bluuebunny/crossref_metadata_2025_split huggingface dataset:
128-OR: DOC2b Boosts Insulin Secretion via a Yes Kinase-Dependent Mechanism
Authors: BHOWMICK DITI CHATTERJEE , ASLAMY ARIANNE , BHATTACHARYA SUPRIYO , OH EUNJIN , AHN MIWON , THURMOND DEBBIE C. 
Published: June 2021

Exocytosis regulatory protein DOC2b is a crucial regulator of SNARE assembly in β-cells and enrichment of DOC2b enhances glucose-stimulated insulin secretion (GSIS). However, the underlying mechanism of how DOC2b boosts GSIS remains to be explored. We hypothesize that tyrosine-phosphorylation of DOC2b’s functionally indispensable C2AB domain is required for DOC2b’s beneficial function on GSIS. Biochemical analysis revealed that DOC2b is tyrosine-phosphorylated specifically by glucose within 1-2 min of stimulation in MIN6 β-cells and human islets. Pervanadate (pV) treatment, which inhibits tyrosine-specific phosphatases, validated the phosphorylation event to be tyrosine-specific. Further, the Src family kinases (SFKs) were implicated in this phosphorylation event, based upon the ability of SFK inhibitor SU-6656 to markedly attenuate the level of tyrosine-phosphorylated DOC2b under pV treated conditions. Phosphorylated/activated SFKY416 co-immunoprecipitated with DOC2b from pV treated β-cells; SU-6656 abrogated the interaction. YES kinase, an SFK, was also co-immunoprecipitated with DOC2b following glucose stimulation or pV treatment, suggesting YES kinase to be the specific SFK that phosphorylates DOC2b in β-cells. All-atom molecular dynamics simulations identified a specific tyrosine residue present in DOC2b’s C2B domain, Y301, as solvent-exposed and available for modification. Our results using phosphodeficient and phosphomimetic point mutants validated the involvement of the Y301 phosphorylation in for the boosting effect of DOC2b on GSIS. Taken together, these results resolve the first glucose-induced post-translational modification of DOC2b in β-cells, pinpointing the kinase and the site of action. These findings support a new model for DOC2b in GSIS: 1) glucose stimulation of the β-cell rapidly phosphorylates DOC2b on residue Y301 via YES kinase at the plasma membrane, yielding 2) an activated form of DOC2b that regulates insulin release.

Disclosure
D. Chatterjee bhowmick: None. A. Aslamy: None. S. Bhattacharya: None. E. Oh: None. M. Ahn: None. D. C. Thurmond: Consultant; Self; Immutics.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (DK067912, DK112917, DK102233 to D.C.T.); JDRF (3-PDF-2020-934-A-N to D.C.B.)
130-OR: Statin Exposure Increases Star (Steroidogenic Acute Regulatory Protein) Expression in Islets: A Novel Mechanism for ß-Cell Dysfunction and Increased Diabetes Risk?
Authors: HOGAN MEGHAN F. , ESSER NATHALIE , TEMPLIN ANDREW T. , CASTILLO JOSEPH J. , AKTER REHANA , HULL REBECCA L. , KAHN STEVEN E. , ZRAIKA SAKENEH 
Published: June 2021

While statin therapy reduces plasma cholesterol, it also impairs β-cell function and increases the risk of developing diabetes. We have shown that the cholesterol transport protein STAR is synthesized in β cells and its upregulation results in increased β-cell mitochondrial cholesterol content, producing β-cell dysfunction. Given statins’ role in cholesterol metabolism, we determined whether statin exposure increased expression of islet STAR, decreased expression of the downstream cholesterol metabolizing enzyme CYP27A1 and inhibited β-cell function.
Atorvastatin treatment of C57Bl/6 islets increased Star gene (4.51±1.12 vs. 1.00±0.19, n=5, p&lt;0.05) and a 3.3-fold increase in relative protein levels (n=2, p&lt;0.005) while decreasing expression of Cyp27a1 (0.55±0.14 vs. 1.00±0.18, n=5, p&lt;0.05). As expected, inhibition of the enzyme HMG-CoA reductase (Hmgcr) with atorvastatin resulted in compensatory increases in expression of Hmgcr and the LDL receptor (Ldlr); (Hmgcr: 5.88±0.65 vs. 1.00±0.05; Ldlr: 3.22±0.58 vs. 1.00±0.12; n=5, p&lt;0.05), and a 5.1-fold increase in relative LDLR protein (n=2, p&lt;0.05). Atorvastatin decreased glucose-stimulated insulin secretion (fold insulin response to 20 mM over 2.8 mM glucose: 28.6±5.86 vs. 52.0±8.25, n=5, p&lt;0.05), but did not change insulin content (51.0±5.64 vs. 47.2±3.51 pmol insulin/5 islets, n=5, p=0.90).
In summary, exposure of islets to atorvastatin increased Star expression, decreased Cyp27a1 expression and reduced β-cell secretory function. These findings suggest that increased Star and impaired cholesterol metabolism, leading to increased cholesterol accumulation and mitochondrial dysfunction, may be a novel mechanism mediating the effects of statins to impair β-cell function and increase risk of type 2 diabetes.

Disclosure
M. F. Hogan: None. N. Esser: None. A. T. Templin: None. J. J. Castillo: None. R. Akter: None. R. L. Hull: None. S. E. Kahn: Advisory Panel; Self; Bayer AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk, Pfizer Inc. S. Zraika: None.

Funding
American Diabetes Association (1-18-PDF-174 to M.F.H.); U.S. Department of Veterans Affairs (BX001060)
135-OR: Impaired Awareness of Hypoglycemia Is Associated with Residual Beta-Cell Function and Glucose Variability Parameters in Patients with Type 1 Diabetes
Authors: KLIMONTOV VADIM , SEMENOVA JULIA F. , KORBUT ANTON I. 
Published: June 2021

The Aim: to evaluate the relationships between impaired awareness of hypoglycemia (IAH), residual beta cell function and short-term glucose variability (GV) in patients with type 1 diabetes (T1D).
Materials and Methods: We observed 400 patients, 145 M/255 F, age 18-85 years (median - 36 years), diabetes duration 0.5-52 years (median - 16 years), HbA1c 4.7-15.1% (median - 8%). The Clarke's questionnaire was used for IAH recognition. Beta cell function was estimated by fasting and 2-h postprandial C-peptide levels. Day-time (6.00-23.59), nocturnal (0.00-5.59) and 24-h Time In target Range (TIR), Time Above target Range (TAR), Time Below target Range (TBR), and GV parameters, including Standard Deviation (SD), Coefficient of Variation (CV), Mean Amplitude of Glucose Excursions (MAGE), 2-h Continuous Overlapping Net Glycemic Action (CONGA), Lability Index (LI), J-index, Low Blood Glucose Index (LBGI), High Blood Glucose Index (HBGI), M-value and Mean Absolute Glucose (MAG), were calculated from short-term (3-7 days) continuous glucose monitoring (CGM).
Results: In our cohort, IAH was recognized in 163 (40.8%) individuals. Patients with IAH, as compared to those without, demonstrated longer diabetes duration (P&lt;0.0001), lower C-peptide postprandial level and increment (p=0.02 and p=0.0003 respectively) and increased day-time and nocturnal mean glucose, SD, CONGA, J-index, HBGI and M-value (all P≤0.02). Nocturnal MAGE, LI and LBGI, as well as 24-h mean glucose, SD, CV, MAGE, CONGA, J-index, HBGI, and M-value were also higher in patients with IAH (all P≤0.01). No differences in HbA1c, TIR, TAR and TBR were found between the groups. Day-time, nocturnal and 24-h SD, CV, LI, J-index, and HBGI, as well as day-time and 24-h MAGE, correlated negatively with postprandial C-peptide.
Conclusion: In patients with T1D, IAH is associated with low (or zero) residual beta cell function. This relationship could be mediated via enhanced GV.

Disclosure
V. Klimontov: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Sanofi, Research Support; Self; Boehringer Ingelheim International GmbH, Speaker’s Bureau; Self; AstraZeneca, Medtronic. J. F. Semenova: None. A. I. Korbut: None.

Funding
Russian Science Foundation (20-15-00057)
136-OR: Nocturnal Hypoglycemia Prevention Strategies Used by People with Type 1 Diabetes According to Their Insulin Delivery and Blood Glucose Monitoring Technology
Authors: TALBO MERYEM K. , MESSIER VIRGINIE , DESJARDINS KATHERINE , RABASA-LHORET RÉMI , BRAZEAU ANNE-SOPHIE , PETERS TRICIA 
Published: June 2021

People with T1D (PWT1D) use many strategies to avoid nocturnal hypoglycemia (NH), however, the current evidence on these strategies is limited. Technologies such as continuous subcutaneous insulin infusion (CSII) or continuous glucose monitors (CGM) could help reduce NH and possibly alter PWT1D’ management behaviors.
Aim: To describe PWT1D’ preferred NH prevention strategies according to their use of technology.
Methods: Self-reported data from an online registry of PWT1D were analyzed. To describe which NH prevention strategies are most often used, we ran a χ2 test with a post hoc pairwise comparison of the groups based on their mode of insulin delivery and glucose monitoring (CSII + self-monitoring of blood glucose (SMBG); CSII + CGM; multiple daily injections (MDI) + CGM; MDI + SMBG).
Results: Among 767 adults (64% female, mean age 45 ± 15 years, T1D duration 25 ± 14 years) 42% used MDI + CGM, 40% CSII + CGM, 5% CSII + SMBG, and 13% MDI + SMBG. About 67% reported waking up ≥1 time in the past month due to NH symptoms. The most widely used strategies were verifying bedtime glycemia (71%), having an evening/bedtime snack (60%), and/or reducing nocturnal basal insulin (30%). PWT1D using CSII + CGM or CSII + SMBG relied more on basal insulin reduction (36% and 33.3%, respectively) compared to those using MDI + CGM (26%) or MDI + SMBG (19%). Less PWT1D using CSII + CGM reported having a snack to prevent NH (51%), compared to CSII + SBMG (61%), MDI + CGM (66%), and MDI + SBGM (67%) groups (p&lt;0.001).
Conclusion: Results suggest that PWT1D using technology choose different strategies to avoid NH than non-users. CSII users relying on basal insulin adjustment was expected as CSII offers more flexibility for insulin delivery. Snacks remain a popular strategy to prevent NH but are less used by PWT1D on CSII + CGM. While our findings provide some real-life insight into the methods PWT1D use to avoid NH, the efficacy of these strategies still needs further investigation.

Disclosure
M. K. Talbo: None. V. Messier: Other Relationship; Self; Eli Lilly and Company. K. Desjardins: None. R. Rabasa-lhoret: Advisory Panel; Self; Bayer Inc., Covance Inc., Insulet Corporation, Pfizer Inc., Other Relationship; Self; Abbott, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Dexcom, Inc., Eli Lilly and Company, HLS Therapeutics Inc., Janssen Pharmaceuticals, Inc., Medtronic, Merck & Co., Inc., Novo Nordisk, Sanofi-Aventis, Research Support; Self; Canadian Institutes of Health Research, Cystic Fibrosis Canada, Diabetes Canada, JDRF, National Institutes of Health, Prometic, Société Francophone du Diabète, Speaker’s Bureau; Self; CMS Canadian Medical&Surgical Knowledge Translation Research Group, CPD Network. A. Brazeau: None. T. Peters: None.

Funding
Canadian Institutes of Health Research (JT1-157204); JDRF (4-SRA-2018-651-Q-R)
138-OR: Indirect Treatment Comparison of Ready-to-Use Glucagon Rescue Treatments for Severe Hypoglycemia: Nasal Glucagon vs. Liquid Stable Glucagon
Authors: YAN YU , CHILD CHRISTOPHER J. , SYRING KRISTEN , WANG QIANQIAN , THRELKELD REBECCA J. 
Published: June 2021

Objective: An indirect treatment comparison (ITC) evaluated the efficacy and safety differences between 2 ready-to-use severe hypoglycemia rescue treatments, nasal glucagon (NG, Eli Lilly and Company) and liquid stable glucagon rescue pen (GRP, Xeris Pharmaceuticals), in adults with type 1 or type 2 diabetes.
Methods: Systematic literature reviews identified 3 randomized clinical trials assessing the efficacy and safety of NG versus reconstituted injectable glucagon (IG), and 3 trials of GRP versus IG. No head-to-head trials of NG versus GRP were identified. The Bayesian fixed-effect network meta-analysis was used to perform the ITC. Endpoints included the proportion of participants achieving treatment success (defined as increase in blood glucose to ≥70 mg/dL or an increase of ≥20 mg/dL from nadir blood glucose within 30 mins), maximum blood glucose, and treatment-emergent adverse events (TEAE). In order to more closely match the study populations, participants with a nadir blood glucose value of ≤54 mg/dL were analyzed.
Results: A similar proportion of GRP (98.9% [279/282]) and NG participants (99.4% [155/156]) achieved treatment success (Wald method p=0.63). The mean max blood glucose values were 220 mg/dL for GRP and 168 mg/dL for NG, with a significant treatment difference between GRP and NG, while adjusting IG as a comparator (17.32 mg/dL, 95% credible interval: [3.94, 30.97]). Proportions of participants experiencing ≥1 TEAE were 48.8% for GRP and 38.5% for NG (odds ratio: 1.31 [0.67, 2.31]). Subgroup analyses showed consistent results.
Conclusion: NG and GRP had comparable efficacy in reversing insulin-induced hypoglycemia in adults with diabetes. NG had a mean max blood glucose below 180 mg/dL, which may have implications on the re-establishment of euglycemia after severe hypoglycemia rescue.

Disclosure
Y. Yan: Employee; Self; Eli Lilly and Company. C. J. Child: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. K. Syring: Employee; Self; Eli Lilly and Company. Q. Wang: Employee; Self; Eli Lilly and Company. R. J. Threlkeld: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company.

Funding
Eli Lilly and Company
139-LB: Understanding Attitudes towards Influenza Vaccination among Children with Diabetes in a NYC Hospital
Authors: APSAN JENNIFER , COPPEDGE EMILY , ANTAL ZOLTAN 
Published: June 2021

Background: It is well established that diabetes serves as a risk factor for morbidity and mortality of Influenza infections in the US. The AAP recommends Influenza vaccinations in all children over 6 months of age with a noted emphasis on ensuring that children in high risk groups are vaccinated. We sought to better understand patient and family attitudes towards Influenza vaccination in our diabetes clinic as the first step in trying to improve vaccination rates in our clinics.
Methods: 64 patients, ages 2 to 20 years, of a NYC diabetes clinics were surveyed between 12/2019 and 3/2020. If responses indicated they had refused a vaccine, patients were asked why they had refused. Regardless of their vaccination status, all patients were asked if they would obtain vaccination if one were available at their diabetes clinic appointment.
Results: Overall, 57% of our patients responded that they had received an influenza vaccine in the 2019-2020 season. Further, 13% of patients indicated that they would be receiving a vaccination while 27% of them responded that they did not wish to receive a vaccination. When viewed by age, the 10-15 year old age group had the highest vaccination rate at 70%. While attitudes varied from family to family, the most the most common reasons for refusal included patient preference (31%), disbelief in efficacy (21%), concerns for side effects of vaccination (21%) and ’too busy’ (10.5%). 70% of all patients surveyed expressed that if a vaccination was offered in their diabetes clinic, they would be interested in receiving it.
Conclusions: Focus should be placed on educating our youngest and oldest patients with diabetes to obtain an annual Influenza vaccine. Understanding the most common hesitations among our patients will allow us to improve communication about the vaccine and access to care.

Disclosure
J. Apsan: None. E. Coppedge: None. Z. Antal: None.
148-LB: Demographic Factors Predict Successful Transition to Adult Care in Adolescents and Emerging Adults with Type 1 Diabetes
Authors: TILDEN DANIEL R. , JASER SARAH S. 
Published: June 2021

Background: Adolescents and emerging adults with T1D are a particularly vulnerable group among those with this chronic disease. Previous work has shown that this group has the highest HgbA1c of any age cohort with the disease. While it has been shown that maintaining engagement with care can help improve disease control, there is limited evidence to identify those at most risk of being lost to follow up at this care transition. The current study used visit-level EHR data to analyze demographic and visit data to determine predictors of successful pediatric to adult transition.
Methods: This is a retrospective cohort study of 4,185 patients with T1D who were seen in the pediatric diabetes clinic at least once in three consecutive calendar years between 2004 and 2020. The primary outcome of interest was completion of at least 1 adult endocrinology clinic visit for T1D care. Patients were compared using descriptive statistics and logistic regression to analyze demographic factors and key disease metrics including HgbA1c and hospital admission.
Results: Among study subjects, 730 completed transition to adult care within our health system. Those completing transition has about one fifth the odds (aOR 0.22 95%CI: 0.15 - 0.32) of having private insurance compared to patients who did not transition. No other significant demographic differences were found between the two groups. Among those who did transition, the median time from last pediatric to the first adult visit was 190 days (IQR 100 - 542) with only 53.2% completing their first adult visit within 6 months.
Discussion: Our data suggest that insurance is the most significant barrier to transition from our pediatric to adult clinics for patients with T1D. Importantly, even among those who do ultimately receive care from our adult clinics, we identified significant gaps in care. Improving our processes for transitions should focus on closing these gaps to help emerging adults maintain engagement in their T1D care.

Disclosure
D. R. Tilden: None. S. S. Jaser: None.

Funding
National Institutes of Health (DK007061CTSA); National Center for Advancing Translational Sciences (UL1TR002243)
148-OR: Usefulness of CGM Metrics to Assess Glycemic Control in Non-White Subjects with Diabetes
Authors: TOSCHI ELENA , SLYNE CHRISTINE , MICHALS AMY , SIFRE KAYLA , DEWAR RACHEL , ATAKOV-CASTILLO ASTRID , DAVIS DAI’QUANN J. , MUNSHI MEDHA 
Published: June 2021

Introduction: Glucose management indicator (GMI), a CGM-based metric, of mean glucose is thought to give more information on glycemic excursion than laboratory measured A1c. We have shown differences in relationship between A1c and GMI in different age groups, however it is not known whether racial differences affect the relationship between A1c and GMI.
Methods: We analyzed data from patients with diabetes undergoing professional CGM (proCGM) at a tertiary care diabetes center between year 2017 and 2020, who had at least 10 days of CGM data. Medical records were queried to obtain demographic information and laboratory A1c results from within 1 month of CGM wear. GMI was calculated as Formula =3.31 + (0.02392 × mean glucose in mg/dL).
Results: We evaluated 316 patients (mean age 60 ±18, 51% female, duration of diabetes 24±15 years, T1D 45% and T2D 55%, 78% white and 22% non-white). Subjects were identified by race as non-white (T1D 22%; T2D 78%) or white (T1D 45%; T2D 55%). CGM metrics in the non-white and white cohort were similar; time in range (728 ± 342 vs. 722 ± 307 min/day; p=ns), time &lt;70 mg/dL (90 ± 98 vs. 97 ± 108 min/day; p=ns ), and time &gt;180 mg/dL (568 ± 324 vs. 569 ± 346 min/day; p=ns). While GMI was not different in the nonwhite vs. white cohort (7.6 ± 1.3 vs. 7.7 ± 1.5; p=ns), A1c was higher in non-whites (8.7 ± 1.6 vs. 8.1 ±1.3; p=0.004). An absolute difference between A1c and GMI was higher in nonwhite vs. white (1.5 ± 0.88 vs. 1.1 ± 0.82 vs; p=0.006) and the absolute difference of 0.5% was observed in higher proportion of nonwhite patients (50 [75%] vs. 165 [68%]).
Conclusions: In our study cohort, the relationship between GMI and A1c is different in non-white versus white population despite similar CGM metrics. This difference might be important to consider when assessing glycemic control and goals in diverse patient population.

Disclosure
E. Toschi: Consultant; Self; Medtronic. C. Slyne: None. A. Michals: None. K. Sifre: None. R. Dewar: None. A. Atakov-castillo: None. D. J. Davis: None. M. Munshi: Consultant; Self; Sanofi.

Funding
National Institutes of Health (1DP3DK112214-01)
154-LB: Impact of Maternal Diabetes Exposure on Soluble Adhesion Molecules
Authors: LANDRETH SAMANTHA B. , TEAGUE APRIL M. , JENSEN MARY ELLEN , GULATI SHELLY , TRYGGESTAD JEANIE B. 
Published: June 2021

Soluble adhesion molecules are associated with cardiovascular disease and increased in individuals with diabetes. The current study assesses the impact of diabetes exposure in utero on the abundance of circulating adhesion molecules in cord serum as well as soluble adhesion molecules released from human umbilical vein endothelial cells (HUVEC) upon exposure to high levels of glucose. Women with and without diabetes (DM; gestational or type 2) were recruited at delivery. DM was diagnosed based on the criteria by the American Diabetes Association. Primary cultures of HUVEC were established in M199 medium with growth supplements. For the high glucose treatment, medium was adjusted to a final glucose concentration of 25mM with media collected 48 hours post treatment. The soluble adhesion molecules intracellular adhesion molecule (ICAM), vascular cell adhesion molecule (VCAM) and E-selectin were measured by ELISA in the cord blood serum and the conditioned HUVEC media. Serum adhesion molecules were measured in 42 infants born to mothers with normal glycemia and 35 infants of mothers with DM. The mothers with DM were older with higher BMI (p=0.027 and 0.008, respectively). In a fully adjusted model, VCAM was significantly increased in the cord serum of infants born to mothers with diabetes (p=0.046), but ICAM and E-selectin were not different. ICAM was significantly correlated with E-selectin (r2=0.25, p&lt;0.001), but not VCAM. ICAM was also significantly correlated with maternal HbA1c (r2=0.16, p=0.004) and cord serum non-esterified fatty acids (r2=0.08, p=0.013). From the HUVEC, the abundance of adhesion molecules was not different based on DM or high glucose exposure; however, VCAM abundance in the HUVEC supernatant was significantly correlated with ICAM (r2=0.27, p=0.010) and cord serum insulin (r2=0.19, p=0.042). Alterations in soluble adhesion molecule abundance in infants exposed to the diabetic milieu of pregnancy may reflect early alterations in vascular function predicting future cardiovascular disease.

Disclosure
S. B. Landreth: None. A. M. Teague: None. M. Jensen: None. S. Gulati: None. J. B. Tryggestad: None.

Funding
National Institutes of Health (1K23DK106533)