bluuebunny/crossref_metadata_2025 huggingface dataset:
1594-P: Deciphering Postprandial Hypoglycemia—Dominant Influence of Insulin Sensitivity in Patients without Diabetes
Authors: HUMMEL JULIA , UFER GISA , SABIA ROZA , MÄRKER MILENA , HAUG CORNELIA , WAGNER ROBERT , PETER ANDREAS , WAGNER MARTIN , HENI MARTIN
Published: June 2024

Introduction & Objective: Postprandial hypoglycemia describes a condition with abnormally low glucose within a few hours after carbohydrate-rich meals. Underlying mechanisms are still unclear, with hypotheses including an unusually rapid increase in blood glucose, excessive insulin release, or prolonged presence of elevated insulin. We now analyzed these possibilities in a large sample of oral glucose tolerance tests (oGTT).

Methods: Patients without diabetes underwent prolonged (180 min) 75 g oGTT as part of clinical work up. Blood samples were taken before, 15 min after glucose ingestion and every 30 min thereafter.

Results: Of the analyzed 1511 patients (median age: 43 years (IQR: 33), 966 women), 387 had plasma glucose below 70 mg/dl at 180 min post oral glucose load. Blood glucose even below 54 mg/dl occurred in 107 patients (HYPO group). The groups with and without postprandial hypoglycemia were comparable in sex while the HYPO group was older (p=0.02). The HYPO group had a slightly lower HbA1c (5.4 vs 5.5%; p=0.047 adjusted for age) and fasting glucose (p<0.001). Peak glycemia was reached in both groups at 30 min and the increment in plasma glucose was comparable between groups. Insulin secretion, as assessed from insulin- or C-peptide-based indices, was lower in the HYPO group in unadjusted models. Even after adjustment for insulin sensitivity and age, second phase insulin secretion was still lower in the HYPO group. Insulin sensitivity, as assessed at fasting and during the oGTT was higher in the HYPO group which remained significant after adjustment for age.

Conclusion: Postprandial hypoglycemia affects a significant number of patients in a university hospital's endocrinology setting. Rise in blood glucose and excessive insulin secretion seem not to substantially contribute, but those with postprandial hypoglycemia exhibited notably higher insulin sensitivity. This likely contributes to better everyday glucose control, as reflected by lower HbA1c.

Disclosure

J. Hummel: None. G. Ufer: Other Relationship; Amgen Inc., Boehringer-Ingelheim, Novo Nordisk, Vitaflo. R. Sabia: Other Relationship; Amgen Inc., Novo Nordisk, Novartis AG, Vitaflo, MetaX, Biomarin, Alexion Pharmaceuticals, Inc. M. Märker: None. C. Haug: None. R. Wagner: Speaker's Bureau; Sanofi. Advisory Panel; Lilly Diabetes. Speaker's Bureau; Boehringer-Ingelheim, Novo Nordisk. A. Peter: None. M. Wagner: None. M. Heni: Research Support; Boehringer-Ingelheim. Advisory Panel; Amryt Pharma Plc. Speaker's Bureau; Amryt Pharma Plc. Advisory Panel; Boehringer-Ingelheim, Boehringer-Ingelheim. Speaker's Bureau; Lilly Diabetes, Novartis AG, Novo Nordisk, Sanofi.
16-OR: Preadministration of SGLT2 Inhibitor Reduces Frequency of Anti-VEGF Agent Administration in Patients with Mild Diabetic Macular Edema—A Multicenter Randomized Controlled Open-Label Trial
Authors: ISHIBASHI RYOICHI , KOSHIZAKA MASAYA , TAKATSUNA YOKO , TATSUMI TOMOAKI , YAMAMOTO SHUICHI , YOKOTE KOUTARO
Published: June 2024

Introduction & Objective: There are various unmet needs for anti-vascular endothelial growth factor (VEGF) therapy for diabetic macular edema (DME). We previously reported that using sodium-glucose cotransporter 2 inhibitor (SGLT2i) reduced the frequency of anti-VEGF agent administration through observational studies. However, no interventional studies have been conducted.

Methods: Sixty patients with DME were enrolled and divided into an SGLT2i group (SG) treated with luseogliflozin and a control group treated with glimepiride. Ranibizumab (R) was first administered to the eyes with more severe DME (target eyes); hypoglycemic drugs were started simultaneously. R was administered for 48 weeks to the target eyes according to regulations, and companion eyes in cases of bilateral DME received regular medical treatment. The doses of R were evaluated using analysis of covariance.

Results: A total of 54 patients were analyzed. We found no intergroup differences in ophthalmological parameters and the number of R injections of the target eyes (Table). Significant decreases in central thickness of retina and number of R injections were observed for the companion eyes in the SG group.

Conclusion: The pre-administration of SGLT2i reduced the frequency of anti-VEGF agent administration for mild DME.

Disclosure

R. Ishibashi: Research Support; Astellas Pharma Inc., Taiho Pharmaceutical Co. Ltd. M. Koshizaka: None. Y. Takatsuna: None. T. Tatsumi: Research Support; Taisho Pharmaceutical Holdings Co., Ltd. Advisory Panel; Astellas Pharma Inc. S. Yamamoto: None. K. Yokote: Research Support; Taisho Pharmaceutical Holdings Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Boehringer-Ingelheim, Sumitomo Dainippon Pharma Co., Ltd., Kowa Company, Ltd. Speaker's Bureau; Kowa Company, Ltd., Sumitomo Dainippon Pharma Co., Ltd., Novo Nordisk, Novartis Pharmaceuticals Corporation, Daiichi Sankyo.
1601-P: Regulation of Circadian Rhythmicity of Human Adipose Tissue in Obesity
Authors: LYTLE KELLI , PETRUS PAUL , SAVVA CHRISTINA , JENSEN MICHAEL D.
Published: June 2024

Adipose tissue (AT) is highly responsive to nutrient delivery associated with conventional feed/fast cycles over 24 hr and also has a molecular circadian clock that regulates transcriptional rhythms. The joint contribution of these dual inputs to human AT function has not been studied, nor how this interplay changes in obesity. Ten lean (BMI 20-25 kg/m2) and 7 people with upper body obesity (UBO) (BMI 30-35 kg/m2) were within group randomized to either continuous feeding (“CONT”) or intermittent feeding (“INT”) of Ensure via nasogastric tube (NG). CONT was fed at rates to meet 24 hr caloric needs and INT fed 3 evenly spaced feedings (1/3 of daily caloric needs per meal) during daylight hours and fasted overnight. Each person received 4 abdominal AT biopsies across 24 hr. We performed RNA-Seq analysis on AT samples; dryR was used to assess circadian rhythmicity of genes differential between groups and GO and ClusterProfiler for pathway analysis. Most rhythmic genes were driven by feed/fast cycles, 538 transcripts were significantly rhythmic in INT groups and lost rhythmicity in CONT groups (adj. P <0.02)(BICW > 0.1). These genes were enriched for lipid metabolism pathways including biosynthesis and oxidation. Many genes (237) were significantly rhythmic in lean and not UBO individuals regardless of feeding regime (adj. P<0.05)(BICW > 0.1), these were enriched for pathways related to immune response. 399 genes were significantly rhythmic (adj. P<0.02)(BICW > 0.13) in lean CONT and INT and UBO INT, but lost rhythmicity only in UBO CONT. These were enriched for metabolic pathways related to glucose and carbohydrate homeostasis and molecular circadian system. Overall, the fast/feed cycle over 24 hr drives a significant portion of AT gene rhythmicity. Our data suggests lean individuals maintain AT clock system integrity independent of feeding time while patients with UBO require feed-fast cycles to sustain AT clock circadian rhythmicity, suggesting feeding time might be particularly relevant for patients with obesity.

Disclosure

K. Lytle: None. P. Petrus: None. C. Savva: None. M.D. Jensen: Advisory Panel; Biohaven.
1619-P: Insulin Resistance Stimulates Intraislet GLP-1 Secretion from a-Cells in Diet-Induced Obese Mice
Authors: DI GIUSEPPE GIANFRANCO , JEPSEN SARA L. , VERGARA UCIN JON , HARTMANN BOLETTE , GIACCARI ANDREA , HOLST JENS J. , MEZZA TERESA
Published: June 2024

It has been recently hypothesized that alpha α-cells are a potential source of intraislet GLP-1, eventually exerting paracrine effects on islet function. However, it is still unknown whether intraislet GLP-1 production and secretion is modulated by insulin resistance and glucose dysmetabolism. In this study, we aim to explore the impact of insulin resistance on intraislet proglucagon-derived peptides in a population of Diet-Induced Obese (DIO) mice.

We performed a 75 min pancreatic perfusion on n=8 DIO vs. n=8 C57BL/6 control mice at low (3.5 mM) and medium (7 mM) glucose concentrations + 3.5 mM Vamine and 10 mM arginine stimulation; at the end, we infused insulin receptor antagonist S961 (n=4) or GLP-1 receptor antagonist Exendin 9 (n=4) to investigate possible involvement of insulin and GLP-1 receptor signaling. Total GLP-1 levels were measured using RIA; Insulin and Glucagon levels were measured through commercial ELISA kit (Mercodia). Compared to controls, DIO mice showed a significant secretion of total GLP-1 over time during perfusions (p<0.0001), with no differences between 3.5 and 7 mM glucose and with a preserved response to arginine. Further, S961 did not affect total GLP-1 secretion, whereas Exendin 9 led to increased intra-islet total GLP-1 secretion, as in a positive feedback-control mechanism. As expected, DIO mice showed increased insulin secretion at 7 mM glucose and during arginine stimulation, while no differences were observed in the glucagon secretion. S961 and Exendin 9 did not affect insulin nor glucagon secretion in the 2 groups. Our data demonstrate that intraislet GLP-1 secretion is significantly increased in a rodent model of obesity and insulin resistance. In particular, this secretion pattern seems to be regulated by the activity of GLP-1 receptor itself. Further studies will be necessary to clarify the pathophysiologic action of intrapancreatic GLP-1 on insular environment.

Disclosure

G. Di Giuseppe: None. S.L. Jepsen: None. J. Vergara Ucin: None. B. Hartmann: Board Member; Bainan Biotech. A. Giaccari: None. J.J. Holst: Advisory Panel; Novo Nordisk A/S, Merck Sharp & Dohme Corp., Kallyope. Board Member; Antag Therapeutics. T. Mezza: None.

Funding

This study was supported by grants from the Universita Cattolica del Sacro Cuore (Fondi Ateneo Linea D.3.2, Fondi Ateneo Linea D.1, anno 2019, and Fondi Ateneo Linea D.1, anno 2020); the Italian Ministry of Education, University, and Research (MIUR; GR-2018-12365577 and RF-2019û12369293); the European Foundation for the Study of Diabetes award supported by Astra Zeneca and MIUR and MUIR (PRIN 2020SH2ZZA)
1654-P: Low Dietary Vitamin D Leads to Glucose Abnormalities in an Obese Animal Model
Authors: GINNARD OLIVIA Z.B. , SISLEY STEPHANIE
Published: June 2024

Introduction: Both obesity and type 2 diabetes (T2D) are linked to vitamin D deficiency. However, we have limited understanding of the role of vitamin D in feeding and glucose homeostasis among its vast target tissues. Furthermore, using the storage form of vitamin D may not be an accurate indicator of vitamin D status in individuals with obesity. Thus, measuring expression levels of vitamin D receptor (VDR)-target genes may be a more promising marker for vitamin D status. The aim of this study was to elucidate the impact of vitamin D on feeding and glucose homeostasis in the context of VDR-target gene expression across multiple tissues.

Methods: We fed C57/BJ mice high-fat diets (58% fat) with low (100 IU/kg), regular (1000 IU/kg), or high (5000 IU/kg) vitamin D content. After 18 weeks, we performed an intraperitoneal glucose (1.0 g/kg D20W) tolerance test (GTT). After 26 weeks, we obtained blood samples for liver function testing. qPCR was performed for Insr, and Glut-4 in subcutaneous adipose tissue (SAT) and liver tissue.

Results: Mice fed a low-D diet had higher blood glucoses than the regular and high-D groups during GTT (p<0.05). Body weights were the same in all groups (p >0.05). Mice fed a low-D diet had worsened liver function compared to the regular and high-D groups (p<0.05). Mice fed the low-D diet had significantly higher expression levels of Glut-4 in both tissues. We found that in both tissues, there was a significant correlation between Insr and Glut4 expression (p<0.05).

Conclusion: These preliminary findings suggest that a low vitamin D diet exacerbates obesity-related complications, such as dysglycemia and liver dysfunction. In addition, VDR-target gene expression correlates with glucose metabolism-related gene expression, proposing a relationship between vitamin D and glycemic pathways in obesity. Further work should investigate the role of vitamin D in hepatic glucose metabolism pathways. This study may provide the first step in utilizing vitamin D more effectively in individuals with T2D.

Disclosure

O.Z.B. Ginnard: None. S. Sisley: Speaker's Bureau; Rhythm Pharmaceuticals, Inc.
1669-P: The Joint Effect of Low Skeletal Muscle Mass and Abdominal Obesity on the Incidence of Cardiovascular Events—A 7.6-Year Follow-up
Authors: HU TINGTING , XU YITING , SHEN YUN , WANG YUFEI , MA XIAOJING , BAO YUQIAN
Published: June 2024

Introduction & Objective: Skeletal muscle loss often accompanies with abdominal obesity in the aging process. This study was aimed to assess the joint effect of low skeletal muscle mass and abdominal obesity on incident cardiovascular events.

Methods: A total of 1330 community residents (582 men and 748 postmenopausal women) aged 50−80 years were recruited in 2013−2014. During 2021−2022, a follow-up was conducted to record their cardiovascular events via phone calls. All events were further validated by medical records. Skeletal muscle mass was estimated by bioelectrical impedance analysis and converted to skeletal muscle index (SMI) adjusted for body weight. Pre-sarcopenia was defined as SMI less than 1SD of the sex-specific mean for a young reference group. Magnetic resonance imaging was used to assess visceral fat area (VFA). VFA ≥ 80 cm2 was defined as abdominal obesity. Participants were classified into 4 groups as, normal, pre-sarcopenia alone, abdominal alone, pre-sarcopenic obesity.

Results: The prevalence of pre-sarcopenia and abdominal obesity were 15.9% and 56.5%, respectively. During a mean of 7.6-year follow-up, 139 participants (10.5%) developed cardiovascular events. SMI was negatively associated with the risk of cardiovascular events (adjusted HR 0.92, 95%CI 0.87-0.97), while VFA was positively associated with the risk of cardiovascular events (adjusted HR 1.04, 95%CI 1.00-1.09). Pre-sarcopenic obesity conferred the highest risk of incident cardiovascular events (adjusted HR 2.17, 95%CI 1.31-3.59) compared with normal body composition, pre-sarcopenia alone, or abdominal obesity.

Conclusion: Low skeletal muscle mass and abdominal obesity could additively increase the risk of cardiovascular events.

Disclosure

T. Hu: None. Y. Xu: None. Y. Shen: None. Y. Wang: None. X. Ma: None. Y. Bao: None.
1671-P: Safety and Effectiveness of Bariatric and Metabolic Surgery in Older Japanese Patients
Authors: HAYASHI AIKO , TAKEMOTO MINORU , TANAKA TOMOHIRO
Published: June 2024

Introduction & Objective: According to the current guidelines in Japan, the upper age limit for bariatric and metabolic surgery is 65 y. This study aimed to examine the appropriateness of this upper age limit.

Methods: Using the database maintained by the Japanese Society for Treatment of Obesity, we conducted an analysis of patients in two age groups: those aged <65 y and those aged ≥65 y. Our analysis focused on postoperative weight loss, improvement in comorbidities, and frequency of perioperative complications.

Results: A total of 3649 patients aged <65 y (mean, 43.9 ± 9.5 y) with a preoperative body mass index of 42.5 ± 8.1 kg/m2, while 70 aged ≥65 y (mean, 67.2 ± 3.1 y; maximum,78 y) with a preoperative body mass index of 40.7 ± 6.9 kg/m2. Patients aged ≥65 y had a higher rate of diabetes, dyslipidemia and hypertension. The rates of reoperation, intraoperative complications, and postoperative complications did not differ between the age groups. Both groups achieved significant weight loss postoperatively, and no differences in the improvement of comorbidities were noted.

Conclusion: Metabolic surgery is safe and effective for older patients with clinically severe obesity. Weight loss was less in patients aged ≥65 y, but the percentage of total weight loss did not differ between the groups.

Disclosure

A. Hayashi: None. M. Takemoto: None. T. Tanaka: None.
1690-P: Clinical Outcomes among Nondiabetic Obese Population with Concomitant Metabolic Dysfunction–Associated Steatotic Liver Disease—A Nationwide Study
Authors: KISHORE SINDHU , KHOKHLOV LEONID , MATEO FERNANDO R. , RAJBHANDARI PRANITA , IKPEZE TOCHUKWU , KISHORE MEHWISH , AJENAGHUGHRURE GODBLESS E. , THAPA ANUP
Published: June 2024

Obesity, a disease increasing cardiometabolic risks and mortality, often accompanies metabolic dysfunction-associated steatotic liver disease (MASLD). MASLD is characterized by fat accumulation in the liver without other secondary causes. This study explores clinical outcomes in obese patients without DM co-diagnosed with MASLD. Conducted as an observational study, it utilized data from the National Inpatient Sample from 2017 to 2020 focusing on obese adults over 18 years, with a BMI >30 kg/m^2, and MASLD diagnosis, excluding those under 18 or with DM. Multivariable logistic and Poisson regression analyses determined the clinical outcomes, considering a p-value <0.05 significant. Among 1,140,000 obese adults without DM, 23.4% had MASLD, predominantly white males aged 53-57. The study compared MASLD and non-MASLD groups, revealing higher rates in % in the MASLD group for conditions like anemia (21.8 vs 13.5), pulm HTN (7.6 vs 4), HF (26.6 vs 15.9), Afib (18.7 vs 13.7), PVD (2.4 vs 2.2), ACS (7 vs 4.2), STEMI (1.1 vs 0.6), COPD (19 vs 14.6), CKD (19.5 vs 11), PE (7.2 vs 5.2) and incidences of nicotine (19 vs 15.8) and alcohol use (16 vs 4.3). The former group also had worse primary and secondary outcomes as detailed in Table 1. The findings underscore the importance of obesity detection and management in such populations for better clinical outcomes and prognosis.

Disclosure

S. Kishore: None. L. Khokhlov: None. F.R. Mateo: None. P. Rajbhandari: None. T. Ikpeze: None. M. Kishore: None. G.E. Ajenaghughrure: None. A. Thapa: None.
1704-P: Misperception of One’s Own Obesity Status—Causes and Consequences—Insights from a Large Nationwide Survey
Authors: AGARWAL SANJAY , VISWANATHAN VIJAY , SHARMA JK , SHUNMUGAVELU MINAKSHISUNDARAM , VIRMANI ANIL , MAKKAR BRIJ , KAPOOR NITIN , DESHPANDE NEETA
Published: June 2024

Introduction & Objective: Correct self-perception of BMI (Body Mass index) status is essential to adopt a healthy lifestyle and experience improved quality of life. The current study evaluates the extent of misperception in the Indian population and its influence on an individual’s perspective on obesity management.

Methods: A large-scale pan-Indian electronically captured survey was conducted using a translated and validated form and disseminated to the public using multiple modalities. The survey responses included demographics, history of comorbidities, perception of BMI, lifestyle practices, and attitude towards obesity management. Chi-square test for proportions was used to compare the responses between groups with correct perception or misperception (overperception - perceived BMI status is higher than actual BMI; undermisperception - perceived BMI status is lower than their actual BMI.

Results: Among the participants (N = 60285), 35.75% had a misperception of their BMI status, higher among men (35%) than women (29.6%). Almost 91% of those with misperception had underperceived their BMI status. The history of comorbid illness was significantly lower with misperception. Among those with a high actual BMI, 73% were unaware of overweight status and 92% of these participants had not taken efforts to lose weight. One-third of the population with misperception did not consider obesity as a disease and were reluctant to receive weight loss information (84.5%).

Conclusion: Misperception of self BMI status is high among the Indian population and could contribute to a setback in their self-awareness of health status (co-morbidities) and reluctance attitude towards obesity management.

Disclosure

S. Agarwal: None. V. Viswanathan: None. J. Sharma: None. M. Shunmugavelu: None. A. Virmani: None. B. Makkar: None. N. Kapoor: None. N. Deshpande: None.
1708-P: Effect of Oral Semaglutide in Glycemic Control and Weight Reduction for People with Type 2 Diabetes Mellitus Having a BMI ≥25 kg/m2—A Six-Month Real-World Study
Authors: KESAVADEV JOTHYDEV , SHANKAR ARUN , SABOO BANSHI D. , ASHIK ASHA , NAINA JUNAID , JOTHYDEV KRISHNADEV , BASANTH ANJANA , RAJ K SOURAV , JOTHYDEV SUNITHA
Published: June 2024

Overweight and obesity are increasingly recognized as potential targets for early intervention. Unlike injectable treatments, oral formulations are more easily accepted by people with diabetes. In Asian Indians, BMI ≥ 25 kg/m2 is considered obesity. Study participants were de-identified from the electronic medical records of a comprehensive diabetes centre in Kerala, India. The primary outcome variables were assessed at baseline and again at 6 months. Subjects with data spanning from March 2022 to July 2023 and a BMI ≥ 25 kg/m2 were included in the study. Those without follow-up data were excluded. Over six months, oral semaglutide (N=221) significantly reduced HbA1c by 1.38% (95% CI = 0.7 to 2.1, p < 0.001) in T2DM with BMI ≥ 25 kg/m2. A significant reduction was observed with a Mean Absolute Difference (MAD) of 2.2 kg/m2 in BMI (95% CI = 1.1 to 3.3, p < 0.001) and 4.76 kg in weight (95% CI = 2.7 to 6.8, p < 0.001). 27 participants (8%) discontinued due to side effects. (Figure). In this real world study 1 in 3 T2D with obesity achieved a weight loss of 5% and 1 in 2 T2D with obesity achieved reduction in insulin dose. This study provides real-world evidence of sustainable improvements in A1C, weight, and BMI among T2D treated with oral semaglutide.

Disclosure

J. Kesavadev: None. A. Shankar: None. B.D. Saboo: None. A. Ashik: None. J. Naina: None. K. Jothydev: None. A. Basanth: None. S. Raj K: None. S. Jothydev: None.
1711-P: A 3D High-Content Islet Imaging Toolbox
Authors: TITLE ALEXANDRA C. , JAWUREK SAYRO , RUFER CHANTAL , FORSCHLER FELIX , KODIYAN BEN , YESILDAG BURCAK
Published: June 2024

Previously, we optimized hanging-drop based, scaffold-free and high-throughput reaggregation of primary islet cells to obtain uniform islets that display long-term and robust function. Using our model, we reported type 1 and 2 diabetes relevant stress models that rely on analysis of insulin secretion and insulin and ATP contents. While these biochemical assays effectively assess islet function and viability, they lack the ability to report at a single-cell resolution. Here, we showcase multiple 3D high-content confocal microscopy applications that provide single-cell insights into pancreatic cell function, identity, survival and proliferation. During islet culture, inflammatory stress was induced using proinflammatory cytokines, activated peripheral blood mononuclear cells or islet-specific cytotoxic T lymphocytes. For metabolic stress, glucolipotoxic culture conditions were used. Gene expression was modified via adeno-associated viral transduction during reaggregation. Islet function and viability were analyzed through basal and stimulated insulin secretion, insulin and ATP contents. 3D confocal imaging protocols of key diabetes-relevant targets were established by optimization of islet fixation, permeabilization, blocking, antibody staining, clearing, and high-content imaging followed by high-resolution, multicolor 3D microscopy. In addition, cell tracker dyes were utilized to observe longitudinal real-time islet-immune cell interactions. Images were analyzed with custom CellPathFinder pipelines. These established methods enable quantitative analysis of islet hormone content, amyloid deposition, HLA expression, transduction efficiency, T-cell infiltration, and β- and non-β-cell death, survival, mass and proliferation. In summary, by combining cutting-edge spheroid and 3D high-content imaging technologies, we developed unique tools for quantitative, high-throughput, and automated phenotypic characterization of pancreatic islets in parallel with a variety of functional parameters.

Disclosure

A.C. Title: Other Relationship; Biomea Fusion, Inc., Boehringer-Ingelheim, Novo Nordisk, Merck & Co., Inc. S. Jawurek: Other Relationship; Boehringer-Ingelheim, Merck & Co., Inc., Biomea Fusion, Inc., Novo Nordisk. C. Rufer: Other Relationship; Boehringer-Ingelheim, Novo Nordisk, Merck & Co., Inc., Biomea Fusion, Inc. F. Forschler: Other Relationship; Biomea Fusion, Inc., Boehringer-Ingelheim, Merck & Co., Inc., Novo Nordisk. B. Kodiyan: Other Relationship; Biomea Fusion, Inc., Novo Nordisk, Boehringer-Ingelheim, Merck & Co., Inc. B. Yesildag: Other Relationship; Novo Nordisk, Boehringer-Ingelheim, Biomea Fusion, Inc., Merck & Co., Inc.
1716-P: MiR-106b-5p Protects against Islet ß-Cell Dysfunction and Apoptosis by Modulating the Endoplasmic Reticulum Homeostasis Pathway
Authors: XU WEILONG , YU JIANGYI , ZHOU XIQIAO
Published: June 2024

Introduction & Objective: Apoptosis plays important roles in the pathophysiology of Type 2 diabetes mellitus (T2DM). Loss of functional β-cell mass is one mechanism by which diabetes can develop. ER stress plays an important role in the progressive reductions in insulin secretion that are associated with β-cell failure and apoptotic β-cell death.We aimed to elucidate the specific molecular mechanisms of β-cell apoptosis by exploring the relationship between miRNA and endoplasmic reticulum homeostasis.

Methods: RNA sequencing was performed to analyse the islets of high-fat diet (HFD)-fed mice and those of normal chow-fed mice (NCD). The function in β-cells of the selected miR-106b-5p was assessed after its overexpression or knockdown in MIN6 cells and primary islet cells, as well as in siRNA-treated mice. Then, RNA pull-down, RNA immunoprecipitation and coimmunoprecipitation were performed to investigate the mechanism of miR-106b-5p regulation of islet function.

Results: MiR-106b-5p was dramatically downregulated in the islets of the obese mice, as well as in the sera of obese donors with type 2 diabetes. Treatment with miR-106b-5p showed a significant decrease in the number of apoptotic β-cells and increased β-cell mass in HFD mice.Furthermore, we demonstrated that miR-106b-5p reshapes endoplasmic reticulum homeostasis and improves β-cells’function by downregulating the expression of GRP78.

Conclusion: Taken together, we clarified that the modulation of the ER homeostasis pathways by miR-106b-5p shifts the translational status from repression to the recovery phase and improves the survival of β-cells by protecting them from apoptosis.

Disclosure

W. Xu: None. J. Yu: None. X. Zhou: None.

Funding

National Natural Science Foundation of China(82174293, 82205025, 82104751)
1732-P: ATP Dynamics in ß-Cell Primary Cilia Depend on Bidirectional Signaling from Ciliary Glycolysis to Mitochondria
Authors: MING HUANG SHIH , FOSTER HANNAH R. , HUGHES JING , MERRINS MATTHEW J.
Published: June 2024

Primary cilia are specialized antenna-like sensory and signaling organelles present in pancreatic β-cells that play important roles in mediating insulin secretion. However, it remains unclear how cilia are provided with ATP. Here, β-cell deletion of the ATP-generating enzyme pyruvate kinase (PK) was used to investigate autonomous ciliary signaling, while β-cell deletion of mitochondrial Pck2, which supplies PK with mitochondrial PEP, was used to assess extraciliary signaling from the mitochondria. The dynamics of plasma membrane and ciliary signaling were examined in intact islets using live-cell 3D imaging of 5HT6 targeted biosensors. At elevated glucose, plasma membrane ATP/ADP, fructose 1,6-bisphosphate (FBP), and cAMP/PKA exhibit regular oscillatory patterns. Glucose elevation elicited a pronounced drop in plasma membrane ATP/ADP that contrasted with the sustained rise in ATP/ADP observed in cilia, and in many cases antiphasic ATP/ADP oscillations were observed between the two compartments. The cytosol represents a third “compartment” where glucose induced a monotonic rise in ATP/ADP, as shown with untargeted biosensors. In contrast with ATP/ADP, ciliary FBP did not rise in response to glucose, suggesting highly efficient glycolytic signaling within the axoneme. Experiments performed at low glucose with leucine stimulation were used to isolate retrograde PEP signaling from mitochondria to cilia. The leucine-dependent rise in ciliary ATP/ADP observed in control cells was strongly reduced by β-cell deletion of PCK2 or PKm1, with a further reduction in the PKm1/2 double knockout. Taken together, our findings indicate distinct signaling dynamics in the plasma membrane and ciliary domains, and demonstrate the importance of PK and an extraciliary PEP cycle for control of ciliary bioenergetics.

Disclosure

S. Huang: None. H.R. Foster: None. J. Hughes: None. M.J. Merrins: None.

Funding

NIH/NIDDK (R01DK113103 and R01DK127637); United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service (I01BX005113)
1750-P: Rescuing Human Beta-Cell Dysfunction Induced by Proinflammatory Cytokines and Glucotoxicity
Authors: TESI MARTA , SULEIMAN MARA , SEMERARO ROBERTO , DE LUCA CARMELA , BOSI EMANUELE , DEL GUERRA SILVIA , MAGI ALBERTO , CNOP MIRIAM , EIZIRIK DECIO L. , MARSELLI LORELLA , MARCHETTI PIERO
Published: June 2024

Introduction & Objective: Residual insulin secretion (IS) from surviving beta cells (BC) can be hampered by a stressful T1D islet microenvironment (e.g. cytokines - Cyt, increased glucose - G). We evaluated the effects of Cyt and Cyt+G on isolated human islet (HI) IS, assessed if BC dysfunction is reversible, and explored the associated molecular mechanisms.

Methods: HI from five nondiabetic organ donors (age, 78±15 yrs; BMI, 24.4±3.8 kg/m2) were exposed to Cyt (50 U/ml IL-1β + 1000 U/ml IFN-γ) at 5.5 or 11.1 mM G for 24h, followed by 72h culture in normal medium (wash-out, WO). IS at 3.3 and 16.7 mM G was assessed, and HI transcriptome evaluated by RNA sequencing.

Results: Cyt increased IS by 2-fold at 3.3 and 16.7 mM G, with an insulin stimulation index (ISI) of 5.3±2.3 (similar to that of control HI: 5.0±2.7). After WO, no change in IS was observed. Combined Cyt+G decreased ISI by > 50% (2.1±0.6); it improved after WO (4.0±1.1), due to better IS at 16.7 mM glucose. Transcriptome of Cyt+G washed-out vs exposed HI showed 3,137 differentially expressed genes (padj<0.01, log2FC≥1, ≤-1, 1,443 up- and 1,694 down-regulated). By GSEA, 10 pathways were positively enriched (including Glycolysis/Gluconeogenesis, AMPK signaling and Metabolic pathways) and 65 negatively enriched (including Cytokine-cytokine receptor interaction, signaling by IL-17, TNF, JAK-STAT and NF-kB, Spliceosome, Protein processing in ER).

Conclusion: Short-term exposure to Cyt increased HI IS, which persisted after WO. Combined Cyt+G impaired BC function, which recovered after WO. The improvement was associated with transcriptomic changes in metabolic processes, inflammatory pathways and the innate immune system. These data suggest that human BC function can be rescued in a T1D-like environment by alleviating the insult and/or targeting underlying molecular mechanisms.

Disclosure

M. Tesi: None. M. Suleiman: None. R. Semeraro: None. C. De Luca: None. E. Bosi: None. S. Del Guerra: None. A. Magi: None. M. Cnop: None. D.L. Eizirik: None. L. Marselli: None. P. Marchetti: Speaker's Bureau; Eli Lilly and Company, Novo Nordisk.

Funding

Innovative Medicines Initiative 2 (115,797 and 945,268), European Commission and Italian Ministry of University and Research within the PNRR Project (M4C2-I1.3 PE_00000019 HEAL ITALIA)
1786-LB: Twenty-Four-Hour Ambulatory Blood Pressure and Vascular Complications in Type 1 Diabetes Subjects—Systematic Review and Meta-analysis of Prospective Studies
Authors: HOFFMEISTER MARIANA C. , FRIEDRICH EDUARDO P. , LOVISON VINÍCIUS H. , RODRIGUES TICIANA
Published: June 2024

Introduction & Objective: Office blood pressure (BP) measures may not identify early changes in BP that may indicate risk of development or progression of complications in diabetic individuals. The 24hour ambulatory blood pressure (ABP) offers more BP measures, including sleeping time. Our objective was to evaluate the ABP as a predictor of vascular outcomes in office normotensive patients with type 1 diabetes subjects (T1D) over time.

Methods: Systematic review with meta-analysis at Embase, PubMed/Medline and Web of Science database including cohort studies in normotensive T1D patients underwent to ABP at baseline and subsequent evaluation of vascular complications during follow-up. Measurements of difference (mmHg) were obtained using a random effect model for each variable of ABP (systolic and diastolic BP - day, night and 24h).

Results: Only 7 out of 364 articles were included, 635 participants were evaluated, age 25.8±6.2 years, 57% male, diabetes duration 11.8±5.3 years, HbA1c 8.5%±1.6, over 4.2 years. Lower nighttime systolic BP -4.37 mmHg (95%CI -6.96;-1.79, p0.0009, I²30%) and nighttime diastolic BP-3.97 mmHg (95%CI -5.85;-2.10, p <0.0001, I²0%,) at baseline were associated to renal protection. Lower nighttime diastolic BP -3.62 mmHg (95%CI -7.18;-0.06, p0.042, I²0%), daytime diastolic BP -2.69 mmHg (95%CI -4.84;-0.55, p0.0138, I²0%) and 24h diastolic BP -3.65 mmHg (95%CI -6.56;-0.75, p0.037, I²0%) were associated with better ocular outcomes. Macrovascular and neuropathy outcomes were not found.

Conclusion: In T1D patients lower nocturnal BP values ​​were associated with better microvascular outcomes. The office BP would not be able to identify these cases. ABP should be included in the care of patients with diabetes.

Disclosure

M.C. Hoffmeister: None. E.P. Friedrich: None. T. Rodrigues: None.

Funding

CAPES and CNPq
18-OR: The Effect of a Dietary Intervention on Insulin Sensitivity in Type 1 Diabetes and the Role of Dietary Advanced Glycation End-Products—A 12-Week Randomized Clinical Trial
Authors: KAHLEOVA HANA , ZNAYENKO-MILLER TATIANA , BARNARD NEAL
Published: June 2024

Background: This study compared the effect of a low-fat vegan diet with a portion-controlled diet on insulin sensitivity in people with type 1 diabetes and explored the role of dietary advanced glycation end-products (AGEs).

Methods: Fifty-eight adults with type 1 diabetes were randomly assigned to a vegan (n=29), or a portion-controlled group (n=29) for 12 weeks. Insulin sensitivity was assessed, using the carbohydrate to insulin ratio. The content of all meals was recorded using the Cronometer mobile application. Total insulin dose was calculated as a sum of basal and bolus insulin units injected per day.

Results: Insulin sensitivity increased in the vegan group by 6.6 (p=0.002), compared with no significant change in the portion-controlled group (-1.6; p=0.26; treatment effect +8.2 [95% CI, +3.6 to +12.8]; p=0.001). Total dietary AGEs decreased in the vegan group by 7,123 ku/day (95% CI, -9,493 to -4,756; p<0.001), compared with no significant change in the portion-controlled group (treatment effect -5,076 ku/day [95% CI, -8,605 to -1,548]; p=0.006). Change in total dietary AGEs correlated negatively with changes in insulin sensitivity (r=-0.48; p=0.004) and remained significant after adjustment for changes in BMI (r=-0.35; p=0.048). A 1-unit increase in insulin sensitivity was associated with a reduction in dietary AGEs by 2,090 ku/day.

Conclusions and Interpretation: This study suggests that a low-fat vegan diet improves insulin sensitivity in people with type 1 diabetes compared with a portion-controlled diet, and the reduction in dietary AGEs seems to be one of the mediating mechanisms. Larger trials are needed to confirm these findings.

Disclosure

H. Kahleova: None. T. Znayenko-Miller: None. N. Barnard: None.

Funding

Institute for Technology in HealthcarePhysicians Committee for Responsible Medicine
1801-LB: Discovering Novel Cathepsin L Inhibitors Using Artificial Intelligence for Diabetic Nephropathy
Authors: LI QI
Published: June 2024

Introduction & Objective: Cathepsin L (CTSL) has been demonstrated to play a significant role in the pathogenesis and progression of Diabetic Nephropathy (DN). However, there are currently no CTSL inhibitors available for clinical use. This study utilizes artificial intelligence models to discovering novel CTSL inhibitors and explores their application in DN.

Methods: We developed a neural network model to predict the inhibitory potential of molecules against CTSL activity. This model was then applied to a library of biologically active compounds and conducted activity assays on the top-ranked molecules. We then co-treated HK2 cells with selected CTSL inhibitors and free fatty acids to observe changes in epithelial-mesenchymal transition and inflammation levels between the medicated and normal groups.

Results: We identified five small molecules significantly reduced the activity of CTSL in a live-cell system at the nanomolar level. Notably,10μM of S7391 significantly reduced CTSL expression levels in HK2 cells, while restoring the levels of epithelial-mesenchymal transition-related genes and inflammatory factors to those of the control group.

Conclusion: We successfully developed a deep learning model capable of predicting whether small molecule compounds can inhibit the enzymatic activity of CTSL and identified five small molecules that can inhibit CTSL's enzymatic activity at the nanomolar level. Among these, S7391 was able to reverse renal tubular damage induced by free fatty acids, indicating its potential as a therapeutic drug for diabetic kidney disease through the inhibition of CTSL activity.

Disclosure

Q. Li: None.

Funding

National Natural Science Foundation of China (81930019)
1810-LB: Diagnostic Accuracy of Automated Pupillometry for Diabetic Retinopathy Screening
Authors: GAJARDO ABRAHAM I.J. , SANDOVAL DANIELA B. , VIDAL RODRIGO , BRAVO MIGUEL , ULLOA VIVIANA E. , ROJAS VERONICA , ZAMORANO NICOLLAS A. , SARAVIA GÉNESIS , GOMEZ PATRICIA C. , MORAL MACARENA , NIVELO MONICA
Published: June 2024

Introduction: Diabetic retinopathy (DR) is a major and preventable cause of blindness. Although regular fundoscopic examination (FE) is recommended to detect DR, screening coverage remains low in Latin America, the USA, and other regions, supporting the need for new screening tools. Because pupillary reactivity to a short light stimulus is decreased in patients with DR, this study aimed to assess the diagnostic accuracy of automated pupillometry (AP), an inexpensive tool, for DR screening in type diabetes mellitus (T2DM) patients.

Methods: Diagnostic accuracy study performed prospectively in 93 adults with T2DM (186 eyes) referred for FE from three public primary care health centers in Santiago, Chile. Patients underwent a clinical evaluation, AP assessment, and FE during the same visit. AP was performed to obtain three valid trials by eye with a clinical pupilometer. For DR diagnosis, pupil-dilated eye fundus images were taken with a retinal camera and later informed by an ophthalmologist. Patients and AP/FE operators were blind to FE/AP data. The diagnostic accuracy of AP for DR was assessed by the area under the curve (AUC), sensitivity, specificity, and predictive values (PV).

Results: 50% females, 64±10 years old, 68% hypertension, 34% insulin users. Frequency of DR was 22%. All AP-derived parameters were lower in those with DR (p-value<0.001). Of all eye assessments, 75% had increased the inverse of basal pupillary diameter (BPD-1), 12% had a decreased pupillary constriction (PC) and 51% had both parameters altered. The AUC, sensitivity, specificity, negative PV, and positive PV for DR were, respectively: 0.778, 95%, 32%, 27%, and 96% for BPD-1 and 0.765, 43%, 96%, 76%, and 86% for PC. Only 4% of patients with a conserved BPD-1 and 7% of those with a conserved BPD-1 or PC had DR.

Conclusion: This study proves for the first time that AP is a viable screening tool for DR, with a sensitivity and negative PV of about 95%. Further studies are needed to confirm if AP avoids FE or helps triage diabetics waiting for FE.

Disclosure

A.I.J. Gajardo: None. R. Vidal: None. M. Bravo: None. V. Rojas: None. G. Saravia: None. P.C. Gomez: None. M. Moral: None.

Funding

National Fund for Research and Development in Health, FONIS N? SA21I0148, National Agency of Investigation and Development (ANID), Government of Chile.
1814-LB: Hypertriglyceridemic-Waist Phenotype Is Associated with Diabetic Foot Ulcer in Chinese Patients with Type 2 Diabetes
Authors: LIU ZHENYU , ZHANG LEI , WANG MEILING , ZHANG QI , LIU YUQING , DONG YANHU
Published: June 2024

It is still unclear whether the hypertriglyceridemic-waist (HTGW) phenotype is related to increased risk of diabetic foot ulcer (DFU) in Chinese patients with type 2 diabetes. A total of 2651 consecutive in-patients with type 2 diabetes (mean age 56±11 years, 58% women), with a mean duration of diabetes of 9.3 years, were included to identify the relationship. The diagnosis of HTGW was made if TG≧1.70mmol/L plus waist circumference≧90cm for men (or ≧80cm for women) according to the IDF criteria for the metabolic syndrome. The study population was then divided into HTGW subgroup and Non-HTGW subgroup. DFU was diagnosed according to guidelines on the diagnosis and treatment of foot infection in persons with diabetes (IWGDF 2019). Logistic regression analysis was applied to relate HTGW phenotype to DFU. The prevalence of DFU was 9.3% and 4.2% respectively in patients with and without HTGW. Compared with participants who had no HTGW, those with the HTGW phenotype had higher levels of systolic blood pressure (139.2 mmHg vs. 132.7 mmHg, p<0.05), fasting plasma glucose (9.1 mmol/L vs. 8.5 mmol/L, p<0.05), HbA1c [73 mmol/mol (8.83%) vs. 63 mmol/mol (7.95%), p<0.05], apolipoprotein B ( 0.95 g/L vs. 0.89 g/L, p<0.05), C-reactive protein (8.23 mg/L vs. 4.92 mg/L, p<0.05), and TNF-α ( 26.46 pg/ml vs. 16.80 pg/ml, p<0.05) but lower levels of apolipoprotein A1 (1.21g/L vs. 1.33g/L, p<0.05). The hypertriglyceridemic-waist phenotype was associated with DFU (OR 1.33, 95% CI 1.03-2.71), after adjusting for age, sex, duration of diabetes, body mass index, smoking, HbA1c, apolipoprotein B and C-reactive protein. Among patients with type 2 diabetes, simultaneous measurement of waist circumference and triglycerides could be used as an inexpensive and simple approach to identify individuals with increased risk of DFU.

Disclosure

Z. Liu: None. L. Zhang: None. M. Wang: None. Q. Zhang: None. Y. Liu: None. Y. Dong: None.

Funding

IDF BRIDGES Researchnet Grant (rn13-016)
1839-LB: A Randomized Crossover Study Comparing the Effects of Diabetes-Specific Formula with Asian Breakfasts on Glycemic Control and Satiety in People with Type 2 Diabetes
Authors: TEANG KONG SING , HUYNH DIEU , SRIVANICHAKORN WEERACHAI , KHOVIDHUNKIT WEERAPAN , PAUNIKAR SWAPNIL L. , YALAWAR MENAKA , LING TEY SIEW
Published: June 2024

Introduction & Objective: Medical nutrition therapy including diabetes-specific formula (DSF) is important for diabetes management. This study aimed to evaluate the effects of consuming a DSF in comparison to two common Asian breakfasts on postprandial glucose, insulin, and satiety in people with type 2 diabetes (T2D).

Methods: This was a randomized, crossover study with three treatments; DSF, noodle soup (NS), and glutinous rice (GR). Blood glucose, insulin, and subjective appetite were assessed at 0, 15, 30, 45, 60, 90, 120, 150, and 180 min. Sixty-four adults with T2D (7% ≤ HbA1c < 10%) and taking oral glucose-lowering drug were randomized and completed this study. Each continuous variable was analyzed using parametric or nonparametric (if declared non-normal) three-treatment three-period crossover analysis. All hypothesis tests were done using 2-sided, 0.05 level tests.

Results: The mean ± SD age was 54.5 ± 1.0 years, body mass index was 27.6 ± 0.5 kg/m2, and HbA1c was 7.8 ± 0.8%. Glucose positive area under the curve from 0 to 180 min (pAUC0-180) for DSF was significantly lower than GR (LSM ± SE: DSF 354 ± 32 vs. GR 451 ± 32, p = 0.033). Insulin pAUC0-180 was significantly lower with DSF compared to GR (Median [25th, 75th percentile]: DSF 2733 [1542, 4204] vs. GR 3359 [2193, 4744]), p = 0.042). There were no significant differences in glucose and insulin pAUC0-180 between DSF and NS, and between GR and NS (both p ≥ 0.216). No significant differences were found in subjective appetite between any of the three treatments (all p ≥ 0.827). The estimated time for hunger returning to baseline was the shortest for NS (165 min), which was 20 and 30 minutes earlier than DSF (186 min) and GR (197 min).

Conclusion: DSF significantly reduced postprandial glucose and insulin responses compared with GR and had a higher satiating value when compared to NS.

Disclosure

S. Kong: Employee; Abbott Nutrition. D. Huynh: Employee; Abbott Nutrition. W. Srivanichakorn: Research Support; Abbott. Other Relationship; Merck & Co., Inc., AstraZeneca, Boehringer-Ingelheim. W. Khovidhunkit: Advisory Panel; Amgen Inc., Novartis AG. Speaker's Bureau; Novo Nordisk, AstraZeneca. Other Relationship; Abbott. Advisory Panel; Daiichi Sankyo. Speaker's Bureau; Meiji. S.L. Paunikar: Employee; Cognizant Technology Solutions Private Limited. M. Yalawar: Employee; Cognizant Technology Solutions India Private Limited. S. Tey: Employee; Abbott Nutrition.
1849-LB: Social Determinants of Health and Early-Onset Type 2 Diabetes—A Qualitative Study
Authors: JANG HYESUN , SUNG GOWOON , FAULKNER MELISSA S. , CHA EUNSEOK
Published: June 2024

Objective: To explore how social determinants of health (SoDH) affect disease perception and diabetes care in Koreans with early-onset type 2 diabetes (T2D).

Methods: A qualitative research study included 35 Koreans (54.29% men) out of 83 contacts, diagnosed with T2D prior to 40 years of age. Interviews lasted 40 to120 minutes, occurring between June 2023 and February 2024. The verbatim transcriptions of semi-structured interview data were analyzed using conventional content analysis.

Findings: The primary means of diabetes awareness was (bi)-annual free check-ups (42.86%) provided by the Korea National Health Insurance Service, followed by recognition of symptoms (22.86%), visits to the emergency room or clinic due to acute illness (22.86%), and follow-up check-ups after gestational diabetes (8.57%). Major themes identified were doomed, self-blamed or depressed. With a family history of diabetes, the patients often felt doomed or blamed themselves for not adopting a healthier lifestyle earlier despite being aware of their risk. Others without family history reported having limited knowledge of T2D. They expressed a sense of "why me," leading to negative emotions. Connecting with peers in the eCommunity brought relief, making them feel less isolated in their experiences. Since Koreans with early-onset T2D felt flawed due to a familial risk and their diagnosis, they felt inadequate about intimate relationships, including marriage and pregnancy. The timing and extent of disease disclosure to a partner depended on the level of relationship.

Conclusions: SoDH play a significant role in early screening, diagnosis and care possibly influencing diabetes remission. Peer norms and familial risk affect diabetes perception in this population. Emphasizing weight loss or a healthy lifestyle may unintentionally deepen the stigma by reinforcing feelings of self-blame. Clinical discussion and messages need to be framed to mitigate self-blame and encourage motivation for positive change.

Disclosure

H. Jang: None. G. Sung: None. M.S. Faulkner: None. E. Cha: None.

Funding

Korea Research Foundation (NRF2023R1A2C2004541)