bluuebunny/crossref_metadata_2025 huggingface dataset:
1373-P: Longitudinal Associations of Dietary Exposures and Hypothalamic Gliosis in the Framingham Heart Study
Authors: YEUM DABIN , LO JUSTIN , MELHORN SUSAN J. , OLERICH KELSEY , HUANG ALYSSA , KEE SARAH , DECARLI CHARLES , BEISER ALEXA , SESHADRI SUDHA , SCHUR ELLEN A.
Published: June 2024

Introduction: Hypothalamic gliosis is linked to obesity and is known to be induced by dietary factors in rodent models including high-fat, fructose-rich, and sucrose-enriched diet. This longitudinal analysis evaluated whether dietary exposures are associated with the degree of hypothalamic gliosis as assessed at MRI examinations obtained 5-8 years later.

Methods: Dietary exposures and brain MRI images were collected from 867 adults. Self-reported food frequency questionnaires were obtained and daily consumption of % total fat, % total carbohydrates, % total protein, % saturated fat, % fructose, and % sucrose of total energy intake were calculated and used as dietary exposures. To calculate the primary outcome, MRI T2 signal intensities were extracted to calculate a ratio of mediobasal hypothalamus (MBH)/amygdala (AMY), a greater ratio suggesting evidence of gliosis; a positive control ratio of MBH/putamen (PUT); and a negative control ratio of PUT/AMY. Linear regression evaluated the association between each dietary exposure and the outcomes of T2 signal ratios adjusting for age, sex, and BMI.

Results: The average age was 54.9±8.8 y (54.9% female). There were no statistically significant associations between % total fat, % saturated fat, % fructose, % sucrose, % total carbohydrates, and % total protein with the degree of MBH gliosis (MBH/AMY) as assessed at MRI examinations obtained 5-8y later (P = 0.89, 0.79, 0.42, 0.90, 0.71, 0.63, respectively). No associations were found between the dietary exposures and the positive or negative control ratio.

Conclusion: We did not find evidence of prospective associations between self-reported diet and MRI evidence of MBH gliosis. However, further research is warranted given the limitations of self-reported diet data and the extended time interval between the dietary exposure and MRI measurements.

Disclosure

D. Yeum: None. J. Lo: None. S.J. Melhorn: None. K. Olerich: None. A. Huang: None. S. Kee: None. C. DeCarli: None. A. Beiser: None. S. Seshadri: None. E.A. Schur: Consultant; Amgen Inc.

Funding

National Institute of Health (5K24HL144917)
1379-P: Detection of Type 2 Diabetes—Evidence from a Pilot Screening Study in Denmark
Authors: CAYUELAS MATEU NURIA , ROSSING PETER , NEERGAARD KIRSTEN P. , THYBO TANJA
Published: June 2024

Introduction & Objective: Early detection of type 2 diabetes mellitus (T2DM) increases the quality of life and the life expectancy of individuals with T2DM and reduces societal health care costs. The aim of the study is to evaluate the efficiency of targeted and free screening using at-home self-sampling A1c tests for early detection of T2DM.

Methods: In October 2022 to June 2023, the Danish Diabetes Association mailed free capillary at-home self-sampling A1c tests to 8,000 randomly selected individuals aged 50 to 75 years, who had not had their A1c measured within the past two years. The Clinical Laboratory Information Register, including all laboratory measurements covering hospitals and GPs, was used to identify the population.

Results: 3,040 individuals, 38%, returned a blood sample. This is in line with screening studies for other diseases in Denmark. The participation rate was 3.8 %-points higher for women than for men and approximately U-shaped across age for both sexes with the highest participation rate among the 50-year-olds. The age-adjusted share of participants with A1c of 42-47 mmol/mol was 11%, equivalent to the estimated share of individuals with unknown prediabetes in the Danish population aged 50-75 years. The age-adjusted share of the participants with A1c ≥48 mmol/mol was 1.2% for women and 2.5% for men. It is slightly lower than the estimated shares of individuals with unknown T2DM, 1.6% for women and 2.7% for men. Further, individuals between 50-59 years of age constituted 51% of the participants with A1c ≥48 mmol/mol compared to 40% of the population, when diagnosed by the Danish Health Care System (DHCS). Similarly, the median A1c was 52 mmol/mol among the participants with A1c ≥48 mmol/mol compared to a median A1c of 60 mmol/mol in the population, when diagnosed with T2DM by the DHCS.

Conclusion: The pilot screening study for at-home self-sampling prove highly efficient in detecting individuals with A1c ≥48 mmol/mol earlier compared to individuals in the same age group diagnosed by the DHCS.

Disclosure

N. Cayuelas Mateu: Research Support; Novo Nordisk A/S, Bayer Inc., Boehringer-Ingelheim, Sanofi, AstraZeneca, Abbott, Abbott Diagnostics. P. Rossing: Other Relationship; AstraZeneca, Bayer Inc., Boehringer-Ingelheim, Gilead Sciences, Inc., Novo Nordisk, Eli Lilly and Company, Novartis AG, Abbott Diagnostics. K.P. Neergaard: None. T. Thybo: Research Support; Novo Nordisk A/S, Bayer Inc., Boehringer-Ingelheim, Sanofi, AstraZeneca, Abbott, Abbott Diagnostics.
1382-P: Pilot Study of the Healthy Immigrant Effect in Africans Living in America
Authors: HUEFNER ELIZA A. , WORTHY CHARLITA , SAYED MARIAM , HURSTON JAMAIICA , DUBOSE CHRISTOPHER , MABUNDO LILIAN , HORLYCK-ROMANOVSKY MARGRETHE F. , SUMNER ANNE E.
Published: June 2024

Since the mid-20th century, the Healthy Immigrant Effect (HIE) has been used to describe better cardiometabolic health in African immigrants than African Americans (AA). However, with heart disease and diabetes (DM) rapidly increasing in Africa, it is unknown whether African immigrants who entered the United States (US) in the 21st century have better cardiometabolic health than AA. Therefore, we undertook a pilot study of 17 African immigrants and 17 AA who were matched by sex, age, and BMI (Male: 35% (12/34), Age: 42±16, (mean±SD), range 20-67y, BMI: 30.2±5.8, range 20.2-41.9 kg/m2). Africans entered the US from 2000 to 2022 and were 18y or older at immigration. Biological Age was determined by the Phenotypic Age equation. The Framingham Risk Score (FRS) was used to estimate the 10y risk of a cardiac event. To detect DM, OGTT were performed. Biological Age tended to be lower in African immigrants than AA (38±16 vs 41±16y, P=0.06). Yet, there was no difference by group in FRS (4.4±5.5 vs 4.5±5.2, P=0.95) or DM prevalence (12% (2/17) vs 12% (2/17), P=0.99). African immigrants had a lower rate of health insurance coverage (59% (10/17) vs 88% (15/17), P=0.05) and a higher rate of low income (<45k)(47% (8/17) vs 29% (5/17), P=0.29) than AA. Yet, African immigrants had better diet, activity, sleep, smoking and alcohol habits than AA (Table). Overall, based on lower Biological Age, the HIE may be valid in the 21st century and explained by health behaviors.

Disclosure

E.A. Huefner: None. C. Worthy: None. M. Sayed: None. J. Hurston: None. C. DuBose: None. L. Mabundo: None. M.F. Horlyck-Romanovsky: None. A.E. Sumner: None.
1385-P: Association of Glycemic Variability with Brain Imaging Abnormalities in Persons with Type 2 Diabetes
Authors: LI TSAI-CHUNG , LIN CHENG-CHIEH , LI CHIA-ING , LIU CHIU-SHONG , YANG CHUAN-WEI
Published: June 2024

Introduction & Objective: Persons with diabetes are prone to have atherosclerosis, stenosis, poor blood fluid properties, and other adverse blood vessel health conditions, leading to occurrence of stroke. Thus, this study aims to examine the effects of glycemic variability on brain imaging abnormalities in persons with type 2 diabetes (T2DM).

Methods: This study consisted of 2,536 persons with T2DM who underwent magnetic resonance imaging (MRI) of the brain after they attended the Diabetes Care Management Program of a medical center in Taichung from 2001-2015. After 1:1 age and sex matching, we identified 958 persons with or without white matter hyperintensity (WMH) and 1,106 persons with or without cerebrovascular abnormality (CA). Glycemic variability is estimated using the coefficient of variation in fasting plasma glucose (FPG-CV) within one year of index date (date of first MRI assessment). Logistic regression models were used to assess whether FPG-CV is associated with brain imaging abnormalities.

Results: FPG-CV was associated with CA in multivariable analysis (tertile 2 vs. 1: odds ratios [ORs] 1.48, 95% confidence intervals [95% CI] 1.20-1.83 for unmatched population and 1.35, 1.08-1.68 for matched population; tertile 3 vs. 1: 2.07, 1.65-2.60 for unmatched population and 1.83, 1.44-2.33 for matched population; both P for trend <0.001) but not with WMH.

Conclusion: Our finding indicated glycemic variability may be used as markers to predict cerebrovascular abnormality in persons with T2DM. In addition, glycemic management might guide clinicians toward specific strategies to prevent cerebrovascular abnormality in clinical practice.

Disclosure

T. Li: None. C. Lin: None. C. Li: None. C. Liu: None. C. Yang: None.
1412-P: Visceral Adiposity Is an Independent Predictor of Incident Type 2 Diabetes in Japanese
Authors: HAYASHI TOMOSHIGE , KOH HIDEO , SHIBATA MIKIKO , SHIBATA IZUMI , HIKITA YONEZO , BOYKO EDWARD J. , SATO KYOKO K.
Published: June 2024

Introduction & Objective: Visceral adiposity has been reported to be an important risk factor for type 2 diabetes (T2D). However, whether directly measured visceral adiposity is associated with the risk of developing T2D independent of other fat depots and insulin resistance and whether this association holds true in normal-weight individuals has not been investigated in a prospective cohort study of native Asians.

Methods: Study participants were 1244 Japanese men and women without diabetes at baseline. Intra-abdominal fat area (IAFA) and abdominal, thoracic, and thigh subcutaneous fat areas (SFA) were measured by CT. Total fat area (TFA) was calculated as the sum of these fat areas and total SFA as TFA minus IAFA. T2D was defined as a fasting plasma glucose level ≥126 mg/dL, or an A1c value ≥6.5%, or use of glucose-lowering medications or insulin. Cox proportional hazards model was used to estimate hazard ratios for T2D in relation to exposures.

Results: The mean BMI at baseline was 23.1 kg/m2 and the mean age was 50.2 years. During the 10520 person-years of follow-up, we confirmed 112 cases of T2D. IAFA was associated with an increased risk for T2D. The multiple-adjusted hazard ratios of T2D for tertiles of IAFA were 2.76 (95% CI, 1.20-16.36) for tertile 2 and 4.96 (2.07-11.93) for tertile 3 compared with tertile 1 after adjustment for abdominal SFA, age, sex, family history of diabetes, smoking habit, regular physical activity, daily alcohol consumption, and fasting immunoreactive insulin. IAFA remained a significant risk factor for T2D even after adjustment for TFA, total SFA, abdominal SFA, waist circumference, or BMI, but none of these measures of fat area were associated with the risk of T2D in models including IAFA. In individuals with BMI <25 kg/m2, these associations did not change.

Conclusions: Greater visceral adiposity increased the risk of T2D independent of other fat depots and insulin resistance in Japanese. These associations were similar in normal-weight individuals.

Disclosure

T. Hayashi: None. H. Koh: None. M. Shibata: None. I. Shibata: None. Y. Hikita: None. E.J. Boyko: None. K.K. Sato: None.
1431-P: Dramatic Reduction in Prevalence of Increase of Insulin Resistance in 14- to 15-Year-Old Students after the COVID-19 Pandemic
Authors: OHNO TAKAYUKI , ISHIGURO MIZUKI , SUGANUMA YUKA , NISHIMURA RIMEI
Published: June 2024

Introduction & Objective: In the midst of the COVID-19 pandemic in 2020 and 2021, we reported a significant increase in homeostatic model assessment for insulin resistance (HOMA-IR) values among 14-15 years old students. In this study, we conducted prolonged surveys incorporating data until 2023.

Methods: The study included 430 students aged 14-15 who underwent health examinations between 2015 and 2023 (236 males, 194 females). Using its data, HOMA-IR, BMI, and obesity levels were calculated, and temporal changes were assessed using the Kruskal-Wallis test. Insulin resistance (IR) is defined as HOMA-IR ≥2.5 and temporal changes were assessed using the Chi-square test.

Results: A significant change in the median HOMA-IR was observed over the 8-year period (p < 0.001). Conversely, no significant differences were observed in the median BMI and obesity levels over the 8-year period (p = 0.055, p = 0.064). Figure1 illustrated changes in the proportion of study participants with IR over time.

Conclusion: The significant increase in HOMA-IR observed after 2020 significantly decreased to values similar to pre-COVID-19 levels by 2023. However, BMI and obesity levels showed no temporal changes. Our findings suggest that changes in lifestyle due to the COVID-19 pandemic may have influenced insulin resistance in 14-15 years old students, irrespective of obesity status during 2020-2022.

Disclosure

T. Ohno: None. M. Ishiguro: None. Y. Suganuma: None. R. Nishimura: Speaker's Bureau; Abbott. Advisory Panel; Abbott Japan Co., Ltd. Speaker's Bureau; Boehringer-Ingelheim, Mitsubishi Tanabe Pharma Corporation, Kowa Company, Ltd., Medtronic, Sanofi, Taiho Pharmaceutical Co. Ltd., Sumitomo Dainippon Pharma Co., Ltd., Teijin Pharma Limited, Eli Lilly and Company, Novo Nordisk A/S. Consultant; Terumo Corporation.

Funding

Ministry of Education, Culture, Sports, Science, and Technology, Japan (Kiban [c] 23590815 and Kiban [c] 19590600)
1440-P: C-Peptide Preservation and Diabetic Ketoacidosis (DKA) Risk in Type 1 Diabetes
Authors: ABUABAT MOHAMMAD I. , BUDHRAM DALTON R. , BAPAT PRIYA , BAKHSH ABDULMOHSEN M.K. , VERHOEFF NATASHA , MUMFORD DOUG , ORSZAG ANDREJ , FRALICK MICHAEL , WEISMAN ALANNA , ERIK LOVBLOM LEIF , PERKINS BRUCE A.
Published: June 2024

Introduction & Objective: Endogenous insulin production in T1D, as measured by detectable C-peptide, is associated with lower HbA1c and insulin dose, as well as lower hypoglycemia and retinopathy risk. We aimed to determine if detectable C-peptide is also associated with decreased risk of DKA.

Methods: We accessed data from the Diabetes Control and Complications Trial (DCCT) from the NIDDK central repository to investigate the effects of detectable stimulated C-peptide measured annually (≥0.2 pmol/ml, exposure) on DKA incidence (outcome) over mean 6.5-year trial follow-up. Analysis was conducted using the Andersen-Gill model for recurrent DKA events with time-varying covariates; crude unadjusted models and models adjusted for age, sex, diabetes duration, and trial assignment (intensive vs. conventional) were fit. Sensitivity analysis also adjusted for HbA1c.

Results: Of the 1441 participants with a median age of 27 years and median duration of diabetes of 49 months, 53% were male, 21% had detectable C-peptide levels (>0.2 pmol/ml) at baseline, and the median HbA1c level was 8.8%. During the trial, 129 participants (9%) had 180 DKA events. Only 1 of these 129 DKA events occurred in an individual with detectable C-peptide, while 128 events occurred in individuals after C-peptide became undetectable. In crude analysis, detectable C-peptide level had a 93% reduction in the hazard for recurrent DKA [hazard ratio (HR) 0.07, 95% CI 0.01 to 0.48, p=0.007]. Results were similar in the first adjusted model (HR 0.06, 95% CI 0.01 to 0.44, p=0.006) and in the final adjusted model (HR 0.08, 95% CI 0.01 to 0.60, p=0.012).

Conclusion: In addition to previously identified clinical benefits, this analysis demonstrates that endogenous insulin production dramatically lowers the risk of DKA in T1D. This implies that therapies that may preserve insulin production - such as immune, cell-based, or other therapies - are likely to reduce the burden of DKA.

Disclosure

M.I. Abuabat: None. D.R. Budhram: None. P. Bapat: None. A.M.K. Bakhsh: None. N. Verhoeff: None. D. Mumford: None. A. Orszag: None. M. Fralick: Consultant; singal1, proofdx. A. Weisman: None. L. Lovblom: None. B.A. Perkins: Advisory Panel; Abbott. Other Relationship; Novo Nordisk. Advisory Panel; Insulet Corporation, Nephris. Other Relationship; Medtronic. Advisory Panel; Sanofi, Vertex Pharmaceuticals Incorporated, Dexcom, Inc.

Funding

Diabetes Canada (Operating Grant OG-3-21-5572-BP)
1443-P: Natural History of Type 1 Diabetes (T1D)—Contrasting Adult vs. Pediatric At-Risk Populations
Authors: TEMPLEMAN ERIN , FERRAT LAURIC A. , THOMAS NICHOLAS , SPEAKE CATE , WHERRETT DIANE K. , SHERR JENNIFER L. , REDONDO MARIA J. , EVANS-MOLINA CARMELLA , SOSENKO JAY , SIMS EMILY K. , ORAM RICHARD A.
Published: June 2024

Introduction: Adults represent over half of incident T1D cases but most studies on risk prediction focus on children.

Methods: We studied 135,970 children (<18 years old) and 99,795 adult relatives in the TrialNet Pathway to Prevention study screened for autoantibody positivity (AB+). Kaplan Meier curves and log rank tests compare T1D progression. We tested discrimination of existing metabolic risk scores: Index60 (I60) and DPT1 (DPTRS) using area under time dependent receiver operating characteristic curve (ROC AUC).

Results: Adults had lower confirmed AB+ rates (adults 4.9% (n=4843); children 5.4% (n=7364), p < 0.001), particularly for multiple AB+ (adults 0.9% (n=939); children 3% (n=4062), p < 0.001). AB+ adults at all stages of disease exhibited lower 3 year progression risk compared to children (Table 1) but risk scores remained discriminative (DPTRS ROC AUC: adults 0.91 [0.87 - 0.94], children 0.86 [0.84 - 0.87]; I60: adults 0.87 [0.83 - 0.91], children 0.83 [0.82 - 0.85]).

Conclusion: Key differences and similarities between children and adult relatives are highlighted: fewer adults presented with early stage T1D (multiple AB+), progression rates were lower in AB+ adults, and those at highest risk can be identified with metabolic risk scores. Large datasets of AB+ adults are needed to refine and calibrate T1D prediction models in adults.

Disclosure

E. Templeman: None. L.A. Ferrat: Consultant; Johnson & Johnson Medical Devices Companies. N. Thomas: None. C. Speake: None. D.K. Wherrett: None. J.L. Sherr: Consultant; Medtronic. Advisory Panel; Medtronic, Insulet Corporation. Speaker's Bureau; Insulet Corporation. Advisory Panel; Vertex Pharmaceuticals Incorporated, MannKind Corporation, StartUp Health T1D Moonshot, Bigfoot Biomedical, Inc., Cecelia Health. Speaker's Bureau; Zealand Pharma A/S. M.J. Redondo: None. C. Evans-Molina: Other Relationship; Bristol-Myers Squibb Company, Nimbus Therapeutics. Research Support; Lilly Diabetes, Astellas Pharma Inc. Advisory Panel; Avotres Inc., Neurodon, DiogenX, Isla Technologies. J. Sosenko: None. E.K. Sims: Consultant; Sanofi. Board Member; American Diabetes Association. Other Relationship; American Diabetes Association, Medscape. Consultant; DRI. R.A. Oram: Research Support; Randox R & D. Consultant; Provention Bio, Inc., Sanofi.

Funding

Randox Ltd
1448-P: The Role of a Glucose Fraction Independent of Insulin Secretion in Predicting Hyperglycemia Endpoints in Autoantibody-Positive Individuals (Ab+I)
Authors: NATHAN BRANDON M. , CUTHBERTSON DAVID D. , ISMAIL HEBA M. , JACOBSEN LAURA M. , SIMS EMILY K. , SOSENKO JAY
Published: June 2024

Objective and Introduction: It has been shown that AUC glucose from oral glucose tolerance tests (OGTTs) can be divided into fractions dependent or independent of insulin secretion. We assessed whether the independent fraction is predictive of incident IGT, a pre-diagnostic marker (2-hr glucose ≥140 to <200 mg/dl), and T1D among Ab+I.

Methods: AUC glucose, calculated from baseline OGTTs of 5182 normoglycemic TrialNet Pathway to Prevention participants with ≥1 Ab+, was divided into fractions dependent (dAUCGLU) or independent (iAUCGLU) of insulin secretion. Fractions were derived from linear regression of AUC glucose vs. Index60 (insulin secretion proxy). dAUCGLU was the expected AUC glucose value, while iAUCGLU was the residual value of AUC glucose above or below the regression slope. Fractions were assessed for predicting IGT and T1D.

Results: dAUCGLU and iAUCGLU were each predictive of both IGT and T1D (p<0.0001 for both, Figure). iAUCGLU was a stronger predictor of IGT, while dAUCGLU was a stronger predictor of T1D. When added to dAUCGLU in regression models, iAUCGLU contributed to the prediction (p<0.0001) of both IGT and T1D.

Conclusion: A glucose fraction independent of insulin secretion predicts both IGT and T1D in Ab+I. This merits investigation into other factors (e.g., insulin resistance) contributing to these hyperglycemic endpoints.

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
1454-P: Major Adverse Cardiovascular Events, Advanced Foot Complications, and Subsequent Risk of Diabetic Ketoacidosis in Type 1 Diabetes
Authors: BAPAT PRIYA , BUDHRAM DALTON R. , BAKHSH ABDULMOHSEN M.K. , ABUABAT MOHAMMAD I. , VERHOEFF NATASHA , MUMFORD DOUG , ORSZAG ANDREJ , FRALICK MICHAEL , WEISMAN ALANNA , ERIK LOVBLOM LEIF , PERKINS BRUCE A.
Published: June 2024

Introduction & Objective: People with type 1 diabetes and diabetes-related complications, including cardiovascular disease, are at increased risk of morbidity and mortality. We aimed to determine if major adverse cardiovascular events (MACE) and microvascular complications independently predict the risk of subsequent diabetic ketoacidosis (DKA).

Methods: We accessed previously-collected data from the DCCT/EDIC Study through the NIDDK Central Repository. We used Multivariable Cox Proportional Hazard models with time-varying exposures and co-variates to examine associations of MACE and microvascular complications (early- and late-stages of neuropathy, nephropathy, and retinopathy) as the exposure, with the subsequent occurrence of DKA as the outcome.

Results: Of 1441 participants, 297 individuals experienced 488 DKA events over 34 years of follow-up. MACE [hazard ratio (HR) 3.11, 95% confidence interval (CI) 1.56-6.17, p=0.001] and late-stage neuropathy, which comprised of foot ulcer or amputation, (HR 1.61, 95% CI 1.06-2.45 p=0.026) were independently associated with higher risk of DKA. Higher DKA risk was also associated with insulin pump use (HR 3.01, 95% CI 2.28-3.98, p<0.001), higher insulin dose (HR for 1 unit/kg/day 2.39, 95% CI 1.72-3.33, p<0.001), female sex (HR 2.01, 95% CI 1.58-2.56, p<0.001), and higher time-updated HbA1c (HR for 1 percent 1.41, 95% CI 1.32-1.51, p<0.001).

Conclusion: In those with type 1 diabetes, a major cardiovascular event, foot ulcer or amputation confers the greatest risk of future DKA independent of previously-recognized risk factors. These findings imply a need to target patients with these events for DKA prevention interventions such as self-management skills for metabolic control, management of depression, and education around DKA.

Disclosure

P. Bapat: None. D.R. Budhram: None. A.M.K. Bakhsh: None. M.I. Abuabat: None. N. Verhoeff: None. D. Mumford: None. A. Orszag: None. M. Fralick: Consultant; singal1, proofdx. A. Weisman: None. L. Lovblom: None. B.A. Perkins: Advisory Panel; Abbott. Other Relationship; Novo Nordisk. Advisory Panel; Insulet Corporation, Nephris. Other Relationship; Medtronic. Advisory Panel; Sanofi, Vertex Pharmaceuticals Incorporated, Dexcom, Inc.

Funding

Diabetes Canada (Operating Grant OG-3-21-5572-BP)
1468-P: Massively Parallel Reporter Assay Reveals Position-, Promoter-, and Strand-Dependent Effects in Islet TSSs Overlapping Type 2 Diabetes GWAS Loci
Authors: BOSE MAYA L. , TOVAR ADELAIDE , VARSHNEY ARUSHI , PARKER STEPHEN , KITZMAN JACOB , KYONO YASUHIRO
Published: June 2024

Introduction & Objective: Massively parallel reporter assays (MPRAs) are an increasingly popular method of assessing the sequence-dependent activity of variants associated with complex diseases such as type 2 diabetes (T2D). Many MPRA libraries use a single plasmid configuration, a minimal promoter, and a single strand orientation, which may fail to capture the context-dependent expression of T2D-associated cis-regulatory elements. Here, we interrogate the potential activity differences introduced by variable MPRA plasmid construction.

Methods: We used an MPRA library to quantify the activity of 1,305 human pancreatic islet transcription start sites (TSSs). We cloned TSS fragments in either the upstream or downstream position of either the human insulin promoter or a synthetic housekeeping promoter. Activity was measured in the rat pancreatic islet beta cell line 832/13. We used statistical models to calculate position- and promoter-specific fragment activity and enrichment of transcription factor motifs (TFMs) and fragment strand-of-origin.

Results: The non-zero position-bias coefficients for the fragments were significantly stronger than the promoter-bias coefficients (p < 0.05) and strongly biased towards the upstream configuration. Fragments that displayed preferential activity upstream of the reporter gene were enriched for TFMs such as BHLHE22, NR2E1, and E2F, which have been implicated in insulin production and glucose metabolism. 28% of fragments with significant promoter effects overlapped a 99% T2D genome-wide annotation study credible set. Positive strand-of-origin (β = 11.91, p < 0.001) predicted significantly higher fragment activity.

Conclusion: Our MPRA library demonstrates the position-, promoter-, and strand-dependence of activity at islet TSSs that may contribute to T2D development. Future MPRA studies should seek to account for such factors when assaying T2D-associated regulatory element variants.

Disclosure

M.L. Bose: None. A. Tovar: None. A. Varshney: None. S. Parker: Research Support; Pfizer Inc. J. Kitzman: Advisory Panel; Myome Inc. Y. Kyono: None.

Funding

National Human Genome Research Institute (T32HG000040-22)
1471-P: Impaired Delta Opioid Receptor Function Protects against Type 2 Diabetes and Results in Enhanced Insulin Secretion—A Functional Genetic Study
Authors: BONNEFOND AMELIE , GROUP RADIO , SCHARFMANN RAPHAEL , MARCHETTI PIERO , CNOP MIRIAM , FROGUEL PHILIPPE
Published: June 2024

Introduction & Objective: Human genetics has proven powerful to pinpoint novel drug targets for metabolic disorders. While the influence of opioids on metabolic homeostasis has been largely acknowledged, the underlying mechanisms remain unclear. We used functional genomics focusing on OPRD1 encoding delta opioid receptor (DOP), aiming to unravel its effects on type 2 diabetes (T2D).

Methods: OPRD1 was sequenced in 7K participants from the French RaDiO study followed by functional investigation of rare and frequent variants. Association analyses between OPRD1 variants and metabolic traits were performed in RaDiO and confirmed in up to 222K individuals. Glucose-stimulated insulin secretion assays were done in human beta cells and islets utilizing DOP agonist or DOP antagonist. RNA-sequencing was done in human beta cells upon DOP antagonist treatment and in human islets subjected to various diabetogenic treatments.

Results: Loss-of-function OPRD1 variants were associated with higher adiposity and lower hyperglycemia risk, while gain-of-function variants were associated with lower adiposity and higher T2D risk. OPRD1 is expressed in human pancreatic islets and beta cells, but not in rodents, and this expression is decreased when exposed to diabetogenic conditions. DOP activation in human beta cells inhibited insulin secretion while DOP inhibition by a specific antagonist strongly enhanced insulin secretion in human islets and beta cells. We identified several pathways regulated by DOP antagonism in human beta cells, including nerve growth factor, circadian clock and nuclear receptor pathways.

Conclusion: Our study highlights the delta opioid receptor as a major link between opioids and metabolic homeostasis in humans, which directly modulates insulin secretion. A peripherally acting DOP antagonist unable to cross the blood-brain barrier might represent a new drug to restore optimal insulin secretion in response to glucose.

Disclosure

A. Bonnefond: None. R. Scharfmann: Consultant; Human Cell Design, Adocia. P. Marchetti: Speaker's Bureau; Eli Lilly and Company, Novo Nordisk. M. Cnop: None. P. Froguel: None.
1484-P: Six-Class Clustering and Its Complication Prediction in Chinese Aged Diabetes Cohorts Based on Deep Contrast Clustering Analysis
Authors: WANG WEIHAO , GUO LIXIN
Published: June 2024

Aims: This work aims to establish an innovative clustering method predicting variable categories of diabetic complications in aged Chinese diabetes cohort.

Methods: We selected and extracted data of elderly diabetic patients (n=4980) from a medical examination group of 51,400 people followed-up yearly from 2014 to now in Kunshan, China.

Result: The patients were clustered into 6 categories by analyzing 20 indicators. Cluster 1 (n=592) was characterized by heavy smoking and high risk of complications of CVD (Cumulative 10-year incidence rate was 6%). Cluster 2 (n=1130) was characterized by high alcohol consumption, high aminotransferases, the highest risk of complications of stroke (Cumulative 10-year incidence rate was 12.3%) and high risk of FLD (60.5%). Cluster 3 (n=837) was characterized by high blood lipids, high risk of complications of FLD (69.6%) and stroke (11.8%). Cluster 4 (n=886) was characterized by good healthy indicators and a low risk of complications such as FLD (Cumulative 10-year incidence rate was 27.3%), stroke (Cumulative 10-year incidence rate was 6.9%) and CVD. Cluster 5 (n=749) was characterized by older age, higher uric acid, higher creatinine, and the highest risk of complications of CVD. Cluster 6 (n=786) was characterized by high waist circumference, high BMI, high blood pressure and the highest risk of complications of FLD. All three complications, stroke, CVD, and FLD, were analyzed by the Kruskal-Wallis test (p<0.05). The gene of nonalcoholic fatty liver disease (NAFLD) in the cluster 2 was the highest risk coefficient: 1.277 (95% CI:1.522-1.165, P<0.05). It was consistent with the cluster 2 having a higher prevalence of FLD.

Conclusions: A new clustering method has been developed in two large Chinese cohorts of aged diabetes, which may effectively predict complications by clustered in different categories.

Disclosure

W. Wang: None. L. Guo: Consultant; Abbott, AstraZeneca, Bayer Inc., Boehringer-Ingelheim, Eli Lilly and Company, Hengrui (USA) Ltd., Dreisamtech, Dongbao, Gan & Lee, Hansoh.
1504-P: AdoShell, a Nonfibrotic Encapsulation System for Human Islets Transplantation, Shows Promising Results for Clinical Application as a Cure for People with Type 1 Diabetes
Authors: GAUME XAVIER , BESNARD ROMAIN , BRUN JULIE , LECLERC NATHALIE , GAUTIER CAMILLE , JOUANNOT OUARDANE , LAURENT NICOLAS , GAFFURI ANNE-LISE , ELOY ROSY , BOUZAKRI KARIM , SOULA OLIVIER
Published: June 2024

AdoShell® is an easily implantable and fully retrievable scaffold for islet transplantation aiming to cure diabetes by cell therapy without requiring immunosuppression. It is based on a permselective hydrogel film allowing insulin diffusion while preventing immune cell invasion. Allogenic transplant of rat islets in immunocompetent diabetic rats has already demonstrated encapsulated islets survival, insulin secretion, and glycemic regulation.

Compatibility with human islets, good local tolerance, and scalability to deliver a therapeutic dose were studied to meet requirements for a first in human.

In vitro, AdoShell® Human Islets has shown gluco-responsive insulin secretion up to 7 months.

AdoShell® tolerance was evaluated in the intraperitoneal site of immunocompetent rodent species, with or without human islets: AdoShell was well tolerated and did not trigger inflammatory reaction or fibrosis.

AdoShell® Human Islets in vivo functionality was evaluated in immunodeficient mice. Human C-peptide secretion increased during the first two weeks to reach an average of 446 ± 130 pM/day and was maintained until explantation on day 62 (n=4 mice). These results were confirmed in a second study. In vitro analysis of the explants by static GSIS (n=6 explants) showed 21% ± 15 of preimplantation insulin secretion levels, while the mean secretion index was maintained. Therefore, AdoShell favors human islets in vivo functionality.

A human sized AdoShell® with the potential to deliver a therapeutic islet dose was successfully manufactured and implanted by laparoscopy in domestic pig.

AdoShell® Islets is suitable for human islets delivery showing good local tolerance without fibrosis and sustained islet functionality.

Disclosure

X. Gaume: Employee; ADOCIA. Stock/Shareholder; ADOCIA. R. Besnard: Employee; ADOCIA. Stock/Shareholder; ADOCIA. J. Brun: Employee; ADOCIA. N. Leclerc: Employee; ADOCIA. Stock/Shareholder; ADOCIA. C. Gautier: Employee; ADOCIA. Stock/Shareholder; ADOCIA. O. Jouannot: Employee; ADOCIA. Stock/Shareholder; ADOCIA. N. Laurent: Employee; ADOCIA. Stock/Shareholder; ADOCIA. A. Gaffuri: Employee; ADOCIA. Stock/Shareholder; ADOCIA. R. Eloy: Employee; ADOCIA. K. Bouzakri: None. O. Soula: Board Member; ADOCIA. Stock/Shareholder; ADOCIA.
1529-P: Medial Preoptic Area FoxO1 Controls Thermogenesis in a Sexually Dimorphic Manner
Authors: LUO PEI , YANG XIAOHUA , TORRES IRIZARRY VALERIA C. , YE HUI , XU QI , CARRILLO-SÁENZ LESLIE , MUNOZ MARCOS D. , SCHAUL SARAH , PATEL NIRALI , ANTONY NIMISHA , DIXIT DEVIN , UNTERMAN TERRY , XU PINGWEN
Published: June 2024

The medial preoptic area (MPOA) is a thermointegrative center that mediates metabolic adaptation to temperature change, contributing to body weight homeostasis. The Forkhead transcription factor O1 (FoxO1) plays a crucial role in mediating the effects of leptin and insulin on metabolic homeostasis in the hypothalamus. However, the metabolic function of FoxO1 in the MPOA has not been explored. In our study, we observed that the mRNA and protein expression of FoxO1 in the MPOA decreased in female mice after a 2-week high-fat diet (HFD) challenge, but not in male mice. Specific deletion of FoxO1 in MPOA neurons (FoxO1MPOA-KO) did not affect body weight in animals fed a chow diet at room temperature. However, it prevented HFD-induced obesity (DIO) in female mice, but not in male mice. This female-specific protection was associated with increased lean mass, decreased fat mass, enhanced thermogenic activity in adipose tissues, increased energy expenditure, and unchanged food intake compared to control mice with DIO. Female FoxO1MPOA-KO mice also showed increased temperature-dependent changes in energy expenditure, specifically when exposed to cold (6 °C), but not when exposed to thermoneutrality (30 °C) or at a room temperature (22 °C). Furthermore, the protection against DIO in females induced by FoxO1MPOA-KO was diminished by ovariectomy (OVX), and supplementation with 17β-estradiol after OVX failed to restore this protection, suggesting an estrogen-independent mechanism. Finally, mice with constitutively activated FoxO1 in MPOA neurons (FoxO1MPOA-CA) showed significantly increased DIO and poor glucose tolerance in both sexes, further supporting the essential metabolic role of FoxO1MPOA. These findings indicate that FoxO1MPOA plays a crucial role in directing and coordinating the metabolic adaptation to nutritional or environmental temperature challenges in female mice.

Disclosure

P. Luo: None. X. Yang: None. V.C. Torres Irizarry: None. H. Ye: None. Q. Xu: None. L. Carrillo-Sáenz: None. M.D. Munoz: None. S. Schaul: None. N. Patel: None. N. Antony: None. D. Dixit: None. T. Unterman: None. P. Xu: None.
1542-P: Association between Fasting Plasma Glucose Levels and the Development of Alzheimer’s Disease—A Longitudinal Cohort Study
Authors: SHARMA HEM S. , KUMAR SANJAY , CHOUDHARY BINOD K. , KHAN KAMRAN
Published: June 2024

Introduction: Alzheimer's disease (AD) is progressively linked to metabolic factors, with fasting plasma glucose (FPG) levels emerging as a potential predictor. This longitudinal study examines how baseline FPG relates to AD development, shedding light on metabolic pathways in AD pathogenesis.

Methodology: In this 2-year longitudinal study with 600 participants, subjects were divided into low, normal, and high fasting plasma glucose (FPG) groups to explore the risk of developing Alzheimer's disease (AD). They underwent annual cognitive tests and FPG monitoring. The study employed Cox models and Kaplan-Meier curves for risk and survival analysis respectively, considering factors like age and sex.

Results: Over the 2-year period, 120 participants (20%) developed AD. The incidence rate of AD was significantly higher in the high FPG group (28%) compared to the normal (14%) and low (9%) groups (p<0.001). Cox regression revealed that high baseline FPG levels were associated with a two-fold increased risk of developing AD (HR=2.01, 95% CI=1.35-2.99, p<0.001) after adjusting for confounders. Kaplan-Meier survival analysis showed a significantly lower AD-free survival in the high FPG group (p<0.001).

Conclusion: This study reveals that higher FPG levels significantly increase the risk of Alzheimer's disease over 2 years. FPG could be a crucial predictor for early detection and intervention in AD. Further research is essential to understand the mechanisms and assess glucose management's role in AD prevention.

Disclosure

H.S. Sharma: None. S. Kumar: None. B.K. Choudhary: None. K. Khan: None.
1558-P: Postprandial CPR Index Is Valuable in Assessing Beta-Cell Function in Japanese Patients with Type 2 Diabetes
Authors: ABE TAKAHIRO , MATSUHASHI YUKI , FUJITA TOMOYUKI , CHIKAZAWA SHINJI , FUJITA YUKIHIRO
Published: June 2024

Residual β-cell function is a key factor in achieving optimal glycemic control in patients with diabetes, Glucagon stimulation test (GST) is secure and reliable to evaluate β-cell function, but is difficult to be examined in usual clinical settings. While F-CPR-index (Fasting C-peptide (CPR) [ng/ml] / glucose[mg/dl] x100) is widely used as a surrogate marker of insulin secretion. We hypothesized postprandial CPR to glucose ratio (P-CPR-index) can be another efficient marker for evaluating β-cell function in patients with type 2 diabetes (T2DM).Five hundred of Japanese T2DM patients with inadequate glycemic control (HbA1c>7.0) were eligible in this study. HbA1c, fasting CPR and glucose, postprandial (120 min after breakfast) CPR and glucose were measured, and then F-CPR-index and P-CPR-index were calculated. GST was performed as follows: 1mg of glucagon was injected intravenously, CPR was determined before and 6 min after injection, GSTΔCPR (CPR [6 min] - CPR [0 min]) was calculated. Factors correlated with GSTΔCPR were analyzed using simple and multiple stepwise regression analysis. P value<0.05 was defined as statistical difference.Average F-CPR-index, P-CPR-index and GSTΔCPR were 1.60+0.95, 2.67+1.92 and 1.93+1.21, respectively. Simple regression analysis showed that GSTΔCPR was significantly correlated with urinary CPR, F-CPR-index and P-CPR-index as well as age, height, body weight (BW), BMI, waist circumference, duration of diabetes, retinopathy, insulin therapy. Multiple stepwise regression analysis revealed that independent factors contributing to GSTΔCPR were P-CPR-index (β= 0.432), BW (β= 0.336), duration of diabetes (β= -0.107), presence of retinopathy (β= -0.121), use of DPP-4i (β= -0.099), metformin (β= -0.109), SGLT2i (β= -0.108, p= 0.002) but not F-CPR-index.Our date suggested that P-CPR-index was valuable and simple method in assessing residual beta-cell function in daily clinical practice.

Disclosure

T. Abe: None. Y. Matsuhashi: None. T. Fujita: None. S. Chikazawa: None. Y. Fujita: None.
159-OR: Sequential Measurements of Insulin Resistance in the Assessment of Individuals Participating In Diabetes Prevention Programs
Authors: MCPHAUL MICHAEL J.
Published: June 2024

A number of studies have found that programs such as the Diabetes Prevention Program (DPP) delay or prevent the progression from prediabetes to type 2 diabetes mellitus. However, a substantial proportion of the participants in these programs eventually develop type 2 diabetes. To explore possible reasons for this persistent progression, we previously developed an Insulin Resistance Risk Score (IRRS) to assess insulin resistance (IR) using insulin and C-peptide levels measured by mass spectrometry. This method correlates well with formal assessment of whole-body insulin resistance (IR) as measured by the steady-state plasma glucose (SSPG) during the insulin suppression test. We used this relationship to create a risk score called the Insulin Resistance Risk Score (IRRS) that assesses the risk of top tertile insulin resistance as measured by SSPG and used it to examine the association of changes in IR during the course of DPPs. We found that although the IRRS declines in some individuals (4/15) with high baseline IRRS in parallel with observed weight loss and normalization of glycemic indices, this did not occur in most participants (11/15) with a high baseline IRRS. Furthermore, a substantial number of individuals who did achieve DPP targets for weight loss and normalization of fasting glucose and HbA1c, had a high IRRS at baseline and throughout the DPP. This suggests that persistence of insulin resistance at the conclusion of a DPP may contribute to the future development of diabetes and that the assessment the IRRS of participants at the conclusion of a DPP might assist in the identification of those at risk of progression to type 2 diabetes and who may benefit from additional weight loss.

Disclosure

M.J. McPhaul: Consultant; Quest Diagnostics.
1610-P: Cardiomyocyte N-acetyltransferase 10 Overexpression Protects against Diabetic Cardiomyopathy
Authors: KANG JIAYI , WANG CHUNYAN , SUGAI-MUNSON AYA , LI GUOPING , RHEE JAMES , PAN ZHIQIANG , LI HAOBO
Published: June 2024

Introduction & Objective: Diabetic cardiomyopathy is a major complication and a leading cause of death in patients with diabetes. Treatment specific to improve outcomes of diabetic cardiomyopathy is lacking. Iron overload-induced cell death, known as ferroptosis, contributes to the development of diabetic cardiomyopathy. N-acetyltransferase (NAT10), the only known writer of N4-acetylcytidine, has been implicated in myocardial ischemia reperfusion and heart failure. However, the role of NAT10 in diabetic cardiomyopathy and its regulatory effect on ferroptosis in diabetic cardiomyopathy, are unclear.

Methods: Six-week-old wild-type mice were subjected to either chow diet or high-fat (HFD) diet feeding and injection of streptozotocin (STZ) to induce diabetic cardiomyopathy. Some of the mice were injected with AAV9 encoding cardiac troponin-T (cTnT)-driven NAT10 to overexpress NAT10 in cardiomyocytes (CMs).

Results: Mice treated with HFD+STZ exhibited decreased E/A (Chow: 1.547±0.17 vs HFD+STZ: 1.166±0.07, p<0.05, n=8) and reduced global longitudinal strain as well as decreased fractional shortening (FS, Chow: 45.72%±3.18 vs HFD+STZ: 38.32%±2.04, p=0.04, n=8) and a ~50% downregulation of cardiac NAT10 protein expression (p<0.05). These changes were associated with a 3-fold increase in iron accumulation in the heart (p<0.01). In HFD+STZ mice, CM-specific NAT10 overexpression increased E/A (Control: 1.11±0.13 vs Overexpression: 1.47±0.11, p<0.01, n=8) and FS (Control: 37.06 %±4.22: vs Overexpression: 43.58%±4.57) as well as reduced iron accumulation in the heart. In CMs exposed to high glucose and palmitate, lentiviral overexpression of NAT10 reduced while its gene knockdown increased cell death and markers of ferroptosis as well as oxidative stress (all p<0.05).

Conclusion: NAT10 protects the heart against diabetic cardiomyopathy through reducing ferroptosis. NAT10 is a promising therapeutic target in preventing diabetic cardiomyopathy.

Disclosure

J. Kang: None. C. Wang: None. A. Sugai-Munson: None. G. Li: None. J. Rhee: Consultant; Takeda Pharmaceutical Company Limited. Z. Pan: None. H. Li: None.

Funding

National Institutes of Health (R21AG077040); American Heart Association (20CDA35310184)
1630-P: Therapeutic Potential of Olfactory Receptor OR51T1 in Obesity
Authors: BLEYMEHL KATHERIN
Published: June 2024

Olfactory receptors (ORs) are classic GPCRs primarily expressed in the olfactory epithelium, where they transmit real-time sensory signals to the brain. However, they are also expressed in multiple non-olfactory tissues like brain, gut, muscle etc., which often has been described as ectopic expression. Elucidation of the physiological roles of these ectopic receptors is revealing therapeutic potential in several conditions including obesity. Indeed, the results from our collaboration with Circuit Therapeutics suggest an important role of the ectopic expressed OR51T1 mouse homologue Olfr544 in body weight regulation. This orphan OR is located in the glutamatergic Area postrema (AP) brainstem circuitry. The AP specific overexpression of Olfr574 in lean mice leads to resistance against weight gain over 7 weeks caused by high fat diet. Surprisingly these mice showed no effect on food intake and high fat preference. To test the involvement of Olfr674 further, we used complementary manipulations (shRNA) to generate AP specific Olfr574-KO mice. These mice exhibit increased body weight in the absence of any change in food intake and high fat diet. Together, these observations demonstrate Olfr574 is involved in regulation of body weight effects and further suggest the human homologue OR51T1 as a possible target for treating obesity in humans. Next steps will include the de-orphanization of the human OR51T1 and murine Olfr574 as well as ligand structure improvement and selectivity-screening of ligands against an OR-library in order to further validate the role of OR51T1 in obesity.

Disclosure

K. Bleymehl: None.
1633-P: CRISPLD2 Is Secreted by Adipocytes and Can Reduce Adipocyte Size
Authors: GRIESEL BETH A. , OLSON ANN L. , SPARLING DAVID
Published: June 2024

Obesity is a primary risk factor for type 2 diabetes, with excess adiposity leading to worsening insulin resistance and an increase in adipose tissue inflammation. Conversely, during weight loss there is improved insulin sensitivity with decreased adiposity, including a decrease in adipocyte size, clearance of lipid, and changes to the inflammatory signaling milieu. Adipocyte-secreted factors during weight loss could be a novel target to aid in improved outcomes in diabetes and obesity. We previously identified a novel adipocyte-secreted protein, CRISPLD2, that is uniquely up-regulated in expression and secretion during weight loss. CRISPLD2 secretion is up-regulated by lipolytic signals, down-regulated by insulin, and correlates strongly with insulin sensitivity in humans. We have now found that secreted CRISPLD2 is able to specifically alter gene expression, including an increase ccl2 transcription in 3T3-L1 adipocytes by almost 2-fold (p<0.005). However, the signaling pathways, receptor, and function of CRISPLD2 within adipocytes and adipose tissue have yet to be determined. To determine if excess exogenous CRISPLD2 can alter adipose function, we developed a transgenic mouse with doxycycline-inducible adipose-specific overexpression of CRISPLD2. Induced CRISPLD2 overexpression over 4 weeks leads to a significant decrease in adipocyte size in visceral adipose tissue in lean animals, despite no change in overall adipose depot size. Finally, utilizing IP-MS, we found that CRISPLD2 binds several adipocyte cell surface proteins, intriguingly including nucleolin, which has been previously shown to function as a receptor in inflammatory pathways. Taken together, these data suggest that CRISPLD2 may function as a novel adipokine, playing a role in lipid turnover and adipocyte size in weight loss.

Disclosure

B.A. Griesel: Stock/Shareholder; Pfizer Inc., Moderna, Inc., Weight Watchers International. Other Relationship; Weight Watchers International. A.L. Olson: None. D. Sparling: None.

Funding

Oklahoma Center for the Advancement of Science and Technology (PR-HR21-005)