from ob/ob mice and control mice were used. siRNA against MST1 and XMU-MP-1 rescued high glucose (25 mM)/high palmitate (500 µM) induced apoptosis in Min6 and INS-1E cells. The rescue of MIN6 and INS-1E cells were associated with the lowering of phospho-MST1, cleaved MST1 and pro-apoptotic markers such as cleaved caspase-3, phospho-H2B, and BIM. Further, once daily (1 mg/kg) dosing of XMU-MP-1 protected the β-cells in an acute streptozotocin-induced diabetic animal model. Increased numbers of insulin-stained pancreatic islets were observed in XMU-MP-1 treated group compared to disease control. Our data suggest that inhibition of MST1 can protect β-cell mass under diabetogenic conditions. Identification and development of specific small molecule inhibitors of MST1 are underway.

Disclosure
Z. Sameermahmood: None. D. Sivanandhan: None. B. Kalita: None. S. Ramaiah: None. A. Siddiqui: None. B.R. Zope: None. S.V. Kadnur: None. M. Kanavalli: None. K. V.: None. S. Swaminathan: None. R. G.: None. S. Mohire: None. R.R. Burri: None. R. Kristam: None. J. D.a: None. S. Rajagopal: None. S. Dhakshinamoorthy: None.

Funding
Jubilant Innovation Inc.
2199-PUB: Insulin Use and Hypoglycemia Prevalence in an Australian Public Hospital Setting
Authors: PIYA MILAN K. , FLETCHER THERESE , MYINT KYAW PHONE , ZARORA REETU , SIMMONS DAVID 
Published: June 2019

Aims: Diabetes management in hospital often focuses on tight glycemic control. Insulin use is, therefore, more common in the hospital inpatient setting. We sought to determine the prevalence and patterns of insulin use and hypoglycemia among inpatients with diabetes on medical wards in a tertiary Sydney hospital.
Methods: A daily census was conducted on three medical wards (79 beds) over 44 weeks from June 2017. Inpatients with diabetes were audited using a questionnaire based on the UK National Diabetes Inpatient Audit. Those admitted for &gt;7 days were audited for the last 7 days of admission.
Results: Among 822 patients with diabetes, 96% had T2DM, mean age (SD) was 69.1(12.3) years, 54.8% male. Overall, 29.6% were on insulin on admission but 44.7% were prescribed insulin during their hospital stay. Hypoglycemia (&lt;4.0mmol/L) occurred in 111 patients (13.5%) with 225 episodes, and severe hypoglycemia (&lt;3.0mmol/L) occurred in 39 patients (4.8%) with 52 episodes. Insulin was prescribed during hospital stay in 78.4% of patients who had hypoglycemia, and 92.3% who had severe hypoglycemia. There was a greater prevalence of hypoglycemia out of hours (5pm-8am) compared to 8am-5pm (167 vs. 58 episodes).
Conclusions: Hypoglycemia and severe hypoglycemia were common among hospital inpatients, and insulin use in this group was high. Insulin use was a major risk factor for hypoglycemia, particularly with new insulin initiation and after hours. These data highlight the need to weigh the risk of hypoglycemia against the benefit of tight glycemic control when considering insulin initiation in hospital. Extra vigilance is also needed after hours when there is a higher risk of hypos with fewer staff.

Disclosure
M.K. Piya: None. T. Fletcher: None. K. Myint: None. R. Zarora: None. D. Simmons: Speaker's Bureau; Self; Sanofi-Aventis. Other Relationship; Self; Medtronic.

Funding
South Western Sydney Local Health District
2224-PUB: Comparative Effectiveness of Second-Line Initiation of Basal Insulin Therapy vs. Oral Antidiabetic Drugs Added to Metformin among Patients with Type 2 Diabetes in Taiwan
Authors: CHEN PIN-HAO , KUO SHIHCHEN , OU HUANG-TZ 
Published: June 2019

Objective: This study was aimed to assess comparative effectiveness of basal insulin vs. oral antidiabetic drugs (OADs) as 2nd-line added-on treatment to metformin monotherapy on macro- and microvascular complications, hypoglycemic events, and all-cause mortality in patients with type 2 diabetes (T2DM).
Methods: A population-based cohort study was conducted using Taiwan’s National Health Insurance Research Database. Study population was newly-diagnosed with T2DM in 1999-2011, and the new and stable users of basal insulin or OADs (i.e., sulphonylurea [SU], dipeptidyl peptidase-4 inhibitor [DPP-4i]) as 2nd-line add-on treatment to metformin during 2009-2011, and followed until death or the end of 2013. Propensity score matching was applied to achieve comparability in patient baseline characteristics at the time of 2nd-line treatment initiation between basal insulin and OAD users. Cox models were used to evaluate risks of study outcomes associated with use of basal insulin vs. OADs.
Result: Our analyses included 1,064 and 951 basal insulin users 1:1 matched with SU and DPP-4i users, respectively. Compared to SU, use of basal insulin was associated with significantly higher risks of macrovascular events (hazard ratio: 1.36 [95% confidence interval: 1.08-1.71]), microvascular events (1.25 [1.21-1.40]), hypoglycemia (1.88 [1.44-2.46]), and all-cause death (1.50 [1.03-2.20]). Compared to DPP-4i, use of basal insulin yielded a greater risk increase in macrovascular events (1.52 [1.18-1.97]), microvascular events (1.43 [1.27-1.61]), hypoglycemia (3.28 [2.33-4.64]), and all-cause death (2.58 [1.59-4.19]).
Conclusion: T2DM patients who initiated basal insulin vs. SU or DPP-4i as 2nd-line added-on treatment to metformin had higher risks of vascular complications, hypoglycemia, and all-cause death.

Disclosure
P. Chen: None. S. Kuo: None. H. Ou: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (P30DK092926)
2260-PUB: Inpatient Diabetes Patient Brochure: What You Need to Know while You Are in the Hospital
Authors: RUSHAKOFF ROBERT J. , MACMASTER HEIDEMARIE W. 
Published: June 2019

Hospitalized patients with diabetes, whether previously on insulin or not, are generally treated with insulin. This change from outpatient medication, the type of insulin, and insulin regimen may be significantly different from what the patient is familiar with and may result in confusion, discomfort or even confrontation about the treatment plan. To ease the transition from outpatient to inpatient, we developed a “Brochure for Patients with Diabetes: What you need to know while you are in the hospital” to help make the patient feel more comfortable about the glycemic care they receive and improve patient satisfaction. The specific items covered in the brochure are: 1) Why the management of your diabetes may be quite different from what you usually do at home; 2) Goals for blood sugars (why different from home: fighting infections, avoiding hypoglycemia); 3) How we manage your blood sugar levels; 4) Blood sugar checks (how often); 5) Diet (restrictions, meals on demand); 6) Discharge planning; 7) Common questions such as use of own meter, reasons for different insulins, pumps, and CGM. The brochure is printed for the patient with the first time any insulin order set is ordered. The brochure is available in Spanish, Chinese and Russian.
Evaluation: We audited brochure distribution to determine percentage of patients who received the brochure and developed a survey to determine the patient’s understanding of the brochure.
Results: Audit results: After upgrades to the order sets so brochure would be printed, 100% of 50 charts had printed brochures. The survey: was hand delivered to 40 consecutive patients on insulin. 32 of the patients had ≧90% correct responses. The remaining 8 averaged 60% correct response.
Conclusion: We successfully produced a brochure that explains inpatient diabetes management to newly admitted patients. Whether the patients who had decreased understanding may have been too ill to completely understand the brochure and possible changes in patient satisfaction remain to be explored.

Disclosure
R.J. Rushakoff: None. H.W. MacMaster: None.
231-LB: Innovative Blood Sampling Technology for Convenient, Nearly Painless, and Accurate Monitoring of Diabetes
Authors: ROMEO ELISA , BRYANT-GREENWOOD PETER K. , CASTORINO KRISTIN N. , LILJENQUIST DAVID R. , JORDAN BRETT L. , HARRINGTON MINDY , HOLSCHER TODD , ALEXANDER CLAIRE , DOKUKIN VICTOR , NERLEKAR MUKUL , WILLIAMSON LUCY , SLOANE JESSICA 
Published: June 2019

Monitoring HbA1c levels in individuals affected by diabetes remains the standard of care for ensuring proper management of the condition. Typically, HbA1c is measured by venipuncture or fingerstick blood collection methods at regular intervals, and for nearly all diabetic patients, monitoring HbA1c is a lifelong endeavor. In general, venipuncture and fingerstick are standard blood collection procedures, which are considered inconvenient and painful. Patient surveys have shown that venipuncture induces fear (needle phobia) in more than 20% of adults and in 60% of children. We have designed, developed, and validated an innovative blood sampling device to collect and stabilize capillary blood from the patient’s upper arm. Using small skin incisions and vacuum, the device draws and deposits the blood onto self-contained matrices. The matrices’ cartridge is then shipped at room temperature to a clinical laboratory for HbA1c measurement. We conducted a clinical study at three sites within the U.S. to validate the use of the device on 146 enrolled participants. The primary study objective was to compare HbA1c measurement in samples collected by the device and venipuncture. Pain measurements were conducted to assess the discomfort associated with the use of the device, in comparison to venipuncture and fingerstick. The data demonstrated a strong correlation between the device and venipuncture (y=1.01-0.0131, R2=0.997) over a range of HbA1c values between 4.91 and 13.34%. Device lot-to-lot and operator-to-operator reproducibility studies showed CVs of 0.7% and 0.8%, respectively. Assessment of discomfort showed an average pain score of 1 for the device (on a scale 0 to 10) and the device was preferred over venipuncture and fingerstick by 79% of the subjects. We clinically validated an innovative blood sampling technology that provides a convenient, nearly painless, safe and effective alternative to venipuncture and fingerstick for HbA1c measurement in diabetic individuals.

Disclosure
E. Romeo: Employee; Self; Drawbridge Health, Inc. P.K. Bryant-Greenwood: None. K.N. Castorino: Consultant; Self; Abbott. Research Support; Self; Abbott, Dexcom, Inc., Drawbridge, Novo Nordisk Inc., Sanofi US. D.R. Liljenquist: None. B.L. Jordan: Employee; Self; Drawbridge Health. Employee; Spouse/Partner; Innovation Endeavors, LLC. M. Harrington: Employee; Self; Drawbridge Health. T. Holscher: Employee; Self; Drawbridge Health. C. Alexander: Consultant; Self; CAlexanderConsulting, LLC. V. Dokukin: Employee; Self; Drawbridge Health. M. Nerlekar: Employee; Self; Drawbridge Health. L. Williamson: Other Relationship; Self; Drawbridge Health. J. Sloane: Other Relationship; Self; Drawbridge Health.