bluuebunny/crossref_metadata_2025 huggingface dataset:
2040-LB: Antidiabetic Effects and Mechanisms of Saccharum sinense Roxb. Polysaccharides
Authors: XIE CEN , LIU YAMENG
Published: June 2024

Introduction & Objective: Diabetes is a chronic metabolic disease characterized by insulin resistance or insufficient insulin secretion, resulting in hyperglycemia. The global prevalence of diabetes is on the rise, especially among younger age groups, presenting significant public health challenges. China has the most diabetes patients worldwide, with nearly 61 million new cases in the past decade. Therefore, there is an urgent need for safer, more effective, and cost-effective antidiabetic medications. This study aims to investigate the potential of Saccharum sinense Roxb. polysaccharides as a novel herbal medicine for diabetes treatment.

Methods: We administered a single dose of Saccharum sinense Roxb. polysaccharides to C57BL/6 mice to assess its impact on peak blood glucose levels during oral glucose tolerance tests. Additionally, we utilized diabetic mouse models for drug screening, using metformin as the positive control, to identify Z300 as a potential component.

Results: Our findings revealed that Z300 effectively improved disturbances in glucose metabolism, kidney injury, and lipid metabolism. It regulated body weight gain, prevented fatty liver, and exhibited actions such as promoting insulin secretion and inhibiting α-glucosidase activity. Cell and organoid experiments validated the beneficial effects of Z300 on insulin and GLP-1 secretion. Mechanistic studies indicated that Z300 influenced the expression of various metabolism-sensing-related proteins such as p-AMPK, p-AKT, and p-GSK3β, highlighting its broad therapeutic applications.

Conclusion: This research emphasizes the potential of Saccharum sinense Roxb. polysaccharides, particularly Z300, as a promising herbal medicine for diabetes management. These results support the efficacy of Z300 in improving various aspects of glucose metabolism and insulin regulation, offering a valuable avenue for further exploration and development of novel antidiabetic therapies.

Disclosure

C. Xie: None. Y. Liu: None.
2090-LB: Characters of Intra-islet Ductal Cells Related to Alpha-Cell Regeneration in Zinc-Binding Site–Mutated CRY1-Expressing Diabetic Mice
Authors: OKANO SATOSHI , YASUI AKIRA , KANNO SHINICHIRO , SASAKI YU , SATOH KENNICHI , IGARASHI MASAHIKO , NAKAJIMA OSAMU
Published: June 2024

Introduction & Objective: We previously suggested that the regions of intra-islet ductal cells (IIDCs) play roles as the source for endocrine cells, particularly for α-cells, in C414A-CRY1 transgenic mice (TG) (ADA 2023), the characters of IIDCs relevant to the α-cell neogenesis are yet unknown. To clarify the points, we conducted experiments in terms of reactivity to DBA-lectin as well as of the expression of TFF2.

Methods: The cells constituting developed IIDC (of duct periphery longer than 500 µm) in TG were classified as strongly or weakly positive both for anti-TFF2 antibodies and for DBA-lectin. The positional correlation among glucagon-producing cells present in IIDC compartments and the classified IIDC were examined.

Results: Immature IIDCs embedded inside islets were homogeneous for DBA-lectin-reactivity as reported previously: DBA-lectin-weakly positive (ADA 2019). By contrast, it was newly uncovered that developed IIDCs showed variations in phenotypes for the reactivities to DBA-lectin. Heterogeneity in TFF2 expression was also observed in developed IIDCs. Glucagon-producing cells were more frequently located near DBA-lectin-weakly positive IIDCs (~54% higher than near DBA-lectin-strongly positive ones; P<0.01, t-test). While glucagon-producing cells were more frequently located near TFF2-strongly expressing IIDCs (~42% higher than near TFF2-weakly expressing ones; P<0.001, t-test). Furthermore, DBA-lectin-strongly positive IIDCs tended to be TFF2-weakly expressing ones.

Conclusion: Our results suggest that TFF2 in IIDCs promotes α-cell neogenesis and/or plays some important roles in the maintenance of newborn α-cells. DBA-lectin-strongly positive characteristics of IIDCs possibly suppress TFF2 expression, thereby acting inhibitory manner for α-cell neogenesis in such IIDCs.

Disclosure

S. Okano: None. S. Kanno: None. Y. Sasaki: None. M. Igarashi: None. O. Nakajima: None.

Funding

Grants-in-Aid for Scientific Research (19K07498); Tohoku University Institute of Development, Aging and Cancer.
2104-LB: Alpha- and Beta-Cell Intercellular Communication via Extracellular Vesicles
Authors: KALIVARATHAN JAGAN , BALAJI SARAVANAN PRATHAB , MOHAMMED SHUJAUDDIN , LEVY MARLON F. , KANAK MAZHAR A.
Published: June 2024

Introduction & Objective: Type-1 diabetes (T1D) is characterized by autoimmune destruction of β-cells which is further associated with α-cells dysfunction leading to hypoglycemic unawareness. Both α and β cell types regulate each other in a paracrine manner. Exosomes are extracellular vesicles naturally secreted by most cell types and are involved in cell-to-cell communication. β-cells and α-cells also release exosomes, but the pathophysiological function needs investigation. Thus, the main objective is to study the intercellular communication between α and β-cell via exosomes.

Methods: Mouse α-TC-1 and βTC-6 cell lines were stimulated in low (2.5mM), basal (5.5mM) and high glucose (25mM) exosome depleted media for 24hrs. Exosomes are isolated using differential centrifugation and their presence were confirmed by using TEM, and western blot for exosomal markers. Quantification and characterization were done using micro-BCA, ELISA, and nanosight analysis. Exosomes were further used to cross-stimulate α and β cells under low and high glucose at various time points (6h, 12h, 24h, 48h). Insulin and Glucagon levels in media was measured by ELISA and regulation of transcription factors were measured by qPCR.

Results: TEM analysis revealed that α and β cells released cup-shaped, rounded vesicles of exosomes (30-300nm). Western blot analysis for exosomal markers (CD9) was confirmed. Glucagon expression in α-cells was significantly increased when stimulated with β-cell exosomes under low glucose condition (6h:P=0.0134; 24h:P=0.0455; 48h:P= 0.0532). The expression of glucagon in α-cell was not affected by β-cell exosomes under high glucose. MafB expression in α-cells correlated with glucagon expression. Interestingly, expression of insulin in β-cells was not significantly affected by α-cell exosomes.

Conclusion: Exosomes from β-cells seem to play a role in regulation of glucagon. Further investigation relating to production and release of insulin and glucagon in response to exosomes is warranted.

Disclosure

J. Kalivarathan: None. P. Saravanan: None. S. Mohammed: None. M.F. Levy: None. M.A. Kanak: None.
212-OR: Differential Cell-Type-Specific Gene Expression and Chromatin Accessibility by Type 2 Diabetes Status and Physical Activity Levels in Human Skeletal Muscle
Authors: CIOTLOS DAN , HANKS SARAH , VARSHNEY ARUSHI , ERDOS MICHAEL , MANICKAM NANDINI , STRINGHAM HEATHER M. , HILL-BURNS ERIN , ORCHARD PETER , NARISU NARISU , BONNYCASTLE LORI L. , SWEENEY MICHAEL D. , LAAKSO MARKKU , TUOMILEHTO JAAKKO , LAKKA TIMO A. , MOHLKE KAREN L. , BOEHNKE MICHAEL , KOISTINEN HEIKKI A. , COLLINS FRANCIS S. , PARKER STEPHEN , SCOTT LAURA
Published: June 2024

Introduction: Skeletal muscle plays a role in regulation of glucose metabolism, and physical activity is a preventive factor for type 2 diabetes (T2D). To understand the relationships of T2D status and vigorous physical activity with gene expression and chromatin regulation in skeletal muscle cell types, we analyzed skeletal muscle single nucleus RNA-sequencing and ATAC-sequencing data from 279 Finnish adults from the FUSION Tissue Biopsy Study.

Methods: Participants had varying glucose tolerance, ranging from normal glucose tolerance (NGT) to newly-diagnosed T2D, based on an oral glucose tolerance test. We estimated the level of 12-month vigorous physical activity (VPA) based on a questionnaire. Nucleus-level data were clustered using LIGER. We used negative binomial models to test for associations between glucose tolerance or VPA and cell-type composition, gene expression, or chromatin accessibility (genes: 23,841; peaks: 924,519).

Results: Participants were 60.2 (SD 7.4) years-of-age, and 41.5% were female, where 102 participants had NGT and 72 had T2D. Of 12 cell types, individuals with lower VPA had a higher proportion of type 2x muscle fibers (Log2 fold change=0.96, p=3.9e-2) with no significant difference by T2D status. Across muscle fiber types, associated genes generally had the same direction of gene expression when having higher VPA or NGT (as compared to T2D). We observed a similar pattern for chromatin accessibility. For example, in type 1 muscle fiber, NGT (as compared to T2D) or higher VPA were each associated with higher expression of cellular respiration genes (VPA: OR=1.77, p=1.4e-9, T2D vs. NGT: OR=0.80, p=8.9e-5) and lower expression of protein K48-linked polyubiquitination genes (VPA: OR=0.64, p=5.2e-3, T2D vs. NGT: OR=2.03, p=6.2e-5).

Conclusion: These findings suggest that both normal glucose tolerance and higher vigorous physical activity have similar regulatory effects on gene expression.

Disclosure

D. Ciotlos: None. S. Hanks: None. A. Varshney: None. M. Erdos: None. N. Manickam: Employee; 10x Genomics. H.M. Stringham: None. E. Hill-Burns: Other Relationship; GE HealthCare. P. Orchard: None. N. Narisu: None. L.L. Bonnycastle: None. M.D. Sweeney: None. M. Laakso: None. J. Tuomilehto: Stock/Shareholder; Orion Pharma, Aktivolabs, Digostics. T.A. Lakka: None. K.L. Mohlke: None. M. Boehnke: None. H.A. Koistinen: Other Relationship; AstraZeneca, Novo Nordisk. F.S. Collins: None. S. Parker: Research Support; Pfizer Inc. L. Scott: None.
219-OR: Loss of Insulin Signaling in Microglia Impairs Cellular Uptake of Aß and Neuroinflammatory Response Exacerbating Alzheimer-Like Neuropathology
Authors: CHEN WENQIANG , MUÑOZ VITOR R. , RONALD KAHN C.
Published: June 2024

Insulin receptors are present on cells throughout the body. Dysregulation of insulin signaling in the brain has been implicated in mood, cognitive disorders, and pathogenesis of Alzheimer’s disease (AD). However, the brain is composed of multiple cells types, and little is known as to how brain insulin resistance in particular in different brain cell types contributes to the comorbidity of type 2 diabetes (T2D) and AD. In this regard, microglia are particularly interesting, since microglia are involved in the uptake and clearance of amyloid-β (Aβ) and formation of neuroinflammation. To investigate the role of insulin signaling in microglial function and development of AD, we have created an inducible microglia-specific insulin receptor knockout (MG-IRKO) and found that loss of microglial insulin signaling in these mice results in alterations in mood, social behavior and impairment in systemic metabolism. At a molecular level, utilizing RiboTag to isolate and profile microglial-specific ribosome-bounded mRNA, we found that loss of insulin receptor resulted in alterations in pathways associated with innate immunity and cellular metabolism in microglia. In vitro, loss of insulin signaling in microglial resulted in metabolic reprograming with a switch to more glycolytic metabolism, and this was associated with impaired ability of microglia in Aβ uptake. When the MG-IRKO mice were crossed with an AD mouse model (5xFAD mice) to create MGIRKO/5xFAD mice, the resultant mice exhibit increased levels of Aβ plaque formation and elevated neuroinflammation marked by increased IFN-γ. Thus, insulin signaling in microglia plays a key role in microglial cellular metabolism, neuroinflammation and the ability of the cells to uptake Aβ, such that loss of insulin signaling in microglia accelerates AD pathogenesis. Together, these data indicate the potential importance of targeting insulin signaling in microglia in treatment of AD.

Disclosure

W. Chen: None. V.R. Muñoz: None. C. Kahn: Consultant; Cellarity. Other Relationship; 1825 Therapeutics. Advisory Panel; TIXiMED, Senseion, ERX.

Funding

National Institutes of Health (R01 DK031036)
22-OR: Burden of Diabetes Survey—Perspectives from People Living with Diabetes in the United States
Authors: YEHL KIRSTEN , FIELDS SHERECCE A. , LEE FELIX , SHOGER ERIK , SMALLMAN RACHEL , ELLBOGEN KATE A. , KERR DAVID
Published: June 2024

Objective: People with diabetes (PWD) have limited access to healthcare professionals. To provide PWD with the support they need, there must be a comprehensive understanding of the daily burdens associated with self-management.

Methods: An on-line questionnaire using the dQ&A US Patient Panel was created to understand the daily burden associated with self-management. Respondents from this survey (n=3,241) included adults with type 1 diabetes (T1DM), adults with type 2 diabetes (T2DM) on intensive insulin therapy, adults with T2DM on non-intensive insulin therapy, and adults with T2DM not on insulin. The sample included demographic and health characteristics.

Results: 1,204 respondents had an annual income of less than $50,000. PWD in this income category are more likely to have housing and food insecurity and problems with paying their bills. Both PWD with an annual income of less than $50,000 and PWD with T1DM are more likely to report experiencing severe psychological and practical diabetes management burdens. PWD with T1DM are more likely to think about the impact of their diabetes on future events and experience sleep disruptions on a weekly basis.

Conclusion: Concerns about long-term health and food choices are the leading causes of distress for all groups. Respondents have more difficulty ‘affording’ rather than ‘accessing’ items/facilities. There are many burdens related to diabetes, many caused by SDOH.

Disclosure

K. Yehl: None. S.A. Fields: None. F. Lee: Employee; Sanofi. Stock/Shareholder; Sanofi. E. Shoger: Other Relationship; Dexcom, Inc., Abbott, Tandem Diabetes Care, Inc., Beta Bionics, Inc., MannKind Corporation, Insulet Corporation, Medtronic, Association of Diabetes Care & Education Specialists. R. Smallman: None. K.A. Ellbogen: None. D. Kerr: Advisory Panel; Abbott Diagnostics. Consultant; Sanofi, Better Therapeutics, Inc. Stock/Shareholder; Glooko, Inc.

Funding

Sanofi US (77230685)
22-PUB: Machine Learning–Based Optimization of Patient Eligibility for Oral Insulin Treatment—A Post Hoc Analysis of Phase III Trial Results
Authors: KIDRON MIRIAM , BERKMAN ELAD , MACHLUF OSHRI , PRYLUK RAVIV , HOMER KENNETH E. , NEUTEL JOEL M.
Published: June 2024

Background & Objectives: The growing shift toward implementation of precision medicine to improve the prospects of achieving treatment targets requires comprehensive profiling of an array of patient-specific data. Research efforts in this arena include review of anthropometric, epidemiological and clinical features to optimize eligibility criteria for specific treatments. In a recent Phase III, randomized, placebo-controlled, multi-center study in which T2DM patients were treated with oral insulin QD or BID for 26 weeks, the primary endpoint defined as a decrement of 0.6% HbA1c by treatment end was not met. The current post hoc analysis aimed to identify subpopulations with substantial clinical responses to active treatment.

Methods: Data were fitted with a nonparametric causal machine learning model to estimate the impact of various baseline covariates on the expected treatment effect. A recursive partitioning search was then conducted to identify clinically meaningful patient subgroups with high predicted susceptibility to treatment. Results were validated on external datasets, and by running a permutation test and sensitivity analyses to the exact criteria and sample.

Results: Patients with baseline BMI <30.5 kg/m2 and age >58 years achieved a conditional average 0.6% reduction in HbA1c by Week 26. Stricter criteria of BMI < 27.0 kg/m2 and age >58 years were associated with a mean 0.96% reduction in HbA1c. Gender-specific training of the models suggested different impacts of age and BMI across sex. Male subjects with BMI<30 kg/m2 and female subjects > 60 years exhibited improved clinical outcomes.

Conclusions: Variability in response to oral insulin can be minimized by segmenting the patient population based on BMI, age and sex. These findings will inform eligibility criteria for a newly planned Phase III study.

Disclosure

M. Kidron: Employee; Oramed Pharmaceuticals. E. Berkman: Consultant; Oramed Pharmaceuticals. O. Machluf: Consultant; Oramed Pharmaceuticals. R. Pryluk: Consultant; Oramed Pharmaceuticals. K.E. Homer: None. J.M. Neutel: None.
234-OR: Performance of a Machine-Learning Gene Risk Score Biomarker to Predict Weight-Loss Response to Tirzepatide and Semaglutide
Authors: TAMA ELIF , FANSA SIMA , ANAZCO DIEGO , RIVERA RENE , GHUSN WISSAM , CIFUENTES LIZETH , ACOSTA ANDRES , HURTADO MARIA D.
Published: June 2024

Introduction: Abnormal post-prandial satiety obesity phenotype (APS+) is characterized by rapid gastric emptying. The GLP-1 analog liraglutide delays gastric emptying and in adults with APS+, its use is associated with greater weight loss compared to individuals without APS (APS-). A machine-learning gene risk score (ML-GRS) biomarker has been shown to predict APS and the response to liraglutide with accuracy. Our aim is to determine the applicability of this ML-GRS to predict weight loss response to semaglutide and tirzepatide.

Methods: From a Mayo Clinic multi-center biobank and outcomes registry of adults with obesity undergoing weight loss interventions, we selected those taking semaglutide or tirzepatide. Using saliva or blood samples, we generated an ML-GRS to determine APS phenotype (“APS+” or “APS-”). Endpoints: total body weight loss (TBWL) % at 3, 6, and 12 months by APS status, percentage of adults achieving ≥5, 10, 15, and 20% TBWL at 12 months by APS status; and the probability of the ML-GRS to predict ≥5% of TBWL after 12 months of semaglutide and/or tirzepatide.

Results: We included 137 adults: 91 APS+ and 46 APS-. There were no significant differences in age, race, weight, BMI, medication used and dosage achieved, or co-morbidities among the two groups. Compared to APS-, APS+ had superior TBWL% at 12 months (-13 ± 10% vs -19 ± 10%, n=57, p=0.01) but not at 3 or 6 months. The percentage of adults achieving ≥5, 10, and 20% TBWL at 12 months was significantly greater in APS+. When analyzed by medication, differences in TBWL% and categorical TBWL outcomes among the two groups were replicated with semaglutide but not with tirzepatide. The AUC of the ML-GRS to predict ≥5% of TBWL after 12 months of semaglutide was 0.7 (95% CI [0.5-0.9], p=0.06).

Conclusion: An APS+ ML-GRS is associated with greater weight loss response to semaglutide but not tirzepatide at 12 months. Larger and more diverse studies are needed to better assess the accuracy of this biomarker.

Disclosure

E. Tama: None. S. Fansa: None. D. Anazco: None. R. Rivera: None. W. Ghusn: None. L. Cifuentes: None. A. Acosta: Consultant; Amgen Inc., Regeneron Pharmaceuticals Inc., Nestlé Health Science, Structure Therapeutics, Inc., Boehringer-Ingelheim. Research Support; Vivus. Consultant; Currax. Other Relationship; Gila Therapeutics, Phenomix Sciences. Speaker's Bureau; Eli Lilly and Company. M.D. Hurtado: None.
242-OR: The Impact of Glucose Threshold on the Number and Duration of Glucose Episodes
Authors: THOMAS JONAH J.C. , KOUTROUKAS VAIOS , DIVILLY PATRICK , MARTINE-EDITH GILBERTE , ZAREMBA NATALIE , AMIEL STEPHANIE A. , CHOUDHARY PRATIK , CONSORTIUM HYPO-METRICS
Published: June 2024

Introduction and Objectives: The number of sensor-detected hypoglycemia (SDH) episodes depends on the hypoglycemia threshold used. We investigated the relationship between glucose threshold and the number and duration of events in the Hypo-METRICS dataset.

Methods: Individuals with insulin-treated diabetes wore a blinded continuous glucose monitor for 10 weeks. SDH was defined as 15 min below each threshold between 5 mmol/L (90 mg/dL) and 2.2 mmol/L (40 mg/dL) at 0.1 mmol/L increments. The number and average duration of episodes was calculated at each glucose threshold.

Results: Data from 599 (T1D=276 and T2D=323) people were analyzed; median age 56 years, HbA1c 7.4%. Event rate was higher for events between 3-5 mmol/L than < 3mmol/L (10.5 vs 1.1 episodes/week, p < 0.01) and average duration longer (63.1 vs 35.5 minutes/episode, p < 0.01). This is shown in Figure 1a and b. Each 0.1 mmol/L increment in hypoglycemia threshold resulted in 0.5 more episodes/week between 3-5 mmol/L vs 0.05 additional episodes/week at a threshold < 3 mmol/l (p < 0.01). Each 0.1 mmol/l increment in hypoglycemia threshold increased average duration by 3.1 minutes/episode between 3-5 mmol/l vs 0.4 minutes/episodes for those < 3 mmol/l (p < 0.01).

Conclusion: These results may be useful in understanding the alarm burden at different thresholds allowing personalization in proportion to individual risks.

Disclosure

J.J.C. Thomas: None. V. Koutroukas: Other Relationship; KelCon GmbH. P. Divilly: None. G. Martine-Edith: Other Relationship; Novo Nordisk A/S. N. Zaremba: None. S.A. Amiel: Advisory Panel; Vertex Pharmaceuticals Incorporated. Other Relationship; Sanofi. P. Choudhary: Advisory Panel; Abbott, Biolinq. Speaker's Bureau; Dexcom, Inc., Eli Lilly and Company, Novo Nordisk, Sanofi. Advisory Panel; Ypsomed AG, Vertex Pharmaceuticals Incorporated.

Funding

Hypo-RESOLVE (the consortium to which the Hypo-METRICS study belongs) has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 777460. Abbott Diabetes Care providedthe continuous glucose monitors used in the study
244-OR: Association of Type 1 Diabetes Duration or Duration of Advanced Technology Utilization with Severe Hypoglycemic Event Frequency
Authors: BOATENG-KUFFOUR ADRIANA , CALLAHAN PATRICK , CHANDARANA KEVAL , BARRY DIANNE , CHEN LIANG , KELLY CAITLIN S. , NGUYEN HUYEN , CHAPMAN KATHERINE S.M. , CORNELIUS EMILEE M. , WOLF WENDY , POLONSKY WILLIAM H.
Published: June 2024

Introduction & Objective: Adults with type 1 diabetes (T1D) may experience severe hypoglycemic events (SHE) and impaired awareness of hypoglycemia (IAH) despite use of advanced technologies. It is unclear how a longer duration of T1D or continuous glucose monitor (CGM) use is associated with SHE.

Methods: Adult CGM users in the T1D Exchange Registry completed an online survey including SHE frequency, IAH, duration of CGM use, and years since T1D diagnosis. SHE cohorts were created based on SHE frequency in the past 12 months and presence/absence of IAH (defined in the Table). Descriptive results (mean [M], standard deviation) were reported. Bivariate correlations were used to test associations between duration of T1D or duration of CGM use with SHE frequency using Pearson’s correlation.

Results: Among 1,847 CGM users, the mean age was 45.9 years. Mean T1D duration was 29.0 years. Most participants (55.0%) used CGM for ≥5 years (Table). There were no significant associations between SHE frequency and T1D duration (r=0.03; p=0.25) or duration of CGM use (r=-0.03; p=0.15). The problematic SHE cohort reported slightly longer T1D duration (M=31.9 years) than other cohorts (M=26.8-28.6 years).

Conclusion: Severe hypoglycemia remains an important clinical risk for adults with T1D regardless of time spent living with T1D or duration of advanced monitoring technology use.

Disclosure

A. Boateng-Kuffour: Employee; Vertex Pharmaceuticals Incorporated. P. Callahan: Employee; Vertex Pharmaceuticals Incorporated. K. Chandarana: Employee; Vertex Pharmaceuticals Incorporated. Stock/Shareholder; Vertex Pharmaceuticals Incorporated, Novo Nordisk, Eli Lilly and Company. D. Barry: Employee; Vertex Pharmaceuticals Incorporated. L. Chen: None. C.S. Kelly: None. H. Nguyen: None. K.S.M. Chapman: None. E.M. Cornelius: None. W. Wolf: None. W.H. Polonsky: Research Support; Abbott Diagnostics, Dexcom, Inc. Consultant; Eli Lilly and Company, Sanofi. Advisory Panel; embecta. Consultant; Vertex Pharmaceuticals Incorporated. Advisory Panel; 9am Health.

Funding

Vertex Pharmaceuticals Incorporated
251-OR: COIN2DOSE—Proof of Concept That a Behavioral Economics Intervention Can Increase Mealtime Insulin Use in Adolescents with Type 1 Diabetes
Authors: PATTON SUSANA R. , LOCKEE BRENT , MORGA KRISTEN , MCDONOUGH RYAN , FOX LARRY A. , CLEMENTS MARK A.
Published: June 2024

Many adolescents with type 1 diabetes (T1D) miss or skip mealtime insulin boluses, contributing to higher glycated hemoglobin (HbA1c). We designed a novel mHealth intervention, called COIN2DOSE, that uses behavioral economics theories to promote mealtime insulin use among adolescents. Here, we present preliminary data evaluating COIN2DOSE. We enrolled 10 adolescents with T1D in a 12-week mHealth intervention that included weekly data sharing and automated remote patient monitoring via a digital dashboard. Adolescents earned money (up to $1.50/day or $15.50/week) based on their daily mealtime BOLUS score, a valid measure of insulin use during predetermined meal windows. Parents and adolescents completed surveys assessing diabetes distress and diabetes family conflict and adolescents completed a valid HbA1c home kit pre- and post-treatment. We measured treatment satisfaction post-treatment. Adolescents were [mean±SD] 13.4±1.01 years old, 50% boys, 80% Non-Hispanic White, 100% using a personal continuous glucose monitor (CGM), 60% using hybrid closed loop (HCL), and 40% using standard open pump therapy (open pump). Daily BOLUS scores increased from 1.50±1.10 to 2.14±0.72 (p=0.053) pre- to post-treatment. Mean HbA1c decreased from 8.8±2.8% to 8.2±1.6% for adolescents on HCL and increased slightly for adolescents on open pump (7.1±1.6 and 7.3±1.6%). We found no changes in parent- and adolescent-reported diabetes distress and parent-reported diabetes family conflict, though adolescent-reported diabetes family conflict decreased (p<0.01). Parent- and adolescent-reported satisfaction with COIN2DOSE was moderately high. We provide proof of concept that COIN2DOSE and its supporting technology can promote mealtime insulin use, achieve reductions in adolescent-reported diabetes family conflict, and clinically reduce HbA1c in adolescents with T1D.

Disclosure

S.R. Patton: None. B. Lockee: None. K. Morga: None. R. McDonough: Speaker's Bureau; Provention Bio, Inc. L.A. Fox: Advisory Panel; Ki Health. Research Support; Dexcom, Inc. M.A. Clements: Research Support; Abbott. Consultant; Glooko, Inc. Research Support; Dexcom, Inc.

Funding

National Institutes of Health (R01DK128862)
254-OR: Sleep Disturbance and Diabetes Symptom Burden in Young Adults with Type 1 Diabetes
Authors: GRIGGS STEPHANIE , HOWARD QUIANA , HICKMAN RONALD
Published: June 2024

Introduction: Sleep disturbance including difficulty initiating or maintaining sleep (insomnia symptoms) are associated with diabetes symptoms, precursors to micro-and macrovascular complications, among young adults with type 1 diabetes (T1D). About 50% of young adults develop vascular complications; however, modifiable contributors of diabetes symptoms are understudied in this population. Therefore, the purpose of this quantitative descriptive study was to determine the associations between sleep disturbance and diabetes symptom burden in young adults with T1D.

Methods: Baseline data from two longitudinal cohorts of young adults aged 18 to 26 years with T1D (61.3% female, 81.2% Non-Hispanic White) were analyzed. Sleep disturbance was measured with the 19-item Pittsburgh Sleep Quality Index, insomnia symptoms with the 7-item Insomnia Severity Index, and diabetes symptom burden with the 34-item Diabetes Symptom Checklist Revised. Associations were analyzed using multivariable linear and logistic regression models adjusted for age, race, sex at birth, T1D duration, and insulin pump use.

Results: Higher sleep disturbance and higher insomnia symptom severity were associated with a higher diabetes symptom burden even after considering covariates in the linear regression models. In logistic regression models, those with significant insomnia symptoms had 4 times higher odds of a high diabetes symptom burden in the unadjusted and adjusted models. Those with high sleep disturbance had 2.6 times higher odds of a high diabetes symptom burden; however, the association was no longer significant after adjusting for covariates.

Conclusion: Reducing sleep disturbance including difficulty initiating or maintaining sleep may alleviate the burden of diabetes symptoms among young adults with T1D.

Disclosure

S. Griggs: None. Q. Howard: None. R. Hickman: None.

Funding

National Institutes of Health (R00NR018886)
272-OR: Effect of 48 Months of Closed-Loop Insulin Delivery on Residual C-Peptide Secretion and Glycemic Control in Newly Diagnosed Youth with Type 1 Diabetes
Authors: WARE JULIA , BOUGHTON CHARLOTTE K. , ALLEN JANET M. , WILINSKA MALGORZATA E. , HARTNELL SARA , THANKAMONY AJAY , RANDELL TABITHA , BESSER RACHEL , GHATAK ATRAYEE , ELLERI DANIELA , TREVELYAN NICOLA , CAMPBELL FIONA , SIBAYAN JUDY , BAILEY RYAN , CALHOUN PETER , DUNSEATH GARETH J. , HOVORKA ROMAN , CONSORTIUM CLOUD
Published: June 2024

Background: We evaluated the effect of long-term intensive metabolic control with hybrid closed loop on residual C-peptide secretion and glucose control compared to standard insulin therapy in youth with type 1 diabetes over 48 months.

Methods: Following the 24 month primary phase of a multicentre, randomised, parallel trial of 96 newly diagnosed youth aged 10-16.9 years, participants entered an extension phase using either hybrid closed-loop with Cambridge algorithm (CL) or standard insulin therapy (control) until 48 months post diagnosis. Analysis was intention-to-treat.

Results: At 24 months after diagnosis, 81 participants (mean±SD age 12±2 years) continued in the extension (47 CL). There was no difference in fasting C-peptide corrected for fasting glucose at 48 months between groups (CL: 0.3±0.5 vs control: 0.3±0.8pmol/L per mg/dL; mean adjusted difference ‑0.1 [95% CI ‑0.4, 0.2; p=0.54]). Central lab HbA1c remained lower in CL group by 10mmol/mol [0.9%] (95% CI 3, 17 [0.2, 1.5%]; p=0.01) at 48 months. Eleven severe hypoglycaemic events (6 CL, 5 control) and seven DKA occurred (3 CL, 4 control).

Conclusions: Improved glycaemic control was sustained over 48 months after diagnosis with closed loop insulin delivery compared to standard therapy in youth with type 1 diabetes. This did not appear to confer a protective effect on residual C-peptide secretion.

Disclosure

J. Ware: Other Relationship; Novo Nordisk, Ypsomed AG. C.K. Boughton: Consultant; CamDiab. Speaker's Bureau; Ypsomed AG. J.M. Allen: None. M.E. Wilinska: Consultant; CamDiab. S. Hartnell: Speaker's Bureau; Ypsomed AG. Employee; CamDiab. A. Thankamony: None. T. Randell: Consultant; Abbott. Speaker's Bureau; Novo Nordisk. R. Besser: Advisory Panel; Provention Bio, Inc. Speaker's Bureau; Medscape, Health Partners Institute. A. Ghatak: None. D. Elleri: None. N. Trevelyan: None. F. Campbell: None. J. Sibayan: None. R. Bailey: None. P. Calhoun: None. G.J. Dunseath: None. R. Hovorka: Other Relationship; CamDiab. Research Support; Abbott, Dexcom, Inc., Ypsomed AG. Speaker's Bureau; Ypsomed AG, Abbott, Novo Nordisk, Novartis Pharmaceuticals Corporation.

Funding

NIHR EME (14/23/09); Helmsley Trust (2016PG-T1D045 and 2016PG-T1D046); JDRF (22-2013-266 and 2-RSC-2019-828-M-N); National Institute for Health Research Cambridge Biomedical Research Centre
274-OR: Population-Scale Single-Nucleus Skeletal Muscle Chromatin Dynamics and Nucleosome Positioning in the Context of Type 2 Diabetes
Authors: WANG XIAOOU , ROBERTSON CASSIE , VARSHNEY ARUSHI , MANICKAM NANDINI , ORCHARD PETER , LAAKSO MARKKU , TUOMILEHTO JAAKKO , LAKKA TIMO A. , MOHLKE KAREN L. , BOEHNKE MICHAEL , SCOTT LAURA , KOISTINEN HEIKKI A. , COLLINS FRANCIS S. , PARKER STEPHEN
Published: June 2024

Motivation: Insulin resistance in skeletal muscle plays a central role in the development of type 2 diabetes (T2D). T2D genome-wide association studies (GWAS) have nominated > 600 signals potentially linked to cell type-specific regulatory processes, with most lying in the non-coding region. Studying the genetic regulation of local chromatin patterns in muscle fibers can provide mechanistic insights into T2D GWAS hits. Here, we employ population-scale single-nucleus ATAC-sequencing (snATAC) to better understand T2D mechanisms.

Methods: Leveraging snATAC profiles from 281 individuals, we used statistical models to infer nucleosome positioning and nucleosome-free regions (NFR). We then combined genetic variation with chromatin accessibility patterns to identify cis-quantitative trait loci (QTL) for both NFR (nfrQTL) and nucleosome positioning (nucQTL) globally and at T2D-related trait GWAS signals.

Results: We identified 14,417 nfrQTLs and 19,265 nucQTLs (5% FDR) in type 1 muscle fibers. NfrQTLs were significantly enriched to overlap T2D and fasting insulin signals (P < 0.005). Colocalization analyses revealed that 5,890 pairs of nfr- and nucQTLs contained shared causal variants. Furthermore, mediation analyses revealed that at 765 pairs of colocalized nfr&nucQTLs, genetic variant(s) regulated the nucleosome positioning through NFRs and 65 pairs with the reverse direction (5% FDR). Notably, 25 nfrQTLs colocalized with T2D GWAS signals. Interestingly, signals at FARSA and PLEKHA1 colocalized with both nfr- and nucQTLs, and the nfrQTLs were causal on the nucQTLs. These findings imply that genetic variants in these GWAS signals regulate the NFR's position, which subsequently influences nucleosome positioning.

Conclusion: These results provide single-nucleus resolution mechanistic hypotheses for local chromatin dynamics in skeletal muscle, providing significant insights into T2D therapeutic strategies involving NFRs.

Disclosure

X. Wang: None. C. Robertson: None. A. Varshney: None. N. Manickam: Employee; 10x Genomics. P. Orchard: None. M. Laakso: None. J. Tuomilehto: Stock/Shareholder; Orion Pharma, Aktivolabs, Digostics. T.A. Lakka: None. K.L. Mohlke: None. M. Boehnke: None. L. Scott: None. H.A. Koistinen: Other Relationship; AstraZeneca, Novo Nordisk. F.S. Collins: None. S. Parker: Research Support; Pfizer Inc.
28-OR: Posttranslational Modifications in Skeletal Muscle Direct Divergent Metabolic Responses to Different Exercise Training Modes
Authors: PATAKY MARK W. , HEPPELMANN CARRIE J. , SEVITS KYLE , ASOKAN ANEESH K. , KLAUS KATHERINE , SREEKUMARAN NAIR K.
Published: June 2024

Different exercise modes yield distinct metabolic outcomes, yet the underlying molecular mechanisms driving these exercise responses remain unclear. Here, we investigated the impact of post-translational modifications (PTM) to skeletal muscle proteins in response to 3 months of high intensity aerobic interval training (HIIT) and resistance exercise training (RT). Frozen muscle biopsy tissue was obtained from a sub-cohort of our previously published study which showed significantly enhanced insulin sensitivity following either HIIT (n=7) or RET (n=7). After digestion, peptides were isobarically labeled and either acetyl- or phospho-enriched and fractionated by high-performance liquid chromatography (HPLC). Mass spectra were measured using a Thermo Fusion Tribrid coupled to Ultimate 3000 HPCL, revealing global-, phospho-, and acetyl-proteomic responses in muscle to HIIT or RT. Reactome analysis was used to determine exercise-regulated PTM pathways. HIIT significantly (p-value <0.05, fold-change ≥ 0.3) increased the abundance of ~9% of the global proteome (444 proteins) and ~22% of the acetylproteome (504 peptides), with primarily global and acetyl modifications occurring on mitochondrial pathways. HIIT also significantly (P < 0.05) increased the abundance of the deacetylase, SIRT3, which was positively associated with mitochondrial respiration. RT significantly (p-value <0.05, fold-change ≥ 0.3) altered the abundance of ~3% of the global proteome (144 proteins) and ~7% of the phosphoproteome (817 peptides), with minimal effect on the acetylproteome (~1%). RT primarily regulated contractile function and muscle structure pathways. These results indicate that the divergent metabolic responses to HIIT or RT are related to differential PTM mechanisms that contribute to cardiometabolic outcomes.

Disclosure

M.W. Pataky: None. C.J. Heppelmann: None. K. Sevits: None. A.K. Asokan: None. K. Klaus: None. K. Nair: None.

Funding

NIH (R01AG062859); NIH (T32DK007352)
293-OR: Improvement of Tissue-Specific Insulin Sensitivity after Bariatric Surgery Does Not Restore Hepatic OXPHOS Capacity
Authors: KAHL SABINE , PUETZER-FURMANCZAK JENNIFER , TRINKS NINA , DEWIDAR BEDAIR , PAFILI KALLIOPI , TRENKAMP SANDRA , ESPOSITO IRENE , SCHLENSAK MATTHIAS , GRANDERATH FRANK A. , RODEN MICHAEL
Published: June 2024

Common insulin resistance relates to positive energy balance and is central to obesity, type 2 diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD). In early MASLD, the liver adapts to increased energy supply by upregulating its oxidative phosphorylation (OXPHOS) capacity (mitochondrial plasticity), which is lost during MASLD progression and in type 2 diabetes. This study examined whether improvements in insulin sensitivity after bariatric surgery restore hepatic mitochondrial plasticity and thereby ameliorate liver histology. Persons with insulin resistance and obesity (n=16, BMI 52±8 kg/m2; HbA1c 5.5±0.1%) underwent bariatric and follow-up surgeries, at which liver biopsies were taken. MASLD was assessed histologically. Hepatic maximal ADP-stimulated respiration, reflecting OXPHOS capacity, was measured by high-resolution respirometry, tissue-specific insulin sensitivity by hyperinsulinemic-euglycemic clamps with 2H2-glucose. Mean body weight loss (-48.5 kg over 0.5-5 years) increased whole-body (stimulated glucose disposal) as well as hepatic (suppressed endogenous glucose production) insulin sensitivity by 57 and 32% (both p<0.05), respectively. Fasting adipose tissue insulin resistance (Adipo-IR) decreased by 61% (p=0.005). Steatosis grade decreased in all participants, whereas lobular inflammation and ballooning did not uniformly change after surgery. Hepatic mitochondrial DNA (mtDNA) content slightly rose (p=0.02), whereas OXPHOS capacity remained unchanged for TCA cycle- and β-oxidation-linked respiration upon normalization for both tissue wet weight and mtDNA.

In conclusion, bariatric surgery led to robust improvements in whole-body, hepatic and adipose tissue insulin sensitivity as well as hepatic steatosis. However, the failure to restore hepatic mitochondrial plasticity and to reverse inflammation indicates the need for novel mitochondria-targeted concepts for MASLD treatment.

Disclosure

S. Kahl: None. J. Puetzer-Furmanczak: None. N. Trinks: None. B. Dewidar: None. K. Pafili: None. S. Trenkamp: None. I. Esposito: None. M. Schlensak: None. F.A. Granderath: None. M. Roden: Advisory Panel; Eli Lilly and Company. Research Support; Boehringer-Ingelheim. Advisory Panel; Novo Nordisk. Research Support; Novo Nordisk. Advisory Panel; TARGET PharmaSolutions, Inc. Speaker's Bureau; AstraZeneca.

Funding

German Federal Ministry of Health (BMG); Ministry of Culture and Science of the State North Rhine-Westphalia (MKW NRW) to DDZGerman Federal Ministry of Education and Research (BMBF) to German Center for Diabetes Research (DZD e. V.). HORIZON-HLTH-2022-STAYHLTH-02-01: Panel A to the INTERCEPT-T2D consortium EUREKA Eurostars-2 (E!-113230-DIA-PEP)German Science Foundation (DFG; SFB/CRC1116, RTG/GRK 2576) Schmutzler-Stiftung "Profilbildung 2020"
298-OR: Precision-Engineered Activin and GDF Ligand Trap HS235—A Novel Lean Mass–Preserving Treatment for Obesity
Authors: SCHANG GAUTHIER , DE MOLLIENS MATHILDE , BRÛLÉ EMILIE , SOURS ARIANE , DENIS JEAN-FRANCOIS , CHAUVET CRISTINA , GANESH VANN , TREMBLAY GILLES , SCHOELERMANN JULIA , O'CONNOR MAUREEN
Published: June 2024

Introduction: Incretin mimetics have revolutionized the pharmacotherapy of obesity leading to unprecedented weight loss and improvement of cardiometabolic health. However, incretins reduce body mass in a non-selective manner. In obese patients treated with incretins, undesirable loss of lean body mass (LBM) can account for up to 40% of overall weight loss. Loss of LBM negatively impacts resting metabolic rate, leading to a weight loss plateau and often unsustainable results. LBM preservation is a desirable treatment goal for obesity pharmacotherapy and overall cardiometabolic health. Activins and growth differentiation factors (GDFs), members of the TGF-beta superfamily, are validated targets controlling body composition and metabolism. Specific and selective blockade of activins and GDFs represents a novel anti-obesity treatment strategy which can act orthogonally to incretins. HS235 is an activin receptor ectodomain-based Fc-fusion protein that has been rationally designed to attain optimal inhibition of ligands controlling body composition in obesity.

Methods: To validate the anti-obesogenic potential of HS235, diet-induced obese (DIO) mice were injected with HS235, an incretin mimetic, or a combination of both. Fat mass, LBM, muscle weights, and biomarker readouts were assessed at the end of study.

Results: In DIO mice, HS235 and the incretin mimetic significantly improved metabolic parameters and decreased fat mass, but only HS235 increased LBM, while incretin-based treatment led to LBM loss. Importantly, the addition of HS235 to the incretin mimetic lead to a synergistic fat mass loss and prevented loss of LBM.

Conclusion: Potent and selective inhibition of activins and GDFs by HS235 represents a novel LBM preserving weight loss strategy orthogonal to incretin mimetics. This data supports the development of HS235 as a novel anti-obesity agent to complement currently approved incretin-based medications to improve quality of weight loss.

Disclosure

G. Schang: Employee; 35Pharma. M. De Molliens: Employee; 35Pharma. E. Brûlé: Employee; 35Pharma. A. Sours: Employee; 35Pharma. J. Denis: Employee; 35Pharma. C. Chauvet: Employee; 35Pharma. V. Ganesh: Employee; 35Pharma. G. Tremblay: Employee; 35Pharma. J. Schoelermann: Employee; 35Pharma. M. O'Connor: Employee; 35Pharma.
31-PUB: Efficacy and Safety of Sodium–Glucose Cotransporter 2 Inhibitors (SGLT2i) vs. Dipeptidyl Peptidase 4 Inhibitor (DPP4i) as Initiator Therapy with Type 2 Diabetes on Cardiovascular Outcomes—A Systematic Review and Meta-analysis
Authors: SHRESTHA ABHIGAN B. , RAJAK KRIPA , TUMMALA NAYANIKA , RESEARCH HUB MEDICAL , MADDINENI GAUTAM
Published: June 2024

Introduction & Objective: SGLT2i are recommended for the treatment of heart failure due to their cardioprotective effects, despite primarily being used as antidiabetic medications. However, the comparative profile of SGLT2i with DPP4i remains unclear. This study aims to compare the efficacy and safety of SGLT2is versus DPP4is as initial therapy in older adults with type 2 diabetes.

Methods: A comprehensive search was conducted in PubMed, EMBASE, ScienceDirect, Google Scholar, and Cochrane Central using appropriate Mesh terms from inception until February 23, 2023. The outcomes were pooled using a random-effects model for Hazard ratio (HR) with a 95% confidence interval. A p-value of <0.05 was considered statistically significant.

Results: 12 studies were included after systematic screening, with a sample size of 745,688 for SGLT2is and 769,386 for DPP4is. The mean age in each group was 61.1 (8.52) and 61.28 (9.25) years, respectively. Upon pooling the included articles with SGLT2i versus DPP4i, the primary outcome of all-cause death demonstrated an HR of 0.64 [0.57, 0.70], I2: 65.54%, p<0.001, and major adverse cardiovascular events (MACE) yielded an HR of 0.76 [0.65, 0.86], I2: 87.83%, p<0.001. The secondary outcomes included myocardial infarction with an HR of 0.84 [0.78, 0.90], I2: 47.64%, p<0.001, stroke with an HR of 0.81 [0.75, 0.87], I2: 36.78%, p<0.001, and Hospitalization with an HR of 0.62 [0.53, 0.70], I2: 83.32%, p<0.001.

Conclusion: Our findings suggest that compared to DPP4is, initiating treatment with SGLT2is provides cardiovascular disease protection and can be considered for use in patients with type 2 diabetes.

Disclosure

A.B. Shrestha: None. K. Rajak: None. N. Tummala: None. G. Maddineni: None.
317-OR: Identification of Genetic Regulators of Circulating Biomarkers of Kidney Decline in Diabetes
Authors: STUCKI DEVORAH , SATAKE EIICHIRO , KROLEWSKI ANDRZEJ , PEZZOLESI MARCUS G.
Published: June 2024

Background: Over the past decade, major progress has been made in identifying predictors of kidney disease progression in patients with diabetes mellitus (DM). Despite this progress, however, a key feature that has yet to be considered in current prognostic models, and one that is critical toward implementing Precision Medicine and Precision Diagnostics in diabetic kidney disease (DKD), is the contribution of genetic factors on the levels of these biomarkers. To advance this area, we set out to define the genetic drivers of circulating biomarkers of kidney disease progression in individuals with diabetes.

Methods: Leveraging genetic and proteomic data from 3,267 participants with diabetes from the UK Biobank Pharma Proteomics Project (UKB-PPP), we performed genome-wide association study (GWAS) analyses using REGENIE, adjusting for age, gender, BMI, and principal components, and biomarker data for 21 Joslin Kidney Panel (JKP) biomarkers measured on the OLINK Explore 3072 platform.

Results: We identified genome-wide significant (p-value < 5x10-8) cis-protein quantitative trait loci (pQTLs) at 12 of the 21 JKP biomarkers (57%). In total, 1,855 SNPs achieved genome-wide significance across these 12 cis-pQTLs. The strongest association was observed at rs13278062 (p-value = 1.25x10-54) with TNFRSF10A protein levels. In addition to cis-pQTLs, we also identified genome-wide significant trans-pQTLs for 4 JKP biomarkers. Colocalization of transcriptomic and epigenomic data nominate 237 putative regulatory SNPs across the 12 cis-pQTLs.

Conclusion: Our results indicate that genetic variation (both cis and trans) is associated with circulating levels of the majority of JKP biomarkers (14/21, 67%) and suggest that incorporating information on genetic regulators (i.e., genetic-biomarkers) of protein-biomarkers of kidney disease progression in prognostic models may further improve risk stratification in DKD.

Disclosure

D. Stucki: None. E. Satake: None. A. Krolewski: None. M.G. Pezzolesi: None.

Funding

American Diabetes Association (11-22-ICTSPM-09)