bluuebunny/crossref_metadata_2025_split huggingface dataset:
121-LB: Glucose- and Glucagon-Lowering Effect of a Single Oral Leptin Dose in Type 1 Diabetes Patients
Authors: KIDRON MIRIAM , PERLES SHARON , WEISS RAM 
Published: June 2021

Recent understandings of the role of leptin in glucagon and glucose homeostasis, have flagged it as a target for management of type 1 diabetes (T1D). While historically thought to be involved in long-term regulation of appetite and energy expenditure, leptin is now known to regulate food absorption, mucus secretion, intestinal motility and inflammatory processes. Leptin was shown to directly inhibit glucose uptake and reduce glucagon levels and insulin requirements in NOD mice, to ameliorate hyperglycemia in a T1D mouse model, and reduce insulin requirements in patients with insulin-resistant diabetes. Leptin-based drugs are currently only available in injectable forms, and suffer from a short half-life in the circulation. ORMD-0701 is an oral leptin drug, specially formulated to protect the active ingredient from degradative forces in the gut and enhance its uptake across the intestinal mucosa. This first-in-human study assessed the short-term effects of a single ORMD-0701 dose (3 mg leptin) administered to fasting patients with T1D. Patients on an insulin pump and with glucose levels &gt;100 mg% and &lt;280 mg%, received an ORMD-0701 (n=7) or placebo (n=3) capsule. Basal insulin pump rates were then lowered to 50% of the regular program and blood glucose, glucagon and leptin levels were monitored for 3 h. Glucagon area under the curve 30-120-min post-treatment (AUC30-120) was 0.60 ng*min/L lower than baseline values, while it rose by 0.69 ng*min/L in the placebo group. Similar trends were recorded for glucose AUC30-120 measures, with an 0.43 mmol*min/L decrease from baseline AUC in the active group versus a 0.24 mmol*min/L increase in the placebo group. By the end of the monitoring period, glucose and glucagon levels returned to baseline levels in all patients. No significant changes in blood leptin levels were detected in either cohort. These preliminary findings set the stage for further assessment of oral leptin and its impact on normalizing the insulin-glucagon balance in patients with T1D.

Disclosure
M. Kidron: Employee; Self; Oramed Pharmaceuticals, Inc., Stock/Shareholder; Self; Oramed Pharmaceuticals, Inc. S. Perles: Employee; Self; Oramed Ltd. R. Weiss: Consultant; Self; Lilly Global Health Partnership, Medtronic, Speaker’s Bureau; Self; Novo Nordisk.
1211-P: The Mechanistic Role of Thymidine Phosphorylase in the Development of Obesity
Authors: YUE HONG , BELCHER ADAM M. , BICAK ADAM , LI WEI 
Published: June 2021

Obesity is a major independent risk factor for the development of type II diabetes (T2DM), nonalcoholic fatty liver disease (NAFLD), and cardiovascular disease (CVD). Consequently, controlling obesity constitutes a key strategy for reducing the prevalence of these diseases. The majority of drugs developed for treating obesity over the past 20 years have been withdrawn due to the increased risk of cardiovascular and psychiatric complications. Therefore, developing novel mechanism-mediated therapeutics for controlling obesity and its consequent complications is a top priority and urgently needed. Our studies indicate that thymidine phosphorylase (TYMP) could be a promising target. The traditional role of TYMP is to catalyze the reversible conversion of thymidine to thymine and 2-deoxy-D-ribose-1 phosphate and maintain the homeostatic nuclear pool of these molecules. TYMP expression is increased in several diseased conditions, including obesity, T2DM, and NAFLD. However, whether TYMP plays a role in the development of these diseases is unknown. We found that Tymp-deficient (Tymp-/-) male mice exhibited significantly limited body weight gain as well as liver and perigonadal fat weight when fed either a western diet (TD.88137) or a prodiabetic high-fat diet (D12492) compared with the wild-type mice. Male Tymp-/- mice showed better glucose tolerance. TYMP-deficiency reduced expression of enzymes that confer glycolysis and de novo lipogenesis in the liver. TYMP-deficiency enhanced the sensitivity of primary hepatocytes to insulin as evidenced by the increase of AKT activation. Inhibition of TYMP with tipiracil, a selective, potent, and the FDA approved TYMP inhibitor, dramatically reduced western diet and high-fat diet-induced body weight gain. We conclude that TYMP plays a pivotal role in liver glucose and lipid metabolism, which promotes the development of obesity and T2DM. Targeting TYMP with tipiracil could be a new therapy for obesity.

Disclosure
H. Yue: None. A. M. Belcher: None. A. Bicak: None. W. Li: None.
1225-P: Prevalence of Obesity and Bariatric Surgery Use in T1DM
Authors: WEST WILLIAM A. , ROMO KARINA G. , UWAIFO GABRIEL I. 
Published: June 2021

With the increased prevalence of obesity, the phenotype of T1DM has changed. The prevalence of obesity in pts with T1DM is increasing, but there is limited data on how it compares to pts with T2DM. Bariatric surgery is effective for glycemic, weight and cardiometabolic risk surrogate amelioration in T2DM with obesity. However, the role of bariatric surgery in T1DM with obesity is largely unexplored. Retrospective chart review was done of patients with T1DM seen in Ochsner clinic system from January 2015 to January 2018. Obesity prevalence was quantified. Pts with bariatric surgery (BS) history were identified and their cardiometabolic surrogates pre and post BS were obtained. This was compared to pts with T2DM over the same time period. More in depth chart analysis of 300 pts from this cohort of T1DM pts was done to better characterize features of these pts 10, 282 pts with T1DM were identified over the observation period vs. 146,617 pts with T2DM. The prevalence of obesity in the T1DM cohort was 48.3% vs. 59.7% in the T2DM cohort while the prevalence of morbid obesity was 14.5% vs. 19% in the T1DM vs. T2DM groups. The number of pts who had bariatric surgery was 25 vs. 307 in the T1DM vs. T2DM groups. The percentage utilization of bariatric surgery as an intervention for obesity was very low in both cohorts (0.5 vs. 0.35 % in the T1DM vs. T2DM groups). Of the 300 pts with detailed chart review, actual diabetes subtypes were 163 (54%) T1DM, 43 (14.3%) as LADA, 1 (0.3%) as maturity-onset diabetes of the young, 2 (0.7%) as type 1.5 (essentially LADA), 8 (2.7%) as type 1+2 (T1DM with obesity and insulin resistance), 11 (3.7%) deceased, 71 (23.7%) as T2DM that had been miscoded as T1DM. For subsequent analyses, T1DM, LADA, type 1.5, and type 1+2 were included in the T1DM cohort. The weight and cardiometabolic surrogate changes in T1DM subjects were inconsistent and less marked than in T2DM subjects. Obesity prevalence in T1DM is close to that in T2DM and the use of bariatric surgery as an intervention remains very low both in T1DM and T2DM pts with obesity.

Disclosure
W. A. West: None. K. G. Romo: None. G. I. Uwaifo: None.
1231-P: Impact of Obesity on Patients Admitted for Diastolic Heart Failure: Insights from the National Inpatient Sample
Authors: ASEMOTA IRIAGBONSE R. , SHAKA HAFEEZ , ALMANI MUHAMMAD USMAN , AKUNA EMMANUEL , EDIGIN EHIZOGIE 
Published: June 2021

Background: Obesity is one of the common comorbidities in patients with diastolic heart failure(HF). Though recognized as a risk factor for incidence of diastolic HF, the relationship of obesity to outcomes in patient with this diagnosis of is not clear and the obesity paradox has been suggested in the literature. Purpose The aim of this study was to compare the outcome of patient admitted for diastolic HF with and without obesity.
Method: Data were obtained from The National Inpatient Sample (NIS) 2016 and 2017 Database. The NIS was searched for hospitalization for diastolic HF as principal diagnosis with and without a secondary diagnosis of obesity using International Classification of Diseases, Tenth Revision (ICD-10) codes. Multivariate logistic and linear regression analysis was used accordingly to adjust for possible confounders.
Results: The combined 2016 and 2017 NIS database contained 367,395 hospitalizations for adult patients (aged ≥ 18 years) with a principal ICD-10 diagnosis for diastolic HF. Among this group, 107,790 (29%) had co-existing obesity. Of note, diastolic heart failure with obesity had decreased inpatient mortality that reached statistical significance (2.8% vs. 1.4%, AOR:0.71, 95% CI 0.62-0.81, p&lt;0.0001) compared to those without obesity. The adjusted mean LOS in patients with diastolic HF and coexisting obesity was 0.68 days longer than those without obesity(5.65 days vs. 4.92 days, 95% CI 0.60-0.77, p&lt;0.0001). Patient hospitalized with diastolic HF and obesity also had higher adjusted mean total hospital charge of $3,257 ($45,660 vs. $39,815, CI 2,134-4,379, p&lt;0.0001) compared to diastolic HF patient without obesity.
Conclusion: Patients admitted for diastolic heart failure with co-existing obesity have reduced inpatient mortality compared to those without obesity. However, Total hospital charges and LOS were increased in the obesity group compared to the patient without obesity. Further prospective studies on this topic are needed.

Disclosure
I. R. Asemota: None. H. Shaka: None. M. Almani: None. E. Akuna: None. E. Edigin: None.
1236-P: Association between Body Mass Index (BMI) and Brachial-Ankle Pulse Wave Velocity (BAPWV) in Women with Type 2 Diabetes
Authors: CHEN YAO , MA BINGWEI , QU SHEN , WANG XINGCHUN , WEI DONG 
Published: June 2021

Abstract Aims: The aim of this study was to investigate the association between body mass index (BMI) and brachial-ankle pulse wave velocity (baPWV) in Chinese woman with type 2 diabetes (T2DM).
Methods: We identified 1148 diabetes patients between 1 November 2017 and 1 November 2019 from Shanghai Tenth People’s Hospital. 407 women over were enrolled in this cross-sectional study. BaPWV was assessed as a marker of subclinical atherosclerosis. According to baPWV values, arteriosclerosis (AS) was set as 3 degrees: mild AS (baPWV ≥ 1400 cm/s), moderate AS (baPWV ≥ 1700 cm/s) and severe AS (baPWV ≥ 2000 cm/s). The multivariate linear regression analysis was used to explore the relationship between BMI and baPWV.
Results: Compared with the mild AS group, BMI was significantly lower in the moderate AS and severe AS groups (25.63±4.15 kg/m2 vs. 24.59±4.12 kg/m2 p=0.030; 25.63±4.15 kg/m2 vs. 24.49±3.60 kg/m2 p=0.025) There were no statistical difference between the moderate AS and the severe AS groups (p=0.838). BMI was significantly negatively associated with baPWV (r=-0.118, P=0.018). The associations were still significant after age and blood pressure adjustment (r=-0.160, P=0.001). Using multiple linear regression, BMI was negatively associated with baPWV (β=-0.152, P=0.001).
Conclusion: Arterial stiffness, as measured by baPWV, is lower in overweight and obesity Chinese woman with type 2 diabetes. High BMI was found to be a protective factor for AS. These findings may contribute to the explanation of the “obesity paradox” in T2DM.

Disclosure
Y. Chen: None. B. Ma: None. S. Qu: None. X. Wang: None. D. Wei: None.

Funding
Cheng du Committee of Health, China (20PJ201)
125-OR: Synaptotagmin 9 Regulates Tomosyn-2 Protein Abundance to Affect Early Phase of Insulin Secretion
Authors: PATHAK ASMITA , ALSHARIF HAIFA , TROMBLEY JOHN E. , RAHMAN MD MOSTAFIZUR , BHATNAGAR SUSHANT 
Published: June 2021

Insulin secretion from pancreatic β-cells occurs in a biphasic manner. The loss of the early phase of insulin secretion, which occurs due to the inability of insulin granules to fuse with the plasma membrane (PM) via the formation of the SNARE complex, acts as a key determinant in impaired glucose tolerance and development of type 2 diabetes (T2D). Thus, it is critical to elucidate molecular mechanisms underlying early-phase insulin secretion. Tomosyn-2 binds to Stx1A, a key component of the SNARE complex, and functions as an endogenous inhibitor of insulin secretion. The mechanism by which Tomosyn-2 regulates the fusion of insulin granules is not completely understood. Our preliminary data show that Tomosyn-2 binds, colocalizes, and co-fractionates with synaptotagmin-9 (Syt9) at high glucose; Syt9 protein is present in the insulin granule membrane, and its role in insulin secretion remains poorly defined. Our data show that mice lacking Syt9 (Syt9-/-) have improved glucose clearance, increased in vivo early-phase insulin secretion at 5 min and 15 min post-glucose challenge with no change in insulin tolerance vs. the wild type control mice, suggesting that Syt9 regulates the early phase of insulin secretion from β-cells. Strikingly, Syt9-/- mouse islets have reduced Tomosyn-2 levels (∼50%) without altering the levels of other key SNARE proteins. The knockdown of Tomosyn in INS1 β-cells treated with KCL prevents the localization of Syt9 with Stx1A. These results show that Syt9 binding stabilizes Tomosyn-2 protein in a non-fusogenic complex by potentially blocking insulin granules’ access to the PM-Stx1A for membrane fusion and insulin secretion.
In summary, our data reveal a novel molecular complex in Stx1A-Tomosyn-2-Syt-9 to regulate the early-phase insulin secretion.

Disclosure
A. Pathak: None. H. Alsharif: None. J. E. Trombley: None. M. Rahman: None. S. Bhatnagar: None.

Funding
National Institutes of Health (R01DK120684-01)
1256-P: Insights into Acetyl-Coa-Carboxylase (ACC1) Phospho-Regulation in Pancreatic Beta Cells
Authors: BAKAR RULA BANY , LIBERATORI SABRINA , VEPRIK ANNA , TEBEKA NCHIMUNYA N. , KEMP BRUCE E. , MOHAMMED SHABAZ , CANTLEY JAMES 
Published: June 2021

Aims: ACC1 couples glucose metabolism with de novo lipogenesis in lipogenic tissues, by converting acetyl-CoA to malonyl-CoA. In β-cells, ACC1 plays a critical role in β-cell growth and insulin secretion. However, very little is known about ACC1 regulation in β-cell. The aims of this study were to 1) assess the role of ACC1S79 in β-cell function and whole body glucose homeostasis; and 2) screen for novel phosphosites that may regulate ACC1 activity in β-cell.
Methods: 1) ACC1 single knock-in mouse model, with ACC1S79 mutated to alanine ACC1S79A, was obtained by crossing ACC1 double knock-in mice with wild type mice to isolate the ACC1S79A point mutation. 2) ACC1 protein was purified from INS1 β-cell following culture with different glucose concentrations. Quantitative phosphoproteomics was performed to characterise ACC1 phosphosites using a Q-Executive MS. Data analysed using MaxQuant and Perseus.
Results: 1) Female ACC1S79A mice exhibited no alternations in glucose homeostasis. In male mice we found no differences in serum insulin, GTT or ITT, although a small but significant reduction in fasting blood glucose was recorded in ACC1S79A mice compared to littermate controls. There was no significant change in GSIS from isolated ACC1S79A islets at 2mM glucose or in response to 7.5 and 20mM glucose, suggesting that ACC1S79 phosphorylation does not play a role in insulin secretion under physiological conditions.2) Using phosphoproteomics, we identified twenty phosphosites on ACC1 protein in β-cells. ACC1S1215 was highly phosphorylated at 2mM glucose, and showed a significant reduction in phosphorylation in response to 15mM glucose. In contrast, phosphorylation of ACC1S25 was lower at basal glucose and increased upon glucose stimulation.
Conclusions: Our data show that ACC1S79 phosphorylation does not play a major role as a glucose-regulated phosphosite in β-cells. However, other phosphosites show greater dynamic regulation by glucose and may play a role in regulating β-cell ACC1 activity.

Disclosure
R. Bany bakar: None. S. Liberatori: Employee; Self; LONZA. A. Veprik: None. N. N. Tebeka: None. B. E. Kemp: None. S. Mohammed: None. J. Cantley: Other Relationship; Self; Oxstem Beta.
1269-PUB: Evaluating the Response to GLP-1 Agonists in Veterans with Type 2 Diabetes Mellitus
Authors: BEGLEY BRETT A. , DESOUZA CYRUS , SHIVASWAMY VIJAY , SAMSON KAELI , SILVERMAN EMILY 
Published: June 2021

Purpose: To delineate which factors help predict whether a patient is likely to respond or not respond to treatment with a glucagon-like peptide-1 (GLP-1) agonist.
Methods: The medical records for veterans with type 2 diabetes mellitus who began treatment with any GLP-1 agonist at the Veterans Affairs Nebraska-Western Iowa Health Care system from January 1, 2015, to December 31, 2019, were retrospectively reviewed. Patient demographics and baseline objective data were collected at treatment onset. Defined decreases in hemoglobin A1C (HbA1c), body weight, and insulin dose over a minimum 6-month period were used to identify responders and nonresponders. Associations between categorical variables and response status were assessed using Chi-Square tests or Fisher’s exact tests, and Wilcoxon Rank Sum tests were used to examine differences in distributions of variables of interest between response status groups.
Results: Of the 55 veterans evaluated during the study period, forty-two subjects (78%) responded to treatment with a GLP-1 agonist whereas twelve subjects (22%) did not respond. The median baseline HbA1c of those who responded was 8.7 (IQR: 8.3, 10.0) compared to 8.1 (IQR: 7.6, 8.8) for those who did not respond (p = 0.03). Among patients with peripheral neuropathy, 88.5% responded while only 65.5% of those without peripheral neuropathy responded (p = 0.046).
Conclusion: We demonstrate that a response to GLP-1 agonist treatment was associated with a higher baseline HbA1C and the presence of peripheral neuropathy. These findings warrant future multivariate analyses of a larger cohort to determine the ideal candidates for GLP-1 agonist therapy.

Disclosure
B. A. Begley: None. C. Desouza: Advisory Panel; Self; Bayer AG, Novo Nordisk, Consultant; Self; AstraZeneca. V. Shivaswamy: Research Support; Self; Eli Lilly and Company, Kowa Pharmaceuticals, Novo Nordisk. K. Samson: None. E. Silverman: None.
1274-PUB: Clinical Comparison of Hospitalized Patients with Diabetic Ketoacidosis Admitted to Intensive Care Unit (ICU) vs. Non-ICU Areas
Authors: LIU AIQUN , CARMICHAEL KIM , SCHALLOM MARILYN , ARROYO CASSANDRA 
Published: June 2021

Many patients with DKA are admitted to Intensive Care Units (ICUs) due to restriction of insulin infusions outside of ICU areas. Our previous retrospective study showed that 37.0% of patients did not require admission to ICUs. Notably, reduced ICU admissions decrease costs and preserve bed availability for critical patients.
Aim: To compare the clinical characteristics and hospital care among patients with DKA admitted to the ICU to those admitted to the non-ICU areas.
Methods: A secondary analysis of collected data from the previous DKA study included 170 patients admitted from April-December 2017.
Results: Of 170 emergency department (ED) patients, 96 (56.5%) were admitted to an ICU and 74 (43.5%) to non-ICUs; 72 (42.4%) had T1D, 82 (48.2%) had T2D, and 16 (9.4%) had other types of DM. Mean age was 46.9±16.0 years old. The length of ED stay was significantly shorter (4.68±2.4 vs. 9.5±4.4 hours, p&lt;0.001) and the length of hospital stay significantly longer (6.2±11.2 vs. 3.1±3.9 days, p=0.03) in the ICU group than in the non-ICU group. Acute kidney injury (p=0.01), stroke and deep vein thrombosis (p=0.05), and substance abuse (p=0.03) were more common in the ICU group. Mean blood glucose, pH, anion gap, ketone, potassium, and lactate levels were significantly higher, while bicarbonate levels were significantly lower in the ICU group. Insulin (96.9%) and fluid (97.9%) infusions were more commonly used in the ICU group. Patients in the ICU group received more endocrine (p&lt;0.001) and dietitian (p&lt;0.006) consultations than those in the non-ICU group.
Conclusions: Patients in the ICU group had more severe metabolic acidosis and other critical illnesses. Patients with uncomplicated DKA can be safely treated in the ED. Insulin drips should not be the criteria for ICU admission. Further study along with these data can help with the development of a severity scoring tool to identify the appropriate patients for ICU admissions.

Disclosure
A. Liu: None. K. Carmichael: None. M. Schallom: None. C. Arroyo: None.
1276-PUB: Diagnosis and Management of Inpatient Corticosteroid-Induced Hyperglycaemia in an Acute Respiratory Cohort in a Tertiary Centre
Authors: LONERGAN EIBHLÍN M. , CROWLEY MAIREAD , O’HALLORAN DOMHNALL J. 
Published: June 2021

Corticosteroid-induced hyperglycaemia (CIH) is commonly encountered among acute respiratory inpatients, particularly those with diabetes mellitus (DM). Guidelines dictate frequency of inpatient capillary blood glucose (CBG) monitoring and treatment modification in the context of exogenous corticosteroid administration. Patients admitted with acute respiratory illness requiring corticosteroids were reviewed to evaluate monitoring, diagnosis and treatment of CIH. A re-audit was performed at a 3-month interval. Twenty patients were treated acutely with corticosteroids; median age 68 years (range 40-88); 13 male. Seven of these patients were diabetic; 6 type 2 DM; 1 type 1 DM. The most common conditions requiring admission included COPD, IPF, pneumonia, asthma, covid-19 and lung cancer. Of the twenty patients included, 13/20 (65%) had CBG monitoring. Within the monitored group, 6/13 (46%) showed readings consistent with hyperglycaemia (&gt;12mmol/L) on more than one reading, of whom all were diabetic. Patients who exhibited hyperglycaemia had appropriate escalation of CBG checks in 3/6 (50%) cases. One patient of six (17%) with persistent CIH was treated appropriately with oral hypoglycaemics. The remaining five patients remained untreated. After education of respiratory medical staff, re-audit revealed persistently infrequent CBG checks (8/15 monitored - 53%). However, of those monitored, escalation of treatment was undertaken in 2/3 cases (67%) in cases of CIH. A high proportion of respiratory inpatients require treatment acutely with corticosteroids. Co-existent DM indicates a higher likelihood of developing CIH. Overall, CBG checks are sporadically performed despite hyperglycaemia. Appropriate treatment escalation of CIH is inadequate. Further education of medical and nursing staff regarding CIH guidelines is required for optimal glycaemic control in this cohort.

Disclosure
E. M. Lonergan: None. M. Crowley: None. D. J. O’halloran: None.