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Sample records for islet hormonal responses

  1. Inflammatory Response in Islet Transplantation

    PubMed Central

    Kanak, Mazhar A.; Kunnathodi, Faisal; Lawrence, Michael C.; Levy, Marlon F.

    2014-01-01

    Islet cell transplantation is a promising beta cell replacement therapy for patients with brittle type 1 diabetes as well as refractory chronic pancreatitis. Despite the vast advancements made in this field, challenges still remain in achieving high frequency and long-term successful transplant outcomes. Here we review recent advances in understanding the role of inflammation in islet transplantation and development of strategies to prevent damage to islets from inflammation. The inflammatory response associated with islets has been recognized as the primary cause of early damage to islets and graft loss after transplantation. Details on cell signaling pathways in islets triggered by cytokines and harmful inflammatory events during pancreas procurement, pancreas preservation, islet isolation, and islet infusion are presented. Robust control of pre- and peritransplant islet inflammation could improve posttransplant islet survival and in turn enhance the benefits of islet cell transplantation for patients who are insulin dependent. We discuss several potent anti-inflammatory strategies that show promise for improving islet engraftment. Further understanding of molecular mechanisms involved in the inflammatory response will provide the basis for developing potent therapeutic strategies for enhancing the quality and success of islet transplantation. PMID:24883060

  2. Compensatory Islet Response to Insulin Resistance Revealed by Quantitative Proteomics

    PubMed Central

    Gedeon, Nicholas; Kahraman, Sevim; De Jesus, Dario F.; Bhatt, Shweta; Kim, Jong-Seo; Clauss, Therese RW; Camp, David G.; Smith, Richard D.; Qian, Wei-Jun; Kulkarni, Rohit N.

    2015-01-01

    Compensatory islet response is a distinct feature of the pre-diabetic insulin resistant state in humans and rodents. To identify alterations in the islet proteome that characterize the adaptive response, we analyzed islets from five-month-old male control, high-fat diet fed (HFD) or obese ob/ob mice by LC-MS(/MS) and quantified ~1,100 islet proteins (at least two peptides) with a false discovery rate <1%. Significant alterations in abundance were observed for ~350 proteins between groups. A majority of alterations were common to both models, and the changes of a subset of ~40 proteins and 12 proteins were verified by targeted quantification using selected reaction monitoring and Western blots, respectively. The insulin resistant islets in both groups exhibited reduced expression of proteins controlling energy metabolism, oxidative phosphorylation, hormone processing, and secretory pathways. Conversely, an increased expression of molecules involved in protein synthesis and folding suggested effects in endoplasmic reticulum stress response, cell survival, and proliferation in both insulin resistant models. In summary, we report a unique comparison of the islet proteome that is focused on the compensatory response in two insulin resistant rodent models that are not overtly diabetic. These data provide a valuable resource of candidate proteins to the scientific community to undertake further studies aimed at enhancing β-cell mass in patients with diabetes. The data are available via the MassIVE repository, with accession MSV000079093. PMID:26151086

  3. Compensatory islet response to insulin resistance revealed by quantitative proteomics

    SciTech Connect

    El Ouaamari, Abdelfattah; Zhou, Jian -Ying; Liew, Chong Wee; Shirakawa, Jun; Dirice, Ercument; Gedeon, Nicholas; Kahraman, Sevim; De Jesus, Dario F.; Bhatt, Shweta; Kim, Jong -Seo; Clauss, Therese R. W.; Camp, II, David G.; Smith, Richard D.; Qian, Wei -Jun; Kulkarni, Rohit N.

    2015-07-07

    Compensatory islet response is a distinct feature of the pre-diabetic insulin resistant state in humans and rodents. To identify alterations in the islet proteome that characterize the adaptive response, we analyzed islets from five-month-old male control, high-fat diet fed (HFD) or obese ob/ob mice by LC-MS(/MS) and quantified ~1,100 islet proteins (at least two peptides) with a false discovery rate <1%. Significant alterations in abundance were observed for ~350 proteins between groups. A majority of alterations were common to both models, and the changes of a subset of ~40 proteins and 12 proteins were verified by targeted quantification using selected reaction monitoring and Western blots, respectively. The insulin resistant islets in both groups exhibited reduced expression of proteins controlling energy metabolism, oxidative phosphorylation, hormone processing, and secretory pathways. Conversely, an increased expression of molecules involved in protein synthesis and folding suggested effects in endoplasmic reticulum stress response, cell survival, and proliferation in both insulin resistant models. In conclusion, we report a unique comparison of the islet proteome that is focused on the compensatory response in two insulin resistant rodent models that are not overtly diabetic. In conclusion, these data provide a valuable resource of candidate proteins to the scientific community to undertake further studies aimed at enhancing β-cell mass in patients with diabetes. The data are available via the MassIVE repository, with accession MSV000079093.

  4. Compensatory islet response to insulin resistance revealed by quantitative proteomics

    DOE PAGES

    El Ouaamari, Abdelfattah; Zhou, Jian -Ying; Liew, Chong Wee; ...

    2015-07-07

    Compensatory islet response is a distinct feature of the pre-diabetic insulin resistant state in humans and rodents. To identify alterations in the islet proteome that characterize the adaptive response, we analyzed islets from five-month-old male control, high-fat diet fed (HFD) or obese ob/ob mice by LC-MS(/MS) and quantified ~1,100 islet proteins (at least two peptides) with a false discovery rate <1%. Significant alterations in abundance were observed for ~350 proteins between groups. A majority of alterations were common to both models, and the changes of a subset of ~40 proteins and 12 proteins were verified by targeted quantification using selectedmore » reaction monitoring and Western blots, respectively. The insulin resistant islets in both groups exhibited reduced expression of proteins controlling energy metabolism, oxidative phosphorylation, hormone processing, and secretory pathways. Conversely, an increased expression of molecules involved in protein synthesis and folding suggested effects in endoplasmic reticulum stress response, cell survival, and proliferation in both insulin resistant models. In conclusion, we report a unique comparison of the islet proteome that is focused on the compensatory response in two insulin resistant rodent models that are not overtly diabetic. In conclusion, these data provide a valuable resource of candidate proteins to the scientific community to undertake further studies aimed at enhancing β-cell mass in patients with diabetes. The data are available via the MassIVE repository, with accession MSV000079093.« less

  5. Enhanced insulin sensitivity mediated by adipose tissue browning perturbs islet morphology and hormone secretion in response to autonomic nervous activation in female mice.

    PubMed

    Omar, Bilal A; Kvist-Reimer, Martina; Enerbäck, Sven; Ahrén, Bo

    2016-01-01

    Insulin resistance results in a compensatory increase in insulin secretion to maintain normoglycemia. Conversely, high insulin sensitivity results in reduced insulin secretion to prevent hypoglycemia. The mechanisms for this inverse adaptation are not well understood. We utilized highly insulin-sensitive mice, due to adipocyte-specific overexpression of the FOXC2 transcription factor, to study mechanisms of the reversed islet adaptation to increased insulin sensitivity. We found that Foxc2TG mice responded to mild hyperglycemia with insulin secretion significantly lower than that of wild-type mice; however, when severe hyperglycemia was induced, Foxc2TG mice demonstrated insulin secretion equal to or greater than that of wild-type mice. In response to autonomic nervous activation by 2-deoxyglucose, the acute suppression of insulin seen in wild-type mice was absent in Foxc2TG mice, suggesting impaired sympathetic signaling to the islet. Basal glucagon was increased in Foxc2TG mice, but they displayed severely impaired glucagon responses to cholinergic and autonomic nervous stimuli. These data suggest that the autonomic nerves contribute to the islet adaptation to high insulin sensitivity, which is compatible with a neuro-adipo regulation of islet function being instrumental for maintaining glucose regulation.

  6. Improvement of islet function in a bioartificial pancreas by enhanced oxygen supply and growth hormone releasing hormone agonist

    PubMed Central

    Ludwig, Barbara; Rotem, Avi; Schmid, Janine; Weir, Gordon C.; Colton, Clark K.; Brendel, Mathias D.; Neufeld, Tova; Block, Norman L.; Yavriyants, Karina; Steffen, Anja; Ludwig, Stefan; Chavakis, Triantafyllos; Reichel, Andreas; Azarov, Dimitri; Zimermann, Baruch; Maimon, Shiri; Balyura, Mariya; Rozenshtein, Tania; Shabtay, Noa; Vardi, Pnina; Bloch, Konstantin; de Vos, Paul; Schally, Andrew V.; Bornstein, Stefan R.; Barkai, Uriel

    2012-01-01

    Islet transplantation is a feasible therapeutic alternative for metabolically labile patients with type 1 diabetes. The primary therapeutic target is stable glycemic control and prevention of complications associated with diabetes by reconstitution of endogenous insulin secretion. However, critical shortage of donor organs, gradual loss in graft function over time, and chronic need for immunosuppression limit the indication for islet transplantation to a small group of patients. Here we present a promising approach to address these limitations by utilization of a macrochamber specially engineered for islet transplantation. The s.c. implantable device allows for controlled and adequate oxygen supply and provides immunological protection of donor islets against the host immune system. The minimally invasive implantable chamber normalized blood glucose in streptozotocin-induced diabetic rodents for up to 3 mo. Sufficient graft function depended on oxygen supply. Pretreatment with the growth hormone-releasing hormone (GHRH) agonist, JI-36, significantly enhanced graft function by improving glucose tolerance and increasing β-cell insulin reserve in rats thereby allowing for a reduction of the islet mass required for metabolic control. As a result of hypervascularization of the tissue surrounding the device, no relevant delay in insulin response to glucose changes has been observed. Consequently, this system opens up a fundamental strategy for therapy of diabetes and may provide a promising avenue for future approaches to xenotransplantation. PMID:22393012

  7. Effect of copper deficiency on the content and secretion of pancreatic islet hormones

    SciTech Connect

    Bhathena, S.J.; Voyles, N.R.; Timmers, K.I.; Fields, M.; Kennedy, B.W.; Recant, L.

    1986-03-01

    Experimental copper (Cu) deficiency in rats is characterized by glucose intolerance and hyperlipemia. Its severity is increased by dietary fructose (F) as compared to starch (S). Since islet hormones are intimately involved in carbohydrate metabolism the authors studied the effects of Cu deficiency on their content and secretion. Rats were fed Cu deficient (CuD) (0.6 ..mu..g Cu/g) or Cu supplemented (6.0 ..mu..g Cu/g) diets with either 62% F or S for 7 weeks after weaning. Feeding CuD diets decreased plasma insulin (I) (P < 0.001) but not plasma glucagon (G). F feeding compared to S magnified the effects of Cu deficiency. Total pancreatic content of I in CuD rats was increased threefold (P < 0.001). Total somatostatin content increased significantly only in the pancreas of CuD rats fed F. Although total G content was not altered in CuD rats, when G was expressed per g protein or g wet weight, significant increases were found in CuD rats fed F. Thus, of the islet hormones, the major effect of Cu deficiency was on I. When pancreata were perfused in vitro with high glucose, pancreas from CuD rats had reduced insulin response. Thus, cellular functions dependent on Cu are involved in maintaining the ability of the islets of Langerhans to secrete I in a normal fashion.

  8. Morphological assessment of pancreatic islet hormone content following aerobic exercise training in rats with poorly controlled Type 1 diabetes mellitus.

    PubMed

    McDonald, Matthew W; Murray, Michael R; Hall, Katharine E; Noble, Earl G; Melling, C W James

    2014-01-01

    Regular exercise has been shown to improve many complications of Type 1 diabetes mellitus (T1DM) including enhanced glucose tolerance and increased cardiac function. While exercise training has been shown to increase insulin content in pancreatic islets of rats with T1DM, experimental models were severely hyperglycemic and not undergoing insulin treatment. Further, research to date has yet to determine how exercise training alters glucagon content in pancreatic islets. The purpose of the present investigation was to determine the impact of a 10-week aerobic training program on pancreatic islet composition in insulin-treated rats with T1DM. Second, it was determined whether the acute, exercise-mediated reduction in blood glucose experienced in rats with T1DM would become larger in magnitude following aerobic exercise training. Diabetes was induced in male Sprague-Dawley rats by multiple low dose injections of streptozotocin (20mg/kg i.p.) and moderate intensity aerobic exercise training was performed on a motorized treadmill for one hour per day for a total of 10 weeks. Rats with T1DM demonstrated significantly less islet insulin, and significantly more islet glucagon hormone content compared with non-T1DM rats, which did not significantly change following aerobic training. The reduction in blood glucose in response to a single exercise bout was similar across 10 weeks of training. Results also support the view that different subpopulations of islets exist, as small islets (<50 μm diameter) had significantly more insulin and glucagon in rats with and without T1DM.

  9. Different responses of mouse islets and MIN6 pseudo-islets to metabolic stimulation: a note of caution.

    PubMed

    Schulze, Torben; Morsi, Mai; Brüning, Dennis; Schumacher, Kirstin; Rustenbeck, Ingo

    2016-03-01

    MIN6 cells and MIN6 pseudo-islets are popular surrogates for the use of primary beta cells and islets. Even though it is generally agreed that the stimulus-secretion coupling may deviate from that of beta cells or islets, direct comparisons are rare. The present side-by-side comparison of insulin secretion, cytosolic Ca(2+) concentration ([Ca(2+)] i ) and oxygen consumption rate (OCR) points out where similarities and differences exist between MIN6 cells and normal mouse beta cells. In mouse islets and MIN6 pseudo-islets depolarization by 40 mM KCl was a more robust insulinotropic stimulus than 30 mM glucose. In MIN6 pseudo-islets, but not in mouse islets, the response to 30 mM glucose was much lower than to 40 mM KCl and could be suppressed by a preceding stimulation with 40 mM KCl. In MIN6 pseudo-islets, glucose was less effective to raise [Ca(2+)] i than in primary islets. In marked contrast to islets, the OCR response of MIN6 pseudo-islets to 30 mM glucose was smaller than to 40 mM KCl and was further diminished by a preceding stimulation with 40 mM KCl. The same pattern was observed when MIN6 pseudo-islets were cultured in 5 mM glucose. As with insulin secretion memory effects on the OCR remained after wash-out of a stimulus. The differences between MIN6 cells and primary beta cells were generally larger in the responses to glucose than to depolarization by KCl. Thus, the use of MIN6 cells in investigations on metabolic signalling requires particular caution.

  10. Peptidergic hormones and neuropeptides, and aminergic neurotransmitters of the pancreatic islets of the Houbara bustard (Chlamydotis undulata).

    PubMed

    Mensah-Brown, E P; Bailey, T A; Pallot, D J; Garner, A

    2000-02-01

    Immunoreactivity to insulin (Ins), somatostatin (Som), glucagon (Glu) and pancreatic polypeptide (PP) was found in 70%, 22%, 15% and 11% respectively of Houbara pancreatic endocrine islet cells. Whilst Ins occurred centrally and SOM was observed both in peripherally and centrally located islets, the other hormones were localised in peripheral islet cells; Som was also observed in neuronal cell bodies and nerve fibres. In addition, the islet cells contained substance P (SP) (65%) in the centre and vasoactive intestinal polypeptide (VIP) (2%) at the periphery. Immunoreactivity to choline acetyltransferase (ChAT), VIP and galanin (Gal) occurred in the walls of blood vessels located mainly at the periphery of islets. Occasionally, VIP and Gal immunoreactive varicose nerve terminals and ChAT immunoreactive cell bodies were also observed in the centre of islets. SP neuronal cell bodies were not observed but prominent SP immunoreactive varicose terminals were discernible in capillary walls within the islets. Neuropeptide Y (NPY) immunoreactive neurons were detected in neuronal cell bodies located mainly peripherally. Neuronal nitric oxide synthase (nNOS) immunoreactivity occurred in neuronal cell bodies and nerve fibres mainly at the periphery and also in centrally located islet endocrine cells. Immunoreactivity to tyrosine hydroxylase (TH) was similar in distribution to that of ChAT. In comparison with other avian species, the islets of the dorsal pancreatic lobe of the bustard contain all the peptidergic hormones normally present in the islets of other avian species, but are not segregated into dark A and light B cells. Many of the insulin containing cells also contained SP. The islets also contained several neuropeptides which are probably involved in their regulation.

  11. The role of rosiglitazone treatment in the modulation of islet hormones and hormone-like peptides: a combined in situ hybridization and immunohistochemical study.

    PubMed

    Yildirim, Sukriye; Bolkent, Sema; Sundler, Frank

    2008-12-01

    Rosiglitazone, peroxisome proliferator-activated receptor-gamma agonist, is an insulin sensitizing agent in peripheral tissues. This study investigated islet hormones and hormone-like peptides expression patterns in rosiglitazone treated streptozotocin (STZ)-diabetic rats by using immunohistochemistry and in situ hybridization methods. Animals were divided into four groups. I. Group: Intact control rats. II. Group: Rosiglitazone-treated controls. III. Group: STZ-diabetic rats. IV. Group: Rosiglitazone-treated diabetic animals. Rosiglitazone was given for 7 days at a dose of 20 mg/kg body weight. In the STZ-diabetic group, there were significant differences in islet hormones and hormone like peptides cell numbers compared to rosiglitazone control group and intact control group. There were significant differences in cocaine- and amphetamine-regulated transcript (CART) and pancreatic polypeptide (PP) cell numbers between rosiglitazone control group and rosiglitazone + STZ-diabetic group. We detected a significant decrease in glucagon mRNA signals in rosiglitazone-treated control group compared to intact controls. We found a statistically significant difference in islet amyloid polypeptide (IAPP) mRNA signals between the STZ-diabetic group and the rosiglitazone + STZ-diabetic group. Besides, we also demonstrated co-localization of peptides by using double and triple histochemistry. In conclusion, our results show that short-term rosiglitazone treatment had a preservative effect to some extent on the expression of islet hormones and hormone-like peptides to maintain the islet function.

  12. Regulation of pancreatic islet beta-cell mass by growth factor and hormone signaling.

    PubMed

    Huang, Yao; Chang, Yongchang

    2014-01-01

    Dysfunction and destruction of pancreatic islet beta cells is a hallmark of diabetes. Better understanding of cellular signals in beta cells will allow development of therapeutic strategies for diabetes, such as preservation and expansion of beta-cell mass and improvement of beta-cell function. During the past several decades, the number of studies analyzing the molecular mechanisms, including growth factor/hormone signaling pathways that impact islet beta-cell mass and function, has increased exponentially. Notably, somatolactogenic hormones including growth hormone (GH), prolactin (PRL), and insulin-like growth factor-1 (IGF-1) and their receptors (GHR, PRLR, and IGF-1R) are critically involved in beta-cell growth, survival, differentiation, and insulin secretion. In this chapter, we focus more narrowly on GH, PRL, and IGF-1 signaling, and GH-IGF-1 cross talk. We also discuss how these signaling aspects contribute to the regulation of beta-cell proliferation and apoptosis. In particular, our novel findings of GH-induced formation of GHR-JAK2-IGF-1R protein complex and synergistic effects of GH and IGF-1 on beta-cell signaling, proliferation, and antiapoptosis lead to a new concept that IGF-1R may serve as a proximal component of GH/GHR signaling.

  13. Islet-like organoids derived from human pluripotent stem cells efficiently function in the glucose responsiveness in vitro and in vivo

    PubMed Central

    Kim, Youngjin; Kim, Hyeongseok; Ko, Ung Hyun; Oh, Youjin; Lim, Ajin; Sohn, Jong-Woo; Shin, Jennifer H.; Kim, Hail; Han, Yong-Mahn

    2016-01-01

    Insulin secretion is elaborately modulated in pancreatic ß cells within islets of three-dimensional (3D) structures. Using human pluripotent stem cells (hPSCs) to develop islet-like structures with insulin-producing ß cells for the treatment of diabetes is challenging. Here, we report that pancreatic islet-like clusters derived from hESCs are functionally capable of glucose-responsive insulin secretion as well as therapeutic effects. Pancreatic hormone-expressing endocrine cells (ECs) were differentiated from hESCs using a step-wise protocol. The hESC-derived ECs expressed pancreatic endocrine hormones, such as insulin, somatostatin, and pancreatic polypeptide. Notably, dissociated ECs autonomously aggregated to form islet-like, 3D structures of consistent sizes (100–150 μm in diameter). These EC clusters (ECCs) enhanced insulin secretion in response to glucose stimulus and potassium channel inhibition in vitro. Furthermore, ß cell-deficient mice transplanted with ECCs survived for more than 40 d while retaining a normal blood glucose level to some extent. The expression of pancreatic endocrine hormones was observed in tissues transplanted with ECCs. In addition, ECCs could be generated from human induced pluripotent stem cells. These results suggest that hPSC-derived, islet-like clusters may be alternative therapeutic cell sources for treating diabetes. PMID:27731367

  14. Neurotransmitters act as paracrine signals to regulate insulin secretion from the human pancreatic islet.

    PubMed

    Rodriguez-Diaz, Rayner; Menegaz, Danusa; Caicedo, Alejandro

    2014-08-15

    In this symposium review we discuss the role of neurotransmitters as paracrine signals that regulate pancreatic islet function. A large number of neurotransmitters and their receptors has been identified in the islet, but relatively little is known about their involvement in islet biology. Interestingly, neurotransmitters initially thought to be present in autonomic axons innervating the islet are also present in endocrine cells of the human islet. These neurotransmitters can thus be released as paracrine signals to help control hormone release. Here we propose that the role of neurotransmitters may extend beyond controlling endocrine cell function to work as signals modulating vascular flow and immune responses within the islet.

  15. Pancreatic α- and β-cellular clocks have distinct molecular properties and impact on islet hormone secretion and gene expression.

    PubMed

    Petrenko, Volodymyr; Saini, Camille; Giovannoni, Laurianne; Gobet, Cedric; Sage, Daniel; Unser, Michael; Heddad Masson, Mounia; Gu, Guoqiang; Bosco, Domenico; Gachon, Frédéric; Philippe, Jacques; Dibner, Charna

    2017-02-15

    A critical role of circadian oscillators in orchestrating insulin secretion and islet gene transcription has been demonstrated recently. However, these studies focused on whole islets and did not explore the interplay between α-cell and β-cell clocks. We performed a parallel analysis of the molecular properties of α-cell and β-cell oscillators using a mouse model expressing three reporter genes: one labeling α cells, one specific for β cells, and a third monitoring circadian gene expression. Thus, phase entrainment properties, gene expression, and functional outputs of the α-cell and β-cell clockworks could be assessed in vivo and in vitro at the population and single-cell level. These experiments showed that α-cellular and β-cellular clocks are oscillating with distinct phases in vivo and in vitro. Diurnal transcriptome analysis in separated α and β cells revealed that a high number of genes with key roles in islet physiology, including regulators of glucose sensing and hormone secretion, are differentially expressed in these cell types. Moreover, temporal insulin and glucagon secretion exhibited distinct oscillatory profiles both in vivo and in vitro. Altogether, our data indicate that differential entrainment characteristics of circadian α-cell and β-cell clocks are an important feature in the temporal coordination of endocrine function and gene expression.

  16. Peptidomic profiling of secreted products from pancreatic islet culture results in a higher yield of full-length peptide hormones than found using cell lysis procedures.

    PubMed

    Taylor, Steven W; Nikoulina, Svetlana E; Andon, Nancy L; Lowe, Carolyn

    2013-08-02

    Peptide Hormone Acquisition through Smart Sampling Technique-Mass Spectrometry (PHASST-MS) is a peptidomics platform that employs high resolution liquid chromatography-mass spectrometry (LC-MS) techniques to identify peptide hormones secreted from in vitro or ex vivo cultures enriched in endocrine cells. Application of the methodology to the study of murine pancreatic islets has permitted evaluation of the strengths and weaknesses of the approach, as well as comparison of our results with published islet studies that employed traditional cellular lysis procedures. We found that, while our PHASST-MS approach identified fewer peptides in total, we had greater representation of intact peptide hormones. The technique was further refined to improve coverage of hydrophilic as well as hydrophobic peptides and subsequently applied to human pancreatic islet cultures derived from normal donors or donors with type 2 diabetes. Interestingly, in addition to the expected islet hormones, we identified alpha-cell-derived bioactive GLP-1, consistent with recent reports of paracrine effects of this hormone on beta-cell function. We also identified many novel peptides derived from neurohormonal precursors and proteins related to the cell secretory system. Taken together, these results suggest the PHASST-MS strategy of focusing on cellular secreted products rather than the total tissue peptidome may improve the probability of discovering novel bioactive peptides and also has the potential to offer important new insights into the secretion and function of known hormones.

  17. Inhibition of instant blood-mediated inflammatory responses by co-immobilization of sCR1 and heparin on islets.

    PubMed

    Luan, Nguyen Minh; Iwata, Hiroo

    2013-07-01

    Intraportal transplantation of islets of Langerhans is followed by marked islet loss, mainly caused by instant blood-mediated inflammatory responses (IBMIR). We previously developed a method of co-immobilizing sCR1 and heparin on islets. Here we examined whether this process could reduce islet loss following intraportal islet transplantation in a syngeneic mouse model. sCR1-heparin islets or unmodified islet controls were transplanted into the livers of streptozotocin-induced diabetic mice. Transplantation of 100 and 125 sCR1-heparin islets normalized blood glucose levels in 8 of 9 (88.9%) and 9 of 9 diabetic mice (100%), respectively, whereas transplantation of 100 and 125 non-treated islets induced normoglycemia in 0 of 9 and 2 of 9 diabetic mice, respectively. Fibrin staining and plasma insulin measurements indicated that, compared to non-treated islets, sCR1-heparin islet transplantation was associated with fewer blood clots around islets, and significantly less insulin leakage from damaged islets at 1 h post-transplantation. Long-term follow-up of the sCR1-heparin islet group showed islet cells in the livers and insulin expression. In conclusion, co-immobilization of sCR1 and heparin on islets could effectively reduce islet damage by IBMIR, and might be useful to enable transplantation with only one donor and one recipient.

  18. Modelling hormonal response and development.

    PubMed

    Voß, Ute; Bishopp, Anthony; Farcot, Etienne; Bennett, Malcolm J

    2014-05-01

    As our knowledge of the complexity of hormone homeostasis, transport, perception, and response increases, and their outputs become less intuitive, modelling is set to become more important. Initial modelling efforts have focused on hormone transport and response pathways. However, we now need to move beyond the network scales and use multicellular and multiscale modelling approaches to predict emergent properties at different scales. Here we review some examples where such approaches have been successful, for example, auxin-cytokinin crosstalk regulating root vascular development or a study of lateral root emergence where an iterative cycle of modelling and experiments lead to the identification of an overlooked role for PIN3. Finally, we discuss some of the remaining biological and technical challenges.

  19. Glucose- and Hormone-Induced cAMP Oscillations in α- and β-Cells Within Intact Pancreatic Islets

    PubMed Central

    Tian, Geng; Sandler, Stellan; Gylfe, Erik; Tengholm, Anders

    2011-01-01

    OBJECTIVE cAMP is a critical messenger for insulin and glucagon secretion from pancreatic β- and α-cells, respectively. Dispersed β-cells show cAMP oscillations, but the signaling kinetics in cells within intact islets of Langerhans is unknown. RESEARCH DESIGN AND METHODS The subplasma-membrane cAMP concentration ([cAMP]pm) was recorded in α- and β-cells in the mantle of intact mouse pancreatic islets using total internal reflection microscopy and a fluorescent translocation biosensor. Cell identification was based on the opposite effects of adrenaline on cAMP in α- and β-cells. RESULTS In islets exposed to 3 mmol/L glucose, [cAMP]pm was low and stable. Glucagon and glucagon-like peptide-1(7-36)-amide (GLP-1) induced dose-dependent elevation of [cAMP]pm, often with oscillations synchronized among β-cells. Whereas glucagon also induced [cAMP]pm oscillations in most α-cells, <20% of the α-cells responded to GLP-1. Elevation of the glucose concentration to 11–30 mmol/L in the absence of hormones induced slow [cAMP]pm oscillations in both α- and β-cells. These cAMP oscillations were coordinated with those of the cytoplasmic Ca2+ concentration ([Ca2+]i) in the β-cells but not caused by the changes in [Ca2+]i. The transmembrane adenylyl cyclase (AC) inhibitor 2′5′-dideoxyadenosine suppressed the glucose- and hormone-induced [cAMP]pm elevations, whereas the preferential inhibitors of soluble AC, KH7, and 1,3,5(10)-estratrien-2,3,17-β-triol perturbed cell metabolism and lacked effect, respectively. CONCLUSIONS Oscillatory [cAMP]pm signaling in secretagogue-stimulated β-cells is maintained within intact islets and depends on transmembrane AC activity. The discovery of glucose- and glucagon-induced [cAMP]pm oscillations in α-cells indicates the involvement of cAMP in the regulation of pulsatile glucagon secretion. PMID:21444924

  20. Immune responses to an encapsulated allogeneic islet {beta}-cell line in diabetic NOD mice

    SciTech Connect

    Black, Sasha P. . E-mail: Sasha.Black@ca.crl.com; Constantinidis, Ioannis; Cui, Hong; Tucker-Burden, Carol; Weber, Collin J.; Safley, Susan A.

    2006-02-03

    Our goal is to develop effective islet grafts for treating type 1 diabetes. Since human islets are scarce, we evaluated the efficacy of a microencapsulated insulin-secreting conditionally transformed allogeneic {beta}-cell line ({beta}TC-tet) in non-obese diabetic mice treated with tetracycline to inhibit cell growth. Relatively low serum levels of tetracycline controlled proliferation of {beta}TC-tet cells without inhibiting effective control of hyperglycemia in recipients. There was no significant host cellular reaction to the allografts or host cell adherence to microcapsules, and host cytokine levels were similar to those of sham-operated controls. We conclude that encapsulated allogeneic {beta}-cell lines may be clinically relevant, because they effectively restore euglycemia and do not elicit a strong cellular immune response following transplantation. To our knowledge, this is First extensive characterization of the kinetics of host cellular and cytokine responses to an encapsulated islet cell line in an animal model of type 1 diabetes.

  1. Transcriptional Regulation of the Pancreatic Islet: Implications for Islet Function

    PubMed Central

    Stitzel, Michael L.; Kycia, Ina; Kursawe, Romy; Ucar, Duygu

    2015-01-01

    Islets of Langerhans contain multiple hormone-producing endocrine cells controlling glucose homeostasis. Transcription establishes and maintains islet cellular fates and identities. Genetic and environmental disruption of islet transcription triggers cellular dysfunction and disease. Early transcriptional regulation studies of specific islet genes, including insulin (INS) and the transcription factor PDX1, identified the first cis-regulatory DNA sequences and trans-acting factors governing islet function. Here, we review how human islet “omics” studies are reshaping our understanding of transcriptional regulation in islet (dys)function and diabetes. First, we highlight the expansion of islet transcript number, form, and function and of DNA transcriptional regulatory elements controlling their production. Next, we cover islet transcriptional effects of genetic and environmental perturbation. Finally, we discuss how these studies’ emerging insights should empower our diabetes research community to build mechanistic understanding of diabetes pathophysiology and to equip clinicians with tailored, precision medicine options to prevent and treat islet dysfunction and diabetes. PMID:26272056

  2. The effect of two different polyethylene glycol (PEG) derivatives on the immunological response of PEG grafted pancreatic islets.

    PubMed

    Aghajani-Lazarjani, Hamideh; Vasheghani-Farahani, Ebrahim; Shojaosadati, Seyed Abbas; Hashemi-Najafabadi, Sameereh; Zahediasl, Saleh; Tiraihi, Taki; Atyabi, Fatemeh

    2010-12-01

    Islet transplantation is one of the promising ways to treat diabetes. To reduce the immune system response, several methods have been developed, a novel one being the grafting of methoxy polyethylene glycol (mPEG) derivatives onto collagen capsules of islets. In this study, the effects of the first and second generations of activated mPEG on the immunological response of polyethylene glycol (PEG) grafted pancreatic islets were studied. mPEG-Succinimidyl carbonate (mPEG-SC) and mPEG-succinimidyl propionic acid (mPEG-SPA) (with nominal molecular weight 5 kDa), typical of the first and second generations of activated mPEG, were selected, respectively. Both activated mPEGs did not affect the morphology, viability, or functionality of PEGylated islets compared to free islets (naked islets). The amount of IL-2 secreted from lymphocytes co-cultured with mPEG-SPA grafted islets (131.83 ± 15.28 pg/ml) was not significantly different from that with mPEG-SC grafted islets (156.09 ± 27.94 pg/ml). These results indicated that both mPEG-SC and mPEG-SPA had the same effect for camouflaging Langerhans islets, but the former is more suitable due to its easier synthesis process.

  3. Hormone-sensitive lipase deficiency suppresses insulin secretion from pancreatic islets of Lep{sup ob/ob} mice

    SciTech Connect

    Sekiya, Motohiro; Yahagi, Naoya; Tamura, Yoshiaki; Okazaki, Hiroaki; Igarashi, Masaki; Ohta, Keisuke; Takanashi, Mikio; Kumagai, Masayoshi; Takase, Satoru; Nishi, Makiko; Takeuchi, Yoshinori; Izumida, Yoshihiko; Kubota, Midori; Ohashi, Ken; Iizuka, Yoko; Yagyu, Hiroaki; Gotoda, Takanari; Nagai, Ryozo; Shimano, Hitoshi; Yamada, Nobuhiro; and others

    2009-09-25

    It has long been a matter of debate whether the hormone-sensitive lipase (HSL)-mediated lipolysis in pancreatic {beta}-cells can affect insulin secretion through the alteration of lipotoxicity. We generated mice lacking both leptin and HSL (Lep{sup ob/ob}/HSL{sup -/-}) and explored the role of HSL in pancreatic {beta}-cells in the setting of obesity. Lep{sup ob/ob}/HSL{sup -/-} developed elevated blood glucose levels and reduced plasma insulin levels compared with Lep{sup ob/ob}/HSL{sup +/+} in a fed state, while the deficiency of HSL did not affect glucose homeostasis in Lep{sup +/+} background. The deficiency of HSL exacerbated the accumulation of triglycerides in Lep{sup ob/ob} islets, leading to reduced glucose-stimulated insulin secretion. The deficiency of HSL also diminished the islet mass in Lep{sup ob/ob} mice due to decreased cell proliferation. In conclusion, HSL affects insulin secretary capacity especially in the setting of obesity.

  4. Pancreatic islet cell tumor

    MedlinePlus

    ... functions. These include blood sugar level and the production of stomach acid. Tumors that arise from islet ... try and shrink the tumors. If the abnormal production of hormones is causing symptoms, you may receive ...

  5. Multiple effector pathways regulate the insulin secretory response to the imidazoline RX871024 in isolated rat pancreatic islets

    PubMed Central

    Mourtada, Mirna; Chan, Sue L F; Smith, Stephen A; Morgan, Noel G

    1999-01-01

    When isolated rat islets were cultured for 18 h prior to use, the putative imidazoline binding site ligand, RX871024 caused a dose-dependent increase in insulin secretion at both 6 mM and 20 mM glucose. By contrast, a second ligand, efaroxan, was ineffective at 20 mM glucose whereas it did stimulate insulin secretion in response to 6 mM glucose. Exposure of islets to RX871024 (50 μM) for 18 h, resulted in loss of responsiveness to this reagent upon subsequent re-exposure. However, islets that were unresponsive to RX871024 still responded normally to efaroxan. The imidazoline antagonist, KU14R, blocked the insulin secretory response to efaroxan, but failed to prevent the stimulatory response to RX871024. By contrast with its effects in cultured islets, RX871024 inhibited glucose-induced insulin release from freshly isolated islets. Efaroxan did not inhibit insulin secretion under any conditions studied. In freshly isolated islets, the effects of RX871024 on insulin secretion could be converted from inhibitory to stimulatory, by starvation of the animals. Inhibition of insulin secretion by RX871024 in freshly isolated islets was prevented by the cyclo-oxygenase inhibitors indomethacin or flurbiprofen. Consistent with this, RX871024 caused a marked increase in islet PGE2 formation. Efaroxan did not alter islet PGE2 levels. The results suggest that RX871024 exerts multiple effects in the pancreatic β-cell and that its effects on insulin secretion cannot be ascribed only to interaction with a putative imidazoline binding site. PMID:10455276

  6. Immune responses to an encapsulated allogeneic islet beta-cell line in diabetic NOD mice.

    PubMed

    Black, Sasha P; Constantinidis, Ioannis; Cui, Hong; Tucker-Burden, Carol; Weber, Collin J; Safley, Susan A

    2006-02-03

    Our goal is to develop effective islet grafts for treating type 1 diabetes. Since human islets are scarce, we evaluated the efficacy of a microencapsulated insulin-secreting conditionally transformed allogeneic beta-cell line (betaTC-tet) in non-obese diabetic mice treated with tetracycline to inhibit cell growth. Relatively low serum levels of tetracycline controlled proliferation of betaTC-tet cells without inhibiting effective control of hyperglycemia in recipients. There was no significant host cellular reaction to the allografts or host cell adherence to microcapsules, and host cytokine levels were similar to those of sham-operated controls. We conclude that encapsulated allogeneic beta-cell lines may be clinically relevant, because they effectively restore euglycemia and do not elicit a strong cellular immune response following transplantation. To our knowledge, this is the first extensive characterization of the kinetics of host cellular and cytokine responses to an encapsulated islet cell line in an animal model of type 1 diabetes.

  7. Glucagon-like peptide-1 and cholecystokinin production and signaling in the pancreatic islet as an adaptive response to obesity.

    PubMed

    Linnemann, Amelia K; Davis, Dawn Belt

    2016-04-01

    Precise control of blood glucose is dependent on adequate β-cell mass and function. Thus, reductions in β-cell mass and function lead to insufficient insulin production to meet demand, and result in diabetes. Recent evidence suggests that paracrine signaling in the islet might be important in obesity, and disruption of this signaling could play a role in the pathogenesis of diabetes. For example, we recently discovered a novel islet incretin axis where glucagon-like peptide-1 regulates β-cell production of another classic gut hormone, cholecystokinin. This axis is stimulated by obesity, and plays a role in enhancing β-cell survival. In the present review, we place our observations in the wider context of the literature on incretin regulation in the islet, and discuss the potential for therapeutic targeting of these pathways.

  8. Hormonal component of tumor photodynamic therapy response

    NASA Astrophysics Data System (ADS)

    Korbelik, Mladen; Merchant, Soroush

    2008-02-01

    The involvement of adrenal glucocorticoid hormones in the response of the treatment of solid tumors by photodynamic therapy (PDT) comes from the induction of acute phase response by this modality. This adrenal gland activity is orchestrated through the engagement of the hypothalamic-pituitary-adrenal hormonal axis incited by stress signals emanating from the PDT-treated tumor. Glucocorticoid hormone activity engendered within the context of PDT-induced acute phase response performs multiple important functions; among other involvements they beget acute phase reactant production, systemic neutrophil mobilization, and control the production of inflammation-modulating and immunoregulatory proteins.

  9. Reduced early and late phase insulin response to glucose in isolated spiny mouse (Acomys cahirinus) islets: a defective link between glycolysis and adenylate cyclase.

    PubMed

    Nesher, R; Abramovitch, E; Cerasi, E

    1989-09-01

    The spiny mouse (Acomys cahirinus) exhibits low insulin responsiveness to glucose with a nearly absent early phase release. The alternative fuel-secretagogue glyceraldehyde (10 mmol/l) produced a maximal early insulin response in rat islets but failed to affect early response in Acomys; however, it potentiated the late insulin response in both species alike. Glucagon (1.5 mumol/l) potentiated the early insulin response to intermediate (8.3 mmol/l) glucose in rat and Acomys islets by two- and four-fold, respectively. Glucose doubled cyclic AMP levels in rat islets but no significant response was noted in Acomys islets. Isobutylmethylxanthine (0.1 mmol/l) and forskolin (25 mumol/l) caused a significant rise in islet cyclic AMP levels in both types of islets; however, neither agent restored the glucose stimulation of cyclic AMP in spiny mouse islets. Forskolin and isobutylmethylxanthine potentiated early and late phase insulin release in both species; however, neither augmented the early response in the Acomys to the degree observed in rat islets. Thus: (1) A deficient link exists in Acomys between glycolysis and subsequent signals. (2) These islets contain a glucose-insensitive adenylate cyclase. (3) The early insulin response may be potentiated by direct activation of adenylate cyclase. (4) The glucose effects on early and late phase insulin release are probably mediated by distinct pathways. (5) In the spiny mouse the signals mediating the early response are deranged to a greater extent than those activating the late phase insulin release.

  10. Islet and stem cell encapsulation for clinical transplantation.

    PubMed

    Krishnan, Rahul; Alexander, Michael; Robles, Lourdes; Foster, Clarence E; Lakey, Jonathan R T

    2014-01-01

    Over the last decade, improvements in islet isolation techniques have made islet transplantation an option for a certain subset of patients with long-standing diabetes. Although islet transplants have shown improved graft function, adequate function beyond the second year has not yet been demonstrated, and patients still require immunosuppression to prevent rejection. Since allogeneic islet transplants have experienced some success, the next step is to improve graft function while eliminating the need for systemic immunosuppressive therapy. Biomaterial encapsulation offers a strategy to avoid the need for toxic immunosuppression while increasing the chances of graft function and survival. Encapsulation entails coating cells or tissue in a semipermeable biocompatible material that allows for the passage of nutrients, oxygen, and hormones while blocking immune cells and regulatory substances from recognizing and destroying the cell, thus avoiding the need for systemic immunosuppressive therapy. Despite advances in encapsulation technology, these developments have not yet been meaningfully translated into clinical islet transplantation, for which several factors are to blame, including graft hypoxia, host inflammatory response, fibrosis, improper choice of biomaterial type, lack of standard guidelines, and post-transplantation device failure. Several new approaches, such as the use of porcine islets, stem cells, development of prevascularized implants, islet nanocoating, and multilayer encapsulation, continue to generate intense scientific interest in this rapidly expanding field. This review provides a comprehensive update on islet and stem cell encapsulation as a treatment modality in type 1 diabetes, including a historical outlook as well as current and future research avenues.

  11. Islet and Stem Cell Encapsulation for Clinical Transplantation

    PubMed Central

    Krishnan, Rahul; Alexander, Michael; Robles, Lourdes; Foster 3rd, Clarence E.; Lakey, Jonathan R.T.

    2014-01-01

    Over the last decade, improvements in islet isolation techniques have made islet transplantation an option for a certain subset of patients with long-standing diabetes. Although islet transplants have shown improved graft function, adequate function beyond the second year has not yet been demonstrated, and patients still require immunosuppression to prevent rejection. Since allogeneic islet transplants have experienced some success, the next step is to improve graft function while eliminating the need for systemic immunosuppressive therapy. Biomaterial encapsulation offers a strategy to avoid the need for toxic immunosuppression while increasing the chances of graft function and survival. Encapsulation entails coating cells or tissue in a semipermeable biocompatible material that allows for the passage of nutrients, oxygen, and hormones while blocking immune cells and regulatory substances from recognizing and destroying the cell, thus avoiding the need for systemic immunosuppressive therapy. Despite advances in encapsulation technology, these developments have not yet been meaningfully translated into clinical islet transplantation, for which several factors are to blame, including graft hypoxia, host inflammatory response, fibrosis, improper choice of biomaterial type, lack of standard guidelines, and post-transplantation device failure. Several new approaches, such as the use of porcine islets, stem cells, development of prevascularized implants, islet nanocoating, and multilayer encapsulation, continue to generate intense scientific interest in this rapidly expanding field. This review provides a comprehensive update on islet and stem cell encapsulation as a treatment modality in type 1 diabetes, including a historical outlook as well as current and future research avenues. PMID:25148368

  12. Anti-Donor HLA Antibody Response After Pancreatic Islet Grafting: Characteristics, Risk Factors, and Impact on Graft Function.

    PubMed

    Pouliquen, E; Baltzinger, P; Lemle, A; Chen, C-C; Parissiadis, A; Borot, S; Frimat, L; Girerd, S; Berney, T; Lablanche, S; Benhamou, P Y; Morelon, E; Badet, L; Dubois, V; Kessler, L; Thaunat, O

    2017-02-01

    Pancreatic islet grafting restores endogenous insulin production in type 1 diabetic patients, but long-term outcomes remain disappointing as a result of immunological destruction of allogeneic islets. In solid organ transplantation, donor-specific anti-HLA antibodies (DSA) are the first cause of organ failure. This retrospective multicentric study aimed at providing in-depth characterization of DSA response after pancreatic islet grafting, identifying the risk factor for DSA generation and determining the impact of DSA on graft function. Forty-two pancreatic islet graft recipients from the Groupe Rhin-Rhône-Alpes-Genève pour la Greffe d'Ilots de Langerhans consortium were enrolled. Pre- and postgrafting sera were screened for the presence of DSA and their ability to activate complement. Prevalence of DSA was 25% at 3 years postgrafting. The risk of sensitization increased steeply after immunosuppressive drug withdrawal. DSA repertoire diversity correlated with the number of HLA and eplet mismatches. DSA titer was significantly lower from that observed in solid organ transplantation. No detected DSA bound the complement fraction C3d. Finally, in contrast with solid organ transplantation, DSA did not seem to negatively affect pancreatic islet graft survival. This might be due to the low DSA titers, specific features of IgG limiting their ability to activate the complement and/or the lack of allogenic endothelial targets in pancreatic islet grafts.

  13. Thyroid hormone and dehydroepiandrosterone permit gluconeogenic hormone responses in hepatocytes.

    PubMed

    Kneer, N; Lardy, H

    2000-03-01

    The importance of the sn-glycerol- 3-phosphate (G-3-P) electron transfer shuttle in hormonal regulation of gluconeogenesis was examined in hepatocytes from rats with decreased mitochondrial G-3-P dehydrogenase activity (thyroidectomized) or increased G-3-P dehydrogenase activity [triiodothyronine (T(3)) or dehydroepiandrosterone (DHEA) treated]. Rates of glucose formation from 10 mM lactate, 10 mM pyruvate, or 2.5 mM dihydroxyacetone were somewhat less in hypothyroid cells than in cells from normal rats but gluconeogenic responses to calcium addition and to norepinephrine (NE), glucagon (G), or vasopressin (VP) were similar to the responses observed in cells from normal rats. However, with 2. 5 mM glycerol or 2.5 mM sorbitol, substrates that must be oxidized in the cytosol before conversion to glucose, basal gluconeogenesis was not appreciably altered by hypothyroidism but responses to calcium and to the calcium-mobilizing hormones were abolished. Injecting thyroidectomized rats with T(3) 2 days before preparing the hepatocytes greatly enhanced gluconeogenesis from glyc erol and restored the response to Ca(2+) and gluconeogenic hormones. Feeding dehydroepiandrosterone for 6 days depressed gluconeogenesis from lactate or pyruvate but substantially increased glucose production from glycerol in euthyroid cells and restored responses to Ca(2+) in hypothyroid cells metabolizing glycerol. Euthyroid cells metabolizing glycerol or sorbitol use the G-3-P and malate/aspartate shuttles to oxidize excess NADH generated in the cytosol. The transaminase inhibitor aminooxyacetate (AOA) decreased gluconeogenesis from glycerol 40%, but had little effect on responses to Ca(2+) and NE. However, in hypothyroid cells, with minimal G-3-P dehydrogenase, AOA decreased gluconeogenesis from glycerol more than 90%. Thus, the basal rate of gluconeogenesis from glycerol in the euthyroid cells is only partly dependent on electron transport from cytosol to mitochondria via the malate

  14. Meal feeding improves oral glucose tolerance in male rats and causes adaptations in postprandial islet hormone secretion that are independent of plasma incretins or glycemia

    PubMed Central

    P., Torsten; Aulinger, Benedikt A.; Smith, Eric P.; Drazen, Deborah L.; Ulrich-Lai, Yve; Seeley, Randy J.; Woods, Stephen C.

    2014-01-01

    Meal-fed (MF) rats with access to food for only 4 consecutive hours during the light cycle learn to eat large meals to maintain energy balance. MF animals develop behavioral and endocrine changes that permit glucose tolerance despite increased meal size. We hypothesized that enhanced activity of the enteroinsular axis mediates glucose homeostasis during MF. Cohorts of rats were allocated to MF or ad libitum (AL) regimens for 2–4 wk. Insulin secretion and glucose tolerance were determined after oral carbohydrate and intraperitoneal (ip) and intravenous (iv) glucose. MF rats ate less than AL in the first week but maintained a comparable weight trajectory thereafter. MF rats had decreased glucose excursions after a liquid mixed meal (AUC: MF 75 ± 7, AL 461 ± 28 mmol·l−1·min, P < 0.001), with left-shifted insulin secretion (AUC0–15: MF 31.0 ± 4.9, AL 9.6 ± 4.4 pM·min, P < 0.02), which peaked before a significant rise in blood glucose. Both groups had comparable fasting glucagon levels, but postprandial responses were lower with MF. However, neither intestinal expression of proGIP and proglucagon mRNA nor plasma incretin levels differed between MF and AL groups. There were no differences in the insulin response to ip or iv glucose between MF and AL rats. These findings demonstrate that MF improves oral glucose tolerance and is associated with significant changes in postprandial islet hormone secretion. Because MF enhanced β-cell function during oral but not parenteral carbohydrate administration, and was not accounted for by changes in circulating incretins, these results support a neural mechanism of adaptive insulin secretion. PMID:25159330

  15. Hormonal and biochemical responses to transcendental meditation.

    PubMed Central

    Cooper, R.; Joffe, B. I.; Lamprey, J. M.; Botha, A.; Shires, R.; Baker, S. G.; Seftel, H. C.

    1985-01-01

    This study was designed to assess whether transcendental meditation (TM) could influence various endocrine responses in 10 experienced male meditators. Nine matched subjects, uninformed of the TM procedure, acted as controls. Meditators successfully practised their technique for 40 min in the morning while controls relaxed for this period. No significant differences emerged between these 2 groups with respect to carbohydrate metabolism (plasma glucose, insulin and pancreatic glucagon concentrations), pituitary hormones (growth hormone and prolactin) or the 'stress' hormones, cortisol and total catecholamines-although meditators tended to have higher mean catecholamine levels. Plasma free fatty acids were significantly elevated in meditators 40 min after completing the period of TM. No clear evidence was thus obtained that any of the stress, or stress-related, hormones were suppressed during or after meditation in the particular setting examined. PMID:3895206

  16. Unraveling pancreatic islet biology by quantitative proteomics

    SciTech Connect

    Zhou, Jianying; Dann, Geoffrey P.; Liew, Chong W.; Smith, Richard D.; Kulkarni, Rohit N.; Qian, Weijun

    2011-08-01

    The pancreatic islets of Langerhans play a critical role in maintaining blood glucose homeostasis by secreting insulin and several other important peptide hormones. Impaired insulin secretion due to islet dysfunction is linked to the pathogenesis underlying both Type 1 and Type 2 diabetes. Over the past 5 years, emerging proteomic technologies have been applied to dissect the signaling pathways that regulate islet functions and gain an understanding of the mechanisms of islet dysfunction relevant to diabetes. Herein, we briefly review some of the recent quantitative proteomic studies involving pancreatic islets geared towards gaining a better understanding of islet biology relevant to metabolic diseases.

  17. Islet-Specific T-Cell Responses and Proinflammatory Monocytes Define Subtypes of Autoantibody-Negative Ketosis-Prone Diabetes

    PubMed Central

    Brooks-Worrell, Barbara M.; Iyer, Dinakar; Coraza, Ivonne; Hampe, Christiane S.; Nalini, Ramaswami; Ozer, Kerem; Narla, Radhika; Palmer, Jerry P.; Balasubramanyam, Ashok

    2013-01-01

    OBJECTIVE Ketosis-prone diabetes (KPD) is characterized by diabetic ketoacidosis (DKA) in patients lacking typical features of type 1 diabetes. A validated classification scheme for KPD includes two autoantibody-negative (“A−”) phenotypic forms: “A−β−” (lean, early onset, lacking β-cell functional reserve) and “A−β+” (obese, late onset, with substantial β-cell functional reserve after the index episode of DKA). Recent longitudinal analysis of a large KPD cohort revealed that the A−β+ phenotype includes two distinct subtypes distinguished by the index DKA episode having a defined precipitant (“provoked,” with progressive β-cell function loss over time) or no precipitant (“unprovoked,” with sustained β-cell functional reserve). These three A− KPD subtypes are characterized by absence of humoral islet autoimmune markers, but a role for cellular islet autoimmunity is unknown. RESEARCH DESIGN AND METHODS Islet-specific T-cell responses and the percentage of proinflammatory (CD14+CD16+) blood monocytes were measured in A−β− (n = 7), provoked A−β+ (n = 15), and unprovoked A−β+ (n = 13) KPD patients. Genotyping was performed for type 1 diabetes–associated HLA class II alleles. RESULTS Provoked A−β+ and A−β− KPD patients manifested stronger islet-specific T-cell responses (P < 0.03) and higher percentages of proinflammatory CD14+CD16+ monocytes (P < 0.01) than unprovoked A−β+ KPD patients. A significant relationship between type 1 diabetes HLA class II protective alleles and negative T-cell responses was observed. CONCLUSIONS Provoked A−β+ KPD and A−β− KPD are associated with a high frequency of cellular islet autoimmunity and proinflammatory monocyte populations. In contrast, unprovoked A−β+ KPD lacks both humoral and cellular islet autoimmunity. PMID:24130366

  18. Pancreatic islet blood flow and its measurement.

    PubMed

    Jansson, Leif; Barbu, Andreea; Bodin, Birgitta; Drott, Carl Johan; Espes, Daniel; Gao, Xiang; Grapensparr, Liza; Källskog, Örjan; Lau, Joey; Liljebäck, Hanna; Palm, Fredrik; Quach, My; Sandberg, Monica; Strömberg, Victoria; Ullsten, Sara; Carlsson, Per-Ola

    2016-05-01

    Pancreatic islets are richly vascularized, and islet blood vessels are uniquely adapted to maintain and support the internal milieu of the islets favoring normal endocrine function. Islet blood flow is normally very high compared with that to the exocrine pancreas and is autonomously regulated through complex interactions between the nervous system, metabolites from insulin secreting β-cells, endothelium-derived mediators, and hormones. The islet blood flow is normally coupled to the needs for insulin release and is usually disturbed during glucose intolerance and overt diabetes. The present review provides a brief background on islet vascular function and especially focuses on available techniques to measure islet blood perfusion. The gold standard for islet blood flow measurements in experimental animals is the microsphere technique, and its advantages and disadvantages will be discussed. In humans there are still no methods to measure islet blood flow selectively, but new developments in radiological techniques hold great hopes for the future.

  19. Pancreatic islet blood flow and its measurement

    PubMed Central

    Jansson, Leif; Barbu, Andreea; Bodin, Birgitta; Drott, Carl Johan; Espes, Daniel; Gao, Xiang; Grapensparr, Liza; Källskog, Örjan; Lau, Joey; Liljebäck, Hanna; Palm, Fredrik; Quach, My; Sandberg, Monica; Strömberg, Victoria; Ullsten, Sara; Carlsson, Per-Ola

    2016-01-01

    Pancreatic islets are richly vascularized, and islet blood vessels are uniquely adapted to maintain and support the internal milieu of the islets favoring normal endocrine function. Islet blood flow is normally very high compared with that to the exocrine pancreas and is autonomously regulated through complex interactions between the nervous system, metabolites from insulin secreting β-cells, endothelium-derived mediators, and hormones. The islet blood flow is normally coupled to the needs for insulin release and is usually disturbed during glucose intolerance and overt diabetes. The present review provides a brief background on islet vascular function and especially focuses on available techniques to measure islet blood perfusion. The gold standard for islet blood flow measurements in experimental animals is the microsphere technique, and its advantages and disadvantages will be discussed. In humans there are still no methods to measure islet blood flow selectively, but new developments in radiological techniques hold great hopes for the future. PMID:27124642

  20. Beta-endorphin and islet hormone release in type-2 diabetes mellitus the effects of normoglycemia, enkephalin, naloxone and somatostatin.

    PubMed

    Giugliano, D; Cozzolino, D; Salvatore, T; Ceriello, A; Giunta, R; Torella, R; D'Onofrio, F

    1987-01-01

    The present study was aimed at characterizing the effects of beta-endorphin on plasma glucose, insulin and glucagon plasma levels in subjects with type-2 diabetes mellitus. Infusion of 0.5 mg/h human beta-endorphin produced significant and simultaneous increments in both insulin and glucagon concentrations and decreased plasma glucose levels (-18 +/- 4 mg/dl, 60 min level, p less than 0.01). When the same diabetics were rendered euglycemic by an insulin infusion (1 mU/kg/min), beta-endorphin did not produce the expected decrease in plasma glucose concentrations nor raise plasma insulin levels; only the response of glucagon was preserved. Normal subjects were rendered hyperglycemic by an intravenous glucose infusion to match the plasma glucose levels of diabetic subjects. In this condition, beta-endorphin produced a significant increase of insulin concentrations, whereas glucagon remained suppressed. The intravenous administration of the long-acting met-enkephalin analogue DAMME (0.25 mg) blunted the hormonal responses to the subsequent beta-endorphin infusion in diabetic patients, although the inhibition was short-lived (30-40 min). Naloxone (5 mg), an opiate antagonist, did not produce any significant change in the insulin and glucagon responses to beta-endorphin, while somatostatin (0.25 mg/h) completely abolished the hormonal responses to the opioid.(ABSTRACT TRUNCATED AT 250 WORDS)

  1. Hyposmolar medium and ethanol in isosmotic solution induce the release of thyrotropin-releasing hormone (TRH) by isolated rat pancreatic islets.

    PubMed

    Benický, J; Greer, M A; Strbák, V

    1997-01-01

    Cell swelling induced by hypotonic medium or small isotonic permeant molecules results in an immediate secretory response in various types of cells. We have expanded exploration of this phenomenon by examining the effect of either isotonic ethanol or hyposmotic medium on the release of TRH by freshly isolated islets of Langerhans in static incubation and perifusion. Ethanol (40, 80 or 160 mM in isotonic solution) dose-dependently evoked the release of TRH by statically incubated islets. The dynamics of TRH release induced by 80 mM isotonic ethanol or 30% hypotonic medium were similar to those induced by 50 mM KCl, with the highest secretion rate during the first 5 min of incubation irrespective of the duration of stimulation. Ca2+ depletion of the incubation medium abolished the response to 50 mM KCl but did not diminish the response to 80 mM isotonic ethanol. We conclude that osmotic stimuli known to induce cell swelling also induce release of TRH by isolated pancreatic islets.

  2. Physical exercise introduced after weaning enhances pancreatic islet responsiveness to glucose and potentiating agents in adult MSG-obese rats.

    PubMed

    Ribeiro, R A; Bonfleur, M L; Vanzela, E C; Zotti, A I; Scomparin, D X; Boschero, A C; Balbo, S L

    2014-08-01

    Physical exercise represents an alternative way to prevent and/or ameliorate chronic metabolic diseases. Disruption of sympathetic nervous system (SNS) activity contributes to adiposity in obese subjects. Here, we verified the preventive effect of swimming training upon adiposity, adrenal catecholamine storage, and pancreatic islet function in obese monosodium glutamate (MSG)-treated rats. Male neonatal Wistar rats received MSG (4 mg/g body weight) during the first 5 days of life and, at weaning, half of the rats were submitted to swimming training, 30 min/day, 3 days a week, until 90 days of age (exercised rats: MSGex). Half of the rats were used as controls (sedentary group, MSGsd). Exercise training (ET) decreased insulinemia and fat deposition in MSGex, and increased adrenal catecholamine content, compared with MSGsd rats. Insulinemia during the ivGTT was lower in MSGex rats, despite a lack of difference in glycemia. Swimming training enhanced insulin release in islets challenged by 2.8-8.3 mmol/l glucose, whereas, at supraphysiological glucose concentrations (11.1-16.7 mmol/l), MSGex islets secreted less insulin than MSGsd. No differences in insulin secretion were observed following l-arginine (Arg) or K(+) stimuli. In contrast, islets from MSGex rats secreted more insulin when exposed to carbachol (100 μmol/l), forskolin (10 μmol/l), or IBMX (1 mmol/l) at 8.3 mmol/l glucose. Additionally, MSGex islets presented a better epinephrine inhibition upon insulin release. These results demonstrate that ET prevented the onset of obesity in MSG rats, probably by enhancing adrenal catecholamine levels. ET ameliorates islet responsiveness to several compounds, as well as insulin peripheral action.

  3. Anti-diabetic and neuroprotective effects of pancreatic islet transplantation into the central nervous system.

    PubMed

    Lazard, Daniel; Vardi, Pnina; Bloch, Konstantin

    2016-01-01

    During the last decades, the central nervous system (CNS) was intensively tested as a site for islet transplantation in different animal models of diabetes. Immunoprivilege properties of intracranial and intrathecal sites were found to delay and reduce rejection of transplanted allo-islets and xeno-islets, especially in the form of dispersed single cells. Insulin released from islets grafted in CNS was shown to cross the blood-brain barrier and to act as a regulator of peripheral glucose metabolism. In diabetic animals, sufficient nutrition and oxygen supply to islets grafted in the CNS provide adequate insulin response to increase glucose level resulting in rapid normoglycemia. In addition to insulin, pancreatic islets produce and secrete several other hormones, as well as neurotrophic and angiogenic factors with potential neuroprotective properties. Recent experimental studies and clinical trials provide a strong support for delivery of islet-derived macromolecules to CNS as a promising strategy to treat various brain disorders. This review article focuses mainly on analysis of current status of intracranial and intrathecal islet transplantations for treatment of experimental diabetes and discusses the possible neuroprotective properties of grafted islets into CNS as a novel therapeutic approach to brain disorders with cognitive dysfunctions characterized by impaired brain insulin signalling. Copyright © 2015 John Wiley & Sons, Ltd.

  4. A Metabolomic Approach (1H HRMAS NMR Spectroscopy) Supported by Histology to Study Early Post-transplantation Responses in Islet-transplanted Livers

    PubMed Central

    Vivot, Kevin; Benahmed, Malika A.; Seyfritz, Elodie; Bietiger, William; Elbayed, Karim; Ruhland, Elisa; Langlois, Allan; Maillard, Elisa; Pinget, Michel; Jeandidier, Nathalie; Gies, Jean-Pierre; Namer, Izzie-Jacques; Sigrist, Séverine; Reix, Nathalie

    2016-01-01

    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. 1H 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. To study islet specific inflammatory events, immunohistochemistry was performed on sections of islet transplanted livers for thrombin (indicator of the instant blood-mediated inflammatory reaction (IBMIR)) and granulocytes and macrophages. We observed a specific correlation between IBMIR and granulocyte and macrophage infiltration after 12 h. In parallel, we identified a metabolic response associated with transplantation: after 12 h, glucose, alanine, aspartate, glutamate and glutathione were significantly increased. An increase of glucose is a marker of tissue degradation, and could be explained by immune cell infiltration. Alanine, aspartate and glutamate are inter-connected in a common metabolic pathway known to be activated during hypoxia. An increase of glutathione revealed the presence of antioxidant protection. In this study, IBMIR visualization combined with 1H HRMAS NMR facilitated the characterization of cellular and molecular pathways recruited following islet transplantation. PMID:27766032

  5. Acute insulin responses to glucose and arginine as predictors of beta-cell secretory capacity in human islet transplantation.

    PubMed

    Rickels, Michael R; Naji, Ali; Teff, Karen L

    2007-11-27

    Islet transplantation for type 1 diabetes can enable the achievement of near-normal glycemic control without severe hypoglycemic episodes. How much an islet (beta-cell) graft may be contributing to glycemic control can be quantified by stimulatory tests of insulin (or C-peptide) secretion. Glucose-potentiation of arginine-induced insulin secretion provides a measure of functional beta-cell mass, the beta-cell secretory capacity, as either AIR(pot) or AIR(max), but requires conduct of a hyperglycemic clamp. We sought to determine whether acute insulin responses to intravenous glucose (AIR(glu)) or arginine (AIR(arg)) could predict beta-cell secretory capacity in islet recipients. AIR(arg) was a better predictor of both AIR(pot) and AIR(max) (n=10, r2=0.98, P<0.0001 and n=7, r2=0.97, P<0.0001) than was AIR(glu) (n=9, r2=0.78, P=0.002 and n=6, r2=0.76, P=0.02). Also, the measures of beta-cell secretory capacity were highly correlated (n=7, r2=0.98, P<0.0001). These results support the use of AIR(arg) as a surrogate indicator of beta-cell secretory capacity in islet transplantation.

  6. Hormonal and lactational responses to growth hormone-releasing hormone treatment in lactating Japanese Black cows.

    PubMed

    Shingu, H; Hodate, K; Kushibiki, S; Ueda, Y; Touno, E; Shinoda, M; Ohashi, S

    2004-06-01

    Ten multiparous lactating Japanese Black cows (beef breed) were used to evaluate the effects of bovine growth hormone-releasing hormone (GHRH) analog on milk yield and profiles of plasma hormones and metabolites. The cows received 2 consecutive 21-d treatments (a daily s.c. injection of 3-mg GHRH analog or saline) in a 2 (group) x 2 (period) Latin square crossover design. The 5 cows in group A received GHRH analog during period 1 (from d 22 to 42 postpartum) and saline during period 2 (from d 57 to 77 postpartum), and those in group B received saline and GHRH analog during periods 1 and 2, respectively. Mean milk yield decreased in saline treated compared with that during the 1-wk period before treatment 7.4 and 19.1% during periods 1 (group B) and 2 (group A), respectively. Treatment with GHRH analog increased milk yield 17.4% (period 1, group A) and 6.3% (period 2, group B). Treatment with GHRH analog induced higher basal plasma concentrations of growth hormone (GH), insulin-like growth factor-1 (IGF-1), insulin, and glucose compared with saline-treated cows. In glucose challenge, the GHRH analog-treated beef cows had greater insulin secretion than the saline-treated beef cows. In insulin challenge, however, there were no significant differences in the areas surrounded by hypothetical lines of basal glucose concentrations and glucose response curves between GHRH analog- and saline-treated cows. These results demonstrate that GHRH analog treatment facilitates endogenous GH secretion in lactating Japanese Black cows, leading to increases in milk yield and plasma concentrations of IGF-1, insulin, and glucose.

  7. Selection of polymers for application in scaffolds applicable for human pancreatic islet transplantation.

    PubMed

    Smink, Alexandra M; de Haan, Bart J; Paredes-Juarez, Genaro A; Wolters, Anouk H G; Kuipers, Jeroen; Giepmans, Ben N G; Schwab, Leendert; Engelse, Marten A; van Apeldoorn, Aart A; de Koning, Eelco; Faas, Marijke M; de Vos, Paul

    2016-05-13

    The liver is currently the site for transplantation of islets in humans. This is not optimal for islets, but alternative sites in humans are not available. Polymeric scaffolds in surgically accessible areas are a solution. As human donors are rare, the polymers should not interfere with functional survival of human-islets. We applied a novel platform to test the adequacy of polymers for application in scaffolds for human-islet transplantation. Viability, functionality, and immune parameters were included to test poly(D,L-lactide-co-ε-caprolactone) (PDLLCL), poly(ethylene oxide terephthalate)/polybutylene terephthalate (PEOT/PBT) block copolymer, and polysulfone. The type of polymer influenced the functional survival of human islets. In islets cultured on PDLLCL the glucagon-producing α-cells and insulin-producing β-cells contained more hormone granules than in islets in contact with PEOT/PBT or polysulfone. This was studied with ultrastructural analysis by electron microscopy (nanotomy) during 7 d of culture. PDLLCL was also associated with statistically significant lower release of double-stranded DNA (dsDNA, a so called danger-associate molecular pattern (DAMP)) from islets on PDLLCL when compared to the other polymers. DAMPs support undesired immune responses. Hydrophilicity of the polymers did not influence dsDNA release. Islets on PDLLCL also showed less cellular outgrowth. These outgrowing cells were mainly fibroblast and some β-cells undergoing epithelial to mesenchymal cell transition. None of the polymers influenced the glucose-stimulated insulin secretion. As PDLLCL was associated with less release of DAMPs, it is a promising candidate for creating a scaffold for human islets. Our study demonstrates that for sensitive, rare cadaveric donor tissue such as pancreatic islets it might be necessary to first select materials that do not influence functionality before proposing the biomaterial for in vivo application. Our presented platform may facilitate

  8. Elevation of cytosolic calcium by imidazolines in mouse islets of Langerhans: implications for stimulus-response coupling of insulin release.

    PubMed Central

    Shepherd, R. M.; Hashmi, M. N.; Kane, C.; Squires, P. E.; Dunne, M. J.

    1996-01-01

    1. Microfluorimetry techniques with fura-2 were used to characterize the effects of efaroxan (200 microM), phenotolamine (200-500 microM) and idazoxan (200-500 microM) on the intracellular free Ca2+ concentration ([Ca2+]i) in mouse isolated islets of Langerhans. 2. The imidazoline receptor agonists efaroxan and phentolamine consistently elevated cytosolic Ca2+ by mechanisms that were dependent upon Ca2+ influx across the plasma membrane; there was no rise in [Ca2+]i when Ca2+ was removed from outside of the islets and diazoxide (100-250 microM) attenuated the responses. 3. Modulation of cytosolic [Ca2+]i by efaroxan and phentolamine was augmented by glucose (5-10 mM) which both potentiated the magnitude of the response and reduced the onset time of imidazoline-induced rises in [Ca2+]i. 4. Efaroxan- and phentolamine-evoked increases in [Ca2+]i were unaffected by overnight pretreatment of islets with the imidazolines. Idazoxan failed to increase [Ca2+]i under any experimental condition tested. 5. The putative endogenous ligand of imidazoline receptors, agmatine (1 microM-1 mM), blocked KATP channels in isolated patches of beta-cell membrane, but effects upon [Ca2+]i could not be further investigated since agmatine disrupts fura-2 fluorescence. 6. In conclusion, the present study shows that imidazolines will evoke rises in [Ca2+]i in intact islets, and this provides an explanation to account for the previously described effects of imidazolines on KATP channels, the cell membrane potential and insulin secretion in pancreatic beta-cells. PMID:8922740

  9. Fast surface acoustic wave-matrix-assisted laser desorption ionization mass spectrometry of cell response from islets of Langerhans.

    PubMed

    Bllaci, Loreta; Kjellström, Sven; Eliasson, Lena; Friend, James R; Yeo, Leslie Y; Nilsson, Staffan

    2013-03-05

    A desire for higher speed and performance in molecular profiling analysis at a reduced cost is driving a trend in miniaturization and simplification of procedures. Here we report the use of a surface acoustic wave (SAW) atomizer for fast sample handling in matrix-assisted laser desorption ionization mass spectrometry (MALDI MS) peptide and protein profiling of Islets of Langerhans, for future type 2 diabetes (T2D) studies. Here the SAW atomizer was used for ultrasound (acoustic) extraction of insulin and other peptide hormones released from freshly prepared islets, stimulated directly on a membrane. A high energy propagating SAW atomizes the membrane-bound liquid into approximately 2 μm diameter droplets, rich in cell-released molecules. Besides acting as a sample carrier, the membrane provides a purification step by entrapping cell clusters and other impurities within its fibers. A new SAW-based sample-matrix deposition method for MALDI MS was developed and characterized by a strong insulin signal, and a limit of detection (LOD) lower than 100 amol was achieved. Our results support previous work reporting the SAW atomizer as a fast and inexpensive tool for ultrasound, membrane-based sample extraction. When interfaced with MALDI MS, the SAW atomizer constitutes a valuable tool for rapid cell studies. Other biomedical applications of SAW-MALDI MS are currently being developed, aiming at fast profiling of biofluids. The membrane sampling is a simplistic and noninvasive collection method of limited volume biofluids such as the gingival fluid and the tearfilm.

  10. Islet Xeno/transplantation and the risk of contagion: local responses from Canada and Australia to an emerging global technoscience.

    PubMed

    Cheng, Myra

    2015-01-01

    This paper situates the public debate over the use of living animal organs and tissue for human therapies within the history of experimental islet transplantation. Specifically, the paper compares and contrasts the Canadian and Australian responses on xenotransplantation to consider what lessons can be learnt about the regulation of a complex and controversial biotechnology. Sobbrio and Jorqui described public engagement on xenotransplantation in these countries as 'important forms of experimental democracy.' While Canada experimented with a novel nation-wide public consultation, Australia sought public input within the context of a national inquiry. In both instances, the outcome was a temporary moratorium on all forms of clinical xenotransplantation comparable to the policies adopted in some European countries. In addition, the Australian xenotransplantation ban coincided with a temporary global ban on experimental islet allotransplantation in 2007. Through historical and comparative research, this paper investigates how public controversies over organ and tissue transplantation can inform our understanding of the mediation of interspeciality and the regulation of a highly contested technoscience. It offers an alternative perspective on the xenotransplantation controversy by exploring the ways in which coinciding moratoriums on islet allograft and xenograft challenge, complicate and confound our assumptions regarding the relationships between human and animal, between routine surgery and clinical experimentation, between biomedical science and social science, and between disease risks and material contagion.

  11. Distinct differences in the responses of the human pancreatic β-cell line EndoC-βH1 and human islets to proinflammatory cytokines.

    PubMed

    Oleson, Bryndon J; McGraw, Jennifer A; Broniowska, Katarzyna A; Annamalai, Mani; Chen, Jing; Bushkofsky, Justin R; Davis, Dawn B; Corbett, John A; Mathews, Clayton E

    2015-09-01

    While insulinoma cells have been developed and proven to be extremely useful in studies focused on mechanisms controlling β-cell function and viability, translating findings to human β-cells has proven difficult because of the limited access to human islets and the absence of suitable insulinoma cell lines of human origin. Recently, a human β-cell line, EndoC-βH1, has been derived from human fetal pancreatic buds. The purpose of this study was to determine whether human EndoC-βH1 cells respond to cytokines in a fashion comparable to human islets. Unlike most rodent-derived insulinoma cell lines that respond to cytokines in a manner consistent with rodent islets, EndoC-βH1 cells fail to respond to a combination of cytokines (IL-1, IFN-γ, and TNF) in a manner consistent with human islets. Nitric oxide, produced following inducible nitric oxide synthase (iNOS) expression, is a major mediator of cytokine-induced human islet cell damage. We show that EndoC-βH1 cells fail to express iNOS or produce nitric oxide in response to this combination of cytokines. Inhibitors of iNOS prevent cytokine-induced loss of human islet cell viability; however, they do not prevent cytokine-induced EndoC-βH1 cell death. Stressed human islets or human islets expressing heat shock protein 70 (HSP70) are resistant to cytokines, and, much like stressed human islets, EndoC-βH1 cells express HSP70 under basal conditions. Elevated basal expression of HSP70 in EndoC-βH1 cells is consistent with the lack of iNOS expression in response to cytokine treatment. While expressing HSP70, EndoC-βH1 cells fail to respond to endoplasmic reticulum stress activators, such as thapsigargin. These findings indicate that EndoC-βH1 cells do not faithfully recapitulate the response of human islets to cytokines. Therefore, caution should be exercised when making conclusions regarding the actions of cytokines on human islets when using this human-derived insulinoma cell line.

  12. 'Giving and taking': endothelial and beta-cells in the islets of Langerhans.

    PubMed

    Eberhard, Daniel; Kragl, Martin; Lammert, Eckhard

    2010-08-01

    The beta-cells of the islets of Langerhans are embedded in a dense capillary network. The blood vessels supply the islet cells with nutrients and oxygen, and in turn take up the secreted islet hormones to deliver them to target tissues. In addition, vessels provide a basement membrane, which optimizes islet function. In this review we focus on the dynamic interactions between blood vessels and beta-cells, which are pivotal for enhancing insulin expression and beta-cell proliferation in response to increased insulin demand during body growth, pregnancy, and virtually all conditions associated with insulin resistance. Importantly, a failure in this adaptive response might contribute to the onset of type 2 diabetes mellitus.

  13. Metabolomics applied to the pancreatic islet

    PubMed Central

    Gooding, Jessica R.; Jensen, Mette V.; Newgard, Christopher B.

    2016-01-01

    Metabolomics, the characterization of the set of small molecules in a biological system, is advancing research in multiple areas of islet biology. Measuring a breadth of metabolites simultaneously provides a broad perspective on metabolic changes as the islets respond dynamically to metabolic fuels, hormones, or environmental stressors. As a result, metabolomics has the potential to provide new mechanistic insights into islet physiology and pathophysiology. Here we summarize advances in our understanding of islet physiology and the etiologies of type-1 and type-2 diabetes gained from metabolomics studies. PMID:26116790

  14. Enzyme action in the regulation of plant hormone responses.

    PubMed

    Westfall, Corey S; Muehler, Ashley M; Jez, Joseph M

    2013-07-05

    Plants synthesize a chemically diverse range of hormones that regulate growth, development, and responses to environmental stresses. The major classes of plant hormones are specialized metabolites with exquisitely tailored perception and signaling systems, but equally important are the enzymes that control the dose and exposure to the bioactive forms of these molecules. Here, we review new insights into the role of enzyme families, including the SABATH methyltransferases, the methylesterases, the GH3 acyl acid-amido synthetases, and the hormone peptidyl hydrolases, in controlling the biosynthesis and modifications of plant hormones and how these enzymes contribute to the network of chemical signals responsible for plant growth, development, and environmental adaptation.

  15. Protein-Mediated Interactions of Pancreatic Islet Cells

    PubMed Central

    Meda, Paolo

    2013-01-01

    The islets of Langerhans collectively form the endocrine pancreas, the organ that is soley responsible for insulin secretion in mammals, and which plays a prominent role in the control of circulating glucose and metabolism. Normal function of these islets implies the coordination of different types of endocrine cells, noticeably of the beta cells which produce insulin. Given that an appropriate secretion of this hormone is vital to the organism, a number of mechanisms have been selected during evolution, which now converge to coordinate beta cell functions. Among these, several mechanisms depend on different families of integral membrane proteins, which ensure direct (cadherins, N-CAM, occludin, and claudins) and paracrine communications (pannexins) between beta cells, and between these cells and the other islet cell types. Also, other proteins (integrins) provide communication of the different islet cell types with the materials that form the islet basal laminae and extracellular matrix. Here, we review what is known about these proteins and their signaling in pancreatic β-cells, with particular emphasis on the signaling provided by Cx36, given that this is the integral membrane protein involved in cell-to-cell communication, which has so far been mostly investigated for effects on beta cell functions. PMID:24278783

  16. Enhanced insulin secretion responsiveness and islet adrenergic desensitization after chronic norepinephrine suppression is discontinued in fetal sheep

    PubMed Central

    Chen, Xiaochuan; Green, Alice S.; Macko, Antoni R.; Yates, Dustin T.; Kelly, Amy C.

    2013-01-01

    Intrauterine growth-restricted (IUGR) fetuses experience prolonged hypoxemia, hypoglycemia, and elevated norepinephrine (NE) concentrations, resulting in hypoinsulinemia and β-cell dysfunction. Previously, we showed that acute adrenergic blockade revealed enhanced insulin secretion responsiveness in the IUGR fetus. To determine whether chronic exposure to NE alone enhances β-cell responsiveness afterward, we continuously infused NE into fetal sheep for 7 days and, after terminating the infusion, evaluated glucose-stimulated insulin secretion (GSIS) and glucose-potentiated arginine-induced insulin secretion (GPAIS). During treatment, NE-infused fetuses had greater (P < 0.05) plasma NE concentrations and exhibited hyperglycemia (P < 0.01) and hypoinsulinemia (P < 0.01) compared with controls. GSIS during the NE infusion was also reduced (P < 0.05) compared with pretreatment values. GSIS and GPAIS were approximately fourfold greater (P < 0.01) in NE fetuses 3 h after the 7 days that NE infusion was discontinued compared with age-matched controls or pretreatment GSIS and GPAIS values of NE fetuses. In isolated pancreatic islets from NE fetuses, mRNA concentrations of adrenergic receptor isoforms (α1D, α2A, α2C, and β1), G protein subunit-αi-2, and uncoupling protein 2 were lower (P < 0.05) compared with controls, but β-cell regulatory genes were not different. Our findings indicate that chronic exposure to elevated NE persistently suppresses insulin secretion. After removal, NE fetuses demonstrated a compensatory enhancement in insulin secretion that was associated with adrenergic desensitization and greater stimulus-secretion coupling in pancreatic islets. PMID:24253046

  17. Hormone-controlled UV-B responses in plants.

    PubMed

    Vanhaelewyn, Lucas; Prinsen, Els; Van Der Straeten, Dominique; Vandenbussche, Filip

    2016-08-01

    Ultraviolet B (UV-B) light is a portion of solar radiation that has significant effects on the development and metabolism of plants. Effects of UV-B on plants can be classified into photomorphogenic effects and stress effects. These effects largely rely on the control of, and interactions with, hormonal pathways. The fairly recent discovery of the UV-B-specific photoreceptor UV RESISTANCE LOCUS 8 (UVR8) allowed evaluation of the role of downstream hormones, leading to the identification of connections with auxin and gibberellin. Moreover, a substantial overlap between UVR8 and phytochrome responses has been shown, suggesting that part of the responses caused by UVR8 are under PHYTOCHROME INTERACTING FACTOR control. UV-B effects can also be independent of UVR8, and affect different hormonal pathways. UV-B affects hormonal pathways in various ways: photochemically, affecting biosynthesis, transport, and/or signaling. This review concludes that the effects of UV-B on hormonal regulation can be roughly divided in two: inhibition of growth-promoting hormones; and the enhancement of environmental stress-induced defense hormones.

  18. Improved response of growth hormone to growth hormone-releasing hormone and reversible chronic thyroiditis after hydrocortisone replacement in isolated adrenocorticotropic hormone deficiency.

    PubMed

    Inagaki, Miho; Sato, Haruhiro; Miyamoto, Yoshiyasu; Hirukawa, Takashi; Sawaya, Asako; Miyakogawa, Takayo; Tatsumi, Ryoko; Kakuta, Takatoshi

    2009-07-20

    We report a 44-year-old Japanese man who showed a reversible blunted response of growth hormone (GH) to GH-releasing hormone (GRH) stimulation test and reversible chronic thyroiditis accompanied by isolated ACTH deficiency. He was admitted to our hospital because of severe general malaise, hypotension, and hypoglycemia. He showed repeated attacks of hypoglycemia, and his serum sodium level gradually decreased. Finally, he was referred to the endocrinology division, where his adrenocorticotropic hormone (ACTH) and cortisol values were found to be low, and his GH level was slightly elevated. An increased value of thyroid stimulating hormone (TSH) and decreased values of free triidothyronine and free thyroxine were observed along with anti-thyroglobulin antibody, suggesting chronic thyroiditis. Pituitary stimulation tests revealed a blunted response of ACTH and cortisol to corticotropin-releasing hormone, and a blunted response of GH to GRH. Hydrocortisone replacement was then started, and this improved the patient's general condition. His hypothyroid state gradually ameliorated and his titer of anti-thyroglobulin antibody decreased to the normal range. Pituitary function was re-evaluated with GRH stimulation test under a maintenance dose of 20 mg/day hydrocortisone and showed a normal response of GH to GRH. It is suggested that re-evaluation of pituitary and thyroid function is useful for diagnosing isolated ACTH deficiency after starting a maintenance dose of hydrocortisone in order to avoid unnecessary replacement of thyroid hormone.

  19. D-Alanine in the islets of Langerhans of rat pancreas.

    PubMed

    Ota, Nobutoshi; Rubakhin, Stanislav S; Sweedler, Jonathan V

    2014-05-02

    Relatively high levels of D-alanine (D-Ala), an endogenous D-amino acid, have been found in the endocrine systems of several animals, especially in the anterior pituitary; however, its functional importance remains largely unknown. We observed D-Ala in islets of Langerhans isolated from rat pancreas in significantly higher levels than in the anterior/intermediate pituitary; specifically, 180±60 fmol D-Ala per islet (300±100 nmol/gislet), and 10±2.5 nmol/g of wet tissue in pituitary. Additionally, 12±5% of the free Ala in the islets was in the d form, almost an order of magnitude higher than the percentage of D-Ala found in the pituitary. Surprisingly, glucose stimulation of the islets resulted in D-Ala release of 0.6±0.5 fmol per islet. As D-Ala is stored in islets and released in response to changes in extracellular glucose, D-Ala may have a hormonal role.

  20. High-resolution two-dimensional polyacrylamide gel electrophoresis reveals a glucose-response protein of 65 kDa in pancreatic islet cells

    SciTech Connect

    Collins, H.W.; Buettger, C.; Matschinsky, F. )

    1990-07-01

    High-resolution two-dimensional PAGE was used to search for glucose-response proteins in isolated pancreatic islets that were labeled with ({sup 35}S)methionine at ambient glucose concentrations of 0-18 mM. A 65-kDa protein, isoelectric focusing point of approximately 6.6-7.0, was discovered that showed at least a 20-fold stimulation of radiolabeling when glucose in the labeling medium was increased from 3 to 18 mM, in contrast to a 2.5-fold enhancement of label incorporation into total islet proteins. This 65-kDa protein is evident after 30 min of labeling with 18 mM glucose and is preferentially synthesized compared to its nearest neighbors after both 30 and 60 min of labeling. Glucose induction of the 65-kDa protein was virtually blocked by D-mannoheptulose. Glucose induction of this 65-kDa protein is in practically all aspects comparable to glucose induction of insulin and glucokinase in pancreatic beta cells. A working hypothesis is developed proposing that glucose-response proteins or glucospondins are pivotal constituents of pancreatic islet cells and that their discovery and exploration promise new insights into normal and pathological islet cell function.

  1. No improvement of pancreas transplant endocrine function by exogenous insulin infusion (islet rest) in the postoperative period.

    PubMed

    Dafoe, D C; Campbell, D A; Rosenberg, L; Merion, R M; Ucros, I; Vinik, A I; Klandorf, H; Turcotte, J G

    1989-07-01

    The concept of islet exhaustion maintains that exposure of pancreatic islets to hyperglycemia and other stresses leads to islet dysfunction and irreparable damage. The process of pancreatic transplantation places many stresses on islets (e.g., counter-regulatory hormones, steroids, cyclosporine toxicity). As practiced by some centers, it may be important to administer exogenous insulin in the postoperative period to provide islet rest. Using a porcine pancreas transplant model that simulates clinical transplantation, we studied 2 groups: 1 group (n = 8) received constant insulin infusion for 7 days after transplantation; the control group (n = 5) received vehicle only. The islets in the insulin infusion group were rested as evidenced by a significantly decreased mean C-peptide level (0.27 +/- 0.04 ng/ml) as compared to the control group (0.66 +/- 0.08 ng/ml) (P less than 0.05). After insulin infusion was discontinued, intravenous glucose tolerance testing found insulin, C-peptide and glucagon responses were not different between groups. Glucose clearance was also comparable; K values were -1.79 and -1.60 in the insulin infusion and control groups, respectively. In conclusion, islet rest by insulin infusion for 7 postoperative days did not improve subsequent pancreas transplant endocrine function.

  2. Noninvasive evaluation of the vascular response to transplantation of alginate encapsulated islets using the dorsal skin-fold model.

    PubMed

    Krishnan, Rahul; Arora, Rajan P; Alexander, Michael; White, Sean M; Lamb, Morgan W; Foster, Clarence E; Choi, Bernard; Lakey, Jonathan R T

    2014-01-01

    Alginate encapsulation reduces the risk of transplant rejection by evading immune-mediated cell injury and rejection; however, poor vascular perfusion results in graft failure. Since existing imaging models are incapable of quantifying the vascular response to biomaterial implants after transplantation, in this study, we demonstrate the use of in vivo laser speckle imaging (LSI) and wide-field functional imaging (WiFI) to monitor the microvascular environment surrounding biomaterial implants. The vascular response to two islet-containing biomaterial encapsulation devices, alginate microcapsules and a high-guluronate alginate sheet, was studied and compared after implantation into the mouse dorsal window chamber (N = 4 per implant group). Images obtained over a 14-day period using LSI and WiFI were analyzed using algorithms to quantify blood flow, hemoglobin oxygen saturation and vascular density. Using our method, we were able to monitor the changes in the peri-implant microvasculature noninvasively without the use of fluorescent dyes. Significant changes in blood flow, hemoglobin oxygen saturation and vascular density were noted as early as the first week post-transplant. The dorsal window chamber model enables comparison of host responses to transplanted biomaterials. Future experiments will study the effect of changes in alginate composition on the vascular and immune responses.

  3. Hormonal responses to exercise in chronic fatigue syndrome.

    PubMed

    Ottenweller, J E; Sisto, S A; McCarty, R C; Natelson, B H

    2001-01-01

    Chronic fatigue syndrome (CFS) is a debilitating disease characterized by severe, unexplained fatigue and postexertional exacerbation of symptoms. We examined basal endocrine function in a group of CFS patients and a carefully matched group of sedentary controls. The subjects then completed a graded, maximal exercise test on a treadmill, and additional blood samples were drawn 4 min and a day after the end of exercise. There were no differences in basal hormone levels before exercise. Plasma adrenocorticotropin, epinephrine, prolactin and thyrotropin responses 4 min after exercise were lower in the CFS group, but the growth hormone response may have been exaggerated, and the plasma norepinephrine response was similar to that in controls. The next day, there were no differences in hormone levels between the groups, which suggests that long-term changes in endocrine function are unlikely to be a cause of the prolonged fatigue that occurs in CFS patients after a bout of exertion.

  4. Signal-Response Modeling of Partial Hormone Feedback Networks

    PubMed Central

    Johnson, Michael L.; Veldhuis, Paula P.; Evans, William S.

    2009-01-01

    Background Endocrine feedback control networks are typically complex and contain multiple hormones, pools, and compartments. The hormones themselves commonly interact via multiple pathways and targets within the networks, and a complete description of such relationships may involve hundreds of parameters. In addition, it is often difficult, if not impossible, to collect experimental data pertaining to every component within the network. Therefore, the complete simultaneous analysis of such networks is challenging. Nevertheless, an understanding of these networks is critical for furthering our knowledge of hormonal regulation in both physiologic and pathophysiologic conditions. Methods We propose a novel approach for the analysis of dose-response relationships of subsets of hormonal feedback networks. The algorithm and signal-response quantification (SRQuant) software is based on convolution integrals, and tests whether several discretely measured input signals can be individually delayed, spread in time, transformed, combined, and discretely convolved with an elimination function to predict the time course of the concentration of an output hormone. Signal-response quantification is applied to examples from the endocrine literature to demonstrate its applicability to the analysis of the different endocrine networks. Results In one example, SRQuant determines the dose-response relationship by which one hormone regulates another, highlighting its advantages over other traditional methods. In a second example, for the first time (to the best of our knowledge), we show that the secretion of glucagon may be jointly controlled by the β and the δ cells. Conclusion We have developed a novel convolution integral-based approach, algorithm, and software (SRQuant) for the analysis of dose-response relationships within subsets of complex endocrine feedback control networks. PMID:20046649

  5. SIKs control osteocyte responses to parathyroid hormone.

    PubMed

    Wein, Marc N; Liang, Yanke; Goransson, Olga; Sundberg, Thomas B; Wang, Jinhua; Williams, Elizabeth A; O'Meara, Maureen J; Govea, Nicolas; Beqo, Belinda; Nishimori, Shigeki; Nagano, Kenichi; Brooks, Daniel J; Martins, Janaina S; Corbin, Braden; Anselmo, Anthony; Sadreyev, Ruslan; Wu, Joy Y; Sakamoto, Kei; Foretz, Marc; Xavier, Ramnik J; Baron, Roland; Bouxsein, Mary L; Gardella, Thomas J; Divieti-Pajevic, Paola; Gray, Nathanael S; Kronenberg, Henry M

    2016-10-19

    Parathyroid hormone (PTH) activates receptors on osteocytes to orchestrate bone formation and resorption. Here we show that PTH inhibition of SOST (sclerostin), a WNT antagonist, requires HDAC4 and HDAC5, whereas PTH stimulation of RANKL, a stimulator of bone resorption, requires CRTC2. Salt inducible kinases (SIKs) control subcellular localization of HDAC4/5 and CRTC2. PTH regulates both HDAC4/5 and CRTC2 localization via phosphorylation and inhibition of SIK2. Like PTH, new small molecule SIK inhibitors cause decreased phosphorylation and increased nuclear translocation of HDAC4/5 and CRTC2. SIK inhibition mimics many of the effects of PTH in osteocytes as assessed by RNA-seq in cultured osteocytes and following in vivo administration. Once daily treatment with the small molecule SIK inhibitor YKL-05-099 increases bone formation and bone mass. Therefore, a major arm of PTH signalling in osteocytes involves SIK inhibition, and small molecule SIK inhibitors may be applied therapeutically to mimic skeletal effects of PTH.

  6. SIKs control osteocyte responses to parathyroid hormone

    PubMed Central

    Wein, Marc N.; Liang, Yanke; Goransson, Olga; Sundberg, Thomas B.; Wang, Jinhua; Williams, Elizabeth A.; O'Meara, Maureen J.; Govea, Nicolas; Beqo, Belinda; Nishimori, Shigeki; Nagano, Kenichi; Brooks, Daniel J.; Martins, Janaina S.; Corbin, Braden; Anselmo, Anthony; Sadreyev, Ruslan; Wu, Joy Y.; Sakamoto, Kei; Foretz, Marc; Xavier, Ramnik J.; Baron, Roland; Bouxsein, Mary L.; Gardella, Thomas J.; Divieti-Pajevic, Paola; Gray, Nathanael S.; Kronenberg, Henry M.

    2016-01-01

    Parathyroid hormone (PTH) activates receptors on osteocytes to orchestrate bone formation and resorption. Here we show that PTH inhibition of SOST (sclerostin), a WNT antagonist, requires HDAC4 and HDAC5, whereas PTH stimulation of RANKL, a stimulator of bone resorption, requires CRTC2. Salt inducible kinases (SIKs) control subcellular localization of HDAC4/5 and CRTC2. PTH regulates both HDAC4/5 and CRTC2 localization via phosphorylation and inhibition of SIK2. Like PTH, new small molecule SIK inhibitors cause decreased phosphorylation and increased nuclear translocation of HDAC4/5 and CRTC2. SIK inhibition mimics many of the effects of PTH in osteocytes as assessed by RNA-seq in cultured osteocytes and following in vivo administration. Once daily treatment with the small molecule SIK inhibitor YKL-05-099 increases bone formation and bone mass. Therefore, a major arm of PTH signalling in osteocytes involves SIK inhibition, and small molecule SIK inhibitors may be applied therapeutically to mimic skeletal effects of PTH. PMID:27759007

  7. Dose Response Data for Hormonally Active Chemicals ...

    EPA Pesticide Factsheets

    The shape of the dose response curve in the low dose region has been debated since the late 1940s. The debate originally focused on linear no threshold (LNT) vs threshold responses in the low dose range for cancer and noncancer related effects. For noncancer effects the default assumption is that noncancer effects generally display threshold rather than LNT responses. More recently, claims have arisen that the chemicals, like endocrine disrupters (EDS), which act via high affinity, low capacity nuclear receptors, may display LNT or nonmonotonic low dose responses: responses that could be missed in multigenerational guideline toxicity testing. This presentation will discuss LNT, threshold and nonmonotonic dose response relationships from case studies of chemicals that disrupt reproductive development and function via the ER, AR and AhR pathways and will include in vitro and in vivo multigenerational data. The in vivo studies in this discussion include only robust, well designed, comprehensive studies that administered the chemical via a relevant route(s) of exposure over a broad dose response range, including low dose(s) in the microgram/kg/d range. The chemicals include ethinyl estradiol, estradiol, genistein, bisphenol a, trenbolone, finasteride, flutamide, phthalate esters and 2,3,7,8 TCDD. The objective is to critically evaluate the data from well done studies in this field to address concerns that current multigenerational reproductive test gui

  8. Acute hormonal responses following different velocities of eccentric exercise.

    PubMed

    Libardi, Cleiton A; Nogueira, Felipe R D; Vechin, Felipe C; Conceição, Miguel S; Bonganha, Valéria; Chacon-Mikahil, Mara Patricia T

    2013-11-01

    The aim of this study was to compare the acute hormonal responses following two different eccentric exercise velocities. Seventeen healthy, untrained, young women were randomly placed into two groups to perform five sets of six maximal isokinetic eccentric actions at slow (30° s(-1) ) and fast (210° s(-1) ) velocities with 60-s rest between sets. Growth hormone, cortisol, free and total testosterone were assessed by blood samples collected at baseline, immediately postexercise, 5, 15 and 30 min following eccentric exercise. Changes in hormonal responses over time were compared between groups, using a mixed model followed by a Tukey's post hoc test. The main findings of the present study were that the slow group showed higher growth hormone values immediately (5·08 ± 2·85 ng ml(-1) , P = 0·011), 5 (5·54 ± 3·01 ng ml(-1) , P = 0·004) and 15 min (4·30 ± 2·87 ng ml(-1) , P = 0·021) posteccentric exercise compared with the fast group (1·39 ± 2·41 ng ml(-1) , 1·34 ± 1·97 ng ml(-1) and 1·24 ± 1·87 ng ml(-1) , respectively), and other hormonal responses were not different between groups (P>0·05). In conclusion, slow eccentric exercise velocity enhances more the growth hormone(GH) response than fast eccentric exercise velocity without cortisol and testosterone increases.

  9. Mouse hypothalamic growth hormone-releasing hormone and somatostatin responses to probes of signal transduction systems.

    PubMed

    Sato, M; Downs, T R; Frohman, L A

    1993-01-01

    Signal transduction mechanisms involved in mouse growth hormone-releasing hormone (GRH) and somatostatin (SRIH) release were investigated using an in vitro perifusion system. Hypothalamic fragments were exposed to depolarizing agents, protein kinase A and C activators, and a calcium ionophore. The depolarizing agents, KCl (60 mM) and veratridine (50 microM), induced similar patterns of GRH and SRIH release. Somatostatin release in response to both agents was twofold greater than that of GRH. Forskolin (10 microM and 100 microM), an adenylate cyclase activator, stimulated both GRH and SRIH release, though with different secretory profiles. The SRIH response was prolonged and persisted beyond removal of the drug from the system, while the GRH response was brief, ending even prior to forskolin removal. Neither GRH nor SRIH were stimulated by 1,9-dideoxy-forskolin (100 microM), a forskolin analog with cAMP-independent actions. A23187 (5 microM), a calcium ionophore, stimulated the release of SRIH to a much greater extent than that of GRH. The GRH and SRIH secretory responses to PMA (1 microM), a protein kinase C activator, were similar, though delayed. The results suggest that 1) GRH and SRIH secretion are regulated by both protein kinase A and C pathways, and 2) depolarizing agents are important for the release of both hormones.

  10. Response of the corpus luteum to luteinizing hormone.

    PubMed Central

    Niswender, G D

    1981-01-01

    The response of steroidogenic tissues to tropic hormones is regulated in part by specific receptors in the target cells for the stimulatory hormone. As a result of hormone binding to receptor the enzyme adenylate cyclase is activated with a resultant increase in intracellular levels of cAMP. Enhanced protein kinase activity then leads to increased steroidogenesis via several possible mechanisms, including direct activation of components of steroidogenic enzyme systems via phosphorylation. The initial effects of tropic hormones such as LH are dependent upon the number of receptors present on the surface of the target cell. Numerous factors influence the number of LH receptors in the corpus luteum. A model is presented for the mechanisms involved in the loss and renewal of LH receptors in the luteal cell. The life of the LH receptor on luteal cells appears to be a single binding of hormone. The hormone-receptor complex is then internalized by endocytosis and the hormone is degraded in lysosomes. After internalization the receptor is also degraded in lysosomes or recycled via the Golgi apparatus. New or recycled receptors for LH are incorporated into the limiting membrane of protein containing secretory granules. One of the actions of LH is enhancement of the exocytosis of these secretory granules with incorporation of the limiting membrane (and the LH receptors?) of the granule into the plasma membrane of the cell. These proposed mechanisms explain the increase in the number of receptors for LH seen immediately after stimulation of the luteal cell with massive doses of LH and also explain the "down-regulation" of LH receptors 24 hr after administration of LH. PMID:6263609

  11. Hormonal modulation of the heat shock response: insights from fish with divergent cortisol stress responses.

    PubMed

    LeBlanc, Sacha; Höglund, Erik; Gilmour, Kathleen M; Currie, Suzanne

    2012-01-01

    Acute temperature stress in animals results in increases in heat shock proteins (HSPs) and stress hormones. There is evidence that stress hormones influence the magnitude of the heat shock response; however, their role is equivocal. To determine whether and how stress hormones may affect the heat shock response, we capitalized on two lines of rainbow trout specifically bred for their high (HR) and low (LR) cortisol response to stress. We predicted that LR fish, with a low cortisol but high catecholamine response to stress, would induce higher levels of HSPs after acute heat stress than HR trout. We found that HR fish have significantly higher increases in both catecholamines and cortisol compared with LR fish, and LR fish had no appreciable stress hormone response to heat shock. This unexpected finding prevented further interpretation of the hormonal modulation of the heat shock response but provided insight into stress-coping styles and environmental stress. HR fish also had a significantly greater and faster heat shock response and less oxidative protein damage than LR fish. Despite these clear differences in the physiological and cellular responses to heat shock, there were no differences in the thermal tolerance of HR and LR fish. Our results support the hypothesis that responsiveness to environmental change underpins the physiological differences in stress-coping styles. Here, we demonstrate that the heat shock response is a distinguishing feature of the HR and LR lines and suggest that it may have been coselected with the hormonal responses to stress.

  12. Preservation of pancreatic islets in cold UW solution before transplantation.

    PubMed

    Ishii, Show; Saito, Takuro; Ise, Kazuya; Yamashita, Michitoshi; Sato, Yoshihiro; Saito, Takaharu; Tsukada, Manabu; Oshibe, Ikuro; Kenjo, Akira; Kimura, Takashi; Anazawa, Takayuki; Suzuki, Shigeya; Gotoh, Mitsukazu

    2012-01-01

    Culture of islets prior to transplantation needs to be revisited for maintaining functional islet capacity. This study was conducted to compare cold UW (University of Wisconsin) preservation with conventional culture based on insulin secretory capacity in vitro and in vivo. Islets isolated from Wistar rats were either cultured for 24 h at 37°C in RPMI1640 medium or DMEM containing various concentrations of glucose or preserved for the same period in UW solution or in DMEM solution at 4°C. The islet yield in UW group, but not in other groups, was maintained as comparable with that of fresh islets. Insulin secretory capacity in response to glucose was maintained only in the islets of UW group, but not in other groups. SCID mice given 300 IEQ islets of UW group showed gradual restoration of normoglycemia as found in the mice given freshly isolated islets. Meanwhile, those mice given cultured islets for 24 h at 37°C in RPMI1640 medium showed rapid decrease of blood glucose levels on day 1 followed by relatively elevated levels on day 2, suggesting unstable insulin secretory capacity of islets.   Morphological staining with anti-HMGB1 (high mobility group B1) antibody revealed central damage of islets in all culture groups regardless of glucose concentration and in islets of cold DMEM group, whereas those in the UW group were quite intact. These results suggest that cold preservation in UW solution is simple and beneficial in protecting islets morphologically and functionally before transplantation.

  13. The role of thyroid hormones in stress response of fish.

    PubMed

    Peter, M C Subhash

    2011-06-01

    Thyroxine (T(4)) and triiodothyronine (T(3)), the principal thyroid hormones (THs) secreted from the hypothalamic-pituitary-thyroid (HPT) axis, produce a plethora of physiologic actions in fish. The diverse actions of THs in fishes are primarily due to the sensitivity of thyroid axis to many physical, chemical and biological factors of both intrinsic and extrinsic origins. The regulation of THs homeostasis becomes more complex due to extrathyroidal deiodination pathways by which the delivery of biologically active T(3) to target cells has been controlled. As primary stress hormones and the end products of hypothalamic-pituitary-interrenal (HPI) and brain-sympathetic-chromaffin (BSC) axes, cortisol and adrenaline exert its actions on its target tissues where it promote and integrate osmotic and metabolic competence. Despite possessing specific osmoregulatory and metabolic actions at cellular and whole-body levels, THs may fine-tune these processes in accordance with the actions of hormones like cortisol and adrenaline. Evidences are presented that THs can modify the pattern and magnitude of stress response in fishes as it modifies either its own actions or the actions of stress hormones. In addition, multiple lines of evidence indicate that hypothalamic and pituitary hormones of thyroid and interrenal axes can interact with each other which in turn may regulate THs/cortisol-mediated actions. Even though it is hard to define these interactions, the magnitude of stress response in fish has been shown to be modified by the changes in the status of THs, pointing to its functional relationship with endocrine stress axes particularly with the interrenal axis. The fine-tuned mechanism that operates in fish during stressor-challenge drives the THs to play both fundamental and modulator roles in stress response by controlling osmoregulation and metabolic regulation. A major role of THs in stress response is thus evident in fish.

  14. The antilipolytic agent 3,5-dimethylpyrazole inhibits insulin release in response to both nutrient secretagogues and cyclic adenosine monophosphate agonists in isolated rat islets.

    PubMed

    Masiello, P; Novelli, M; Bombara, M; Fierabracci, V; Vittorini, S; Prentki, M; Bergamini, E

    2002-01-01

    This study intended to test the hypothesis that intracellular lipolysis in the pancreatic beta cells is implicated in the regulation of insulin secretion stimulated by nutrient secretagogues or cyclic adenosine monophosphate (cAMP) agonists. Indeed, although lipid signaling molecules were repeatedly reported to influence beta-cell function, the contribution of intracellular triglycerides to the generation of these molecules has remained elusive. Thus, we have studied insulin secretion of isolated rat pancreatic islets in response to various secretagogues in the presence or absence of 3,5-dimethylpyrazole (DMP), a water-soluble and highly effective antilipolytic agent, as previously shown in vivo. In vitro exposure of islets to DMP resulted in an inhibition (by approximately 50%) of the insulin release stimulated not only by high glucose, but also by another nutrient secretagogue, 2-ketoisocaproate, as well as the cAMP agonists 3-isobutyl-1-methylxanthine and glucagon. The inhibitory effect of DMP, which was not due to alteration of islet glucose oxidation, could be reversed upon addition of sn-1,2-dioctanoylglycerol, a synthetic diglyceride, which activates protein kinase C. The results provide direct pharmacologic evidence supporting the concept that endogenous beta-cell lipolysis plays an important role in the generation of lipid signaling molecules involved in the control of insulin secretion in response to both fuel stimuli and cAMP agonists.

  15. Hormonal contraception use alters stress responses and emotional memory.

    PubMed

    Nielsen, Shawn E; Segal, Sabrina K; Worden, Ian V; Yim, Ilona S; Cahill, Larry

    2013-02-01

    Emotionally arousing material is typically better remembered than neutral material. Since norepinephrine and cortisol interact to modulate emotional memory, sex-related influences on stress responses may be related to sex differences in emotional memory. Two groups of healthy women - one naturally cycling (NC women, n=42) and one using hormonal contraceptives (HC women, n=36) - viewed emotionally arousing and neutral images. Immediately after, they were assigned to Cold Pressor Stress (CPS) or a control procedure. One week later, participants received a surprise free recall test. Saliva samples were collected and later assayed for salivary alpha-amylase (biomarker for norepinephrine) and cortisol. Compared to NC women, HC women exhibited significantly blunted stress hormone responses to the images and CPS. Recall of emotional images differed between HC and NC women depending on noradrenergic and cortisol responses. These findings may have important implications for understanding the neurobiology of emotional memory disorders, especially those that disproportionately affect women.

  16. Endogenous growth hormone (GH)-releasing hormone is required for GH responses to pharmacological stimuli.

    PubMed Central

    Jaffe, C A; DeMott-Friberg, R; Barkan, A L

    1996-01-01

    The roles of hypothalamic growth hormone-releasing hormone (GHRH) and of somatostatin (SRIF) in pharmacologically stimulated growth hormone (GH) secretion in humans are unclear. GH responses could result either from GHRH release or from acute decline in SRIF secretion. To assess directly the role of endogenous GHRH in human GH secretion, we have used a competitive GHRH antagonist, (N-Ac-Tyr1,D-Arg2)GHRH(1-29)NH2 (GHRH-Ant), which we have previously shown is able to block the GH response to GHRH. We first tested whether an acute decline in SRIF, independent of GHRH action, would release GH. Pretreatment with GHRH-Ant abolished the GH response to exogenous GHRH (0.33 microgram/kg i.v.) but did not modify the GH rise after termination of an SRIF infusion. We then investigated the role of endogenous GHRH in the GH responses to pharmacologic stimuli of GH release. The GH responses to arginine (30 g i.v. over 30 min), L-dopa (0.5 g orally), insulin hypoglycemia (0.1 U/Kg i.v.), clonidine (0.25 mg orally), or pyridostigmine (60 mg orally) were measured in healthy young men after pretreatment with either saline of GHRH-Ant 400 microgram/kg i.v. In every case, GH release was significantly suppressed by GHRH-Ant. We conclude that endogenous GHRH is required for the GH response to each of these pharmacologic stimuli. Acute release of hypothalamic GHRH may be a common mechanism by which these compounds mediate GH secretion. PMID:8613546

  17. Pancreatic Islet Transplantation

    MedlinePlus

    ... allo-transplantation?" For each pancreatic islet allo-transplant infusion, researchers use specialized enzymes to remove islets from ... in a lab. Transplant patients typically receive two infusions with an average of 400,000 to 500, ...

  18. The Langerhans islet cells of female rabbits are differentially affected by hypothyroidism depending on the islet size.

    PubMed

    Rodríguez-Castelán, J; Nicolás, L; Morimoto, S; Cuevas, E

    2015-04-01

    Effects of hypothyroidism on the glucose and insulin levels are controversial, and its impact on the Langerhans islet morphology of adult subjects has been poorly addressed. In spite of hypothyroidism and diabetes mellitus are more frequent in females than in males, most studies using animal models have been done in males. The effect of hypothyroidism on the immunolabeling of thyroid hormone receptors (TRs) and thyrotropin receptor (TSHR) of islet cells is unknown. The aim of this study was to determine the effect of hypothyroidism on the glucose and insulin concentrations, morphometry of islets, and immunostaining of TRs α1-2 and β1 and TSHR of islet cells in female rabbits. Control and hypothyroid (0.02% of methimazole for 30 days) animals were used to quantify blood levels of glucose and insulin, density of islets, cross-sectional area (CSA) of islets, number of cells per islet, cell proliferation, and the immunolabeling of TRs α1-2, TRβ1, and TSHR. Student's t or Mann-Whitney-U tests, two-way ANOVAs, and Fischer's tests were applied. Concentrations of glucose and insulin, as well as the insulin resistance were similar between groups. Hypothyroidism did not affect the density or the CSA of islets. The analysis of islets by size showed that hypothyroidism reduced the cell number in large and medium islets, but not in small ones. In small islets, cell proliferation was increased. The immunoreactivity of TRα1-2, TRβ1, and TSHR was increased by hypothyroidism in all islet sizes. Our results show that hypothyroidism affects differentially the islet cells depending on the size of islets.

  19. Islet Cell Transplantation

    MedlinePlus

    ... person who has type 1 diabetes must take insulin daily to live. Transplanted islet cells, however, can take over the work of the destroyed cells. The beta cells in these islets will begin to make and release insulin. Researchers hope islet transplantation will help people with ...

  20. Blood lactate and hormonal responses to prototype flywheel ergometer workouts.

    PubMed

    Caruso, John F; Coday, Michael A; Monda, Julie K; Ramey, Elizabeth S; Hastings, Lori P; Vingren, Jakob L; Potter, William T; Kraemer, William J; Wickel, Eric E

    2010-03-01

    The purpose of the study was to compare blood lactate and hormonal responses with flywheel ergometer (FERG) leg presses for preliminary assessment of workouts best suited for future in-flight resistance exercise. Comprised of 10 repetition sets, the workouts entailed 3 sets of concentric and eccentric (CE3) actions, or concentric-only actions done for 3 (CO3) or 6 (CO6) sets. Methods employed included assessment of blood lactate concentrations ([BLa-]) before and 5 minutes postexercise. Venous blood was also collected before and at 1 and 30 minutes postexercise to assess growth hormone, testosterone, cortisol concentrations ([GH], [T], [C]) and [T/C] ratios. [BLa-] were compared with 2 (time) x 3 (workout) analysis of variance. Hormones were assessed with 2 (gender) x 3 (time) x 3 (workout) analysis of covariances. Results showed [BLa-] had a time effect. Growth hormone concentration showed gender x workout, gender x time, and workout x time interactions, whereas [T] had a 3-way interaction. [C] had gender, time, and workout effects. [T/C] yielded a gender x time interaction. It was concluded that, because CO6 and CE3 yielded similar anabolic hormonal data but the latter had a lower [C] 30 minutes postexercise, CE3 served as the best workout. Although the FERG was originally designed for microgravity, the effort put forth by current subjects was like that for workouts aimed at greater athletic performance and conditioning. Practical applications suggest that eccentric actions should be used for FERG workouts geared toward muscle mass and strength improvement.

  1. Diverse Hormone Response Networks in 41 Independent Drosophila Cell Lines

    DOE PAGES

    Stoiber, Marcus; Celniker, Susan; Cherbas, Lucy; ...

    2016-01-15

    Steroid hormones induce cascades of gene activation and repression with transformative effects on cell fate . Steroid transduction plays a major role in the development and physiology of nearly all metazoan species, and in the progression of the most common forms of cancer. Despite the paramount importance of steroids in developmental and translational biology, a complete map of transcriptional response has not been developed for any hormone . In the case of 20-hydroxyecdysone (ecdysone) in Drosophila melanogaster, these trajectories range from apoptosis to immortalization. We mapped the ecdysone transduction network in a cohort of 41 cell lines, the largest suchmore » atlas yet assembled. We found that the early transcriptional response mirrors the distinctiveness of physiological origins: genes respond in restricted patterns, conditional on the expression levels of dozens of transcription factors. Only a small cohort of genes is constitutively modulated independent of initial cell state. Ecdysone-responsive genes tend to organize into directional same-stranded units, with consecutive genes induced from the same strand. Here, we identify half of the ecdysone receptor heterodimer as the primary rate-limiting step in the response, and find that initial receptor isoform levels modulate the activated cohort of target transcription factors. In conclusion, this atlas of steroid response reveals organizing principles of gene regulation by a model type II nuclear receptor and lays the foundation for comprehensive and predictive understanding of the ecdysone transduction network in the fruit fly.« less

  2. Diverse Hormone Response Networks in 41 Independent Drosophila Cell Lines

    SciTech Connect

    Stoiber, Marcus; Celniker, Susan; Cherbas, Lucy; Brown, Ben; Cherbas, Peter

    2016-01-15

    Steroid hormones induce cascades of gene activation and repression with transformative effects on cell fate . Steroid transduction plays a major role in the development and physiology of nearly all metazoan species, and in the progression of the most common forms of cancer. Despite the paramount importance of steroids in developmental and translational biology, a complete map of transcriptional response has not been developed for any hormone . In the case of 20-hydroxyecdysone (ecdysone) in Drosophila melanogaster, these trajectories range from apoptosis to immortalization. We mapped the ecdysone transduction network in a cohort of 41 cell lines, the largest such atlas yet assembled. We found that the early transcriptional response mirrors the distinctiveness of physiological origins: genes respond in restricted patterns, conditional on the expression levels of dozens of transcription factors. Only a small cohort of genes is constitutively modulated independent of initial cell state. Ecdysone-responsive genes tend to organize into directional same-stranded units, with consecutive genes induced from the same strand. Here, we identify half of the ecdysone receptor heterodimer as the primary rate-limiting step in the response, and find that initial receptor isoform levels modulate the activated cohort of target transcription factors. In conclusion, this atlas of steroid response reveals organizing principles of gene regulation by a model type II nuclear receptor and lays the foundation for comprehensive and predictive understanding of the ecdysone transduction network in the fruit fly.

  3. Diverse Hormone Response Networks in 41 Independent Drosophila Cell Lines

    PubMed Central

    Stoiber, Marcus; Celniker, Susan; Cherbas, Lucy; Brown, Ben; Cherbas, Peter

    2016-01-01

    Steroid hormones induce cascades of gene activation and repression with transformative effects on cell fate . Steroid transduction plays a major role in the development and physiology of nearly all metazoan species, and in the progression of the most common forms of cancer. Despite the paramount importance of steroids in developmental and translational biology, a complete map of transcriptional response has not been developed for any hormone . In the case of 20-hydroxyecdysone (ecdysone) in Drosophila melanogaster, these trajectories range from apoptosis to immortalization. We mapped the ecdysone transduction network in a cohort of 41 cell lines, the largest such atlas yet assembled. We found that the early transcriptional response mirrors the distinctiveness of physiological origins: genes respond in restricted patterns, conditional on the expression levels of dozens of transcription factors. Only a small cohort of genes is constitutively modulated independent of initial cell state. Ecdysone-responsive genes tend to organize into directional same-stranded units, with consecutive genes induced from the same strand. Here, we identify half of the ecdysone receptor heterodimer as the primary rate-limiting step in the response, and find that initial receptor isoform levels modulate the activated cohort of target transcription factors. This atlas of steroid response reveals organizing principles of gene regulation by a model type II nuclear receptor and lays the foundation for comprehensive and predictive understanding of the ecdysone transduction network in the fruit fly. PMID:26772746

  4. Restoration of Glucose Counterregulation by Islet Transplantation in Long-standing Type 1 Diabetes.

    PubMed

    Rickels, Michael R; Fuller, Carissa; Dalton-Bakes, Cornelia; Markmann, Eileen; Palanjian, Maral; Cullison, Kevin; Tiao, Janice; Kapoor, Shiv; Liu, Chengyang; Naji, Ali; Teff, Karen L

    2015-05-01

    Patients with long-standing type 1 diabetes (T1D) may exhibit defective glucose counterregulation and impaired hypoglycemia symptom recognition that substantially increase their risk for experiencing severe hypoglycemia. The purpose of this study was to determine whether intrahepatic islet transplantation improves endogenous glucose production (EGP) in response to hypoglycemia in T1D patients experiencing severe hypoglycemia. We studied longitudinally subjects (n = 12) with ∼30 years, disease duration before and 6 months after intrahepatic islet transplantation using stepped hyperinsulinemic-hypoglycemic and paired hyperinsulinemic-euglycemic clamps with infusion of 6,6-(2)H2-glucose and compared the results with those from a nondiabetic control group (n = 8). After islet transplantation, HbA1c was normalized, and time spent while hypoglycemic (<70 mg/dL) was nearly abolished as indicated by continuous glucose monitoring. In response to insulin-induced hypoglycemia, C-peptide (absent before transplant) was appropriately suppressed, glucagon secretion was recovered, and epinephrine secretion was improved after transplantation. Corresponding to these hormonal changes, the EGP response to insulin-induced hypoglycemia, which was previously absent, was normalized after transplantation, with a similar effect seen for autonomic symptoms. Because the ability to increase EGP is ultimately required to circumvent the development of hypoglycemia, these results provide evidence that intrahepatic islet transplantation can restore glucose counterregulation in long-standing T1D and support its consideration as treatment for patients with hypoglycemia unawareness experiencing severe hypoglycemia.

  5. Modulation of taste responsiveness by the satiation hormone peptide YY

    PubMed Central

    La Sala, Michael S.; Hurtado, Maria D.; Brown, Alicia R.; Bohórquez, Diego V.; Liddle, Rodger A.; Herzog, Herbert; Zolotukhin, Sergei; Dotson, Cedrick D.

    2013-01-01

    It has been hypothesized that the peripheral taste system may be modulated in the context of an animal's metabolic state. One purported mechanism for this phenomenon is that circulating gastrointestinal peptides modulate the functioning of the peripheral gustatory system. Recent evidence suggests endocrine signaling in the oral cavity can influence food intake (FI) and satiety. We hypothesized that these hormones may be affecting FI by influencing taste perception. We used immunohistochemistry along with genetic knockout models and the specific reconstitution of peptide YY (PYY) in saliva using gene therapy protocols to identify a role for PYY signaling in taste. We show that PYY is expressed in subsets of taste cells in murine taste buds. We also show, using brief-access testing with PYY knockouts, that PYY signaling modulates responsiveness to bitter-tasting stimuli, as well as to lipid emulsions. We show that salivary PYY augmentation, via viral vector therapy, rescues behavioral responsiveness to a lipid emulsion but not to bitter stimuli and that this response is likely mediated via activation of Y2 receptors localized apically in taste cells. Our findings suggest distinct functions for PYY produced locally in taste cells vs. that circulating systemically.—La Sala, M. S., Hurtado, M. D., Brown, A. R., Bohórquez, D. V., Liddle, R. A., Herzog, H., Zolotukhin, S., Dotson, C. D. Modulation of taste responsiveness by the satiation hormone peptide YY. PMID:24043261

  6. Endoplasmic reticulum stress and the unfolded protein response in pancreatic islet inflammation.

    PubMed

    Meyerovich, Kira; Ortis, Fernanda; Allagnat, Florent; Cardozo, Alessandra K

    2016-07-01

    Insulin-secreting pancreatic β-cells are extremely dependent on their endoplasmic reticulum (ER) to cope with the oscillatory requirement of secreted insulin to maintain normoglycemia. Insulin translation and folding rely greatly on the unfolded protein response (UPR), an array of three main signaling pathways designed to maintain ER homeostasis and limit ER stress. However, prolonged or excessive UPR activation triggers alternative molecular pathways that can lead to β-cell dysfunction and apoptosis. An increasing number of studies suggest a role of these pro-apoptotic UPR pathways in the downfall of β-cells observed in diabetic patients. Particularly, the past few years highlighted a cross talk between the UPR and inflammation in the context of both type 1 (T1D) and type 2 diabetes (T2D). In this article, we describe the recent advances in research regarding the interplay between ER stress, the UPR, and inflammation in the context of β-cell apoptosis leading to diabetes.

  7. Antibody Response to Serpin B13 Induces Adaptive Changes in Mouse Pancreatic Islets and Slows Down the Decline in the Residual Beta Cell Function in Children with Recent Onset of Type 1 Diabetes Mellitus.

    PubMed

    Kryvalap, Yury; Lo, Chi-Wen; Manuylova, Ekaterina; Baldzizhar, Raman; Jospe, Nicholas; Czyzyk, Jan

    2016-01-01

    Type 1 diabetes mellitus (T1D) is characterized by a heightened antibody (Ab) response to pancreatic islet self-antigens, which is a biomarker of progressive islet pathology. We recently identified a novel antibody to clade B serpin that reduces islet-associated T cell accumulation and is linked to the delayed onset of T1D. As natural immunity to clade B arises early in life, we hypothesized that it may influence islet development during that time. To test this possibility healthy young Balb/c male mice were injected with serpin B13 mAb or IgG control and examined for the number and cellularity of pancreatic islets by immunofluorescence and FACS. Beta cell proliferation was assessed by measuring nucleotide analog 5-ethynyl-2'-deoxyuridine (5-EdU) incorporation into the DNA and islet Reg gene expression was measured by real time PCR. Human studies involved measuring anti-serpin B13 autoantibodies by Luminex. We found that injecting anti-serpin B13 monoclonal Ab enhanced beta cell proliferation and Reg gene expression, induced the generation of ∼80 pancreatic islets per animal, and ultimately led to increase in the beta cell mass. These findings are relevant to human T1D because our analysis of subjects just diagnosed with T1D revealed an association between baseline anti-serpin activity and slower residual beta cell function decline in the first year after the onset of diabetes. Our findings reveal a new role for the anti-serpin immunological response in promoting adaptive changes in the endocrine pancreas and suggests that enhancement of this response could potentially help impede the progression of T1D in humans.

  8. Antibody Response to Serpin B13 Induces Adaptive Changes in Mouse Pancreatic Islets and Slows Down the Decline in the Residual Beta Cell Function in Children with Recent Onset of Type 1 Diabetes Mellitus*

    PubMed Central

    Kryvalap, Yury; Lo, Chi-Wen; Manuylova, Ekaterina; Baldzizhar, Raman; Jospe, Nicholas; Czyzyk, Jan

    2016-01-01

    Type 1 diabetes mellitus (T1D) is characterized by a heightened antibody (Ab) response to pancreatic islet self-antigens, which is a biomarker of progressive islet pathology. We recently identified a novel antibody to clade B serpin that reduces islet-associated T cell accumulation and is linked to the delayed onset of T1D. As natural immunity to clade B arises early in life, we hypothesized that it may influence islet development during that time. To test this possibility healthy young Balb/c male mice were injected with serpin B13 mAb or IgG control and examined for the number and cellularity of pancreatic islets by immunofluorescence and FACS. Beta cell proliferation was assessed by measuring nucleotide analog 5-ethynyl-2′-deoxyuridine (5-EdU) incorporation into the DNA and islet Reg gene expression was measured by real time PCR. Human studies involved measuring anti-serpin B13 autoantibodies by Luminex. We found that injecting anti-serpin B13 monoclonal Ab enhanced beta cell proliferation and Reg gene expression, induced the generation of ∼80 pancreatic islets per animal, and ultimately led to increase in the beta cell mass. These findings are relevant to human T1D because our analysis of subjects just diagnosed with T1D revealed an association between baseline anti-serpin activity and slower residual beta cell function decline in the first year after the onset of diabetes. Our findings reveal a new role for the anti-serpin immunological response in promoting adaptive changes in the endocrine pancreas and suggests that enhancement of this response could potentially help impede the progression of T1D in humans. PMID:26578518

  9. The acute hormonal response to the kettlebell swing exercise.

    PubMed

    Budnar, Ronald G; Duplanty, Anthony A; Hill, David W; McFarlin, Brian K; Vingren, Jakob L

    2014-10-01

    The purpose of this investigation was to examine the acute hormonal response to the kettlebell swing exercise. Ten recreationally resistance trained men (age, 24 ± 4 years; height, 175 ± 6 cm; body mass, 78.7 ± 9.9 kg) performed 12 rounds of 30 seconds of 16 kg kettlebell swings alternated with 30 seconds of rest. Blood samples were collected before (PRE), immediately after (IP), and 15 (P15) and 30 minutes after exercise (P30) and analyzed for testosterone (T), immunoreactive growth hormone, cortisol (C), and lactate concentrations. Heart rate and rating of perceived exertion were measured at the end of each round. Testosterone was significantly higher (p ≤ 0.05) at IP than at PRE, P15, or P30 (PRE: 28 ± 3; IP: 32 ± 4; P15: 29 ± 3; P30: 27 ± 3 nmol·L). Growth hormone was higher at IP, P15, and P30 than at PRE (PRE: 0.1 ± 0.1; IP: 1.8 ± 1.2; P15: 2.1 ± 1.1; P30: 1.6 ± 1.3 μg·L). Cortisol was higher at IP and P15 than at PRE and P30 (PRE: 617 ± 266; IP: 894 ± 354; P15: 875 ± 243; P30: 645 ± 285 nmol·L). Lactate was higher at IP, P15, and P30 than at PRE (PRE: 1.1 ± 0.5; IP: 7.0 ± 3.0; P15: 4.0 ± 2.7; P30: 2.5 ± 1.8 mmol·L). Heart rate increased progressively from 57 ± 12 at PRE to 170 ± 10 at IP. The exercise protocol produced an acute increase in hormones involved in muscle adaptations. Thus, the kettlebell swing exercise might provide a good supplement to resistance training programs.

  10. Hormones

    MedlinePlus

    ... affect many different processes, including Growth and development Metabolism - how your body gets energy from the foods you eat Sexual function Reproduction Mood Endocrine glands, which are special groups of cells, make hormones. The major endocrine glands are the ...

  11. Role of counterregulatory hormones in the catabolic response to stress.

    PubMed Central

    Gelfand, R A; Matthews, D E; Bier, D M; Sherwin, R S

    1984-01-01

    Patients with major injury or illness develop protein wasting, hypermetabolism, and hyperglycemia with increased glucose flux. To assess the role of elevated counterregulatory hormones in this response, we simultaneously infused cortisol (6 mg/m2 per h), glucagon (4 ng/kg per min), epinephrine (0.6 microgram/m2 per min), and norepinephrine (0.8 micrograms/m2 per min) for 72 h into five obese subjects receiving only intravenous glucose (150 g/d). Four obese subjects received cortisol alone under identical conditions. Combined infusion maintained plasma hormone elevations typical of severe stress for 3 d. This caused a sustained increase in plasma glucose (60-80%), glucose production (100%), and total glucose flux (40%), despite persistent hyperinsulinemia. In contrast, resting metabolic rate changed little (9% rise, P = NS). Urinary nitrogen excretion promptly doubled and remained increased by approximately 4 g/d, reflecting increased excretion of urea and ammonia. Virtually all plasma amino acids declined. The increment in nitrogen excretion was similar in three additional combined infusion studies performed in 3-d fasted subjects not receiving glucose. Cortisol alone produced a smaller glycemic response (20-25%), an initially smaller insulin response, and a delayed rise in nitrogen excretion. By day 3, however, daily nitrogen excretion was equal to the combined group as was the elevation in plasma insulin. Most plasma amino acids rose rather than fell. In both infusion protocols nitrogen wasting was accompanied by only modest increments in 3-methylhistidine excretion (approximately 20-30%) and no significant change in leucine flux. We conclude: (a) Prolonged elevations of multiple stress hormones cause persistent hyperglycemia, increased glucose turnover, and increased nitrogen loss; (b) The sustained nitrogen loss is no greater than that produced by cortisol alone; (c) Glucagon, epinephrine, and norepinephrine transiently augment cortisol-induced nitrogen loss

  12. Growth Hormone Response after Administration of L-dopa, Clonidine, and Growth Hormone Releasing Hormone in Children with Down Syndrome.

    ERIC Educational Resources Information Center

    Pueschel, Seigfried M.

    1993-01-01

    This study of eight growth-retarded children with Down's syndrome (aged 1 to 6.5 years) found that administration of growth hormone was more effective than either L-dopa or clonidine. Results suggest that children with Down's syndrome have both anatomical and biochemical hypothalamic derangements resulting in decreased growth hormone secretion and…

  13. Growth Hormone Response to L-Dopa and Clonidine in Autistic Children.

    ERIC Educational Resources Information Center

    Realmuto, George M.; And Others

    1990-01-01

    Seven medication-free autistic subjects (ages 6-19) were administered clonidine and L-Dopa to investigate neuroendocrine responses through changes in growth hormone levels. Findings showed that, compared to normal controls, the L-Dopa-stimulated growth hormone peak was delayed and the clonidine growth hormone peak was premature. (Author/JDD)

  14. AKT Regulates BRCA1 Stability in Response to Hormone Signaling

    PubMed Central

    Nelson, Andrew C.; Lyons, Traci R.; Young, Christian D.; Hansen, Kirk C.; Anderson, Steven M.; Holt, Jeffrey T.

    2015-01-01

    BRCA1, with its binding partner BARD1, regulates the cellular response to DNA damage in multiple tissues, yet inherited mutations within BRCA1 result specifically in breast and ovarian cancers. This observation, along with several other lines of evidence, suggests a functional relationship may exist between hormone signaling and BRCA1 function. Our data demonstrates that AKT activation promotes the expression of BRCA1 in response to estrogen and IGF-1 receptor signaling. Further, we have identified a novel AKT phosphorylation site in BRCA1 at S694 which is responsive to activation of these signaling pathways. This rapid increase in BRCA1 protein levels appears to occur independently of new protein synthesis and treatment with the clinically utilized proteasome inhibitor bortezomib similarly leads to a rapid increase in BRCA1 protein levels. Together, these data suggest that AKT phosphorylation of BRCA1 increases total protein expression by preventing proteasomal degradation. AKT activation also appears to support nuclear localization of BRCA1, and co-expression of activated AKT with BRCA1 decreases radiation sensitivity, suggesting this interaction has functional consequences for BRCA1's role in DNA repair. We conclude that AKT regulates BRCA1 protein stability and function through direct phosphorylation of BRCA1. Further, the responsiveness of the AKT-BRCA1 regulatory pathway to hormone signaling may, in part, underlie the tissue specificity of BRCA1 mutant cancers. Pharmacological targets within this pathway could provide strategies for modulation of BRCA1 protein, which may prove therapeutically beneficial for the treatment of breast and ovarian cancers. PMID:20085797

  15. Extrahepatic islet transplantation with microporous polymer scaffolds in syngeneic mouse and allogeneic porcine models.

    PubMed

    Gibly, Romie F; Zhang, Xiaomin; Graham, Melanie L; Hering, Bernhard J; Kaufman, Dixon B; Lowe, William L; Shea, Lonnie D

    2011-12-01

    Intraportal transplantation of islets has successfully treated select patients with type 1 diabetes. However, intravascular infusion and the intrahepatic site contribute to significant early and late islet loss, yet a clinical alternative has remained elusive. We investigated non-encapsulating, porous, biodegradable polymer scaffolds as a vehicle for islet transplantation into extrahepatic sites, using syngeneic mouse and allogeneic porcine models. Scaffold architecture was modified to enhance cell infiltration leading to revascularization of the islets with minimal inflammatory response. In the diabetic mouse model, 125 islets seeded on scaffolds implanted into the epididymal fat pad restored normoglycemia within an average of 1.95 days and transplantation of only 75 islets required 12.1 days. Increasing the pore size to increase islet-islet interactions did not significantly impact islet function. The porcine model was used to investigate early islet engraftment. Increasing the islet seeding density led to a greater mass of engrafted islets, though the efficiency of islet survival decreased. Transplantation into the porcine omentum provided greater islet engraftment than the gastric submucosa. These results demonstrate scaffolds support murine islet transplantation with high efficiency, and feasibility studies in large animals support continued pre-clinical studies with scaffolds as a platform to control the transplant microenvironment.

  16. Development of gonadotropin-releasing hormone secretion and pituitary response.

    PubMed

    Glanowska, Katarzyna M; Burger, Laura L; Moenter, Suzanne M

    2014-11-05

    Acquisition of a mature pattern of gonadotropin-releasing hormone (GnRH) secretion from the CNS is a hallmark of the pubertal process. Little is known about GnRH release during sexual maturation, but it is assumed to be minimal before later stages of puberty. We studied spontaneous GnRH secretion in brain slices from male mice during perinatal and postnatal development using fast-scan cyclic voltammetry (FSCV) to detect directly the oxidation of secreted GnRH. There was good correspondence between the frequency of GnRH release detected by FSCV in the median eminence of slices from adults with previous reports of in vivo luteinizing hormone (LH) pulse frequency. The frequency of GnRH release in the late embryonic stage was surprisingly high, reaching a maximum in newborns and remaining elevated in 1-week-old animals despite low LH levels. Early high-frequency GnRH release was similar in wild-type and kisspeptin knock-out mice indicating that this release is independent of kisspeptin-mediated excitation. In vivo treatment with testosterone or in vitro treatment with gonadotropin-inhibitory hormone (GnIH) reduced GnRH release frequency in slices from 1-week-old mice. RF9, a putative GnIH antagonist, restored GnRH release in slices from testosterone-treated mice, suggesting that testosterone inhibition may be GnIH-dependent. At 2-3 weeks, GnRH release is suppressed before attaining adult patterns. Reduction in early life spontaneous GnRH release frequency coincides with the onset of the ability of exogenous GnRH to induce pituitary LH secretion. These findings suggest that lack of pituitary secretory response, not lack of GnRH release, initially blocks downstream activation of the reproductive system.

  17. Postprandial parathyroid hormone response to four calcium-rich foodstuffs.

    PubMed

    Kärkkäinen, M U; Wiersma, J W; Lamberg-Allardt, C J

    1997-06-01

    We studied the effects of four calcium-rich foodstuffs on postprandial parathyroid hormone secretion. Four hundred milligrams calcium from either Emmental cheese, milk, sesame seeds, spinach, or calcium salt (calcium lactate gluconate + calcium carbonate) or no additional calcium (control session) were given to nine female volunteers immediately after a first blood sample (at 0900) in random order with a light standardized meal containing 37 mg Ca. Blood samples were taken at 0900 (before the calcium load), 1000, 1100, 1300, and 1500 at every study session. Urine was collected during the sessions. Serum ionized calcium, phosphate, magnesium, intact parathyroid hormone, and urinary calcium excretion were measured. The serum ionized calcium concentration increased significantly after ingesting cheese (P = 0.004, contrast analysis) or calcium salt (P = 0.05, contrast analysis) compared with the control session. Compared with the control session, the serum phosphate concentration increased after the cheese session (P = 0.004, contrast analysis) and after the milk session (P = 0.02, contrast analysis). Calcium salt (P = 0.007, contrast analysis) and cheese (P = 0.002, contrast analysis) caused a significant decline in serum intact parathyroid hormone compared with the control session. The urinary calcium excretion with cheese was 141% (P = 0.001), with milk was 107% (P = 0.004), and with calcium salt was 75% (P = 0.02) above that of the control session. Our results show that calcium from sesame seeds and spinach does not cause an acute response in calcium metabolism. Our results indicate that fermented cheese could be a better dietary source of calcium than milk when the metabolic effects of the foodstuffs are considered.

  18. Microfluidic platform for assessing pancreatic islet functionality through dielectric spectroscopy

    PubMed Central

    Heileman, K.; Daoud, J.; Hasilo, C.; Gasparrini, M.; Paraskevas, S.; Tabrizian, M.

    2015-01-01

    Human pancreatic islets are seldom assessed for dynamic responses to external stimuli. Thus, the elucidation of human islet functionality would provide insights into the progression of diabetes mellitus, evaluation of preparations for clinical transplantation, as well as for the development of novel therapeutics. The objective of this study was to develop a microfluidic platform for in vitro islet culture, allowing the multi-parametric investigation of islet response to chemical and biochemical stimuli. This was accomplished through the fabrication and implementation of a microfluidic platform that allowed the perifusion of islet culture while integrating real-time monitoring using impedance spectroscopy, through microfabricated, interdigitated electrodes located along the microchamber arrays. Real-time impedance measurements provide important dielectric parameters, such as cell membrane capacitance and cytoplasmic conductivity, representing proliferation, differentiation, viability, and functionality. The perifusion of varying glucose concentrations and monitoring of the resulting impedance of pancreatic islets were performed as proof-of-concept validation of the lab-on-chip platform. This novel technique to elucidate the underlying mechanisms that dictate islet functionality is presented, providing new information regarding islet function that could improve the evaluation of islet preparations for transplantation. In addition, it will lead to a better understanding of fundamental diabetes-related islet dysfunction and the development of therapeutics through evaluation of potential drug effects. PMID:26339324

  19. Islet formation in mice and men: lessons for the generation of functional insulin-producing β-cells from human pluripotent stem cells.

    PubMed

    Nair, Gopika; Hebrok, Matthias

    2015-06-01

    The Islets of Langerhans are crucial 'micro-organs' embedded in the glandular exocrine pancreas that regulate nutrient metabolism. They not only synthesize, but also secrete endocrine hormones in a modulated fashion in response to physiologic metabolic demand. These highly sophisticated structures with intricate organization of multiple cell types, namely endocrine, vascular, neuronal and mesenchymal cells, have evolved to perform this task to perfection over time. Not surprisingly, islet architecture and function are dissimilar between humans and typically studied model organisms, such as rodents and zebrafish. Further, recent findings also suggest noteworthy differences in human islet development from that in mouse, including delayed appearance and gradual resolution of key differentiation markers, a single-phase of endocrine differentiation, and prenatal association of developing islets with neurovascular milieu. In light of these findings, it is imperative that a systematic study is undertaken to compare islet development between human and mouse. Illuminating inter-species differences in islet development will likely be critical in furthering our pursuit to generate an unlimited supply of truly functional and fully mature β-cells from human pluripotent stem cell (hPSC) sources for therapeutic purposes.

  20. Single-Cell Phenotypic Characterization of Human Pituitary GHomas and Non-Functioning Adenomas Based on Hormone Content and Calcium Responses to Hypothalamic Releasing Hormones.

    PubMed

    Senovilla, Laura; Núñez, Lucía; de Campos, José María; de Luis, Daniel A; Romero, Enrique; García-Sancho, Javier; Villalobos, Carlos

    2015-01-01

    Human pituitary tumors are generally benign adenomas causing considerable morbidity due to excess hormone secretion, hypopituitarism, and other tumor mass effects. Pituitary tumors are highly heterogeneous and difficult to type, often containing mixed cell phenotypes. We have used calcium imaging followed by multiple immunocytochemistry to type growth hormone secreting (GHomas) and non-functioning pituitary adenomas (NFPAs). Individual cells were typed for stored hormones and calcium responses to classic hypothalamic releasing hormones (HRHs). We found that GHomas contained growth hormone cells either lacking responses to HRHs or responding to all four HRHs. However, most GHoma cells were polyhormonal cells responsive to both thyrotropin-releasing hormone (TRH) and GH-releasing hormone. NFPAs were also highly heterogeneous. Some of them contained ACTH cells lacking responses to HRHs or polyhormonal gonadotropes responsive to LHRH and TRH. However, most NFPAs were made of cells storing no hormone and responded only to TRH. These results may provide new insights on the ontogeny of GHomas and NFPAs.

  1. Growth hormone response to apomorphine in obsessive-compulsive disorder.

    PubMed Central

    Pitchot, W; Hansenne, M; Moreno, A G; Ansseau, M

    1996-01-01

    Several lines of evidence suggest that dopamine plays a role in the pathophysiology of obsessive-compulsive disorder (OCD). Indeed, some trials have shown the efficacy of neuroleptic addition in the treatment of OCD patients. In this study, we assessed the growth hormone (GH) response to 0.5 mg apomorphine(sc) in 8 drug-free inpatients (6 male, 2 female; mean age +/- SD = 34.7 +/- 12.6) meeting DSM-III-R criteria for OCD without major depression and compared their responses with those of 8 healthy male volunteers (mean age = 27.1 +/- 8.5). The groups did not differ in their mean GH peak response: 12.4 +/- 9.7 ng/mL in OCD patients versus 21.1 +/- 14.2 ng/mL in normal controls (F = 0.9, df1, 14, P = 0.37). These results do not support the hypothesis of dopaminergic overactivity in OCD. In fact, the completely blunted GH response to apomorphine in 2 OCD patients suggests the biological heterogeneity of OCD. Some dopaminergic disturbances could be observed in patients with comorbid diagnoses or patients unresponsive to serotonin reuptake inhibitors, but the results of this study require confirmation from a larger sample with a precise assessment of comorbidity. PMID:8973055

  2. Sympathomimetic pressor responses to thyrotropin-releasing hormone in rats

    SciTech Connect

    Mattila, J.; Bunag, R.D.

    1986-07-01

    Cardiovascular responses to centrally administered thyrotropin-releasing hormone (TRH) were studied in urethan-anesthetized rats to allow continuous recording of attendant changes in sympathetic nerve activity. Intracerebroventricular infusions of TRH consistently increased not only blood pressure and heart rate, but also spike frequency in splanchnic, renal, or cervical sympathetic nerves. Parasympathetic inhibition seemed unlikely because TRH responses were unaltered by cholinergic blockade with atropine, and efferent vagal nerve firing, instead of being reduced, was actually increased by TRH. An increased secretion of endogenous vasopressin also appeared unlikely, since TRH responses were essentially unaffected by either hypophysectomy or pretreatment with a vasopressin antagonist. Inasmuch as pharmacological ganglion blockade with pentolinium eliminated increases in splanchnic nerve firing but reduced the attendant tachycardia by only 50%, residual tachycardia after ganglion blockade was considered partly due to persistent sympathetic cardioaccelerator tone. On the other hand, because pressor responses to TRH were always accompanied by increased sympathetic nerve firing and were completely abolished after pentolinium-induced ganglioplegia, they were attributed solely to sympathetic hyperactivity.

  3. Hormonal contraceptives, menstrual cycle and brain response to faces

    PubMed Central

    Marečková, Klara; Perrin, Jennifer S.; Nawaz Khan, Irum; Lawrence, Claire; Dickie, Erin; McQuiggan, Doug A.

    2014-01-01

    Both behavioral and neuroimaging evidence support a female advantage in the perception of human faces. Here we explored the possibility that this relationship may be partially mediated by female sex hormones by investigating the relationship between the brain’s response to faces and the use of oral contraceptives, as well as the phase of the menstrual cycle. First, functional magnetic resonance images were acquired in 20 young women [10 freely cycling and 10 taking oral contraception (OC)] during two phases of their cycle: mid-cycle and menstruation. We found stronger neural responses to faces in the right fusiform face area (FFA) in women taking oral contraceptives (vs freely cycling women) and during mid-cycle (vs menstruation) in both groups. Mean blood oxygenation level-dependent response in both left and right FFA increased as function of the duration of OC use. Next, this relationship between the use of OC and FFA response was replicated in an independent sample of 110 adolescent girls. Finally in a parallel behavioral study carried out in another sample of women, we found no evidence of differences in the pattern of eye movements while viewing faces between freely cycling women vs those taking oral contraceptives. The imaging findings might indicate enhanced processing of social cues in women taking OC and women during mid-cycle. PMID:23175677

  4. Hormonal contraceptives, menstrual cycle and brain response to faces.

    PubMed

    Marecková, Klara; Perrin, Jennifer S; Nawaz Khan, Irum; Lawrence, Claire; Dickie, Erin; McQuiggan, Doug A; Paus, Tomás

    2014-02-01

    Both behavioral and neuroimaging evidence support a female advantage in the perception of human faces. Here we explored the possibility that this relationship may be partially mediated by female sex hormones by investigating the relationship between the brain's response to faces and the use of oral contraceptives, as well as the phase of the menstrual cycle. First, functional magnetic resonance images were acquired in 20 young women [10 freely cycling and 10 taking oral contraception (OC)] during two phases of their cycle: mid-cycle and menstruation. We found stronger neural responses to faces in the right fusiform face area (FFA) in women taking oral contraceptives (vs freely cycling women) and during mid-cycle (vs menstruation) in both groups. Mean blood oxygenation level-dependent response in both left and right FFA increased as function of the duration of OC use. Next, this relationship between the use of OC and FFA response was replicated in an independent sample of 110 adolescent girls. Finally in a parallel behavioral study carried out in another sample of women, we found no evidence of differences in the pattern of eye movements while viewing faces between freely cycling women vs those taking oral contraceptives. The imaging findings might indicate enhanced processing of social cues in women taking OC and women during mid-cycle.

  5. Hormonal responses to psychological stress in men preparing for skydiving.

    PubMed

    Chatterton, R T; Vogelsong, K M; Lu, Y C; Hudgens, G A

    1997-08-01

    The purpose of the study was to examine the relationship between the hormonal and psychological responses of young men about to engage in a potentially life-threatening event. Subjects were recruited to take their first skydiving jump. The scores on questionnaires designed to assess anxiety were not significantly increased at 0800 h on the morning before the jump by comparison with scores obtained from the same subjects 3-5 days previously. However, a psychological instrument for rating of events indicated significantly increased intensity, and sympathetic nervous system activity, as measured by the salivary amylase response, was increased over self-control values. Salivary cortisol and testosterone levels were significantly lower on the morning of the jump than self-control values and values in control subjects determined at the same time of day. However, plasma LH was not suppressed. The anxiety and stress measures as well as the rating of events rose to high levels just before the jump. With the exception of testosterone, which remained low, serum cortisol, PRL, and GH all increased greatly subsequent to the rise in psychological measures, reached peak values before or shortly after landing, and declined significantly within the next hour. Anxiety and subjective stress scores declined to those of the self-control values within 15 min after landing, but the rating of events scale remained significantly elevated. In summary, reported anxiety associated with a purely psychological stressor was suppressed until within a few hours preceding the event, but was preceded by an increase in sympathetic nervous system activity and suppression of plasma cortisol and salivary testosterone levels. The event itself was associated with a reversal of the cortisol decline; other stress-associated hormones increased, but salivary testosterone remained low.

  6. Postprandial gut hormone responses and glucose metabolism in cholecystectomized patients.

    PubMed

    Sonne, David P; Hare, Kristine J; Martens, Pernille; Rehfeld, Jens F; Holst, Jens J; Vilsbøll, Tina; Knop, Filip K

    2013-02-15

    Preclinical studies suggest that gallbladder emptying, via bile acid-induced activation of the G protein-coupled receptor TGR5 in intestinal L cells, may play a significant role in the secretion of the incretin hormone glucagon-like peptide-1 (GLP-1) and, hence, postprandial glucose homeostasis. We examined the secretion of gut hormones in cholecystectomized subjects to test the hypothesis that gallbladder emptying potentiates postprandial release of GLP-1. Ten cholecystectomized subjects and 10 healthy, age-, gender-, and body mass index-matched control subjects received a standardized fat-rich liquid meal (2,200 kJ). Basal and postprandial plasma concentrations of glucose, insulin, C-peptide, glucagon, GLP-1, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-2 (GLP-2), cholecystokinin (CCK), and gastrin were measured. Furthermore, gastric emptying and duodenal and serum bile acids were measured. We found similar basal glucose concentrations in the two groups, whereas cholecystectomized subjects had elevated postprandial glucose excursions. Cholecystectomized subjects had reduced postprandial concentrations of duodenal bile acids, but preserved postprandial plasma GLP-1 responses, compared with control subjects. Also, cholecystectomized patients exhibited augmented fasting glucagon. Basal plasma CCK concentrations were lower and peak concentrations were higher in cholecystectomized patients. The concentrations of GIP, GLP-2, and gastrin were similar in the two groups. In conclusion, cholecystectomized subjects had preserved postprandial GLP-1 responses in spite of decreased duodenal bile delivery, suggesting that gallbladder emptying is not a prerequisite for GLP-1 release. Cholecystectomized patients demonstrated a slight deterioration of postprandial glycemic control, probably because of metabolic changes unrelated to incretin secretion.

  7. A Method for Performing Islet Transplantation Using Tissue-Engineered Sheets of Islets and Mesenchymal Stem Cells

    PubMed Central

    Hirabaru, Masataka; Kuroki, Tamotsu; Adachi, Tomohiko; Kitasato, Amane; Ono, Shinichiro; Tanaka, Takayuki; Matsushima, Hajime; Sakai, Yusuke; Soyama, Akihiko; Hidaka, Masaaki; Yamanouchi, Kosho; Takatsuki, Mitsuhisa; Okano, Teruo

    2015-01-01

    Mesenchymal stem cells (MSCs) are known to have a protective effect on islet cells. Cell sheets developed using tissue engineering help maintain the function of the cells themselves. This study describes a tissue engineering approach using islets with MSC sheets to improve the therapeutic effect of islet transplantation. MSCs were obtained from Fischer 344 rats and engineered into cell sheets using temperature-responsive culture dishes. The islets obtained from Fischer 344 rats were seeded onto MSC sheets, and the islets with MSC sheets were harvested by low-temperature treatment after coculture. The functional activity of the islets with MSC sheets was confirmed by a histological examination, insulin secretion assay, and quantification of the levels of cytokines. The therapeutic effects of the islets with MSC sheets were investigated by transplanting the sheets at subcutaneous sites in severe combined immunodeficiency (SCID) mice with streptozotocin-induced diabetes. Improvement of islet function and viability was shown in situ on the MSC sheet, and the histological examination showed that the MSC sheet maintained adhesion factor on the surface. In the recipient mice, normoglycemia was maintained for at least 84 days after transplantation, and neovascularization was observed. These results demonstrated that islet transplantation in a subcutaneous site would be possible by using the MSC sheet as a scaffold for islets. PMID:26066973

  8. Thyroid hormone responsive QTL and the evolution of paedomorphic salamanders.

    PubMed

    Voss, S R; Kump, D K; Walker, J A; Shaffer, H B; Voss, G J

    2012-11-01

    The transformation of ancestral phenotypes into novel traits is poorly understood for many examples of evolutionary novelty. Ancestrally, salamanders have a biphasic life cycle with an aquatic larval stage, a brief and pronounced metamorphosis, followed by a terrestrial adult stage. Repeatedly during evolution, metamorphic timing has been delayed to exploit growth-permissive environments, resulting in paedomorphic salamanders that retain larval traits as adults. We used thyroid hormone (TH) to rescue metamorphic phenotypes in paedomorphic salamanders and then identified quantitative trait loci (QTL) for life history traits that are associated with amphibian life cycle evolution: metamorphic timing and adult body size. We demonstrate that paedomorphic tiger salamanders (Ambystoma tigrinum complex) carry alleles at three moderate effect QTL (met1-3) that vary in responsiveness to TH and additively affect metamorphic timing. Salamanders that delay metamorphosis attain significantly larger body sizes as adults and met2 explains a significant portion of this variation. Thus, substitution of alleles at TH-responsive loci suggests an adaptive pleiotropic basis for two key life-history traits in amphibians: body size and metamorphic timing. Our study demonstrates a likely pathway for the evolution of novel paedomorphic species from metamorphic ancestors via selection of TH-response alleles that delay metamorphic timing and increase adult body size.

  9. Thyroid hormone responsive QTL and the evolution of paedomorphic salamanders

    PubMed Central

    Voss, S R; Kump, D K; Walker, J A; Shaffer, H B; Voss, G J

    2012-01-01

    The transformation of ancestral phenotypes into novel traits is poorly understood for many examples of evolutionary novelty. Ancestrally, salamanders have a biphasic life cycle with an aquatic larval stage, a brief and pronounced metamorphosis, followed by a terrestrial adult stage. Repeatedly during evolution, metamorphic timing has been delayed to exploit growth-permissive environments, resulting in paedomorphic salamanders that retain larval traits as adults. We used thyroid hormone (TH) to rescue metamorphic phenotypes in paedomorphic salamanders and then identified quantitative trait loci (QTL) for life history traits that are associated with amphibian life cycle evolution: metamorphic timing and adult body size. We demonstrate that paedomorphic tiger salamanders (Ambystoma tigrinum complex) carry alleles at three moderate effect QTL (met1–3) that vary in responsiveness to TH and additively affect metamorphic timing. Salamanders that delay metamorphosis attain significantly larger body sizes as adults and met2 explains a significant portion of this variation. Thus, substitution of alleles at TH-responsive loci suggests an adaptive pleiotropic basis for two key life-history traits in amphibians: body size and metamorphic timing. Our study demonstrates a likely pathway for the evolution of novel paedomorphic species from metamorphic ancestors via selection of TH-response alleles that delay metamorphic timing and increase adult body size. PMID:22850698

  10. Human Islets Exhibit Electrical Activity on Microelectrode Arrays (MEA).

    PubMed

    Schönecker, S; Kraushaar, U; Guenther, E; Gerst, F; Ullrich, S; Häring, H-U; Königsrainer, A; Barthlen, W; Drews, G; Krippeit-Drews, P

    2015-05-01

    This study demonstrates for the first time that the microelectrode array (MEA) technique allows analysis of electrical activity of islets isolated from human biopsies. We have shown before that this method, i.e., measuring beta cell electrical activity with extracellular electrodes, is a powerful tool to assess glucose responsiveness of isolated murine islets. In the present study, human islets were shown to exhibit glucose-dependent oscillatory electrical activity. The glucose responsiveness could be furthermore demonstrated by an increase of insulin secretion in response to glucose. Electrical activity was increased by tolbutamide and inhibited by diazoxide. In human islets bursts of electrical activity were markedly blunted by the Na(+) channel inhibitor tetrodotoxin which does not affect electrical activity in mouse islets. Thus, the MEA technique emerges as a powerful tool to decipher online the unique features of human islets.Additionally, this technique will enable research with human islets even if only a few islets are available and it will allow a fast and easy test of metabolic integrity of islets destined for transplantation.

  11. Islet cell hyperexpression of HLA class I antigens: a defining feature in type 1 diabetes

    PubMed Central

    Rodriguez-Calvo, Teresa; Gerling, Ivan C.; Mathews, Clayton E.; Kaddis, John S.; Russell, Mark A.; Zeissler, Marie; Leete, Pia; Krogvold, Lars; Dahl-Jørgensen, Knut; von Herrath, Matthias; Pugliese, Alberto; Atkinson, Mark A.

    2016-01-01

    Aims/hypothesis Human pancreatic beta cells may be complicit in their own demise in type 1 diabetes, but how this occurs remains unclear. One potentially contributing factor is hyperexpression of HLA class I antigens. This was first described approximately 30 years ago, but has never been fully characterised and was recently challenged as artefactual. Therefore, we investigated HLA class I expression at the protein and RNA levels in pancreases from three cohorts of patients with type 1 diabetes. The principal aims were to consider whether HLA class I hyperexpression is artefactual and, if not, to determine the factors driving it. Methods Pancreas samples from type 1 diabetes patients with residual insulin-containing islets (n = 26) from the Network for Pancreatic Organ donors with Diabetes (nPOD), Diabetes Virus Detection study (DiViD) and UK recent-onset type 1 diabetes collections were immunostained for HLA class I isoforms, signal transducer and activator of transcription 1 (STAT1), NLR family CARD domain containing 5 (NLRC5) and islet hormones. RNA was extracted from islets isolated by laser-capture microdissection from nPOD and DiViD samples and analysed using gene-expression arrays. Results Hyperexpression of HLA class I was observed in the insulin-containing islets of type 1 diabetes patients from all three tissue collections, and was confirmed at both the RNA and protein levels. The expression of β2-microglobulin (a second component required for the generation of functional HLA class I complexes) was also elevated. Both ‘classical’ HLA class I isoforms (i.e. HLA-ABC) as well as a ‘non-classical’ HLA molecule, HLA-F, were hyperexpressed in insulin-containing islets. This hyperexpression did not correlate with detectable upregulation of the transcriptional regulator NLRC5. However, it was strongly associated with increased STAT1 expression in all three cohorts. Islet hyperexpression of HLA class I molecules occurred in the insulin-containing islets

  12. Cyproheptadine metabolites inhibit proinsulin and insulin biosynthesis and insulin release in isolated rat pancreatic islets

    SciTech Connect

    Chow, S.A.; Falany, J.L.; Fischer, L.J. )

    1989-06-01

    The contribution of drug metabolites to cyproheptadine (CPH)-induced alterations in endocrine pancreatic beta-cells was investigated by examining the inhibitory activity of CPH and its biotransformation products, desmethylcyproheptadine (DMCPH), CPH-epoxide and DMCPH-epoxide, on hormone biosynthesis and secretion in pancreatic islets isolated from 50-day-old rats. Measurement of (pro)insulin (proinsulin and insulin) synthesis using incorporation of 3H-leucine showed that DMCPH-epoxide, DMCPH and CPH-epoxide were 22, 10 and 4 times, respectively, more potent than CPH in inhibiting hormone synthesis. The biosynthesis of (pro)insulin was also inhibited by CPH and DMCPH-epoxide in islets isolated from 21-day-old rat fetuses. The inhibitory action of CPH and its metabolites was apparently specific for (pro)insulin, and the synthesis of other islet proteins was not affected. Other experiments showed the metabolites of CPH were active in inhibiting glucose-stimulated insulin secretion but were less potent than the parent drug in producing this effect. CPH and its structurally related metabolites, therefore, have differential inhibitory activities on insulin synthesis and release. The observation that CPH metabolites have higher potency than CPH to inhibit (pro)insulin synthesis, when considered with published reports on the disposition of the drug in rats, indicate that CPH metabolites, particularly DMCPH-epoxide, are primarily responsible for the insulin depletion observed when the parent compound is given to fetal and adult animals.

  13. Heterogeneity and nearest-neighbor coupling can explain small-worldness and wave properties in pancreatic islets

    NASA Astrophysics Data System (ADS)

    Cappon, Giacomo; Pedersen, Morten Gram

    2016-05-01

    Many multicellular systems consist of coupled cells that work as a syncytium. The pancreatic islet of Langerhans is a well-studied example of such a microorgan. The islets are responsible for secretion of glucose-regulating hormones, mainly glucagon and insulin, which are released in distinct pulses. In order to observe pulsatile insulin secretion from the β-cells within the islets, the cellular responses must be synchronized. It is now well established that gap junctions provide the electrical nearest-neighbor coupling that allows excitation waves to spread across islets to synchronize the β-cell population. Surprisingly, functional coupling analysis of calcium responses in β-cells shows small-world properties, i.e., a high degree of local coupling with a few long-range "short-cut" connections that reduce the average path-length greatly. Here, we investigate how such long-range functional coupling can appear as a result of heterogeneity, nearest-neighbor coupling, and wave propagation. Heterogeneity is also able to explain a set of experimentally observed synchronization and wave properties without introducing all-or-none cell coupling and percolation theory. Our theoretical results highlight how local biological coupling can give rise to functional small-world properties via heterogeneity and wave propagation.

  14. Islet transplantation: immunological perspectives.

    PubMed

    Inverardi, Luca; Kenyon, Norma S; Ricordi, Camillo

    2003-10-01

    Clinical trials of islet transplantation are showing remarkable success, but they require administration of chronic immunosuppression, and are underscoring the large gap that exists between the number of human donors available and the number of patients that could benefit from the procedure. Recent progress has been made in the definition of key immunological mechanisms that are involved in determining islet transplant outcome. Clinical and preclinical studies, and studies in small animal model systems, will all eventually contribute to the definition of efficient and safe protocols for islet transplantation. If the use of xenografts is successful, it might represent a solution to the shortage of human organs.

  15. Hormonal and cardiovascular responses to DDAVP in man.

    PubMed

    Williams, T D; Lightman, S L; Leadbeater, M J

    1986-01-01

    Hormonal and cardiovascular responses to 1-desamino-8-D-arginine vasopressin (DDAVP) were investigated in six normal adult volunteers. After overnight fluid deprivation, an intravenous injection of either DDAVP (0.4 microgram/kg) or the same volume of normal saline was administered. One hour later an intravenous infusion of hypertonic saline was commenced and continued over two hours. Five minutes following the DDAVP injection, facial flushing, a fall in diastolic blood pressure by an average of 13% and a rise in pulse rate by an average of 18% were observed. There was a significant increase in plasma renin activity and plasma cortisol concentration, but no significant changes were observed in plasma concentrations of LH, FSH, TSH, prolactin or GH. Following osmotic stimulation by hypertonic saline plasma AVP rose to the same extent in both the DDAVP and control studies. DDAVP (0.4 microgram/kg) was also administered to five subjects with cranial diabetes insipidus. Again facial flushing, increased facial temperature, a fall in diastolic pressure and a rise in heart rate were all observed, suggesting that DDAVP exerts its cardiovascular actions by a mechanism other than antagonism of circulating endogenous AVP.

  16. Luteinizing hormone release and androgen production of avian hybrids in response to luteinizing hormone releasing hormone injection.

    PubMed

    Mathis, G F; Burke, W H; McDougald, L R

    1983-04-01

    The levels of luteinizing hormone (LH) and androgens were measured in sterile avian hybrids. Guinea fowl-chicken and peafowl-guinea fowl hybrids were bled before and after injection with LH- releasing hormone (LHRH). The preinjection LH levels for the guinea fowl-chicken hybrids were below or at the very lower limit of the assay sensitivity and the peafowl-guinea fowl hybrids averaged 1.3 ng/ml. Within 10 min after LHRH injection, LH had increased dramatically in both hybrids and then began to slowly decline. Androgen levels in the guinea fowl-chicken hybrids increased from 16.2 pg/ml to 95.2 pg/ml and continued to increase, reaching 287 pg/ml at the last bleeding 60 min after injection.

  17. Normal pituitary hormone response to thyrotrophin and gonadotrophin releasing hormones in subjects exposed to elemental mercury vapour.

    PubMed Central

    Erfurth, E M; Schütz, A; Nilsson, A; Barregård, L; Skerfving, S

    1990-01-01

    Exposure to elemental mercury (Hg) vapour results in an accumulation of Hg in the pituitary, the thyroid, and the testis. In this study, basal serum concentrations of pituitary hormones (thyrotrophin (TSH), prolactin (PRL), follicle stimulating hormone (FSH), and luteinising hormone (LH] or their response after administration of thyrotrophin and gonadotrophin releasing hormones did not differ between 11 male workers (mean urinary Hg (U Hg) concentration 26 nmol/mmol creatinine) and nine male dentists (U Hg concentration 1.3 nmol/mmol creatinine) exposed to elemental Hg vapour when compared with matched referent groups (U Hg concentration 0.6 and 0.4 nmol/mmol creatinine). Thus there was no evidence of an effect of Hg on the pituitary. Neither was there any association between exposure to Hg and serum concentrations of free thyroid hormones (S FT3, S FT4), testosterone, or cortisol. Increased plasma concentrations of selenium (Se) were associated with increased basal serum concentrations of TSH, decreased concentrations of basal serum cortisol, and decreased release of FSH. PMID:2119795

  18. Phenotypic integration and independence: Hormones, performance, and response to environmental change

    PubMed Central

    Ketterson, Ellen D.; Atwell, Jonathan W.; McGlothlin, Joel W.

    2009-01-01

    Hormones coordinate the co-expression of behavioral, physiological, and morphological traits, giving rise to correlations among traits and organisms whose parts work well together. This article considers the implications of these hormonal correlations with respect to the evolution of hormone-mediated traits. Such traits can evolve owing to changes in hormone secretion, hormonal affinity for carrier proteins, rates of degradation and conversion, and interaction with target tissues to name a few. Critically, however, we know very little about whether these changes occur independently or in tandem, and thus whether hormones promote the evolution of tight phenotypic integration or readily allow the parts of the phenotype to evolve independently. For example, when selection favors a change in expression of hormonally mediated characters, is that alteration likely to come about through changes in hormone secretion (signal strength), changes in response to a fixed level of secretion (sensitivity of target tissues), or both? At one extreme, if the phenotype is tightly integrated and only the signal responds via selection's action on one or more hormonally mediated traits, adaptive modification may be constrained by past selection for phenotypic integration. Alternatively, response to selection may be facilitated if multivariate selection favors new combinations that can be easily achieved by a change in signal strength. On the other hand, if individual target tissues readily “unplug” from a hormone signal in response to selection, then the phenotype may be seen as a loose confederation that responds on a trait-by-trait basis, easily allowing adaptive modification, although perhaps more slowly than if signal variation were the primary mode of evolutionary response. Studies reviewed here and questions for future research address the relative importance of integration and independence by comparing sexes, individuals, and populations. Most attention is devoted to the

  19. A mathematical model of pulse-coded hormone signal responses in pituitary gonadotroph cells

    PubMed Central

    Magill, John C.; Ciccone, Nick A.; Kaiser, Ursula B.

    2014-01-01

    Cells in the pituitary that synthesize luteinizing and follicle-stimulating hormones regulate the relative production of these two key reproductive hormones in response to signals from the hypothalamus. These signals are encoded in the frequency of gonadotrophin-releasing-hormone pulses. In vitro experiments with a murine-derived cell line have identified key elements of the processes that decode the signal to regulate transcription of the subunits encoding these hormones. The mathematical model described in this paper is based on the results of those experiments and advances quantitative understanding of the biochemical decoder. The model consists of non-linear differential equations for each of six processes that lead to the synthesis of follicle-stimulating hormone. Simulations of the model exhibit key characteristics found in the experiments, including a preference for follicle-stimulating hormone synthesis at low pulse frequencies and a loss of this characteristic when a mutation is introduced. PMID:24095971

  20. Fetal endocannabinoids orchestrate the organization of pancreatic islet microarchitecture.

    PubMed

    Malenczyk, Katarzyna; Keimpema, Erik; Piscitelli, Fabiana; Calvigioni, Daniela; Björklund, Peyman; Mackie, Kenneth; Di Marzo, Vincenzo; Hökfelt, Tomas G M; Dobrzyn, Agnieszka; Harkany, Tibor

    2015-11-10

    Endocannabinoids are implicated in the control of glucose utilization and energy homeostasis by orchestrating pancreatic hormone release. Moreover, in some cell niches, endocannabinoids regulate cell proliferation, fate determination, and migration. Nevertheless, endocannabinoid contributions to the development of the endocrine pancreas remain unknown. Here, we show that α cells produce the endocannabinoid 2-arachidonoylglycerol (2-AG) in mouse fetuses and human pancreatic islets, which primes the recruitment of β cells by CB1 cannabinoid receptor (CB1R) engagement. Using subtractive pharmacology, we extend these findings to anandamide, a promiscuous endocannabinoid/endovanilloid ligand, which impacts both the determination of islet size by cell proliferation and α/β cell sorting by differential activation of transient receptor potential cation channel subfamily V member 1 (TRPV1) and CB1Rs. Accordingly, genetic disruption of TRPV1 channels increases islet size whereas CB1R knockout augments cellular heterogeneity and favors insulin over glucagon release. Dietary enrichment in ω-3 fatty acids during pregnancy and lactation in mice, which permanently reduces endocannabinoid levels in the offspring, phenocopies CB1R(-/-) islet microstructure and improves coordinated hormone secretion. Overall, our data mechanistically link endocannabinoids to cell proliferation and sorting during pancreatic islet formation, as well as to life-long programming of hormonal determinants of glucose homeostasis.

  1. Fetal endocannabinoids orchestrate the organization of pancreatic islet microarchitecture

    PubMed Central

    Malenczyk, Katarzyna; Keimpema, Erik; Piscitelli, Fabiana; Calvigioni, Daniela; Björklund, Peyman; Mackie, Kenneth; Di Marzo, Vincenzo; Hökfelt, Tomas G. M.; Dobrzyn, Agnieszka; Harkany, Tibor

    2015-01-01

    Endocannabinoids are implicated in the control of glucose utilization and energy homeostasis by orchestrating pancreatic hormone release. Moreover, in some cell niches, endocannabinoids regulate cell proliferation, fate determination, and migration. Nevertheless, endocannabinoid contributions to the development of the endocrine pancreas remain unknown. Here, we show that α cells produce the endocannabinoid 2-arachidonoylglycerol (2-AG) in mouse fetuses and human pancreatic islets, which primes the recruitment of β cells by CB1 cannabinoid receptor (CB1R) engagement. Using subtractive pharmacology, we extend these findings to anandamide, a promiscuous endocannabinoid/endovanilloid ligand, which impacts both the determination of islet size by cell proliferation and α/β cell sorting by differential activation of transient receptor potential cation channel subfamily V member 1 (TRPV1) and CB1Rs. Accordingly, genetic disruption of TRPV1 channels increases islet size whereas CB1R knockout augments cellular heterogeneity and favors insulin over glucagon release. Dietary enrichment in ω-3 fatty acids during pregnancy and lactation in mice, which permanently reduces endocannabinoid levels in the offspring, phenocopies CB1R−/− islet microstructure and improves coordinated hormone secretion. Overall, our data mechanistically link endocannabinoids to cell proliferation and sorting during pancreatic islet formation, as well as to life-long programming of hormonal determinants of glucose homeostasis. PMID:26494286

  2. Induction of Protective Genes Leads to Islet Survival and Function

    PubMed Central

    Wang, Hongjun; Ferran, Christiane; Attanasio, Chiara; Calise, Fulvio; Otterbein, Leo E.

    2011-01-01

    Islet transplantation is the most valid approach to the treatment of type 1 diabetes. However, the function of transplanted islets is often compromised since a large number of β cells undergo apoptosis induced by stress and the immune rejection response elicited by the recipient after transplantation. Conventional treatment for islet transplantation is to administer immunosuppressive drugs to the recipient to suppress the immune rejection response mounted against transplanted islets. Induction of protective genes in the recipient (e.g., heme oxygenase-1 (HO-1), A20/tumor necrosis factor alpha inducible protein3 (tnfaip3), biliverdin reductase (BVR), Bcl2, and others) or administration of one or more of the products of HO-1 to the donor, the islets themselves, and/or the recipient offers an alternative or synergistic approach to improve islet graft survival and function. In this perspective, we summarize studies describing the protective effects of these genes on islet survival and function in rodent allogeneic and xenogeneic transplantation models and the prevention of onset of diabetes, with emphasis on HO-1, A20, and BVR. Such approaches are also appealing to islet autotransplantation in patients with chronic pancreatitis after total pancreatectomy, a procedure that currently only leads to 1/3 of transplanted patients being diabetes-free. PMID:22220267

  3. Disease resistance or growth: the role of plant hormones in balancing immune responses and fitness costs

    PubMed Central

    Denancé, Nicolas; Sánchez-Vallet, Andrea; Goffner, Deborah; Molina, Antonio

    2013-01-01

    Plant growth and response to environmental cues are largely governed by phytohormones. The plant hormones ethylene, jasmonic acid, and salicylic acid (SA) play a central role in the regulation of plant immune responses. In addition, other plant hormones, such as auxins, abscisic acid (ABA), cytokinins, gibberellins, and brassinosteroids, that have been thoroughly described to regulate plant development and growth, have recently emerged as key regulators of plant immunity. Plant hormones interact in complex networks to balance the response to developmental and environmental cues and thus limiting defense-associated fitness costs. The molecular mechanisms that govern these hormonal networks are largely unknown. Moreover, hormone signaling pathways are targeted by pathogens to disturb and evade plant defense responses. In this review, we address novel insights on the regulatory roles of the ABA, SA, and auxin in plant resistance to pathogens and we describe the complex interactions among their signal transduction pathways. The strategies developed by pathogens to evade hormone-mediated defensive responses are also described. Based on these data we discuss how hormone signaling could be manipulated to improve the resistance of crops to pathogens. PMID:23745126

  4. A specific area of olfactory cortex involved in stress hormone responses to predator odours.

    PubMed

    Kondoh, Kunio; Lu, Zhonghua; Ye, Xiaolan; Olson, David P; Lowell, Bradford B; Buck, Linda B

    2016-04-07

    Instinctive reactions to danger are critical to the perpetuation of species and are observed throughout the animal kingdom. The scent of predators induces an instinctive fear response in mice that includes behavioural changes, as well as a surge in blood stress hormones that mobilizes multiple body systems to escape impending danger. How the olfactory system routes predator signals detected in the nose to achieve these effects is unknown. Here we identify a specific area of the olfactory cortex in mice that induces stress hormone responses to volatile predator odours. Using monosynaptic and polysynaptic viral tracers, we found that multiple olfactory cortical areas transmit signals to hypothalamic corticotropin-releasing hormone (CRH) neurons, which control stress hormone levels. However, only one minor cortical area, the amygdalo-piriform transition area (AmPir), contained neurons upstream of CRH neurons that were activated by volatile predator odours. Chemogenetic stimulation of AmPir activated CRH neurons and induced an increase in blood stress hormones, mimicking an instinctive fear response. Moreover, chemogenetic silencing of AmPir markedly reduced the stress hormone response to predator odours without affecting a fear behaviour. These findings suggest that AmPir, a small area comprising <5% of the olfactory cortex, plays a key part in the hormonal component of the instinctive fear response to volatile predator scents.

  5. A specific area of olfactory cortex involved in stress hormone responses to predator odors

    PubMed Central

    Kondoh, Kunio; Lu, Zhonghua; Ye, Xiaolan; Olson, David P.; Lowell, Bradford B.; Buck, Linda B.

    2016-01-01

    Instinctive reactions to danger are critical to the perpetuation of species and are observed throughout the animal kingdom. The scent of predators induces an instinctive fear response in mice that includes behavioral changes as well as a surge in blood stress hormones that mobilizes multiple body systems to escape impending danger1,2. How the olfactory system routes predator signals detected in the nose to achieve these effects is unknown. Here we identify a specific area of the olfactory cortex that induces stress hormone responses to volatile predator odors. Using monosynaptic and polysynaptic viral tracers, we found that multiple olfactory cortical areas transmit signals to hypothalamic CRH (corticotropin releasing hormone) neurons, which control stress hormone levels. However, only one minor cortical area, the amygdalo-piriform transition area (AmPir), contained neurons upstream of CRH neurons that were activated by volatile predator odors. Chemogenetic stimulation of AmPir activated CRH neurons and induced an increase in blood stress hormone, mimicking an instinctive fear response. Moreover, chemogenetic silencing of AmPir markedly reduced the stress hormone response to predator odors without affecting a fear behavior. These findings suggest that AmPir, a small area comprising <5% of the olfactory cortex, plays a key role in the hormonal component of the instinctive fear response to volatile predator scents. PMID:27001694

  6. Alpha1-antitrypsin monotherapy prolongs islet allograft survival in mice.

    PubMed

    Lewis, Eli C; Shapiro, Leland; Bowers, Owen J; Dinarello, Charles A

    2005-08-23

    Islet transplantation for type 1 diabetic patients shows promising results with the use of nondiabetogenic immunosuppressive therapy. However, in addition to compromising the immune system of transplant recipients, long-term studies demonstrate that islet viability is impaired. Here, we demonstrate that, in the absence of immunosuppressive agents, monotherapy with clinical-grade human alpha1-antitrypsin (hAAT), the major serum serine-protease inhibitor, prolongs islet graft survival and normoglycemia in transplanted allogeneic diabetic mice, lasting until the development of anti-hAAT antibodies. Compared to untreated or albumin-control-treated graft recipients, which rejected islets at day 10, AAT-treated mice displayed diminished cellular infiltrates and intact intragraft insulin production throughout treatment. Using peritoneal infiltration models, we demonstrate that AAT decreases allogeneic fibroblast-elicited natural-killer-cell influx by 89%, CD3-positive cell influx by 44%, and thioglycolate-elicited neutrophil emigration by 66%. ATT also extended islet viability in mice after streptozotocin-induced beta cell toxicity. In vitro, several islet responses to IL-1beta/IFNgamma stimulation were examined. In the presence of AAT, islets displayed enhanced viability and inducible insulin secretion. Islets also released 36% less nitric oxide and 82% less macrophage inflammatory protein 1 alpha and expressed 63% fewer surface MHC class II molecules. TNFalpha release from IL-1beta/IFNgamma-stimulated islet cells was reduced by 99%, accompanied by an 8-fold increase in the accumulation of membrane TNFalpha on CD45-positive islet cells. In light of the established safety record and the nondiabetogenic potential of AAT, these data suggest that AAT may be beneficial as adjunctive therapy in patients undergoing islet transplantation.

  7. Pancreatic Ductal Perfusion at Organ Procurement Enhances Islet Yield in Human Islet Isolation

    PubMed Central

    Shimoda, Masayuki; Kanak, Mazhar A.; Shahbazov, Rauf; Kunnathodi, Faisal; Lawrence, Michael C.; Naziruddin, Bashoo; Levy, Marlon F.

    2015-01-01

    Objective Pancreas preservation is a major factor influencing the results of islet cell transplantation. This study evaluated the effects of two different solutions for pancreatic ductal perfusion (PDP) at organ procurement. Methods Eighteen human pancreases were assigned to three groups: non-PDP (control), PDP with ET-Kyoto solution, and PDP with cold storage/purification stock solution. Pancreatic islets were isolated according to the modified Ricordi method. Results No significant differences in donor characteristics, including cold ischemia time, were observed between the three groups. All islet isolations in the PDP groups had >400,000 IEQ in total islet yield post-purification, a significant increase when compared with the control (P = 0.04 and <0.01). The islet quality assessments—including an in vivo diabetic nude mice assay and the response of high-mobility group box protein 1 to cytokine stimulation—also showed no significant differences. The proportion of TUNEL-positive cells showing apoptosis in islets in the PDP groups was significantly lower than in the control group (P < 0.05). Conclusion Both ET-Kyoto solution and cold storage/purification stock solution are suitable for PDP and consistently resulted in isolation success. Further studies with a larger number of pancreas donors should be done to compare the effects of the PDP solutions. PMID:25058879

  8. Streptozotocin is responsible for the induction and progression of renal tumorigenesis in diabetic Wistar-Furth rats treated with insulin or transplanted with agarose encapsulated porcine islets.

    PubMed

    Vinerean, Horatiu V; Gazda, Lawrence S; Hall, Richard D; Smith, Barry H

    2011-01-01

    Streptozotocin (STZ), a nitrosourea with DNA alkylating properties, has been widely used to induce hyperglycemia by specifically destroying the insulin-producing β-cells of the islets of Langerhans in experimental models of Type I diabetes. STZ's known carcinogenic properties, however, raise concerns about its suitability for long-term studies. We conducted a formal study of STZ's carcinogenic effects in long-term surviving diabetic Wistar-Furth rats. To determine if insulin therapy or islet transplantation exacerbated tumorigenesis, rats were randomly assigned to one of four experimental groups: normal animals with no treatment (Group 1, n=12); normal animals that underwent peritoneal implantation of porcine islets encapsulated in a double layer of agarose to form islet macrobeads (normal + islets; group 2, n=12); STZ treatment followed by daily exogenous insulin (STZ + insulin; group 3, n=18) and STZ treatment followed by the intraperitoneal implantation of porcine islet macrobeads (STZ + islets; group 4, n=14). At 215 days post-STZ induction, no renal proliferative lesions were observed in animals that did not receive STZ (group 1 and group 2) whereas adenoma incidences of 57% for group 3 and 34% for group 4 were observed. By terminal necropsy at day 351, the incidence and severity of renal proliferative lesions increased with tubular carcinoma observed in 67% of group 3 and 60% of group 4 animals. We conclude that the STZ-induced diabetic rat model is not suitable for long-term studies because of progressive renal tumorigenesis. Our experiments also demonstrate the safety and effectiveness of porcine islet macrobeads for the treatment of diabetes.

  9. Overexpression of Pref-1 in pancreatic islet β-cells in mice causes hyperinsulinemia with increased islet mass and insulin secretion.

    PubMed

    Wang, Yuhui; Lee, Kichoon; Moon, Yang Soo; Ahmadian, Maryam; Kim, Kee-Hong; Roder, Karim; Kang, Chulho; Sul, Hei Sook

    2015-06-12

    Preadipocyte factor-1 (Pref-1) is made as a transmembrane protein containing EGF-repeats at the extracellular domain that can be cleaved to generate a biologically active soluble form. Pref-1 is found in islet β-cells and its level has been reported to increase in neonatal rat islets upon growth hormone treatment. We found here that Pref-1 can promote growth of pancreatic tumor derived AR42J cells. To examine Pref-1 function in pancreatic islets in vivo, we generated transgenic mouse lines overexpressing the Pref-1/hFc in islet β-cells using rat insulin II promoter (RIP). These transgenic mice exhibit an increase in islet mass with higher proportion of larger islets in pancreas compared to wild-type littermates. This is in contrast to pancreas from Pref-1 null mice that show higher proportion of smaller islets. Insulin expression and insulin secretion from pancreatic islets from RIP-Pref-1/hFc transgenic mice are increased also. Thus, RIP-Pref-1/hFc transgenic mice show normal glucose levels but with higher plasma insulin levels in both fasting and fed conditions. These mice show improved glucose tolerance. Taken together, we conclude Pref-1 as a positive regulator of islet β-cells and insulin production.

  10. The proapoptotic BH3-only proteins Bim and Puma are downstream of endoplasmic reticulum and mitochondrial oxidative stress in pancreatic islets in response to glucotoxicity.

    PubMed

    Wali, J A; Rondas, D; McKenzie, M D; Zhao, Y; Elkerbout, L; Fynch, S; Gurzov, E N; Akira, S; Mathieu, C; Kay, T W H; Overbergh, L; Strasser, A; Thomas, H E

    2014-03-13

    Apoptosis of pancreatic beta cells is a feature of type 2 diabetes and its prevention may have therapeutic benefit. High glucose concentrations induce apoptosis of islet cells, and this requires the proapoptotic Bcl-2 homology domain 3 (BH3)-only proteins Bim and Puma. We studied the stress pathways induced by glucotoxicity in beta cells that result in apoptosis. High concentrations of glucose or ribose increased expression of the transcription factor CHOP (C/EBP homologous protein) but not endoplasmic reticulum (ER) chaperones, indicating activation of proapoptotic ER stress signaling. Inhibition of ER stress prevented ribose-induced upregulation of Chop and Puma mRNA, and partially protected islets from glucotoxicity. Loss of Bim or Puma partially protected islets from the canonical ER stressor thapsigargin. The antioxidant N-acetyl-cysteine also partially protected islets from glucotoxicity. Islets deficient in both Bim and Puma, but not Bim or Puma alone, were significantly protected from killing induced by the mitochondrial reactive oxygen species donor rotenone. Our data demonstrate that high concentrations of glucose induce ER and oxidative stress, which causes cell death mediated by Bim and Puma. We observed significantly higher Bim and Puma mRNA in islets of human donors with type 2 diabetes. This indicates that inhibition of Bim and Puma, or their inducers, may prevent beta-cell destruction in type 2 diabetes.

  11. Automated separation of merged Langerhans islets

    NASA Astrophysics Data System (ADS)

    Švihlík, Jan; Kybic, Jan; Habart, David

    2016-03-01

    This paper deals with separation of merged Langerhans islets in segmentations in order to evaluate correct histogram of islet diameters. A distribution of islet diameters is useful for determining the feasibility of islet transplantation in diabetes. First, the merged islets at training segmentations are manually separated by medical experts. Based on the single islets, the merged islets are identified and the SVM classifier is trained on both classes (merged/single islets). The testing segmentations were over-segmented using watershed transform and the most probable back merging of islets were found using trained SVM classifier. Finally, the optimized segmentation is compared with ground truth segmentation (correctly separated islets).

  12. Sex differences in immune responses: Hormonal effects, antagonistic selection, and evolutionary consequences.

    PubMed

    Roved, Jacob; Westerdahl, Helena; Hasselquist, Dennis

    2017-02-01

    Males and females differ in both parasite load and the strength of immune responses and these effects have been verified in humans and other vertebrates. Sex hormones act as important modulators of immune responses; the male sex hormone testosterone is generally immunosuppressive while the female sex hormone estrogen tends to be immunoenhancing. Different sets of T-helper cells (Th) have important roles in adaptive immunity, e.g. Th1 cells trigger type 1 responses which are primarily cell-mediated, and Th2 cells trigger type 2 responses which are primarily humoral responses. In our review of the literature, we find that estrogen and progesterone enhance type 2 and suppress type 1 responses in females, whereas testosterone suppresses type 2 responses and shows an inconsistent pattern for type 1 responses in males. When we combine these patterns of generally immunosuppressive and immunoenhancing effects of the sex hormones, our results imply that the sex differences in immune responses should be particularly strong in immune functions associated with type 2 responses, and less pronounced with type 1 responses. In general the hormone-mediated sex differences in immune responses may lead to genetic sexual conflicts on immunity. Thus, we propose the novel hypothesis that sexually antagonistic selection may act on immune genes shared by the sexes, and that the strength of this sexually antagonistic selection should be stronger for type 2- as compared with type 1-associated immune genes. Finally, we put the consequences of sex hormone-induced effects on immune responses into behavioral and ecological contexts, considering social mating system, sexual selection, geographical distribution of hosts, and parasite abundance.

  13. Single-Cell Phenotypic Characterization of Human Pituitary GHomas and Non-Functioning Adenomas Based on Hormone Content and Calcium Responses to Hypothalamic Releasing Hormones

    PubMed Central

    Senovilla, Laura; Núñez, Lucía; de Campos, José María; de Luis, Daniel A.; Romero, Enrique; García-Sancho, Javier; Villalobos, Carlos

    2015-01-01

    Human pituitary tumors are generally benign adenomas causing considerable morbidity due to excess hormone secretion, hypopituitarism, and other tumor mass effects. Pituitary tumors are highly heterogeneous and difficult to type, often containing mixed cell phenotypes. We have used calcium imaging followed by multiple immunocytochemistry to type growth hormone secreting (GHomas) and non-functioning pituitary adenomas (NFPAs). Individual cells were typed for stored hormones and calcium responses to classic hypothalamic releasing hormones (HRHs). We found that GHomas contained growth hormone cells either lacking responses to HRHs or responding to all four HRHs. However, most GHoma cells were polyhormonal cells responsive to both thyrotropin-releasing hormone (TRH) and GH-releasing hormone. NFPAs were also highly heterogeneous. Some of them contained ACTH cells lacking responses to HRHs or polyhormonal gonadotropes responsive to LHRH and TRH. However, most NFPAs were made of cells storing no hormone and responded only to TRH. These results may provide new insights on the ontogeny of GHomas and NFPAs. PMID:26106585

  14. 2,4,6-Tribromophenol Interferes with the Thyroid Hormone System by Regulating Thyroid Hormones and the Responsible Genes in Mice

    PubMed Central

    Lee, Dongoh; Ahn, Changhwan; Hong, Eui-Ju; An, Beum-Soo; Hyun, Sang-Hwan; Choi, Kyung-Chul; Jeung, Eui-Bae

    2016-01-01

    2,4,6-Tribromophenol (TBP) is a brominated flame retardant (BFR). Based on its affinity for transthyretin, TBP could compete with endogenous thyroid hormone. In this study, the effects of TBP on the thyroid hormone system were assessed in mice. Briefly, animals were exposed to 40 and 250 mg/kg TBP. Thyroid hormones were also administered with or without TBP. When mice were treated with TBP, deiodinase 1 (Dio1) and thyroid hormone receptor β isoform 2 (Thrβ2) decreased in the pituitary gland. The levels of deiodinase 2 (Dio2) and growth hormone (Gh) mRNA increased in response to 250 mg/kg of TBP, and the relative mRNA level of thyroid stimulating hormone β (Tshβ) increased in the pituitary gland. Dio1 and Thrβ1 expression in the liver were not altered, while Dio1 decreased in response to co-treatment with thyroid hormones. The thyroid gland activity decreased in response to TBP, as did the levels of free triiodothyronine and free thyroxine in serum. Taken together, these findings indicate that TBP can disrupt thyroid hormone homeostasis and the presence of TBP influenced thyroid actions as regulators of gene expression. These data suggest that TBP interferes with thyroid hormone systems PMID:27420076

  15. 2,4,6-Tribromophenol Interferes with the Thyroid Hormone System by Regulating Thyroid Hormones and the Responsible Genes in Mice.

    PubMed

    Lee, Dongoh; Ahn, Changhwan; Hong, Eui-Ju; An, Beum-Soo; Hyun, Sang-Hwan; Choi, Kyung-Chul; Jeung, Eui-Bae

    2016-07-12

    2,4,6-Tribromophenol (TBP) is a brominated flame retardant (BFR). Based on its affinity for transthyretin, TBP could compete with endogenous thyroid hormone. In this study, the effects of TBP on the thyroid hormone system were assessed in mice. Briefly, animals were exposed to 40 and 250 mg/kg TBP. Thyroid hormones were also administered with or without TBP. When mice were treated with TBP, deiodinase 1 (Dio1) and thyroid hormone receptor β isoform 2 (Thrβ2) decreased in the pituitary gland. The levels of deiodinase 2 (Dio2) and growth hormone (Gh) mRNA increased in response to 250 mg/kg of TBP, and the relative mRNA level of thyroid stimulating hormone β (Tshβ) increased in the pituitary gland. Dio1 and Thrβ1 expression in the liver were not altered, while Dio1 decreased in response to co-treatment with thyroid hormones. The thyroid gland activity decreased in response to TBP, as did the levels of free triiodothyronine and free thyroxine in serum. Taken together, these findings indicate that TBP can disrupt thyroid hormone homeostasis and the presence of TBP influenced thyroid actions as regulators of gene expression. These data suggest that TBP interferes with thyroid hormone systems.

  16. Adaptation of pancreatic islet cyto-architecture during development

    NASA Astrophysics Data System (ADS)

    Striegel, Deborah A.; Hara, Manami; Periwal, Vipul

    2016-04-01

    Plasma glucose in mammals is regulated by hormones secreted by the islets of Langerhans embedded in the exocrine pancreas. Islets consist of endocrine cells, primarily α, β, and δ cells, which secrete glucagon, insulin, and somatostatin, respectively. β cells form irregular locally connected clusters within islets that act in concert to secrete insulin upon glucose stimulation. Varying demands and available nutrients during development produce changes in the local connectivity of β cells in an islet. We showed in earlier work that graph theory provides a framework for the quantification of the seemingly stochastic cyto-architecture of β cells in an islet. To quantify the dynamics of endocrine connectivity during development requires a framework for characterizing changes in the probability distribution on the space of possible graphs, essentially a Fokker-Planck formalism on graphs. With large-scale imaging data for hundreds of thousands of islets containing millions of cells from human specimens, we show that this dynamics can be determined quantitatively. Requiring that rearrangement and cell addition processes match the observed dynamic developmental changes in quantitative topological graph characteristics strongly constrained possible processes. Our results suggest that there is a transient shift in preferred connectivity for β cells between 1-35 weeks and 12-24 months.

  17. Hormonal responses to complete or hydrolyzed protein diets in patients after upper gastrointestinal surgery.

    PubMed

    Simko, V; Chen, M H

    1986-01-01

    Six gastrointestinal hormones were measured in the plasma of six healthy controls and long-term changes were evaluated in six patients 2-20 years after upper gastrointestinal surgery. In a metabolic unit study we determined fasting hormonal levels, the time to peak hormonal response, and a 135-minute hormonal response to the meal. Test meals were isocaloric, 500 kcal, and isonitrogenous, consisting either of natural breakfast components or of complete liquid diets with intact protein (Ensure) or hydrolyzed protein (Vital). Postsurgical subjects were in good health and had no postcibal complaints. Nevertheless, their hemoglobin and serum albumin were significantly lower than in controls. Postsurgical subjects had higher fasting gastrin (121.3 +/- 11.6 vs 65.4 +/- 6.6 pg/ml, P less than .01) and motilin (148.7 +/- 32.9 vs 70.4 +/- 13.1 pg/ml, P less than .05) than controls. In postsurgical patients the peak gastrin and pancreatic glucagon responses to meals were obtained in significantly shorter time. Their total response to motilin and secretin to meals was significantly lower than in controls. Fasting glucose and the meal-induced responses of insulin and vasoactive intestinal polypeptide were not different from controls. The nature of dietary protein did not significantly affect hormonal responses to feeding. We conclude that gastrointestinal hormonal changes persist many years after surgery. These changes are probably related to faster transit of meals with a generally weaker total hormonal response to feeding. Although these differences from normal may be nutritionally well compensated, they may become important in periods of metabolic stress.

  18. TFAP2C controls hormone response in breast cancer cells through multiple pathways of estrogen signaling.

    PubMed

    Woodfield, George W; Horan, Annamarie D; Chen, Yizhen; Weigel, Ronald J

    2007-09-15

    Breast cancers expressing estrogen receptor-alpha (ERalpha) are associated with a favorable biology and are more likely to respond to hormonal therapy. In addition to ERalpha, other pathways of estrogen response have been identified including ERbeta and GPR30, a membrane receptor for estrogen, and the key mechanisms regulating expression of ERs and hormone response remain controversial. Herein, we show that TFAP2C is the key regulator of hormone responsiveness in breast carcinoma cells through the control of multiple pathways of estrogen signaling. TFAP2C regulates the expression of ERalpha directly by binding to the ERalpha promoter and indirectly via regulation of FoxM1. In so doing, TFAP2C controls the expression of ERalpha target genes, including pS2, MYB, and RERG. Furthermore, TFAP2C controlled the expression of GPR30. In distinct contrast, TFAP2A, a related factor expressed in breast cancer, was not involved in estrogen-mediated pathways but regulated expression of genes controlling cell cycle arrest and apoptosis including p21(CIP1) and IGFBP-3. Knockdown of TFAP2C abrogated the mitogenic response to estrogen exposure and decreased hormone-responsive tumor growth of breast cancer xenografts. We conclude that TFAP2C is a central control gene of hormone response and is a novel therapeutic target in the design of new drug treatments for breast cancer.

  19. Endoscopic biopsy of islet transplants in the gastric submucosal space provides evidence of islet graft rejection in diabetic pigs

    PubMed Central

    Tanaka, Takayuki; Fujita, Minoru; Bottino, Rita; Piganelli, Jon D.; McGrath, Kevin; Li, Jiang; Lee, Whayoung; Iwase, Hayato; Wijkstrom, Martin; Bertera, Suzanne; Long, Cassandra; Landsittel, Douglas; Haruma, Ken; Cooper, David K.C.; Hara, Hidetaka

    2016-01-01

    ABSTRACT Transplantation of islets into the gastric submucosal space (GSMS) has several advantages (e.g., avoidance of the instant blood-mediated inflammatory response [IBMIR], ability to biopsy). The aim of this study was to determine whether endoscopic biopsy of islet allografts transplanted into the GSMS in diabetic pigs can provide histopathological and immunohistochemical information that correlates with the clinical course (e.g.,, blood glucose level, insulin requirement). Islet allografts (Group1: 10,000 kIEq /kg [n = 4]; Group2: 15,000 kIEq /kg [n = 2]) were transplanted into the GSMS of diabetic pigs under immunosuppression. In Group2, the anti-oxidant, BMX-001 was applied during preservation, isolation, and culture of the islets, and at the time of transplantation. Endoscopic biopsies of the islet grafts were obtained one or 2 weeks after transplantation, and histopathological features were compared with the clinical course (e.g., blood glucose, insulin requirement). In Group1, in the absence of anti-oxidant therapy, most of the islets became fragmented, and there was no reduction in exogenous insulin requirement. In Group2, with an increased number of transplanted islets in the presence of BMX-001, more healthy insulin-positive islet masses were obtained at biopsy and necropsy (4 weeks), and these correlated with reductions in both blood glucose level and insulin requirement. In all cases, inflammatory cell infiltrates were present. After islet transplantation into the GSMS, endoscopic biopsy can provide information on graft rejection, which would be an immense advantage in clinical islet transplantation. PMID:26857703

  20. Ethylene-induced transcriptional and hormonal responses at the onset of sugarcane ripening

    PubMed Central

    Cunha, Camila P.; Roberto, Guilherme G.; Vicentini, Renato; Lembke, Carolina G.; Souza, Glaucia M.; Ribeiro, Rafael V.; Machado, Eduardo C.; Lagôa, Ana M. M. A.; Menossi, Marcelo

    2017-01-01

    The effects of ethephon as a sugarcane ripener are attributed to ethylene. However, the role of this phytohormone at the molecular level is unknown. We performed a transcriptome analysis combined with the evaluation of sucrose metabolism and hormone profiling of sugarcane plants sprayed with ethephon or aminoethoxyvinylglycine (AVG), an ethylene inhibitor, at the onset of ripening. The differential response between ethephon and AVG on sucrose level and sucrose synthase activity in internodes indicates ethylene as a potential regulator of sink strength. The correlation between hormone levels and transcriptional changes suggests ethylene as a trigger of multiple hormone signal cascades, with approximately 18% of differentially expressed genes involved in hormone biosynthesis, metabolism, signalling, and response. A defence response elicited in leaves favoured salicylic acid over the ethylene/jasmonic acid pathway, while the upper internode was prone to respond to ethylene with strong stimuli on ethylene biosynthesis and signalling genes. Besides, ethylene acted synergistically with abscisic acid, another ripening factor, and antagonistically with gibberellin and auxin. We identified potential ethylene target genes and characterized the hormonal status during ripening, providing insights into the action of ethylene at the site of sucrose accumulation. A molecular model of ethylene interplay with other hormones is proposed. PMID:28266527

  1. Ethylene-induced transcriptional and hormonal responses at the onset of sugarcane ripening.

    PubMed

    Cunha, Camila P; Roberto, Guilherme G; Vicentini, Renato; Lembke, Carolina G; Souza, Glaucia M; Ribeiro, Rafael V; Machado, Eduardo C; Lagôa, Ana M M A; Menossi, Marcelo

    2017-03-07

    The effects of ethephon as a sugarcane ripener are attributed to ethylene. However, the role of this phytohormone at the molecular level is unknown. We performed a transcriptome analysis combined with the evaluation of sucrose metabolism and hormone profiling of sugarcane plants sprayed with ethephon or aminoethoxyvinylglycine (AVG), an ethylene inhibitor, at the onset of ripening. The differential response between ethephon and AVG on sucrose level and sucrose synthase activity in internodes indicates ethylene as a potential regulator of sink strength. The correlation between hormone levels and transcriptional changes suggests ethylene as a trigger of multiple hormone signal cascades, with approximately 18% of differentially expressed genes involved in hormone biosynthesis, metabolism, signalling, and response. A defence response elicited in leaves favoured salicylic acid over the ethylene/jasmonic acid pathway, while the upper internode was prone to respond to ethylene with strong stimuli on ethylene biosynthesis and signalling genes. Besides, ethylene acted synergistically with abscisic acid, another ripening factor, and antagonistically with gibberellin and auxin. We identified potential ethylene target genes and characterized the hormonal status during ripening, providing insights into the action of ethylene at the site of sucrose accumulation. A molecular model of ethylene interplay with other hormones is proposed.

  2. Characterisation of the Xenogeneic Immune Response to Microencapsulated Fetal Pig Islet-Like Cell Clusters Transplanted into Immunocompetent C57BL/6 Mice

    PubMed Central

    Ratnapala, Sabina; Foster, Jayne; Vaghjiani, Vijesh; Manuelpillai, Ursula; Tuch, Bernard E.

    2013-01-01

    Xenotransplantation of microencapsulated fetal pig islet-like cell clusters (FP ICCs) offers a potential cellular therapy for type 1 diabetes. Although microcapsules prevent direct contact of the host immune system with the xenografted tissue, poor graft survival is still an issue. This study aimed to characterise the nature of the host immune cells present on the engrafted microcapsules and effects on encapsulated FP ICCs that were transplanted into immunocompetent mice. Encapsulated FP ICCs were transplanted into the peritoneal cavity of C57BL/6 mice. Grafts retrieved at days 1, 3, 7, 14 and 21 post-transplantation were analysed for pericapsular fibrotic overgrowth (PFO), cell viability, intragraft porcine gene expression, macrophages, myofibroblasts and intraperitoneal murine cytokines. Graft function was assessed ex vivo by insulin secretion studies. Xenogeneic immune response to encapsulated FP ICCs was associated with enhanced intragraft mRNA expression of porcine antigens MIP-1α, IL-8, HMGB1 and HSP90 seen within the first two weeks post-transplantation. This was associated with the recruitment of host macrophages, infiltration of myofibroblasts and collagen deposition leading to PFO which was evident from day 7 post-transplantation. This was accompanied by a decrease in cell viability and loss of FP ICC architecture. The only pro-inflammatory cytokine detected in the murine peritoneal flushing was TNF-α with levels peaking at day 7 post transplantation. This correlated with the onset of PFO at day 7 implying activated macrophages as its source. The anti-inflammatory cytokines detected were IL-5 and IL-4 with levels peaking at days 1 and 7, respectively. Porcine C-peptide was undetectable at all time points post-transplantation. PFO was absent and murine intraperitoneal cytokines were undetectable when empty microcapsules were transplanted. In conclusion, this study demonstrated that the macrophages are direct effectors of the xenogeneic immune response to

  3. Hormonal Responses to Cholinergic Input Are Different in Humans with and without Type 2 Diabetes Mellitus

    PubMed Central

    Dunai, Judit; Kilpatrick, Rachel; Oestricker, Lauren Z.; Wallendorf, Michael J.; Patterson, Bruce W.; Reeds, Dominic N.; Wice, Burton M.

    2016-01-01

    Peripheral muscarinic acetylcholine receptors regulate insulin and glucagon release in rodents but their importance for similar roles in humans is unclear. Bethanechol, an acetylcholine analogue that does not cross the blood-brain barrier, was used to examine the role of peripheral muscarinic signaling on glucose homeostasis in humans with normal glucose tolerance (NGT; n = 10), impaired glucose tolerance (IGT; n = 11), and type 2 diabetes mellitus (T2DM; n = 9). Subjects received four liquid meal tolerance tests, each with a different dose of oral bethanechol (0, 50, 100, or 150 mg) given 60 min before a meal containing acetaminophen. Plasma pancreatic polypeptide (PP), glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), glucose, glucagon, C-peptide, and acetaminophen concentrations were measured. Insulin secretion rates (ISRs) were calculated from C-peptide levels. Acetaminophen and PP concentrations were surrogate markers for gastric emptying and cholinergic input to islets. The 150 mg dose of bethanechol increased the PP response 2-fold only in the IGT group, amplified GLP-1 release in the IGT and T2DM groups, and augmented the GIP response only in the NGT group. However, bethanechol did not alter ISRs or plasma glucose, glucagon, or acetaminophen concentrations in any group. Prior studies showed infusion of xenin-25, an intestinal peptide, delays gastric emptying and reduces GLP-1 release but not ISRs when normalized to plasma glucose levels. Analysis of archived plasma samples from this study showed xenin-25 amplified postprandial PP responses ~4-fold in subjects with NGT, IGT, and T2DM. Thus, increasing postprandial cholinergic input to islets augments insulin secretion in mice but not humans. Trial Registration: ClinicalTrials.gov NCT01434901 PMID:27304975

  4. QUANTITATIVE ASSESSMENT OF BETA CELL APOPTOSIS AND CELL COMPOSITION OF ISOLATED, UNDISRUPTED HUMAN ISLETS BY LASER SCANNING CYTOMETRY

    PubMed Central

    Todorov, Ivan; Nair, Indu; Avakian-Mansoorian, Alina; Rawson, Jeffrey; Omori, Keiko; Ito, Taihei; Valiente, Luis; Iglesias-Meza, Itzia; Orr, Chris; Shiang, Keh D.; Ferreri, Kevin; Al-Abdullah, Ismail H.; Mullen, Yoko; Kandeel, Fouad

    2010-01-01

    Background Assays for assessing human islet cell quality which provide results prior to transplantation would be very beneficial to improving outcomes for islet transplantation therapy. Parameters such as percent beta cell apoptosis and cell composition are found to vary markedly between different islet preparations, and may serve as markers of islet quality. We have developed fluorescence-based assays using laser scanning cytometry (LSC) for assessing beta cell apoptosis and islet cell composition on serial sections of intact isolated islets. Methods Isolated human islets were fixed in formalin and embedded in paraffin. Serial sections were immunostained for the pancreatic hormones, acinar and ductal cell markers. DNA fragmentation was used to label apoptotic cells. Stained cells were quantified using an iCys laser scanning cytometer. Results Islet preparations from 102 human pancreatic islet isolations were analyzed. For the whole set of islet preparations we found a mean islet cell composition of 54.5±1.2% insulin positive; 33.9±1.2% glucagon; 12.1±0.7% somatostatin and 1.5±0.2% pancreatic polypeptide positive cells. The apoptotic beta cells were 2.85±0.4% with a range of 0.27% to 18.3%. The percentage of apoptotic beta cells correlated well (p<0.0001, n=59) with results obtained in vivo by transplantation of the corresponding islets in diabetic NODscid mice. Conclusions The analysis of whole, non-dissociated islets for cell composition and beta cell apoptosis using LSC is giving reliable and reproducible results and could be done both before islet transplantation, as well as on preserved cell blocks at any future time. Thus, they can be a powerful tool for islet quality assessment. PMID:20697327

  5. Role of various hormones in photosynthetic responses of green plants under environmental stresses.

    PubMed

    Poonam; Bhardwaj, Renu; Kaur, Ravdeep; Bali, Shagun; Kaur, Parminder; Sirhindi, Geetika; Thukral, Ashwani K; Ohri, Puja; Vig, Adarsh P

    2015-01-01

    Environmental stress includes adverse factors like water deficit, high salinity, enhanced temperature and heavy metals etc. These stresses alter the normal growth and metabolic processes of plants including photosynthesis. Major photosynthetic responses under various stresses include inhibition of photosystems (I and II), changes in thylakoid complexes, decreased photosynthetic activity and modifications in structure and functions of chloroplasts etc. Various defense mechanisms are triggered inside the plants in response to these stresses that are regulated by plant hormones or plant growth regulators. These phytohormones include abscisic acid, auxins, cytokinins, ethylene, brassinosteroids, jasmonates and salicylic acid etc. The present review focuses on stress protective effects of plants hormones on the photosynthetic responses.

  6. Sexual dimorphism of stress response and immune/ inflammatory reaction: the corticotropin releasing hormone perspective

    PubMed Central

    Vamvakopoulos, Nicholas V.

    1995-01-01

    This review higlghts key aspects of corticotropin releasing hormone (CRH) biology of potential relevance to the sexual dimorphism of the stress response and immune/inflammatory reaction, and introduces two important new concepts based on the regulatory potential of the human (h) CRH gene: (1) a proposed mechanism to account for the tissue-specific antithetical responses of hCRH gene expression to glucocorticolds, that may also explain the frequently observed antithetical effects of chronic glucocorticoid administration in clinical practice and (2) a heuristic diagram to illustrate the proposed modulation of the stress response and immune/ inflammatory reaction by steroid hormones, from the perspective of the CRH system. PMID:18475634

  7. Predicting the Probability of Abnormal Stimulated Growth Hormone Response in Children After Radiotherapy for Brain Tumors

    SciTech Connect

    Hua Chiaho; Wu Shengjie; Chemaitilly, Wassim; Lukose, Renin C.; Merchant, Thomas E.

    2012-11-15

    Purpose: To develop a mathematical model utilizing more readily available measures than stimulation tests that identifies brain tumor survivors with high likelihood of abnormal growth hormone secretion after radiotherapy (RT), to avoid late recognition and a consequent delay in growth hormone replacement therapy. Methods and Materials: We analyzed 191 prospectively collected post-RT evaluations of peak growth hormone level (arginine tolerance/levodopa stimulation test), serum insulin-like growth factor 1 (IGF-1), IGF-binding protein 3, height, weight, growth velocity, and body mass index in 106 children and adolescents treated for ependymoma (n = 72), low-grade glioma (n = 28) or craniopharyngioma (n = 6), who had normal growth hormone levels before RT. Normal level in this study was defined as the peak growth hormone response to the stimulation test {>=}7 ng/mL. Results: Independent predictor variables identified by multivariate logistic regression with high statistical significance (p < 0.0001) included IGF-1 z score, weight z score, and hypothalamic dose. The developed predictive model demonstrated a strong discriminatory power with an area under the receiver operating characteristic curve of 0.883. At a potential cutoff point of probability of 0.3 the sensitivity was 80% and specificity 78%. Conclusions: Without unpleasant and expensive frequent stimulation tests, our model provides a quantitative approach to closely follow the growth hormone secretory capacity of brain tumor survivors. It allows identification of high-risk children for subsequent confirmatory tests and in-depth workup for diagnosis of growth hormone deficiency.

  8. Can pancreatic duct-derived progenitors be a source of islet regeneration?

    SciTech Connect

    Xia, Bing; Zhan, Xiao-Rong; Yi, Ran; Yang, Baofeng

    2009-06-12

    The regenerative process of the pancreas is of interest because the main pathogenesis of diabetes mellitus is an inadequate number of insulin-producing {beta}-cells. The functional mass of {beta}-cells is decreased in type 1 diabetes, so replacing missing {beta}-cells or triggering their regeneration may allow for improved type 1 diabetes treatment. Therefore, expansion of the {beta}-cell mass from endogenous sources, either in vivo or in vitro, represents an area of increasing interest. The mechanism of islet regeneration remains poorly understood, but the identification of islet progenitor sources is critical for understanding {beta}-cell regeneration. One potential source is the islet proper, via the dedifferentiation, proliferation, and redifferentiation of facultative progenitors residing within the islet. Neogenesis, or that the new pancreatic islets can derive from progenitor cells present within the ducts has been reported, but the existence and identity of the progenitor cells have been debated. In this review, we focus on pancreatic ductal cells, which are islet progenitors capable of differentiating into islet {beta}-cells. Islet neogenesis, seen as budding of hormone-positive cells from the ductal epithelium, is considered to be one mechanism for normal islet growth after birth and in regeneration, and has suggested the presence of pancreatic stem cells. Numerous results support the neogenesis hypothesis, the evidence for the hypothesis in the adult comes primarily from morphological studies that have in common the production of damage to all or part of the pancreas, with consequent inflammation and repair. Although numerous studies support a ductal origin for new islets after birth, lineage-tracing experiments are considered the 'gold standard' of proof. Lineage-tracing experiments show that pancreatic duct cells act as progenitors, giving rise to new islets after birth and after injury. The identification of differentiated pancreatic ductal cells as

  9. Analysis of plant hormone profiles in response to moderate dehydration stress.

    PubMed

    Urano, Kaoru; Maruyama, Kyonoshin; Jikumaru, Yusuke; Kamiya, Yuji; Yamaguchi-Shinozaki, Kazuko; Shinozaki, Kazuo

    2017-04-01

    Plant responses to dehydration stress are mediated by highly complex molecular systems involving hormone signaling and metabolism, particularly the major stress hormone abscisic acid (ABA) and ABA-dependent gene expression. To understand the roles of plant hormones and their interactions during dehydration, we analyzed the plant hormone profiles with respect to dehydration responses in Arabidopsis thaliana wild-type (WT) plants and ABA biosynthesis mutants (nced3-2). We developed a procedure for moderate dehydration stress, and then investigated temporal changes in the profiles of ABA, jasmonic acid isoleucine (JA-Ile), salicylic acid (SA), cytokinin (trans-zeatin, tZ), auxin (indole-acetic acid, IAA), and gibberellin (GA4 ), along with temporal changes in the expression of key genes involved in hormone biosynthesis. ABA levels increased in a bi-phasic pattern (at the early and late phases) in response to moderate dehydration stress. JA-Ile levels increased slightly in WT plants and strongly increased in nced3-2 mutant plants at 72 h after the onset of dehydration. The expression profiles of dehydration-inducible genes displayed temporal responses in an ABA-dependent manner. The early phase of ABA accumulation correlated with the expression of touch-inducible genes and was independent of factors involved in the major ABA regulatory pathway, including the ABA-responsive element-binding (AREB/ABF) transcription factor. JA-Ile, SA, and tZ were negatively regulated during the late dehydration response phase. Transcriptome analysis revealed important roles for hormone-related genes in metabolism and signaling during dehydration-induced plant responses.

  10. Association of hormonal responses and performance of student pilots during acceleration training on the human centrifuge

    NASA Astrophysics Data System (ADS)

    Wirth, D.; Rohleder, N.; Welsch, H.

    2005-08-01

    Prediction of student pilots' +Gz tolerance by stress hormone levels would be a useful tool in aviation medicine. The aim of the present study was to analyze the relationship between neuroendocrine parameters with performance during acceleration training on the human centrifuge (HC).We investigated 21 student pilots during self-controlled acceleration training on the HC. Adrenocorticotropic hormone (ACTH), cortisol, epinephrine, and norepinephrine were measured after individual training sessions and at rest. Performance was defined by several characteristics including maximum tolerated acceleration. ACTH and cortisol, were significantly higher 20 minutes after acceleration training compared to the resting condition. Subjects tolerated a maximal acceleration of +6.69 Gz. HPA hormone levels and responses were associated with maximum tolerated acceleration +Gz. These findings support the expectation that acceleration- induced increases in stress hormones may enable the organism to tolerate a higher acceleration and could therefore be used as predictors for acceleration tolerance.

  11. Microfluidic device for multimodal characterization of pancreatic islets.

    PubMed

    Mohammed, Javeed Shaikh; Wang, Yong; Harvat, Tricia A; Oberholzer, Jose; Eddington, David T

    2009-01-07

    A microfluidic device to perfuse pancreatic islets while simultaneously characterizing their functionality through fluorescence imaging of the mitochondrial membrane potential and intracellular calcium ([Ca(2+)](i)) in addition to enzyme linked immunosorbent assay (ELISA) quantification of secreted insulin was developed and characterized. This multimodal characterization of islet function will facilitate rapid assessment of tissue quality immediately following isolation from donor pancreas and allow more informed transplantation decisions to be made which may improve transplantation outcomes. The microfluidic perfusion chamber allows flow rates of up to 1 mL min(-1), without any noticeable perturbation or shear of islets. This multimodal quantification was done on both mouse and human islets. The ability of this simple microfluidic device to detect subtle variations in islet responses in different functional assays performed in short time-periods demonstrates that the microfluidic perfusion chamber device can be used as a new gold standard to perform comprehensive islet analysis and obtain a more meaningful predictive value for islet functionality prior to transplantation into recipients, which is currently difficult to predict using a single functional assay.

  12. Biomolecular Surface Engineering of Pancreatic Islets with Thrombomodulin

    PubMed Central

    Wilson, John T.; Haller, Carolyn A.; Qu, Zheng; Cui, Wanxing; Urlam, Murali K.; Chaikof, Elliot L.

    2010-01-01

    Islet transplantation has emerged as a promising treatment for Type 1 diabetes, but its clinical impact remains limited by early islet destruction mediated by prothrombotic and innate inflammatory responses elicited upon transplantation. Thrombomodulin (TM) acts as an important regulator of thrombosis and inflammation through its capacity to channel the catalytic activity of thrombin towards generation of activated protein C (APC), a potent anti-coagulant and anti-inflammatory agent. We describe herein a novel biomolecular strategy for re-engineering the surface of pancreatic islets with TM. A biosynthetic approach was employed to generate recombinant human TM (rTM) bearing a C-terminal azide group, which facilitated site-specific biotinylation of rTM through Staudinger ligation. Murine pancreatic islets were covalently biotinylated through targeting of cell surface amines and aldehydes, and both islet viability and the surface density of streptavidin were maximized through optimization of biotinylation conditions. rTM was immobilized on islet surfaces through streptavidin-biotin interactions, resulting in a nearly three-fold increase in the catalytic capacity of islets to generate APC. PMID:20102751

  13. Growth hormones therapy in immune response against Trypanosoma cruzi.

    PubMed

    Frare, Eduardo Osório; Santello, Fabricia Helena; Caetano, Leony Cristina; Caldeira, Jerri C; Toldo, Míriam Paula Alonso; Prado, José Clóvis do

    2010-04-01

    Growth hormone (GH) is an important hypophyseal hormone that is primarily involved in body growth and metabolism. In mammals, control of Trypanosoma cruzi parasitism during the acute phase of infection is considered to be critically dependent on direct macrophage activation by cytokines. To explore the possibility that GH might be effective in the treatment of Chagas' disease, we investigated its effects on the course of T. cruzi infection in rats, focusing our analyses on its influences on parasitemia, NO, TNF-alpha and IFN-gamma concentration and on histopathological alterations and parasite burden in heart tissue. T. cruzi-infected male Wistar rats were intraperitoneally treated with 5 ng/10 g body weight/day of GH. Animals treated with GH showed a significant reduction in the number of blood trypomastigotes during the acute phase of infection compared with untreated animals (P<0.05). For all experimental days (7, 14 and 21 post infection) of the acute phase, infected and GH treated animals reached higher concentrations of TNF-alpha, IFN-gamma and nitric oxide as compared to untreated and infected counterparts (P<0.05) Histopathological observations of heart tissue revealed that GH administration also resulted in fewer and smaller amastigote burdens, and less inflammatory infiltrate and tissue disorganization, indicating a reduced parasitism of this tissue. These results show that GH can be considered as an immunomodulator substance for controlling parasite replication and combined with the current drug used may represent in the future a new therapeutic tool to reduce the harmful effects of Chagas' disease.

  14. How plants handle multiple stresses: hormonal interactions underlying responses to abiotic stress and insect herbivory.

    PubMed

    Nguyen, Duy; Rieu, Ivo; Mariani, Celestina; van Dam, Nicole M

    2016-08-01

    Adaptive plant responses to specific abiotic stresses or biotic agents are fine-tuned by a network of hormonal signaling cascades, including abscisic acid (ABA), ethylene, jasmonic acid (JA) and salicylic acid. Moreover, hormonal cross-talk modulates plant responses to abiotic stresses and defenses against insect herbivores when they occur simultaneously. How such interactions affect plant responses under multiple stresses, however, is less understood, even though this may frequently occur in natural environments. Here, we review our current knowledge on how hormonal signaling regulates abiotic stress responses and defenses against insects, and discuss the few recent studies that attempted to dissect hormonal interactions occurring under simultaneous abiotic stress and herbivory. Based on this we hypothesize that drought stress enhances insect resistance due to synergistic interactions between JA and ABA signaling. Responses to flooding or waterlogging involve ethylene signaling, which likely reduces plant resistance to chewing herbivores due to its negative cross-talk with JA. However, the outcome of interactions between biotic and abiotic stress signaling is often plant and/or insect species-dependent and cannot simply be predicted based on general knowledge on the involvement of signaling pathways in single stress responses. More experimental data on non-model plant and insect species are needed to reveal general patterns and better understand the molecular mechanisms allowing plants to optimize their responses in complex environments.

  15. Diffusion into human islets is limited to molecules below 10 kDa.

    PubMed

    Williams, S J; Schwasinger-Schmidt, T; Zamierowski, D; Stehno-Bittel, L

    2012-10-01

    Isolated islets are important tools in diabetes research and are used for islet transplantation as a treatment for type 1 diabetes. Yet these cell clusters have a dramatic diffusion barrier that leads to core cell death. Computer modeling has provided theoretical size limitations, but little has been done to measure the actual rate of diffusion in islets. The purpose of this study was to directly measure the diffusion barrier in intact human islets and determine its role in restricting insulin secretion. Impeded diffusion into islets was monitored with fluorescent dextran beads. Dextran beads of 10-70 kDa failed to diffuse into the core of the intact islets, while 0.9 kDa probe was observed within the core of smaller islets. Diffusion of the fluorescent form of glucose, 2-NBDG, had similar diffusion limitations as the beads, with an average intra-islet diffusion rate of 1.5 ± 0.2 μm/min. The poor diffusion properties were associated with core cell death from necrosis, not apoptosis. Short-term exposure to a mild papain/0 Ca(2+) cocktail, dramatically reduced the diffusion barrier so that all cells within islets were exposed to media components. Lowering the diffusion barrier increased the immediate and long-term viability of islet cells, and tended to increase the amount of insulin released, especially in low glucose conditions. However, it failed to improve the large islet's glucose-stimulated insulin secretion. Thus, the islet diffusion barrier leads to low viability and poor survival of large islets, but is not solely responsible for the reduced insulin secretion of large isolated islets.

  16. The Nutrient-Responsive Hormone CCHamide-2 Controls Growth by Regulating Insulin-like Peptides in the Brain of Drosophila melanogaster

    PubMed Central

    Sano, Hiroko; Nakamura, Akira; Texada, Michael J.; Truman, James W.; Ishimoto, Hiroshi; Kamikouchi, Azusa; Nibu, Yutaka; Kume, Kazuhiko; Ida, Takanori; Kojima, Masayasu

    2015-01-01

    The coordination of growth with nutritional status is essential for proper development and physiology. Nutritional information is mostly perceived by peripheral organs before being relayed to the brain, which modulates physiological responses. Hormonal signaling ensures this organ-to-organ communication, and the failure of endocrine regulation in humans can cause diseases including obesity and diabetes. In Drosophila melanogaster, the fat body (adipose tissue) has been suggested to play an important role in coupling growth with nutritional status. Here, we show that the peripheral tissue-derived peptide hormone CCHamide-2 (CCHa2) acts as a nutrient-dependent regulator of Drosophila insulin-like peptides (Dilps). A BAC-based transgenic reporter revealed strong expression of CCHa2 receptor (CCHa2-R) in insulin-producing cells (IPCs) in the brain. Calcium imaging of brain explants and IPC-specific CCHa2-R knockdown demonstrated that peripheral-tissue derived CCHa2 directly activates IPCs. Interestingly, genetic disruption of either CCHa2 or CCHa2-R caused almost identical defects in larval growth and developmental timing. Consistent with these phenotypes, the expression of dilp5, and the release of both Dilp2 and Dilp5, were severely reduced. Furthermore, transcription of CCHa2 is altered in response to nutritional levels, particularly of glucose. These findings demonstrate that CCHa2 and CCHa2-R form a direct link between peripheral tissues and the brain, and that this pathway is essential for the coordination of systemic growth with nutritional availability. A mammalian homologue of CCHa2-R, Bombesin receptor subtype-3 (Brs3), is an orphan receptor that is expressed in the islet β-cells; however, the role of Brs3 in insulin regulation remains elusive. Our genetic approach in Drosophila melanogaster provides the first evidence, to our knowledge, that bombesin receptor signaling with its endogenous ligand promotes insulin production. PMID:26020940

  17. Hormonal responses to acute exercise, training and overtraining. A review with emphasis on the horse.

    PubMed

    de Graaf-Roelfsema, E; Keizer, H A; van Breda, E; Wijnberg, I D; van der Kolk, J H

    2007-09-01

    Overtraining is an imbalance between training and recovery leading to symptoms associated with a neuroendocrine dysbalance called the overtraining syndrome, a disease characterized by behavioral, emotional and physical symptoms similar with depression. Although the prevalence of overtraining is high in human and equine athletes, at present no sensitive and specific test is available to prevent or diagnose overtraining. Nowadays, it is believed that combination of different (hormonal) parameters appear to be the best indicators of overtraining. Therefore, this review provides a summary of previous literature examining the response of the hypothalamic-pituitary-adrenal (HPA) axis and the growth hormone-insulin-like growth factor-I (GH-IGF-I) axis to acute and chronic exercise as well as overtraining in humans and horses. The exercise induced hormonal responses seem to be equal for the equine as well as the human athlete, which makes comparisons possible. Repeated bouts of exercise are suggested to provide a way to detect subtle changes in hormonal responses in the individual athlete, which may make them an important tool in detecting early overtraining. This should be combined with corticotropin releasing hormone (CRH) stimulation tests and basal ACTH and GH pulsatility determination. Further research is needed to establish the correct training intensity and rest period for the exercise test in equines.

  18. Central stimulation of hormone release and the proliferative response of lymphocytes in humans.

    PubMed

    Juránková, E; Jezová, D; Vigas, M

    1995-01-01

    The central nervous system (CNS) may communicate with the immune system by direct innervation of lymphoid organs and/or by neurotransmitters and changes in neuroendocrine functioning and hormone release. The consequences of selective transient changes in circulating hormones on immune functioning in humans have not yet been studied. To address this problem, the authors evaluated the lymphoproliferative responses to optimal and suboptimal concentrations of phytohemagglutinin (PHA) and pokeweek mitogen (PWM) under selective enhancement of circulating growth hormone, prolactin, or norepinephrine. The authors failed to demonstrate any effect of elevated growth hormone levels after clonidine challenge on the lymphoproliferative response to mitogens. Similarly, the results did not show any effect of elevated prolactin concentrations induced by domperidone administration on the immune test. Exposure of volunteers to cold resulted in elevation of plasma norepinephrine levels without changes in growth hormone, epinephrine, or cortisol secretion. Cold exposure induced elevation of plasma norepinephrine and reduction of the lymphoproliferative response to the suboptimal dosage of PHA. The reduction was significant 180 and 240 min after exposure. These results are indicative of a relationship between norepinephrine and immunity.

  19. A Combinatorial Protein Microarray for Probing Materials Interaction with Pancreatic Islet Cell Populations

    PubMed Central

    Delalat, Bahman; Rojas-Canales, Darling M.; Rasi Ghaemi, Soraya; Waibel, Michaela; Harding, Frances J.; Penko, Daniella; Drogemuller, Christopher J.; Loudovaris, Thomas; Coates, Patrick T. H.; Voelcker, Nicolas H.

    2016-01-01

    Pancreatic islet transplantation has become a recognized therapy for insulin-dependent diabetes mellitus. During isolation from pancreatic tissue, the islet microenvironment is disrupted. The extracellular matrix (ECM) within this space not only provides structural support, but also actively signals to regulate islet survival and function. In addition, the ECM is responsible for growth factor presentation and sequestration. By designing biomaterials that recapture elements of the native islet environment, losses in islet function and number can potentially be reduced. Cell microarrays are a high throughput screening tool able to recreate a multitude of cellular niches on a single chip. Here, we present a screening methodology for identifying components that might promote islet survival. Automated fluorescence microscopy is used to rapidly identify islet derived cell interaction with ECM proteins and immobilized growth factors printed on arrays. MIN6 mouse insulinoma cells, mouse islets and, finally, human islets are progressively screened. We demonstrate the capability of the platform to identify ECM and growth factor protein candidates that support islet viability and function and reveal synergies in cell response. PMID:27600088

  20. Hormone withdrawal triggers a premature and sustained gene activation from delayed secondary glucocorticoid response elements.

    PubMed

    Hess, P; Payvar, F

    1992-02-15

    Glucocorticoid regulatory elements, denoted GREs and delayed secondary GREs (sGREs), bind the purified glucocorticoid receptors via distinctive sequence motifs and confer a primary and delayed secondary hormone inducibility, respectively, upon a linked reporter construct in stably transfected mammalian cells. The delayed secondary responses, but not the primary responses, are preceded by a time lag of several hours and blocked by protein synthesis inhibitors. In this report, we further characterized and distinguished these hormonal inductions. A 206-base pair DNA fragment from the hepatic rat alpha 2u-globulin (RUG) gene, containing at least two delayed sGREs, was specifically activated by glucocorticoids in a dose-dependent manner via a process which is sensitive to receptor antagonist RU486. Delayed sGRE-stimulated production of correctly initiated transcripts was preceded by a time lag of 2 h, a time when the GRE-mediated induction had reached maximal levels. A pulse of glucocorticoids sustained maximal activation of the delayed secondary response but not the primary response. In fact, hormone withdrawal triggered a premature induction of this delayed secondary response, suggesting that delayed sGREs are under both negative and positive control of the hormone receptor. Two separable elements of the 206-base pair fragment, including the 29-base pair sequence of a single receptor binding site, activated the reporter expression as effectively with transient, pulsatile exposure to hormone as with continuous exposure. Our results suggest that the information content of a hormonal pulse is retained, or "memorized," more persistently by a receptor binding site of delayed sGREs than those of the prototypical GREs.

  1. Response of extrapancreatic glucagon to gastrointestinal hormones in pancreatectomized dogs.

    PubMed

    Ohneda, A; Kobayashi, T; Nihei, J

    1985-08-01

    In order to investigate the effect of gastrointestinal hormones upon the secretion of extrapancreatic glucagon, tetragastrin, secretin, caerulein and cholecytokinin-pancreozymin octapeptide (CCK-octa) were administered during saline or arginine infusion in pancreatectomized dogs. Intravenous administration of tetragastrin (7 micrograms/kg) did not elicit any changes in plasma glucagon during saline infusion, while the plasma glucagon increased significantly following tetragastrin infusion during arginine infusion. The administration of secretin (3 U/kg) did not affect the plasma level of glucagon during saline or arginine infusion at all. Plasma glucagon did not change after the administration of caerulein (0.5 microgram/kg) during saline infusion, whereas it increased significantly following caerulein administration during arginine infusion. Intravenous administration of CCK-octa in a dose of 20 U/kg did not affect the plasma level of glucagon during saline infusion but exerted a significant rise of extrapancreatic glucagon during arginine infusion. It is concluded from the present experiment that the administration of tetragastrin, caerulein or CCK-octa enhances the release of extrapancreatic glucagon stimulated by arginine infusion while secretin infusion does not affect the secretion of extrapancreatic glucagon.

  2. Oral glucose tolerance and hormonal response in heroin-dependent males.

    PubMed

    Reed, J L; Ghodse, A H

    1973-06-09

    Tests on 12 heroin addicts showed that their response to a glucose load differed from that in normal controls. Though the fasting blood sugar was normal, the rise in blood glucose after a standard 50-g oral glucose tolerance test was delayed and the rise smaller than in the controls. The heroin addicts had high resting insulin levels and a delayed peak response to an oral glucose load, and their growth hormone response was also abnormal.

  3. Response of the pigeon crop sac to mammotrophic hormones: Comparison between relaxin and prolactin

    SciTech Connect

    Bani, G.; Sacchi, T.B.; Bigazzi, M. )

    1990-10-01

    The effects of relaxin (RLX), a hormone that has previously been demonstrated to have mammotrophic properties, were studied in the pigeon crop sac, a well-known target organ for mammotrophic and lactogenic hormones, and compared with the effects produced by prolactin (PRL). The two hormones were injected directly over the crop at different doses and the response was evaluated after differing times of exposure. RLX causes a dose-related increase in wet and dry weights and ({sup 3}H)thymidine and ({sup 3}H)uridine uptake by the crop mucosa, as well as morphological changes indicating growth and differentiation of the epithelial cells similar to those occurring during physiological activation in incubation and hatching. At the doses assayed, the effects of RLX were nearly identical to those obtained following PRL in the short-term experiments, but differences in functional responses were found in the long-term experiment.

  4. Cutaneous microvascular response during local cold exposure - the effect of female sex hormones and cold perception.

    PubMed

    Cankar, Ksenija; Music, Mark; Finderle, Zare

    2016-11-01

    It is generally known that differences exist between males and females with regard to sensitivity to cold. Similar differences even among females in different hormonal balance might influence microvascular response during cold provocation testing. The aim of the present study was to measure sex hormone levels, cold and cold pain perception thresholds and compare them to cutaneous laser-Doppler flux response during local cooling in both the follicular and luteal phases of the menstrual cycle. In the luteal phase a more pronounced decrease in laser-Doppler flux was observed compared to follicular phase during local cooling at 15°C (significant difference by Dunnett's test, p<0.05). In addition, statistically significant correlations between progesterone level and laser-Doppler flux response to local cooling were observed during the follicular (R=-0.552, p=0.0174) and during the luteal phases (R=0.520, p=0.0271). In contrast, the correlation between estradiol level and laser-Doppler flux response was observed only in the follicular phase (R=-0.506, p=0.0324). Our results show that individual sensitivity to cold influences cutaneous microvascular response to local cooling; that microvascular reactivity is more pronounced during the luteal phase of the menstrual cycle; and that reactivity correlates with hormone levels. The effect of specific sex hormone levels is related to the cold-provocation temperature.

  5. Functional imaging of glucose-evoked rat islet activities using transient intrinsic optical signals

    NASA Astrophysics Data System (ADS)

    Yao, Xin-Cheng; Cui, Wan-Xing; Li, Yi-Chao; Zhang, Wei; Lu, Rong-Wen; Thompson, Anthony; Amthor, Franklin; Wang, Xu-Jing

    2012-05-01

    We demonstrate intrinsic optical signal (IOS) imaging of intact rat islet, which consists of many endocrine cells working together. A near-infrared digital microscope was employed for optical monitoring of islet activities evoked by glucose stimulation. Dynamic NIR images revealed transient IOS responses in the islet activated by low-dose (2.75 mM) and high-dose (5.5 mM) glucose stimuli. Comparative experiments and quantitative analysis indicated that both glucose metabolism and calcium/insulin dynamics might contribute to the observed IOS responses. Further investigation of the IOS imaging technology may provide a high resolution method for ex vivo functional examination of the islet, which is important for advanced study of diabetes associated islet dysfunctions and for improved quality control of donor islets for transplantation.

  6. Islet inflammation: A unifying target for diabetes treatment?

    PubMed Central

    Imai, Yumi; Dobrian, Anca D.; Morris, Margaret A.; Nadler, Jerry L.

    2013-01-01

    In the last decade, islet inflammation has emerged as a contributor to the loss of functional β cell mass in both type 1 (T1D) and type 2 diabetes (T2D). Evidence supports that over-nutrition and insulin resistance result in the production of proinflammatory mediators by β cells. In addition to compromising β cell function and survival, cytokines may recruit macrophages into islets, thus augmenting inflammation. Limited, but intriguing, data implies a role of adaptive immune response in islet dysfunction in T2D. Clinical trials validated anti-inflammatory therapies in T2D, while immune therapy for T1D remains challenging. Further research is required to improve our understanding of islet inflammatory pathways, and to identify more effective therapeutic targets for T1D and T2D. PMID:23484621

  7. HPA-axis hormone modulation of stress response circuitry activity in women with remitted major depression.

    PubMed

    Holsen, L M; Lancaster, K; Klibanski, A; Whitfield-Gabrieli, S; Cherkerzian, S; Buka, S; Goldstein, J M

    2013-10-10

    Decades of clinical and basic research indicate significant links between altered hypothalamic-pituitary-adrenal (HPA)-axis hormone dynamics and major depressive disorder (MDD). Recent neuroimaging studies of MDD highlight abnormalities in stress response circuitry regions which play a role in the regulation of the HPA-axes. However, there is a dearth of research examining these systems in parallel, especially as related to potential trait characteristics. The current study addresses this gap by investigating neural responses to a mild visual stress challenge with real-time assessment of adrenal hormones in women with MDD in remission and controls. Fifteen women with recurrent MDD in remission (rMDD) and 15 healthy control women were scanned on a 3T Siemens MR scanner while viewing neutral and negative (stress-evoking) stimuli. Blood samples were obtained before, during, and after scanning for the measurement of HPA-axis hormone levels. Compared to controls, rMDD women demonstrated higher anxiety ratings, increased cortisol levels, and hyperactivation in the amygdala and hippocampus, p<0.05, family-wise error (FWE)-corrected in response to the stress challenge. Among rMDD women, amygdala activation was negatively related to cortisol changes and positively associated with the duration of remission. Findings presented here provide evidence for differential effects of altered HPA-axis hormone dynamics on hyperactivity in stress response circuitry regions elicited by a well-validated stress paradigm in women with recurrent MDD in remission.

  8. Within subject variation of satiety hormone responses to a standard lunch

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: Insulin (Ins), leptin (Lep), GLP-1, and glucagon (Glg) are known regulators of glucose metabolism and food intake, but reproducibility in response to a meal challenge is not well characterized. We assessed within-subject variation of these hormones in 14 young adult women.Methods: Subjec...

  9. A novel fluorescence imaging approach for comparative measurements of pancreatic islet function in vitro.

    PubMed

    Corbin, Kathryn L; Hall, Thomas E; Haile, Ruth; Nunemaker, Craig S

    2011-01-01

    Pancreatic islet dysfunction is a key element in the development of type 2 diabetes. Determining possible early warning signs of dysfunction is thus important to determining the underlying causes of diabetes. We describe an improved fluorescent imaging approach to detect potential islet dysfunction. Using Cell Tracker Red (CTR, a mildly thiol-reactive fluorescent probe) to positively label particular islets, we measured intracellular free calcium with fura-2 AM in both CTR-labeled and unlabeled sets of pancreatic islets simultaneously in vitro. This approach enhances sensitivity by controlling for differences in background fluorescence, temperature, and perifusion dynamics. We confirmed that 200 nM CTR produced no spectral overlap with fura-2 and no significant physiological effects in selective tests of islet function. To demonstrate the utility of dual-labeling, we compared untreated islets with islets pretreated with low-dose pro-inflammatory cytokines (IL-6 + IL-1B) to induce mild dysfunction. We alternated CTR-labeling between control and test islets and identified consistent reductions in the amplitude and trajectory of glucose-stimulated calcium responses (GSCa) among cytokine-treated islets that were independent of labeling. Observations were verified using a MATLAB program specifically designed to identify key features in the GSCa. Our findings thus demonstrate the utility of CTR-labeling in identifying islet dysfunction and propose that this technique can be adapted for other cells and tissues.

  10. Characterization of the Human Pancreatic Islet Proteome by Two-Dimensional LC/MS/MS

    SciTech Connect

    Metz, Thomas O.; Jacobs, Jon M.; Gritsenko, Marina A.; Fontes, Ghislaine; Qian, Weijun; Camp, David G.; Poitout, Vincent J.; Smith, Richard D.

    2006-12-01

    Research to elucidate the pathogenesis of type 1 diabetes mellitus has traditionally focused on the genetic and immunological factors associated with the disease, and, until recently, has not considered the target cell. While there have been reports detailing proteomic analyses of established islet cell lines or isolated rodent islets, the information gained is not always easily extrapolated to humans. Therefore, extensive characterization of the human islet proteome could result in better understanding of islet biology and lead to more effective treatment strategies. We have applied a two-dimensional LC-MS/MS-based analysis to the characterization of the human islet proteome, resulting in the detection of 29,021 unique peptides corresponding to 4,925 proteins. As expected, major islet hormones (insulin, glucagon, somatostatin), beta-cell enriched secretory products (IAPP), ion channels (K-ATP channel), and transcription factors (PDX-1, Nkx 6.1, HNF-1 beta) were detected. In addition, significant proteome coverage of metabolic enzymes and cellular pathways was obtained, including the insulin signaling cascade and the MAP kinase, NF-κβ, and JAK/STAT pathways. This work represents the most extensive characterization of the human islet proteome to date and provides a peptide reference library that may be utilized in future studies of islet biology and type 1 diabetes.

  11. Prolactin and growth hormone responses to hypoglycemia in patients with systemic sclerosis and psoriatic arthritis.

    PubMed

    Rovensky, Jozef; Raffayova, Helena; Imrich, Richard; Radikova, Zofia; Penesova, Adela; Macho, Ladislav; Lukac, Jozef; Matucci-Cerinic, Marco; Vigas, Milan

    2006-06-01

    This study compared prolactin (PRL) and growth hormone (GH) responses to hypoglycemia in premenopausal females with systemic sclerosis (SSc) and psoriatic arthritis (PsA) with those in matched healthy controls. No differences were found in glucose and GH responses to hypoglycemia in both groups of patients compared to controls. SSc patients had lower PRL response (P < 0.05) to hypoglycemia compared to controls. PRL response tended to be lower also in PsA patients, however the difference did not reach level of statistical significance (P = 0.11). The present study showed decreased PRL response to hypoglycemia in premenopausal females with SSc.

  12. The response of serum growth hormone and prolactin to training in weight-maintaining healthy males.

    PubMed

    Hurley, R S; Bossetti, B M; O'Dorisio, T M; Welch, M A; Rice, R R; Tenison, E B; Wasson, C J; Malarkey, W B

    1990-03-01

    Resting levels of serum growth hormone (GH) and prolactin (PRL) were measured pretraining, 3 weeks and 10 weeks posttraining in seven college age males. The exercise consisted of thrice weekly sessions at 70% VO2max for 20 minutes plus warmup and cool down. Body weight remained constant during the ten week training period. However, body fat decreased significantly. Resting daytime levels of GH decreased significantly with training while resting PRL levels were unchanged. The hormone responses suggest attenuation of resting GH levels with training and may relate to changes in body fat.

  13. Influence of age on pulsatile luteinizing hormone release and responsiveness of the gonadotrophs to sex hormone feedback in men.

    PubMed

    Deslypere, J P; Kaufman, J M; Vermeulen, T; Vogelaers, D; Vandalem, J L; Vermeulen, A

    1987-01-01

    The influence of aging on serum LH and testosterone (T) pulse frequency and gonadotroph sensitivity to androgen and estrogen feedback was studied in young (less than 55 yr old) and elderly (greater than 65 yr) Trappist monks. LH pulse frequency (sampling interval, 20 min) was significantly lower [0.25 +/- 0.03 (+/- SEM) vs. 0.38 +/- 0.02 pulses/h; P less than 0.01] in elderly (n = 21) than in young monks (n = 27); the pulse amplitudes were similar. Similarly, T pulse frequency was lower in the elderly than in the young monks (0.13 +/- 0.04 vs. 0.23 +/- 0.02 pulses/h; P less than 0.01). In elderly men, the hypothalamo-pituitary complex was more sensitive to 5 alpha-androstan-17 beta-ol-3-one feedback, as determined by the decrease in serum LH and T levels. Moreover, during 5 alpha-androstan-17 beta-ol-3-one (125 mg/day, percutaneously, for 10 days) administration, the LH response to LHRH (100 micrograms, iv) was significantly higher in the elderly men compared to the pretreatment response. During estradiol (1.5 mg/day, percutaneously for 10 days) administration, the LH response to LHRH was decreased in the elderly men, but unchanged in the young men, suggesting greater responsiveness to estradiol in the elderly men. We conclude that in aged men, decreased testicular androgen secretion is not exclusively the consequence of a primary testicular alteration, but that important changes occur in hypothalamo-pituitary function, specifically decreased LH pulse frequency and increased LH responsiveness to sex hormone feedback.

  14. Beneficial effects of growth hormone-releasing hormone agonists on rat INS-1 cells and on streptozotocin-induced NOD/SCID mice

    PubMed Central

    Zhang, Xianyang; Cui, Tengjiao; He, Jinlin; Wang, Haibo; Cai, Renzhi; Popovics, Petra; Vidaurre, Irving; Sha, Wei; Schmid, Janine; Ludwig, Barbara; Block, Norman L.; Bornstein, Stefan R.; Schally, Andrew V.

    2015-01-01

    Agonists of growth hormone-releasing hormone (GHRH) have been previously reported to promote growth, function, and engraftment of islet cells following transplantation. Here we evaluated recently synthesized GHRH agonists on the proliferation and biological functions of rat pancreatic β-cell line (INS-1) and islets. In vitro treatment of INS-1 cells with GHRH agonists increased cell proliferation, the expression of cellular insulin, insulin-like growth factor-1 (IGF1), and GHRH receptor, and also stimulated insulin secretion in response to glucose challenge. Exposure of INS-1 cells to GHRH agonists, MR-356 and MR-409, induced activation of ERK and AKT pathways. Agonist MR-409 also significantly increased the levels of cellular cAMP and the phosphorylation of cAMP response element binding protein (CREB) in INS-1 cells. Treatment of rat islets with agonist, MR-409 significantly increased cell proliferation, islet size, and the expression of insulin. In vivo daily s.c. administration of 10 μg MR-409 for 3 wk dramatically reduced the severity of streptozotocin (STZ)-induced diabetes in nonobese diabetic severe combined immunodeficiency (NOD/SCID) mice. The maximal therapeutic benefits with respect to the efficiency of engraftment, ability to reach normoglycemia, gain in body weight, response to high glucose challenge, and induction of higher levels of serum insulin and IGF1 were observed when diabetic mice were transplanted with rat islets preconditioned with GHRH agonist, MR-409, and received additional treatment with MR-409 posttransplantation. This study provides an improved approach to the therapeutic use of GHRH agonists in the treatment of diabetes mellitus. PMID:26474831

  15. Hormonal and Growth Factor Responses to Heavy Resistance Exercise Protocols

    DTIC Science & Technology

    1990-01-01

    among HREPs sent to participate in this investigation. The physical and did not consistently follow hGH changes . Whereas tem- characteristics of the...subjects were the following: age, poral changes were observed, no integrated time (AT "-) differ- 24.66 ± 4.27 (SD) yr; height, 178.41 ± 7.77 cm; body...EXERCISE 1443 random order and by all nine subjects. Subsequent sta- differences in responses occurred as a result of changes tistical analysis

  16. A microfluidic array for real-time live-cell imaging of human and rodent pancreatic islets.

    PubMed

    Nourmohammadzadeh, Mohammad; Xing, Yuan; Lee, Jin Wuk; Bochenek, Matthew A; Mendoza-Elias, Joshua E; McGarrigle, James J; Marchese, Enza; Chun-Chieh, Yeh; Eddington, David T; Oberholzer, José; Wang, Yong

    2016-04-21

    In this study, we present a microfluidic array for high-resolution imaging of individual pancreatic islets. The device is based on hydrodynamic trapping principle and enables real-time analysis of islet cellular responses to insulin secretagogues. This device has significant advantages over our previously published perifusion chamber device including significantly increased analytical power and assay sensitivity, as well as improved spatiotemporal resolution. The islet array, with live-cell multiparametric imaging integration, provides a better tool to understand the physiological and pathophysiological changes of pancreatic islets through the analysis of single islet responses. This platform demonstrates the feasibility of array-based islet cellular analysis and opens up a new modality to conduct informative and quantitive evaluation of islets and cell-based screening for new diabetes treatments.

  17. Nifedipine does not impair the hormonal responses to graded exercise in healthy subjects.

    PubMed

    Joffe, B I; Shires, R; Lamprey, J M; Kalk, W J; Botha, A; Haitas, B; Seftel, H C

    1985-01-01

    The aim of this study was to assess whether the potent calcium antagonist nifedipine was capable of modifying the hormonal response to graded exercise in 7 healthy young men. After fasting overnight, each subject came to the laboratory on 2 consecutive mornings. On one day he was given 10 mg of nifedipine sublingually and on the other an identical placebo capsule; the order was randomised in a double-blind fashion over the 2 days. Thereafter each subject performed 2 successive short treadmill runs, equivalent to 60 and 100%, respectively, of maximal aerobic power. While significantly blunting the rise in mean systolic blood pressure and inducing a greater fall in diastolic blood pressure during and after exercise compared with the placebo, nifedipine did not impair the brisk response to pituitary-adrenal hormones (ACTH, cortisol and total catecholamines). Nifedipine also did not modify the effects of short-term exercise in raising mean plasma glucose levels, stimulating pancreatic glucagon secretion and producing a delayed increase in plasma insulin concentrations. Nor did the drug blunt the significant rise of growth hormone and prolactin levels occurring during and after the treadmill run. It was concluded that, apart from inducing significant changes in blood pressure, a single dose of nifedipine does not appear to suppress the counterregulatory hormonal responses to short-term physical activity in healthy men.

  18. MRI in predicting the response of ovarian endometriomas to hormone therapy

    SciTech Connect

    Sugimura, Kazuro; Okizuka, Hiromi; Kaji, Yasushi

    1996-01-01

    Our goal was to investigate the usefulness of MRI in predicting the response of endometriomas to hormone therapy. MRI and laparoscopy at the onset of treatment and follow-up MRI after 6 months of hormone therapy were performed in 21 patients with 49 endometriomas. T1- and T2-weighted images were obtained with a 1.5 T apparatus using a body coil. The lesions were divided into a responder group and a nonresponder group according to whether the lesion size decreased by 50% or not. With MRI, shading was seen in 25 of 27 lesions (93%) from the nonresponder group, but in only 6 of 22 (27%) from the responder group. Low SI rim was seen in 59% of the responders and 89% of the nonresponders. Multiplicity in 68% of the responders and in 85% of the nonresponders and irregularity in 41% of the responders and in 78% of the nonresponders were shown. Multiple logistic analysis revealed shading was the most important factor in prediction of the response to hormone therapy. Shading was an important sign in evaluating the response of endometriomas to hormone therapy. MRI may assist in selecting the appropriate therapy for endometriomas. 16 refs., 3 figs., 2 tabs.

  19. Engineering a glucose-responsive human insulin-secreting cell line from islets of Langerhans isolated from a patient with persistent hyperinsulinemic hypoglycemia of infancy.

    PubMed

    MacFarlane, W M; Chapman, J C; Shepherd, R M; Hashmi, M N; Kamimura, N; Cosgrove, K E; O'Brien, R E; Barnes, P D; Hart, A W; Docherty, H M; Lindley, K J; Aynsley-Green, A; James, R F; Docherty, K; Dunne, M J

    1999-11-26

    Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is a neonatal disease characterized by dysregulation of insulin secretion accompanied by profound hypoglycemia. We have discovered that islet cells, isolated from the pancreas of a PHHI patient, proliferate in culture while maintaining a beta cell-like phenotype. The PHHI-derived cell line (NES2Y) exhibits insulin secretory characteristics typical of islet cells derived from these patients, i.e. they have no K(ATP) channel activity and as a consequence secrete insulin at constitutively high levels in the absence of glucose. In addition, they exhibit impaired expression of the homeodomain transcription factor PDX1, which is a key component of the signaling pathway linking nutrient metabolism to the regulation of insulin gene expression. To repair these defects NES2Y cells were triple-transfected with cDNAs encoding the two components of the K(ATP) channel (SUR1 and Kir6.2) and PDX1. One selected clonal cell line (NISK9) had normal K(ATP) channel activity, and as a result of changes in intracellular Ca(2+) homeostasis ([Ca(2+)](i)) secreted insulin within the physiological range of glucose concentrations. This approach to engineering PHHI-derived islet cells may be of use in gene therapy for PHHI and in cell engineering techniques for administering insulin for the treatment of diabetes mellitus.

  20. Small Molecule Inhibited Parathyroid Hormone Mediated cAMP Response by N–Terminal Peptide Binding

    PubMed Central

    Kumar, Amit; Baumann, Monika; Balbach, Jochen

    2016-01-01

    Ligand binding to certain classes of G protein coupled receptors (GPCRs) stimulates the rapid synthesis of cAMP through G protein. Human parathyroid hormone (PTH), a member of class B GPCRs, binds to its receptor via its N–terminal domain, thereby activating the pathway to this secondary messenger inside cells. Presently, GPCRs are the target of many pharmaceuticals however, these drugs target only a small fraction of structurally known GPCRs (about 10%). Coordination complexes are gaining interest due to their wide applications in the medicinal field. In the present studies we explored the potential of a coordination complex of Zn(II) and anthracenyl–terpyridine as a modulator of the parathyroid hormone response. Preferential interactions at the N–terminal domain of the peptide hormone were manifested by suppressed cAMP generation inside the cells. These observations contribute a regulatory component to the current GPCR–cAMP paradigm, where not the receptor itself, but the activating hormone is a target. To our knowledge, this is the first report about a coordination complex modulating GPCR activity at the level of deactivating its agonist. Developing such molecules might help in the control of pathogenic PTH function such as hyperparathyroidism, where control of excess hormonal activity is essentially required. PMID:26932583

  1. Changes in satiety hormone concentrations and feed intake in rats in response to lactic acid bacteria.

    PubMed

    Forssten, Sofia D; Korczyńska, Marta Z; Zwijsen, Renate M L; Noordman, Wouter H; Madetoja, Mari; Ouwehand, Arthur C

    2013-12-01

    A negative energy balance can be accomplished by reducing the caloric intake which results in an increased feeling of hunger. This physiological state is regulated by secretion of satiety hormones. The secretion of these hormones can be influenced by ingestion of e.g. fat. Fat, dairy beverage and synbiotic mixture have been found to have satiety-inducing effects in humans and rats. Thus, the aim of this study was to investigate the change of satiety hormone concentration in rats in response to feeding of fermented milks containing lactic acid bacteria. Two studies were conducted with Wistar rats randomly allocated into groups receiving Lactobacillus fermented (2 L. acidophilus, L. bulgaricus, L. salivarius and L. rhamnosus) milk. A single isocaloric oral dose with the test item or control was given to the rats. Blood samples were taken after dosing with the test product and the satiety hormones were measured. For the test groups, significant changes could be detected in PYY concentrations after 60 min, although some groups had a significant lower feed intake. In conclusion, some probiotic Lactobacillus strains may modify satiety hormones production. However, more studies are needed to evaluate their potential of prolonging satiety.

  2. Insulin secretion from beta cells within intact islets: location matters.

    PubMed

    Hoang Do, Oanh; Thorn, Peter

    2015-04-01

    The control of hormone secretion is central to body homeostasis, and its dysfunction is important in many diseases. The key cellular steps that lead to hormone secretion have been identified, and the stimulus-secretion pathway is understood in outline for many endocrine cells. In the case of insulin secretion from pancreatic beta cells, this pathway involves the uptake of glucose, cell depolarization, calcium entry, and the triggering of the fusion of insulin-containing granules with the cell membrane. The wealth of information on the control of insulin secretion has largely been obtained from isolated single-cell studies. However, physiologically, beta cells exist within the islets of Langerhans, with structural and functional specializations that are not preserved in single-cell cultures. This review focuses on recent work that is revealing distinct aspects of insulin secretion from beta cells within the islet.

  3. Hormonal responses to opioid receptor blockade: during rest and exercise in cold and hot environments.

    PubMed

    Armstrong, David W; Hatfield, Bradley D

    2006-05-01

    Opioid receptors appear to modulate a variety of physiological and metabolic homeostatic responses to stressors such as exercise and thermally extreme environments. To more accurately determine the role of the naloxone (NAL) sensitive opioid receptor system during rest and exercise, subjects were subjected to concomitant environmental thermal stress. Fifteen untrained men rested or performed low intensity (60% VO2peak) or high intensity (80% VO2peak) exercise on a cycle ergometer for 60 min in an environmental chamber during cold (0 degrees C) hot (35 degrees C) air exposure while receiving an infusion of normal saline (SAL) or NAL (0.1 mg kg(-1)). Plasma adrenocorticotropin hormone (ACTH), immunoreactive beta-endorphin (IBE), cortisol and growth hormone were measured at baseline and every 15 min while in the chamber. Time to exhaustion was significantly reduced during high intensity exercise in the heat (P<0.0001). NAL significantly (P=0.0004) reduced the time to exhaustion (38.3+/-2.1 min) during high intensity exercise in the heat compared to SAL (49.4+/-2.1 min). ACTH and IBE increased during hot conditions and cold attenuated this response. Plasma concentrations of IBE, ACTH, and growth hormone increased significantly with NAL during high intensity exercise in the heat compared to SAL. Cold attenuated the response of ACTH, IBE and cortisol to NAL. NAL administration exaggerates plasma hormone concentration during high intensity exercise in the heat, but not cold. These results support a regulatory effect of the opioid receptor system on physiological responses during exercise in thermally stressful environments. Future research should be directed to more clearly defining the effect of environmental temperature on the mechanism of hypothalamic-pituitary-adrenal hormonal release during exercise and hot environmental temperatures.

  4. Expression of Innate Immunity Genes and Damage of Primary Human Pancreatic Islets by Epidemic Strains of Echovirus: Implication for Post-Virus Islet Autoimmunity

    PubMed Central

    Sarmiento, Luis; Frisk, Gun; Anagandula, Mahesh; Cabrera-Rode, Eduardo; Roivainen, Merja; Cilio, Corrado M.

    2013-01-01

    Three large-scale Echovirus (E) epidemics (E4,E16,E30), each differently associated to the acute development of diabetes related autoantibodies, have been documented in Cuba. The prevalence of islet cell autoantibodies was moderate during the E4 epidemic but high in the E16 and E30 epidemic. The aim of this study was to evaluate the effect of epidemic strains of echovirus on beta-cell lysis, beta-cell function and innate immunity gene expression in primary human pancreatic islets. Human islets from non-diabetic donors (n = 7) were infected with the virus strains E4, E16 and E30, all isolated from patients with aseptic meningitis who seroconverted to islet cell antibody positivity. Viral replication, degree of cytolysis, insulin release in response to high glucose as well as mRNA expression of innate immunity genes (IFN-b, RANTES, RIG-I, MDA5, TLR3 and OAS) were measured. The strains of E16 and E30 did replicate well in all islets examined, resulting in marked cytotoxic effects. E4 did not cause any effects on cell lysis, however it was able to replicate in 2 out of 7 islet donors. Beta-cell function was hampered in all infected islets (P<0.05); however the effect of E16 and E30 on insulin secretion appeared to be higher than the strain of E4. TLR3 and IFN-beta mRNA expression increased significantly following infection with E16 and E30 (P<0.033 and P<0.039 respectively). In contrast, the expression of none of the innate immunity genes studied was altered in E4-infected islets. These findings suggest that the extent of the epidemic-associated islet autoimmunity may depend on the ability of the viral strains to damage islet cells and induce pro-inflammatory innate immune responses within the infected islets. PMID:24223733

  5. The glucose intolerance of acute pancreatitis: hormonal response to arginine.

    PubMed

    Solomon, S S; Duckworth, W C; Jallepalli, P; Bobal, M A; Iyer, R

    1980-01-01

    Patients with acute pancreatitis were studied by arginine infusion at 48--72 h. 7--10 days, and 18--21 days after onset of their illness. Plasma glucose, insulin, and glucagon values were determined. Acute pancreatitis was characterized by fasting hyperglycemia and hyperglucagonemia, associated with relative hyoinsulinemia. Arginine stimulation early in the disease (48--72 h) demonstrated hyperglycemia and hyperglucagonemia, which normalized by 18--21 days. Both phases of the normal biphasic insulin response to arginine were decreased during the initial arginine infusion. By 18--21 days, although the first phase was completely normal, the second phase of insulin secretion remained depressed. Acute pancreatitis is associated with damage to both the endocrine and exocrine pancreas. Glucose intolerance seen with this disease appears to be the result of hyperglucagonemia and relative hypoinsulinemia. Although the healing process at 3 wk is associated with return of plasma glucose and glucagon concentrations to normal, the impaired second phase insulin secretion persists.

  6. Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells.

    PubMed

    D'Amour, Kevin A; Bang, Anne G; Eliazer, Susan; Kelly, Olivia G; Agulnick, Alan D; Smart, Nora G; Moorman, Mark A; Kroon, Evert; Carpenter, Melissa K; Baetge, Emmanuel E

    2006-11-01

    Of paramount importance for the development of cell therapies to treat diabetes is the production of sufficient numbers of pancreatic endocrine cells that function similarly to primary islets. We have developed a differentiation process that converts human embryonic stem (hES) cells to endocrine cells capable of synthesizing the pancreatic hormones insulin, glucagon, somatostatin, pancreatic polypeptide and ghrelin. This process mimics in vivo pancreatic organogenesis by directing cells through stages resembling definitive endoderm, gut-tube endoderm, pancreatic endoderm and endocrine precursor--en route to cells that express endocrine hormones. The hES cell-derived insulin-expressing cells have an insulin content approaching that of adult islets. Similar to fetal beta-cells, they release C-peptide in response to multiple secretory stimuli, but only minimally to glucose. Production of these hES cell-derived endocrine cells may represent a critical step in the development of a renewable source of cells for diabetes cell therapy.

  7. Genetic Architecture of a Hormonal Response to Gene Knockdown in Honey Bees

    PubMed Central

    Rueppell, Olav; Huang, Zachary Y.; Wang, Ying; Fondrk, M. Kim; Page, Robert E.; Amdam, Gro V.

    2015-01-01

    Variation in endocrine signaling is proposed to underlie the evolution and regulation of social life histories, but the genetic architecture of endocrine signaling is still poorly understood. An excellent example of a hormonally influenced set of social traits is found in the honey bee (Apis mellifera): a dynamic and mutually suppressive relationship between juvenile hormone (JH) and the yolk precursor protein vitellogenin (Vg) regulates behavioral maturation and foraging of workers. Several other traits cosegregate with these behavioral phenotypes, comprising the pollen hoarding syndrome (PHS) one of the best-described animal behavioral syndromes. Genotype differences in responsiveness of JH to Vg are a potential mechanistic basis for the PHS. Here, we reduced Vg expression via RNA interference in progeny from a backcross between 2 selected lines of honey bees that differ in JH responsiveness to Vg reduction and measured JH response and ovary size, which represents another key aspect of the PHS. Genetic mapping based on restriction site-associated DNA tag sequencing identified suggestive quantitative trait loci (QTL) for ovary size and JH responsiveness. We confirmed genetic effects on both traits near many QTL that had been identified previously for their effect on various PHS traits. Thus, our results support a role for endocrine control of complex traits at a genetic level. Furthermore, this first example of a genetic map of a hormonal response to gene knockdown in a social insect helps to refine the genetic understanding of complex behaviors and the physiology that may underlie behavioral control in general. PMID:25596612

  8. Evolutionary Endocrinology of Juvenile Hormone Esterase in Gryllus Assimilis: Direct and Correlated Responses to Selection

    PubMed Central

    Zera, A. J.; Zhang, C.

    1995-01-01

    Hemolymph juvenile hormone esterase (JHE) activity on the third day of the last stadium in the cricket, Gryllus assimilis, exhibited a significant response to selection in each of six replicate lines. Mean realized heritability was 0.26 +/- 0.04. The response was due to changes in whole-organism enzyme activity as well as to changes in the proportion of enzyme allocated to the hemolymph compartment. In vivo juvenile hormone metabolism differed between some lines selected for high vs. low enzyme activity. Only minimal differences were observed between lines with respect to hemolymph protein concentration or whole-cricket activity of juvenile hormone epoxide hydrolase, the other major JH-degrading enzyme. Dramatic correlated responses to selection, equal in magnitude to the direct response, were observed for JHE activity on each of three other days of the last juvenile stadium. In contrast, no correlated responses in JHE activity were observed in adults. This indicates that JHE activities throughout the last stadium will evolve as a highly correlated unit independent of adult activities and the evolution of endocrine mechanisms regulating juvenile development can be decoupled from those controlling adult reproduction. This study represents the first quantitative-genetic analysis of naturally occurring endocrine variation in an insect species. PMID:8582618

  9. Quantitative trait loci controlling light and hormone response in two accessions of Arabidopsis thaliana.

    PubMed Central

    Borevitz, Justin O; Maloof, Julin N; Lutes, Jason; Dabi, Tsegaye; Redfern, Joanna L; Trainer, Gabriel T; Werner, Jonathan D; Asami, Tadao; Berry, Charles C; Weigel, Detlef; Chory, Joanne

    2002-01-01

    We have mapped quantitative trait loci (QTL) responsible for natural variation in light and hormone response between the Cape Verde Islands (Cvi) and Landsberg erecta (Ler) accessions of Arabidopsis thaliana using recombinant inbred lines (RILs). Hypocotyl length was measured in four light environments: white, blue, red, and far-red light and in the dark. In addition, white light plus gibberellin (GA) and dark plus the brassinosteroid biosynthesis inhibitor brassinazole (BRZ) were used to detect hormone effects. Twelve QTL were identified that map to loci not previously known to affect light response, as well as loci where candidate genes have been identified from known mutations. Some QTL act in all environments while others show genotype-by-environment interaction. A global threshold was established to identify a significant epistatic interaction between two loci that have few main effects of their own. LIGHT1, a major QTL, has been confirmed in a near isogenic line (NIL) and maps to a new locus with effects in all light environments. The erecta mutation can explain the effect of the HYP2 QTL in the blue, BRZ, and dark environments, but not in far-red. LIGHT2, also confirmed in an NIL, has effects in white and red light and shows interaction with GA. The phenotype and map position of LIGHT2 suggest the photoreceptor PHYB as a candidate gene. Natural variation in light and hormone response thus defines both new genes and known genes that control light response in wild accessions. PMID:11861571

  10. Beneficial Effect of Insulin Treatment on Islet Transplantation Outcomes in Akita Mice

    PubMed Central

    Kikawa, Kazuhide; Sakano, Daisuke; Shiraki, Nobuaki; Tsuyama, Tomonori; Kume, Kazuhiko; Endo, Fumio; Kume, Shoen

    2014-01-01

    Islet transplantation is a promising potential therapy for patients with type 1 diabetes. The outcome of islet transplantation depends on the transplantation of a sufficient amount of β-cell mass. However, the initial loss of islets after transplantation is problematic. We hypothesized the hyperglycemic status of the recipient may negatively affect graft survival. Therefore, in the present study, we evaluated the effect of insulin treatment on islet transplantation involving a suboptimal amount of islets in Akita mice, which is a diabetes model mouse with an Insulin 2 gene missense mutation. Fifty islets were transplanted under the left kidney capsule of the recipient mouse with or without insulin treatment. For insulin treatment, sustained-release insulin implants were implanted subcutaneously into recipient mice 2 weeks before transplantation and maintained for 4 weeks. Islet transplantation without insulin treatment did not reverse hyperglycemia. In contrast, the group that received transplants in combination with insulin treatment exhibited improved fasting blood glucose levels until 18 weeks after transplantation, even after insulin treatment was discontinued. The group that underwent islet transplantation in combination with insulin treatment had better glucose tolerance than the group that did not undergo insulin treatment. Insulin treatment improved graft survival from the acute phase (i.e., 1 day after transplantation) to the chronic phase (i.e., 18 weeks after transplantation). Islet apoptosis increased with increasing glucose concentration in the medium or blood in both the in vitro culture and in vivo transplantation experiments. Expression profile analysis of grafts indicated that genes related to immune response, chemotaxis, and inflammatory response were specifically upregulated when islets were transplanted into mice with hyperglycemia compared to those with normoglycemia. Thus, the results demonstrate that insulin treatment protects islets from

  11. Virus-induced alterations in insulin release in hamster islets of Langerhans.

    PubMed

    Rayfield, E J; Seto, Y; Walsh, S; McEvoy, R C

    1981-11-01

    After the inoculation of Golden Syrian hamsters with the TC-83 vaccine strain of Venezuelan encephalitis (VE) virus, a sustained diminution in glucose-stimulated insulin release and glucose intolerance of shorter duration develops. To understand better the mechanism of this defect in insulin release, we examined insulin secretion in response to several test agents in isolated perifused islets from control and 24-d post-VE virus-infected hamsters. 50 islets were used in all perifusion experiments, and data were expressed as total insulin released as well as peak response for each test agent during a 30-min perifusion period from control and VE-infected islets. After perifusion with 20 mM glucose, a 45% diminution of insulin release was noted in VE-infected islets in comparison with control islets, which in turn was similar to in vivo findings. However, following 1-mM tolbutamide stimulation, insulin release was similar in control and VE-infected islets. In separate studies, 1 mM tolbutamide, 10 mM theophilline, 1 mM dibutyryl cyclic (c)AMP, and 1 mM 8-bromo-cAMP resulted in statistically similar insulin-release curves in control and VE-infected islets. Additional experiments assessing [5-3H]glucose use in control and infected islets after 20 min of perifusion with 20 mM glucose revealed virtually identical values (239 +/- 30-control; and 222 +/- 27-VE-infected islets). Morphological and morphometric evaluation of VE-infected islets (21 d following virus inoculation) showed no changes in islet volume density, beta cell density, and beta cell granulation. Thus, VE virus induces a defect in glucose-stimulated insulin release from hamster beta cells that can be corrected by cAMP analogues and does not alter islet glucose use.

  12. Coping style and stress hormone responses in genetically heterogeneous rats: comparison with the Roman rat strains.

    PubMed

    Díaz-Morán, Sira; Palència, Marta; Mont-Cardona, Carme; Cañete, Toni; Blázquez, Gloria; Martínez-Membrives, Esther; López-Aumatell, Regina; Tobeña, Adolf; Fernández-Teruel, Alberto

    2012-03-01

    The purpose of the present study was to evaluate for the first time the stress-induced hypothalamus-pituitary-adrenal (HPA), adrenocorticotropic hormone (ACTH), corticosterone and prolactin responses of the National Institutes of Health genetically heterogeneous rat stock (N/Nih-HS rats) in comparison with responses of the relatively high and low stress-prone Roman Low- (RLA-I) and High-Avoidance (RHA-I) rat strains. The same rats were also compared (experiment 1) with respect to their levels of unconditioned anxiety (elevated zero-maze test), novelty-induced exploratory behavior, conditioned fear and two-way active avoidance acquisition. In experiment 2, naive rats from these three strains/stocks were evaluated for "depressive-like" behavior in the forced swimming test. N/Nih-HS and RLA-I rats showed significantly higher post-stress ACTH, corticosterone and prolactin levels than RHA-I rats. N/Nih-HS rats also presented the highest context-conditioned freezing responses, extremely poor two-way avoidance acquisition and very low novelty-induced exploratory behavior. Experiment 2 showed that, compared to RHA-I rats, N/Nih-HS and RLA-I rats displayed significantly less struggling (escape-directed) and increased immobility responses in the forced swimming test. Factor analysis of data from experiment 1 showed associations among behavioral and hormonal responses, with a first factor comprising high loadings of elevated zero-maze variables and lower loadings of conditioned fear, two-way avoidance acquisition and hormonal measures, while a second factor mainly grouped conditioned fear and two-way avoidance acquisition with novelty-induced exploration and post-stress prolactin. Thus, regarding their anxiety/fearfulness, passive coping style, "depressive-like" and stress-induced hormonal responses the N/Nih-HS rats resemble the phenotype profiles of the relatively high-anxious and stress-prone RLA-I rat strain.

  13. Behavioural and Hormonal Stress Responses to Social Separation in Ravens, Corvus corax.

    PubMed

    Munteanu, Alexandru M; Stocker, Martina; Stöwe, Mareike; Massen, Jorg J M; Bugnyar, Thomas

    2017-02-01

    Social life is profitable, but it facilitates conflicts over resources and creates interdependence between individuals. Separating highly social animals triggers intense reactions aimed at re-establishing lost connections. Less is known, however, about behavioural and physiological responses to separation in socially facultative species, where individuals temporarily form groups and may subsequently leave them. Non-breeding common ravens (Corvus corax) gather in large numbers at feeding and roosting sites, but otherwise spend time seemingly solitary or in small subgroups. We here studied how ravens cope with being socially isolated, and investigated the life characteristics that might explain potential individual differences. For this, we individually separated captive subadult ravens (n = 25) and housed them in physical and visual isolation from their group members across 4 d. During the separation period, we collected behavioural data and measured the amount of immunoreactive corticosterone metabolites from bird droppings to assess the ravens' physiological stress response. We found behavioural indicators of stress at the start of the separation, when ravens showed higher levels of tension than of comfort - a pattern that reversed at the end of the separation. Furthermore, we found that the upbringing of ravens affected their behaviour during separation. Hand-raised birds produced more vocalisations in the beginning of the separation, and were less active at the end, while the reverse pattern occurred with parent-raised ravens. Contrary to our predictions, we did not find differences in hormonal responses between the beginning and end of the separation period or any link between hormonal responses and behaviours. Ravens' behavioural responses to social separation stress seem to be dependent on their arousal states, although possible links with hormonal reactions remain unclear. Our results show that behavioural reactions are not always linked with hormonal

  14. AUXIN RESPONSE FACTOR 2 Intersects Hormonal Signals in the Regulation of Tomato Fruit Ripening.

    PubMed

    Breitel, Dario A; Chappell-Maor, Louise; Meir, Sagit; Panizel, Irina; Puig, Clara Pons; Hao, Yanwei; Yifhar, Tamar; Yasuor, Hagai; Zouine, Mohamed; Bouzayen, Mondher; Granell Richart, Antonio; Rogachev, Ilana; Aharoni, Asaph

    2016-03-01

    The involvement of ethylene in fruit ripening is well documented, though knowledge regarding the crosstalk between ethylene and other hormones in ripening is lacking. We discovered that AUXIN RESPONSE FACTOR 2A (ARF2A), a recognized auxin signaling component, functions in the control of ripening. ARF2A expression is ripening regulated and reduced in the rin, nor and nr ripening mutants. It is also responsive to exogenous application of ethylene, auxin and abscisic acid (ABA). Over-expressing ARF2A in tomato resulted in blotchy ripening in which certain fruit regions turn red and possess accelerated ripening. ARF2A over-expressing fruit displayed early ethylene emission and ethylene signaling inhibition delayed their ripening phenotype, suggesting ethylene dependency. Both green and red fruit regions showed the induction of ethylene signaling components and master regulators of ripening. Comprehensive hormone profiling revealed that altered ARF2A expression in fruit significantly modified abscisates, cytokinins and salicylic acid while gibberellic acid and auxin metabolites were unaffected. Silencing of ARF2A further validated these observations as reducing ARF2A expression let to retarded fruit ripening, parthenocarpy and a disturbed hormonal profile. Finally, we show that ARF2A both homodimerizes and interacts with the ABA STRESS RIPENING (ASR1) protein, suggesting that ASR1 might be linking ABA and ethylene-dependent ripening. These results revealed that ARF2A interconnects signals of ethylene and additional hormones to co-ordinate the capacity of fruit tissue to initiate the complex ripening process.

  15. AUXIN RESPONSE FACTOR 2 Intersects Hormonal Signals in the Regulation of Tomato Fruit Ripening

    PubMed Central

    Meir, Sagit; Panizel, Irina; Puig, Clara Pons; Hao, Yanwei; Yifhar, Tamar; Yasuor, Hagai; Zouine, Mohamed; Bouzayen, Mondher; Granell Richart, Antonio; Rogachev, Ilana; Aharoni, Asaph

    2016-01-01

    The involvement of ethylene in fruit ripening is well documented, though knowledge regarding the crosstalk between ethylene and other hormones in ripening is lacking. We discovered that AUXIN RESPONSE FACTOR 2A (ARF2A), a recognized auxin signaling component, functions in the control of ripening. ARF2A expression is ripening regulated and reduced in the rin, nor and nr ripening mutants. It is also responsive to exogenous application of ethylene, auxin and abscisic acid (ABA). Over-expressing ARF2A in tomato resulted in blotchy ripening in which certain fruit regions turn red and possess accelerated ripening. ARF2A over-expressing fruit displayed early ethylene emission and ethylene signaling inhibition delayed their ripening phenotype, suggesting ethylene dependency. Both green and red fruit regions showed the induction of ethylene signaling components and master regulators of ripening. Comprehensive hormone profiling revealed that altered ARF2A expression in fruit significantly modified abscisates, cytokinins and salicylic acid while gibberellic acid and auxin metabolites were unaffected. Silencing of ARF2A further validated these observations as reducing ARF2A expression let to retarded fruit ripening, parthenocarpy and a disturbed hormonal profile. Finally, we show that ARF2A both homodimerizes and interacts with the ABA STRESS RIPENING (ASR1) protein, suggesting that ASR1 might be linking ABA and ethylene-dependent ripening. These results revealed that ARF2A interconnects signals of ethylene and additional hormones to co-ordinate the capacity of fruit tissue to initiate the complex ripening process. PMID:26959229

  16. The Pancreatic Islet Regulome Browser

    PubMed Central

    Mularoni, Loris; Ramos-Rodríguez, Mireia; Pasquali, Lorenzo

    2017-01-01

    The pancreatic islet is a highly specialized tissue embedded in the exocrine pancreas whose primary function is that of controlling glucose homeostasis. Thus, understanding the transcriptional control of islet-cell may help to puzzle out the pathogenesis of glucose metabolism disorders. Integrative computational analyses of transcriptomic and epigenomic data allows predicting genomic coordinates of putative regulatory elements across the genome and, decipher tissue-specific functions of the non-coding genome. We herein present the Islet Regulome Browser, a tool that allows fast access and exploration of pancreatic islet epigenomic and transcriptomic data produced by different labs worldwide. The Islet Regulome Browser is now accessible on the internet or may be installed locally. It allows uploading custom tracks as well as providing interactive access to a wealth of information including Genome-Wide Association Studies (GWAS) variants, different classes of regulatory elements, together with enhancer clusters, stretch-enhancers and transcription factor binding sites in pancreatic progenitors and adult human pancreatic islets. Integration and visualization of such data may allow a deeper understanding of the regulatory networks driving tissue-specific transcription and guide the identification of regulatory variants. We believe that such tool will facilitate the access to pancreatic islet public genomic datasets providing a major boost to functional genomics studies in glucose metabolism related traits including diabetes. PMID:28261261

  17. Ethylene Response Factors: A Key Regulatory Hub in Hormone and Stress Signaling.

    PubMed

    Müller, Maren; Munné-Bosch, Sergi

    2015-09-01

    Ethylene is essential for many developmental processes and a key mediator of biotic and abiotic stress responses in plants. The ethylene signaling and response pathway includes Ethylene Response Factors (ERFs), which belong to the transcription factor family APETALA2/ERF. It is well known that ERFs regulate molecular response to pathogen attack by binding to sequences containing AGCCGCC motifs (the GCC box), a cis-acting element. However, recent studies suggest that several ERFs also bind to dehydration-responsive elements and act as a key regulatory hub in plant responses to abiotic stresses. Here, we review some of the recent advances in our understanding of the ethylene signaling and response pathway, with emphasis on ERFs and their role in hormone cross talk and redox signaling under abiotic stresses. We conclude that ERFs act as a key regulatory hub, integrating ethylene, abscisic acid, jasmonate, and redox signaling in the plant response to a number of abiotic stresses.

  18. Ethylene Response Factors: A Key Regulatory Hub in Hormone and Stress Signaling1

    PubMed Central

    Müller, Maren; Munné-Bosch, Sergi

    2015-01-01

    Ethylene is essential for many developmental processes and a key mediator of biotic and abiotic stress responses in plants. The ethylene signaling and response pathway includes Ethylene Response Factors (ERFs), which belong to the transcription factor family APETALA2/ERF. It is well known that ERFs regulate molecular response to pathogen attack by binding to sequences containing AGCCGCC motifs (the GCC box), a cis-acting element. However, recent studies suggest that several ERFs also bind to dehydration-responsive elements and act as a key regulatory hub in plant responses to abiotic stresses. Here, we review some of the recent advances in our understanding of the ethylene signaling and response pathway, with emphasis on ERFs and their role in hormone cross talk and redox signaling under abiotic stresses. We conclude that ERFs act as a key regulatory hub, integrating ethylene, abscisic acid, jasmonate, and redox signaling in the plant response to a number of abiotic stresses. PMID:26103991

  19. Hormonal responses to resistance exercise after ingestion of carnosine and anserine.

    PubMed

    Goto, Kazushige; Maemura, Hirohiko; Takamatsu, Kaoru; Ishii, Naokata

    2011-02-01

    Intramuscular carnosine buffers protons (H+) in skeletal muscle. We examined the effects of supplementation with chicken breast meat extract (CBEX) containing carnosine and anserine on hormonal responses to resistance exercise. Twenty-two men were assigned to a CBEX drink group (CBEX containing total 2 g of carnosine and anserine) (n = 14) or a placebo drink group (n = 8). The subjects ingested the prescribed drink (100 mL) twice daily for 30 days without physical training. Before and after the supplementation period, the subjects completed 5 sets of bilateral knee extension exercises (with a 90-s rest between sets). The magnitude of the increase in exercise-induced free testosterone did not change significantly after supplementation in either group. The blood lactate response to exercise was attenuated after supplementation in both groups (p < 0.05). In the CBEX group, the plasma epinephrine and norepinephrine concentrations after exercise were significantly lower after supplementation (p < 0.05). The serum growth hormone response to exercise was also reduced in the CBEX group after supplementation (delta value: 5.4 ± 1.9 ng/mL [pre] vs. 1.6 ± 0.5 ng/mL [post], p = 0.05). No significant differences in exercise-induced strength reduction (fatigue index) were observed in the 2 groups after supplementation. These results suggest that short-term supplementation with CBEX attenuates the exercise-induced epinephrine, norepinephrine, and growth hormone responses.

  20. Efficient Gene Transduction of Dispersed Islet Cells in Culture Using Fiber-Modified Adenoviral Vectors

    PubMed Central

    Hanayama, Hiroyuki; Ohashi, Kazuo; Utoh, Rie; Shimizu, Hirofumi; Ise, Kazuya; Sakurai, Fuminori; Mizuguchi, Hiroyuki; Tsuchiya, Hiroyuki; Okano, Teruo; Gotoh, Mitsukazu

    2015-01-01

    To establish novel islet-based therapies, our group has recently developed technologies for creating functional neo-islet tissues in the subcutaneous space by transplanting monolithic sheets of dispersed islet cells (islet cell sheets). Improving cellular function and viability are the next important challenges for enhancing the therapeutic effects. This article describes the adenoviral vector-mediated gene transduction of dispersed islet cells under culture conditions. Purified pancreatic islets were obtained from Lewis rats and dissociated into single islet cells. Cells were plated onto laminin-5-coated temperature-responsive polymer poly(N-isopropylacrylamide)-immobilized plastic dishes. At 0 h, islet cells were infected for 1 h with either conventional type 5 adenoviral vector (Ad-CA-GFP) or fiber-modified adenoviral vector (AdK7-CA-GFP) harboring a polylysine (K7) peptide in the C terminus of the fiber knob. We investigated gene transduction efficiency at 48 h after infection and found that AdK7-CA-GFP yielded higher transduction efficiencies than Ad-CA-GFP at a multiplicity of infection (MOI) of 5 and 10. For AdK7-CA-GFP at MOI = 10, 84.4 ± 1.5% of islet cells were found to be genetically transduced without marked vector infection-related cellular damage as determined by viable cell number and lactate dehydrogenase (LDH) release assay. After AdK7-CA-GFP infection at MOI = 10, cells remained attached and expanded to nearly full confluency, showing that this adenoviral infection protocol is a feasible approach for creating islet cell sheets. We have shown that dispersed and cultured islet cells can be genetically modified efficiently using fiber-modified adenoviral vectors. Therefore, this gene therapy technique could be used for cellular modification or biological assessment of dispersed islet cells. PMID:26858906

  1. In Vivo Magnetic Resonance Imaging of Small Interfering RNA Nanodelivery to Pancreatic Islets.

    PubMed

    Wang, Ping; Moore, Anna

    2016-01-01

    Pancreatic islet transplantation is a promising therapeutic approach for type 1 diabetes.However, recent advances in islet transplantation are limited by significant graft loss after transplantation. Multiple immunological and nonimmunological factors contribute to this loss. Novel therapies that could target the core reasons for the islet graft loss are desperately needed. Small interfering RNA can be used to inhibit the expression of virtually any gene with single-nucleotide specificity including genes responsible for islet damage. Applying adequate delivery of siRNA molecules to pancreatic islets prior to transplantation holds a great potential for improving the survival of islet grafts. Noninvasive imaging provides means for monitoring the survival of transplanted islets in real time. Here, we summarize the approach that has been developed to deliver siRNA to pancreatic islets in conjunction with tracking of the graft outcome by in vivo magnetic resonance imaging (MRI). We synthesize a nano-sized theranostic agent consisting of magnetic nanoparticles (MN), a reporter for MRI, labeled with Cy5.5 dye for near-infrared fluorescence (NIRF) imaging, and conjugated to siRNA molecule targeting genes that are harmful to islet grafts. Pre-labeling of islets by MN-Cy5.5-siRNA allowed us to monitor the survival of transplanted islet grafts by MRI and NIRF imaging and resulted in efficient silencing of the target genes in vivo. This novel approach combines a therapeutic effect provided by RNA interference technology with in vivo MR imaging and is expected to significantly improve the outcome of islet transplantation in patients with type 1 diabetes.

  2. Diazoxide, a K(ATP) channel opener, prevents ischemia-reperfusion injury in rodent pancreatic islets.

    PubMed

    Wang, Yong; Wang, Shusen; Harvat, Tricia; Kinzer, Katie; Zhang, Lisa; Feng, Feng; Qi, Meirigeng; Oberholzer, Jose

    2015-01-01

    Diazoxide (DZ) is a pharmacological opener of ATP-sensitive K(+) channels that has been used for mimicking ischemic preconditioning and shows protection against ischemic damage. Here we investigated whether diazoxide supplementation to University of Wisconsin (UW) solution has cellular protection during islet isolation and improves in vivo islet transplant outcomes in a rodent ischemia model. C57/B6 mice pancreata were flushed with UW or UW + DZ solution and cold preserved for 6 or 10 h prior to islet isolation. Islet yield, in vitro and in vivo function, mitochondrial morphology, and apoptosis were evaluated. Significantly higher islet yields were observed in the UW + DZ group than in the UW group (237.5 ± 25.6 vs. 108.7 ± 49.3, p < 0.01). The islets from the UW + DZ group displayed a significantly higher glucose-induced insulin secretion (0.97 ng/ml ± 0.15 vs. 0.758 ng/ml ± 0.21, p = 0.009) and insulin content (60.96 ng/islet ± 13.94 vs. 42.09 ng/islet ± 8.15, p = 0.002). The DZ-treated islets had well-preserved mitochondrial morphology with superior responses of mitochondrial potentials, and calcium influx responded to glucose. A higher number of living cells and less late apoptotic cells were observed in the UW + DZ group (p < 0.05). Additionally, the islets from the UW + DZ group had a significantly higher cure rate and improved glucose tolerance. This study is the first to report mitoprotective effects of DZ for pancreas preservation and islet isolation. In the future, it will be necessary to further understand the underlying mechanism for the mitoprotection and to test this promising approach for pancreas preservation and the islet isolation process in nonhuman primates and ultimately humans.

  3. Diazoxide, a KATP Channel Opener, Prevents Ischemia-Reperfusion Injury in Rodent Pancreatic Islets

    PubMed Central

    Wang, Yong; Wang, Shusen; Harvat, Tricia; Kinzer, Katie; Zhang, Lisa; Feng, Feng; Qi, Meirigeng; Oberholzer, Jose

    2014-01-01

    Objective Diazoxide (DZ) is a pharmacological opener of ATP-sensitive K+ channels and has been used for mimicking ischemic preconditioning and shows protection against ischemic damage. Here, we investigated whether Diazoxide supplementation to University of Wisconsin (UW) solution has cellular protection during islet isolation and improves in vivo islet transplant outcomes in rodent ischemia model. Research Design and Methods C57/B6 mice pancreata were flushed with UW or UW+DZ solution and cold preserved for 6 or 10 hrs prior to islet isolation. Islet yield, in vitro and in vivo function, mitochondrial morphology, and apoptosis were evaluated. Results Significantly higher islet yields were observed in the UW+DZ group than in the UW group (237.5 ± 25.6 vs. 108.7 ± 49.3, p < 0.01). The islets from the UW+DZ group displayed a significantly higher glucose-induced insulin secretion (0.97 ng/ml ± 0.15 vs. 0.758 ng/ml ± 0.21, p = 0.009) and insulin content (6095.6 ng/islet ± 1394.5 vs. 4209.2 ng/islet ± 815.1, p = 0.002). The DZ-treated islets had well-preserved mitochondrial morphology with superior responses of mitochondrial potentials and calcium influx responded to glucose. Higher living cells and less late apoptotic cells were observed in the UW+DZ group (p < 0.05). Additionally, the transplanted islets from the UW+DZ group had a significantly higher cure rate and improved glucose tolerance. Conclusion This study is the first to report mitoprotective effects of DZ for pancreas preservation and islet isolation. It remains to be tested whether these findings can be replicated in human islet isolation and transplantation. PMID:24070013

  4. Constitutional Delay Influences the Auxological Response to Growth Hormone Treatment in Children with Short Stature and Growth Hormone Sufficiency

    PubMed Central

    Gunn, Katherine C.; Cutfield, Wayne S.; Hofman, Paul L.; Jefferies, Craig A.; Albert, Benjamin B.; Gunn, Alistair J.

    2014-01-01

    In a retrospective, population based cohort study, we examined whether constitutional delay was associated with the growth response to growth hormone (GH) in children with short stature and normal GH responses. 70 patients were treated with 21 GH iu/m2/week from 1975 to 2013 throughout New Zealand. Demographic and auxological data were prospectively collected and standard deviation scores (SDS) were calculated for height (HtSDS), yearly growth velocity (GV-SDS), body mass index (BMI-SDS) and predicted adult height (PAH-SDS) at time of the last available bone age. In the first year, GH was associated with marked increase in HtSDS (+0.46 (0.19, 0.76), p < 0.001) and GV-SDS (from −1.9 (−3.6, −0.7) to +2.7 (0.45, 4.2), p < 0.001). The increase in HtSDS but not in GV-SDS was greatest with younger patients and greater bone age delay, with no effect of sex, BMI-SDS or baseline HtSDS. PAH-SDS increased with treatment (+0.94 (0.18, 1.5)); increased PAH-SDS was associated with less bone age delay and greater initial increase in HtSDS. This study shows that greater bone age delay was associated with greater initial improvement in height but less improvement in predicted adult heights, suggesting that children with very delayed bone ages may show accelerated maturation during GH treatment. PMID:25317732

  5. No hormone to rule them all: Interactions of plant hormones during the responses of plants to pathogens.

    PubMed

    Shigenaga, Alexandra M; Argueso, Cristiana T

    2016-08-01

    Plant hormones are essential regulators of plant growth and immunity. In the last few decades, a vast amount of information has been obtained detailing the role of different plant hormones in immunity, and how they work together to ultimately shape the outcomes of plant pathogen interactions. Here we provide an overview on the roles of the main classes of plant hormones in the regulation of plant immunity, highlighting their metabolic and signaling pathways and how plants and pathogens utilize these pathways to activate or suppress defence.

  6. The lizard fauna of Guam's fringing islets: Island biogeography, phylogenetic history, and conservation implications

    USGS Publications Warehouse

    Perry, G.; Rodda, G.H.; Fritts, T.H.; Sharp, T.R.

    1998-01-01

    We sampled the lizard fauna of twenty-two small islets fringing the Pacific island of Guam and used these data to shed light on the processes responsible for present-day diversity. Habitat diversity, measured by islet area and vegetation complexity, was significantly correlated with the number of species found on an islet. However, islet distance and elevation were not significant predictors of diversity. Distribution patterns were slightly different for the two major families in our sample, Scincidae and Gekkonidae: skinks needed larger islets to maintain a population than did geckos. Presence/absence patterns were highly and significantly nested, and population density was correlated with the number of islets on which a species was found. An area cladogram was poorly supported and showed no faunal similarity between nearby islands. These patterns indicate that extinctions on most islets were due mostly to non-catastrophic, long-acting biological causes. The presence on the islets of species extirpated on Guam and the lack of significant nestedness on islands with greater maximum elevation highlight the impact that predators (primarily brown treesnakes) can have. Our findings also show that small reserves will not suffice to protect endangered lizard faunas, and that the islets may serve as a short-term repository of such species until snake-free areas can be established on Guam.

  7. Beta-cell metabolic alterations under chronic nutrient overload in rat and human islets

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The aim of this study was to assess multifactorial Beta-cell responses to metabolic perturbations in primary rat and human islets. Treatment of dispersed rat islet cells with elevated glucose and free fatty acids (FFAs, oleate:palmitate = 1:1 v/v) resulted in increases in the size and the number of ...

  8. Sex differences in acute hormonal and subjective response to naltrexone: The impact of menstrual cycle phase.

    PubMed

    Roche, Daniel J O; King, Andrea C

    2015-02-01

    Women often exhibit larger hormonal and subjective responses to opioid receptor antagonists than men, but the biological mechanisms mediating this effect remain unclear. Among women, fluctuations in estradiol (E2) and progesterone (P4) across the menstrual cycle (MC) affect the endogenous opioid system. Therefore, the goal of the current study was to compare acute naltrexone response between women in the early follicular phase of the MC (low E2 and P4), women in the luteal phase of the MC (high E2 and P4), and men. Seventy healthy controls (n=46 women) participated in two morning sessions in which they received 50mg naltrexone or placebo in a randomized, counterbalanced order. Women were randomized to complete both sessions in either the early follicular (n=23) or luteal phase of the MC. Serum cortisol, salivary cortisol, prolactin, luteinizing hormone (LH), and subjective response were assessed upon arrival to the laboratory and at regular intervals after pill administration. In luteal and early follicular women but not men, naltrexone (vs. placebo) increased serum cortisol and prolactin levels from baseline; however, the naltrexone-induced increases in these hormones were significantly greater in luteal women than early follicular women. Additionally, only luteal women demonstrated an increase from baseline in salivary cortisol levels and the severity of adverse drug effects in response to naltrexone. In sum, the results indicate that luteal phase women are more sensitive to acute hormonal and subjective effects of naltrexone than early follicular women and men. These findings may have important implications for the use of naltrexone in women.

  9. Upregulated insulin secretion in insulin-resistant mice: evidence of increased islet GLP1 receptor levels and GPR119-activated GLP1 secretion.

    PubMed

    Ahlkvist, L; Brown, K; Ahrén, B

    2013-06-01

    We previously demonstrated that the overall incretin effect and the β-cell responsiveness to glucagon-like peptide-1 (GLP1) are increased in insulin-resistant mice and may contribute to the upregulated β-cell function. Now we examined whether this could, first, be explained by increased islet GLP1 receptor (GLP1R) protein levels and, secondly, be leveraged by G-protein-coupled receptor 119 (GPR119) activation, which stimulates GLP1 secretion. Female C57BL/6J mice, fed a control (CD, 10% fat) or high-fat (HFD, 60% fat) diet for 8 weeks, were anesthetized and orally given a GPR119 receptor agonist (GSK706A; 10 mg/kg) or vehicle, followed after 10 min with gavage with a liquid mixed meal (0.285 kcal). Blood was sampled for determination of glucose, insulin, intact GLP1, and glucagon, and islets were isolated for studies on insulin and glucagon secretion and GLP1R protein levels. In HFD vs CD mice, GPR119 activation augmented the meal-induced increase in the release of both GLP1 (AUCGLP1 81±9.6 vs 37±6.9 pM×min, P=0.002) and insulin (AUCINS 253±29 vs 112±19 nM×min, P<0.001). GPR119 activation also significantly increased glucagon levels in both groups (P<0.01) with, however, no difference between the groups. By contrast, GPR119 activation did not affect islet hormone secretion from isolated islets. Glucose elimination after meal ingestion was significantly increased by GPR119 activation in HFD mice (0.57±0.04 vs 0.43±0.03% per min, P=0.014) but not in control mice. Islet GLP1R protein levels was higher in HFD vs CD mice (0.8±0.1 vs 0.5±0.1, P=0.035). In conclusion, insulin-resistant mice display increased islet GLP1R protein levels and augmented meal-induced GLP1 and insulin responses to GPR119 activation, which results in increased glucose elimination. We suggest that the increased islet GLP1R protein levels together with the increased GLP1 release may contribute to the upregulated β-cell function in insulin resistance.

  10. Thyroid hormones inhibit TGF-β signaling and attenuate fibrotic responses

    PubMed Central

    Alonso-Merino, Elvira; Martín Orozco, Rosa; Ruíz-Llorente, Lidia; Martínez-Iglesias, Olaia A.; Velasco-Martín, Juan Pedro; Fanjul-Rodríguez, Luisa; Contreras-Jurado, Constanza; Regadera, Javier; Aranda, Ana

    2016-01-01

    TGF-β, the most potent profibrogenic factor, acts by activating SMAD (mothers against decapentaplegic) transcription factors, which bind to SMAD-binding elements in target genes. Here, we show that the thyroid hormone triiodothyronine (T3), through binding to its nuclear receptors (TRs), is able to antagonize transcriptional activation by TGF-β/SMAD. This antagonism involves reduced phosphorylation of SMADs and a direct interaction of the receptors with SMAD3 and SMAD4 that is independent of T3-mediated transcriptional activity but requires residues in the receptor DNA binding domain. T3 reduces occupancy of SMAD-binding elements in response to TGF-β, reducing histone acetylation and inhibiting transcription. In agreement with this transcriptional cross-talk, T3 is able to antagonize fibrotic processes in vivo. Liver fibrosis induced by carbon tetrachloride is attenuated by thyroid hormone administration to mice, whereas aged TR knockout mice spontaneously accumulate collagen. Furthermore, skin fibrosis induced by bleomycin administration is also reduced by the thyroid hormones. These findings define an important function of the thyroid hormone receptors and suggest TR ligands could have beneficial effects to block the progression of fibrotic diseases. PMID:27247403

  11. Differential responses of cortisol and corticosterone to adrenocorticotropic hormone (ACTH) in a subterranean rodent (Ctenomys talarum).

    PubMed

    Vera, Federico; Zenuto, Roxana Rita; Antenucci, Carlos Daniel

    2012-03-01

    We aimed to evaluate the responses of cortisol, corticosterone, and blood glucose to adrenocorticotropic hormone (ACTH) in males and females of the subterranean rodent Ctenomys talarum and addressed interannual variations in the plasma levels of both hormones. The most important results indicate that: (1) cortisol positively responds to the ACTH signal but corticosterone does not, even though corticosterone levels were higher than cortisol concentrations, (2) plasma corticosterone concentrations in free-living animals were 20 times higher compared to values reported for the same population during previous annual periods and, as cortisol levels were similar, this resulted in much lower cortisol/corticosterone ratios, (3) cortisol and corticosterone differentiated in their relative proportions in plasma in free-living males and females. These results indicate that cortisol and corticosterone are differentially regulated in our study species and emphasize that a remarkable temporal variation in the relative proportions of these hormones may occur in natural populations. Therefore, the conclusions regarding the presence of cortisol and corticosterone in plasma of wild animals may differ substantially depending on the moment when the study is conducted. Recent data indicate that cortisol and corticosterone are not interchangeable hormones in species of free-living vertebrates. We suggest that, in addition to the classical roles of glucocorticoids (GCs), it is crucial that other physiological functions be kept in mind when interpreting GC data from wild species.

  12. Human islet preparations distributed for research exhibit a variety of insulin-secretory profiles.

    PubMed

    Kayton, Nora S; Poffenberger, Gregory; Henske, Joseph; Dai, Chunhua; Thompson, Courtney; Aramandla, Radhika; Shostak, Alena; Nicholson, Wendell; Brissova, Marcela; Bush, William S; Powers, Alvin C

    2015-04-01

    Human islet research is providing new insights into human islet biology and diabetes, using islets isolated at multiple US centers from donors with varying characteristics. This creates challenges for understanding, interpreting, and integrating research findings from the many laboratories that use these islets. In what is, to our knowledge, the first standardized assessment of human islet preparations from multiple isolation centers, we measured insulin secretion from 202 preparations isolated at 15 centers over 11 years and noted five distinct patterns of insulin secretion. Approximately three quarters were appropriately responsive to stimuli, but one quarter were dysfunctional, with unstable basal insulin secretion and/or an impairment in stimulated insulin secretion. Importantly, the patterns of insulin secretion by responsive human islet preparations (stable Baseline and Fold stimulation of insulin secretion) isolated at different centers were similar and improved slightly over the years studied. When all preparations studied were considered, basal and stimulated insulin secretion did not correlate with isolation center, biological differences of the islet donor, or differences in isolation, such as Cold Ischemia Time. Dysfunctional islet preparations could not be predicted from the information provided by the isolation center and had altered expression of genes encoding components of the glucose-sensing pathway, but not of insulin production or cell death. These results indicate that insulin secretion by most preparations from multiple centers is similar but that in vitro responsiveness of human islets cannot be predicted, necessitating preexperimental human islet assessment. These results should be considered when one is designing, interpreting, and integrating experiments using human islets.

  13. Hormonal Regulation of Response to Oxidative Stress in Insects—An Update

    PubMed Central

    Kodrík, Dalibor; Bednářová, Andrea; Zemanová, Milada; Krishnan, Natraj

    2015-01-01

    Insects, like other organisms, must deal with a wide variety of potentially challenging environmental factors during the course of their life. An important example of such a challenge is the phenomenon of oxidative stress. This review summarizes the current knowledge on the role of adipokinetic hormones (AKH) as principal stress responsive hormones in insects involved in activation of anti-oxidative stress response pathways. Emphasis is placed on an analysis of oxidative stress experimentally induced by various stressors and monitored by suitable biomarkers, and on detailed characterization of AKH’s role in the anti-stress reactions. These reactions are characterized by a significant increase of AKH levels in the insect body, and by effective reversal of the markers—disturbed by the stressors—after co-application of the stressor with AKH. A plausible mechanism of AKH action in the anti-oxidative stress response is discussed as well: this probably involves simultaneous employment of both protein kinase C and cyclic adenosine 3′,5′-monophosphate pathways in the presence of extra and intra-cellular Ca2+ stores, with the possible involvement of the FoxO transcription factors. The role of other insect hormones in the anti-oxidative defense reactions is also discussed. PMID:26516847

  14. Paired hormone response elements predict caveolin-1 as a glucocorticoid target gene.

    PubMed

    van Batenburg, Marinus F; Li, Hualing; Polman, J Annelies; Lachize, Servane; Datson, Nicole A; Bussemaker, Harmen J; Meijer, Onno C

    2010-01-21

    Glucocorticoids act in part via glucocorticoid receptor binding to hormone response elements (HREs), but their direct target genes in vivo are still largely unknown. We developed the criterion that genomic occurrence of paired HREs at an inter-HRE distance less than 200 bp predicts hormone responsiveness, based on synergy of multiple HREs, and HRE information from known target genes. This criterion predicts a substantial number of novel responsive genes, when applied to genomic regions 10 kb upstream of genes. Multiple-tissue in situ hybridization showed that mRNA expression of 6 out of 10 selected genes was induced in a tissue-specific manner in mice treated with a single dose of corticosterone, with the spleen being the most responsive organ. Caveolin-1 was strongly responsive in several organs, and the HRE pair in its upstream region showed increased occupancy by glucocorticoid receptor in response to corticosterone. Our approach allowed for discovery of novel tissue specific glucocorticoid target genes, which may exemplify responses underlying the permissive actions of glucocorticoids.

  15. Global epigenomic analysis of primary human pancreatic islets provides insights into type 2 diabetes susceptibility loci

    PubMed Central

    Stitzel, Michael L.; Sethupathy, Praveen; Pearson, Daniel S.; Chines, Peter S.; Song, Lingyun; Erdos, Michael R.; Welch, Ryan; Parker, Stephen C. J.; Boyle, Alan P.; Scott, Laura J.; Margulies, Elliott H.; Boehnke, Michael; Furey, Terrence S.; Crawford, Gregory E.; Collins, Francis S.

    2010-01-01

    Summary Identifying cis-regulatory elements is important to understand how human pancreatic islets modulate gene expression in physiologic or pathophysiologic (e.g., diabetic) conditions. We conducted genome-wide analysis of DNase I hypersensitive sites, histone H3 lysine methylation modifications (K4me1, K4me3, K79me2), and CCCTC factor (CTCF) binding in human islets. This identified ~18,000 putative promoters (several hundred unannotated and islet-active). Surprisingly, active promoter modifications were absent at genes encoding islet-specific hormones, suggesting a distinct regulatory mechanism. Of 34,039 distal (non-promoter) regulatory elements, 47% are islet-unique and 22% are CTCF-bound. In the 18 type 2 diabetes (T2D)-associated loci, we identified 118 putative regulatory elements and confirmed enhancer activity for 12/33 tested. Among 6 regulatory elements harboring T2D-associated variants, 2 exhibit significant allele-specific differences in activity. These findings present a global snapshot of the human islet epigenome and should provide functional context for non-coding variants emerging from genetic studies of T2D and other islet disorders. PMID:21035756

  16. Fibrillar dimer formation of islet amyloid polypeptides

    NASA Astrophysics Data System (ADS)

    Chiu, Chi-cheng; de Pablo, Juan J.

    2015-09-01

    Amyloid deposits of human islet amyloid polypeptide (hIAPP), a 37-residue hormone co-produced with insulin, have been implicated in the development of type 2 diabetes. Residues 20 - 29 of hIAPP have been proposed to constitute the amyloidogenic core for the aggregation process, yet the segment is mostly unstructured in the mature fibril, according to solid-state NMR data. Here we use molecular simulations combined with bias-exchange metadynamics to characterize the conformational free energies of hIAPP fibrillar dimer and its derivative, pramlintide. We show that residues 20 - 29 are involved in an intermediate that exhibits transient β-sheets, consistent with recent experimental and simulation results. By comparing the aggregation of hIAPP and pramlintide, we illustrate the effects of proline residues on inhibition of the dimerization of IAPP. The mechanistic insights presented here could be useful for development of therapeutic inhibitors of hIAPP amyloid formation.

  17. Fibrillar dimer formation of islet amyloid polypeptides

    SciTech Connect

    Chiu, Chi -cheng; de Pablo, Juan J.

    2015-05-08

    Amyloid deposits of human islet amyloid polypeptide (hIAPP), a 37-residue hormone co-produced with insulin, have been implicated in the development of type 2 diabetes. Residues 20 – 29 of hIAPP have been proposed to constitute the amyloidogenic core for the aggregation process, yet the segment is mostly unstructured in the mature fibril, according to solid-state NMR data. Here we use molecular simulations combined with bias-exchange metadynamics to characterize the conformational free energies of hIAPP fibrillar dimer and its derivative, pramlintide. We show that residues 20 – 29 are involved in an intermediate that exhibits transient β-sheets, consistent with recent experimental and simulation results. By comparing the aggregation of hIAPP and pramlintide, we illustrate the effects of proline residues on inhibition of the dimerization of IAPP. The mechanistic insights presented here could be useful for development of therapeutic inhibitors of hIAPP amyloid formation.

  18. Pubertal shifts in adrenal responsiveness to stress and adrenocorticotropic hormone in male rats.

    PubMed

    Romeo, Russell D; Minhas, Sumeet; Svirsky, Sarah E; Hall, Baila S; Savenkova, Marina; Karatsoreos, Ilia N

    2014-04-01

    Studies have indicated significant pubertal-related differences in hormonal stress reactivity. We report here that prepubertal (30 days) male rats display a more protracted stress-induced corticosterone response than adults (70 days), despite showing relatively similar levels of adrenocorticotropic hormone (ACTH). Additionally, we show that adrenal expression of the ACTH receptor, melanocortin 2 receptor (Mc2r), is higher in prepubertal compared to adult animals, and that expression of melanocortin receptor accessory protein (Mrap), a molecule that chaperones MC2R to the cell surface, is greater in prepubertal males following stress. Given that these data suggest a pubertal shift in adrenal sensitivity to ACTH, we directly tested this possibility by injecting prepubertal and adult males with 6.25 or 9.375μg/kg of exogenous rat ACTH and measured their hormone levels 30 and 60min post-injection. As these doses resulted in different circulating levels of ACTH at these two ages, we performed regression analyses to assess the relationship between circulating ACTH and corticosterone concentrations. We found no difference between the ages in the correlation between ACTH and corticosterone levels at the 30min time point. However, 60min following the ACTH injection, we found prepubertal rats had significantly higher corticosterone concentrations at lower levels of ACTH compared to adults. These data suggest that prolonged exposure to ACTH leads to greater corticosterone responsiveness prior to puberty, and indicate that changes in adrenal sensitivity to ACTH may, in part, contribute to the protracted hormonal stress response in prepubertal rats.

  19. Effects of supplementary treatment with bovine growth hormone on hormonal and ovulatory responses to inhibin immunization in ewes.

    PubMed

    Tannetta, D S; Fray, M D; Wrathall, J H; Bleach, E C; Glencross, R G; Knight, P G

    1997-07-01

    The aim of this study was to determine whether supplementary treatment with recombinant bovine growth hormone(rbGH) can enhance the ovulatory response of ewes to inhibin immunization. Crossbred ewes (n = 20) were actively immunized against bovine inhibin a1-29 peptide conjugate while 20 ewes served as controls. Oestrus was synchronized using progestagen sponges and ewes were allocated to four groups: control ewes (n = 10); control ewes given rbGH (n = 10); inhibin-immunized ewes (n = 10) and inhibin-immunized ewes given rbGH (n = 10). A single s.c. dose of rbGH (50 mg) was given 7 days before sponge removal. Blood was collected for measurement of inhibin antibody titre, and concentrations of insulin-like growth factor I (IGF-I), FSH, oestradiol and progesterone. Ovulation, pregnancy and lambing rates were also recorded. All inhibin-immunized ewes produced antibodies that bound 125I-labelled (32 kDa) inhibin. The concentration of FSH in the plasma of the ewes after the second booster inhibin immunization was higher than that in control ewes (P < 0.005). Treatment with rbGH promoted a 2-3-fold increase in plasma concentration of IGF-I (P < 0.001); the response was less (P < 0.01) in immunized compared with control ewes. Treatment with rbGH alone had no significant effect on the concentration of FSH or oestradiol or on ovulation rate or litter size. Overall, inhibin-immunized ewes had higher mean FSH concentrations (P < 0.002), higher preovulatory oestradiol surges (P < 0.05) and higher progesterone concentrations in the luteal phase (P < 0.0001). Treatment with rbGH reduced the effects of immunization on FSH (P < 0.01) and progesterone (P < 0.02) concentrations. Immunized ewes showed a threefold increase in ovulation rate (P < 0.001) and a 1.8-fold increase in litter size (P < 0.05) compared with control ewes. In immunized ewes given rbGH, ovulation rate was increased by a factor of 2.2 and litter size by a factor of 1.8. In conclusion, these data do not support the

  20. Effect of dark pretreatment on the kinetics of response of barley pulvini to gravistimulation and hormones

    NASA Technical Reports Server (NTRS)

    Brock, T. G.; Kaufman, P. B.

    1988-01-01

    Starch in pulvinus amyloplasts of barley (Hordeum vulgare cv Larker) disappears when 45-day-old, light-grown plants are given 5 days of continuous darkness. The effect of this loss on the pulvinus graviresponse was evaluated by following changes in the kinetics of response during the 5-day dark period. Over 5 days of dark pretreatment, the lag to initial graviresponse and the subsequent half-time to maximum steady state bending rate increased significantly while the maximum bending rate did not change. The change in response to applied indoleacetic acid (100 micromolar) plus gibberellic acid (10 micromolar) without gravistimulation, under identical dark pretreatments, was used as a model system for the response component of gravitropism. Dark pretreatment did not change the lag to initial response following hormone application to vertical pulvini, but both the maximum bending rate and the half-time to the maximum rate were significantly reduced. Also, after dark pretreatment, significant bending responses following hormone application were observed in vertical segments with or without added sucrose, while gravistimulation produced a response only if segments were given sucrose. These results indicate that starch-filled amyloplasts are required for the graviresponse of barley pulvini and suggest that they function in the stimulus perception and signal transduction components of gravitropism.

  1. Pregnancy and pregnancy-associated hormones alter immune responses and disease pathogenesis.

    PubMed

    Robinson, Dionne P; Klein, Sabra L

    2012-08-01

    During pregnancy, it is evolutionarily advantageous for inflammatory immune responses that might lead to fetal rejection to be reduced and anti-inflammatory responses that promote transfer of maternal antibodies to the fetus to be increased. Hormones modulate the immunological shift that occurs during pregnancy. Estrogens, including estradiol and estriol, progesterone, and glucocorticoids increase over the course of pregnancy and affect transcriptional signaling of inflammatory immune responses at the maternal-fetal interface and systemically. During pregnancy, the reduced activity of natural killer cells, inflammatory macrophages, and helper T cell type 1 (Th1) cells and production of inflammatory cytokines, combined with the higher activity of regulatory T cells and production of anti-inflammatory cytokines, affects disease pathogenesis. The severity of diseases caused by inflammatory responses (e.g., multiple sclerosis) is reduced and the severity of diseases that are mitigated by inflammatory responses (e.g., influenza and malaria) is increased during pregnancy. For some infectious diseases, elevated inflammatory responses that are necessary to control and clear a pathogen have a negative consequence on the outcome of pregnancy. The bidirectional interactions between hormones and the immune system contribute to both the outcome of pregnancy and female susceptibility to disease.

  2. Taste matters - effects of bypassing oral stimulation on hormone and appetite responses.

    PubMed

    Spetter, Maartje S; Mars, Monica; Viergever, Max A; de Graaf, Cees; Smeets, Paul A M

    2014-10-01

    The interaction between oral and gastric signals is an important part of food intake regulation. Previous studies suggest that bypassing oral stimulation diminishes the suppression of hunger and increases gastric emptying rate. However, the role of appetite hormones, like cholecystokinin-8 and ghrelin, in this process is still unclear. Our objective was to determine the contributions of gastric and oral stimulation to subsequent appetite and hormone responses and their effect on ad libitum intake. Fourteen healthy male subjects (age 24.6±3.8y, BMI 22.3±1.6kg/m(2)) completed a randomized, single-blinded, cross-over experiment with 3 treatment-sessions: 1) Stomach distention: naso-gastric infusion of 500mL/0kJ water, 2) Stomach distention with caloric content: naso-gastric infusion of 500mL/1770kJ chocolate milk, and 3) Stomach distention with caloric content and oral exposure: oral administration of 500mL/1770kJ chocolate milk. Changes in appetite ratings and plasma glucose, insulin, cholecystokinin-8, and active and total ghrelin concentrations were measured at fixed time-points up to 30min after infusion or oral administration. Subsequently, subjects consumed an ad libitum buffet meal. Oral administration reduced appetite ratings more than both naso-gastric infusions (P<0.0001). Gastric infusion of a caloric load increased insulin and cholecystokinin-8 and decreased total ghrelin concentrations more than ingestion (all P<0.0001). No differences in active ghrelin response were observed between conditions. Ad libitum intake did not differ between oral and gastric administration of chocolate milk (P>0.05). Thus, gastric infusion of nutrients induces greater appetite hormone responses than ingestion does. These data provide novel and additional evidence that bypassing oral stimulation not only affects the appetite profile but also increases anorexigenic hormone responses, probably driven in part by faster gastric emptying. This confirms the idea that learned

  3. Cysteamine blocks somatostatin secretion without altering the course of insulin or glucagon release. A new model for the study of islet function

    SciTech Connect

    Sorenson, R.L.; Grouse, L.H.; Elde, R.P.

    1983-04-01

    Cysteamine (300 mg/kg) administered subcutaneously depletes pancreatic somatostatin to 36% of control levels, but does not alter pancreatic insulin or glucagon content. Although perfusion of pancreata from normal animals with glucose (300 mg/dl) markedly stimulated somatostatin release, pancreata from cysteamine-treated animals failed to secrete somatostatin in response to glucose. Cysteamine treatment was without effect on insulin and glucagon release under the conditions tested. The isolated perfused pancreas from the cysteamine-treated rat provides a model for further investigations into regulation of islet hormone release in the absence of stimulated somatostatin release.

  4. Effects of luteinizing hormone-releasing hormone and arginine-vasotocin on the sperm-release response of Günther's Toadlet, Pseudophryne guentheri

    PubMed Central

    2010-01-01

    Background Luteinizing hormone-releasing hormone (LHRH) is an exogenous hormone commonly used to induce spermiation in anuran amphibians. Over the past few decades, the LHRH dose administered to individuals and the frequency of injection has been highly variable. The sperm-release responses reported have been correspondingly diverse, highlighting a need to quantify dose-response relationships on a species-specific basis. This study on the Australian anuran Pseudophryne guentheri first evaluated the spermiation response of males administered one of five LHRHa doses, and second, determined whether AVT administered in combination with the optimal LHRHa dose improved sperm-release. Methods Male toadlets were administered a single dose of 0, 1, 2, 4 or 8 micrograms/g body weight of LHRHa. A 4 micrograms/g dose of AVT was administered alone or in combination with 2 micrograms/g LHRHa. Spermiation responses were evaluated at 3, 7 and 12 h post hormone administration (PA), and sperm number and viability were quantified using fluorescent microscopy. Results LHRHa administration was highly effective at inducing spermiation in P. guentheri, with 100% of hormone-treated males producing sperm during the experimental period. The number of sperm released in response to 2 micrograms/g LHRHa was greater than all other doses administered and sperm viability was highest in the 1 microgram/g treatment. The administration of AVT alone or in combination with LHRHa resulted in the release of significantly lower sperm numbers. Conclusion Overall, results from this study suggest that in P. guentheri, LHRHa is effective at inducing spermiation, but that AVT inhibits sperm-release. PMID:21059269

  5. Interaction between hormonal and mitochondrial signalling during growth, development and in plant defence responses.

    PubMed

    Berkowitz, Oliver; De Clercq, Inge; Van Breusegem, Frank; Whelan, James

    2016-05-01

    Mitochondria play a central role in plant metabolism as they are a major source of ATP through synthesis by the oxidative phosphorylation pathway and harbour key metabolic reactions such as the TCA cycle. The energy and building blocks produced by mitochondria are essential to drive plant growth and development as well as to provide fuel for responses to abiotic and biotic stresses. The majority of mitochondrial proteins are encoded in the nuclear genome and have to be imported into the organelle. For the regulation of the corresponding genes intricate signalling pathways exist to adjust their expression. Signals directly regulate nuclear gene expression (anterograde signalling) to adjust the protein composition of the mitochondria to the needs of the cell. In parallel, mitochondria communicate back their functional status to the nucleus (retrograde signalling) to prompt transcriptional regulation of responsive genes via largely unknown signalling mechanisms. Plant hormones are the major signalling components regulating all layers of plant development and cellular functions. Increasing evidence is now becoming available that plant hormones are also part of signalling networks controlling mitochondrial function and their biogenesis. This review summarizes recent advances in understanding the interaction of mitochondrial and hormonal signalling pathways.

  6. Sex differences, hormones, and fMRI stress response circuitry deficits in psychoses.

    PubMed

    Goldstein, Jill M; Lancaster, Katie; Longenecker, Julia M; Abbs, Brandon; Holsen, Laura M; Cherkerzian, Sara; Whitfield-Gabrieli, Susan; Makris, Nicolas; Tsuang, Ming T; Buka, Stephen L; Seidman, Larry J; Klibanski, Anne

    2015-06-30

    Response to stress is dysregulated in psychosis (PSY). fMRI studies showed hyperactivity in hypothalamus (HYPO), hippocampus (HIPP), amygdala (AMYG), anterior cingulate (ACC), orbital and medial prefrontal (OFC; mPFC) cortices, with some studies reporting sex differences. We predicted abnormal steroid hormone levels in PSY would be associated with sex differences in hyperactivity in HYPO, AMYG, and HIPP, and hypoactivity in PFC and ACC, with more severe deficits in men. We studied 32 PSY cases (50.0% women) and 39 controls (43.6% women) using a novel visual stress challenge while collecting blood. PSY males showed BOLD hyperactivity across all hypothesized regions, including HYPO and ACC by FWE-correction. Females showed hyperactivity in HIPP and AMYG and hypoactivity in OFC and mPFC, the latter FWE-corrected. Interaction of group by sex was significant in mPFC (F = 7.00, p = 0.01), with PSY females exhibiting the lowest activity. Male hyperactivity in HYPO and ACC was significantly associated with hypercortisolemia post-stress challenge, and mPFC with low androgens. Steroid hormones and neural activity were dissociated in PSY women. Findings suggest disruptions in neural circuitry-hormone associations in response to stress are sex-dependent in psychosis, particularly in prefrontal cortex.

  7. Sex Differences in Stress Response Circuitry Activation Dependent on Female Hormonal Cycle

    PubMed Central

    Goldstein, Jill M.; Jerram, Matthew; Abbs, Brandon; Whitfield-Gabrieli, Susan; Makris, Nikos

    2010-01-01

    Understanding sex differences in stress regulation has important implications for understanding basic physiological differences in the male and female brain and their impact on vulnerability to sex differences in chronic medical disorders associated with stress response circuitry. In this fMRI study, we demonstrated that significant sex differences in brain activity in stress response circuitry were dependent on women's menstrual cycle phase. Twelve healthy Caucasian premenopausal women were compared to a group of healthy men from the same population, based on age, ethnicity, education, and right-handedness. Subjects were scanned using negative valence/high arousal versus neutral visual stimuli that we demonstrated activated stress response circuitry (amygdala, hypothalamus, hippocampus, brainstem, orbitofrontal and medial prefrontal cortices (OFC and mPFC), and anterior cingulate gyrus (ACG). Women were scanned twice based on normal variation in menstrual cycle hormones (i.e., early follicular (EF) compared with late follicular-midcycle menstrual phases (LF/MC)). Using SPM8b, there were few significant differences in BOLD signal changes in men compared to EF women, except ventromedial (VMN) and lateral (LHA) hypothalamus, left amygdala, and ACG. In contrast, men exhibited significantly greater BOLD signal changes compared to LF/MC women on bilateral ACG and OFC, mPFC, LHA, VMN, hippocampus, and periaqueductal gray, with largest effect sizes in mPFC and OFC. Findings suggest that sex differences in stress response circuitry are hormonally regulated via the impact of subcortical brain activity on the cortical control of arousal, and demonstrate that females have been endowed with a natural hormonal capacity to regulate the stress response that differs from males. PMID:20071507

  8. Functional interaction of hybrid response elements with wild-type and mutant steroid hormone receptors.

    PubMed Central

    Truss, M; Chalepakis, G; Slater, E P; Mader, S; Beato, M

    1991-01-01

    Steroid hormone receptors can be divided into two subfamilies according to the structure of their DNA binding domains and the nucleotide sequences which they recognize. The glucocorticoid receptor and the progesterone receptor (PR) recognize an imperfect palindrome (glucocorticoid responsive element/progesterone responsive element [GRE/PRE]) with the conserved half-sequence TGTYCY, whereas the estrogen receptor (ER) recognizes a palindrome (estrogen responsive element) with the half-sequence TGACC. A series of symmetric and asymmetric variants of these hormone responsive elements (HREs) have been tested for receptor binding and for the ability to mediate induction in vivo. High-resolution analysis demonstrates that the overall number and distribution of contacts with the N-7 position of guanines and with the phosphate backbone of various HREs are quite similar for PR and ER. However, PR and glucocorticoid receptor, but not ER, are able to contact the 5'-methyl group of thymines found in position 3 of HREs, as shown by potassium permanganate interference. The ER mutant HE84, which contains a single amino acid exchange, Glu-203 to Gly, in the knuckle of ER, creates a promiscuous ER that is able to bind to GRE/PREs by contacting this thymine. Elements with the sequence GGTCAcagTGTYCT that represent hybrids between an estrogen response element and a GRE/PRE respond to estrogens, glucocorticoids, and progestins in vivo and bind all three wild-type receptors in vitro. These hybrid HREs could serve to confer promiscuous gene regulation. Images PMID:2038329

  9. Hormonal contraceptive use diminishes salivary cortisol response to psychosocial stress and naltrexone in healthy women.

    PubMed

    Roche, Daniel J O; King, Andrea C; Cohoon, Andrew J; Lovallo, William R

    2013-08-01

    The use of hormonal contraception (HC) may affect salivary cortisol levels at rest and in response to a pharmacological or stress challenge. Therefore, the current study used a secondary data analysis to investigate the effect of HC on salivary cortisol levels in response to the mu-opioid receptor antagonist naltrexone and a psychosocial stressor, and also across the diurnal curve. Two hundred and nine women (n=72 using hormonal contraception; HC+) completed a two-session stress response study that consisted of a stress day, in which they were exposed to public speaking and mental arithmetic, and a rest day, in which unstimulated cortisol levels were measured to assess the diurnal rhythm. A subset of seventy women (n=24 HC+) also completed a second study in which they were administered oral naltrexone (50mg) or placebo in a randomized, placebo-controlled, double blind fashion. Women who were HC+ had a significantly reduced salivary cortisol response to both the psychosocial stressor (p<0.001) and naltrexone (p<0.05) compared to HC- women. Additionally, HC+ women had a significantly altered morning diurnal cortisol rhythm (p<0.01), with a delayed peak and higher overall levels. The results of the current study confirm that HC attenuates salivary cortisol response to a psychosocial stressor and mu-opioid receptor antagonism, and also alters the morning diurnal cortisol curve.

  10. Angiopoetin-2 Signals Do Not Mediate the Hypervascularization of Islets in Type 2 Diabetes

    PubMed Central

    Shah, Payal; Lueschen, Navina; Ardestani, Amin; Oberholzer, Jose; Olerud, Johan; Carlsson, Per-Ola; Maedler, Kathrin

    2016-01-01

    hypovascularized islets in response to HFD together with increased apoptosis and reduced β-cell mass. Conclusions Islet hypervascularization occurs in T2D. A balanced expression of the Ang1/Ang2 system is important for islet physiology. Ang-2 prevents β-cell mass and islet vascular adaptation in response to HFD feeding with no major influence on glucose homeostasis. PMID:27617438

  11. Oxygenation of the Intraportally Transplanted Pancreatic Islet

    PubMed Central

    2016-01-01

    Intraportal islet transplantation (IT) is not widely utilized as a treatment for type 1 diabetes. Oxygenation of the intraportally transplanted islet has not been studied extensively. We present a diffusion-reaction model that predicts the presence of an anoxic core and a larger partly functional core within intraportally transplanted islets. Four variables were studied: islet diameter, islet fractional viability, external oxygen partial pressure (P) (in surrounding portal blood), and presence or absence of a thrombus on the islet surface. Results indicate that an islet with average size and fractional viability exhibits an anoxic volume fraction (AVF) of 14% and a function loss of 72% at a low external P. Thrombus formation increased AVF to 30% and function loss to 92%, suggesting that the effect of thrombosis may be substantial. External P and islet diameter accounted for the greatest overall impact on AVF and loss of function. At our institutions, large human alloislets (>200 μm diameter) account for ~20% of total islet number but ~70% of total islet volume; since most of the total transplanted islet volume is accounted for by large islets, most of the intraportal islet cells are likely to be anoxic and not fully functional. PMID:27872862

  12. Impact of islet size on pancreatic islet transplantation and potential interventions to improve outcome.

    PubMed

    Zorzi, Daria; Phan, Tammy; Sequi, Marco; Lin, Yong; Freeman, Daniel H; Cicalese, Luca; Rastellini, Cristiana

    2015-01-01

    Better results have been recently reported in clinical pancreatic islet transplantation (ITX) due mostly to improved isolation techniques and immunosuppression; however, some limitations still exist. It is known that following transplantation, 30% to 60% of the islets are lost. In our study, we have investigated 1) the role of size as a factor affecting islet engraftment and 2) potential procedural manipulations to increase the number of smaller functional islets that can be transplanted. C57/BL10 mice were used as donors and recipients in a syngeneic islet transplant model. Isolated islets were divided by size (large, >300 μm; medium 150-300 μm; small, <150 μm). Each size was transplanted in chemically induced diabetic mice as full (600 IEQ), suboptimal (400 IEQ), and marginal mass (200 IEQ). Control animals received all size islets. Engraftment was defined as reversal of diabetes by day 7 posttransplantation. When the superiority of smaller islets was observed, strategies of overdigestion and fragmentation were adopted during islet isolation in the attempt to reduce islet size and improve engraftment. Smaller islets were significantly superior in engraftment compared to medium, large, and control (all sizes) groups. This was more evident when marginal mass data were compared. In all masses, success decreased as islet size increased. Once islets were engrafted, functionality was not affected by size. When larger islets were fragmented, a significant decrease in islet functionality was observed. On the contrary, if pancreata were slightly overdigested, although not as successful as small naive islets, an increase in engraftment was observed when compared to the control group. In conclusion, smaller islets are superior in engraftment following islet transplantation. Fragmentation has a deleterious effect on islet engraftment. Islet isolations can be performed by reducing islet size with slight overdigestion, and it can be safely adopted to improve clinical

  13. Characterization of the mouse pancreatic islet proteome and comparative analysis with other mouse tissues

    SciTech Connect

    Petyuk, Vladislav A.; Qian, Weijun; Hinault, Charlotte; Gritsenko, Marina A.; Singhal, Mudita; Monroe, Matthew E.; Camp, David G.; Kulkarni, Rohit N.; Smith, Richard D.

    2008-08-01

    The pancreatic islets of Langerhans and insulin-producing beta cells in particular play a central role in the maintenance of glucose homeostasis and the islet dysfunction is associated with the pathogenesis of both type 1 and type 2 diabetes mellitus. To contribute to the understanding of the biology of the pancreatic islets we applied proteomic techniques based on liquid chromatography coupled with mass spectrometry. Here as an initial step we present the first comprehensive proteomic characterization of pancreas islets of the mouse, the commonly used animal model for diabetes research. Two-dimensional SCX LC/RP LC-MS/MS has been applied to characterize of the mouse islet proteome, resulting in the confident identification of 17,350 different tryptic peptides covering 2,612 proteins with at least two unique peptide identifications per protein. The dataset also allowed identification of a number of post-translational modifications including several modifications relevant to oxidative stress and phosphorylation. While many of the identified phosphorylation sites corroborates with previous known sites, the oxidative modifications observed on cysteinyl residues potentially reveal novel information related to the role of oxidation stress in islet functions. Comparative analysis of the islet proteome database with 15 available proteomic datasets from other mouse tissues and cells revealed a set of 68 proteins uniquely detected only in the pancreatic islets. Besides proteins with known functions, like islet secreted peptide hormones, this unique set contains a number of proteins with yet unknown functions. The resulting peptide and protein database will be available at ncrr.pnl.gov web site of the NCRR proteomic center (ncrr.pnl.gov).

  14. Response of Vibrio cholerae to the Catecholamine Hormones Epinephrine and Norepinephrine

    PubMed Central

    Halang, Petra; Toulouse, Charlotte; Geißel, Bernadette; Michel, Bernd; Flauger, Birgit; Müller, Manuel; Voegele, Ralf T.; Stefanski, Volker

    2015-01-01

    ABSTRACT In Escherichia coli or Salmonella enterica, the stress-associated mammalian hormones epinephrine (E) and norepinephrine (NE) trigger a signaling cascade by interacting with the QseC sensor protein. Here we show that Vibrio cholerae, the causative agent of cholera, exhibits a specific response to E and NE. These catecholates (0.1 mM) enhanced the growth and swimming motility of V. cholerae strain O395 on soft agar in a medium containing calf serum, which simulated the environment within the host. During growth, the hormones were converted to degradation products, including adrenochrome formed by autooxidation with O2 or superoxide. In E. coli, the QseC sensor kinase, which detects the autoinducer AI-3, also senses E or NE. The genome of V. cholerae O395 comprises an open reading frame coding for a putative protein with 29% identity to E. coli QseC. Quantitative reverse transcriptase PCR (qRT-PCR) experiments revealed increased transcript levels of the qseC-like gene and of pomB, a gene encoding a structural component of the flagellar motor complex, under the influence of E or NE. Phentolamine blocks the response of E. coli QseC to E or NE. A V. cholerae mutant devoid of the qseC-like gene retained the phentolamine-sensitive motility in the presence of E, whereas NE-stimulated motility was no longer inhibited by phentolamine. Our study demonstrates that V. cholerae senses the stress hormones E and NE. A sensor related to the histidine kinase QseC from E. coli is identified and is proposed to participate in the sensing of NE. IMPORTANCE Vibrio cholerae is a Gram-negative bacterium that may cause cholera, a severe illness with high mortality due to acute dehydration caused by diarrhea and vomiting. Pathogenic V. cholerae strains possess virulence factors like the cholera toxin (CTX) and the toxin-coregulated pilus (TCP) produced in response to signals provided by the host. In pathogenic enterobacteria, the stress-associated hormones epinephrine (E) and

  15. Salivary Hormones Response to Preparation and Pre-competitive Training of World-class Level Athletes

    PubMed Central

    Guilhem, Gaël; Hanon, Christine; Gendreau, Nicolas; Bonneau, Dominique; Guével, Arnaud; Chennaoui, Mounir

    2015-01-01

    This study aimed to compare the response of salivary hormones of track and field athletes induced by preparation and pre-competitive training periods in an attempt to comment on the physiological effects consistent with the responses of each of the proteins measured. Salivary testosterone, cortisol, alpha-amylase, immunoglobulin A (IgA), chromogranin A, blood creatine kinase activity, and profile of mood state were assessed at rest in 24 world-class level athletes during preparation (3 times in 3 months) and pre-competitive (5 times in 5 weeks) training periods. Total mood disturbance and fatigue perception were reduced, while IgA (+61%) and creatine kinase activity (+43%) increased, and chromogranin A decreased (−27%) during pre-competitive compared to preparation period. A significant increase in salivary testosterone (+9 to +15%) and a decrease in testosterone/cortisol ratio were associated with a progressive reduction in training load during pre-competitive period (P < 0.05). None of the psycho-physiological parameters were significantly correlated to training load during the pre-competitive period. Results showed a lower adrenocortical response and autonomic activity, and an improvement of immunity status, in response to the reduction in training load and fatigue, without significant correlations of salivary hormones with training load. Our findings suggest that saliva composition is sensitive to training contents (season period) but could not be related to workload resulting from track and field athletics training. PMID:26635619

  16. Pancreatic islet-specific overexpression of Reg3β protein induced the expression of pro-islet genes and protected the mice against streptozotocin-induced diabetes mellitus.

    PubMed

    Xiong, Xiaoquan; Wang, Xiao; Li, Bing; Chowdhury, Subrata; Lu, Yarong; Srikant, Coimbatore B; Ning, Guang; Liu, Jun-Li

    2011-04-01

    Reg family proteins have been implicated in islet β-cell proliferation, survival, and regeneration. The expression of Reg3β (pancreatitis-associated protein) is highly induced in experimental diabetes and acute pancreatitis, but its precise role has not been established. Through knockout studies, this protein was shown to be mitogenic, antiapoptotic, and anti-inflammatory in the liver and pancreatic acinars. To test whether it can promote islet cell growth or survival against experimental damage, we developed β-cell-specific overexpression using rat insulin I promoter, evaluated the changes in normal islet function, gene expression profile, and the response to streptozotocin-induced diabetes. Significant and specific overexpression of Reg3β was achieved in the pancreatic islets of RIP-I/Reg3β mice, which exhibited normal islet histology, β-cell mass, and in vivo and in vitro insulin secretion in response to high glucose yet were slightly hyperglycemic and low in islet GLUT2 level. Upon streptozotocin treatment, in contrast to wild-type littermates that became hyperglycemic in 3 days and lost 15% of their weight, RIP-I/Reg3β mice were significantly protected from hyperglycemia and weight loss. To identify specific targets affected by Reg3β overexpression, a whole genome DNA microarray on islet RNA isolated from the transgenic mice revealed more than 45 genes significantly either up- or downregulated. Among them, islet-protective osteopontin/SPP1 and acute responsive nuclear protein p8/NUPR1 were significantly induced, a result further confirmed by real-time PCR, Western blots, and immunohistochemistry. Our results suggest that Reg3β is unlikely an islet growth factor but a putative protector that prevents streptozotocin-induced damage by inducing the expression of specific genes.

  17. Metabolic and hormonal responses to long-distance swimming in cold water.

    PubMed

    Dulac, S; Quirion, A; DeCarufel, D; LeBlanc, J; Jobin, M; Côte, J; Brisson, G R; Lavoie, J M; Diamond, P

    1987-10-01

    The acute effects of long-distance swimming in cold water on selected hormonal and metabolic variables were evaluated on 22 long-distance swimmers (16 males and 6 females) during a 32-km swimming competition (La Traversée Internationale du Lac St-Jean). The water temperature was 18.5 degrees C and the mean performance times were 8 h and 32 min for men (M) and 9 h and 1 min for women (F). The blood samples were withdrawn in the fasting state during the week preceding the event and within 30 min after completion of the race. A positive correlation was obtained, for both groups, between percent body fat and rectal temperature measured at the end of the competition. After the competition, an increase in plasma epinephrine, norepinephrine, cortisol, thyroxine, free fatty acids, lactate, a decrease in glucose and insulin and no change in growth hormone, triiodothyronine, triglycerides, and cholesterol concentrations were observed in both groups. The increase in plasma thyroxine was more pronounced in the slower swimmers while the change in blood cortisol concentrations was higher in the subjects having the most acute decrease in body temperature. Male and female swimmers have a similar metabolic and hormonal response to a long-distance swimming competition in cold water.

  18. Differential expression of ferritin genes in response to abiotic stresses and hormones in pear (Pyrus pyrifolia).

    PubMed

    Xi, Li; Xu, Kuanyong; Qiao, Yushan; Qu, Shenchun; Zhang, Zhen; Dai, Wenhao

    2011-10-01

    In this study, the expression patterns of four ferritin genes (PpFer1, PpFer2, PpFer3, and PpFer4) in pear were investigated using quantitative real-time PCR. Analysis of tissue-specific expression revealed higher expression level of these genes in leaves than in other tested tissues. These ferritin genes were differentially expressed in response to various abiotic stresses and hormones treatments. The expression of ferritin wasn't affected by Fe(III)-citrate treatment. Abscisic acid significantly enhanced the expression of all four ferritin genes, especially PpFer2, followed by N-benzylyminopurine, gibberellic acid, and indole-3-acetic acid. The expression peaks of PpFer1 and PpFer3 in leaves appeared at 6, 6, and 12 h, respectively, after pear plant was exposed to oxidative stress (5 mM H(2)O(2)), salt stress (200 mM NaCl), and heat stress (40°C). A significant increase in PpFer4 expression was detected at 6 h after salt stress or heat stress. The expression of ferritin genes was not altered by cold stress. These results suggested that ferritin genes might be functionally important in acclimation of pear to salt and oxidative stresses. Hormone treatments had no significant effect on expression of ferritin genes compared to abiotic stresses. This showed accumulation of ferritin genes could be operated by different transduction pathways under abiotic stresses and hormones treatments.

  19. Chronopharmacological effects of growth hormone on the executive function and oxidative stress response in rats

    PubMed Central

    Ferrari, Carlos K B; França, Eduardo L; Monteiro, Luciane A; Santos, Bruno L; Pereira-Junior, Alfredo; Honorio-França, Adenilda C

    2017-01-01

    Objective(s): To investigate the chronopharmacological effects of growth hormone on executive function and the oxidative stress response in rats. Materials and Methods: Fifty male Wistar rats (36-40 weeks old) had ad libitum access to water and food and were separated into four groups: diurnal control, nocturnal control, diurnal GH-treated, and nocturnal GH-treated animals. Levels of Cu, Zn superoxide dismutase (Cu, Zn-SOD), and superoxide release by spleen macrophages were evaluated. For memory testing, adaptation and walking in an open field platform was used. GH-treated animals demonstrated better performance in exploratory and spatial open-field tests. Results: The latency time in both GH-treated groups was significantly lower compared with the latency time of the control groups. The diurnal GH treatment did not stimulate superoxide release but increased the CuZn-SOD enzyme levels. The nocturnal GH treatment did not influence the superoxide release and CuZn-SOD concentration. GH treatment also resulted in heart atrophy and lung hypertrophy. Conclusion: Growth hormone treatment improved the performance of executive functions at the cost of oxidative stress triggering, and this effect was dependent on the circadian period of hormone administration. However, GH treatment caused damaging effects such as lung hypertrophy and heart atrophy. PMID:28133519

  20. Short term response of insulin, glucose, growth hormone and corticosterone to acute vibration in rats.

    NASA Technical Reports Server (NTRS)

    Dolkas, C. B.; Leon, H. A.; Chackerian, M.

    1971-01-01

    Study carried out to obtain some notion of the initial phasing and interactive effects among some hormones known to be responsive to vibration stress. Sprague-Dawley derived rats were exposed to the acute effects of confinement and confinement with lateral (plus or minus G sub y) vibration. The coincident monitoring of glucose, insulin, growth hormone, and corticosterone plasma levels, during and immediately subsequent to exposure to brief low level vibration, exhibits the effects of inhibition of insulin release by epinephrine. The ability of insulin (IRI) to return rapidly to basal levels, from appreciably depressed levels during vibration, in the face of elevated levels of glucose is also shown. Corticosterone responds with almost equal rapidity, but in opposite phase to the IRI. The immuno-assayable growth hormone (IGH) dropped from a basal level of 32 ng/ml to 7.3 ng/ml immediately subsequent to vibration and remained at essentially that level throughout the experiment (60 min). Whether these levels represent a real fall in the rat or whether they merely follow the immuno-logically deficient form is still in question.

  1. Local and systemic hormonal responses in pepper leaves during compatible and incompatible pepper-tobamovirus interactions.

    PubMed

    Dziurka, Michał; Janeczko, Anna; Juhász, Csilla; Gullner, Gábor; Oklestková, Jana; Novák, Ondrej; Saja, Diana; Skoczowski, Andrzej; Tóbiás, István; Barna, Balázs

    2016-12-01

    Phytohormone levels and the expression of genes encoding key enzymes participating in hormone biosynthetic pathways were investigated in pepper leaves inoculated with two different tobamoviruses. Obuda pepper virus (ObPV) inoculation led to the development of hypersensitive reaction (incompatible interaction), while Pepper mild mottle virus (PMMoV) inoculation resulted in a systemic, compatible interaction. ObPV-inoculation markedly increased not only the levels of salicylic acid (SA) (73-fold) and jasmonic acid (8-fold) but also those of abscisic acid, indole-3-acetic acid, indole-3-butyric acid, cis-zeatin, cis-zeatin-9-riboside and trans-zeatin-9-riboside in the inoculated pepper leaves 3 days post inoculation. PMMoV infection increased only the contents of gibberellic acid and SA. Hormone contents did not change significantly after ObPV or PMMoV infection in non-infected upper leaves 20 days post inoculation. Concentrations of some brassinosteroids (BRs) and progesterone increased both in ObPV- and PMMoV inoculated leaves. ObPV inoculation markedly induced the expression of three phenylalanine ammonia-lyase (PAL) and a 1-aminocyclopropane-1-carboxylate oxidase (ACO) genes, while that of an isochorismate synthase (ICS) gene was not modified. PMMoV inoculation did not alter the expression of PAL and ICS genes but induced the transcript abundance of ACO although later than ObPV. Pre-treatment of pepper leaves with exogenous 24-epi-brassinolide (24-epi-BR) prior to ObPV-inoculation strongly mitigated the visible symptoms caused by ObPV. In addition, 24-epi-BR pre-treatment markedly altered the level of several hormones in pepper leaves following ObPV-inoculation. These data indicate that ObPV- and PMMoV-inoculations lead to intricate but well harmonized hormonal responses that are largely determined by the incompatible or compatible nature of plant-virus interactions.

  2. The hyperbolic effect of density and strength of inter beta-cell coupling on islet bursting: a theoretical investigation

    PubMed Central

    Nittala, Aparna; Wang, Xujing

    2008-01-01

    Background Insulin, the principal regulating hormone of blood glucose, is released through the bursting of the pancreatic islets. Increasing evidence indicates the importance of islet morphostructure in its function, and the need of a quantitative investigation. Recently we have studied this problem from the perspective of islet bursting of insulin, utilizing a new 3D hexagonal closest packing (HCP) model of islet structure that we have developed. Quantitative non-linear dependence of islet function on its structure was found. In this study, we further investigate two key structural measures: the number of neighboring cells that each β-cell is coupled to, nc, and the coupling strength, gc. Results β-cell clusters of different sizes with number of β-cells nβ ranging from 1–343, nc from 0–12, and gc from 0–1000 pS, were simulated. Three functional measures of islet bursting characteristics – fraction of bursting β-cells fb, synchronization index λ, and bursting period Tb, were quantified. The results revealed a hyperbolic dependence on the combined effect of nc and gc. From this we propose to define a dimensionless cluster coupling index or CCI, as a composite measure for islet morphostructural integrity. We show that the robustness of islet oscillatory bursting depends on CCI, with all three functional measures fb, λ and Tb increasing monotonically with CCI when it is small, and plateau around CCI = 1. Conclusion CCI is a good islet function predictor. It has the potential of linking islet structure and function, and providing insight to identify therapeutic targets for the preservation and restoration of islet β-cell mass and function. PMID:18673579

  3. Distinctions between islet neogenesis and β-cell replication: implications for reversal of Type 1 and 2 diabetes.

    PubMed

    Levetan, Claresa

    2010-06-01

    The terms "islet" and "β-cell" are often used interchangeably, yet islets are highly complex multicellular organelles that contain the insulin-producing β-cells and four other cells types, all of which play a role in maintaining glucose homeostasis within a very narrow range. Although the formation of new islets in adults is rare, occurring primarily in response to pancreatic injury and major stress to the pancreas, β-cell replication from existing cells occurs throughout adulthood. An understanding of the regulatory factors controlling pancreatic development has more clearly defined the differences between new islet formation from progenitor cells located throughout the adult pancreas and β-cell replication occurring within existing islets. The present review sets forth to more clearly distinguish the differences between the postnatal pathways of islet neogenesis and β-cell replication with a discussion of the potential implications for reversal of Type 1 and 2 diabetic patients using islet neogenesis agents that are now in development. For Type 1 diabetic patients, an immune tolerance agent in conjunction with an islet neogenesis agent may allow achievement of adequate islet mass, perhaps with subsequent potential to withdraw medications. For Type 2 diabetic patients, lifestyle changes and/or medications may sustain the production of new islets and limit the accelerated β-cell apoptosis characteristic of the condition.

  4. Hormone responses to a continuous bout of rock climbing in men.

    PubMed

    Sherk, Vanessa D; Sherk, Kyle A; Kim, SoJung; Young, Kaelin C; Bemben, Debra A

    2011-04-01

    Rock climbing is rapidly increasing in popularity as a recreational activity and as a competitive sport. Few studies have tested acute physiological responses to climbing, and no studies to date have tested hormone responses to a climbing-based workout. This study aimed to measure testosterone (T), growth hormone (GH), and cortisol (C) responses to continuous vertical climbing in young male rock climbers. Ten male rock climbers, aged between 21 and 30 years, climbed laps on a submaximal 55' climbing route for 30 min, or until exhaustion, whichever came first. Heart rate (HR) was recorded after every lap. Blood samples were collected by venipuncture before (Pre), immediately post (IP), and 15 min after the climbing exercise (P15) to assess blood lactate and plasma GH, T, and C. Subjects climbed 24.9 ± 1.9 min and 507.5 ± 82.5 feet. Peak HR was 182.1 ± 2.3 bpm, and lactate (Pre: 2.9 ± 0.6 mmol/dL, IP: 11.1 ± 1.0 mmol/dL) significantly (P < 0.05) increased from Pre to IP. T concentrations significantly (P < 0.05) increased from Pre (6.04 ± 0.31 ng/mL) to IP (7.39 ± 0.40 ng/mL) and returned to baseline at P15 (6.23 ± 0.33 ng/mL). Cortisol levels did not significantly change during the protocol. GH significantly (P < 0.01) increased from Pre (0.63 ± 0.17 ng/mL) to IP (19.89 ± 4.53 ng/mL) and remained elevated at P15 (15.03 ± 3.89 ng/mL). An acute, short-term bout of high-intensity continuous climbing was an effective exercise stimulus for elevating plasma testosterone and growth hormone levels in young males.

  5. Plasma nesfatin-1 and glucoregulatory hormone responses to two different anaerobic exercise sessions.

    PubMed

    Ghanbari-Niaki, Abbass; Kraemer, Robert R; Soltani, Raheleh

    2010-11-01

    Nesfatin-1 is a recently discovered anorectic protein derived from posttranslational processing of the nucleobindin 2 (NUCB2) gene. It is expressed in adipose tissue and is also found in plasma. Nesfatin-1 expression is significantly affected by nutritional status and its actions may be involved in the inhibition of the orexigenic effect of ghrelin. Although the effects of physical exercise on several anorectic and orexigenic hormones have been reported, no studies have investigated its effects upon circulating concentrations of nesfatin-1. We investigated the effects of acute strenuous interval exercise and circuit exercise on nesfatin and other hormones affected by metabolic stress. Fourteen provincial and national level young male-kickboxing volunteers participated [age 20.71 ± 2.6 years, height 176.6 ± 2.8 cm, body weight 67.2 ± 3.3 kg, and body mass index (BMI) 21.56 ± 1.42 kg/m(2)]. After an overnight fast, responses to a running-based anaerobic sprint test (RAST; 7 sets of 6 × 35 m every 10 s with 1 min rest in between sets) and a non-combat kickboxing session (NCKB; 7 sets of 6 techniques, 20 s per technique with 1 min rest in between sets) were determined. Venous blood samples were collected before, immediately after, and 45 as well as 95 min following the exercises. Plasma GH, insulin, glucose and lactate concentrations significantly increased immediately following the RAST and NCKB protocols, however, plasma nesfatin-1 concentrations were not significantly altered. Higher plasma cortisol and glucose concentrations occurred in response to the RAST compared with the NCKB protocols. Although the exercise protocols elicited metabolic stress that significantly altered circulating glucoregulatory hormones, plasma glucose and lactate, there was no significant change in plasma nesfatin-1. A lack of nesfatin-1 response to the exercise protocols may be partially due to the fasting condition.

  6. 48-h glucose infusion in humans: effect on hormonal responses, hunger and food intake.

    PubMed

    Teff, Karen L; Petrova, Maja; Havel, Peter J; Townsend, Raymond R

    2007-04-23

    Experimentally-induced hyperglycemia by prolonged glucose infusion allows investigation of the effects of sustained stimulation of the pancreatic beta-cell on insulin secretion and sensitivity. Hormonal responses to a meal following prolonged glucose infusions have not been investigated. To determine if a 48-h glucose infusion alters hormonal responses to a test meal as well as food intake and hunger in normal weight individuals, 16 subjects (8 men, 8 women, age 18-30 years, mean BMI=21.7+/-1.6 kg/m2) were infused for 48 h with either saline (50 ml/h) or 15% glucose (200 mg/m2/min). Subjects ingested a 600 kcal mixed nutrient meal 3 h after infusion termination. Blood samples were taken during the 48 h and for 4 h following food ingestion. The 48-h glucose infusion elicited a metabolic profile of a glucose intolerant obese subjects, with increased plasma glucose, insulin and leptin (all P<0.01) and increased HOMA-IR (P<0.001). During meal ingestion, early insulin secretion was increased (P<0.05) but post-prandial glucose (P<0.01) and insulin (P<0.01) excursions were lower following the glucose infusion. Post-prandial plasma triglyceride concentrations were increased after glucose compared with saline. Food intake and hunger ratings were not different between the two conditions. Plasma leptin levels were inversely correlated with hunger (P<0.03) in both conditions and with food intake (P<0.003) during the glucose condition only. Thus, a 48-h glucose infusion does not impair post-prandial hormonal responses, alter food intake or hunger in normal weight subjects. The glucose-induced increases in plasma leptin result in a stronger inverse relationship between plasma leptin and hunger as well as food intake. These data are the first to demonstrate a relationship between leptin and hunger in normal weight, non-calorically restricted human subjects.

  7. Tasting fat: cephalic phase hormonal responses and food intake in restrained and unrestrained eaters.

    PubMed

    Crystal, Susan R; Teff, Karen L

    2006-09-30

    Restrained eaters exhibit strict cognitive control over their food intake, primarily by limiting intake of high-fat foods. Earlier studies indicate a relationship between dietary restraint and cephalic phase insulin release, which is hypothesized to influence hunger and food intake. To compare cephalic phase hormonal responses to high- and low-fat stimuli and determine if the sensory experience of tasting fat alters hormonal responses and influences subsequent food intake in restrained and unrestrained eaters, normal weight women classified as unrestrained (n=11) or restrained (n=11) eaters were tested under 3 conditions: (1) fasting, (2) sham-feeding a non-fat cake, and (3) sham-feeding a high-fat cake. Following an overnight fast, arterialized venous blood was drawn prior to and for 30 min immediately following a 3-min sham feed. Plasma samples were analyzed for insulin, glucose, glucagon and pancreatic polypeptide (PP). Subjects were subsequently given a selection of high-fat and low-fat foods and allowed to select what they wished to eat. Cephalic phase PP was significantly greater following oral sensory stimulation by the high-fat food (205.4+/-83.6) compared to the fasting control (11.1+/-38.8, p=0.04). No significant differences in hormonal responses to the food stimuli were found between restrained and unrestrained eaters but the restrained eaters consumed more food after the high-fat condition (p<0.05) relative to the fasted condition and compared to the unrestrained group (p<0.05). In conclusion, the sensory experience of tasting fat increases food intake in restrained eaters and increases vagal efferent activity compared to a non-fat food in both populations.

  8. Whole body, regional fat accumulation, and appetite-related hormonal response after hypoxic training.

    PubMed

    Morishima, Takuma; Kurihara, Toshiyuki; Hamaoka, Takafumi; Goto, Kazushige

    2014-03-01

    The present study was conducted to determine change in regional fat accumulation and appetite-related hormonal response following hypoxic training. Twenty sedentary subjects underwent hypoxic (n = 9, HYPO, FiO(2) = 15%) or normoxic training (n = 11, NOR, FiO(2) = 20·9%) during a 4-week period (3 days per week). They performed a 4-week training at 55% of maximal oxygen uptake (V·O(2max)) for each condition. Before and after the training period, V·O(2max), whole body fat mass, abdominal fat area, intramyocellular lipid content (IMCL), fasting and postprandial appetite-related hormonal responses were determined. Both groups showed a significant increase in V·O(2max) following training (P<0·05). Whole body and segmental fat mass, abdominal fat area, IMCL did not change in either group. Fasting glucose and insulin concentrations significantly reduced in both groups (P<0·05). Although area under the curve for the postprandial blood glucose concentrations significantly decreased in both groups (P<0·05), the change was significantly greater in the HYPO group than in the NOR group (P<0·05). Changes in postprandial plasma ghrelin were similar in both groups. A significant reduction of postprandial leptin response was observed in both groups (P<0·05), while postprandial glucagon-like peptide-1 (GLP-1) concentrations increased significantly in the NOR group only (P<0·05). In conclusion, hypoxic training for 4 weeks resulted in greater improvement in glucose tolerance without loss of whole body fat mass, abdominal fat area or IMCL. However, hypoxic training did not have synergistic effect on the regulation of appetite-related hormones.

  9. Intronic hormone response elements mediate regulation of FKBP5 by progestins and glucocorticoids.

    PubMed

    Hubler, Tina R; Scammell, Jonathan G

    2004-01-01

    Expression of FKBP51, a large molecular weight immunophilin, is strongly enhanced by glucocorticoids, progestins, and androgens. However, the activity of a 3.4-kb fragment of the FKBP51 gene (FKBP5) promoter was only weakly increased by progestin and we show here that it is unresponsive to glucocorticoids and androgens. The entire FKBP5 was scanned for consensus hormone response elements (HREs) using MatInspector. We found that 2 regions of intron E, which are conserved in rat and mouse FKBP5, contain HRE-like sequences with high match scores. Deoxyribonucleic acid fragments (approximately 1 kb in length) containing these regions were amplified and tested in reporter gene assays for steroid responsiveness. One region of intron E of FKBP5 (pIE2) conferred both glucocorticoid and progestin responsiveness to 2 heterologous reporter genes, whereas the other, less-conserved region of intron E (pIE1) was responsive only to progestins. The inclusion of pIE1 upstream of pIE2 (pIE1IE2) enhanced progestin but not glucocorticoid responsiveness. None of the constructs containing intronic sequences was responsive to androgens. Mutation of the putative HREs within pIE1 and pIE2 eliminated hormone responsiveness. Electrophoretic mobility shift assays demonstrated that progesterone receptors (PR) bound to the HRE in pIE1, whereas both PR and glucocorticoid receptors interacted with the HRE in pIE2. These data suggest that distal intronic elements significantly contribute to transcriptional regulation of FKBP5 by glucocorticoids and progestins.

  10. Crustacean hyperglycemic hormones directly modulate the immune response of hemocytes in shrimp Litopenaeus vannamei.

    PubMed

    Wang, Lin; Chen, Hao; Xu, Jianchao; Xu, Qingsong; Wang, Mengqiang; Zhao, Depeng; Wang, Lingling; Song, Linsheng

    2017-03-01

    A robust immune response against invading pathogens is crucial for host to survive, which depends greatly on the well balance of metabolism. Increasing evidence has indicated that some metabolic hormones, such as insulin, could modulate immune responses directly. Crustacean hyperglycemic hormone (CHH) family is a group of ecdysozoans-specific peptide hormone involved in glucose metabolism and other biological events. In the present study, two members of CHH family (designated as LvCHH I and LvCHH II) in shrimp Litopenaeus vannamei with one and two crustacean neurohormone domains respectively were chosen to investigate their putative modulatory roles in both glucose metabolism and immune response. LvCHH I and LvCHH II were both expressed in the sinus gland and lamina ganglionalis of eyestalks and were significantly induced after white spot syndrome virus (WSSV) infection. Meanwhile, significant increases of hemolymph glucose levels were observed in shrimp at 12 and 24 h after WSSV infection while the glucose inside the hemocytes decreased at 6 h and then increased at 12 h. Gain-of-function of rLvCHHs was subsequently conducted in vivo by injecting the recombinant proteins (rLvCHH I and rLvCHH II). The hemolymph glucose increased significantly from 0.5 h to 3 h after the shrimps received an injection of rLvCHH I, while it decreased at 0.5 h and increased afterward at 3 h post rLvCHH II injection. At the meantime, significant decreases of reactive oxygen species level in hemocytes were observed at 3 h and 6 h post rLvCHH I injection, while it remained unchanged in rLvCHH II injection group. rLvCHH I and rLvCHH II could bind to the cytomembrane of primary shrimp hemocytes in vitro, and the expressions of superoxide dismutase and LvRelish increased when the hemocytes were incubated with rLvCHH I for 3 h. Meanwhile, the expression of antimicrobial peptides, crustin and penaeidin-4, were also induced by rLvCHH I and rLvCHH II. These results demonstrated that

  11. Impaired counterregulatory hormonal and metabolic response to exhaustive exercise in obese subjects.

    PubMed

    Vettor, R; Macor, C; Rossi, E; Piemonte, G; Federspil, G

    1997-08-01

    A reduction of postprandial thermogenesis has been described in obesity; insulin resistance and/or decreased sympathetic nervous system activity seem to play the major role in its pathogenesis. On the other hand, a normal energy expenditure during exercise has been reported. At present, the response and the role of catecholamines in energy metabolism during exercise in obesity have not been well clarified yet. The aim of this work was to study the metabolic and hormonal changes caused by intense exercise in obesity. Nine obese subjects and ten normal weight controls were submitted to exhaustive exercise on a cycloergometer. Blood glucose, free fatty acids (FFA), glycerol, lactate, beta-OH-butyrate, insulin, glucagon, plasma growth hormone (HGH), catecholamine plasma levels were assayed before and at the end of exercise, and after a recovery period. The energy cost of exercise was evaluated by indirect calorimetry. In our experiment muscular exercise did not provoke any change in blood glucose and FFA plasma levels in either of our groups. In the obese subjects the insulin plasma levels were higher than in the controls. Glucagon plasma levels did not change. The exercise responses of norepinephrine (NE) (4.28 +/- 0.74 vs 8.81 +/- 1.35 nmol/l; P < 0.01), epinephrine (E) (234.21 +/- 64.18 vs 560.51 +/- 83.38 pmol/l; P < 0.01) and plasma growth hormone (HGH) (134.84 +/- 58.97 vs 825.92 +/- 195.25 pmol/l; P < 0.01) were significantly lower in obese subjects. At the end of exercise, the thermic effect of exercise did not differ between obese and control subjects (0.335 +/- 0.038 vs 0.425 +/- 0.040 kJ/min x kg fat-free mass. Our findings indicate that an impaired counterregulatory hormone response to exercise exists in obese subjects. The thermic effect of exercise does not seem to be affected by either the reduced catecholamine response nor insulin resistance.

  12. Fibroblast populated collagen matrix promotes islet survival and reduces the number of islets required for diabetes reversal.

    PubMed

    Jalili, Reza B; Moeen Rezakhanlou, Alireza; Hosseini-Tabatabaei, Azadeh; Ao, Ziliang; Warnock, Garth L; Ghahary, Aziz

    2011-07-01

    Islet transplantation represents a viable treatment for type 1 diabetes. However, due to loss of substantial mass of islets early after transplantation, islets from two or more donors are required to achieve insulin independence. Islet-extracellular matrix disengagement, which occurs during islet isolation process, leads to subsequent islet cell apoptosis and is an important contributing factor to early islet loss. In this study, we developed a fibroblast populated collagen matrix (FPCM) as a novel scaffold to improve islet cell viability and function post-transplantation. FPCM was developed by embedding fibroblasts within type-I collagen and used as scaffold for islet grafts. Viability and insulin secretory function of islets embedded within FPCM was evaluated in vitro and in a syngeneic murine islet transplantation model. Islets embedded within acellular matrix or naked islets were used as control. Islet cell survival and function was markedly improved particularly after embedding within FPCM. The composite scaffold significantly promoted islet isograft survival and reduced the critical islet mass required for diabetes reversal by half (from 200 to 100 islets per recipient). Fibroblast embedded within FPCM produced fibronectin and growth factors and induced islet cell proliferation. No evidence of fibroblast over-growth within composite grafts was noticed. These results confirm that FPCM significantly promotes islet viability and functionality, enhances engraftment of islet grafts and decreases the critical islet mass needed to reverse hyperglycemia. This promising finding offers a new approach to reducing the number of islet donors per recipient and improving islet transplant outcome.

  13. Pituitary response to thyrotropin releasing hormone in children with overweight and obesity

    PubMed Central

    Rijks, Jesse; Penders, Bas; Dorenbos, Elke; Straetemans, Saartje; Gerver, Willem-Jan; Vreugdenhil, Anita

    2016-01-01

    Thyroid stimulating hormone (TSH) concentrations in the high normal range are common in children with overweight and obesity, and associated with increased cardiovascular disease risk. Prior studies aiming at unravelling the mechanisms underlying these high TSH concentrations mainly focused on factors promoting thyrotropin releasing hormone (TRH) production as a cause for high TSH concentrations. However, it is unknown whether TSH release of the pituitary in response to TRH is affected in children with overweight and obesity. Here we describe TSH release of the pituitary in response to exogenous TRH in 73 euthyroid children (39% males) with overweight or (morbid) obesity. Baseline TSH concentrations (0.9–5.5 mU/L) were not associated with BMI z score, whereas these concentrations were positively associated with TSH concentrations 20 minutes after TRH administration (r2 = 0.484, p < 0.001) and the TSH incremental area under the curve during the TRH stimulation test (r2 = 0.307, p < 0.001). These results suggest that pituitary TSH release in response to TRH stimulation might be an important factor contributing to high normal serum TSH concentrations, which is a regular finding in children with overweight and obesity. The clinical significance and the intermediate factors contributing to pituitary TSH release need to be elucidated in future studies. PMID:27485208

  14. The hypothalamic-pituitary response in SLE. Regulation of prolactin, growth hormone and cortisol release.

    PubMed

    Rovenský, J; Blazícková, S; Rauová, L; Jezová, D; Koska, J; Lukác, J; Vigas, M

    1998-01-01

    It has been suggested that neuroendocrine regulation plays an important role in the pathogenesis and activation of autoimmune diseases. The aim of this investigation was to clarify the hypothalamic-pituitary response to a well-defined stimulus under standardised conditions in patients with SLE. Plasma concentrations of prolactin (PRL), growth hormone (GH) and cortisol were determined in venous blood drawn through an indwelling cannula during insulin-induced hypoglycaemia (0.1 U/kg b.w., i.v.) in ten patients and in 12 age-, gender- and weight-matched healthy subjects. Basal PRL concentrations were higher in patients vs healthy controls (12 vs 6 ng/ml, P < 0.01), though still within the physiological range. Insulin-induced plasma PRL and GH were significantly increased both in patients and healthy subjects; however, the increments or areas under the curves were not different in the two groups. Plasma cortisol response showed moderate attenuation in patients. Sensitivity of pituitary lactotrothrops to thyrotropin-releasing hormone (TRH) administration (200 microg, i.v.) was the same in patients and control subjects. In SLE patients with low activity of the disease the sensitivity of pituitary PRL release to TRH administration remained unchanged. The hypothalamic response to stress stimulus (hypoglycaemia) was comparable in patients and healthy subjects.

  15. Multi-responsiveness of single anterior pituitary cells to hypothalamic-releasing hormones: A cellular basis for paradoxical secretion

    PubMed Central

    Villalobos, Carlos; Núñez, Lucía; Frawley, L. Stephen; García-Sancho, Javier; Sánchez, Ana

    1997-01-01

    The classic view for hypothalamic regulation of anterior pituitary (AP) hormone secretion holds that release of each AP hormone is controlled specifically by a corresponding hypothalamic-releasing hormone (HRH). In this scenario, binding of a given HRH (thyrotropin-, growth hormone-, corticotropin-, and luteinizing hormone-releasing hormones) to specific receptors in its target cell increases the concentration of cytosolic Ca2+ ([Ca2+]i), thereby selectively stimulating the release of the appropriate hormone. However, “paradoxical” responses of AP cells to the four well-established HRHs have been observed repeatedly with both in vivo and in vitro systems, raising the possibility of functional overlap between the different AP cell types. To explore this possibility, we evaluated the effects of HRHs on [Ca2+]i in single AP cells identified immunocytochemically by the hormone they stored. We found that each of the five major AP cell types contained discrete subpopulations that were able to respond to several HRHs. The relative abundance of these multi-responsive cells was 59% for lactotropes, 33% for thyrotropes, and in the range of 47–55% for gonadotropes, corticotropes, and somatotropes. Analysis of prolactin release from single living cells revealed that each of the four HRHs tested were able to induce hormone release from a discrete lactotrope subpopulation, the size of which corresponded closely to that in which [Ca2+]i changes were induced by the same secretagogues. When viewed as a whole, our diverse functional measurements of multi-responsiveness suggest that hypothalamic control of pituitary function is more complicated than previously envisioned. Moreover, they provide a cellular basis for the so-called “paradoxical” behavior of pituitary cells to hypothalamic hypophysiotropic agents. PMID:9391165

  16. Identification of in vitro parameters predictive of graft function: a study in an animal model of islet transplantation.

    PubMed

    Migliavacca, B; Nano, R; Antonioli, B; Marzorati, S; Davalli, A M; Di Carlo, V; Bertuzzi, F

    2004-04-01

    The quality of human islets is one of the factors decisive for the success of human islet transplantation. Several parameters have been proposed to characterize islet quality, but none of them has been able to predict the fate of a transplant. The aim of our study was to correlate a panel of in vitro parameters for islet viability with their in vivo function after transplantation in nude mice. Islets were obtained after enzymatic digestion of a human pancreas; they were purified from exocrine tissue using a continuous-density gradient. Two aliquots of islets (1000 and 2000 islets) were transplanted under the kidney capsule of diabetic nude mice. The animals were followed for 1 month with repeated measurements of blood glucose and body weight. One month after transplantation, mice were killed and their graft harvested for histologic analysis. In parallel we studied in vitro islet viability with propidium iodide and fura-2, their insulin content, their purity, and their insulin response to glucose upon static incubation. Ten islet preparations were transplanted: 3 out of 10 preparations did not restore normoglycemia; 4 out of 10 normalized glycemia only in mice receiving 2000 islets, and 3 out of 10 fully restore normoglycemia in all mice. The purity of preparations (R(2) = 0.63 and 0.85, respectively, with 1000 and 2000 islets) and the insulin content (R(2) = 0.75 with 2000 IE) correlated with transplant success. These data show that purity of islet preparations and their insulin content should be useful parameters for the selection of islet preparations for transplant purposes.

  17. Hormonal response to lipid and carbohydrate meals during the acute postprandial period

    PubMed Central

    2011-01-01

    Background Optimizing the hormonal environment during the postprandial period in favor of increased anabolism is of interest to many active individuals. Data are conflicting regarding the acute hormonal response to high fat and high carbohydrate feedings. Moreover, to our knowledge, no studies have compared the acute hormonal response to ingestion of lipid and carbohydrate meals of different size. Methods We compared the hormonal response to lipid and carbohydrate meals of different caloric content during the acute postprandial period. Nine healthy men (22 ± 2 years) consumed in a random order, cross-over design one of four meals/beverages during the morning hours in a rested and fasted state: dextrose at 75 g (300 kcals), dextrose at 150 g (600 kcals), lipid at 33 g (300 kcals), lipid at 66 g (600 kcals). Blood samples were collected Pre meal, and at 0.5 hr, 1 hr, 2 hr, and 3 hr post meal. Samples were assayed for testosterone, cortisol, and insulin using ELISA techniques. Area under the curve (AUC) was calculated for each variable, and a 4 × 5 ANOVA was used to further analyze data. Results A meal × time effect (p = 0.0003) was noted for insulin, with values highest for the dextrose meals at the 0.5 hr and 1 hr times, and relatively unaffected by the lipid meals. No interaction (p = 0.98) or meal (p = 0.39) effect was noted for testosterone, nor was an interaction (p = 0.99) or meal (p = 0.65) effect noted for cortisol. However, a time effect was noted for both testosterone (p = 0.04) and cortisol (p < 0.0001), with values decreasing during the postprandial period. An AUC effect was noted for insulin (p = 0.001), with values higher for the dextrose meals compared to the lipid meals (p < 0.05). No AUC effect was noted for testosterone (p = 0.85) or cortisol (p = 0.84). Conclusions These data indicate that 1) little difference is noted in serum testosterone or cortisol during the acute postprandial period when healthy men consume lipid and dextrose meals of

  18. Sex differences, hormones, and fMRI stress response circuitry deficits in psychoses

    PubMed Central

    Goldstein, Jill M.; Lancaster, Katie; Longenecker, Julia M.; Abbs, Brandon; Holsen, Laura M.; Cherkerzian, Sara; Whitfield-Gabrieli, Susan; Makris, Nicolas; Tsuang, Ming T.; Buka, Stephen L.; Seidman, Larry J.; Klibanski, Anne

    2015-01-01

    Psychosis involves dysregulation of response to stress, particularly to negative valence stimuli. Functional magnetic resonance imaging studies of psychosis have shown hyperactivity in hypothalamus, hippocampus, amygdala, and anterior cingulate cortex, and orbitofrontal and medial prefrontal cortices. Sex differences in these deficits may be associated with steroid hormone pathway abnormalities, i.e., dysregulation of the hypothalamic pituitary-adrenal and -gondal axes. We predicted abnormal steroid hormone levels in psychosis cases would be associated with hyperactivity in hypothalamus, amygdala, and hippocampus, and hypoactivity in prefrontal and anterior cingulate cortices in a sex-dependent way, with more severe deficits in men than women with psychosis. We studied 32 psychosis cases (50.0% women) and 39 controls (43.6% women) using a novel visual stress challenge while collecting blood throughout functional magnetic resonance imaging procedures. Males with psychosis showed hyperactivity across all hypothesized regions, including the hypothalamus and anterior cingulate cortex by family-wise corrected significance. Females showed hyperactivity in the hippocampus and amygdala and hypoactivity in orbital and medial prefrontal cortices, the latter by family-wise correction. Interaction of case status by sex was significant in the medial prefrontal cortex and, marginally so, in the left orbitofrontal cortex, with female cases (vs. healthy females and males) exhibiting the lowest activity. Male and female cases compared with their healthy counterparts were hypercortisolemic, which was associated with hyperactivity in prefrontal cortices in male cases and hypoactivity in female cases. This was further associated, respectively, with low bioavailable testosterone in male cases and low estradiol in female cases. Findings suggest disruptions in neural-hormone associations in response to stress are sex-dependent in psychosis, particularly in the prefrontal cortex. PMID

  19. Acute hormonal responses to heavy resistance exercise in strength athletes versus nonathletes.

    PubMed

    Ahtiainen, Juha P; Pakarinen, Arto; Kraemer, William J; Häkkinen, Keijo

    2004-10-01

    The aim of the present study was to investigate acute hormonal and neuromuscular responses and recovery in strength athletes versus nonathletes during heavy resistance exercise performed with the forced and maximum repetitions training protocol. Eight male strength athletes (SA) with several years of continuous resistance training experience and 8 physically active but non-strength athletes (NA) volunteered as subjects. The experimental design comprised two loading sessions: maximum repetitions (MR) and forced repetitions (FR). MR included 12-RM squats for 4 sets with a 2-min recovery between sets. In FR the initial load was higher than in MR so that the subject could lift approximately 8 repetitions by himself and 4 additional repetitions with assistance. Before and after the loading protocols, blood samples were drawn to determine serum testosterone, free testosterone, cortisol and growth hormone concentrations, and blood lactate. Maximal voluntary isometric force and EMG activity of the leg extensors was measured before and after the loading as well as 24 and 48 hrs after the loading. The concentrations of the hormones measured increased significantly (p < .01-.001) after both loadings in both groups. The responses tended to be higher in FR than the MR loading and the increases of testosterone concentrations were significantly (p < .01) greater in both loadings in SA than in NA. Both loading protocols in both groups also led to neuromuscular fatigue observable with significant acute decreases in isometric strength by 32-52% (p < .001) and in maximal iEMG (p < .05-01) associated with large increases in blood lactate. These data suggest that, at least in experienced strength athletes, the forced-repetition protocol is a viable alternative to the more traditional maximum-repetition protocol and may even be a superior approach.

  20. Caffeine Attenuates Acute Growth Hormone Response to a Single Bout of Resistance Exercise

    PubMed Central

    Wu, Bo-Han; Lin, Jung-Chang

    2010-01-01

    The purpose of this study was to investigate the effects of caffeine consume on substrate metabolism and acute hormonal responses to a single bout of resistance exercise (RE). Ten resistance-trained men participated in this study. All subjects performed one repetition maximum (1RM) test and then performed two protocols: caffeine (CAF, 6 mg·kg-1) and control (CON) in counter balanced order. Subjects performed RE (8 exercises, 3 sets of 10 repetitions at 75% of 1RM) after caffeine or placebo ingestion one hour prior to RE. Blood samples collected prior to treatment ingestion (pre-60), immediately prior to RE (pre-exe), and 0, 15, 30 min post to RE (P0, P15, P30) for analysis of insulin, testosterone, cortisol, growth hormone, glucose, free fatty acid and lactic acid. Each experiment was separated by seven days. In this study, statistical analysis of a two-way analysis of variance (treatment by time) with repeated measures was applied. After ingesting caffeine, the concentrations of free fatty acid (pre- exe, P0, P15, P30) in CAF were significantly higher than CON (p < 0.05). Additionally, the responses of GH (P0, P15, P30) in CAF were significantly lower than CON (p < 0.05), whereas the concentrations of insulin, testosterone and cortisol were not different between CAF and CON (p < 0.05) after RE. The results of this study indicated that caffeine ingestion prior to RE might attenuate the response of GH. This effect might be caused by the elevation in blood FFA concentration at the beginning of RE. Key points Caffeine ingestion may attenuate the response of GH to a single bout of resistance exercise. The depression of GH response may be caused by the elevation in serum FFA concentration at the beginning of resistance exercise. Caffeine ingestion before resistance exercise may not alert the concentration of cortisol and testosterone. PMID:24149694

  1. Hormonal and electrolyte responses to acute isohemic volume expansion in unanesthetized rats

    NASA Technical Reports Server (NTRS)

    Chenault, V. M.; Morris, M.; Lynch, C. D.; Maultsby, S. J.; Hutchins, P. M.

    1993-01-01

    This study was undertaken to explore the time course of the metabolic response to isohemic blood volume expansion (30%) in normotensive, unanesthetized Sprague-Dawley rats. Whole blood, drawn from a femoral artery catheter of conscious donor rats, was infused into the jugular vein of recipient rats. Blood samples were drawn from a carotid artery of recipient rats at time points beginning immediately post-volume expansion (IPVE) up through 5 days post-volume expansion (PVE). To characterize the attendant compensatory mechanisms, the plasma concentrations of electrolytes and fluid regulatory hormones were determined. Hematocrit began to raise IPVE and was significantly elevated above control IPVE 20, 30, 40, 60, and 90 min, and 2, 4, 6, 8, 12, and 24 hr PVE. Consistent with our current understanding of the hormonal response to excess volume, atrial natriuretic factor was significantly increased above the prevolume expansion (control) values 0-30 min PVE. Surprisingly, plasma aldosterone levels were significantly increased above control at 20 and 30 min and 6 hr PVE, whereas plasma renin activity was significantly decreased 30-40 min PVE. Plasma sodium was not changed from control values except for a significant increase at 6 hr post-volume expansion. Plasma potassium, osmolality, and arginine vasopressin levels were not altered by the volume expansion. These studies delineate the physiologic time scheme operative in the regulation of fluid volume during acute ischemic volume expansion.

  2. Metabolic and hormonal response to short term fasting after endurance training in the rat.

    PubMed

    Guezennec, C Y; Serrurier, B; Aymonod, M; Merino, D; Pesquies, P C

    1984-11-01

    The metabolic and hormonal response to short term fasting was studied after endurance exercise training. Rats were kept running on a motor driven rodent treadmill 5 days/wk for periods up to 1 h/day for 6 wk. Trained and untrained rats were then fasted for 24 h and 48 h. Liver and muscle glycogen, blood glucose, lactate, beta OH butyrate, glycerol, plasma insulin, testosterone and corticosterone were measured in fed and fasted trained and untrained rats. 48 h fasted trained rats show a lower level of blood lactate (1.08 +/- 0.05 vs 1.33 +/- 0.08 mmol/l-1 of blood glycerol (1 +/- 0.11 vs 0.84 +/- 0.08 mmol/l-1), and of muscle glycogen. There is a significant increase in plasma corticosterone in 48 h fasted trained rats from fed values. Plasma testosterone decreases during fasting, the values are higher in trained rats. Plasma insulin decreases during fasting without any difference between the two groups. These results show higher lipolysis, and decreased glycogenolysis in trained animals during 48 h fasting. The difference between the groups in steroid hormone response could reduce neoglucogenesis and muscle proteolysis in trained animals.

  3. Hormones, immune response, and pregnancy in healthy women and SLE patients.

    PubMed

    Zen, Margherita; Ghirardello, Anna; Iaccarino, Luca; Tonon, Michele; Campana, Carla; Arienti, Silvia; Rampudda, Mariaelisa; Canova, Mariagrazia; Doria, Andrea

    2010-04-03

    During pregnancy the maternal immune system is modified in order to achieve immune tolerance toward paternal antigen expressed on foetal cells. These modifications, which occur both at the foeto-maternal interface and in the systemic circulation, are driven by oestrogens and progesterone whose blood concentrations increase during pregnancy. The cytokine profile is also modified. Th2 cytokines are enhanced while the Th1 response is inhibited. This could explain why Th1-mediated autoimmune diseases tend to improve and Th2-mediated diseases, such as systemic lupus erythematosus (SLE), tend to worsen during pregnancy. However, whether or not SLE relapses more frequently during pregnancy is still a matter of debate. Steroid hormone and cytokine profiles differ in SLE patients compared with healthy subjects during pregnancy leading to a dysregulation of the balance between cell-mediated and humoral immune response, which, in turn, could explain the variability of the SLE course during gestation. This review focuses on hormonal-related cytokine changes observed during pregnancy in healthy subjects and SLE patients.

  4. The effect of potential fall distance on hormonal response in rock climbing.

    PubMed

    Baláš, Jiří; Giles, David; Chrastinová, Leona; Kárníková, Kateřina; Kodejška, Jan; Hlaváčková, Alžběta; Vomáčko, Ladislav; Draper, Nick

    2017-05-01

    The aim of this study was to examine the effect of alterations in potential lead fall distance on the hormonal responses of rock climbers. Nine advanced female climbers completed two routes while clipping all (PRO-all) or half (PRO-½) of the fixed points of protection. Venous blood samples were analysed for total catecholamines, noradrenaline (norepinephrine), adrenaline (epinephrine), dopamine, lactate, cortisol and serotonin. Differences between the two conditions pre, immediately post and 15 min post climbing were assessed using a 2 × 3 repeated measures ANOVA. All hormones and blood lactate concentrations increased significantly (P < 0.05) immediately post climb, except for cortisol. Peak cortisol concentrations did not occur until 15 min post ascent. Further, significant interactions between climbing and clipping conditions were found for total catecholamines (890% of basal concentration in PRO-½ vs. 568% in PRO-all), noradrenaline (794% vs. 532%) and dopamine (500% vs. 210%). There were no significant interactions for adrenaline (1920% vs. 1045%), serotonin (150% vs. 127%) or lactate (329% vs. 279%). The study showed a greater catecholamine response with an increase in potential lead fall distance. The most pronounced increases seen in catecholamine concentration were reported for dopamine and noradrenaline.

  5. Sexual fantasies and gender/sex: a multimethod approach with quantitative content analysis and hormonal responses.

    PubMed

    Goldey, Katherine L; Avery, Lanice R; van Anders, Sari M

    2014-01-01

    Research links explicit sexuality (e.g., physical attraction and pleasure) to high testosterone (T) and nurturance (loving contact) to low T. Engaging in sexual fantasy, which can include explicit sexual and nurturant elements, increases T in women but not in men. We examined whether individual differences in the explicit sexual and nurturant content of fantasy were linked with T or with estradiol (E2). In addition, we explored whether fantasy content differed or overlapped by gender/sex. Participants (26 women, 23 men) provided saliva samples for hormones before and after imagining a self-defined positive sexual encounter and responding to open-ended questions about the situation they imagined. We systematically content-coded responses for explicit sexual and nurturant content. In men, lower inclusion of nurturant content predicted larger T responses to fantasy. Fantasy content was not linked with T in women or with E2 in women or men. Women and men did not differ significantly in explicit sexual and nurturant content. Our findings suggest that individual experiences of fantasy as more or less nurturant affect T in men, provide support for the Steroid/Peptide Theory of Social Bonds, and highlight the value of integrating hormones and content analysis to investigate research questions relevant to sexuality and gender/sex.

  6. Neuromuscular, hormonal, and metabolic responses to different plyometric training volumes in rugby players.

    PubMed

    Cadore, Eduardo L; Pinheiro, Eraldo; Izquierdo, Mikel; Correa, Cleiton S; Radaelli, Régis; Martins, Jocelito B; Lhullier, Francisco L R; Laitano, Orlando; Cardoso, Marcelo; Pinto, Ronei S

    2013-11-01

    The purpose of this study was to investigate the effect of different volumes of plyometric exercise (i.e., 100, 200, or 300 hurdle jumps) on acute strength and jump performance and on the acute hormonal and lactate responses in rugby players. Eleven young male elite rugby players (age, 23.5 ± 0.9 years; height, 173 ± 4.8 cm) volunteered for the study. Maximal isometric peak torque (PT), maximal rate of force development (RFD), squat jump (SJ), and drop jump (DJ) performance were assessed before and 5 minutes, 8 hours, and 24 hours after 100, 200, or 300 jumps. In addition, total testosterone (TT), cortisol (COR), and lactate were measured before and after the 3 different plyometric exercise volumes. There were significant decreases in the PT (p < 0.02) and maximal RFD (p < 0.001) 5 minutes, 8 hours, and 24 hours after 100, 200, and 300 jumps, with no differences between the exercise volumes. Additionally, there were significant decreases in the SJ (p < 0.001) and DJ (p < 0.01) performances 24 hours after 100, 200, and 300 jumps, with no differences between the exercise volumes. However, there were significant increases in the TT (p < 0.001), COR (p < 0.05), and lactate (p < 0.001) after 100, 200, and 300 jumps, with no differences between the exercise volumes. All plyometric exercise volumes (100, 200, and 300 jumps) resulted in similar neuromuscular, metabolic, and hormonal responses.

  7. Phosphatidylinositol hydrolysis in isolated guinea-pig islets of Langerhans.

    PubMed Central

    Schrey, M P; Montague, W

    1983-01-01

    Previous studies have reported an increased turnover of phospholipid in isolated islets of Langerhans in response to raised glucose concentrations. The present investigation was thus undertaken to determine the nature of any phospholipases that may be implicated in this phenomenon by employing various radiolabelled exogenous phospholipids. Hydrolysis of 1-acyl-2-[14C]arachidonoylglycerophosphoinositol by a sonicated preparation of islets optimally released radiolabelled lysophosphatidylinositol, arachidonic acid and 1,2-diacylglycerol at pH 5,7 and 9 respectively. This indicates the presence of a phospholipase A1 and a phospholipase C. However, the lack of any labelled lysophosphatidylinositol production when 2-acyl-1-[14C]stearoylglycerophosphoinositol was hydrolysed argues against a role for phospholipase A2 in the release of arachidonic acid. Phospholipase C activity as measured by phosphatidyl-myo-[3H]inositol hydrolysis was optimal around pH8, required Ca2+ for activity and was predominantly cytosolic in origin. The time course of phosphatidylinositol hydrolysis at pH 6 indicated a precursor-product relationship for 1,2-diacylglycerol and arachidonic acid respectively. The release of these two products when phosphatidylinositol was hydrolysed by either islet or acinar tissue was similar. However, phospholipase A1 activity was 20-fold higher in acinar tissue. Substrate specificity studies with islet tissue revealed that arachidonic acid release from phosphatidylethanolamine and phosphatidylcholine was only 8% and 2.5% respectively of that from phosphatidylinositol. Diacylglycerol lipase was also demonstrated in islet tissue being predominantly membrane bound and stimulated by Ca2+. The availability of non-esterified arachidonic acid in islet cells could be regulated by changes in the activity of a phosphatidylinositol-specific phospholipase C acting in concert with a diacylglycerol lipase. PMID:6362663

  8. Altered radiation responses of breast cancer cells resistant to hormonal therapy.

    PubMed

    Luzhna, Lidiya; Lykkesfeldt, Anne E; Kovalchuk, Olga

    2015-01-30

    Endocrine therapy agents (the selective estrogen receptor (ER) modulators such as tamoxifen or the selective ER down-regulators such as ICI 182,780) are key treatment regimens for hormone receptor-positive breast cancers. While these drugs are very effective in controlling ER-positive breast cancer, many tumors that initially respond well to treatment often acquire drug resistance, which is a major clinical problem. In clinical practice, hormonal therapy agents are commonly used in combination or sequence with radiation therapy. Tamoxifen treatment and radiotherapy improve both local tumor control and patient survival. However, tamoxifen treatment may render cancer cells less responsive to radiation therapy. Only a handful of data exist on the effects of radiation on cells resistant to hormonal therapy agents. These scarce data show that cells that were resistant to tamoxifen were also resistant to radiation. Yet, the existence and mechanisms of cross-resistance to endocrine therapy and radiation therapy need to be established. Here, we for the first time examined and compared radiation responses of MCF-7 breast adenocarcinoma cells (MCF-7/S0.5) and two antiestrogen resistant cell lines derived from MCF-7/S0.5: the tamoxifen resistant MCF-7/TAMR-1 and ICI 182,780 resistant MCF-7/182R-6 cell lines. Specifically, we analyzed the radiation-induced changes in the expression of genes involved in DNA damage, apoptosis, and cell cycle regulation. We found that the tamoxifen-resistant cell line in contrast to the parental and ICI 182,780-resistant cell lines displayed a significantly less radiation-induced decrease in the expression of genes involved in DNA repair. Furthermore, we show that MCF-7/TAMR-1 and MCF-7/182R-6 cells were less susceptible to radiation-induced apoptosis as compared to the parental line. These data indicate that tamoxifen-resistant breast cancer cells have a reduced sensitivity to radiation treatment. The current study may therefore serve as a

  9. Growth Hormone-Releasing Hormone in Diabetes

    PubMed Central

    Fridlyand, Leonid E.; Tamarina, Natalia A.; Schally, Andrew V.; Philipson, Louis H.

    2016-01-01

    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. This review considers the role of GHRHR in the beta-cell and addresses the unique engineered GHRH agonists and antagonists for treatment of type 2 diabetes mellitus. We discuss the similarity of signaling pathways activated by GHRHR in pituitary somatotrophs and in pancreatic beta-cells and possible ways as to how the GHRHR pathway can interact with glucose and other secretagogues to stimulate insulin secretion. We also consider the hypothesis that novel GHRHR agonists can improve glucose metabolism in Type 2 diabetes by preserving the function and survival of pancreatic beta-cells. Wound healing and cardioprotective action with new GHRH agonists suggest that they may prove useful in ameliorating certain diabetic complications. These findings highlight the future potential therapeutic effectiveness of modulators of GHRHR activity for the development of new therapeutic approaches in diabetes and its complications. PMID:27777568

  10. Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway.

    PubMed

    Lehmann, J M; Kliewer, S A; Moore, L B; Smith-Oliver, T A; Oliver, B B; Su, J L; Sundseth, S S; Winegar, D A; Blanchard, D E; Spencer, T A; Willson, T M

    1997-02-07

    Accumulation of cholesterol causes both repression of genes controlling cholesterol biosynthesis and cellular uptake and induction of cholesterol 7alpha-hydroxylase, which leads to the removal of cholesterol by increased metabolism to bile acids. Here, we report that LXRalpha and LXRbeta, two orphan members of the nuclear receptor superfamily, are activated by 24(S), 25-epoxycholesterol and 24(S)-hydroxycholesterol at physiologic concentrations. In addition, we have identified an LXR response element in the promoter region of the rat cholesterol 7alpha-hydroxylase gene. Our data provide evidence for a new hormonal signaling pathway that activates transcription in response to oxysterols and suggest that LXRs play a critical role in the regulation of cholesterol homeostasis.

  11. In vitro reconstitution of pancreatic islets.

    PubMed

    Kojima, Nobuhiko

    2014-01-01

    The lack of transplantable pancreatic islets is a serious problem that affects the treatment of patients with type 1 diabetes mellitus. Beta cells can be induced from various sources of stem or progenitor cells, including induced pluripotent stem cells in the near future; however, the reconstitution of islets from β cells in culture dishes is challenging. The generation of highly functional islets may require three-dimensional spherical cultures that resemble intact islets. This review discusses recent advances in the reconstitution of islets. Several factors affect the reconstitution of pseudoislets with higher functions, such as architectural similarity, cell-to-cell contact, and the production method. The actual transplantation of naked or encapsulated pseudoislets and islet-like cell clusters from various stem cell sources is also discussed. Advancing our understanding of the methods used to reconstitute pseudoislets should expand the range of potential strategies available for developing de novo islets for therapeutic applications.

  12. Classification of microscopy images of Langerhans islets

    NASA Astrophysics Data System (ADS)

    Å vihlík, Jan; Kybic, Jan; Habart, David; Berková, Zuzana; Girman, Peter; Kříž, Jan; Zacharovová, Klára

    2014-03-01

    Evaluation of images of Langerhans islets is a crucial procedure for planning an islet transplantation, which is a promising diabetes treatment. This paper deals with segmentation of microscopy images of Langerhans islets and evaluation of islet parameters such as area, diameter, or volume (IE). For all the available images, the ground truth and the islet parameters were independently evaluated by four medical experts. We use a pixelwise linear classifier (perceptron algorithm) and SVM (support vector machine) for image segmentation. The volume is estimated based on circle or ellipse fitting to individual islets. The segmentations were compared with the corresponding ground truth. Quantitative islet parameters were also evaluated and compared with parameters given by medical experts. We can conclude that accuracy of the presented fully automatic algorithm is fully comparable with medical experts.

  13. Human pancreatic islets develop through fusion of distinct β and α/δ islets.

    PubMed

    Lee, Inchul

    2016-10-01

    Human pancreatic islets show unique architecture in which α and δ cells are mostly at the peripheral and perivascular areas. It has remained unknown how such prototype is realized in every islet. Here, I report that fetal islets develop first in two distinct types consisting of β or α/δ cells, respectively. The α/δ islets are variable in shape, composed of α and δ cells evenly intermixed. They are vascularized better but encapsulated poorer than β islets in general. During the development, the β and α/δ islets adjoin and fuse with each other in such a way that α and δ cells form a crescent on β cells and, then, progress to encompass and encroach into β cells. Most mature-form islets appear to develop through the fusion. Islets at various stages of fusion are present concurrently until late gestation, suggesting that the islet fusion is an ongoing developmental process. The α/δ islets appear to play a primary role for the process, approaching toward the fusion partner actively. Direct connection is present between the α/δ islets and neural ganglia undergoing active neurogenesis, suggesting an organ-wide neuroendocrine network development. The fusion of precursor islets appears to be a principle of human pancreatic development providing the prototype of mature islets. The complex development might be a reference for in vitro reproduction of biologically competent islets.

  14. Dependency of maximum goitrogenic response on some minimal level of thyroid hormone production

    SciTech Connect

    March, B.E.; Poon, R.

    1981-04-01

    Thyroidal activity was studied in chicks given dietary thiouracil in conjunction with daily doses of thyroxine and with diets adequate and deficient in iodine. DL-thyroxine administered at doses up to 1.0 microgram per day for 10 to 12 days had no effect or slightly increased thyroid weight. Both the epithelial and colloid components of the thyroid gland were increased in response to thiouracil and to thiouracil in combination with low dosages of exogenous thyroxine. Radioiodine uptake was increased above the control with thiouracil and with thiouracil in conjunction with .5 and 1.0 microgram DL-thyroxine given daily. Birds receiving thiouracil, with and without exogenous thyroxine, showed a different pattern of radioiodine uptake and release than the control birds. Thiouracil-treated birds showed a rapid uptake of iodine following its administration, which was followed by a rapid decline immediately after peak accumulation, whereas in control birds thyroidal radioiodine concentration reached a plateau at the maximum concentration attained. The goitrogenic response to thiouracil was much greater when the diet was supplemented with iodine than when the diet was iodine-deficient. Thyroids under iodine deficiency contained greater percentages of epithelial tissue than with iodine-supplemented diets. Thyroid glands of chicks given thiouracil in an iodine-supplemented diet contained much more colloid than glands from iodine-deficient chicks with or without thiouracil. DL-thyroxine at a dosage of .5 microgram per day to chicks given thiouracil in an iodine-adequate diet increased, whereas higher dosages decreased thyroidal colloid. It is concluded that some minimal concentration of thyroid hormone is required for maximum goitrogenic response. It is not clear whether the response is entirely due to an effect on thyrotropin production or whether there is an effect of thyroid hormone on the thyroid gland itself.

  15. Effect of sleep deprivation on the growth hormone response to the alpha-3 adrenergic receptor agonist, clonidine, in normal subjects.

    PubMed

    Lal, S; Thavundayil, J X; Krishnan, B; Nair, N P; Schwartz, G; Kiely, M E; Guyda, H

    1997-01-01

    One night's sleep deprivation (SD) increased the growth hormone (GH) response to clonidine (20 ug/kg i.v.) in 11 normal men ( p < 0.005). This finding may indicate that SD enhances alpha-2 adrenergic receptor function or that the GH response to GH releasing factor in increased by SD.

  16. Predicting Treatment Response for Oppositional Defiant and Conduct Disorder Using Pre-treatment Adrenal and Gonadal Hormones.

    PubMed

    Shenk, Chad E; Dorn, Lorah D; Kolko, David J; Susman, Elizabeth J; Noll, Jennie G; Bukstein, Oscar G

    2012-12-01

    Variations in adrenal and gonadal hormone profiles have been linked to increased rates of oppositional defiant disorder (ODD) and conduct disorder (CD). These relationships suggest that certain hormone profiles may be related to how well children respond to psychological treatments for ODD and CD. The current study assessed whether pre-treatment profiles of adrenal and gonadal hormones predicted response to psychological treatment of ODD and CD. One hundred five children, 6 - 11 years old, participating in a randomized, clinical trial provided samples for cortisol, testosterone, dehydroepiandrosterone, and androstenedione. Diagnostic interviews of ODD and CD were administered up to three years post-treatment to track treatment response. Group-based trajectory modeling identified two trajectories of treatment response: 1) a High-response trajectory where children demonstrated lower rates of an ODD or CD diagnosis throughout follow-up, and 2) a Low-response trajectory where children demonstrated higher rates of an ODD or CD diagnosis throughout follow-up. Hierarchical logistic regression predicting treatment response demonstrated that children with higher pre-treatment concentrations of testosterone were four times more likely to be in the Low-response trajectory. No other significant relationship existed between pre-treatment hormone profiles and treatment response. These results suggest that higher concentrations of testosterone are related to how well children diagnosed with ODD or CD respond to psychological treatment over the course of three years.

  17. Factors controlling pancreatic islet neogenesis.

    PubMed Central

    Vinik, A.; Pittenger, G.; Rafaeloff, R.; Rosenberg, L.

    1992-01-01

    We have established a model in which cellophane wrapping induces reiteration of the normal ontogeny of beta-cell differentiation from ductal tissue. The secretion of insulin is physiologic and coordinated to the needs of the animal. Streptozotocin-induced diabetes in hamsters can be "cured" at least half the time. There appears to be activation of growth factor(s) within the pancreas, acting in an autocrine, paracrine, or juxtacrine manner to induce ductal cell proliferation and differentiation into functioning beta cells. Given the results of our studies to date, it does not seem premature to envisage new approaches to the treatment of diabetes mellitus. Identification of the factor(s) regulating islet-cell proliferation and differentiation in our model may permit islets to be grown in culture. This concept could be extended to induce endocrine cell differentiation in vitro as well. Furthermore, islet-cell growth factors could be used to provide "trophic support" to islet transplants as a means of maintaining graft viability. There may also be greater scope for gene therapy when the growth factor(s) have been isolated, purified, sequenced, and cloned. Images FIG. 2 FIG. 5 FIG. 6 FIG. 9 PMID:1364089

  18. Acute metabolic, hormonal, and psychological responses to different endurance training protocols.

    PubMed

    Wahl, P; Mathes, S; Köhler, K; Achtzehn, S; Bloch, W; Mester, J

    2013-10-01

    In the last years, mainly 2 high-intensity-training (HIT) protocols became common: first, a Wingate-based "all-out" protocol and second, a 4×4 min protocol. However, no direct comparison between these protocols exists, and also a comparison with high-volume-training (HVT) is missing. Therefore, the aim of the present study was to compare these 3 endurance training protocols on metabolic, hormonal, and psychological responses. Twelve subjects performed: 1) HVT [130 min at 55% peak power output (PPO)]; 2) 4×4 min at 95% PPO; 3) 4×30 s all-out. Human growth hormone (hGH), testosterone, and cortisol were determined before (pre) and 0', 30', 60', 180' after each intervention. Metabolic stimuli and perturbations were characterized by lactate, blood gas (pH, BE, HCO₃⁻, pO₂, PCO₂), and spirometric analysis. Furthermore, changes of the person's perceived physical state were determined. The 4×30 s training caused the highest increases in cortisol and hGH, followed by 4 × 4 min and HVT. Testosterone levels were significantly increased by all 3 exercise protocols. Metabolic stress was highest during and after 4×30 s, followed by 4×4 min and HVT. The 4×30 s training was also the most demanding intervention from an athlete's point of view. In conclusion, the results suggest that 4×30 s and 4×4 min promote anabolic processes more than HVT, due to higher increases of hGH, testosterone, and the T/C ratio. It can be speculated that the acute hormonal increase and the metabolic perturbations might play a positive role in optimizing training adaptation and in eliciting health benefits as it has been shown by previous long term training studies using similar exercise protocols.

  19. Growth hormone response to different consecutive stress stimuli in healthy men: is there any difference?

    PubMed

    Jezova, D; Radikova, Z; Vigas, M

    2007-06-01

    The contribution of growth hormone (GH), released during acute and repeated stressful situations, to the development of stress-related disorders is often neglected. We have hypothesized that the modulation of the GH response to sequential stress exposure in humans depends mainly on the nature of the stressor. To test this hypothesis, we compared GH responses to different stressful situations, namely aerobic exercise, hypoglycemia and hyperthermia, which were applied in two sequential sessions separated by 80-150 min. In addition, administration of the dopaminergic drug apomorphine was used as a pharmacological stimulus. GH responses to submaximal exercise (bicycle ergometer, increasing work loads of 1.5, 2.0 and 2.5 W/kg, total duration 20 min) and hyperthermia in a sauna (80 degrees C, 30 min) were prevented when preceded by the same stress stimulus. Hypoglycemia induced by insulin (0.1 IU/kg intravenously) resulted in a significant GH response also during the second of the two consecutive insulin tests, though the response was reduced. Administration of apomorphine (0.75 mg subcutaneously) or insulin prevented the increase in GH release in response to a sequential bolus of apomorphine, while hypoglycemia induced a significant elevation in GH levels even if applied after a previous treatment with apomorphine. In conclusion, the feedback inhibition of the GH response to a sequential stress stimulus depends on the stimulus used. Unlike in the case of exercise and hyperthermia, mechanisms involved in the stress response to hypoglycemia appear to overcome the usual feedback mechanisms and to re-induce the GH response when applied after another stimulus.

  20. β-cell metabolic alterations under chronic nutrient overload in rat and human islets.

    PubMed

    Vernier, Stephanie; Chiu, Angela; Schober, Joseph; Weber, Theresa; Nguyen, Phuong; Luer, Mark; McPherson, Timothy; Wanda, Paul E; Marshall, Connie A; Rohatgi, Nidhi; McDaniel, Michael L; Greenberg, Andrew S; Kwon, Guim

    2012-01-01

    The aim of this study was to assess multifactorial β-cell responses to metabolic perturbations in primary rat and human islets. Treatment of dispersed rat islet cells with elevated glucose and free fatty acids (FFAs, oleate:palmitate = 1:1 v/v) resulted in increases in the size and the number of lipid droplets in β-cells in a time- and concentration-dependent manner. Glucose and FFAs synergistically stimulated the nutrient sensor mammalian target of rapamycin complex 1 (mTORC1). A potent mTORC1 inhibitor, rapamycin (25 nM), significantly reduced triglyceride accumulation in rat islets. Importantly, lipid droplets accumulated only in β-cells but not in α-cells in an mTORC1-dependent manner. Nutrient activation of mTORC1 upregulated the expression of adipose differentiation related protein (ADRP), known to stabilize lipid droplets. Rat islet size and new DNA synthesis also increased under nutrient overload. Insulin secretion into the culture medium increased steadily over a 4-day period without any significant difference between glucose (10 mM) alone and the combination of glucose (10 mM) and FFAs (240 μM). Insulin content and insulin biosynthesis, however, were significantly reduced under the combination of nutrients compared with glucose alone. Elevated nutrients also stimulated lipid droplet formation in human islets in an mTORC1-dependent manner. Unlike rat islets, however, human islets did not increase in size under nutrient overload despite a normal response to nutrients in releasing insulin. The different responses of islet cell growth under nutrient overload appear to impact insulin biosynthesis and storage differently in rat and human islets.

  1. Modulation of. beta. -adrenergic response in rat brain astrocytes by serum and hormones

    SciTech Connect

    Wu, D.K.; Morrison, R.S.; de Vellis, J.

    1985-01-01

    Purified astrocyte cultures from neonatal rat cerebrum respond to isoproterenol, a ..beta..-adrenergic agonist, with a transient rise in cAMP production. This astroglial property was regulated by serum, a chemically defined medium (serum-free medium plus hydrocortisone, putrescine, prostaglandin F/sub 2/, insulin, and fibroblast growth factor) and epidermal growth factor. Compared to astrocytes grown in serum-supplemented medium, astrocytes grown in the chemically defined medium were nonresponsive to isoproterenol stimulation, and this difference did not appear to be due to selection of a subpopulation of cells by either medium. The data suggest that a decreased ..beta..-adrenergic receptor number and an increased degradation of cAMP may account for the reduced response to ..beta..-adrenergic stimulation. The nonresponsive state of astrocytes in the defined medium was reversible when the medium was replaced with serum-supplemented medium. An active substance(s) in serum was responsible for restoring the responsiveness of astrocytes. Each of the five components of the defined medium had little effect by itself; however, together they acted synergistically to desensitize astrocytes to ..beta..-adrenergic stimulation. On the other hand, epidermal growth factor, a potent mitogen for astrocytes, was very competent by itself in reducing the cAMP response of astrocytes to ..beta..-adrenergic stimulation. Thus purified astrocytes grown in the chemically defined medium appear to be a good model for the study of hormonal interactions and of serum factors which may modulate the ..beta..-adrenergic response.

  2. Parathyroid hormone modulates the response of osteoblast-like cells to mechanical stimulation

    NASA Technical Reports Server (NTRS)

    Ryder, K. D.; Duncan, R. L.

    2000-01-01

    Mechanical loading stimulates many responses in bone and osteoblasts associated with osteogenesis. Since loading and parathyroid hormone (PTH) activate similar signaling pathways in osteoblasts, we postulate that PTH can potentiate the effects of mechanical stimulation. Using an in vitro four-point bending device, we found that expression of COX-2, the inducible isoform of cyclooxygenase, was dependent on fluid forces generated across the culture plate, but not physiologic levels of strain in MC3T3-E1 osteoblast-like cells. Addition of 50 nM PTH during loading increased COX-2 expression at both subthreshold and threshold levels of fluid forces compared with either stimuli alone. We also demonstrated that application of fluid shear to MC3T3-E1 cells induced a rapid increase in [Ca(2+)](i). Although PTH did not significantly change [Ca(2+)](i) levels, flow and PTH did produce a significantly greater [Ca(2+)](i) response and increased the number of responding cells than is found in fluid shear alone. The [Ca(2+)](i) response to these stimuli was significantly decreased when the mechanosensitive channel inhibitor, gadolinium, was present. These studies indicate that PTH increases the cellular responses of osteoblasts to mechanical loading. Furthermore, this response may be mediated by alterations in [Ca(2+)](i) by modulating the mechanosensitive channel.

  3. Leptin is a potent stimulator of spontaneous pulsatile growth hormone (GH) secretion and the GH response to GH-releasing hormone.

    PubMed

    Tannenbaum, G S; Gurd, W; Lapointe, M

    1998-09-01

    Pulsatile GH secretion is exquisitely sensitive to perturbations in nutritional status, but the underlying mechanisms are largely unknown. Leptin, a recently discovered adipose cell hormone, is thought to be a sensor of energy stores and to regulate body mass, appetite, and metabolism at the level of the brain. Receptors for leptin are abundantly expressed in hypothalamic nuclei known to be involved in GH regulation, suggesting that leptin may serve as an important hormonal signal to the GH neuroendocrine axis in normal animals. To test this hypothesis, we examined the effects of intracerebroventricular infusion of recombinant murine leptin, at a dose of 1.2 microg/day for 7 days, on both spontaneous and GH-releasing hormone (GHRH)-stimulated GH secretion in free-moving adult male rats. Concomitant with suppressive effects on food intake, body weight, and basal plasma insulin-like growth factor I, insulin, and glucose concentrations, central infusion of leptin resulted in a 2- to 3-fold augmentation of GH pulse amplitude, 5-fold higher GH nadir levels, and a 2- to 3-fold increase in the integrated area under the 6-h GH response curve compared with those in vehicle-infused controls (P < 0.001). The intracerebroventricular infusion of leptin also produced a 3- to 4-fold increase in GHRH-induced GH release at GH trough times (P < 0.01). These studies demonstrate a potent stimulatory action of leptin on both spontaneous pulsatile GH secretion and the GH response to GHRH. The results suggest that the GH-releasing activity of leptin is mediated, at least in part, by an inhibition of hypothalamic somatostatin release. Thus, leptin may be a critical hormonal signal of nutritional status in the neuroendocrine regulation of pulsatile GH secretion.

  4. Identification of Primary Gene Targets of TFAP2C in Hormone Responsive Breast Carcinoma Cells

    PubMed Central

    Woodfield, George W.; Chen, Yizhen; Bair, Thomas B.; Domann, Frederick E.; Weigel, Ronald J.

    2010-01-01

    The TFAP2C transcription factor is involved in mammary development, differentiation and oncogenesis. Previous studies established a role for TFAP2C in the regulation of ESR1 (ERα) and ERBB2 (Her2) in breast carcinomas. However, the role of TFAP2C in different breast cancer phenotypes has not been examined in detail. To develop a more complete characterization of TFAP2C target genes, ChIP-seq with anti-TFAP2C antibody and expression arrays with TFAP2C knock down were analyzed in MCF-7 breast carcinoma cells. Genomic sequences common to the ChIP-seq data set defined the consensus sequence for TFAP2C chromatin binding as the nine base sequence SCCTSRGGS (S=G/C, R=A/G), which closely matches the previously defined optimal in vitro binding site. Comparing expression arrays before and after knock down of TFAP2C with ChIP-seq data demonstrated a conservative estimate that 8% of genes altered by TFAP2C expression are primary target genes and includes genes that are both induced and repressed by TFAP2C. A set of 447 primary target genes of TFAP2C was identified, which included ESR1 (ERα), FREM2, RET, FOXA1, WWOX, GREB1, MYC and members of the retinoic acid response pathway. The identification of ESR1, WWOX, GREB1 and FOXA1 as primary targets confirmed the role of TFAP2C in hormone response. TFAP2C plays a critical role in gene regulation in hormone responsive breast cancer and its target genes are different than for the Her2 breast cancer phenotype. PMID:20629094

  5. Effects of lifting tempo on one repetition maximum and hormonal responses to a bench press protocol.

    PubMed

    Headley, Samuel A; Henry, Kelley; Nindl, Bradley C; Thompson, Brian A; Kraemer, William J; Jones, Margaret T

    2011-02-01

    This study was carried out in 2 parts: part 1 was designed to measure the 1 repetition maximum (1RM) bench press with 2 different moderate-velocity tempos (2/0/2) vs. (2/0/4) in male lifters while part 2 compared the hormonal responses at the same tempos as described in part 1. In both parts 1 and 2, the 1RMs (lbs) were higher on the 2/0/2 tempo than on the 2/0/4 tempo. The change in plasma volume (PV) was greater after the 2/0/4 tempo (-5.7 ± 1.7% vs. 0.96 ± 1.2%, p < 0.05). All blood parameters were significantly (p < 0.05) higher post-exercise compared with baseline. With PV corrected, insulin-like growth factor 1 (IGF-1) (ng·mL⁻¹) was higher with the 2/0/2 tempo only (pre-exercise: 277.4 ± 21.8, post-exercise: 308.1 ± 22.9; 2/0/4 tempo pre-exercise: 277.2 ± 17.6, post-exercise: 284.8 ± 21.2). In conclusion, heavier loads can be lifted and more total work can be performed using a (2/0/2) tempo compared with a slower (2/0/4) tempo, but with the exception of IGF-1, the hormonal responses are similar. Individuals may get the same metabolic responses to training by using different tempos, but they will need to use less weight at a slower tempo.

  6. Obese adolescents show impaired meal responses of the appetite-regulating hormones ghrelin and PYY.

    PubMed

    Mittelman, Steven D; Klier, Katie; Braun, Sharon; Azen, Colleen; Geffner, Mitchell E; Buchanan, Thomas A

    2010-05-01

    Ghrelin and peptide YY (PYY) stimulate hunger and satiety, respectively. The physiology of these hormones during normal meal intake remains unclear. This study was designed to compare the responses of these two hormones to meal intake between lean and obese Hispanic adolescents. A total of 10 obese and 7 lean Hispanic youth, aged 11-14 years, consumed two mixed meals, one small and one large, during which plasma measurements of active and total ghrelin and total PYY were obtained. Obese subjects tended to consume more calories during the small meal than lean subjects, although this did not reach statistical significance. Intake of the small meal significantly suppressed active ghrelin and stimulated PYY levels in the lean subjects, and these changes were further accentuated by the large meals. In obese subjects, the suppression of active ghrelin and stimulation of PYY by caloric intake were blunted. Interestingly, a paradoxical stimulation of active ghrelin levels was noted during the small meals in both lean and obese subjects. This stimulation was not seen during the larger meals in lean subjects, but remained present in the obese subjects. Thus, meal-related changes in active ghrelin and PYY are blunted in obese as compared to lean Hispanic subjects. This blunting could contribute to the development or worsening of obesity.

  7. Characterization of the interaction of the human mineralocorticosteroid receptor with hormone response elements.

    PubMed Central

    Lombès, M; Binart, N; Oblin, M E; Joulin, V; Baulieu, E E

    1993-01-01

    Although the mineralocorticosteroid receptor (MR) belongs to the superfamily of hormone-dependent transcription factors, the molecular mechanism by which it regulates gene expression is poorly understood. Binding of the MR to target gene promoters has never been characterized, and specific mineralocorticosteroid response elements (MREs) remain to be identified. The human MR (hMR) was overexpressed in Sf21 insect cells using the baculovirus system. The high degree of similarity between the glucocorticosteroid receptor (GR) and the MR prompted us to examine the DNA-binding properties of the recombinant MR with glucocorticosteroid-regulated genes. Gel shift mobility assays demonstrated that the recombinant receptor interacted with oligonucleotides containing perfect and imperfect palindromic sequences of GRE. A monoclonal anti-hMR antibody (FD4) induced a supershift of protein-DNA complexes and identified the MR in Western blot analysis. In vitro DNAse I protection assays with the hormone-regulated murine mammary tumour virus promoter showed that recombinant hMR generated four footprints whose limits encompassed the GRE motifs. By means of these two complementary approaches, no difference between the interaction of free, agonist- or antagonist-bound MR and DNA was detected. We provide evidence that hMR functions as a sequence-specific DNA-binding protein. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 PMID:8389140

  8. Growth of short children born small for gestational age and their response to growth hormone therapy.

    PubMed

    Prasad, Hemchand Krishna; Khadilkar, Vaman V; Chiplonkar, Shashi A; Khadilkar, Anuradha V

    2013-05-08

    Growth hormone [GH] is licensed for use in children born small for gestational age (SGA) who fail to catch-up. We retrospectively compared the response of twenty children born SGA (who satisfied the auxological criteria) to growth hormone (Group I) versus randomly selected age and sex matched controls from a group of SGA children with growth related complaints, not treated with GH (Group II). After 2 years of GH therapy the HAZ increased from -2.8 to -1.6 in Group I, compared 2.2 to -1.7 in group II (P-value < 0.05). The percentage of pubertal children rose from 55% to 65% in cases versus 60% to 75% in the controls (P>0.05). GH resulted in increase in growth velocity Z-score during the first year and (4.3±0.5 in Group-I versus - 0.5±0.6 in Group-II, P<0.05) second year of treatment (1.7±0.4 in cases versus -0.6±0.7 in controls, P<0.05).Thus, GH improves height of short SGA children without accelerating pubertal progression.

  9. Regulation of hormonal responses of sweet pepper as affected by salinity and elevated CO2 concentration.

    PubMed

    Piñero, María Carmen; Houdusse, Fabrice; Garcia-Mina, Jose M; Garnica, María; Del Amor, Francisco M

    2014-08-01

    This study examines the extent to which the predicted CO2 -protective effects on the inhibition of growth, impairment of photosynthesis and nutrient imbalance caused by saline stress are mediated by an effective adaptation of the endogenous plant hormonal balance. Therefore, sweet pepper plants (Capsicum annuum, cv. Ciclón) were grown at ambient or elevated [CO2] (400 or 800 µmol mol(-1)) with a nutrient solution containing 0 or 80 mM NaCl. The results show that, under saline conditions, elevated [CO2] increased plant dry weight, leaf area, leaf relative water content and net photosynthesis compared with ambient [CO2], whilst the maximum potential quantum efficiency of photosystem II was not modified. In salt-stressed plants, elevated [CO2 ] increased leaf NO3(-) concentration and reduced Cl(-) concentration. Salinity stress induced ABA accumulation in the leaves but it was reduced in the roots at high [CO2], being correlated with the stomatal response. Under non-stressed conditions, IAA was dramatically reduced in the roots when high [CO2] was applied, which resulted in greater root DW and root respiration. Additionally, the observed high CK concentration in the roots (especially tZR) could prevent downregulation of photosynthesis at high [CO2], as the N level in the leaves was increased compared with the ambient [CO2], under salt-stress conditions. These results demonstrate that the hormonal balance was altered by the [CO2], which resulted in significant changes at the growth, gas exchange and nutritional levels.

  10. Morphologic responses of the mouse ovarian surface epithelium to ovulation and steroid hormonal milieu.

    PubMed

    Gotfredson, Garry S; Murdoch, William J

    2007-02-01

    Ovarian cancer of surface epithelial origin is an ovulation- and endocrine-related disease. It appears that a cell transformed by genotoxins generated at follicular rupture is propagated during postovulatory wound repair. A consequent steroid hormonal imbalance favoring the mitogenic estrogens is a prospective predisposing factor in ovarian neoplasia. Protection against epithelial ovarian cancer is conferred by progesterone. The objective of this study was to characterize the acute effects of ovulation and steroid hormonal exposure on morphologic responses of surface epithelial cells of mouse ovaries. Follicular development and ovulation were induced in immature animals with equine and human (=Day 0) choriogonadotropins, respectively. On Day 2 (approximately 36 hrs after ovulation), surface epithelial classifications presented in histologic sections were altered from simple (single-layered) squamous and cuboidal toward stratification; this trend was reversed (i.e., reverted to the control status) on Days 4-8. Shifts in the ovarian epithelium from simple to stratified were accentuated following postovulatory (Days 1-8) treatment with estradiol. Surface epithelia of ovaries obtained after 1 week of progesterone administration were exclusively of a simple phenotype. We conclude that the proliferative/procarcinogenic reaction of the ovarian surface epithelium to ovulation is exacerbated by estrogen and counteracted by progesterone.

  11. Melatonin and Pancreatic Islets: Interrelationships between Melatonin, Insulin and Glucagon

    PubMed Central

    Peschke, Elmar; Bähr, Ina; Mühlbauer, Eckhard

    2013-01-01

    The pineal hormone melatonin exerts its influence in the periphery through activation of two specific trans-membrane receptors: MT1 and MT2. Both isoforms are expressed in the islet of Langerhans and are involved in the modulation of insulin secretion from β-cells and in glucagon secretion from α-cells. De-synchrony of receptor signaling may lead to the development of type 2 diabetes. This notion has recently been supported by genome-wide association studies identifying particularly the MT2 as a risk factor for this rapidly spreading metabolic disturbance. Since melatonin is secreted in a clearly diurnal fashion, it is safe to assume that it also has a diurnal impact on the blood-glucose-regulating function of the islet. This factor has hitherto been underestimated; the disruption of diurnal signaling within the islet may be one of the most important mechanisms leading to metabolic disturbances. The study of melatonin–insulin interactions in diabetic rat models has revealed an inverse relationship: an increase in melatonin levels leads to a down-regulation of insulin secretion and vice versa. Elucidation of the possible inverse interrelationship in man may open new avenues in the therapy of diabetes. PMID:23535335

  12. Melatonin and pancreatic islets: interrelationships between melatonin, insulin and glucagon.

    PubMed

    Peschke, Elmar; Bähr, Ina; Mühlbauer, Eckhard

    2013-03-27

    The pineal hormone melatonin exerts its influence in the periphery through activation of two specific trans-membrane receptors: MT1 and MT2. Both isoforms are expressed in the islet of Langerhans and are involved in the modulation of insulin secretion from β-cells and in glucagon secretion from α-cells. De-synchrony of receptor signaling may lead to the development of type 2 diabetes. This notion has recently been supported by genome-wide association studies identifying particularly the MT2 as a risk factor for this rapidly spreading metabolic disturbance. Since melatonin is secreted in a clearly diurnal fashion, it is safe to assume that it also has a diurnal impact on the blood-glucose-regulating function of the islet. This factor has hitherto been underestimated; the disruption of diurnal signaling within the islet may be one of the most important mechanisms leading to metabolic disturbances. The study of melatonin-insulin interactions in diabetic rat models has revealed an inverse relationship: an increase in melatonin levels leads to a down-regulation of insulin secretion and vice versa. Elucidation of the possible inverse interrelationship in man may open new avenues in the therapy of diabetes.

  13. Feasibility of islet magnetic resonance imaging using ferumoxytol in intraportal islet transplantation.

    PubMed

    Jin, Sang-Man; Oh, Seung-Hoon; Oh, Bae Jun; Shim, Wooyoung; Choi, Jin Myung; Yoo, Dongkyeom; Hwang, Yong Hwa; Lee, Jung Hee; Lee, Dong Yun; Kim, Jae Hyeon

    2015-06-01

    There is a clinical need for an alternative labeling agent for magnetic resonance imaging (MRI) in islet transplantation. We aimed to evaluate the feasibility of islet MRI using ferumoxytol, which is the only clinically-available ultrasmall superparamagnetic iron oxide. We compared islet function and viability of control islets and islets labeled with ferumoxytol and/or a heparin-protamine complex (HPF). Efficacy of ferumoxytol labeling was assessed in both ex vivo and in vivo models. Labeling for 48 h with HPF, but not up to 800 μg/mL ferumoxytol, deranged ex vivo islet viability and function. The T2∗ relaxation time was optimal when islets were labeled with 800 μg/mL of ferumoxytol for 48 h. Prussian blue stain, iron content assay, transmission electron microscopy (TEM) supported internalization of ferumoxytol particles. However, the labeling intensity in the ex vivo MRI of islets labeled with ferumoxytol was much weaker than that of islets labeled with ferucarbotran. In syngeneic intraportal islet transplantation, there was a correlation between the total area of visualized islets and the transplanted islet mass. In conclusion, islet MRI using ferumoxytol was feasible in terms of in vitro and in vivo efficacy and safety. However, the weak labeling efficacy is still a hurdle for the clinical application.

  14. Hormone-regulated defense and stress response networks contribute to heterosis in Arabidopsis F1 hybrids.

    PubMed

    Groszmann, Michael; Gonzalez-Bayon, Rebeca; Lyons, Rebecca L; Greaves, Ian K; Kazan, Kemal; Peacock, W James; Dennis, Elizabeth S

    2015-11-17

    Plant hybrids are extensively used in agriculture to deliver increases in yields, yet the molecular basis of their superior performance (heterosis) is not well understood. Our transcriptome analysis of a number of Arabidopsis F1 hybrids identified changes to defense and stress response gene expression consistent with a reduction in basal defense levels. Given the reported antagonism between plant immunity and growth, we suggest that these altered patterns of expression contribute to the greater growth of the hybrids. The altered patterns of expression in the hybrids indicate decreases to the salicylic acid (SA) biosynthesis pathway and increases in the auxin [indole-3-acetic acid (IAA)] biosynthesis pathway. SA and IAA are hormones known to control stress and defense responses as well as plant growth. We found that IAA-targeted gene activity is frequently increased in hybrids, correlating with a common heterotic phenotype of greater leaf cell numbers. Reduced SA concentration and target gene responses occur in the larger hybrids and promote increased leaf cell size. We demonstrated the importance of SA action to the hybrid phenotype by manipulating endogenous SA concentrations. Increasing SA diminished heterosis in SA-reduced hybrids, whereas decreasing SA promoted growth in some hybrids and phenocopied aspects of hybrid vigor in parental lines. Pseudomonas syringae infection of hybrids demonstrated that the reductions in basal defense gene activity in these hybrids does not necessarily compromise their ability to mount a defense response comparable to the parents.

  15. The effects of age, sex, and hormones on emotional conflict-related brain response during adolescence.

    PubMed

    Cservenka, Anita; Stroup, Madison L; Etkin, Amit; Nagel, Bonnie J

    2015-10-01

    While cognitive and emotional systems both undergo development during adolescence, few studies have explored top-down inhibitory control brain activity in the context of affective processing, critical to informing adolescent psychopathology. In this study, we used functional magnetic resonance imaging to examine brain response during an Emotional Conflict (EmC) Task across 10-15-year-old youth. During the EmC Task, participants indicated the emotion of facial expressions, while disregarding emotion-congruent and incongruent words printed across the faces. We examined the relationships of age, sex, and gonadal hormones with brain activity on Incongruent vs. Congruent trials. Age was negatively associated with middle frontal gyrus activity, controlling for performance and movement confounds. Sex differences were present in occipital and parietal cortices, and were driven by activation in females, and deactivation in males to Congruent trials. Testosterone was negatively related with frontal and striatal brain response in males, and cerebellar and precuneus response in females. Estradiol was negatively related with fronto-cerebellar, cingulate, and precuneus brain activity in males, and positively related with occipital response in females. To our knowledge, this is the first study reporting the effects of age, sex, and sex steroids during an emotion-cognition task in adolescents. Further research is needed to examine longitudinal development of emotion-cognition interactions and deviations in psychiatric disorders in adolescence.

  16. Growth hormone response to the GABA-B agonist baclofen in 3-week abstinent alcoholics.

    PubMed

    Ozsoy, Saliha; Esel, Ertugrul; Turan, Tayfun; Kula, Mustafa

    2007-12-01

    Gamma-aminobutyric acid (GABA) dysfunction is a known feature of alcoholism. We investigated GABA-B receptor activity in 3-week abstinent alcoholics using the growth hormone (GH) response to baclofen, a GABA-B receptor agonist. The study aimed to investigate the relationship between GABA-B receptor activity and alcohol withdrawal. GH response to baclofen was measured in alcohol-dependent males without depression (n = 22) who were on day 21 of alcohol abstinence and in healthy control male subjects (n = 23). After 20mg baclofen was given orally to the subjects, blood samples for GH assay were obtained every 30 min for the subsequent 150 min. The patients were divided into two subgroups (continuing withdrawal and recovered withdrawal subgroups) according to their withdrawal symptom severity scores on day 21 of alcohol cessation. Baclofen administration significantly altered GH secretion in the controls, but not in the patients. When GH response to baclofen was assessed as DeltaGH, it was lower in the patients with continuing withdrawal symptoms than in the controls and in the recovered withdrawal group. Impaired GH response to baclofen in all patients mainly pertained to the patients whose withdrawal symptoms partly continued. Our results suggest that reduced GABA-B receptor activity might be associated with longer-term alcohol withdrawal symptoms in alcoholic patients.

  17. Validating genetic markers of response to recombinant human growth hormone in children with growth hormone deficiency and Turner syndrome: the PREDICT validation study

    PubMed Central

    Stevens, Adam; Murray, Philip; Wojcik, Jerome; Raelson, John; Koledova, Ekaterina; Chatelain, Pierre

    2016-01-01

    Objective Single-nucleotide polymorphisms (SNPs) associated with the response to recombinant human growth hormone (r-hGH) have previously been identified in growth hormone deficiency (GHD) and Turner syndrome (TS) children in the PREDICT long-term follow-up (LTFU) study (Nbib699855). Here, we describe the PREDICT validation (VAL) study (Nbib1419249), which aimed to confirm these genetic associations. Design and methods Children with GHD (n = 293) or TS (n = 132) were recruited retrospectively from 29 sites in nine countries. All children had completed 1 year of r-hGH therapy. 48 SNPs previously identified as associated with first year growth response to r-hGH were genotyped. Regression analysis was used to assess the association between genotype and growth response using clinical/auxological variables as covariates. Further analysis was undertaken using random forest classification. Results The children were younger, and the growth response was higher in VAL study. Direct genotype analysis did not replicate what was found in the LTFU study. However, using exploratory regression models with covariates, a consistent relationship with growth response in both VAL and LTFU was shown for four genes – SOS1 and INPPL1 in GHD and ESR1 and PTPN1 in TS. The random forest analysis demonstrated that only clinical covariates were important in the prediction of growth response in mild GHD (>4 to <10 μg/L on GH stimulation test), however, in severe GHD (≤4 μg/L) several SNPs contributed (in IGF2, GRB10, FOS, IGFBP3 and GHRHR). Conclusions The PREDICT validation study supports, in an independent cohort, the association of four of 48 genetic markers with growth response to r-hGH treatment in both pre-pubertal GHD and TS children after controlling for clinical/auxological covariates. However, the contribution of these SNPs in a prediction model of first-year response is not sufficient for routine clinical use. PMID:27651465

  18. Selected hormonal and immunological responses to strenuous live-fire firefighting drills.

    PubMed

    Smith, D L; Petruzzello, S J; Chludzinski, M A; Reed, J J; Woods, J A

    2005-01-01

    This study investigated the effects of strenuous live-fire firefighting drills and a 90 min recovery period on selected hormonal, immunological and psychological variables. Apparently healthy, male, professional firefighters (n = 11) performed three trials of standardized firefighting tasks in a live-fire training structure. There was significant leukocytosis immediately post firefighting activity that persisted following recovery, although there was a variable response among the leukocyte subsets. Most notable was the decrease in number and percentage of lymphocytes following 90 min of recovery. Plasma levels of ACTH and cortisol were significantly elevated post firefighting activity and cortisol remained elevated following 90 min of recovery. Elevated cortisol immediately following activity was related to reduced feelings of energy. These data demonstrate the magnitude of the physiological and psychological disruption following strenuous firefighting activity and suggest that immune function may be altered following such activity. This is a finding that may have practical consequences for this group of first responders.

  19. Effects of tributyltin (TBT) on in vitro hormonal and biotransformation responses in Atlantic salmon (Salmo salar).

    PubMed

    Mortensen, Anne S; Arukwe, Augustine

    2009-01-01

    The mechanisms by which the biocide tributyltin (TBT) and its metabolites affect the hormonal and xenobiotic biotransformation pathways in aquatic species are not well understood. In this study hepatocytes isolated from salmon were used to evaluate the mechanistical effects of TBT on fish hormonal and xenobiotic biotransformation pathways. Cells were exposed to 0.01, 0.1, 1, or 5 microM TBT and samples were collected at 0, 12, 24, or 48 h following exposure. Gene expression patterns were evaluated using quantitative polymerase chain reaction (PCR), and cytochrome P-450 (CYP)-mediated enzyme activities were evaluated by ethoxyresorufin, benzyloxyresorufin, and pentoxyresorufin O-deethylase (EROD, BROD, and PROD, respectively) activity assays. Generally, exposure of hepatocytes to 1 microM (at 48 h) and 5 microM TBT (at 12, 24, and 48 h) consistently produced reductions in all mRNA species investigated. TBT produced significant decreases of vitellogen (Vtg) expression at 48 h and modified the expression patterns of estrogen receptors (ERalpha and ERbeta) and androgen receptor-beta (ARbeta) that were dependent on time and TBT concentration. In the xenobiotic biotransformation pathway, TBT produced differential expression patterns that were dependent on exposure time and concentration for all salmonid AhR2 isoforms (AhR2alpha, AhR2beta, AhR2delta, and AhR2gamma). For CYP1A1, CYP3A, AhRR, and Arnt mRNA, TBT produced exposure- and time-specific modulations. Catalytic CYP activities showed that BROD activity increased in an apparent concentration-specific manner in cells exposed to TBT for 12 h. Interestingly, EROD activity showed a TBT concentration-dependent increase at 24 h and PROD at 12 and 48 h of exposure. In general our data show that TBT differentially modulated hormonal and biotransformation responses in the salmon in vitro system. The apparent and consistent decrease of the studied responses with time in 1 and 5 microM exposed hepatocytes suggest a possible

  20. Metabolic and hormonal responses during exercise at 20°, 0° and -20°C

    NASA Astrophysics Data System (ADS)

    Quirion, A.; Laurencelle, L.; Paulin, L.; Therminarias, A.; Brisson, G. R.; Audet, A.; Dulac, S.; Vogelaere, P.

    1989-12-01

    This study was designed to clarify the effects of cold air exposure on metabolic and hormonal responses during progressive incremental exercise. Eight healthy males volunteered for the study. Informed consent was obtained from every participant. The following protocol was administered to each subject on three occasions in a climatic chamber in which the temperature was 20°, 0° or -20°C with relative humidity at 60%±1%. Exercise tests were conducted on an electrically braked ergocycle, and consisted of a propressive incremental maximal exercise. Respiratory parameters were continuously monitored by an automated open-circuit sampling system Exercise blood lactate (LA), free fatty acids (FFA), glucose levels, bicarbonate concentration (HCO{3/-}), acidbase balance, plasma epinephrine (E) and norepinephrine (NE) were determined from venous blood samples obtained through an indwelling brachial catheter. Maximal oxygen uptake was significantly different between conditions: 72.0±5.4 ml kg-1 min-1 at 20°C; 68.9±5.1 ml kg-1 min-1 at 0°C and 68.5±4.6 ml kg-1 min-1 at -20°C. Workload, time to exhaustion, glucose levels and rectal Catecholamines and lactate values were not significantly altered by thermal conditions after maximal exercise but the catecholamines were decreased during rest. Bicarbonate, respiratory quotient, lactate and ventilatory thresholds increased significantly at -20°C. The data support the contention that metabolic and hormonal responses following progressive incremental exercise are altered by cold exposure and they indicate a marked decrease in maximal oxygen uptake, time to exhaustion and workload.

  1. Favorable Growth Hormone Treatment Response in a Young Boy with Achondroplasia

    PubMed Central

    Krstevska-Konstantinova, Marina; Stamatova, Ana; Gucev, Zoran

    2016-01-01

    Background: Achondroplasia is a skeletal dysplasia, the most common cause of rhizomelic dwarfism. Case presentation: This is a ten year old boy who was first diagnosed prenatally. He had a mutation c1138G>A in the gene FGFR3 in a heterozygotic constellation. His IGF1 and IGFBP3 levels were normal. Two stimulation tests for growth hormone were performed with values within the reference range. His psychomotor development was adequate for his age except for speech difficulty. He started with recombinant hGH (r-hGH) at the age of 3.4 years in a dose of 0.06 mg/kg. His mean Height SDS (HtSDS) was -2.2. Results: The growth increased to 10 cm/year in the first year of therapy (HtSDS -1.1). It decreased during the second year to 4 cm (HtSDS -1.7) and again increased during the third year to 8 cm/year (HtSDS–1.3). In the next years the growth was constant (6.5, 2.3, 3.5 cm / year). He is still growing in the 3rd percentile of the growth curve (HtSDS – 1.2) under GH treatment. The body disproportion remained the same. Conclusion: The growth response on GH treatment was satisfactory in the first 4 years of treatment, and the boy still continued to grow. The young age at the start of treatment was also of importance. Our other patients with achondroplasia who started treatment older had a poor response to growth hormone. PMID:27147792

  2. Induction of a rapidly responsive hepatic gene product by thyroid hormone requires ongoing protein synthesis.

    PubMed Central

    Jacoby, D B; Engle, J A; Towle, H C

    1987-01-01

    The regulation of a gene, designated spot 14, which is rapidly induced in rat liver in response to 3,5,3'-triiodo-L-thyronine (T3) was studied as a model for exploring the molecular basis of thyroid hormone action. The time course of induction of the nuclear precursor to spot 14 mRNA after intramuscular injection of T3 displayed a very short lag period of between 10 and 20 min. The rapidity of this effect suggests that the induction in gene expression occurs as a primary response to the hormone-receptor interaction. The protein synthesis inhibitor cycloheximide injected 15 min before T3 completely blocked the accumulation of nuclear precursor RNA 30 min after T3 treatment. Emetine, an inhibitor of protein synthesis which acts by a different mechanism than cycloheximide, also blocked the induction of the spot 14 nuclear precursor RNA. The increased rate of spot 14 gene transcription observed after T3 treatment, as measured by nuclear run-on assay, was similarly completely abolished in the presence of cycloheximide. In addition, ongoing protein synthesis was required for maintaining spot 14 nuclear precursor RNA at induced levels in animals previously treated with T3. On the other hand, cycloheximide had no effect on T3 uptake or binding to the nuclear receptor during the 45-min time frame studied. The paradox of the rapid kinetics of induction and the requirement of ongoing protein synthesis may be explained by a protein with an extremely short half-life which is necessary for T3 induction of the spot 14 gene. PMID:3648478

  3. Biphasic hormonal responses to the adrenocorticolytic DDT metabolite 3-methylsulfonyl-DDE in human cells

    SciTech Connect

    Asp, Vendela; Ulleras, Erik; Lindstroem, Veronica; Bergstroem, Ulrika; Oskarsson, Agneta; Brandt, Ingvar

    2010-02-01

    The DDT metabolite 3-methylsulfonyl-DDE (3-MeSO{sub 2}-DDE) has been proposed as a lead compound for an improved adrenocortical carcinoma (ACC) treatment. ACC is a rare malignant disorder with poor prognosis, and the current pharmacological therapy o,p'-DDD (mitotane) has limited efficacy and causes severe adverse effects. 3-MeSO{sub 2}-DDE is bioactivated by cytochrome P450 (CYP) 11B1 in mice and causes formation of irreversibly bound protein adducts, reduced glucocorticoid secretion, and cell death in the adrenal cortex of several animal species. The present study was carried out to assess similarities and differences between mice and humans concerning the adrenocorticolytic effects of 3-MeSO{sub 2}-DDE. The results support previous indications that humans are sensitive to the adrenocorticolytic actions of 3-MeSO{sub 2}-DDE by demonstrating protein adduct formation and cytotoxicity in the human adrenocortical cell line H295R. However, neither the irreversible binding nor the cytotoxicity of 3-MeSO{sub 2}-DDE in H295R cells was inhibited by the CYP11B1 inhibitor etomidate. We also report biphasic responses to 3-MeSO{sub 2}-DDE in cortisol and aldosterone secretion as well as in mRNA levels of the steroidogenic genes StAR, CYP11B1 and CYP11B2. Hormone levels and mRNA levels were increased at lower concentrations of 3-MeSO{sub 2}-DDE, while higher concentrations decreased hormone levels. These biphasic responses were not observed with o,p'-DDD or with the precursor DDT metabolite p,p'-DDE. Based on these results, 3-MeSO{sub 2}-DDE remains a viable lead compound for drug design, although the adrenocorticolytic effects of 3-MeSO{sub 2}-DDE in human cells seem more complex than in murine cells.

  4. Leptin modulates β cell expression of IL-1 receptor antagonist and release of IL-1β in human islets

    PubMed Central

    Maedler, Kathrin; Sergeev, Pavel; Ehses, Jan A.; Mathe, Zoltan; Bosco, Domenico; Berney, Thierry; Dayer, Jean-Michel; Reinecke, Manfred; Halban, Philippe A.; Donath, Marc Y.

    2004-01-01

    High concentrations of glucose induce β cell production of IL-1β, leading to impaired β cell function and apoptosis in human pancreatic islets. IL-1 receptor antagonist (IL-1Ra) is a naturally occurring antagonist of IL-1β and protects cultured human islets from glucotoxicity. Therefore, the balance of IL-1β and IL-1Ra may play a crucial role in the pathogenesis of diabetes. In the present study, we observed expression of IL-1Ra in human pancreatic β cells of nondiabetic individuals, which was decreased in tissue sections of type 2 diabetic patients. In vitro, chronic exposure of human islets to leptin, a hormone secreted by adipocytes, decreased β cell production of IL-1Ra and induced IL-1β release from the islet preparation, leading to impaired β cell function, caspase-3 activation, and apoptosis. Exogenous addition of IL-1Ra protected cultured human islets from the deleterious effects of leptin. Antagonizing IL-1Ra by introduction of small interfering RNA to IL-1Ra into human islets led to caspase-3 activation, DNA fragmentation, and impaired β cell function. Moreover, siIL-1Ra enhanced glucose-induced β cell apoptosis. These findings demonstrate expression of IL-1Ra in the human β cell, providing localized protection against leptin- and glucose-induced islet IL-1β. PMID:15141093

  5. The role of endothelial cells on islet function and revascularization after islet transplantation

    PubMed Central

    Del Toro-Arreola, Alicia; Robles-Murillo, Ana Karina; Daneri-Navarro, Adrian; Rivas-Carrillo, Jorge David

    2016-01-01

    ABSTRACT Islet transplantation has become a widely accepted therapeutic option for selected patients with type 1 diabetes mellitus. However, in order to achieve insulin independence a great number of islets are often pooled from 2 to 4 pancreata donors. Mostly, it is due to the massive loss of islets immediately after transplant. The endothelium plays a key role in the function of native islets and during the revascularization process after islet transplantation. However, if a delayed revascularization occurs, even the remaining islets will also undergo to cell death and late graft dysfunction. Therefore, it is essential to understand how the signals are released from endothelial cells, which might regulate both differentiation of pancreatic progenitors and thereby maintenance of the graft function. New strategies to facilitate islet engraftment and a prompt revascularization could be designed to intervene and might lead to improve future results of islet transplantation. PMID:27002241

  6. Potentiation of Hormonal Responses to Hemorrhage and Fasting, but not Hypoglycemia in Conscious Adrenalectomized Rats

    NASA Technical Reports Server (NTRS)

    Darlington, Daniel N.; Keil, Lanny C.; Dallman, Mary F.

    1989-01-01

    Bilateral adrenalectomy (ADRX) in rats removes the source of two major stress-responsive hormones, corticosterone and epinephrine. To test how ADRX rats with-stand stress, we performed the following experiments in adult male rats provided with indwelling femoral arterial and venous cannulae and either ADRX or sham-adrenalectomized (Sham) 3 days later and given 0.5% NaCl to drink. Five to 6 days after adrenal surgery the rats were studied after either a 15 ml/kg.5 min hemorrhage or after an overnight fast followed by insulin-induced hypoglycemia. In fed unstressed ADRX rats, basal mean arterial blood pressure was slightly decreased; heart rate was increased; blood volume, vasopressin, and oxytocin concentrations were not different from sham values; and renin and norepinephrine were significantly elevated. The recovery of arterial pressure after hemorrhage in the ADRX rats was similar to that in the sham group over a 5-h period; however, the responses of vasopressin and oxytocin were significantly greater, and those of renin and norepinephrine were markedly potentiated in the ADRX group. Heart rate recovered faster in the ADRX group and was elevated, compared to the sham value, for most of the 5-h period. Restitution of blood volume was attenuated in the ADRX group, although the restitution of plasma protein was not different between the groups. A significant difference in the change in plasma osmolality between groups after hemorrhage may account for the attenuated restitution of blood volume. After an overnight fast, which reduced blood volume in both groups of rats, the plasma renin concentration rose still further in ADRX rats; the differences in other measured variables observed between fed ADRX and sham groups remained the same. The insulin-induced 50% decrease in glucose caused minor effects on arterial blood pressure and heart rate and occasioned responses in renin and norepinephrine of similar magnitudes in the two groups. We conclude that in the absence of

  7. Nmp4/CIZ suppresses the response of bone to anabolic parathyroid hormone by regulating both osteoblasts and osteoclasts

    PubMed Central

    Childress, Paul; Philip, Binu K.; Robling, Alexander G.; Bruzzaniti, Angela; Kacena, Melissa A.; Bivi, Nicoletta; Plotkin, Lilian I.; Heller, Aaron; Bidwell, Joseph P.

    2011-01-01

    How parathyroid hormone (PTH) increases bone mass is unclear but understanding this phenomenon is significant to the improvement of osteoporosis therapy. Nmp4/CIZ is a nucleocytoplasmic shuttling transcriptional repressor that suppresses PTH-induced osteoblast gene expression and hormone-stimulated gains in murine femoral trabecular bone. To further characterize Nmp4/CIZ suppression of hormone-mediated bone growth we treated 10 wk-old Nmp4-knockout (KO) and wild-type (WT) mice with intermittent human PTH (1-34) at 30μg/kg/day or vehicle, 7 days/wk, for 2, 3, or 7 wks. Null mice treated with hormone (7 wks) gained more vertebral and tibial cancellous bone than WT animals paralleling the exaggerated response in the femur. Interestingly, Nmp4/CIZ suppression of this hormone-stimulated bone formation was not apparent during the first 2 wks of treatment. Consistent with the null mice enhanced PTH-stimulated addition of trabecular bone these animals exhibited an augmented hormone-induced increase in serum osteocalcin 3 wks into treatment. Unexpectedly the Nmp4-KO mice displayed an osteoclast phenotype. Serum C-terminal telopeptides, a marker for bone resorption, was elevated in the null mice, irrespective of treatment. Nmp4-KO bone marrow cultures produced more osteoclasts, which exhibited an elevated resorbing activity, compared to WT cultures. The expression of several genes critical to the development of both osteoblasts and osteoclasts were elevated in Nmp4-KO mice at 2 wks but not 3 wks of hormone exposure. We propose that Nmp4/CIZ dampens PTH-induced improvement of trabecular bone throughout the skeleton by transiently suppressing hormone-stimulated increases in the expression of proteins key to the required enhanced activity/number of both osteoblasts and osteoclasts. PMID:21607813

  8. Microbiome, sex hormones, and immune responses in the reproductive tract: challenges for vaccine development against sexually transmitted infections.

    PubMed

    Brotman, Rebecca M; Ravel, Jacques; Bavoil, Patrik M; Gravitt, Patti E; Ghanem, Khalil G

    2014-03-20

    The female and male reproductive tracts are complex eco-systems where immune cells, hormones, and microorganisms interact. The characteristics of the reproductive tract mucosa are distinct from other mucosal sites. Reproductive tract mucosal immune responses are compartmentalized, unique, and affected by resident bacterial communities and sex hormones. The female and male genital microbiomes are complex environments that fluctuate in response to external and host-associated stimuli. The female vaginal microbiota play an important role in preventing colonization by pathogenic organisms. Sex hormones and their duration of exposure affect the composition and stability of the microbiome as well as systemic and mucosal immune responses. In addition to the characteristics of the pathogen they are targeting, successful vaccines against sexually transmitted pathogens must take into account the differences between the systemic and mucosal immune responses, the compartmentalization of the mucosal immune responses, the unique characteristics of the reproductive tract mucosa, the role of the mucosal bacterial communities, the impact of sex hormones, and the interactions among all of these factors.

  9. A Simple Method to Replace Islet Equivalents for Volume Quantification of Human Islets.

    PubMed

    Ramachandran, Karthik; Huang, Han-Hung; Stehno-Bittel, Lisa

    2015-01-01

    Human islets come in a variety of sizes and shapes, and the total volume of islets used for research or clinical transplants must be estimated in a manner that is simple and valid. Islet equivalent (IEQ) measurements are the standard estimate of islet volume. We published a new method (the Kansas method) for estimating rat islet volume using cell numbers that was reliable and valid. Here we modified the method for human islets. We measured the dimensions of isolated human islets showing that they are not spherical and became less so in larger islets, with an average smallest/largest diameter ratio of 0.73 in large islets and 0.85 in small islets. Human islets were individually loaded into 96-well plates, dissociated into single cells, and the total cell number per islet determined with computer-assisted cytometry. Based on the counted cell number per islet, a regression model was created to convert islet diameter to cell number with a high R(2) value (0.99). Separate regression equations for male and female donors or young and old donors were not significantly different than the pooled data and did not improve the regression values. There was an inverse correlation between the cell number per IEQ and islet size. The Kansas method was validated with ATP/cell and cell viability data. Compared to the actual cell count, conventional IEQ measurements overestimated tissue volume of large islets by nearly double. Examples of differences in results obtained from the same data sets normalized to IEQ or the Kansas method included viability and insulin secretion concentrations. The implications of the error associated with the current IEQ method of volume estimation are discussed.

  10. OB-Rb gene transfer to leptin-resistant islets reverses diabetogenic phenotype

    PubMed Central

    Wang, May-Yun; Koyama, Kazunori; Shimabukuro, Michio; Newgard, Christopher B.; Unger, Roger H.

    1998-01-01

    In obese Zucker diabetic fatty (ZDF) rats with mutant leptin receptors, pancreatic islets have an ≈50-fold increase in fat (TG), overproduce nitric oxide (NO), and lack a normal proinsulin mRNA response to fatty acids. We overexpressed the wild-type full-length “b” isoform of the leptin receptor (OB-Rb) in ZDF islets by perfusing ZDF pancreata with recombinant adenovirus containing the cDNA encoding OB-Rb. In cultured islets isolated from these animals, leptin lowered islet TG by 87% and completely blocked TG formation from free fatty acids. Overproduction of NO was reduced, and the preproinsulin mRNA response to free fatty acids was restored. This establishes defective leptin action as the proximate cause of lipotoxic diabetes in ZDF rats. PMID:9435258

  11. Histidine kinases in plants: cross talk between hormone and stress responses.

    PubMed

    Nongpiur, Ramsong; Soni, Praveen; Karan, Ratna; Singla-Pareek, Sneh L; Pareek, Ashwani

    2012-10-01

    Two-component signaling pathways involve sensory histidine kinases (HK), histidine phosphotransfer proteins (HpT) and response regulators (RR). Recent advancements in genome sequencing projects for a number of plant species have established the TCS family to be multigenic one. In plants, HKs operate through the His-Asp phosphorelay and control many physiological and developmental processes throughout the lifecycle of plants. Despite the huge diversity reported for the structural features of the HKs, their functional redundancy has also been reported via mutant approach. Several sensory HKs having a CHASE domain, transmembrane domain(s), transmitter domain and receiver domain have been reported to be involved in cytokinin and ethylene signaling. On the other hand, there are also increasing evidences for some of the sensory HKs to be performing their role as osmosensor, clearly indicating toward a possible cross-talk between hormone and stress responsive cascades. In this review, we bring out the latest knowledge about the structure and functions of histidine kinases in cytokinin and ethylene signaling and their role(s) in development and the regulation of environmental stress responses.

  12. Hormonal contraceptives suppress oxytocin-induced brain reward responses to the partner's face.

    PubMed

    Scheele, Dirk; Plota, Jessica; Stoffel-Wagner, Birgit; Maier, Wolfgang; Hurlemann, René

    2016-05-01

    The hypothalamic peptide oxytocin (OXT) has been identified as a key modulator of pair-bonding in men, but its effects in women are still elusive. Moreover, there is substantial evidence that hormonal contraception (HC) influences partner preferences and sexual satisfaction, which constitute core domains of OXT function. We thus hypothesized that OXT effects on partner-related behavioral and neural responses could be significantly altered in women using HC. In this functional magnetic resonance imaging study involving 40 pair-bonded women, 21 of whom were using HC, we investigated whether a 24-IU nasal dose of OXT would modulate brain reward responses evoked by the romantic partner's face relative to the faces of familiar and unfamiliar people. Treatment with OXT increased the perceived attractiveness of the partner relative to other men, which was paralleled by elevated responses in reward-associated regions, including the nucleus accumbens. These effects of OXT were absent in women using HC. Our results confirm and extend previous findings in men that OXT interacts with the brain reward system to reinforce partner value representations, indicating a common OXT-dependent mechanism underlying partner attraction in both sexes. This mechanism may be disturbed in women using HC, suggesting that gonadal steroids could alter partner-specific OXT effects.

  13. Plant responses to insect herbivory: interactions between photosynthesis, reactive oxygen species and hormonal signalling pathways.

    PubMed

    Kerchev, Pavel I; Fenton, Brian; Foyer, Christine H; Hancock, Robert D

    2012-02-01

    Under herbivore attack plants mount a defence response characterized by the accumulation of secondary metabolites and inhibitory proteins. Significant changes are observed in the transcriptional profiles of genes encoding enzymes of primary metabolism. Such changes have often been interpreted in terms of a requirement for an increased investment of resources to 'fuel' the synthesis of secondary metabolites. While enhanced secondary metabolism undoubtedly exerts an influence on primary metabolism, accumulating evidence suggests that rather than stimulating photosynthesis insect herbivory reduces photosynthetic carbon fixation and this response occurs by a re-programming of gene expression. Within this context, reactive oxygen species (ROS) and reductant/oxidant (redox) signalling play a central role. Accumulating evidence suggests that ROS signalling pathways are closely interwoven with hormone-signalling pathways in plant-insect interactions. Here we consider how insect infestation impacts on the stress signalling network through effects on ROS and cellular redox metabolism with particular emphasis on the roles of ROS in the plant responses to phloem-feeding insects.

  14. Bovine growth hormone gene polymorphism affects stress response in Japanese Black cattle.

    PubMed

    Tachi, Noriko; Tanaka, Sigefumi; Ardiyanti, Astrid; Katoh, Kazuo; Sato, Shusuke

    2014-06-01

    We investigate the associations between growth hormone (GH) gene polymorphism and behavioral and physiological responses to stressors and learning ability in Japanese Black cattle. Flight distance test was conducted in the first experiment. Steers with haplotype C of GH gene polymorphism avoided human approaches at a significantly greater distance than ones without haplotype C (C: 1.9 ± 0.9, non-C: 1.0 ± 0.2 m, P < 0.05). An open-field test was conducted in the second experiment. Behavioral responses did not differ significantly between steers with and without haplotype C. Increases of heart rates to dropping of iron pipes was significantly higher in steers with haplotype C (C:161.7 ± 21.8, non-C:130.7 ± 31.3%, P < 0.05). Despite basal serum concentrations not being different between steers with and without haplotype C, serum cortisol in blood sampling immediately after severe confinement in a race tended to be higher in steers with haplotype C (P = 0.1). The maze test was conducted as the third experiment. There was no difference in performance in the maze test between steers with and without haplotype C. It is concluded that genetic polymorphism of GH may affect stress responses through GH concentration in steers.

  15. Endothelial Cells Derived from the Blood-Brain Barrier and Islets of Langerhans Differ in their Response to the Effects of Bilirubin on Oxidative Stress Under Hyperglycemic Conditions.

    PubMed

    Kapitulnik, Jaime; Benaim, Clara; Sasson, Shlomo

    2012-01-01

    Unconjugated bilirubin (UCB) is a neurotoxic degradation product of heme. Its toxic effects include induction of apoptosis, and ultimately neuronal cell death. However, at low concentrations, UCB is a potent antioxidant that may protect cells and tissues against oxidative stress by neutralizing toxic metabolites such as reactive oxygen species (ROS). High glucose levels (hyperglycemia) generate reactive metabolites. Endothelial cell dysfunction, an early vascular complication in diabetes, has been associated with hyperglycemia-induced oxidative stress. Both glucose and UCB are substrates for transport proteins in microvascular endothelial cells of the blood-brain barrier (BBB). In the current study we show that UCB (1-40 μM) induces apoptosis and reduces survival of bEnd3 cells, a mouse brain endothelial cell line which serves as an in vitro model of the BBB. These deleterious effects of UCB were enhanced in the presence of high glucose (25 mM) levels. Interestingly, the bEnd3 cells exhibited an increased sensitivity to the apoptotic effects of UCB when compared to the MS1 microcapillary endothelial cell line. MS1 cells originate from murine pancreatic islets of Langerhans, and are devoid of the barrier characteristics of BBB-derived endothelial cells. ROS production was increased in both bEnd3 and MS1 cells exposed to high glucose, as compared with cells exposed to normal (5.5 mM) glucose levels. While UCB (0.1-40 μM) did not alter ROS production in cells exposed to normal glucose, relatively low ("physiological") UCB concentrations (0.1-5 μM) attenuated ROS generation in both cell lines exposed to high glucose levels. Most strikingly, higher UCB concentrations (20-40 μM) increased ROS generation in bEnd3 cells exposed to high glucose, but not in similarly treated MS1 cells. These results may be of critical importance for understanding the vulnerability of the BBB endothelium upon exposure to increasing UCB levels under hyperglycemic conditions.

  16. Basic fibroblast growth factor priming increases the responsiveness of immortalized hypothalamic luteinizing hormone releasing hormone neurones to neurotrophic factors.

    PubMed

    Gallo, F; Morale, M C; Tirolo, C; Testa, N; Farinella, Z; Avola, R; Beaudet, A; Marchetti, B

    2000-10-01

    The participation of growth factors (GFs) in the regulation of luteinizing hormone releasing hormone (LHRH) neuronal function has recently been proposed, but little is known about the role played by GFs during early LHRH neurone differentiation. In the present study, we have used combined biochemical and morphological approaches to study the ability of a number of GFs normally expressed during brain development, including basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), insulin and insulin-like growth factor I (IGF-I) to induce survival, differentiation, proliferation, and phenotypic expression of immortalized (GT1-1) LHRH neurones in vitro, at early (3-days in vitro, 3-DIV) and late (8-DIV) stages of neuronal differentiation. Comparison of GF-treated vs untreated neurones grown in serum-deprived (SD) medium demonstrated bFGF to be the most potent, and insulin the least active in promoting neuronal differentiation. Thus, at both 3-DIV and 8-DIV, but especially at 8-DIV, bFGF induced the greatest increase in the total length and number of LHRH processes/cell and in growth cone surface area. bFGF was also the most active at 3-DIV, and IGF-I at 8-DIV, in counteracting SD-induced cell death, whereas EGF was the most potent in increasing [3H]thymidine incorporation. All GFs studied decreased the spontaneous release of LHRH from GT1-1 cells when applied at 3-DIV or 8-DIV, except for insulin which was inactive at both time-points and bFGF which was inactive at 8-DIV. Pre-treatment of GT1-1 cells with a suboptimal ('priming') dose of bFGF for 12 h followed by application of the different GFs induced a sharp potentiation of the neurotrophic and proliferative effects of the latter and particularly of those of IGF-I. Moreover, bFGF priming counteracted EGF-induced decrease in LHRH release and significantly stimulated LHRH secretion following IGF-I or insulin application, suggesting that bFGF may sensitize LHRH neurones to differentiating effects of

  17. Pancreas preservation for pancreas and islet transplantation

    PubMed Central

    Iwanaga, Yasuhiro; Sutherland, David E.R.; Harmon, James V.; Papas, Klearchos K.

    2010-01-01

    Purpose of review To summarize advances and limitations in pancreas procurement and preservation for pancreas and islet transplantation, and review advances in islet protection and preservation. Recent findings Pancreases procured after cardiac death, with in-situ regional organ cooling, have been successfully used for islet transplantation. Colloid-free Celsior and histidine-tryptophan-ketoglutarate preservation solutions are comparable to University of Wisconsin solution when used for cold storage before pancreas transplantation. Colloid-free preservation solutions are inferior to University of Wisconsin solution for pancreas preservation prior to islet isolation and transplantation. Clinical reports on pancreas and islet transplants suggest that the two-layer method may not offer significant benefits over cold storage with the University of Wisconsin solution: improved oxygenation may depend on the graft size; benefits in experimental models may not translate to human organs. Improvements in islet yield and quality occurred from pancreases treated with inhibitors of stress-induced apoptosis during procurement, storage, isolation or culture. Pancreas perfusion may be desirable before islet isolation and transplantation and may improve islet yields and quality. Methods for real-time, noninvasive assessment of pancreas quality during preservation have been implemented and objective islet potency assays have been developed and validated. These innovations should contribute to objective evaluation and establishment of improved pancreas preservation and islet isolation strategies. Summary Cold storage may be adequate for preservation before pancreas transplants, but insufficient when pancreases are processed for islets or when expanded donors are used. Supplementation of cold storage solutions with cytoprotective agents and perfusion may improve pancreas and islet transplant outcomes. PMID:18685343

  18. Storage and microencapsulation of islets for transplantation.

    PubMed

    Charles, K; Harland, R C; Ching, D; Opara, E C

    2000-01-01

    Microencapsulation is an effective means of immunoisolation for pancreatic islet transplants. However, the process of isolating, purifying, encapsulating, and transplanting islets in a single day is labor intensive and difficult for routine use. There is an apparent need for reliable methods of islet storage, and cryopreservation has emerged as an attractive system of islet banking. While studies have shown that cryopreserved islets are viable when tested unencapsulated after thawing, it is not clear if the combination of freezing and encapsulation would affect islet function. The purpose of the present study was to determine the in vitro function of cryopreserved islets following thawing and microencapsulation. Islets were isolated from the pancreata of Sprague-Dawley rats and cryopreserved under liquid nitrogen for either 1 week or 1 month, following an overnight culture at 37 degrees C. Upon thawing, the islets were tested either unencapsulated or after encapsulation in polylysine-alginate membrane. In all experiments islets were preperifused for 1 h at 37 degrees C with a modified Krebs-Ringer bicarbonate buffer containing 3.3 mM (60 mg/dl) glucose and maintained at pH 7.4 by continuous gassing with 95% air/5% CO2. Following basal effluent sample collection on ice, the glucose concentration was raised to 16.7 mM (300 mg/dl). It was found that, within 10 min of high glucose stimulation, an average of twofold increase in insulin secretion (p < 0.01) was obtained in islets within or without microcapsules. We conclude that islets cryopreserved for 1 month prior to thawing and microencapsulation retained functional viability as determined in in vitro experiments.

  19. Bed rest suppresses bioassayable growth hormone release in response to muscle activity

    NASA Technical Reports Server (NTRS)

    McCall, G. E.; Goulet, C.; Grindeland, R. E.; Hodgson, J. A.; Bigbee, A. J.; Edgerton, V. R.

    1997-01-01

    Hormonal responses to muscle activity were studied in eight men before (-13 or -12 and -8 or -7 days), during (2 or 3, 8 or 9, and 13 or 14 days) and after (+2 or +3 and +10 or +11 days) 17 days of bed rest. Muscle activity consisted of a series of unilateral isometric plantar flexions, including 4 maximal voluntary contractions (MVCs), 48 contractions at 30% MVC, and 12 contractions at 80% MVC, all performed at a 4:1-s work-to-rest ratio. Blood was collected before and immediately after muscle activity to measure plasma growth hormone by radioimmunoassay (IGH) and by bioassay (BGH) of tibia epiphyseal cartilage growth in hypophysectomized rats. Plasma IGH was unchanged by muscle activity before, during, or after bed rest. Before bed rest, muscle activity increased (P < 0.05) BGH by 66% at -13 or -12 days (2,146 +/- 192 to 3,565 +/- 197 microg/l) and by 92% at -8 or -7 days (2,162 +/- 159 to 4,161 +/- 204 microg/l). After 2 or 3 days of bed rest, there was no response of BGH to the muscle activity, a pattern that persisted through 8 or 9 days of bed rest. However, after 13 or 14 days of bed rest, plasma concentration of BGH was significantly lower after than before muscle activity (2,594 +/- 211 to 2,085 +/- 109 microg/l). After completion of bed rest, muscle activity increased BGH by 31% at 2 or 3 days (1,807 +/- 117 to 2,379 +/- 473 microg/l; P < 0.05), and by 10 or 11 days the BGH response was similar to that before bed rest (1,881 +/- 75 to 4,160 +/- 315 microg/l; P < 0.05). These data demonstrate that the ambulatory state of an individual can have a major impact on the release of BGH, but not IGH, in response to a single bout of muscle activity.

  20. Multiplex Sequential Immunoprecipitation of Insulin Secretory Granule Proteins from Radiolabeled Pancreatic Islets.

    PubMed

    Guest, Paul C

    2017-01-01

    Pulse radiolabeling of cells with radioactive amino acids is a common method for tracking the biosynthesis of proteins. Specific proteins can then be immunoprecipitated and analyzed by electrophoresis and imaging techniques. This chapter presents a protocol for the biosynthetic labeling of pancreatic islets with (35)S-methionine, followed by multiplex sequential immunoprecipitation of insulin and three other secretory granule accessory proteins. This provided a means of distinguishing those pancreatic islet proteins with different biosynthetic rates in response to the media glucose concentrations.

  1. Autologous and Allogenous Antibodies in Lung and Islet Cell Transplantation

    PubMed Central

    Nayak, Deepak Kumar; Saravanan, Prathab Balaji; Bansal, Sandhya; Naziruddin, Bashoo; Mohanakumar, Thalachallour

    2016-01-01

    The field of organ transplantation has undoubtedly made great strides in recent years. Despite the advances in donor–recipient histocompatibility testing, improvement in transplantation procedures, and development of aggressive immunosuppressive regimens, graft-directed immune responses still pose a major problem to the long-term success of organ transplantation. Elicitation of immune responses detected as antibodies to mismatched donor antigens (alloantibodies) and tissue-restricted self-antigens (autoantibodies) are two major risk factors for the development of graft rejection that ultimately lead to graft failure. In this review, we describe current understanding on genesis and pathogenesis of antibodies in two important clinical scenarios: lung transplantation and transplantation of islet of Langerhans. It is evident that when compared to any other clinical solid organ or cellular transplant, lung and islet transplants are more susceptible to rejection by combination of allo- and autoimmune responses. PMID:28066448

  2. Islet Transplantation in Type I Diabetes Mellitus

    PubMed Central

    Jamiolkowski, Ryan M.; Guo, Lucie Y.; Li, Yun Rose; Shaffer, Sydney M.; Naji, Ali

    2012-01-01

    For most patients with type I diabetes, insulin therapy and glucose monitoring are sufficient to maintain glycemic control. However, hypoglycemia is a potentially lethal side effect of insulin treatment in patients who are glycemically labile or have hypoglycemia-associated autonomic failure [1]. For those patients, an alternative therapy is beta cell replacement via pancreas or islet transplantation. Pancreas transplants using cadaveric donor organs reduce insulin dependence but carry risks involved in major surgery and chronic immunosuppression. Islet transplantation, in which islets are isolated from donor pancreases and intravenously infused, require no surgery and can utilize islets isolated from pancreases unsuitable for whole organ transplantation. However, islet transplantation also requires immunosuppression, and standard steroid regimens may be toxic to beta cells [2]. The 2000 Edmonton Trial demonstrated the first long-term successful islet transplantation by using a glucocorticoid-free immunosuppressive regimen (sirolimus and tacrolimus). The Clinical Islet Transplantation (CIT) Consortium seeks to improve upon the Edmonton Protocol by using anti-thymocyte globulin (ATG) and TNFα antagonist (etanercept). The trials currently in progress, in addition to research efforts to find new sources of islet cells, reflect enormous potential for islet transplantation in treatment of type I diabetes. PMID:22461742

  3. Sexual differentiation of oxytocin stress responsiveness: effect of neonatal androgenization, castration and a luteinizing hormone-releasing hormone antagonist.

    PubMed

    Carter, D A; Saridaki, E; Lightman, S L

    1988-04-01

    The plasma OT increment following stress in rats is sexually dimorphic, females exhibiting greater responses than males. We have investigated the role of neonatal androgen secretion in determining the sex-typical level of response. Castration of male pups either surgically or functionally (GnRH antagonist treatment) within either 2 h or 5 days of birth did not elevate the OT responses of adult males. In contrast, androgenization of female pups (testosterone, 1.25 mg/pup) within 5 days of birth markedly reduced the OT stress responses of adults to a level insignificantly different to males. The results show that neonatal androgens can exert organizational effects on OT regulatory mechanisms. Since neonatal castration was ineffective it would appear that a prenatal defeminization or masculinization event determines OT stress responsiveness in males.

  4. In vivo response-based identification of direct hormone target cell populations using high-density tissue arrays.

    PubMed

    LeBaron, M J; Ahonen, T J; Nevalainen, M T; Rui, H

    2007-03-01

    To identify cell populations directly responsive to prolactin (PRL), GH, erythropoietin, or granulocyte-colony stimulating factor within the physiological setting of an intact mammal, we combined in situ detection of hormone-activated signal transducer and activator of transcription (Stat)-5 in rats with high-throughput tissue array analysis using cutting-edge matrix assembly (CEMA). Inducible activation of Stat5a/b, as judged by levels of nuclear-localized, phosphoTyr694/699-Stat5a/b, served as an immediate and sensitive in situ marker of receptor signaling in rat tissues after injection into male and female rats of a single, receptor-saturating dose of hormone for maximal receptor activation. CEMA tissue arrays facilitated analysis of most tissues, including architecturally complex, thin-walled, and stratified tissues such as gut and skin. In 40 tissues analyzed, 35 PRL-responsive and 32 GH-responsive cell types were detected, of which 22 cell types were responsive to both hormones. Interestingly, PRL but not GH activated Stat5 in nearly all of the endocrine glands. In mammary glands, PRL activated Stat5 in a majority of luminal epithelial cells but not myoepithelial cells, stromal fibroblasts, or adipocytes, whereas GH activated Stat5 in a significant fraction of myoepithelial cells, fibroblasts, and adipocytes but only in a minority of luminal cells. Finally, the organism-wide screening revealed a yet-to-be identified erythropoietin-responsive cell type in connective tissue. CEMA tissue arrays provide cost-effective in situ analysis of large numbers of tissues. Biomarker-based identification of cell populations responsive to individual hormones may shed new light on endocrine disease as well as improve understanding of effects and side effects of hormones and drugs.

  5. Treatment with Tacrolimus and Sirolimus Reveals No Additional Adverse Effects on Human Islets In Vitro Compared to Each Drug Alone but They Are Reduced by Adding Glucocorticoids

    PubMed Central

    Kloster-Jensen, Kristine; Sahraoui, Afaf; Vethe, Nils Tore; Korsgren, Olle; Bergan, Stein; Foss, Aksel; Scholz, Hanne

    2016-01-01

    Tacrolimus and sirolimus are important immunosuppressive drugs used in human islet transplantation; however, they are linked to detrimental effects on islets and reduction of long-term graft function. Few studies investigate the direct effects of these drugs combined in parallel with single drug exposure. Human islets were treated with or without tacrolimus (30 μg/L), sirolimus (30 μg/L), or a combination thereof for 24 hrs. Islet function as well as apoptosis was assessed by glucose-stimulated insulin secretion (GSIS) and Cell Death ELISA. Proinflammatory cytokines were analysed by qRT-PCR and Bio-Plex. Islets exposed to the combination of sirolimus and tacrolimus were treated with or without methylprednisolone (1000 μg/L) and the expression of the proinflammatory cytokines was investigated. We found the following: (i) No additive reduction in function and viability in islets existed when tacrolimus and sirolimus were combined compared to the single drug. (ii) Increased expression of proinflammatory cytokines mRNA and protein levels in islets took place. (iii) Methylprednisolone significantly decreased the proinflammatory response in islets induced by the drug combination. Although human islets are prone to direct toxic effect of tacrolimus and sirolimus, we found no additive effects of the drug combination. Short-term exposure of glucocorticoids could effectively reduce the proinflammatory response in human islets induced by the combination of tacrolimus and sirolimus. PMID:26885529

  6. Common and divergent physiological, hormonal and metabolic responses of Arabidopsis thaliana and Thellungiella halophila to water and salt stress.

    PubMed

    Arbona, Vicent; Argamasilla, Rosa; Gómez-Cadenas, Aurelio

    2010-11-01

    To explain the higher tolerance of Thellungiella to abiotic stress in comparison to Arabidopsis, several studies have focused on differences in ion absorption and gene expression. However, little is known about hormone regulation and metabolic responses. In this work, plants of both species were subjected to desiccation and salt stress to compare common and divergent responses. In control conditions, the number of significantly upregulated mass features as well as proline levels was higher in Tellungiella than in Arabidopsis. When subjected to desiccation, both species exhibited similar rates of water loss but proline over accumulation only occurred in Thellungiella; both species accumulated ABA and JA with a similar trend although Arabidopsis showed higher concentrations of both hormones which indicated a stronger impact of desiccation on Arabidopsis. However, Arabidopsis showed a higher number of significantly altered mass features than Thellungiella. Under salt stress, Thellungiella plants accumulated lower amounts of Cl(-) ions than Arabidopsis but exhibited a similar proline response. Under these conditions, ABA and JA levels increased in Arabidopsis whereas minimal changes in both hormone concentrations were recorded in Thellungiella. Contrastingly, the impact of salt stress on metabolite profiles was higher in Thellungiella than in Arabidopsis. Overall, data indicated that physiological responses in Arabidopsis are induced after stress imposition through hormonal regulation whereas Thellungiella has a basal metabolic configuration, better prepared to endure environmental cues.

  7. Skeletal response of male mice to anabolic hormone therapy in the absence of the Igfals gene.

    PubMed

    Kennedy, Oran D; Sun, Hui; Wu, Yingjie; Courtland, Hayden-William; Williams, Garry A; Cardoso, Luis; Basta-Pljakic, Jelena; Schaffler, Mitchell B; Yakar, Shoshana

    2014-03-01

    IGF-I is a critical regulator of skeletal acquisition, which acts in endocrine and autocrine/paracrine modes. In serum, IGF-I is carried by the IGF-binding proteins in binary complexes. Further stabilization of these complexes is achieved by binding to the acid labile subunit (ALS) in a ternary complex (of IGF-I-IGF-binding protein 3/5-ALS). Ablation of the Igfals gene in humans (ALS deficiency) and mice (ALS knockout [ALSKO]) leads to markedly decreased serum IGF-I levels, growth retardation, and impaired skeletal acquisition. To investigate whether hormonal replacement therapy would improve the skeletal phenotype in cases of Igfals gene ablation, we treated male ALSKO mice with GH, IGF-I, or a combination of both. Treatments were administered to animals between 4 and 16 weeks of age or from 8 to 16 weeks of age. Although all treatment groups showed an increase (20%) in serum IGF-I levels, there was no increase in body weight, weight gain, or bone length in either age group. Despite the blunted linear growth in response to hormone therapy, ALSKO mice treated with GH showed radial bone growth, which contributed to bone strength tested by 4-point bending. We found that ALSKO mice treated with GH showed increased total cross-sectional area, cortical bone area, and cortical thickness by microtomography. Dynamic histomorphometry showed that although GH and double treatment groups resulted in trends towards increased bone formation parameters, these did not reach significance. However, bone resorption parameters were significantly increased in all treatment groups. ALSKO mice treated between 4 and 16 weeks of age showed minor differences in bone traits compared with vehicle-treated mice. In conclusion, treatment with GH and IGF-I do not work synergistically to rescue the stunted growth found in mice lacking the Igfals gene. Although GH alone appears to increase bone parameters slightly, it does not affect body weight or linear growth.

  8. Fibrillar dimer formation of islet amyloid polypeptides

    DOE PAGES

    Chiu, Chi -cheng; de Pablo, Juan J.

    2015-05-08

    Amyloid deposits of human islet amyloid polypeptide (hIAPP), a 37-residue hormone co-produced with insulin, have been implicated in the development of type 2 diabetes. Residues 20 – 29 of hIAPP have been proposed to constitute the amyloidogenic core for the aggregation process, yet the segment is mostly unstructured in the mature fibril, according to solid-state NMR data. Here we use molecular simulations combined with bias-exchange metadynamics to characterize the conformational free energies of hIAPP fibrillar dimer and its derivative, pramlintide. We show that residues 20 – 29 are involved in an intermediate that exhibits transient β-sheets, consistent with recent experimentalmore » and simulation results. By comparing the aggregation of hIAPP and pramlintide, we illustrate the effects of proline residues on inhibition of the dimerization of IAPP. The mechanistic insights presented here could be useful for development of therapeutic inhibitors of hIAPP amyloid formation.« less

  9. Anx7 is required for nutritional control of gene expression in mouse pancreatic islets of Langerhans.

    PubMed Central

    Srivastava, Meera; Eidelman, Ofer; Leighton, Ximena; Glasman, Mirta; Goping, Gertrude; Pollard, Harvey B.

    2002-01-01

    BACKGROUND: Gene expression in islets of Langerhans is profoundly sensitive to glucose and other nutrients. Islets of Langerhans in the Anx7(+/-) knockout mouse exhibit a profound reduction in ITPR3 protein expression, defective intracellular calcium signaling, and defective insulin secretion. Additional data presented here also show that mRNA for ITPR3 is virtually undetectable in isolated Anx7(+/-) islets. IP3Receptor type 3 (ITPR3) expression in islets of Langerhans is closely regulated by secretory stimuli, and it has been suggested that the level of the ITPR3 expression controls the ability of the islets to respond to nutritional signals. We report that although control islets respond to glucose in vitro by a transient increment in ITPR3 mRNA, the islets from the Anx7(+/-) mouse remain low. We therefore hypothesized that the Anx7/IP3 Receptor(3)/Ca(2+) signaling pathway plays a role in beta cell responses to glucose, and that in the absence of the Anx7/ITPR3 signaling system, the islets would be unable to discriminate between fed or fasted states in vivo. MATERIALS AND METHODS: To test this hypothesis, we subjected Anx7(+/-) and control mice to either food and water ad libidum or to an overnight fast with access to water only. We then isolated the respective islets and compared nutrient-dependent changes in global gene expression under the four conditions using genome-based microarray technology. RESULTS: Anx7 protein expression in these islets is only about 50% of control levels in normal littermate controls, and IPTR3 message and protein are virtually zero. cDNA microarray analyses show that in control animals gene expression is significantly affected by the fasting state. Many of the affected genes have historical relevance to development and differentiation of islets. These include preproglucagon, APOJ, cadherin2, phosphoglucoisomerase, oncostatin M, PAX6, HGF, and cytokeratin 18. However, there are also many other nutritionally sensitive genes in control

  10. Immunologic Intervention in HIV Infection: Anti-Polymerase Responses and Hormonal Regulation.

    DTIC Science & Technology

    1992-05-01

    patients. Growth hormone (somatotropin) has been used as an adjuvant in animal models to enhance B and T cell reactivity against various viral vaccines...properties, is of great interest in HIV disease. We have discovered that not only is growth hormone a potent T cell stimulant but it is capable of synergizing...phenotype in SCID mice. This work has implications for the pathogenisis of B cell lymphomas in AIDS patients. 5. Growth hormone (somatotropin) has been

  11. Effect of 6 weeks of sprint training on growth hormone responses to sprinting.

    PubMed

    Stokes, Keith A; Nevill, Mary E; Cherry, Paul W; Lakomy, Henryk K A; Hall, George M

    2004-06-01

    This study examined the effect of 6 weeks of prescribed sprint training on the human growth hormone (hGH) response to cycle ergometer sprinting. Sixteen male subjects were randomly assigned to a training (n=8) or a control (n=8) group. Each subject completed two main trials, consisting of two all-out 30-s cycle-ergometer sprints separated by 60 min of passive recovery, once before, and once after a 6-week training period. The training group completed three supervised sprint-training sessions per week in addition to their normal activity, whilst control subjects continued with their normal activity. In the training group, peak and mean power increased post-training by 6% (P<0.05) and 5% (P<0.05), respectively. Post-exercise blood pH did not change following training, but the highest post-exercise blood lactate concentrations were greater [highest measured value: 13.3 (1.0) vs 15.0 (1.1) mmol l(-1)], with lower blood lactate concentrations for the remainder of the recovery period (P<0.05). Post-exercise plasma ammonia concentrations were lower after training [mean highest measured value: 184.1 (9.8) vs 139.0 (11.7) micromol l(-1), P<0.05]. Resting serum hGH concentrations did not change following training, but the peak values measured post-exercise decreased by over 40% in the training group [10.3 (3.1) vs 5.8 (2.5) microg l(-1), P<0.05], and mean integrated serum hGH concentrations were 55% lower after training [567 (158) vs 256 (121) min microg l(-1), P<0.05]. The hGH response to the second sprint was attenuated similarly before and after training. This study showed that 6 weeks of combined speed- and speed-endurance training blunted the human growth hormone response to sprint exercise, despite an improvement in sprint performance.

  12. Early spring sex differences in luteinizing hormone response to gonadotropin releasing hormone in co-occurring resident and migrant dark-eyed juncos (Junco hyemalis).

    PubMed

    Greives, Timothy J; Fudickar, Adam M; Atwell, Jonathan W; Meddle, Simone L; Ketterson, Ellen D

    2016-09-15

    To optimally time reproduction, animals must coordinate changes in the hypothalamo-pituitary-gonadal (HPG) axis. The extent of intra-species variation in seasonal timing of reproductive function is considerable, both within and among populations. Dark-eyed junco (Junco hyemalis) populations are known to differ in their reproductive timing response to cues experienced in the same habitat in late winter/early spring. Specifically in juncos cohabitating on shared wintering grounds, residents initiate breeding and reproductive activity but migrants delay reproductive development and prepare to migrate before breeding. Here, we test the hypothesis that the pituitary gland acts as a 'control point' to modulate differential HPG axis activity across populations. We sampled free-living resident and migrant juncos on their shared over-wintering grounds in March, thus all individuals were experiencing the same environmental cues, including photoperiod. We predicted that during this critical time of transition, residents would more readily respond to repeated gonadotropin releasing hormone (GnRH) stimulation with increases in luteinizing hormone (LH), in contrast to migrants, which should delay full reproductive activity. Our data indicate that migrant females, while still on the overwintering grounds, have a reduced LH response to repeated GnRH injections compared to resident females. Male migrant and resident birds did not differ in their responsiveness to repeated GnRH. Our results suggest a sex difference in the costs of mistimed activation of the HPG axis, with female migrants being less responsive than residents females and males to repeated stimulation. Further, our data implicate a key role for the pituitary in regulating appropriate reproductive timing responses.

  13. Synthesis and Screening of Novel Substituted Biphenyl Proteomimetics as Potential Anti-Estrogenic Agents for the Treatment of Hormone-Responsive Breast Cancer

    DTIC Science & Technology

    2005-07-01

    Agents for the Treatment of Hormone-Responsive Breast Cancer PRINCIPAL INVESTIGATOR: Robert...Anti-Estrogenic Agents for the Treatment of Hormone-Responsive Breast Cancer 5b. GRANT NUMBER W81XWH-04-1-0647 5c. PROGRAM ELEMENT NUMBER

  14. Isolation of a thyroid hormone-responsive gene by immunoprecipitation of thyroid hormone receptor-DNA complexes.

    PubMed Central

    Bigler, J; Eisenman, R N

    1994-01-01

    Thyroid hormone (T3) receptor (TR) is a ligand-dependent transcription factor that acts through specific binding sites in the promoter region of target genes. In order to identify new genes that are regulated by T3, we used anti-TR antiserum to immunoprecipitate TR-DNA complexes from GH4 cell nuclei that had previously been treated with a restriction enzyme. Screening of the immunopurified, cloned DNA for TR binding sites by electrophoretic mobility shift assay yielded 53 positive clones. A subset of these clones was specifically immunoprecipitated with anti-TR antiserum and may therefore represent biologically significant binding sites. One of these clones, clone 122, was characterized in detail. It includes sequences highly related to the NICER long terminal repeat-like element and contains three TR binding sites as determined by DNase I footprinting. Two of the clone 122 TR binding sites are located upstream of the TATA box, and one is located downstream. The TR binding site downstream from the promoter was necessary and sufficient to confer T3-dependent regulation in transient transfection experiments. Expression of a reporter construct under the control of the clone 122 promoter region was activated by TR in the absence of ligand and returned to basal levels after T3 addition. Clone 122 sequences hybridize to at least two different mRNAs of approximately 6 and 10 kb from GH4 cells. The levels of both of these mRNAs increased upon removal of T3. Our studies suggest that specific immunoprecipitation of chromatin allows identification of binding sites and target genes for transcription factors. Images PMID:7935476

  15. Thyroid-stimulating hormone, 5-HTTLPR genotype, and antidepressant response in depressed women.

    PubMed

    Gressier, Florence; Trabado, Séverine; Verstuyft, Céline; Bouaziz, Elodie; Hardy, Patrick; Fève, Bruno; Becquemont, Laurent; Corruble, Emmanuelle

    2011-10-01

    Basal serum thyroid-stimulating hormone (TSH) levels may predict antidepressant efficacy in patients with major depressive episodes (MDE), but data are inconsistent. As the SS genotype of the 5-HTTLPR polymorphism has been associated with a lower antidepressant efficacy in women with MDE, we aimed at assessing the relationship between normal basal TSH, 5-HTTLPR, and antidepressant efficacy in women. A total of 71 women and 28 men, with normal baseline TSH serum levels, hospitalized for a MDE, were assessed for 5-HTTLPR genotypes and prospectively followed for short-term antidepressant efficacy. Women with SS genotype had higher TSH levels (P=0.002) and a worse antidepressant response (P=0.046) than the women with LL/LS genotype, whereas no significant difference was shown in men. In multivariate analyses, antidepressant response in women was explained by TSH and 5-HTTLPR, but not by other variables. Further research is needed to understand the underlying mechanism explaining interactions between sex, TSH, and serotonergic function.

  16. Hormones and Endocrine-Disrupting Chemicals: Low-Dose Effects and Nonmonotonic Dose Responses

    PubMed Central

    Colborn, Theo; Hayes, Tyrone B.; Heindel, Jerrold J.; Jacobs, David R.; Lee, Duk-Hee; Shioda, Toshi; Soto, Ana M.; vom Saal, Frederick S.; Welshons, Wade V.; Zoeller, R. Thomas

    2012-01-01

    For decades, studies of endocrine-disrupting chemicals (EDCs) have challenged traditional concepts in toxicology, in particular the dogma of “the dose makes the poison,” because EDCs can have effects at low doses that are not predicted by effects at higher doses. Here, we review two major concepts in EDC studies: low dose and nonmonotonicity. Low-dose effects were defined by the National Toxicology Program as those that occur in the range of human exposures or effects observed at doses below those used for traditional toxicological studies. We review the mechanistic data for low-dose effects and use a weight-of-evidence approach to analyze five examples from the EDC literature. Additionally, we explore nonmonotonic dose-response curves, defined as a nonlinear relationship between dose and effect where the slope of the curve changes sign somewhere within the range of doses examined. We provide a detailed discussion of the mechanisms responsible for generating these phenomena, plus hundreds of examples from the cell culture, animal, and epidemiology literature. We illustrate that nonmonotonic responses and low-dose effects are remarkably common in studies of natural hormones and EDCs. Whether low doses of EDCs influence certain human disorders is no longer conjecture, because epidemiological studies show that environmental exposures to EDCs are associated with human diseases and disabilities. We conclude that when nonmonotonic dose-response curves occur, the effects of low doses cannot be predicted by the effects observed at high doses. Thus, fundamental changes in chemical testing and safety determination are needed to protect human health. PMID:22419778

  17. Direct Stimulation of Islet Insulin Secretion by Glycolytic and Mitochondrial Metabolites in KCl-Depolarized Islets

    PubMed Central

    Deeney, Jude T.; Corkey, Barbara E.

    2016-01-01

    We have previously demonstrated that islet depolarization with 70 mM KCl opens Cx36 hemichannels and allows diffusion of small metabolites and cofactors through the β-cell plasma membrane. We have investigated in this islet “permeabilized” model whether glycolytic and citric acid cycle intermediates stimulate insulin secretion and how it correlates with ATP production (islet content plus extracellular nucleotide accumulation). Glycolytic intermediates (10 mM) stimulated insulin secretion and ATP production similarly. However, they showed differential sensitivities to respiratory chain or enzyme inhibitors. Pyruvate showed a lower secretory capacity and less ATP production than phosphoenolpyruvate, implicating an important role for glycolytic generation of ATP. ATP production by glucose-6-phosphate was not sensitive to a pyruvate kinase inhibitor that effectively suppressed the phosphoenolpyruvate-induced secretory response and islet ATP rise. Strong suppression of both insulin secretion and ATP production induced by glucose-6-phosphate was caused by 10 μM antimycin A, implicating an important role for the glycerophosphate shuttle in transferring reducing equivalents to the mitochondria. Five citric acid cycle intermediates were investigated for their secretory and ATP production capacity (succinate, fumarate, malate, isocitrate and α-ketoglutarate at 5 mM, together with ADP and/or NADP+ to feed the NADPH re-oxidation cycles). The magnitude of the secretory response was very similar among the different mitochondrial metabolites but α-ketoglutarate showed a more sustained second phase of secretion. Gabaculine (1 mM, a GABA-transaminase inhibitor) suppressed the second phase of secretion and the ATP-production stimulated by α-ketoglutarate, supporting a role for the GABA shuttle in the control of glucose-induced insulin secretion. None of the other citric acid intermediates essayed showed any suppression of both insulin secretion or ATP-production by the

  18. Characterization of anti-islet cytotoxic human T-cell clones from patients with type 1 diabetes mellitus.

    PubMed

    Sobel, Douglas O; Creswell, Karen

    2006-06-01

    To identify important anti-islet T-cells and their target antigen(s), we have isolated and characterized seventeen human T-cell clones which are reactive to an extract of rat insulinoma (RIN) cells from three children with new onset type 1 diabetes mellitus (T1D). Of these 17 clones, 15 were found tissue specific. Six of eight tested tissue specific clones did not recognize known islet antigens such as GAD, 52 kDa islet protein, insulin, ICA512, and heat shock protein 60 (hsp60), suggesting that these clones recognize an autoantigen not previously identified. All tested clones were phenotypically CD4 and functionally Th0 or Th0/Th1 cells. One RIN extract reactive clone (2E9) recognized hsp60 and was CD4 and TCR alpha/beta positive. This clone also proliferated in response to human and rat islets suggesting that the antigen is conserved between species. This clone and 75% of all the tested RIN reactive clones exhibited anti-islet cytotoxicity by lysing target cells coated with RIN extract. HLA DR determinants may play a role in this cytotoxic activity since preincubation with HLA DR antibody decreased the anti-islet cytoxicity of the two tested clones. In conclusion, we have isolated RIN reactive CD4+T-cell clones from diabetic subjects, six of which appears tissue specific and non-reactive to putative important islet antigens, and in turn may be recognizing yet undiscovered islet antigens. The high frequency anti-islet cytotoxic properties of the islet reactive clones provides evidence for a role of CD4+ cytotoxic T-lymphocytes in the diabetic process. Further, the isolation of hsp60 reactive clone with anti-islet cytotoxic properties suggests that cell mediated immunity against hsp60 may be important in the pathogenesis of diabetes.

  19. Influence of enteral glutamine on inflammatory and hormonal response in patients with rectal cancer during preoperative radiochemotherapy.

    PubMed

    Rotovnik Kozjek, N; Kompan, L; Žagar, T; Mrevlje, Ž

    2017-03-08

    We conducted a randomized double-blind placebo-controlled study evaluating the influence of 5 weeks' duration of 30 g enteral glutamine supplementation on inflammatory and hormonal responses in 73 patients with rectal cancer undergoing preoperative radiochemotherapy. Plasma levels of inflammatory and hormonal parameters were controlled at the beginning and at the end of supplementation. Enteral glutamine resulted in modulation of inflammatory and hormonal responses as shown by a decreased plasma interleukin 6 and cortisol levels in glutamine compared with placebo group: 5.5±3.8 versus 11.1±19.9 ng/l (P=0.02) for IL-6 and 386±168.4 to 312.7±111.7 nmol/l (P=0.03) for cortisol. We conclude that enteral glutamine exhibits some anti-inflammatory activity and, consequently, leads to a lower hormonal stress response during radiochemotherapy in patients with rectal cancer.European Journal of Clinical Nutrition advance online publication, 8 March 2017; doi:10.1038/ejcn.2017.11.

  20. Incretin hormone receptors are required for normal beta cell development and function in female mice.

    PubMed

    Omar, Bilal; Ahlkvist, Linda; Yamada, Yuchiro; Seino, Yutaka; Ahrén, Bo

    2016-05-01

    The incretin hormones, glucose dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1), potentiate insulin secretion and are responsible for the majority of insulin secretion that occurs after a meal. They may also, however, have a fundamental role in pancreatic beta cell development and function, independently of their role in potentiating insulin secretion after a meal. This has led to observations that a loss of GIP or GLP-1 action affects normal beta cell function, however each one of the incretin hormones may compensate when the action of the other is lost and therefore the overall impact of the incretin hormones on beta cell function is not known. We therefore utilized a mouse line deficient in both the GLP-1 and GIP receptor genes, the double incretin receptor knockout (DIRKO), to determine the consequences of a lifelong, complete lack of incretin hormone action on beta cell function, in vivo, in intact animals. We found that DIRKO mice displayed impaired glucose tolerance and insulin secretion in response to both oral glucose and mixed meal tolerance tests compared to wild-type mice. Assessment of beta cell function using the hyperglycemic clamp technique revealed an 80% decrease in first phase insulin response in DIRKO mice, but a normal second phase insulin secretion. A similar decline was seen when wild-type mice were given acute intravenous injection of glucose together with the GLP-1 receptor antagonist Ex9-39. Ex vivo assessments of the pancreas revealed significantly fewer islets in the pancreata of DIRKO mice despite no differences in total pancreatic mass. Insulin secretion from isolated islets of DIRKO mice was impaired to a similar extent to that seen during the hyperglycemic clamp. Insulin secretion in wild-type islets was impaired by acute treatment with Ex9-39 to a similar extent as the in vivo intravenous glucose tolerance tests. In conclusion, a loss of the action of both incretin hormones results in direct impairment

  1. Engineered VEGF-releasing PEG-MAL hydrogel for pancreatic islet vascularization

    PubMed Central

    Phelps, Edward A.; Templeman, Kellie L.; Thulé, Peter M.; García, Andrés J.

    2013-01-01

    Biofunctionalized polyethylene glycol maleimide (PEG-MAL) hydrogels were engineered as a platform to deliver pancreatic islets to the small bowel mesentery and promote graft vascularization. VEGF, a potent stimulator of angiogenesis, was incorporated into the hydrogel to be released in an on-demand manner through enzymatic degradation. PEG-MAL hydrogel enabled extended in vivo release of VEGF. Isolated rat islets encapsulated in PEG-MAL hydrogels remained viable in culture and secreted insulin. Islets encapsulated in PEG-MAL matrix and transplanted to the small bowel mesentery of healthy rats grafted to the host tissue and revascularized by 4 weeks. Addition of VEGF release to the PEG-MAL matrix greatly augmented the vascularization response. These results establish PEG-MAL engineered matrices as a vascular-inductive cell delivery vehicle and warrant their further investigation as islet transplantation vehicles in diabetic animal models. PMID:25787738

  2. Growth hormone deficiency in a dopa-responsive dystonia patient with a novel mutation of guanosine triphosphate cyclohydrolase 1 gene.

    PubMed

    Lin, Yu; Wang, Dan-Ni; Chen, Wan-Jin; Lin, Xiang; Lin, Min-Ting; Wang, Ning

    2015-05-01

    Dopa-responsive dystonia is a rare hereditary movement disorder caused by mutations in the guanosine triphosphate cyclohydrolase 1 (GCH1) gene. This disease typically manifests in dystonia, with marked diurnal fluctuation and a dramatic response to levodopa. However, growth retardation in dopa-responsive dystonia has rarely been reported, and the etiology of short stature is not clarified. Here, we report a 14-year-old patient with extremities dystonia and short stature. Treatment with levodopa relieved his symptoms and resulted in a height increase. We also investigated the mutation in GCH1 and the etiology of short stature in this case. Sequence analysis of GCH1 revealed a novel mutation (c.695G>T). Laboratory examinations and imaging confirmed the diagnosis of growth hormone deficiency. We conclude that our case reveals a rare feature for dopa-responsive dystonia and suggests a possible pathogenic link between growth hormone deficiency and dopa-responsive dystonia. We recommend levodopa as the first choice for treating dopa-responsive dystonia in children with growth hormone deficiency.

  3. Continuous Quadrupole Magnetic Separation of Islets during Digestion Improves Purified Porcine Islet Viability

    PubMed Central

    Kumar Sajja, Venkata Sunil; Rizzari, Michael D.; Scott III, William E.; Kitzmann, Jennifer P.; Kennedy, David J.; Todd, Paul W.; Balamurugan, Appakalai N.; Hering, Bernhard J.

    2016-01-01

    Islet transplantation (ITx) is an emerging and promising therapy for patients with uncontrolled type 1 diabetes. The islet isolation and purification processes require exposure to extended cold ischemia, warm-enzymatic digestion, mechanical agitation, and use of damaging chemicals for density gradient separation (DG), all of which reduce viable islet yield. In this paper, we describe initial proof-of-concept studies exploring quadrupole magnetic separation (QMS) of islets as an alternative to DG to reduce exposure to these harsh conditions. Three porcine pancreata were split into two parts, the splenic lobe (SPL) and the combined connecting/duodenal lobes (CDL), for paired digestions and purifications. Islets in the SPL were preferentially labeled using magnetic microparticles (MMPs) that lodge within the islet microvasculature when infused into the pancreas and were continuously separated from the exocrine tissue by QMS during the collection phase of the digestion process. Unlabeled islets from the CDL were purified by conventional DG. Islets purified by QMS exhibited significantly improved viability (measured by oxygen consumption rate per DNA, p < 0.03) and better morphology relative to control islets. Islet purification by QMS can reduce the detrimental effects of prolonged exposure to toxic enzymes and density gradient solutions and substantially improve islet viability after isolation. PMID:27843954

  4. Continuous Quadrupole Magnetic Separation of Islets during Digestion Improves Purified Porcine Islet Viability.

    PubMed

    Weegman, Bradley P; Kumar Sajja, Venkata Sunil; Suszynski, Thomas M; Rizzari, Michael D; Scott Iii, William E; Kitzmann, Jennifer P; Mueller, Kate R; Hanley, Thomas R; Kennedy, David J; Todd, Paul W; Balamurugan, Appakalai N; Hering, Bernhard J; Papas, Klearchos K

    2016-01-01

    Islet transplantation (ITx) is an emerging and promising therapy for patients with uncontrolled type 1 diabetes. The islet isolation and purification processes require exposure to extended cold ischemia, warm-enzymatic digestion, mechanical agitation, and use of damaging chemicals for density gradient separation (DG), all of which reduce viable islet yield. In this paper, we describe initial proof-of-concept studies exploring quadrupole magnetic separation (QMS) of islets as an alternative to DG to reduce exposure to these harsh conditions. Three porcine pancreata were split into two parts, the splenic lobe (SPL) and the combined connecting/duodenal lobes (CDL), for paired digestions and purifications. Islets in the SPL were preferentially labeled using magnetic microparticles (MMPs) that lodge within the islet microvasculature when infused into the pancreas and were continuously separated from the exocrine tissue by QMS during the collection phase of the digestion process. Unlabeled islets from the CDL were purified by conventional DG. Islets purified by QMS exhibited significantly improved viability (measured by oxygen consumption rate per DNA, p < 0.03) and better morphology relative to control islets. Islet purification by QMS can reduce the detrimental effects of prolonged exposure to toxic enzymes and density gradient solutions and substantially improve islet viability after isolation.

  5. Islet preconditioning via multimodal microfluidic modulation of intermittent hypoxia.

    PubMed

    Lo, Joe F; Wang, Yong; Blake, Alexander; Yu, Gene; Harvat, Tricia A; Jeon, Hyojin; Oberholzer, Jose; Eddington, David T

    2012-02-21

    Simultaneous stimulation of ex vivo pancreatic islets with dynamic oxygen and glucose is a critical technique for studying how hypoxia alters glucose-stimulated response, especially in transplant environments. Standard techniques using a hypoxic chamber cannot provide both oxygen and glucose modulations, while monitoring stimulus-secretion coupling factors in real-time. Using novel microfluidic device with integrated glucose and oxygen modulations, we quantified hypoxic impairment of islet response by calcium influx, mitochondrial potentials, and insulin secretion. Glucose-induced calcium response magnitude and phase were suppressed by hypoxia, while mitochondrial hyperpolarization and insulin secretion decreased in coordination. More importantly, hypoxic response was improved by preconditioning islets to intermittent hypoxia (IH, 1 min/1 min 5-21% cycling for 1 h), translating to improved insulin secretion. Moreover, blocking mitochondrial K(ATP) channels removed preconditioning benefits of IH, similar to mechanisms in preconditioned cardiomyocytes. Additionally, the multimodal device can be applied to a variety of dynamic oxygen-metabolic studies in other ex vivo tissues.

  6. Microarray Analysis of Juvenile Hormone Response in Drosophila melanogaster S2 cells

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A microchip array encompassing probes for 14,010 genes of Drosophila melanogaster was used to analyze the effect of juvenile hormone (JH) on genome-wide gene expression. JH is a member of a key group of insect hormones involved in regulating larval development and adult reproductive processes. Altho...

  7. Dynamic Regulation of Auxin Response during Rice Development Revealed by Newly Established Hormone Biosensor Markers

    PubMed Central

    Yang, Jing; Yuan, Zheng; Meng, Qingcai; Huang, Guoqiang; Périn, Christophe; Bureau, Charlotte; Meunier, Anne-Cécile; Ingouff, Mathieu; Bennett, Malcolm J.; Liang, Wanqi; Zhang, Dabing

    2017-01-01

    The hormone auxin is critical for many plant developmental processes. Unlike the model eudicot plant Arabidopsis (Arabidopsis thaliana), auxin distribution and signaling in rice tissues has not been systematically investigated due to the absence of suitable auxin response reporters. In this study we observed the conservation of auxin signaling components between Arabidopsis and model monocot crop rice (Oryza sativa), and generated complementary types of auxin biosensor constructs, one derived from the Aux/IAA-based biosensor DII-VENUS but constitutively driven by maize ubiquitin-1 promoter, and the other termed DR5-VENUS in which a synthetic auxin-responsive promoter (DR5rev) was used to drive expression of the yellow fluorescent protein (YFP). Using the obtained transgenic lines, we observed that during the vegetative development, accumulation of DR5-VENUS signal was at young and mature leaves, tiller buds and stem base. Notably, abundant DR5-VENUS signals were observed in the cytoplasm of cortex cells surrounding lateral root primordia (LRP) in rice. In addition, auxin maxima and dynamic re-localization were seen at the initiation sites of inflorescence and spikelet primordia including branch meristems (BMs), female and male organs. The comparison of these observations among Arabidopsis, rice and maize suggests the unique role of auxin in regulating rice lateral root emergence and reproduction. Moreover, protein localization of auxin transporters PIN1 homologs and GFP tagged OsAUX1 overlapped with DR5-VENUS during spikelet development, helping validate these auxin response reporters are reliable markers in rice. This work firstly reveals the direct correspondence between auxin distribution and rice reproductive and root development at tissue and cellular level, and provides high-resolution auxin tools to probe fundamental developmental processes in rice and to establish links between auxin, development and agronomical traits like yield or root architecture. PMID

  8. Islet Amyloid in Whole Pancreas Transplants for Type 1 Diabetes Mellitus (DM): Possible Role of Type 2 DM for Graft Failure.

    PubMed

    León Fradejas, M; Kandil, D; Papadimitriou, J C; del Pino Flórez Rial, M; Prieto Sánchez, E; Drachenberg, C B

    2015-09-01

    Long-term results with whole pancreas (WPTx) and islet transplantation (IT) continue to be suboptimal. Graft failure with undetectable C-peptide level is attributed to graft sclerosis (chronic rejection), recurrence of Type 1 diabetes mellitus (DM), or insufficient islet mass. In contrast, graft failure with measurable C-peptide has overlapping clinical features with Type 2 DM (suggesting persistent but insufficient β cell function), but is poorly understood. In general, the morphological substrate for islet failure is unclear because grafted islets are not routinely evaluated. We present two patients with graft failure at 5 and 8 years after successful WPTx for Type 1 DM, presenting with preserved C-peptide levels. On histopathology, the islets had preserved both α and β cell populations but also prominent accumulation of islet amyloid (IA), the morphological hallmark of Type 2 DM. IA previously reported in IT, represents fibrillary aggregates of islet amyloid polypeptide, a hormone normally cosecreted with insulin. Accumulation of IA correlates quantitatively with the development of hyperglycemia and is known to cause β cell dysfunction and loss. Accumulation of IA and development of Type 2 DM should be considered and studied as a potential cause of long-term islet failure in IT and WPTx.

  9. Changes in plasma melanocyte-stimulating hormone, ACTH, prolactin, GH, LH, FSH, and thyroid-stimulating hormone in response to injection of sulpiride, thyrotropin-releasing hormone, or vehicle in insulin-sensitive and -insensitive mares.

    PubMed

    Valencia, N Arana; Thompson, D L; Mitcham, P B

    2013-05-01

    Six insulin-sensitive and 6 insulin-insensitive mares were used in a replicated 3 by 3 Latin square design to determine the pituitary hormonal responses (compared with vehicle) to sulpiride and thyrotropin-releasing hormone (TRH), 2 compounds commonly used to diagnose pituitary pars intermedia dysfunction (PPID) in horses. Mares were classified as insulin sensitive or insensitive by their previous glucose responses to direct injection of human recombinant insulin. Treatment days were February 25, 2012, and March 10 and 24, 2012. Treatments were sulpiride (racemic mixture, 0.01 mg/kg BW), TRH (0.002 mg/kg BW), and vehicle (saline, 0.01 mL/kg BW) administered intravenously. Blood samples were collected via jugular catheters at -10, 0, 5, 10, 20, 30, 45, 60, 90, and 120 min relative to treatment injection. Plasma ACTH concentrations were variable and were not affected by treatment or insulin sensitivity category. Plasma melanocyte-stimulating hormone (MSH) concentrations responded (P < 0.01) to both sulpiride and TRH injection and were greater (P < 0.05) in insulin-insensitive mares than in sensitive mares. Plasma prolactin concentrations responded (P < 0.01) to both sulpiride and TRH injection, and the response was greater (P < 0.05) for sulpiride; no effect of insulin sensitivity was observed. Plasma thyroid-stimulating hormone (TSH) concentrations responded (P < 0.01) to TRH injection only and were higher (P < 0.05) in insulin-sensitive mares in almost all time periods. Plasma LH and FSH concentrations varied with time (P < 0.05), particularly in the first week of the experiment, but were not affected by treatment or insulin sensitivity category. Plasma GH concentrations were affected (P < 0.05) only by day of treatment. The greater MSH responses to sulpiride and TRH in insulin-insensitive mares were similar to, but not as exaggerated as, those observed by others for PPID horses. In addition, the reduced TSH concentrations in insulin-insensitive mares are

  10. Leptin alters the response of the growth hormone releasing factor- growth hormone--insulin-like growth factor-I axis to fasting.

    PubMed

    LaPaglia, N; Steiner, J; Kirsteins, L; Emanuele, M; Emanuele, N

    1998-10-01

    Proper nutritional status is critical for maintaining growth and metabolic function, playing an intimate role in neuroendocrine regulation. Leptin, the recently identified product of the obese gene, may very well be an integral signal which regulates neuroendocrine responses in times of food deprivation. The present study examines leptin's ability to regulate hormonal synthesis and secretion within the GRF-GH-IGF axis in the adult male rat during almost 3 days of fasting. Serum levels of GH and IGF-I were drastically suppressed by fasting. Daily leptin administration was able to fully prevent the fasting-induced fall in serum GH. Leptin failed to restore IGF-I to control levels, however, suggesting possible GH resistance. Fasting caused an insignificant increase in GH mRNA, while leptin injections significantly increased steady-state levels of this message. The GRF receptor (GRFr) message was not altered with fasting or leptin treatment. Leptin also exhibited effects at the hypothalamic level. Fasting induced a sharp fall in GRF mRNA expression and leptin injections partially prevented this fall. However, there were no observed changes in the hypothalamic GRF content. These results provide evidence that leptin may function as a neuromodulator of the GRF-GH-IGF axis communicating to this hormonal system the nutritional status of the animal.

  11. Characterization of the hormone responsive element involved in the regulation of the progesterone receptor gene.

    PubMed Central

    Savouret, J F; Bailly, A; Misrahi, M; Rauch, C; Redeuilh, G; Chauchereau, A; Milgrom, E

    1991-01-01

    The transcription of the progesterone receptor gene is induced by estrogens and decreased by progestins. Studies were performed to define the regions of the gene and the molecular mechanisms involved. No hormonal regulation could be observed using 5' flanking regions of the gene up to -2762 in front of a heterologous gene. Estrogen and progestin regulation could be observed only when using fragments of the gene extending down to +788. Progressive deletions from the 5' and 3' ends, site-directed mutagenesis and DNase protection experiments with purified estrogen receptor suggested that the biologically active estrogen responsive element (ERE) is present at +698/+723, overlapping the initiation of translation. An oligonucleotide was synthesized bearing this ERE and shown to impart estrogen inducibility to a heterologous gene. Its regulation by anti-estrogens corresponded to that of the in situ progesterone receptor gene since tamoxifen was a partial agonist whereas ICI 164384 was a full antagonist. This ERE also mediated down-regulation by progestins in the presence of the progesterone receptor, even though it has no progesterone receptor binding ability. DNase footprinting showed that this effect was not due to a decrease of estrogen receptor affinity for the ERE in the presence of progesterone receptor. Finally, use of deletion mutants of the progesterone receptor showed that the steroid binding and the DNA binding domains were necessary for down-regulation whereas deletions of various parts of the N-terminal domain were without effect. Images PMID:2050123

  12. Adenylate cyclase of human articular chondrocytes. Responsiveness to prostaglandins and other hormones.

    PubMed Central

    Houston, J P; McGuire, M K; Meats, J E; Ebsworth, N M; Russell, R G; Crawford, A; Mac Neil, S

    1982-01-01

    Adenylate cyclase [ATP pyrophosphate lyase (cyclizing), EC 4.6.1.1] was shown to be present in cultured human articular chondrocytes. Optimal conditions of incubation time, protein and substrate concentrations and pH were determined in whole cell lysates. Maximal activity occurred at pH 8.5 with no decrease in activity up to pH 10.0. Adenylate cyclase activity of particulate membrane preparations was enhanced by the addition of crude cytosol preparations. The prostaglandins E1, E2, F1 alpha, F2 alpha, D2, B1, B2, A1 and A2, as well as adrenaline and isoprenaline, stimulated adenylate cyclase derived from either adult or foetal chondrocytes. No significant stimulation was observed in the presence of human calcitonin or glucagon. Bovine parathyroid hormone always significantly stimulated the adenylate cyclase derived from foetal chondrocytes, but not from adult chondrocytes. Preincubation of the chondrocytes in culture with indomethacin and with or without supernatant medium from cultured mononuclear cells increased the responsiveness of the adenylate cyclase to prostaglandin E1. PMID:7159397

  13. Somatotropic gene response to recombinant growth hormone treatment in buffalo leucocytes.

    PubMed

    Castigliego, Lorenzo; Li, Xiao-Ning; Armani, Andrea; Razzano, Maria; Mazzi, Marco; Rosati, Remo; Gianfaldoni, Daniela; Guidi, Alessandra

    2011-12-01

    The use of recombinant bovine growth hormone (rbGH) to increase milk yield in cows is banned in some countries. In others, where it is authorised, it has triggered harsh debates on labelling of dairy products. If many studies have been performed on bovines, there is a lack of information on buffaloes, which are sometimes treated with rbGH and re-present an important economical resource for dairy products in some countries. Analytical methods with legal value for surveillance of rbGH treatments do not yet exist. Research on gene expression biomarkers is one of the most promising approaches to this purpose. For this reason, we treated five buffaloes for 10 weeks with a sustained-release formulation of rbGH and analysed the response of 20 somatotropic axis genes in leucocytes by real-time polymerase chain reaction. Overall changes in gene expression levels were of low magnitude and sometimes affected by the 'time' factor. Only the IGFBP-1 gene showed a significant under-expression (about two-fold; p <0.001) in treated animals. Taken together, these results give evidence that expression analysis of the somatotropic axis genes in leucocytes is little helpful for discrimination of rbGH-treated buffaloes, but do not exclude that another array of genes could provide useful patterns of variation.

  14. Effects of age and sex on hormonal responses to weightlessness simulation

    NASA Technical Reports Server (NTRS)

    Larochelle, F.; Leach, C.; Vernikos-Danellis, J.

    1982-01-01

    The effects of horizontal bedrest on the excretion of catecholamines, aldosterone, and cortisol by human subjects grouped by age and sex are examined. The responses are assessed by assays of 24-hr urine samples collected throughout the studies. In 36-45-yr-olds, the excretion of epinephrine increases, whereas it decreases in the 46-55- and 56-65-yr-old groups. Norepinephrine excretion decreases (5-27%) in all groups during bedrest. Aldosterone excretion increases in the younger two groups of both males (19 and 6%) and females (47 and 9%). A slight decrease is observed in 56-65-yr-old males (6%), whereas excretion in females is unchanged. Cortisol excretion increases in the youngest groups of both men (12%) and women (13%) but decreases in the 56-65-yr-old groups (6 and 5%). For the two groups of intermediate age (46-55 yr), excretion in females decreases (15%), whereas in males it increases (19%). It is believed that hormone measurements may be of value in explaining variation in stress tolerance due to age and/or sex during space flight.

  15. Maturation of the inhibitory response of growth hormone secretion to ether stress in postnatal rat.

    PubMed

    Strbák, V; Jurcovicová, J; Vigas, M

    1985-05-01

    To study the maturation of inhibitory influences on growth hormone (GH) secretion the effect of ether stress on plasma GH levels was studied during postnatal ontogenesis in female rats. Ether stress did not affect plasma GH levels in 1-day-old pups. A distinct decrease of plasma GH was found in 3- and 9-day-old pups, and the response was prevented by treatment of 3-day-old animals with somatostatin antiserum. No effect of ether stress on plasma GH was noted in 12-, 15-, 18- and 21-day-old rats. Treatment of intact 12-day-old pups with the somatostatin antiserum increased plasma GH level under basal conditions. The inhibitory effect of ether stress on plasma GH was noted again at the age 30 days and in adult animals. It is concluded that the hypothalamus of 3-day-old rats is able to release enough somatostatin to inhibit GH secretion after stress. At the period 12-18 days a phase of pituitary refractoriness was noted: ether stress as well as TRH injection (our previous observation) fail to affect plasma GH in female pups, probably due to high somatostatin secretion under basal conditions and (or) low capacity of pituitary to release GH. It is suggested that regulation of GH secretion is not mature until after the 21st day of life.

  16. Stress hormones and immunological responses to a dual challenge in professional firefighters.

    PubMed

    Huang, Chun-Jung; Webb, Heather E; Garten, Ryan S; Kamimori, Gary H; Evans, Ronald K; Acevedo, Edmund O

    2010-03-01

    The purpose of this study was to examine the changes in heart rate (HR), catecholamines (norepinephrine [NE] and epinephrine [EPI]), pro-inflammatory cytokines (interleukin-2 [IL-2] and interleukin-6 [IL-6]), and lymphocytes (CD8+ and CD56+) in firefighters exposed to a decision-making challenge (firefighting strategies and tactics drill) while participating in moderate intensity exercise. Nine professional male firefighters participated in two counterbalanced exercise conditions on a cycle ergometer: (1) 37 min of cycle ergometry at 60% VO(2max) (exercise alone condition ; EAC) and (2) 37 min of cycle ergometry at 60% VO(2max) along with 20 min of a computerized firefighting strategy and tactics decision-making challenge (firefighting strategy condition; FSC). FSC elicited significantly greater HR, NE, EPI, and IL-2 when compared to EAC. These elevations may suggest that the addition of a mental challenge to physical stress can alter the hormonal and immunological responses during firefighting. In addition, this evidence provides insight into the possible mechanisms that explain the link between physical activity, psychological stress, and stress-related diseases.

  17. Beneficial effects of the transgenic expression of human sTNF-αR-Fc and HO-1 on pig-to-mouse islet xenograft survival.

    PubMed

    Yan, Ji-Jing; Yeom, Hye-Jeong; Jeong, Jong Cheol; Lee, Jae-Ghi; Lee, Eun Won; Cho, Bumrae; Lee, Han Sin; Kim, Su Jin; Hwang, Jong-Ik; Kim, Sung Joo; Lee, Byeong-Chun; Ahn, Curie; Yang, Jaeseok

    2016-02-01

    Both human soluble tumor necrosis factor-α receptor-Fc (sTNF-αR-Fc) and heme oxygenase-1 (HO-1) transgenic pigs have been generated previously for xenotransplantation. Here, we investigated whether overexpression of sTNF-αR-Fc or HO-1 in pig islets prolongs islet xenograft survival. Adult porcine islets were isolated from human sTNF-αR-Fc or HO-1 transgenic and wild type pigs, and were transplanted into diabetic nude mice. Effects of the expression of both genes on islet apoptosis, chemokine expression, cellular infiltration, antibody production, and islet xenograft survival were analyzed. Human sTNF-αR-Fc transgenic pigs successfully expressed sTNF-αR-Fc in the islets; human HO-1 transgenic pigs expressed significant levels of HO-1 in the islets. Pig-to-mouse islet xenograft survival was significantly prolonged in both the sTNF-αR-Fc and HO-1 groups compared with that in the wild type group. Both the sTNF-αR-Fc and HO-1 groups exhibited suppressed intragraft expression of monocyte chemoattractant protein-1 (MCP-1) and decreased perigraft infiltration of immune cells. However, there was no difference in the anti-pig antibody levels between the groups. Apoptosis of islet cells during the early engraftment was suppressed only in the HO-1 group. Porcine islets from both sTNF-αR-Fc and HO-1 transgenic pigs prolonged xenograft survival by suppressing islet cell apoptosis or secondary inflammatory responses following islet death, indicating that these transgenic pigs might have applications in successful islet xenotransplantation.

  18. The influence of collagenase solvent on the isolation of islets from 5 week old pigs: a comparison of TCM-199 and UW.

    PubMed

    Heald, K A; Jay, T R; Topham, D; Downing, R

    1999-01-01

    Islet transplantation is a potential treatment for diabetes, but the techniques for islet isolation are inefficient and the recovery rates for isolated islets are often low. As the solutions employed during the isolation process may affect islet yield, we have investigated the effect of collagenase solvent, and compared the effect of dissolving collagenase in TCM-199 (TCM) or University of Wisconsin (UW) solution on yield and viability of islets isolated from 5 week old pigs. Pancreata were transported to the laboratory in UW solution, and the islets isolated using a manual method of collagenase digestion. The optimum concentration of collagenase which would liberate the maximum number of islets was determined for each solvent, and then the yield and viability of islets isolated using collagenase in TCM and UW were compared. It was found that, when UW was used as collagenase solvent, a higher concentration of collagenase was required to liberate the maximum number of islets. Comparative experiments revealed that although the total number of isolated islets was greater using UW as the solvent, the number of islet equivalents was similar in both preparations. More than 90% of the cells in both preparations excluded trypan blue, although according to a scoring system, preparations isolated using UW showed greater viability. The stimulation indices in response to glucose and theophylline were similar for both preparations, but islets isolated using UW generally responded with a lower but more sustained insulin release. In conclusion, there was no difference between the total amount of islet tissue isolated using TCM or UW as solvent for collagenase. The preparations isolated using UW were more fragmented, but exhibited superior viability.

  19. Mink aging is associated with a reduction in ovarian hormone release and the response to FSH and ghrelin.

    PubMed

    Sirotkin, Alexander V; Mertin, Dušan; Süvegová, Karina; Lauričik, Jozef; Morovič, Martin; Harrath, Abdel Halim; Kotwica, Jan

    2016-09-15

    The endocrine mechanisms of mink ovarian hormones release and reproductive aging are poorly investigated. The aims of our study were to: (1) identify hormones produced by mink ovaries (the steroids progesterone [P] and estradiol [E], the peptide hormone oxytocin [OT], and the prostaglandin F [PGF] and prostaglandin E [PGE]); (2) examine the effect of FSH and ghrelin on the release of the hormones listed previously; and (3) understand whether these hormones can be involved in the control of mink reproductive aging, i.e., whether aging can be associated with changes (a) in the basal release of P, E, OT, PGF, or PGE and (b) their response to FSH and ghrelin. Fragments of ovaries of young (yearlings) and old (3-5 years of age) minks were cultured with and without FSH and ghrelin (0, 1, 10, or 100 ng/mL), and the release of hormones was analyzed by EIA/RIA. We found that isolated ovaries were able to release P, E, OT, PGF, and PGE, and the levels of P produced in the ovaries of old animals were lower than those produced in the ovaries of young animals, whereas the levels of other hormones did not differ. FSH was able to stimulate P and E and suppress OT and PGF and did not affect PGE release. Aging was associated with the inhibition of the effect of FSH on ovarian P and E, the appearance of the inhibitory action of FSH on OT, and the disappearance of this action on ovarian PGF. PGE was not affected by FSH, irrespective of animal age. Ghrelin was able to promote E (but not P) and suppress OT, PGF, and PGE output. Aging was associated with the appearance of an inhibitory influence of ghrelin on ovarian OT and PGE and with the disappearance of this influence on PGF output. Aging did not affect the action of ghrelin on ovarian P and E. Our observations (1) confirm the production of P and E and show that OT, PGF, and PGE are released from mink ovaries, (2) confirm the involvement of FSH and demonstrate the involvement of ghrelin in the control of mink ovarian hormone

  20. Identification of Donor Origin and Condition of Transplanted Islets In Situ in the Liver of a Type 1 Diabetic Recipient.

    PubMed

    van der Torren, Cornelis R; Suwandi, Jessica S; Lee, DaHae; Van't Wout, Ernst-Jan T; Duinkerken, Gaby; Swings, Godelieve; Mulder, Arend; Claas, Frans H J; Ling, Zhidong; Gillard, Pieter; Keymeulen, Bart; In't Veld, Peter; Roep, Bart O

    2017-01-24

    Transplantation of islet allografts into type 1 diabetic recipients usually requires multiple pancreas donors to achieve insulin independence. This adds to the challenges of immunological monitoring of islet transplantation currently relying on surrogate immune markers in peripheral blood. We investigated donor origin and infiltration of islets transplanted in the liver of a T1D patient who died of hemorrhagic stroke 4 months after successful transplantation with two intraportal islet grafts combining six donors. Immunohistological staining for donor HLA using a unique panel of human monoclonal HLA-specific alloantibodies was performed on liver cryosections after validation on cryopreserved kidney, liver, and pancreas and compared with auto- and alloreactive T-cell immunity in peripheral blood. HLA-specific staining intensity and signal-to-noise ratio varied between tissues from very strong on kidney glomeruli, less in liver, kidney tubuli, and endocrine pancreas to least in exocrine pancreas, complicating the staining of inflamed islets in an HLA-disparate liver. Nonetheless, five islets from different liver lobes could be attributed to donors 1, 2, and 5 by staining patterns with multiple HLA types. All islets showed infiltration with CD8+ cytotoxic T cells that was mirrored by progressive alloreactive responses in peripheral blood mononuclear cells (PBMCs) to donors 1, 2, and 5 after transplantation. Stably low rates of peripheral islet autoreactive T-cell responses after islet infusion fit with a complete HLA mismatch between grafts and recipient and exclude the possibility that the islet-infiltrating CD8 T cells were autoreactive. HLA-specific immunohistochemistry can identify donor origin in situ and differentiate graft dysfunction and immunological destruction.

  1. Hormone responses to an acute bout of low intensity blood flow restricted resistance exercise in college-aged females.

    PubMed

    Kim, Eonho; Gregg, Lee D; Kim, Ldaeyeol; Sherk, Vanessa D; Bemben, Michael G; Bemben, Debra A

    2014-01-01

    The purpose of this study was to determine whether the acute hormone response to exercise differed between low intensity blood flow restricted resistance exercise and traditional high-intensity resistance exercise in college-aged women. A total of 13 healthy women (aged 18-25 yrs), who were taking oral contraceptives, volunteered for this randomized crossover study. Subjects performed a session of low intensity blood flow restricted resistance exercise (BFR) (20% of 1-RM, 1 set 30 reps, 2 sets 15 reps) and a session of traditional high intensity resistance exercise without blood flow restriction (HI) (3 sets of 10 repetitions at 80% of 1-RM) on separate days. Fasting serum cortisol and growth hormone (GH) and blood lactate responses were measured in the morning pre and post exercise sessions. GH (Change: HI: 6.34 ± 1.72; BFR: 4.22 ± 1.40 ng·mL(-1)) and cortisol (Change: HI: 4.46 ± 1.53; BFR: 8.10 ± 2.30 ug·dL(-1)) significantly (p < 0.05) increased immediately post exercise for both protocols compared to baseline and there were no significant differences between the protocols for these responses. In contrast, blood lactate levels (HI: 7.35 ± 0.45; BFR: 4.02 ± 0.33 mmol·L(-1)) and ratings of perceived exertion were significantly (p < 0.01) higher for the HI protocol. In conclusion, acute BFR restricted resistance exercise stimulated similar increases in anabolic and catabolic hormone responses in young women. Key PointsGrowth hormone and cortisol levels significantly increased after a single bout of low intensity blood flow restricted resistance exercise in young women.There were no significant differences in hormone responses between the low intensity blood flow restricted protocol and the traditional high intensity higher total workload protocol.Low intensity blood flow restricted resistance exercise provides a sufficient stimulus to elicit anabolic and catabolic hormone responses in young women.

  2. Measurement and modeling of glucose-6-phosphatase in pancreatic islets.

    PubMed

    Sweet, I R; Najafi, H; Li, G; Grodberg, J; Matschinsky, F M

    1997-04-01

    In the beta-cells of the pancreas, glucose phosphorylation carried out by glucokinase is the rate-controlling step in glycolysis, and the kinetic characteristics of glucokinase govern to a high degree the dose-response relationship between glucose and insulin release. Because glucose-6-phosphatase (G-6-Pase) opposes the action of glucokinase, it may have a regulatory role in the release of insulin in response to glucose if the enzyme is present in the beta-cells. A number of researchers have reported finding high levels of G-6-Pase in islets, but quantitation of its activity remains controversial, mainly because of difficulties in solubilizing a particulate enzyme. Therefore a method developed to measure functional glucose phosphorylation activity in intact brain was applied (Chi, M. M.-Y., M. E. Pusateri, J. G. Carter, B. J. Norris, D. B. McDougal, Jr., and O. H. Lowry. Anal. Biochem. 161: 508-513, 1987), and the rates of accumulation and disappearance of 2-deoxyglucose 6-phosphate (DG-6-P) in freshly harvested islets were determined as a measure of glucose cycling. Islets were incubated in the presence of 30 mM 2-deoxyglucose (DG) for 60 min, and subsequently the incubation medium was replaced with medium containing no DG, but instead high levels of mannoheptulose as a blocker of phosphorylation. The content of DG-6-P in the islets was measured at strategic times during the protocol. As predicted by a mathematical model, DG-6-P accumulated in the presence of DG and decayed after its washout. Both of these results are consistent with islets containing dephosphorylation activity for this substrate. The kinetic curves were fit using a mathematical model, and the maximal G-6-Pase activity was estimated to be 0.13 +/- 0.005 micromol x g(-1) x min(-1). However, when the physiological effect of this amount of G-6-Pase activity was assessed by use of a model of glycolysis, it was found that the impact on glucose cycling and usage was insignificant. It was concluded that

  3. Inhibition of thyrotropin response to TSH-releasing hormone by thyroxine in hypothyroid rats

    SciTech Connect

    Boado, R.J.; Zaninovich, A.A.; Ulloa, E.R.; Fernandez Pol, J.A.

    1985-05-01

    Pharmacological amounts of throxine (T4) can inhibit the thyrotropin (TSH) response to TSH-releasing hormone (TRH) before its conversion to triiodothyronine (T3) in the hypophysis of euthyroid rate. The present work tested physiological doses of T4 in hypothyroid rats. Rats were treated with iopanoic acid (IOP) 5 mg/100 g BW 24, 12 and 1.5 hours preceding the study, to prevent intrapituitary conversion of T4 to T3. Nonradioactive T4 was injected iv at time 0. At 20 min a 1 ..mu..g/100 g BW dose of TRH was injected iv. Blood samples were drawn at times 0, 20, and 30 min for determination by radioimmunoassay of plasma T4, T3, and TSH. In untreated rats basal TSH was 1450 +- 200 (SEM) ..mu..U/ml. At 20 min it was 105 +- 12% the basal value and at 30 min (10 min post-TRH) plasma TSH rose to 165 +- 14%. In T4-treated rats, those injected with IOP or with the vehicle alone both had the TSH response suppressed. IOP reduced intrapitutiary T3 from 4.6 +- 2.4 to 0.5 +- 0.2 fmol/min/gland. Thirty min. following the iv injection of 150 ..mu..Ci of double-labeled /sup 125/I-T4, the in vitro cytoplasmic radioactivity in control rats was 1.3 +- 0.13 x 10-/sup 2/% of the injected dose (75% T4, 17% T3), while in nuclei it was 4.2 +- 3.6 x 10-/sup 3/% (5l% T4, 28% T3). The injection of 25 ..mu..g of nonradioactive T4 decreased /sup 125/I-T4 in cytoplasm with no changes in nuclei. These findings suggest an intrinsic capacity of T4 to control TRH stimulation of TSH through binding to cytoplasmic receptors.

  4. Growth hormone isoforms release in response to physiological and pharmacological stimuli.

    PubMed

    Pagani, S; Cappa, M; Meazza, C; Ubertini, G; Travaglino, P; Bozzola, E; Bozzola, M

    2008-06-01

    Ten healthy subjects used to performing regular physical activity and eight subjects affected by idiopathic isolated GH deficiency (GHD) were enrolled; 22- and 20-kDa GH secretion and its biological activity were evaluated in response to pharmacological stimuli such as arginine, L-dopa or glucagon in GHD children, while the hormonal response to exercise was studied according to Bruce protocol in healthy subjects. We found a significant increase in 22- and 20-kDa GH level in healthy subjects after monitored physical exercise (MPE; basal 0.28+/-0.12 vs 7.37+/-2.08 ng/ml and basal 0.076+/-0.04 vs 0.18+/-0.05 ng/ml, respectively). Furthermore, the 22-kDa/20-kDa ratio significantly increased in children who had undergone MPE and the GH bioactivity basal mean value also increased significantly after exercise (basal 2.86+/-0.76 vs 7.64+/-1.9 ng/ml). The mean value of 22-kDa GH in GHD patients increased significantly following GH pharmacological stimulation (2.78+/-0.63 ng/ml) when compared with mean basal (0.20+/-0.11 ng/ml) value. In the GHD group the basal concentration of 20-kDa GH significantly increased following GH pharmacological stimulation (0.34+/-0.11 vs 0.72+/-0.2 ng/ml); the 22-kDa/20-kDa ratio significantly increased too. Likewise, GH bioactivity in children with GHD increased significantly after pharmacological stimulation test (basal 2.53+/-0.56 vs 7.33+/-1.26 ng/ml). Both GH isoform concentrations and their biological activity are significantly increased in healthy subjects after submaximal exercise protocol and in GHD children after pharmacological stimuli.

  5. OsERF2 controls rice root growth and hormone responses through tuning expression of key genes involved in hormone signaling and sucrose metabolism.

    PubMed

    Xiao, Guiqing; Qin, Hua; Zhou, Jiahao; Quan, Ruidang; Lu, Xiangyang; Huang, Rongfeng; Zhang, Haiwen

    2016-02-01

    Root determines plant distribution, development progresses, stress response, as well as crop qualities and yields, which is under the tight control of genetic programs and environmental stimuli. Ethylene responsive factor proteins (ERFs) play important roles in plant growth and development. Here, the regulatory function of OsERF2 involved in root growth was investigated using the gain-function mutant of OsERF2 (nsf2857) and the artificial microRNA-mediated silenced lines of OsERF2 (Ami-OsERF2). nsf2857 showed short primary roots compared with the wild type (WT), while the primary roots of Ami-OsERF2 lines were longer than those of WT. Consistent with this phenotype, several auxin/cytokinin responsive genes involved in root growth were downregulated in nsf2857, but upregulated in Ami-OsERF2. Then, we found that nsf2857 seedlings exhibited decreased ABA accumulation and sensitivity to ABA and reduced ethylene-mediated root inhibition, while those were the opposite in Ami-ERF2 plants. Moreover, several key genes involved in ABA synthesis were downregulated in nsf2857, but unregulated in Ami-ERF2 lines. In addition, OsERF2 affected the accumulation of sucrose and UDPG by mediating expression of key genes involved in sucrose metabolism. These results indicate that OsERF2 is required for the control of root architecture and ABA- and ethylene-response by tuning expression of series genes involved in sugar metabolism and hormone signaling pathways.

  6. Metabolic responses to adrenocorticotropic hormone (ACTH) vary with life-history stage in adult male northern elephant seals.

    PubMed

    Ensminger, David C; Somo, Derek A; Houser, Dorian S; Crocker, Daniel E

    2014-08-01

    Strong individual and life-history variation in serum glucocorticoids has been documented in many wildlife species. Less is known about variation in hypothalamic-pituitary-adrenal (HPA) axis responsiveness and its impact on metabolism. We challenged 18 free-ranging adult male northern elephant seals (NES) with an intramuscular injection of slow-release adrenocorticotropic hormone (ACTH) over 3 sample periods: early in the breeding season, after 70+ days of the breeding fast, and during peak molt. Subjects were blood sampled every 30 min for 2h post-injection. Breeding animals were recaptured and sampled at 48 h. In response to the ACTH injection, cortisol increased 4-6-fold in all groups, and remained elevated at 48 h in early breeding subjects. ACTH was a strong secretagogue for aldosterone, causing a 3-8-fold increase in concentration. Cortisol and aldosterone responses did not vary between groups but were correlated within individuals. The ACTH challenge produced elevations in plasma glucose during late breeding and molting, suppressed testosterone and thyroid hormone at 48 h in early breeding, and increased plasma non-esterified fatty acids and ketoacids during molting. These data suggest that sensitivity of the HPA axis is maintained but the metabolic impacts of cortisol and feedback inhibition of the axis vary with life history stage. Strong impacts on testosterone and thyroid hormone suggest the importance of maintaining low cortisol levels during the breeding fast. These data suggest that metabolic adaptations to extended fasting in NES include alterations in tissue responses to hormones that mitigate deleterious impacts of acute or moderately sustained stress responses.

  7. Hypothalamic-pituitary-adrenal axis response to acute psychosocial stress: Effects of biological sex and circulating sex hormones.

    PubMed

    Stephens, Mary Ann C; Mahon, Pamela B; McCaul, Mary E; Wand, Gary S

    2016-04-01

    Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis influences the risk for developing stress-related disorders. Sex-dependent differences in the HPA axis stress response are believed to contribute to the different prevalence rates of stress-related disorders found in men and women. However, studies examining the HPA axis stress response have shown mixed support for sex differences, and the role of endogenous sex hormones on HPA axis response has not been adequately examined in humans. This study utilized the largest sample size to date to analyze the effects of biological sex and sex hormones on HPA axis social stress responses. Healthy, 18- to 30- year-old community volunteers (N=282) completed the Trier Social Stress Test (TSST), a widely used and well-validated stress-induction laboratory procedure. All women (n=135) were tested during the follicular phase of their menstrual cycle (when progesterone levels are most similar to men). Adrenocorticotropic hormone (ACTH) and cortisol measures were collected at multiple points throughout pre- and post-TSST. Testosterone and progesterone (in men) and progesterone and estradiol (in women) were determined pre-TSST. Following the TSST, men had greater ACTH and cortisol levels than women. Men had steeper baseline-to-peak and peak-to-end ACTH and cortisol response slopes than women; there was a trend for more cortisol responders among men than women. Testosterone negatively correlated with salivary cortisol response in men, while progesterone negatively correlated with ACTH and cortisol responses in women. These data confirm that men show more robust activation of the HPA axis response to the TSST than do women in the follicular phase of the menstrual cycle. Testosterone results suggest an inhibitory effect on HPA axis reactivity in men. Progesterone results suggest an inhibitory effect on HPA axis reactivity in women. Future work is needed to explain why men mount a greater ACTH and cortisol response to the

  8. Immunoreactive and bioactive growth hormone responses to resistance exercise in men who are lean or obese.

    PubMed

    Thomas, Gwendolyn A; Kraemer, William J; Kennett, Mary J; Comstock, Brett A; Maresh, Carl M; Denegar, Craig R; Volek, Jeff S; Hymer, Wesley C

    2011-08-01

    It has been suggested that obese individuals have a blunted growth hormone (GH) response to spontaneous and stimulated GH secretion. The present study was designed to examine the effects of a high-volume, whole body acute resistance exercise (RE) protocol on immunoreactive GH (iGH), bioactive GH (bGH), and GH-binding protein (GHBP) in sedentary lean and obese men. Nine obese (mean ± SD: 20.8 ± 2.1 yr old, 177.0 ± 4.1 cm height, 108.7 ± 15.9 kg body mass, 37.6 ± 5.29% body fat) and nine lean (20.1 ± 2.1 yr old, 177.8 ± 8.7 cm height, 71.7 ± 5.8 kg body mass, 14.7 ± 3.54% body fat) men completed an acute RE protocol (6 exercises, 3 sets of 10 repetitions at 85-95% of 10 repetitions maximum with 120- and 90-s rest periods), and blood samples were collected before, at the midpoint, and immediately after exercise and during recovery (+50, +70, and +110). In contrast to prior studies, which examined acute responses to cardiovascular exercise protocols, groups did not differ in iGH response to the exercise stimulus. However, bGH concentrations overall were significantly lower in the obese than the lean participants (P < 0.001). Additionally, obese individuals had significantly higher GHBP concentrations (P < 0.001). Results suggest that obese and lean sedentary men performing a high-volume, whole body acute RE protocol demonstrate similar increases in iGH. Blunted bGH and elevated GHBP concentrations are indicative of altered GH activity associated with obesity. Prior research findings of blunted iGH response may be attributable to RE protocols not equated on relative intensity or volume. These results underscore the complexity of pituitary biology and its related mechanisms and may have implications for exercise prescription in the treatment of obesity.

  9. IDX-1: a new homeodomain transcription factor expressed in rat pancreatic islets and duodenum that transactivates the somatostatin gene.

    PubMed Central

    Miller, C P; McGehee, R E; Habener, J F

    1994-01-01

    We describe the cloning from a rat islet somatostatin-producing cell line of a 1.4 kb cDNA encoding a new homeoprotein, IDX-1 (islet/duodenum homeobox-1), with close sequence similarity to the Drosophila melanogaster homeobox protein Antennapedia (Antp) and the Xenopus laevis endoderm-specific homeoprotein XlHbox8. Analyses of IDX-1 mRNA and protein in rat tissues show that IDX-1 is expressed in pancreatic islets and ducts and in the duodenum. In electrophoretic mobility shift assays IDX-1 binds to three sites in the 5' flanking region of the rat somatostatin gene. In co-transfection experiments IDX-1 transactivates reporter constructs containing somatostatin promoter sequences, and mutation of the IDX-1 binding sites attenuates transactivation. Reverse transcription-polymerase chain reaction of islet RNA using degenerate amplimers for mRNAs encoding homeoproteins indicates that IDX-1 is the most abundant of 12 different Antp-like homeodomain mRNAs expressed in adult rat islets. The pattern of expression, relative abundance and transcriptional regulatory activity suggests that IDX-1 may be involved in the regulation of islet hormone genes and in cellular differentiation in the endocrine pancreas and the duodenum. Images PMID:7907546

  10. Activation of human macrophages by allogeneic islets preparations: inhibition by AOP-RANTES and heparinoids.

    PubMed

    Sigrist, Séverine; Oberholzer, José; Bohbot, Alain; Esposito, Guy; Mandes, Karim; Lamartine, Roger; Toso, Christian; Bucher, Pascal; Pinget, Michel; Kessler, Laurence

    2004-04-01

    During transplantation, pancreatic islets release chemokines which promote macrophage attraction, hampering engraftment of islets. The aim of this study was to modulate chemotaxis and the immune response of human macrophages induced by islets. Human monocyte-derived macrophages of healthy subjects were exposed to supernatants of human islets. Chemotaxis, tumour necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) release were evaluated. To modulate migration, human macrophages were incubated in the presence of aminooxypentane-regulated on activation, normal, T-cell expressed, and secreted (AOP-RANTES), a potent antagonist of CCR5. Chemotactic activity of islets supernatant was modulated by the addition of heparin or heparinoids [pentosan and calix[8S]arene (C8S)]. AOP-RANTES significantly reduced, in a dose-dependent manner, macrophage chemotaxis and cytokine release induced by islets supernatant. The chemotactic index was reduced from 3.05 +/- 0.27 to 0.71 +/- 12, TNF-alpha from 1205 +/- 52 to 202 +/- 12 pg/ml, and IL-1beta from 234 +/- 12 to 10 +/- 6 pg/ml. The trapping of chemokines by heparinoids reduced the chemotactic activity of islets supernatant from 3.05 +/- 0.27 to 1.2 +/- 0.1 with heparin or pentosan and to 1.72 +/- 0.22 with C8S, and also decreased the TNF-alpha release by human macrophages from 1205 +/- 35 to 1000 +/- 26 (C8S), 250 +/- 21 (heparin) and 320 +/- 19 (pentosan) pg/ml, and IL-1beta from 234 +/- 13 to 151 +/- 5 (C8S), 50 +/- 3 (heparin) and 57 +/- 4 (pentosan) pg/ml. In conclusion, AOP-RANTES and heparinoids inhibit human macrophage activation and migration induced by islets supernatant.

  11. Activation of human macrophages by allogeneic islets preparations: inhibition by AOP-RANTES and heparinoids

    PubMed Central

    Sigrist, Séverine; Oberholzer, José; Bohbot, Alain; Esposito, Guy; Mandes, Karim; Lamartine, Roger; Toso, Christian; Bucher, Pascal; Pinget, Michel; Kessler, Laurence

    2004-01-01

    During transplantation, pancreatic islets release chemokines which promote macrophage attraction, hampering engraftment of islets. The aim of this study was to modulate chemotaxis and the immune response of human macrophages induced by islets. Human monocyte-derived macrophages of healthy subjects were exposed to supernatants of human islets. Chemotaxis, tumour necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) release were evaluated. To modulate migration, human macrophages were incubated in the presence of aminooxypentane-regulated on activation, normal, T-cell expressed, and secreted (AOP-RANTES), a potent antagonist of CCR5. Chemotactic activity of islets supernatant was modulated by the addition of heparin or heparinoids [pentosan and calix[8S]arene (C8S)]. AOP-RANTES significantly reduced, in a dose-dependent manner, macrophage chemotaxis and cytokine release induced by islets supernatant. The chemotactic index was reduced from 3·05 ± 0·27 to 0·71 ± 12, TNF-α from 1205 ± 52 to 202 ± 12 pg/ml, and IL-1β from 234 ± 12 to 10 ± 6 pg/ml. The trapping of chemokines by heparinoids reduced the chemotactic activity of islets supernatant from 3·05 ± 0·27 to 1·2 ± 0·1 with heparin or pentosan and to 1·72 ± 0·22 with C8S, and also decreased the TNF-α release by human macrophages from 1205 ± 35 to 1000 ± 26 (C8S), 250 ± 21 (heparin) and 320 ± 19 (pentosan) pg/ml, and IL-1β from 234 ± 13 to 151 ± 5 (C8S), 50 ± 3 (heparin) and 57 ± 4 (pentosan) pg/ml. In conclusion, AOP-RANTES and heparinoids inhibit human macrophage activation and migration induced by islets supernatant. PMID:15056378

  12. A protective effect of endomorphins on the oxidative injury of islet.

    PubMed

    Tian, L M; Liu, J; Sun, X L; Gao, C X; Fan, Y; Guo, Q

    2010-08-01

    The antioxidative capacity of endomorphins (EMs), endogenous μ-opioid receptor agonists, has been demonstrated by IN VIVO assays. In this study, we attempt to evaluate the effects of endomorphin 1 (EM1) and endomorphin 2 (EM2) on pancreatic islet injuries induced by streptozotocin (STZ), alloxan (ALX) and H(2)O(2), respectively. Wistar rats' islets were isolated and purified. The function of the islet cells, the insulin response to glucose stimulation was examined by insulin Radio Immuno Assay and the cell viability was measured by MTT assay. DNA fragments were performed to evaluate the apoptosis, while the cell cycle distribution was analyzed by PI staining flow cytometric analysis. Furthermore, the islet were treated with EM1, EM2 or ALX for 24 h, and the expression of p53 and p21 protein were determined by Western blot. The results showed that STZ, ALX, and H(2)O(2) displayed clear concentration-dependent inhibitory effects on the pancreatic islet cells. While EMs improved the viability of islet induced by STZ, ALX or H(2)O(2), and EMs enhanced insulin accumulation of the cell supernatant after ALX and STZ stimulation. Our data also showed both that EMs inhibited cell apoptosis and cell cycle G1 arrest induced by STZ and ALX through down-regulaing p53 and p21 expression. Taken together, these results demonstrate that EMs can protect islet cells from STZ, ALX and H(2)O(2) induced injuries. Our observations imply that the endomorphins may have protective effects on islet cells oxidative injury.

  13. Transcriptome response to hormonal manipulation of follicle-enclosed oocytes in rainbow trout

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Captive fish often display reproductive dysfunction associated with follicle maturation. Gonadotropins and the progestogen maturation-inducing hormones (MIH) are important regulators of follicle maturation; however, their actions including regulating follicle maturation are not fully understood. The...

  14. DEVELOPMENTAL THYROID HORMONE INSUFFICIENCY ALTERS THE AMPLITUDE OF THE ACOUSTIC STARTLE RESPONSE IN RATS

    EPA Science Inventory

    Purpose: The thyroid hormone (TH) system is one of the targets of endocrine disrupting chemicals. Since TH is essential for proper brain development, disruption by exposure to chemicals during development can result in adverse neurological outcomes. Previous studies revealed th...

  15. Effects of gonadectomy and testosterone replacement on growth hormone response to alpha 2 adrenergic stimulation in the male rat.

    PubMed

    Jansson, J O; Eriksson, E; Edén, S; Modigh, K

    1982-01-01

    The growth hormone (GH) response to clonidine in reserpine-pretreated rats is a putative in vivo model to reflect activation of central postsynaptic alpha 2 receptors. In the present study the influence of testosterone on the responsiveness of central alpha 2 receptors was investigated using this method. One week after operation the GH response to clonidine was drastically reduced in gonadectomized adult male rats compared to sham-operated controls. Testosterone replacement completely antagonized the effect. The results suggest an influence of testosterone on central postsynaptic alpha 2 receptors or on structures connected to these receptors.

  16. The effect of Yohimbine, an alpha2 adrenergic receptor antagonist, on the growth hormone response to apomorphine in normal subjects.

    PubMed Central

    Lal, S; Thavundayil, J X; Krishnan, B; Nair, N P; Schwartz, G; Guyda, H

    1996-01-01

    Yohimbine HCl (16 mg po) administered 30 min before clonidine (CLON) (2 ug/kg infused over 10 min) (N = 5) or apomorphine HCl (Apo) (0.5 mg sc) (N = 10) antagonized the growth hormone (GH) response to CLON but had no effect on the GH response to Apo in normal men. This finding suggests that in humans, alpha2 adrenergic mechanisms do not modulate dopaminergic function, at least not in the hypothalamic-pituitary axis, and that the GH response to Apo is not mediated via an alpha2 adrenergic link. PMID:8820174

  17. PAX4 Defines an Expandable β-Cell Subpopulation in the Adult Pancreatic Islet

    PubMed Central

    Lorenzo, Petra I.; Fuente-Martín, Esther; Brun, Thierry; Cobo-Vuilleumier, Nadia; Jimenez-Moreno, Carmen María; G. Herrera Gomez, Irene; López Noriega, Livia; Mellado-Gil, José Manuel; Martin-Montalvo, Alejandro; Soria, Bernat; Gauthier, Benoit R.

    2015-01-01

    PAX4 is a key regulator of pancreatic islet development whilst in adult acute overexpression protects β-cells against stress-induced apoptosis and stimulates proliferation. Nonetheless, sustained PAX4 expression promotes β-cell dedifferentiation and hyperglycemia, mimicking β-cell failure in diabetic patients. Herein, we study mechanisms that allow stringent PAX4 regulation endowing favorable β-cell adaptation in response to changing environment without loss of identity. To this end, PAX4 expression was monitored using a mouse bearing the enhanced green fluorescent protein (GFP) and cre recombinase construct under the control of the islet specific pax4 promoter. GFP was detected in 30% of islet cells predominantly composed of PAX4-enriched β-cells that responded to glucose-induced insulin secretion. Lineage tracing demonstrated that all islet cells were derived from PAX4+ progenitor cells but that GFP expression was confined to a subpopulation at birth which declined with age correlating with reduced replication. However, this GFP+ subpopulation expanded during pregnancy, a state of active β-cell replication. Accordingly, enhanced proliferation was exclusively detected in GFP+ cells consistent with cell cycle genes being stimulated in PAX4-overexpressing islets. Under stress conditions, GFP+ cells were more resistant to apoptosis than their GFP- counterparts. Our data suggest PAX4 defines an expandable β-cell sub population within adult islets. PMID:26503027

  18. Use of perfluorocarbon nanoparticles for non-invasive multimodal cell tracking of human pancreatic islets

    PubMed Central

    Barnett, Brad P.; Ruiz-Cabello, Jesus; Hota, Partha; Ouwerkerk, Ronald; Shamblott, Michael J.; Lauzon, Cal; Walczak, Piotr; Gilson, Wesley D.; Chacko, Vadappuram P.; Kraitchman, Dara L.; Arepally, Aravind; Bulte, Jeff W. M.

    2011-01-01

    In vivo imaging of engraftment and immunorejection of transplanted islets is critical for further clinical development, with 1H MR imaging of superparamagnetic iron oxide-labeled cells being the current premier modality. Using perfluorocarbon nanoparticles, we present here a strategy for non-invasive imaging of cells using other modalities. To this end, human cadaveric islets were labeled with rhodamine-perfluorooctylbromide (PFOB) nanoparticles, rhodamine-perfluoropolyether (PFPE) nanoparticles or Feridex® as control and tested in vitro for cell viability and c-peptide secretion for 1 week. 19F MRI, computed tomography (CT) and ultrasound (US) imaging was performed on labeled cell phantoms and on cells following transplantation beneath the kidney capsule of mice and rabbits. PFOB and PFPE-labeling did not reduce human islet viability or glucose responsiveness as compared with unlabeled cells or SPIO-labeled cells. PFOB- and PFPE-labeled islets were effectively fluorinated for visualization by 19F MRI. PFOB-labeled islets were acoustically reflective for detection by US imaging and became sufficiently brominated to become radiopaque allowing visualization with CT. Thus, perfluorocarbon nanoparticles are multimodal cellular contrast agents that may find applications in real-time targeted delivery and imaging of transplanted human islets or other cells in a clinically applicable manner using MRI, US or CT imaging. PMID:21861285

  19. Use of perfluorocarbon nanoparticles for non-invasive multimodal cell tracking of human pancreatic islets.

    PubMed

    Barnett, Brad P; Ruiz-Cabello, Jesus; Hota, Partha; Ouwerkerk, Ronald; Shamblott, Michael J; Lauzon, Cal; Walczak, Piotr; Gilson, Wesley D; Chacko, Vadappuram P; Kraitchman, Dara L; Arepally, Aravind; Bulte, Jeff W M

    2011-01-01

    In vivo imaging of engraftment and immunorejection of transplanted islets is critical for further clinical development, with (1)H MR imaging of superparamagnetic iron oxide-labeled cells being the current premier modality. Using perfluorocarbon nanoparticles, we present here a strategy for non-invasive imaging of cells using other modalities. To this end, human cadaveric islets were labeled with rhodamine-perfluorooctylbromide (PFOB) nanoparticles, rhodamine-perfluoropolyether (PFPE) nanoparticles or Feridex as control and tested in vitro for cell viability and c-peptide secretion for 1 week. (19)F MRI, computed tomography (CT) and ultrasound (US) imaging was performed on labeled cell phantoms and on cells following transplantation beneath the kidney capsule of mice and rabbits. PFOB and PFPE-labeling did not reduce human islet viability or glucose responsiveness as compared with unlabeled cells or SPIO-labeled cells. PFOB- and PFPE-labeled islets were effectively fluorinated for visualization by (19)F MRI. PFOB-labeled islets were acoustically reflective for detection by US imaging and became sufficiently brominated to become radiopaque allowing visualization with CT. Thus, perfluorocarbon nanoparticles are multimodal cellular contrast agents that may find applications in real-time targeted delivery and imaging of transplanted human islets or other cells in a clinically applicable manner using MRI, US or CT imaging.

  20. The fractal spatial distribution of pancreatic islets in three dimensions: a self-avoiding growth model.

    PubMed

    Jo, Junghyo; Hörnblad, Andreas; Kilimnik, German; Hara, Manami; Ahlgren, Ulf; Periwal, Vipul

    2013-06-01

    The islets of Langerhans, responsible for controlling blood glucose levels, are dispersed within the pancreas. A universal power law governing the fractal spatial distribution of islets in two-dimensional pancreatic sections has been reported. However, the fractal geometry in the actual three-dimensional pancreas volume, and the developmental process that gives rise to such a self-similar structure, has not been investigated. Here, we examined the three-dimensional spatial distribution of islets in intact mouse pancreata using optical projection tomography and found a power law with a fractal dimension of 2.1. Furthermore, based on two-dimensional pancreatic sections of human autopsies, we found that the distribution of human islets also follows a universal power law with a fractal dimension of 1.5 in adult pancreata, which agrees with the value previously reported in smaller mammalian pancreas sections. Finally, we developed a self-avoiding growth model for the development of the islet distribution and found that the fractal nature of the spatial islet distribution may be associated with the self-avoidance in the branching process of vascularization in the pancreas.

  1. The fractal spatial distribution of pancreatic islets in three dimensions: a self-avoiding growth model

    NASA Astrophysics Data System (ADS)

    Jo, Junghyo; Hörnblad, Andreas; Kilimnik, German; Hara, Manami; Ahlgren, Ulf; Periwal, Vipul

    2013-06-01

    The islets of Langerhans, responsible for controlling blood glucose levels, are dispersed within the pancreas. A universal power law governing the fractal spatial distribution of islets in two-dimensional pancreatic sections has been reported. However, the fractal geometry in the actual three-dimensional pancreas volume, and the developmental process that gives rise to such a self-similar structure, has not been investigated. Here, we examined the three-dimensional spatial distribution of islets in intact mouse pancreata using optical projection tomography and found a power law with a fractal dimension of 2.1. Furthermore, based on two-dimensional pancreatic sections of human autopsies, we found that the distribution of human islets also follows a universal power law with a fractal dimension of 1.5 in adult pancreata, which agrees with the value previously reported in smaller mammalian pancreas sections. Finally, we developed a self-avoiding growth model for the development of the islet distribution and found that the fractal nature of the spatial islet distribution may be associated with the self-avoidance in the branching process of vascularization in the pancreas.

  2. Efficient gene delivery and silencing of mouse and human pancreatic islets

    PubMed Central

    2010-01-01

    Background In view of the importance of beta cells in glucose homeostasis and the profound repercussions of beta cell pathology on human health, the acquisition of tools to study pancreatic islet function is essential for the design of alternative novel therapies for diabetes. One promising approach toward this goal involves the modification of gene expression profile of beta cells. Results This study describes a new method of gene and siRNA delivery into human pancreatic islets by microporation technology. We demonstrated that mild islet distention with accutase greatly enhanced the transfection efficiency without compromising in vitro function (secretion, apoptosis and viability). As an example, the recently identified gene involved in type 2 diabetes, ZnT8, can be over-expressed or silenced by RNA interference using this technology. Microporation can also be used on rodent islets. Conclusions Taken together, our results demonstrate that microporation technology can be used to modify gene expression in whole rodent and human islets without altering their in vitro function and will be key to the elucidation of the factors responsible for proper islet function. PMID:20353585

  3. Hypohydration and Acclimation: Effects on Hormone Responses to Excercise/Heat Stress.

    DTIC Science & Technology

    1983-03-15

    During acclimation and test intervals, Ss wore shorts, t-shirts, and tennis shoes; ad lib water was available during the acclimation regimen, and in... anaerobic exercise on GH while Okada et al. (18) " reported the effects of passive heat exposure. As in our own experiments several earlier studies... anaerobic running exercise on plasma growth hormone, cortisol, luteinizing hormone, testosterone, androstenedione, estrone and estradiol. 3. Ster

  4. Total Pancreatectomy With Islet Autotransplantation

    PubMed Central

    Bellin, Melena D.; Gelrud, Andres; Arreaza-Rubin, Guillermo; Dunn, Ty B.; Humar, Abhinav; Morgan, Katherine A.; Naziruddin, Bashoo; Rastellini, Cristiana; Rickels, Michael R.; Schwarzenberg, Sarah J.; Andersen, Dana K.

    2015-01-01

    A workshop sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases focused on research gaps and opportunities in total pancreatectomy with islet autotransplantation (TPIAT) for the management of chronic pancreatitis. The session was held on July 23, 2014 and structured into 5 sessions: (1) patient selection, indications, and timing; (2) technical aspects of TPIAT; (3) improving success of islet autotransplantation; (4) improving outcomes after total pancreatectomy; and (5) registry considerations for TPIAT. The current state of knowledge was reviewed; knowledge gaps and research needs were specifically highlighted. Common themes included the need to identify which patients best benefit from and when to intervene with TPIAT, current limitations of the surgical procedure, diabetes remission and the potential for improvement, opportunities to better address pain remission, GI complications in this population, and unique features of children with chronic pancreatitis considered for TPIAT. The need for a multicenter patient registry that specifically addresses the complexities of chronic pancreatitis and total pancreatectomy outcomes and postsurgical diabetes outcomes was repeatedly emphasized. PMID:25599324

  5. A second glucagon in the pancreatic islets of the daddy sculpin Cottus scorpius.

    PubMed

    Cutfield, S M; Cutfield, J F

    1993-09-01

    The peptide hormone glucagon has been isolated from the islet tissue (Brockmann bodies) of the teleost Cottus scorpius (daddy sculpin) and sequenced. The sequence is HSEGTSNDYSKYLEDRKAQDFVQWLMNN differing at four positions from the glucagon found earlier in the same species by Conlon and coworkers (1987b, Eur. J. Biochem, 164, 117-122). Thus sculpin, in common with anglerfish, possesses two distinct glucagons. Comparative sequence data are presented as a phylogenetic tree.

  6. The meaning of anti-Müllerian hormone levels in patients at a high risk of poor ovarian response

    PubMed Central

    Park, Hyun Jong; Lee, Geun Ho; Gong, Du Sik; Yoon, Tae Ki

    2016-01-01

    Measurements of ovarian reserve play an important role in predicting the clinical results of assisted reproductive technology (ART). The ideal markers of ovarian reserve for clinical applications should have high specificity in order to determine genuine poor responders. Basal follicle-stimulating hormone levels, antral follicle count, and serum anti-Müllerian hormone (AMH) levels have been suggested as ovarian reserve tests that may fulfill this requirement, with serum AMH levels being the most promising parameter. Serum AMH levels have been suggested to be a predictor of clinical pregnancy in ART for older women, who are at a high risk for decreased ovarian response. We reviewed the prognostic significance of ovarian reserve tests for patients undergoing ART treatment, with a particular focus on the significance of serum AMH levels in patients at a high risk of poor ovarian response. PMID:27689035

  7. Hormone levels

    MedlinePlus

    Blood or urine tests can determine the levels of various hormones in the body. This includes reproductive hormones, thyroid hormones, adrenal hormones, pituitary hormones, and many others. For more information, see: ...

  8. Glutathione Ethyl Ester Supplementation during Pancreatic Islet Isolation Improves Viability and Transplant Outcomes in a Murine Marginal Islet Mass Model

    PubMed Central

    Raposo do Amaral, Alexandre S.; Pawlick, Rena L.; Rodrigues, Erika; Costal, Flavia; Pepper, Andrew; Ferreira Galvão, Flávio H.; Correa-Giannella, Maria Lucia; Shapiro, A. M.James

    2013-01-01

    Background The success of pancreatic islet transplantation still faces many challenges, mainly related to cell damage during islet isolation and early post-transplant. The increased generation of reactive oxygen species (ROS) during islet isolation and the consumption of antioxidant defenses appear to be an important pathway related to islet damage. Methodology/Principal Findings In the present study we evaluated whether supplementation of glutathione-ethyl-ester (GEE) during islet isolation could improve islet viability and transplant outcomes in a murine marginal islet mass model. We also cultured human islets for 24 hours in standard CMRL media with or without GEE supplementation. Supplementation of GEE decreased the content of ROS in isolated islets, leading to a decrease in apoptosis and maintenance of islet viability. A higher percentage of mice transplanted with a marginal mass of GEE treated islets became euglycemic after transplant. The supplementation of 20 mM GEE in cultured human islets significantly reduced the apoptosis rate in comparison to untreated islets. Conclusions/Significance GEE supplementation was able to decrease the apoptosis rate and intracellular content of ROS in isolated islets and might be considered a potential intervention to improve islet viability during the isolation process and maintenance in culture before islet transplantation. PMID:23424628

  9. Taurine supplementation modulates glucose homeostasis and islet function.

    PubMed

    Carneiro, Everardo M; Latorraca, Marcia Q; Araujo, Eliana; Beltrá, Marta; Oliveras, Maria J; Navarro, Mónica; Berná, Genoveva; Bedoya, Francisco J; Velloso, Licio A; Soria, Bernat; Martín, Franz

    2009-07-01

    Taurine is a conditionally essential amino acid for human that is involved in the control of glucose homeostasis; however, the mechanisms by which the amino acid affects blood glucose levels are unknown. Using an animal model, we have studied these mechanisms. Mice were supplemented with taurine for 30 d. Blood glucose homeostasis was assessed by intraperitoneal glucose tolerance tests (IPGTT). Islet cell function was determined by insulin secretion, cytosolic Ca2+ measurements and glucose metabolism from isolated islets. Islet cell gene expression and translocation was examined via immunohistochemistry and quantitative real-time polymerase chain reaction. Insulin signaling was studied by Western blot. Islets from taurine-supplemented mice had: (i) significantly higher insulin content, (ii) increased insulin secretion at stimulatory glucose concentrations, (iii) significantly displaced the dose-response curve for glucose-induced insulin release to the left, (iv) increased glucose metabolism at 5.6 and 11.1-mmol/L concentrations; (v) slowed cytosolic Ca2+ concentration ([Ca2+]i) oscillations in response to stimulatory glucose concentrations; (vi) increased insulin, sulfonylurea receptor-1, glucokinase, Glut-2, proconvertase and pancreas duodenum homeobox-1 (PDX-1) gene expression and (vii) increased PDX-1 expression in the nucleus. Moreover, taurine supplementation significantly increased both basal and insulin stimulated tyrosine phosphorylation of the insulin receptor in skeletal muscle and liver tissues. Finally, taurine supplemented mice showed an improved IPGTT. These results indicate that taurine controls glucose homeostasis by regulating the expression of genes required for glucose-stimulated insulin secretion. In addition, taurine enhances peripheral insulin sensitivity.

  10. Combinatorial interaction network of transcriptomic and phenotypic responses to nitrogen and hormones in the Arabidopsis thaliana root.

    PubMed

    Ristova, Daniela; Carré, Clément; Pervent, Marjorie; Medici, Anna; Kim, Grace Jaeyoon; Scalia, Domenica; Ruffel, Sandrine; Birnbaum, Kenneth D; Lacombe, Benoît; Busch, Wolfgang; Coruzzi, Gloria M; Krouk, Gabriel

    2016-10-25

    Plants form the basis of the food webs that sustain animal life. Exogenous factors, such as nutrients and sunlight, and endogenous factors, such as hormones, cooperate to control both the growth and the development of plants. We assessed how Arabidopsis thaliana integrated nutrient and hormone signaling pathways to control root growth and development by investigating the effects of combinatorial treatment with the nutrients nitrate and ammonium; the hormones auxin, cytokinin, and abscisic acid; and all binary combinations of these factors. We monitored and integrated short-term genome-wide changes in gene expression over hours and long-term effects on root development and architecture over several days. Our analysis revealed trends in nutrient and hormonal signal crosstalk and feedback, including responses that exhibited logic gate behavior, which means that they were triggered only when specific combinations of signals were present. From the data, we developed a multivariate network model comprising the signaling molecules, the early gene expression modulation, and the subsequent changes in root phenotypes. This multivariate network model pinpoints several genes that play key roles in the control of root development and may help understand how eukaryotes manage multifactorial signaling inputs.

  11. Systemic above- and belowground cross talk: hormone-based responses triggered by Heterodera schachtii and shoot herbivores in Arabidopsis thaliana

    PubMed Central

    Kammerhofer, Nina; Egger, Barbara; Dobrev, Petre; Vankova, Radomira; Hofmann, Julia; Schausberger, Peter; Wieczorek, Krzysztof

    2015-01-01

    Above- and belowground plant parts are simultaneously attacked by different pests and pathogens. The host mediates these interactions and physiologically reacts, e.g. with local and systemic alterations of endogenous hormone levels coupled with coordinated transcriptional changes. This in turn affects attractiveness and susceptibility of the plant to subsequent attackers. Here, the model plant Arabidopsis thaliana is used to study stress hormone-based systemic responses triggered by simultaneous root parasitism by the cyst nematode Heterodera schachtii and shoot herbivory by the thrips Frankliniella occidentalis and the spider mite Tetranychus urticae. First, HPLC/MS and quantitative reverse transcriptase PCR are used to show that nematode parasitism strongly affects stress hormone levels and expression of hormone marker genes in shoots. Previous nematode infection is then demonstrated to affect the behavioural and life history performance of both arthropods. While thrips explicitly avoid nematode-infected plants, spider mites prefer them. In addition, the life history performance of T. urticae is significantly enhanced by nematode infection. Finally, systemic changes triggered by shoot-feeding F. occidentalis but not T. urticae are shown to make the roots more attractive for H. schachtii. This work emphasises the importance of above- and belowground signalling and contributes to a better understanding of plant systemic defence mechanisms against plant-parasitic nematodes. PMID:26324462

  12. Effects of growth hormone-releasing factor on growth hormone response, growth and feed conversion efficiency in buffalo heifers (Bubalus bubalis).

    PubMed

    Haldar, A; Prakash, B S

    2007-09-01

    The aim of this study was to determine the benefits of growth hormone-releasing factor (GRF) on growth and feed conversion efficiency (FCE) in buffaloes. Twelve Murrah buffalo heifers (Bubalus bubalis) of mean age 24.8 months and mean body weight 302.4kg were divided into two groups (treatment and control) with six animals in each group. The buffaloes were given intravenous injections of bovine GRF (bGRF) at a dose rate of 10microg/100kg body weight or an equal volume of saline at 15-day intervals for a period of 9 months. Plasma growth hormone (GH) responses to bGRF challenge were measured in blood samples collected at 90-day intervals on days 1, 90, 180 and 270 and samples were taken at -60, -30, 0, +10, +20, +30, +60, +120 and +180min relative to bGRF injection. Blood samples were also collected weekly by jugular venepuncture for the quantification of plasma GH. The average growth rate (AGR) and FCE of all animals were recorded at 15-day intervals. Plasma GH concentrations increased (P=0.001) steadily following bGRF challenge, peaking 10-20min after challenge and declining to baseline by 180min. In the treatment group, there were no significant differences (P>0.05) in either the peak heights of the GH response or the area under the curve (AUC) of the GH response after bGRF challenge on any of the four occasions of intensive bleeding. There were overall increases in plasma GH concentrations (P<0.01), AGR (P<0.01) and FCE (P=0.05) in the treatment group compared with the control animals. The study showed that GH responsiveness to administration of bGRF at 15-day intervals over 9 months of treatment remained unchanged in buffalo heifers. Exogenous bGRF treatment for a long period can therefore enhance GH release leading to higher growth rates and better feed conversion efficiency in buffalo heifers.

  13. Seasonal changes of responses to gonadotropin-releasing hormone analog in expression of growth hormone/prolactin/somatolactin genes in the pituitary of masu salmon.

    PubMed

    Bhandari, Ramji Kumar; Taniyama, Shinya; Kitahashi, Takashi; Ando, Hironori; Yamauchi, Kohei; Zohar, Yonathan; Ueda, Hiroshi; Urano, Akihisa

    2003-01-01

    Gonadotropin-releasing hormone (GnRH) is considered to stimulate secretion of growth hormone (GH), prolactin (PRL), and somatolactin (SL) at particular stages of growth and sexual maturation in teleost fishes. We therefore examined seasonal variation in the pituitary levels of GH/PRL/SL mRNAs, and tried to clarify seasonal changes of responses to GnRH in expression of GH/PRL/SL genes, in the pituitaries of growing and maturing masu salmon (Oncorhynchus masou). Pituitary samples were monthly collected one week after implantation with GnRH analog (GnRHa). The levels of mRNAs encoding GH, PRL, and SL precursors in single pituitaries were determined by a real-time polymerase chain reaction method. The fork lengths and body weights of control and GnRHa-implanted fish of both sexes gradually increased and peaked out in September of 2-year-old (2+) when fish spawned. GnRHa implantation did not stimulate somatic growth, nor elevate gonadosomatic index (GSI) of 1+ and 2+ males, whereas it significantly increased GSI of 2+ females in late August to early September. The GnRHa-implanted 1+ males had higher levels of GH and PRL mRNAs in July, and SL mRNA from June to August than the control males. The levels of GH, PRL, and SL mRNAs in the control and GnRHa-implanted 1+ females, however, did not show any significant changes. Afterward, the PRL mRNA levels elevated in the control 2+ fish of both sexes in spring. GnRHa elevated the GH mRNA levels in both males and females in 2+ winter, and the PRL mRNA levels in females in early spring. Regardless of sex and GnRHa-implantation, the SL mRNA levels increased during sexual maturation. In growing and maturing masu salmon, expression of genes encoding GH, PRL, and SL in the pituitary is thus sensitive to GnRH in particular seasons probably in relation to physiological roles of the hormones.

  14. Inhibitory effect of kisspeptins on insulin secretion from isolated mouse islets.

    PubMed

    Vikman, J; Ahrén, B

    2009-11-01

    Islet hormone secretion is regulated by a variety of factors, and many of these signal through G protein-coupled receptors (GPCRs). A novel islet GPCR is GPR54, which couples to the Gq isoform of G proteins, which in turn signal through the phospholipase C pathway. Ligands for GPR54 are kisspeptins, which are peptides encoded in the KISS1 gene and also expressed in islet beta-cells. The KISS1 gene encodes a hydrophobic 145-amino acid protein that is cleaved into a 54-amino acid protein, kisspeptin-54 or KP54. Shorter kisspeptins also exist, such as kisspeptin-10 (KP10) and kisspeptin-13 (KP13). The involvement of GPR54 and kisspeptins in the regulation of islet function is not known. To address this problem, we incubated isolated mouse islets in the presence of KP13 and KP54 for 60 min and measured insulin secretion. We found that both KP13 and KP54 at 10 nM, 100 nM and 1microM inhibited insulin secretion in the presence of 2.8 mM glucose. However, by increasing the glucose concentration, this inhibitory action of the kisspeptins vanished. Thus, at 11.1 mM glucose, KP13 and KP54 inhibited insulin secretion only at high doses, and at 16.7 mM they no longer inhibited insulin secretion in any of the doses. We conclude that kisspeptins inhibit insulin secretion at glucose concentrations below 11.1 mM. This suggests that kisspeptins are regulating insulin secretion at physiological concentrations of glucose. The mechanisms by which kisspeptins regulate islet function and insulin secretion are unknown and will be further investigated.

  15. Delayed apoptosis allows islet β-cells to implement an autophagic mechanism to promote cell survival

    PubMed Central

    Hayes, Heather L.; Peterson, Brett S.; Haldeman, Jonathan M.; Newgard, Christopher B.; Hohmeier, Hans E.

    2017-01-01

    Increased β-cell death coupled with the inability to replicate existing β-cells drives the decline in β-cell mass observed in the progression of both major forms of diabetes. Understanding endogenous mechanisms of islet cell survival could have considerable value for the development of novel strategies to limit β-cell loss and thereby promote β-cell recovery. Insulinoma cells have provided useful insight into β-cell death pathways but observations made in cell lines sometimes fail to translate to primary islets. Here, we report dramatic differences in the temporal regulation and engagement of the apoptotic program in primary rodent islets relative to the INS-1 derived 832/13 cell line. As expected, 832/13 cells rapidly induced cell stress markers in response to ER stress or DNA damage and were fully committed to apoptosis, resulting in >80% cell death within 24 h. In contrast, primary rat islets were largely refractory to cell death in response to ER stress and DNA damage, despite rapid induction of stress markers, such as XBP-1(s), CHOP, and PUMA. Gene expression profiling revealed a general suppression of pro-apoptotic machinery, such as Apaf-1 and caspase 3, and sustained levels of pro-survival factors, such as cIAP-1, cIAP-2, and XIAP, in rat islets. Furthermore, we observed sustained induction of autophagy following chronic ER stress and found that inhibition of autophagy rendered islet β-cells highly vulnerable to ER stress-induced cell death. We propose that islet β-cells dampen the apoptotic response to delay the onset of cell death, providing a temporal window in which autophagy can be activated to limit cellular damage and promote survival. PMID:28212395

  16. The corticotropin-releasing hormone test in normal short children: comparison of plasma adrenocorticotropin and cortisol responses to human corticotropin-releasing hormone and insulin-induced hypoglycemia.

    PubMed

    Goji, K

    1989-03-01

    The human corticotropin-releasing hormone (hCRH) tests were performed in twelve normal short children, and the responses of plasma ACTH and cortisol to iv administration of 1 micrograms/kg hCRH were compared with those to insulin-induced hypoglycemia. After administration of hCRH, the mean plasma ACTH level rose from a basal value of 3.3 +/- 0.4 pmol/l (mean +/- SEM) to a peak value of 9.2 +/- 0.8 pmol/l at 30 min, and the mean plasma cortisol level rose from a basal value of 231 +/- 25 nmol/l to a peak value of 546 +/- 30 nmol/l at 30 min. The ACTH response after insulin-induced hypoglycemia was greater than that after hCRH administration; the mean peak level (P less than 0.01), the percent maximum increment (P less than 0.01), and the area under the ACTH response curve (P less than 0.01) were all significantly greater after insulin-induced hypoglycemia than those after hCRH administration. Although the mean peak cortisol level after insulin-induced hypoglycemia was about 1.3-fold higher than that after hCRH administration (P less than 0.01), neither the percent maximum increment in plasma cortisol nor the area under the cortisol response curve after insulin-induced hypoglycemia was significantly different from that after hCRH administration. Consequently, the acute increases in plasma ACTH after the administration of 1 microgram/kg hCRH stimulated the adrenal gland to almost the same cortisol response as that obtained with a much greater increase in plasma ACTH after insulin-induced hypoglycemia. These results suggest that a plasma ACTH peak of 9-11 pmol/l produces near maximum acute stimulation of adrenal steroidogenesis.

  17. The determination of membrane permeability coefficients of canine pancreatic islet cells and their application to islet cryopreservation.

    PubMed

    Liu, J; Zieger, M A; Lakey, J R; Woods, E J; Critser, J K

    1997-08-01

    Sufficient numbers of pancreatic islets for successful allotransplantation can be achieved by storing and then pooling islets from several donors. Optimal MHC matching and infectious disease screening also require long-term storage of islets, and cryopreservation is currently the only practical approach. Cryopreservation protocols may be optimized by modeling the changes in cell volume and the associated damage incurred during cryoprotectant addition and dilution and during cooling and warming. The objective of the present work was to determine the following biophysical parameters of canine islet cells; the osmotically inactive cell volume (Vb), hydraulic conductivity (Lp), cryoprotectant permeability coefficient (Ps), and the reflection coefficient sigma. A determination of these parameters allows the simulation of cell responses using computer models. Islets were isolated by collagenase digestion and Euro-Ficoll purification. After 24 h culture, islets were dissociated into single cells using trypsin and 2 mM EGTA. The kinetic change in cell volume as a function of time after exposure to 2 M dimethyl sulfoxide (Me2SO) was measured using an electronic particle counter at 22, 5, and -3 degrees C. At -11 degrees C, cells were preloaded with 1 M Me2SO and exposed to 4 M Me2SO to prevent the formation of ice in the working solution. Kedem-Katchalsky theory was used to describe the cell volume change kinetics, and a three-parameter curve fitting was performed using the Marquardt-Levenberg method to determine Lp, Ps, and sigma values. The Lp was determined to be 0.19 +/- 0.05, 0.037 +/- 0.005, 0.020 +/- 0.003, and 0.013 +/- 0.005 micron.min-1.atm-1 (mean +/- SD) at 22, 5, -3, and -11 degrees C, respectively. The Ps values were 1.05 +/- 0.50, 0.15 +/- 0.04, 0.096 +/- 0.028, and 0.067 +/- 0.029 x 10(-3) cm.min-1 at 22, 5, -3, and -11 degrees C, respectively. The sigma values were 0.81 +/- 0.16, 0.91 +/- 0.09, 0.80 +/- 0.21, and 0.98 +/- 0.04 at 22, 5, -3, and -11 degrees

  18. Thyroid hormones directly activate the expression of the human and mouse uncoupling protein-3 genes through a thyroid response element in the proximal promoter region

    PubMed Central

    2004-01-01

    The transcription of the human UCP3 (uncoupling protein-3) gene in skeletal muscle is tightly regulated by metabolic signals related to fatty acid availability. However, changes in thyroid status also modulate UCP3 gene expression, albeit by unknown mechanisms. We created transgenic mice bearing the entire human UCP3 gene to investigate the effect of thyroid hormones on human UCP3 gene expression. Treatment of human UCP3 transgenic mice with thyroid hormones induced the expression of the human gene in skeletal muscle. In addition, transient transfection experiments demonstrate that thyroid hormones activate the transcription of the human UCP3 gene promoter when MyoD and the TR (thyroid hormone receptor) were co-transfected. The action of thyroid hormones on UCP3 gene transcription is mediated by the binding of the TR to a proximal region in the UCP3 gene promoter that contains a direct repeat structure. An intact DNA sequence of this site is required for thyroid hormone responsiveness and TR binding. Chromatin immunoprecipitation assays revealed that the TR binds this element in vivo. The murine Ucp3 gene promoter was also dependent on MyoD and responsive to thyroid hormone in transient transfection assays. However, it was much less sensitive to thyroid hormone than the human UCP3 promoter. In summary, UCP3 gene transcription is activated by thyroid hormone treatment in vivo, and this activation is mediated by a TRE (thyroid hormone response element) in the proximal promoter region. Such regulation suggests a link between UCP3 gene expression and the effects of thyroid hormone on mitochondrial function in skeletal muscle. PMID:15496137

  19. Does aerobic exercise affect the hypothalamic-pituitary-adrenal hormonal response in patients with fibromyalgia syndrome?

    PubMed Central

    Genc, Aysun; Tur, Birkan Sonel; Aytur, Yesim Kurtais; Oztuna, Derya; Erdogan, Murat Faik

    2015-01-01

    [Purpose] The hypothalamic-pituitary-adrenal (HPA) axis in the etiopathogenesis of fibromyalgia is not clear. This study aimed to analyze the effects of a 6-week aerobic exercise program on the HPA axis in patients with fibromyalgia and to investigate the effects of this program on the disease symptoms, patients’ fitness, disability, and quality of life. [Subjects and Methods] Fifty fibromyalgia patients were randomized to Group 1 (stretching and flexibility exercises at home for 6 weeks) and Group 2 (aerobic exercise three times a week and the same at-home exercises as Group 1 for 6 weeks). Serum levels of cortisol, adrenocorticotropic hormone, insulin-like growth factor-1, and growth hormone were analyzed at baseline and at the end of, and 1 hr after an exercise stress test. [Results] Group 2 showed better improvement in morning stiffness duration and pain. Growth hormone levels significantly increased after intervention and cortisol levels significantly decreased at time-time interaction in both groups. No significant differences in adrenocorticotropic hormone and insulin-like growth factor-1 were found. [Conclusion] The results of this study seem to support the hypothesis that there is a dysregulation of the HPA axis in patients with FM, and that a six-week exercise program can influence symptoms and affect the HPA axis hormones. PMID:26311959

  20. Changes in somatotropic axis response and body composition during growth hormone administration in progressive cachectic parasitism.

    PubMed

    Elsasser, T H; Sartin, J L; McMahon, C; Romo, G; Fayer, R; Kahl, S; Blagburn, B

    1998-07-01

    A multistage protozoan parasitic disease was used as a cachexia model to study the effects of daily administration of bovine growth hormone (GH) on endocrine and body composition changes of young calves from the onset of the acute phase response (APR). Male calves averaging 127.5 +/- 2.0 kg body weight were assigned to control, ad libitum fed, noninfected (C); ad libitum fed, infected (250,000 oocysts Sarcocystis cruzi, per os, I); noninfected, pair-fed (PF) to matched I-treatment calves and these respective same treatments in calves injected daily with GH (USDA-bGH-B1), 12.5 mg/calf/day, im) designated as CGH, IGH and PFGH. GH injections were initiated on Day 20 postinfection (PI), 3 to 4 d before the onset of clinical signs of APR, and continued to Day 56 PI, at which time animals were euthanized for tissue collections. Abrupt increases in rectal temperature commensurate with up to 70% reduction in voluntary feed intake were observed in I and IGH beginning 23-25 d PI. For the trial period between Days 20 and 56 PI, average daily carcass protein gains were 123, 52, 109, 124, 48, and 67 g/d and average daily carcass fat gains were 85, 11, 43, 71, -23, and 29 g/d for C, I, PF, CGH, IGH, and PFGH, respectively. Effects of GH were significant for fat accretion and plasma urea depression. Rectus femoris was highly refractory to catabolic effects of infection while psoas major was significantly catabolized during infection. Plasma concentrations of insulin-like growth factor-I (IGF-I) increased significantly in all GH-treated calves between Day 20 and 23 PI. Plasma IGF-I declined well below Day 20 values in all infected calves from the onset of the APR through the end of the study. The decrease in plasma IGF-I concentrations in I and IG was highly correlated with the magnitude of the fever response. Hepatic mRNA for GH receptor and IGF-I was decreased in infected calves. Hepatic microsomal membrane binding of 125I-GH did not differ between groups. The data suggest that

  1. Possible role of the aromatase-independent steroid metabolism pathways in hormone responsive primary breast cancers.

    PubMed

    Hanamura, Toru; Niwa, Toshifumi; Gohno, Tatsuyuki; Kurosumi, Masafumi; Takei, Hiroyuki; Yamaguchi, Yuri; Ito, Ken-ichi; Hayashi, Shin-ichi

    2014-01-01

    Aromatase inhibitors (AIs) exert antiproliferative effects by reducing local estrogen production from androgens in postmenopausal women with hormone-responsive breast cancer. Previous reports have shown that androgen metabolites generated by the aromatase-independent enzymes, 5α-androstane-3β, 17β-diol (3β-diol), androst-5-ene-3β, and 17β-diol (A-diol), also activate estrogen receptor (ER) α. Estradiol (E2) can also reportedly be generated from estrone sulfate (E1S) pooled in the plasma. Estrogenic steroid-producing aromatase-independent pathways have thus been proposed as a mechanism of AI resistance. However, it is unclear whether these pathways are functional in clinical breast cancer. To investigate this issue, we assessed the transcriptional activities of ER in 45 ER-positive human breast cancers using the adenovirus estrogen-response element-green fluorescent protein assay and mRNA expression levels of the ER target gene, progesterone receptor, as indicators of ex vivo and in vivo ER activity, respectively. We also determined mRNA expression levels of 5α-reductase type 1 (SRD5A1) and 3β-hydroxysteroid dehydrogenase type 1 (3β-HSD type 1; HSD3B1), which produce 3β-diol from androgens, and of steroid sulfatase (STS) and 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD type 1; HSD17B1), which produce E2 or A-diol from E1S or dehydroepiandrosterone sulfate. SRD5A1 and HSD3B1 expression levels were positively correlated with ex vivo and in vivo ER activities. STS and HSD17B1 expression levels were positively correlated with in vivo ER activity alone. Elevated expression levels of these steroid-metabolizing enzymes in association with high in vivo ER activity were particularly notable in postmenopausal patients. Analysis of the expression levels of steroid-metabolizing enzymes revealed positive correlations between SRD5A1 and HSD3B1, and STS and HSD17B1. These findings suggest that the SRD5A1-HSD3B1 as well as the STS-HSD17B pathways, could contributes

  2. The evolution of endothermy is explained by thyroid hormone-mediated responses to cold in early vertebrates.

    PubMed

    Little, Alexander G; Seebacher, Frank

    2014-05-15

    The evolution of endothermy is one of the most intriguing and consistently debated topics in vertebrate biology, but the proximate mechanisms that mediated its evolution are unknown. Here, we suggest that the function of thyroid hormone in regulating physiological processes in response to cold is key to understanding the evolution of endothermy. We argue that the capacity of early chordates to produce thyroid hormone internally was the first step in this evolutionary process. Selection could then act on the capacity of thyroid hormone to regulate metabolism, muscle force production and cardiac performance to maintain their function against the negative thermodynamic effects of decreasing temperature. Thyroid-mediated cold acclimation would have been the principal selective advantage. The actions of thyroid hormone during cold acclimation in zebrafish are very similar to its role during endothermic thermogenesis. The thyroid-mediated increases in metabolism and locomotor performance in ectotherms eventually resulted in sufficient heat production to affect body temperature. From this point onwards, increased body temperature per se could be of selective advantage and reinforce thyroid-induced increases in physiological rates. Selection for increased body temperature would promote those mechanisms that maximise heat production, such as increased Na(+)/K(+)-ATPase activity, futile cycling by SERCA, and mitochondrial uncoupling, all of which are regulated by thyroid hormone. The specific end point of this broader evolutionary process would be endothermic thermoregulation. However, considering the evolution of endothermy in isolation is misleading because the selective advantages that drove the evolutionary process were independent from endothermy. In other words, without the selective advantages of thyroid-mediated cold acclimation in fish, there would be no endotherms.

  3. The heterogeneity of islet autoantibodies and the progression of islet failure in type 1 diabetic patients.

    PubMed

    Liu, Jin; Bian, Lingling; Ji, Li; Chen, Yang; Chen, Heng; Gu, Yong; Ma, Bingqin; Gu, Wei; Xu, Xinyu; Shi, Yun; Wang, Jian; Zhu, Dalong; Sun, Zilin; Ma, Jianhua; Jin, Hui; Shi, Xing; Miao, Heng; Xin, Bing; Zhu, Yan; Zhang, Zhenwen; Bu, Ruifang; Xu, Lan; Shi, Guangde; Tang, Wei; Li, Wei; Zhou, Dongmei; Liang, Jun; Cheng, Xingbo; Shi, Bimin; Dong, Jixiang; Hu, Ji; Fang, Chen; Zhong, Shao; Yu, Weinan; Lu, Weiping; Wu, Chenguang; Qian, Li; Yu, Jiancheng; Gao, Jialin; Fei, Xiaoqiang; Zhang, Qingqing; Wang, Xueqin; Cui, Shiwei; Cheng, Jinluo; Xu, Ning; Wang, Guofeng; Han, Guoqing; Xu, Chunrong; Xie, Yun; An, Minmin; Zhang, Wei; Wang, Zhixiao; Cai, Yun; Fu, Qi; Fu, Yu; Zheng, Shuai; Yang, Fan; Hu, Qingfang; Dai, Hao; Jin, Yu; Zhang, Zheng; Xu, Kuanfeng; Li, Yifan; Shen, Jie; Zhou, Hongwen; He, Wei; Zheng, Xuqin; Han, Xiao; Yu, Liping; She, Jinxiong; Zhang, Mei; Yang, Tao

    2016-09-01

    Type 1 diabetes mellitus is heterogeneous in many facets. The patients suffered from type 1 diabetes present several levels of islet function as well as variable number and type of islet-specific autoantibodies. This study was to investigate prevalence and heterogeneity of the islet autoantibodies and clinical phenotypes of type 1 diabetes mellitus; and also discussed the process of islet failure and its risk factors in Chinese type 1 diabetic patients. A total of 1,291 type 1 diabetic patients were enrolled in this study. Demographic information was collected. Laboratory tests including mixed-meal tolerance test, human leukocyte antigen alleles, hemoglobinA1c, lipids, thyroid function and islet autoantibodies were conducted. The frequency of islet-specific autoantibody in newly diagnosed T1DM patients (duration shorter than half year) was 73% in East China. According to binary logistic regressions, autoantibody positivity, longer duration and lower Body Mass Index were the risk factors of islet failure. As the disease developed, autoantibodies against glutamic acid decarboxylase declined as well as the other two autoantibodies against zinc transporter 8 and islet antigen 2. The decrease of autoantibodies was positively correlated with aggressive beta cell destruction. Autoantibodies can facilitate the identification of classic T1DM from other subtypes and predict the progression of islet failure. As there were obvious heterogeneity in autoantibodies and clinical manifestation in different phenotypes of the disease, we should take more factors into consideration when identifying type 1 diabetes mellitus.

  4. Administration of exogenous hormones in ovulatory and embryonic response in Pelibuey sheep.

    PubMed

    García-Salas, A; Cortez-Romero, C; Salazar-Ortiz, J; Arroyo-Ledezma, J; Ruíz-Vera, V M; Vaquera-Huerta, H; Gallegos-Sánchez, J

    2017-02-08

    The objective of this study was to evaluate the effect of two sources of commercial porcine pituitary-derived follicle-stimulating hormone (pFSH) and pFSH-porcine Luteinizing Hormone (pLH), including equine chorionic gonadotropin (eCG), in ovulatory and embryonic response in Pelibuey sheep. Twenty-four Pelibuey sheep were used and were assigned randomly to four treatments (n = 6): (T1; 200 mg pFSH-Folltropin(®) ); (T2; 200 mg pFSH + 300 UI eCG-Folligon(®) ); (T3; 250 UI pFSH/pLH-Pluset(®) ) and (T4; 250 UI pFSH/pLH + 300 UI eCG). The interval of hours from withdrawal of the device to the beginning of oestrus (BO) was lower (p < .05) in sheep treated with eCG (T2 = 8.0 ± 1.4 and T4 = 10.0 ± 2.8) than in those without eCG (T1 = 12.6 ± 0.6 and T3 = 20.6 ± 2.4). The ovulatory rate (OR) was higher (p < .05) in T1 = 15.5 ± 2.8 and T2 = 15.6 ± 1.4, compared to T3 = 8.1 ± 3.2 and T4 = 11.8 ± 2.8; a significant difference was not shown between them (T1 vs. T2 and T3 vs. T4) when including eCG. The number of non-fertilized oocytes (NFO) was lower (p ˂ .05) in T1 = 0.8 ± 0.4 and T3 = 1.8 ± 1.8, compared to those that included eCG (T2 = 6.3 ± 2.4 and T4 = 2.1 ± 1.2). The number of transferable embryos (TE) was higher (p < .05) when FSH was applied (T1 = 5.8 ± 1.1), compared with (T2 = 2.6 ± 1.1, T3 = 2.3 ± 1.4 and T4 = 2.8 ± 1.5). The commercial treatments (pFSH or pFSH-pLH) in combination with eCG did not improve OR, NFO and TE. However, the exclusive pFSH (Folltropin) treatment presented a higher OR, lower number of NFO and higher number of TE.

  5. Noninvasive imaging of islet grafts using positron-emission tomography

    NASA Astrophysics Data System (ADS)

    Lu, Yuxin; Dang, Hoa; Middleton, Blake; Zhang, Zesong; Washburn, Lorraine; Stout, David B.; Campbell-Thompson, Martha; Atkinson, Mark A.; Phelps, Michael; Gambhir, Sanjiv Sam; Tian, Jide; Kaufman, Daniel L.

    2006-07-01

    Islet transplantation offers a potential therapy to restore glucose homeostasis in type 1 diabetes patients. However, islet transplantation is not routinely successful because most islet recipients gradually lose graft function. Furthermore, serological markers of islet function are insensitive to islet loss until the latter stages of islet graft rejection. A noninvasive method of monitoring islet grafts would aid in the assessment of islet graft survival and the evaluation of interventions designed to prolong graft survival. Here, we show that recombinant adenovirus can engineer isolated islets to express a positron-emission tomography (PET) reporter gene and that these islets can be repeatedly imaged by using microPET after transplantation into mice. The magnitude of signal from engineered islets implanted into the axillary cavity was directly related to the implanted islet mass. PET signals attenuated over the following weeks because of the transient nature of adenovirus-mediated gene expression. Because the liver is the preferred site for islet implantation in humans, we also tested whether islets could be imaged after transfusion into the mouse liver. Control studies revealed that both intrahepatic islet transplantation and hyperglycemia altered the biodistribution kinetics of the PET probe systemically. Although transplanted islets were dispersed throughout the liver, clear signals from the liver region of mice receiving PET reporter-expressing islets were detectable for several weeks. Viral transduction, PET reporter expression, and repeated microPET imaging had no apparent deleterious effects on islet function after implantation. These studies lay a foundation for noninvasive quantitative assessments of islet graft survival using PET. diabetes | transplantation

  6. Hormonal responses of metoclopramide-treated subjects experiencing nausea or emesis during parabolic flight

    NASA Technical Reports Server (NTRS)

    Kohl, Randall L.

    1987-01-01

    The concentrations of adrenocorticotropic hormone (ACTH), vasopressin (AVP), epinephrine (EPI), and norepinephrine (NE) in 22 subjects administered 10 to 20 mg of metoclopramide prior to parabolic flight are measured. The effect of metoclopramide on motion sickness is examined. It is observed that metoclopramide is ineffective in the modulation of motion sickness due to stressful linear and angular acceleration and orbital flight, and it does not affect serum hormones prior to parabolic flight. It is detected that the serum level of AVP declines following emesis induced by parabolic flight and stressful angular acceleration; the serum levels of ACTH and EPI are elevated by parabolic flight and stressful angular acceleration; and serum NE is significantly elevated immediately following emesis. The possible roles of these hormones in the etiology of space motion sickness are discussed.

  7. Control of IBMIR in Neonatal Porcine Islet Xenotransplantation in Baboons

    PubMed Central

    Hawthorne, W J; Salvaris, E J; Phillips, P; Hawkes, J; Liuwantara, D; Burns, H; Barlow, H; Stewart, A B; Peirce, S B; Hu, M; Lew, A M; Robson, S C; Nottle, M B; D'Apice, A J F; O'Connell, P J; Cowan, P J

    2014-01-01

    The instant blood-mediated inflammatory reaction (IBMIR) is a major obstacle to the engraftment of intraportal pig islet xenografts in primates. Higher expression of the galactose-α1,3-galactose (αGal) xenoantigen on neonatal islet cell clusters (NICC) than on adult pig islets may provoke a stronger reaction, but this has not been tested in the baboon model. Here, we report that WT pig NICC xenografts triggered profound IBMIR in baboons, with intravascular clotting and graft destruction occurring within hours, which was not prevented by anti-thrombin treatment. In contrast, IBMIR was minimal when recipients were immunosuppressed with a clinically relevant protocol and transplanted with NICC from αGal-deficient pigs transgenic for the human complement regulators CD55 and CD59. These genetically modified (GM) NICC were less susceptible to humoral injury in vitro than WT NICC, inducing significantly less complement activation and thrombin generation when incubated with baboon platelet-poor plasma. Recipients of GM NICC developed a variable anti-pig antibody response, and examination of the grafts 1 month after transplant revealed significant cell-mediated rejection, although scattered insulin-positive cells were still present. Our results indicate that IBMIR can be attenuated in this model, but long-term graft survival may require more effective immunosuppression or further donor genetic modification. PMID:24842781

  8. Mutations in the hormone regulatory element of mouse mammary tumor virus differentially affect the response to progestins, androgens, and glucocorticoids.

    PubMed Central

    Gowland, P L; Buetti, E

    1989-01-01

    Transcription of the mouse mammary tumor virus DNA is known to be induced by several steroid hormones. Using chimeric MMTV plasmids containing mutations within the hormone regulatory element, we have previously studied the regions required for the glucocorticoid response in mouse fibroblasts. Here we report the characterization of elements essential for the stimulation by progestins and androgens as compared with glucocorticoids. The same set of mutant plasmids was transfected into the human mammary tumor cell line T47D, and the specific transcripts were analyzed by an S1 nuclease protection assay. Androgen-mediated stimulation, although weak, showed an extended sensitivity to mutations, with a slight preference for the proximal region. The results with progestin suggest that sequences within all the described sites protected by the receptor in vitro are required and that the promoter-proximal region (-128 to -78 from the RNA start site) is more important than the distal one (-190 to -160). Moreover, a binding site for nuclear factor I was not required for the progestin response, whereas it was required for glucocorticoids. Thus, the various steroid receptors play a role in the differential regulation of mouse mammary tumor virus transcription by recognizing distinct sequence differences in the hormone regulatory element and interacting with different factors bound to the promoter. Images PMID:2550809

  9. Behavioural and hormonal stress responses during chick rearing do not predict brood desertion by female in a small Arctic seabird.

    PubMed

    Wojczulanis-Jakubas, Katarzyna; Jakubas, Dariusz; Chastel, Olivier

    2013-08-01

    We examined behavioural and hormonal stress responses in a small seabird (little auk, Alle alle), which exhibits a transition from biparental to male-only care towards the end of the nesting period, in order to understand the mechanisms underlying this parental strategy. We hypothesized that the male staying with the chick should be less sensitive to stressors. As such the male might offer the offspring more efficient protection during the fledging period than the female. We tested this hypothesis by observing male and female behaviour in a neophobia test. We also measured the birds' baseline and stress-induced levels of corticosterone and prolactin using the standardized capture-and-restraint protocol. Both sexes respond rapidly to foreign objects, delaying the entry time to the nest with food, consuming the food load, and/or temporarily abandoning feeding. However, we did not find any differences between the sexes in the frequency of each behaviour or in the time of the first reaction to the experimental treatment. Level of both corticosterone and prolactin increased after the experimental treatment. However, we did not find sex differences in baseline and stress-induced hormone levels. The results indicate that the males are as much sensitive to the stress situation as the females. Thus, the pattern of male and female behavioural and hormonal responses to stress does not predict their behaviour at the final breeding stage.

  10. Aging influences steroid hormone release by mink ovaries and their response to leptin and IGF-I.

    PubMed

    Sirotkin, Alexander V; Mertin, Dušan; Süvegová, Karin; Harrath, Abdel Halim; Kotwica, Jan

    2016-01-21

    The aim of our study was to understand whether ovarian steroid hormones, and their response to the metabolic hormones leptin and IGF-I leptin, could be involved in the control of mink reproductive aging via changes in basal release of ovarian progesterone and estradiol. For this purpose, we compared the release of progesterone and estradiol by ovarian fragments isolated from young (yearlings) and old (3-5 years of age) minks cultured with and without leptin and IGF-I (0, 1, 10 or 100 ng/ml). We observed that isolated ovaries of older animals produced less progesterone but not less estradiol than the ovaries of young animals. Leptin addition stimulated estradiol release by the ovarian tissue of young animals but inhibited it in older females. Leptin did not influence progesterone output by the ovaries of either young or older animals. IGF-I inhibited estradiol output in young but not old animals, whereas progesterone release was inhibited by IGF-I irrespective of the animal age. Our observations demonstrate the involvement of both leptin and IGF-I in the control of mink ovarian steroid hormones release. Furthermore, our findings suggest that reproductive aging in minks can be due to (a) reduction in basal progesterone release and (b) alterations in the response of estradiol but not of progesterone to leptin and IGF-I.

  11. Aging influences steroid hormone release by mink ovaries and their response to leptin and IGF-I

    PubMed Central

    Sirotkin, Alexander V.; Mertin, Dušan; Süvegová, Karin; Harrath, Abdel Halim; Kotwica, Jan

    2016-01-01

    ABSTRACT The aim of our study was to understand whether ovarian steroid hormones, and their response to the metabolic hormones leptin and IGF-I leptin, could be involved in the control of mink reproductive aging via changes in basal release of ovarian progesterone and estradiol. For this purpose, we compared the release of progesterone and estradiol by ovarian fragments isolated from young (yearlings) and old (3-5 years of age) minks cultured with and without leptin and IGF-I (0, 1, 10 or 100 ng/ml). We observed that isolated ovaries of older animals produced less progesterone but not less estradiol than the ovaries of young animals. Leptin addition stimulated estradiol release by the ovarian tissue of young animals but inhibited it in older females. Leptin did not influence progesterone output by the ovaries of either young or older animals. IGF-I inhibited estradiol output in young but not old animals, whereas progesterone release was inhibited by IGF-I irrespective of the animal age. Our observations demonstrate the involvement of both leptin and IGF-I in the control of mink ovarian steroid hormones release. Furthermore, our findings suggest that reproductive aging in minks can be due to (a) reduction in basal progesterone release and (b) alterations in the response of estradiol but not of progesterone to leptin and IGF-I. PMID:26794607

  12. Culture and characteristics of hormone-responsive neuroblastoma x glioma hybrid cells

    SciTech Connect

    Hamprecht, B.; Glaser, T.; Reiser, G.; Bayer, E.; Propst, F.

    1985-01-01

    Neuroblastoma x glioma hybrid cells were generated by cell fusion of the 6-thioguanine-resistant clonal mouse neuroblastoma cells and the bromodeoxyuridine-resistant rat glioma cells, selection, and cloning. Every characteristics generally ascribed to neurons has been observed with the hybrid cells. The paper explores the morphological differentiation of hybrid cells, procedures for testing the hormonal regulation of intracellular levels of cyclic, (/sup 3/H)AMP in hybrid cells, hormonal regulation of adenylate cyclase in homogenates of hyrbid cells, intracellular levels of cyclic GMP, and uptake of guanidinium ions in hybrid cells.

  13. [Complete hormonal and metabolic response after iodine-131 metaiodobenzylguanidine treatment in a patient diagnosed of malignant pheochromocytoma].

    PubMed

    García Alonso, M P; Balsa Bretón, M A; Paniagua Correa, C; Castillejos Rodríguez, L; Rodríguez Pelayo, E; Mendoza Paulini, A; Ortega Valle, A; Penín González, J

    2013-01-01

    Radiolabeled metaiodobenzylguanidine is an analogue of norepinephrine used to localize tumors that express the neurohormone transporters, specifically those derived from the neural crest having a neuroendocrine origin. It is also used to treat non-surgical metastases derived from them. A review of the literature revealed symptomatic improvements associated to a decrease in hormone levels in a significant percentage of patients after (131)I-MIBG treatment. However, complete tumor remission has been described only in very few cases and hardly ever when bone metastases exist. We present a case of a patient diagnosed of malignant pheochromocytoma who achieved complete hormonal and metabolic response after (131)I-MIBG treatment (600 mCi) in spite of the presence of bone metastases.

  14. Sequence elements in the human osteocalcin gene confer basal activation and inducible response to hormonal vitamin D3.

    PubMed

    Kerner, S A; Scott, R A; Pike, J W

    1989-06-01

    Osteoblast-specific expression of the bone protein osteocalcin is controlled at the transcriptional level by the steroid hormone 1 alpha,25-dihydroxyvitamin D3. As this protein may represent a marker for bone activity in human disease, we examined the regulation of its expression at the molecular level by evaluating human osteocalcin gene promoter function. We describe regions within the promoter that contribute to basal expression of the gene in osteoblast-like cells in culture. Further, we define a 21-base-pair DNA element with the sequence 5'-GTGACTCACCGGGTGAACGGG-3', which acts in cis to mediate 1 alpha,25-dihydroxyvitamin D3 inducibility of the osteocalcin gene. This response element bears sequence similarity with other short DNA segments, particularly those for estrogen and thyroid hormone, which act together with their respective trans-acting receptors to modulate gene transcription.

  15. IDDM: an islet or an immune disease?

    PubMed

    Boitard, C; Larger, E; Timsit, J; Sempe, P; Bach, J F

    1994-09-01

    Insulin-dependent diabetes develops as a consequence of the selective destruction of insulin-producing cells by an autoimmune reaction. However, the precise series of events which trigger anti-islet autoreactive T cells is still being investigated. Major issues will need to be raised before a comprehensive view of the anti-islet autoimmune reaction can be delineated. These include defining the primary site of activation of autoreactive lymphocytes and exploring hypotheses to explain the chronicity of the diabetes process. These issues all relate with the more general dilemma of the actual role of the islets of Langerhans in breaking self tolerance to beta-cell antigens. By studying non-obese diabetic mice deprived of beta cells following a single injection of a high dose of alloxan at 3 weeks of age, we recently obtained evidence that the activation of autoreactive T cells requires the presence of target islet cells in order to develop.

  16. Hemodynamic and hormonal responses to lower body negative pressure in men with varying profiles of strength and aerobic power

    NASA Technical Reports Server (NTRS)

    Convertino, V. A.; Mathes, K. L.; Lasley, M. L.; Tomaselli, C. M.; Frey, M. A.; Hoffler, G. W.

    1993-01-01

    Hemodynamic, cardiac, and hormonal responses to lower-body negative pressure (LBNP) were examined in 24 healthy men to test the hypothesis that responsiveness of reflex control of blood pressure during orthostatic challenge is associated with interactions between strength and aerobic power. Subjects underwent treadmill tests to determine peak oxygen uptake (VO2max) and isokinetic dynamometer tests to determine knee extensor strength. Based on predetermined criteria, subjects were classified into one of four fitness profiles of six subjects each, matched for age, height, and body mass: (a) low strength/average aerobic fitness, (b) low strength/high aerobic fitness, (c) high strength/average aerobic fitness, and (d) high strength/high aerobic fitness. Following 90 min of 0.11 rad (6 degrees) head-down tilt (HDT), each subject underwent graded LBNP to -6.7 kPa or presyncope, with maximal duration 15 min, while hemodynamic, cardiac, and hormonal responses were measured. All groups exhibited typical hemodynamic, hormonal, and fluid shift responses during LBNP, with no intergroup differences between high and low strength characteristics. Subjects with high aerobic power exhibited greater (P < 0.05) stroke volume and lower (P < 0.05) heart rate, vascular peripheral resistance, and mean arterial pressure during rest, HDT, and LBNP. Seven subjects, distributed among the four fitness profiles, became presyncopal. These subjects showed greatest reduction in mean arterial pressure during LBNP, had greater elevations in vasopressin, and lesser increases in heart rate and peripheral resistance. Neither VO2max nor leg strength were associated with fall in arterial pressure or with syncopal episodes. We conclude that interactions between aerobic and strength fitness characteristics do not influence responses to LBNP challenge.

  17. Hormonal and Behavioral Responses to Stress in Lactating and Non-lactating Female Common Marmosets (Callithrix jacchus)

    PubMed Central

    Saltzman, Wendy; Abbott, David H.

    2011-01-01

    In several mammalian species, hypothalamic-pituitary-adrenal (HPA) and behavioral responses to stressors are down-regulated in lactating females, possibly preventing stress-induced disruptions of maternal care. Experimental elevations of HPA axis hormones have been found to inhibit maternal behavior in lactating common marmoset monkeys (Callithrix jacchus), raising the question of whether lactating female marmosets also have blunted endogenous responses to stress. Therefore, we compared HPA and behavioral responses to standardized stressors in reproductively experienced female common marmosets that were undergoing ovulatory cycles and that either were (N=7) or were not lactating (N=8). Each marmoset underwent (1) a restraint stressor during the early follicular phase of the ovarian cycle (approximately 5 weeks postpartum for lactating females) and (2) exposure to a simulated hawk predator during the early to mid-luteal phase (approximately 7 weeks postpartum for lactating females). Lactating females were tested in the presence of one of their infants. Blood samples were collected before, during, and immediately after each test for determination of plasma adrenocorticotropic hormone (ACTH) and cortisol concentrations. Both stressors caused significant elevations in plasma ACTH and cortisol levels, and significant decreases in cortisol:ACTH ratios; however, lactating and non-lactating females showed no significant differences in their endocrine or behavioral responses to either stressor, or in baseline ACTH or cortisol levels. These findings suggest that in contrast to several other mammalian species, lactating female marmosets maintain full behavioral and HPA responsiveness to stress, at least in the presence of their infants. PMID:21600906

  18. Negative energy balance in a male songbird, the Abert's towhee, constrains the testicular endocrine response to luteinizing hormone stimulation.

    PubMed

    Davies, Scott; Gao, Sisi; Valle, Shelley; Bittner, Stephanie; Hutton, Pierce; Meddle, Simone L; Deviche, Pierre

    2015-09-01

    Energy deficiency can suppress reproductive function in vertebrates. As the orchestrator of reproductive function, endocrine activity of the hypothalamo-pituitary-gonadal (HPG) axis is potentially an important mechanism mediating such effects. Previous experiments in wild-caught birds found inconsistent relationships between energy deficiency and seasonal reproductive function, but these experiments focused on baseline HPG axis activity and none have investigated the responsiveness of this axis to endocrine stimulation. Here, we present data from an experiment in Abert's towhees, Melozone aberti, using gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) challenges to investigate whether energy deficiency modulates the plasma testosterone responsiveness of the HPG axis. Wild-caught birds were either ad libitum fed or energetically constrained via chronic food restriction during photoinduced reproductive development. Energy deficiency did not significantly affect the development of reproductive morphology, the baseline endocrine activity of the HPG axis, or the plasma testosterone response to GnRH challenge. Energy deficiency did, however, decrease the plasma testosterone responsiveness to LH challenge. Collectively, these observations suggest that energy deficiency has direct gonadal effects consisting of a decreased responsiveness to LH stimulation. Our study, therefore, reveals a mechanism by which energy deficiency modulates reproductive function in wild birds in the absence of detectable effects on baseline HPG axis activity.

  19. Negative energy balance in a male songbird, the Abert's Towhee, constrains the testicular endocrine response to luteinizing hormone stimulation.

    PubMed

    Davies, Scott; Gao, Sisi; Valle, Shelley; Bittner, Stephanie; Hutton, Pierce; Meddle, Simone L; Deviche, Pierre

    2015-07-10

    Energy deficiency can suppress reproductive functions in vertebrates. As the orchestrator of reproductive function, endocrine activity of the hypothalamo-pituitary-gonadal (HPG) axis is potentially an important mechanism mediating such effects. Previous experiments in wild-caught birds found inconsistent relationships between energy deficiency and seasonal reproductive function, but these experiments focused on baseline HPG axis activity and none has investigated the responsiveness of this axis to endocrine stimulation. Here, we present data from an experiment in Abert's Towhees, Melozone aberti, using gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) challenges to investigate whether energy deficiency modulates the plasma testosterone (T) responsiveness of the HPG axis. Wild-caught birds were either ad libitum-fed or energetically constrained via chronic food restriction during photoinduced reproductive development. Energy deficiency did not significantly affect the development of reproductive morphology, the baseline endocrine activity of the HPG axis, or the plasma T response to GnRH challenge. Energy deficiency did, however, decrease the plasma T responsiveness to LH challenge. Collectively, these observations suggest that energy deficiency has direct gonadal effects consisting in decreased responsiveness to LH stimulation. Our study, therefore, reveals a mechanism by which energy deficiency modulates reproductive function in wild birds in the absence of detectable effects on baseline HPG axis activity.

  20. Negative energy balance in a male songbird, the Abert's towhee, constrains the testicular endocrine response to luteinizing hormone stimulation

    PubMed Central

    Davies, Scott; Gao, Sisi; Valle, Shelley; Bittner, Stephanie; Hutton, Pierce; Meddle, Simone L.; Deviche, Pierre

    2015-01-01

    ABSTRACT Energy deficiency can suppress reproductive function in vertebrates. As the orchestrator of reproductive function, endocrine activity of the hypothalamo-pituitary–gonadal (HPG) axis is potentially an important mechanism mediating such effects. Previous experiments in wild-caught birds found inconsistent relationships between energy deficiency and seasonal reproductive function, but these experiments focused on baseline HPG axis activity and none have investigated the responsiveness of this axis to endocrine stimulation. Here, we present data from an experiment in Abert's towhees, Melozone aberti, using gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) challenges to investigate whether energy deficiency modulates the plasma testosterone responsiveness of the HPG axis. Wild-caught birds were either ad libitum fed or energetically constrained via chronic food restriction during photoinduced reproductive development. Energy deficiency did not significantly affect the development of reproductive morphology, the baseline endocrine activity of the HPG axis, or the plasma testosterone response to GnRH challenge. Energy deficiency did, however, decrease the plasma testosterone responsiveness to LH challenge. Collectively, these observations suggest that energy deficiency has direct gonadal effects consisting of a decreased responsiveness to LH stimulation. Our study, therefore, reveals a mechanism by which energy deficiency modulates reproductive function in wild birds in the absence of detectable effects on baseline HPG axis activity. PMID:26333925

  1. L-arginine does not improve biochemical and hormonal response in trained runners after 4 weeks of supplementation.

    PubMed

    Alvares, Thiago Silveira; Conte-Junior, Carlos Adam; Silva, Joab Trajano; Paschoalin, Vânia Margaret Flosi

    2014-01-01

    It has been hypothesized that L-arginine improves exercise performance by increasing nitric oxide synthesis and levels of insulin and growth hormone (GH). Metabolic and hormonal responses to chronic L-arginine supplementation may clarify the mechanisms underlying its putative physiologic effects on physical performance. Therefore, the aim of this study was to investigate the effects that 4 weeks of supplementation with L-arginine would have on metabolic and hormonal parameters at rest and in response to exercise. Fifteen healthy runners were divided into treatment (ARG; 6 g L-arginine) and placebo (PLA; 6 g cornstarch) groups. On the first visit, blood samples were collected for baseline, and the supplement or placebo was provided. After 4 weeks of supplementation (second visit), blood samples were collected at the following intervals: at rest, immediately after the first 5-km time-trial running test (5km-TT), immediately after the second 5km-TT, and after 20 minutes of recovery (+20). In addition to exercise performance (total running time), plasma nitrate, nitrite, nitrate plus nitrite, cyclic guanosine monophosphate, lactate, ammonia and serum insulin, GH, insulin-like growth factor 1, and cortisol concentrations were evaluated. There were significant increases in plasma nitrite, cyclic guanosine monophosphate, lactate, ammonia and serum GH, and cortisol at the first 5km-TT, immediately after the second 5km-TT, and +20 in both ARG and PLA. Nitrate plus nitrite and nitrate increased only at +20. No significant change was observed in serum insulin and insulin-like growth factor 1 in any sample period. Total running time did not differ significantly between the 2 tests, in either ARG or PLA. Thus, according to our results, 4 weeks of L-arginine supplementation did not cause beneficial changes in metabolic and hormonal parameters, beyond those achieved with exercise alone.

  2. Effects of complexation with in vivo enhancing monoclonal antibodies on activity of growth hormone in two responsive cell culture systems.

    PubMed

    Beattie, J; Borromeo, V; Bramani, S; Secchi, C; Baumbach, W R; Mockridge, J

    1999-12-01

    We describe the properties of three monoclonal antibodies (MAbs) to ovine GH, two of which have previously been shown to enhance, in vivo, the biological activity of bovine and ovine growth hormone. We have examined the effects of these MAbs on GH activity in two appropriate GH-responsive cell culture systems, investigating both acute signalling effects (Janus-activated kinase (Jak)-2 tyrosine phosphorylation -5 min) and longer-term (MTT-formazan production -24 h) effects of hormone-antibody complexes. In the 3T3-F442A pre-adipocyte cell line (which has been demonstrated to be GH responsive), we show that complexation of recombinant bovine (rb) GH with either of the two enhancing anti-ovine GH MAbs (OA11 and OA15) and the non-enhancing MAb, OA14, attenuates the ability of GH to stimulate tyrosine phosphorylation of Jak-2 at a 5-min time point. Using the mouse myeloid cell line, FDC-P1, stably transfected with the full-length ovine GH receptor (oGHR), we demonstrate that rbGH causes a dose-dependent increase in MTT-formazan production by these cells. Further, we demonstrate that OA11 and OA14, but not OA15, cause a decrease in this stimulatory activity of rbGH over a hormone concentration range of 5-50 ng/ml at both 24 and 48 h. We conclude that the different in vitro activities of the two in vivo enhancing MAbs are most probably related to the time-courses over which these two assays are performed, and also to the relative affinities between antibody, hormone and receptor. In addition, the in vitro inhibitory activity of the enhancing MAb OA11 in both short- and long-term bioassay lends further support to an exclusively in vivo model for MAb-mediated enhancement of GH action.

  3. Adult Human Biliary Tree Stem Cells Differentiate to β-Pancreatic Islet Cells by Treatment with a Recombinant Human Pdx1 Peptide

    PubMed Central

    Scafetta, Gaia; Renzi, Anastasia; De Canio, Michele; Sicilia, Francesca; Nevi, Lorenzo; Casa, Domenico; Panetta, Rocco; Berloco, Pasquale Bartolomeo; Reid, Lola M.; Federici, Giorgio; Gaudio, Eugenio; Maroder, Marella; Alvaro, Domenico

    2015-01-01

    Generation of β-pancreatic cells represents a major goal in research. The aim of this study was to explore a protein-based strategy to induce differentiation of human biliary tree stem cells (hBTSCs) towards β-pancreatic cells. A plasmid containing the sequence of the human pancreatic and duodenal homeobox 1 (PDX1) has been expressed in E. coli. Epithelial-Cell-Adhesion-Molecule positive hBTSCs or mature human hepatocyte cell line, HepG2, were grown in medium to which Pdx1 peptide was added. Differentiation toward pancreatic islet cells were evaluated by the expression of the β-cell transcription factors, Pdx1 and musculoapo-neurotic fibrosarcoma oncogene homolog A, and of the pancreatic hormones, insulin, glucagon, and somatostatin, investigated by real time polymerase chain reaction, western blot, light microscopy and immunofluorescence. C-peptide secretion in response to high glucose was also measured. Results indicated how purified Pdx1 protein corresponding to the primary structure of the human Pdx1 by mass spectroscopy was efficiently produced in bacteria, and transduced into hBTSCs. Pdx1 exposure triggered the expression of both intermediate and mature stage β-cell differentiation markers only in hBTSCs but not in HepG2 cell line. Furthermore, hBTSCs exposed to Pdx1 showed up-regulation of insulin, glucagon and somatostatin genes and formation of 3-dimensional islet-like structures intensely positive for insulin and glucagon. Finally, Pdx1-induced islet-like structures exhibited glucose-regulated C-peptide secretion. In conclusion, the human Pdx1 is highly effective in triggering hBTSC differentiation toward functional β-pancreatic cells. PMID:26252949

  4. Hormonal modulation of food intake in response to low leptin levels induced by hypergravity

    NASA Technical Reports Server (NTRS)

    Moran, M. M.; Stein, T. P.; Wade, C. E.

    2001-01-01

    A loss in fat mass is a common response to centrifugation and it results in low circulating leptin concentrations. However, rats adapted to hypergravity are euphagic. The focus of this study was to examine leptin and other peripheral signals of energy balance in the presence of a hypergravity-induced loss of fat mass and euphagia. Male Sprague-Dawley rats were centrifuged for 14 days at gravity levels of 1.25, 1.5, or 2 G, or they remained stationary at 1 G. Urinary catecholamines, urinary corticosterone, food intake, and body mass were measured on Days 11 to 14. Plasma hormones and epididymal fat pad mass were measured on Day 14. Mean body mass of the 1.25, 1.5, and 2 G groups were significantly (P < 0.05) lower than controls, and no differences were found in food intake (g/day/100 g body mass) between the hypergravity groups and controls. Epididymal fat mass was 14%, 14%, and 21% lower than controls in the 1.25, 1.5, and 2.0 G groups, respectively. Plasma leptin was significantly reduced from controls by 46%, 45%, and 65% in the 1.25, 1.5, and 2 G groups, respectively. Plasma insulin was significantly lower in the 1.25, 1.5, and 2.0 G groups than controls by 35%, 38%, and 33%. No differences were found between controls and hypergravity groups in urinary corticosterone. Mean urinary epinephrine was significantly higher in the 1.5 and 2.0 G groups than in controls. Mean urinary norepinephrine was significantly higher in the 1.25, 1.5 and 2.0 G groups than in controls. Significant correlations were found between G load and body mass, fat mass, leptin, urinary epinephrine, and norepinephrine. During hypergravity exposure, maintenance of food intake is the result of a complex relationship between multiple pathways, which abates the importance of leptin as a primary signal.

  5. Rapid Weight Loss Elicits Harmful Biochemical and Hormonal Responses in Mixed Martial Arts Athletes.

    PubMed

    Coswig, Victor Silveira; Fukuda, David Hideyoshi; Del Vecchio, Fabrício Boscolo

    2015-10-01

    The purpose of this study was to compare biochemical and hormonal responses between mixed martial arts (MMA) competitors with minimal prefight weight loss and those undergoing rapid weight loss (RWL). Blood samples were taken from 17 MMA athletes (Mean± SD; age: 27.4 ±5.3yr; body mass: 76.2 ± 12.4kg; height: 1.71 ± 0.05m and training experience: 39.4 ± 25 months) before and after each match, according to the official events rules. The no rapid weight loss (NWL, n = 12) group weighed in on the day of the event (~30 min prior fight) and athletes declared not having used RWL strategies, while the RWL group (n = 5) weighed in 24 hr before the event and the athletes claimed to have lost 7.4 ± 1.1kg, approximately 10% of their body mass in the week preceding the event. Results showed significant (p < .05) increases following fights, regardless of group, in lactate, glucose, lactate dehydrogenase (LDH), creatinine, and cortisol for all athletes. With regard to group differences, NWL had significantly (p < .05) greater creatinine levels (Mean± SD; pre to post) (NWL= 101.6 ± 15-142.3 ± 22.9μmol/L and RWL= 68.9 ± 10.6-79.5 ± 15.9μmol/L), while RWL had higher LDH (median [interquartile range]; pre to post) (NWL= 211.5[183-236] to 231[203-258]U/L and RWL= 390[370.5-443.5] to 488[463.5-540.5]U/L) and AST (NWL= 30[22-37] to 32[22-41]U/L and 39[32.5-76.5] to 72[38.5-112.5] U/L) values (NWL versus RWL, p < .05). Post hoc analysis showed that AST significantly increased in only the RWL group, while creatinine increased in only the NWL group. The practice of rapid weight loss showed a negative impact on energy availability and increased both muscle damage markers and catabolic expression in MMA fighters.

  6. HLA class I sensitization in islet transplant recipients: report from the Collaborative Islet Transplant Registry.

    PubMed

    Naziruddin, Bashoo; Wease, Steve; Stablein, Donald; Barton, Franca B; Berney, Thierry; Rickels, Michael R; Alejandro, Rodolfo

    2012-01-01

    Pancreatic islet transplantation is a promising treatment option for patients severely affected with type 1 diabetes. This report from CITR presents pre- and posttransplant human leukocyte antigen (HLA) class I sensitization rates in islet-alone transplantation. Data came from 303 recipients transplanted with islet-alone between January 1999 and December 2008. HLA class I sensitization was determined by the presence of anti-HLA class I antibodies. Panel-reactive antibodies (PRA) from prior to islet infusion and at 6 months, and yearly posttransplant was correlated to measures of islet graft failure. The cumulative number of mismatched HLA alleles increased with each additional islet infusion from a median of 3 for one infusion to 9 for three infusions. Pretransplant PRA was not predictive of islet graft failure. However, development of PRA >20% posttransplant was associated with 3.6-fold (p < 0.001) increased hazard ratio for graft failure. Patients with complete graft loss who had discontinued immunosuppression had significantly higher rate of PRA ≥ 20% compared to those with functioning grafts who remained on immunosuppression. Exposure to repeat HLA class I mismatch at second or third islet infusions resulted in less frequent development of de novo HLA class I antibodies when compared to increased class I mismatch. The development of HLA class I antibodies while on immunosuppression is associated with subsequent islet graft failure. The risk of sensitization may be reduced by minimizing the number of islet donors used per recipient, and in the absence of donor-specific anti-HLA antibodies, repeating HLA class I mismatches with subsequent islet infusions.

  7. HLA Class I Sensitization in Islet Transplant Recipients – Report from the Collaborative Islet Transplant Registry

    PubMed Central

    Naziruddin, Bashoo; Wease, Steve; Stablein, Donald; Barton, Franca B.; Berney, Thierry; Rickels, Michael R.; Alejandro, Rodolfo

    2015-01-01

    Pancreatic islet transplantation is a promising treatment option for patients severely affected with type 1 diabetes. This report from CITR presents pre- and post-transplant human leukocyte antigen (HLA) class I sensitization rates in islet alone transplantation. Data came from 303 recipients transplanted with islet alone between January 1999 and December 2008. HLA class I sensitization was determined by the presence of anti-HLA class I antibodies. Panel-reactive antibodies (PRA) from prior to islet infusion and at 6 months, and yearly post-transplant was correlated to measures of islet graft failure. The cumulative number of mismatched HLA alleles increased with each additional islet infusion from a median of 3 for one infusion to 9 for three infusions. Pre-transplant PRA was not predictive of islet graft failure. However, development of PRA ≥20% post-transplant was associated with 3.6 fold (p=.001) increased hazard ratio for graft failure. Patients with complete graft loss who had discontinued immunosuppression had significantly higher rate of PRA ≥ 20% compared to those with functioning grafts who remained on immunosuppression. Exposure to repeat HLA class I mismatch at second or third islet infusions resulted in less frequent development of de novo HLA class I antibodies when compared to increased class I mismatch. The development of HLA class I antibodies while on immunosuppression is associated with subsequent islet graft failure. The risk of sensitization may be reduced by minimizing the number of islet donors used per recipient, and in the absence of donor-specific anti-HLA antibodies, repeating HLA class I mismatches with subsequent islet infusions. PMID:22080832

  8. PD-L1-driven tolerance protects neurogenin3-induced islet neogenesis to reverse established type 1 diabetes in NOD mice.

    PubMed

    Li, Rongying; Lee, Jeongkyung; Kim, Mi-sun; Liu, Victoria; Moulik, Mousumi; Li, Haiyan; Yi, Qing; Xie, Aini; Chen, Wenhao; Yang, Lina; Li, Yimin; Tsai, Tsung Huang; Oka, Kazuhiro; Chan, Lawrence; Yechoor, Vijay

    2015-02-01

    A breakdown in self-tolerance underlies autoimmune destruction of β-cells and type 1 diabetes. A cure by restoring β-cell mass is limited by the availability of transplantable β-cells and the need for chronic immunosuppression. Evidence indicates that inhibiting costimulation through the PD-1/PD-L1 pathway is central to immune toleran