bluuebunny/crossref_metadata_2025_split huggingface dataset:
1746-P: Differential Depletion and Expansion of Autoreactive CD8+ T Cell Subsets after Alefacept Treatment in Type 1 Diabetes (T1D)
Authors: WIEDEMAN ALICE E. , MUIR VIRGINIA S. , NEPOM GERALD T. , LINSLEY PETER , LONG S. ALICE 
Published: June 2019

The T1DAL clinical trial, NCT00965458, demonstrated that alefacept (LFA-3-Ig) treatment was associated with preservation of c-peptide in subjects with new-onset T1D. Previous analysis of peripheral blood from these subjects showed reduction of CD2-expressing lymphocytes, including memory T cell populations. We now have interrogated the islet antigen-specific (autoreactive) T cell profiles from subjects in this trial using single-cell mass cytometry in combination with peptide-loaded MHC class I tetramer (Tmr) staining. We then applied a new analytical method, DISCOV-R, for phenotyping rare cell subsets using a multiparameter clustering algorithm. As expected among polyclonal CD8+ T cells, alefacept treatment preferentially reduced memory subsets, particularly those with higher expression of CD2 (Helios- transitional memory, exhausted effector memory, and Helios- effector memory CD45RA+). Prior to treatment, autoreactive Tmr+ CD8+ T cells were phenotypically heterogeneous, with three prominent phenotypes across T1D subjects (CXCR3+ naïve, Helios- and Helios+ transitional memory). Following alefacept treatment, the overall frequencies of autoreactive cells did not consistently change; however, their phenotypes were altered. CD2-high CD8+ T cells were diminished; naïve cells were expanded; and notably, a stem cell-like memory phenotype, indicative of early memory with high proliferative potential but low effector function, was also substantially expanded among autoreactive cells in most individuals. Similar phenotypic alterations occurred among polyclonal CD8+ T cells, indicating that the effects were not limited to the islet-specific T cell population. These findings suggest that alefacept treatment alters the composition of autoreactive CD8+ T cells that are not depleted, and that phenotype, not just frequency, of autoreactive cells is an important consideration for development of other immunomodulatory therapies.

Disclosure
A.E. Wiedeman: None. V.S. Muir: Research Support; Self; Celgene Corporation. G.T. Nepom: Advisory Panel; Self; GlaxoSmithKline plc., Pfizer Inc. Research Support; Self; JDRF, National Institute of Allergy and Infectious Diseases. Other Relationship; Self; Diabetes UK. P. Linsley: None. S. Long: None.
1749-P: A Case Report of IgE-Mediated Insulin Allergy Successfully Managed with a Fixed Combination of Degludec and Liraglutide
Authors: GREGORIC NADAN , OBLAK MAJA RAVNIK , KOPAC PETER 
Published: June 2019

Background: Insulin allergy is a rare condition that poses a great challenge particularly in diabetics who are insulin dependent. If feasible, switching to different antidiabetic agents or immunotherapy is the common approach, but the universal consensus on insulin allergy management in diabetics is lacking. Here we present a clinical case of a diabetic with allergy to insulin successfully managed with a combination of degludec and liraglutide.
Case Report: A 51-year-old female patient with type 2 diabetes presented with poorly controlled glycaemia (HbA1c 8.6%) on dual oral antidiabetic treatment, metformin and sitagliptin. Due to pronounced fasting hyperglycaemia the NPH insulin before bedtime, but soon began to complain of urticariform skin lesions on insulin injection sites. Despite the adverse reaction the patient continued to up-titrate the insulin, but the effect on glycaemia was negligible. After switching to different NPH insulin manufacturer, to no avail, the insulin analogs detemir and glargin were introduced, respectively, but produced same adverse reaction. The elevated levels of specific IgE immunoglobulins to human insulin (2.58 klU/L) confirmed the allergy to insulin. Conversely, the novel insulin analog degludec yielded no skin reaction. The patient was then titrated to a fixed combination of degludec and GLP-1 receptor agonist liraglutide which provoked no allergic reaction and promptly improved glycemic control (HbA1c 6.7% 4 months after treatment commencement). Understandably, treatment with sitagliptin was stopped, whereas metformin was continued.
Conclusion: The patient with confirmed IgE mediated allergy to insulin exhibited allergic reaction to all types of basal insulin but degludec. It can be assumed that the unique structure of degludec has different epitopes than other insulin analogues and therefore provides safe and combined with GLP-1 receptor agonist effective therapeutic approach to patient with allergy to insulin.

Disclosure
N. Gregoric: Other Relationship; Self; Lilly Diabetes, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S. M. Ravnik Oblak: None. P. Kopac: Speaker's Bureau; Self; AstraZeneca, Novartis Pharmaceuticals Corporation, Shire.
175-LB: Effect of a Telemedicine Diabetic Foot Ulcer Intervention on Health and Well-Being: A Cluster Randomized Controlled Trial
Authors: IVERSEN MARJOLEIN MEMELINK , IGLAND JANNICKE , SMITH-STRøM HILDE , OSTBYE TRULS , TELL GRETHE S. , SKEIE SVEIN , COOPER JOHN GRAHAM , GRAUE MARIT 
Published: June 2019

Objective: To assess change in health and well-being using generic and disease-specific self-report instruments among patients with diabetes-related foot ulcers (DFU) receiving a telemedicine intervention compared to patients receiving standard hospital outpatient care.
Research Design and Methods: This cluster randomized controlled trial (RCT) included 182 adults with DFU (94/88 in the telemedicine/standard care groups) in 42 municipalities/districts, recruited from three clinical sites in Western Norway. The main purpose of the trial was to evaluate whether ulcer healing time in the telemedicine intervention was non-inferior to standard outpatient care. The intervention group received care in the community in collaboration with specialist health care via telemedicine; the control group received standard care. In the current study secondary endpoints as health and well-being were evaluated by four generic health and well-being questionnaires (e.g., WHO-5, EQ-5D) and two disease-specific questionnaires (Neuro-QoL, PAID). We used linear mixed-effects regression to investigate differences in change in the sum scores between the intervention and control group at the end of follow-up. Results are reported as regression coefficients with 95% CIs.
Results: In intention to treat analyses, differences between treatment groups were small and non-significant for the generic health and well-being scale scores, as well as for diabetes-related distress and foot ulcer-specific quality of life.
Conclusion: This is the first RCT assessing the effect of a telemedicine diabetic foot ulcer intervention on health and well-being. There were no significant differences in change in sum scores for health and well-being between the intervention and control group. TM was non-inferior to SOC regarding healing time. Further studies are needed to investigate long-term intervention effects on new or recurrent foot ulcers and corresponding health and well-being.

Disclosure
M.M. Iversen: None. J. Igland: None. H. Smith-Strøm: None. T. Ostbye: None. G.S. Tell: None. S. Skeie: None. J.G. Cooper: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH. Speaker's Bureau; Self; Novo Nordisk A/S. M. Graue: None.

Funding
Norwegian Directorate of Health and Innovation; Western Norway Regional Health Authority (911716, 911605); Norwegian Diabetes Association; Western Norway University of Applied Sciences; Norwegian Research Council (221065)
1754-P: Follistatin-Like Protein 1 (FSTL1) Plays an Important Role in Human Primary Adipocyte Metabolism
Authors: AHN CHUL WOO , CHOI ARIM , KIM JUNG HYE , PARK KAHUI , LEE SANG BAE , NAM JUNGEUN , PARK SU JEONG , KIM MIN KYUNG , KIM YU SIK , NAM JI SUN , KANG SHINAE , PARK JONG SUK 
Published: June 2019

Objective: FSTL1, an extracellular glycoprotein, is a novel myokine that is secreted by skeletal muscle. However, its functions in metabolism remain unclear, Adipose tissue is one of the important organs for maintaining energy homeostasis. FSTL1 is known to induce inflammatory response and inhibit insulin-mediated Akt signaling pathway, we aimed to investigate whether FSTL1 play metabolic roles in human adipose tissue. We hypothesized that FSTL1 increases lipolysis through its putative receptor DIP2A (Disco interacting protein 2 homolog A).
Methods: Human primary adipocytes were treated with recombinant FSTL1 in dose and time dependent manner. To determine its lipolytic activity, pHSL ser563,565,660, perilipin, AMPK, PKA were determined by western blot and the rate of free fatty acid was assessed. Expression of DIP2A was determined by PCR and western blot. DIP2A was knocked-down to examine whether it mediates metabolic effects of FSTL1.
Results: FSTL1 did not affect catecholamine-induced lipolysis via PKA. FSTL1, however, increased lipolysis through AMPK activation and, subsequently, HSL ser565 phosphorylation in dose dependent manner. It was found that DIP2A expression did not change during differentiation of human primary adipocyte, suggesting that it is not involved in adipocyte maturation.
Conclusion: FSTL1 increased basal lipolysis through AMPK activation. AMPK is well known sensor of the intracellular energy state and serves to regulate various signals. Its activation provides ATP by FA oxidation. Therefore, FSTL1 may play an important in the regulation of energy homeostasis. FSTL1 also has effect through DIP2A. These findings suggest that DIP2A plays important roles in FSTL1 mediated lipolysis.

Disclosure
C. Ahn: None. A. Choi: None. J. Kim: None. K. Park: None. S. Lee: None. J. Nam: None. S. Park: None. M. Kim: None. Y. Kim: None. J. Nam: None. S. Kang: None. J. Park: None.
1761-P: Brain-Restricted CB1-Receptor Antagonists Increase Oxygen Consumption Rate and Promote Beiging in 3T3-L1 Adipocytes Similar to Rimonabant Suggesting that Central Effects Can Be Avoided
Authors: PASZKIEWICZ REBECCA K. , BERGMAN RICHARD N. , FRANK AARON , WOOLCOTT ORISON O. , SOUZA SANTOS ROBERTA DE , IYER MALINI S. , CLEGG DEBORAH , KABIR MORVARID 
Published: June 2019

We have previously demonstrated in dogs that following exposure to a high fat diet for 16 weeks, the brain and peripheral penetrating CB1R antagonist Rimonabant (RIM) promoted adipose tissue beiging and decreased adipocyte cell size. It is hoped that peripherally restricted CB1R antagonists, such as AM6545, will allow for the substantial beneficial metabolic effects of CB1R antagonism without the possible negative consequences associated with brain penetrance. Studies demonstrated beneficial metabolic effects of AM6545 in adipose tissue including increased energy expenditure and decreased adipocytes cell size. We thus compared the effects of RIM versus AM6545 on oxygen consumption and beiging in the well-characterized 3T3-L1 cell line model. Mature 3T3-L1s were treated for 4 or 48 hours with RIM, AM6545, vehicle or isoproterenol (ISO) (positive control). Baseline oxygen consumption and the proportional contribution of proton leak to maximal respiratory capacity was greater for cells exposed to RIM, ISO, and, in lesser extent, AM6545 after 48 hours, demonstrating greater mitochondrial uncoupling. Further, markers of adipose tissue beiging (UCP1, Prdm16, PGC1α) were also unregulated by approximately 2-fold (P&lt;0.05) at 48 hours with RIM treatment and, in lesser extent, with AM6545. Hence, peripheral and central CB1R antagonists act directly on 3T3-L1 to increase mitochondrial function and adopt features of beige adipocytes. Thus, a direct role for CB1R antagonism on adipocytes does not require brain penetrance, supporting the importance of peripheral CB1R antagonism pharmacology for reducing the incidence of obesity and type 2 diabetes.

Disclosure
R.K. Paszkiewicz: None. R.N. Bergman: Consultant; Self; Zafgen, Inc. A. Frank: None. O.O. Woolcott: None. R. de Souza Santos: None. M.S. Iyer: None. D. Clegg: None. M. Kabir: None.
1764-P: Insulin Sensitive Induction of Adipogenesis
Authors: PEDERSEN THOMAS Å. , PEICS JULIA , OLSEN GRITH SKYTTE 
Published: June 2019

Healthy adipose tissue has a remarkable ability to adapt to energy intake through contraction and expansion. A large body of evidence pin-points the ability expand adipose tissue as vital to maintain whole body lipid homeostasis and insulin sensitivity in humans as well as in mice. Increases in fat mass can be driven by expansion of existing adipocytes or by recruitment of new adipocytes from adipose tissue pre-courser cells or preadipocytes (Adipogenesis). Failure to expand adipose tissues as well as appearance of dysfunctional large adipocytes both result in local and systemic insulin resistance. Conversely, strategies to preserve adipocyte function during tissue expansion through enhanced adipogenesis could preserve insulin function in the face of obesity or high caloric intake.
In order to study the hormonal control of adipose tissue expansion we have examined the ability of insulin and IGF-1 to induce adipogenesis in isolated rodent primary SVF cells. We find that both insulin and IGF-1 dose dependently induce lipid droplet accumulation and expression of adipocyte genes in primary cells isolated from mouse epididymal and subcutaneous adipose depots. Surprisingly, adipogenesis in mouse SVF cells is a very insulin sensitive process and more specifically we identify CD45neg/Ly6c low SVF cells isolated from epididymal fat pads as extremely sensitive to insulin induced adipogenesis. These results indicate that insulin signaling directly in preadipocytes could drive adipocyte differentiation in vivo e.g., during high insulin levels in serum in response to prolonged periods of high caloric intake or lipid induced insulin resistance.

Disclosure
T.Å. Pedersen: Employee; Spouse/Partner; Cook Medical. Employee; Self; Novo Nordisk A/S. J. Peics: Employee; Self; Novo Nordisk A/S. G.S. Olsen: Employee; Self; Novo Nordisk A/S.
1765-P: Adipose Sirtuin 6 Drives Macrophage Polarization Toward M2 through IL-4 Production and Maintains Systemic Insulin Sensitivity in Mice and Human
Authors: SONG MI-YOUNG 
Published: June 2019

Adipose tissue inflammation is a reproducible feature of obesity and obesity-linked insulin resistance. Here, using adipocyte-specific Sirt6 knockout mice, we explored whether adipocyte Sirt6 inhibits adipose tissue inflammation and its underlying mechanism. aS6KO mice fed normal chow gained more body weight and fat mass than wild type mice and exhibited glucose intolerance and systemic insulin resistance. Measurement of plasma and tissue cytokines and flow cytometric analysis of adipose stromal vascular cells indicated a decrease in alternatively activated M2 macrophages in adipose tissue of aS6KO mice. Mechanistically, Sirt6 regulated the expression of a canonical type 2 cytokine IL-4 by adipocytes in a cell autonomous manner, which in turn affects M2 macrophage polarization. Consistent with animal experiment data, the degree of obesity and insulin resistance demonstrated by body mass index, fasting blood glucose and HbA1c correlated negatively with the expression of Sirt6 in human visceral fat tissues. Collectively, these results suggest that adipocyte Sirt6 regulates body weight gain and insulin sensitivity independent of diet, and the increased IL-4 production by Sirt6 and resultant M2 polarization of adipose tissue macrophages may attenuate proinflammatory responses in adipose tissue.

Disclosure
M. Song: None.
1774-P: Maternal Apical Periodontitis Promotes Insulin Resistance in Adult Offspring
Authors: TSOSURA THAÍS V. , CHIBA FERNANDO Y. , MATTERA MARIA S. , PEREIRA RENATO F. , GARBIN CLÉA A. , CINTRA LUCIANO T. , SUMIDA DORIS H. 
Published: June 2019

Background: Adverse stimuli applied during early fetal development can increase the risk of diseases in adulthood.
Aim: This study investigated the plasma concentrations of glucose, insulin, and tumor necrosis factor-α (TNF-α) of rats with maternal apical periodontitis (AP). We also explored the effect of maternal inflammation on the initial steps of insulin signaling and the inflammatory pathway in the gastrocnemius muscle (GM) of adult offspring.
Methodology: Fifteen female Wistar rats were distributed into control group (CN), group with 1 AP (1AP) and group with 4 AP (4AP). Thirty days following induction of AP, female rats from all groups were mated with healthy male rats. When male offspring reached 75 days of age, plasma concentrations of glucose, insulin, and TNF-α were quantified. Insulin resistance was evaluated by the homeostasis model assessment of insulin resistance (HOMA-IR) index. Phosphorylation status of pp185 tyrosine, insulin receptor substrate 1 (IRS-1) serine, IκB kinase α/β (IKKα/β), and c-Jun N-terminal kinase (JNK) in the GM were measured by western blot.
Results: Maternal AP promotes insulin resistance, impairs the initial steps of insulin signaling, increases plasma concentrations of insulin and TNF-α, and enhances IKKα/β phosphorylation in the GM of adult offspring. However, maternal AP does not seem to affect fasting glycemia and JNK phosphorylation in the GM of adult offspring.
Conclusions: Maternal AP promotes important alterations in insulin signaling and inflammation pathways, and leads to insulin resistance in adult offspring.

Disclosure
T.V. Tsosura: None. F.Y. Chiba: None. M.S. Mattera: None. R.F. Pereira: None. C.A. Garbin: None. L.T. Cintra: None. D.H. Sumida: None.

Funding
São Paulo Research Foundation (2017-01128-1)
1785-P: Mice with Muscle-Specific Insulin Receptor Overexpression Are Protected from Diet-Induced Obesity and Glucose Intolerance but Develop Post-Receptor Insulin Resistance
Authors: WANG GUOXIAO , CAI WEIKANG , BATISTA THIAGO M. , SOFTIC SAMIR , KAHN C. RONALD 
Published: June 2019

Skeletal muscle insulin resistance is a prominent feature of type 2 diabetes (T2D) that precedes and predicts the development of disease in high risk populations. In individuals with T2D or pre-T2D, this insulin resistance is due, at least in part, to a decrease in the number of functional insulin receptors (IR) that localize on the cell membrane. To restore the number of IR, we generated mice that specifically overexpress IR in skeletal muscle (IRMOE). On chow diet, IRMOE mice had similar body weight compared to control, but displayed reduced body fat and higher lean mass percentage. Basal phosphorylation of IR, IRS and Akt were significantly higher in muscles from IRMOE mice compared to control, resulting in their improved glucose tolerance. Surprisingly, however, after i.v. injection of insulin, stimulated Akt phosphorylation was significantly lower in IRMOE muscle compared to control, despite persistent higher phosphorylation in IR and IRS, indicating activation of negative regulators in the IR signaling pathway when IR is chronically activated. Consistent with this, euglycemic-hyperinsulinemic clamp studies revealed significantly lower glucose infusion rate in insulin stimulated IRMOE mice compared to control. Increased basal and decreased insulin stimulated Akt phosphorylation was also observed in muscles of IRMOE mice after challenge with HFD. However, when fed HFD, IRMOE mice displayed both improved glucose tolerance and insulin tolerance which was in part due to being resistant to diet-induced obesity, despite consuming more calories. Taken together, these data indicate that muscle specific IR overexpression can protect mice from diet-induced obesity and its effects on glucose metabolism, but that chronic overexpression of IR can lead to post-receptor desensitization indicating additional post-receptor regulators of insulin signaling, which could provide new targets for therapy of T2D.

Disclosure
G. Wang: None. W. Cai: None. T.M. Batista: None. S. Softic: None. C. Kahn: Advisory Panel; Self; MedImmune. Board Member; Self; Kaleido Biosciences. Consultant; Self; AntriaBio, Inc., Cobalt Therapeutics, Flagship Pioneering. Research Support; Self; Alnylam.

Funding
American Diabetes Association (9-17-CMF-016 to G.W.)
1798-P: Insulin Modulates Dopaminergic Tone in the Human Brain—A Combined PET/MRI Study
Authors: KULLMANN STEPHANIE , BLUM DOMINIK , JAGHUTRIZ BENJAMIN , BENDER BENJAMIN , HAERING HANS-ULRICH , FOUGÈRE CHRISTIAN LA , PREISSL HUBERT , FRITSCHE ANDREAS , REIMOLD MATTHIAS , HENI MARTIN 
Published: June 2019

Insulin and dopamine signaling in the human brain are known modulators of whole-body glucose metabolism. Brain insulin resistance contributes to impaired postprandial glycemia and could predispose to type 2 diabetes. Experimental evidence suggests a crucial interaction between insulin and dopamine with dopaminergic dysfunction in brain insulin resistance. We now investigated the presence of such an interaction in the human brain.
In 10 healthy young men (age 27±3 years, BMI 23.6±2.3 kg/m², HOMA-IR 1.8±1.1), we performed combined PET/MRI measurements using dynamic [11C]-Raclopride in combination with the intranasal application of 160 U insulin and placebo on two separate days in randomized, blinded order. Dopamine receptor binding potential as a measure of dopaminergic tone was estimated in regions of interests (ROI). Intranasal insulin delivery to the human brain increased dopamine receptor binding potential in the bilateral ventral and dorsal striatum, a major dopaminergic brain region (pFWE&lt;0.001 cluster level). This response tended to be stronger in participants with higher BMI but was not statistically associated with HbA1c, fasting glucose, or HOMA-IR.
Hence, insulin delivery to the human brain influences dopaminergic tone in the striatum. As earlier studies found insulin sensitivity of this region to be involved in the postprandial modulation of whole-body insulin sensitivity, the detected mechanism might be involved in the regulation of postprandial glycaemia. Alterations in this mechanism could therefore predispose to type 2 diabetes, a hypothesis that must be tested in further studies.

Disclosure
S. Kullmann: None. D. Blum: None. B. Jaghutriz: None. B. Bender: None. H. Haering: None. C. la Fougère: None. H. Preissl: None. A. Fritsche: None. M. Reimold: None. M. Heni: Research Support; Self; Boehringer Ingelheim International GmbH, Sanofi. Speaker's Bureau; Self; Lilly Diabetes, Merck Sharp & Dohme Corp., Sanofi.

Funding
German Federal Ministry of Education and Research