bluuebunny/crossref_metadata_2025 huggingface dataset:
1647-P: Nonhuman Primate Obesity Model for the Translation of Target-Based Precision Medicine
Authors: JI SHAOHUI , ZHU ZHENGHUA , WANG GUANZHONG , GABRIEL JOSEPH A. , PEREZ ROSARIO M. , YANG LICHUAN
Published: June 2024

The prevalence of obesity has increased worldwide in the past few decades. Because of the similarity of their absorption, distribution, metabolism, and excretion profile compared to that of humans, non-human primates (NHP) models are highly valuable in predicting the clinical response to new drugs for obesity associated disease, particularly for biological products such as siRNA, oligo and antibodies. Reported here are our profiling of the characteristic features from > 2000 obese male cynomolgus monkeys (Macaca fascicularis), either spontaneous or induced with a KBI proprietary high fat diet (HFD). Multiple methods were used for the profiling, such as body weight, food intake, crown-rump length (for BMI calculation) measurement, MRI or DXA scanning for body fat, tissue biopsy, and clinical chemistry measurement. Based on the results from >200 monkeys, we have defined the reference range of BMI in healthy monkeys (20.05 to 36.73 kg/m2). Therefore, monkeys with BMI >40 kg/m2 were used for the obesity-related metabolic studies. Monkeys with BMI >40 kg/m2 were observed with significantly higher liver fat fraction (9.5 ± 4.8% vs 4.3 ± 0.5%, p <0.01) and % fat (42.36 ± 8.24% vs 18.47 ± 4.43%, p<0.0001) compared to monkeys with BMI <40 kg/m2. Compared with obese monkeys on low fat diet, the obese monkeys on HFD displayed more severe dyslipidemia and a greater incidence of diabetes and liver fibrosis. Furthermore, monkeys showed similar response as observed in humans after the administration of reference or test compounds, such as liraglutide, semaglutide, inclisiran, pioglitazone, empagliflozin etc. Significant reduction in food intake (-38.5 ± 14.4%) and body weight (-10.9 ± 4.7%) was observed after administration of Liraglutide for 6 weeks. Administration of a novel FGF21 analog for 11 weeks resulted a reduction in liver fat fraction (-40.3±18.8%). These findings indicate that our non-human primate obesity model is uniquely valuable for the translation of target-based precision medicine for humans.

Disclosure

S. Ji: None. Z. zhu: None. G. Wang: None. J.A. Gabriel: None. R.M. Perez: None. L. Yang: None.
1652-P: The Effectiveness of Semaglutide on Glucose Tolerance and Body Composition in Obese Diabetic Rhesus Monkeys
Authors: YANG ZUNYUAN , GONG LI , LIANG YINAN , YAO ZUNWEI , ZENG LICAI , WU MINGLING , YANG ZHENYAN , ZENG WEN
Published: June 2024

Introduction & Objective: This study aimed to investigate the changes of obesity severity, glucose metabolism, and body composition in obese and diabetic rhesus monkeys treated with semaglutide.

Methods: We enrolled 12 rhesus monkeys aged between 12-20 years with fasting plasma glucose (FPG) > 5.5 mmol/L, body weight (BW) ranging from 12-20 kg, and fat mass proportion between 20-55%, and randomly assigned them to 4 weeks of treatment with once-weekly subcutaneous semaglutide or placebo, followed by an 8-week washout period. The BW, waist circumference (WC), and metabolic parameters were examined. Body composition was measured using DEXA and MRI monthly. Proportions of total fat body mass (TFM) and total lean body mass (TLM) were shown relative to total body mass.

Results: At week 4, in semaglutide group, the changes in BW and WC from baseline were -14.82±2.73% and -12.4±9.3% (vs. placebo, P<0.001). This resulted in reductions from baseline in TFM (-24.08±14.21%, vs. 2.35±9.12% placebo; P=0.0025). TLM decreased from baseline (-7.32±3.37% vs. -0.12±5.99% placebo; P=0.0197); however, there was an increase from baseline in the muscle-to-weight ratio (13.15±7.03% vs. -1.24±5.35 placebo; P=0.0018) and the muscle-to-fat ratio (32.07±15.95% vs. -4.35±14.91% placebo; P=0.0014). Significant declines in FPG (-21.86±7.56% vs. 1.83±4.16% placebo, P=0.0000) and HOMA-IR (-62.46±18.11% vs. -10.58±39.49% placebo; P=0.0026) were noted compared to baseline.

Conclusion: These results suggest that semaglutide effectively improves glucose tolerance, reduces BW while increases proportion of TLM in obese T2DM rhesus monkeys. This nonhuman primate model showed similar response to GLP-1 receptor agonist in humans.

Disclosure

Z. Yang: None. L. Gong: None. Y. Liang: None. Z. Yao: None. L. Zeng: None. M. Wu: None. Z. Yang: None. W. Zeng: None.
1664-P: An Observation of an Increase in the Metabolic Syndrome Parameters after Stopping GLP-1RA Medications in STEP-4 and SURMOUNT-4 Trials
Authors: ALSAEED ABDULGHANI H.
Published: June 2024

Introduction and Objective: GLP-1 RA (Receptor Agonist) medications are commonly used by overweight and obese individuals for weight reduction, however, there is still a question about the metabolic consequences of stopping these agents.

Methodology: Exploring the metabolic parameters in those who switched to placebo in two large clinical trials (STEP-4 and SURMOUNT-4).

Results: In SURMOUNT-4 trial, after one year of stopping Tarazepide; there was an increase of metabolic syndrome parameters in the switched placebo group as follows; an increase in waist circumference by a mean of 8.3cm(7.4to9.2), raised in HbA1c by 0.25%(0.22to0.28), an increase of fasting blood sugar by 7.7mg/dl(6.6to8.8), systolic BP by 8.4mmHg(7.2to9.7), and an increase of triglyceride by 15.6%(10.9to 20).In the STEP-4 trial, stopping semaglutide for 48 months, there were similar adverse effects on metabolic syndrome parameters in the switched placebo group. The waist circumference increased by 3.0cm(2.1to4.0), fasting blood sugar increased by 7.1mg(6.0 to 8.2), HbA1c by 0.1%(0.1to0.1), systolic BP by 4.9mmHg(3.3to6.5), and Triglyceride by 9%(4to14). The level of HDL cholesterol was increased in both groups (+18 for the semaglutide group, and +19 for the switched placebo group) which might indicate that both groups were highly motivated to do physical activities as part of the clinical trial.

Conclusion: Most of the metabolic syndrome parameters were found to be adversely increased after stopping GLP-1RA medications in individuals without diabetes mellitus. Such observation warrants further studies to check the safety of stopping such medications once used for individuals who are not affected by T2DM.

Disclosure

A.H. Alsaeed: Advisory Panel; Abbott. Speaker's Bureau; Sanofi. Advisory Panel; Novo Nordisk. Speaker's Bureau; Eli Lilly and Company, Boehringer-Ingelheim.
1665-P: Analysis of Glucose Biomarkers in Phase I and Phase II Studies of Survodutide in People with Type 2 Diabetes or Living with Overweight/Obesity
Authors: EKINCI ELIF I. , ARRUBLA MARTINEZ JORGE , HENNIGE ANITA M. , SCHÖLCH CORINNA
Published: June 2024

Introduction & Objective: Survodutide, a glucagon receptor/glucagon-like peptide-1 receptor (GCGR/GLP-1R) dual agonist, elicited greater HbA1c reduction up to -1.71% vs semaglutide 1 mg (-1.47%) in a Phase 2 trial in patients with type 2 diabetes. This analysis evaluated changes in insulin sensitivity, pancreatic islet cell function, and glucose biomarkers from three Phase I/II trials of survodutide.

Methods: Descriptive statistics were derived from a Phase 2 trial in patients living with obesity/overweight without diabetes (NCT04667377), a Phase 2 trial in patients with type 2 diabetes (NCT04153929), and a Phase 1 study in patients living with obesity/overweight (NCT03591718).

Results: High survodutide doses improved insulin sensitivity as reflected in a decrease in mean absolute HOMA-IR scores from baseline (BL) to the end of treatment (EOT), in contrast to no change or increase with placebo (PBO): NCT04667377, -1.1 (4.8 mg QW) vs -0.2 at Week 46; NCT04153929, -0.9 (1.8 mg twice weekly [BIW]) vs 0.9 at Week 17; and NCT03591718, -1.0 (2.4 mg BIW following up titration) vs 0.3 at Week 16. Survodutide improved HOMA-β, with mean percentage change from BL to EOT consistently higher vs PBO: NCT04667377, 8.6% vs -1.1%; NCT04153929, 88.0% vs 18.0%. In NCT04667377, change from BL to Week 46 in FPG with survodutide vs PBO was 0.4 vs 0.0 mmol/L. Change from BL in insulin and non-fasting plasma glucose levels with survodutide 4.8 mg vs PBO, was -23.4 vs 0.4 pmol/L and -0.0 vs 0.6 mmol/L, respectively. Additionally, mean change from BL to Week 46 in adiponectin, glucagon, and c-peptide levels with survodutide 4.8 mg vs PBO was 1.9 vs

-0.15 mg/L, -15.2 vs -0.8 pmol/L, and -0.1 vs 0.0 nmol/L, respectively.

Conclusion: Survodutide treatment showed improvement in markers of insulin sensitivity, pancreatic islet cell function, and glucose biomarkers, in patients living with obesity/overweight and those with type 2 diabetes.

Disclosure

E.I. Ekinci: Advisory Panel; Lilly Diabetes. Research Support; Novo Nordisk, Boehringer-Ingelheim, Eli Lilly and Company. Board Member; Eli Lilly and Company. Advisory Panel; Abbott. Research Support; Endogenex, Versanis, AstraZeneca. J. Martinez: Employee; Boehringer-Ingelheim. A.M. Hennige: Employee; Boehringer-Ingelheim. C. Schölch: Employee; Boehringer-Ingelheim.

Funding

Boehringer Ingelheim
167-OR: Targeting Alpha Cells to Treat Hypoglycemia in Type 1 Diabetes
Authors: PANZER JULIA , LANG ANNA L. , PUGLIESE ALBERTO
Published: June 2024

Increased glucagon release from alpha cells is the main defense against hypoglycemia, a mechanism lost in Type 1 Diabetes (T1D). We hypothesize that the absence of neighboring beta cells, and consequently the loss of their inhibitory signals, plays a crucial role in the impaired responsiveness of alpha cells to hypoglycemic conditions. We conducted experiments using isolated islets and pancreatic tissue slices from both nondiabetic organ donors and donors with T1D, revealing significant differences between slices and islets. Despite a decline, isolated islets exhibited residual insulin secretion similar to healthy islets, a phenomenon absent in slices. This discrepancy may imply a survival bias during isolation or the influence of the microenvironment, undetectable when using isolated islets. Unlike beta cells, alpha cells did not faithfully track glucose concentrations and their responses were transient, contrasting with the sustained responses of beta cells. Without inhibitory input reset, alpha cells couldn't mount subsequent responses. Remarkably, activating paracrine signals inhibiting alpha cells successfully restored glucagon secretion, with complete recovery observed after a 15-minute or longer reset using high glucose in healthy islets. In tissues from T1D donors, alpha cells failed to respond to declining glucose levels despite maintaining normal glucagon content. We systematically explored the inhibitory effects of three paracrine signaling molecules—serotonin, somatostatin, and GABA, and their potential to revive glucagon secretion. Surprisingly, all molecules demonstrated the ability to increase glucagon secretion in response to low glucose, contrary to anticipated inhibitory responses. This resulted in a significant sustained increase even after stimulus removal. Building on these insights, our latest findings show that these paracrine signaling molecules can rescue glucagon secretion in T1D.

Disclosure

J. Panzer: None. A.L. Lang: None. A. Pugliese: Advisory Panel; Provention Bio, Inc.

Funding

American Diabetes Association (4-22-PDFPM-12); The Leona M. & Harry B. Helmsley Charitable Trust (Grant#2018PG-T1D053, G-2108-04793)
1689-P: Clinical Outcomes among Nondiabetic Obese Population with Concomitant Protein-Calorie Malnutrition—A Nationwide Study
Authors: KISHORE SINDHU , KHOKHLOV LEONID , AJENAGHUGHRURE GODBLESS E. , MATEO FERNANDO R. , KISHORE GEHNA , IKPEZE TOCHUKWU , RAJBHANDARI PRANITA , RAI SHILPA , MISHRA AAVASH
Published: June 2024

Introduction & Objective: Obesity, a disease increasing cardiometabolic risks and mortality, often accompanies protein-calorie malnutrition (PCM). PCM has been associated with delayed recovery from diseases. This study explores clinical outcomes in obese patients without DM co-diagnosed with PCM. 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 PCM 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 11,979,333 obese adults without DM, 1.5% had PCM who were predominantly white males. The study compared PCM and non-PCM groups, revealing higher rates in % in the PCM group for conditions like anemia (26.8 vs 13.4), dyslipidemia (33 vs 31.6) pulm HTN (7 vs 4), HF (26.6 vs 16), Afib (22.8 vs 13.7), PVD (3.7 vs 2.1), ACS (5.4 vs 4.3), COPD (21.4 vs 14.6), CKD (21.9 vs 11), PE (7.8 vs 5) and incidence alcohol use (8.4 vs 4.5). The former group also had worse primary and secondary outcomes as detailed in Table 1. The findings underscore the importance of obesity management in such populations for better clinical outcomes and prognosis.

Disclosure

S. Kishore: None. L. Khokhlov: None. G.E. Ajenaghughrure: None. F.R. Mateo: None. G. Kishore: None. T. Ikpeze: None. P. Rajbhandari: None. S. Rai: None. A. Mishra: None.
169-OR: LC3+ Extracellular Vesicles (EVs) Are Associated with Altered ß-Cell Autophagy, Islet Inflammation, and Diabetes
Authors: XU JERRY , AUSTIN MATTHEW , LINNEMANN AMELIA K. , SIMS EMILY K.
Published: June 2024

Introduction: EVs, nanoparticles housing molecular cargo, change based on parent cell health and contribute to cell-cell communication. Yet, mechanisms governing changes and physiological significance of β cell EV cargo remain unclear. Autophagy is a critical intracellular degradation and recycling process to clear damaged cellular components. EV-autophagy crosstalk is an emerging area of interest with implications for both physiological and pathological states. We have described altered β cell autophagy associated with islet inflammation and type 1 diabetes (T1D). Based on this and reports of autophagy machinery such as LC3 in EVs from other systems, we hypothesized that changes in the LC3+ EV population could yield insight into β cell autophagy.

Methods: Small EVs (<200nm) were isolated from INS-1 and EndoC β cells, islets, or plasma using tetraspanin (CD9, CD81, CD63) or LC3 antibody-based bead pulldown and quantified with flow cytometry.

Results: We detected LC3 on the surface of EVs from β cells and normal islets. EV LC3 staining was also significantly increased by 24-hr treatment with 10 ng/mL IL-1β or 10μM caffeic acid phenethyl ester, a neutral sphingomyelinase-2 activator linked to regulation of EV subpopulations during inflammatory stress. Alternatively, LC3 staining was reduced in islet EVs from mice with β cell deletion of the critical autophagy enzyme ATG7, linking LC3+ EVs to autophagosome formation. LC3 pulldown specifically isolated β cell EVs and demonstrated the presence of proinsulin in LC3+ EVs. Finally, LC3 staining was significantly increased in plasma EVs of 20 children with new-onset T1D compared to age, sex, and BMI matched controls.

Conclusion: LC3 is present on the surface of β cell EV membranes, and both β cell and circulating EV LC3 are impacted by defects in autophagy, islet inflammation, and T1D. Future studies will determine whether and how the population of LC3+ EVs participate in specific stages of autophagy or β cell pathophysiology.

Disclosure

J. Xu: None. M. Austin: None. A.K. Linnemann: None. E.K. Sims: Consultant; Sanofi. Board Member; American Diabetes Association. Other Relationship; American Diabetes Association, Medscape. Consultant; DRI.
1692-P: Prevalence, Characteristics, and Clinical Burden among Patients with Overweight or Obesity and Established ASCVD in a U.S. Real-World Setting
Authors: MICHALAK WOJCIECH , BOAME NANA , ZHAO XIN , LAMARRE NEIL , RAVA ANDREW , DOAN QUAN V. , FAURBY MADS , O HARTAIGH BRIAIN , FABRICATORE ANTHONY , ZHAO ZHENXIANG
Published: June 2024

This study aimed to estimate the prevalence of overweight or obesity (Ov/Ob; BMI ≥ 25.0 kg/m2) in individuals with established ASCVD (eASCVD; included MI, stroke, and PAD) and to compare patient characteristics and clinical burden of this population to those with eASCVD and normal weight (NW; BMI 18.5 - 24.9 kg/m2). The IQVIA’s US claims-linked EHR database (2017-2022) was used to include patients with eASCVD (index date). Prevalence was calculated based on the latest BMI in the 12 months before index (baseline). Characteristics and clinical burden in the baseline period were compared among patients with eASCVD, with vs. without Ov/Ob. Of 28,021 patients with eASCVD, the prevalence of Ov/Ob was 80.7% (95% CI: 80.2%; 81.2%). Those with Ov/Ob were more frequently male (59.1% vs. 44.6%, p<0.001), had higher triglycerides (152 vs. 116 mg/dL, p<0.001) and lower HDL levels (50.3 vs. 63.1 mg/dL, p<0.001), and had a higher prevalence of several cardiometabolic comorbidities compared to those with NW (Figure 1). Among patients with eASCVD, Ov/Ob was highly prevalent, it was associated with an adverse lipid profile and increased prevalence of additional metabolic disease, including MAFLD, OSA, and type 2 diabetes. Treating excess adiposity in this population may confer benefits beyond managing ASCVD.

Disclosure

W. Michalak: Employee; Novo Nordisk. Stock/Shareholder; Novo Nordisk, Eli Lilly and Company. N. Boame: None. X. Zhao: None. N. Lamarre: Consultant; Novo Nordisk. A. Rava: Other Relationship; Novo Nordisk. Employee; Genesis Research Group. Q.V. Doan: Consultant; Novo Nordisk, Daiichi Sankyo, Akebia Therapeutics, Inc., AbbVie Inc. M. Faurby: Employee; Novo Nordisk. B. O Hartaigh: Employee; Novo Nordisk A/S. A. Fabricatore: Employee; Novo Nordisk. Stock/Shareholder; Novo Nordisk. Z. Zhao: None.
1703-P: Integrated Transcriptome, Proteome, Metabolome, and Microbiome Analyses Identify Multiomics Signature of Glycolipid Metabolism Disorder—A Cross-Sectional Study
Authors: FANG XINYI , MIAO RUNYU , WU HAORAN , ZHANG YANJIAO , TIAN JIAXING
Published: June 2024

Introduction: The prevalence of glycolipid metabolism disorder continues to increase globally and has become a serious threat to human health. Multi-omics provide unprecedented insights into the underlying pathophysiological mechanisms of glycolipid metabolism disorder and identifying potential biomarkers and therapeutic targets.

Methods: We collected blood/stool samples from 30 patients with type 2 diabetes and dyslipidemia (GL), 30 patients with hyperlipidemia (HL), and 30 healthy controls, conducted transcriptome/proteome/metabolome/microbiome analysis, and correlated it with clinical phenotypes. We further integrated multi-omics features and tested the discriminant efficacy of multi-omics datasets using receiver operating characteristic curves.

Results: Among patients with GL, insulin like growth factor binding protein 3 (IGFBP3) in the p53 signaling pathway was highly expressed at both the transcription and protein levels. Joint analysis of proteomics and metabolomics confirmed the link between fructose-bisphosphate aldolase B and altered N-acetylornithine metabolism in the amino acid biosynthetic pathway. The gut microbiota dysbiosis in patients with GL was characterized by a significantly reduced abundance of short-chain fatty acids-producing bacteria, and this reduction was related to a decrease in dodecanoic acid. The extracellular matrix-receptor interaction pathway was associated with HL, and collagen type I alpha 1 chain in this pathway was lowly expressed at both the transcription and protein levels. The abundance of Parabacteroides gordonii was significantly reduced in patients with HL. Matrix metallopeptidase 2 and IGFBP3, key differential molecules between GL and HL, were highly expressed at both the transcription and protein levels.

Conclusion: This study revealed the multi-omics signature and key drivers of glycolipid metabolism disorder.

Disclosure

X. Fang: None. R. Miao: None. H. Wu: None. Y. Zhang: None. J. Tian: None.

Funding

Capital Health Development Research Project (CD2020-4-4155); CACMS Outstanding Young Scientific and Technological Talents Program (ZZ13-YQ-026); Scientific and technological innovation project of China Academy of Chinese Medical Sciences (CI2021A01601); Open Project of National Facility for Translational Medicine (TMSK-2021-407); CACMS Guang'anmen Hospital Sustainability Project-Young Top-Notch Talent Project (NO.CZ40907).
1705-P: Obesity Phenotype Exhibit Differential Signatures of Circulating Biomarkers with Susceptible Obesity-Related Comorbidities
Authors: QI WEIER , TU XIAO , ROBERTSON DARREN , ACOSTA ANDRES , PARKER VICTORIA E.
Published: June 2024

Background: Obesity is a heterogeneous disease with different phenotypes based on physiological and biological differences in energy intake and expenditure. A recent study determined that guided therapy based on the classification of obesity phenotypes achieved better outcomes with respect to body weight loss (Acosta et al 2021). We aimed to identify potential circulating biomarkers to predict phenotypes and susceptibility to comorbidities.

Methods: In a randomized placebo-controlled study which enrolled overweight and obese participants with T2DM, 18 subjects was subphenotype into 3 groups: hungry brain (HB) N=5, hungry gut (HG) N=5 and slow burn (SB) N=5 and unclassified N=3. Global plasma metabolomics and proteomics analysis were performed at baseline to identify the molecular signatures associated with each phenotype.

Results: In the metabolomics analysis with p<0.05 cutoff, SB had lower homocysteine by 46% vs. HB. In contrast, SB had higher levels of proline, Lauroyl-L-carnitine and DL-2-Aminocaprylic acid (by 43%, 385% and 476% respectively) vs. HB. Consistently, SB had also increased levels of proline by 43% p<0.43 vs. HG. In the proteomics analysis with p<0.05 cutoff, Apolipoprotein M (APOM) decreased in SB by 39% with concomitant lipid oxidation protein (PCYNOX1) decreased by 40% vs. HB. Lower CV risks biomarkers of homocysteine and PCYNOX1 have been observed in SB. In contrast, SB had higher levels of liver collagen synthesis, and liver fat accumulation biomarkers (proline, Lauroyl-L-carnitine, and DL-2-Aminocaprylic acid.

Conclusions: These results suggest there may be some differential circulating biomarkers in different phenotypes that are susceptible to comorbidity differences such as CV and NASH-related risks. Further exploration of these differences may help better

understand metabolic mechanisms in these groups and permit more targeted therapy in the future. Larger studies are required to substantiate these findings.

Disclosure

W. Qi: Employee; AstraZeneca. X. Tu: Employee; AstraZeneca. D. Robertson: Employee; AstraZeneca. Stock/Shareholder; AstraZeneca. 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. V.E. Parker: Employee; AstraZeneca. Stock/Shareholder; AstraZeneca.
1734-P: ADP Privation of Human Beta-Cell Mitochondria by Pyruvate Kinase
Authors: RUZ-MALDONADO INMA , CARDONE REBECCA L. , KIBBEY RICHARD
Published: June 2024

Introduction & Objective: A revised mechanism for glucose stimulated insulin secretion (GSIS) in beta-cells endorses that pyruvate kinase (PK) outcompetes oxidative phosphorylation (OxPhos) for ADP and generate the ATP/ADP ratio to close KATP channels. Here we investigate how PK deprives mitochondria of ADP.

Methods: Competition between OxPhos vs. PK for ADP was assessed by monitoring OxPhos-dependent oxygen consumption rate (OCR) in intact and permeabilized human islets using allosteric, nutrient modulation of enzyme and mitochondrial function including substrate transport.

Results: Up and down titration of mitochondrial coupling ruled out significant substrate-driven OxPhos. Phosphoenolpyruvate (PEP) decreased OxPhos-dependent OCR in a dose-dependent manner when ADP was limiting (33±0.6, 40±1.3 and 59±0.7% reduction by PEP at 156, 313 and 625µM, respectively; p<0.0001). At submaximal PEP, the PK activator PKa1 further reduced respiration 10µM (55±2.3% reduction respect to PEP; p<0.01). At maximal PEP, 4mM of the PK inhibitor L-phenylalanine partially improved OxPhos by 65±1.8% (p<0.0001). Likewise, 10mM creatine rescued OCR by 35% (p<0.0001) OxPhos by regenerating intramitochondrial ADP. PEP inhibition of OxPhos required 1) PEP hydrolysis to pyruvate by PK, 2) ADP/ATP exchange, and 3) ADP privation but 4) did not inhibit leak pathways 5) regardless of whether electrons entered at Complex I, II, III, or IV.

Conclusion: PEP metabolism by PK starves OxPhos by ristricting mitochondrial ADP availability in human beta-cells. These data are consistent with the newly proposed role for PEP and PK regulating the ATP/ADP mediated closure of KATP channels during GSIS.

Disclosure

I. Ruz-Maldonado: None. R.L. Cardone: None. R. Kibbey: None.

Funding

5R01DK127673-02
1741-P: The Type 2 Diabetes–Associated K+ Channel TALK-2 Is Localized to the Endoplasmic Reticulum and Modulates Beta Cell Ca2+ Handling and Insulin Secretion
Authors: DOBSON JORDYN , DADI PRASANNA , NAKHE ARYA Y. , JACOBSON DAVID
Published: June 2024

Introduction and Objective: KCNK17, which encodes TALK-2, is one of the most abundant β-cell K+ channel transcripts. Polymorphisms in KCNK17 are associated with an increased predisposition for developing T2D. Therefore, our objective was to determine the β-cell functions of TALK-2.

Methods: Localization of TALK-2 was investigated with immunofluorescent staining and TALK-2-GFP constructs. TALK-2 function was tested with Ca2+ imaging of inducible TALK-2 cells, adenoviral KCNK17 shRNA mediated knockdown (KD) of dispersed human islets, and β-cell TALK-2 KD pseudoislets. Insulin secretion was performed with pseudoislets.

Results: TALK-2 protein displayed ER localization in β-cells within human pancreatic sections. Additionally, TALK-2-GFP colocalized with an ER-RFP marker and a plasmalemma dye in HEK293 cells. Overexpression of TALK-2 in HEK293 cells accelerated ER Ca2+ release (by 62±13%), reduced ER Ca2+ storage (by 67±12%) and increased basal cytosolic Ca2+ (by 11±0.5%). In human β-cells TALK-2 KD increased ER Ca2+ storage (by 16±5%). Moreover, TALK-2 KD increased Ca2+ influx at 11mM glucose in human β-cells that were dispersed (by 20±6%) and in pseudoislet preps (by 208±64%). Finally, β-cell TALK-2 KD pseudoislets showed reduced insulin secretion at 1mM (by 36±10%).

Conclusion: These data support that ER and plasmalemma localized TALK-2 channels function to reduce β-cell ER Ca2+ stores and limit glucose-induced Ca2+ influx respectively. Furthermore, TALK-2-mediated augmentation of ER Ca2+ leak likely enhanced basal insulin secretion by increasing cytosolic Ca2+. Therefore, polymorphisms in KCNK17 that increase TALK-2 activity or expression would be predicted to diminish β-cell ER Ca2+ stores, impair glucose-stimulated Ca2+ influx, elevate basal insulin secretion, and thus enhance insulin resistance.

Disclosure

J. Dobson: None. P. Dadi: None. A.Y. Nakhe: None. D. Jacobson: None.

Funding

Initiative for Maximizing Student Development at Vanderbilt (T32GM139800)Multidisciplinary Training in Molecular Endocrinology(T32DK007563); National Institutes of Health (DK-097392)
176-OR: Association between Clustering of Hypoglycemic Symptoms, Psychological Traits, and Problem-Solving Abilities in Adults with Type 1 Diabetes
Authors: SAKANE NAOKI , SAKANE SEIKO
Published: June 2024

Background: Precision medicine in diabetes care requires a dedicated focus on hypoglycemic symptoms. This study aimed to explore the interrelationship between the clustering of hypoglycemic symptoms, psychological characteristics, and problem-solving capabilities in adults with type 1 diabetes (T1D).

Methods: A total of 251 adults with T1D (mean age: 51.5±12.9 years, mean HbA1c: 7.7 ± 0.9%) participated in this survey. Hierarchical clustering was employed to analyze eleven hypoglycemic symptoms (Edinburgh). Data encompassed diabetic complications, fear of hypoglycemia (HFS-behaviour and HFS-worry), depressive symptoms (PHQ-9), the hypoglycemia problem-solving scale (HPSS), and treatment details.

Results: Three distinct clusters emerged: individuals not sensitive to autonomic and neuroglycopenic symptoms (cluster 1, n=138), those sensitive to both autonomic and neuroglycopenic symptoms (cluster 2, n=19), and those sensitive to autonomic but not to neuroglycopenic symptoms (cluster 3, n=94). Compared to cluster 1, clusters 2 and 3 exhibited younger ages, higher fear of hypoglycemia, increased depressive symptoms, and greater use of CSII. Cluster 2 also displayed enhanced HPSS scores, indicating better detection control and a more proactive approach to seeking preventive strategies compared to cluster 1. No significant differences were observed in terms of diabetes duration, BMI, HbA1c levels, or diabetic complications. However, certain lifestyle factors, such as breakfast skipping, snack and sweetened beverage intake, and sleep deficits, varied among the clusters.

Conclusion: This study identifies three distinct clusters among adults with T1D. The findings may serve as valuable insights for diabetes professionals seeking to educate these individuals on how to effectively manage hypoglycemia.

Disclosure

N. Sakane: None. S. Sakane: None.
1773-LB: Impact of SSTR2a Treatment in Hypoglycemia in Male (M) and Female (F) Rat Models of Type 2 Diabetes (T2D)
Authors: DSOUZA NINOSCHKA , ALEALI NADIA , SHAKERI DORSA , ATHERLEY SARA C. , HOFFMAN EMILY G. , KARIMI-CHAHARTASH SINA , JAVANBAKHSH SAHEL , CHAN OWEN , LIGGINS RICHARD , RIDDELL MICHAEL C.
Published: June 2024

Introduction: This study characterized a F rodent model of T2D and examined SSTR2a treatment in hypoglycemia in M and F rats with T2D.

Methods: A high fat fed streptozotocin-treated (35 mg/kg) T2D model (n=8-10/group) with impaired glucagon (GNC) counterregulation to hypoglycemia was characterized in terms of basal hyperglycemia and response to an oral glucose tolerance test (2 g/kg, OGTT). The effect of SSTR2a (3 mg/kg ZT-01) was assessed in F rats with 12 U/kg insulin-induced (aspart) hypoglycemia and compared to previously reported data for M.

Results: F had basal blood glucose 16.8 ± 5.3mmol/L and HbA1c (6.3 ± 0.6%) similar to T2D males. With OGTT, M and F glycemia were similar, but F had higher baseline c-peptide (F: 2.3 ± 0.7 vs M: 0.85 ± 0.5 ng/ml) and lower GNC (F: <5.2 vs M: 36 ± 28 ng/mL). M GNC declined during the OGTT to levels similar to F, which were unchanged throughout. ZT-01 increased GNC response in hypoglycemia which was greater in F than M (Fig).

Conclusion: We observed apparent sex-related differences to the hormonal responses to hyper- and hypoglycemia, and SSTR2a may increase glucagon responses more so in F rats with T2D.

Disclosure

N. DSouza: None. N. Aleali: None. D. Shakeri: None. E.G. Hoffman: None. S. Karimi-Chahartash: None. S. Javanbakhsh: None. O. Chan: None. R. Liggins: Employee; Zucara Therapeutics. Stock/Shareholder; Zucara Therapeutics. M.C. Riddell: Consultant; Eli Lilly and Company. Speaker's Bureau; Novo Nordisk. Advisory Panel; Supersapiens. Consultant; Dexcom, Inc. Speaker's Bureau; Sanofi. Advisory Panel; Zealand Pharma A/S. Speaker's Bureau; Dexcom, Inc. Stock/Shareholder; Zucara Therapeutics.

Funding

GlycoNet Strategic Initiatives (CD-85); Zucara Therapeutics Inc
1774-LB: The Glucagon Stimulating Effect in Hypoglycemia of Somatostatin Receptor 2 Antagonist (SSTR2a) Is Maintained with Repeat Dosing
Authors: DSOUZA NINOSCHKA , ALEALI NADIA , SHAKERI DORSA , ATHERLEY SARA C. , HOFFMAN EMILY G. , KARIMI-CHAHARTASH SINA , JAVANBAKHSH SAHEL , CHAN OWEN , LIGGINS RICHARD , RIDDELL MICHAEL C.
Published: June 2024

Introduction: A single dose of SSTR2a, ZT-01, reduces hypoglycemia exposure in diabetic rat models. However, the pharmacology of daily dosing in type 2 diabetes (T2D) rats has not been reported. The purpose of this study was to determine the effects of repeat ZT-01 dosing in a rat model of T2D with recurrent hypoglycemia.

Methods: In a high-fat-fed (HFF) low dose streptozotocin (35mg/kg) T2D rat model, ZT-01 was dosed daily (0.3 mg/kg/d) for 14 days (n=10-11/group). Rats underwent 4 insulin-induced (6-12 U/kg insulin aspart) hypoglycemic challenges 2-3 days apart, beginning on dosing day 8, with blood glucose and plasma glucagon and c-peptide measured over 2 hours post-insulin dose.

Results: ZT-01-treated rats showed improved glycemia with lower HbA1c vs controls (4.3 ± 0.9 vs 5.3 ± 0.8%, p<0.05) after 2-weeks of treatment. Glucagon response to hypoglycemia across all challenges was 9.7 ± 3.1 vs 22.6 ± 4.8-fold over baseline, with vehicle and ZT-01, respectively. ZT-01 reduced hypoglycemia exposure only in challenges 1 and 2, perhaps due to conditioning from antecedent hypoglycemia and a lower baseline blood glucose in challenge 4, particularly in the ZT-01-treated group (21.95 ± 5.4 vs 16.2 ± 6.3 mmol/L, p<0.05).

Conclusion: Daily dosing of SSTR2a resulted in a consistent increase in glucagon during repeated hypoglycemic challenges, and reduced hypoglycemia exposure in initial challenges. It may also improve overall glycemia in this T2D rat model of recurrent hypoglycemia.

Disclosure

N. DSouza: None. N. Aleali: None. D. Shakeri: None. E.G. Hoffman: None. S. Karimi-Chahartash: None. S. Javanbakhsh: None. O. Chan: None. R. Liggins: Employee; Zucara Therapeutics. Stock/Shareholder; Zucara Therapeutics. M.C. Riddell: Consultant; Eli Lilly and Company. Speaker's Bureau; Novo Nordisk. Advisory Panel; Supersapiens. Consultant; Dexcom, Inc. Speaker's Bureau; Sanofi. Advisory Panel; Zealand Pharma A/S. Speaker's Bureau; Dexcom, Inc. Stock/Shareholder; Zucara Therapeutics.

Funding

GlycoNet Strategic Initiatives (CD-85) Zucara Therapeutics Inc.
1793-LB: Subclinical Atherosclerosis in Latent Autoimmune Diabetes—Insights from a Multicenter Prospective Interventional Study
Authors: XIANG YUFEI , LI XIA , XIAO YANG , HUANG GAN , ZHOU ZHIGUANG , CHINA STUDY GROUP LADA
Published: June 2024

Objective: To compare subclinical atherosclerosis (AS) between latent autoimmune diabetes in adults (LADA) and type 2 diabetes mellitus (T2D) and to evaluate the impact of early insulin intervention on AS progression in LADA.

Methods: Sixty-four LADA patients and forty T2D patients, matched for diabetes duration, were enrolled from the LADA China multicenter study. Baseline assessments included ultrasound examination of carotid arteries (common carotid artery [CCA], internal carotid artery [ICA], and femoral carotid artery [FCA]). Additionally, demographic and clinical parameters including body mass index (BMI), waist circumference (WC), waist-hip ratio (WHR), systolic blood pressure (SBP), diastolic blood pressure (DBP), glycated hemoglobin (A1c), lipid panel, fasting C-peptide (FCP), and postprandial C-peptide (PCP) levels were measured. Medical history was recorded. LADA diagnosis was confirmed with positive glutamic acid decarboxylase antibodies (GADA). Subclinical AS was defined as an increase in intima-media thickness (IMT) greater than 1.0mm or the presence of plaque. Statistical analysis was performed using SPSS with significance set at p < 0.05.

Results: Regression analysis identified age, obesity, and lipid levels (total cholesterol and free fatty acids [FFA]) as risk factors for subclinical AS. After adjusting for age, LADA patients demonstrated similar IMT thickness compared to T2D patients, but a significantly lower AS diagnosis rate and smaller plaque area. Following a three-year follow-up with insulin or non-insulin interventions in LADA patients, the insulin intervention group exhibited a significantly lower AS progression rate.

Conclusion: Our study challenges previous findings by showing that LADA patients have less AS than T2D patients at baseline. Moreover, early insulin intervention may effectively reduce AS progression in LADA, emphasizing the importance of timely management in this population.

Disclosure

Y. Xiang: None. X. Li: None. Y. Xiao: None. G. Huang: None. Z. Zhou: None.
1821-LB: Differences on Clinical Experiences with Health Care Providers and Disease Perceptions in Early-Onset vs. Later-Onset Koreans with Type 2 Diabetes
Authors: SUNG GOWOON , GWON SO-HYEON , JANG HYESUN , FAULKNER MELISSA S. , CHA EUNSEOK
Published: June 2024

Objective: To examine clinical experiences with healthcare providers and illness perceptions in Koreans with type 2 diabetes (T2D) categorized by age at diagnosis.

Methods: A cross-sectional research design was employed. Of 315 contacts, 165 participants were recruited, comprising 60% men, mean age 46.9 ±12.3 years (range: 20 to 76 years) and mean HbA1c 7.3 ±1.5 %. Participants were divided into two groups based on their age at diagnosis: early-onset (<40 years) or later-onset ( ≥ 40 years). Clinical experiences with healthcare providers and illness perceptions were assessed using self-reported Patient Assessment of Chronic Illness Care survey (PACIC), rated on a scale of 1 to 5, and the Brief Illness Perception Questionnaire, rated on a scale of 0 to 10, respectively. Statistical analyses were conducted using SAS for Windows (version 9.2). The significance level was set at α = .05 (two-tailed).

Findings: Overall, patients were well-informed about treatment plans and options (mean ±SD: 3.8± 0.8), but there was less counseling on goal setting and action plans by healthcare providers, particularly for the later-onset group (mean± SD: 3.0±.8 vs. 2.7±.9, p = .04). Compared to the later-onset group, early-onset group reported that T2D significantly affected their life (6.1±2.5 vs.4.9±2.7, p=.003), experienced more severe symptoms (4.9±2.6 vs.3.9±2.6, p=.02), and had a greater negative impact of emotional well-being (5.5±2.6 vs.4.5±2.9, p=.02). Conclusions: Substantial evidence supports the effectiveness of behavioral goals in promoting behavior change. Individualized behavioral goal-setting and personalized counseling should be provided in clinical practice, especially for those with early-onset T2D who often require strategies to enhance their self-efficacy, mitigate negative perceptions of their health, and bolster empowerment in diabetes management.

Disclosure

S. Gwon: None. H. Jang: None. M.S. Faulkner: None. E. Cha: None.

Funding

Korea Research Foundation (NRF-2023R1A2C2004541)
1824-LB: A Qualitative Analysis of the DM-BOOST Program—Enhancing Patient Engagement and Experience with Diabetes Self-Management Education and Support
Authors: BOAKYE MICHELLE , SHENETTE LISA L. , GERBER BEN S. , AMANTE DANIEL J.
Published: June 2024

Introduction and Objectives: Diabetes Self-Management Education and Support (DSMES) is a recommended component of diabetes care. Despite proven benefits, patient engagement with DSMES needs improvement. The DM-BOOST program, based on principles of Self-Determination Theory and Behavioral Economics and co-designed with patients, was developed to increase patient engagement with DSMES. DM-BOOST included peer-written text messages and digital health training to improve patient portal and telehealth use. The purpose of this study is to explore the feasibility of implementing DM-BOOST in an established DSMES program and its impact on engagement and experiences among individuals with type 2 diabetes (T2D).

Methods: A feasibility pilot was conducted from November 2021-November 2022. Upon conclusion, semi-structured phone interviews were conducted with 36 individuals with T2D. The interviews were audio recorded and transcribed verbatim. An inductive thematic analysis was conducted by two independent coders using MAXQDA24 software. The data collection, analysis, and interpretation of findings were guided by the Unified Theory of Acceptance and Use of Technology (UTAUT).

Results: Participants (n=36) were mean (SD) 45.9 (8.9) years old, 61% female, with a mean baseline HbA1c of 10.1% (1.8). The racial/ethnic distribution was 64.9% White, 11.1% Black, 5.6% Asian, 8.3% more than one race and 11.1% preferred not to answer (with 27.8% overall Hispanic/Latino). Four themes emerged: (1) empowering autonomy through accessible and personalized DSMES, (2) perceived transformative impact on self-management competency and health outcomes, (3) empathetic experience with diabetes educators and research team, and (4) timely, additional support that was coordinated with their care providers.

Conclusion: DM-BOOST was found to be feasible to implement and positively impacted patient engagement and experience with DSMES.

Disclosure

M. Boakye: None. L.L. Shenette: None. B.S. Gerber: None. D.J. Amante: None.

Funding

National Institutes of Health (KL2TR001455, K01DK131318)
1840-LB: Referral, Participation, and Reimbursement Patterns of an Integrated Behavioral Health Program for Diabetes
Authors: ESPINOSA DE LOS MONTEROS KARLA , SPIERLING BAGSIC SAMANTHA R. , SORIANO EMILY C. , FORTMANN ADDIE L. , NOUHI NUSHA , PHILIS-TSIMIKAS ATHENA
Published: June 2024

Introduction: Psychosocial factors are known to impact diabetes outcomes. The Diabetes Behavioral Health Integration Program (BeHIP) offers integrated psychosocial assessment and care for people with diabetes at a large health system in Southern California. Objective: To describe referral, participation, and reimbursement patterns of the BeHIP.

Methods: BeHIP services are provided by licensed clinical psychologists co-located with physicians and CDCESs in the Division of Endocrinology. Patients identified for BeHIP support are referred via warm hand-off or through their EHR and undergo an individualized assessment followed by individual psychotherapy when indicated. Patients with severe mental illness or concerns unrelated to diabetes are referred out to appropriate services. Data was collected and analyzed via an EHR extraction. Comparisons between those who did versus did not complete at least 1 BeHIP visit were tested by unpaired t-test for continuous data or Chi Square test for categorical data.

Results: Of 953 BeHIP referrals placed between 2017 and 2023, 45% participated in the program. Individuals with T2D (48%), T1D (45%), GDM or other diagnoses (7%) were referred, with no associations between diabetes type and participation. Compared to non-participants, participants were older [55.4±17.1 vs 53.2±17.6] * and referred by an endocrinologist [75.6% vs 60%] *. While the majority of BeHIP referrals were women (70%), gender did not impact the participation status of those referred (47% vs 41%, for women and men, respectively) ≠. Finally, 78% of Health and Behavior CPT codes billed for BeHIP services were reimbursed by insurance, with the reimbursement rate varying widely across insurance plans.

Conclusion: This project provides real-world information to guide our understanding of factors that can impact participation and financial viability of clinical programs targeting psychosocial and behavioral needs within routine diabetes care. *p≤.05, ≠p≥.10

Disclosure

E.C. Soriano: None. A.L. Fortmann: None. N. Nouhi: None. A. Philis-Tsimikas: Advisory Panel; Dexcom, Inc., Lilly Diabetes, Novo Nordisk, Sanofi, Medtronic, Bayer Inc.
1859-LB: PG-102, a Novel Bispecific GLP-1R/GLP-2R Fc-Fused Agonist—Data on Safety, Tolerability, and Pharmacokinetics (PK) in Single Ascending Dose Trial in Healthy Subjects and Preliminary Population PK Modeling
Authors: HAN SEUNGHOON , HAN SUNGPIL , SON KYOUNG-HWA , SUNG YOUNGCHUL
Published: June 2024

PG-102, a novel bi-specific GLP-1R/GLP-2R Fc-fused agonist, exhibits promising therapeutic option for metabolic disorders, particularly obesity and diabetes, showing superior efficacy in preclinical studies.

In this Phase 1a study, we conducted a randomized placebo-controlled, and double-blind study to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary pharmacodynamics (PD) of single ascending doses of PG-102 in healthy subjects. Additionally, we employed PK/PD modeling to propose preliminary dosing intervals for further clinical studies.

Forty volunteers (33 men, 7 women; mean age 30.1 years, mean BMI 23.8 kg/m2) received PG-102 (5, 15, 30, and 60 mg) or placebo in an 8:2 ratio. PG-102 demonstrated acceptable safety and a favorable PK profile. Treatment-emergent adverse events (TEAEs) were primarily gastrointestinal, including dyspepsia, nausea, and vomiting, consistent with the GLP-1RA drug class. Notably, no nausea or vomiting occurred up to the 30 mg dose and TEAEs were generally mild to moderate in severity. The PK profile demonstrated a prolonged sustenance effect of PG-102, enabling sustained high concentrations in the bloodstream, thereby contributing to its prolonged effectiveness compared to other Fc-fused protein agonist.

Utilizing basic population PK modeling with simulated human PK profiles, we proposed efficacious doses and dosing intervals for PG-102. PK/PD modeling suggests weekly injections of 5 mg and 15 mg, and biweekly or longer interval for 30 mg and 60 mg doses. Additionally, simulated dose of 90 mg* are expected to have monthly intervals. These findings will be further refined and updated with the results from the ongoing multiple ascending dose study.

*50% dose of NOAEL in toxicity study

Disclosure

S. Han: None. S. Han: None. K. Son: Employee; Progen Co., Ltd. Y. Sung: Advisory Panel; Progen Co., Ltd.
187-OR: Pathway between Race, Historic and Contemporary Measures of Structural Racism, and Prevalence of Diabetes in the U.S.
Authors: EGEDE LEONARD E. , WALKER REBEKAH J. , LINDE SEBASTIAN
Published: June 2024

This study investigated direct and indirect relationships between historic structural racism and a novel measure of contemporary structural racism on prevalence of diabetes, accounting for distribution of race across counties in the US. Structural equation modeling in Stata v17 and an analytic sample of 15,190 census tracts across 157 counties, within 50 states including DC were used. Historic structural racism was defined as Home Owners’ Loan Corporation (HOLC) redlining neighborhood grades. Contemporary structural racism was defined as the structural racism effect index (SREI), a summary score of nine social determinant domains. Mean diabetes prevalence was 11.8%. Historic redlining, SREI, and Black race were directly associated with increased diabetes prevalence. Historic redlining was indirectly associated with increased diabetes prevalence via SREI. Black race was indirectly associated with increased diabetes prevalence through more exposure to historic redlining and higher levels of contemporary structural racism. Both historic and contemporary measures of structural racism are associated with increased diabetes prevalence. Contemporary structural racism is a stronger relationship for the pathway through which Black race is associated with diabetes prevalence and is a pathway through which historic residential redlining influences diabetes prevalence.

Disclosure

L.E. Egede: None. R.J. Walker: None. S. Linde: None.

Funding

National Institutes of Health (R01DK118038, R01DK120861, R01MD013826, R01MD017574, R01MD018012)