bluuebunny/crossref_metadata_2025_split huggingface dataset:
Energy Expenditure during Sleep Is an Independent Marker of Insulin-Resistance—A Cross-Sectional Study of Overweight/Obese Subjects
Authors: TUCCINARDI DARIO , MADDALONI ERNESTO , CAPASSO ILARIA , RAMPA LORENZO , SOARE ANDREEA , MAGGI DARIA , DEFEUDIS GIUSEPPE , KYANVASH SHADI , MAURIZI ANNA RITA , POZZILLI PAOLO , MANFRINI SILVIA 
Published: June 2018

Normal sleep is characterized by increased glycogen stores and reduced glucose turnover by metabolically active tissues, thus it is a state of decreased metabolism. It has been reported that reduced sleep quality is associated with increased insulin-resistance and disrupted metabolism. However, the relationship between energy expenditure during sleep (EEDS) and insulin-resistance (homeostasis model assessment, HOMA-IR) has not been clarified. The aim of this study was to investigate the role of EEDS in the association between sleep quality and insulin resistance. A total of 226 individuals [women 72.1%; mean (DS) age 50.46 (±13.1) years; BMI 33.4 (±8.41) Kg / m2] undergoing the oral glucose tolerance test (OGTT) were also asked to wear a metabolic holter (Armband) for 3-days, to assess their daily energy expenditure. The Armband is capable of measuring energy expenditure every minute, but also the duration and quality of sleep. The EEDS corrected for weight (EEDS/WEIGHT) was lower in patients with insulin resistance, HOMA-IR above 2.5 (p &lt;.001). The EEDS/WEIGHT was inversely related to HOMA-IR (r = -0.23; p &lt;.001) and directly to the quality of sleep (r = 0.15; p &lt;.001). Using a multivariate linear regression, with sleep quality, age, gender, glucose and insulin area under the curve (AUC) and EEDS/ WEIGHT as independent variables, the HOMA-IR value was independently and significantly predicted by the insulin AUC (p &lt;.001, beta = 0.538), by gender (p &lt;.01, beta = 0.155) and by the EEDS/WEIGHT (p &lt;.004, beta = -0.173). EEDS is an independent marker of insulin resistance. The mechanism underlying this correlation may be explained by the state of reduced glucose uptake during sleep, which it is further increased during insulin-resistance conditions, with a consequential reduction in energy production. This finding may provide another explanation to the inverse association between sleep quality and metabolic disorders such as type 2 diabetes and obesity.

Disclosure
D. Tuccinardi: None. E. Maddaloni: Speaker's Bureau; Self; Merck & Co., Inc.. Research Support; Self; European Foundation for the Study of Diabetes. I. Capasso: None. L. Rampa: None. A. Soare: None. D. Maggi: None. G. Defeudis: None. S. Kyanvash: None. A. Maurizi: None. P. Pozzilli: Research Support; Self; Sanofi. Speaker's Bureau; Self; Eli Lilly and Company. Research Support; Self; Merck Sharp & Dohme Corp.. S. Manfrini: None.
First Risk–Benefit Data from the Worldwide Endobarrier Registry
Authors: RYDER ROBERT E.J. , MUNRO LYNNE , MCMASTER JESSICA J. , BESSELL JUSTIN , BASCOMB JEANINE M. , COLLINS JANE E. , KOW LILIAN , CHISHOLM JACOB , SOURIJ HARALD , PFERSCHY PETER N. , TEARE JULIAN P. , MASON JOHN C. , BYRNE JAMES P. , WYRES MELANIE C. , CULL MELISSA L. , BURBRIDGE WYN , IRWIN SUSAN P. , YADAGIRI MAHENDER , FOGDEN EDWARD , ANDERSON MARK , GUPTA PIYA SEN , BENES MAREK 
Published: June 2018

Uncertainty exists about risk:benefit of proximal intestinal exclusion with Endobarrier (EB), a novel endoscopic duodenal jejunal liner device for obesity, both with and without diabetes. In view of this, during 2017, an independent, secure, on-line registry was established under the auspices of the Association of British Clinical Diabetologists, for the collection of safety and efficacy data worldwide. As of December 2017, data had been entered on 403 patients {age 51.3 ± 11.8 year, 62% male, 89% europid, 74% diabetes, BMI 42.6 ± 10.2 kg/m2} from 13 centres in 4 countries: Australia, Austria, Czech Republic and United Kingdom. EB led to many benefits, including: in those with both baseline and explant data, mean ± SD weight fell by 14.5 ± 10.3 kg from 125.3 ± 26.7 to 110.8 ± 26.4 kg (n = 265 p&lt;0.001), HbA1c by 1.4 ± 1.6%, from 8.7 ± 1.8 to 7.2 ± 1.2% (n = 195, p&lt;0.001) and systolic BP fell from 138.5 ± 18.1 to 130.0 ± 17.2 mmHg (n = 149, &lt;0.001). There were 23 (5.7%) serious adverse events (SAE) and 37 (9.2%) less serious AEs (Table). All SAE patients made a full recovery. The median (range) weight loss in those with early removal for GI bleed was 6.5 (0-29) and with early removal for liver abscess was 17.2 (7-21) kg. Some SAEs could have been avoided if patients had adhered to guidelines. The benefits of EB therapy are likely to reduce the complications of diabetes. This 1st international data from the EB registry suggests that the likely benefits of EB, far outweigh the risks.

Disclosure
R.E.J. Ryder: Other Relationship; Self; AstraZeneca. Speaker's Bureau; Self; Bioquest, Janssen Pharmaceuticals, Inc.. Other Relationship; Self; Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Novo Nordisk A/S. L. Munro: None. J.J. McMaster: None. J. Bessell: None. J.M. Bascomb: None. J.E. Collins: None. L. Kow: None. J. Chisholm: None. H. Sourij: Speaker's Bureau; Self; Boehringer Ingelheim GmbH, Novo Nordisk A/S, Amgen Inc., Sanofi, MSD K.K.. Research Support; Self; AstraZeneca, Boehringer Ingelheim GmbH, MSD K.K., GI Dynamics Inc.. P.N. Pferschy: None. J.P. Teare: Research Support; Self; GI Dynamics Inc.. J.C. Mason: None. J.P. Byrne: None. M.C. Wyres: None. M.L. Cull: None. W. Burbridge: Other Relationship; Self; Menarini Group. S.P. Irwin: None. M. Yadagiri: None. E. Fogden: None. M. Anderson: None. P. Sen Gupta: None. M. Benes: None.
Polygenic Risk Testing at the Time of Diagnosis of Diabetes Could Help Prevent Its Micro- and Macrovascular Complications
Authors: HAMET PAVEL , HARVEY FRANCOIS , HALOUI MOUNSIF , WOODWARD MARK , TAHIR RAMZAN , MAROIS-BLANCHET FRANÇOIS-CHRISTOPH , LONG CAROLE , MARRE MICHEL , HARRAP STEPHEN , CHALMERS JOHN , TREMBLAY JOHANNE 
Published: June 2018

Cardiovascular and renal complications of T2D represent a human and societal burden. Early detection of susceptibility to complications could help their prevention. Clinical scores are useful to predict hard outcomes but genomic score can be applied earlier than a risk factor based score and thus save morbidity. We have constructed a polygenic risk score (PRS) based on genetic variants associated to risk factors and outcomes of T2D available from GWAS catalog and tested it on 5,000 genotyped Caucasian subjects with T2D of ADVANCE trial and its 5 year extension in ADVANCE-ON. We selected 620 SNPs which in combination with geo-ethnic principal component, age of onset and diabetes duration achieved a highly significant prediction of outcomes, including cardiovascular (AUC=0.80) and total mortality (AUC=0.77), equalling and surpassing such clinical scores as Framingham and UKPDS. The highest positive predictive values for micro- and macro-vascular prevalent cases were 81% and 78%, respectively. Individuals within the highest tertile of genetic risk for total prevalence of both microvascular and macrovascular events, had significantly higher cardiovascular death than subjects with the lowest genetic score (p=2.02x10-12). The number needed to treat to prevent one CV death over 5 years by ADVANCE therapies, was 12 in subjects with high PRS (p=0.0045) compared to 45 (p=0.14) in subjects with low PRS. Cox cumulative hazard plots demonstrated persistence of benefits for all cause and cardiovascular mortality in high PRS tertile over 10 years of intensive blood pressure control, while for glucose intensive therapy the benefit was restricted to the high PRS group for end-stage renal disease. We conclude that the use of a PRS that detects the risk of micro- and macrovascular complications at the time of T2D diagnosis could effectively assist in preventive and therapeutic measures to attenuate diabetes complications.

Disclosure
P. Hamet: Consultant; Self; Servier. F. Harvey: None. M. Haloui: None. M. Woodward: None. R. Tahir: None. F. Marois-Blanchet: None. C. Long: None. M. Marre: Board Member; Self; Abbott. Consultant; Self; AstraZeneca. Board Member; Self; Intarcia Therapeutics, Inc.. Consultant; Self; Eli Lilly and Company. Board Member; Self; Merck Sharp & Dohme Corp., Novo Nordisk A/S. Research Support; Self; Sanofi. Board Member; Self; Servier. S. Harrap: Research Support; Self; Servier. J. Chalmers: Research Support; Self; Servier. Other Relationship; Self; Servier. J. Tremblay: Consultant; Self; Servier.
GDF15 Is Induced by T1D-Associated Cytokines and ER Stress and Promotes Beta-Cell Apoptosis
Authors: XU GUANLAN , THIELEN LANCE , CHEN JUNQIN , JO SEONGHO , SHALEV ANATH 
Published: June 2018

Type 1 diabetes (T1D) is characterized by T-cell and cytokine-mediated pancreatic beta cell loss, but some of the mechanisms involved are still unknown. Growth differentiation factor 15 (GDF15), which is a distant member of the transforming growth factor β (TGFβ) family, has been shown to be increased in various diseases including cancer, heart failure and type 2 diabetes and to promote cancer cell apoptosis. Although we found that GDF15 is highly expressed in adult human beta cells, its role in beta cells and T1D has not been studied. In the present study, we found that GDF15 is significantly elevated in the islets of diabetic female NOD mice compared to nondiabetic female NOR and male NOD mice. In addition, by using human islets, Akita beta cells and INS-1 beta cells, we found that the expression and content of GDF15 are significantly increased by T1D-associated cytokines and thapsigargin/ER stress. Furthermore, we demonstrated that GDF15 knockdown significantly blunts cytokines-induced beta cell apoptosis, while GDF15 overexpression exacerbates T1D-associated cytokines-induced beta cell apoptosis. Taken together, these findings suggest that GDF15 is induced by cytokine-induced ER-stress in beta cells and might contribute to the beta cell loss in T1D. Targeting beta cell GDF15 may therefore represent a novel strategy to inhibit beta cell loss in T1D.

Disclosure
G. Xu: None. L. Thielen: None. J. Chen: None. S. Jo: None. A. Shalev: None.
Alpha-1 Antitrypsin (AAT) Protects ß Cells via Clathrin-Mediated Endocytosis
Authors: WANG JINGJING , KIM DO-SUNG , STRANGE CHARLIE , WANG HONGJUN 
Published: June 2018

AAT, an acute phase reactant serine protease inhibitor, exerts protective effects on islets under stress. We reported that AAT inhibits β cell death through the suppression of cytokine-induced c-Jun N-terminal kinases (JNK) activation, in addition to its anti-inflammatory effects extracellularly in an islet transplantation model. To further understand the direct effects of AAT on β cells, we studied AAT endocytosis in human islets and a murine insulinoma cell line, βTC3 cells. We found that AAT was internalized by β cells in a time- and dose-dependent manner. AAT internalization was mediated by clathrin as treatment with chlorpromazine (CPZ), a drug that disrupts clathrin-mediated endocytosis, profoundly decreased AAT internalization. Besides, AAT inhibited cytokine-induced JNK activation, caspase 9 cleavage and DNA fragmentation, which were also overturned by the addition of CPZ. Meanwhile, although evidence suggests that clathrin interacts with autophagy related 16 like 1 (Atg16L1) which results in autophagy in several types of cells, we observed only mild induction of Atg16L1 and autophagy after AAT treatment in β cells.
In summary, as shown in the image, we found that AAT is internalized by β cells via clathrin-mediated endocytosis. Moreover, our finding that AAT endocytosis is required for its protective effects on β cells provides new insight into the usage of AAT-based therapy in diabetes and related diseases.

Disclosure
J. Wang: None. D. Kim: None. C. Strange: Research Support; Self; Grifols, CSL Behring, Shire. Consultant; Self; Shire. Stock/Shareholder; Self; Abeona. Consultant; Self; CSL Behring. Research Support; Self; Adverum. Consultant; Self; Adverum. Research Support; Self; MatRx. H. Wang: None.
Altering ß-Cell Proliferation In Vivo by Pharmacological Manipulation of the Nrf2 Pathway
Authors: KATZ LIORA S. , GARCIA-OCANA ADOLFO , SCOTT DONALD 
Published: June 2018

Glucose is a natural mitogen that drives adaptive β-cell mass expansion by promoting proliferation. We previously demonstrated that induction of Nrf2 is required for glucose-stimulated and carbohydrate response element binding protein (ChREBPa)-augmented β-cell proliferation. Here we found that adenoviral delivery of Nrf2 increased human β-cell proliferation by 8.9 ± 0.2 fold (n=6), which exceeded the effect of 20 mM glucose (4.3 ± 0.4 fold). To test if activation of the Nrf2 pathway is necessary for adaptive β-cell expansion in vivo, we used pharmacological inhibitors and activators of Nrf2. Mice were placed on a high fat diet (HFD) or standard chow diet (SD) for 7 days and treated with vehicle or brusatol, which depletes Nrf2 by a post-translational mechanism. Treatment with brusatol effectively diminished Nrf2 abundance in β-cells as determined by immunofluorescence. Further, brusatol treatment ameliorated the increased β-cell proliferation normally seen with a one-week HFD (2.7±03% ki67 positive β-cells in control HFD mice, vs. 1.6±0.3% in HFD mice treated with brusatol, p &lt; 0.05, n=5). Brusatol-treated mice also displayed significantly diminished glucose tolerance on a HFD by IPGTT, without altering the food intake or weight of the animals. Using an activator of Nrf2, bardoxolone methyl (CDDO-Me), for 7 days in the presence or absence of HFD. We found, consistent with previous reports, improved glycemic levels and decreased body weight in mice treated with CDDO-Me on a HFD. Remarkably, we also found increased β-cell proliferation in mice fed a SD and treated with CDDO-Me (1.7 ± 0.1% controls compared to 2.6±0.1% ki67 positive, insulin positive β-cells in mice treated with CDDO-Me). Crucially, in human β-cells, brusatol inhibited glucose-stimulated proliferation (1.9 fold vs. 12.7 fold, n=2) and CDDO-Me increased proliferation in 5 mM glucose (37.5 fold, n=2). Thus, we conclude that the Nrf2 pathway is an exciting novel target for manipulation of β-cell proliferation in vivo.

Disclosure
L.S. Katz: None. A. Garcia-Ocana: None. D. Scott: None.
The Patterning of Pancreatic Progenitors Is Regulated by the Temporal Control of NOTCH Signaling
Authors: BUKYS MICHAEL A. , JENSEN JAN 
Published: June 2018

Pancreatic development occurs through the specification of three main lineages from a single progenitor cell. Previous studies have shown the importance of NOTCH signaling in both endocrine and exocrine differentiation during pancreatic development. Here we use the directed differentiation of pluripotent cells to demonstrate that the duration a culture remains in a NOTCH engaged progenitor state contributes to downstream lineage specification. Short-duration Pancreatic Progenitor (PP) cultures that were exposed to NOTCH inhibition showed significant up regulation of the Pro-endocrine genes NGN3, NKX2.2 and NEUROD with a corresponding activation of the endocrine genes INS, GCG and SST. The expression levels of these genes were greatly blunted when NOTCH inhibition of the PP culture was delayed. Cultures that were kept at the PP state lost endocrine competence when challenged by NOTCH inhibition, and displayed patterning towards exocrine lineages (DUCT/ACINAR) as evident through the up-regulation of CPB1, MIST1 and ONECUT1. Terminal differentiation of prolonged PP culture, adopted a ductal phenotype as evident through increased expression of F3, HNF1B and PROM1. Using the PP population in subsequent DoE based computer modeling experiments to optimize for either INS, MIST1 or F3 expression demonstrated that NKX6.1 was significantly up-regulated in short term PP cultures optimized for insulin expression as compared to the delayed cultures. Acinar conditions achieved through optimization for MIST1 expression displayed highly increased PTF1A expression. Finally, PP cultures that were maintained in the absence NOTCH inhibition and subsequently optimized for F3 expression displayed increased HNF1B and DBA expression. Altogether this suggests that the lineage specification within the pancreatic field of pluripotent derived cells is partially dictated by the duration a cell spends in a NOTCH active state, confirming findings of the embryonic murine developing organ.

Disclosure
M.A. Bukys: None. J. Jensen: Stock/Shareholder; Self; Trailhead Biosystems inc.
Noninvasive Longitudinal Evaluation of GPR-119 Agonist Effects on ß-Cell Mass Using GLP-1 Receptor-Targeting SPECT/CT
Authors: MURAKAMI TAKAAKI , FUJIMOTO HIROYUKI , FUJITA NAOTAKA , HAMAMATSU KEITA , MATSUMOTO KOJI , INAGAKI NOBUYA 
Published: June 2018

Aims:Type 2 diabetes mellitus (T2DM) is known as a progressive disease with loss of pancreatic β-cell mass (BCM) and functions. However, longitudinal changes of BCM remain veiled since non-invasive techniques for observation of BCM in vivo have not been established. We developed [Lys12(111In-BnDTPA-Ahx)]exendin-4 (111In-Ex4) targeting a glucagon-like peptide 1 (GLP-1) receptor, which enabled to quantify BCM non-invasively. DS8500a, a G protein-coupled receptor 119 (GPR119) agonist, is under investigation for the treatment of T2DM. Some GPR119 agonists showed the possible stimulation of β-cell replication, which suggested some preferable effects of GPR119 agonists on BCM. Therefore, we investigated this GPR119 agonist effect on BCM in diabetic mice using our 111In-Ex4 SPECT/CT technique.
Method: Five-week-old male db/db mice with dietary restriction were assigned to the following two groups: mice fed with normal chaw (group C) and those with DS8500a-mixed chaw (group DS). We performed 111In-Ex4 SPECT/CT every four weeks until 13 weeks old and evaluated the RI accumulations in the pancreas. Ex-vivo pancreatic RI intensities, together with pathological and immunohistochemical analysis of BCM were also examined.
Results: As for 111In-Ex4 SPECT/CT, pancreatic RI intensities in group DS were significantly higher than those of group C, at the age of 9 and 13 weeks old. Moreover, ex-vivo pancreatic RI intensities in group DS were significantly higher than those of group C. Pathological BCM analysis revealed significantly larger BCM in group DS than in group C.
Conclusion: 111In-Ex4 SPECT/CT as wells as ex-vivo pancreatic analysis showed preserved BCM in mice with DS8500a. This result was corroborated by the conventional pathological method. Taken together, 111In-Ex4 SPECT/CT showed DS8500a, a GPR119 agonist, could attenuate the progression of BCM loss in diabetic mice.

Disclosure
T. Murakami: None. H. Fujimoto: None. N. Fujita: None. K. Hamamatsu: None. K. Matsumoto: None. N. Inagaki: Research Support; Self; Daiichi Sankyo Company, Limited, AstraZeneca, Ono Pharmaceutical Co., Ltd., Sanofi K.K., Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Company Limited, Japan Tobacco Inc., MSD K.K., Sumitomo Dainippon Pharma Co., Ltd., Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Kissei Pharmaceutical Co., Ltd., Novo Nordisk Pharma Ltd., Eli Lilly and Company, Sanwa Chemical Industrial Co., Ltd., Teijin Pharma Limited.
Unusual Duct-Like Cells in the Islet of Diabetic C414A-CRY1 Transgenic Mice
Authors: OKANO SATOSHI , YASUI AKIRA , KANNO SHIN-ICHIRO , SATOH KENNICHI , IGARASHI MASAHIKO , NAKAJIMA OSAMU 
Published: June 2018

Cryptochrome (CRY) proteins play indispensable roles in the mammalian circadian clock. We previously generated transgenic mice ubiquitously expressing mCRY1 with a mutation in cysteine414 (the zinc-binding site of CRY1). The Tg mice overexpressing the mutant CRY1 (C414A-CRY1) showed early onset diabetes mellitus characterized by β-cell dysfunction in addition to unusual circadian rhythms in locomotor activities. We have already shown that the decrease of insulin secretion from β-cells along with the lowered proliferation of β-cells due to the senescence-associated secretory phenotype (SASP)-like changes in the Tg mice (Okano S., 2016). We have also demonstrated that, atypical duct-like structures having some common morphological characters to pancreatic intraepithelial neoplasias (PanINs) that can cause pancreatic ductal adenocarcinoma, frequently appeared in the aged Tg mice. In this study, to explore the relation between the unique features of β-cells and the generation of PanIN-like structures, we further performed detailed studies of the pancreases of Tg mice. We found that unusual duct-like structures producing mucin emerged not only in the exocrine areas but also in the inside islets in the Tg mice frequently with age. These results may suggest that islet cells in the Tg mice can transdifferentiate to duct-like cells, thereby contributing to generate PanIN-like lesions in the Tg mice. In addition, the extent of fibrosis in the islet increased in the Tg mice compared with wild type controls. Taken together, our results suggest the SASP-like microenvironment in the islet play some roles to modify the integrity of endocrine cells as well as the architecture of the islet.

Disclosure
S. Okano: None. A. Yasui: None. S. Kanno: None. K. Satoh: None. M. Igarashi: None. O. Nakajima: None.
T3 and Glucose Increase Expression of ChREBPß to Induce Expression of Phosphoenolpyruvate Carboxykinase (Pck1) Leading to Increased ß-Cell Proliferation
Authors: KATZ LIORA S. , SCOTT DONALD 
Published: June 2018

Thyroid hormone (T3) is required for islet development and function. Both T3 and high glucose concentrations are critical components of differentiation protocols of stem cells to β-cells. We previously demonstrated that in brown adipose tissue, T3 and glucose synergistically regulate carbohydrate response element binding protein (ChREBP), which in turn upregulates Ucp1, Glut4 and Fasn, resulting in increased thermogenesis, decreased body weight and improved glycemic levels. In the present study, we asked whether T3 and glucose signaling pathways can coordinately regulate transcription of genes important for β-cell function and mass. RNA-seq analysis was performed on cadaveric human islets from five different donors in response to low and high glucose concentrations (6 and 20 mM, respectively) and in the presence or absence of T3 (10 nM). We found that T3 and glucose coordinately regulate the expression of ChREBPβ and Pck1 (phosphoenolpyruvate carboxykinase-1). Typically, it is thought that Pck1 is not expressed in pancreatic β-cells, but it is a known target of T3 in hepatocytes. However, in FACS sorted adult human β-cells, we found that high concentrations of glucose (20 mM) and T3 (10 nM) induced the expression of Pck1 by 17.2±1.3 fold for mRNA levels. In addition, we found that overexpression of Pck1 together with its substrate dimethyl malate (DMM) increased β- cell proliferation in human islets (0.49±0.03% for human islets overexpressing Pck1, treated with DMM compared with 0.01±0.01% for control islets, n=4). Finally, using a sh-RNA knockdown approach, we demonstrated that in Ins-1 cells, ChREBPβ is necessary for Pck1 dependent β-cell proliferation. We conclude that T3 and glucose act together to regulate ChREBPβ which in turn upregulates expression of Pck1. In turn, Pck1 activity leads to increased β-cell mass.

Disclosure
L.S. Katz: None. D. Scott: None.