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‣ AMINO-ACID-SEQUENCE OF TSTX-V, AN ALPHA-TOXIN FROM TITYUS-SERRULATUS SCORPION-VENOM, AND ITS EFFECT ON K+ PERMEABILITY OF BETA-CELLS FROM ISOLATED RAT ISLETS OF LANGERHANS

Marangoni, S.; Toyama, M. H.; Arantes, E. C.; GIGLIO, JR; Dasilva, C. A.; Carneiro, E. M.; Goncalves, A. A.; Oliveira, B.
Fonte: Elsevier B.V. Publicador: Elsevier B.V.
Tipo: Artigo de Revista Científica Formato: 309-314
Português
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Highly purified Tityustoxin V (TsTX-V), an alpha-toxin isolated from the venom of the Brazilian scorpion Tityus serrulatus, was obtained by ion exchange chromatography on carboxymethylcellulose-52. It was shown to be homogeneous by reverse phase high performance liquid chromatography, N-terminal sequencing (first 39 residues) of the reduced and alkylated protein and by polyacrylamide gel electrophoresis in the presence of sodium dodecylsulfate and tricine. Following enzymatic digestion, the complete amino acid sequence (64 residues) was determined. The sequence showed higher homology with the toxins from the venoms of the North African than with those of the North and South American scorpions. Using the rate of Rb-86(+) release from depolarized rat pancreatic beta-cells as a measure of K+ permeability changes, TsTX-V (5.6 mu g/ml) was found to increase by 2.0-2.4-fold the rate of marker outflow in the presence of 8.3 mM glucose. This effect was persistent and slowly reversible, showing similarity to that induced by 100 mu-M veratridine, an agent that increases the open period of Na+ channels, delaying their inactivation. It is suggested that, by extending the depolarized period, TsTX-V indirectly affects beta-cell voltage-dependent K+ channels...

‣ Localization of myosin-Va in subpopulations of cells in rat endocrine organs

Espindola, Foued S.; Banzi, Silmara R.; Calabria, Luciana K.; Custódio, Rodrigo J.; Oliveira, Ricardo A.; Procópio, Leandro D.; Lima, Andreia B. P.; Cunha-Junior, Jair P.; Coelho, Milton V.; Guedes, Iêda M. L.; Pellizzon, Cláudia H.; Larson, Roy E.; E
Fonte: Universidade Estadual Paulista Publicador: Universidade Estadual Paulista
Tipo: Artigo de Revista Científica Formato: 263-279
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Myosin-Va is a Ca 2+/calmodulin-regulated unconventional myosin involved in the transport of vesicles, membranous organelles, and macromolecular complexes composed of proteins and mRNA. The cellular localization of myosin-Va has been described in great detail in several vertebrate cell types, including neurons, melanocytes, lymphocytes, auditory tissues, and a number of cultured cells. Here, we provide an immunohistochemical view of the tissue distribution of myosin-Va in the major endocrine organs. Myosin-Va is highly expressed in the pineal and pituitary glands and in specific cell populations of other endocrine glands, especially the parafollicular cells of the thyroid, the principal cells of the parathyroid, the islets of Langerhans of the pancreas, the chromaffin cells of the adrenal medulla, and a subpopulation of interstitial testicular cells. Weak to moderate staining has been detected in steroidogenic cells of the adrenal cortex, ovary, and Leydig cells. Myosin-Va has also been localized to non-endocrine cells, such as the germ cells of the seminiferous epithelium and maturing oocytes and in the intercalated ducts of the exocrine pancreas. These data provide the first systematic description of myosin-Va localization in the major endocrine organs of rat. © 2008 Springer-Verlag.

‣ Maturação da resposta secretoria a glicose pelo INGAP (Islet Neongenesis Associated Protein) em ilhotas de Langerhans de ratos neonatos; Maturation of the secretory response to glucose by INGAP (Islet Neongenesis Associated Protein) in islets of Langerhans of neonatal rats

Helena Cristina de Lima Barbosa
Fonte: Biblioteca Digital da Unicamp Publicador: Biblioteca Digital da Unicamp
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 15/08/2008 Português
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Islet Neogenesis Associated Protein (INGAP) aumenta a massa das células ß e potencializa a secreção de insulina induzida por glicose. Neste projeto, estudamos os efeitos de um pentadecapeptídeo contendo a seqüência 104 a 118 de aminoácidos do INGAP (INGAP-PP) sobre a expressão de genes das células insulares, expressão e fosforilação de componentes das vias PI3K e MAPK, sinalização colinérgica, bem como secreções dinâmica e estática de insulina, em ilhotas isoladas de ratos neonatos. Ilhotas cultivadas com INGAP-PP por 4 dias secretaram significativamente mais insulina em resposta a glicose, comparado às ilhotas controle. Análise do padrão da expressão, por macroarray, de ilhotas cultivadas com INGAP-PP, mostrou que de 2.352 genes fixados na membrana de nylon 210 apresentaram expressão aumentada e apenas 4 diminuída. Dentre os genes modulados positivamente pelo INGAP-PP vários estão relacionados com o metabolismo das células insulares, mecanismo de secreção de insulina, crescimento, maturação, manutenção da massa celular e exocitose. Exposição aguda de ilhotas neonatais ao INGAP-PP aumentou significativamente a fosforilação de Akt-Ser473 e ERK1/2-Thr202/Tyr204 bem como a secreção dinâmica de insulina frente a 2 e 20 mM de glicose. Ilhotas tratadas durante 4 dias com INGAP-PP também apresentaram aumento da expressão do receptor muscarínico M3 e da PLC-ß2. Essas ilhotas...

‣ Comparação dos efeitos do gangliosideo GM1 e do fator de crescimento neural (NGF) sobre a expressão de receptor de alta afinidade para NGF, TrkA e insulina em ilhotas pancreaticas isoladas de camundongos NOD (diabetico não obeso); Comparison of the effect of ganglioside GM1 and the Nerve Growth Factor (NGF) on the expression of receiver of high affinity for NGF, TrkA and insulin in isolated pancreatic islets of NOD mice (non obese diabetic)

Priscila Perez Domingos
Fonte: Biblioteca Digital da Unicamp Publicador: Biblioteca Digital da Unicamp
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 29/02/2008 Português
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O camundongo não obeso diabético (NOD) é caracterizado por desenvolver naturalmente diabetes mellitus tipo 1 (DM-1) com similaridade ao diabetes mellitus tipo 1 em humanos. A manifestação espontânea do diabetes neste modelo animal é caracterizado por infiltração progressiva das ilhotas de Langerhans por células mononucleares linfócitos T (CD4+ e CD8+) e destruição das células ß pancreáticas produtoras de insulina. O fator de crescimento neural (NGF) e algumas citocinas estão associados a regeneração neural, além de atuarem sobre células do sistema imune. Em adição a estes efeitos, NGF age na liberação de insulina pelas células betas das ilhotas pancreáticas, tornando-se foco de interesse com relação as suas propriedades moduladoras no processo inflamatório na ilhota pancreática. O gangliosídeo GM1 liga-se ao receptor de alta afinidade (TrkA) do NGF-ß, mimetizando seus efeitos. No presente trabalho, avaliamos a ação modulatória de GM1 e NGF em cultura de ilhotas pancreáticas, provenientes de camundongos NOD. Foram avaliados por meio de RT-PCR a expressão gênica de NGF-ß, TrkA e insulina e, por ensaio imunoenzimático, a concentração de citocinas IL-1ß, IL-12, TNF-a, INF-y e insulina. Nossos resultados sugerem ação moduladora similar entre GM1 e NGF sobre as ilhotas de NOD não diabéticos e pré-diabéticos. NGF e GM1 aumentam a expressão gênica de NGF e TrkA e diminuem a expressão gênica de insulina em NOD não diabéticos e pré-diabéticos. Além disso...

‣ ADENOMA OF THE ISLETS OF LANGERHANS

Saint, James H.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /09/1952 Português
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An adenoma of the islets of Langerhans may be found anywhere in the pancreas but is more common in the body and tail, and more than one tumor may be present. When such a tumor produces insulin the symptoms observed are those of hyperinsulinism, varying from pallor, sweating, weakness and amnesia in mild cases to coma and convulsions in the more severe.

‣ Dendritic cells in islets of Langerhans constitutively present β cell-derived peptides bound to their class II MHC molecules

Calderon, Boris; Suri, Anish; Miller, Mark J.; Unanue, Emil R.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
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Islets of Langerhans from normal mice contained dendritic cells (DCs) in the range of 8–10 per islet. DCs were found in several mouse strains, including those from lymphocyte-deficient mice. DCs were absent in islets from colony stimulating factor-1 deficient mice and this absence correlated with small size islets. Most DCs were found next to blood vessels and resided in islets for several days. Some DCs contained insulin-like granules, and most expressed peptide–MHC complexes derived from β cell proteins. Islet DCs were highly effective in presenting β cell antigens to CD4 T cells ex vivo. Presentation of β cell-derived peptide–MHC complexes by DCs neither depended on islet inflammation nor correlated with the extent of spontaneous β cell death. Periislet stroma DCs did not contain β cell peptide–MHC complexes; however, 50% of DCs in pancreatic node were positive. Hence, presentation of high levels of β cell antigens normally takes place by islet DCs, a finding that has to be placed in the perspective of autoimmune diabetes.

‣ Cellular and molecular events in the localization of diabetogenic T cells to islets of Langerhans

Calderon, Boris; Carrero, Javier A.; Miller, Mark J.; Unanue, Emil R.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
Português
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Understanding the entry of autoreactive T cells to their target organ is important in autoimmunity because this entry initiates the inflammatory process. Here, the events that lead to specific localization of diabetogenic CD4 T cells into islets of Langerhans resulting in diabetes were examined. This was evaluated in two models, one in which T cells specific for a hen-egg white lysozyme (HEL) peptide were injected into mice expressing HEL on β cells and the other using T cells in the nonobese diabetic mouse strain, which develops spontaneous diabetes. Only T cells specific for β-cell antigens localized in islets within the first hours after their injection and were found adherent to intraislet dendritic cells (DCs). DCs surrounded blood vessels with dendrites reaching into the vessels. Localization of antigen-specific T cells did not require chemokine receptor signaling but involved class II histocompatibility and intercellular adhesion molecule 1 molecules. We found no evidence for nonspecific localization of CD4 T cells into normal noninflamed islets. Thus, the anatomy of the islet of Langerhans permits the specific localization of diabetogenic T cells at a time when there is no inflammation in the islets.

‣ Rapid Insulinotropic Action of Low Doses of Bisphenol-A on Mouse and Human Islets of Langerhans: Role of Estrogen Receptor β

Soriano, Sergi; Alonso-Magdalena, Paloma; García-Arévalo, Marta; Novials, Anna; Muhammed, Sarheed J.; Salehi, Albert; Gustafsson, Jan-Ake; Quesada, Ivan; Nadal, Angel
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 08/02/2012 Português
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Bisphenol-A (BPA) is a widespread endocrine-disrupting chemical (EDC) used as the base compound in the manufacture of polycarbonate plastics. It alters pancreatic β-cell function and can be considered a risk factor for type 2 diabetes in rodents. Here we used ERβ−/− mice to study whether ERβ is involved in the rapid regulation of KATP channel activity, calcium signals and insulin release elicited by environmentally relevant doses of BPA (1 nM). We also investigated these effects of BPA in β-cells and whole islets of Langerhans from humans. 1 nM BPA rapidly decreased KATP channel activity, increased glucose-induced [Ca2+]i signals and insulin release in β-cells from WT mice but not in cells from ERβ−/− mice. The rapid reduction in the KATP channel activity and the insulinotropic effect was seen in human cells and islets. BPA actions were stronger in human islets compared to mouse islets when the same BPA concentration was used. Our findings suggest that BPA behaves as a strong estrogen via nuclear ERβ and indicate that results obtained with BPA in mouse β-cells may be extrapolated to humans. This supports that BPA should be considered as a risk factor for metabolic disorders in humans.

‣ Diabetes imaging—quantitative assessment of islets of Langerhans distribution in murine pancreas using extended-focus optical coherence microscopy

Berclaz, Corinne; Goulley, Joan; Villiger, Martin; Pache, Christophe; Bouwens, Arno; Martin-Williams, Erica; Van de Ville, Dimitri; Davison, Anthony C.; Grapin-Botton, Anne; Lasser, Theo
Fonte: Optical Society of America Publicador: Optical Society of America
Tipo: Artigo de Revista Científica
Publicado em 14/05/2012 Português
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Diabetes is characterized by hyperglycemia that can result from the loss of pancreatic insulin secreting β-cells in the islets of Langerhans. We analyzed ex vivo the entire gastric and duodenal lobes of a murine pancreas using extended-focus Optical Coherence Microscopy (xfOCM). To identify and quantify the islets of Langerhans observed in xfOCM tomograms we implemented an active contour algorithm based on the level set method. We show that xfOCM reveals a three-dimensional islet distribution consistent with Optical Projection Tomography, albeit with a higher resolution that also enables the detection of the smallest islets (≤ 8000 μm3). Although this category of the smallest islets represents only a negligible volume compared to the total β-cell volume, a recent study suggests that these islets, located at the periphery, are the first to be destroyed when type I diabetes develops. Our results underline the capability of xfOCM to contribute to the understanding of the development of diabetes, especially when considering islet volume distribution instead of the total β-cell volume only.

‣ Glucose-Stimulated Calcium Dynamics in Islets of Langerhans in Acute Mouse Pancreas Tissue Slices

Stožer, Andraž; Dolenšek, Jurij; Rupnik, Marjan Slak
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 24/01/2013 Português
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In endocrine cells within islets of Langerhans calcium ions couple cell stimulation to hormone secretion. Since the advent of modern fluorimetry, numerous in vitro studies employing primarily isolated mouse islets have investigated the effects of various secretagogues on cytoplasmic calcium, predominantly in insulin-secreting beta cells. Due to technical limitations, insights of these studies are inherently limited to a rather small subpopulation of outermost cells. The results also seem to depend on various factors, like culture conditions and duration, and are not always easily reconcilable with findings in vivo. The main controversies regard the types of calcium oscillations, presence of calcium waves, and the level of synchronized activity. Here, we set out to combine the in situ acute mouse pancreas tissue slice preparation with noninvasive fluorescent calcium labeling and subsequent confocal laser scanning microscopy to shed new light on the existing controversies utilizing an innovative approach enabling the characterization of responses in many cells from all layers of islets. Our experiments reproducibly showed stable fast calcium oscillations on a sustained plateau rather than slow oscillations as the predominant type of response in acute tissue slices...

‣ Functional Connectivity in Islets of Langerhans from Mouse Pancreas Tissue Slices

Stožer, Andraž; Gosak, Marko; Dolenšek, Jurij; Perc, Matjaž; Marhl, Marko; Rupnik, Marjan Slak; Korošak, Dean
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Português
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We propose a network representation of electrically coupled beta cells in islets of Langerhans. Beta cells are functionally connected on the basis of correlations between calcium dynamics of individual cells, obtained by means of confocal laser-scanning calcium imaging in islets from acute mouse pancreas tissue slices. Obtained functional networks are analyzed in the light of known structural and physiological properties of islets. Focusing on the temporal evolution of the network under stimulation with glucose, we show that the dynamics are more correlated under stimulation than under non-stimulated conditions and that the highest overall correlation, largely independent of Euclidean distances between cells, is observed in the activation and deactivation phases when cells are driven by the external stimulus. Moreover, we find that the range of interactions in networks during activity shows a clear dependence on the Euclidean distance, lending support to previous observations that beta cells are synchronized via calcium waves spreading throughout islets. Most interestingly, the functional connectivity patterns between beta cells exhibit small-world properties, suggesting that beta cells do not form a homogeneous geometric network but are connected in a functionally more efficient way. Presented results provide support for the existing knowledge of beta cell physiology from a network perspective and shed important new light on the functional organization of beta cell syncitia whose structural topology is probably not as trivial as believed so far.

‣ Label-Free Detection of Insulin and Glucagon within Human Islets of Langerhans Using Raman Spectroscopy

Hilderink, Janneke; Otto, Cees; Slump, Cees; Lenferink, Aufried; Engelse, Marten; van Blitterswijk, Clemens; de Koning, Eelco; Karperien, Marcel; van Apeldoorn, Aart
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 22/10/2013 Português
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Intrahepatic transplantation of donor islets of Langerhans is a promising therapy for patients with type 1 diabetes. It is of critical importance to accurately monitor islet quality before transplantation, which is currently done by standard histological methods that are performed off-line and require extensive sample preparation. As an alternative, we propose Raman spectroscopy which is a non-destructive and label-free technique that allows continuous real-time monitoring of the tissue to study biological changes as they occur. By performing Raman spectroscopic measurements on purified insulin and glucagon, we showed that the 520 cm-1 band assigned to disulfide bridges in insulin, and the 1552 cm-1 band assigned to tryptophan in glucagon are mutually exclusive and could therefore be used as indirect markers for the label-free distinction between both hormones. High-resolution hyperspectral Raman imaging for these bands showed the distribution of disulfide bridges and tryptophan at sub-micrometer scale, which correlated with the location of insulin and glucagon as revealed by conventional immunohistochemistry. As a measure for this correlation, quantitative analysis was performed comparing the Raman images with the fluorescence images...

‣ Device design and materials optimization of conformal coating for islets of Langerhans

Tomei, Alice A.; Manzoli, Vita; Fraker, Christopher A.; Giraldo, Jaime; Velluto, Diana; Najjar, Mejdi; Pileggi, Antonello; Molano, R. Damaris; Ricordi, Camillo; Stabler, Cherie L.; Hubbell, Jeffrey A.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
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Cell encapsulation with biocompatible and permeable hydrogels may allow transplantation without immunosuppression. As an alternative to standard microencapsulation approaches that create single-sized capsules around cell clusters of different sizes, we have designed and optimized a novel approach for conformal coating of islets of Langerhans, resulting in thin, complete, and uniform coatings of similar thickness on differently sized islets. Coated islets exhibited no delay in glucose-stimulated insulin release or loss of function during culture, which is often observed with naked islets. The conformal coating reduces transplant volume relative to traditional encapsulation approaches. When transplanted in syngeneic diabetic mice, conformally coated islets restored and maintained euglycemia for more than 100 d with no foreign body reaction and normal revascularization.

‣ The Beta Cell in Its Cluster: Stochastic Graphs of Beta Cell Connectivity in the Islets of Langerhans

Striegel, Deborah A.; Hara, Manami; Periwal, Vipul
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 12/08/2015 Português
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Pancreatic islets of Langerhans consist of endocrine cells, primarily α, β and δ cells, which secrete glucagon, insulin, and somatostatin, respectively, to regulate plasma glucose. β cells form irregular locally connected clusters within islets that act in concert to secrete insulin upon glucose stimulation. Due to the central functional significance of this local connectivity in the placement of β cells in an islet, it is important to characterize it quantitatively. However, quantification of the seemingly stochastic cytoarchitecture of β cells in an islet requires mathematical methods that can capture topological connectivity in the entire β-cell population in an islet. Graph theory provides such a framework. Using large-scale imaging data for thousands of islets containing hundreds of thousands of cells in human organ donor pancreata, we show that quantitative graph characteristics differ between control and type 2 diabetic islets. Further insight into the processes that shape and maintain this architecture is obtained by formulating a stochastic theory of β-cell rearrangement in whole islets, just as the normal equilibrium distribution of the Ornstein-Uhlenbeck process can be viewed as the result of the interplay between a random walk and a linear restoring force. Requiring that rearrangements maintain the observed quantitative topological graph characteristics strongly constrained possible processes. Our results suggest that β-cell rearrangement is dependent on its connectivity in order to maintain an optimal cluster size in both normal and T2D islets.

‣ Development of quantitative methods for quality assessment of islets of Langerhans

Pisania, Anna
Fonte: Massachusetts Institute of Technology Publicador: Massachusetts Institute of Technology
Tipo: Tese de Doutorado Formato: 257 p.
Português
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Transplantation of isolated islets of Langerhans has promising potential to cure type 1 diabetes by inducing long-term normoglycemia and insulin independence. The feasibility of clinical islet transplantations has been established according to the Edmonton Protocol. However, results are variable, and it is not yet possible to predict transplantation outcome from in vitro measurements with islet preparations. Currently, islet enumeration is based on microscopic visualization after staining with a zinc-specific binding dye (dithizone, DTZ) and manual counting with normalization on the basis of an islet equivalent (IE), an islet with volume equivalent to that of a sphere with a 150 Pm diameter. Islet viability is based on a live/dead staining test with two fluorescent dyes, fluorescein diacetate (FDA) and propidium iodide (PI). These methods are operator- dependent and prone to error due to the variability in islet size and shape and are not predictive of transplantation outcome. We developed quantitative assays that allowed reproducible evaluation of meaningful properties that affect the clinical outcome in impure human islet preparations. For purity estimation, we examined light microscopic (LM) morphological analysis of 1-jm sections to estimate the islet volume fraction and compared the results with those of electron microscopy (EM) ultrastructural analysis on the same preparations.; (cont.) For quantifying the total number of cells in a preparation...

‣ Immunocytochemical identification of cells containing insulin, glugacon, somatostatin, and pancreatic polypeptide in islets of Langerhans of the wombat pancreas with electron microscopy

Leigh, C.; Edwin, N.
Fonte: LUIGI PONZIO E FIGLIO Publicador: LUIGI PONZIO E FIGLIO
Tipo: Artigo de Revista Científica
Publicado em //1997 Português
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The endocrine pancreas of the southern hairy-nosed wombat (Lasiorhinus latifrons) was investigated by means of electron-microscope immunocytochemistry using the protein A--gold technique on London resin (LR) white-embedded tissue. The primary antibodies used were raised against insulin, glucagon, somatostatin and pancreatic polypeptide. The morphology of the secretory granules differed in the four cell types. The insulin cells are pleiomorphic, and the secretory granules composed of an electron-dense core surrounded by an electron-lucent halo. The glucagon cells possess granules of varying density. Somatostatin cells have large, less dense secretory granules. The pancreatic polypeptide cells show small dense secretory granules. It is essential that it be corroborated by immunocytochemical data at the light or preferably electron-microscopical level for the definite identification of endocrine cell types. Recent developments in immuno-electron-microscopic techniques have contributed to a better knowledge of cells responsible for the secretion of a wide variety of hormones, as in this study.

‣ Immunohistochemical analysis of pancreatic islets of platypus (Ornithorhynchus anatinus) and echidna (Tachyglossus aculeatus ssp.)

He, C.; Myers, M.A.; Forbes, B.E.; Grützner, F.
Fonte: Wiley Publicador: Wiley
Tipo: Artigo de Revista Científica
Publicado em //2015 Português
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Monotremes have undergone remarkable changes to their digestive and metabolic control system; however, the monotreme pancreas remains poorly characterized. Previous work in echidna demonstrated the presence of pancreatic islets, but no information is available for platypus and the fine structure has not been described for either monotreme. Based on our recent finding that monotremes lack the ghrelin gene, which is expressed in mouse and human pancreatic islets, we investigated the structure of monotreme islets in more detail. Generally, as in birds, the islets of monotremes were smaller but greater in number compared with mouse. β-cells were the most abundant endocrine cell population in platypus islets and were located peripherally, while α-cells were observed both in the interior and periphery of the islets. δ-cells and pancreatic polypeptide (PP)-cells were mainly found in the islet periphery. Distinct PP-rich (PP-lobe) and PP-poor areas (non-PP-lobe) are present in therian mammals, and we identified these areas in echidna but not platypus pancreas. Interestingly, in some of the echidna islets, α- and β-cells tended to form two poles within the islets, which to our knowledge is the first time this has been observed in any species. Overall...

‣ Proinsulin-specific, HLA-DQ8, and HLA-DQ8-transdimer-restricted CD4⁺ T cells infiltrate islets in type 1 diabetes; Proinsulin-specific, HLA-DQ8, and HLA-DQ8-transdimer-restricted CD4(+) T cells infiltrate islets in type 1 diabetes

Pathiraja, V.; Kuehlich, J.P.; Campbell, P.D.; Krishnamurthy, B.; Loudovaris, T.; Coates, P.T.H.; Brodnicki, T.C.; O'Connell, P.J.; Kedzierska, K.; Rodda, C.; Bergman, P.; Hill, E.; Purcell, A.W.; Dudek, N.L.; Thomas, H.E.; Kay, T.W.H.; Mannering, S.I.
Fonte: American Diabetes Association Publicador: American Diabetes Association
Tipo: Artigo de Revista Científica
Publicado em //2015 Português
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Type 1 diabetes (T1D) develops when insulin-secreting β-cells, found in the pancreatic islets of Langerhans, are destroyed by infiltrating T cells. How human T cells recognize β-cell-derived antigens remains unclear. Genetic studies have shown that HLA and insulin alleles are the most strongly associated with risk of T1D. These long-standing observations implicate CD4(+) T-cell responses against (pro)insulin in the pathogenesis of T1D. To dissect the autoimmune T-cell response against human β-cells, we isolated and characterized 53 CD4(+) T-cell clones from within the residual pancreatic islets of a deceased organ donor who had T1D. These 53 clones expressed 47 unique clonotypes, 8 of which encoded proinsulin-specific T-cell receptors. On an individual clone basis, 14 of 53 CD4(+) T-cell clones (26%) recognized 6 distinct but overlapping epitopes in the C-peptide of proinsulin. These clones recognized C-peptide epitopes presented by HLA-DQ8 and, notably, HLA-DQ8 transdimers that form in HLA-DQ2/-DQ8 heterozygous individuals. Responses to these epitopes were detected in the peripheral blood mononuclear cells of some people with recent-onset T1D but not in HLA-matched control subjects. Hence, proinsulin-specific, HLA-DQ8, and HLA-DQ8-transdimer-restricted CD4(+) T cells are strongly implicated in the autoimmune pathogenesis of human T1D.; Vimukthi Pathiraja...

‣ Low Doses of Bisphenol A and Diethylstilbestrol Impair Ca2+ Signals in Pancreatic α-Cells through a Nonclassical Membrane Estrogen Receptor within Intact Islets of Langerhans

Alonso-Magdalena, Paloma; Laribi, Ouahiba; Ropero, Ana B.; Fuentes, Esther; Ripoll, Cristina; Soria, Bernat; Nadal, Angel
Fonte: National Institute of Environmental Health Sciences Publicador: National Institute of Environmental Health Sciences
Tipo: Artigo de Revista Científica
Português
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Glucagon, secreted from pancreatic α-cells integrated within the islets of Langerhans, is involved in the regulation of glucose metabolism by enhancing the synthesis and mobilization of glucose in the liver. In addition, it has other extrahepatic effects ranging from lipolysis in adipose tissue to the control of satiety in the central nervous system. In this article, we show that the endocrine disruptors bisphenol A (BPA) and diethylstilbestrol (DES), at a concentration of 10−9 M, suppressed low-glucose–induced intracellular calcium ion ([Ca2+]i) oscillations in α-cells, the signal that triggers glucagon secretion. This action has a rapid onset, and it is reproduced by the impermeable molecule estradiol (E2) conjugated to horseradish peroxidase (E-HRP). Competition studies using E-HRP binding in immunocytochemically identified α-cells indicate that 17β-E2, BPA, and DES share a common membrane-binding site whose pharmacologic profile differs from the classical ER. The effects triggered by BPA, DES, and E2 are blocked by the Gαi- and Gαo-protein inhibitor pertussis toxin, by the guanylate cyclase–specific inhibitor 1H-[1,2,4] oxadiazolo[4,3-a] quinoxalin-1-one, and by the nitric oxide synthase inhibitor N-nitro-l-arginine methyl ester. The effects are reproduced by 8-bromo-guanosine 3′...

‣ Pancreatic islet regeneration: Therapeutic potential, unknowns and controversy

Cockburn,Ingrid L.; Ferris,William F.
Fonte: South African Journal of Science Publicador: South African Journal of Science
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/08/2015 Português
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Glucose homeostasis in mammals is primarily maintained by the insulin-secreting β-cells contained within pancreas-resident islets of Langerhans. Gross disruption of this glucose regulation as a result of pancreatic dysfunction frequently results in diabetes, which is currently a major health concern in South Africa, as well as globally. For many years, researchers have realised that the pancreas, and specifically the islets of Langerhans, have a regenerative capacity, as islet mass has frequently been shown to increase following induced pancreatic injury. Given that gross β-cell loss contributes significantly to the pathogenesis of both type 1 and type 2 diabetes, endogenous pancreatic islet regeneration has been investigated extensively as a potential β-cell replacement therapy for diabetes. From the extensive research conducted on pancreatic regeneration, opposing findings and opinions have arisen as to how, and more recently even if, pancreatic regeneration occurs following induced injury. In this review, we outline and discuss the three primary mechanisms by which pancreatic regeneration is proposed to occur: neogenesis, β-cell replication and transdifferentiation. We further explain some of the advanced techniques used in pancreatic regeneration research...