bluuebunny/crossref_metadata_2025 huggingface dataset:
216-LB: Genetic Influences on Beta-Cell Function before Type 1 Diabetes Diagnosis
Authors: TRIOLO TAYLOR M. , PARIKH HEMANG M. , TOSUR MUSTAFA , FERRAT LAURIC A. , YOU LU , GOTTLIEB PETER , ORAM RICHARD A. , ONENGUT-GUMUSCU SUNA , KRISCHER JEFFREY , RICH STEPHEN S. , STECK ANDREA , REDONDO MARIA J.
Published: June 2023

Autoimmune loss of beta-cell function (measured by C-peptide) is the hallmark of type 1 diabetes (T1D) targeted by interventions that aim to prevent T1D or its progression after onset. We sought to determine whether T1D genetic risk score-2 (T1D-GRS2) and single nucleotide polymorphisms (SNPs) that have been previously associated with C-peptide preservation after T1D diagnosis (e.g., SNPs in CLEC16A, G6CP2, INS, JAZF1, PTPN22, SLC30A8 and TCF7L2) influence C-peptide levels before diagnosis.

We studied islet autoantibody (Ab)-positive participants in the TrialNet Pathway to Prevention Study who had T1DExomeChip data and assessed the influence of these 12 SNPs and the T1D-GRS2 on area under the curve (AUC) C-peptide levels during oral glucose tolerance tests conducted between 0-9 months prior to the diagnosis of T1D. Participants (n=702) had a mean age of 13.5±10.3 years, 47% were female, mean BMI was 20.7±6.0 kg/m2, and mean HbA1c 5.4±0.4%. The T1D high-risk HLA-DR3-DQ2 haplotype was present in 47% and the high-risk HLA-DR4-DQ8 haplotype was present in 67% of participants. We performed univariate and multivariate analyses adjusting for BMI, age, sex, number of positive Ab, and the first 3 principal components of ancestry.

A higher T1D-GRS2 was associated with lower C-peptide AUC 0-9 months prior to T1D diagnosis in univariate (β=-0.06, P<0.0001) and multivariate (β=-0.03, p=0.008) analyses. Participants with the JAZF1 rs864745 G allele had lower C-peptide AUC 0-9 months prior to T1D diagnosis in univariate (β=-0.10, p=0.003) and multivariate (β=-0.05, p=0.047) analysis.

In conclusion, the JAZF1 rs864745 G allele (which has also been associated with type 2 diabetes risk) and higher T1D-GRS2 predict lower C-peptide AUC prior to the diagnosis of T1D. Studies on their effect on response to trials to prevent or delay T1D onset are warranted.

Disclosure

T. M. Triolo: None. S. S. Rich: None. A. Steck: None. M. J. Redondo: None. H. M. Parikh: None. M. Tosur: Advisory Panel; Provention Bio, Inc. L. A. Ferrat: Consultant; Johnson & Johnson. L. You: None. P. Gottlieb: Advisory Panel; ViaCyte, Inc., Board Member; ImmunoMolecular Therapeutics, Research Support; Imcyse, Hemsley Charitable Trust, Novartis, National Institute of Diabetes and Digestive and Kidney Diseases, Precigen, Inc., Dompé, Nova Pharmaceuticals, Provention Bio, Inc. R. A. Oram: Consultant; Janssen Research & Development, LLC, Research Support; Randox R & D. S. Onengut-gumuscu: None. J. Krischer: None.

Funding

National Institutes of Health (R01DK121843, R01DK124395)
217-OR: The Supporting Emerging Adults with Diabetes (SEAD) Program—An Adult-Based Clinical Model That Improves Glycemic Control and Diabetes Technology Uptake in Underserved Young Adults (YA) with Type 1 Diabetes (T1D)
Authors: AGARWAL SHIVANI , MATHIAS PRIYANKA M. , SCHECHTER CLYDE , GREENBERG MICHAEL , FINNAN MOLLY , LONG JUDITH A.
Published: June 2023

Background: Underserved YA with T1D transitioning from pediatric to adult care experience adverse outcomes, which stem from simultaneously unmet social, glycemic, and health system navigation needs. We developed a multidisciplinary clinical program called SEAD to address these challenges. In this analysis, we compared outcomes in YA with TID who were enrolled in SEAD to comparable YA in non-SEAD usual care.

Methods: The SEAD model was integrated into routine adult diabetes care at Montefiore in 2019, offering equal access to all YA with T1D aged 18-35 years old. SEAD provides YA-centered care, ongoing T1D education, diabetes technology support, psychological focus, and equity-based social need screening and referrals. We collected data prospectively on YA receiving care in SEAD vs. non-SEAD at Montefiore from 2019-2022 for a priori program evaluation, using multivariate linear regression to compare primary glycemic outcomes and Kaplan-Meier analysis for secondary technology outcomes, adjusted for age, sex, race/ethnicity, DKA, and complications.

Results: We included 416 YA with T1D (SEAD n=244, non-SEAD n=172): mean age 23 ± 4y, 49% F, 35% Black, 47% Hispanic, 73% Medicaid-insured (no baseline differences, p>0.05). Compared to non-SEAD care, YA in SEAD care experienced double the HbA1c improvement with a cumulative effect size of -0.9% vs. -0.45% over the 3-year study period [SEAD: -0.30%/yr (-0.43, -0.18); non-SEAD: -0.15%/yr (-0.27, 0.04)], and had higher likelihood of accepting insulin pump (HR 1.96, [1.24, 3.12]) and CGM therapy (HR 1.63, [0.97, 2.72]).

Conclusion: Integration of the SEAD model into adult diabetes care to offer YA-centered T1D and social needs support improved glycemic control and diabetes technology uptake for underserved YA with T1D, compared to usual care. Cumulative effects over time could change YA trajectories into adulthood.

Disclosure

S.Agarwal: Advisory Panel; Medtronic, Consultant; Beta Bionics, Inc., Research Support; Abbott Diabetes, Dexcom, Inc. P.M.Mathias: None. C.Schechter: None. M.Greenberg: None. M.Finnan: None. J.A.Long: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (K23DK115896-05)
218-OR: Predictors of Young Adults’ (YAs) Engagement in a Type 1 Diabetes (T1D) Self-Management Intervention—The Resilient, Empowered, Active Living–Telehealth (REAL-T) Diabetes Study
Authors: PYATAK ELIZABETH , SIDERIS JOHN , STEVEN FOX D. , GRANADOS GABRIELLE , DIAZ JESUS , BLANCHARD JEANINE , KHURANA ANYA R. , SALCEDO-RODRIGUEZ ELIZABETH , RAYMOND JENNIFER
Published: June 2023

Background: YAs with T1D have more complications and mental health challenges, and are less engaged in care, than other age groups. Few studies have examined factors predicting engagement in self-management interventions, which may support YAs’ T1D care and overall well-being.

Methods: Using data from a T1D self-management RCT, we analyzed predictors of engagement among those randomized to the intervention who had reached the 6 month endpoint. Engagement was defined as the number of completed intervention sessions. Control variables were measured at baseline. Ordinary least-squares regression was used, entering categories of predictors in separate steps: 1) demographics: age, gender, race/ethnicity, insurance status, parental education; 2) clinical: A1c, duration of T1D, device use; 3) behavioral: medication adherence, diabetes self-management (DSMQ); 4) psychosocial: diabetes distress (DDS), self-efficacy (DES-SF), and autonomous motivation (TSRQ).

Results: Participants (n=87) were 24 (±4) yrs old, 60% female, 49% Hispanic/Latinx and 43% White, and completed a mean of 9.5 intervention sessions (range: 0-24). In the final model (p=0.0003), engagement was associated with low parental education (parameter estimate -4.1 visits), being uninsured (+3.6 visits), and higher glucose monitoring (-1.1 visits) and physical activity (-0.6 visits) on the DSMQ.

Discussion: Clinical and psychosocial variables were unrelated to OT visits; to an extent, poorer self-management predicted more visits. Indicators of SES were most predictive: low parental education decreased, and uninsured status increased, number of OT visits. Given that the factors most associated with engagement were indicators of SES, clinicians are encouraged to assess barriers and external factors that may impact access and participation as soon as possible in the therapeutic process, to facilitate engagement in services.

Disclosure

E.Pyatak: Research Support; Abbott Diabetes. J.Sideris: None. D.Fox: None. G.Granados: None. J.Diaz: None. J.Blanchard: None. A.R.Khurana: None. E.Salcedo-rodriguez: None. J.Raymond: None.
220-LB: Characterizing the Role of 99 Cardiometabolic Candidate Genes Using CRISPR/Cas9, In Vivo Imaging, and Deep Learning in Zebrafish Larvae
Authors: MUJICA ENDRINA , ZHANG HANQING , EMMANOUILIDOU ANASTASIA , MAZZAFERRO EUGENIA , COOK NAOMI , METZENDORF CHRISTOPH , ALAVIOON GHAZAL , BANDARU MANOJ , ROTTNER ANTJE , SUN HAN , NYBERG MICHAEL , DJORDJEVIC DJORDJE , GRY VIENBERG SARA , GLOYN ANNA L. , LARSSON ANDERS , ALLALOU AMIN , DEN HOED MARCEL
Published: June 2023

Introduction: Genome-wide association studies identified 100s of loci that are associated with the risk of common cardio-metabolic diseases (T2D and CVD). Here we functionally characterise 99 candidate genes for a role in relevant traits using zebrafish larvae.

Methods: Fifty-six T2D and 46 CVD candidate genes (three overlap) were functionally characterised by targeting their zebrafish orthologs using CRISPR/Cas9. On day 9-11 post-fertilisation, we acquired optical sections of the pancreatic islet, liver and vasculature using semi-automated fluorescence microscopy, in 16,141 CRISPR/Cas9-edited zebrafish larvae, followed by image analysis using deep learning.

Results: Perturbing all nine T2D genes with at least moderate prior evidence affects ≥1 T2D trait (i.e., beta cell mass, beta cell insulin expression, liver fat, and/or glucose content), while no consequence is observed for 22 genes without prior evidence of a role in T2D. For 12 genes with at most modest prior evidence, perturbation also affects at least 1 T2D trait. Perturbation of 23 genes prioritised for a role in CVD affects at least one vascular trait, while no consequence is observed for 15 non-prioritised genes. Effects of mutations in mice and/or humans are published for 14 of 23 genes, 78% of which show directionally consistent effects across zebrafish larvae and mammals. Of the 15 genes influencing liver fat upon CRISPR/Cas9 editing, mutations in 12 previously showed an effect on liver fat in mice and/or humans, with 75% congruence in direction of effect across species.

Conclusion: Systematically characterising candidate genes for a role in image-based T2D, liver fat and CVD traits in CRISPR/Cas9-edited zebrafish larvae shows highly congruent results with mice and humans, and prioritises promising genes for further in-depth characterisation.

Disclosure

E. Mujica: None. H. Sun: None. M. Nyberg: Employee; Novo Nordisk A/S. D. Djordjevic: Employee; Novo Nordisk. S. Vienberg: Employee; Novo Nordisk A/S. A. L. Gloyn: Other Relationship; Genentech, Inc., Roche Pharmaceuticals. A. Larsson: None. A. Allalou: None. M. Den hoed: None. H. Zhang: None. A. Emmanouilidou: None. E. Mazzaferro: None. N. Cook: None. C. Metzendorf: None. G. Alavioon: None. M. Bandaru: None. A. Rottner: Employee; AstraZeneca.

Funding

Swedish Research Council (201901417); Swedish Heart and Lung Foundation (20200602, 20200781)
222-LB: Global Equity in Precision Medicine in Diabetes Research—A Scientometric Review
Authors: SONIWALA AAMNA , KIM SOPHIA , VENKAT NARAYAN K M , SAM VARGHESE JITHIN
Published: June 2023

Objective: While non-Europid populations contribute to nearly 80% of the global diabetes burdens, they are grossly underrepresented in research. Given the growing interest in precision diabetes research, we investigated the proportion of such research in these populations.

Methods: We undertook an electronic search of literature in PubMed from 2010 to 2023 to identify studies in precision medicine in diabetes in populations from East Asia (EA), Latin America & Caribbean (LAC), Middle East & North Africa (MENA), South Asia (SA) and South East Asia & Pacific Islands (SEAP). We did not include Central Asia, Eastern Europe, and Sub-Saharan Africa in the current analysis. Two reviewers independently screened titles and abstracts selected by region-stratified sampling to identify articles relevant to precision diabetes. A third reviewer resolved any differences. We estimated the proportion of relevant research using probability sampling weights, and key themes using computational text abstraction.

Results: Of the 197,570 studies identified from PubMed, only 15,756 (8.0%) were in populations from EA (4.8%), LAC (1.0%), MENA (0.8%), SA (1.4%) and SEAP (<0.1%) regions. After screening titles and abstracts of 1,686 studies, we estimate only 39.1% [95%CI: 36.1, 42.1] were research relevant to precision medicine in diabetes. Among research relevant to precision diabetes, only 5.9% [5.0, 6.9] of studies are from non-Europid populations (EA: 3.5% [2.7, 4.3], LAC: 0.9% [0.7, 1.2], MENA: <0.1%, SA: 1.5% [1.2, 1.8], SEAP: <0.1%). Nearly 48.9% [46.8, 51.2] of the relevant research used genomics technologies for precision medicine in diabetes.

Conclusions: While the vast majority of the global diabetes burden stem from non-Europid populations, only 6% of precision diabetes research are from these populations. This knowledge asymmetry should be addressed to maximize scientific advances and health equity.

Disclosure

A. Soniwala: None. S. Kim: None. K. Narayan: None. J. Varghese: None.

Funding

National Institutes of Health (1P30DK111024-01, 1P01HL154996-01A1 to K.M.V.N.)
223-LB: Associations between Genetic Risk for Insulin Resistance and Measured Insulin Sensitivity Are Impacted by Race and BMI Status
Authors: YURCHISHIN MARIAN L. , FOWLER LAUREN A. , PARCHA VIBHU , ARORA PANKAJ , GARVEY W. TIMOTHY , GOWER BARBARA
Published: June 2023

African Americans (AA) are at greater risk for type 2 Diabetes (T2D) compared to European Americans (EA). This greater risk may derive in part from genetic factors. The genetic risk for insulin resistance (IR) has been linked to the failure to expand adipose tissue and is reflected in a genetic risk score (GRS) that is inversely associated with adiposity. In this study, we investigated whether associations between the GRS and measured insulin sensitivity (IS) differ by BMI status and/or race in a sample of 107 EA and AA adults without diabetes. IS was measured with the euglycemic clamp with an insulin dose of 120 µU/m²/min/kg lean body mass. In addition, surrogate indices of IS were calculated using glucose and insulin values obtained from an oral glucose tolerance test. Participants were classified as “high” or “low” BMI using the sample median (25.9 kg/m^2) as the cut-point. GRS were derived from imputed genotypes and weighted for clamp-derived IS. Multiple linear regression models were used to assess interactions between BMI status and GRS on measures of IS. Models were stratified by race and adjusted for percent body fat, sex, and age. In EA, associations of GRS with HOMA-IR and Matsuda differed by BMI status (pint=0.024 and pint=0.007, respectively), where GRS was inversely associated with IS in the high BMI group only (p=0.027 and p=0.010, respectively), suggesting that genetic risk for IR in EA is driven by greater adiposity. Conversely in AA, associations of GRS with IS from the clamp differed by BMI status (pint=0.083), but an inverse association was observed only in the low BMI group (p=0.035), suggesting that in AA, genetic risk for IR is associated with lower adiposity. Our results indicate that obesity status may differentially impact the link between genetic risk for IR and measured IS within and between races. Further, these results suggest that with a larger sample, a distinct phenotype may exist in AA where higher adiposity permits greater IS.

Disclosure

M. L. Yurchishin: None. L. A. Fowler: None. V. Parcha: None. P. Arora: None. W. Garvey: Advisory Panel; Boehringer-Ingelheim, Novo Nordisk, Eli Lilly and Company, Merck & Co., Inc., Alnylam Pharmaceuticals, Inc., Fractyl Health, Inc. Research Support; Novo Nordisk, Eli Lilly and Company, Epitomee, Pfizer Inc. Advisory Panel; Inogen. Research Support; Neurovalens. B. Gower: Consultant; Abbott.
226-LB: Repurposing a Cancer Drug, AZD6738 (ATRi), for the Prevention of Type 1 Diabetes
Authors: SUGITANI NORIE , MASON HANNAH R. , ROY SAPTARSHI , PIGANELLI JON D.
Published: June 2023

Type 1 diabetes (T1D) is a chronic, incurable autoimmune disorder caused by the destruction of pancreatic β cells by diabetogenic T cells, leading to insulin deficiency and hyperglycemia. It affects 3 million Americans and 80 new people are diagnosed daily. Despite treatment with insulin, patients have a significantly reduced life expectancy. This study proposes a new approach to prevent T1D by specifically targeting diabetogenic T cells undergoing the Warburg effect, a metabolic process similar to cancer cells, with a cancer drug approved by the FDA. The use of FDA-approved drugs accelerates the development of new therapies as these agents have already undergone initial efficacy and toxicity tests in humans. One promising drug for this purpose is AZD6738 (ATRi), a cancer drug that is currently in clinical trials. ATRi is a small molecule inhibitor that targets ATR, a central DNA damage response kinase, whose inhibition blocks DNA replication. We demonstrate that ATRi treatment significantly delays T1D onset in an adoptive transfer mouse model by reducing the survival of diabetogenic CD4+ T cells by inhibiting their proliferation. Furthermore, an FDA-approved glycolysis inhibitor PFK158 potentiates inhibition of diabetogenic CD4+ T cells by ATRi. These agents target different properties of the Warburg effect. While ATRi inhibits rapid proliferation, PFK158 blocks glycolysis. Combination therapy allows for increased efficacy while reducing potential toxicity by allowing the use of lower doses of each agent. These data show promise in the rapid establishment of novel T1D prevention methods by repurposing FDA-approved cancer drugs.

Disclosure

N. Sugitani: None. H. R. Mason: None. S. Roy: None. J. D. Piganelli: None.

Funding

National Institutes of Health (R01DK132583); JDRF (2-SRA2020-910-S-B)
23-OR: Reduction in Insulin Uncovers a Novel Effect of VEGFB on Cardiac Substrate Utilization
Authors: SHANG RUI , SYNG LEE CHAE , HUSSEIN BAHIRA , RODRIGUES BRIAN
Published: June 2023

VEGFB is known to up-regulate FA delivery through its effect on EC FA transporters. In its absence, intracellular lipid accumulation was reduced. Paradoxically, cardiac-specific overexpression of VEGFB demonstrated a lowered heparin-releasable lipoprotein lipase (LPL) activity with reduced FA utilization in vivo. Currently, the mechanism behind this in vivo metabolic effect of VEGFB on cardiac LPL is unclear. In transgenic (Tg) hearts, the vectorial transfer of LPL from myocytes to the vascular lumen is obstructed, resulting in LPL buildup within cardiomyocytes. Given that insulin is known to inhibit LPL translocation and thus FA metabolism in the heart, this observation is likely a secondary effect of VEGFB on vascular development with its associated augmentation of insulin delivery. We tested whether lowering of insulin by fasting would validate our hypothesis. WT fasted hearts enhanced their heparin-releasable LPL activity in an attempt to switch substrate utilization to FA. Intriguingly, this increase in LPL activity following fasting was even more dramatic in Tg hearts. Thus, with insulin deficiency following fasting, VEGFB works unimpeded to facilitate LPL movement. This effect occurred through the activation of p38 MAPK. PET imaging using 18FTHA revealed augmented LPL-derived FA and impaired FDG glucose uptake in the Tg fasted heart. Additionally, this increased delivery of LPL-derived FA correlated to augmented mitochondrial oxidation determined by high resolution oxygraphy. We examined whether this property of VEGFB on FA uptake and oxidation could be useful following diabetes, with its attendant loss of metabolic flexibility. Unexpectedly, in Tg hearts, diabetes inhibited myocyte VEGFB gene expression and protein secretion together with its downstream receptor signaling. Our data suggests that following diabetes, loss of VEGFB action may contribute towards the metabolic inflexibility, lipotoxicity and diabetic cardiomyopathy.

Disclosure

R.Shang: None. C.Lee: None. B.Hussein: None. B.Rodrigues: None.

Funding

Canadian Institutes of Health Research (PJT180558); Diabetes Canada (OG3215585BR)
230-LB: A Composite Capsule Strategy Support Longevity of Microencapsulated Pancreatic ß Cells
Authors: QIN TIAN , SMINK ALEXANDRA M. , DE VOS PAUL
Published: June 2023

Microencapsulation of islets in immunoprotective membranes offers an alternative treatment for type 1 diabetes in absence of systemic immunosuppression. However, periods of survival of transplanted islets are still limited. A factor that might be involved in a limited duration of survival is permanent damage to the extracellular matrix (ECM) during enzymatic islet-isolation which enhances susceptibility of islets for inflammatory stress. Here we investigated whether a combination of inclusion of ECM components (collagen IV and RGD), necroptosis inhibitor necrostatin-1 (Nec-1), amino acids (AA), and inclusion of the immunomodulatory polymer pectin in microcapsules can enhance the functionality of β-cells. The impact of these factors individually or combined was tested on MIN6 β-cells and human islet-cells. Viability, function, and immune activation via danger-associated molecular patterns (DAMPs) release and NF-κB activation in THP1-reporter cells were determined. Also, impact on mitochondrial dynamics was tested. Our data show that composite capsules of pectin/ECM/Nec-1/AA improve insulin secretion and enhance the mitochondrial activity of β-cells in vitro till day 7 after encapsulation. The alginate-pectin based microcapsules also showed immunomodulatory effects with decreased DAMPs release and lower NF-κB activation. After cytokine exposure, pectin/ECM/Nec-1/AA prevented the cytokine-induced decrease of mitochondrial activity and prevented viability loss until day 5. The rescuing effects were accompanied by modulation of mitochondrial fusion and fission gene expression, similar to that of untreated controls. Our data suggest that this composite capsule strategy using pectin/ECM/Nec-1/AA supports survival of microencapsulated β-cells and lowers susceptibility of β-cells for inflammatory stress. This strategy to create a better intracapsular microenvironment is a potentially promising way to preserve islet function and enhance graft survival time.

Disclosure

T. Qin: None. A. M. Smink: None. P. De vos: None.

Funding

JDRF (2-SRA-2018-523-S-B); China Scholarship Council (201906230339)
230-OR: Hybrid Continuous Glucose Monitoring Protocols in the Intensive Care Unit—Multicenter Experience
Authors: FAULDS EILEEN R. , BADAKHSHI YASAMAN , BOUTSICARIS ANDREW , EXLINE MATTHEW C. , HESTER JOI , JONES LAUREEN G. , MCNETT MOLLY , MILLER JOSHUA D. , SHAH ROHAN , GARCIA MARLENE , CHANDRA SUVRAT , PASQUEL FRANCISCO J. , DUNGAN KATHLEEN M.
Published: June 2023

There is limited experience with continuous glucose monitoring (CGM) in intensive care units (ICUs). We assessed the effectiveness, safety, and accuracy of real-time CGM use in COVID-19 ICUs. We pooled data from three academic centers using hybrid protocols combining point of care (POC) blood glucose (BG) with non-adjunctive CGM. At hospitals A and B, CGM was used non-adjunctively with POC at least every 6 hours. At hospital C, POC BG was performed every two hours. We also examined CGM performance during lowest pAO2, oxygen saturation, pH, and mean arterial pressure. Of 169 patients, mean age was 60.9±12.2 years, and 82%, 93%, and 62% received corticosteroids, mechanical ventilation, and vasopressors respectively. Median duration of IV insulin was 118, 156, and 50 hours at hospitals A, B, and C respectively. Mean POC BG frequency was 10.2±6.1, 7.0±5.2, and 16±6.5 times/day on day 1 of IV insulin and 6.7±3.1, 6.0±3.5, and 12.2±5.8 times/day thereafter. The median percent CGM time in range (TIR, 70-180mg/dl) was 72%, 70% and 46% during IV insulin. Median time <70mg/dl was <0.1% for all hospitals. The absolute relative difference between CGM and POC did not correlate with hemodynamic instability, Figure. This data indicates hybrid monitoring can reduce POC frequency while safely maintaining glucose. Sensor-meter agreement was not associated with abnormal physiologic parameters and requires further study.

Disclosure

E.R.Faulds: Advisory Panel; Dexcom, Inc., Other Relationship; A1Control, LLC, Research Support; Dexcom, Inc., Speaker's Bureau; Dexcom, Inc., Medscape. M.Garcia: None. S.Chandra: None. F.J.Pasquel: Consultant; Dexcom, Inc., Medscape, Research Support; Dexcom, Inc., Ideal Medical Technologies. K.M.Dungan: Board Member; Elsevier, Consultant; Eli Lilly and Company, Dexcom, Inc., Other Relationship; UpToDate, Research Support; Dexcom, Inc., Abbott, ViaCyte, Inc., Sanofi, Speaker's Bureau; Academy for Continued Healthcare Learning, Cardiometabolic Health Congress, Medscape, Integritas. Y.Badakhshi: None. A.Boutsicaris: None. M.C.Exline: Other Relationship; Abbott Nutrition. J.Hester: None. L.G.Jones: None. M.Mcnett: Research Support; Dexcom, Inc., National Institutes of Health. J.D.Miller: Advisory Panel; MannKind Corporation, Employee; Medtronic, Research Support; Dexcom, Inc. R.Shah: None.
231-LB: Prolactin Modulates the Differentiation of Pancreatic Ductal Cell to Islet-Like Cell
Authors: WANG YI
Published: June 2023

Objective: Pancreatic ductal cells will be differentiated into islet-like cell with the activation of PRL-PRLR signaling pathway in vitro.

Methods: Primary mouse and human pancreatic ductal cells were obtained by CK-19 labelling and MACS sorting of digested pancreatic tissue, and selected cells were cultured with recombinant mouse prolactin and recombinant human prolactin. Subsequently, the cell clusters formed by the pancreatic ductal cells were stained by anti-insulin, anti-GCK, anti-GLUT2, anti-PC1/3 Abs. In vitro, glucose stimulated insulin secretion (GSIS) was quantified. Prolactin related signaling pathway, glucose transportation and insulin secretion related proteins were assessed by immunoblotting. Lastly, the in vitro formed islet-like cells were transplanted under the kidney capsule of diabetic mice. To assess the role for blood glucose regulation of transplanted islet-like cells, blood glucose, c-peptide and intravenous glucose tolerance tests were performed and immunofluorescence staining for insulin and glucagon was performed on the grafts.

Results: At day 7, the pancreatic ductal cells, also called progenitor cells, expressed CK-19; at day 14, the ductal cells were aggregated and formed sphere-shaped cell clusters. At day 21, the cell clusters stained positive for insulin and etc. By in vitro GSIS test, we measured a 2.58±0.32-fold increase of insulin secretion in response to a 16.7 mM glucose stimulation. Immunoblotting demonstrated that PDX-1, MafA and other genes were expressed. At day 21, the cell clusters expressed PDX-1, insulin and glucagon. In vivo studies showed that diabetic mice transplanted with islet-like cells, maintained blood glucose levels below 300 mg/dL with c-peptide detected in the serum. Further tissue staining indicated that the transplanted islet-like cells contained both β-cells and α-cells.

Conclusion: Out study shows that in vitro stimulation by prolactin might differentiate pancreatic ductal cells into islet-like cells.

Disclosure

Y. Wang: None.

Funding

National Natural Science Foundation of China (81802504); Sichuan Science and Technology Bureau (2022YFH0005, 2023YFH0010)
232-LB: Transcriptional Regulation of Adipocyte Insulin and Inflammatory Signaling by Early B-Cell Factor-1 (Ebf1)
Authors: GUTIERREZ ALEX , MARTINEZ YADIRA , IBARRA KIMBERLY , BAILEY ZACHARY , GRIFFIN MICHAEL
Published: June 2023

Overnutrition is causally associated with many chronic diseases, including insulin resistance and diabetes, heart disease, hypertension, and cancer. Chronic activation of the innate immune system may lie at the heart of a majority of T2DM cases; the bulk of the evidence suggests that a litany of inflammatory cytokines and toxic lipid species released from irritated adipocytes contribute significantly to disrupted insulin signaling in metabolic tissues and may eventually lead to frank type 2 diabetes. However, the molecular mechanisms that initiate these inflammatory events in adipocytes remain unknown, particularly at the transcriptional level. Our previous work showed that the transcription factor Ebf1 regulates insulin signaling and promotes inflammation in adipocytes; however, the precise molecular mechanisms through which Ebf1 regulates the expression of inflammatory loci remain unknown (as evidence had suggested Ebf1 regulates these genes indirectly). We have recently discovered that Ebf1 can physically interact with multiple subunits of the well-known inflammatory transcription factor NF-κB, and many of the critical inflammatory loci showing impaired expression in Ebf1-deficient 3T3-L1 adipocytes also happen to be well-established NF-κB target genes. This striking result likely explains our paradoxical observations that EBF1 directly (and positively) regulates several core insulin signaling genes (Pik3r1, Akt, etc.) but also promotes insulin resistance in adipocytes—apparently without directly occupying inflammatory loci. We are currently working on physically and functionally characterizing these interactions and propose a model to explain the previously-mentioned paradox. If our hypothesis is correct, we anticipate that the eventual development of pharmaceutical agents designed to interfere with EBF1-NF-κB protein-protein interactions may represent a viable treatment for overnutrition-associated diabetes.

Disclosure

A. Gutierrez: None. Y. Martinez: None. K. Ibarra: None. Z. Bailey: None. M. Griffin: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases
233-LB: Role of SUMO-Specific Protease 2 (SENP2) in Modulating Brown Adipose Tissue Activity
Authors: JEE CHOE HUN , SEON LEE JI , PARK JONGYOEN , LEE SEUNG-AH , SOO CHUNG SUNG , SOO PARK KYONG
Published: June 2023

Brown adipose tissue (BAT) is a metabolically active endocrine organ. Activation of BAT contributes to increased energy expenditure through systemic glucose and lipid utilization. SUMO-specific protease 2 (SENP2) is a post-translational protein modifier that is involved in regulation of metabolism in different tissues. We had previously showed that while SENP2 suppresses browning of white adipose tissues, morphologic defect in BAT was observed in adipose specific SENP2 deficient mice fed with high fat diet. How SENP2 may modulate BAT activity has not been elucidated yet. BAT-specific Senp2 knockout (Senp2-BKO, Ucp1-Cre;Senp2f/f) mice were more insulin resistant in response to high fat diet than controls. They were also intolerant to acute cold exposure. Mechanistically, knockdown of Senp2 in brown adipocytes resulted in reduced levels of Ucp1 and Cidea through SUMOylation of ERRα. SUMOylation of ERRα interrupted binding of ERRα to ERRα response element (ERRE) in the Ucp1 promoter, and deSUMOylation of ERRα via SENP2 enhanced the synergistic effect of ERRα/PGC-1α complex required for the transcription of Ucp1. Collectively, these results suggest that SENP2 is intimately involved in modulating the activity of Ucp1 in BAT through deSUMOylation of ERRα/PGC-1α complex, especially ERRα.

Disclosure

H. Choe: None. J. Lee: None. J. Park: None. S. Lee: None. S. Chung: None. K. Park: None.

Funding

National Research Foundation of Korea (2015R1D1A1A09059551, 2016R1A2B3010373, 2019R1A2C3009517)
234-LB: Cell-State Dependent Regulation of PPARg Signaling by Zbtb9 in Adipocytes
Authors: XU XUAN , BUCHNER DAVID
Published: June 2023

The discovery of new genes involved in adipocyte development and function can shed light on the pathophysiology of obesity and T2D and provide new therapeutic targets for these disorders. Towards this end, GWAS and rare variant association studies in the T2D Knowledge Portal revealed associations between ZBTB9 and T2D, BMI, and hip circumference. However, the function of ZBTB9 in organismal physiology was not known. We found that Zbtb9 plays a key role in adipocyte biology and differentiation via cell-state dependent regulation of PPARγ signaling. Zbtb9 directly interacts with the PPARγ/RXRα complex as shown by co-IP, and acts as a positive regulator of PPARγ transcriptional activity as shown by a PPARγ reporter assay, together establishing Zbtb9 as a new PPARγ cofactor. In line with these findings, endogenous PPARγ target gene expression was decreased in the context of Zbtb9 deficiency in adipocytes. Given the central role of PPARγ in adipogenesis, we also sought to investigate the role of Zbtb9 in this process. Surprisingly, loss of Zbtb9 in preadipocytes increased adipogenesis and the expression of adipogenic genes, including PPARγ. Transcriptome analysis prior to and during adipogenesis revealed enhanced expression of E2F target genes prior to the initiation of differentiation and later induction of adipogenic gene expression. Treatment of Zbtb9 deficient preadipocytes with an E2F1 inhibitor (HLM006474) blocked the effects of Zbtb9 deficiency on adipogenic gene expression and adipogenesis. Collectively, these results demonstrate that Zbtb9 inhibits adipogenesis as a negative regulator of PPARγ expression via altered E2F1 signaling. We further demonstrated that E2F1 activation by Zbtb9 is associated with increased phosphorylation of Rb, which is known to cause dissociation of the Rb/E2F complex, and activation of E2F. Our findings revealed cell-state dependent roles of Zbtb9 in adipocytes, identifying a new molecule that may be important in the pathogenesis and treatment of obesity and T2D.

Disclosure

X. Xu: None. D. Buchner: None.

Funding

National Institutes of Health (DK119305)
235-LB: Incretin-Linked Adipose Tissue Microvascular Blood Flow in Healthy People With and Without a Family History of Type 2 Diabetes
Authors: ROBERTS-THOMSON KATHERINE , PARKER LEWAN , KESKE MICHELLE
Published: June 2023

Adipose tissue microvascular blood flow (ATMBF) increases in response to a mixed meal challenge (MMC) to promote nutrient storage. This vascular action is impaired in apparently healthy people with a parent with type 2 diabetes (FH+). The mechanisms for this vascular impairment in FH+ are unknow. We aimed to investigate whether incretins [glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1)] are associated with ATMBF responses to a MMC. Thirteen healthy (FH-, no parents or grandparents with type 2 diabetes) and fourteen FH+ underwent a 2-hr MMC after an overnight fast. Age, BMI, fasting and peak postprandial blood glucose and plasma insulin concentrations were similar between FH- and FH+ (Table 1). Baseline ATMBF, assessed by contrast ultrasound, was similar between groups, but was impaired in FH+ in response to the MMC (Table 1). Peak plasma GLP-1 and GIP concentrations, but not their ratio (GLP-1:GIP), were higher in FH+ in response to the MMC (Table 1). GLP-1 and GIP concentrations were not associated with ATMBF, however, GLP-1:GIP was significantly associated with postprandial ATMBF at 1-hr (p=0.025, r=0.46). We conclude that impaired postprandial ATMBF in FH+ is not exclusively linked to incretin levels. However, lower GLP-1:GIP ratios may be linked to impaired ATMBF responses in the postprandial state.

Disclosure

K. Roberts-thomson: None. L. Parker: None. M. Keske: None.
245-OR: Impaired Mitochondrial Respiration in Peripheral Blood Mononuclear Cells Is Associated with Increased Obesity Classified by Waist-to-Hip Ratio in Nondiabetes EGAT Population
Authors: ATTACHAIPANICH TANAWAT , SRIWICHAIIN SIRAWIT , APAIJAI NATTAYAPORN , KERDPHOO SASIWAN , THONGMUNG NISAKRON , VATHESATOGKIT PRIN , KITIYAKARA CHAGRIYA , SRITARA PIYAMITR , CHATTIPAKORN NIPON , CHATTIPAKORN SIRIPORN C.
Published: June 2023

This study aimed to determine the impact of waist-to-hip ratio (WHR)-classified obesity and diabetes (DM) status on mitochondrial respiration in peripheral blood mononuclear cells (PBMCs) using a large cohort from the Electricity Generation Authority of Thailand (EGAT) during 2017-2018. The 1954 participants were included in this study with an average age of 67.1±7.7 years old. The mitochondrial respiration in PBMCs obtained from fresh blood samples was analyzed by the Seahorse Flux Analyzer. The participants were classified based on DM status and WHR including 1) non-DM non-obese, 2) non-DM obese, 3) DM non-obese and 4) DM obese. We found that the non-DM obese group had lower basal respiration (BR), maximal respiration, spare respiratory capacity (SRC), and proton leak (PL), compared to those of the non-DM non-obese group (Figure 1). The BR, SRC, and PL of non-DM obese group were not significantly different from those of the DM group with or without adjusting with age. All of these findings suggest that WHR-classified obesity in people with non-DM is associated with impaired mitochondrial respiration in PBMCs at a level comparable to that in people with DM. Thus, not only DM, but also obesity, may play an important role on impaired mitochondrial respiration in PBMCs.

Disclosure

T.Attachaipanich: None. S.C.Chattipakorn: None. S.Sriwichaiin: None. N.Apaijai: None. S.Kerdphoo: None. N.Thongmung: None. P.Vathesatogkit: None. C.Kitiyakara: None. P.Sritara: None. N.Chattipakorn: None.
247-LB: Link between Hyperglycemia and Cognitive Deficits in T2DM Animal Model
Authors: CHEN LI , NI JIANGXIA , FENG LINGGE , ZHANG XUEXIN , WANG QIUYAN , CHEN YELIN
Published: June 2023

The Goto-Kakizaki (GK) rat is a model of spontaneously developing non-obese type 2 diabetes mellitus (T2DM). With age, GK rats exhibit insulin resistance, decreased pancreatic function, and hyperglycemia. Studies have shown that GK rats experience cognitive impairment concurrent with hyperglycemia, but the mechanisms is unclear. In this study, we aimed to elucidate the potential link between hyperglycemia and cognitive impairment in this unique T2DM model. Longitudinal assessments of fasting blood glucose (FBG) were performed in male GK rats and age-matched Wistar rats. Our results showed that FBG in GK group was significantly higher than that in the Wistar group starting from 6 weeks of age, and there was progressive fasting hyperglycemia in GK group. In the spatial probe test of Morris water maze (MWM) at 33 weeks old, the GK rats spent less time in the target quadrant (12.16 ± 2.18s vs. 22.17 ± 1.21, P<0.001) and took more time to reach the location of the formerly hidden platform (36.78 ± 6.141 vs. 6.422 ± 0.8783s, P<0.001) than Wistar rats, suggesting that GK rats showed spatial memory deficits. In mechanistic studies, insulin receptors (IR) and synaptic proteins were down-regulated and impaired insulin signaling pathways in the hippocampus of GK rats (Figure), suggesting impaired neuroplasticity and neuropathological processes may lead to cognitive dysfunction.

Disclosure

L. Chen: Board Member; Hua Medicine. J. Ni: None. L. Feng: Employee; Hua Medicine. X. Zhang: None. Q. Wang: None. Y. Chen: Stock/Shareholder; Silaiputai (Shanghai) Biopharmaceutical Company.

Funding

Hua Medicine Co., Ltd.
253-OR: Effect of Continuous Glucose Monitoring on Hypoglycemia, Diet Liberalization, and Quality of Life in Post-bariatric Hypoglycemia
Authors: RAMANUJAN SURUCHI , TURK NICOLE , AYHAN EKREM M. , CRAIG COLLEEN M. , MCLAUGHLIN TRACEY
Published: June 2023

Post-bariatric hypoglycemia (PBH), affecting up to 39% of patients with Roux-en-Y gastric bypass (RYGB), is associated with episodes of disabling hypoglycemia, chronic diet restriction and reduced quality of life (QoL). We evaluated the effects of unblinded vs blinded CGM on hypoglycemia, dietary liberalization, and QoL. 15 RYGB patients with confirmed PBH wore in random order, a Dexcom G6 Pro for 10 days blinded and 10 days unblinded with alarm set to 65 mg/dL. The Hypoglycemia Fear Survey II (HFS-II) was administered after each phase to assess hypoglycemia-based worries and behaviors. The number of hypoglycemia events <70, 54, and 40 mg/dL and proportion of time below each threshold was assessed (diurnal and nocturnal) and adjusted for meal intake. The number of diurnal hypoglycemic events <40 and <54 mg/dL were reduced by 66% and 25% respectively, and proportion of time was reduced by 71% and 50% respectively during unblinded vs blinded CGM use, though neither measure reached statistical significance. Diet liberalization was significantly greater during unblinded CGM use (54 vs 45 glucose spikes/10-day period, p=0.012). HFS-II showed improvement in 16/19 worry measures, reaching statistical significance in six. CGM use in patients with PBH enabled diet liberalization, reduced hypoglycemia-based worries, and reduced diurnal hypoglycemia, indicating improved QoL.

Disclosure

S.Ramanujan: None. N.Turk: None. E.M.Ayhan: None. C.M.Craig: Employee; Eiger BioPharmaceuticals, Stock/Shareholder; Eiger BioPharmaceuticals. T.Mclaughlin: Board Member; January, Inc., Research Support; Merck & Co., Inc., Stock/Shareholder; Eiger Bio.

Funding

American Diabetes Association (1-19-ICTS-073 to T.M.)
255-OR: Postpartum Weight Retention and the Early Evolution of Cardiovascular Risk over the First 5 Years after Delivery
Authors: KRAMER CAROLINE K. , YE CHANG , HANLEY ANTHONY , CONNELLY PHILIP W. , ZINMAN BERNARD , RETNAKARAN RAVI
Published: June 2023

The cumulative effect of postpartum weight retention from each pregnancy in a woman’s life may contribute to her risk of ultimately developing cardiovascular (CV) disease and type 2 diabetes. However, there is limited direct evidence supporting this hypothesis. Thus, we sought to characterize the impact of postpartum weight retention on the trajectories of cardiometabolic risk factors over the first 5 years after pregnancy. Three-hundred-and-thirty women underwent cardiometabolic characterization in pregnancy and at 3-months, 1-yr, 3-yr, and 5-yrs postpartum. They were stratified into 3 groups based on the magnitude of weight change between pre-pregnancy and 5-yrs postpartum as follows: weight gain <0% (n=100), weight gain 0-6% (n=110), and weight gain >6% (n=120). CV risk factors did not differ between these groups at 1-yr postpartum but showed a stepwise worsening across the groups at 3- and 5-yrs (Fig). Specifically, adverse lipids, insulin resistance, and CRP progressively worsened from the weight gain <0% group to weight gain 0-6% to weight gain >6% (all p<0.05). On logistic regression analyses of prediabetes/diabetes at 5-years postpartum, weight gain >6% was shown to be significant (adjusted OR 3.40 [1.63 to 7.09]). In conclusion, postpartum weight retention predicts trajectories of enhanced CV risk and rising glycemia over the first 5-yrs after delivery.

Disclosure

C.K. Kramer: Research Support; Boehringer Ingelheim Inc. C. Ye: None. A. Hanley: None. P.W. Connelly: None. B. Zinman: Consultant; Abbott Diabetes, Eli Lilly and Company, Novo Nordisk A/S, Novo Nordisk Canada Inc., Boehringer Ingelheim Inc., Merck & Co., Inc. R. Retnakaran: Research Support; Boehringer Ingelheim/Mount Sinai Hospital, Novo Nordisk. Other Relationship; Sanofi, Eli Lilly and Company.
257-LB: Defining the Stage-Dependent Transcriptome and Methylome in the Mouse Liver during Perinatal Metabolic Maturation
Authors: YANO SEIICHI , SATO NAOICHI , ARAKI HIROMITSU , MIURA FUMIHITO , ITO TAKASHI , OGAWA YOSHIHIRO
Published: June 2023

A mammalian liver serves as an extramedullary hematopoietic organ during fetus, and matures into a metabolic organ after birth, thereby adapting to the changes in nutritional environment. PPARα-dependent DNA demethylation upregulates hepatic fatty acid β-oxidation (FAO) genes in the postnatal mouse liver to produce energy from breast milk lipids. However, the detailed interaction between DNA methylation (DNAme) and gene expression in the liver through perinatal stages remain poorly understood. Here, we perform an integrative analysis of transcriptome and methylome of the mice liver at fetal, neonatal, and postweaning stages. While the level of global DNAme gradually increased from fetal to postweaning stages, we found a drastic loss of DNAme in specific regions that are associated with metabolic pathways such as FAO, gluconeogenesis, and amino acid metabolism within the neonatal stage in concordance with the activation of such metabolic processes. Moreover, in silico analysis predicted transcription factors, such as HNF4α, PPARα, NR1H2, and NR1H3, as key epigenetic regulators within lactation period. We also observed an inactivation of erythrocyte development with a concordant gain of DNAme. This analysis extends the epigenetic landscape for understanding the hepatic maturation during early life, and suggests the importance of lactation period in epigenetic regulation.

Disclosure

S. Yano: None. N. Sato: None. H. Araki: None. F. Miura: None. T. Ito: None. Y. Ogawa: None.
257-OR: Diabetic Kidney Disease (DKD) and Nonalcoholic Fatty Liver Disease (NAFLD) Confer Worsening All-Cause Mortality and Cardiovascular Disease (CVD) Risk in Type 2 Diabetes (T2D)
Authors: GAROFOLO MONIA , LUCCHESI DANIELA , GIAMBALVO MASSIMO , CAPOBIANCO MARTINA , FRANCESCONI PAOLO , PENNO GIUSEPPE , DEL PRATO STEFANO
Published: June 2023

Aim: In T2D, the prevalence of NAFLD is 56-60% and approximately 40% have DKD; thus, a sizable proportion of subjects may have both conditions. We explored to which extent the coexistence of the two could further worsen mortality and CVD risk in T2D.

Methods: We recorded vital status and data for major CVD (the latter available for 98.5% subjects) were retrieved on December 31st, 2017. DKD (eGFR <60 ml/min/1.73 m2 and/or ACR ≥30 mg/g) and NAFLD (fatty liver index ≥60) effects assessed by Kaplan-Meier curves and hazard ratios (HR, 95% CI) by adjusted Cox regressions.

Results: Distributions of NAFLD and DKD are reported in Table. HbA1c was similar in subgroups; NAFLD had worse metabolic and inflammatory profile, DKD higher hypertension rate. Over a follow-up of 13.1±2.8 years, we recorded 229 deaths (23.8%) and 273 major CV (28.8%). Rates of other outcomes are reported in Table. Death rate was 16.3, 21.8, 25.6 and 43.8% (p<0.0001) across groups with full adjusted HR (Model 2), of 1.50 (1.07-2.10, p=0.020) in NAFLD only, 1.15 (0.58-2.27, p=0.697) in DKD only, and 2.73 (1.90-3.93, p<0.0001) in DKD/NAFLD. Table reports effects of DKD-NAFLD combinations on CV outcomes.

Conclusions: DKD and NAFLD concur increasing mortality and CVD risk in T2D patients. Monitoring and managing DKD and NAFLD is required to prevent CVD and reduce mortality.

Disclosure

M.Garofolo: Consultant; Novo Nordisk, Employee; Eli Lilly and Company. D.Lucchesi: None. M.Giambalvo: None. M.Capobianco: None. P.Francesconi: None. G.Penno: Advisory Panel; Eli Lilly and Company, Bayer Inc., Consultant; Novo Nordisk, AstraZeneca, Boehringer Ingelheim Inc. S.Del prato: Advisory Panel; Abbott Diagnostics, Altimmune, Amarin Corporation, Applied Therapeutics Inc., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk A/S, Vertex Pharmaceuticals Incorporated, Novartis, Consultant; A. Menarini Diagnostics, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk A/S, Sanofi.