bluuebunny/crossref_metadata_2025_split huggingface dataset:
183-LB: Incidence and Characteristics of Type 1 and Type 2 Diabetes among Youths in the COVID-19 Pandemic
Authors: NIP ANGEL , AHMAD TARIQ 
Published: June 2021

Background: The impact of SARS-COV-2 on islet cell function and immune dysregulation is unclear. Though adults with diabetes suffer higher rates of morbidity and mortality from COVID-19, pediatric data is limited. We aimed to study the number and characteristics of new onset type 1 (T1D) and type 2 (T2D) diabetes pre- and during the pandemic.
Method: This was a retrospective study using inpatient data at UCSF Benioff Children’s Hospital Oakland. We examined newly diagnosed T1D and T2D, aged &lt; 18 years old, from May 2019 to Jan 2021. COVID-19 pandemic was defined from Mar 2020 onward.
Results: Respectively, there were 59 and 64 new T1D, and 25 and 34 new T2D pre- and during COVID-19 pandemic. No difference was observed in time-adjusted incidence rate in T1D, but a rising trend in T2D was seen. A higher infection rate (PCR or IgG) was shown in T2D than T1D (11.8% vs. 3.1%, p = 0.05). During COVID-19, individuals with T1D had higher BMI z-scores (0.4 vs. -0.2, p = 0.03) and c-peptide levels (0.8 ng/ml vs. 0.5 ng/ml, p &lt;0.01), and more Hispanics were diagnosed (46.9% vs. 27.1%, p = 0.02). Individuals with T2D were younger (mean age 12.8 yr vs. 14.5 yr, p = 0.02) and had more DKA on presentation (35.3% vs. 12.0%, p = 0.04) during the pandemic. Insurance and income were not associated with T1D nor T2D. No differences in patient demographics were observed in relation to COVID-19.
Conclusion: We observed a rising trend of new onset T2D in the pediatric population during COVID-19, who were younger and sicker at presentation, and had a higher COVID-19 positivity rate than T1D. T1D incidence was similar, but individuals were more obese, had greater beta cell reserve at presentation, and a higher proportion were Hispanic compared to pre-pandemic. The roles of COVID-19, stress, and/or lifestyle changes associated with shelter-in-place orders, contributing to increased BMI and c-peptide levels in T1D, or increasing the risk for new onset diabetes and DKA in youths with T2D needs to be elucidated further and studied.

Disclosure
A. Nip: None. T. Ahmad: None.
189-LB: Using Genetics to Separate Childhood from Adult BMI Shows That Higher Childhood BMI Has No Direct Effect on Reduced Insulin Secretion or Sensitivity in Later Life
Authors: HAWKES GARETH , RICHARDSON TOM G. , POWER GRACE M. , SMITH GEORGE DAVEY , FRAYLING TIMOTHY M. 
Published: June 2021

Higher BMI during childhood is associated with an increased likelihood of remaining overweight later in life, leading to higher risk of developing type 2 diabetes (T2D). Using a Mendelian randomisation approach, a recent study found no evidence that childhood BMI has a direct causal effect on T2D. However, the extent to which high BMI in childhood directly alters insulin secretion and sensitivity in later life requires further investigation.
We aimed to use genetic variants associated with differential effects on childhood and adult BMI to test their separate effects on insulin secretion and insulin sensitivity. We first generated a measure of childhood BMI aged 10 using self-reported categories in the UK Biobank, which we approximated to a normal distribution. We then performed separate genome wide association studies (GWAS) of childhood and adult BMI. This approach increased the number of genetic instruments by a factor of two as compared to previous methods. We used a multivariable Mendelian Randomisation approach, with childhood and adult BMI as exposure variables, and 5 measures of insulin secretion and insulin sensitivity in nondiabetic adults from previous GWAS studies as outcome variables.
We found no evidence (at p&lt;0.05) that higher BMI in childhood has a direct adverse effect on type 2 diabetes (OR 0.94, 95%CI 0.82-1.08), fasting insulin (OR 1.00, 0.95 - 1.05), insulin sensitivity (OR 1.11, 0.97-1.27) or sensitivity-index adjusted acute insulin response (OR 1.11, 0.88-1.42) in adults. There was some evidence of a protective effect, with higher childhood BMI associated with lower fasting glucose (OR 0.96, 0.93 - 1.00) and insulin secretion (OR 1.30, 1.04 - 1.63). Crucially, our results are consistent with no adverse direct effect of higher childhood BMI on adult type 2 diabetes, insulin secretion or sensitivity.

Disclosure
G. Hawkes: None. T. G. Richardson: None. G. M. Power: None. G. Davey smith: None. T. M. Frayling: None.

Funding
Innovative Medicines Initiative 2 Joint Undertaking (875534)
196-LB: Stem Cell–Derived Islet Replacement Therapy (VC-02) Demonstrates Production of C-Peptide in Patients with Type 1 Diabetes (T1D) and Hypoglycemia Unawareness
Authors: KEYMEULEN BART , JACOBS-TULLENEERS-THEVISSEN DANIEL , KROON EVERT J. , JAIMAN MANASI S. , DANIELS MARK , WANG RICHARD , PIPELEERS DANIEL , D’AMOUR KEVIN , FOYT HOWARD L. 
Published: June 2021

Patients with T1D exhibit a major loss in beta cell mass, associated with low or undetectable circulating markers of beta cell function. C-peptide serves as a biomarker used to assess the residual mass of functional insulin-producing pancreatic beta cells present in patients with T1D on insulin replacement therapies; this measurement is not confounded by exogenous insulin. Novel cell replacement therapies to address T1D, including VC-02 (PEC-Direct), have demonstrated the ability to control disease state and mitigate diabetes-related complications due to the absence of insulin and glycemic variability.
In the current VC02-101 study, T1D patients were required to be C-peptide negative (during a mixed meal tolerance test) upon enrollment. Study participants received subcutaneous implanted VC-02 combination product containing pancreatic precursor cells (PEC-01 cells) derived from ViaCyte’s proprietary CyT49 pluripotent stem cell line. When effectively engrafted, these cells are capable of producing circulating C-peptide, as previously shown in rodent models, and now for the first time at clinically relevant levels in patients.
Preliminary data for one patient implanted with the most current device configuration are presented through 6 months study duration. Stimulated C-peptide Cmax concentrations increased from 0.1 ng/mL (baseline) to 0.5 ng/mL (week 26), and AUC0-4hr increased from 0.225 to 1.775 ng x hr/mL. These results are corroborated by histology evidencing successful engraftment and cell survival. This effect was accompanied by an increase in time-in-range from 56 to 86% and reduction in HbA1C by 0.5%. Together, these data provide clinical proof-of-concept that further optimization of this therapy can result in a functional cure for T1D.

Disclosure
B. Keymeulen: None. D. Jacobs-tulleneers-thevissen: None. E. J. Kroon: Employee; Self; Viacyte, Inc. M. S. Jaiman: Employee; Self; Viacyte, Inc., Stock/Shareholder; Self; Viacyte, Inc. M. Daniels: Employee; Self; Viacyte, Inc. R. Wang: Employee; Self; Viacyte, Inc. D. Pipeleers: Board Member; Self; Beta-Cell NV. K. D’amour: Employee; Self; Viacyte, Inc. H. L. Foyt: Employee; Self; Viacyte, Inc., Stock/Shareholder; Self; Viacyte, Inc.

Funding
European Commission, Horizon 2020 (681070); California Institute of Regenerative Medicine (CLIN2-09672); JDRF (2011)
211-OR: Differential Cerebral Blood Flow in Controlled and Uncontrolled Patients with Type 2 Diabetes Mellitus
Authors: CHOI SARAH E. , ROY BHASWATI , FREEBY MATTHEW , KUMAR RAJESH 
Published: June 2021

Introduction: Patients with type 2 diabetes mellitus (T2DM) show variable brain tissue changes and mood and cognitive symptoms, which may result from altered cerebral blood flow (CBF). However, the regional CBF status in controlled and uncontrolled T2DM patients remains unclear, which can be examined with arterial spin labeling (ASL) imaging. Our aim was to examine regional CBF between controlled and uncontrolled T2DM patients using ASL imaging procedures.
Methods: We collected hemoglobin A1c (A1C) data and 3D pseudo-continuous ASL data from 32 T2DM patients (16 controlled [A1C &lt; 7%], age, 56.5±6.5 years; BMI, 29.6±6.2 kg/m2; 8 female; 16 uncontrolled [A1C ≥ 7%], age, 57.6±7.5 years; BMI, 30.0±5.1 kg/m2; 11 female) using a 3.0-Tesla MRI. A1C was measured by point-of-care testing. Whole-brain CBF maps were calculated, normalized to a common space, smoothed, and compared between groups (controlled T2DM patients vs. uncontrolled T2DM patients) using analysis of covariance (SPM12; covariates, age and sex; p&lt;0.05).
Results: No significant differences in age or sex appeared between groups. Multiple brain areas showed decreased CBF values in the cingulate, caudate, putamen, insula, hippocampus, amygdala, thalamus, hypothalamus, midbrain, cerebellum, prefrontal and frontal, and temporal cortices in uncontrolled T2DM patients over controlled T2DM patients. However, few brain sites in controlled T2DM patients, including the cerebellum, pons, medulla, parahippocampal gyrus, and temporal cortices showed reduced CBF over uncontrolled T2DM patients.
Conclusion: Uncontrolled T2DM patients show significant reduction in CBF compared to controlled T2DM in areas that are involved in mood and cognition regulation. The findings suggest that uncontrolled levels may contribute to reduce regional CBF leading to site-specific tissue changes resulting to mood and cognition deficits in the condition.

Disclosure
S. E. Choi: None. B. Roy: None. M. Freeby: Research Support; Self; Abbott Diabetes, Novo Nordisk Inc. R. Kumar: None.

Funding
National Institutes of Health (1R01NR017190-03, 3R01NR017190-03S1)
215-OR: Performance of a Dual Hormone Closed-Loop System vs. an Insulin-Only Closed-Loop System during Challenging Inpatient Conditions: A Single-Blinded Randomized Controlled Crossover Trial
Authors: RANJAN AJENTHEN G. , BOIROUX DIMITRI , LAUGESEN CHRISTIAN , SCHMIDT SIGNE , REENBERG ASBJØRN T. , JØRGENSEN JOHN B. , NØRGAARD KIRSTEN 
Published: June 2021

Objective: To assess the efficacy and safety of an insulin-glucagon dual-hormone (DH) compared with an insulin-only single-hormone (SH) closed-loop system.
Methods: In a 33-h, randomized, crossover, inpatient study, 13 participants with type 1 diabetes used two modes of the DiaCon Artificial Pancreas system: DH and SH closed-loop control. During each study period, participants had two overnight stays, received an underbolus (50%) for their breakfast, normal bolus (100%) for lunch, overbolus (130%) for dinner and performed unannounced exercise for 45 min (bicycled at estimated 50% V02max). The co-primary endpoints were sensor-based percentage of time in hypoglycemia (&lt;3.9 mmol/L) and the number of 15 g carbohydrate rescues whenever plasma glucose &lt;3.0 mmol/L from 0 to 33 h after initiation of the systems.
Results: Overall, the average number of carbohydrate rescues was significantly lower during DH compared with SH (mean±SD: 0.8±1.3 vs. 1.4±1.4 per 33 h, p = 0.04). The percentages of time in hypoglycemia (3.6±2.1% vs. 3.8±3.3%, p = 0.46), target range (3.9-10.0 mmol/L: 67.2±15.4% vs. 65.3±12.4%, p = 0.41) and hyperglycemia (&gt;10.0 mmol/L: 26.8±16.0% vs. 28.7±12.7%, p = 0.41) were similar between study arms. Mean glucose was lower for DH than SH (8.3±1.2 vs. 8.6±1.0 mmol/L, p = 0.04) with similar coefficient of variation (40±8.3 vs. 38±5.0%, p = 0.30). From exercise start and 4 h onwards, DH achieved more time in range (86.7±11.7 vs. 74.7±16.5%, p = 0.01), but similar time in hypoglycemia (10.5±18.7 vs. 12.6±24.3%, p = 0.32) and numbers of carbohydrate rescues (5±0.7 vs. 6±0. 7, p = 0.38). No differences were observed on visual analog scale-measured nausea (p = 0.47), headache (p = 0.77), hunger (p = 0.66), and palpitation (p = 0.11).
Conclusions: During challenging inpatient conditions, the DH system achieved similar glucose control but significantly reduced need for carbohydrate rescue compared with SH.

Disclosure
A. G. Ranjan: None. D. Boiroux: Consultant; Self; Novo Nordisk A/S, Employee; Spouse/Partner; Novo Nordisk A/S. C. Laugesen: None. S. Schmidt: None. A. T. Reenberg: None. J. B. Jørgensen: None. K. Nørgaard: Advisory Panel; Self; Medtronic, Other Relationship; Self; Novo Nordisk Inc., Zealand Pharma A/S, Speaker’s Bureau; Self; Medtronic.

Funding
Danish Diabetes Association; Danish Diabetes Academy (PD002-19)
220-LB: Serum Lipocalin-2 (LCN2): Potential Indices Associated with Weight Loss and Metabolic Improvement after Laparoscopic Sleeve Gastrectomy (LSG)
Authors: LI NANNAN , MUTAILIPU KELIBINUER , YOU HUI , HUANG YUEYE , ZHU BING , SU LILI , WEN XIN , LEI SHIHUI , QU SHEN , BU LE 
Published: June 2021

Background: The aims of study are to observe laparoscopic sleeve gastrectomy (LSG) surgery mediated change in LCN2 level, and to ascertain relevance of LCN2 to efficacy indicators of LSG surgery.
Methods: The retrospective study of 58 obese individuals who have undergone LSG surgery was held between July 2016 and July 2017 in the Shanghai Tenth People’s Hospital in China. Anthropometric and biochemical measurements were recorded at baseline and 12 months after surgery. Body fat was measured by dual-energy X-ray absorptiometry. Serum LCN2 level was measured by enzyme-linked immunosorbent assay. We analyzed association between serum LCN2 level and efficacy indicators 12 months post-surgery, and further explored the dose-dependent relation across the baseline / decrease LCN2 tertiles.
Results: From baseline to 12 months after LSG, serum LCN2 level was significantly decreased; we found independent association between baseline / decreased LCN2 and efficacy indicators, including changes in weight, waist circumference, fat mass and triglyceride; further, across the decreased LCN2 tertiles, intragroup difference analysis showed significantly higher level of percent extra weight, waist circumference, and trunk fat mass loss, decreased total fat percent on the top tertile, compared to the lowest tertile; and binary logistic regression analysis showed direct dose-dependent relation between decreased LCN2 level and weight loss efficacy (the lowest tertile as reference, adjusted odds ratio (95%CI) = 42.66 (1.41-1290.28), 70.42 (1.82-2723.43), per decreased LCN2 tertile respectively); across the baseline LCN2 tertiles, we found significantly higher level of percent waist circumference on the top tertile, compared to the lowest tertile.
Conclusion: In our study, LCN2 level was decreased at 12 months after LSG surgery. Baseline and decreased LCN2 levels were associated with some weight loss efficacy indicators in a dose-dependent way.

Disclosure
N. Li: None. L. Bu: None. K. Mutailipu: None. H. You: None. Y. Huang: None. B. Zhu: None. L. Su: None. X. Wen: None. S. Lei: None. S. Qu: None.
223-LB: Jagged 1- Notch Signaling Determines ß-Cell Maturity and Function
Authors: SUDA NINA , PAJVANI UTPAL 
Published: June 2021

Obesity-induced Type 2 Diabetes (T2DM) continues to increase at an alarming rate resulting in a substantial burden of long-term complications and healthcare costs. As such, understanding mechanisms of T2DM pathogenesis is key in tackling the growing prevalence. Although insulin resistance is the hallmark of T2DM, it manifests as hyperglycemia only in the setting of β cell insufficiency. Pathophysiologic mechanisms underlying this failure requires further elucidation. We have recently shown that Notch signaling is a novel regulator of β cell function, and glucose homeostasis. Notch activity is regulated by ligand (Jagged 1/2, and Delta-like 1/3/4) availability. We find that islets isolated from HFD-fed or leptin receptor-deficient db/db mice have increased Jagged1 expression as compared to chow or db/+ controls, without change in other Notch ligands, in parallel to increased Notch activity. These data led us to hypothesize that Jagged1 is both sufficient and necessary to transduce Notch signaling in β cells and is a potential regulator of β cell function, maturity and glucose homeostasis. To investigate this, we generated novel β cell specific Jagged1 gain-of-function and knock-out mice. Preliminary data from our inducible gain of function model show progressively impaired glucose intolerance through decreased insulin secretion in parallel with an increase in Notch activity, despite normal weight and adiposity. By identifying the ligand-receptor interaction, we postulate that we can take advantage of this knowledge for therapeutic benefit. To this end, we have generated dominant negative mutants of the Notch receptor lacking the intracellular Notch domain that specifically block either Jagged or Delta-like ligands. The current data on Notch signaling in β cells shows promise for furthering the understanding of the pathophysiology in T2DM. In studying this mechanism further, we hope to provide a novel therapeutic strategy in preventing a disease that continues to be a growing concern worldwide.

Disclosure
N. Suda: None. U. Pajvani: None.

Funding
Endocrine Fellows Foundation
224-OR: Cardiac Imaging and Metabolomics Studies Suggest Shared and Distinct Risk Factors for Atherosclerosis and Cardiomyopathy in Renoprotected, Long-Duration Type 1 Diabetes
Authors: YU MARC GREGORY , SHAH HETAL , WOLFSON EMILY , ADAM ATIF , GAUTHIER JOHN , JHA VIBHAV , TSAO CONNIE , KING GEORGE L. 
Published: June 2021

Cardiovascular disease (CVD) is a major cause of mortality in long-duration type 1 diabetes (T1D) despite the absence of nephropathy (DN). However, its mechanisms are incompletely understood. Joslin 50-Year “Medalists”, with T1D≥50 years, are ideal for studying CVD in a renoprotected T1D cohort, as only 13% have DN, yet 40% have CVD. A Medalist subset underwent coronary artery calcification scans (CAC; n=75) and cardiac magnetic resonance (CMR; n=60) of left ventricular (LV) mass and volumes. In exploratory analyses, we studied the association of these imaging parameters with Medalists’ cardiometabolic profiles. Compared to males, females were less likely to have CAC&gt;200 (p=0.02) and had lower (more favorable) values for CMR structure parameters such as LV mass index (MI) and end-systolic (ESV) and end-diastolic (EDV) volumes (all p&lt;0.05). Higher HbA1C showed a trend towards association with CAC&gt;200 and higher LV MI (both p=0.1). CAC&gt;200 also associated with retinopathy (PDR; p=0.04) and lower superficial capillary density on retinal imaging (p=0.049), and a trend towards association with lower HDL and higher C-reactive protein (both p=0.09). LV MI and EDV were associated with DN (p=0.04 and p=0.05, respectively). In untargeted metabolomics, LV MI, EDV, and ESV were also associated with higher levels of short-medium chain acylcarnitines and histamine metabolites, and lower levels of tryptophan metabolites via the indole pathway (all FDR&lt;0.1). These preliminary findings suggest that while sex and glycemic control are shared contributors to atherosclerosis and cardiomyopathy in T1D, PDR, lipids and inflammation appear distinctly tied to atherosclerosis; while DN and endogenous metabolites may play a role in cardiomyopathy. Our findings suggest the need for targeted therapeutic approaches for CVD in T1D, depending on whether manifestations are predominantly atherosclerotic or cardiomyopathic.

Disclosure
M. Yu: None. H. Shah: None. E. Wolfson: None. A. Adam: None. J. Gauthier: None. V. Jha: None. C. Tsao: None. G. L. King: Consultant; Self; Agios, Inc., Medtronic, Other Relationship; Self; Janssen Pharmaceuticals, Inc.

Funding
American Diabetes Association (9-18-CVD1-005 to M.G.Y.); Thomas J. Beatson Jr. Foundation (2185 20008 2800200)
26-LB: Glycemic Control in People with Type 1 Diabetes Mellitus after the First Portuguese COVID-19–Related State of Emergency
Authors: RAMALHO DIOGO , CORREIA SARA , ALMEIDA LÚCIA , ALVES HELENA , ROCHA GUSTAVO , FERREIRA MARTA , OLIVEIRA MARIA J. 
Published: June 2021

Introduction: The first Portuguese COVID-19-related state of emergency (SE) extended between March and May 2020. The relevance of achieving the glycemic target for the person with type 1 Diabetes Mellitus (T1DM) is deepened in these circumstances, given the forced changes in daily routine.
Objective: To determine the influence of work activity (WA) on glycemic control (GC) of adults with T1DM after the first SE.
Material and methods: A retrospective cohort study was designed to enroll adults with ≥2 years from T1DM diagnosis. Cases of pregnancy/hospitalizations in 2019/2020, factors that affect interpretation of glycated hemoglobin (HbA1c) and/or SARS-CoV-2 infections were excluded. The participants were stratified into groups of WA after the SE: g1 (telework/lay-off/students), g2 (retired/unemployed) and g3 (WA without lockdown). HbA1c were obtained from 4 periods: t3 (4/1-6/1/2020); t4 (7/1-9/1/2020); t1 and t2 (homologous periods of 2019). Differences in HbA1c were calculated in both years and compared to each other in the same group and between groups in the same year. Hypoglycemia and insulin regimens (insulin pump and multiple injections daily) were analyzed in intragroup (t3 vs. t4) and intergroup (t3 and t4) comparisons.
Results: Two hundred and seven participants were included [106 (51.2%) men; median age of 35 (25;47) years]: 144 (69.6%) in g1, 44 (21.3%) in g2 and 19 (9.2%) in g3. HbA1c increased significantly between t4 and t3 (vs. t2 and t1) in g1 (p=0.001), but not in g2 (p=0.077) and g3 (p=0.744). In 2020, HbA1c raised significantly in the analysis "g1 vs. g3" (p=0.004), but not in "g1 vs. g2" (p=0.213) and "g2 vs. g3" (p=0.083). No differences were reported in 2019, along with all the comparisons involving hypoglycemia and insulin regimens.
Conclusions: This study found an overall worsening of GC in participants who returned to higher levels of activity after a total lockdown. This is probably explained by the time spent on T1DM self-care during the lockdown.

Disclosure
D. Ramalho: None. S. Correia: None. L. Almeida: None. H. Alves: None. G. Rocha: None. M. Ferreira: None. M. J. Oliveira: None.