bluuebunny/crossref_metadata_2025_split huggingface dataset:
1464-P: Computational Modeling for Design of Next Generation Microphysiological Systems for Evaluation of ß-Cell Health and Function
Authors: VANDERLAAN EMMA , TEPOLE ADRIAN BUGANZA , HARBIN SHERRY L. 
Published: May 2022

Dynamic insulin secretion is a key focus of β cell research, with microfluidic devices emerging as a potential means to effectively evaluate this performance parameter in vitro. However, most devices maintain isolated islets in suspension despite evidence that collagen-islet interactions are critical to β cell viability and function. When designing a microphysiological system with encapsulated islets, important considerations include 1) sufficient oxygenation, 2) rapid exchange of glucose and insulin between cells and perfusate, and 3) detectable levels of secreted insulin. Computational models provide a means to simulate different device design parameters prior to fabrication, reducing the time and cost of testing multiple physical devices and microenvironmental conditions. For this study, COMSOL was used to model a microfluidic device containing islets macroencapsulated in a fibrillar collagen scaffold. A range of flow rates, collagen fibril densities, and islet-collagen construct dimensions were tested, with outcome measures including spatiotemporal changes in oxygen, glucose, and insulin. Simulations for all designs tested showed maintenance of islet viability as indicated by less than 1% of the construct area falling below the hypoxia-induced dysfunction threshold. Additionally, decreasing the construct thickness and increasing the medium glucose concentration yielded more rapid delivery of the target glucose stimulus to the islets, since glucose transport is primarily driven by diffusion within the construct. By contrast, transport of secreted insulin was found to be flow-limited and the presence of an encapsulation material altered the shape of the insulin secretion curve. Collectively, these results support the integrated use of computational models, together with experimental validation, as an efficient strategy for the creation of next generation microphysiological systems for evaluation of β cell health and function.

Disclosure
E.Vanderlaan: None. A.Buganza tepole: None. S.L.Harbin: Other Relationship; GeniPhys, Inc.
1467-P: Chemical Profiles of Acinar Tissue and Pancreatic Islets from Healthy and T2D-Affected Pancreata
Authors: RUBAKHIN STANISLAV , ROMANOVA ELENA V. , SWEEDLER JONATHAN V. 
Published: May 2022

Both the endocrine and exocrine pancreas demonstrate morphological and chemical changes associated with T2D development. Despite significant progress, chemical profiles of the islets and acinar tissue following disease progression are not well characterized. In this work we investigated isolated populations of pancreatic islets (n=18) and acinar tissues (n=7) collected from healthy and T2D affected pancreata using several mass spectrometry (MS) approaches. Samples are provided by the ADI IsletCore and the Network for Pancreatic Organ Donors with Diabetes (nPOD) . Both peptide and metabolite profiles were determined and compared via chemical profiling with matrix-assisted laser desorption/ionization Fourier-transform ion cyclotron resonance MS. Not surprisingly, the peptide profiles from T2D islets demonstrated lower signal intensities compared to healthy islets (ROC analysis, AUC=0.9) . Somatostatin, pancreatic icosapeptide, and insulin-related signals are most decreased. Preliminary data for acinar tissues indicate lower peptide levels in samples collected from T2D-affected (n=2) vs. healthy (n=5) pancreata. Several unique peptides are detected specifically in acinar tissue obtained from T2D-affected pancreata. Liquid chromatography-MS reveals a complex endogenous peptide complement of acinar tissue. Analysis of extracellular media for both islet types demonstrated similar differences (AUC=0.7) indicating higher levels of observed peptides in preparations from healthy islets, perhaps suggesting that peptides are released from the islets during shipment. Integrity of received islets was verified using dithizone staining prior to measurement. In contrast, almost no peptide markers of acinar tissue are found in corresponding extracellular media. Our results enhance knowledge on biochemical signature of T2D in the pancreas.

Disclosure
S.Rubakhin: None. E.V.Romanova: None. J.V.Sweedler: None.

Funding
American Diabetes Association (1-18-VSN-19)
1468-P: Effect of Kcnq1ot1 on Influencing the Function of Pancreatic ß-Cells Targeting miR-92a-1-5p
Authors: CHEN YALAN , LI YANLI , XU WEN , LIN BEISI , MAI XIAODONG , PENG YUEYUE , CHEN DANRUI , SU YANNA , LI WANGEN 
Published: May 2022

Objective: To study the role and mechanism of Kcnq1ot1 by targeting to regulate miR-92a-1-5p to effect insulin secretion in pancreatic β cells.
Methods: The qRT-PCR was used to detect the expression of Kcnq1ot1 in different tissues of C57BL/6J mice, Min6 with PA intervention, islets of T2D model mice and the serum of T2D patients. The biological information website was used to predict that Kcnq1ot1 had complementary binding sites with miR-92a-1-5p, which was verified by the luciferase reporting gene system. The si-Kcnq1ot1, miR-92a-1-5p mimics, miR-92a-1-5p inhibitors and their respective controls were respectively transfected into Min6, and the effect of Ins1, Ins2, Insr, Nkx6.1, Irs1 and Ngn3 were detected by qRT-PCR, the Western blot method was used to detect the expression of insulin and Insr, and the GSIS experiment was used to detect its effect on insulin secretion.
Results: The expression of Kcnq1ot1 in pancreas was significantly higher than that in other tissues. Compared with the control group, the expression of Kcnq1ot1 in T2D patients' serum, Min6 after PA treatment and the islets of T2D model mice were lower. And the expression of Kcnq1ot1 in serum is negatively correlated with FBG or HbA1c. Low expression of Kcnq1ot1 led to remarkable reduction of insulin secretion in Min6 cells. Down-regulation of Kcnq1ot1 or overexpression of miR-92a-1-5p reduced the mRNA expression levels of Ins1, Ins2, Insr, Nkx6.1, Irs1 and Ngn3, and the protein levels of insulin and Insr. We screened miR-92a-1-5p as targets of Kcnq1ot1, and their interaction was validated with dual luciferase reporter gene experiment. After knocking down Kcnq1ot1, the expression of miR-92a-1-5p was found to increase. Further rescue experiments showed that down-regulation of miR-92a-1-5p could reverse the effect of low Kcnq1ot1 expression on the function of pancreatic β-cells.
Conclusion: Kcnq1ot1 may regulate the function of pancreatic β cells by targeting to negatively regulate miR-92a-1-5p.

Disclosure
Y.Chen: None. Y.Li: None. W.Xu: None. B.Lin: None. X.Mai: None. Y.Peng: None. D.Chen: None. Y.Su: None. W.Li: n/a.

Funding
Science & Technology Project of Guangzhou（202102010175）
1470-P: GABA Stimulates or Inhibits Insulin and Somatostatin Secretion in Human Pancreatic Islets Depending on Glucose Concentration
Authors: FERREIRA SANDRA MARA , HAGAN DAVID W. , PHELPS EDWARD 
Published: May 2022

GABA is an inhibitory neurotransmitter synthesized and secreted by β-cells that is reported to modulate glucagon, somatostatin (SST) , and insulin secretion. However, the direction of the effect of GABA, whether stimulatory or inhibitory, on insulin secretion is controversial. Our results from human islets show that GABA is inhibitory to insulin secretion under glucose-stimulating conditions. Further, islets from conditional knockout mice lacking the GABA-synthesizing enzymes GAD65 and GAD67 oversecrete insulin during glucose stimulation, consistent with GABA being inhibitory. However, the inhibitory effect of GABA is somewhat paradoxical as ligation of GABA-A receptor Cl channels are expected to depolarize the β-cell that should contribute to stimulating insulin secretion. It is also unclear if GABA signaling in β-cells is strictly autocrine or if the observed inhibition is mediated through an indirect effect of inducing SST secretion which, in turn, inhibits β-cells. Here, we improve understanding of GABA’s effect on insulin secretion by transiently applying 100 μM of GABA to human islets during perifusion with low (3 mM) and high glucose (16.7 mM) . GABA stimulated both insulin and SST in low glucose but inhibited insulin and SST when applied in high glucose. Thus, the modulation of GABA presents both stimulatory and inhibitory effects on β- and δ-cells depending on glucose concentration. In addition, the effect of GABA on β-cells appears to be direct and independent of SST signaling because SST and insulin secretion both change in the same direction with applied GABA. These results suggest the hypothesis that β-cell GABA-A receptors convey stimulatory responses to GABA under low glucose, but that G-protein coupled GABA-B receptors mediate inhibitory GABA signaling under high glucose. This mechanism would provide a consensus model that reconciles decades of seemingly antithetical studies where GABA is either inhibitory or stimulatory.

Disclosure
S.Ferreira: None. D.W.Hagan: None. E.Phelps: Research Support; Immunocore, Ltd.

Funding
National Institutes of Health (R01DK124267)
1472-P: Dual Pancreatic Adrenergic and Dopaminergic Signaling as a Therapeutic Mechanism for Treatment of Dysglycemia by Bromocriptine
Authors: ASLANOGLOU DESPOINA , BERTERA SUZANNE , FRIGGERI LAURA , SOTO MARTA SANCHEZ , LEE JEONGKYUNG , XUE XIANGNING , LOGAN RYAN , LANE ROB , YECHOOR VIJAY , FREE R BENJAMIN , SIBLEY DAVID R. , BOTTINO RITA , FREYBERG ZACHARY 
Published: May 2022

Dopaminergic agonism effectively treats dysglycemia, with dopaminergic agonist bromocriptine approved as a type 2 diabetes therapy. Though bromocriptine’s actions have been mainly attributed to stimulation of dopamine D2 receptors (D2R) in the brain, we previously showed that bromocriptine also targets metabolically-relevant peripheral tissues including the endocrine pancreas. Here, we employ bromocriptine as a tool to elucidate roles of dopaminergic and adrenergic signaling in regulation of pancreatic hormone secretion. Using bromocriptine, we demonstrate a new mechanism for metabolic actions in pancreatic α-cells and β-cells via D2R and adrenergic α2A receptor (α2A-AR) signaling. In β-cells, bromocriptine acts jointly on D2R and α2A-AR to reduce glucose-stimulated insulin secretion (GSIS) , while in α-cells, bromocriptine acts via D2R to reduce glucagon secretion. Bromocriptine reduces cAMP in β-cells via concurrent actions on D2R and α2A-AR, further emphasizing shared roles of adrenergic and dopaminergic receptor agonism in GSIS regulation. At the receptor level, α2A-AR activation by bromocriptine leads to receptor recruitment of an ensemble of G proteins driven mainly via G protein signaling with no β-arrestin2 recruitment. In contrast, D2R recruits both G proteins and β-arrestin2 upon bromocriptine stimulation, demonstrating signaling unique to each receptor. Docking studies also reveal that bromocriptine binding to α2A-AR is distinct from bromocriptine-bound D2R, providing a structural basis for bromocriptine’s dual actions on β-cell α2A-AR and D2R. Together, joint dopaminergic and adrenergic receptor actions on α-cell and β-cell hormone release provide a new therapeutic mechanism to improve dysglycemia in diabetes.

Disclosure
S. Bertera: None. L. Friggeri: None. R. Logan: None. R. Free: None. R. Bottino: Employee; Imagine Pharma.

Funding
Department of Defense (PR141292) , National Institutes of Health (R01DK124219, R01DK097160, RDA046138) , the John F. and Nancy A. Emmerling Fund of The Pittsburgh Foundation, Intramural Research Program of the National Institute of Neurological Disorders and Stroke (ZIA-NS002263) , Veterans Affairs VA-ORD-BLR&D (I01BX002678) , the Deutsche Forschungsgemeinschaft (SFB1423, project number 421152132) .
152-LB: Decision Tree Modeling Identifies Factors Associated with Increased Time-in-Range (TIR) during Inpen Smart Insulin Pen and Continuous Glucose Monitor (CGM) Use In Youth
Authors: SMITH MADISON , HEUNGYONG IM GLEN , GAETANO ANGELA , THANASEKARAN SNEHA , MACLEOD JANICE , VIGERSKY ROBERT A. 
Published: May 2022

Background: Previous InPen decision tree modeling (DTM) in adults indicated that missed meal dosing was a major modifiable factor associated with TIR (70-180mg/dL) . We used DTM to find characteristics/use-behaviors associated with TIR for InPen+CGM users &lt;18 years of age.
Methods: InPen+CGM data from youth (N=883) with T1D starting InPen between 7/20 and 6/21 were used to identify characteristics (prior delivery method, diabetes duration) and use-behaviors (frequency of missed/correction doses, priming/bolus count, meal therapy mode, InPen bolus calculator use, app reminders, time settings, and report generation) associated with TIR. A variance inflation factor &gt;10 was used to reduce multicollinearity for feature importance. Those with insufficient CGM and/or bolus data and lack of consistent insulin therapy settings were excluded.
Results: DTM of users determined 1) diabetes duration, 2) frequency of missed meal doses, 3) bolus count and 4) correction frequency as the top variables associated with TIR (Figure) . Highest average TIR (68.0%) was observed in newly diagnosed (≤1 year) users. Users with &gt;2 years diabetes duration, &lt;5.5 boluses/day, and &gt;35.1% missed dose frequency demonstrated lowest average TIR (35%) .
Conclusions: DTM is a novel application for understanding glycemic outcomes due to modifiable and non-modifiable factors.

Disclosure
M. Smith: Employee; Medtronic. G. Im: Employee; Medtronic. A. Gaetano: None. S. Thanasekaran: None. J. Macleod: Employee; Medtronic. R. A. Vigersky: Employee; Medtronic.
156-OR: Central Neural Processing of Sweet Taste Is Altered following Bariatric Surgery
Authors: ALESSI JONATHAN , SAWIN KEEGAN , CHITTUM GEORGE D. , OSWALT SARAH E. , DZEMIDZIC MARIO , KAREKEN DAVID A. , CONSIDINE ROBERT V. 
Published: May 2022

Bariatric surgery causes marked changes in eating behavior, including reduced preference for highly sweet foods. No studies have addressed the brain response to receipt of this primary taste modality following weight loss surgery. Eighteen women (BMI 47.5±7.6 kg/m2, age 43.1±10.2 y) rated perceived intensity and liking of sucrose solutions (0, 0.1, 0.4, 0.86 & 1.M) in a three-block randomized design, and underwent functional magnetic resonance imaging (fMRI) to assess brain responses to 0.40 M and 0.M sucrose sprayed onto the tongue relative to water (14 sucrose and 34 water trials in two 5:52 min long scans) , before and after bariatric surgery-induced weight loss. Eight women underwent Roux-en-Y and had sleeve gastrectomy. The post-surgery visit occurred 4.7 months (range 3-9) following the pre-surgery assessment. BMI was significantly reduced to 38.0±7.8 kg/m2. There was no effect of weight loss on rated sucrose solution intensity. However, post-surgical “preferred sweetness” of the test solutions was significantly lower (0.53±0.12 vs. 0.22±0.M; p&lt;0.008) . Across the whole sample (pre- and post-surgery) , both sucrose concentrations relative to water activated bilateral insula and lateral frontal/orbitofrontal areas (p&lt;0.001, k=5) . However, only 0.4M sucrose elicited the left nucleus accumbens (NAc) response (pFW E=0.005, k=17, family wise error-corrected within a bilateral NAc mask) . Pre-surgery activations included the anterior cingulate cortex (ACC) and bilateral insula as well as NAc (left: p=0.001, k=33; right p=0.009, k=17) . Post-surgery activations were present only in the ACC and bilateral insula. NAc responses were significantly greater pre-surgery relative to post-surgery (pFWE =0.026, k=6) . These data strongly suggest that bariatric surgery significantly affects central neural processing of sweet taste. While salience-assigning ACC and insula responses did not differ, nucleus accumbens region coding reward responded less post-surgically.

Disclosure
J.Alessi: None. K.Sawin: None. G.D.Chittum: None. S.E.Oswalt: None. M.Dzemidzic: None. D.A.Kareken: None. R.V.Considine: Other Relationship; Lilly.

Funding
American Diabetes Association (1-18-ICTS-036)
157-OR: High-Fat–Diet Feeding Disrupts Thermal Responsiveness of AgRP Neurons
Authors: DEEM JENNIFER D. , DOAN TAMMY P. , PHAN BAO ANH N. , OGIMOTO KAYOKO , HU SHANNON J.W. , WU BRANDON , SCHWARTZ MICHAEL W. , MORTON GREGORY J. 
Published: May 2022

To defend energy homeostasis in the cold requires energy expenditure (to support thermogenesis) and energy intake increase, enabling core temperature to be maintained with no change to body fat stores. When acutely housed at a mild cold (14°C) , mice increase both food intake and heat production rapidly (∼minutes) , and these responses occur in parallel. We hypothesized a role for Agouti-related peptide (AgRP) neurons in this response and find their activity is regulated by thermal sensory input, and they increase activity, measured by Fos induction and fiber photometry, upon cold sensation, and reduce activity as sensed temperatures rise. By inhibiting AgRP neurons during acute cold exposure, we also find this increase in AgRP neuron activity is required for the hyperphagic response to cold. Recent evidence found high-fat diet (HFD) feeding reduced AgRP neuron responsiveness to gastric hormones and standard chow diet presentation, and we hypothesized that their response to thermal input might also be blunted. We find that although 12-week HFD-fed mice exhibit intact thermogenic responses to cold and defend a normal core body temperature, they fail to increase energy intake and consequently experience weight loss not observed in chow-fed controls. This uncoupling of energy intake from energy expenditure is present even after a shorter, 2-week exposure to HFD-feeding, implying a role for diet separate from obesity in the phenotype. Using Agrp-Cre/GFP marker mice, we find acute cold exposure rapidly induces Fos in chow-fed mice, but this response is lacking in HFD-fed mice. This effect correlates with a failure to increase hypothalamic Agrp mRNA even after five days of mild cold exposure. Using photometry to measure AgRP neuron calcium activity, we find activity changes associated with thermal input, both cold and warm, are blunted with HFD feeding. Further testing will determine exactly how the food intake response to cold has become uncoupled from other thermoregulatory responses across the development of obesity.

Disclosure
J.D.Deem: None. T.P.Doan: None. B.N.Phan: None. K.Ogimoto: None. S.J.W.Hu: None. B.Wu: None. M.W.Schwartz: None. G.J.Morton: Research Support; Novo Nordisk A/S.

Funding
American Diabetes Association (1-19-PDF-103) ; NIDDK (K01 DK126793) , NIDDK (DK089056) , NIDDK (DK124238) , NIDDK (DK035816) , NIDA (P30 DA048736) , NIDDK (DK035816) , NIDDK (DK17047)
158-LB: Effect of Vitamin D Replacement on Glycemic Status and Pregnancy Outcomes in Vitamin D–Deficient Subjects with Gestational Diabetes Mellitus
Authors: BAIDYA ARJUN , PATHAK YASHASWI , SENGUPTA NILANJAN , KUMAR SAHANA PRANAB , GOSWAMI SOUMIK , TARENIA SILIMA , BANERJEE ABHIRUP , CHATTOPADHAYAY MOUNAM , HATHI DEEP , GAIKWAD PRASHANT MANOHAR , DAS NILADRI 
Published: May 2022

Aims: To study the effect of Vitamin D replacement on glycaemic control and pregnancy outcomes in Gestational Diabetes Mellitus patient with Vitamin D deficiency.
Methods: In this prospective, open-label interventional study 60 GDM subjects with Vitamin D deficiency were divided into 2 groups of 30 each, and the intervention group received 60,000 IU of cholecalciferol weekly for 6 weeks and then monthly for the duration of pregnancy. while the control group did not. Vitamin D status was re-assessed at 32 weeks of gestation for both groups. The glycaemic status was assessed using fasting plasma glucose and 1-hour and 2-hour postprandial glucose at 30 weeks of gestation and at time of delivery. Feto-maternal outcomes: Time of delivery (weeks of gestation) , method of delivery, pre-eclampsia, still-birth, neonatal hypoglycaemia, neonatal jaundice, birth weight, head circumference of the baby, APGAR score at 5 minutes in both groups were also assessed.
Results: In the intervention group 87% (26 out of 30) of subjects had become vitamin D sufficient. None of the subjects in the control group had become vitamin D sufficient. Fasting Plasma Glucose was significantly lower in the intervention group as compared to the control group) at 30 weeks of gestation (99.57±18.12 vs. 107.90±17.53 mg/dl; p=0.039) and at time of delivery (98.53±15.41 vs. 104.47±18.71mg/dl; p=0.044) . Both 1 hour and 2-hour postprandial plasma glucose (136.81±20.29 vs. 152.58±16.76; p=0.004 and 118±22.10 vs. 132.64±18.48 mg/dl; p=0.017 respectively) values were also significantly lower in the intervention group at the time of delivery. Birth weight was significantly lower in the control group as compared to the intervention group (2348.13±388.965 vs. 2778.67±270.288 gm; p=0.034) . All other neonatal parameters were similar in the two groups. Two subjects in the control group had still-births.
Conclusion: Correction of Vitamin D deficiency in GDM subjects may result in better control of their plasma glucose levels. Low Vitamin D levels in GDM subjects may be associated with lower birth weight.

Disclosure
A. Baidya: None. P. Gaikwad: None. N. Das: None. Y. Pathak: None. N. Sengupta: None. P. Sahana: None. S. Goswami: None. S. Tarenia: None. A. Banerjee: None. M. Chattopadhayay: None. D. Hathi: None.
161-LB: Intensive Blood Pressure Lowering and the Risk of New-Onset Diabetes in Patients with Hypertension—A Post Hoc Analysis of the STEP Randomized Trial
Authors: YANG RUIXUE , CAI JUN 
Published: May 2022

Background: The STEP (Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients) trial reported the cardiovascular benefit of intensive blood pressure (BP) control. The objective of this analysis was to evaluate the effect of intensive BP lowering on the new-onset diabetes incidence.
Methods: The patients of STEP who had a baseline fasting serum glucose (FSG) &lt;7.0 mmol/L without diabetes history and hypoglycemic medication use were included in the main analysis. The primary outcome was the new-onset diabetes, defined as the time to first occurrence of a FSG ≥7.0 mmol/l. The secondary outcome was the new-onset impaired fasting glucose (IFG: FSG 5.6-6.9 mmol/l) among patients with normoglycemia. The competing risk proportional hazards regression model was used in the main analysis.
Results: Over a median follow-up of 3.42 years, 273 (9.6%) in the intensive group and 262 (9.5%) in the standard group developed new-onset diabetes (adjusted HR 1.03; 95% CI 0.87-1.22) . The adjusted hazard ratio for the secondary outcome was 1.05 (95% CI 0.92-1.19) . The mean of the highest FSG was 5.82 mmol/l for intensive group and 5.84 mmol/l for standard group. The sensitivity analyses showed no significant difference with respect to the effect of the treatment arms.
Conclusions: Intensive BP lowering (target, 110 to &lt;130 mmHg) , as compared with standard BP lowering (target, 130 to &lt;150 mmHg) , did not increase the risk of new-onset diabetes and IFG in patients with hypertension.

Disclosure
R. Yang: None. J. Cai: None.