bluuebunny/crossref_metadata_2025 huggingface dataset:
1340-P: The Association of SGLT2i vs. DPP4i on Fracture—Cohort Study of Veterans with Diabetes
Authors: SNYDER KATHRYN D. , HACKSTADT AMBER J. , GRIFFIN KATHERINE E. , HORTON THOMAS G. , HOSSEIN JAVID AMIR , HUNG ADRIANA M. , GREEVY ROBERT A. , ROUMIE CHRISTIANNE
Published: June 2024

Objective: Increased bone turnover is associated with SGLT2i use. Patients with diabetes have adverse effects on bone metabolism. Our aim was to evaluate if SGLT2i was associated with fractures versus DPP4i.

Methods: A retrospective cohort combined Veterans Administration, Medicare, and National Death Index databases. New users of SGLT2i with diabetes (87% empagliflozin; 10.2% canagliflozin; 2.6% dapagliflozin) or DPP4i (51% saxagliptin; 30% sitagliptin; 12% alogliptin) were followed from the prescription fill until a fracture event, death or study end. Fractures included: face/skull, spine, ribs, long bones, hand/feet/ digits, or hip. Fractures were identified based on a validated algorithm with PPV 91.3% (86.8, 94.4) compared to medical records. Cox models compared fractures between SGLT2i and DPP4i in a propensity score weighted cohort adjusted for clinical and lab data including vitamin D levels, smoking, and medications.

Results: The weighted cohort included 36253 SGLT2i vs 36189 DPP4i episodes. Median age was 69 years and diabetes duration 9.3 (5.7, 13.7) years. In matched weighted analyses, there were 468 and 549 fractures among SGLT2i and DPP4i users, respectively. There were no clinical differences in fractures per 1000 person years: 18.1 (16.6, 19.7) vs. 20.2 (19.1, 21.4) [aHR 0.89 (0.80, 0.99)].

Conclusions: SGLT2i use for diabetes was not associated with increased fracture outcomes compared to DPP4i

Disclosure

K.D. Snyder: None. A.J. Hackstadt: None. K.E. Griffin: None. T.G. Horton: None. A. Javid: None. A.M. Hung: None. R.A. Greevy: None. C. Roumie: None.

Funding

VA Clinical Science research and Development investigator initiated grant CX000570-11 (Roumie)
1343-P: Association of SGLT2i on Amputation, Stent Placement, or Revascularization vs. DPP4—Cohort Study in Veterans
Authors: GRIFFIN KATHERINE E. , SNYDER KATHRYN D. , HOSSEIN JAVID AMIR , HACKSTADT AMBER J. , GREEVY ROBERT A. , GRIJALVA CARLOS G. , ROUMIE CHRISTIANNE
Published: June 2024

Objective: The association between SGLT2i and peripheral artery disease (PAD) remains unclear for high-risk patients. The aim of this study was to test the hypothesis that SGLT2i is associated with a composite PAD outcome compared to DPP4i.

Methods: A retrospective cohort combined Veterans Administration, Medicare, and National Death Index databases. New users of SGLT2i or DPP4i were followed from the prescription fill until a composite PAD event, death, or end study. The PAD event was defined as the earliest surgery: amputation, peripheral stent placement, or revascularization. Covariate adjusted Cox models compared PAD event between SGLT2i users and DPP4i users in a propensity score weighted cohort allowing for events to occur up to 90 days or 360 days after stopping SGLT2i.

Results: The weighted cohort included 36,190 SGLT2i vs 36,254 DPP4i episodes. Median age was 69 years, HbA1c was 8.40 [7.60, 9.30] and diabetes duration 9.3 (5.7, 13.7) years. There were 319 and 286 PAD events among SGLT2i and DPP4i users, respectively, for an event rate of 12.3 (11.0, 13.6) and 10.4 (9.6, 11.4) per 1000 person-years (aHR 1.21 [1.05, 1.41]). When allowing for PAD events for 360 days after SGLT2i use ended, the aHR was 1.27 [1.13, 1.44]).

Conclusions: Use of SGLT2i for diabetes treatment was associated with increased amputation and revascularization surgery outcomes compared to DPP4i.

Disclosure

K.E. Griffin: None. K.D. Snyder: None. A. Javid: None. A.J. Hackstadt: None. R.A. Greevy: None. C.G. Grijalva: Advisory Panel; Merck Sharp & Dohme Corp. C. Roumie: None.

Funding

VA Clinical Science research and Development investigator initiated grant CX000570-12 (Roumie)
1346-P: Association between Chronic Constipation and All-Cause Mortality among Adult Women With and Without Type 2 Diabetes
Authors: VISARIA AAYUSH , SHAH NISHALI
Published: June 2024

Introduction: Chronic constipation (CC) is common among women with type 2 diabetes (T2D), likely due to microvascular, neuropathic, and microbiome changes. It is unknown whether CC confers additional mortality risk. We determined the association between CC and risk of all-cause mortality in U.S. adult women with & without T2D.

Methods: We included non-pregnant women ≥20 years from the National Health and Nutrition Examination Survey 2005-2010 linked to the National Death Index through 2019. We excluded women taking insulin, with inflammatory bowel disease, prior bowel surgeries, or chronic diarrhea. T2D was defined as HbA1c ≥6.5%, fasting blood glucose ≥126 mg/dl, or self-reported diagnosis. CC was defined as bowel frequency <4 BMs/week and bowel consistency using Bristol Stool Form Scale (BSFS) Type 1-2. The reference was women with >3 BMs/week & BSFS Type 3-5. We used survey design-adjusted Cox regression with covariates determined a priori (demographics, smoking, exercise, diet, waist size, BP, HbA1c, T2D medication use, laxative use).

Results: Among 5,620 women (mean age 47y, 72% non-Hispanic White [NHW], 8.3% T2D), 154 (2.6%) had CC. Across a mean 11.4y (SD, 2.7y) of follow-up, 678 (10%) died. Women with CC were more likely to have lower income & education, poor self-reported health, and other T2D complications. Among women with T2D, CC had 2 times the risk of mortality (HR [95% CI]; unadjusted: 3.27 [1.62, 6.58], adjusted: 2.06 [1.11, 3.85]). Income & education most significantly attenuated risk estimates (34% change). There was no association between CC and mortality in women without T2D (unadjusted: 0.94 [0.51, 1.71], adjusted: 1.04 [0.62, 1.74]).

Conclusion: CC was present in nearly 3% of women. Only in women with T2D was CC associated with more than twice the risk of mortality, suggesting CC may be a symptom of T2D complication. Further longitudinal studies are needed to examine temporality of CC onset with other complications.

Disclosure

A. Visaria: None. N. Shah: None.
1378-P: The Association between Baseline Hemoglobin A1c (A1C) and Risk of Progression from Prediabetes to Diabetes across Adult Age Groups
Authors: FAZLI GHAZAL S. , LIPSCOMBE LORRAINE , THIRUCHELVAM DEVA , KENASZCHUK CHRIS , SHAH BAIJU R. , KE CALVIN , ALI FATEMA M. , ROSELLA LAURA , BOOTH GILLIAN L.
Published: June 2024

Introduction & Objectives: While A1c is a strong predictor of conversion from prediabetes to type 2 diabetes, it is unclear whether A1c values within the prediabetes range confer the same risk of conversion to type 2 diabetes within different adult age groups.

Methods: Using linked population-based administrative health databases, we investigated the progression from prediabetes to diabetes among adults (≥20 years) with laboratory criteria for prediabetes living in Ontario, Canada between 2012-2022. New diabetes cases were captured using a well-validated administrative data algorithm. Competing risk and Cox proportional hazards models were used to assess the association between A1c increments (~0.2%) within the prediabetes range (5.70-6.49%, vs <5.7%) and diabetes incidence in different decades.

Results: Among 3,022,169 individuals with prediabetes, 139,450 (4.6%; mean age 54.1 ± 15.8 yrs) progressed to diabetes over a mean follow up of 4.78 years. The cumulative incidence of diabetes was greatest among those with baseline A1C levels of 6.30-6.49% in both younger (20-29 yrs: 34.5%) and older adults (≥70 yrs: 19.2%). Increased A1c conferred a far greater relative risk of progression to diabetes in adults aged 20-29 and 30-39 (A1c 6.30-6.49%: HR 51.7, 95% CI 45.0-59.3 and HR 41.3, 38.8-44.0, respectively). Relative conversion rates were more modest in adults aged ≥70 years across all A1c categories (A1c 6.30-6.49%: HR 9.7, 9.3-10.1).

Conclusion: Baseline A1c was a stronger predictor of conversion from prediabetes to diabetes among younger adults, suggesting that diabetes prevention efforts should consider baseline A1C and age to reduce future risk of progression.

Disclosure

G.S. Fazli: None. L. Lipscombe: Other Relationship; Novo Nordisk Canada Inc. D. Thiruchelvam: None. C. Kenaszchuk: None. B.R. Shah: None. C. Ke: Advisory Panel; Sanofi. Speaker's Bureau; AstraZeneca. F.M. Ali: None. L. Rosella: None. G.L. Booth: None.
1400-P: Hepatic Effectiveness of SGLT2 Inhibitors in Patients with Nonalcoholic Fatty Liver Disease and Type 2 Diabetes
Authors: BEA SUNGHO , YEON KO HWA , SHIN JU-YOUNG
Published: June 2024

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have demonstrated promising effects on liver outcomes. However, comprehensive evidence regarding liver outcomes in direct comparison with thiazolidinediones (TZD) and glucagon-like peptide-1 receptor agonists (GLP1RA), which are recommended in guidelines for patients with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D), is still lacking. Using health insurance claims data from South Korea, we established two pairwise 1:1 propensity score (PS)-matched cohorts who initiated SGLT2i, GLP1 RA (cohort #1, median age=57 years, 60% male), or TZD (cohort #2, median age=57 years, 72% male) between January 2014 and December 2022. The primary outcome was a composite of hepatic decompensation events, including ascites, esophageal varices with bleeding, hepatic failure, or liver transplant. Hazard ratios (HR) with 95% confidence intervals (CI) were calculated. In cohort #1, compared to GLP1RA, SGLT2i showed a similar risk of hepatic decompensation events (HR 0.92, 95% CI 0.76-1.12). In cohort #2, compared to TZD, SGLT2i demonstrated a reduced risk of hepatic decompensation events (HR 0.77, 95% CI 0.72-0.82). In this nationwide cohort study, SGLT2i was associated with a reduced risk of hepatic decompensation events in patients with NAFLD and T2D compared to TZDs, showing similar effectiveness to GLP1RA.

Disclosure

S. Bea: None. H. Ko: None. J. Shin: Research Support; Pfizer Inc., Celltrion, SK Bioscience, GlaxoSmithKline plc.

Funding

This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: RS-2023-00273553)
1406-P: Accessibility of Diabetes Prevention Programs in Historically Redlined Areas of the U.S.
Authors: ROY DARIUS J. , CHANTARAT TONGTAN , JIANG DAVID H. , GOLDEN SHERITA , DAVIS ESA , DING MARISSA L. , HUANG SHUO J. , MCCOY ROZALINA G.
Published: June 2024

Introduction & Objective: Prior research demonstrated an association between historical redlining practices and diabetes-related mortality. The National DPP is an evidence-based, cost-effective, structured lifestyle change intervention to prevent type 2 diabetes (T2D). Whether historical redlining practices drive the present-day availability of DPP programs across the US is unknown.

Methods: In person and hybrid DPPs across the US and their addresses were identified from the CDC. Walking distance accessibility was defined as a 0.8 km radius. Redlining was assessed using the 1930s federal Home Owners’ Loan Corporation (HOLC) maps by intersect spatial join onto 2020 census tracts. HOLC areas are classified into 4 grades: A (best), B (still desirable), C (declining), and D (hazardous). We examined the association between grade D vs. A-C tracts and the number of DPPs using a negative binomial mixed-effects model with random intercepts by geographic level and controlling for tract-level population, proportion uninsured people, and <150% of federal poverty line (FPL).

Results: Of 1730 DPPs, 347 were within walking access of a HOLC-graded tract centroid in 38 states. Nationally, after controlling for tract-level characteristics, grade D tracts and tracts with greater proportion <150% of FPL were associated with greater number of DPPs, while tracts with greater proportion of uninsured were associated with fewer DPPs within walking distance. In state-specific analyses for 7 of 33 examined states, there was statistically significant greater than expected DPP availability in grade D tracts. There was no difference in 20 states, while remaining 11 states could not be examined due to lack of HOLC data, model diagnostics, data sparsity, or convergence failure.

Conclusion: While availability of walking distance DPPs is higher in historically redlined areas in 7 states, there was no such enrichment in 20 states. Future research needs to examine DPP utilization by residents in these communities.

Disclosure

D.J. Roy: None. T. Chantarat: None. D.H. Jiang: None. S. Golden: None. E. Davis: None. M.L. Ding: None. S.J. Huang: None. R.G. McCoy: Research Support; American Diabetes Association. Other Relationship; American Diabetes Association. Consultant; Wolters Kluwer Health. Research Support; National Institutes of Health, Patient-Centered Outcomes Research Institute. Consultant; Yale New Haven Health System.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (K23DK114497)
1418-P: Prevalence of Self-Reported Diagnosed Diabetes among U.S. Adults According to Metropolitan Residence and Region, United States 2019–2022
Authors: ONUFRAK STEPHEN J. , KOYAMA ALAIN , MIYAMOTO YOSHIHISA , SAELEE RYAN , XU FANG , BULLARD KAI M. , IMPERATORE GIUSEPPINA , PAVKOV MEDA E.
Published: June 2024

Background: Previous research suggests that rural/urban disparities in diabetes mortality, hospitalization, and incidence rates may manifest differently across US regions. However, no studies have examined disparities in diabetes prevalence by metropolitan residence and region.

Methods: Using data from the 2019-2022 National Health Interview Survey (NHIS), diabetes status, socioeconomic characteristics, and weight status were compared among adults within each Census region (Northeast, Midwest, South, West) according to county metropolitan status of residence (large central metro, large fringe metro, small/medium metro, and non-metro) using Chi-squared tests. Logistic regression models were fit to assess the association of metropolitan residence and diabetes prevalence within each region.

Results: Diabetes prevalence ranged from 7.0% in large fringe metro counties in the Northeast to 14.8% in non-metro counties in the South. Compared to adults from large central metro counties, those from small/medium metro counties had significantly higher odds of diabetes in the Midwest (age, sex, and race/ethnicity adjusted odds ratio [OR]=1.24; 95% confidence interval [CI]: 1.06-1.45) and South (OR=1.15; 95% CI: 1.02-1.30). Non-metro residence was also associated with diabetes in the South (OR=1.62 vs large central metro; 95% CI: 1.43-1.84). After further adjustment for socioeconomic and body weight status, small/medium metro associations with diabetes became attenuated and nonsignificant but non-metro residence in the South remained significantly associated with diabetes (OR=1.22; 95% CI: 1.07-1.39).

Conclusion: The association between metropolitan residence and diabetes prevalence differs across regions of the United States. These findings can help to guide efforts in areas where diabetes prevention and care resources may be better directed.

Disclosure

S.J. Onufrak: None. A. Koyama: None. Y. Miyamoto: None. R. Saelee: None. F. Xu: None. K.M. Bullard: None. G. Imperatore: None. M.E. Pavkov: None.
1422-P: Understanding COVID-19 Impacts among Underserved Adults with Diabetes Using the Social-Ecological Model
Authors: MAIZEL JENNIFER , ATTANTI RITHWIK , PRASANNA CHENNURI KEERTHI , SMITH RILEY , FILIPP STEPHANIE L. , HECHAVARRIA MELANIE , HALLER MICHAEL J. , WESTEN SARAH , DIXON BRITTNEY , MAAHS DAVID M. , LAL RAYHAN , ADDALA ANANTA , WALKER ASHBY F.
Published: June 2024

Introduction & Objective: People with diabetes reported disparate health, psychosocial, and financial outcomes from COVID-19. This study aimed to understand experiences of underserved adults with diabetes during the COVID-19 pandemic.

Methods: A survey assessing COVID-19 impacts was administered to adults with insulin-requiring diabetes (n=450) at federally qualified health centers in CA and FL between Nov. 2021-Jul. 2022. This qualitative study analyzed responses to an open-ended question asking patients to describe the pandemic’s impact on their lives (n=263, mean age=53.5 ± 14.3 years, 60.5% T2D). Responses were coded via a thematic analysis guided by CDC’s Social-Ecological Model (SEM), which asserts that health occurs at and is affected by 4 levels: Individual, Relationship, Community, and Societal. Descriptive statistics (n, %) determined the frequency of impacts reported; some patients noted multiple impacts.

Results: A total of 546 codes were identified; 490 reported COVID-19 impacts (89.7%); 56 noted no impact (10.3%). Among reported impacts, most were Individual-level (n=208, 42.5%), e.g., diagnoses of COVID-19 or other illnesses, mental health issues, higher blood glucose, and weight gain. Societal impacts (n=158, 32.2%) included concerns regarding COVID-19 information, income loss, and challenges scheduling medical appointments, ordering diabetes supplies, and accessing healthy foods. Relationship impacts (n=65, 13.3%) included social isolation and reduced family/peer interactions. Community impacts (n=44, 9.0%) included occupational changes, extra precautions in high-risk areas, and challenges with local transportation and housing. The remainder were unspecific (n=15, 3.1%).

Conclusion: COVID-19 impacts among underserved adults with diabetes stem from factors across the SEM. Multi-level interventions are needed to improve patients’ healthcare, promote social support, enhance local preventive efforts, and reduce inequities.

Disclosure

J. Maizel: None. R. Attanti: None. K. Chennuri: None. R. Smith: None. S.L. Filipp: None. M. Hechavarria: None. M.J. Haller: Consultant; Sanofi. Advisory Panel; SAB Biotherapeutics, Inc. Consultant; MannKind Corporation. S. Westen: None. B. Dixon: None. D.M. Maahs: Advisory Panel; Medtronic. Consultant; Abbott, LifeScan Diabetes Institute, Sanofi, Provention Bio, Inc., Bayer Inc., Kriya Therapeutics, BioSpex. R. Lal: Consultant; Abbott, Adaptyx Biosciences, Biolinq, Capillary Biomedical, Inc., Deep Valley Labs, Gluroo, PhysioLogic Devices, Portal Insulin, Tidepool. Advisory Panel; Lilly Diabetes. A. Addala: None. A.F. Walker: None.

Funding

The Leona M. and Harry B. Helmsley Charitable Trust (G-2005-03934)
1447-P: Metabolic Heterogeneity of Antibody-Positive Individuals (Ab+I) with Impaired Glucose Tolerance (IGT) according to Glucose Fractions
Authors: NATHAN BRANDON M. , CUTHBERTSON DAVID D. , ISMAIL HEBA M. , JACOBSEN LAURA M. , SIMS EMILY K. , SOSENKO JAY
Published: June 2024

Introduction and Objective: Among Ab+I, we examined the metabolic heterogeneity of IGT, a marker of progression toward stage 3 type 1 diabetes (T1D), using glucose fractions dependent or independent of insulin secretion.

Methods: Data from Ab+I with baseline OGTTs meeting IGT criteria (2-hr glucose ≥140 to <200 mg/dl, n=1103) enrolled in TrialNet Pathway to Prevention were analyzed. AUC glucose was divided into fractions dependent (dAUCGLU) or independent (iAUCGLU) of insulin secretion, defined by the linear regression of AUC glucose vs. Index60 (as an insulin secretion proxy). dAUCGLU was the AUC glucose value predicted by Index60, while iAUCGLU was the AUC glucose residual value above or below the regression slope.

Results: AUC C-peptide decreased as dAUCGLU quartiles increased, whereas AUC C-peptide increased as iAUCGLU quartiles increased (Figure). AUC C-peptide was inversely correlated with dAUCGLU (r=-0.84) and positively correlated with iAUCGLU (r=0.62) (p<0.0001 for both). AUC C-peptide trended little with unfractionated AUC glucose quartiles.

Conclusion: Opposite associations of AUC C-peptide with dAUCGLU and iAUCGLU indicate that AUC C-peptide was not only attributable to insulin secretion, but also to other factors (e.g. insulin resistance). It appears that among Ab+I, IGT is a heterogeneous metabolic state that may not be an optimal marker for T1D.

Disclosure

B.M. Nathan: None. D.D. Cuthbertson: None. H.M. Ismail: Consultant; Sanofi, Rise Therapeutics. L.M. Jacobsen: Advisory Panel; Insulet Corporation. E.K. Sims: Consultant; Sanofi. Board Member; American Diabetes Association. Other Relationship; American Diabetes Association, Medscape. Consultant; DRI. J. Sosenko: None.

Funding

National Institutes of Health (U01 DK061010, U01 DK061034, U01 DK061042, U01 DK061058, U01 DK085461, U01 DK085465, U01 DK085466, U01 DK085476, U01 DK085499, U01 DK085509, U01 DK103180, U01 DK103153, U01 DK103266, U01 DK103282, U01 DK106984, U01 DK106994, U01 DK107013, U01 DK107014, UC4 DK106993, UC4 DK117009)JDRF
1452-P: Financial Toxicity and Cost-Related Nonadherence (CRN) in Adults with Type 1 Diabetes (T1D)—Prevalence and Associations with Social Determinants of Health
Authors: WENTZELL KATHERINE , SMITH ALYSSA N. , PATEL MINAL R.
Published: June 2024

Introduction: Financial toxicity with healthcare needs and CRN, such as insulin rationing, are increasingly recognized as challenges to optimal T1D self-care in the US. This study examined prevalence of financial toxicity, CRN, and associations with SDOH.

Methods: This study included 130 adults with T1D with A1c ≥7.5% and unmet social needs. Sociodemographic and clinical variables, as well as the COST-FACIT modified for diabetes (lower score=more financial toxicity; cut-point ≤20) were collected. CRN was defined as endorsing at least 1 diabetes-specific behavior in the past year: took less medication, skipped medication, delayed/did not fill prescription, delayed/did not see healthcare provider because of cost. SDOH-related factors included income, employment, and insurance status. T-tests, ANOVAs, chi square, Fisher’s exact tests, and Pearson correlations determined the strength and direction of relationships.

Results: Mean age of the sample was 41 years (range 19-74), 65% female, 79% Non-Hispanic White, T1D duration was 24 years, A1c was 8.0±1.4%, 55% reported financial toxicity, and 32% reported CRN. Participants who endorsed CRN had significantly more financial toxicity (17±7 vs 21±8, p=.007). Financial toxicity and A1c were not correlated and A1c did not differ between those endorsing vs not endorsing CRN. Financial toxicity was substantial in those with lower income, not in the workforce, or with public health insurance (p<.01) while CRN did not differ statistically by these SDOH. Financial toxicity and CRN did not differ by gender or race/ethnicity. While financial toxicity did not differ by age, adults over age 30 endorsed less CRN vs those ≤30 (p=.03).

Conclusion: More than half of this sample endorsed financial toxicity and nearly one third reported CRN. Multiple SDOH appear related to financial toxicity. Financial concerns should be further probed among patients with T1D to facilitate disease management.

Disclosure

K. Wentzell: None. A.N. Smith: None. M.R. Patel: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (R01 DK116715-01A1); (P30DK092926) (Michigan Center for Diabetes and Translational Research); Mary K. Iacocca Foundation
1505-P: Dipeptidyl Peptidase 6–Targeted Nanobody—A Precision Medicine Tool for Noninvasive Detection of Pancreatic Islets by PET
Authors: KHALIL AMINA , ROCA RIVADA ARTURO , VELIKYAN IRINA , BITZIOS ATHANASIOS , SERAFINI PAOLO , EIZIRIK DECIO L. , ERIKSSON OLOF
Published: June 2024

Background: Nanobodies are single-domain antibodies that have gained popularity for various imaging techniques, including positron emission tomography (PET) due to their small size, high affinity and specificity to the target, and rapid blood clearance. A novel nanobody, NOTA-4hD29 with nanomolar affinity for human dipeptidyl peptidase 6 (DPP6) was developed as an alpha and beta cell-specific biomarker for the detection of pancreatic islets by PET. It enables non-invasive, longitudinal detection and quantification of islets of Langerhans, in the human pancreas or graft site post islet transplantation.

Method: The synthesis of [68Ga]NCS-NOTA-4hD29 was performed manually using a 68Ge/68Ga generator. Binding specificity was assessed via autoradiography with frozen sections of human islets (24%, 43%, and 90% purity) and islet-devoid exocrine pancreatic tissue. Specificity was validated by pre-blocking with excess unlabeled NOTA-4hD29. Stability of [68Ga]NCS-NOTA-4hD29 was tested in human plasma and in vivo in rats. In vivo biodistribution and plasma stability were evaluated in healthy rats and pig using PET/CT. Fluorescence labeling of 4hD29 evaluated its stability and internalization in EndoC-βH1 cells.

Results: [68Ga]NCS-NOTA-4hD29 radiosynthesis yielded 96.9% ± 1.47, with 99.6% ± 0.2 radiochemical purity. It demonstrated high affinity to human islets (r=0.98, p<0.05), minimal binding to the exocrine pancreas, and complete signal abolition with blocking. In vitro stability in human plasma exceeded 90% after 60 min; in vivo rat plasma stability was ∼55% after 60 min. In vivo biodistribution in rats and pig showed renal excretion (kidney SUV > 10) with low background. The 4hD29 nanobody underwent EndoC-βH1 cell endocytosis, remaining detectable in the cytosol for 6 h.

Conclusions: [68Ga]NCS-NOTA-4hD29 demonstrated excellent specificity and could differentiate between small differences in islet numbers.

Disclosure

A. Khalil: None. A. Roca Rivada: None. I. Velikyan: None. A. Bitzios: None. P. Serafini: None. D.L. Eizirik: None. O. Eriksson: Employee; Antaros Medical. Stock/Shareholder; Antaros Tracer AB.
1511-P: Fas Apoptosis Inhibitory Molecule (FAIM) Regulates Adipose Browning, Glucose Homeostasis, and Thermogenesis
Authors: NORIEGA LLOYD , WANG CHIH-HAO
Published: June 2024

Brown/beige adipocyte activation triggers adipose thermogenesis, which is crucial for maintaining homeostasis in the body as it helps regulate glucose metabolism, reduce fat accumulation, and enhance insulin sensitivity. However, the underlying mechanisms remain unclear. Thus, our research aims to identify the master regulator for brown/beige activation and non-dependent UCP1 thermogenesis. Using engineered Cas9 activation complexes to explore the transcriptional activation of thermogenesis using single-guide RNA, we discovered Fas apoptosis inhibitory molecule (FAIM) as the top candidate. Previous studies have demonstrated that FAIM is negatively correlated with BMI and obesity and is highly expressed in brown adipocytes compared to white adipocytes. Interestingly, our further validation using ERthermAC dye showed that thermogenesis is highly activated in FAIM-overexpressed white adipocytes. Moreover, RT-qPCR showed that the thermogenic marker UCP1, browning marker CIDEA and glucose uptake marker Glut1 are increased in FAIM-overexpressed white adipocytes. Collectively, our study proves that FAIM is essential in the regulation of browning, glucose, and thermogenesis. Therefore, targeting FAIM poses a good strategy to combat obesity and type 1 and 2 diabetes.

Disclosure

L. Noriega: None. C. Wang: None.
1536-P: DEP-1 Is a Novel Modulator of Brain Energy Metabolism
Authors: CHOPRA SIMRAN , KADIRI OTSUWARE L.J. , ULKE JANNIS , HAUFFE ROBERT , JONAS WENKE , BISHOP CHRISTOPHER A. , CHESHMEH SAHAR , RATH MICHAELA , SCHELL MAREIKE , KAPPERT KAI , KLEINRIDDERS ANDRE
Published: June 2024

Obesity's metabolic impact goes beyond peripheral insulin resistance, influencing the brain and thereby disrupting energy homeostasis by altering anabolic and catabolic reactions. Density-enhanced phosphatase-1 (DEP-1), a ubiquitously expressed receptor-like tyrosine phosphatase, has emerged as a novel regulator with a specific role in dephosphorylating the insulin receptor (IR). Strikingly, diet-induced obese mice exhibit elevated DEP-1 expression in metabolically sensitive tissues. In this study, we sought to elucidate the role of DEP-1 in brain insulin signaling and highlight its potential impact on the central regulation of metabolism in vitro and in vivo.

To explore DEP-1 deficiency in vitro, CRISPR/Cas9 was employed to create a DEP-1 knockout (KO) in mouse Neuro-2a cells. Given DEP-1’s high expression in the forebrain and the region's abundant IR expression, we examined the metabolic consequences of DEP-1 deficiency in the forebrain by deleting Dep-1 using CamKIIa Cre mice (DEFO KO).

DEP-1 KO cells exhibited an increase in IR phosphorylation and downstream signaling upon acute insulin stimulation, coupled with unexpected activation of AMP-activated protein kinase (AMPK) cascade. Similarly, male DEFO KO mice showed heightened insulin and AMPK signaling in the forebrain under random-fed conditions. A notable outcome manifested in the gonadal white adipose tissue of DEFO KO mice, where an ex vivo lipolysis assay revealed elevated basal lipolytic potential compared to control mice stimulated with isoproterenol, indicating enhanced sympathetic activation. Brown adipose tissue (BAT) of DEFO KO mice also demonstrated in a mitochondrial respiration assay, an upregulation of fatty acid oxidation, signifying increased BAT activity. Both tissues also revealed higher beta-adrenergic receptor gene expression, suggestive of sympathetic activity.

In conclusion, DEP-1 is a pivotal neuronal IR phosphatase, that prevents the establishment of futile cycles and emerges as a novel modulator of energy metabolism.

Disclosure

S. Chopra: None. O.L.J. Kadiri: None. J. Ulke: None. R. Hauffe: None. W. Jonas: None. C.A. Bishop: None. S. Cheshmeh: None. M. Rath: None. M. Schell: None. K. Kappert: None. A. Kleinridders: Speaker's Bureau; Novo Nordisk A/S, Daiichi Sankyo.

Funding

German Research Foundation (DFG)KL2399/6-1
1538-P: KCNQ2/3 Voltage Gated Potassium Channels Regulate the Activity of Intrapancreatic Neurons
Authors: LEVI NOAH , TAMAYO ALEJANDRO M. , MAKHMUTOVA MADINA , CAICEDO ALEJANDRO
Published: June 2024

Introduction & Objective: Input from the parasympathetic nervous system is necessary to adapt pancreatic islet and acinar function to the internal and behavioral status of an organism. pancreancreatic neurons, which form a vast interconnected ganglionated plexus, serve as mandatory targets of the parasympathetic vagus nerve. However, the exact mechanisms by which this local neuronal network conveys parasympathetic signals to the endocrine and exocrine pancreas are not well understood.

Methods: To interrogate the physiology of local pancreatic neurons in response to cholinergic input, we generated living pancreas slices from transgenic mice expressing the genetically encoded calcium indicator GCaMP3 in cholinergic neurons.

Results: We found that pancreatic neurons exhibit differential intracellular Ca2+ dynamics in response to nicotinic (nAChR) and/or muscarinic acetylcholine receptor (mAChR) agonists. While the nAChR agonist nicotine produces a single transient of intracellular Ca2+, the mAChR agonist Oxotremorine-M produces a long lasting Ca2+ response consisting of several oscillations. Furthermore, we were able to show that the intracellular Ca2+ responses elicited by Oxotremorine-M could be suppressed by compounds that activate KCNQ2/3 channels—voltage gated potassium channels that regulate membrane excitability. Concomitant application of KCNQ2/3 channel activators retigabine or ICA-069673 with Oxotremorine-M resulted in a roughly 60% reduction in response duration and number of Ca2+ transients.

Conclusion: These data suggest that pancreatic neurons may not represent canonical postganglionic neurons of the parasympathetic nervous system since they respond to mAChR stimulation and that KCNQ2/3 channel function may be required for the delivery of cholinergic input to pancreatic tissues. These data aid in providing a more complete understanding of the autonomic control of pancreas physiology and provide insight for potential therapeutic targets.

Disclosure

N. Levi: None. A.M. Tamayo: None. M. Makhmutova: None. A. Caicedo: None.

Funding

R01DK30328
1546-P: Autonomic Intrapancreatic Neurons Alterations in Type 1 Diabetes
Authors: EWING SAM , HASELDEN SYDNEY , NAIR MALAVIKA , BUTTERWORTH ELIZABETH A. , CAMPBELL-THOMPSON MARTHA
Published: June 2024

Introduction: Little is known about parasympathetic intrapancreatic neurons despite their important role in regulation of endocrine and exocrine functions. 3D imaging studies show innervation of these ganglia and islets in organ donors with type 1 diabetes (T1D). This study analyzed intrapancreatic ganglia from organ donors without and with T1D.

Methods: Paraffin sections from donors with no diabetes (ND, n=15) or T1D (n=9) were obtained from nPOD. Multiplex immunofluorescence was performed using antibodies to HuC/D, synapsin (SYN), and allograft inhibitory factor 1 (IBA1) to define neurons, synapses, and macrophages, respectively. Confocal images from 83 ganglia were analyzed using QuPATH software to quantify each ganglia area and immunopositive areas within ganglia. Ganglion sizes were binned into four groups. Neuron analyses included area (size) and numbers/ganglion (density). Statistical comparisons were made using non-parametric t-tests.

Results: A significant reduction in HuC/D+ area/ganglia was observed in T1D donors compared to ND (p < 0.01). Neuron sizes were smallest in T1D donors in the smallest ganglia (<3000 µm2). Comparisons of all neuron sizes, regardless of ganglia size, showed trends for smaller neurons and lower neuron density in T1D donors. No significant differences were found in synaptic or macrophage areas between groups.

Conclusions: Our results represent the first study analyzing human intrapancreatic ganglia for neurons, synapses, and macrophages. Our analysis indicates a significant reduction in neuronal HuC/D expression and trends for smaller and fewer neurons in T1D donor intrapancreatic ganglia. However, synapse loss or increased macrophage-mediated inflammation were not observed. Future studies will examine whether these findings are observed in at-risk autoantibody-positive donors. Understanding which neuron subtypes are affected by T1D is important for understanding altered islet compositions and dysregulated hormone secretion in the natural history of T1D.

Disclosure

S. Ewing: None. S. Haselden: None. M. Nair: None. E.A. Butterworth: None. M. Campbell-Thompson: None.

Funding

National Institutes of Health (OT2 OD023861, R01DK123329)
1572-P: Lipotoxicity-Induced TET1 Mediates CD36 DNA Demethylation in Liver Macrophages to Aggravate NAFLD Progression
Authors: YU PIAOJIAN , XIAN YINGXIN , CAO HUANYI , DENG XIAOJIE , CAI MENGYIN , XU FEN
Published: June 2024

Aims: DNA methylation is dysregulated in nonalcoholic fatty liver disease (NAFLD), yet the dominant genes and regulatory mechanisms remain obscure. Here, whole-genome bisulfite (WGBS) and RNA-seq revealed significantly downregulated DNA methylation and upregulated mRNA expression of Cd36 in a high fat diet (HFD)-induced murine fatty liver, particularly in macrophages. Meanwhile, ten-eleven translocation-1 (TET1), a DNA demethylase, was upregulated. We investigated whether lipotoxicity-induced TET1 erases the methylation at Cd36 promoter in liver macrophages and aggravates NAFLD progression.

Methods: The livers of 16-week HFD-induced male C57BL/6J mice were subjected to WGBS, RNA-seq and pyrosequencing. Hydroxymethylated DNA immunoprecipitation- and chromatin immunoprecipitation-qPCR were conducted to detect the level of 5-hydroxymethylcytosine on DNA, and the binding efficiency to the Cd36 promoter, respectively. TET1 expression was knocked down by adeno-associated virus in HFD-induced NAFLD mice. In vitro, Palmitate acid was applied to simulate lipotoxicity in Kupffer cell- and THP-1 cell line. CRISPR/Cas9 sg-Tet1 knockout lentivirus and TETs enzyme inhibitor were applied, and CD36 expression was knocked down by siRNA.

Results: In macrophages of fatty liver, the expression of CD36 and TET1 is markedly increased. Lipotoxicity enhances TET1 localization and demethylase activity at the Cd36 promoter. RXRα is recruited to the Cd36 promoter following the DNA demethylation of Cd36 by TET1 and increases Cd36 expression. Moreover, lipotoxicity-induced CD36 promotes M1 macrophage polarization and exacerbates inflammation. And the deficient TET1 activity restores DNA methylation of the Cd36 promoter, reducing its expression and M1 polarization.

Conclusion: TET1-mediated DNA demethylation has a crucial role in lipotoxicity-driven CD36 transcription in liver macrophage that boosts steatosis-to-nonalcoholic steatohepatitis progression.

Disclosure

P. Yu: None. Y. Xian: None. H. Cao: None. X. Deng: None. M. Cai: None. F. Xu: None.

Funding

National Natural Science Foundation of China grants (81970741, 82270942); the Local Innovative and Research Teams Projects of Guangdong Pearl River Talents Program (2017BT01S131); and the Guangdong Basic and Applied Basic Research Foundation (2022A1515012633).
1596-P: Personalized Glycemic Response to Carbohydrates and Associated Physiological Signatures in Multiomics
Authors: WU YUE , EHLERT BENJAMIN W. , PERELMAN DALIA , PARK HEYJUN , METWALLY AHMED A. , LU YINGZHOU , CELLI ALESSANDRA , BEJIKIAN CAROLINE , MCLAUGHLIN TRACEY , SNYDER MICHAEL
Published: June 2024

Introduction & Objective: Individuals with type 2 diabetes (T2D) exhibit heterogeneous metabolic dysfunction (e.g., muscle insulin resistance (IR), beta-cell dysfunction) and varying intervention needs. People also have different dynamic responses to daily activities (e.g., exercise and food), which are associated with their metabolic function. Understanding personalized glycemic control and specific metabolic dysfunctions is crucial for T2D subtyping and personal intervention.

Methods: Here, we incorporated real-life continuous glucose monitoring (CGM) to evaluate the personal responses to 7 different carbohydrate foods (each 50 grams of carbohydrate) and 3 different nutrients (fat, protein, and fiber) that tend to mitigate glycemic spikes in 50 participants (25 with prediabetes and 25 with normoglycemic levels). We built a computational workflow to extract 20 different metrics (e.g. peak height and time to peak) related to metabolic functions, subtype participants according to their relative response to different foods, and uncover physiological and pathological associations in multi-omics.

Results: We found that the average glycemic response depends on carbohydrate types and fiber contents. Worst metabolic control (e.g., IR) is also significantly associated with higher glycemic spikes. In addition, we discovered different CarbResponders, that different groups of people have different relative glycemic spikes to different foods. Some people spike more on rice and others on grapes. We found a higher proportion of rice spiking in Asians (p=0.007), better metabolic functions (e.g., IR) associated with lower spikes in starch food, and signature of diet habits in metabolomics and proteomics.

Conclusions: Food response profiles provide individualized food recommendations and indicate underlying metabolic functions for personalized interventions.

Disclosure

Y. Wu: None. B.W. Ehlert: None. D. Perelman: None. H. Park: None. A.A. Metwally: Employee; Google. Y. Lu: None. A. Celli: None. C. Bejikian: None. T. McLaughlin: Stock/Shareholder; Eiger BioPharmaceuticals. Board Member; January, Inc. Research Support; Eli Lilly and Company, Weight Watchers International, Merck & Co., Inc., Vogenyx. M. Snyder: Stock/Shareholder; January, Inc., Personalis, Inc, Iollo, Qbio, RTHM, Enovone, Marble Therpeutics, Fodsel, Mirvie. Advisory Panel; Applied Cognition.

Funding

American Diabetes Association (11-23-PDF-76); National Institutes of Health (NIDDK1R01 DK110186-01); Leona M & Harry B Helmsley Charitable Trust
1598-P: Transcriptional Profiling of the Intestinal Tract in Type 2 Diabetes—Unraveling Pathophysiological Pathways for Therapeutic Insights
Authors: GILLIAM-VIGH HANNAH , ELLEGAARD ANNE-MARIE , MADSEN MARTIN R. , JENSEN BENJAMIN A.H. , RIGBOLT KRISTOFFER , KNOP FILIP K.
Published: June 2024

Introduction and Objective: Investigating the intestinal gene expression in type 2 Diabetes (T2D) may reveal novel insights into its pathophysiology. We conducted a comprehensive investigation to compare gene expression profiles along the entire human intestinal tract of individuals with T2D and healthy counterparts, aiming to identify unique gene expression patterns associated with T2D.

Methods: Mucosal biopsies from 16 intestinal sites were collected via anterograde and retrograde double-balloon endoscopy in 12 individuals with T2D and 12 matched individuals. Bulk transcriptome profiles were compared between T2D individuals and healthy individuals.

Results: Healthy participants (8M/4F, mean age: 50 years, BMI: 27.1 kg/m2, HbA1c: 5.3%) were compared to individuals of T2D (9M/3F, mean age: 51 years, BMI: 26.8 kg/m2, HbA1c: 6.5%, diabetes duration: 5 years). All were of European descent. Altered mitochondrial function and immune system activity were observed in the ileocecal segment and large intestine, respectively, in individuals with T2D compared to healthy individuals.

Conclusion: The notable changes in mitochondrial function and immune system activity in the ileocecal segment and the large intestine of individuals with T2D underscore the complex pathophysiology of the disease and its influence on intestinal function and health. The publicly and freely available database generated from this study provides a comprehensive reference for future research on intestinal gene expression in T2D and is a valuable resource for the exploration of the mucosal transcriptome along the human intestinal tract.

Disclosure

H. Gilliam-Vigh: Research Support; Zealand Pharma A/S. A. Ellegaard: None. M.R. Madsen: Employee; Gubra. B.A.H. Jensen: None. K. Rigbolt: None. F.K. Knop: Advisory Panel; AstraZeneca. Consultant; AstraZeneca. Speaker's Bureau; AstraZeneca. Advisory Panel; Boehringer-Ingelheim. Consultant; Boehringer-Ingelheim. Speaker's Bureau; Boehringer-Ingelheim. Advisory Panel; Eli Lilly and Company. Consultant; Eli Lilly and Company. Speaker's Bureau; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. Advisory Panel; Novo Nordisk A/S. Consultant; Novo Nordisk A/S. Employee; Novo Nordisk A/S. Research Support; Novo Nordisk A/S. Speaker's Bureau; Novo Nordisk A/S. Stock/Shareholder; Novo Nordisk A/S. Advisory Panel; Sanofi. Speaker's Bureau; Lundbeck. Advisory Panel; Zealand Pharma A/S. Consultant; Zealand Pharma A/S. Research Support; Zealand Pharma A/S. Speaker's Bureau; Zealand Pharma A/S. Stock/Shareholder; Zealand Pharma A/S.

Funding

This work was supported by a research grant from the Danish Diabetes and Endocrine Academy, which is funded by the Novo Nordisk Foundation, grant number NNF22SA0079901
1616-P: MENTSH—A Mitochondrial Microprotein and SNP-Associated with Diabetes in People with Native American Ancestry
Authors: YEN KELVIN , COHEN PINCHAS
Published: June 2024

Introduction & Objective: The mitochondria has been implicated in the etiology of diabetes, but the role of mitochondrial microproteins in this process has not been thoroughly investigated. Furthermore, diabetes prevalence differs between races and ethnicities, and although social economic factors are a major cause, we wanted to examine if genetics also played a role. Our objective was to 1) determine if variations in the mitochondrial genome correlated with diabetes and 2) determine if mitochondrial microproteins played a role in diabetes.

Methods: We performed a mitochondrial genome focused GWAS on the Health and Retirement Study, which a study of over 15,000 individuals over the age of 50 years in the USA. In vivo studies were performed in mice on a high fat diet (60% fat) or ob/ob mice that lack leptin. Western blots and other molecular biology techniques were performed using standard procedures.

Results: While performing a mitochondrial focused GWAS (miWAS), we have discovered a common SNP in populations of Native American descent that is associated with an increased chance of diabetes and also interrupts the start codon of a novel mitochondrial microprotein that we call MENTSH. Supporting this finding, administration of this microprotein in different mouse models of diabetes (60% high fat diet and ob/ob mice that lack leptin) can attenuate the disease progression. Treatment with MENTSH and MENTSH analogues improved glucose tolerance as measured by GTT and reduced weight gain. Molecularly, we find that MENTSH differentially affects AKT phosphorylation in muscle and fat.

Conclusion: We have discovered a SNP and a previously unknown microprotein that are now implicated in diabetes. Administration of this microprotein to mouse models of diabetes improves their outcomes. This discovery opens up the possibility of using MENTSH or its analogues as a novel therapeutic approach for diabetes.

Disclosure

K. Yen: None. P. Cohen: None.
1627-P: A Novel Compound Identified by High-Throughput Screening Activates UCP1 and Inhibits Obesity and Related-Metabolic Disorders
Authors: ONODERA KEN , HASEGAWA YUTAKA , ISHIGAKI YASUSHI
Published: June 2024

Introduction and Objective: Obesity and its related metabolic complications are major public health problems. Promoting thermogenesis in adipose tissue has been a promising strategy for the treatment of obesity and related metabolic complications. Our objective is to identify compounds that promote thermogenesis in adipocytes and to elucidate their functions and roles in metabolism.

Methods: To identify compounds that directly promote thermogenesis from a structurally diverse set of 4800 compounds, we utilized a cell-based platform for high-throughput screening that activates uncoupling protein 1 (Ucp1) expression in adipocytes.

Results: Through consecutive screenings, we identified one candidate compound as a potential UCP1 activator. Further characterization of this compound revealed that it induced cellular thermogenesis in adipocytes with little cytotoxicity. In addition, mice treated with this compound exhibited a slower rate of weight gain, improved insulin sensitivity, and increased energy expenditure in a diet-induced obesity model. Mechanistically, this compound increases mitochondrial biogenesis by elevating maximal respiration, which is partly mediated by the protein kinase A (PKA)-p38 mitogen-activated protein kinase (MAPK) signaling pathway. A further comprehensive genetic analysis of adipocytes treated with these compounds revealed two novel UCP1-dependent thermogenic genes, potassium voltage-gated channel subfamily C member 2 (Kcnc2) and predicted gene 5627 (Gm5627).

Conclusions: The identified compound can serve as a potential therapeutic drug for the treatment of obesity and its related metabolic disorders. Furthermore, our newly clarified thermogenic genes play a crucial role in UCP1-dependent thermogenesis in adipocytes.

Disclosure

K. Onodera: None. Y. Hasegawa: None. Y. Ishigaki: None.
1631-P: Cardiac-Specific mGPDH Deficiency Promotes Adipose Tissue Thermogenesis and Improves Obesity via SERPINA1E Secretion
Authors: QU HUA
Published: June 2024

Despite its well-documented effectiveness for treating obesity and type 2 diabetes, the clinical approved medicines for weight loss are still limited due to the unclear underlying mechanisms. Current study identified a mitochondrial protein mGPDH, and found that its globally knockout (GKO) resistant to HFD-induced obesity. mGPDH GKO showed 16.7% reduction of body weight compared with WT mice. Further MRI composition analyzer showed that fat mass, but not lean mass was significantly reduced after GKO. The volume and mass of iWAT were reduced significantly in GKO mice, but not eWAT or BAT. Food consumption was similar between GKO and WT mice fed with HFD, while energy expenditure assessed by metabolic cage system was significantly increased in both light and dark phases in HFD-GKO mice. Unexpectedly, neither the adipose- nor liver-specific mGPDH KO could repeat the protective role of GKO on HFD-induced obesity, while the cardiac-specific KO did. Mechanically, by compared tissue and serum proteomics, we identified a secretory protein SERPINA1E and preliminarily proved that it might mediate the obesity against effects of cardiac mGPDH. In sum, our study highlights a novel cross-organ mechanisms underlying weight loss, and mGPDH/SERPINA1E pathway might serve as a potential therapeutic target for obesity and its related diseases.

Disclosure

H. Qu: None.