bluuebunny/crossref_metadata_2025_split huggingface dataset:
363-OR: Weight Loss, Lifestyle Intervention, and Metformin Effects on the Longitudinal Relationship between Insulin Secretion and Sensitivity in the Diabetes Prevention Program (DPP)
Authors: ARREOLA ELSA VAZQUEZ , KNOWLER WILLIAM C. , HANSON ROBERT L. 
Published: May 2022

Insulin secretion and sensitivity regulate glycemia, with inadequately compensated deficiencies in either or both leading to diabetes. Using data from 2931 participants in the DPP repository, we investigate the effects of lifestyle and metformin interventions and of weight loss on the relationship between insulin secretion and sensitivity. Insulin secretion and sensitivity were estimated from insulin concentrations in fasting and 30-minute post-load serum samples at baseline and at 1, 2, and 3 years after randomization during the active intervention phase of the DPP. The relationship of secretion and sensitivity was evaluated by standardized major axis regression and was found to change over time for participants in the lifestyle and metformin interventions. Distances along and away from the regression line were taken to characterize insulin secretory demand and insulin secretion in compensation to the demand, respectively. Both the metformin and lifestyle interventions decreased secretory demand while increasing compensatory insulin secretion, with greater effects of the lifestyle intervention. Improvements were directly related to the amount of weight loss; decreases in weight significantly reduced secretory demand [b=-0.088 SD (-0.102, -0.074) /5 kg loss] and increased compensatory insulin secretion [b=0.169 SD (0.149, 0.189) /5 kg loss]. In time-dependent hazard models, increasing secretory demand associated with increased diabetes risk [hazard ratio (HR) =1.189 per baseline SD (1.004, 1.413) ] while increasing compensatory insulin secretion associated with lower risk [HR=0.1 (0.080, 0.145) ]. These results are consistent with earlier observations in the DPP that diabetes risk reduction was directly related to the amount of weight loss and suggest that this effect is mediated by lowered insulin secretory demand coupled with improved compensatory insulin secretion.

Disclosure
W.C. Knowler: None. R.L. Hanson: None.
364-OR: Apolipoprotein A-I and Clinical Remission in Adults with Type 1 Diabetes-InLipoDiab1 Study
Authors: URUSKA ALEKSANDRA , ROHATGI SR., ANAND , CIELUCH ALEKSANDRA , GRZELKA-WOZNIAK AGATA , FLOTYNSKA JUSTYNA , PYPEC ALEKSANDRA , ZOZULINSKA-ZIOLKIEWICZ DOROTA 
Published: May 2022

Introduction: Apolipoprotein A-I (Apo A-I) , the main protein in high-density lipoproteins, improves beta-cell function and insulin sensitivity in experimental models and in people with type 2 diabetes. In those with type 1 diabetes (DM1) , clinical remission (CR) is a key factor for improved prognosis. However, predictors of CR in DM1 are not well described. Whether Apo A-I predicts CR in patients with DM1 remains unknown. Aim To assess the relationship between baseline Apo A-I at the time of diagnosis of DM1 with the presence of CR after 12 months of the disease.
Methods: The participants of Insulin Therapy and Lipoproteins' Profile in Type 1 Diabetes Study (InLipoDiab1; NCT02306005) were prospectively observed from the onset of the disease (the blood collection was performed before exogenous insulin administration) through 12 months. The final observation included 53 adults (62% men, age at onset 27±6 years) . DM1 was confirmed with guideline-based criteria on the presence of specific autoantibodies. The endpoint was the presence of pCR at the end of observation, which was defined as IDAA1C ≤ 9, according to the definition by Mortensen et al.: A1C (%) + [4 × insulin dose (U/kg/day) ]. Apo A-I was measured in serum with an ELISA kit. The group was divided into two according to the presence and absence of pCR.
Results: At 12 months, pCR was present in 43 participants (81%) . Baseline serum Apo A-I was significantly lower in participants without pCR versus those with the presence of pCR [0.79 (0.39-1.58) vs. 4.51 (0.95-5.93) mg/dl, p=0.002, respectively]. In multiple logistic regression, higher baseline Apo A-I was associated with the presence of pCR after 12 months, adjusted for sex, age, weight and the presence of diabetic ketoacidosis at onset (OR 1.74 (CI 95% 1.02-2.96) , p=0.03) .
Conclusion: The higher Apo A-I serum concentration at onset of DM1 the higher chance is for pCR in adults with DM1, after 12 months of observation. Higher serum Apo A-I levels seem to be a good prognostic factor for pCR of DM1.

Disclosure
A.Uruska: Other Relationship; Lilly, Novo Nordisk. A.Rohatgi: Speaker's Bureau; CSL Behring. A.Cieluch: None. A.Grzelka-wozniak: Other Relationship; Novo Nordisk, Roche Diabetes Care. J.Flotynska: None. A.Pypec: None. D.Zozulinska-ziolkiewicz: Advisory Panel; Dexcom, Inc., Medtronic, Speaker's Bureau; Abbott Diabetes, Ascensia Diabetes Care, AstraZeneca, BIOTON S.A., Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk, Sanofi.

Funding
Kosciuszko Foundation and Poznan University of Medical Sciences
365-OR: Interruption of Glucagon Signaling Increases Delta-Cell Proliferation in Mouse and Human Islets
Authors: DAI CHUNHUA , BRADLEY AMBER , SPEARS ERICK , SINGH AJAY K. , OLADIPUPO FAVOUR O. , JENKINS REGINA , COATE KATIE C. , POWERS ALVIN C. 
Published: May 2022

The determinants of delta cell mass are not known. As part of studies showing interruption of glucagon signaling (IGS) stimulates alpha cell proliferation in an amino acid (AA) -dependent manner, we noted an increase in delta cells. To investigate, we examined delta cell proliferation and mass in 3 mouse models and a human islet xenograft model. Adult mice with deletion of glucagon (Gcg-/- ) had a 4.7-fold increase in Ki67-positive delta cells (1.50±0.14% vs. 0.32±0.12%, P&lt;0.001, n=8) and a 3.1-fold increase in delta cell mass (0.49±0.vs. 0.16±0.mg, P=0.003, n=10) . Treatment of adult C57BL/6J mice with a Gcg receptor antibody (GCGR Ab) elicited a 6.3-fold increase in delta cell proliferation (2.01±0.4% vs. 0.32±0.07%, P=0.002, n=10) and a 2.6-fold increase in delta cell mass (0.20±0.03 vs. 0.078±0.mg, P=0.001, n=10) , respectively, compared to IgG-treated controls. Since hyperaminoacidemia is necessary for alpha cell proliferation in response to IGS, we investigated the requirement for Slc7a2, a cationic AA transporter, in delta cell growth. Indeed, Slc7a2+/+ mice, but not Slc7a2-/- mice, treated with GCGR Ab had a 3.8-fold increase in delta cell proliferation (3.29±0.14% vs. 0.86±0.05%, P&lt;0.001) and 1.6-fold increase in delta cell mass (0.20±0.02 vs. 0.126±0.mg, P=0.016, n=8) . Given that mTOR is a known intracellular mediator of AA-regulated cellular growth, we evaluated phospho-ribosomal protein S6 (pS6) expression in situ and found a marked increase in pS6 labeling of delta cells in Gcg-/- , but not Gcg+/+ , mice. We also observed a 3.6-fold increase in delta cell proliferation (1.75±0.25% vs. 0.49±0.06%, P=0.004, n=3 adult normal donors) in human islets transplanted into immunodeficient mice treated with GCGR Ab. Taken together, these data indicate that IGS promotes delta cell proliferation and mass through mechanisms involving Slc7a2 and the mTOR signaling pathway and that AAs may be a determinant of delta cell mass.

Disclosure
C.Dai: None. A.Bradley: None. E.Spears: None. A.K.Singh: None. F.O.Oladipupo: None. R.Jenkins: None. K.C.Coate: None. A.C.Powers: None.
37-OR: Childhood Screening and Interception Strategies: An Economic Cohort Simulation Model
Authors: TRUSHEIM MARK , KOSTENSE STEFAN , FERRAT LAURIC A. , MCQUEEN R. BRETT , NEUSNER ROBERT D. , ORAM RICHARD A. , REWERS MARIAN , DUNNE JESSICA L. 
Published: May 2022

T1D screening and monitoring studies suggest opportunities for scaling up to public health population-based programs. Genetic Risk Scores (GRS) for T1D are also demonstrating the ability to identify those at higher risk of progressing to T1D as well as an increased opportunity for implementation into public health settings potential as a result of practical considerations, including falling gene sequencing costs.Previous studies have shown that screening and monitoring children for T1D progression significantly decreases DKA events at diagnosis, which has been shown to have both short- and long-term benefits. Furthermore, identification of those at higher risk of T1D provides an opportunity to intervene and delay T1D onset. A non-stochastic, state transition cohort simulation projected 20US births through adolescence. Data from previously collected natural history studies, including TEDDY, DIPP & DAISY were used to model the patient journey. Children seroconverting to islet autoantibodies (IAB) each year and children with lower T1D risk were simulated as separate cohorts with distinct progressions. Interception strategies were layered over this natural history projection. Success of GRS screening followed by annual IAB and glucose monitoring to intercept T1D progression and reduce DKA events was explored. Therapeutic intervention to delay T1D onset was also simulated.Real-world benchmarks for newborn screening (85%) and patient follow-up (80%) as well as rapid T1D progression (&lt;12 months) for some children limited maximum interception at dysglycemia to 52% of children progressing to T1D by age 15 using a GRS screening strategy. Short-term net incremental costs range reach $1.1B at current test costs or $225K per T1D case interception. Breakeven costs could be achieved with $40 IAB test cost and $5 GRS costs with a therapeutic to delay T1D onset by 3 years or possibly by including assessment potential long-term benefits of early intervention and improved glycemic control.

Disclosure
M.Trusheim: Other Relationship; CO BIO CONSULTING LLC. S.Kostense: Employee; Janssen Research & Development, LLC. L.A.Ferrat: None. R.Mcqueen: Consultant; Merck & Co., Inc., Monument Analytics, Research Support; Eli Lilly and Company. R.D.Neusner: Employee; Janssen Pharmaceuticals, Inc. R.A.Oram: Consultant; Janssen Research & Development, LLC, Research Support; Randox R & D. M.Rewers: Consultant; Janssen Research & Development, LLC, Medscape, Provention Bio, Inc., Research Support; Dexcom, Inc., JDRF, Roche Diagnostics USA. J.L.Dunne: Employee; Janssen Research & Development, LLC, JDRF.
38-OR: Glycemic Control with Ultrarapid Lispro (URLi) vs. Lispro in Children and Adolescents with T1D: PRONTO-Peds
Authors: WADWA R. PAUL , LAFFEL LORI M. , FRANCO DENISE R. , DELLVA MARY A. , POLLOM ROBYN K. 
Published: May 2022

This phase 3, treat-to-target study evaluated efficacy and safety of URLi vs. lispro in 716 pediatric patients (pts) with type 1 diabetes (T1D) . After 4-week lead-in to optimize basal insulin, pts were randomized to double-blind URLi (n=280) or lispro (n=298) injected 0-2 min prior to meals, or open-label URLi (n=138) injected up to 20 min after meals (URLi+20) . Pts remained on prestudy basal insulin (degludec, detemir, or glargine) . Primary endpoint was HbA1c change from baseline after 26 weeks.
Noninferiority was shown in HbA1c change with URLi vs. lispro: estimated treatment difference (ETD) -0.02% (95% CI -0.17, 0.13) and with URLi+20 vs. lispro: ETD -0.02% (95% CI -0.20, 0.17) . Postprandial glucose (PPG) measured by self-monitored blood glucose (SMBG) was lower with URLi vs. lispro 1 h after breakfast (p&lt;0.001) and dinner (p=0.006) . URLi significantly reduced 1 h postmeal glucose daily mean vs. lispro (p=0.001) . Total daily insulin dose was similar between treatments.
There were no significant differences among treatments in rate or incidence of severe, nocturnal or documented hypoglycemia (&lt;54 mg/dL) . With URLi vs. lispro, rate of postdose hypoglycemia (&lt;54 mg/dL) was higher at ≤2 h (p=0.034) . Incidence of treatment-emergent adverse events was similar between groups. More pts reported an injection site reaction related event with URLi (7.9%) and URLi+20 (2.9%) vs. lispro (2.7%) . All injection site reactions were mild or moderate in severity. Two URLi patients discontinued the study due to injection site reactions.
In children and adolescents with T1D, URLi demonstrated similar overall glycemic control and greater PPG lowering with an acceptable safety and tolerability profile compared with lispro. URLi dosed at the start of meals or up to 20 min after the start of meals showed noninferiority for HbA1c change from baseline vs. lispro. URLi dosed at the beginning of meals showed lower PPG at 1 h after breakfast and dinner and lower 1 h postmeal glucose daily mean vs. lispro.

Disclosure
R. Wadwa: Advisory Panel; Dompé. Consultant; Beta Bionics, Inc. Research Support; Dexcom, Inc., Eli Lilly and Company, Tandem Diabetes Care, Inc. Other Relationship; Tandem Diabetes Care, Inc. L.M. Laffel: Advisory Panel; Medtronic, Roche Diabetes Care. Consultant; Boehringer Ingelheim International GmbH, Dexcom, Inc., Dompé, Insulet Corporation, Janssen Pharmaceuticals, Inc., Lilly Diabetes, Novo Nordisk, Provention Bio, Inc. D.R. Franco: Advisory Panel; Abbott Diabetes, Medtronic, Novo Nordisk, Sanofi. Research Support; Eli Lilly and Company. Speaker's Bureau; Abbott Diabetes, AstraZeneca, Medtronic, Roche Diabetes Care, Sanofi. M.A. Dellva: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. R.K. Pollom: Employee; Eli Lilly and Company.

Funding
Eli Lilly and Company
393-P: SGLT2 Inhibitors Reduce Cardiovascular and Renal Risks Compared with GLP-1 Receptor Agonists and DPP4 Inhibitors in Patients with Diabetic Kidney Disease: A Systematic Review and Network Meta-analysis
Authors: CAO HONGWEI , LIU TAO , WANG LI , JI QIUHE 
Published: May 2022

Background: This systematic review and network meta-analysis compared the effectiveness of sodium-glucose co-transporter 2 inhibitors (SGLT2Is) , glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 inhibitors (DPP4Is) on cardiovascular (CV) and renal outcomes in patients with diabetic kidney disease (DKD) (INPLASY2021120070) .
Methods: The MEDLINE database was searched systematically to identify articles that reported CV and renal outcomes from Phase III or IV randomised, placebo-controlled trials after intervention with SGLT2Is, GLP-1 RAs or DPP4Is in patients with DKD. HRs and 95% CIs were calculated using a network meta-analysis.
Results: 16 trials representing a total of 46,292 patients were analysed. SGLT2Is significantly reduced the risks of kidney-specific composite outcome by 26% (HR=0.74, 95% CI 0.62-0.88) and 36% (HR=0.64, 95% CI 0.52-0.79) ; and the risks of hospitalisation for heart failure (HHF) by 28% (HR=0.72, 95% CI 0.56-0.92) and 41% (HR=0.59, 95% CI 0.49-0.71) , compared to GLP-1 RAs and DPP4Is respectively. SGLT2Is also reduced the risk of major adverse cardiovascular events (MACE) by 18% (HR=0.82, 95% CI 0.69-0.96) compared to DPP4Is. The risk of MACE was comparable between SGLT2Is and GLP-1 RAs (HR=0.95, 95% CI 0.82-1.10) . The risk of CV death was not significantly different between the three treatments.
Conclusions: This meta-analysis integrated data from recent high-quality CV and renal outcome trials, providing high statistical power. SGLT2Is significantly lowered risks of kidney-specific outcome, MACE and HHF compared to DPP4Is and placebo, and reduced risks of kidney-specific outcome and HHF compared to GLP-1 RAs. GLP-1 RAs also showed CV and renal outcome benefits compared to placebo, but not compared to SGLT2Is or DPP4Is for most outcomes. DPP4Is did not improve either CV or renal outcomes compared to placebo.

Disclosure
H.Cao: None. T.Liu: None. L.Wang: None. Q.Ji: None.
395-P: BeAM Value and Glycemia Assessed by Continuous Glucose Monitoring among Participants with Type 2 Diabetes and Chronic Kidney Disease
Authors: MAYEDA LAURA , ZELNICK LEILA , TRIKUDANATHAN SUBBULAXMI , HIRSCH IRL B. , DE BOER IAN 
Published: May 2022

Introduction: The difference between bedtime and morning glucose levels (BeAM value) is a clinically relevant measure that can guide clinicians regarding insulin titrations. As chronic kidney disease (CKD) develops, changes in insulin sensitivity and kinetics and limitations to available medications may contribute to over-basalization, insufficient prandial control, and large BeAM. We hypothesized that CKD and less time in range (TIR) derived from continuous glucose monitoring (CGM) are associated with large BeAM in T2DM.
Methods: This was a prospective observational cohort study of 1people with T2DM treated with insulin or sulfonylurea, 81 participants with CKD (eGFR &lt;60 mL/min/1.73 m2) , and 24 controls with eGFR ≥60 frequency matched on age, duration of diabetes, HbA1c, and glucose-lowering medications. Each participant wore a CGM for two 6-day periods. BeAM was calculated as the difference between mean bedtime sensor glucose values and mean morning sensor values, with large BeAM defined as ≥30 mg/dL glucose drop from bedtime to morning.
Results: Participants had a mean age of 68 years, diabetes duration years and HbA1c 7.7%. CKD and controls had a mean eGFR 38 and 83 mL/min/1.73 m2 respectively. Median (IQR) BeAM was 29 (9-52) mg/dL for participants with CKD and (-4-31) mg/dL for controls (p = 0.11) . Forty participants with CKD (49%) and 7 controls (29%) had a large BeAM. Those with a large BeAM had less TIR (58 v 68%) , higher HbA1c (8.0 vs. 7.5%) , and higher glucose management indicator (GMI, 7.5 vs. 7.2%) compared to those with BeAM &lt;30 mg/dL (each p&lt;0.05, adjusting for age, sex, and race) . Coefficient of variation, diabetes duration, and insulin dose (total or basal) did not correlate with BeAM.
Conclusions: Large BeAM was common among participants with long-standing T2DM and CKD and was associated with less TIR and higher GMI. These data suggest that there is opportunity for improvement in daytime and prandial diabetes management among patients with CKD.

Disclosure
L.Mayeda: None. L.Zelnick: None. S.Trikudanathan: Research Support; Bionic pancreas, Bionic pancreas , Insulet Corporation, Insulet Corporation. I.B.Hirsch: Consultant; Abbott Diabetes, Bigfoot Biomedical, Inc., GWave, Roche Diabetes Care, Research Support; Beta Bionics, Inc., Insulet Corporation, Medtronic. I.De boer: Advisory Panel; AstraZeneca, Bayer AG, Cyclerion Therapeutics, Inc., George Clinical, Goldfinch Bio, Inc., Other Relationship; American Society of Nephrology, Research Support; Dexcom, Inc.

Funding
American Diabetes Association (4-15-CKD-20) ; National Institute of Diabetes and Digestive and Kidney Diseases (R01DK088762, R01087726)
4-LB: Remission of Type 2 Diabetes and Improvement in Metabolic Markers with the Twin Precision Treatment Technology (TPT) —A Multicenter, Randomized, Controlled Trial
Authors: SHAMANNA PARAMESH , SHAH LISA , MOHAMMED JAHANGIR , MOHAMED MALUK , POON TERRENCE , DHARMALINGAM MALA , SABOO BANSHI , DAMODHARAN SURESH , VADAVI ARUN , THAJUDEEN MOHAMED , KESHAVAMURTHY ASHOK , KAUFMAN FRANCINE R. , JOSHI SHASHANK R. 
Published: May 2022

The study was designed to determine the effect of TPT vs. standard care (SC) on change in A1C and T2DM remission at 90 day intervals, in addition to multiple secondary endpoints. The TPT intervention uses the Whole-Body Digital Twin Platform, with AI and Internet of Things, to integrate multi-dimensional data to give precision nutrition and health recommendations via the TPT app and by coaches. Baseline mean age, diabetes duration and A1C obtained in 319 pts were 45y (±9.7y) , 3.9y (±2.9y) and 9.0% (±1.9%) , respectively. Interim analysis of 262 pts (TPT n=199; SC n=63) who reached 180d showed 94.9% (189/199) of TPT pts had A1C &lt; 6.5%, on no medications or metformin only; 83.9% (167/199) achieved diabetes remission based on ADA criteria. All 9 insulin-using pts stopped insulin before 90d. The Table shows significant improvement in secondary endpoints in TPT pts at baseline and 180d, including A1C (9.0% to 5.7%, P&lt;0.001) . TPT pts had -3.3% change in A1C (95% CI -3.6 to -3%, P=&lt;0.001) compared to SC with -0.39% (95% CI -0.73 to -0.043%, P=0.028) , with a significant between-group difference (P=&lt;0.0001) . The TPT intervention in pts with T2DM allowed for significant reduction in A1C, diabetes remission (∼84%) and improvement in multiple metabolic parameters at 6 months. Future long-term studies are needed to support these initial findings.

Disclosure
P. Shamanna: None. M. Thajudeen: None. A. Keshavamurthy: None. F. R. Kaufman: Consultant; Twin Health, Employee; Senseonics. S. R. Joshi: Advisory Panel; AstraZeneca, Consultant; Biocon, Franco India, Glenmark Pharmaceuticals, Marico, Sanofi, Twinhealth, Zydus Cadila, Speaker’s Bureau; Abbott, Serdia Pharmaceuticals (India) Pvt. Ltd. L. Shah: None. J. Mohammed: None. M. Mohamed: None. T. Poon: None. M. Dharmalingam: None. B. Saboo: None. S. Damodharan: None. A. Vadavi: None.
40-LB: Mobile Health App Can Be Effective in a Real-World Environment for Those with Diabetes Needing Weight Loss
Authors: HORVAT SHERRI L. , NOVAK LUCIA M. , VALENTINE VIRGINIA , CHILDS BELINDA P. , BARRY ROMIYA , WARNER JAY 
Published: May 2022

BEATdiabetes is based on Joslin Diabetes Center’s Why WAIT program, a 12-week program designed to help improve weight and diabetes glycemia, incorporating structured diet, learning sessions and individualized exercises. The Why WAIT program has demonstrated effectiveness virtually. Endpoints included weight, BMI, and A1c. The program employed a version of BEATdiabetes app (developed by Healthimation Inc®, licensed by Nemaura Medical) and utilized gamification to engage users. In addition, participants shared 2-hour, weekly virtual visits to review food logs, exercise sessions, and CGM data with diabetes medications adjusted accordingly. This initial pilot study uses the BEATdiabetes app and seeks to identify if results can be replicated in a real-world environment (RWE) without virtual visits, CGM data and program medication adjustment. The APRN, CDCES live coach had phone calls with users weekly for the first 4 weeks, then 4-week intervals for the next 8 weeks with more touchpoints available (emails, in-app chat, phone calls) . Self-reported endpoints showed users remained engaged utilizing the app 70/84 days, completed 74% of 7 daily tasks, and positively received education, resulting in weight loss, reduction in BMI and waist circumference, and improvement/maintenance in glycemia all during the holiday season. Based upon pilot study learnings changes were identified for next steps in RWE.

Disclosure
S. L. Horvat: Consultant; Nemaura Medical, Employee; W5 Insights, LLC. L. M. Novak: Advisory Panel; Novo Nordisk, Provention Bio, Inc., Xeris Pharmaceuticals, Inc., Consultant; Abbott Diabetes, Novo Nordisk, Xeris Pharmaceuticals, Inc., Speaker’s Bureau; Abbott Diabetes, Eli Lilly and Company, Novo Nordisk, Xeris Pharmaceuticals, Inc. V. Valentine: Advisory Panel; Abbott Diabetes, Xeris Pharmaceuticals, Inc., Consultant; Nemaura, Pendulum, Zealand Pharma A/S, Speaker’s Bureau; Lilly Diabetes. B. P. Childs: Consultant; W5 Insight LLC, Other Relationship; Sanofi-Aventis U. S., Research Support; Abbott Diabetes. R. Barry: Consultant; W5 Insights, LLC. J. Warner: Consultant; Nemaura Medical, Tandem Diabetes Care, Inc.