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Da Hae Lee, Bart Keymeulen, Robert Hilbrands, Zhidong Ling, Ursule Van de Velde, Daniel Jacobs-Tulleneers-Thevissen, Geert Maleux, Bruno Lapauw, Laurent Crenier, Christophe De Block, Chantal Mathieu, Daniel Pipeleers, Pieter Gillard
BACKGROUND: Induction therapy with a T cell depleting agent followed by mycophenolate mofetil (MMF) and tacrolimus (Tac) is presently the most frequently used immune suppression (IS) regimen in islet transplantation. This study assesses its safety and tolerability in nonuremic type 1 diabetic recipients. METHODS: Fifty-one patients (ages between 29-63 years) with high glycemic variability and problematic hypoglycemia received intraportal islet grafts under anti-thymocyte globulin (ATG)-MMF-Tac protocol...
October 25, 2016: Transplantation
Vaibhav Sidarala, Anjan Kowluru
BACKGROUND: Glucose-stimulated insulin secretion (GSIS) from the pancreatic β-cell involves several intracellular metabolic events which lead to the translocation of insulin granules towards the membrane for fusion and release. It is well established that loss of β-cell function and decreased GSIS underlie the pathogenesis of diabetes. Evidence from several laboratories, including our own, demonstrated requisite roles of Rac1 and phagocyte-like NADPH oxidase (Nox2)-derived reactive oxygen species (ROS) in optimal function of the pancreatic β-cell, including GSIS...
October 20, 2016: Recent Patents on Endocrine, Metabolic & Immune Drug Discovery
Aaron J Martin, Matthew Clark, Gregory Gojanovich, Fatima Manzoor, Keith Miller, Douglas E Kline, Y Maurice Morillon, Bo Wang, Roland Tisch
There continues to be a need for immunotherapies to treat type 1 diabetes in the clinic. We previously reported that nondepleting anti-CD4 and -CD8 Ab treatment effectively reverses diabetes in new-onset NOD mice. A key feature of the induction of remission is the egress of the majority of islet-resident T cells. How this occurs is undefined. Herein, the effects of coreceptor therapy on islet T cell retention were investigated. Bivalent Ab binding to CD4 and CD8 blocked TCR signaling and T cell cytokine production, while indirectly downregulating islet chemokine expression...
October 20, 2016: JCI Insight
Leonid E Fridlyand, Natalia A Tamarina, Andrew V Schally, Louis H Philipson
Growth hormone-releasing hormone (GHRH) is produced by the hypothalamus and stimulates growth hormone synthesis and release in the anterior pituitary gland. In addition, GHRH is an important regulator of cellular functions in many cells and organs. Expression of GHRH G-Protein Coupled Receptor (GHRHR) has been demonstrated in different peripheral tissues and cell types, including pancreatic islets. Among the peripheral activities, recent studies demonstrate a novel ability of GHRH analogs to increase and preserve insulin secretion by beta-cells in isolated pancreatic islets, which makes them potentially useful for diabetes treatment...
2016: Frontiers in Endocrinology
Brie Sorrenson, Emmanuelle Cognard, Kathryn L Lee, Waruni C Dissanayake, Yanyun Fu, Weiping Han, William E Hughes, Peter R Shepherd
The processes regulating glucose-stimulated insulin secretion (GSIS) and its modulation by incretins in pancreatic β-cells are only partly understood. Here we investigate the involvement of β-catenin in these processes. Reducing β-catenin levels using siRNA knockdown attenuated GSIS in a range of β-cell models and blocked the ability of GLP-1 agonists and the depolarizing agent KCl to potentiate this. This could be mimicked in both β-cell models and isolated islets by short-term exposure to the β-catenin inhibitory drug pyrvinium...
October 24, 2016: Journal of Biological Chemistry
Hideki Ushiku, Keishi Yamashita, Hiroshi Kawamata, Mina Waraya, Hiroshi Katoh, Keigo Yokoi, Toshimichi Tanaka, Satoru Ishii, Nobuyuki Nishizawa, Mariko Kikuchi, Naoko Minatani, Ken Kojo, Hiroshi Tajima, Ryo Nishiyama, Takashi Kaizu, Yusuke Kumamoto, Masahiko Watanabe
OBJECTIVES: We have identified homeobox-only protein (HOPX) as a tumor suppressor gene in various human cancer, and its expression was reduced by promoter DNA hypermethylation. Homeobox-only protein is strongly expressed on pancreatic islet cells; however, clinical relevance of HOPX expression has remained elusive in pancreatic neuroendocrine tumor (pNET). METHODS: We investigated 36 patients with pNET who undertook surgical resection between 1988 and 2012 for HOPX expression and DNA methylation to reveal its clinical significance...
October 2016: Pancreas
Hyun-Je Kim, Nari Byun, Ohsang Kwon, Chung-Gyu Park
The number of patients in need of organ transplantation is continuously on the rise. However, because of organ donor shortage, xenotransplantation has been highlighted as an alternative. Among the various porcine organs and tissues, porcine islets are considered to be the best-matching implantable candidates for clinical application based on recent progress in nonhuman primate pre-clinical studies. Nevertheless, before initiation of clinical trials, it should be confirmed whether the requisite xeno-antigen sensitization would have a deleterious effect on subsequent allo-transplantation or vice versa...
October 20, 2016: Biochemical and Biophysical Research Communications
Angus Baumann, Jane Conway, Hannah Rosenfeld, Tam Le Cong, David J Torpy, Wayne Rankin
No abstract text is available yet for this article.
February 2016: Pathology
Akos A Gerencser, Shona A Mookerjee, Martin Jastroch, Martin D Brand
Analysis of the cellular mechanisms of metabolic disorders, including type 2 diabetes mellitus, is complicated by the large number of reactions and interactions in metabolic networks. Metabolic control analysis with appropriate modularization is a powerful method for simplifying and analyzing these networks. To analyze control of cellular energy metabolism in adherent cell cultures of the INS-1832/13 pancreatic β-cell model we adapted our microscopy assay of absolute mitochondrial membrane potential (ΔψM) to a fluorescence microplate reader format, and applied it in conjunction with cell respirometry...
October 20, 2016: Biochimica et Biophysica Acta
Kathrin Fielitz, Kristina Althoff, Katleen De Preter, Julie Nonnekens, Jasmin Ohli, Sandra Elges, Wolfgang Hartmann, Günter Klöppel, Thomas Knösel, Marc Schulte, Ludger Klein-Hitpass, Daniela Beisser, Henning Reis, Annette Eyking, Elke Cario, Johannes H Schulte, Alexander Schramm, Ulrich Schüller
Amplification or overexpression of MYCN is involved in development and maintenance of multiple malignancies. A subset of these tumors originates from neural precursors, including the most aggressive forms of the childhood tumors, neuroblastoma and medulloblastoma. In order to model the spectrum of MYCN-driven neoplasms in mice, we transgenically overexpressed MYCN under the control of the human GFAP-promoter that, among other targets, drives expression in neural progenitor cells. However, LSL-MYCN;hGFAP-Cre double transgenic mice did neither develop neural crest tumors nor tumors of the central nervous system, but presented with neuroendocrine tumors of the pancreas and, less frequently, the pituitary gland...
October 19, 2016: Oncotarget
Bradley P Weegman, Ahmad Essawy, Peter Nash, Alexandra L Carlson, Kristin J Voltzke, Zhaohui Geng, Marjan Jahani, Benjamin B Becker, Klearchos K Papas, Meri T Firpo
In this demonstration, spheroids formed from the β-TC6 insulinoma cell line were cultured as a model of manufacturing a mammalian islet cell product to demonstrate how regulating nutrient levels can improve cell yields. In previous studies, bioreactors facilitated increased culture volumes over static cultures, but no increase in cell yields were observed. Limitations in key nutrients such as glucose, which were consumed between batch feedings, can lead to limitations in cell expansion. Large fluctuations in glucose levels were observed, despite the increase in glucose concentrations in the media...
September 25, 2016: Journal of Visualized Experiments: JoVE
Chen Luo, Lu-Ting Yu, Meng-Qi Yang, Xiang Li, Zhi-Yuan Zhang, Martin O Alfred, Jun-Li Liu, Min Wang
Regenerating genes (Reg) have been found during the search for factors involved in pancreatic islet regeneration. Our recent study discovered that pancreatic β-cell-specific overexpression of Reg3β protects against streptozotocin (Stz) -induced diabetes in mice. To investigate its potential roles in the treatment of diabetes, we produced a recombinant Reg3β protein and provided evidence that it is active in promoting islet β-cell survival against Stz- triggered cell death. Though ineffective in alleviating preexisting diabetes, pretreatment of recombinant Reg3β was capable of minimizing the Stz-induced hyperglycemia and weight loss, by preserving serum and pancreatic insulin levels, and islet β-cell mass...
October 21, 2016: Scientific Reports
Kevin Vivot, Malika A Benahmed, Elodie Seyfritz, William Bietiger, Karim Elbayed, Elisa Ruhland, Allan Langlois, Elisa Maillard, Michel Pinget, Nathalie Jeandidier, Jean-Pierre Gies, Izzie-Jacques Namer, Séverine Sigrist, Nathalie Reix
Intrahepatic transplantation of islets requires a lot of islets because more than 50% of the graft is lost during the 24 hours following transplantation. We analyzed, in a rat model, early post-transplantation inflammation using systemic inflammatory markers, or directly in islet-transplanted livers by immunohistochemistry. (1)H HRMAS NMR was employed to investigate metabolic responses associated with the transplantation. Inflammatory markers (Interleukin-6, α2-macroglobulin) are not suitable to follow islet reactions as they are not islet specific...
2016: International Journal of Biological Sciences
Tina M Mitre, Anmar Khadra, Massimo Pietropaolo
The expression level of tissue-restricted autoantigens (TSA) in the thymus is crucial for the negative selection of autoreactive T cells during central tolerance. The autoimmune regulator factor (AIRE) plays an important role in the positive regulation of these TSA in medullary thymic epithelial cells and, consequently, in the negative selection of high-avidity autoreactive T cells. Recent studies, however, revealed that thymic islet cell autoantigen (ICA69) expression level in non-obese diabetic (NOD) mice, prone to developing type 1 diabetes (T1D), is reduced due to an increase in the binding affinity of AIRE to the Ica1-promoter region, which regulates ICA69 protein synthesis...
October 17, 2016: Mathematical Biosciences
Ingrid K Hals, Rinku Singh, Zuheng Ma, Hanne Scholz, Anneli Björklund, Valdemar Grill
We tested whether exposure of beta cells at reduced glucose leads to mitochondrial adaptions and whether such adaptions modulate effects of hypoxia. Rat islets, human islets and INS-1 832/13 cells were pre-cultured short term at half standard glucose concentrations (5.5 mM for rat islets and cells, 2.75 mM for human islets) without overtly negative effects on subsequently measured function (insulin secretion and cellular insulin contents) or on viability. Culture at half standard glucose upregulated complex I and tended to upregulate complex II in islets and INS-1 cells alike...
October 20, 2016: Islets
Attilio Pingitore, Edward S Chambers, Thomas Hill, Inmaculada Ruz Maldonado, Bo Liu, Gavin Bewick, Douglas J Morrison, Tom Preston, Gareth A Wallis, Catriona Tedford, Ramón Castañera González, Guo Cai Huang, Pratik Choudhary, Gary Frost, Shanta J Persaud
AIMS: Diet-derived short chain fatty acids (SCFAs) improve glucose homeostasis in vivo, but the role of individual SCFAs and their mechanisms of action have not been defined. This study evaluated the effects of increasing colonic delivery of the SCFA propionate on β-cell function in humans and the direct effects of propionate on isolated human islets in vitro. MATERIALS AND METHODS: For 24 weeks human subjects ingested an inulin-propionate ester that delivers propionate to the colon...
October 20, 2016: Diabetes, Obesity & Metabolism
Yoichi Oikawa, Hajime Tanaka, Junko Uchida, Yoshihiro Atsumi, Masaya Osawa, Takeshi Katsuki, Toshihide Kawai, Akira Shimada
Slowly progressive insulin-dependent (type 1) diabetes mellitus (SPIDDM), believed to be caused by β-cell destruction through islet-cell autoimmunity, gradually progresses to an insulin-dependent state over time. Although the presence of anti-glutamic acid decarboxylase antibody (GADA) is required for the diagnosis of SPIDDM, a recent change in the GADA assay kit from radioimmunoassay (RIA) to enzyme-linked immunosorbent assay (ELISA) yields mismatched GADA test results between the two kits, leading to confusion in understanding the pathological conditions of SPIDDM in Japan...
October 18, 2016: Endocrine Journal
Rauf Shahbazov, Gumpei Yoshimatsu, Waqas Z Haque, Omar S Khan, Giovanna Saracino, Michael C Lawrence, Peter T Kim, Nicholas Onaca, Bashoo Naziruddin, Marlon F Levy
BACKGROUND: The impact of pylorus preserving procedures (PP) on total pancreatectomy with islet autotransplantation (TPIAT) has not been examined. This study aimed to investigate the clinical impact of the PP on TPIAT. METHODS: The Baylor Simmons Transplant Institute database was queried to identify seventy-three patients who underwent TPIAT from 2006 to 2014. All patients were investigated in postoperative complications, long-term nutritional status, and graft function...
October 8, 2016: American Journal of Surgery
Q F Liang, C Gao, H Liang, B Li, X H Du, Antoine Labbe
Objective: To observe the characteristics of pterygium with in vivo confocal microscopy (IVCM) and understand pterygium activity with the density of inflammatory cells, formation of new blood vessels, and the number of activated keratocytes within the stroma. Methods: A prospective case-controlled study. Thirty-six pterygia from 28 patients were analyzed in this study. A pterygium activity score was obtained by summing four scores of ocular discomfort, pterygium hyperemia, keratitis, and the presence of Fuchs patches...
October 11, 2016: [Zhonghua Yan Ke za Zhi] Chinese Journal of Ophthalmology
Qin Qiao, Ruxi Qi, Guanghong Wei, Xuhui Huang
Amyloid deposits of human islet amyloid polypeptide (hIAPP) are identified in 95% of type II diabetes patients. The oligomers during the early stage of hIAPP aggregation are believed to be more cytotoxic than the mature fibrils. However, the structural details during the initial stage of hIAPP aggregation are still under debate experimentally. To understand its initial nucleation mechanism, we investigate the thermodynamics and kinetics of hIAPP(11-25) dimerization, which is the first manifestation of the interplay between intra- and inter-molecular interactions, via the construction of Markov state models from extensive molecular dynamics simulations...
October 19, 2016: Physical Chemistry Chemical Physics: PCCP
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