bluuebunny/crossref_metadata_2025_split huggingface dataset:
146-OR: Clustering Pediatric Type 2 Diabetes Patients Exposes Differential Responses to Therapeutic Interventions
Authors: KREIENKAMP RAYMOND J. , SMITH KIRK , WANGDEN THINLEY Y. , JENSEN ELIZABETH T. , SHAH AMY S. , PIHOKER CATHERINE , SZCZERBINSKI LUKASZ , FLOREZ JOSE C. , UDLER MIRIAM , SRINIVASAN SHYLAJA 
Published: June 2024

Introduction & Objective: Diabetes is a heterogeneous disease, with patients displaying varying degrees of adiposity, beta-cell dysfunction, and insulin resistance. Ahlqvist et al. established five distinct sub-types of adult-onset diabetes, with differing disease progression and risk for complications, based on clustering of six clinical variables. These clusters were developed and validated in adult populations, but their reproducibility in pediatric diabetes remains unknown. We sought to determine if pediatric patients can be sub-classified into clusters based on the same variables, and if these clusters had differing responses to treatment.
Methods: We analyzed Progress in Diabetes Genetics in Youth (ProDiGY), a multi-ethnic resource that brings together youth with clinician-diagnosed type 2 diabetes (T2D) before age 20 years from SEARCH (n=428) and the Treatment Options for T2D in Adolescents and Youth (TODAY) study (n=455). In participants with negative autoantibodies, we used a k-means (k=3) clustering method, with variables BMI, HOMA2_B, HOMA2_IR, and HbA1c; we excluded age of diagnosis given its limited range in a pediatric population.
Results: We identified three distinct pediatric clusters in each cohort-sex group. Cluster 1 had high HbA1c and low HOMA2_B, denoting low beta-cell function. Cluster 2 had the highest BMI, HOMA2_IR, and HOMA2_B, denoting insulin resistance. Cluster 3 had intermediate levels of HOMA2_IR and HOMA2_B but the lowest HbA1c, denoting milder diabetes. In TODAY, participants in cluster 1 had the highest rates of treatment failure (76% versus 46% overall, p&lt;0.0001). Metformin alone was most likely to be successful in cluster 3 (failure rate 19%) and had the highest rates of failure in cluster 1 (failure rate 86%, p&lt;0.0001).
Conclusion: Clustering pediatric T2D by clinical measures reveals distinct sub-types with differing responses to treatment. Clustering might be used to inform treatment choices in pediatric T2D patients.

Disclosure
R.J. Kreienkamp: None. K. Smith: None. T.Y. Wangden: None. E.T. Jensen: Advisory Panel; TARGET PharmaSolutions, Inc. Research Support; TARGET PharmaSolutions, Inc. Consultant; Regeneron Pharmaceuticals Inc. A.S. Shah: None. C. Pihoker: None. L. Szczerbinski: None. J.C. Florez: Research Support; Novo Nordisk. Other Relationship; Novo Nordisk, AstraZeneca. M. Udler: Other Relationship; Up-To-Date. S. Srinivasan: None.

Funding
American Diabetes Association (11-22-PDFPM-03); RJK is supported by NIH (T32DK007699). JCF is supported by NIH/NHLBI (K24 HL157960). SS is supported by NIH (K23DK120932 and R03DK138213).
1499-P: Possible Association of GAD65 Antibody with Pancreatic Adenocarcinoma
Authors: VALLABH SEAN , PELTSVERGER MAYA Y. , YESAULAVA LIUDMILA 
Published: June 2024

Objective: To demonstrate a role of serum anti-glutamic acid decarboxylase 65 antibodies titer (GAD65) as a possible paraneoplastic marker of pancreatic adenocarcinoma.
Case Presentation: A 29-year-old male with polysubstance abuse presented to the emergency room with polyuria, polydipsia, and polyphagia. Laboratory findings were consistent with DKA.
GAD65 antibody was elevated to over 25,000U/mL (0-5- U/mL) leading to a diagnosis of Type 1 Diabetes. The titer was confirmed on dilution and remained unchanged 3 months later Insulin regimen was initiated. Glycemic control was challenging.
Eight months later he presented with epigastric pain, dark urine, and jaundice. An endoscopic ultrasound demonstrated a 7 cm pancreatic head mass with venous abutment. Biopsy revealed a primary adenocarcinoma. Genomic microsatellite testing did not reveal actionable mutations.He underwent 7 cycles of neoadjuvant chemotherapy with Folfirnox; and second-line therapy with radiation and Gemcitabine, Abraxane. Upon completion of these therapies his GAD 65 antibody had decreased to 9,686.3U/mL(0-5 U/mL), his CA 19-9 tumor also decreased to 43.22 U/mL from 47.5 U/mL at diagnosis (0-35 U/mL); while his CEA increased to 4.09 ng/mL from 3.5 ng/mL at diagnosis (0-2.5 ng/mL). His disease is maintained with palliative Folfiri. Glycemic control remains suboptimal.
Conclusion: The degree of GAD65 antibody elevation via enzyme-linked immunosorbent assay could have a role in detecting pancreatic adenocarcinoma. There is no current literature placing the association between GAD65 and pancreatic adenocarcinoma, making this a novel case.

Disclosure
S. Vallabh: None. M.Y. Peltsverger: None. L. Yesaulava: None.
1503-P: Nano-thin Conformal Coating onto Human Islets to Preserve Cell Function and Induce Immunoprotection for Islet Transplantation
Authors: YITAYEW MICHAEL Y. , LI LING , TABRIZIAN MARYAM 
Published: June 2024

Allogenic islet transplantation is a promising treatment option for patients with Type 1 Diabetes (T1D). Systemic immunosuppression is required to mitigate donor islet rejection, but this can present with adverse side-effects and reduce patient quality of life. To address this, it has been proposed that biocompatible materials can be used to form a protective capsule around islets and modulate islet-induced immune reactions while maintaining cellular and secretory functions. A key feature of such capsules is minimal implant volume to ensure cells have adequate diffusion across their membrane while allowing for islet infusion into the portal vein. Conformal coatings have been described in the literature to exhibit the desired characteristics of an ideal protective capsule mentioned above. Our work investigates a novel combination of non-immunogenic polyelectrolytes, namely tetrahydropyran triazole phenyl-alginate (TZ-AL) and quaternized phosphocholine-chitosan (PC-QCH), for a nano-thin film formation onto human islet surfaces. After thorough characterization of material properties, we demonstrated successful coating formation (540nm thickness), and biocompatibility using human-derived beta cell lines and donor human islets. Our results indicate that coated islets cultured upto 7 days in vitro preserved their cell viability, GSIS, and gene expression (INS, GLUT2, Glucagon, PDX1) compared to non-coated controls. In vitro immune assays revealed that our materials do not stimulate the innate immune system and reduce pro-inflammatory cytokine secretion. Furthermore, coated islets implanted into STZ-induced diabetic mice restored normoglycemia up to one month and islet morphology is maintained according to histology data. Additional studies to investigate the in vivo immunomodulatory properties of our coating are ongoing and ultimately, the findings from this study can help to further improve the outcomes of islet transplantation.

Disclosure
M.Y. Yitayew: None. L. Li: None. M. Tabrizian: None.

Funding
Canadian Institutes of Health Research (91435)
1519-P: Endothelial Injury Predicts Carbohydrate Metabolism Trajectories after COVID-19
Authors: REUSCH JANE E.B. , ALBERS DAVID , WANG YANRAN , BRIGGS JENNIFER , MAICKI RICHARD , STROH J.N. , GUPTA AANCHAL , GARCIA ANN , SINGH VATSALA , HILLER TERRA D. , SHERMAN ARTHUR , RASOULI NEDA , DOUGLAS IVOR S. 
Published: June 2024

Introduction & Objective: Diabetes and SARS-CoV-2 infection target the endothelium causing perfusion abnormalities. We hypothesized that COVID-19 impairs insulin action and/or insulin secretion, and that systemic endothelial injury (EI) slows post-hospitalization recovery of these parameters.
Methods: 20 hospitalized adults with COVID-19 and acute hypoxemia (8 with DM) were tested for markers of endothelial function (hospital discharge, 1, 3 months) and oral glucose tolerance tests (OGTT) (1 and 3 months). Insulin sensitivity and insulin & C-peptide secretion metrics were assessed with empirical models (HOMA β, HOMA-IR) and mathematical ordinary differential equation (ODE) based models [(ISS (Sigma, SI), CSR (CSR0 (fasting), CSR-km (non-fasting)), ISR (ISR-km (non-fasting)), and ultradian ULS (a1, Rg)].
Results: Table 1 indicates significant correlations between patient-specific changes normalized over time (slopes) in EI and endocrine metrics. Uncertainty was estimated with linear mixed models adjusted for diabetes status and sex, respectively for each metric. Individually paired marker and metric slopes characterizing changes in participant physiological states were associated using linear regression models. Significance of predictive impact was interpreted from associated p-values of each slope pairing.
Conclusion: Changes in EI predict post-hospital recovery of carbohydrate metabolism.

Disclosure
J.E.B. Reusch: Advisory Panel; Medtronic. D. Albers: None. Y. Wang: None. J. Briggs: None. R. Maicki: None. J. Stroh: None. A. Gupta: None. A. Garcia: None. V. Singh: None. T.D. Hiller: None. A. Sherman: None. N. Rasouli: Advisory Panel; Eli Lilly and Company, Novo Nordisk. Research Support; Novo Nordisk. I.S. Douglas: None.

Funding
R01 DK130351
1520-P: Pyridylnidulin, a Semisynthesized Fungal Metabolite, Exerts the Insulin-Mimicking Effect and Improves Glucose Homeostasis in Mice
Authors: TEPAAMORNDECH SURAPUN , ISAKA MASAHIKO , CHANTARASAKHA KANITTHA , LIKITNUKUL SUTHARINEE 
Published: June 2024

Fungal metabolites have contributed significantly to medication development. However, there are few reports of the fungal metabolites beneficial for type 2 diabetes (T2D) treatment. This study performed a semi-synthesis converting nornidulin, a secondary metabolite of Aspergillus unguis ATCC10032, to pyridylnidulin. We aimed to investigate the stimulatory effect of pyridylnidulin on glucose uptake and the mechanism of action, and determine an improvement in glucose homeostasis in mice fed high-fat diet. Our results showed that pyridylnidulin stimulated 2-[3H]-deoxy-glucose greater than nornidulin in 3T3-L1 adipocytes and L6 myotubes. Pyridylnidulin-stimulated glucose uptake was found in a dose- and time-dependent manner. Our study also provided evidence that pyridylnidulin enhanced upregulation of GLUT4, and phosphorylation of IRS1, AKT, and AMPK. Importantly, the levels of GLUT4 in the plasma membrane were increased in response to nidulin treatment. The presence of the PI3K/AKT inhibitor, wortmannin, but not AMPK inhibitor, compound C, largely lowered pyridylnidulin-stimulated glucose uptake. In addition, pyridylnidulin triggered p42/p44 MAPK phosphorylation of which inhibition by PD98059 limited pyridylnidulin-stimulated glucose uptake. In palmitic acid-induced insulin resistance in myotubes, pyridylnidulin-stimulated glucose uptake remained significant. In C57BL/6 mice fed high-fat diet for 10 weeks, oral administration of 120 mg/kg pyridylnidulin for 4 weeks not only improved glucose homeostasis in IPGTT, but also ameliorated hepatic steatosis. Taken together, pyridylnidulin exerts the insulin-mimicking effect stimulating glucose uptake mainly through PI3K/AKT-dependent GLUT4 translocation, and improved T2D pathogenesis in a mouse model.

Disclosure
S. Tepaamorndech: None. M. Isaka: None. K. Chantarasakha: None. S. Likitnukul: None.

Funding
Ratchadapiseksompotch Fund, Faculty of Medicine, Chulalongkorn University (RA67/015); Development of new faculty staff, Ratchadaphiseksomphot Fund, Chulalongkorn University (DNS_66_089_3000_011); Thailand Research Fund (DBG6280008)
1527-P: G Protein Gsα Is Required for Normal Glucose Sensing in POMC Neurons
Authors: LAYTON DANIEL , SUN HUI , GUPTA MEENAKSHI , CUI ZHENZHONG , CHEN MIN , GAVRILOVA OKSANA , COLLINS MICHAEL T. , WEINSTEIN LEE 
Published: June 2024

Proopiomelanocortin (POMC) neurons are glucose-sensing neurons in which increased ambient glucose concentrations lead to neuronal activation by a mechanism involving KATP channels. Since glucose sensing in pancreatic β-cells occurs by a similar mechanism and requires G protein Gsα/cAMP signaling, we hypothesized that Gsα may also be involved in glucose sensing in POMC neurons. To test this hypothesis, we generated mouse models with POMC neuron-specific Gsα deficiency (POMCGsKO) or expression of a constitutively activated Gsα (POMCGsR201C). Despite having normal body weight and composition, POMCGsKO mice were hyperglycemic, hypoinsulinemic, glucose intolerant, and had impaired insulin response to glucose loading in vivo. In contrast, POMCGsR201C mice showed increased fat mass but improved glucose tolerance and enhanced insulin response to i.p. glucose administration. This altered glucose homeostasis by Gsα deficiency or activation in POMC neurons was not due to an autonomous pancreatic β-cell defect as both POMCGsKO and POMCGsR201C mice displayed normal pancreatic islet size and number, unchanged β-cell mass and intact glucose-stimulated insulin secretion from isolated islets ex vivo compared to controls. Instead, POMCGsKO mice lacked glucose-stimulated POMC neuron activation as determined by induction of c-fos expression, while POMCGsR201C mice exhibited higher basal c-fos activity in POMC neurons. These results indicate that Gsα is required for normal glucose sensing in POMC neurons which provide feedback to pancreatic islets to maintain glucose homeostasis.

Disclosure
D. Layton: None. H. Sun: None. M. Gupta: None. Z. Cui: None. M. Chen: None. O. Gavrilova: None. M.T. Collins: None. L. Weinstein: None.

Funding
NIDDK Intramural Research Program
1545-P: Differences in Brain Anatomy between Diabetes Endotypes—Results from the UK-Biobank
Authors: CERRAI CERONI MARIACLAUDIA , HUMMEL JULIA , PRYSTUPA KATSIARYNA , MÜLLER HANS-PETER , YAMAZAKI HAJIME , KASSUBEK JAN , WAGNER ROBERT , HENI MARTIN 
Published: June 2024

Introduction & Objectives: Research suggests that reduced regional brain volumes in specific areas are important for cognitive functions in persons with type 2 diabetes. How this relates to novel diabetes endotypes is unknown.
Methods: We therefore investigated MRI-derived brain volumes from 464 participants of the UK-Biobank, who had up to 5 years of type 2 diabetes duration and available clinical data. We estimated group membership to the diabetes clusters introduced by Ahlqvist et al. using the approach proposed by Antonio-Villa et al. that relies on BMI, HDL, triglycerides, waist, height, age at fMRI and age at diagnosis, sex, glucose, and HbA1c. Differences in brain volumetry between endotypes were tested by ANCOVA adjusting for age with Bonferroni correction for multiple comparisons and post-hoc Tukey tests.
Results: Grey matter volume (p &lt; 0.0001) as well as bilateral volumes of hippocampus (p &lt; 0.01), and ventral striatum (p &lt; 0.0001) showed differences between endotypes. This remained significant even after adjustment for age and correction for multiple testing. Lowest volumes in these brain areas were present in patients of the insulin deficient SIID cluster, who also had significantly lower volumes than healthy controls. Volumes of white matter, thalamus, caudate, putamen, pallidum, and amygdala did not show significant differences between groups.
Conclusion: There are differences in global and subcortical brain volumes between diabetes endotypes even after a short diabetes duration. Most affected areas are important for cognitive functions, suggesting higher risks for cognitive decline especially in the insulin-deficient SIID endotype.&lt;u&gt; &lt;/u&gt;

Disclosure
M. Cerrai Ceroni: None. J. Hummel: None. K. Prystupa: None. H. Müller: None. H. Yamazaki: Other Relationship; AstraZeneca, Janssen Pharmaceuticals, Inc., Mitsubishi Tanabe Pharma Corporation, Kowa Company, Ltd., Kyorin Pharmaceutical Co. Ltd, Takeda Pharmaceutical Company Limited, Takeda Pharmaceutical Company Limited, Magmitt Pharmaceutical Co. J. Kassubek: None. R. Wagner: Speaker's Bureau; Sanofi. Advisory Panel; Lilly Diabetes. Speaker's Bureau; Boehringer-Ingelheim, Novo Nordisk. M. Heni: Research Support; Boehringer-Ingelheim. Advisory Panel; Amryt Pharma Plc. Speaker's Bureau; Amryt Pharma Plc. Advisory Panel; Boehringer-Ingelheim, Boehringer-Ingelheim. Speaker's Bureau; Lilly Diabetes, Novartis AG, Novo Nordisk, Sanofi.
1548-P: Functional and Behavioral Dynamics of GLP-1 Receptors in the Central Amygdala
Authors: DURAN MIGUEL , VIRKUS SONJA , HARDAWAY JAMES A. 
Published: June 2024

Introduction: Glucagon-like peptide-1 receptor (GLP-1R) activation reduces food intake via multiple brain sites, i.e., hypothalamus, hindbrain, and limbic systems. Peripheral and central administration of GLP-1R agonists activate the central nucleus of the amygdala (CeA), yet the mechanisms mediating this action are understudied. In the present study, in vivo fiber photometry and calcium indicator, GCaMP, in the CeA in freely behaving mice was used to determine the role of GLP-1Rs in modulating neural activity in response to peripheral administration of a GLP-1R agonist.
Methods: Fiber photometry
Results: Freely behaving mice with fiber optic cannulas implanted in CeA were attached to a fiber photometry system and neural activity recorded in response to intraperitoneal administration of saline, Exendin-4 (5 µg/kg, Ex4, agonist), or Exendin-9 (50 µg/kg, Ex9, antagonist). We found that Ex4 activates CeA neurons, and this effect is blocked by prior administration of Ex9.
Conclusion: These measurements from freely behaving mice suggest that CeA GLP-1Rs are potentially mediating changes in neuronal activity when activated by a GLP-1R agonist. Currently, we are assessing the behavioral consequences of inhibiting the neuronal signaling of the CeA and its GLP-1R on feeding behavior.

Disclosure
M. Duran: None. S. Virkus: None. J.A. Hardaway: None.

Funding
National Institutes of Diabetes and Digestion and Kidney Disease (K01DK115902, R03DK129561); Dr. Tim Gavey (P30DK079626); Dr. James Hill (P30DK056336)
1565-P: Morning Hyperglucagonemia Disrupts the Priming Action of AM Insulin
Authors: WATERMAN HANNAH L. , MOORE MARY C. , SMITH MARTA S. , FARMER BEN , YANKEY KALISHA , EDGERTON DALE S. , CHERRINGTON ALAN D. 
Published: June 2024

The second meal effect describes an improvement in the glycemic response seen following the consumption of a 2nd identical meal. We previously showed that morning (AM) exposure of the liver to hyperinsulinemia can prime the liver so that there is increased hepatic glucose uptake and glycogen storage later in the day, with no effect on non-hepatic glucose uptake (non-HGU). Considering that most individuals consume meals that prompt both insulin and glucagon secretion, we sought to determine if AM hyperglucagonemia can alter the priming effect of AM hyperinsulinemia on PM hepatic glucose metabolism. To explore this aim, canines were exposed to 4h of hyperinsulinemia in the AM in a delivery pattern that mimicked the insulin secretory profile previously observed during a 4h AM duodenal glucose infusion. This 4h period of hyperinsulinemia was accompanied by either basal (INS, n=6) or elevated (I + G, n=8) glucagon. After a 1.5h non-clamp period, the dogs were challenged using a 2.5h afternoon (PM) hyperinsulinemic-hyperglycemic (HIHG) clamp during which the glucose load, insulin and glucagon levels, and the artery to portal vein glucose gradient were identical between the two groups. During the PM clamp, the mean NHGB in I+G was only 54% of that in INS (mean NHGB of -3.3±0.5 vs. -6.2±0.5 mg/kg/min; net AUC of 415±70 vs. 785±73 mg/kg/2.5h, P&lt;0.003), respectively. Additionally, glycogen synthesized during the PM clamp was twice as high in INS vs. I+G (mean PM glycogen storage of 23.6±1.3 vs. 12.0±1.9 mg/g liver, P&lt;0.001), respectively. There was no significant difference in mean PM non-HGU between the two groups. The mean PM NHGB for a group that received basal insulin and basal glucagon in the AM (No Prime) was -2.7±0.5 mg/kg/min, which is not statistically different from PM NHGB for I+G.
In conclusion, exposing the liver to hyperglucagonemia in the morning has the potential to block the priming action of meal-induced AM hyperinsulinemia, preventing enhanced glucose uptake and glycogen storage by the liver later in the day.

Disclosure
H.L. Waterman: None. M.C. Moore: None. M.S. Smith: None. B. Farmer: None. K. Yankey: None. D.S. Edgerton: None. A.D. Cherrington: Consultant; Abvance Therapeutics. Research Support; Abvance Therapeutics. Advisory Panel; AdipoPharma. Research Support; Cellular Longevity, Inc. dba Loyal. Advisory Panel; Fractyl Health, Inc. Consultant; Fractyl Health, Inc. Research Support; Fractyl Health, Inc. Consultant; Novo Nordisk. Research Support; Novo Nordisk. Consultant; Paratus, Portal Insulin. Advisory Panel; Sekkei Bio, Sensulin Labs, LLC. Consultant; Thetis Pharmaceuticals, LLC.

Funding
National Institutes of Health (5R01DK131082); National Institutes of Health (5T32DK007563)
1566-P: Growth Hormone Replacement Treatment Improves Nonalcoholic Fatty Liver Disease in Patients with Pituitary Stalk Interruption Syndrome—A Randomized, Single-Blind, Placebo-Controlled Prospective Cohort Study
Authors: ZHANG JUNYI , WU XUEYAN 
Published: June 2024

Background: Non-alcoholic fatty liver disease (NAFLD) commonly coexists as a comorbidity among patients with pituitary stalk interruption syndrome (PSIS) with growth hormone deficiency (GHD). This study aimed to investigate the impact of GH replacement therapy on liver fat content and metabolic parameters in PSIS patients with GHD and NAFLD.
Methods: In this randomized, single-blind, placebo-controlled prospective trial, 14 adults with PSIS, who have GHD and LFC ≥ 6%, aged 20 to 50 years without diabetes, were randomized to weekly subcutaneous GH (n=8) or placebo (n=6), targeting insulin-like growth factor 1 to normal quartile. The primary endpoint was LFC assessed before and after 32-week treatment using magnetic resonance imaging-derived proton density fat fraction.
Results: The GH group had significantly greater reduction in LFC compared to placebo group (mean ± SD: -11.48±9.26 % vs -3.12±4.12, P=0.046). Additionally, GH group showed a more substantial median decrease in gamma-glutamyl transferase levels than placebo group [-5.50, interquartile range(IQR) -42.75 to -2.25 vs 5.00, IQR -14.75 to 25.00 U/L, P 0.029]. No significant differences were observed in the changes of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). In GH group, both AST and ALT levels after 32-week treatment were significantly lower than baseline values [21.50 (18.50, 30.50) vs 28.00 (21.75, 64.50) IU/L, P = 0.012; 24.00(19.75, 36.00) vs 31.50(23.50, 90.50) IU/L, P = 0.012; respectively), while no such changes could be obtained in placebo group.
Conclusion: GH replacement therapy can reduce LFC in patients with GHD and NAFLD, which may emphasize the need for prompt GH treatment in such specific patient population.

Disclosure
J. Zhang: None. X. Wu: None.

Funding
Project of National Natural Science Foundation of China (81771576); and the Beijing Municipal Natural Science Foundation (7202151)