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Christian M Cohrs, Chunguang Chen, Stephan R Jahn, Julia Stertmann, Helena Chmelova, Jürgen Weitz, Andrea Bähr, Nikolai Klymiuk, Anja Steffen, Barbara Ludwig, Virginia Kamvissi, Eckhard Wolf, Stefan R Bornstein, Michele Solimena, Stephan Speier
Islet cell hormone release is modulated by signals from endothelial and endocrine cells within the islet. However, models of intra-islet vascularization and paracrine cell signaling are mostly based on rodent pancreas. We here assessed for the first time the architecture and endocrine cell interaction of the vascular network in unperturbed human islets in situ and their potential to re-establish their endogenous vascular network after transplantation in vivo. We prepared pancreas tissue slices of fresh tissue obtained from non-diabetic patients undergoing partial pancreatectomy...
January 27, 2017: Endocrinology
Andreas Müller, Martin Neukam, Anna Ivanova, Anke Sönmez, Carla Münster, Susanne Kretschmar, Yannis Kalaidzidis, Thomas Kurth, Jean-Marc Verbavatz, Michele Solimena
Correlative light and electron microscopy (CLEM) is a powerful approach to investigate the molecular ultrastructure of labeled cell compartments. However, quantitative CLEM studies are rare, mainly due to small sample sizes and the sensitivity of fluorescent proteins to strong fixatives and contrasting reagents for EM. Here, we show that fusion of a self-labeling protein to insulin allows for the quantification of age-distinct insulin granule pools in pancreatic beta cells by a combination of super resolution and transmission electron microscopy on Tokuyasu cryosections...
December 2017: Scientific Reports
Gaelle R Carrat, Ming Hu, Marie-Sophie Nguyen-Tu, Pauline Chabosseau, Kyle J Gaulton, Martijn van de Bunt, Afshan Siddiq, Mario Falchi, Matthias Thurner, Mickaël Canouil, Francois Pattou, Isabelle Leclerc, Timothy J Pullen, Matthew C Cane, Priyanka Prabhala, William Greenwald, Anke Schulte, Piero Marchetti, Mark Ibberson, Patrick E MacDonald, Jocelyn E Manning Fox, Anna L Gloyn, Philippe Froguel, Michele Solimena, Mark I McCarthy, Guy A Rutter
Genetic variants near ARAP1 (CENTD2) and STARD10 influence type 2 diabetes (T2D) risk. The risk alleles impair glucose-induced insulin secretion and, paradoxically but characteristically, are associated with decreased proinsulin:insulin ratios, indicating improved proinsulin conversion. Neither the identity of the causal variants nor the gene(s) through which risk is conferred have been firmly established. Whereas ARAP1 encodes a GTPase activating protein, STARD10 is a member of the steroidogenic acute regulatory protein (StAR)-related lipid transfer protein family...
February 2, 2017: American Journal of Human Genetics
Marion Benazra, Marie-José Lecomte, Claire Colace, Andreas Müller, Cécile Machado, Severine Pechberty, Emilie Bricout-Neveu, Maud Grenier-Godard, Michele Solimena, Raphaël Scharfmann, Paul Czernichow, Philippe Ravassard
OBJECTIVES: Access to immortalized human pancreatic beta cell lines that are phenotypically close to genuine adult beta cells, represent a major tool to better understand human beta cell physiology and develop new therapeutics for Diabetes. Here we derived a new conditionally immortalized human beta cell line, EndoC-βH3 in which immortalizing transgene can be efficiently removed by simple addition of tamoxifen. METHODS: We used lentiviral mediated gene transfer to stably integrate a tamoxifen inducible form of CRE (CRE-ERT2) into the recently developed conditionally immortalized EndoC βH2 line...
December 2015: Molecular Metabolism
Laura Sosa, Juha M Torkko, María E Primo, Ramiro E Llovera, Pamela L Toledo, Antonella S Rios, F Luis Gonzalez Flecha, Aldana Trabucchi, Silvina N Valdez, Edgardo Poskus, Michele Solimena, Mario R Ermácora
BACKGROUND: ICA512 (or IA-2/PTPRN) is a transmembrane protein-tyrosine phosphatase located in secretory granules of neuroendocrine cells. Previous studies implied its involvement in generation, cargo storage, traffic, exocytosis and recycling of insulin secretory granules, as well as in β-cell proliferation. While several ICA512 domains have been characterized, the function and structure of a large portion of its N-terminal extracellular (or lumenal) region are unknown. Here, we report a biophysical, biochemical, and functional characterization of ICA512-RESP18HD, a domain comprising residues 35 to 131 and homologous to regulated endocrine-specific protein 18 (RESP18)...
May 2016: Biochimica et Biophysica Acta
Antje Petzold, Michele Solimena, Klaus-Peter Knoch
Type 1 diabetes (T1D) results from genetic predisposition and environmental factors leading to the autoimmune destruction of pancreatic beta cells. Recently, a rapid increase in the incidence of childhood T1D has been observed worldwide; this is too fast to be explained by genetic factors alone, pointing to the spreading of environmental factors linked to the disease. Enteroviruses (EVs) are perhaps the most investigated environmental agents in relationship to the pathogenesis of T1D. While several studies point to the likelihood of such correlation, epidemiological evidence in its support is inconclusive or in some instances even against it...
October 2015: Current Diabetes Reports
Florian Ehehalt, Dorothée Sturm, Manuela Rösler, Marius Distler, Jürgen Weitz, Stephan Kersting, Barbara Ludwig, Uta Schwanebeck, Hans-Detlev Saeger, Michele Solimena, Robert Grützmann
BACKGROUND AND AIM: Partial pancreatic resection is accompanied not only by a reduction in the islet cell mass but also by a variety of other factors that are likely to interfere with glucose metabolism. The aim of this work was to characterize the patient dynamics of blood glucose homeostasis during the course of partial pancreatic resection and to specify the associated clinico-pathological variables. METHODS: In total, 84 individuals undergoing elective partial pancreatic resection were consecutively recruited into this observational trial...
2015: PloS One
Erdinc Sezgin, Theresia Gutmann, Tomasz Buhl, Ron Dirkx, Michal Grzybek, Ünal Coskun, Michele Solimena, Kai Simons, Ilya Levental, Petra Schwille
Lateral compositional and physicochemical heterogeneity is a ubiquitous feature of cellular membranes on various length scales, from molecular assemblies to micrometric domains. Segregated lipid domains of increased local order, referred to as rafts, are believed to be prominent features in eukaryotic plasma membranes; however, their exact nature (i.e. size, lifetime, composition, homogeneity) in live cells remains difficult to define. Here we present evidence that both synthetic and natural plasma membranes assume a wide range of lipid packing states with varying levels of molecular order...
2015: PloS One
Jaber Dehghany, Peter Hoboth, Anna Ivanova, Hassan Mziaut, Andreas Müller, Yannis Kalaidzidis, Michele Solimena, Michael Meyer-Hermann
Insulin secretion from pancreatic β-cells in response to sudden glucose stimulation is biphasic. Prolonged secretion in vivo requires synthesis, delivery to the plasma membrane (PM) and exocytosis of insulin secretory granules (SGs). Here, we provide the first agent-based space-resolved model for SG dynamics in pancreatic β-cells. Using recent experimental data, we consider a single β-cell with identical SGs moving on a phenomenologically represented cytoskeleton network. A single exocytotic machinery mediates SG exocytosis on the PM...
August 2015: Traffic
Peter Hoboth, Andreas Müller, Anna Ivanova, Hassan Mziaut, Jaber Dehghany, Anke Sönmez, Martina Lachnit, Michael Meyer-Hermann, Yannis Kalaidzidis, Michele Solimena
Insulin secretion is key for glucose homeostasis. Insulin secretory granules (SGs) exist in different functional pools, with young SGs being more mobile and preferentially secreted. However, the principles governing the mobility of age-distinct SGs remain undefined. Using the time-reporter insulin-SNAP to track age-distinct SGs we now show that their dynamics can be classified into three components: highly dynamic, restricted, and nearly immobile. Young SGs display all three components, whereas old SGs are either restricted or nearly immobile...
February 17, 2015: Proceedings of the National Academy of Sciences of the United States of America
Juha M Torkko, M Evangelina Primo, Ronald Dirkx, Anne Friedrich, Antje Viehrig, Elisa Vergari, Barbara Borgonovo, Anke Sönmez, Carolin Wegbrod, Martina Lachnit, Carla Münster, Mauricio P Sica, Mario R Ermácora, Michele Solimena
The type 1 diabetes autoantigen ICA512/IA-2/RPTPN is a receptor protein tyrosine phosphatase of the insulin secretory granules (SGs) which regulates the size of granule stores, possibly via cleavage/signaling of its cytosolic tail. The role of its extracellular region remains unknown. Structural studies indicated that β2- or β4-strands in the mature ectodomain (ME ICA512) form dimers in vitro. Here we show that ME ICA512 prompts proICA512 dimerization in the endoplasmic reticulum. Perturbation of ME ICA512 β2-strand N-glycosylation upon S508A replacement allows for proICA512 dimerization, O-glycosylation, targeting to granules, and conversion, which are instead precluded upon G553D replacement in the ME ICA512 β4-strand...
March 2015: Molecular and Cellular Biology
S R Bornstein, S A Amiel, F Rubino, G Mingrone, V Kamvissi, M Solimena, E Bonifacio, P Jones, P Schwarz, A L Birkenfeld, A Behrens, A Barthel, R Lechler, M Peakman
No abstract text is available yet for this article.
December 12, 2014: Hormone and Metabolic Research, Hormon- und Stoffwechselforschung, Hormones et Métabolisme
S R Bornstein, S A Amiel, F Rubino, G Mingrone, V Kamvissi, M Solimena, E Bonifacio, P Jones, P Schwarz, A L Birkenfeld, A Behrens, A Barthel, R Lechler, M Peakman
No abstract text is available yet for this article.
January 2015: Hormone and Metabolic Research, Hormon- und Stoffwechselforschung, Hormones et Métabolisme
Martín E Noguera, María E Primo, Jean Jakoncic, Edgardo Poskus, Michele Solimena, Mario R Ermácora
Phogrin/IA-2β and ICA512/IA-2 are two paralogs receptor-type protein-tyrosine phosphatases (RPTP) that localize in secretory granules of various neuroendocrine cells. In pancreatic islet β-cells, they participate in the regulation of insulin secretion, ensuring proper granulogenesis, and β-cell proliferation. The role of their cytoplasmic tail has been partially unveiled, while that of their luminal region remains unclear. To advance the understanding of its structure-function relationship, the X-ray structure of the mature ectodomain of phogrin (ME phogrin) at pH 7...
March 2015: Journal of Structural and Functional Genomics
Klaus-Peter Knoch, Suchita Nath-Sain, Antje Petzold, Hendryk Schneider, Mike Beck, Carolin Wegbrod, Anke Sönmez, Carla Münster, Anne Friedrich, Merja Roivainen, Michele Solimena
Glucose and GLP-1 stimulate not only insulin secretion, but also the post-transcriptional induction of insulin granule biogenesis. This process involves the nucleocytoplasmic translocation of the RNA binding protein PTBP1. Binding of PTBP1 to the 3'-UTRs of mRNAs for insulin and other cargoes of beta cell granules increases their stability. Here we show that glucose enhances also the binding of PTBP1 to the 5'-UTRs of these transcripts, which display IRES activity, and their translation exclusively in a cap-independent fashion...
August 2014: Molecular Metabolism
Ronald Dirkx, Michele Solimena
The failure of pancreatic β-cells to supply insulin in quantities sufficient to maintain euglycemia is a hallmark of type 2 diabetes. Perturbation of β-cell cholesterol homeostasis, culminating in elevated intracellular cholesterol levels, impairs insulin secretion and has therefore been proposed as a mechanism contributing to β-cell dysfunction. The manner in which this occurs, however, is unclear. Cholesterol is an essential lipid, as well as a major component of membrane rafts, and numerous proteins critical for the regulation of insulin secretion have been reported to associate with these domains...
August 20, 2012: Journal of Diabetes Investigation
Maria Grazia Magro, Michele Solimena
β-cells of the pancreatic islets are highly specialized and high-throughput units for the production of insulin, the key hormone for maintenance of glucose homeostasis. Elevation of extracellular glucose and/or GLP-1 levels triggers a rapid upregulation of insulin biosynthesis through the activation of post-transcriptional mechanisms. RNA-binding proteins are emerging as key factors in the regulation of these mechanisms as well as in other aspects of β-cell function and glucose homeostasis at large, and thus may be implicated in the pathogenesis of diabetes...
2013: Molecular Metabolism
Barbara Ludwig, Andreas Reichel, Anja Steffen, Baruch Zimerman, Andrew V Schally, Norman L Block, Clark K Colton, Stefan Ludwig, Stephan Kersting, Ezio Bonifacio, Michele Solimena, Zohar Gendler, Avi Rotem, Uriel Barkai, Stefan R Bornstein
Transplantation of pancreatic islets is emerging as a successful treatment for type-1 diabetes. Its current stringent restriction to patients with critical metabolic lability is justified by the long-term need for immunosuppression and a persistent shortage of donor organs. We developed an oxygenated chamber system composed of immune-isolating alginate and polymembrane covers that allows for survival and function of islets without immunosuppression. A patient with type-1 diabetes received a transplanted chamber and was followed for 10 mo...
November 19, 2013: Proceedings of the National Academy of Sciences of the United States of America
Julia Phieler, Kyoung-Jin Chung, Antonios Chatzigeorgiou, Anne Klotzsche-von Ameln, Ruben Garcia-Martin, David Sprott, Maria Moisidou, Theodora Tzanavari, Barbara Ludwig, Elena Baraban, Monika Ehrhart-Bornstein, Stefan R Bornstein, Hassan Mziaut, Michele Solimena, Katia P Karalis, Matina Economopoulou, John D Lambris, Triantafyllos Chavakis
Obese adipose tissue (AT) inflammation contributes critically to development of insulin resistance. The complement anaphylatoxin C5a receptor (C5aR) has been implicated in inflammatory processes and as regulator of macrophage activation and polarization. However, the role of C5aR in obesity and AT inflammation has not been addressed. We engaged the model of diet-induced obesity and found that expression of C5aR was significantly upregulated in the obese AT, compared with lean AT. In addition, C5a was present in obese AT in the proximity of macrophage-rich crownlike structures...
October 15, 2013: Journal of Immunology: Official Journal of the American Association of Immunologists
Anna Ivanova, Yannis Kalaidzidis, Ronald Dirkx, Mihail Sarov, Michael Gerlach, Britta Schroth-Diez, Andreas Müller, Yanmei Liu, Cordula Andree, Bernard Mulligan, Carla Münster, Thomas Kurth, Marc Bickle, Stephan Speier, Konstantinos Anastassiadis, Michele Solimena
Insulin is stored within the secretory granules of pancreatic β-cells, and impairment of its release is the hallmark of type 2 diabetes. Preferential exocytosis of newly synthesized insulin suggests that granule aging is a key factor influencing insulin secretion. Here, we illustrate a technology that enables the study of granule aging in insulinoma cells and β-cells of knock-in mice through the conditional and unequivocal labeling of insulin fused to the SNAP tag. This approach, which overcomes the limits encountered with previous strategies based on radiolabeling or fluorescence timer proteins, allowed us to formally demonstrate the preferential release of newly synthesized insulin and reveal that the motility of cortical granules significantly changes over time...
November 2013: Diabetes
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