bluuebunny/crossref_metadata_2025_split huggingface dataset:
214-OR: Results from the Promoting Resilience in Stress Management (PRISM) Intervention—A Multisite Randomized Controlled Trial (RCT) for Teens with Type 1 Diabetes (T1D)
Authors: YI-FRAZIER JOYCE P. , HILLIARD MARISA E. , O'DONNELL MAEVE B. , ZHOU CHUAN , ELLISOR BRITNEY M. , GARCIA PEREZ SAMANTHA , ROJAS YULIANA , MALIK FAISAL , DESALVO DANIEL , PIHOKER CATHERINE , BRADFORD MIRANDA , SCOTT SAMANTHA R. , ROSENBERG ABBY 
Published: June 2023

Introduction: PRISM is a resilience resources intervention that teaches stress-management, goal setting, reframing, and benefit finding. We tested the efficacy of PRISM on glycemic control, diabetes distress, resilience, and quality of life.
Methods: This 2-site (Seattle WA, Houston TX) 1:1 RCT of PRISM vs. usual care (UC) included teens 13-18y with T1D≥12m and diabetes distress (PAID-T) scores ≥30. A1C, distress (PAID-T), diabetes resilience (DSTAR), and diabetes quality of life (T1DAL) were assessed at baseline (BL), 6m and 12m. Regression analyses used treatment arm as the primary predictor, controlling for additional covariates (Table).
Results: Teens (n=172) were 56% female, race = 73% White, 15% Black, 4% Asian, 8% other, ethnicity = 19% Hispanic, BL A1C 8.7% ± 2.0%. No differences were evident between PRISM and UC in A1C, distress, resilience, quality of life at 6 months post-baseline. However, at 12 months, participants in the PRISM arm experienced improvements in distress, resilience, and quality of life versus UC (Table).
Conclusions: Resilience promotion through PRISM had multiple psychosocial benefits for a diverse sample of teens with T1D by 12-months. Integrating resilience skill-building with medical intervention may optimize diabetes outcomes.

Disclosure
J.P.Yi-frazier: None. C.Pihoker: None. M.Bradford: None. S.R.Scott: None. A.Rosenberg: None. M.E.Hilliard: None. M.B.O'donnell: None. C.Zhou: None. B.M.Ellisor: None. S.Garcia perez: None. Y.Rojas: None. F.Malik: None. D.Desalvo: Consultant; Dexcom, Inc., Research Support; Insulet Corporation.

Funding
National Institutes of Health (R01DK121224)
224-LB: Shared Genetic Architecture of Complication of Diabetes
Authors: SALEM RANY M. , CAO STEVEN , RICHARD ERIN L. 
Published: June 2023

Introduction: Approximately 1 in 10 Americans have diabetes (~37 million), 90-95% of which is type 2 diabetes (T2D). T2D is the leading cause of kidney disease (DKD), retinopathy, neuropathy, peripheral vascular disease (PVD), stroke, and coronary heart disease (CHD). Inherited variation is known to contribute to the risk of T2D complications, however, the relationship between and role of genetic variants on risk across complications is not fully understood.
Method: We used data from our recently completed genomic investigations of a broad set of 18 diabetic complications, which included ~64K T2D subjects across five race-ethnic groups (Admixed Americas-, African-, East Asian-, European- and South Asian-ancestry samples) from 24 studies retrieved from dbGaP and UKBB biomedical repositories. Using these GWAS summary statistics, we calculated the genetic correlation between complication pairs with Z-scores (beta/SE) to investigate their relationship and guide post hoc pleiotropy analysis.
Results: Genetic correlation analysis revealed four clusters of complications that shared strong correlation. Pleiotropy analysis identified three novel pleiotropic loci for T2D complications at SNX17 (Albuminuria, CHD & PVD), UBE2E2 (Albuminuria & end-stage kidney disease) and GCKR (Albuminuria, DKD, retinopathy, fatty liver disease, CHD & PVD).
Conclusion: These findings support the hypothesis of shared heritability between diabetic complications. Additional work is needed to increase genetic discovery of pleiotropic variants across diabetic complications.

Disclosure
R. M. Salem: Other Relationship; Travere Inc. S. Cao: None. E. L. Richard: None.

Funding
Foundation for the National Institutes of Health; National Institutes of Health (R00HL122515)
228-LB: Metformin Alleviates Aging-Associated Metabolic Disorders through Intestinal AMPK-Mediated Gut Microbiome Alteration
Authors: ZHANG ERYUN , HUANG WENDONG 
Published: June 2023

The biguanide drug metformin combats age-related disorders and improves health span and is currently the first FDA approved drug to be tested for its age-targeting effects in the large clinical trial. However, the underlying molecular mechanisms remain unclear. AMPK is a key nutrient sensor for maintaining cellular energy status and a known therapeutic target of metformin to treat T2D. Despite current understandings of its well-established roles in regulating glucose metabolism in various tissues, the functions of AMPK in the intestine remain largely unexplored. Our previous study uncovered a novel link between intestinal AMPK activation and energy metabolism through modulating the anti-microbial peptide (AMP)-controlled gut microbiota. We therefore ask whether intestinal AMPK also mediates metformin effects on aging-associated metabolic improvement. In this study, we showed that AMPKα1 deficiency in the intestine resulted in weight gain, impaired glucose tolerance and insulin resistance in aged mice. Interestingly, metformin administration ameliorated these aging-associated metabolic disorders in aged wild type but not intestinal AMPK α1 KO mice, which indicated that the beneficial effects of metformin were dependent on the intestinal AMPKα1 in aging animals. Moreover, we found that metformin treatment significantly altered the abundance of several gut bacterial genera in aged-AMPKα1fl/fl but not intestinal AMPK α1 KO mice. Mechanistically, we identified several key anti-microbial peptides were upregulated by metformin treatment in an intestinal AMPK-dependent manner in aged mice.
In summary, our findings provide a new mechanistic underpinning by which intestinal AMPK regulates aging metabolism, which may shed light on not only the ongoing large clinical trials of metformin in aging patients, but also general drug discoveries utilizing enteral drug administration to treat aging-associated metabolic diseases.

Disclosure
E. Zhang: None. W. Huang: None.
229-LB: Generation of Human CAR-Treg Cells for Inducing Immunological Tolerance against Diabetogenic T Cells in Human Pancreatic Islets
Authors: IMAM SHAHNAWAZ , IMTIAZ RAFIQI SHAFIYA , JAUME JUAN C. 
Published: June 2023

We have developed pancreatic beta-cell, antigen-specific, Chimeric Antigen Receptor (CAR) T regulatory cells (Tregs) and explored their therapeutic potential against type 1 diabetes (T1D)/Latent Autoimmune Diabetes of Adult (LADA) in human pancreatic tissues ex-vivo. Two human Glutamic Acid Decarboxylase 65 kD isoform (GAD65) B-cell paratopes known to bind to two immunodominant regions in the N-terminal (CAR-N) and Middle (CAR-M) regions of human GAD65 were selected for assembly onto T cell receptors of Tregs. We first show that GAD65-CAR Tregs had a superior proliferation index (3 times than naïve Tregs) and were able to suppress diabetogenic, T cells in-vitro and this suppression was significantly superior to naïve Tregs at 2:1 (Tresp vs Treg) ratio (p&lt;0.004). Further, in ex vivo co-culture experimentation with pancreatic islets, confocal images demonstrated homing of GAD65-CAR Tregs to pancreatic islets as early as 24 hrs. With live immunofluorescence imaging and flow cytometry we demonstrated that GAD65-CAR Tregs from T1D/LADA patient were able to suppress diabetogenic cytotoxic T lymphocytes (CTLs) (p&lt;0.04) in the immune cell microenvironment in presence of heterologous pancreatic islet ex vivo. These findings verify that GAD65-CAR Tregs recognize endogenous GAD65 on isolated islets in an MHC-independent manner, are proliferative robustly and suppress autologous CTLs. Thus, GAD65-CAR Tregs can induce tolerance against T1D diabetogenic T cells and the use of GAD65-CAR Tregs can prove a promising strategy for inducing tolerance in islet transplantation to replace the immunosuppressive drugs in a safe potent manner.
Finally, homing of the GAD65-CAR Tregs to the islets, provided evidence for antigen-specific re-directionality. The robust proliferation and superior suppression of diabetogenic T cells by GAD65-CAR Tregs validate the functionality of GAD65-CAR Tregs in inducing tolerance in T1D patients and host vs graft islet rejections.

Disclosure
S. Imam: None. S. Rafiqi: None. J. C. Jaume: None.

Funding
University of Toledo
232-OR: STIM1 Interacts with G Protein–Coupled Estrogen Receptor Signaling to Maintain ß-Cell Identity in Female Mice
Authors: MCLAUGHLIN MADELINE , SOHN PAUL , KRISHNAN PREETHI , LEE CHIH-CHUN , KONO TATSUYOSHI , EVANS-MOLINA CARMELLA 
Published: June 2023

Calcium (Ca2+) plays a vital role in normal β cell function, and the β cell endoplasmic reticulum (ER) serves as the dominant intracellular store of Ca2+. ER Ca2+ depletion triggers a rescue mechanism known as store-operated Ca2+ entry (SOCE), which replenishes ER Ca2+ stores through the ER-localized Ca2+ sensor stromal interaction molecule 1 (STIM1). We have demonstrated pathogenic reductions in β cell SOCE and loss of STIM1 expression in rodent and human models of type 2 diabetes (T2D) and shown that β cell-specific loss of STIM1 (STIM1Δβ) leads to obesity-induced glucose intolerance, decreased β cell and increased cell mass in female but not male STIM1Δβ mice. To test mechanisms underlying these findings, lineage tracing experiments were performed and revealed increased colocalization of tdTomato and glucagon in STIM1Δβ mice compared to control mice, suggesting dedifferentiation of β cells to ⍺ cells. RNA sequencing of islets isolated from female STIM1Δβ mice revealed reductions in G-protein coupled estrogen receptor (GPER) expression and a transcriptional signature indicative of reduced estradiol mediated signaling. To test whether GPER is required for the maintenance of β cell identity, INS-1 cells were transfected with siRNA targeted to Gper1 or treated with the GPER1 antagonist, G-15. RT-qPCR showed that markers of β cell identity were significantly reduced and Gcg expression was significantly increased in Gper1 knockdown and G-15-treated cells. Lastly, to explore the functional connection between SOCE and GPER, STIM1KO and GPER knockdown INS-1 cells were stimulated with glucose, and Ca2+ responses were evaluated. First and second phase Ca2+ responses after glucose treatment were impaired in both STIM1KO and GPER knockdown INS-1 cells compared to WT INS-1 cells, suggesting that STIM1 and GPER may be functionally linked through Ca2+ signaling. Together, these data identify a novel connection between β cell SOCE, GPER signaling, and β cell differentiation status.

Disclosure
M.Mclaughlin: None. P.Sohn: None. P.Krishnan: None. C.Lee: None. T.Kono: None. C.Evans-molina: Advisory Panel; Provention Bio, Inc., DiogenX, Avotres Inc., Neurodon, MaiCell Therapeutics, Other Relationship; Isla Technology, Bristol-Myers Squibb Company, Nimbus Therapeutics, Research Support; Lilly, Astellas Pharma Inc.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK093954, R01DK127236, U01DK127786, R01DK127308, UC4DK104166); U.S. Department of Veterans Affairs (I01BX001733)
233-OR: The Beta-Cell Specific Deletion of Complement 1q-Like-3 Secreted Protein Improves Beta-Cell Function and Glucose Homeostasis
Authors: MOSTAFIZUR RAHMAN MD , ALSHARIF HAIFA , MICHL AVA , BHATNAGAR SUSHANT 
Published: June 2023

Using bioinformatics network analysis, we identified complement-1q like-3 (C1ql3) as a secreted protein that affects pancreatic islet function in obese mice. Previously, we showed that the recombinant C1ql3 protein inhibits insulin secretion stimulated by exendin-4 (an agonist for GLP-1 receptor) from human and mouse islets. Currently, we are elucidating the role of C1ql3 in pancreatic β-cell function by using mice with β-cell-specific deletion of the C1ql3 (βKO) gene on a standard chow diet. C1ql3βKO mice showed significantly improved glucose clearance after oral glucose challenge than the control mice, whereas no difference in insulin sensitivity was observed. Moreover, the plasma insulin levels were significantly increased at 15 min after the glucose challenge in the C1ql3 βKO vs. control mice. However, islets isolated from C1ql3βKO significantly increased insulin secretion stimulated by cAMP and Exendin-4 than control islets. These results suggest that the loss of C1ql3 in β-cells increases insulin secretion to improve glucose tolerance. Adenovirus-mediated overexpression of C1ql3 in islets showed increased ER stress and decreased expression of genes involving β-cell function and maintenance. In pathophysiological conditions, increased C1ql3 expression coupled to secretion was observed from both T2D donor islets and obese mouse islets. Interestingly, reduction in C1ql3 secretion is inversely correlated with increased glucose-stimulated insulin secretion from islets of C1ql3βKOLeptinob/ob compared to Leptinob/ob control mice. These findings suggest that the loss of β-cell C1ql3 maintains ER stress and increases insulin secretion to maintain glucose homeostasis. Our work shows that an autocrine regulation of the C1ql3-signaling pathway contributes to β-cell dysfunction in obesity and type 2 diabetes.

Disclosure
M.Rahman: None. H.Alsharif: None. A.Michl: None. S.Bhatnagar: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK120684-01)
240-OR: Islet Allotransplantation into Prevascularized Sernova Cell Pouch—Early Results from the University of Chicago
Authors: OGLEDZINSKI MATEUSZ , GONDEK SARAH , LIN WILLIAM , MILEJCZYK KAMILA , JUENGEL BRADEN , POTTER LISA , BACHUL PIOTR J. , BASTO LINDSAY , PEREA LAURENCIA , WANG LINGJIA , TIBUDAN MARTIN , BARTH ROLF , FUNG JOHN , WITKOWSKI PIOTR 
Published: June 2023

Each of 6 patients with T1DM and problematic hypoglycemia received 2 islet transplants into pre-implanted Sernova Cell Pouches (SCPs). Each procedure involved transplantation of islets into two 8-channel SCPs and one mini sentinel SCP. SCP implants and the combination of SCP with human cadaveric islets are both well tolerated with durations exceeding 3 years. Detectable islet function (≥0.3ng/ml peak serum c-peptide in mixed meal tolerance test) was achieved in 4 patients following islet transplant to SCP. It was correlated with transplanted islet mass of 300k-500k IEQ per procedure. Transplantation of islet mass &lt;300k IEQ did not lead to detectable c-peptide secretion. C-peptide was detectable for periods ranging from days up to 12 months after the procedure. Three patients with suboptimal levels of immunosuppression due to non-compliance experienced antibody mediated rejection based on de novo donor specific antibodies (DSAs). One patient with DSAs had detectable stimulated c-peptide at 90 days post-transplant. Histological assessment of sentinel SCPs retrieved ≥90 days post-transplant revealed surviving functional islets within vascularized SCP channels via positive immunofluorescence staining of insulin, c-peptide, glucagon and somatostatin in 5 of 6 patients. Five patients received supplemental intraportal islet transplants (IPITx) and all of them remain insulin independent (&gt;2.5Y, &gt;1Y, 10M, 2M, 1M). The sixth patient is awaiting an IPITx in the coming months as per protocol. Safety and dose-response observations from the first cohort of 6 patients led to the implementation of 10-channel SCPs with 50% greater transplant capacity than the 8-channel configuration in a second study cohort. Two additional patients were recently implanted with 10-channel SCPs and are currently awaiting their first islet transplantation.

Disclosure
M.Ogledzinski: None. L.Wang: None. M.Tibudan: None. R.Barth: None. J.Fung: None. P.Witkowski: Advisory Panel; Vertex Pharmaceuticals Incorporated, Novartis. S.Gondek: None. W.Lin: None. K.Milejczyk: None. B.Juengel: None. L.Potter: None. P.J.Bachul: None. L.Basto: None. L.Perea: None.

Funding
Sernova; JDRF
241-OR: Preservation of Islet Graft Function and Blood Glucose Control after Total Pancreatectomy with Islet Autotransplantation in Patients with Chronic Pancreatitis and Intractable Pain—Nine-Year Follow-up
Authors: LIN WILLIAM , OGLEDZINSKI MATEUSZ , GONDEK SARAH , MILEJCZYK KAMILA , JUENGEL BRADEN , POTTER LISA , BACHUL PIOTR J. , BASTO LINDSAY , PEREA LAURENCIA , WANG LINGJIA , TIBUDAN MARTIN , BARTH ROLF , FUNG JOHN , WITKOWSKI PIOTR 
Published: June 2023

Background: Total pancreatectomy is a last resort treatment for patients with chronic pancreatitis and intractable abdominal pain, however its utility has been hampered by the uncertain endocrine outcomes of islet transplantation and risk of postsurgical diabetes. Here, we present our 9-year clinical results after total pancreatectomy and islet transplantation.
Materials and Method: Forty-one patients with chronic or recurrent acute pancreatitis were treated with TPIAT over the last 9 years at the University of Chicago Medical Center. There were 15 male and 26 female with a median age of 33 (6-65) and with median BMI of 25 (17-39). Five (12%) patients were already diabetic prior to surgery. Islet isolation was performed at a local laboratory compliant with current Good Manufacture Practice regulations. Islet purification was implemented in 4 (10%) cases to reduce islet pellet volume below 20mL for intraportal infusion.
Results: All patients required opioids for pain control prior to surgery. Most of the patients (93%) reported resolution of pancreatic-type pain by postoperative year one. The number of patients requiring opioids for different type or location of pain declined over time from 13 (31%) at 1 year to 5 (12%) at 5 years after TPIAT. During TPIAT patients received on average 211,000±111,000 islet equivalents (IEQ), 2,500±1,600,). The majority of patients (95%) maintained endocrine beta cell function during follow up (serum c-peptide &gt;0.5ng/ml). Over 40% of patients maintained long-term insulin independence: 44% (15/34) at 1-year and 45% (5/11) at 5-year follow-up.
Conclusions: TPIAT successfully provided pancreatic pain resolution of pancreatic pain and preservation of the endocrine beta cell function in majority of the patients with no mortality. Islet autotransplantation prevented diabetes in over 40% of patients.

Disclosure
W.Lin: None. L.Wang: None. M.Tibudan: None. R.Barth: None. J.Fung: None. P.Witkowski: Advisory Panel; Vertex Pharmaceuticals Incorporated, Novartis. M.Ogledzinski: None. S.Gondek: None. K.Milejczyk: None. B.Juengel: None. L.Potter: None. P.J.Bachul: None. L.Basto: None. L.Perea: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (P30DK020595)
247-OR: Positive Effects of Bariatric Surgery Are Associated with Attenuation of Cellular Senescence
Authors: STEMBERKOVA HUBACKOVA SONA , HAVRLANTOVA TEREZA , SIMONIK IGOR , MRAZ MILOS , HALUZIK MARTIN 
Published: June 2023

Bariatric surgery represents the most efficient approach to treatment of obesity; however, the detailed mechanism of its positive metabolic effect is still not fully understood. Cellular senescence arrests the cell cycle in damaged cells thus preventing further spreading of the damage. Persistence of senescent cells especially in adipose tissue can, however, contribute to the development of a number of chronic diseases including obesity and its complications. Reduction of adipose tissue after bariatric surgery can therefore reduce the number of senescent cells and their negative effects on organism.
17 patients with obesity (2nd grade and higher) scheduled for bariatric surgery (sleeve gastrectomy) were included into the study. Subcutaneous (SAT) adipose tissue and plasma were collected during and 6 months after surgery. The analysis of samples included RT-qPCR (mRNA transcription in SAT) and ELISA or Luminex for detection of hormones and proteins from plasma.
Our results show that bariatric surgery reduces the amount of senescent cells in adipose tissue, which results in the decrease of oxidative stress and inflammation, partially also by reduced recruitment of pro-inflammatory macrophages. In addition, we detected lower plasma levels of soluble E-selectin and ICAM-1, molecules enhancing cardiovascular damage known to be produced by senescent cells, as well as decreased expression of ACE2, whose increased expression was detected in senescent cells. Importantly, we also observed decreased expression of ADAM17 responsible for producing a soluble form of ACE2, a newly identified predictor of cardiovascular damage.
In conclusion, reduction of senescent cells in adipose tissue after bariatric surgery contributes to improvement of inflammation and metabolic parameters in patients with obesity and decreases the risk of cardiovascular complications.

Disclosure
S.Stemberkova hubackova: None. T.Havrlantova: None. I.Simonik: None. M.Mraz: None. M.Haluzik: Advisory Panel; Novo Nordisk, Lilly Diabetes, Boehringer-Ingelheim, Research Support; Sanofi, Speaker's Bureau; Abbott, AstraZeneca.

Funding
Czech Health Science Foundation (NU22-01-00096); Programme EXCELES (LX22NPO5104); Czech Ministry of Health (IKEM, IN00023001)
250-LB: Ethnic Disparities in Insulin Secretion and Clearance in Normoglycemic Adults with Parental Type 2 Diabetes
Authors: ASUZU PEACE , PATEL AVNISHA , WAN JIM Y. , DAGOGO-JACK SAMUEL 
Published: June 2023

Background: To determine the role of ethnicity vs. heredity in glucoregulation, we assessed insulin secretion in healthy Black and White offspring of parents with T2DM.
Methods: Participants were screened with 75-g OGTT, and normoglycemic enrollees underwent assessments, including anthropometry, insulin sensitivity and secretion. Basal insulin secretion (fasting insulin {FI} and HOMA-B) and dynamic secretion (insulinogenic index; corrected insulin response {CIR} from OGTT data; acute insulin response to i.v. glucose {AIR}, insulin-AUC during FSIGT, and disposition index {DI} were quantified. Insulin sensitivity (ISI) was measured with euglycemic clamp. Basal insulin clearance (molar ratio of fasting C-peptide to insulin) and dynamic clearance (molar ratio of plasma C-peptide to insulin levels during FSIGT) were determined.
Results: We studied 145 Black and 123 White adults (N=268); 72% women; mean age 44.6±10.1 y. At baseline, fasting glucose (91.0 ± 7.26 vs.93.1 ± 6.31 mg/dl, P=0.012) and ISI (0.062 ± 0.048 vs. 0.077 ± 0.04, P=.014) were lower, and BMI (31.6 ± 7.64 vs. 28.9 ± 6.79, P=.0032) higher, in Black vs. White subjects. Basal insulin secretion was similar, but all measures of dynamic secretion were higher in Black vs. White offspring (Table 1).
Conclusions: Insulin clearance is lower but dynamic insulin secretion is greater in Black versus White individuals with parental diabetes.

Disclosure
P. Asuzu: None. A. Patel: None. J. Y. Wan: None. S. Dagogo-jack: None.