bluuebunny/crossref_metadata_2025 huggingface dataset:
1209-P: The Influence of Chronic Metformin Exposure for Gestational Diabetes on Infant Mesenchymal Stem Cell Response
Authors: BIAGIONI ERICKA M. , ROWE JOHN C. , YENDAMURI SRIPALLAVI , ZHENG DONGHAI , WISSEMAN BREANNA L. , FISHER-WELLMAN KELSEY H. , DARRELL NEUFER P. , MAY LINDA , BROSKEY NICHOLAS T.
Published: June 2024

Introduction & Objectives: Offspring exposed to metformin treatment for gestational diabetes (GDM) experience altered growth patterns, increasing the risk of cardiometabolic diseases later in life. The adaptive cellular mechanisms underlying these altered growth patterns in offspring remain unclear. Therefore, the objective of this study was to determine if chronic metformin exposure from GDM treatment elicits infant cellular metabolic adaptations.

Methods: In a cross-sectional design, 22 pregnant women with GDM treated solely with metformin (Met; n=12) were compared to those treated exclusively by diet (A1DM; n=10). GDM was diagnosed between 24-28 weeks gestation by 2-hr 75g oral glucose tolerance test. Women were matched for age, race, BMI, and infant sex. Umbilical cord derived mesenchymal stem cells (MSCs) were used to study infant metabolism in vitro. Content of mitochondrial respiratory complexes were assessed by Western blot and intracellular lipid content was measured by Oil Red O staining. Substrate oxidation and insulin action were measured with 14C radiolabeled glucose, palmitate, and oleate at baseline and following a 24-hr lipid challenge. ANOVAs and t-tests were used to examine differences between groups.

Results: No differences in gestational age at delivery (p=0.55), infant blood glucose at delivery (p=0.52), birth weight (p=0.88), ponderal index (p=0.23), or infant circumferences of abdominal (p=0.38), chest (p=0.88), or head (p=0.46) were observed between groups. MSC outcomes revealed no differences in substrate metabolism except for lower rates of oleate oxidation among Met-MSCs at baseline (p=0.03). No differences in mitochondrial content or lipid content were detected.

Conclusions: Met-MSCs had no differences in substrate oxidation (albeit oleate), lipid storage, or mitochondrial content compared to A1DM. These cellular outcomes may not explain the altered growth patterns in infants exposed to metformin in utero.

Disclosure

E.M. Biagioni: None. J.C. Rowe: None. S. Yendamuri: None. D. Zheng: None. B.L. Wisseman: None. K.H. Fisher-Wellman: None. P. Neufer: None. L. May: None. N.T. Broskey: None.

Funding

National Institutes of Health (R01DK120296)
1227-P: Observational Study on Subclinical Inflammation and Lymphocyte Distribution in Adipose Tissue during Pregnancy and Gestational Diabetes Mellitus
Authors: SHANKAR ANAND , SINHA AJAY K. , DAS AMIT K. , GUHA SHAIBAL , KUMAR SUBHASH
Published: June 2024

Introduction: Subclinical inflammation within adipose tissues is known to influence metabolic health, particularly during pregnancy and in conditions like Gestational Diabetes Mellitus (GDM). This study aims to investigate the patterns of inflammation and lymphocyte presence in subcutaneous and visceral adipose tissues during pregnancy, with a focus on the impact of GDM.

Methods: This observational study included 100 pregnant women, 50 with GDM and 50 without (controls), matched for age and BMI. Biopsies of subcutaneous and visceral adipose tissues were taken during cesarean sections. Histological examinations were performed to identify inflammatory markers and lymphocyte counts. The comparison between groups and tissue types was analyzed using independent t-tests and multivariate regression to adjust for potential confounders.

Results: Subclinical inflammation and lymphocyte counts were significantly higher in GDM patients' adipose tissues (inflammation: 2.5±0.8 GDM vs. 1.3±0.6 controls, p<0.001; lymphocytes: 25±5 vs. 15±4, p<0.001). Visceral tissue showed more inflammation (2.8±0.7) than subcutaneous (2.2±0.7) in GDM (p<0.01). Inflammation severity correlated with HbA1c (r=0.62, p<0.001) and gestational age at diagnosis (r=0.47, p<0.01).

Conclusion: Subclinical inflammation, higher lymphocyte counts in adipose tissues, and GDM have been associated in the study. Visceral adipose tissue had more inflammation, suggesting a therapeutic attention. Understanding these patterns can help reduce GDM's inflammatory effects on mothers and children. Following these findings, additional study is needed to determine mechanisms and therapies.

Disclosure

A. Shankar: None. A.K. Sinha: None. A.K. Das: None. S. Guha: None. S. Kumar: None.
1228-P: Pregnancy Outcomes in Women with HNF4A and HNF1A-MODY
Authors: CROWLEY MAIREAD , BACON SIOBHAN , KINSLEY BRENDAN T. , HATUNIC MENSUD , KENNELLY MARIA , BYRNE MARIA M.
Published: June 2024

Introduction & Objective: HNF4A-MODY is associated with macrosomia and neonatal hypoglycemia. Glycemic control is achieved during pregnancy with insulin or sulphonylurea therapy. We aim to determine pregnancy outcomes in women with HNF4A-MODY and HNF1A-MODY.

Methods: We performed a multi-center retrospective review of pregnancy outcomes (n=39) in 14 women with HNF4A-MODY and (n=145) in 46 women with HNF1A-MODY. Offspring genotype was known in 13 HNF4A-MODY and 36 HNF1A-MODY. Outcomes included offspring birth centile, gestational age, mode of delivery and incidence of neonatal hypoglycemia (NH).

Results: Miscarriage rates were 15% for HNF4A-MODY and 23% for HNF1A-MODY respectively (p=0.24). Overall median birthweight was 3.7±0.5 vs. 3.6±0.5kg (p = 0.11) and birthweight centiles were 85±17 vs. 70±29 (p=0.22). Incidence of LGA was 50% vs 32% (p=0.41). Cesarean section rate was 17% vs 26% respectively (p=0.3). NH was significantly greater in HNF4A-MODY (36% vs 14%, p value = 0.014). HNF4A-MODY genotype positive offspring (n=12) had a median birthweight of 4.78±1.2kg (83% LGA).

Diabetes was confirmed in 137 pregnancies (HNF4A:HNF1A = 26:111). Third trimester median insulin doses were 0.33unit/kg/day vs. 0.61±0.13unit/kg/day for HNF4A vs. HNF1A (p=0.85). HbA1c was similar(trimester one: 42±11 vs. 40±6 mmol/mol, p = 0.86, trimester 3: 37±7 vs. 34±4mmol/mol, p = 0.88). HNF4A-MODY offspring of diabetic mothers were significantly heavier than offspring of nondiabetic mothers (3.82±0.6 vs. 3.3±0.5kg, p=0.048) however HNF1A-MODY offspring were not (3.64±0.43 vs. 3.32±0.5kg, p=0.2).

Conclusion: Increased birthweight and neonatal hypoglycemia was observed in HNF4A-MODY positive offspring. Glycemic control was achieved with relatively low doses of insulin.

Disclosure

M. Crowley: None. S. Bacon: None. B.T. Kinsley: None. M. Hatunic: None. M. Kennelly: None. M.M. Byrne: Speaker's Bureau; Novo Nordisk A/S. Advisory Panel; Novo Nordisk A/S. Research Support; Novo Nordisk A/S.

Funding

Irish Endocrine Society Clinical Science Award 2022
1269-P: Cumulative Effect of Early-Onset Type 2 Diabetes on Cardiac Dysfunction—The Coronary Artery Risk Development in Young Adults (CARDIA) Study
Authors: YOSHIDA YILIN , FERDINAND KEITH C. , AGUILAR DAVID , FONSECA VIVIAN
Published: June 2024

Objective: Adults with early-onset type 2 diabetes (T2D, diagnosed

<age 40)="" experience="" premature="" and="" more="" severe="" cardiovascular="" complications.="" we="" investigated="" cumulative="" hyperglycemia="" insulin="" resistance="" (ir)="" over="" 25="" years="" in="" patients="" with="" early-onset="" t2d="" related="" to="" cardiac="" dysfunction="" midlife.="" Methods: We used Coronary Artery Risk Development in Young Adults study (CARDIA, Year 0 to 25) data. Early-onset T2D was self-reported or by fasting glucose (FG)≥126 or oral glucose≥200 mg/dL at/before Year 10. Left ventricular systolic function was estimated by ejection fraction and global longitudinal strain (GLS); diastolic function by early peak diastolic mitral annular velocity, e’, and mitral E/e′. We used the area under the growth curve (AUC) derived from quadratic random-effects models of≥4 repeated measures of FG and HOMA-IR to estimate the cumulative burden of T2D. We performed linear regressions to examine the associations of the total AUC of FG or HOMA-IR with echocardiographic outcomes, accounting for sex, race, education, mid-life age, smoking, alcohol drinking, hypertension, hyperlipidemia, diabetic medication, and heart rate.

Results: We included 271 CVD-free patients with early-onset T2D and 514 sociodemographic-matched individuals with euglycemia. In adjusted models, an SD higher AUC of FG was significantly associated with the worsening of diastolic function (β coefficients for e’= - 0.18 and E/e’=0.27) and marginally associated with the worsening of GLS (β=0.13). However, these associations were not significant in the euglycemia group. One SD higher AUC of HOMA-IR was associated with the worsening of e’ and GLS irrespective of T2D status (e’ β= -0.2 and -0.16, and GLS β=0.13 and 0.19 in T2D and euglycemia, respectively).

Conclusion: Cumulative hyperglycemia alters midlife diastolic function in patients with early-onset T2D. Sustained IR negatively affects both systolic and diastolic function regardless of T2D status.

Disclosure

Y. Yoshida: None. K.C. Ferdinand: Consultant; Amgen Inc., Novartis Pharmaceuticals Corporation, Lilly Diabetes, Janssen Pharmaceuticals, Inc., Medtronic, Boehringer-Ingelheim. D. Aguilar: None. V. Fonseca: Consultant; Abbott, Bayer Inc. Stock/Shareholder; BRAVO4HEALTH, LLC. Consultant; Corcept Therapeutics. Speaker's Bureau; Eli Lilly and Company. Research Support; Fractyl Health, Inc. Consultant; Sun Pharmaceutical Industries Ltd. Stock/Shareholder; Amgen Inc.

Funding

American Diabetes Association (7-23-JDFWH-10)
1276-P: Insulin Resistance Is Associated with Salt Sensitivity and Endothelial Dysfunction
Authors: SANCHEZ RAMIRO A. , SANCHEZ MARIA J. , RAMIREZ AGUSTIN J.
Published: June 2024

Aims: To evaluate in non-obese young normotensive salt sensitive (SS) or salt resistant (SR) offspring of hypertensive parents (offSS-HT or offSR-HT, respectively) 1) the possible association with insulin resistance and endothelial disfunction

Design and Methods: 41 offSS-HT (29±2 years; 20 female), and 36 offSR-HT (26±2 years; 16 female). Both groups were considered lean with a BMI 25kg/m2 and a waist circumference <98cm in males or <105cm in females. At baseline, creatinine clearance (CrCl), 24h urinary albumin excretion (UAE), glycemia and insulinemia, before and after 60 and 120 min a glucose overload (75 g) were measured. HOMA = fasting glucose (mg/dl × fasting insulin (μU/ml)/22.5 and the area under the curve of the Oral Glycemia Tolerance Test (OGTT) were calculated. Post ischemic minimun vascular resistance and forearm blood flow by pletismography was also assessed at baseline to determine endothelial function

Results: In offSS-HT, UAE (53±3μg.min) and CrCl (124±6ml/min) were significantly higher than in offSR-HT. (UAE: 12±4μg.min; p, 0.01 and CrCl 107±6ml.min; p, 0.01). An impaired vasodilatory post ischemic response was observed in offSS-HT (1.8±0.3 AU) compared to offSR-HT (2.8±0.6 AU; (p<0.01)At 60 min and 120-min, glycemia and insulinemia, post OGTT, were higher in offSS-HT (140.1±18; 130±15mg.dl and 31.8±11; 31.8±11 IU, respectively) than in offSR-HT (116.5±5: 6.5±3mg.dl and 18.8±7; 21.3±4IU, respectively; p<0.01).In a similar way, in SS-HT, glycemia AUC (258.80±25) and HOMA-IR (3.26±1.36 were greater compared to offSR-HT(AUC: 194.39±6, p<0.0001; HOMA-IR: 1.52±0.27, p < 0.002).

Conclusions: Insulin resistance, endothelial disfunction and glomerular hyperfiltration was found in offSS-HT suggesting a familiar aggregation and a higher cardio-reno-metabolic risk when compared with offSR-HT.

Disclosure

R.A. Sanchez: None. M.J. Sanchez: None. A.J. Ramirez: None.
1283-P: Association between Body Shape and the Risk of Cardiovascular Disease in People with Obesity
Authors: HWAN PARK JUNG
Published: June 2024

Background: Although obesity is a significant risk factor of metabolic disorders, some people have metabolically healthy obesity (MHO). Many studies reported inconsistent results about the development of cardiovascular disease (CVD) in individuals with MHO. This study aimed to evaluate the effect of body shape on CVD outcomes in individuals with MHO.

Methods: We analyzed the data of 8,416 participants from the Korean Genome and Epidemiology Study, a 10-year follow-up population-based cohort study. To evaluate the participants’ body shape, we calculated the Z-score of log-transformed A Body Shape Index (LBSIZ) and divided the participants into the following groups: metabolically healthy normal weight (MHNW), MHO, metabolically unhealthy normal weight (MUNW), and metabolically unhealthy obesity (MUO). Then, each group was classified into four subgroups based on the LBSIZ quartile. A multivariate logistic regression analysis was performed to evaluate the effect of LBSIZ for CVD events according to obesity phenotypes. The graphical relationships between LBSIZ and CVD events were also evaluated with restricted cubic spline plots.

Results: During the 10-year study period, 696 CVD events occurred in the participants. In the multivariate Cox regression model, MHO individuals did not have an increased risk of CVD compared with MHNW individuals. However, the further analysis with LBSIZ showed that the MHO participants with 3rd and 4th LBSIZ quartiles had a significantly higher hazards ratio for CVD events, whereas those with 1st and 2nd LBSIZ quartiles did not have an elevated risk of CVD compared to the MHNW participants with 1st quartile. In the restricted cubic spline regression, LBISZ showed a linear relationship with CVD events regardless of obesity phenotypes.

Conclusion: The MHO individuals with a high quartile of LBSIZ have a significant increased risk for CVD events.

Disclosure

J. Park: None.
1329-P: Correlates of Diabetes Mellitus in Care-Seeking Populations at Commercial Eye-Care Centres in Kampala, Uganda
Authors: KAGANDA PASCHAL N. , ANGUZU RONALD , KICONCO ARTHUR , MUTYOBA JOAN N.
Published: June 2024

Introduction & Objective: Incident diabetes mellitus (DM) cases are increasing in urban settings in Uganda. Commercial eye centers are potential options to improve DM detection in urban populations. This study aimed to determine the factors independently associated with DM in an eyecare seeking population in commercial eye centers in Kampala, Uganda.

Methods: This cross-sectional study surveyed 501 consecutively recruited clients attending four private ophthalmology centres in Kampala, Uganda in June 2022. Our outcome was presence of DM measured using random blood sugar tests ≥7 mmol/L (yes) vs <7mmol/L (no). Modified Poisson regression assessed factors independently associated with DM in this study population. Adjusted prevalence rate ratios (PRR) and 95% confidence intervals (CI) were reported.

Results: Among 501 participants, 31.7% (n=159) had DM and 7.4% (n=37) had pre-DM. After adjusting for potential confounders, participants were more likely to be diabetic; (i) 37% times higher among those who have never taken an A1C compared to those who ever had A1C tests (adjusted PRR 0.63, 95%CI 0.48-0.83), (ii) 46% times higher among those who never tested for DM compared to those who had ever tested for DM (adjusted PRR 0.54, 95%CI 0.38-0.75), and (iii) 45% times higher among participants who were aware of DM than those aware of DM (adjusted PRR 0.54, 95%CI 0.38-0.75)

Conclusion: Increasing symptom awareness and testing for DM suggests improvement in DM detection among urban eyecare seeking populations in Kampala. DM awareness and early DM treatment initiation are potential opportunities for future research and practice.

Disclosure

P.N. Kaganda: None. R. Anguzu: None. A. Kiconco: None. J.N. Mutyoba: None.
1338-P: Low Birthweight Is Associated with Elevated Risk of Chronic Kidney Disease in Type 2 Diabetes—A Follow-up Study of Persons Diagnosed with Type 2 Diabetes in the DD2 Cohort
Authors: LÜHR HANSEN ALEKSANDER , FYNBO CHRISTIANSEN CHRISTIAN , BRØNS CHARLOTTE , ENGELHARD LEONIE M. , HANSEN TORBEN , NIELSEN JENS S. , VESTERGAARD PETER , HOJLUND KURT , JESSEN NIELS , HECHT OLSEN MICHAEL , SØRENSEN HENRIK T. , ROSSING PETER , THOMSEN REIMAR W. , VAAG ALLAN A.
Published: June 2024

Introduction & Objective: Low birthweight (BW), a proxy for an adverse intrauterine environment, has been associated with risk of type 2 diabetes (T2D) and chronic kidney disease (CKD) later in life. The extent to which lower birthweight among people with T2D increases risk of CKD is unknown.

Methods: Original midwife records were reviewed for 5979 people recently diagnosed with T2D in the Danish Center for Strategic Research in T2D (DD2) cohort. Individuals were followed for the incidence of CKD, defined by 1) two eGFR values <60ml/min per 1.73m2, 90 to 365 days apart, or 2) two urine albumin/creatinine ratios >30mg/g, 90 to 365 days apart. Ten-year standardized risks of CKD were estimated by the parametric G-formula using the Aalen-Johansen estimator, considering death as a competing risk. Adjusted hazard ratios (aHRs) were computed using Cox regression analysis. Continuous relations between BW and incident CKD were assessed with linear and restricted cubic spline regression. All models were standardized or adjusted for sex, age, calendar year at birth, family history of diabetes, and born-at-term status.

Results: A total of 1443 incident CKD outcomes occurred in people with T2D during median follow-up of 8.5 years. Spline models showed progressively increasing aHRs of CKD with successively lower BW. The 10-year standardized risk of CKD was 39.9% in people with low BW <2500 g, compared with 33.5% in people with a BW of 2500-4500 g, yielding a CKD risk difference of 6.4% (95% CI: -0.3, 13.3) and an aHR of 1.25 (95% CI: 0.99, 1.58). People with T2D and a high BW >4500 g, compared with a BW of 2500-4500 g, had similar 10-year standardized CKD risks of 31.7% vs. 33.5%, respectively, corresponding to an aHR of 0.93 (95% CI: 0.59, 1.47).

Conclusion: Lower birthweight is associated with elevated risk of CKD among people with type 2 diabetes.

Disclosure

A. Lühr Hansen: None. C. Christiansen: None. C. Brøns: Stock/Shareholder; Novo Nordisk A/S. L.M. Engelhard: None. T. Hansen: None. J.S. Nielsen: None. P. Vestergaard: None. K. Hojlund: None. N. Jessen: None. M. Olsen: Other Relationship; AstraZeneca, Novo Nordisk A/S. Advisory Panel; Novo Nordisk A/S. Other Relationship; Teva Pharmaceutical Industries Ltd. H.T. Sørensen: Other Relationship; See text. P. Rossing: Other Relationship; AstraZeneca, Bayer Inc., Boehringer-Ingelheim, Gilead Sciences, Inc., Novo Nordisk, Eli Lilly and Company, Novartis AG, Abbott Diagnostics. R.W. Thomsen: None. A.A. Vaag: None.

Funding

Danish Agency for Science (09-067009 and 09-075724); Novo Nordisk Foundation ( NNF17SA0030962-2, NNF20O0063292, NNF17SA0030364)
1354-P: Diabetes-Related Acute Complications during the COVID-19 Pandemic among Medicare Fee-for-Service Beneficiaries
Authors: ZHOU XILIN , ANDES LINDA J. , ROLKA DEBORAH B.
Published: June 2024

Introduction & Objective: During the COVID-19 pandemic, health care utilization sharply declined, raising concerns about the impact on health outcomes. This study examined changes in diabetes-related acute complications (ACs) over the initial 3 years of the pandemic. ACs require immediate medical attention and may be caused by delaying or canceling essential diabetes care.

Methods: Using Medicare fee-for-service claims, we identified persons with diabetes (≥ 67 years old) and ACs with International Classification of Diseases diagnosis codes. Age- and sex-adjusted monthly AC prevalence, per 1,000 people, were estimated in total and by setting (inpatient and outpatient). We compared data during the pandemic months (03/2020-02/2023) and the corresponding pre-pandemic months (03/2019-02/2020).

Results: Total AC prevalence decreased by 14-30% in the initial 3 months of the pandemic (03/2020-05/2020) and remained 3-15% lower than pre-pandemic levels thereafter. Outpatient AC prevalence mirrored the overall trend. Inpatient AC prevalence had a larger reduction, declining by 14-33% initially and sustaining a 4-22% reduction subsequently.

Conclusion: The findings suggest a decrease in diabetes-related AC prevalence among Medicare beneficiaries during the pandemic. Further analyses may be needed to explore the underlying reasons behind these observed changes.

Disclosure

X. Zhou: None. L.J. Andes: None. D.B. Rolka: None.
1381-P: Beta-Cell Failure Is Frequently the Cause of Diabetes in Africans
Authors: SAYED MARIAM , THYPARAMBIL ARAVINDAKSHAN PRAMODKUMAR , WORTHY CHARLITA , HUEFNER ELIZA A. , HURSTON JAMAIICA , DUBOSE CHRISTOPHER , JAGANNATHAN RAM , SUMNER ANNE E.
Published: June 2024

Emerging data suggests that type 2 diabetes (DM) incidence is rapidly rising in Africa. Beta-cell failure rather than insulin resistance (IR) may be the precipitator. As causative data allows for optimization of therapy, screening strategies to determine when beta-cell failure is the primary cause of DM are essential. OGTT were performed in 589 African-born Blacks (Male: 64% (374/589), Age: 39±11y (mean±SD), BMI: 27.1±4.5 kg/m2). Insulin resistance (IR) was defined by the threshold at the lowest quartile of the population distribution for Matsuda Insulin Sensitivity Index (MISI) (≤2.89) and upper quartile for HOMA-IR, Lipid Accumulation Product (LAP) and TG-Glucose Index (TyG) (Table). With the MISI as the standard, the ability to predict IR by each index was assessed by AUC-ROC. Beta-cell failure was defined by the presence of DM in the absence of IR. K-statistic was used for beta-cell failure detection by each index relative to the MISI. DM was identified in 7% (40/589). In Africans with DM, beta-cell failure occurred in 45% (18/40); IR in 55% (22/40). AUC-ROC for IR prediction was highest for HOMA-IR (Table). By k-statistic criteria, the ability of HOMA-IR to detect beta-cell failure was excellent, but only fair for LAP and TyG. Overall, nearly half of Africans with DM have beta-cell failure as the primary cause, denoting the critical need for determining DM pathophysiology, and HOMA-IR may be the most clinically relevant test to detect etiology.

Disclosure

M. Sayed: None. P. Thyparambil Aravindakshan: None. C. Worthy: None. E.A. Huefner: None. J. Hurston: None. C. DuBose: None. R. Jagannathan: None. A.E. Sumner: None.
1384-P: COVID-19 Vaccination Uptake among 3,779,733 Adults With and Without Diabetes
Authors: BUTALIA SONIA , SHAH BAIJU R. , SIGAL RONALD J. , BENHAM JAMIE L. , WICKLOW BRANDY , YU CATHERINE H. , DASGUPTA KABERI , AMED SHAZHAN , CONSTANTINESCU CORA , LUAN CHU MANH , KAUL PADMA
Published: June 2024

Introduction & Objective: Public health measures, especially vaccination, are important for COVID-19 risk reduction. Population level vaccine uptake in people with diabetes is understudied. We assessed COVID-19 vaccine uptake among adults with and without diabetes and the factors associated with vaccination.

Methods: This retrospective, population-based cohort study included adults (18+ years) living in Alberta, Canada on December 14, 2020, the date of vaccine availability. Diabetes status was determined using a validated algorithm between April 1, 2002 and December 14, 2020. All individuals were followed until March 31, 2022. The primary outcome was full vaccination as defined by the manufacturer. Descriptive statistics were used to compare vaccination status among people with and without diabetes and multivariate logistic regression assessed the factors associated with full vaccination adjusting for age group, sex, diabetes status, material deprivation, urban/rural residence, and comorbidities (Charlson Comorbidity Index (CCI) score).

Results: We identified 3,779,733 adults (49.7% female, mean age 46.8 ± 17.8 years) with 9.8% having diabetes. Overall, 75.5% of the total cohort were fully vaccinated. A higher proportion of people with diabetes, compared to those without, were fully vaccinated (83.9% vs. 74.6%, p<0.001). The presence of diabetes (aOR 1.48; 95% CI 1.46-1.49), female sex (aOR 1.20; 95% CI 1.91-1.21), and CCI score >1 (aOR 1.67; 1.66-1.68) were associated with being fully vaccinated, whereas the age group of ≥ 75 years (aOR 0.84; 95% CI 0.83-0.86), rural residence (aOR 0.60; 95% CI 0.60-0.60) and higher material deprivation (aOR 0.88; 95% CI 0.87-0.89) were associated with lower vaccination.

Conclusions: People with diabetes had high COVID-19 vaccination uptake and were more likely than the general population to be fully vaccinated. We also identified several key factors associated with lower uptake highlighting the need for understanding facilitators of vaccination.

Disclosure

S. Butalia: None. B.R. Shah: None. R.J. Sigal: Research Support; Lexicon Pharmaceuticals, Inc., Bayer Inc., Novo Nordisk. J.L. Benham: None. B. Wicklow: None. C.H. Yu: None. K. Dasgupta: None. S. Amed: None. C. Constantinescu: Research Support; Pfizer Inc. Other Relationship; Sta HealthCare Communications, Canadian Research Network. M. Chu: None. P. Kaul: None.

Funding

Canadian Institutes of Health Research (CIHR) 483868
1423-P: A Longitudinal Analysis of Changes in Therapies and Outcomes among People with Type 2 Diabetes
Authors: BELTRAN ALAN , ZENG ALISON , BELL TREVOR , WOOD RICHARD
Published: June 2024

About 1 in 10 Americans are estimated to have Type 2 diabetes (T2D). The ever-evolving landscape of T2D management demands continual adaptation to diverse therapeutic interventions. Through a 5-year retrospective cohort study, this research assesses therapy usage for people with T2D (PWT2) and the impact unique regimens have on clinical outcomes. From 2018 to 2023, 2,310 PWT2 on various therapy regimens were surveyed four times per year about their diabetes management. Therapy usage included insulin, GLP-1 agonists, SGLT-2 inhibitors, and continuous glucose monitoring (CGM). Key health outcomes assessed were clinically recommended HbA1c of ≤7 and obesity (BMI ≥30). Longitudinal analysis revealed notable shifts in therapy usage among PWT2. From 2018 to 2023, overall insulin usage decreased 3%, GLP-1 (16% to 33%) and SGLT-2 usage (10% to 20%) doubled, and CGM usage increased fourfold (4% to 15%). Notably, among patients on insulin, SGLT-2 usage exceeded GLP-1 usage, while among those not on insulin, GLP-1 usage increased at a higher rate than SGLT-2s. These shifts in therapy combinations had diverse impacts on health outcomes. PWT2 on insulin without any other therapy showed no significant reduction in HbA1c or BMI over the five years, but those on insulin and a GLP-1, SGLT-2, or both showed significant reduction in HbA1c (p<.01). Among insulin users, those on an SGLT-2 only were the only group who did not experience reductions in BMI. PWT2 not on insulin or any other therapy experienced significant increases in HbA1c over the five-year period (p<.01), though all PWT2 not on insulin were able to reduce BMI significantly (p<.05). Results show that PWT2 who take insulin alone experience sub-optimal health outcomes, compared to those who take a combination therapeutic approach. While lifestyle changes will help PWT2 not on insulin, a lack of other therapies may lead to increased HbA1c. These findings underscore the need for tailored approaches to optimize T2D management and patient outcomes.

Disclosure

A. Beltran: Research Support; Abbott, Dexcom, Inc., Eli Lilly and Company, diaTribe, Insulet Corporation, Medtronic, Roche Diabetes Care, Tandem Diabetes Care, Inc., Ypsomed AG, Teladoc Health. A. Zeng: Employee; dQ&A. Research Support; Abbott, Dexcom, Inc., Eli Lilly and Company, diaTribe, Insulet Corporation, Medtronic, Roche Diabetes Care, Tandem Diabetes Care, Inc., Ypsomed AG, Teladoc Health. T. Bell: Research Support; Abbott, Dexcom, Inc., Eli Lilly and Company, diaTribe, Insulet Corporation, Medtronic, Roche Diabetes Care, Tandem Diabetes Care, Inc., Ypsomed AG, Teladoc Health. R. Wood: Research Support; Abbott, Dexcom, Inc., Eli Lilly and Company, diaTribe, Insulet Corporation, Medtronic, Roche Diabetes Care, Tandem Diabetes Care, Inc., Ypsomed AG, Teladoc Health.
15-OR: Diabetic Retinopathy (DR) Is Associated with Markers of Alzheimer's Disease (AD) in Type 1 Diabetes (T1D)
Authors: PAULEY MEGHAN E. , SHAPIRO ALLISON , COUGHLAN CHRISTINA , DONG FRAN , SNELL-BERGEON JANET K.
Published: June 2024

Introduction & Objective: DR is shown to predict AD in type 2 diabetes, but less is known in T1D where DR burden is significant. This study examined differences in levels of phosphorylated tau-181 (pTau181), a validated preclinical biomarker of AD neuropathology, between adults with and without T1D, and its relationships with DR.

Methods: Plasma samples from the Coronary Artery Calcification in Type 1 Diabetes study were analyzed for pTau181 (pg/mL). Participants were adults with T1D and age-similar controls. DR was classified as none/mild (Early Treatment Diabetic Retinopathy Study [ETDRS] score ≤31) or moderate/severe (ETDRS score ≥47). Log transformed pTau181 was examined by group via linear regression adjusted for age, BMI, sex, race, and smoking status.

Results: 121 participants (median age 53 years, 55% female) were included (T1D with moderate/severe DR, n=41; T1D with none/mild DR, n=41; controls, n=39). In the adjusted model, moderate/severe DR was associated with significantly higher pTau181 compared to controls (estimate=0.13, SE=0.05, p=0.01). Age was positively associated with pTau181 (p=0.001).

Conclusion: Adults with T1D and moderate/severe DR show evidence of preclinical AD neuropathology, but adults with T1D and no/mild DR do not differ from people without T1D. Further studies are needed to delineate relationships between DR and AD in T1D.

Disclosure

M.E. Pauley: None. A. Shapiro: None. C. Coughlan: None. F. Dong: None. J.K. Snell-Bergeon: None.

Funding

NIH R01 HL113029; NIH NIDDK (T325T32DK063687); DiabDocs Physician-Scientist Career Development Award: NIH NIDDK (K12DK133995) & The Leona M. and Harry B. Helmsley Charitable Trust to Stanford University (2305-06041)
1510-P: Adipocyte MicroRNA-802 Promotes Adipose Tissue Inflammation and Insulin Resistance by Modulating Macrophages in Obesity
Authors: YANG YUE , ZHANG FANGFANG , JIN LIANG
Published: June 2024

Introduction & Objective: Adipose tissue inflammation is now considered to be a key process underlying metabolic diseases in obese individuals. Macrophages accumulate in the adipose tissue and surround the dying or dead adipocytes like corona, which is witnessed to be the contributors to inflammation and obesity-induced insulin resistance. In this study, we aimed to identify key microRNA that regulates inter-cellular communication between lipid-overloaded adipocytes and macrophages, ultimately leading to adipose tissue inflammation and insulin resistance.

Methods: RNA sequencing was performed to analyze the adipocyte tissue of high-fat diet (HFD)-fed mice and those of normal chow-fed mice (NCD). We found progressive increase of microRNA-802 (miR-802) expression in adipose tissue with the development of dietary obesity in obese mice and humans. Then, the mechanism of miR-802 regulating adipose function was investigated by flow cytometric analysis, mouse metabolic studies, magnetic resonance imaging, and animal energy metabolism monitoring system.

Results: Our findings validated miR-802 increasing prior to macrophage accumulation. Adipose tissue-specific knockout of miR-802 lowered macrophage infiltration and ameliorated systemic insulin resistance. Conversely, the specific miR-802 overexpression in adipose tissue aggravated adipose inflammation in mice fed a high-fat diet. Mechanistically, miR-802 activates noncanonical and canonical NF-κB pathways by targeting its negative regulator, TRAF3, which translated into strong recruitment and M1-like polarization of macrophages.

Conclusion: We established that miR-802 expression is an inflammatory signal in adipocytes, and this effect occurs through sensitization of the NF-kB signaling pathway. Collectively, our data raise the possibility that manipulation of miR-802 action axis represents therapeutic potential for adipose inflammation treatment.

Disclosure

Y. Yang: None. F. Zhang: None. L. Jin: None.

Funding

National Natural Science Foundation of China (82373925,82070801); Natural Science Foundation of Jiangsu Province (BK20221520, BK20200569); The Fundamental Research Funds for the Central Universities (2020M671661,2632023GR07)
1515-P: Pyruvate Kinase Amplifies Insulin Secretion Downstream of the ß-Cell GLP1 Receptor
Authors: FOSTER HANNAH R. , LEWANDOWSKI SOPHIE L. , KIRCHNER RACHEL , CAPOZZI MEGAN , CAMPBELL JONATHAN , MERRINS MATTHEW J.
Published: June 2024

The advent of GPCR agonists and co-agonists that target the β-cell incretin receptors - GLP1R and GIPR - have revolutionized therapeutics for diabetes, though the signaling pathways downstream of these receptors have yet to be fully understood. Previous work in our lab has demonstrated the critical role of the glycolytic enzyme pyruvate kinase (PK) in the closure of KATP channels. However, PK activators also potentiate insulin secretion independent of KATP channel closure, suggesting additional roles for PK. We therefore sought to determine if PK potentiates insulin secretion downstream of GPCRs by modulating cAMP signaling. To elucidate the role of PK downstream of GPCRs, we employed live-cell imaging with subcellularly-targeted biosensors to track cAMP signaling over time in intact human and mouse islets in response to glucagon, GLP1, GIP, and tirzepatide. To further characterize the role of GLP1R and GCGR, chemical antagonism and mice deficient in β-cell GLP1R/GCGR were utilized in combination with TEPP-46, a pharmacologic activator of PKm2 and PKL. Our data demonstrates that PK amplifies cAMP signaling at the plasma membrane downstream of β-cell GPCRs. Specifically, there is enhanced protein kinase A (PKA) activity and increased insulin secretion in the presence of a PK activator with glucagon as a ligand. PK did not potentiate insulin secretion or PKA activity in response to GIP, indicating a receptor specific effect. Chemical antagonists and knockout experiments show that PK potentiates PKA activity primarily downstream GLP1R more than GCGR. These studies, which link glycolysis to GPCR signaling, suggest that biased GLP1R agonists that work via PK will more efficiently increase insulin secretion.

Disclosure

H.R. Foster: None. S.L. Lewandowski: None. R. Kirchner: None. M. Capozzi: None. J. Campbell: Research Support; Eli Lilly and Company, Novo Nordisk, Merck & Co., Inc. Advisory Panel; Structure Therapeutics, Inc. M.J. Merrins: None.

Funding

American Diabetes Association (1-18-JDF-017); NIH/NIDDK (R01DK113103); United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service (I01BX005113); NIH/NIDDK (T32DK007665 and F31DK126403); HRSA (T32HP10010); NIH/NIA (T32AG000213); National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH) (T32 DK007012; F32 DK116542); NIDDK, NIH (DK123075 and DK125353); United States Department of Veterans Affairs (I01 BX003700); NIH/NIDDK (R01 DK102598)
1524-P: Estradiol's Net, Sweet or Not—Estradiol Actions on Amygdalar Perineuronal Nets Regulate Blood Glucose in Male and Female
Authors: ZHANG NAN , ZENG TIANSHU , WANG CHUNMEI , XU YONG
Published: June 2024

Central regulation of blood glucose is getting more and more attention. However, amygdala is not traditionally considered as a regulation center for blood glucose. Here we show that perineuronal nets (PNNs) in posterodorsal medial amygdala (MePD) are required to maintain blood glucose levels and are regulated by estradiol. After gonadectomy (GDX), PNN intensity significantly decreased in both male and female mice in the MePD. Interestingly, 17β-estradiol, but not 5α-dihydrotestosterone, restored PNNs in the MePD and decreased glucose in both GDX male mice and female mice. To investigate the function of PNNs in the MePD, we manipulated PNN levels using the tetracycline-controlled Tet-On gene expression system. In TRE-PH20 mice, stereotaxic injection of AAV-hSynI-rtTAV16 to the MePD decreased PNN intensity in the MePD and caused increases in blood glucose and insulin resistance 3 weeks after the surgery, and increases in body weight gain and fat mass gain 9 weeks after the surgery. These mice showed a decrease in energy expenditure in HFD diet. In TRE-HAS2 mice, stereotaxic injection of AAV-hSynI-rtTAV16 to the MePD increased PNN intensity in the MePD and caused decreases in blood glucose, body weight gain and fat mass gain. PNNs enmesh GABAergic neurons in the MePD and destroying PNNs reduces both excitatory and inhibitor post-synaptic currents in GABAergic neurons. Our findings revealed an important role of estradiol in regulating glucose metabolism in not only female mice but also male mice, and identified PNNs in the MePD as novel participants in the central control of glucose homeostasis by estradiol.

Disclosure

N. Zhang: None. T. Zeng: None. C. Wang: None. Y. Xu: None.
1539-P: LRP1 Mediates Leptin Transport by Coupling with the Short-Form Leptin Receptor in the Choroid Plexus
Authors: KIM YOUNG-BUM , YANG WON-MO , RODRIGUES KELLEN , CHAN KIM SEUNG , FAN SHENGJIE , YOUNG JENNIE
Published: June 2024

Leptin is an adipocyte-derived satiety factor that suppresses food intake and increases energy expenditure by reaching anorexigenic neurons in the brain. While leptin typically interacts with the leptin receptor (LepR), evidence reveals a high binding affinity of leptin to the choroid plexus (ChP), a distinct brain barrier that mediates peripheral-brain signal communication, in LepR-deficient db/db mice and obese Zucker rats. This suggests that the ChP may be a major site for leptin transport through specific receptors other than LepR. Here, we show that LRP1 (low-density-lipoprotein receptor-related protein-1) transports leptin across the blood-CSF barrier in Foxj1-expressing cells highly enriched at the ChP. LRP1 deletion in Foxj1-expressing cells of the ChP leads to impaired leptin transport, resulting in leptin resistance and obesity. Mechanistically, we found that LRP1 is associated with the short-form leptin receptor, LepRa, a crucial step for leptin entry into the brain. In vitro study with ChP-derived Z310 epithelial cells demonstrated that leptin rapidly stimulated a ~1.8-fold increase in LRP1 internalization over control conditions but failed to induce LRP1 internalization in the absence of LepRa, suggesting LepRa is required for leptin-induced LRP1 internalization. Notably, leptin-induced LRP1 binding to LepRa is attenuated in the ChP of diet-induced obese mice, highlighting the pathophysiological relevance of this interaction. Our findings unravel a new cellular mechanism by which LRP1 functions as a key mediator of leptin delivery for maintaining metabolic homeostasis in energy intake.

Disclosure

Y. Kim: None. W. Yang: None. K. Rodrigues: None. S. Kim: None. S. Fan: None. J. Young: None.

Funding

National Institutes of Health (R01 DK123002)
1562-P: A Rare Case of Metastatic Nonfunctional Pancreatic Neuroendocrine Tumor with Transformation into Insulinoma with Refractory Hypoglycemia Requiring Everolimus Use
Authors: WAX PAMELA , OCAMPO MASCARO JAVIER , EADS JENNIFER , AMARO ANASTASSIA
Published: June 2024

Background: Most pancreatic neuroendocrine tumors (pNET) are non-functional and remain so over the course of a patient’s disease. Insulinoma is a form of functional pNET that manifests with hypoglycemia caused by inappropriate autonomous insulin secretion. These rare tumors usually present as a single benign tumor that is treated surgically. Surgery is not possible in patients with metastatic disease which leads to difficult to control often life-threatening hypoglycemia.

Clinical Case: We present a case of a 56 year old woman with a diagnosis of non-functional metastatic pNET that transformed into metastatic insulinoma with subsequent recurrent life-threatening hyperinsulinemic hypoglycemia. At the time of diagnosis, monthly lanreotide and temozolomide/capecitabine chemotherapy was started with initial successful control of disease. Upon disease progression, she was treated with peptide receptor radionuclide therapy (PRRT) during which she began having hyperinsulinemic hypoglycemic episodes refractory to treatment with both long and short acting somatostatin analogue therapy, glucocorticoids, and diazoxide. She received treatment with two cycles of 5-fluorouracil and oxaliplatin chemotherapy but was not well enough to continue. She was eventually started on everolimus in an attempt to control both hypoglycemia and pNET disease burden. This resulted in the resolution of hypoglycemia and later progression into hyperglycemia requiring insulin use. She was unable to tolerate higher doses of everolimus due to mucositis and cytopenias leading to a decreased dose. She passed away several months after initiation of therapy due to progression of malignancy.

Conclusion: This case not only demonstrates the rare ability of pNET to transform into a functional tumor, but also adds to other case reports that propose everolimus use as a potential option for management of hypoglycemia caused by insulinoma.

Disclosure

P. Wax: None. J. Ocampo Mascaro: None. J. Eads: Other Relationship; Janssen Pharmaceuticals, Inc. Advisory Panel; Merck & Co., Inc. Research Support; Seagen, Replimune, Arcus, Gilead Sciences, Inc., Oncolys, Merck & Co., Inc., Hutchmed, Amgen Inc. A. Amaro: Advisory Panel; Novo Nordisk Foundation. Research Support; Fractyl Health, Inc. Consultant; CVS Caremark. Research Support; Altimmune Inc., Novo Nordisk Foundation.
1580-P: FoxO1 Functions to Suppress Hepatic Stellate Cell Activation and Protect against Nonalcoholic Steatohepatitis
Authors: CHHETRI GOMA , GAO JINGYANG , USMAN TAOFEEK , QUAN ZHENG WEN , HENRY DONG H.
Published: June 2024

Nonalcoholic steatohepatitis (NASH) is characterized by hepatic inflammation, steatosis and fibrosis. NASH concomitant with its cardiometabolic comorbidities is an underlying cause for the liver-associated mortalities. Critical for the etiology of NASH is the activation of hepatic stellate cells, liver-resident pericytes that account for 5-10% of the cell population in liver. HSCs remain quiescent in normal physiology, but become activated in response to hepatic inflammation and steatosis. Activated HSCs are primed for increased synthesis and secretion of collagen, contributing to the formation of extracellular matrix in the liver. This effect catalyzes the conversion of nonalcoholic fatty liver (NAFL) to NASH. To gain mechanistic insights into HSC activation, we investigated hepatic regulation of HSC homeostasis by FoxO1, a key transcription factor that mediates insulin and cytokine action on hepatic inflammation and steatosis (PMID:35700043). We found that FoxO1 expression, which remains at a baseline in quiescent HSCs in normal mice, is markedly upregulated in activated HSCs in mice with diet-induced NAFL. We generated HSC-conditional FoxO1-knockout mice, revealing that FoxO1-deficient HSCs, relative to wild-type HSCs, were more susceptible to undergoing HSC activation in response to hepatic inflammation and steatosis. This effect contributed to the development of severe liver fibrosis in HSC-FoxO1-knockout vs. wild-type mice, when fed a NASH-inducing diet. Mechanistically, FoxO1 acts to suppress HSC activation by counteracting TGF-beta, a multifunctional cytokine whose paracrine action on HSCs contributes to HSC activation in NASH. We conclude that FoxO1 is pivotal for safeguarding HSCs against abnormal activation to stem the evolution of NAFL to NASH.

Disclosure

G. Chhetri: None. J. Gao: None. T. Usman: None. W. Zheng: None. H. Dong: None.
1584-P: An Integrative Transcriptome Subtraction Strategy to Identify Human LncRNAs That Specifically Play a Role in Liver Fibrosis
Authors: MA YONGHE , HARRIS JAMIE B. , JIANG CHENGFEI , CAO HAIMING
Published: June 2024

Liver fibrosis constitutes the most prominent predictor of overall mortality in non-alcoholic steatohepatitis. The fibrotic liver features excessive deposition of extracellular matrix, primarily produced from "activated" hepatic stellate cells (HSCs). Whereas targeting HSC in fibrosis therapeutics shows promise, the overall understanding of HSC activation remains limited, partly because defining the role of human long non-coding RNAs (lncRNAs) in HSC activation remains challenging. Although analyzing regulated human lncRNAs by HSC activation provides the most practical means to identify functional lncRNAs in the process, effective downstream approaches to further prioritize the regulated lncRNAs are often lacking. To address this challenge, we conceptualize that profibrogenic human lncRNAs in HSCs could be specifically identified by concurrent analysis of regulated lncRNAs during HSC activation with those in a process under which diverse gene networks are regulated, but the molecular elements of fibrogenesis are the only shared one with HSC activation. To implement this strategy, we compared those genes with TGFbeta-regulated ones in four additional cell types and found that only TGFbeta-induced transdifferentiation of vascular smooth muscle cells share the key elements of fibrogenesis with HSC activation. We utilized this approach to identify a highly filtered list of lncRNA candidates, and experimentally characterized and validated one fibrogenic human lncRNA named CARMN. Our work addresses a bottleneck in identifying human lncRNAs that specifically play a role in HSC activation and liver fibrosis through integrative transcriptome subtractions, and our study provides a framework to effectively select human lncRNAs that are essential for elucidating key pathological processes.

Disclosure

Y. Ma: None. J.B. Harris: None. C. Jiang: None. H. Cao: None.

Funding

NHLBI Division of Intramural Research funds to HC (1ZIAHL006103, 1ZIAHL006159)
1592-P: Evaluating TRIB1 as a Genetic Driver of Fatty Liver Disease in an In Vitro Model of Carbohydrate-Mediated Lipid Accumulation
Authors: DEHGHANI TIMA , SHEWADE LEENA , GUO KARL , LLOYD DAVE , SATAPATI SANTHOSH
Published: June 2024

Metabolic dysfunction associated steatotic liver disease (MASLD) is the most common liver disease and is characterized by increased lipid accumulation in the liver. Though the exact cause of manifestation is largely unknown, insulin resistance, type 2 diabetes and obesity are strongly associated with development and progression of MASLD. Recent literature emphasizes the role of genetics in the pathogenesis of MASLD. In several genome wide association studies, polymorphisms in Tribbles 1 (TRIB1) are significantly associated with MASLD. However, molecular mechanisms underlying TRIB1 and increased hepatic lipid accumulation are poorly understood. In this study we hypothesized that TRIB1 controls hepatic lipid homeostasis by regulating C/EBPα expression which is a known regulator of de novo lipogenesis (DNL). To understand the mechanism of action, we generated TRIB1, CEBPA, and RFWD2 gene knockouts in HepG2 cell line and in primary human hepatocytes and overexpression of TRIB1 in HepG2s. Knockout and overexpression cell lines were challenged for 24-72h with a cocktail of glucose, fructose, and insulin to mimic DNL conditions and evaluated lipid accumulation via confocal microscopy and gene expression analysis to understand mechanism of action. Lack of TRIB1 in primary human hepatocytes significantly increased lipid content compared to control cells under DNL conditions. Knockout of CEBPA and RFWD2 in HepG2’s significantly reduced lipid accumulation compared to controls. Overexpression of TRIB1 led to reductions in CEBPA gene expression and DNL; however, as TRIB1 overexpression waned, so did these attenuations. These data suggest that, while TRIB1 may regulate CEBPA expression, high expression levels are required to lessen the disease phenotype in this cell system. Strong TRIB1 inducers, or alternative regulators of CEBPA, may be required to leverage this mechanism in future therapeutics.

Disclosure

T. Dehghani: Employee; insitro. L. Shewade: Employee; insitro. K. Guo: Employee; insitro. D. Lloyd: Employee; insitro. S. Satapati: None.