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Sample records for beta-cell burst period

  1. Analysis of the noise-induced bursting-spiking transition in a pancreatic beta-cell model

    DEFF Research Database (Denmark)

    Aguirre, J.; Mosekilde, Erik; Sanjuan, M.A.F.

    2004-01-01

    potential signals, such as their periodic or chaotic nature, and their bursting or spiking behavior. We present effective computational tools to obtain as much information as possible from these signals, and we suggest that the methods could be applied to real time series. Finally, a universal dependence...

  2. Polarization of a periodic solar microwave burst

    Energy Technology Data Exchange (ETDEWEB)

    Kaufmann, P [Universidade Mackenzie, Sao Paulo (Brazil). Centro de Radio-Astronomia e Astrofisica

    1976-09-01

    No fluctuations in polarization have been found during a 7 GHz solar burst showing 17s periodic pulses in intensity. Polarization effects can be produced by the propagation media in the active centre, which are not affected directly by the burst source, but situated more deeply than the observed heights at that microwave frequency.

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

    Directory of Open Access Journals (Sweden)

    Wang Xujing

    2008-08-01

    Full Text Available Abstract 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.

  4. The genesis of period-adding bursting without bursting-chaos in the Chay model

    International Nuclear Information System (INIS)

    Yang Zhuoqin; Lu Qishao; Li Li

    2006-01-01

    According to the period-adding firing patterns without chaos observed in neuronal experiments, the genesis of the period-adding 'fold/homoclinic' bursting sequence without bursting-chaos is explored by numerical simulation, fast/slow dynamics and bifurcation analysis of limit cycle in the neuronal Chay model. It is found that each periodic bursting, from period-1 to period-7, is separately generated by the corresponding periodic spiking pattern through two period-doubling bifurcations, except for the period-1 bursting occurring via a Hopf bifurcation. Consequently, it can be revealed that this period-adding bursting bifurcation without chaos has a compound bifurcation structure with transitions from spiking to bursting, which is closely related to period-doubling bifurcations of periodic spiking in essence

  5. The genesis of period-adding bursting without bursting-chaos in the Chay model

    International Nuclear Information System (INIS)

    Yang Zhuoqin; Lu Qishao; Li Li

    2006-01-01

    According to the period-adding firing patterns without chaos observed in neuronal experiments, the genesis of the period-adding 'fold/homoclinic' bursting sequence without bursting-chaos is explored by numerical simulation, fast/slow dynamics and bifurcation analysis of limit cycle in the neuronal Chay model. It is found that each periodic bursting, from period-1 to 7, is separately generated by the corresponding periodic spiking pattern through two period-doubling bifurcations, except for the period-1 bursting occurring via a Hopf bifurcation. Consequently, it can be revealed that this period-adding bursting bifurcation without chaos has a compound bifurcation structure with transitions from spiking to bursting, which is closely related to period-doubling bifurcations of periodic spiking in essence

  6. Beta cell adaptation in pregnancy

    DEFF Research Database (Denmark)

    Nielsen, Jens Høiriis

    2016-01-01

    Pregnancy is associated with a compensatory increase in beta cell mass. It is well established that somatolactogenic hormones contribute to the expansion both indirectly by their insulin antagonistic effects and directly by their mitogenic effects on the beta cells via receptors for prolactin...... and growth hormone expressed in rodent beta cells. However, the beta cell expansion in human pregnancy seems to occur by neogenesis of beta cells from putative progenitor cells rather than by proliferation of existing beta cells. Claes Hellerström has pioneered the research on beta cell growth for decades...... in the expansion of the beta cell mass in human pregnancy, and the relative roles of endocrine factors and nutrients....

  7. Regulation of beta cell replication

    DEFF Research Database (Denmark)

    Lee, Ying C; Nielsen, Jens Høiriis

    2008-01-01

    Beta cell mass, at any given time, is governed by cell differentiation, neogenesis, increased or decreased cell size (cell hypertrophy or atrophy), cell death (apoptosis), and beta cell proliferation. Nutrients, hormones and growth factors coupled with their signalling intermediates have been...... suggested to play a role in beta cell mass regulation. In addition, genetic mouse model studies have indicated that cyclins and cyclin-dependent kinases that determine cell cycle progression are involved in beta cell replication, and more recently, menin in association with cyclin-dependent kinase...... inhibitors has been demonstrated to be important in beta cell growth. In this review, we consider and highlight some aspects of cell cycle regulation in relation to beta cell replication. The role of cell cycle regulation in beta cell replication is mostly from studies in rodent models, but whether...

  8. QUASI-PERIODIC OSCILLATIONS AND BROADBAND VARIABILITY IN SHORT MAGNETAR BURSTS

    Energy Technology Data Exchange (ETDEWEB)

    Huppenkothen, Daniela; Watts, Anna L.; Uttley, Phil; Van der Horst, Alexander J.; Van der Klis, Michiel [Astronomical Institute ' ' Anton Pannekoek' ' , University of Amsterdam, Postbus 94249, 1090-GE Amsterdam (Netherlands); Kouveliotou, Chryssa [Office of Science and Technology, ZP12, NASA Marshall Space Flight Center, Huntsville, AL 35812 (United States); Goegues, Ersin [Sabanc Latin-Small-Letter-Dotless-I University, Orhanl Latin-Small-Letter-Dotless-I -Tuzla, Istanbul 34956 (Turkey); Granot, Jonathan [The Open University of Israel, 1 University Road, P.O. Box 808, Ra' anana 43537 (Israel); Vaughan, Simon [X-Ray and Observational Astronomy Group, University of Leicester, Leicester LE1 7RH (United Kingdom); Finger, Mark H., E-mail: D.Huppenkothen@uva.nl [Universities Space Research Association, Huntsville, AL 35805 (United States)

    2013-05-01

    The discovery of quasi-periodic oscillations (QPOs) in magnetar giant flares has opened up prospects for neutron star asteroseismology. However, with only three giant flares ever recorded, and only two with data of sufficient quality to search for QPOs, such analysis is seriously data limited. We set out a procedure for doing QPO searches in the far more numerous, short, less energetic magnetar bursts. The short, transient nature of these bursts requires the implementation of sophisticated statistical techniques to make reliable inferences. Using Bayesian statistics, we model the periodogram as a combination of red noise at low frequencies and white noise at high frequencies, which we show is a conservative approach to the problem. We use empirical models to make inferences about the potential signature of periodic and QPOs at these frequencies. We compare our method with previously used techniques and find that although it is on the whole more conservative, it is also more reliable in ruling out false positives. We illustrate our Bayesian method by applying it to a sample of 27 bursts from the magnetar SGR J0501+4516 observed by the Fermi Gamma-ray Burst Monitor, and we find no evidence for the presence of QPOs in any of the bursts in the unbinned spectra, but do find a candidate detection in the binned spectra of one burst. However, whether this signal is due to a genuine quasi-periodic process, or can be attributed to unmodeled effects in the noise is at this point a matter of interpretation.

  9. Periodic or chaotic bursting dynamics via delayed pitchfork bifurcation in a slow-varying controlled system

    Science.gov (United States)

    Yu, Yue; Zhang, Zhengdi; Han, Xiujing

    2018-03-01

    In this work, we aim to demonstrate the novel routes to periodic and chaotic bursting, i.e., the different bursting dynamics via delayed pitchfork bifurcations around stable attractors, in the classical controlled Lü system. First, by computing the corresponding characteristic polynomial, we determine where some critical values about bifurcation behaviors appear in the Lü system. Moreover, the transition mechanism among different stable attractors has been introduced including homoclinic-type connections or chaotic attractors. Secondly, taking advantage of the above analytical results, we carry out a study of the mechanism for bursting dynamics in the Lü system with slowly periodic variation of certain control parameter. A distinct delayed supercritical pitchfork bifurcation behavior can be discussed when the control item passes through bifurcation points periodically. This delayed dynamical behavior may terminate at different parameter areas, which leads to different spiking modes around different stable attractors (equilibriums, limit cycles, or chaotic attractors). In particular, the chaotic attractor may appear by Shilnikov connections or chaos boundary crisis, which leads to the occurrence of impressive chaotic bursting oscillations. Our findings enrich the study of bursting dynamics and deepen the understanding of some similar sorts of delayed bursting phenomena. Finally, some numerical simulations are included to illustrate the validity of our study.

  10. Quasi-periodic oscillations in short recurring bursts of the soft gamma repeater J1550–5418

    Energy Technology Data Exchange (ETDEWEB)

    Huppenkothen, D.; D' Angelo, C.; Watts, A. L.; Heil, L.; Van der Klis, M.; Van der Horst, A. J. [Astronomical Institute " Anton Pannekoek," University of Amsterdam, Postbus 94249, 1090 GE Amsterdam (Netherlands); Kouveliotou, C. [Astrophysics Office, ZP 12, NASA-Marshall Space Flight Center, Huntsville, AL 35812 (United States); Baring, M. G. [Department of Physics and Astronomy, Rice University, MS-108, P.O. Box 1892, Houston, TX 77251 (United States); Göğüş, E.; Kaneko, Y. [SabancıUniversity, Orhanlı-Tuzla, İstanbul 34956 (Turkey); Granot, J. [Department of Natural Sciences, The Open University of Israel, 1 University Road, P.O. Box 808, Ra' anana 43537 (Israel); Lin, L. [François Arago Centre, APC, 10 rue Alice Domon et Léonie Duquet, F-75205 Paris (France); Von Kienlin, A. [Max-Planck-Institut für extraterrestrische Physik, Giessenbachstrasse 1, D-85748 Garching (Germany); Younes, G., E-mail: D.Huppenkothen@uva.nl [NSSTC, 320 Sparkman Drive, Huntsville, AL 35805 (United States)

    2014-06-01

    The discovery of quasi-periodic oscillations (QPOs) in magnetar giant flares has opened up prospects for neutron star asteroseismology. The scarcity of giant flares makes a search for QPOs in the shorter, far more numerous bursts from soft gamma repeaters (SGRs) desirable. In Huppenkothen et al., we developed a Bayesian method for searching for QPOs in short magnetar bursts, taking into account the effects of the complicated burst structure, and have shown its feasibility on a small sample of bursts. Here we apply the same method to a much larger sample from a burst storm of 286 bursts from SGR J1550–5418. We report a candidate signal at 260 Hz in a search of the individual bursts, which is fairly broad. We also find two QPOs at ∼93 Hz, and one at 127 Hz, when averaging periodograms from a number of bursts in individual triggers, at frequencies close to QPOs previously observed in magnetar giant flares. Finally, for the first time, we explore the overall burst variability in the sample and report a weak anti-correlation between the power-law index of the broadband model characterizing aperiodic burst variability and the burst duration: shorter bursts have steeper power-law indices than longer bursts. This indicates that longer bursts vary over a broader range of timescales and are not simply longer versions of the short bursts.

  11. MILLIHERTZ QUASI-PERIODIC OSCILLATIONS AND THERMONUCLEAR BURSTS FROM TERZAN 5: A SHOWCASE OF BURNING REGIMES

    Energy Technology Data Exchange (ETDEWEB)

    Linares, M.; Chakrabarty, D. [Massachusetts Institute of Technology, Kavli Institute for Astrophysics and Space Research, Cambridge, MA 02139 (United States); Altamirano, D. [Astronomical Institute ' Anton Pannekoek' , University of Amsterdam and Center for High-Energy Astrophysics, P.O. BOX 94249, 1090 GE Amsterdam (Netherlands); Cumming, A. [Department of Physics, McGill University, 3600 Rue University, Montreal, QC H3A 2T8 (Canada); Keek, L. [School of Physics and Astronomy, University of Minnesota, 116 Church Street SE, Minneapolis, MN 55455 (United States)

    2012-04-01

    We present a comprehensive study of the thermonuclear bursts and millihertz quasi-periodic oscillations (mHz QPOs) from the neutron star (NS) transient and 11 Hz X-ray pulsar IGR J17480-2446, located in the globular cluster Terzan 5. The increase in burst rate that we found during its 2010 outburst, when persistent luminosity rose from 0.1 to 0.5 times the Eddington limit, is in qualitative agreement with thermonuclear burning theory yet contrary to all previous observations of thermonuclear bursts. Thermonuclear bursts gradually evolved into a mHz QPO when the accretion rate increased, and vice versa. The mHz QPOs from IGR J17480-2446 resemble those previously observed in other accreting NSs, yet they feature lower frequencies (by a factor {approx}3) and occur when the persistent luminosity is higher (by a factor 4-25). We find four distinct bursting regimes and a steep (close to inverse cubic) decrease of the burst recurrence time with increasing persistent luminosity. We compare these findings to nuclear burning models and find evidence for a transition between the pure helium and mixed hydrogen/helium ignition regimes when the persistent luminosity was about 0.3 times the Eddington limit. We also point out important discrepancies between the observed bursts and theory, which predicts brighter and less frequent bursts, and suggest that an additional source of heat in the NS envelope is required to reconcile the observed and expected burst properties. We discuss the impact of NS magnetic field and spin on the expected nuclear burning regimes, in the context of this particular pulsar.

  12. Beta Cell Workshop 2013 Kyoto

    DEFF Research Database (Denmark)

    Heller, R Scott; Madsen, Ole D; Nielsen, Jens Høiriis

    2013-01-01

    The very modern Kyoto International Conference Center provided the site for the 8th workshop on Beta cells on April 23-26, 2013. The preceding workshops were held in Boston, USA (1991); Kyoto, Japan (1994); Helsingør, Denmark (1997); Helsinki, Finland (2003); El Perello, Spain (2006); Peebles...

  13. Quasi-periodic Radio Bursts Associated with Fast-mode Waves near a Magnetic Null Point

    Energy Technology Data Exchange (ETDEWEB)

    Kumar, Pankaj [Heliophysics Science Division, NASA Goddard Space Flight Center, Greenbelt, MD 20771 (United States); Nakariakov, Valery M. [Centre for Fusion, Space and Astrophysics, Department of Physics, University of Warwick, CV4 7AL (United Kingdom); Cho, Kyung-Suk, E-mail: pankaj.kumar@nasa.gov [Korea Astronomy and Space Science Institute (KASI), Daejeon, 305-348 (Korea, Republic of)

    2017-08-01

    This paper presents an observation of quasi-periodic rapidly propagating waves observed in the Atmospheric Image Assembly (AIA) 171/193 Å channels during the impulsive phase of an M1.9 flare that occurred on 2012 May 7. The instant period was found to decrease from 240 to 120 s, and the speed of the wavefronts was in the range of ∼664–1416 km s{sup −1}. Almost simultaneously, quasi-periodic bursts with similar instant periods, ∼70 and ∼140 s, occur in the microwave emission and in decimetric type IV and type III radio bursts, and in the soft X-ray emission. The magnetic field configuration of the flare site was consistent with a breakout topology, i.e., a quadrupolar field along with a magnetic null point. The quasi-periodic rapidly propagating wavefronts of the EUV emission are interpreted as a fast magnetoacoustic wave train. The observations suggest that the fast-mode waves are generated during the quasi-periodic magnetic reconnection in the cusp region above the flare arcade loops. For the first time, we provide evidence of a tadpole wavelet signature at about 70–140 s in decimetric (245/610 MHz) radio bursts, along with the direct observation of a coronal fast-mode wave train in EUV. In addition, at AIA 131/193 Å we observed quasi-periodic EUV disturbances with periods of 95 and 240 s propagating downward at apparent speeds of 172–273 km s{sup −1}. The nature of these downward propagating disturbances is not revealed, but they could be connected to magnetoacoustic waves or periodically shrinking loops.

  14. Quasi-periodic Radio Bursts Associated with Fast-mode Waves near a Magnetic Null Point

    International Nuclear Information System (INIS)

    Kumar, Pankaj; Nakariakov, Valery M.; Cho, Kyung-Suk

    2017-01-01

    This paper presents an observation of quasi-periodic rapidly propagating waves observed in the Atmospheric Image Assembly (AIA) 171/193 Å channels during the impulsive phase of an M1.9 flare that occurred on 2012 May 7. The instant period was found to decrease from 240 to 120 s, and the speed of the wavefronts was in the range of ∼664–1416 km s −1 . Almost simultaneously, quasi-periodic bursts with similar instant periods, ∼70 and ∼140 s, occur in the microwave emission and in decimetric type IV and type III radio bursts, and in the soft X-ray emission. The magnetic field configuration of the flare site was consistent with a breakout topology, i.e., a quadrupolar field along with a magnetic null point. The quasi-periodic rapidly propagating wavefronts of the EUV emission are interpreted as a fast magnetoacoustic wave train. The observations suggest that the fast-mode waves are generated during the quasi-periodic magnetic reconnection in the cusp region above the flare arcade loops. For the first time, we provide evidence of a tadpole wavelet signature at about 70–140 s in decimetric (245/610 MHz) radio bursts, along with the direct observation of a coronal fast-mode wave train in EUV. In addition, at AIA 131/193 Å we observed quasi-periodic EUV disturbances with periods of 95 and 240 s propagating downward at apparent speeds of 172–273 km s −1 . The nature of these downward propagating disturbances is not revealed, but they could be connected to magnetoacoustic waves or periodically shrinking loops.

  15. The computerized reactor period measurement system for China fast burst reactor-II

    International Nuclear Information System (INIS)

    Zhao Wuwen; Jiang Zhiguo

    1996-01-01

    The article simply introduces the hardware, principle, and software of the computerized reactor period measurement system for China Fast Burst Reactor-II (CFBR-II). It also gives the relation between fission yield and pre-reactivity of CFBR-II reactor system of bared reactor with decoupled-component and system of bared reactor with multiple light-material. The computerized measurement system makes the reactor period measurement into automatical and intelligent and also improves the speed and precision of period data on-line process

  16. Computer measurement system of reactor period for China fast burst reactor-II

    International Nuclear Information System (INIS)

    Zhao Wuwen; Jiang Zhiguo

    1997-01-01

    The author simply introduces the hardware, principle, and software of the reactor period computer measure system for China Fast Burst Reactor-II (CFBR-II). It also gives the relation between Fission yield and Pre-reactivity of CFBR-II reactor system of bared reactor with decoupled-component and system of bared reactor with multiple light-material. The computer measure system makes the reactor period measurement into automation and intellectualization and also improves the speed and precision of period data process on-line

  17. Periodic lateralized epileptiform discharges can survive anesthesia and result in asymmetric drug-induced burst suppression

    Directory of Open Access Journals (Sweden)

    Edward C. Mader Jr.

    2017-02-01

    Full Text Available Drug-induced burst suppression (DIBS is bihemispheric and bisymmetric in adults and older children. However, asymmetric DIBS may occur if a pathological process is affecting one hemisphere only or both hemispheres disproportionately. The usual suspect is a destructive lesion; an irritative or epileptogenic lesion is usually not invoked to explain DIBS asymmetry. We report the case of a 66-year-old woman with new-onset seizures who was found to have a hemorrhagic cavernoma and periodic lateralized epileptiform discharges (PLEDs in the right temporal region. After levetiracetam and before anesthetic antiepileptic drugs (AEDs were administered, the electroencephalogram (EEG showed continuous PLEDs over the right hemisphere with maximum voltage in the posterior temporal region. Focal electrographic seizures also occurred occasionally in the same location. Propofol resulted in bihemispheric, but not in bisymmetric, DIBS. Remnants or fragments of PLEDs that survived anesthesia increased the amplitude and complexity of the bursts in the right hemisphere leading to asymmetric DIBS. Phenytoin, lacosamide, ketamine, midazolam, and topiramate were administered at various times in the course of EEG monitoring, resulting in suppression of seizures but not of PLEDs. Ketamine and midazolam reduced the rate, amplitude, and complexity of PLEDs but only after producing substantial attenuation of all burst components. When all anesthetics were discontinued, the EEG reverted to the original preanesthesia pattern with continuous non-fragmented PLEDs. The fact that PLEDs can survive anesthesia and affect DIBS symmetry is a testament to the robustness of the neurodynamic processes underlying PLEDs.

  18. Clusters of conserved beta cell marker genes for assessment of beta cell phenotype

    DEFF Research Database (Denmark)

    Martens, Geert A; Jiang, Lei; Hellemans, Karine H

    2011-01-01

    The aim of this study was to establish a gene expression blueprint of pancreatic beta cells conserved from rodents to humans and to evaluate its applicability to assess shifts in the beta cell differentiated state. Genome-wide mRNA expression profiles of isolated beta cells were compared to those...... of a large panel of other tissue and cell types, and transcripts with beta cell-abundant and -selective expression were identified. Iteration of this analysis in mouse, rat and human tissues generated a panel of conserved beta cell biomarkers. This panel was then used to compare isolated versus laser capture...

  19. Dynamics of ponderomotive self-focusing and periodic bursts of stimulated Brillouin backscattering in plasmas

    International Nuclear Information System (INIS)

    Andreev, N.E.; Gorbunov, L.M.; Tarakanov, S.V.; Zykov, A.I.

    1993-01-01

    The space--time evolution of ponderomotive self-focusing of electromagnetic beams in a plasma is investigated. The quasineutral, hydrodynamic plasma response to the ponderomotive force is considered. The set of coupled quasioptic and acoustic equations is solved both analytically and numerically for slab and cylindrical beams. It is shown that the transient process of self-focusing has the form of a nonlinear wave propagating along the beam axis from boundary into the interior of a plasma with velocity considerably higher than the ion-sound velocity. Mutual dynamics of self-focusing and stimulated Brillouin backscattering (SBBS) is computed. It is shown that self-focusing results in the high intensity periodical bursts of SBBS. However, the time average level of scattered radiation is quite low

  20. Clusters of conserved beta cell marker genes for assessment of beta cell phenotype

    DEFF Research Database (Denmark)

    Martens, Geert A; Jiang, Lei; Hellemans, Karine H

    2011-01-01

    The aim of this study was to establish a gene expression blueprint of pancreatic beta cells conserved from rodents to humans and to evaluate its applicability to assess shifts in the beta cell differentiated state. Genome-wide mRNA expression profiles of isolated beta cells were compared to those...... of a large panel of other tissue and cell types, and transcripts with beta cell-abundant and -selective expression were identified. Iteration of this analysis in mouse, rat and human tissues generated a panel of conserved beta cell biomarkers. This panel was then used to compare isolated versus laser capture...... microdissected beta cells, monitor adaptations of the beta cell phenotype to fasting, and retrieve possible conserved transcriptional regulators....

  1. Observation of quasi-periodic solar radio bursts associated with propagating fast-mode waves

    Science.gov (United States)

    Goddard, C. R.; Nisticò, G.; Nakariakov, V. M.; Zimovets, I. V.; White, S. M.

    2016-10-01

    Aims: Radio emission observations from the Learmonth and Bruny Island radio spectrographs are analysed to determine the nature of a train of discrete, periodic radio "sparks" (finite-bandwidth, short-duration isolated radio features) which precede a type II burst. We analyse extreme ultraviolet (EUV) imaging from SDO/AIA at multiple wavelengths and identify a series of quasi-periodic rapidly-propagating enhancements, which we interpret as a fast wave train, and link these to the detected radio features. Methods: The speeds and positions of the periodic rapidly propagating fast waves and the coronal mass ejection (CME) were recorded using running-difference images and time-distance analysis. From the frequency of the radio sparks the local electron density at the emission location was estimated for each. Using an empirical model for the scaling of density in the corona, the calculated electron density was used to obtain the height above the surface at which the emission occurs, and the propagation velocity of the emission location. Results: The period of the radio sparks, δtr = 1.78 ± 0.04 min, matches the period of the fast wave train observed at 171 Å, δtEUV = 1.7 ± 0.2 min. The inferred speed of the emission location of the radio sparks, 630 km s-1, is comparable to the measured speed of the CME leading edge, 500 km s-1, and the speeds derived from the drifting of the type II lanes. The calculated height of the radio emission (obtained from the density) matches the observed location of the CME leading edge. From the above evidence we propose that the radio sparks are caused by the quasi-periodic fast waves, and the emission is generated as they catch up and interact with the leading edge of the CME. The movie associated to Fig. 2 is available at http://www.aanda.org

  2. Beta cell proliferation and growth factors

    DEFF Research Database (Denmark)

    Nielsen, Jens Høiriis; Svensson, C; Møldrup, Annette

    1999-01-01

    Formation of new beta cells can take place by two pathways: replication of already differentiated beta cells or neogenesis from putative islet stem cells. Under physiological conditions both processes are most pronounced during the fetal and neonatal development of the pancreas. In adulthood little...... increase in the beta cell number seems to occur. In pregnancy, however, a marked hyperplasia of the beta cells is observed both in rodents and man. Increased mitotic activity has been seen both in vivo and in vitro in islets exposed to placental lactogen (PL), prolactin (PRL) and growth hormone (GH...... and activation of the tyrosine kinase JAK2 and the transcription factors STAT1 and 3. The activation of the insulin gene however also requires the distal part of the receptor and activation of calcium uptake and STAT5. In order to identify putative autocrine growth factors or targets for growth factors we have...

  3. 4. 7s nearly periodic oscillations superimposed on the solar microwave great burst of 28 March 1976

    Energy Technology Data Exchange (ETDEWEB)

    Kaufmann, P; Piazza, L R; Raffaelli, J C [Universidade Mackenzie, Sao Paulo (Brazil). Centro de Radio-Astronomia e Astrofisica

    1977-09-01

    An unusual fast oscillation was found superimposed on the solar great burst on 28 March 1976, as measured at 7 GHz. The period of the oscillation was 4.7 +- 0.9 s, defined over the entire duration of the event. The amplitude of the oscillation was proportional to the flux density in the range 50periodic time structure.

  4. Millisecond-Period Meltdown Experiments on Prompt - Burst Effects and Molten-Tin-Water Dropping Experiments

    International Nuclear Information System (INIS)

    Wright, R.W.; Coats, R.L.; Schmidt, T.R.; Arakeri, V.H.

    1976-01-01

    The U.S. Nuclear Regulatory Commission has initiated a program of confirmatory research for the safety assessment of LMFBR plants. In the sodium-fuel interactions area, this research includes a series of real-time in-pile experiments on the pressure and work potential of prompt-burst excursions as well as laboratory dropping experiments with molten tin and water. The in-pile experiments are performed by Sandia Laboratories in the Annular Core Pulse Reactor (ACPR), which has a minimum period of 1.3 milliseconds. These single-pin experiments are performed in a piston-loaded, stagnant-sodium autoclave, that is conceptually similar to the one used in the S-11 TREAT test. Unlike the S-11 test, however, realistic radial temperature profiles are obtained in the fuel, the cladding, and the sodium by pre-pulsing the reactor about 1/2 second before the main pulse. A series of preparatory runs have been made with helium-filled capsules and at low energy with sodium-filled capsules. The first significant fuel-coolant interaction run is scheduled for late March 1976. This will be a double-pulsed run at 2700 j/gm UO 2 . A continuing series of experiments is planned with oxide and advanced fuels in both fresh and irradiated form. In molten-tin-water dropping experiments at UCLA, microsecond duration multi-flash photography has been used for event diagnostics. Transition or nucleate boiling was found to trigger energetic interactions or vapor explosions. Temperature stratification in the water was found to reduce the threshold tin temperature necessary to produce vapor explosions below that the predicted by the coolant homogeneous nucleation hypothesis. Interaction zone growth times of a few msec were measured

  5. Proton microprobe analysis of pancreatic. beta. cells

    Energy Technology Data Exchange (ETDEWEB)

    Lindh, U [Uppsala Univ. (Sweden). Gustaf Werner Inst.; Juntti-Berggren, L; Berggren, P O; Hellman, B [Uppsala Univ. (Sweden)

    1985-01-01

    Freeze-dried pancreas sections from obese hyperglycemic mice were subjected to proton bombardment and the elemental contents in the ..beta.. cells and the exocrine part were obtained from the characteristic X-rays emitted. Quantitative data were provided for 18 different elements. The mole ratio between K and Na exceeded 10, implying that neither the sample preparation nor the irradiation had induced significant diffuse changes. With the demonstration of this high K/Na ratio it seems likely that also the ..beta.. cells are equipped with an efficient Na/sup +//K/sup +/ pump. The ..beta.. cells contained about 70 mmoles Cl per litre cell water. Observed amounts of Ca and Mg were equivalent to those previously recorded by electrothermal atomic absorption spectroscopy. The significant role of Zn for the storage of insulin was emphasized by the demonstration of 3 times as much of this element in the ..beta.. cells as compared with the exocrine pancreas. In addition, the sensitivity of the proton microprobe enabled measurements of various trace elements such as Rb, Cr, Cu, Al and Pb not previously demonstrated in the pancreatic ..beta.. cells.

  6. Redox Homeostasis in Pancreatic beta Cells

    Czech Academy of Sciences Publication Activity Database

    Ježek, Petr; Dlasková, Andrea; Plecitá-Hlavatá, Lydie

    2012-01-01

    Roč. 2012, č. 2012 (2012), s. 932838 ISSN 1942-0900 R&D Projects: GA ČR(CZ) GAP302/10/0346; GA ČR(CZ) GPP304/10/P204 Institutional support: RVO:67985823 Keywords : beta cells * reactive oxygen species homeostasis * mitochondria Subject RIV: FB - Endocrinology, Diabetology, Metabolism, Nutrition Impact factor: 3.393, year: 2012

  7. Genetic models rule out a major role of beta cell glycogen in the control of glucose homeostasis.

    Science.gov (United States)

    Mir-Coll, Joan; Duran, Jordi; Slebe, Felipe; García-Rocha, Mar; Gomis, Ramon; Gasa, Rosa; Guinovart, Joan J

    2016-05-01

    Glycogen accumulation occurs in beta cells of diabetic patients and has been proposed to partly mediate glucotoxicity-induced beta cell dysfunction. However, the role of glycogen metabolism in beta cell function and its contribution to diabetes pathophysiology remain poorly understood. We investigated the function of beta cell glycogen by studying glucose homeostasis in mice with (1) defective glycogen synthesis in the pancreas; and (2) excessive glycogen accumulation in beta cells. Conditional deletion of the Gys1 gene and overexpression of protein targeting to glycogen (PTG) was accomplished by Cre-lox recombination using pancreas-specific Cre lines. Glucose homeostasis was assessed by determining fasting glycaemia, insulinaemia and glucose tolerance. Beta cell mass was determined by morphometry. Glycogen was detected histologically by periodic acid-Schiff's reagent staining. Isolated islets were used for the determination of glycogen and insulin content, insulin secretion, immunoblots and gene expression assays. Gys1 knockout (Gys1 (KO)) mice did not exhibit differences in glucose tolerance or basal glycaemia and insulinaemia relative to controls. Insulin secretion and gene expression in isolated islets was also indistinguishable between Gys1 (KO) and controls. Conversely, despite effective glycogen overaccumulation in islets, mice with PTG overexpression (PTG(OE)) presented similar glucose tolerance to controls. However, under fasting conditions they exhibited lower glycaemia and higher insulinaemia. Importantly, neither young nor aged PTG(OE) mice showed differences in beta cell mass relative to age-matched controls. Finally, a high-fat diet did not reveal a beta cell-autonomous phenotype in either model. Glycogen metabolism is not required for the maintenance of beta cell function. Glycogen accumulation in beta cells alone is not sufficient to trigger the dysfunction or loss of these cells, or progression to diabetes.

  8. Characterization of a Commercial Silicon Beta Cell

    International Nuclear Information System (INIS)

    Foxe, Michael P.; Hayes, James C.; Mayer, Michael F.; McIntyre, Justin I.; Sivels, Ciara B.; Suarez, Rey

    2016-01-01

    Silicon detectors are of interest for the verification of the Comprehensive Nuclear-Test-Ban Treaty (CTBT) due to their enhanced energy resolution compared to plastic scintillators beta cells. Previous work developing a figure-of-merit (FOM) for comparison of beta cells suggests that the minimum detectable activity (MDA) could be reduced by a factor of two to three with the use of silicon detectors. Silicon beta cells have been developed by CEA (France) and Lares Ltd. (Russia), with the PIPSBox developed by CEA being commercially available from Canberra for approximately $35k, but there is still uncertainty about the reproducibility of the capabilities in the field. PNNL is developing a high-resolution beta-gamma detector system in the shallow underground laboratory, which will utilize and characterize the operation of the PIPSBox detector. Throughout this report, we examine the capabilities of the PIPSBox as developed by CEA. The lessons learned through the testing and use of the PIPSBox will allow PNNL to strategically develop a silicon detector optimized to better suit the communities needs in the future.

  9. EARLY OPTICAL OBSERVATIONS OF GAMMA-RAY BURSTS BY THE TAROT TELESCOPES: PERIOD 2001-2008

    International Nuclear Information System (INIS)

    Klotz, A.; Boer, M.; Atteia, J. L.; Gendre, B.

    2009-01-01

    The Telescopes a Action Rapide pour les Objets Transitoires telescopes are two robotic observatories designed to observe the prompt optical emission counterpart and the early afterglow of gamma-ray bursts (GRBs). We present data acquired between 2001 and 2008 and discuss the properties of the optical emission of GRBs, noting various interesting results. The optical emission observed during the prompt GRB phase is rarely very bright: we estimate that 5%-20% of GRBs exhibit a bright optical flash (R < 14) during the prompt gamma-ray emission, and that more than 50% of the GRBs have an optical emission fainter than R = 15.5 when the gamma-ray emission is active. We study the apparent optical brightness distribution of GRBs at 1000 s showing that our observations confirm the distribution derived by other groups. The combination of these results with those obtained by other rapid slewing telescopes allows us to better characterize the early optical emission of GRBs and to emphasize the importance of very early multiwavelength GRB studies for the understanding of the physics of the ejecta.

  10. In vitro proliferation of adult human beta-cells.

    Directory of Open Access Journals (Sweden)

    Sabine Rutti

    Full Text Available A decrease in functional beta-cell mass is a key feature of type 2 diabetes. Glucagon-like peptide 1 (GLP-1 analogues induce proliferation of rodent beta-cells. However, the proliferative capacity of human beta-cells and its modulation by GLP-1 analogues remain to be fully investigated. We therefore sought to quantify adult human beta-cell proliferation in vitro and whether this is affected by the GLP-1 analogue liraglutide.Human islets from 7 adult cadaveric organ donors were dispersed into single cells. Beta-cells were purified by FACS. Non-sorted cells and the beta-cell enriched ("beta-cells" population were plated on extracellular matrix from rat (804G and human bladder carcinoma cells (HTB9 or bovine corneal endothelial ECM (BCEC. Cells were maintained in culture+/-liraglutide for 4 days in the presence of BrdU.Rare human beta-cell proliferation could be observed either in the purified beta-cell population (0.051±0.020%; 22 beta-cells proliferating out of 84'283 beta-cells counted or in the non-sorted cell population (0.055±0.011%; 104 proliferating beta-cells out of 232'826 beta-cells counted, independently of the matrix or the culture conditions. Liraglutide increased human beta-cell proliferation on BCEC in the non-sorted cell population (0.082±0.034% proliferating beta-cells vs. 0.017±0.008% in control, p<0.05.These results indicate that adult human beta-cell proliferation can occur in vitro but remains an extremely rare event with these donors and particular culture conditions. Liraglutide increases beta-cell proliferation only in the non-sorted cell population and only on BCEC. However, it cannot be excluded that human beta-cells may proliferate to a greater extent in situ in response to natural stimuli.

  11. A new mechanism for periodic bursting of the recirculation region in the flow through a sudden expansion in a circular pipe

    Science.gov (United States)

    Lebon, Benoit; Nguyen, Minh Quan; Peixinho, Jorge; Shadloo, Mostafa Safdari; Hadjadj, Abdellah

    2018-03-01

    We report the results of a combined experimental and numerical study of specific finite-amplitude disturbances for transition to turbulence in the flow through a circular pipe with a sudden expansion. The critical amplitude thresholds for localized turbulent patch downstream of the expansion scale with the Reynolds number with a power law exponent of -2.3 for experiments and -2.8 for simulations. A new mechanism for the periodic bursting of the recirculation region is uncovered where the asymmetric recirculation flow develops a periodic dynamics: a secondary recirculation breaks the symmetry along the pipe wall and bursts into localized turbulence, which travels downstream and relaminarises. Flow visualizations show a simple flow pattern of three waves forming, growing, and bursting.

  12. Chronic antidiabetic sulfonylureas in vivo: reversible effects on mouse pancreatic beta-cells.

    Directory of Open Access Journals (Sweden)

    Maria Sara Remedi

    2008-10-01

    chronic glibenclamide treatment in vivo causes loss of insulin secretory capacity due to beta-cell hyperexcitability, but also reveal rapid reversibility of this secretory failure, arguing against beta-cell apoptosis or other cell death induced by sulfonylureas. These in vivo studies may help to explain why patients with type 2 diabetes can show long-term secondary failure to secrete insulin in response to sulfonylureas, but experience restoration of insulin secretion after a drug resting period, without permanent damage to beta-cells. This finding suggests that novel treatment regimens may succeed in prolonging pharmacological therapies in susceptible individuals.

  13. Proliferation of sorted human and rat beta cells

    DEFF Research Database (Denmark)

    Parnaud, G; Bosco, D; Berney, T

    2008-01-01

    The aim of the study was to determine whether purified beta cells can replicate in vitro and whether this is enhanced by extracellular matrix (ECM) and growth factors.......The aim of the study was to determine whether purified beta cells can replicate in vitro and whether this is enhanced by extracellular matrix (ECM) and growth factors....

  14. The islet beta-cell: fuel responsive and vulnerable.

    Science.gov (United States)

    Nolan, Christopher J; Prentki, Marc

    2008-10-01

    The pancreatic beta-cell senses blood nutrient levels and is modulated by neurohormonal signals so that it secretes insulin according to the need of the organism. Nutrient sensing involves marked metabolic activation, resulting in the production of coupling signals that promote insulin biosynthesis and secretion. The beta-cell's high capacity for nutrient sensing, however, necessitates reduced protection to nutrient toxicity. This potentially explains why in susceptible individuals, chronic fuel surfeit results in beta-cell failure and type 2 diabetes. Here we discuss recent insights into first, the biochemical basis of beta-cell signaling in response to glucose, amino acids and fatty acids, and second, beta-cell nutrient detoxification. We emphasize the emerging role of glycerolipid/fatty acid cycling in these processes.

  15. Progress in molecular nuclear medicine imaging of pancreatic beta cells

    International Nuclear Information System (INIS)

    Wu Haifei; Yin Hongyan; Liu Shuai; Zhang Yifan

    2010-01-01

    Diabetes mellitus is a common and frequently occurring disease which seriously threaten the health of human beings. Type 1 and type 2 diabetes respectively results from being destroyed and insufficient beta-cell mass. The associated symptoms appear until 50%-60% decrease of beta-cell mass. Because pancreas is deeply located in the body, with few beta-cell mass, the current methods of clinical diagnosis are invasive and late. So diagnosis of metabolism disease of beta-cell early non-invasively becomes more and more popular, imaging diagnosis of diabetes mellitus becomes the focus of researches, but how to estimate the mass of beta-cell still an important subject in imaging technology. (authors)

  16. Chronology of endocrine differentiation and beta-cell neogenesis.

    Science.gov (United States)

    Miyatsuka, Takeshi

    2016-01-01

    Diabetes is a chronic and incurable disease, which results from absolute or relative insulin insufficiency. Therefore, pancreatic beta cells, which are the only type of cell that expresses insulin, is considered to be a potential target for the cure of diabetes. Although the findings regarding beta-cell neogenesis during pancreas development have been exploited to induce insulin-producing cells from non-beta cells, there are still many hurdles towards generating fully functional beta cells that can produce high levels of insulin and respond to physiological signals. To overcome these problems, a solid understanding of pancreas development and beta-cell formation is required, and several mouse models have been developed to reveal the unique features of each endocrine cell type at distinct developmental time points. Here I review our understanding of pancreas development and endocrine differentiation focusing on recent progresses in improving temporal cell labeling in vivo.

  17. Transgenic overexpression of active calcineurin in beta-cells results in decreased beta-cell mass and hyperglycemia.

    Directory of Open Access Journals (Sweden)

    Ernesto Bernal-Mizrachi

    2010-08-01

    Full Text Available Glucose modulates beta-cell mass and function through an initial depolarization and Ca(2+ influx, which then triggers a number of growth regulating signaling pathways. One of the most important downstream effectors in Ca(2+ signaling is the calcium/Calmodulin activated serine threonine phosphatase, calcineurin. Recent evidence suggests that calcineurin/NFAT is essential for beta-cell proliferation, and that in its absence loss of beta-cells results in diabetes. We hypothesized that in contrast, activation of calcineurin might result in expansion of beta-cell mass and resistance to diabetes.To determine the role of activation of calcineurin signaling in the regulation of pancreatic beta-cell mass and proliferation, we created mice that expressed a constitutively active form of calcineurin under the insulin gene promoter (caCn(RIP. To our surprise, these mice exhibited glucose intolerance. In vitro studies demonstrated that while the second phase of Insulin secretion is enhanced, the overall insulin secretory response was conserved. Islet morphometric studies demonstrated decreased beta-cell mass suggesting that this was a major component responsible for altered Insulin secretion and glucose intolerance in caCn(RIP mice. The reduced beta-cell mass was accompanied by decreased proliferation and enhanced apoptosis.Our studies identify calcineurin as an important factor in controlling glucose homeostasis and indicate that chronic depolarization leading to increased calcineurin activity may contribute, along with other genetic and environmental factors, to beta-cell dysfunction and diabetes.

  18. Re-exposure to beta cell autoantigens in pancreatic allograft recipients with preexisting beta cell autoantibodies.

    Science.gov (United States)

    Mujtaba, Muhammad Ahmad; Fridell, Jonathan; Book, Benita; Faiz, Sara; Sharfuddin, Asif; Wiebke, Eric; Rigby, Mark; Taber, Tim

    2015-11-01

    Re-exposure to beta cell autoantigens and its relevance in the presence of donor-specific antibodies (DSA) in pancreatic allograft recipients is not well known. Thirty-three patients requiring a pancreas transplant were enrolled in an IRB approved study. They underwent prospective monitoring for DSA and beta cell autoantibody (BCAA) levels to GAD65, insulinoma-associated antigen 2 (IA-2), insulin (micro-IAA [mIAA]), and islet-specific zinc transporter isoform-8 (ZnT8). Twenty-five (75.7%) had pre-transplant BCAA. Twenty had a single antibody (mIAA n = 15, GAD65 n = 5); five had two or more BCAA (GAD65 + mIAA n = 2, GAD65 + mIAA+IA-2 n = 2, GA65 + mIAA+IA-2 + ZnT8 = 1). No changes in GAD65 (p > 0.29), IA-2 (>0.16), and ZnT8 (p > 0.07) were observed between pre-transplant and post-transplant at 6 or 12 months. A decrease in mIAA from pre- to post-6 months (p BCAA was observed at one yr. Seven (21.0%) developed de novo DSA. The incidence of DSA was 24% in patients with BCAA vs. 25% in patients without BCAA (p = 0.69). Pancreatic allograft function of patients with vs. without BCAA, and with and without BCAA + DSA was comparable until last follow-up (three yr). Re-exposure to beta cell autoantigens by pancreas transplant may not lead to increased levels or development of new BCAA or pancreatic allograft dysfunction. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  19. Millisecond-period meltdown experiments on prompt-burst effects and molten-tin-water dropping experiments

    International Nuclear Information System (INIS)

    Wright, R.W.; Coats, R.L.; Schmidt, T.R.; Arakeri, V.H.

    1976-01-01

    The U.S. Nuclear Regulatory Commission has initiated a program of confirmatory research for the safety assessment of LMFBR plants. In the sodium-fuel interactions area, this research includes a series of real-time in-pile experiments on the pressure and work potential of prompt-burst excursions as well as laboratory dropping experiments with molten tin and water. The in-pile experiments are performed by Sandia Laboratories in the Annular Core Pulse Reactor (ACPR), which has a minimum period of 1.3 milliseconds. These single-pin experiments are performed in a piston-loaded, stagnent-sodium autoclave, that is conceptually similar to the one used in the S-11 TREAT test. Unlike the S-11 test, however, realistic radial temperature profiles are obtained in the fuel, the cladding, and the sodium by pre-pulsing the reactor about 1/2 second before the main pulse. A series of preparatory runs have been made with helium-filled capsules and at low energy with sodium-filled capsules. The first significant fuel-coolant interaction run is scheduled for late March 1976. This will be a double-pulsed run at 2700 j/gm UO 2 . A continuing series of experiments is planned with oxide and advanced fuels in both fresh and irradiated form. In molten-tin-water dropping experiments at UCLA, microsecond duration multi-flash photography has been used for event diagnostics. Transition or nucleate boiling was found to trigger energetic interactions or vapor explosions. Temperature stratification in the water was found to reduce the threshold tin temperature necessary to produce vapor explosions below that the predicted by the coolant homogeneous nucleation hypothesis. Interaction zone growth times of a few msec. were measured. (auth.)

  20. On the coherent behavior of pancreatic beta cell clusters

    Energy Technology Data Exchange (ETDEWEB)

    Loppini, Alessandro, E-mail: a.loppini@unicampus.it [Nonlinear Physics and Mathematical Modeling Lab, University Campus Bio-Medico, Via A. del Portillo 21, I-00128 Rome (Italy); Capolupo, Antonio, E-mail: capolupo@sa.infn.it [Physics Department, University of Salerno, Fisciano, 84084 (Italy); Cherubini, Christian, E-mail: c.cherubini@unicampus.it [Nonlinear Physics and Mathematical Modeling Lab, University Campus Bio-Medico, Via A. del Portillo 21, I-00128 Rome (Italy); International Center for Relativistic Astrophysics, University Campus Bio-Medico, Via A. del Portillo 21, I-00128, Rome (Italy); Gizzi, Alessio, E-mail: a.gizzi@unicampus.it [Nonlinear Physics and Mathematical Modeling Lab, University Campus Bio-Medico, Via A. del Portillo 21, I-00128 Rome (Italy); Bertolaso, Marta, E-mail: m.bertolaso@unicampus.it [Faculty of Engineering and Institute of Philosophy of Scientific and Technological Practice, University Campus Bio-Medico, Via A. del Portillo 21, I-00128 Rome (Italy); Filippi, Simonetta, E-mail: s.filippi@unicampus.it [Nonlinear Physics and Mathematical Modeling Lab, University Campus Bio-Medico, Via A. del Portillo 21, I-00128 Rome (Italy); International Center for Relativistic Astrophysics, University Campus Bio-Medico, Via A. del Portillo 21, I-00128, Rome (Italy); Vitiello, Giuseppe, E-mail: vitiello@sa.infn.it [Physics Department, University of Salerno, Fisciano, 84084 (Italy)

    2014-09-12

    Beta cells in pancreas represent an example of coupled biological oscillators which via communication pathways, are able to synchronize their electrical activity, giving rise to pulsatile insulin release. In this work we numerically analyze scale free self-similarity features of membrane voltage signal power density spectrum, through a stochastic dynamical model for beta cells in the islets of Langerhans fine tuned on mouse experimental data. Adopting the algebraic approach of coherent state formalism, we show how coherent molecular domains can arise from proper functional conditions leading to a parallelism with “phase transition” phenomena of field theory. - Highlights: • Beta cells in pancreas are coupled oscillators able to synchronize their activity. • We analyze scale free self-similarity features for beta cells. • We adopt the algebraic approach of coherent state formalism. • We show that coherent molecular domains arise from functional conditions.

  1. Type I X-ray bursts, burst oscillations and kHz quasi-periodic oscillations in the neutron star system IGR J17191−2821

    NARCIS (Netherlands)

    Altamirano, D.; Linares, M.; Patruno, A.; Degenaar, N.; Wijnands, R.; Klein-Wolt, M.; van der Klis, M.; Markwardt, C.; Swank, J.

    2010-01-01

    We present a detailed study of the X-ray energy and power spectral properties of the neutron star transient IGR J17191−2821. We discovered four instances of pairs of simultaneous kilohertz quasi-periodic oscillations (kHz QPOs). The frequency difference between these kHz QPOs is between 315 and 362

  2. The physiology of rodent beta-cells in pancreas slices.

    Science.gov (United States)

    Rupnik, M

    2009-01-01

    Beta-cells in pancreatic islets form complex syncytia. Sufficient cell-to-cell electrical coupling seems to ensure coordinated depolarization pattern and insulin release that can be further modulated by rich innervation. The complex structure and coordinated action develop after birth during fast proliferation of the endocrine tissue. These emergent properties can be lost due to various reasons later in life and can lead to glucose intolerance and diabetes mellitus. Pancreas slice is a novel method of choice to study the physiology of beta-cells still embedded in their normal cellulo-social context. I present major advantages, list drawbacks and provide an overview on recent advances in our understanding of the physiology of beta-cells using the pancreas slice approach.

  3. Mechanisms of pancreatic beta-cell growth and regeneration

    DEFF Research Database (Denmark)

    Nielsen, Jens Høiriis

    1989-01-01

    Information about the mechanism of beta-cell growth and regeneration may be obtained by studies of insulinoma cells. In the present study the growth and function of the rat insulinoma cell lines RINm5F and 5AH were evaluated by addition of serum, hormones, and growth factors. It was found...... of insulin mRNA content showed that the insulinoma cells only contained about 2% of that of normal rat beta-cells. These results are discussed in relation to the role of growth factors, oncogenes, and differentiation in the growth and regeneration of beta-cells....... that transferrin is the only obligatory factor whereas growth hormone, epidermal growth factor, fibroblast growth factor, and TRH had modulating effects. A heat-labile heparin binding serum factor which stimulated thymidine incorporation but not cell proliferation was demonstrated in human serum. Measurements...

  4. Foodborne cereulide causes beta-cell dysfunction and apoptosis.

    Directory of Open Access Journals (Sweden)

    Roman Vangoitsenhoven

    Full Text Available To study the effects of cereulide, a food toxin often found at low concentrations in take-away meals, on beta-cell survival and function.Cell death was quantified by Hoechst/Propidium Iodide in mouse (MIN6 and rat (INS-1E beta-cell lines, whole mouse islets and control cell lines (HepG2 and COS-1. Beta-cell function was studied by glucose-stimulated insulin secretion (GSIS. Mechanisms of toxicity were evaluated in MIN6 cells by mRNA profiling, electron microscopy and mitochondrial function tests.24 h exposure to 5 ng/ml cereulide rendered almost all MIN6, INS-1E and pancreatic islets apoptotic, whereas cell death did not increase in the control cell lines. In MIN6 cells and murine islets, GSIS capacity was lost following 24 h exposure to 0.5 ng/ml cereulide (P<0.05. Cereulide exposure induced markers of mitochondrial stress including Puma (p53 up-regulated modulator of apoptosis, P<0.05 and general pro-apoptotic signals as Chop (CCAAT/-enhancer-binding protein homologous protein. Mitochondria appeared swollen upon transmission electron microscopy, basal respiration rate was reduced by 52% (P<0.05 and reactive oxygen species increased by more than twofold (P<0.05 following 24 h exposure to 0.25 and 0.50 ng/ml cereulide, respectively.Cereulide causes apoptotic beta-cell death at low concentrations and impairs beta-cell function at even lower concentrations, with mitochondrial dysfunction underlying these defects. Thus, exposure to cereulide even at concentrations too low to cause systemic effects appears deleterious to the beta-cell.

  5. Dynamics and Synchrony of Pancreatic beta-cells and Islets

    DEFF Research Database (Denmark)

    Pedersen, Morten Gram

    2006-01-01

    description of these processes and their interactions would provide important input in the search for a better treatment of the disease. The thesis describes several aspects of mathematical modeling of beta-cells relevant for the understanding of glucose stimulated insulin secretion. It consists...... and the synchronized behavior of many coupled beta-cells as well as to the synchrony of islets. Rather than developing new biophysical models, the thesis investigates existing models, their integration and simplifications, and analyzed the corresponding dynamics, in order to use these models for investigating...

  6. Insulin-like growth factors and pancreas beta cells.

    NARCIS (Netherlands)

    Haeften, T.W. van; Twickler, M.

    2004-01-01

    Abstract Insulin-like growth factors (IGFs) have been implicated in normal growth, and especially foetal pancreas beta-cell development. As low birth weight has been implicated in the development of obesity and type 2 diabetes, much research has evolved into the importance of IGF and their

  7. Insulin-like growth factors and pancreas beta cells

    NARCIS (Netherlands)

    van Haeften, T. W.; Twickler, TB

    Insulin-like growth factors (IGFs) have been implicated in normal growth, and especially foetal pancreas beta-cell development. As low birth weight has been implicated in the development of obesity and type 2 diabetes, much research has evolved into the importance of IGF and their signalling

  8. Imaging the Beta-cell mass: why and how

    DEFF Research Database (Denmark)

    Saudek, Frantisek; Brogren, Carl-Henrik; Manohar, Srirang

    2008-01-01

    is called dihydrotetrabenazine (DTBZ), antibodies to zinc transporter (ZnT-8) and the monoclonal antibody IC2. While DTBZ and antibodies to ZnT-8 showed binding activities to more than beta-cells, the anti-IC2 monoclonal antibody showed binding properties exclusively to insulin-producing beta...

  9. Insulin-like growth factors and pancreas beta cells

    NARCIS (Netherlands)

    van Haeften, T. W.; Twickler, Th B.

    2004-01-01

    Abstract Insulin-like growth factors (IGFs) have been implicated in normal growth, and especially foetal pancreas beta-cell development. As low birth weight has been implicated in the development of obesity and type 2 diabetes, much research has evolved into the importance of IGF and their

  10. Pancreatic beta-cell overexpression of the glucagon receptor gene results in enhanced beta-cell function and mass

    DEFF Research Database (Denmark)

    Gelling, Richard W; Vuguin, Patricia M; Du, Xiu Quan

    2009-01-01

    in vivo, we generated mice overexpressing the Gcgr specifically on pancreatic beta-cells (RIP-Gcgr). In vivo and in vitro insulin secretion in response to glucagon and glucose was increased 1.7- to 3.9-fold in RIP-Gcgr mice compared with controls. Consistent with the observed increase in insulin release...

  11. Gamma Ray Bursts - Observations

    Science.gov (United States)

    Gehrels, N.; Cannizzo, J. K.

    2010-01-01

    We are in an exciting period of discovery for gamma-ray bursts. The Swift observatory is detecting 100 bursts per year, providing arcsecond localizations and sensitive observations of the prompt and afterglow emission. The Fermi observatory is observing 250 bursts per year with its medium-energy GRB instrument and about 10 bursts per year with its high-energy LAT instrument. In addition, rapid-response telescopes on the ground are providing new capabilities to study optical emission during the prompt phase and spectral signatures of the host galaxies. The combined data set is enabling great advances in our understanding of GRBs including afterglow physics, short burst origin, and high energy emission.

  12. Maternal Rat Diabetes Mellitus Deleteriously Affects Insulin Sensitivity and Beta-Cell Function in the Offspring

    Directory of Open Access Journals (Sweden)

    Abdel-Baset M. Aref

    2013-01-01

    Full Text Available This study was designed to assess the effect of maternal diabetes in rats on serum glucose and insulin concentrations, insulin resistance, histological architecture of pancreas and glycogen content in liver of offspring. The pregnant rat females were allocated into two main groups: normal control group and streptozotocin-induced diabetic group. After birth, the surviving offspring were subjected to biochemical and histological examination immediately after delivery and at the end of the 1st and 2nd postnatal weeks. In comparison with the offspring of normal control dams, the fasting serum glucose level of offspring of diabetic mothers was significantly increased at the end of the 1st and 2nd postnatal weeks. Serum insulin level of offspring of diabetic dams was significantly higher at birth and decreased significantly during the following 2 postnatal weeks, while in normal rat offspring, it was significantly increased with progress of time. HOMA Insulin Resistance (HOMA-IR was significantly increased in the offspring of diabetic dams at birth and after 1 week than in normal rat offspring, while HOMA insulin sensitivity (HOMA-IS was significantly decreased. HOMA beta-cell function was significantly decreased at all-time intervals in offspring of diabetic dams. At birth, islets of Langerhans as well as beta cells in offspring of diabetic dams were hypertrophied. The cells constituting islets seemed to have a high division rate. However, beta-cells were degenerated during the following 2 post-natal weeks and smaller insulin secreting cells predominated. Vacuolation and necrosis of the islets of Langerhans were also observed throughout the experimental period. The carbohydrate content in liver of offspring of diabetic dams was at all-time intervals lower than that in control. The granule distribution was more random. Overall, the preexisting maternal diabetes leads to glucose intolerance, insulin resistance, and impaired insulin sensitivity and

  13. THE DISCOVERY OF PERIODIC MODULATIONS IN THE OPTICAL SPECTRA OF GALAXIES, POSSIBLY DUE TO ULTRARAPID LIGHT BURSTS FROM THEIR MASSIVE CENTRAL BLACK HOLES

    Energy Technology Data Exchange (ETDEWEB)

    Borra, Ermanno F., E-mail: borra@phy.ulaval.ca [Centre d' Optique, Photonique et Laser, Departement de Physique, Universite Laval, Quebec, G1K 7P4 Quebec (Canada)

    2013-09-10

    A Fourier transform analysis of 2.5 million spectra in the SDSS survey was carried out to detect periodic modulations contained in the intensity versus frequency spectrum. A statistically significant signal was found for 223 galaxies, while the spectra of 0.9 million galaxies were observed. A plot of the periods as a function of redshift clearly shows that the effect is real without any doubt, because the modulations are quantized at two base periods that increase with redshift in two very tight parallel linear relations. We suggest that this result could be caused by light bursts separated by times on the order of 10{sup -13} s, but other causes may be possible. We investigate the hypothesis that the modulation is generated by the Fourier transform of spectral lines, but conclude that this hypothesis is not valid. Although the light burst suggestion implies absurdly high temperatures, it is supported by the fact that the Crab pulsar also has extremely short unresolved pulses (<0.5 ns) that imply similarly high temperatures. Furthermore, the radio spectrum of the Crab pulsar also has spectral bands similar to those that have been detected. Finally, decreasing the signal-to-noise threshold of detection gives results consistent with beamed signals having a small beam divergence, as expected from non-thermal sources that send a jet, like those seen in pulsars. Considering that galaxy centers contain massive black holes, exotic black hole physics may be responsible for the spectral modulation. However, at this stage, this idea is only a hypothesis to be confirmed with further work.

  14. Microculture system for studying monolayers of functional beta-cells.

    Science.gov (United States)

    Dobersen, M J; Scharff, J E; Notkins, A L

    1980-04-01

    A method is described for growing monolayers of newborn rat beta-cells in microculture trays. After disruption of the pancreas with collagenase, islets were isolated by Ficoll density gradient centrifugation, trypsinized to obtain individual cells, and plated in 96-well tissue culture trays. The cells were incubated for the first 3 days in growth medium containing 0.1 mM 3-isobutyl-1-methylxanthine to promote monolayer formation. The cultures could be maintained in a functional state, as defined by their responsiveness to known modulators of insulin secretion, for at least 2 weeks. As few as 1 X 10(3) islet cells/well gave results that were reproducible within +/- 10%. It is suggested that the microculture system for islet cells might prove to be a rapid and reproducible screening technique for studying drugs, viruses, or other agents that affect beta-cell function.

  15. A Figure-of-Merit for Beta Cell Detector Characterization

    Energy Technology Data Exchange (ETDEWEB)

    Foxe, Michael P. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Miller, Brian W. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Suarez, Rey [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Hayes, James C. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States)

    2015-09-02

    In order to decrease the minimum detectable activities (MDAs) of beta-gamma radioxenon detectors, it is important to increase the ability to resolve the individual isotopes. One proposed method for doing this is to increase the energy resolution of the beta cell through the use of silicon detectors. While silicon detectors can improve the energy resolution, it is accompanied with a decrease in detection efficiency compared to plastic scintillator beta cells. Due to the uncertainty on the impact of the competing variables, we have developed a figure-of-merit (FOM) capable of determining the impact of detector parameters on the MDAs. By utilizing the FOM to analyze different detectors, we are able to directly compare current and future detectors and estimate their impact on the radioxenon MDAs.

  16. Beta-Cell Replacement: Pancreas and Islet Cell Transplantation.

    Science.gov (United States)

    Niclauss, Nadja; Meier, Raphael; Bédat, Benoît; Berishvili, Ekaterine; Berney, Thierry

    2016-01-01

    Pancreas and islet transplantation are 2 types of beta-cell replacement therapies for type 1 diabetes mellitus. Since 1966, when pancreas transplantation was first performed, it has evolved to become a highly efficient procedure with high success rates, thanks to advances in surgical technique and immunosuppression. Pancreas transplantation is mostly performed as simultaneous pancreas-kidney transplantation in patients with end-stage nephropathy secondary to diabetes. In spite of its efficiency, pancreas transplantation is still a major surgical procedure burdened by high morbidity, which called for the development of less invasive and hazardous ways of replacing beta-cell function in the past. Islet transplantation was developed in the 1970s as a minimally invasive procedure with initially poor outcomes. However, since the report of the 'Edmonton protocol' in 2000, the functional results of islet transplantation have substantially and constantly improved and are about to match those of whole pancreas transplantation. Islet transplantation is primarily performed alone in nonuremic patients with severe hypoglycemia. Both pancreas transplantation and islet transplantation are able to abolish hypoglycemia and to prevent or slow down the development of secondary complications of diabetes. Pancreas transplantation and islet transplantation should be seen as two complementary, rather than competing, therapeutic approaches for beta-cell replacement that are able to optimize organ donor use and patient care. © 2016 S. Karger AG, Basel.

  17. Role of MicroRNAs in Islet Beta-Cell Compensation and Failure during Diabetes

    Directory of Open Access Journals (Sweden)

    Valérie Plaisance

    2014-01-01

    Full Text Available Pancreatic beta-cell function and mass are markedly adaptive to compensate for the changes in insulin requirement observed during several situations such as pregnancy, obesity, glucocorticoids excess, or administration. This requires a beta-cell compensation which is achieved through a gain of beta-cell mass and function. Elucidating the physiological mechanisms that promote functional beta-cell mass expansion and that protect cells against death, is a key therapeutic target for diabetes. In this respect, several recent studies have emphasized the instrumental role of microRNAs in the control of beta-cell function. MicroRNAs are negative regulators of gene expression, and are pivotal for the control of beta-cell proliferation, function, and survival. On the one hand, changes in specific microRNA levels have been associated with beta-cell compensation and are triggered by hormones or bioactive peptides that promote beta-cell survival and function. Conversely, modifications in the expression of other specific microRNAs contribute to beta-cell dysfunction and death elicited by diabetogenic factors including, cytokines, chronic hyperlipidemia, hyperglycemia, and oxidized LDL. This review underlines the importance of targeting the microRNA network for future innovative therapies aiming at preventing the beta-cell decline in diabetes.

  18. Workshop on programming beta cell development, impairment and regeneration

    DEFF Research Database (Denmark)

    Heller, Scott; Nielsen, Jens Høiriis

    2012-01-01

    Helsingør, the city of Hamlet in Denmark, provided the site for the workshop "Programming Beta Cell Development, Impairment and Regeneration" on October 23-26th, 2011. The same location has held two EASD Islet study group meetings, while the previous three workshops were held in Helsinki, Finland...... (2003), El Perello, Spain (2006) and Peebles, Scotland (2009). The meeting drew 190 attendees from 12 different countries. There were 37 main oral presentations, and 68 posters covered virtually all aspects of the pancreas and provided a dynamic snapshot of the most interesting areas of current...

  19. Quantifying the contribution of chromatin dynamics to stochastic gene expression reveals long, locus-dependent periods between transcriptional bursts.

    Science.gov (United States)

    Viñuelas, José; Kaneko, Gaël; Coulon, Antoine; Vallin, Elodie; Morin, Valérie; Mejia-Pous, Camila; Kupiec, Jean-Jacques; Beslon, Guillaume; Gandrillon, Olivier

    2013-02-25

    A number of studies have established that stochasticity in gene expression may play an important role in many biological phenomena. This therefore calls for further investigations to identify the molecular mechanisms at stake, in order to understand and manipulate cell-to-cell variability. In this work, we explored the role played by chromatin dynamics in the regulation of stochastic gene expression in higher eukaryotic cells. For this purpose, we generated isogenic chicken-cell populations expressing a fluorescent reporter integrated in one copy per clone. Although the clones differed only in the genetic locus at which the reporter was inserted, they showed markedly different fluorescence distributions, revealing different levels of stochastic gene expression. Use of chromatin-modifying agents showed that direct manipulation of chromatin dynamics had a marked effect on the extent of stochastic gene expression. To better understand the molecular mechanism involved in these phenomena, we fitted these data to a two-state model describing the opening/closing process of the chromatin. We found that the differences between clones seemed to be due mainly to the duration of the closed state, and that the agents we used mainly seem to act on the opening probability. In this study, we report biological experiments combined with computational modeling, highlighting the importance of chromatin dynamics in stochastic gene expression. This work sheds a new light on the mechanisms of gene expression in higher eukaryotic cells, and argues in favor of relatively slow dynamics with long (hours to days) periods of quiet state.

  20. The Fas pathway is involved in pancreatic beta cell secretory function

    DEFF Research Database (Denmark)

    Schumann, Desiree M; Maedler, Kathrin; Franklin, Isobel

    2007-01-01

    Pancreatic beta cell mass and function increase in conditions of enhanced insulin demand such as obesity. Failure to adapt leads to diabetes. The molecular mechanisms controlling this adaptive process are unclear. Fas is a death receptor involved in beta cell apoptosis or proliferation, depending...... on the activity of the caspase-8 inhibitor FLIP. Here we show that the Fas pathway also regulates beta cell secretory function. We observed impaired glucose tolerance in Fas-deficient mice due to a delayed and decreased insulin secretory pattern. Expression of PDX-1, a beta cell-specific transcription factor...... regulating insulin gene expression and mitochondrial metabolism, was decreased in Fas-deficient beta cells. As a consequence, insulin and ATP production were severely reduced and only partly compensated for by increased beta cell mass. Up-regulation of FLIP enhanced NF-kappaB activity via NF...

  1. Implications for the offspring of circulating factors involved in beta cell adaptation in pregnancy

    DEFF Research Database (Denmark)

    Nalla, Amarnadh; Ringholm, Lene; Søstrup, Birgitte

    2014-01-01

    is able to stimulate proliferation of rat beta cells. We have identified several circulating factors that may contribute to beta cell adaptation to pregnancy. Further studies are needed to elucidate their possible role in glucose homeostasis in the mother and her offspring.......OBJECTIVE: Several studies have shown an increase in beta cell mass during pregnancy. Somatolactogenic hormones are known to stimulate the proliferation of existing beta cells in rodents whereas the mechanism in humans is still unclear. We hypothesize that in addition to somatolactogenic hormones...... there are other circulating factors involved in beta cell adaptation to pregnancy. This study aimed at screening for potential pregnancy-associated circulating beta cell growth factors. SAMPLES: Serum samples from nonpregnant and pregnant women. METHODS: The effect of serum from pregnant women...

  2. Semi-automated digital measurement as the method of choice for beta cell mass analysis.

    Directory of Open Access Journals (Sweden)

    Violette Coppens

    Full Text Available Pancreas injury by partial duct ligation (PDL activates beta cell differentiation and proliferation in adult mouse pancreas but remains controversial regarding the anticipated increase in beta cell volume. Several reports unable to show beta cell volume augmentation in PDL pancreas used automated digital image analysis software. We hypothesized that fully automatic beta cell morphometry without manual micrograph artifact remediation introduces bias and therefore might be responsible for reported discrepancies and controversy. However, our present results prove that standard digital image processing with automatic thresholding is sufficiently robust albeit less sensitive and less adequate to demonstrate a significant increase in beta cell volume in PDL versus Sham-operated pancreas. We therefore conclude that other confounding factors such as quality of surgery, selection of samples based on relative abundance of the transcription factor Neurogenin 3 (Ngn3 and tissue processing give rise to inter-laboratory inconsistencies in beta cell volume quantification in PDL pancreas.

  3. Ins1 Cre knock-in mice for beta cell-specific gene recombination

    OpenAIRE

    Thorens Bernard; Tarussio David; Maestro Miguel Angel; Maestro Miguel Angel; Rovira Meritxell; Rovira Meritxell; Heikkilä Eija; Ferrer Jorge; Ferrer Jorge; Ferrer Jorge

    2013-01-01

    Aims/hypothesis Pancreatic beta cells play a central role in the control of glucose homeostasis by secreting insulin to stimulate glucose uptake by peripheral tissues. Understanding the molecular mechanisms that control beta cell function and plasticity has critical implications for the pathophysiology and therapy of major forms of diabetes. Selective gene inactivation in pancreatic beta cells, using the Cre-lox system, is a powerful approach to assess the role of particular genes in beta cel...

  4. Generation of Transplantable Beta Cells for Patient-Specific Cell Therapy

    Directory of Open Access Journals (Sweden)

    Xiaojie Wang

    2012-01-01

    Full Text Available Islet cell transplantation offers a potential cure for type 1 diabetes, but it is challenged by insufficient donor tissue and side effects of current immunosuppressive drugs. Therefore, alternative sources of insulin-producing cells and isletfriendly immunosuppression are required to increase the efficiency and safety of this procedure. Beta cells can be transdifferentiated from precursors or another heterologous (non-beta-cell source. Recent advances in beta cell regeneration from somatic cells such as fibroblasts could circumvent the usage of immunosuppressive drugs. Therefore, generation of patient-specific beta cells provides the potential of an evolutionary treatment for patients with diabetes.

  5. Glucose activates prenyltransferases in pancreatic islet {beta}-cells

    Energy Technology Data Exchange (ETDEWEB)

    Goalstone, Marc [Department of Medicine, University of Colorado, VA Medical Center, Denver, CO 80220 (United States); Kamath, Vasudeva [Department of Pharmaceutical Sciences, Wayne State University, VA Medical Center, Detroit, MI 48201 (United States); Kowluru, Anjaneyulu, E-mail: akowluru@med.wayne.edu [Department of Pharmaceutical Sciences, Wayne State University, VA Medical Center, Detroit, MI 48201 (United States)

    2010-01-01

    A growing body of evidence implicates small G-proteins [e.g., Cdc42 and Rac1] in glucose-stimulated insulin secretion [GSIS] in the islet {beta}-cell. These signaling proteins undergo post-translational modifications [e.g., prenylation] at their C-terminal cysteine residue and appear to be essential for the transport and fusion of insulin-containing secretory granules with the plasma membrane and the exocytotic secretion of insulin. However, potential regulation of the prenylating enzymes by physiological insulin secretogues [e.g., glucose] has not been investigated thus far. Herein, we report immunological localization, sub-cellular distribution and regulation of farnesyltransferases [FTases] and geranylgeranyltransferase [GGTase] by glucose in insulin-secreting INS 832/13 {beta}-cells and normal rat islets. Our findings suggest that an insulinotropic concentration of glucose [20 mM] markedly stimulated the expression of the {alpha}-subunits of FTase/GGTase-1, but not the {beta}-subunits of FTase or GGTase-1 without significantly affecting the predominantly cytosolic distribution of these holoenzymes in INS 832/13 cells and rodent islets. Under these conditions, glucose significantly stimulated [2.5- to 4.0-fold over basal] the activities of both FTase and GGTase-1 in both cell types. Together, these findings provide the first evidence to suggest that GSIS involves activation of the endogenous islet prenyltransferases by glucose, culminating in the activation of their respective G-protein substrates, which is necessary for cytoskeletal rearrangement, vesicular transport, fusion and secretion of insulin.

  6. The Drift Burst Hypothesis

    DEFF Research Database (Denmark)

    Christensen, Kim; Oomen, Roel; Renò, Roberto

    are an expected and regular occurrence in financial markets that can arise through established mechanisms such as feedback trading. At a theoretical level, we show how to build drift bursts into the continuous-time Itô semi-martingale model in such a way that the fundamental arbitrage-free property is preserved......, currencies and commodities. We find that the majority of identified drift bursts are accompanied by strong price reversals and these can therefore be regarded as “flash crashes” that span brief periods of severe market disruption without any material longer term price impacts....

  7. Lysine deacetylase inhibition prevents diabetes by chromatin-independent immunoregulation and beta-cell protection

    NARCIS (Netherlands)

    Christensen, D.P.; Gysemans, C.; Lundh, M.; Dahllof, M.S.; Noesgaard, D.; Schmidt, S.F.; Mandrup, S; Birkbak, N.; Workman, C.T.; Piemonti, L.; Blaabjerg, L.; Monzani, V.; Fossati, G.; Mascagni, P.; Paraskevas, S.; Aikin, R.A.; Billestrup, N.; Grunnet, L.G.; Dinarello, C.A.; Mathieu, C.; Mandrup-Poulsen, T.

    2014-01-01

    Type 1 diabetes is due to destruction of pancreatic beta-cells. Lysine deacetylase inhibitors (KDACi) protect beta-cells from inflammatory destruction in vitro and are promising immunomodulators. Here we demonstrate that the clinically well-tolerated KDACi vorinostat and givinostat revert diabetes

  8. Regulation of pancreatic beta-cell mass and proliferation by SOCS-3

    DEFF Research Database (Denmark)

    Lindberg, K; Rønn, S G; Tornehave, D

    2005-01-01

    Growth hormone and prolactin are important growth factors for pancreatic beta-cells. The effects exerted by these hormones on proliferation and on insulin synthesis and secretion in beta-cells are largely mediated through the Janus kinase (JAK)/signal transducer and activator of transcription (ST...

  9. What are the potential benefits of clinical beta-cell imaging in diabetes mellitus?

    Science.gov (United States)

    Göke, Burkhard

    2010-05-01

    Previously, studies of the endocrine pancreatic beta-cell were mainly performed ex vivo by morphological means. This data supported the analysis of pathophysiological changes in the pancreatic islet during insults such as diabetes mellitus. Metabolic testing of the pancreatic islet by assaying hormone parameters such als plasma insulin or C-peptide combined with more or less sophisticated calculations allowed conclusions about states of insulin resistance or secretory failure. It also allowed certain correlations of endocrine function with beta-cell mass. Today, with firmer pathophysiological concepts about beta-cell failure, modern protocols of islet transplantation, and drugs on the market coming with promises of preservation or even expansion of beta-cell mass in diabetes mellitus it has become very attractive to search for tools measuring beta-cell mass, if possible even repeatingly in the same organism in vivo. From a clinical point of view, the potential of pancreatic beta-cell mass imaging technologies is looked upon with high expectations. Methodologically, the decisive question is whether it is likely that future beta-cell imaging will provide significant advantages over the metabolic methods already in hand. With new in vivo tools, studies of beta-cell mass and function may offer even new approaches stratifying patients to anti-diabetic therapies.

  10. Serum adipokines as biomarkers of beta-cell function in patients with type 1 diabetes

    DEFF Research Database (Denmark)

    Pham, Minh Nguyet; Kolb, Hubert; Mandrup-Poulsen, Thomas

    2013-01-01

    We investigated the adipokines adiponectin, leptin and resistin as serum biomarkers of beta-cell function in patients with type 1 diabetes.......We investigated the adipokines adiponectin, leptin and resistin as serum biomarkers of beta-cell function in patients with type 1 diabetes....

  11. Pancreatic Beta-Cell Purification by Altering FAD and NAD(PH Metabolism

    Directory of Open Access Journals (Sweden)

    P. de Vos

    2008-07-01

    Full Text Available Isolation of primary beta cells from other cells within in the pancreatic islets is of importance for many fields of islet research. However, up to now, no satisfactory method has been developed that gained high numbers of viable beta cells, without considerable alpha-cell contamination. In this study, we investigated whether rat beta cells can be isolated from nonbeta endocrine cells by manipulating the flavin adenine dinucleotide (FAD and nicotinamide-adenine dinucleotide phosphate (NAD(PH autofluorescence. Beta cells were isolated from dispersed islets by flow cytometry, based on their high FAD and NAD(PH fluorescence. To improve beta cell yield and purity, the cellular FAD and NAD(PH contents were altered by preincubation in culture media containing varying amounts of D-glucose and amino acids. Manipulation of the cellular FAD and NAD(PH fluorescence improves beta cell yield and purity after sorting. This method is also a fast and reliable method to measure beta cell functional viability. A conceivable application is assessing beta cell viability before transplantation.

  12. Lysine deacetylases are produced in pancreatic beta cells and are differentially regulated by proinflammatory cytokines

    DEFF Research Database (Denmark)

    Lundh, M; Christensen, D P; Rasmussen, D N

    2010-01-01

    Cytokine-induced beta cell toxicity is abrogated by non-selective inhibitors of lysine deacetylases (KDACs). The KDAC family consists of 11 members, namely histone deacetylases HDAC1 to HDAC11, but it is not known which KDAC members play a role in cytokine-mediated beta cell death. The aim...

  13. Spikes matter for phase-locked bursting in inhibitory neurons

    Science.gov (United States)

    Jalil, Sajiya; Belykh, Igor; Shilnikov, Andrey

    2012-03-01

    We show that inhibitory networks composed of two endogenously bursting neurons can robustly display several coexistent phase-locked states in addition to stable antiphase and in-phase bursting. This work complements and enhances our recent result [Jalil, Belykh, and Shilnikov, Phys. Rev. EPLEEE81539-375510.1103/PhysRevE.81.045201 81, 045201(R) (2010)] that fast reciprocal inhibition can synchronize bursting neurons due to spike interactions. We reveal the role of spikes in generating multiple phase-locked states and demonstrate that this multistability is generic by analyzing diverse models of bursting networks with various fast inhibitory synapses; the individual cell models include the reduced leech heart interneuron, the Sherman model for pancreatic beta cells, and the Purkinje neuron model.

  14. The effect of noise and coupling on beta cell excitation dynamics

    DEFF Research Database (Denmark)

    numerical simulations. We show here how the application of two recent methods allows an analytic treatment of the stochastic effects on the location of the saddle-node and homoclinic bifurcations, which determine the burst period. Thus, the stochastic system can be analyzed similarly to the deterministic...

  15. Do post-translational beta cell protein modifications trigger type 1 diabetes?

    DEFF Research Database (Denmark)

    Størling, Joachim; Overgaard, Anne Julie; Brorsson, Caroline Anna

    2013-01-01

    beta cell-specific neo-epitopes. We suggest that the current paradigm of type 1 diabetes as a classical autoimmune disease should be reconsidered since the immune response may not be directed against native beta cell proteins. A modified model for the pathogenetic events taking place in islets leading...... diabetes exists in the published literature. Furthermore, we report that cytokines change the expression levels of several genes encoding proteins involved in PTM processes in human islets, and that there are type 1 diabetes-associated polymorphisms in a number of these. In conclusion, data from...... the literature and presented experimental data support the notion that PTM of beta cell proteins may be involved in triggering beta cell destruction in type 1 diabetes. If the beta cell antigens recognised by the immune system foremost come from modified proteins rather than native ones, the concept of type 1...

  16. Dysregulation of Dicer1 in Beta Cells Impairs Islet Architecture and Glucose Metabolism

    Directory of Open Access Journals (Sweden)

    Amitai D. Mandelbaum

    2012-01-01

    Full Text Available microRNAs (miRNAs play important roles in pancreas development and in regulation of insulin expression in the adult. Here we show that loss of miRNAs activity in beta-cells during embryonic development results in lower beta-cell mass and in impaired glucose tolerance. Dicer1-null cells initially constitute a significant portion of the total beta-cell population. However, during postnatal development, Dicer1-null cells are depleted. Furthermore, wild-type beta cells are repopulating the islets in complex compensatory dynamics. Because loss of Dicer1 is also associated with changes in the distribution of membranous E-cadherin, we hypothesized that E-cadherin activity may play a role in beta cell survival or islet architecture. However, genetic loss of E-cadherin function does not impair islet architecture, suggesting that miRNAs likely function through other or redundant effectors in the endocrine pancreas.

  17. Enhancing pancreatic Beta-cell regeneration in vivo with pioglitazone and alogliptin.

    Directory of Open Access Journals (Sweden)

    Hao Yin

    Full Text Available Pancreatic beta-cells retain limited ability to regenerate and proliferate after various physiologic triggers. Identifying therapies that are able to enhance beta-cell regeneration may therefore be useful for the treatment of both type 1 and type 2 diabetes.In this study we investigated endogenous and transplanted beta-cell regeneration by serially quantifying changes in bioluminescence from beta-cells from transgenic mice expressing firefly luciferase under the control of the mouse insulin I promoter. We tested the ability of pioglitazone and alogliptin, two drugs developed for the treatment of type 2 diabetes, to enhance beta-cell regeneration, and also defined the effect of the immunosuppression with rapamycin and tacrolimus on transplanted islet beta mass.Pioglitazone is a stimulator of nuclear receptor peroxisome proliferator-activated receptor gamma while alogliptin is a selective dipeptidyl peptidase IV inhibitor. Pioglitazone alone, or in combination with alogliptin, enhanced endogenous beta-cell regeneration in streptozotocin-treated mice, while alogliptin alone had modest effects. In a model of syngeneic islet transplantation, immunosuppression with rapamycin and tacrolimus induced an early loss of beta-cell mass, while treatment with insulin implants to maintain normoglycemia and pioglitazone plus alogliptin was able to partially promote beta-cell mass recovery.These data highlight the utility of bioluminescence for serially quantifying functional beta-cell mass in living mice. They also demonstrate the ability of pioglitazone, used either alone or in combination with alogliptin, to enhance regeneration of endogenous islet beta-cells as well as transplanted islets into recipients treated with rapamycin and tacrolimus.

  18. Beta Cell Mass Restoration in Alloxan-Diabetic Mice Treated with EGF and Gastrin.

    Directory of Open Access Journals (Sweden)

    Imane Song

    Full Text Available One week of treatment with EGF and gastrin (EGF/G was shown to restore normoglycemia and to induce islet regeneration in mice treated with the diabetogenic agent alloxan. The mechanisms underlying this regeneration are not fully understood. We performed genetic lineage tracing experiments to evaluate the contribution of beta cell neogenesis in this model. One day after alloxan administration, mice received EGF/G treatment for one week. The treatment could not prevent the initial alloxan-induced beta cell mass destruction, however it did reverse glycemia to control levels within one day, suggesting improved peripheral glucose uptake. In vitro experiments with C2C12 cell line showed that EGF could stimulate glucose uptake with an efficacy comparable to that of insulin. Subsequently, EGF/G treatment stimulated a 3-fold increase in beta cell mass, which was partially driven by neogenesis and beta cell proliferation as assessed by beta cell lineage tracing and BrdU-labeling experiments, respectively. Acinar cell lineage tracing failed to show an important contribution of acinar cells to the newly formed beta cells. No appearance of transitional cells co-expressing insulin and glucagon, a hallmark for alpha-to-beta cell conversion, was found, suggesting that alpha cells did not significantly contribute to the regeneration. An important fraction of the beta cells significantly lost insulin positivity after alloxan administration, which was restored to normal after one week of EGF/G treatment. Alloxan-only mice showed more pronounced beta cell neogenesis and proliferation, even though beta cell mass remained significantly depleted, suggesting ongoing beta cell death in that group. After one week, macrophage infiltration was significantly reduced in EGF/G-treated group compared to the alloxan-only group. Our results suggest that EGF/G-induced beta cell regeneration in alloxan-diabetic mice is driven by beta cell neogenesis, proliferation and recovery of

  19. Reduced Expression of the Liver/Beta-Cell Glucose Transporter Isoform in Glucose-Insensitive Pancreatic Beta Cells of Diabetic Rats

    Science.gov (United States)

    Thorens, Bernard; Weir, Gordon C.; Leahy, John L.; Lodish, Harvey F.; Bonner-Weir, Susan

    1990-09-01

    Rats injected with a single dose of streptozocin at 2 days of age develop non-insulin-dependent diabetes 6 weeks later. The pancreatic beta islet cells of these diabetic rats display a loss of glucose-induced insulin secretion while maintaining sensitivity to other secretagogues such as arginine. We analyzed the level of expression of the liver/beta-cell glucose transporter isoform in diabetic islets by immunofluorescence staining of pancreas sections and by Western blotting of islet lysates. Islets from diabetic animals have a reduced expression of this beta-cell-specific glucose transporter isoform and the extent of reduction is correlated with the severity of hyperglycemia. In contrast, expression of this transporter isoform in liver is minimally modified by the diabetes. Thus a decreased expression of the liver/beta-cell glucose transporter isoform in beta cells is associated with the impaired glucose sensing characteristic of diabetic islets; our data suggest that this glucose transporter may be part of the beta-cell glucose sensor.

  20. Cocoa Phenolic Extract Protects Pancreatic Beta Cells against Oxidative Stress

    Directory of Open Access Journals (Sweden)

    Laura Bravo

    2013-07-01

    Full Text Available Diabetes mellitus is associated with reductions in glutathione, supporting the critical role of oxidative stress in its pathogenesis. Antioxidant food components such as flavonoids have a protective role against oxidative stress-induced degenerative and age-related diseases. Flavonoids constitute an important part of the human diet; they can be found in most plant foods, including green tea, grapes or cocoa and possess multiple biological activities. This study investigates the chemo-protective effect of a cocoa phenolic extract (CPE containing mainly flavonoids against oxidative stress induced by tert-butylhydroperoxide (t-BOOH on Ins-1E pancreatic beta cells. Cell viability and oxidative status were evaluated. Ins-1E cells treatment with 5–20 μg/mL CPE for 20 h evoked no cell damage and did not alter ROS production. Addition of 50 μM t-BOOH for 2 h increased ROS and carbonyl groups content and decreased reduced glutathione level. Pre-treatment of cells with CPE significantly prevented the t-BOOH-induced ROS and carbonyl groups and returned antioxidant defences to adequate levels. Thus, Ins-1E cells treated with CPE showed a remarkable recovery of cell viability damaged by t-BOOH, indicating that integrity of surviving machineries in the CPE-treated cells was notably protected against the oxidative insult.

  1. Osteocalcin protects pancreatic beta cell function and survival under high glucose conditions

    Energy Technology Data Exchange (ETDEWEB)

    Kover, Karen, E-mail: kkover@cmh.edu [Division of Endocrine/Diabetes, Children' s Mercy Hospital & Clinics, Kansas City, MO 64108 (United States); University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108 (United States); Yan, Yun; Tong, Pei Ying; Watkins, Dara; Li, Xiaoyu [Division of Endocrine/Diabetes, Children' s Mercy Hospital & Clinics, Kansas City, MO 64108 (United States); University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108 (United States); Tasch, James; Hager, Melissa [Kansas City University Medical Biosciences, Kansas City, MO (United States); Clements, Mark; Moore, Wayne V. [Division of Endocrine/Diabetes, Children' s Mercy Hospital & Clinics, Kansas City, MO 64108 (United States); University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108 (United States)

    2015-06-19

    Diabetes is characterized by progressive beta cell dysfunction and loss due in part to oxidative stress that occurs from gluco/lipotoxicity. Treatments that directly protect beta cell function and survival in the diabetic milieu are of particular interest. A growing body of evidence suggests that osteocalcin, an abundant non-collagenous protein of bone, supports beta cell function and proliferation. Based on previous gene expression data by microarray, we hypothesized that osteocalcin protects beta cells from glucose-induced oxidative stress. To test our hypothesis we cultured isolated rat islets and INS-1E cells in the presence of normal, high, or high glucose ± osteocalcin for up to 72 h. Oxidative stress and viability/mitochondrial function were measured by H{sub 2}O{sub 2} assay and Alamar Blue assay, respectively. Caspase 3/7 activity was also measured as a marker of apoptosis. A functional test, glucose stimulated insulin release, was conducted and expression of genes/protein was measured by qRT-PCR/western blot/ELISA. Osteocalcin treatment significantly reduced high glucose-induced H{sub 2}O{sub 2} levels while maintaining viability/mitochondrial function. Osteocalcin also significantly improved glucose stimulated insulin secretion and insulin content in rat islets after 48 h of high glucose exposure compared to untreated islets. As expected sustained high glucose down-regulated gene/protein expression of INS1 and BCL2 while increasing TXNIP expression. Interestingly, osteocalcin treatment reversed the effects of high glucose on gene/protein expression. We conclude that osteocalcin can protect beta cells from the negative effects of glucose-induced oxidative stress, in part, by reducing TXNIP expression, thereby preserving beta cell function and survival. - Highlights: • Osteocalcin reduces glucose-induced oxidative stress in beta cells. • Osteocalcin preserves beta cell function and survival under stress conditions. • Osteocalcin reduces glucose

  2. Osteocalcin protects pancreatic beta cell function and survival under high glucose conditions

    International Nuclear Information System (INIS)

    Kover, Karen; Yan, Yun; Tong, Pei Ying; Watkins, Dara; Li, Xiaoyu; Tasch, James; Hager, Melissa; Clements, Mark; Moore, Wayne V.

    2015-01-01

    Diabetes is characterized by progressive beta cell dysfunction and loss due in part to oxidative stress that occurs from gluco/lipotoxicity. Treatments that directly protect beta cell function and survival in the diabetic milieu are of particular interest. A growing body of evidence suggests that osteocalcin, an abundant non-collagenous protein of bone, supports beta cell function and proliferation. Based on previous gene expression data by microarray, we hypothesized that osteocalcin protects beta cells from glucose-induced oxidative stress. To test our hypothesis we cultured isolated rat islets and INS-1E cells in the presence of normal, high, or high glucose ± osteocalcin for up to 72 h. Oxidative stress and viability/mitochondrial function were measured by H 2 O 2 assay and Alamar Blue assay, respectively. Caspase 3/7 activity was also measured as a marker of apoptosis. A functional test, glucose stimulated insulin release, was conducted and expression of genes/protein was measured by qRT-PCR/western blot/ELISA. Osteocalcin treatment significantly reduced high glucose-induced H 2 O 2 levels while maintaining viability/mitochondrial function. Osteocalcin also significantly improved glucose stimulated insulin secretion and insulin content in rat islets after 48 h of high glucose exposure compared to untreated islets. As expected sustained high glucose down-regulated gene/protein expression of INS1 and BCL2 while increasing TXNIP expression. Interestingly, osteocalcin treatment reversed the effects of high glucose on gene/protein expression. We conclude that osteocalcin can protect beta cells from the negative effects of glucose-induced oxidative stress, in part, by reducing TXNIP expression, thereby preserving beta cell function and survival. - Highlights: • Osteocalcin reduces glucose-induced oxidative stress in beta cells. • Osteocalcin preserves beta cell function and survival under stress conditions. • Osteocalcin reduces glucose-induced TXNIP

  3. Pancreatic beta-cell lipotoxicity induced by overexpression of hormone-sensitive lipase

    DEFF Research Database (Denmark)

    Winzell, Maria Sörhede; Svensson, Håkan; Enerbäck, Sven

    2003-01-01

    Lipid perturbations associated with triglyceride overstorage in beta-cells impair insulin secretion, a process termed lipotoxicity. To assess the role of hormone-sensitive lipase, which is expressed and enzymatically active in beta-cells, in the development of lipotoxicity, we generated transgenic...... mice overexpressing hormone-sensitive lipase specifically in beta-cells. Transgenic mice developed glucose intolerance and severely blunted glucose-stimulated insulin secretion when challenged with a high-fat diet. As expected, both lipase activity and forskolin-stimulated lipolysis was increased...

  4. Effect of aerobic exercise on Pancreas Beta-cells function in adult obese males

    Directory of Open Access Journals (Sweden)

    Mojtaba Eizadi

    2014-08-01

    Conclusion: Aerobic exercise training increases beta cells function and decreases FBS in obese men. These findings support the hypothesis that regular physical activity postpones the occurrence of type 2 diabetes in adult obese subjects.

  5. Evaluation of beta-cell secretory capacity using glucagon-like peptide 1

    DEFF Research Database (Denmark)

    Vilsbøll, Tina; Nielsen, Mette Toft; Krarup, T

    2000-01-01

    Beta-cell secretory capacity is often evaluated with a glucagon test or a meal test. However, glucagon-like peptide 1 (GLP-1) is the most insulinotropic hormone known, and the effect is preserved in type 2 diabetic patients.......Beta-cell secretory capacity is often evaluated with a glucagon test or a meal test. However, glucagon-like peptide 1 (GLP-1) is the most insulinotropic hormone known, and the effect is preserved in type 2 diabetic patients....

  6. Beta-cell lines derived from transgenic mice expressing a hybrid insulin gene-oncogene

    DEFF Research Database (Denmark)

    Efrat, S; Linde, S; Kofod, Hans

    1988-01-01

    Three pancreatic beta-cell lines have been established from insulinomas derived from transgenic mice carrying a hybrid insulin-promoted simian virus 40 tumor antigen gene. The beta tumor cell (beta TC) lines maintain the features of differentiated beta cells for about 50 passages in culture. The ...... both to immortalize a rare cell type and to provide a selection for the maintenance of its differentiated phenotype....

  7. Targeting Cellular Calcium Homeostasis to Prevent Cytokine-Mediated Beta Cell Death.

    Science.gov (United States)

    Clark, Amy L; Kanekura, Kohsuke; Lavagnino, Zeno; Spears, Larry D; Abreu, Damien; Mahadevan, Jana; Yagi, Takuya; Semenkovich, Clay F; Piston, David W; Urano, Fumihiko

    2017-07-17

    Pro-inflammatory cytokines are important mediators of islet inflammation, leading to beta cell death in type 1 diabetes. Although alterations in both endoplasmic reticulum (ER) and cytosolic free calcium levels are known to play a role in cytokine-mediated beta cell death, there are currently no treatments targeting cellular calcium homeostasis to combat type 1 diabetes. Here we show that modulation of cellular calcium homeostasis can mitigate cytokine- and ER stress-mediated beta cell death. The calcium modulating compounds, dantrolene and sitagliptin, both prevent cytokine and ER stress-induced activation of the pro-apoptotic calcium-dependent enzyme, calpain, and partly suppress beta cell death in INS1E cells and human primary islets. These agents are also able to restore cytokine-mediated suppression of functional ER calcium release. In addition, sitagliptin preserves function of the ER calcium pump, sarco-endoplasmic reticulum Ca 2+ -ATPase (SERCA), and decreases levels of the pro-apoptotic protein thioredoxin-interacting protein (TXNIP). Supporting the role of TXNIP in cytokine-mediated cell death, knock down of TXNIP in INS1-E cells prevents cytokine-mediated beta cell death. Our findings demonstrate that modulation of dynamic cellular calcium homeostasis and TXNIP suppression present viable pharmacologic targets to prevent cytokine-mediated beta cell loss in diabetes.

  8. Regulation of Pancreatic Beta Cell Stimulus-Secretion Coupling by microRNAs

    Directory of Open Access Journals (Sweden)

    Jonathan L. S. Esguerra

    2014-11-01

    Full Text Available Increased blood glucose after a meal is countered by the subsequent increased release of the hypoglycemic hormone insulin from the pancreatic beta cells. The cascade of molecular events encompassing the initial sensing and transport of glucose into the beta cell, culminating with the exocytosis of the insulin large dense core granules (LDCVs is termed “stimulus-secretion coupling.” Impairment in any of the relevant processes leads to insufficient insulin release, which contributes to the development of type 2 diabetes (T2D. The fate of the beta cell, when exposed to environmental triggers of the disease, is determined by the possibility to adapt to the new situation by regulation of gene expression. As established factors of post-transcriptional regulation, microRNAs (miRNAs are well-recognized mediators of beta cell plasticity and adaptation. Here, we put focus on the importance of comprehending the transcriptional regulation of miRNAs, and how miRNAs are implicated in stimulus-secretion coupling, specifically those influencing the late stages of insulin secretion. We suggest that efficient beta cell adaptation requires an optimal balance between transcriptional regulation of miRNAs themselves, and miRNA-dependent gene regulation. The increased knowledge of the beta cell transcriptional network inclusive of non-coding RNAs such as miRNAs is essential in identifying novel targets for the treatment of T2D.

  9. CRFR1 is expressed on pancreatic beta cells, promotes beta cell proliferation, and potentiates insulin secretion in a glucose-dependent manner

    DEFF Research Database (Denmark)

    Huising, Mark O; van der Meulen, Talitha; Vaughan, Joan M

    2009-01-01

    Corticotropin-releasing factor (CRF), originally characterized as the principal neuroregulator of the hypothalamus-pituitary-adrenal axis, has broad central and peripheral distribution and actions. We demonstrate the presence of CRF receptor type 1 (CRFR1) on primary beta cells and show that acti...

  10. Solar X-ray bursts

    International Nuclear Information System (INIS)

    Urnov, A.M.

    1980-01-01

    In the popular form the consideration is given to the modern state tasks and results of X-ray spectrometry of solar bursts. The operation of X-ray spectroheliograph is described. Results of spectral and polarization measurings of X-ray radiation of one powerful solar burst are presented. The conclusion has been drawn that in the process of burst development three characteristic stages may be distingwished: 1) the initial phase; just in this period processes which lead to observed consequences-electromagnetic and corpuscular radiation are born; 2) the impulse phase, or the phase of maximum, is characterised by sharp increase of radiation flux. During this phase the main energy content emanates and some volumes of plasma warm up to high temperatures; 3) the phase of burst damping, during which plasma cools and reverts to the initial condition

  11. Co-culture of clonal beta cells with GLP-1 and glucagon-secreting cell line impacts on beta cell insulin secretion, proliferation and susceptibility to cytotoxins.

    Science.gov (United States)

    Green, Alastair D; Vasu, Srividya; Moffett, R Charlotte; Flatt, Peter R

    2016-06-01

    We investigated the direct effects on insulin releasing MIN6 cells of chronic exposure to GLP-1, glucagon or a combination of both peptides secreted from GLUTag L-cell and αTC1.9 alpha-cell lines in co-culture. MIN6, GLUTag and αTC1.9 cell lines exhibited high cellular hormone content and release of insulin, GLP-1 and glucagon, respectively. Co-culture of MIN6 cells with GLUTag cells significantly increased cellular insulin content, beta-cell proliferation, insulin secretory responses to a range of established secretogogues and afforded protection against exposure cytotoxic concentrations of glucose, lipid, streptozotocin or cytokines. Benefits of co-culture of MIN6 cells with αTC1.9 alphacells were limited to enhanced beta-cell proliferation with marginal positive actions on both insulin secretion and cellular protection. In contrast, co-culture of MIN6 with GLUTag cells plus αTC1.9 cells, markedly enhanced both insulin secretory responses and protection against beta-cell toxins compared with co-culture with GLUTag cells alone. These data indicate important long-term effects of conjoint GLP-1 and glucagon exposure on beta-cell function. This illustrates the possible functional significance of alpha-cell GLP-1 production as well as direct beneficial effects of dual agonism at beta-cell GLP-1 and glucagon receptors. Copyright © 2016 Elsevier B.V. and Société française de biochimie et biologie Moléculaire (SFBBM). All rights reserved.

  12. The effect of smoking cessation pharmacotherapies on pancreatic beta cell function

    International Nuclear Information System (INIS)

    Woynillowicz, Amanda K.; Raha, Sandeep; Nicholson, Catherine J.; Holloway, Alison C.

    2012-01-01

    The goal of our study was to evaluate whether drugs currently used for smoking cessation (i.e., nicotine replacement therapy, varenicline [a partial agonist at nicotinic acetylcholine receptors (nAChR)] and bupropion [which acts in part as a nAChR antagonist]) can affect beta cell function and determine the mechanism(s) of this effect. INS-1E cells, a rat beta cell line, were treated with nicotine, varenicline and bupropion to determine their effects on beta cell function, mitochondrial electron transport chain enzyme activity and cellular/oxidative stress. Treatment of INS-1E cells with equimolar concentrations (1 μM) of three test compounds resulted in an ablation of normal glucose-stimulated insulin secretion by the cells. This disruption of normal beta cell function was associated with mitochondrial dysfunction since all three compounds tested significantly decreased the activity of mitochondrial electron transport chain enzyme activity. These results raise the possibility that the currently available smoking cessation pharmacotherapies may also have adverse effects on beta cell function and thus glycemic control in vivo. Therefore whether or not the use of nicotine replacement therapy, varenicline and bupropion can cause endocrine changes which are consistent with impaired pancreatic function warrants further investigation. -- Highlights: ► Smoking cessation drugs have the potential to disrupt beta cell function in vitro. ► The effects of nicotine, varenicline and bupropion are similar. ► The impaired beta cell function is mediated by mitochondrial dysfunction. ► If similar effects are seen in vivo, these drugs may increase the risk of diabetes.

  13. The effect of smoking cessation pharmacotherapies on pancreatic beta cell function

    Energy Technology Data Exchange (ETDEWEB)

    Woynillowicz, Amanda K. [Department of Obstetrics and Gynecology, McMaster University, Hamilton, ON, Canada L8N 3Z5 (Canada); Raha, Sandeep [Department of Pediatrics, McMaster University, Hamilton, ON, Canada L8N 3Z5 (Canada); Nicholson, Catherine J. [Department of Obstetrics and Gynecology, McMaster University, Hamilton, ON, Canada L8N 3Z5 (Canada); Holloway, Alison C., E-mail: hollow@mcmaster.ca [Department of Obstetrics and Gynecology, McMaster University, Hamilton, ON, Canada L8N 3Z5 (Canada)

    2012-11-15

    The goal of our study was to evaluate whether drugs currently used for smoking cessation (i.e., nicotine replacement therapy, varenicline [a partial agonist at nicotinic acetylcholine receptors (nAChR)] and bupropion [which acts in part as a nAChR antagonist]) can affect beta cell function and determine the mechanism(s) of this effect. INS-1E cells, a rat beta cell line, were treated with nicotine, varenicline and bupropion to determine their effects on beta cell function, mitochondrial electron transport chain enzyme activity and cellular/oxidative stress. Treatment of INS-1E cells with equimolar concentrations (1 μM) of three test compounds resulted in an ablation of normal glucose-stimulated insulin secretion by the cells. This disruption of normal beta cell function was associated with mitochondrial dysfunction since all three compounds tested significantly decreased the activity of mitochondrial electron transport chain enzyme activity. These results raise the possibility that the currently available smoking cessation pharmacotherapies may also have adverse effects on beta cell function and thus glycemic control in vivo. Therefore whether or not the use of nicotine replacement therapy, varenicline and bupropion can cause endocrine changes which are consistent with impaired pancreatic function warrants further investigation. -- Highlights: ► Smoking cessation drugs have the potential to disrupt beta cell function in vitro. ► The effects of nicotine, varenicline and bupropion are similar. ► The impaired beta cell function is mediated by mitochondrial dysfunction. ► If similar effects are seen in vivo, these drugs may increase the risk of diabetes.

  14. The Role of Oxidative Stress and Hypoxia in Pancreatic Beta-Cell Dysfunction in Diabetes Mellitus.

    Science.gov (United States)

    Gerber, Philipp A; Rutter, Guy A

    2017-04-01

    Metabolic syndrome is a frequent precursor of type 2 diabetes mellitus (T2D), a disease that currently affects ∼8% of the adult population worldwide. Pancreatic beta-cell dysfunction and loss are central to the disease process, although understanding of the underlying molecular mechanisms is still fragmentary. Recent Advances: Oversupply of nutrients, including glucose and fatty acids, and the subsequent overstimulation of beta cells, are believed to be an important contributor to insulin secretory failure in T2D. Hypoxia has also recently been implicated in beta-cell damage. Accumulating evidence points to a role for oxidative stress in both processes. Although the production of reactive oxygen species (ROS) results from enhanced mitochondrial respiration during stimulation with glucose and other fuels, the expression of antioxidant defense genes is unusually low (or disallowed) in beta cells. Not all subjects with metabolic syndrome and hyperglycemia go on to develop full-blown diabetes, implying an important role in disease risk for gene-environment interactions. Possession of common risk alleles at the SLC30A8 locus, encoding the beta-cell granule zinc transporter ZnT8, may affect cytosolic Zn 2+ concentrations and thus susceptibility to hypoxia and oxidative stress. Loss of normal beta-cell function, rather than total mass, is increasingly considered to be the major driver for impaired insulin secretion in diabetes. Better understanding of the role of oxidative changes, its modulation by genes involved in disease risk, and effects on beta-cell identity may facilitate the development of new therapeutic strategies to this disease. Antioxid. Redox Signal. 26, 501-518.

  15. Sustained beta-cell dysfunction but normalized islet mass in aged thrombospondin-1 deficient mice.

    Directory of Open Access Journals (Sweden)

    Carl Johan Drott

    Full Text Available Pancreatic islet endothelial cells have in recent years been shown to support beta-cell mass and function by paracrine interactions. Recently, we identified an islets endothelial-specific glycoprotein, thrombospondin-1 (TSP-1, that showed to be of importance for islet angiogenesis and beta-cell function in young mice. The present study aimed to investigate long-term consequences for islet morphology and beta-cell function of TSP-1 deficiency. Islet and beta-cell mass were observed increased at 10-12 weeks of age in TSP-1 deficient mice, but were normalized before 16 weeks of age when compared to wild-type controls. Islet vascularity was normal in 10-12 and 16-week-old TSP-1 deficient animals, whereas islets of one-year-old animals lacking TSP-1 were hypervascular. Beta-cell dysfunction in TSP-1 deficient animals was present at similar magnitudes between 10-12 and 52 weeks of age, as evaluated by glucose tolerance tests. The insulin secretion capacity in vivo of islets in one-year-old TSP-1 deficient animals was only ∼15% of that in wild-type animals. Using a transplantation model, we reconstituted TSP-1 in adult TSP-deficient islets. In contrast to neonatal TSP-1 deficient islets that we previously reported to regain function after TSP-1 reconstitution, adult islets failed to recover. We conclude that TSP-1 deficiency in islets causes changing vascular and endocrine morphological alterations postnatally, but is coupled to a chronic beta-cell dysfunction. The beta-cell dysfunction induced by TSP-1 deficiency is irreversible if not substituted early in life.

  16. Complex transitions between spike, burst or chaos synchronization states in coupled neurons with coexisting bursting patterns

    International Nuclear Information System (INIS)

    Gu Hua-Guang; Chen Sheng-Gen; Li Yu-Ye

    2015-01-01

    We investigated the synchronization dynamics of a coupled neuronal system composed of two identical Chay model neurons. The Chay model showed coexisting period-1 and period-2 bursting patterns as a parameter and initial values are varied. We simulated multiple periodic and chaotic bursting patterns with non-(NS), burst phase (BS), spike phase (SS), complete (CS), and lag synchronization states. When the coexisting behavior is near period-2 bursting, the transitions of synchronization states of the coupled system follows very complex transitions that begins with transitions between BS and SS, moves to transitions between CS and SS, and to CS. Most initial values lead to the CS state of period-2 bursting while only a few lead to the CS state of period-1 bursting. When the coexisting behavior is near period-1 bursting, the transitions begin with NS, move to transitions between SS and BS, to transitions between SS and CS, and then to CS. Most initial values lead to the CS state of period-1 bursting but a few lead to the CS state of period-2 bursting. The BS was identified as chaos synchronization. The patterns for NS and transitions between BS and SS are insensitive to initial values. The patterns for transitions between CS and SS and the CS state are sensitive to them. The number of spikes per burst of non-CS bursting increases with increasing coupling strength. These results not only reveal the initial value- and parameter-dependent synchronization transitions of coupled systems with coexisting behaviors, but also facilitate interpretation of various bursting patterns and synchronization transitions generated in the nervous system with weak coupling strength. (paper)

  17. Influence and timing of arrival of murine neural crest on pancreatic beta cell development and maturation.

    Science.gov (United States)

    Plank, Jennifer L; Mundell, Nathan A; Frist, Audrey Y; LeGrone, Alison W; Kim, Thomas; Musser, Melissa A; Walter, Teagan J; Labosky, Patricia A

    2011-01-15

    Interactions between cells from the ectoderm and mesoderm influence development of the endodermally-derived pancreas. While much is known about how mesoderm regulates pancreatic development, relatively little is understood about how and when the ectodermally-derived neural crest regulates pancreatic development and specifically, beta cell maturation. A previous study demonstrated that signals from the neural crest regulate beta cell proliferation and ultimately, beta cell mass. Here, we expand on that work to describe timing of neural crest arrival at the developing pancreatic bud and extend our knowledge of the non-cell autonomous role for neural crest derivatives in the process of beta cell maturation. We demonstrated that murine neural crest entered the pancreatic mesenchyme between the 26 and 27 somite stages (approximately 10.0 dpc) and became intermingled with pancreatic progenitors as the epithelium branched into the surrounding mesenchyme. Using a neural crest-specific deletion of the Forkhead transcription factor Foxd3, we ablated neural crest cells that migrate to the pancreatic primordium. Consistent with previous data, in the absence of Foxd3, and therefore the absence of neural crest cells, proliferation of insulin-expressing cells and insulin-positive area are increased. Analysis of endocrine cell gene expression in the absence of neural crest demonstrated that, although the number of insulin-expressing cells was increased, beta cell maturation was significantly impaired. Decreased MafA and Pdx1 expression illustrated the defect in beta cell maturation; we discovered that without neural crest, there was a reduction in the percentage of insulin-positive cells that co-expressed Glut2 and Pdx1 compared to controls. In addition, transmission electron microscopy analyses revealed decreased numbers of characteristic insulin granules and the presence of abnormal granules in insulin-expressing cells from mutant embryos. Together, these data demonstrate that

  18. A Simple Matter of Life and Death—The Trials of Postnatal Beta-Cell Mass Regulation

    Directory of Open Access Journals (Sweden)

    Elena Tarabra

    2012-01-01

    Full Text Available Pancreatic beta-cells, which secrete the hormone insulin, are the key arbiters of glucose homeostasis. Defective beta-cell numbers and/or function underlie essentially all major forms of diabetes and must be restored if diabetes is to be cured. Thus, the identification of the molecular regulators of beta-cell mass and a better understanding of the processes of beta-cell differentiation and proliferation may provide further insight for the development of new therapeutic targets for diabetes. This review will focus on the principal hormones and nutrients, as well as downstream signalling pathways regulating beta-cell mass in the adult. Furthermore, we will also address more recently appreciated regulators of beta-cell mass, such as microRNAs.

  19. High fat programming of beta cell compensation, exhaustion, death and dysfunction.

    Science.gov (United States)

    Cerf, Marlon E

    2015-03-01

    Programming refers to events during critical developmental windows that shape progeny health outcomes. Fetal programming refers to the effects of intrauterine (in utero) events. Lactational programming refers to the effects of events during suckling (weaning). Developmental programming refers to the effects of events during both fetal and lactational life. Postnatal programming refers to the effects of events either from birth (lactational life) to adolescence or from weaning (end of lactation) to adolescence. Islets are most plastic during the early life course; hence programming during fetal and lactational life is most potent. High fat (HF) programming is the maintenance on a HF diet (HFD) during critical developmental life stages that alters progeny metabolism and physiology. HF programming induces variable diabetogenic phenotypes dependent on the timing and duration of the dietary insult. Maternal obesity reinforces HF programming effects in progeny. HF programming, through acute hyperglycemia, initiates beta cell compensation. However, HF programming eventually leads to chronic hyperglycemia that triggers beta cell exhaustion, death and dysfunction. In HF programming, beta cell dysfunction often co-presents with insulin resistance. Balanced, healthy nutrition during developmental windows is critical for preserving beta cell structure and function. Thus early positive nutritional interventions that coincide with the development of beta cells may reduce the overwhelming burden of diabetes and metabolic disease. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  20. ROS signaling, oxidative stress and Nrf2 in pancreatic beta-cell function

    International Nuclear Information System (INIS)

    Pi Jingbo; Zhang Qiang; Fu Jingqi; Woods, Courtney G.; Hou Yongyong; Corkey, Barbara E.; Collins, Sheila; Andersen, Melvin E.

    2010-01-01

    This review focuses on the emerging evidence that reactive oxygen species (ROS) derived from glucose metabolism, such as H 2 O 2 , act as metabolic signaling molecules for glucose-stimulated insulin secretion (GSIS) in pancreatic beta-cells. Particular emphasis is placed on the potential inhibitory role of endogenous antioxidants, which rise in response to oxidative stress, in glucose-triggered ROS and GSIS. We propose that cellular adaptive response to oxidative stress challenge, such as nuclear factor E2-related factor 2 (Nrf2)-mediated antioxidant induction, plays paradoxical roles in pancreatic beta-cell function. On the one hand, induction of antioxidant enzymes protects beta-cells from oxidative damage and possible cell death, thus minimizing oxidative damage-related impairment of insulin secretion. On the other hand, the induction of antioxidant enzymes by Nrf2 activation blunts glucose-triggered ROS signaling, thus resulting in reduced GSIS. These two premises are potentially relevant to impairment of beta-cells occurring in the late and early stage of Type 2 diabetes, respectively. In addition, we summarized our recent findings that persistent oxidative stress due to absence of uncoupling protein 2 activates cellular adaptive response which is associated with impaired pancreatic beta-cell function.

  1. Role of growth factors in control of pancreatic beta cell mass: focus on betatrophin.

    Science.gov (United States)

    Levitsky, Lynne L; Ardestani, Goli; Rhoads, David B

    2014-08-01

    Betatrophin is a newly described hormone, which potently stimulates beta cell replication in mice. This discovery has engendered great hope that it could prove clinically important in the treatment of type 1 and type 2 diabetes. Betatrophin, a 198-amino acid protein secreted by liver and adipose tissue, stimulates growth of pancreatic beta cell mass in insulin-resistant mice. Betatrophin has previously been named RIFL, lipasin, and ANGPLT8, and its salutory effects on lipid metabolism have been described in mouse and human studies. Serum betatrophin levels in humans correlate with improved adipose tissue lipid storage and lower serum triglyceride levels in the fed state, but do not correlate with insulin resistance or carbohydrate tolerance in humans. Betatrophin has not yet been shown to have an effect on beta cell replication in human pancreatic islets. Many endocrine and paracrine factors, of which betatrophin is the newest described, increase beta cell mass in murine models. None of these factors, including betatrophin, have displayed the same activity in clinical studies. This may reflect a profound species difference in beta cell regeneration pathways in mice and humans.

  2. Inflammatory stress of pancreatic beta cells drives release of extracellular heat-shock protein 90α.

    Science.gov (United States)

    Ocaña, Gail J; Pérez, Liliana; Guindon, Lynette; Deffit, Sarah N; Evans-Molina, Carmella; Thurmond, Debbie C; Blum, Janice S

    2017-06-01

    A major obstacle in predicting and preventing the development of autoimmune type 1 diabetes (T1D) in at-risk individuals is the lack of well-established early biomarkers indicative of ongoing beta cell stress during the pre-clinical phase of disease. Recently, serum levels of the α cytoplasmic isoform of heat-shock protein 90 (hsp90) were shown to be elevated in individuals with new-onset T1D. We therefore hypothesized that hsp90α could be released from beta cells in response to cellular stress and inflammation associated with the earliest stages of T1D. Here, human beta cell lines and cadaveric islets released hsp90α in response to stress induced by treatment with a combination of pro-inflammatory cytokines including interleukin-1β, tumour necrosis factor-α and interferon-γ. Mechanistically, hsp90α release was found to be driven by cytokine-induced endoplasmic reticulum stress mediated by c-Jun N-terminal kinase (JNK), a pathway that can eventually lead to beta cell apoptosis. Cytokine-induced beta cell hsp90α release and JNK activation were significantly reduced by pre-treating cells with the endoplasmic reticulum stress-mitigating chemical chaperone tauroursodeoxycholic acid. The hsp90α release by cells may therefore be a sensitive indicator of stress during inflammation and a useful tool in assessing therapeutic mitigation of cytokine-induced cell damage linked to autoimmunity. © 2017 John Wiley & Sons Ltd.

  3. Polymorphisms within novel risk loci for type 2 diabetes determine beta-cell function.

    Directory of Open Access Journals (Sweden)

    Harald Staiger

    Full Text Available BACKGROUND: Type 2 diabetes arises when insulin resistance-induced compensatory insulin secretion exhausts. Insulin resistance and/or beta-cell dysfunction result from the interaction of environmental factors (high-caloric diet and reduced physical activity with a predisposing polygenic background. Very recently, genetic variations within four novel genetic loci (SLC30A8, HHEX, EXT2, and LOC387761 were reported to be more frequent in subjects with type 2 diabetes than in healthy controls. However, associations of these variations with insulin resistance and/or beta-cell dysfunction were not assessed. METHODOLOGY/PRINCIPAL FINDINGS: By genotyping of 921 metabolically characterized German subjects for the reported candidate single nucleotide polymorphisms (SNPs, we show that the major alleles of the SLC30A8 SNP rs13266634 and the HHEX SNP rs7923837 associate with reduced insulin secretion stimulated by orally or intravenously administered glucose, but not with insulin resistance. In contrast, the other reported type 2 diabetes candidate SNPs within the EXT2 and LOC387761 loci did not associate with insulin resistance or beta-cell dysfunction, respectively. CONCLUSIONS/SIGNIFICANCE: The HHEX and SLC30A8 genes encode for proteins that were shown to be required for organogenesis of the ventral pancreas and for insulin maturation/storage, respectively. Therefore, the major alleles of type 2 diabetes candidate SNPs within these genetic loci represent crucial alleles for beta-cell dysfunction and, thus, might confer increased susceptibility of beta-cells towards adverse environmental factors.

  4. New Therapeutic Approaches to Prevent or Delay Beta-Cell Failure in Diabetes

    Directory of Open Access Journals (Sweden)

    Ionica Floriana Elvira

    2015-09-01

    Full Text Available Background and aims: The most recent estimates of International Diabetes Federation indicate that 382 million people have diabetes, and the incidence of this disease is increasing. While in type 1 diabetes mellitus (T1DM beta-cell death is autoimmunemediated, type 2 diabetes mellitus (T2DM results from an interaction between genetic and environmental factors that impair beta-cell function and insulin action. Many people with T2DM remain unaware of their illness for a long time because symptoms may take years to appear or be recognized, while the body is affected by excess blood glucose. These patients are often diagnosed only when diabetes complications have already developed. The aim of this article was to perform a review based on literature data on therapeutic modalities to prevent/delay beta cell function decline. Material and Methods: We searched MEDLINE from 2000 to the present to identify the therapeutic approaches to prevent or delay beta-cell failure in patients with T2DM. Results and conclusions: Several common polymorphisms in genes linked to monogenic forms of diabetes appear to influence the response to T2DM pharmacotherapy. Recent studies report the role of the G protein coupled receptor 40 (GPR40, also known as Free Fatty Acids Receptor 1 (FFAR1 in the regulation of beta-cell function- CNX-011-67 (a GPR40 agonist has the potential to provide good and durable glycemic control in T2DM patients.

  5. Coexistence between silent and bursting states in a biophysical Hodgkin-Huxley-type of model

    DEFF Research Database (Denmark)

    Stankevich, Nataliya; Mosekilde, Erik

    2017-01-01

    in a slightly modified, biophysical model that describe the dynamics of pancreatic beta-cells. To realize this form of coexistence, we have introduced an additional voltage-dependent potassium current that is activated in the region around the original, unstable equilibrium point. It is interesting to note...... that this modification also leads the model to display a blue-sky catastrophe in the transition region between chaotic and bursting states....

  6. Impact of fetal and neonatal environment on beta cell function and development of diabetes

    DEFF Research Database (Denmark)

    Nielsen, Jens H; Haase, Tobias N; Jaksch, Caroline

    2014-01-01

    on the beta cells in both the mother and the fetus and how various conditions like diabetes, obesity, overnutrition and undernutrition during and after pregnancy may influence the ability of the offspring to adapt to changes in insulin demand later in life. The influence of environmental factors including...... that the intrauterine environment during pregnancy has an impact on the gene expression that may persist until adulthood and cause metabolic diseases like obesity and type 2 diabetes. As the pancreatic beta cells are crucial in the regulation of metabolism this article will describe the influence of normal pregnancy...... nutrients and gut microbiota on appetite regulation, mitochondrial activity and the immune system that may affect beta cell growth and function directly and indirectly is discussed. The possible role of epigenetic changes in the transgenerational transmission of the adverse programming may be the most...

  7. Tissue-specific methylation of human insulin gene and PCR assay for monitoring beta cell death.

    Directory of Open Access Journals (Sweden)

    Mohamed I Husseiny

    Full Text Available The onset of metabolic dysregulation in type 1 diabetes (T1D occurs after autoimmune destruction of the majority of pancreatic insulin-producing beta cells. We previously demonstrated that the DNA encoding the insulin gene is uniquely unmethylated in these cells and then developed a methylation-specific PCR (MSP assay to identify circulating beta cell DNA in streptozotocin-treated mice prior to the rise in blood glucose. The current study extends to autoimmune non-obese diabetic (NOD mice and humans, showing in NOD mice that beta cell death occurs six weeks before the rise in blood sugar and coincides with the onset of islet infiltration by immune cells, demonstrating the utility of MSP for monitoring T1D. We previously reported unique patterns of methylation of the human insulin gene, and now extend this to other human tissues. The methylation patterns of the human insulin promoter, intron 1, exon 2, and intron 2 were determined in several normal human tissues. Similar to our previous report, the human insulin promoter was unmethylated in beta cells, but methylated in all other tissues tested. In contrast, intron 1, exon 2 and intron 2 did not exhibit any tissue-specific DNA methylation pattern. Subsequently, a human MSP assay was developed based on the methylation pattern of the insulin promoter and human islet DNA was successfully detected in circulation of T1D patients after islet transplantation therapy. Signal levels of normal controls and pre-transplant samples were shown to be similar, but increased dramatically after islet transplantation. In plasma the signal declines with time but in whole blood remains elevated for at least two weeks, indicating that association of beta cell DNA with blood cells prolongs the signal. This assay provides an effective method to monitor beta cell destruction in early T1D and in islet transplantation therapy.

  8. Insulin-producing cells generated from dedifferentiated human pancreatic beta cells expanded in vitro.

    Directory of Open Access Journals (Sweden)

    Holger A Russ

    Full Text Available Expansion of beta cells from the limited number of adult human islet donors is an attractive prospect for increasing cell availability for cell therapy of diabetes. However, attempts at expanding human islet cells in tissue culture result in loss of beta-cell phenotype. Using a lineage-tracing approach we provided evidence for massive proliferation of beta-cell-derived (BCD cells within these cultures. Expansion involves dedifferentiation resembling epithelial-mesenchymal transition (EMT. Epigenetic analyses indicate that key beta-cell genes maintain open chromatin structure in expanded BCD cells, although they are not transcribed. Here we investigated whether BCD cells can be redifferentiated into beta-like cells.Redifferentiation conditions were screened by following activation of an insulin-DsRed2 reporter gene. Redifferentiated cells were characterized for gene expression, insulin content and secretion assays, and presence of secretory vesicles by electron microscopy. BCD cells were induced to redifferentiate by a combination of soluble factors. The redifferentiated cells expressed beta-cell genes, stored insulin in typical secretory vesicles, and released it in response to glucose. The redifferentiation process involved mesenchymal-epithelial transition, as judged by changes in gene expression. Moreover, inhibition of the EMT effector SLUG (SNAI2 using shRNA resulted in stimulation of redifferentiation. Lineage-traced cells also gave rise at a low rate to cells expressing other islet hormones, suggesting transition of BCD cells through an islet progenitor-like stage during redifferentiation.These findings demonstrate for the first time that expanded dedifferentiated beta cells can be induced to redifferentiate in culture. The findings suggest that ex-vivo expansion of adult human islet cells is a promising approach for generation of insulin-producing cells for transplantation, as well as basic research, toxicology studies, and drug

  9. Determination of Insulin Resistance and Beta Cell Function in Healthy Obese and Non-obese Individuals

    International Nuclear Information System (INIS)

    Kazmi, A.; Sattar, A.; Tariq, K. M.; Najamussahar; Hashim, R.; Almani, M. I.

    2013-01-01

    Objective: To determine insulin resistance and beta cell function in healthy obese and nonobese individuals of the local population. Study Design: Case control study. Place and Duration of Study: AFIP Rawalpindi in collaboration with department of medicine military hospital(MH) Rawalpindi, from Aug 2008 to Mar 2009. Methods: Eighty obese(n=40) and non-obese(n=40) subjects were selected by non-probability convenience sampling. Plasma insulin, glucose, and serum total cholestrol were estimated in fasting state. Insulin resistance was calculated by HOMA-IR and beta cell function by HOMA- equation. Results: Significant differences were observed between obese and non-obese individuals regarding insulin resistance, beta cell function, and BMI and serum total cholesterol. Mean insulin resistance in obese group was found to be 11.1 +- 5.1(range 7.0-16.2) and in non-obese group it was 0.9+-0.4 (range 0.5-1.3). This difference was highly significant (p=0.001). There was a highly significant difference between the two groups in term of beta cell function with mean rank 60.1 for obese group and 20.9 non obese groups (Asym sig. 2 tailed 0.000). Also the correlation (r = 0.064) between insulin resistance and beta cell function in obese group is highly significant (p = 0.000). Mean serum leptin levels were lower (6.3 ng/ml) in non-obese, and high (57.2 ng/ml) in the obese group. Conclusions: Insulin resistance is found higher in obese individuals. Beta cell function is significantly different between obese and non-obese groups. (author)

  10. Effects of ethanol on pancreatic beta-cell death: interaction with glucose and fatty acids.

    Science.gov (United States)

    Dembele, Korami; Nguyen, K Hoa; Hernandez, Tiffany A; Nyomba, B L Grégoire

    2009-04-01

    Western lifestyle plays an important role in the prevalence of type 2 diabetes by causing insulin resistance and pancreatic beta-cell dysfunction, a prerequisite for the development of diabetes. High fat diet and alcohol are major components of the western diet. The aim of the present study was to investigate the effects of ethanol and fatty acids on beta-cell survival and metabolism. We treated the rat beta-cell line RINm5F with ethanol, a mixture of palmitic and oleic acids, or both. Reactive oxygen species (ROS) were determined by (5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate) (CM-H2DCFDA) fluorescence assay, and mitochondrial activity was assessed by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) reduction assay and by determining ATP production. Cell viability was assessed with a cell counter and trypan blue exclusion, and the mode of cell death by Hoechst33342 and propidium iodide staining. With both ethanol and fatty acid treatments, MTT reduction and ATP production decreased, whereas ROS production increased. Ethanol treatment had no effect on cell number, whereas fatty acid treatment reduced the cell number. Cell incubation with ethanol, fatty acids, or both increased the number of Hoechst 33342-positive nuclei. However, the majority of nuclei from fatty acid-treated cells were stained with propidium iodide, indicating a loss of plasma membrane integrity. We conclude that both ethanol and fatty acids generate cellular oxidative stress, and affect mitochondrial function in RINm5F beta-cells. However, ethanol causes beta-cell death by apoptosis, whereas fatty acids cause cell death predominantly by necrosis. It is not known whether these results are applicable to human beta-cells.

  11. A human beta cell line with drug inducible excision of immortalizing transgenes

    Science.gov (United States)

    Benazra, Marion; Lecomte, Marie-José; Colace, Claire; Müller, Andreas; Machado, Cécile; Pechberty, Severine; Bricout-Neveu, Emilie; Grenier-Godard, Maud; Solimena, Michele; Scharfmann, Raphaël; Czernichow, Paul; Ravassard, Philippe

    2015-01-01

    Objectives Access to immortalized human pancreatic beta cell lines that are phenotypically close to genuine adult beta cells, represent a major tool to better understand human beta cell physiology and develop new therapeutics for Diabetes. Here we derived a new conditionally immortalized human beta cell line, EndoC-βH3 in which immortalizing transgene can be efficiently removed by simple addition of tamoxifen. Methods We used lentiviral mediated gene transfer to stably integrate a tamoxifen inducible form of CRE (CRE-ERT2) into the recently developed conditionally immortalized EndoC βH2 line. The resulting EndoC-βH3 line was characterized before and after tamoxifen treatment for cell proliferation, insulin content and insulin secretion. Results We showed that EndoC-βH3 expressing CRE-ERT2 can be massively amplified in culture. We established an optimized tamoxifen treatment to efficiently excise the immortalizing transgenes resulting in proliferation arrest. In addition, insulin expression raised by 12 fold and insulin content increased by 23 fold reaching 2 μg of insulin per million cells. Such massive increase was accompanied by enhanced insulin secretion upon glucose stimulation. We further observed that tamoxifen treated cells maintained a stable function for 5 weeks in culture. Conclusions EndoC βH3 cell line represents a powerful tool that allows, using a simple and efficient procedure, the massive production of functional non-proliferative human beta cells. Such cells are close to genuine human beta cells and maintain a stable phenotype for 5 weeks in culture. PMID:26909308

  12. The effect of suppressor of cytokine signaling 3 on GH signaling in beta-cells

    DEFF Research Database (Denmark)

    Rønn, Sif G; Hansen, Johnny A; Lindberg, Karen

    2002-01-01

    GH is an important regulator of cell growth and metabolism. In the pancreas, GH stimulates mitogenesis as well as insulin production in beta-cells. The cellular effects of GH are exerted mainly through activation of the Janus kinase-signal transducer and activator of transcription (STAT) pathway...... stable transfection of the beta-cell lines with plasmids expressing SOCS-3 under the control of an inducible promoter, a time- and dose-dependent expression of SOCS-3 in the cells was obtained. EMSA showed that SOCS-3 is able to inhibit GH-induced DNA binding of both STAT3 and STAT5 in RIN-5AH cells...

  13. Planar Cell Polarity Controls Pancreatic Beta Cell Differentiation and Glucose Homeostasis

    DEFF Research Database (Denmark)

    Cortijo, Cedric; Gouzi, Mathieu; Tissir, Fadel

    2012-01-01

    glucose clearance. Loss of Celsr2 and 3 leads to a reduction of Jun phosphorylation in progenitors, which, in turn, reduces beta cell differentiation from endocrine progenitors. These results highlight the importance of the PCP pathway in cell differentiation in vertebrates. In addition, they reveal.......5 synchronously to apicobasal polarization of pancreas progenitors. Loss of function of the two PCP core components Celsr2 and Celsr3 shows that they control the differentiation of endocrine cells from polarized progenitors, with a prevalent effect on insulin-producing beta cells. This results in a decreased...

  14. Burst suppression probability algorithms: state-space methods for tracking EEG burst suppression

    Science.gov (United States)

    Chemali, Jessica; Ching, ShiNung; Purdon, Patrick L.; Solt, Ken; Brown, Emery N.

    2013-10-01

    Objective. Burst suppression is an electroencephalogram pattern in which bursts of electrical activity alternate with an isoelectric state. This pattern is commonly seen in states of severely reduced brain activity such as profound general anesthesia, anoxic brain injuries, hypothermia and certain developmental disorders. Devising accurate, reliable ways to quantify burst suppression is an important clinical and research problem. Although thresholding and segmentation algorithms readily identify burst suppression periods, analysis algorithms require long intervals of data to characterize burst suppression at a given time and provide no framework for statistical inference. Approach. We introduce the concept of the burst suppression probability (BSP) to define the brain's instantaneous propensity of being in the suppressed state. To conduct dynamic analyses of burst suppression we propose a state-space model in which the observation process is a binomial model and the state equation is a Gaussian random walk. We estimate the model using an approximate expectation maximization algorithm and illustrate its application in the analysis of rodent burst suppression recordings under general anesthesia and a patient during induction of controlled hypothermia. Main result. The BSP algorithms track burst suppression on a second-to-second time scale, and make possible formal statistical comparisons of burst suppression at different times. Significance. The state-space approach suggests a principled and informative way to analyze burst suppression that can be used to monitor, and eventually to control, the brain states of patients in the operating room and in the intensive care unit.

  15. Intermittent fasting preserves beta-cell mass in obesity-induced diabetes via the autophagy-lysosome pathway.

    Science.gov (United States)

    Liu, Haiyan; Javaheri, Ali; Godar, Rebecca J; Murphy, John; Ma, Xiucui; Rohatgi, Nidhi; Mahadevan, Jana; Hyrc, Krzysztof; Saftig, Paul; Marshall, Connie; McDaniel, Michael L; Remedi, Maria S; Razani, Babak; Urano, Fumihiko; Diwan, Abhinav

    2017-01-01

    Obesity-induced diabetes is characterized by hyperglycemia, insulin resistance, and progressive beta cell failure. In islets of mice with obesity-induced diabetes, we observe increased beta cell death and impaired autophagic flux. We hypothesized that intermittent fasting, a clinically sustainable therapeutic strategy, stimulates autophagic flux to ameliorate obesity-induced diabetes. Our data show that despite continued high-fat intake, intermittent fasting restores autophagic flux in islets and improves glucose tolerance by enhancing glucose-stimulated insulin secretion, beta cell survival, and nuclear expression of NEUROG3, a marker of pancreatic regeneration. In contrast, intermittent fasting does not rescue beta-cell death or induce NEUROG3 expression in obese mice with lysosomal dysfunction secondary to deficiency of the lysosomal membrane protein, LAMP2 or haplo-insufficiency of BECN1/Beclin 1, a protein critical for autophagosome formation. Moreover, intermittent fasting is sufficient to provoke beta cell death in nonobese lamp2 null mice, attesting to a critical role for lysosome function in beta cell homeostasis under fasting conditions. Beta cells in intermittently-fasted LAMP2- or BECN1-deficient mice exhibit markers of autophagic failure with accumulation of damaged mitochondria and upregulation of oxidative stress. Thus, intermittent fasting preserves organelle quality via the autophagy-lysosome pathway to enhance beta cell survival and stimulates markers of regeneration in obesity-induced diabetes.

  16. A standardized method for in vivo mouse pancreas imaging and semiquantitative beta cell mass measurement by dual isotope SPECT

    NARCIS (Netherlands)

    Mathijs, I.; Xavier, C.; Peleman, C.; Caveliers, V.; Brom, M.; Gotthardt, M.; Herrera, P.L.; Lahoutte, T.; Bouwens, L.

    2015-01-01

    PURPOSE: In order to evaluate future beta cell tracers in vivo, we aimed to develop a standardized in vivo method allowing semiquantitative measurement of a prospective beta cell tracer within the pancreas. PROCEDURES: 2-[(123)I]Iodo-L-phenylalanine ([(123)I]IPA) and

  17. Cell specificity of the cytoplasmic Ca2+ response to tolbutamide is impaired in beta-cells from hyperglycemic mice

    DEFF Research Database (Denmark)

    Gustavsson, Natalia; Larsson-Nyrén, Gerd; Lindström, Per

    2006-01-01

    We recently reported that the timing and magnitude of the nutrient-induced Ca(2+) response are specific and reproducible for each isolated beta-cell. We have now used tolbutamide and arginine to test if the cell specificity exists also for the response to non-nutrient stimulation of beta-cells an...

  18. Cosmic gamma bursts

    International Nuclear Information System (INIS)

    Ehstulin, I.V.

    1980-01-01

    A brief consideration is being given to the history of cosmic gamma burst discovery and modern knowledge of their properties. The time dependence of gamma bursts is described and their possible sources are discussed

  19. Timing of Ca2+ response in pancreatic beta-cells is related to mitochondrial mass

    DEFF Research Database (Denmark)

    Gustavsson, N; Abedi, G; Larsson-Nyrén, G

    2006-01-01

    timing are disturbed in beta-cells from hyperglycemic mice and one of the causes is likely to be an altered mitochondrial metabolism. Mitochondria play a key role in the control of nutrient-induced insulin secretion. Here, we used confocal microscopy with the fluorescent probe MitoTracker Red CMXRos...

  20. Dual role of proapoptotic BAD in insulin secretion and beta cell survival.

    Science.gov (United States)

    Danial, Nika N; Walensky, Loren D; Zhang, Chen-Yu; Choi, Cheol Soo; Fisher, Jill K; Molina, Anthony J A; Datta, Sandeep Robert; Pitter, Kenneth L; Bird, Gregory H; Wikstrom, Jakob D; Deeney, Jude T; Robertson, Kirsten; Morash, Joel; Kulkarni, Ameya; Neschen, Susanne; Kim, Sheene; Greenberg, Michael E; Corkey, Barbara E; Shirihai, Orian S; Shulman, Gerald I; Lowell, Bradford B; Korsmeyer, Stanley J

    2008-02-01

    The proapoptotic BCL-2 family member BAD resides in a glucokinase-containing complex that regulates glucose-driven mitochondrial respiration. Here, we present genetic evidence of a physiologic role for BAD in glucose-stimulated insulin secretion by beta cells. This novel function of BAD is specifically dependent upon the phosphorylation of its BH3 sequence, previously defined as an essential death domain. We highlight the pharmacologic relevance of phosphorylated BAD BH3 by using cell-permeable, hydrocarbon-stapled BAD BH3 helices that target glucokinase, restore glucose-driven mitochondrial respiration and correct the insulin secretory response in Bad-deficient islets. Our studies uncover an alternative target and function for the BAD BH3 domain and emphasize the therapeutic potential of phosphorylated BAD BH3 mimetics in selectively restoring beta cell function. Furthermore, we show that BAD regulates the physiologic adaptation of beta cell mass during high-fat feeding. Our findings provide genetic proof of the bifunctional activities of BAD in both beta cell survival and insulin secretion.

  1. Oxidative Metabolism Genes Are Not Responsive to Oxidative Stress in Rodent Beta Cell Lines

    Directory of Open Access Journals (Sweden)

    Faer Morrison

    2012-01-01

    Full Text Available Altered expression of oxidative metabolism genes has been described in the skeletal muscle of individuals with type 2 diabetes. Pancreatic beta cells contain low levels of antioxidant enzymes and are particularly susceptible to oxidative stress. In this study, we explored the effect of hyperglycemia-induced oxidative stress on a panel of oxidative metabolism genes in a rodent beta cell line. We exposed INS-1 rodent beta cells to low (5.6 mmol/L, ambient (11 mmol/L, and high (28 mmol/L glucose conditions for 48 hours. Increases in oxidative stress were measured using the fluorescent probe dihydrorhodamine 123. We then measured the expression levels of a panel of 90 oxidative metabolism genes by real-time PCR. Elevated reactive oxygen species (ROS production was evident in INS-1 cells after 48 hours (P<0.05. TLDA analysis revealed a significant (P<0.05 upregulation of 16 of the 90 genes under hyperglycemic conditions, although these expression differences did not reflect differences in ROS. We conclude that although altered glycemia may influence the expression of some oxidative metabolism genes, this effect is probably not mediated by increased ROS production. The alterations to the expression of oxidative metabolism genes previously observed in human diabetic skeletal muscle do not appear to be mirrored in rodent pancreatic beta cells.

  2. Beta cell imaging - a key tool in optimized diabetes prevention and treatment

    NARCIS (Netherlands)

    Gotthardt, M.; Eizirik, D.L.; Cnop, M.; Brom, M.

    2014-01-01

    The prevalence of diabetes is 382 million worldwide, and is expected to rise to 592 million in 2035 (http://www.idf.org/diabetesatlas); 2.5-15\\% of national annual healthcare budgets are related to diabetes care, potentially increasing to 40\\% in high-prevalence countries. Beta cell dysfunction and

  3. MicroRNAs as regulators of beta-cell function and dysfunction

    DEFF Research Database (Denmark)

    Osmai, Mirwais; Osmai, Yama; Bang-Berthelsen, Claus Heiner

    2016-01-01

    , recent studies have demonstrated that miRNAs are important regulators of the islet transcriptome, controlling apoptosis, differentiation and proliferation, as well as regulating unique islet and beta-cell functions and pathways such as insulin expression, processing and secretion. Furthermore, a large...

  4. Effect of iron on pancreatic beta cell function and insulin resistance ...

    African Journals Online (AJOL)

    Background: Increase in total body iron store has been reported in the aetiology and development of diabetes mellitus. The effect of iron supplementation in female with respect to the incidence of diabetes mellitus was investigated on the pancreatic beta cell function and insulin resistance in normal female rats. Methods: ...

  5. Growth hormone is a growth factor for the differentiated pancreatic beta-cell

    DEFF Research Database (Denmark)

    Linde, S; Welinder, B S; Billestrup, N

    1989-01-01

    The regulation of the growth of the pancreatic beta-cell is poorly understood. There are previous indications of a role of GH in the growth and insulin production of the pancreatic islets. In the present study we present evidence for a direct long-term effect of GH on proliferation and insulin...

  6. Visualizing pancreatic {beta}-cell mass with [{sup 11}C]DTBZ

    Energy Technology Data Exchange (ETDEWEB)

    Simpson, Norman Ray [Department of Radiology, Columbia University Medical School, New York, NY 10032 (United States); Souza, Fabiola [Department of Surgery, Columbia University Medical School, New York, NY 10032 (United States); Witkowski, Piotr [Department of Medicine, Columbia University Medical School, New York, NY 10032 (United States); Maffei, Antonella [Institute of Genetics and Biophysics ' Adriano Buzzati-Traverso' , CNR, Naples 80131 (Italy); Raffo, Anthony [Department of Surgery, Columbia University Medical School, New York, NY 10032 (United States); Herron, Alan [Center for Comparative Medicine and The Department of Pathology, Baylor College of Medicine, Houston, TX 77030 (United States); Kilbourn, Michael [Department of Radiology, University of Michigan, Ann Arbor, MI 48109-0638 (United States); Jurewicz, Agata [Department of Radiology, Columbia University Medical School, New York, NY 10032 (United States); Herold, Kevan [Department of Surgery, Columbia University Medical School, New York, NY 10032 (United States); Liu, Eric [Diabetes Branch, NIDDK, National Institutes of Health, Bethesda, MD 20854 (United States); Hardy, Mark Adam [Department of Medicine, Columbia University Medical School, New York, NY 10032 (United States); Van Heertum, Ronald [Department of Radiology, Columbia University Medical School, New York, NY 10032 (United States); Harris, Paul Emerson [Department of Surgery, Columbia University Medical School, New York, NY 10032 (United States)]. E-mail: peh1@columbia.edu

    2006-10-15

    {beta}-Cell mass (BCM) influences the total amount of insulin secreted, varies by individual and by the degree of insulin resistance, and is affected by physiologic and pathologic conditions. The islets of Langerhans, however, appear to have a reserve capacity of insulin secretion and, overall, assessments of insulin and blood glucose levels remain poor measures of BCM, {beta}-cell function and progression of diabetes. Thus, novel noninvasive determinations of BCM are needed to provide a quantitative endpoint for novel therapies of diabetes, islet regeneration and transplantation. Built on previous gene expression studies, we tested the hypothesis that the targeting of vesicular monoamine transporter 2 (VMAT2), which is expressed by {beta} cells, with [{sup 11}C]dihydrotetrabenazine ([{sup 11}C]DTBZ), a radioligand specific for VMAT2, and the use of positron emission tomography (PET) can provide a measure of BCM. In this report, we demonstrate decreased radioligand uptake within the pancreas of Lewis rats with streptozotocin-induced diabetes relative to their euglycemic historical controls. These studies suggest that quantitation of VMAT2 expression in {beta} cells with the use of [{sup 11}C]DTBZ and PET represents a method for noninvasive longitudinal estimates of changes in BCM that may be useful in the study and treatment of diabetes.

  7. Cytokines and beta-cell biology: from concept to clinical translation

    DEFF Research Database (Denmark)

    Donath, M.Y.; Storling, J.; Berchtold, L.A.

    2007-01-01

    The tale of cytokines and the beta-cell is a long story, starting with in vitro discovery in 1984, evolving via descriptive and phenomenological studies to detailed mapping of the signalling pathways, gene- and protein expression patterns, molecular and biochemical effector mechanisms to in vivo...

  8. Imaging of beta-Cell Mass and Insulitis in Insulin-Dependent (Type 1) Diabetes Mellitus

    NARCIS (Netherlands)

    Di Gialleonardo, Valentina; de Vries, Erik F. J.; Di Girolamo, Marco; Quintero, Ana M.; Dierckx, Rudi A. J. O.; Signore, Alberto

    2012-01-01

    Insulin-dependent (type 1) diabetes mellitus is a metabolic disease with a complex multifactorial etiology and a poorly understood pathogenesis. Genetic and environmental factors cause an autoimmune reaction against pancreatic beta-cells, called insulitis, confirmed in pancreatic samples obtained at

  9. PDX1, Neurogenin-3, and MAFA: critical transcription regulators for beta cell development and regeneration

    Directory of Open Access Journals (Sweden)

    Yaxi Zhu

    2017-11-01

    Full Text Available Abstract Transcription factors regulate gene expression through binding to specific enhancer sequences. Pancreas/duodenum homeobox protein 1 (PDX1, Neurogenin-3 (NEUROG3, and V-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MAFA are transcription factors critical for beta cell development and maturation. NEUROG3 is expressed in endocrine progenitor cells and controls islet differentiation and regeneration. PDX1 is essential for the development of pancreatic exocrine and endocrine cells including beta cells. PDX1 also binds to the regulatory elements and increases insulin gene transcription. Likewise, MAFA binds to the enhancer/promoter region of the insulin gene and drives insulin expression in response to glucose. In addition to those natural roles in beta cell development and maturation, ectopic expression of PDX1, NEUROG3, and/or MAFA has been successfully used to reprogram various cell types into insulin-producing cells in vitro and in vivo, such as pancreatic exocrine cells, hepatocytes, and pluripotent stem cells. Here, we review biological properties of PDX1, NEUROG3, and MAFA, and their applications and limitations for beta cell regenerative approaches. The primary source literature for this review was acquired using a PubMed search for articles published between 1990 and 2017. Search terms include diabetes, insulin, trans-differentiation, stem cells, and regenerative medicine.

  10. Rac1-NADPH oxidase signaling promotes CD36 activation under glucotoxic conditions in pancreatic beta cells.

    Science.gov (United States)

    Elumalai, Suma; Karunakaran, Udayakumar; Lee, In Kyu; Moon, Jun Sung; Won, Kyu Chang

    2017-04-01

    We recently reported that cluster determinant 36 (CD36), a fatty acid transporter, plays a pivotal role in glucotoxicity-induced β-cell dysfunction. However, little is known about how glucotoxicity influences CD36 expression. Emerging evidence suggests that the small GTPase Rac1 is involved in the pathogenesis of beta cell dysfunction in type 2 diabetes (T2D). The primary objective of the current study was to determine the role of Rac1 in CD36 activation and its impact on β-cell dysfunction in diabetes mellitus. To address this question, we subjected INS-1 cells and human beta cells (1.1B4) to high glucose conditions (30mM) in the presence or absence of Rac1 inhibition either by NSC23766 (Rac1 GTPase inhibitor) or small interfering RNA. High glucose exposure in INS-1 and human beta cells (1.1b4) resulted in the activation of Rac1 and induced cell apoptosis. Rac1 activation mediates NADPH oxidase (NOX) activation leading to elevated ROS production in both cells. Activation of the Rac1-NOX complex by high glucose levels enhanced CD36 expression in INS-1 and human 1.1b4 beta cell membrane fractions. The inhibition of Rac1 by NSC23766 inhibited NADPH oxidase activity and ROS generation induced by high glucose concentrations in INS-1 & human 1.1b4 beta cells. Inhibition of Rac1-NOX complex activation by NSC23766 significantly reduced CD36 expression in INS-1 and human 1.1b4 beta cell membrane fractions. In addition, Rac1 inhibition by NSC23766 significantly reduced high glucose-induced mitochondrial dysfunction. Furthermore, NADPH oxidase inhibition by VAS2870 also attenuated high glucose-induced ROS generation and cell apoptosis. These results suggest that Rac1-NADPH oxidase dependent CD36 expression contributes to high glucose-induced beta cell dysfunction and cell death. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  11. Beta cell 5'-shifted isomiRs are candidate regulatory hubs in type 2 diabetes.

    Directory of Open Access Journals (Sweden)

    Jeanette Baran-Gale

    Full Text Available Next-generation deep sequencing of small RNAs has unveiled the complexity of the microRNA (miRNA transcriptome, which is in large part due to the diversity of miRNA sequence variants ("isomiRs". Changes to a miRNA's seed sequence (nucleotides 2-8, including shifted start positions, can redirect targeting to a dramatically different set of RNAs and alter biological function. We performed deep sequencing of small RNA from mouse insulinoma (MIN6 cells (widely used as a surrogate for the study of pancreatic beta cells and developed a bioinformatic analysis pipeline to profile isomiR diversity. Additionally, we applied the pipeline to recently published small RNA-seq data from primary human beta cells and whole islets and compared the miRNA profiles with that of MIN6. We found that: (1 the miRNA expression profile in MIN6 cells is highly correlated with those of primary human beta cells and whole islets; (2 miRNA loci can generate multiple highly expressed isomiRs with different 5'-start positions (5'-isomiRs; (3 isomiRs with shifted start positions (5'-shifted isomiRs are highly expressed, and can be as abundant as their unshifted counterparts (5'-reference miRNAs. Finally, we identified 10 beta cell miRNA families as candidate regulatory hubs in a type 2 diabetes (T2D gene network. The most significant candidate hub was miR-29, which we demonstrated regulates the mRNA levels of several genes critical to beta cell function and implicated in T2D. Three of the candidate miRNA hubs were novel 5'-shifted isomiRs: miR-375+1, miR-375-1 and miR-183-5p+1. We showed by in silico target prediction and in vitro transfection studies that both miR-375+1 and miR-375-1 are likely to target an overlapping, but distinct suite of beta cell genes compared to canonical miR-375. In summary, this study characterizes the isomiR profile in beta cells for the first time, and also highlights the potential functional relevance of 5'-shifted isomiRs to T2D.

  12. Hypoglycemic and beta cell protective effects of andrographolide analogue for diabetes treatment

    Directory of Open Access Journals (Sweden)

    Larrick James W

    2009-07-01

    Full Text Available Abstract Background While all anti-diabetic agents can decrease blood glucose level directly or indirectly, few are able to protect and preserve both pancreatic beta cell mass and their insulin-secreting functions. Thus, there is an urgent need to find an agent or combination of agents that can lower blood glucose and preserve pancreatic beta cells at the same time. Herein, we report a dual-functional andrographolide-lipoic acid conjugate (AL-1. The anti-diabetic and beta cell protective activities of this novel andrographolide-lipoic acid conjugate were investigated. Methods In alloxan-treated mice (a model of type 1 diabetes, drugs were administered orally once daily for 6 days post-alloxan treatment. Fasting blood glucose and serum insulin were determined. Pathologic and immunohistochemical analysis of pancreatic islets were performed. Translocation of glucose transporter subtype 4 in soleus muscle was detected by western blot. In RIN-m cells in vitro, the effect of AL-1 on H2O2-induced damage and reactive oxidative species production stimulated by high glucose and glibenclamide were measured. Inhibition of nuclear factor kappa B (NF-κB activation induced by IL-1β and IFN-γ was investigated. Results In alloxan-induced diabetic mouse model, AL-1 lowered blood glucose, increased insulin and prevented loss of beta cells and their dysfunction, stimulated glucose transport protein subtype 4 (GLUT4 membrane translocation in soleus muscles. Pretreatment of RIN-m cells with AL-1 prevented H2O2-induced cellular damage, quenched glucose and glibenclamide-stimulated reactive oxidative species production, and inhibited cytokine-stimulated NF-κB activation. Conclusion We have demonstrated that AL-1 had both hypoglycemic and beta cell protective effects which translated into antioxidant and NF-κB inhibitory activity. AL-1 is a potential new anti-diabetic agent.

  13. Trans fatty acids increase nitric oxide levels and pancreatic beta-cell necrosis in rats

    Directory of Open Access Journals (Sweden)

    Kusmiyati Tjahjono DK

    2013-04-01

    Full Text Available Background The prevalence of diabetes in Indonesia is increasing due to various factors, including life style changes such as trans fatty acid (TFA intake. High TFA intake is known to be related to blood lipid profile changes resulting in cardiovascular disorders. This study was to identify the effect of TFA on nitric oxide (NO production and on necrosis of pancreatic beta cells. Methods A study of randomized pre-test post–test design with control group. Thirty Sprague Dawley rats were divided into 3 groups, i.e. group K (control, group P1 receiving a diet with 5% TFA, and P2 receiving 10% TFA. The intervention was performed for 8 weeks. NO level and pancreatic beta-cell necrosis were analyzed using Pearson’s chi square test. Results After 4 weeks of treatment there was no change in NO levels in group K, but increased NO in P2 (2.6-3.8 ìM. At 8 weeks after treatment, NO levels in groups P1 and P2 increased to 2.6-3.4 ìM and 4.2-14.3 ìM, respectively, while in group K only 2 rats had increased NO levels of 2.8-2.9 ìM. With Pearson’s chi-square test, there was a signifant difference in the proportions of necrotic pancreatic beta cells after 4 weeks and 8 weeks (p=0.000. No necrosis of beta cells was found in group K, mild necrosis in group P1 (1-25% and moderate necrosis in group P2 (26-50%. Conclusion TFA consumption significantly increases NO levels in Sprague Dawley rats and also results in moderate grades of necrosis of pancreatic beta cells.

  14. Trans fatty acids increase nitric oxide levels and pancreatic beta-cell necrosis in rats

    Directory of Open Access Journals (Sweden)

    Kusmiyati Tjahjono DK

    2015-12-01

    Full Text Available BACKGROUND The prevalence of diabetes in Indonesia is increasing due to various factors, including life style changes such as trans fatty acid (TFA intake. High TFA intake is known to be related to blood lipid profile changes resulting in cardiovascular disorders. This study was to identify the effect of TFA on nitric oxide (NO production and on necrosis of pancreatic beta cells. METHODS A study of randomized pre-test post–test design with control group. Thirty Sprague Dawley rats were divided into 3 groups, i.e. group K (control, group P1 receiving a diet with 5% TFA, and P2 receiving 10% TFA. The intervention was performed for 8 weeks. NO level and pancreatic beta-cell necrosis were analyzed using Pearson’s chi square test. RESULTS After 4 weeks of treatment there was no change in NO levels in group K, but increased NO in P2 (2.6-3.8 ìM. At 8 weeks after treatment, NO levels in groups P1 and P2 increased to 2.6-3.4 ìM and 4.2-14.3 ìM, respectively, while in group K only 2 rats had increased NO levels of 2.8-2.9 ìM. With Pearson’s chi-square test, there was a signifant difference in the proportions of necrotic pancreatic beta cells after 4 weeks and 8 weeks (p= 0.000. No necrosis of beta cells was found in group K, mild necrosis in group P1 (1-25% and moderate necrosis in group P2 (26-50%. CONCLUSION TFA consumption significantly increases NO levels in Sprague Dawley rats and also results in moderate grades of necrosis of pancreatic beta cells

  15. Hypothyroidism in utero stimulates pancreatic beta cell proliferation and hyperinsulinaemia in the ovine fetus during late gestation.

    Science.gov (United States)

    Harris, Shelley E; De Blasio, Miles J; Davis, Melissa A; Kelly, Amy C; Davenport, Hailey M; Wooding, F B Peter; Blache, Dominique; Meredith, David; Anderson, Miranda; Fowden, Abigail L; Limesand, Sean W; Forhead, Alison J

    2017-06-01

    Thyroid hormones are important regulators of growth and maturation before birth, although the extent to which their actions are mediated by insulin and the development of pancreatic beta cell mass is unknown. Hypothyroidism in fetal sheep induced by removal of the thyroid gland caused asymmetric organ growth, increased pancreatic beta cell mass and proliferation, and was associated with increased circulating concentrations of insulin and leptin. In isolated fetal sheep islets studied in vitro, thyroid hormones inhibited beta cell proliferation in a dose-dependent manner, while high concentrations of insulin and leptin stimulated proliferation. The developing pancreatic beta cell is therefore sensitive to thyroid hormone, insulin and leptin before birth, with possible consequences for pancreatic function in fetal and later life. The findings of this study highlight the importance of thyroid hormones during pregnancy for normal development of the fetal pancreas. Development of pancreatic beta cell mass before birth is essential for normal growth of the fetus and for long-term control of carbohydrate metabolism in postnatal life. Thyroid hormones are also important regulators of fetal growth, and the present study tested the hypotheses that thyroid hormones promote beta cell proliferation in the fetal ovine pancreatic islets, and that growth retardation in hypothyroid fetal sheep is associated with reductions in pancreatic beta cell mass and circulating insulin concentration in utero. Organ growth and pancreatic islet cell proliferation and mass were examined in sheep fetuses following removal of the thyroid gland in utero. The effects of triiodothyronine (T 3 ), insulin and leptin on beta cell proliferation rates were determined in isolated fetal ovine pancreatic islets in vitro. Hypothyroidism in the sheep fetus resulted in an asymmetric pattern of organ growth, pancreatic beta cell hyperplasia, and elevated plasma insulin and leptin concentrations. In pancreatic

  16. Bursting synchronization in scale-free networks

    International Nuclear Information System (INIS)

    Batista, C.A.S.; Batista, A.M.; Pontes, J.C.A. de; Lopes, S.R.; Viana, R.L.

    2009-01-01

    Neuronal networks in some areas of the brain cortex present the scale-free property, i.e., the neuron connectivity is distributed according to a power-law, such that neurons are more likely to couple with other already well-connected ones. Neuron activity presents two timescales, a fast one related to action-potential spiking, and a slow timescale in which bursting takes place. Some pathological conditions are related with the synchronization of the bursting activity in a weak sense, meaning the adjustment of the bursting phase due to coupling. Hence it has been proposed that an externally applied time-periodic signal be applied in order to control undesirable synchronized bursting rhythms. We investigated this kind of intervention using a two-dimensional map to describe neurons with spiking-bursting activity in a scale-free network.

  17. X-Ray Bursts from NGC 6652

    Science.gov (United States)

    Morgan, Edward

    The possibly transient X-ray Source in the globular cluster NGC 6652 has been seen by BeppoSax and the ASM on RXTE to undergo X-ray bursts, possibly Type I. Very little is known about this X-ray source, and confirmation of its bursts type-I nature would identify it as a neutron star binary. Type I bursts in 6 other sources have been shown to exhibit intervals of millisecond ocsillation that most likely indicate the neutron star spin period. Radius-expansion bursts can reveal information about the mass and size of the neutron star. We propose to use the ASM to trigger an observation of this source to maximize the probability of catching a burst in the PCA.

  18. The effect of the deterioration of insulin sensitivity on beta-cell function in growth-hormone-deficient adults following 4-month growth hormone replacement therapy

    DEFF Research Database (Denmark)

    Rosenfalck, A M; Fisker, S; Hilsted, J

    1999-01-01

    The purpose of the present study was to evaluate the combined effect of GH treatment on body composition and glucose metabolism, with special focus on beta-cell function in adult GHD patients. In a double-blind placebo-controlled design, 24 GHD adults (18M/6F), were randomized to 4 months treatment...... with biosynthetic GH 2 IU/m2s.c. daily (n =13) or placebo (n =11). At inclusion and 4 months later an oral glucose tolerance test (OGTT), a frequently sampled intravenous glucose tolerance test (FSIGT) and dual-energy X-ray absorptiometry (DXA) whole-body scanning were performed. During the study period, body...

  19. In silico identification of NF-kappaB-regulated genes in pancreatic beta-cells

    Directory of Open Access Journals (Sweden)

    Eizirik Decio L

    2007-02-01

    Full Text Available Abstract Background Pancreatic beta-cells are the target of an autoimmune attack in type 1 diabetes mellitus (T1DM. This is mediated in part by cytokines, such as interleukin (IL-1β and interferon (IFN-γ. These cytokines modify the expression of hundreds of genes, leading to beta-cell dysfunction and death by apoptosis. Several of these cytokine-induced genes are potentially regulated by the IL-1β-activated transcription factor (TF nuclear factor (NF-κB, and previous studies by our group have shown that cytokine-induced NF-κB activation is pro-apoptotic in beta-cells. To identify NF-κB-regulated gene networks in beta-cells we presently used a discriminant analysis-based approach to predict NF-κB responding genes on the basis of putative regulatory elements. Results The performance of linear and quadratic discriminant analysis (LDA, QDA in identifying NF-κB-responding genes was examined on a dataset of 240 positive and negative examples of NF-κB regulation, using stratified cross-validation with an internal leave-one-out cross-validation (LOOCV loop for automated feature selection and noise reduction. LDA performed slightly better than QDA, achieving 61% sensitivity, 91% specificity and 87% positive predictive value, and allowing the identification of 231, 251 and 580 NF-κB putative target genes in insulin-producing INS-1E cells, primary rat beta-cells and human pancreatic islets, respectively. Predicted NF-κB targets had a significant enrichment in genes regulated by cytokines (IL-1β or IL-1β + IFN-γ and double stranded RNA (dsRNA, as compared to genes not regulated by these NF-κB-dependent stimuli. We increased the confidence of the predictions by selecting only evolutionary stable genes, i.e. genes with homologs predicted as NF-κB targets in rat, mouse, human and chimpanzee. Conclusion The present in silico analysis allowed us to identify novel regulatory targets of NF-κB using a supervised classification method based on

  20. Early peroxisome proliferator-activated receptor gamma regulated genes involved in expansion of pancreatic beta cell mass

    Directory of Open Access Journals (Sweden)

    Vivas Yurena

    2011-12-01

    Full Text Available Abstract Background The progression towards type 2 diabetes depends on the allostatic response of pancreatic beta cells to synthesise and secrete enough insulin to compensate for insulin resistance. The endocrine pancreas is a plastic tissue able to expand or regress in response to the requirements imposed by physiological and pathophysiological states associated to insulin resistance such as pregnancy, obesity or ageing, but the mechanisms mediating beta cell mass expansion in these scenarios are not well defined. We have recently shown that ob/ob mice with genetic ablation of PPARγ2, a mouse model known as the POKO mouse failed to expand its beta cell mass. This phenotype contrasted with the appropriate expansion of the beta cell mass observed in their obese littermate ob/ob mice. Thus, comparison of these models islets particularly at early ages could provide some new insights on early PPARγ dependent transcriptional responses involved in the process of beta cell mass expansion Results Here we have investigated PPARγ dependent transcriptional responses occurring during the early stages of beta cell adaptation to insulin resistance in wild type, ob/ob, PPARγ2 KO and POKO mice. We have identified genes known to regulate both the rate of proliferation and the survival signals of beta cells. Moreover we have also identified new pathways induced in ob/ob islets that remained unchanged in POKO islets, suggesting an important role for PPARγ in maintenance/activation of mechanisms essential for the continued function of the beta cell. Conclusions Our data suggest that the expansion of beta cell mass observed in ob/ob islets is associated with the activation of an immune response that fails to occur in POKO islets. We have also indentified other PPARγ dependent differentially regulated pathways including cholesterol biosynthesis, apoptosis through TGF-β signaling and decreased oxidative phosphorylation.

  1. Beneficial Effect of Jojoba Seed Extracts on Hyperglycemia-Induced Oxidative Stress in RINm5f Beta Cells.

    Science.gov (United States)

    Belhadj, Sahla; Hentati, Olfa; Hamdaoui, Ghaith; Fakhreddine, Khaskhoussi; Maillard, Elisa; Dal, Stéphanie; Sigrist, Séverine

    2018-03-20

    Hyperglycemia occurs during diabetes and insulin resistance. It causes oxidative stress by increasing reactive oxygen species (ROS) levels, leading to cellular damage. Polyphenols play a central role in defense against oxidative stress. In our study, we investigated the antioxidant properties of simmondsin, a pure molecule present in jojoba seeds, and of the aqueous extract of jojoba seeds on fructose-induced oxidative stress in RINm5f beta cells. The exposure of RINm5f beta cells to fructose triggered the loss of cell viability (-48%, p jojoba seed extract makes jojoba a powerful agent to prevent the destruction of RINm5f beta cells induced by hyperglycemia.

  2. Characterization of GLP-1 effects on beta-cell function after meal ingestion in humans

    DEFF Research Database (Denmark)

    Ahrén, Bo; Holst, Jens Juul; Mari, Andrea

    2003-01-01

    OBJECTIVE: Glucagon-like peptide 1 (GLP-1) is an incretin that augments insulin secretion after meal intake and is developed for treatment of type 2 diabetes. As a novel therapeutic agent, characteristics of its beta-cell effects are important to establish. Previously, beta-cell effects of GLP-1...... have been characterized in humans during graded intravenous infusions of glucose, whereas its effects after more physiological stimuli, like meal intake, are not known. RESEARCH DESIGN AND METHODS: Eight women (aged 69 years, fasting glucose 3.7-10.3 mmol/l, BMI 22.4-43.9 kg/m(2)) who had fasted...... meal augments insulin secretion in humans by a dose...

  3. Targeting dysfunctional beta-cell signaling for the potential treatment of type 1 diabetes mellitus.

    Science.gov (United States)

    Fenske, Rachel J; Kimple, Michelle E

    2018-03-01

    Since its discovery and purification by Frederick Banting in 1921, exogenous insulin has remained almost the sole therapy for type 1 diabetes mellitus. While insulin alleviates the primary dysfunction of the disease, many other aspects of the pathophysiology of type 1 diabetes mellitus are unaffected. Research aimed towards the discovery of novel type 1 diabetes mellitus therapeutics targeting different cell signaling pathways is gaining momentum. The focus of these efforts has been almost entirely on the impact of immunomodulatory drugs, particularly those that have already received FDA-approval for other autoimmune diseases. However, these drugs can often have severe side effects, while also putting already immunocompromised individuals at an increased risk for other infections. Potential therapeutic targets in the insulin-producing beta-cell have been largely ignored by the type 1 diabetes mellitus field, save the glucagon-like peptide 1 receptor. While there is preliminary evidence to support the clinical exploration of glucagon-like peptide 1 receptor-based drugs as type 1 diabetes mellitus adjuvant therapeutics, there is a vast space for other putative therapeutic targets to be explored. The alpha subunit of the heterotrimeric G z protein (Gα z ) has been shown to promote beta-cell inflammation, dysfunction, death, and failure to replicate in the context of diabetes in a number of mouse models. Genetic loss of Gα z or inhibition of the Gα z signaling pathway through dietary interventions is protective against the development of insulitis and hyperglycemia. The multifaceted effects of Gα z in regards to beta-cell health in the context of diabetes make it an ideal therapeutic target for further study. It is our belief that a low-risk, effective therapy for type 1 diabetes mellitus will involve a multidimensional approach targeting a number of regulatory systems, not the least of which is the insulin-producing beta-cell. Impact statement The expanding

  4. Glucose-induced lipogenesis in pancreatic beta-cells is dependent on SREBP-1

    DEFF Research Database (Denmark)

    Sandberg, Maria B; Fridriksson, Jakob; Madsen, Lise

    2005-01-01

    High concentrations of glucose induce de novo fatty acid synthesis in pancreatic beta-cells and chronic exposure of elevated glucose and fatty acids synergize to induce accumulation of triglycerides, a phenomenon termed glucolipotoxicity. Here we investigate the role of sterol-regulatory element......, de novo fatty acid synthesis and lipid accumulation are induced primarily through sterol-regulatory elements (SREs) and not E-Boxes. Adenoviral expression of a dominant negative SREBP compromises glucose induction of some lipogenic genes and significantly reduces glucose-induction of de novo fatty...... acid synthesis. Thus, we demonstrate for the first time that SREBP activity is necessary for full glucose induction of de novo fatty acid synthesis in pancreatic beta-cells....

  5. The Importance of REST for Development and Function of Beta Cells

    DEFF Research Database (Denmark)

    Martin, David; Grapin-Botton, Anne

    2017-01-01

    that are crucial for both neuronal and pancreatic endocrine function, through the recruitment of multiple transcriptional and epigenetic co-regulators. REST targets include genes encoding transcription factors, proteins involved in exocytosis, synaptic transmission or ion channeling, and non-coding RNAs. REST......Beta cells are defined by the genes they express, many of which are specific to this cell type, and ensure a specific set of functions. Beta cells are also defined by a set of genes they should not express (in order to function properly), and these genes have been called forbidden genes. Among...... these, the transcriptional repressor RE-1 Silencing Transcription factor (REST) is expressed in most cells of the body, excluding most populations of neurons, as well as pancreatic beta and alpha cells. In the cell types where it is expressed, REST represses the expression of hundreds of genes...

  6. Dual role of proapoptotic BAD in insulin secretion and beta cell survival

    OpenAIRE

    Danial, Nika N.; Walensky, Loren D.; Zhang, Chen-Yu; Choi, Cheol Soo; Fisher, Jill K.; Molina, Anthony J. A.; Datta, Sandeep Robert; Pitter, Kenneth L.; Bird, Gregory H.; Wikstrom, Jakob D.; Deeney, Jude T.; Robertson, Kirsten; Morash, Joel; Kulkarni, Ameya; Neschen, Susanne

    2008-01-01

    The proapoptotic BCL-2 family member BAD resides in a glucokinase-containing complex that regulates glucose-driven mitochondrial respiration. Here, we present genetic evidence of a physiologic role for BAD in glucose-stimulated insulin secretion by beta cells. This novel function of BAD is specifically dependent upon the phosphorylation of its BH3 sequence, previously defined as an essential death domain. We highlight the pharmacologic relevance of phosphorylated BAD BH3 by using cell-permeab...

  7. Reference intervals for glucose, beta-cell polypeptides and counterregulatory factors during prolonged fasting

    DEFF Research Database (Denmark)

    Højlund, Kurt; Wildner-Christensen, M; Eshøj, O

    2001-01-01

    To establish reference intervals for the pancreatic beta-cell response and the counterregulatory hormone response to prolonged fasting, we studied 33 healthy subjects (16 males, 17 females) during a 72-h fast. Glucose, insulin, C-peptide, and proinsulin levels decreased (P ... of counterregulatory factors increased during the fast [P fasting (P ... decreased from the second to third day of fasting (P = 0.03). Males had higher glucose and glucagon levels and lower FFA levels during the fast (P

  8. Intracellular serotonin modulates insulin secretion from pancreatic beta-cells by protein serotonylation.

    Directory of Open Access Journals (Sweden)

    Nils Paulmann

    2009-10-01

    Full Text Available While serotonin (5-HT co-localization with insulin in granules of pancreatic beta-cells was demonstrated more than three decades ago, its physiological role in the etiology of diabetes is still unclear. We combined biochemical and electrophysiological analyses of mice selectively deficient in peripheral tryptophan hydroxylase (Tph1-/- and 5-HT to show that intracellular 5-HT regulates insulin secretion. We found that these mice are diabetic and have an impaired insulin secretion due to the lack of 5-HT in the pancreas. The pharmacological restoration of peripheral 5-HT levels rescued the impaired insulin secretion in vivo. These findings were further evidenced by patch clamp experiments with isolated Tph1-/- beta-cells, which clearly showed that the secretory defect is downstream of Ca(2+-signaling and can be rescued by direct intracellular application of 5-HT via the clamp pipette. In elucidating the underlying mechanism further, we demonstrate the covalent coupling of 5-HT by transglutaminases during insulin exocytosis to two key players in insulin secretion, the small GTPases Rab3a and Rab27a. This renders them constitutively active in a receptor-independent signaling mechanism we have recently termed serotonylation. Concordantly, an inhibition of such activating serotonylation in beta-cells abates insulin secretion. We also observed inactivation of serotonylated Rab3a by enhanced proteasomal degradation, which is in line with the inactivation of other serotonylated GTPases. Our results demonstrate that 5-HT regulates insulin secretion by serotonylation of GTPases within pancreatic beta-cells and suggest that intracellular 5-HT functions in various microenvironments via this mechanism in concert with the known receptor-mediated signaling.

  9. Glucocorticoids Inhibit Basal and Hormone-Induced Serotonin Synthesis in Pancreatic Beta Cells.

    Directory of Open Access Journals (Sweden)

    Moina Hasni Ebou

    Full Text Available Diabetes is a major complication of chronic Glucocorticoids (GCs treatment. GCs induce insulin resistance and also inhibit insulin secretion from pancreatic beta cells. Yet, a full understanding of this negative regulation remains to be deciphered. In the present study, we investigated whether GCs could inhibit serotonin synthesis in beta cell since this neurotransmitter has been shown to be involved in the regulation of insulin secretion. To this aim, serotonin synthesis was evaluated in vitro after treatment with GCs of either islets from CD1 mice or MIN6 cells, a beta-cell line. We also explored the effect of GCs on the stimulation of serotonin synthesis by several hormones such as prolactin and GLP 1. We finally studied this regulation in islet in two in vivo models: mice treated with GCs and with liraglutide, a GLP1 analog, and mice deleted for the glucocorticoid receptor in the pancreas. We showed in isolated islets and MIN6 cells that GCs decreased expression and activity of the two key enzymes of serotonin synthesis, Tryptophan Hydroxylase 1 (Tph1 and 2 (Tph2, leading to reduced serotonin contents. GCs also blocked the induction of serotonin synthesis by prolactin or by a previously unknown serotonin activator, the GLP-1 analog exendin-4. In vivo, activation of the Glucagon-like-Peptide-1 receptor with liraglutide during 4 weeks increased islet serotonin contents and GCs treatment prevented this increase. Finally, islets from mice deleted for the GR in the pancreas displayed an increased expression of Tph1 and Tph2 and a strong increased serotonin content per islet. In conclusion, our results demonstrate an original inhibition of serotonin synthesis by GCs, both in basal condition and after stimulation by prolactin or activators of the GLP-1 receptor. This regulation may contribute to the deleterious effects of GCs on beta cells.

  10. Calcium Co-regulates Oxidative Metabolism and ATP Synthase-dependent Respiration in Pancreatic Beta Cells

    Science.gov (United States)

    De Marchi, Umberto; Thevenet, Jonathan; Hermant, Aurelie; Dioum, Elhadji; Wiederkehr, Andreas

    2014-01-01

    Mitochondrial energy metabolism is essential for glucose-induced calcium signaling and, therefore, insulin granule exocytosis in pancreatic beta cells. Calcium signals are sensed by mitochondria acting in concert with mitochondrial substrates for the full activation of the organelle. Here we have studied glucose-induced calcium signaling and energy metabolism in INS-1E insulinoma cells and human islet beta cells. In insulin secreting cells a surprisingly large fraction of total respiration under resting conditions is ATP synthase-independent. We observe that ATP synthase-dependent respiration is markedly increased after glucose stimulation. Glucose also causes a very rapid elevation of oxidative metabolism as was followed by NAD(P)H autofluorescence. However, neither the rate of the glucose-induced increase nor the new steady-state NAD(P)H levels are significantly affected by calcium. Our findings challenge the current view, which has focused mainly on calcium-sensitive dehydrogenases as the target for the activation of mitochondrial energy metabolism. We propose a model of tight calcium-dependent regulation of oxidative metabolism and ATP synthase-dependent respiration in beta cell mitochondria. Coordinated activation of matrix dehydrogenases and respiratory chain activity by calcium allows the respiratory rate to change severalfold with only small or no alterations of the NAD(P)H/NAD(P)+ ratio. PMID:24554722

  11. Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic beta cells.

    Directory of Open Access Journals (Sweden)

    Laura Bordone

    2006-02-01

    Full Text Available Sir2 and insulin/IGF-1 are the major pathways that impinge upon aging in lower organisms. In Caenorhabditis elegans a possible genetic link between Sir2 and the insulin/IGF-1 pathway has been reported. Here we investigate such a link in mammals. We show that Sirt1 positively regulates insulin secretion in pancreatic beta cells. Sirt1 represses the uncoupling protein (UCP gene UCP2 by binding directly to the UCP2 promoter. In beta cell lines in which Sirt1 is reduced by SiRNA, UCP2 levels are elevated and insulin secretion is blunted. The up-regulation of UCP2 is associated with a failure of cells to increase ATP levels after glucose stimulation. Knockdown of UCP2 restores the ability to secrete insulin in cells with reduced Sirt1, showing that UCP2 causes the defect in glucose-stimulated insulin secretion. Food deprivation induces UCP2 in mouse pancreas, which may occur via a reduction in NAD (a derivative of niacin levels in the pancreas and down-regulation of Sirt1. Sirt1 knockout mice display constitutively high UCP2 expression. Our findings show that Sirt1 regulates UCP2 in beta cells to affect insulin secretion.

  12. Early-Life Origins of Type 2 Diabetes: Fetal Programming of the Beta-Cell Mass

    Directory of Open Access Journals (Sweden)

    Bernard Portha

    2011-01-01

    Full Text Available A substantial body of evidence suggests that an abnormal intrauterine milieu elicited by maternal metabolic disturbances as diverse as undernutrition, placental insufficiency, diabetes or obesity, may program susceptibility in the fetus to later develop chronic degenerative diseases, such as obesity, hypertension, cardiovascular diseases and diabetes. This paper examines the developmental programming of glucose intolerance/diabetes by disturbed intrauterine metabolic condition experimentally obtained in various rodent models of maternal protein restriction, caloric restriction, overnutrition or diabetes, with a focus on the alteration of the developing beta-cell mass. In most of the cases, whatever the type of initial maternal metabolic stress, the beta-cell adaptive growth which normally occurs during gestation, does not take place in the pregnant offspring and this results in the development of gestational diabetes. Therefore gestational diabetes turns to be the ultimate insult targeting the offspring beta-cell mass and propagates diabetes risk to the next generation again. The aetiology and the transmission of spontaneous diabetes as encountered in the GK/Par rat model of type 2 diabetes, are discussed in such a perspective. This review also discusses the non-genomic mechanisms involved in the installation of the programmed effect as well as in its intergenerational transmission.

  13. Imatinib prevents beta cell death in vitro but does not improve islet transplantation outcome.

    Science.gov (United States)

    King, Aileen J F; Griffiths, Lisa A; Persaud, Shanta J; Jones, Peter M; Howell, Simon L; Welsh, Nils

    2016-05-01

    Introduction Improving islet transplantation outcome could not only bring benefits to individual patients but also widen the patient pool to which this life-changing treatment is available. Imatinib has previously been shown to protect beta cells from apoptosis in a variety of in vitro and in vivo models. The aim of this study was to investigate whether imatinib could be used to improve islet transplantation outcome. Methods Islets were isolated from C57Bl/6 mice and pre-cultured with imatinib prior to exposure to streptozotocin and cytokines in vitro. Cell viability and glucose-induced insulin secretion were measured. For transplantation experiments, islets were pre-cultured with imatinib for either 72 h or 24 h prior to transplantation into streptozotocin-diabetic C57Bl/6 mice. In one experimental series mice were also administered imatinib after islet transplantation. Results Imatinib partially protected islets from beta cell death in vitro. However, pre-culturing islets in imatinib or administering the drug to the mice in the days following islet transplantation did not improve blood glucose concentrations more than control-cultured islets. Conclusion Although imatinib protected against beta cell death from cytokines and streptozotocin in vitro, it did not significantly improve syngeneic islet transplantation outcome.

  14. Vanadyl Sulfate Treatment Stimulates Proliferation and Regeneration of Beta Cells in Pancreatic Islets

    Directory of Open Access Journals (Sweden)

    Samira Missaoui

    2014-01-01

    Full Text Available We examined the effects of vanadium sulfate (VOSO4 treatment at 5 and 10 mg/kg for 30 days on endocrine pancreas activity and histology in nondiabetic and STZ-induced diabetic rats. In diabetic group, blood glucose levels significantly increased while insulinemia level markedly decreased. At the end of treatment, VOSO4 at a dose of 10 mg/Kg normalized blood glucose level in diabetic group, restored insulinemia, and significantly improved insulin sensitivity. VOSO4 also increased in a dose-dependent manner the number of insulin immunopositive beta cells in pancreatic islets of nondiabetic rats. Furthermore, in the STZ-diabetic group, the decrease in the number of insulin immunopositive beta cells was corrected to reach the control level mainly with the higher dose of vanadium. Therefore, VOSO4 treatment normalized plasma glucose and insulin levels and improved insulin sensitivity in STZ-experimental diabetes and induced beta cells proliferation and/or regeneration in normal or diabetic rats.

  15. The Drift Burst Hypothesis

    OpenAIRE

    Christensen, Kim; Oomen, Roel; Renò, Roberto

    2016-01-01

    The Drift Burst Hypothesis postulates the existence of short-lived locally explosive trends in the price paths of financial assets. The recent US equity and Treasury flash crashes can be viewed as two high profile manifestations of such dynamics, but we argue that drift bursts of varying magnitude are an expected and regular occurrence in financial markets that can arise through established mechanisms such as feedback trading. At a theoretical level, we show how to build drift bursts into the...

  16. SIRT6-mediated transcriptional suppression of Txnip is critical for pancreatic beta cell function and survival in mice.

    Science.gov (United States)

    Qin, Kunhua; Zhang, Ning; Zhang, Zhao; Nipper, Michael; Zhu, Zhenxin; Leighton, Jake; Xu, Kexin; Musi, Nicolas; Wang, Pei

    2018-04-01

    Better understanding of how genetic and epigenetic components control beta cell differentiation and function is key to the discovery of novel therapeutic approaches to prevent beta cell dysfunction and failure in the progression of type 2 diabetes. Our goal was to elucidate the role of histone deacetylase sirtuin 6 (SIRT6) in beta cell development and homeostasis. Sirt6 endocrine progenitor cell conditional knockout and beta cell-specific knockout mice were generated using the Cre-loxP system. Mice were assayed for islet morphology, glucose tolerance, glucose-stimulated insulin secretion and susceptibility to streptozotocin. Transcriptional regulatory functions of SIRT6 in primary islets were evaluated by RNA-Seq analysis. Reverse transcription-quantitative (RT-q)PCR and immunoblot were used to verify and investigate the gene expression changes. Chromatin occupancies of SIRT6, H3K9Ac, H3K56Ac and active RNA polymerase II were evaluated by chromatin immunoprecipitation. Deletion of Sirt6 in pancreatic endocrine progenitor cells did not affect endocrine morphology, beta cell mass or insulin production but did result in glucose intolerance and defective glucose-stimulated insulin secretion in mice. Conditional deletion of Sirt6 in adult beta cells reproduced the insulin secretion defect. Loss of Sirt6 resulted in aberrant upregulation of thioredoxin-interacting protein (TXNIP) in beta cells. SIRT6 deficiency led to increased acetylation of histone H3 lysine residue at 9 (H3K9Ac), acetylation of histone H3 lysine residue at 56 (H3K56Ac) and active RNA polymerase II at the promoter region of Txnip. SIRT6-deficient beta cells exhibited a time-dependent increase in H3K9Ac, H3K56Ac and TXNIP levels. Finally, beta cell-specific SIRT6-deficient mice showed increased sensitivity to streptozotocin. Our results reveal that SIRT6 suppresses Txnip expression in beta cells via deacetylation of histone H3 and plays a critical role in maintaining beta cell function and viability

  17. CISH has no non-redundant functions in glucose homeostasis or beta cell proliferation during pregnancy in mice.

    Science.gov (United States)

    Jiao, Yang; Rieck, Sebastian; Le Lay, John; Kaestner, Klaus H

    2013-11-01

    Increased beta cell proliferation during pregnancy is mediated by the Janus kinase 2/signal transducer and activator of transcription 5 (JAK2/STAT5) signalling pathway in response to increased lactogen levels. Activation of the pathway leads to transcriptional upregulation of Cish (encoding cytokine-inducible SH2 domain-containing protein), a member of the suppressor of cytokine signalling (SOCS) family of genes, forming a negative-feedback loop. Here, we examined whether conditional gene ablation of Cish in the pancreas improves beta cell proliferation and beta cell function during pregnancy in mice. We derived mice with a novel, conditional loxP allele for Cish. Pancreas-specific ablation of Cish was achieved by crossing Cish (loxP/loxP) mice with Pdx1-Cre (Early) mice. Beta cell proliferation was quantified by BrdU labelling. Glucose homeostasis was examined with glucose tolerance tests and determination of plasma insulin levels. The expression of other Socs genes and target genes of p-STAT5 related to beta cell function and beta cell proliferation was determined by quantitative PCR. There was no difference in beta cell proliferation or glucose homeostasis between the Cish mutant group and the control group. The p-STAT5 protein level was the same in Cish mutant and control mice. Socs2 gene expression was higher in Cish mutant than control mice at pregnancy day 9.5. The expression of other Socs genes was the same between control and mutant mice. Our results show that CISH has no non-redundant functions in beta cell proliferation or glucose homeostasis during pregnancy in mice. Socs2 might compensate for the loss of Cish during pregnancy.

  18. Islet autoantibodies and residual beta cell function in type 1 diabetes children followed for 3-6 years

    DEFF Research Database (Denmark)

    Sørensen, Jesper Sand; Vaziri-Sani, Fariba; Maziarz, M

    2012-01-01

    To test if islet autoantibodies at diagnosis of type 1 diabetes (T1DM) and after 3-6 years with T1D predict residual beta-cell function (RBF) after 3-6 years with T1D.......To test if islet autoantibodies at diagnosis of type 1 diabetes (T1DM) and after 3-6 years with T1D predict residual beta-cell function (RBF) after 3-6 years with T1D....

  19. [Factors causing damage and destruction of beta-cells of the islets of Langerhans in the pancreas].

    Science.gov (United States)

    Anděl, Michal; Němcová, Vlasta; Pavlíková, Nela; Urbanová, Jana; Cecháková, Marie; Havlová, Andrea; Straková, Radka; Večeřová, Livia; Mandys, Václav; Kovář, Jan; Heneberg, Petr; Trnka, Jan; Polák, Jan

    2014-09-01

    Insulin secretion in patients with manifested diabetes mellitus tends to disappear months to decades after the diagnosis, which is a clear sign of a gradual loss of pancreatic islet beta-cells. In our sample of 30 type 2 diabetic patients, whose disease manifested between 30 and 45 years of age, about a half have retained or even increased insulin secretion 30 years later, while the other half exhibit a much diminished or lost insulin secretion. Factors that can damage or destroy beta-cells can be divided into the following groups: Metabolic factors: hyperglycemia and glucotoxicity, lipotoxicity, hypoxia, reactive oxygen species; Pharmacological factors: antimicrobial medication pentamidine, SSRI antidepressants; Factors related to impaired insulin secretion: MODY type diabetes; Environmental toxic factors: rat poison Vacor, streptozotocin, polychlorinated and polybrominated hydrocarbons; Disorders of the exocrine pancreas: tumor infiltration, fibrous infiltration, chronic pancreatitis, cystic fibrosis; Infections, inflammation, autoimmunity, viral factors: Coxsackie viruses, H1N1 influenza, enteroviruses. We are currently working on finding other factors leading to beta-cell damage, studying their effect on apoptosis and necrosis and looking for possible protective factors to prevent this damage. We our increasing knowledge about the mechanisms of beta-cell damage and destruction we come ever closer to suggest measures for their prevention. In this review we offer a brief and simplified summary of some of the findings related to this area.Key words: pancreatic islet beta-cells of Langerhans - factors damaging or destroying beta-cells - insulin secretion.

  20. Increased androgen levels in rats impair glucose-stimulated insulin secretion through disruption of pancreatic beta cell mitochondrial function.

    Science.gov (United States)

    Wang, Hongdong; Wang, Xiaping; Zhu, Yunxia; Chen, Fang; Sun, Yujie; Han, Xiao

    2015-11-01

    Although insulin resistance is recognized to contribute to the reproductive and metabolic phenotypes of polycystic ovary syndrome (PCOS), pancreatic beta cell dysfunction plays an essential role in the progression from PCOS to the development of type 2 diabetes. However, the role of insulin secretory abnormalities in PCOS has received little attention. In addition, the precise changes in beta cells and the underlying mechanisms remain unclear. In this study, we therefore attempted to elucidate potential mechanisms involved in beta cell alterations in a rat model of PCOS. Glucose-induced insulin secretion was measured in islets isolated from DHT-treated and control rats. Oxygen consumption rate (OCR), ATP production, and mitochondrial copy number were assayed to evaluate mitochondrial function. Glucose-stimulated insulin secretion is significantly decreased in islets from DHT-treated rats. On the other hand, significant reductions are observed in the expression levels of several key genes involved in mitochondrial biogenesis and in mitochondrial OCR and ATP production in DHT-treated rat islets. Meanwhile, we found that androgens can directly impair beta cell function by inducing mitochondrial dysfunction in vitro in an androgen receptor dependent manner. For the first time, our study demonstrates that increased androgens in female rats can impair glucose-stimulated insulin secretion partly through disruption of pancreatic beta cell mitochondrial function. This work has significance for hyperandrogenic women with PCOS: excess activation of the androgen receptor by androgens may provoke beta cell dysfunction via mitochondrial dysfunction. Copyright © 2015 Elsevier Ltd. All rights reserved.

  1. Solar energetic particles and radio burst emission

    Directory of Open Access Journals (Sweden)

    Miteva Rositsa

    2017-01-01

    Full Text Available We present a statistical study on the observed solar radio burst emission associated with the origin of in situ detected solar energetic particles. Several proton event catalogs in the period 1996–2016 are used. At the time of appearance of the particle origin (flare and coronal mass ejection we identified radio burst signatures of types II, III and IV by inspecting dynamic radio spectral plots. The information from observatory reports is also accounted for during the analysis. The occurrence of solar radio burst signatures is evaluated within selected wavelength ranges during the solar cycle 23 and the ongoing 24. Finally, we present the burst occurrence trends with respect to the intensity of the proton events and the location of their solar origin.

  2. Chaperones ameliorate beta cell dysfunction associated with human islet amyloid polypeptide overexpression.

    Directory of Open Access Journals (Sweden)

    Lisa Cadavez

    Full Text Available In type 2 diabetes, beta-cell dysfunction is thought to be due to several causes, one being the formation of toxic protein aggregates called islet amyloid, formed by accumulations of misfolded human islet amyloid polypeptide (hIAPP. The process of hIAPP misfolding and aggregation is one of the factors that may activate the unfolded protein response (UPR, perturbing endoplasmic reticulum (ER homeostasis. Molecular chaperones have been described to be important in regulating ER response to ER stress. In the present work, we evaluate the role of chaperones in a stressed cellular model of hIAPP overexpression. A rat pancreatic beta-cell line expressing hIAPP exposed to thapsigargin or treated with high glucose and palmitic acid, both of which are known ER stress inducers, showed an increase in ER stress genes when compared to INS1E cells expressing rat IAPP or INS1E control cells. Treatment with molecular chaperone glucose-regulated protein 78 kDa (GRP78, also known as BiP or protein disulfite isomerase (PDI, and chemical chaperones taurine-conjugated ursodeoxycholic acid (TUDCA or 4-phenylbutyrate (PBA, alleviated ER stress and increased insulin secretion in hIAPP-expressing cells. Our results suggest that the overexpression of hIAPP induces a stronger response of ER stress markers. Moreover, endogenous and chemical chaperones are able to ameliorate induced ER stress and increase insulin secretion, suggesting that improving chaperone capacity can play an important role in improving beta-cell function in type 2 diabetes.

  3. Lactate overrides central nervous but not beta-cell glucose sensing in humans.

    Science.gov (United States)

    Schmid, Sebastian M; Jauch-Chara, Kamila; Hallschmid, Manfred; Oltmanns, Kerstin M; Peters, Achim; Born, Jan; Schultes, Bernd

    2008-12-01

    Lactate has been shown to serve as an alternative energy substrate in the central nervous system and to interact with hypothalamic glucose sensors. On the background of marked similarities between central nervous and beta-cell glucose sensing, we examined whether lactate also interacts with pancreatic glucose-sensing mechanisms in vivo. The effects of intravenously infused lactate vs placebo (saline) on central nervous and pancreatic glucose sensing were assessed during euglycemic and hypoglycemic clamp experiments in 10 healthy men. The release of neuroendocrine counterregulatory hormones during hypoglycemia was considered to reflect central nervous glucose sensing, whereas endogenous insulin secretion as assessed by serum C-peptide levels served as an indicator of pancreatic beta-cell glucose sensing. Lactate infusion blunted the counterregulatory hormonal responses to hypoglycemia, in particular, the release of epinephrine (P = .007) and growth hormone (P = .004), so that higher glucose infusion rates (P = .012) were required to maintain the target blood glucose levels. In contrast, the decrease in C-peptide concentrations during the hypoglycemic clamp remained completely unaffected by lactate (P = .60). During euglycemic clamp conditions, lactate infusion did not affect the concentrations of C-peptide and of counterregulatory hormones, with the exception of norepinephrine levels that were lower during lactate than saline infusion (P = .049) independently of the glycemic condition. Data indicate that glucose sensing of beta-cells is specific to glucose, whereas glucose sensing at the central nervous level can be overridden by lactate, reflecting the brain's ability to rely on lactate as an alternative major energy source.

  4. Expression of transient receptor potential ankyrin 1 (TRPA1 and its role in insulin release from rat pancreatic beta cells.

    Directory of Open Access Journals (Sweden)

    De-Shou Cao

    Full Text Available Several transient receptor potential (TRP channels are expressed in pancreatic beta cells and have been proposed to be involved in insulin secretion. However, the endogenous ligands for these channels are far from clear. Here, we demonstrate the expression of the transient receptor potential ankyrin 1 (TRPA1 ion channel in the pancreatic beta cells and its role in insulin release. TRPA1 is an attractive candidate for inducing insulin release because it is calcium permeable and is activated by molecules that are produced during oxidative glycolysis.Immunohistochemistry, RT-PCR, and Western blot techniques were used to determine the expression of TRPA1 channel. Ca²⁺ fluorescence imaging and electrophysiology (voltage- and current-clamp techniques were used to study the channel properties. TRPA1-mediated insulin release was determined using ELISA.TRPA1 is abundantly expressed in a rat pancreatic beta cell line and freshly isolated rat pancreatic beta cells, but not in pancreatic alpha cells. Activation of TRPA1 by allyl isothiocyanate (AITC, hydrogen peroxide (H₂O₂, 4-hydroxynonenal (4-HNE, and cyclopentenone prostaglandins (PGJ₂ and a novel agonist methylglyoxal (MG induces membrane current, depolarization, and Ca²⁺ influx leading to generation of action potentials in a pancreatic beta cell line and primary cultured pancreatic beta cells. Activation of TRPA1 by agonists stimulates insulin release in pancreatic beta cells that can be inhibited by TRPA1 antagonists such as HC030031 or AP-18 and by RNA interference. TRPA1-mediated insulin release is also observed in conditions of voltage-gated Na⁺ and Ca²⁺ channel blockade as well as ATP sensitive potassium (K(ATP channel activation.We propose that endogenous and exogenous ligands of TRPA1 cause Ca²⁺ influx and induce basal insulin release and that TRPA1-mediated depolarization acts synergistically with K(ATP channel blockade to facilitate insulin release.

  5. Multilayer network representation of membrane potential and cytosolic calcium concentration dynamics in beta cells

    International Nuclear Information System (INIS)

    Gosak, Marko; Dolenšek, Jurij; Markovič, Rene; Slak Rupnik, Marjan; Marhl, Marko; Stožer, Andraž

    2015-01-01

    Highlights: • Physiological processes within and among pancreatic beta cells are very complex. • We analyze the simultaneous recordings of membrane potential and calcium dynamics. • We represent the interaction patterns among beta cells as a multilayer network. • The nature of the intracellular dynamics is found to rely on the network structure. - Abstract: Modern theory of networks has been recognized as a very successful methodological concept for the description and analysis of complex systems. However, some complex systems are more complex than others. For instance, several real-life systems are constituted by interdependent subsystems and their elements are subjected to different types of interactions that can also change with time. Recently, the multilayer network formalism has been proposed as a general theoretical framework for the description and analysis of such multi-dimensional complex systems and is acquiring more and more prominence in terms of a new research direction. In the present study, we use this methodology for the description of functional connectivity patterns and signal propagation between pancreatic beta cells in an islet of Langerhans at the levels of membrane potential (MP) and cytosolic calcium concentration ([Ca"2"+]_c) dynamics to study the extent of overlap in the two networks and to clarify whether time lags between the two signals in individual cells are in any way dependent on the role these cells play in the functional networks. The two corresponding network layers are constructed on the basis of signal directions and pairwise correlations, whereas the interlayer connections represent the time lag between both measured signals. Our results confirm our previous finding that both MP and [Ca"2"+]_c change spread across an islet in the form of a depolarization and a [Ca"2"+]_c wave, respectively. Both types of waves follow nearly the same path and the networks in both layers have a similar but not entirely the same structure

  6. Antioxidant and regulatory role of mitochondrial uncoupling protein UCP2 in pancreatic beta-cells

    Czech Academy of Sciences Publication Activity Database

    Ježek, Petr; Olejár, Tomáš; Smolková, Katarína; Ježek, Jan; Dlasková, Andrea; Plecitá-Hlavatá, Lydie; Zelenka, Jaroslav; Špaček, Tomáš; Engstová, Hana; Reguera Pajuelo, David; Jabůrek, Martin

    2014-01-01

    Roč. 63, Suppl.1 (2014), S73-S91 ISSN 0862-8408 R&D Projects: GA ČR(CZ) GAP302/10/0346; GA ČR(CZ) GAP305/12/1247; GA ČR(CZ) GPP304/10/P204; GA MŠk(CZ) EE2.3.30.0025 Institutional support: RVO:67985823 Keywords : mitochondria * uncoupling protein UCP2 * pancreatic beta-cells * reactive oxygen species * glucose-stimulated insulin secretion Subject RIV: EA - Cell Biology Impact factor: 1.293, year: 2014

  7. Use of digitonin permeabilization for characterization of calcium incorporated into. beta. cells in response to glucose

    Energy Technology Data Exchange (ETDEWEB)

    Wesslen, N [Uppsala Univ. (Sweden)

    1985-01-01

    ..beta.. cell-rich pancreatic islets were used to characterize /sup 45/Ca uptake into pools with different sensitivities to permeabilization with digitonin. The plasma and secretory granule membranes were among the membranes most sensitive to digitonin treatment whereas the mitochondria were more resistant. Most of the /sup 45/Ca incorporated in response to glucose was found in a fraction released after exposure to a high concentration of digitonin. The results suggest that glucose promotes active sequestration of calcium in mitochondria and that the uptake of /sup 45/Ca in the secretory granules in secondary to a raised cytosolic Ca/sup 2 +/ activity.

  8. The time has come to test the beta cell preserving effects of exercise in patients with new onset type 1 diabetes

    DEFF Research Database (Denmark)

    Narendran, Parth; Solomon, Thomas; Kennedy, Amy

    2015-01-01

    Type 1 diabetes is characterised by immune-mediated destruction of insulin-producing beta cells. Significant beta cell function is usually present at the time of diagnosis with type 1 diabetes, and preservation of this function has important clinical benefits. The last 30 years have seen a number...... for physical exercise as a therapy for the preservation of beta cell function in patients with newly diagnosed type 1 diabetes. We highlight possible mechanisms by which exercise could preserve beta cell function and then present evidence from other models of diabetes that demonstrate that exercise preserves...... beta cell function. We conclude by proposing that there is now a need for studies to explore whether exercise can preserve beta cell in patients newly diagnosed with type 1 diabetes....

  9. Involvement of interleukin 1 and interleukin 1 antagonist in pancreatic beta-cell destruction in insulin-dependent diabetes mellitus

    DEFF Research Database (Denmark)

    Mandrup-Poulsen, T; Zumsteg, U; Reimers, J

    1993-01-01

    In this review we propose that the balance between the action of interleukin 1 (IL-1) and its natural antagonist IL-1ra on the level of the insulin-producing pancreatic beta-cell may play a decisive role in the pathogenesis of insulin-dependent diabetes mellitus (IDDM). We argue that IL-1...... potentiated by other cytokines (tumor necrosis factor alpha, interferon gamma) is an important effector molecule involved in both early and late events in the immune-mediated process that leads to beta-cell destruction and IDDM. We also point out that surprisingly high molar excesses of IL-1ra over IL-1...... are necessary to block the action of IL-1 on islet beta-cells compared to islet alpha-cells in vitro and in animals. We suggest that the selectivity of beta-cell destruction in IDDM may be conferred on several levels: (1) homing of beta-cell antigen specific T cells, (2) targeted delivery of cytokines...

  10. T Cell-Mediated Beta Cell Destruction: Autoimmunity and Alloimmunity in the Context of Type 1 Diabetes

    Directory of Open Access Journals (Sweden)

    Adam L. Burrack

    2017-12-01

    Full Text Available Type 1 diabetes (T1D results from destruction of pancreatic beta cells by T cells of the immune system. Despite improvements in insulin analogs and continuous blood glucose level monitoring, there is no cure for T1D, and some individuals develop life-threatening complications. Pancreas and islet transplantation have been attractive therapeutic approaches; however, transplants containing insulin-producing cells are vulnerable to both recurrent autoimmunity and conventional allograft rejection. Current immune suppression treatments subdue the immune system, but not without complications. Ideally a successful approach would target only the destructive immune cells and leave the remaining immune system intact to fight foreign pathogens. This review discusses the autoimmune diabetes disease process, diabetic complications that warrant a transplant, and alloimmunity. First, we describe the current understanding of autoimmune destruction of beta cells including the roles of CD4 and CD8 T cells and several possibilities for antigen-specific tolerance induction. Second, we outline diabetic complications necessitating beta cell replacement. Third, we discuss transplant recognition, potential sources for beta cell replacement, and tolerance-promoting therapies under development. We hypothesize that a better understanding of autoreactive T cell targets during disease pathogenesis and alloimmunity following transplant destruction could enhance attempts to re-establish tolerance to beta cells.

  11. Analysis of the effect of diabetes type 2 duration on beta cell secretory function and insulin resistance

    Directory of Open Access Journals (Sweden)

    Popović Ljiljana

    2006-01-01

    Full Text Available Diabetes type 2 is a chronic metabolic disorder. Pathogenesis of diabetes type 2 results from the impaired insulin secretion, impaired insulin action and increased endogenous glucose production. Diabetes evolves through several phases characterized by qualitative and quantitative changes of beta cell secretory function. The aim of our study was to analyze the impact of diabetes duration on beta cell secretory function and insulin resistance. The results indicated significant negative correlation of diabetes duration and fasting insulinemia, as well as beta cell secretory function assessed by HOMA β index. Our study also found significant negative correlation of diabetes duration and insulin resistance assessed by HOMA IR index. Significant positive correlation was established between beta cell secretory capacity (fasting insulinemia and HOMA β and insulin resistance assessed by HOMA IR index, independently of diabetes duration. These results indicate that: beta cell secretory capacity, assessed by HOMA β index, significantly decreases with diabetes duration. In parallel with decrease of fasting insulinemia, reduction of insulin resistance assessed by HOMA IR index was found as well.

  12. Nuclear orphan receptor TLX affects gene expression, proliferation and cell apoptosis in beta cells

    Energy Technology Data Exchange (ETDEWEB)

    Shi, Xiaoli; Xiong, Xiaokan; Dai, Zhe; Deng, Haohua; Sun, Li; Hu, Xuemei; Zhou, Feng; Xu, Yancheng, E-mail: oxyccc@163.com

    2015-12-04

    Nuclear orphan receptor TLX is an essential regulator of the growth of neural stem cells. However, its exact function in pancreatic islet cells is still unknown. In the present study, gene expression profiling analysis revealed that overexpression of TLX in beta cell line MIN6 causes suppression of 176 genes and upregulation of 49 genes, including a cadre of cell cycle, cell proliferation and cell death control genes, such as Btg2, Ddit3 and Gadd45a. We next examined the effects of TLX overexpression on proliferation, apoptosis and insulin secretion in MIN6 cells. Proliferation analysis using EdU assay showed that overexpression of TLX increased percentage of EdU-positive cells. Cell cycle and apoptosis analysis revealed that overexpression of TLX in MIN6 cells resulted in higher percentage of cells exiting G1 into S-phase, and a 58.8% decrease of cell apoptosis induced by 0.5 mM palmitate. Moreover, TLX overexpression did not cause impairment of insulin secretion. Together, we conclude that TLX is among factors capable of controlling beta cell proliferation and survival, which may serve as a target for the development of novel therapies for diabetes. - Highlights: • TLX overexpression in MIN6 cell causes significant expression changes of 225 genes. • TLX overexpression promotes MIN6 cell proliferation and decreases cell apoptosis. • TLX overexpression does not cause impairment of insulin secretion.

  13. Nuclear orphan receptor TLX affects gene expression, proliferation and cell apoptosis in beta cells

    International Nuclear Information System (INIS)

    Shi, Xiaoli; Xiong, Xiaokan; Dai, Zhe; Deng, Haohua; Sun, Li; Hu, Xuemei; Zhou, Feng; Xu, Yancheng

    2015-01-01

    Nuclear orphan receptor TLX is an essential regulator of the growth of neural stem cells. However, its exact function in pancreatic islet cells is still unknown. In the present study, gene expression profiling analysis revealed that overexpression of TLX in beta cell line MIN6 causes suppression of 176 genes and upregulation of 49 genes, including a cadre of cell cycle, cell proliferation and cell death control genes, such as Btg2, Ddit3 and Gadd45a. We next examined the effects of TLX overexpression on proliferation, apoptosis and insulin secretion in MIN6 cells. Proliferation analysis using EdU assay showed that overexpression of TLX increased percentage of EdU-positive cells. Cell cycle and apoptosis analysis revealed that overexpression of TLX in MIN6 cells resulted in higher percentage of cells exiting G1 into S-phase, and a 58.8% decrease of cell apoptosis induced by 0.5 mM palmitate. Moreover, TLX overexpression did not cause impairment of insulin secretion. Together, we conclude that TLX is among factors capable of controlling beta cell proliferation and survival, which may serve as a target for the development of novel therapies for diabetes. - Highlights: • TLX overexpression in MIN6 cell causes significant expression changes of 225 genes. • TLX overexpression promotes MIN6 cell proliferation and decreases cell apoptosis. • TLX overexpression does not cause impairment of insulin secretion.

  14. Nuclear orphan receptor TLX affects gene expression, proliferation and cell apoptosis in beta cells.

    Science.gov (United States)

    Shi, Xiaoli; Xiong, Xiaokan; Dai, Zhe; Deng, Haohua; Sun, Li; Hu, Xuemei; Zhou, Feng; Xu, Yancheng

    Nuclear orphan receptor TLX is an essential regulator of the growth of neural stem cells. However, its exact function in pancreatic islet cells is still unknown. In the present study, gene expression profiling analysis revealed that overexpression of TLX in beta cell line MIN6 causes suppression of 176 genes and upregulation of 49 genes, including a cadre of cell cycle, cell proliferation and cell death control genes, such as Btg2, Ddit3 and Gadd45a. We next examined the effects of TLX overexpression on proliferation, apoptosis and insulin secretion in MIN6 cells. Proliferation analysis using EdU assay showed that overexpression of TLX increased percentage of EdU-positive cells. Cell cycle and apoptosis analysis revealed that overexpression of TLX in MIN6 cells resulted in higher percentage of cells exiting G1 into S-phase, and a 58.8% decrease of cell apoptosis induced by 0.5 mM palmitate. Moreover, TLX overexpression did not cause impairment of insulin secretion. Together, we conclude that TLX is among factors capable of controlling beta cell proliferation and survival, which may serve as a target for the development of novel therapies for diabetes. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. LGR5 and Nanog identify stem cell signature of pancreas beta cells which initiate pancreatic cancer.

    Science.gov (United States)

    Amsterdam, Abraham; Raanan, Calanit; Schreiber, Letizia; Polin, Nava; Givol, David

    2013-04-05

    Pancreas cancer, is the fourth leading cause of cancer death but its cell of origin is controversial. We compared the localization of stem cells in normal and cancerous pancreas using antibodies to the stem cell markers Nanog and LGR5. Here we show, for the first time, that LGR5 is expressed in normal pancreas, exclusively in the islets of Langerhans and it is co-localized, surprisingly, with Nanog and insulin in clusters of beta cells. In cancerous pancreas Nanog and LGR5 are expressed in the remaining islets and in all ductal cancer cells. We observed insulin staining among the ductal cancer cells, but not in metastases. This indicates that the islet's beta cells, expressing LGR5 and Nanog markers are the initiating cells of pancreas cancer, which migrated from the islets to form the ductal cancerous tissue, probably after mutation and de-differentiation. This discovery may facilitate treatment of this devastating cancer. Copyright © 2013 Elsevier Inc. All rights reserved.

  16. Planar Cell Polarity Controls Pancreatic Beta Cell Differentiation and Glucose Homeostasis

    Directory of Open Access Journals (Sweden)

    Cedric Cortijo

    2012-12-01

    Full Text Available Planar cell polarity (PCP refers to the collective orientation of cells within the epithelial plane. We show that progenitor cells forming the ducts of the embryonic pancreas express PCP proteins and exhibit an active PCP pathway. Planar polarity proteins are acquired at embryonic day 11.5 synchronously to apicobasal polarization of pancreas progenitors. Loss of function of the two PCP core components Celsr2 and Celsr3 shows that they control the differentiation of endocrine cells from polarized progenitors, with a prevalent effect on insulin-producing beta cells. This results in a decreased glucose clearance. Loss of Celsr2 and 3 leads to a reduction of Jun phosphorylation in progenitors, which, in turn, reduces beta cell differentiation from endocrine progenitors. These results highlight the importance of the PCP pathway in cell differentiation in vertebrates. In addition, they reveal that tridimensional organization and collective communication of cells are needed in the pancreatic epithelium in order to generate appropriate numbers of endocrine cells.

  17. Effect on pancreatic beta cells and nerve cells by low let x-ray

    Energy Technology Data Exchange (ETDEWEB)

    Park, Kwang Hun [Dept. of Nuclear Medicine, Kyungbuk National University Hospital, Daegu (Korea, Republic of); Kim, Kgu Hwan [Dept. of Radiological Technology, Daegu health College, Daegu (Korea, Republic of)

    2014-03-15

    Cultured pancreatic beta cells and nerve cells, it is given normal condition of 10% FBS (fetal bovine serum), 11.1 mM glucose and hyperglycemia condition of 1% FBS, 30 mM glucose. For low LET X-ray irradiated with 0.5 Gy/hr dose-rate(total dose: 0.5 to 5 Gy). Survival rates were measured by MTT assay. When non irradiated, differentiated in the pancreatic beta cells experiment is hyperglycemia conditions survival rate compared to normal conditions survival rate seemed a small reduction. However increasing the total dose of X-ray, the survival rate of normal conditions decreased slightly compared to the survival rate of hyperglycemia conditions, the synergistic effect was drastically reduced. When non irradiated, undifferentiated in the nerve cells experiment is hyperglycemia conditions survival rate compared to normal conditions survival rate seemed a large reduction. As the cumulative dose of X-ray normal conditions and hyperglycemia were all relatively rapid cell death. But the rate of decreased survivals by almost parallel to the reduction proceed and it didn't show synergistic effect.

  18. IKKβ inhibition prevents fat-induced beta cell dysfunction in vitro and in vivo in rodents.

    Science.gov (United States)

    Ivovic, Aleksandar; Oprescu, Andrei I; Koulajian, Khajag; Mori, Yusaku; Eversley, Judith A; Zhang, Liling; Nino-Fong, Rodolfo; Lewis, Gary F; Donath, Marc Y; Karin, Michael; Wheeler, Michael B; Ehses, Jan; Volchuk, Allen; Chan, Catherine B; Giacca, Adria

    2017-10-01

    We have previously shown that oxidative stress plays a causal role in beta cell dysfunction induced by fat. Here, we address whether the proinflammatory kinase inhibitor of (nuclear factor) κB kinase β (IKKβ), which is activated by oxidative stress, is also implicated. Fat (oleate or olive oil) was infused intravenously in Wistar rats for 48 h with or without the IKKβ inhibitor salicylate. Thereafter, beta cell function was evaluated in vivo using hyperglycaemic clamps or ex vivo in islets isolated from fat-treated rats. We also exposed rat islets to oleate in culture, with or without salicylate and 4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline; BMS-345541 (BMS, another inhibitor of IKKβ) and evaluated beta cell function in vitro. Furthermore, oleate was infused in mice treated with BMS and in beta cell-specific Ikkb-null mice. 48 h infusion of fat impaired beta-cell function in vivo, assessed using the disposition index (DI), in rats (saline: 1.41 ± 0.13; oleate: 0.95 ± 0.11; olive oil [OLO]: 0.87 ± 0.15; p < 0.01 for both fats vs saline) and in mice (saline: 2.51 ± 0.39; oleate: 1.20 ± 0.19; p < 0.01 vs saline) and ex vivo (i.e., insulin secretion, units are pmol insulin islet -1  h -1 ) in rat islets (saline: 1.51 ± 0.13; oleate: 1.03 ± 0.10; OLO: 0.91 ± 0.13; p < 0.001 for both fats vs saline) and the dysfunction was prevented by co-infusion of salicylate in rats (oleate + salicylate: 1.30 ± 0.09; OLO + salicylate: 1.33 ± 0.23) or BMS in mice (oleate + BMS: 2.25 ± 0.42) in vivo and by salicylate in rat islets ex vivo (oleate + salicylate: 1.74 ± 0.31; OLO + salicylate: 1.54 ± 0.29). In cultured islets, 48 h exposure to oleate impaired beta-cell function ([in pmol insulin islet -1  h -1 ] control: 0.66 ± 0.12; oleate: 0.23 ± 0.03; p < 0.01 vs saline), an effect prevented by both inhibitors (oleate + salicylate: 0.98 ± 0.08; oleate + BMS: 0.50 ± 0.02). Genetic

  19. The Role of Helicobacter pylori Seropositivity in Insulin Sensitivity, Beta Cell Function, and Abnormal Glucose Tolerance

    Directory of Open Access Journals (Sweden)

    Lou Rose Malamug

    2014-01-01

    Full Text Available Infection, for example, Helicobacter pylori (H. pylori, has been thought to play a role in the pathogenesis of type 2 diabetes mellitus (T2DM. Our aim was to determine the role of H. pylori infection in glucose metabolism in an American cohort. We examined data from 4,136 non-Hispanic white (NHW, non-Hispanic black (NHB, and Mexican Americans (MA aged 18 and over from the NHANES 1999-2000 cohort. We calculated the odds ratios for states of glucose tolerance based on the H. pylori status. We calculated and compared homeostatic model assessment insulin resistance (HOMA-IR and beta cell function (HOMA-B in subjects without diabetes based on the H. pylori status. The results were adjusted for age, body mass index (BMI, poverty index, education, alcohol consumption, tobacco use, and physical activity. The H. pylori status was not a risk factor for abnormal glucose tolerance. After adjustment for age and BMI and also adjustment for all covariates, no difference was found in either HOMA-IR or HOMA-B in all ethnic and gender groups except for a marginally significant difference in HOMA-IR in NHB females. H. pylori infection was not a risk factor for abnormal glucose tolerance, nor plays a major role in insulin resistance or beta cell dysfunction.

  20. Effects of exendin-4 on glucose tolerance, insulin secretion, and beta-cell proliferation depend on treatment dose, treatment duration and meal contents

    International Nuclear Information System (INIS)

    Arakawa, Masayuki; Ebato, Chie; Mita, Tomoya; Hirose, Takahisa; Kawamori, Ryuzo; Fujitani, Yoshio; Watada, Hirotaka

    2009-01-01

    Beta-cell proliferation is regulated by various metabolic demands including peripheral insulin resistance, obesity, and hyperglycemia. In addition to enhancement of glucose-induced insulin secretion, agonists for glucagon-like peptide-1 receptor (GLP-1R) stimulate proliferation and inhibit apoptosis of beta-cells, thereby probably preserve beta-cell mass. To evaluate the beta-cell preserving actions of GLP-1R agonists, we assessed the acute and chronic effects of exendin-4 on beta-cell proliferation, mass and glucose tolerance in C57BL/6J mice under various conditions. Short-term administration of high-dose exendin-4 transiently stimulated beta-cell proliferation. Comparative transcriptomic analysis showed upregulation of IGF-1 receptor and its downstream effectors in islets. Treatment of mice with exendin-4 daily for 4 weeks (long-term administration) and feeding high-fat diet resulted in significant inhibition of weight gain and improvement of glucose tolerance with reduced insulin secretion and beta-cell mass. These findings suggest that long-term GLP-1 treatment results in insulin sensitization of peripheral organs, rather than enhancement of beta-cell proliferation and function, particularly when animals are fed high-fat diet. Thus, the effects of exendin-4 on glucose tolerance, insulin secretion, and beta-cell proliferation largely depend on treatment dose, duration of treatment and meal contents. While GLP-1 enhances proliferation of beta-cells in some diabetic mice models, our results suggest that GLP-1 stimulates beta-cell growth only when expansion of beta-cell mass is required to meet metabolic demands.

  1. Effects of exendin-4 on glucose tolerance, insulin secretion, and beta-cell proliferation depend on treatment dose, treatment duration and meal contents

    Energy Technology Data Exchange (ETDEWEB)

    Arakawa, Masayuki; Ebato, Chie; Mita, Tomoya [Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo (Japan); Hirose, Takahisa [Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo (Japan); Center for Therapeutic Innovations in Diabetes, Juntendo University School of Medicine, Tokyo (Japan); Kawamori, Ryuzo [Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo (Japan); Center for Therapeutic Innovations in Diabetes, Juntendo University School of Medicine, Tokyo (Japan); Center for Beta Cell Biology and Regeneration, Juntendo University School of Medicine, Tokyo (Japan); Sportology Center, Juntendo University School of Medicine, Tokyo (Japan); Fujitani, Yoshio, E-mail: fujitani@juntendo.ac.jp [Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo (Japan); Center for Therapeutic Innovations in Diabetes, Juntendo University School of Medicine, Tokyo (Japan); Watada, Hirotaka, E-mail: hwatada@juntendo.ac.jp [Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo (Japan); Sportology Center, Juntendo University School of Medicine, Tokyo (Japan)

    2009-12-18

    Beta-cell proliferation is regulated by various metabolic demands including peripheral insulin resistance, obesity, and hyperglycemia. In addition to enhancement of glucose-induced insulin secretion, agonists for glucagon-like peptide-1 receptor (GLP-1R) stimulate proliferation and inhibit apoptosis of beta-cells, thereby probably preserve beta-cell mass. To evaluate the beta-cell preserving actions of GLP-1R agonists, we assessed the acute and chronic effects of exendin-4 on beta-cell proliferation, mass and glucose tolerance in C57BL/6J mice under various conditions. Short-term administration of high-dose exendin-4 transiently stimulated beta-cell proliferation. Comparative transcriptomic analysis showed upregulation of IGF-1 receptor and its downstream effectors in islets. Treatment of mice with exendin-4 daily for 4 weeks (long-term administration) and feeding high-fat diet resulted in significant inhibition of weight gain and improvement of glucose tolerance with reduced insulin secretion and beta-cell mass. These findings suggest that long-term GLP-1 treatment results in insulin sensitization of peripheral organs, rather than enhancement of beta-cell proliferation and function, particularly when animals are fed high-fat diet. Thus, the effects of exendin-4 on glucose tolerance, insulin secretion, and beta-cell proliferation largely depend on treatment dose, duration of treatment and meal contents. While GLP-1 enhances proliferation of beta-cells in some diabetic mice models, our results suggest that GLP-1 stimulates beta-cell growth only when expansion of beta-cell mass is required to meet metabolic demands.

  2. The zinc transporter ZNT3 co-localizes with insulin in INS-1E pancreatic beta cells and influences cell survival, insulin secretion capacity, and ZNT8 expression

    DEFF Research Database (Denmark)

    Smidt, Kamille; Larsen, Agnete; Brønden, Andreas

    2016-01-01

    Zinc trafficking in pancreatic beta cells is tightly regulated by zinc transporting (ZNTs) proteins. The role of different ZNTs in the beta cells is currently being clarified. ZNT8 transports zinc into insulin granules and is critical for a correct insulin crystallization and storage in the granu......Zinc trafficking in pancreatic beta cells is tightly regulated by zinc transporting (ZNTs) proteins. The role of different ZNTs in the beta cells is currently being clarified. ZNT8 transports zinc into insulin granules and is critical for a correct insulin crystallization and storage...

  3. A search for optical bursts from the repeating fast radio burst FRB 121102

    Science.gov (United States)

    Hardy, L. K.; Dhillon, V. S.; Spitler, L. G.; Littlefair, S. P.; Ashley, R. P.; De Cia, A.; Green, M. J.; Jaroenjittichai, P.; Keane, E. F.; Kerry, P.; Kramer, M.; Malesani, D.; Marsh, T. R.; Parsons, S. G.; Possenti, A.; Rattanasoon, S.; Sahman, D. I.

    2017-12-01

    We present a search for optical bursts from the repeating fast radio burst FRB 121102 using simultaneous observations with the high-speed optical camera ULTRASPEC on the 2.4-m Thai National Telescope and radio observations with the 100-m Effelsberg Radio Telescope. A total of 13 radio bursts were detected, but we found no evidence for corresponding optical bursts in our 70.7-ms frames. The 5σ upper limit to the optical flux density during our observations is 0.33 mJy at 767 nm. This gives an upper limit for the optical burst fluence of 0.046 Jy ms, which constrains the broad-band spectral index of the burst emission to α ≤ -0.2. Two of the radio pulses are separated by just 34 ms, which may represent an upper limit on a possible underlying periodicity (a rotation period typical of pulsars), or these pulses may have come from a single emission window that is a small fraction of a possible period.

  4. The ectopic expression of Pax4 in the mouse pancreas converts progenitor cells into alpha and subsequently beta cells

    DEFF Research Database (Denmark)

    Collombat, Patrick; Xu, Xiaobo; Ravassard, Philippe

    2009-01-01

    We have previously reported that the loss of Arx and/or Pax4 gene activity leads to a shift in the fate of the different endocrine cell subtypes in the mouse pancreas, without affecting the total endocrine cell numbers. Here, we conditionally and ectopically express Pax4 using different cell......-specific promoters and demonstrate that Pax4 forces endocrine precursor cells, as well as mature alpha cells, to adopt a beta cell destiny. This results in a glucagon deficiency that provokes a compensatory and continuous glucagon+ cell neogenesis requiring the re-expression of the proendocrine gene Ngn3. However......, the newly formed alpha cells fail to correct the hypoglucagonemia since they subsequently acquire a beta cell phenotype upon Pax4 ectopic expression. Notably, this cycle of neogenesis and redifferentiation caused by ectopic expression of Pax4 in alpha cells is capable of restoring a functional beta cell...

  5. Phosphorylation events implicating p38 and PI3K mediate tungstate-effects in MIN6 beta cells

    International Nuclear Information System (INIS)

    Piquer, Sandra; Barcelo-Batllori, Silvia; Julia, Marta; Marzo, Nuria; Nadal, Belen; Guinovart, Joan J.; Gomis, Ramon

    2007-01-01

    Oral administration of sodium tungstate is an effective treatment for diabetes in animal models. Several lines of evidence indicate the pancreatic beta cell as one of the targets of tungstate action. Here, we examined the molecular mechanism by which this compound exerts its effects on the beta cell line MIN6. Tungstate treatment induced phosphorylation and subsequent activation of p38 and PI3K which in turn are implicated in tungstate PDX-1 nuclear localization and activation. Although no effect was observed in glucose-induced insulin secretion we found that tungstate activates basal insulin release, a process driven, at least in part, by activation of p38. These results show a direct involvement of p38 and PI3K phosphorylation in the mechanism of action of tungstate in the beta cell

  6. The long-acting GLP-1 derivative NN2211 ameliorates glycemia and increases beta-cell mass in diabetic mice

    DEFF Research Database (Denmark)

    Rolin, Bidda; Larsen, Marianne O; Gotfredsen, Carsten F

    2002-01-01

    in food intake, there were no significant differences between NN2211 and vehicle treatment, and body weight was not affected. Histological examination revealed that beta-cell proliferation and mass were not increased significantly in ob/ob mice with NN2211, although there was a strong tendency...... for increased proliferation. In db/db mice, exendin-4 and NN2211 decreased blood glucose compared with vehicle, but NN2211 had a longer duration of action. Food intake was lowered only on day 1 with both compounds, and body weight was unaffected. beta-Cell proliferation rate and mass were significantly...

  7. Activation of transmembrane bile acid receptor TGR5 stimulates insulin secretion in pancreatic {beta} cells

    Energy Technology Data Exchange (ETDEWEB)

    Kumar, Divya P.; Rajagopal, Senthilkumar; Mahavadi, Sunila [Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA (United States); Mirshahi, Faridoddin [Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA (United States); Grider, John R. [Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA (United States); Murthy, Karnam S., E-mail: skarnam@vcu.edu [Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA (United States); Sanyal, Arun J., E-mail: asanyal@mcvh-vcu.edu [Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA (United States)

    2012-10-26

    Highlights: Black-Right-Pointing-Pointer G protein coupled receptor TGR5 is expressed in mouse and human islets. Black-Right-Pointing-Pointer TGR5 is coupled to activation of Gs and Ca{sup 2+} release via cAMP/Epac/PLC-{epsilon} pathway. Black-Right-Pointing-Pointer Activation of TGR5 by bile salts and selective ligands causes insulin secretion. Black-Right-Pointing-Pointer TGR5 could be a potential therapeutic target to treat diabetes. -- Abstract: Bile acids act as signaling molecules and stimulate the G protein coupled receptor, TGR5, in addition to nuclear farnesoid X receptor to regulate lipid, glucose and energy metabolism. Bile acid induced activation of TGR5 in the enteroendocrine cells promotes glucagon like peptide-1 (GLP-1) release, which has insulinotropic effect in the pancreatic {beta} cells. In the present study, we have identified the expression of TGR5 in pancreatic {beta} cell line MIN6 and also in mouse and human pancreatic islets. TGR5 selective ligands, oleanolic acid (OA) and INT-777 selectively activated G{alpha}{sub s} and caused an increase in intracellular cAMP and Ca{sup 2+}. OA and INT-777 also increased phosphoinositide (PI) hydrolysis and the increase was blocked by NF449 (a selective G{alpha}{sub s} inhibitor) or (U73122) (PI hydrolysis inhibitor). OA, INT-777 and lithocholic acid increased insulin release in MIN6 and human islets and the increase was inhibited by treatment with NF449, (U73122) or BAPTA-AM (chelator of calcium), but not with myristoylated PKI (PKA inhibitor), suggesting that the release is dependent on G{sub s}/cAMP/Ca{sup 2+} pathway. 8-pCPT-2 Prime -O-Me-cAMP, a cAMP analog, which activates Epac, but not PKA also stimulated PI hydrolysis. In conclusion, our study demonstrates that the TGR5 expressed in the pancreatic {beta} cells regulates insulin secretion and highlights the importance of ongoing therapeutic strategies targeting TGR5 in the control of glucose homeostasis.

  8. Peroxisome proliferator-activated receptor alpha (PPARalpha) protects against oleate-induced INS-1E beta cell dysfunction by preserving carbohydrate metabolism

    DEFF Research Database (Denmark)

    Frigerio, F; Brun, T; Bartley, C

    2009-01-01

    and investigated key metabolic pathways and genes responsible for metabolism-secretion coupling during a culture period of 3 days in the presence of 0.4 mmol/l oleate. RESULTS: In INS-1E cells, the secretory dysfunction primarily induced by oleate was aggravated by silencing of PPARalpha. Conversely, PPARalpha...... enzyme pyruvate carboxylase. PPARalpha overproduction increased both beta-oxidation and fatty acid storage in the form of neutral triacylglycerol, revealing overall induction of lipid metabolism. These observations were substantiated by expression levels of associated genes. CONCLUSIONS....../INTERPRETATION: PPARalpha protected INS-1E beta cells from oleate-induced dysfunction, promoting both preservation of glucose metabolic pathways and fatty acid turnover....

  9. Study of beta-cell function (by HOMA model) in metabolic syndrome.

    Science.gov (United States)

    Garg, M K; Dutta, M K; Mahalle, Namita

    2011-07-01

    The clustering of cardiovascular risk factors is termed the metabolic syndrome (MS), which strongly predict risk of diabetes and cardiovascular disease. Many studies implicate insulin resistance (IR) in the development of diabetes, but ignore the contribution of beta-cell dysfunction. Hence, we studied beta-cell function, as assessed by HOMA model, in subjects with MS. We studied 50 subjects with MS diagnosed by IDF criteria and 24 healthy age- and sex-matched controls. Clinical evaluation included anthropometry, body fat analysis by bioimpedance, biochemical, and insulin measurement. IR and secretion were calculated by HOMA model. Subjects with MS had more IR (HOMA-IR) than controls (3.35 ± 3.14 vs. 1.76 ± 0.53, P = 0.029) and secreted less insulin (HOMA-S) than controls (66.80 ± 69.66 vs. 144.27 ± 101.61, P = 0.0003), although plasma insulin levels were comparable in both groups (10.7 ± 10.2 vs. 8.2 ± 2.38, P = 0.44). HOMA-IR and HOMA-S were related with number of metabolic abnormalities. HOMA-IR was positively associated with body mass index, waist hip ratio, body fat mass, and percent body fat. HOMA-S was negatively associated with waist hip ratio, fasting plasma glucose and total cholesterol and positively with basal metabolic rate. Percent body fat was an independent predictor of HOMA-IR and waist hip ratio of HOMA-S in multiple regression analysis. Subjects with MS have increased IR and decreased insulin secretion compared with healthy controls. Lifestyle measures have been shown to improve IR, insulin secretion, and various components and effects of MS. Hence, there is an urgent need for public health measures to prevent ongoing epidemic of diabetes and cardiovascular disease.

  10. The putative imidazoline receptor agonist, harmane, promotes intracellular calcium mobilisation in pancreatic beta-cells.

    Science.gov (United States)

    Squires, Paul E; Hills, Claire E; Rogers, Gareth J; Garland, Patrick; Farley, Sophia R; Morgan, Noel G

    2004-10-06

    beta-Carbolines (including harmane and pinoline) stimulate insulin secretion by a mechanism that may involve interaction with imidazoline I(3)-receptors but which also appears to be mediated by actions that are additional to imidazoline receptor agonism. Using the MIN6 beta-cell line, we now show that both the imidazoline I(3)-receptor agonist, efaroxan, and the beta-carboline, harmane, directly elevate cytosolic Ca(2+) and increase insulin secretion but that these responses display different characteristics. In the case of efaroxan, the increase in cytosolic Ca(2+) was readily reversible, whereas, with harmane, the effect persisted beyond removal of the agonist and resulted in the development of a repetitive train of Ca(2+)-oscillations whose frequency, but not amplitude, was concentration-dependent. Initiation of the Ca(2+)-oscillations by harmane was independent of extracellular calcium but was sensitive to both dantrolene and high levels (20 mM) of caffeine, suggesting the involvement of ryanodine receptor-gated Ca(2+)-release. The expression of ryanodine receptor-1 and ryanodine receptor-2 mRNA in MIN6 cells was confirmed using reverse transcription-polymerase chain reaction (RT-PCR) and, since low concentrations of caffeine (1 mM) or thimerosal (10 microM) stimulated increases in [Ca(2+)](i), we conclude that ryanodine receptors are functional in these cells. Furthermore, the increase in insulin secretion induced by harmane was attenuated by dantrolene, consistent with the involvement of ryanodine receptors in mediating this response. By contrast, the smaller insulin secretory response to efaroxan was unaffected by dantrolene. Harmane-evoked changes in cytosolic Ca(2+) were maintained by nifedipine-sensitive Ca(2+)-influx, suggesting the involvement of L-type voltage-gated Ca(2+)-channels. Taken together, these data imply that harmane may interact with ryanodine receptors to generate sustained Ca(2+)-oscillations in pancreatic beta-cells and that this effect

  11. Characterization of the distal promoter of the human pyruvate carboxylase gene in pancreatic beta cells.

    Directory of Open Access Journals (Sweden)

    Ansaya Thonpho

    Full Text Available Pyruvate carboxylase (PC is an enzyme that plays a crucial role in many biosynthetic pathways in various tissues including glucose-stimulated insulin secretion. In the present study, we identify promoter usage of the human PC gene in pancreatic beta cells. The data show that in the human, two alternative promoters, proximal and distal, are responsible for the production of multiple mRNA isoforms as in the rat and mouse. RT-PCR analysis performed with cDNA prepared from human liver and islets showed that the distal promoter, but not the proximal promoter, of the human PC gene is active in pancreatic beta cells. A 1108 bp fragment of the human PC distal promoter was cloned and analyzed. It contains no TATA box but possesses two CCAAT boxes, and other putative transcription factor binding sites, similar to those of the distal promoter of rat PC gene. To localize the positive regulatory region in the human PC distal promoter, 5'-truncated and the 25-bp and 15-bp internal deletion mutants of the human PC distal promoter were generated and used in transient transfections in INS-1 832/13 insulinoma and HEK293T (kidney cell lines. The results indicated that positions -340 to -315 of the human PC distal promoter serve as (an activator element(s for cell-specific transcription factor, while the CCAAT box at -71/-67, a binding site for nuclear factor Y (NF-Y, as well as a GC box at -54/-39 of the human PC distal promoter act as activator sequences for basal transcription.

  12. Advances in gamma-ray burst astronomy

    International Nuclear Information System (INIS)

    Cline, T.L.; Desai, U.D.

    1976-01-01

    Work at Goddard is presently being carried out in three major areas of gamma-ray burst research: (1) A pair of simultaneously operating 0.8-m 2 burst detectors were successfully balloon-borne at locations 800 miles apart on 9 May, 1975, each to atmospheric depths of 3 to 4 g cm -2 , for a 20-h period of coincident data coverage. This experiment investigates the size spectrum of bursts in the 10 -7 to 10 -6 erg cm -2 size region where dozens of events per day are expected on a -1.5 index integral power-law extrapolation. Considerable separation in latitude was used to avoid possible atmospheric and auroral secondary effects. Its results are not yet available. (2) A deep-space burst detector, the first spacecraft instrument built specifically for gamma-ray burst studies, was recently successfully integrated into the Helios-B space probe. Its use at distances of up to 2 AU will make possible the first high-resolution directional study of gamma-ray burst source locations. Similar modifications to several other space vehicles are also being prepared. (3) The gamma-ray instrument on the IMP-7 satellite is presently the most sensitive burst detector still operating in orbit. Its results have shown that all measured event-average energy spectra are consistent with being alike. Using this characteristic spectrum to select IMP-7 candidate events of smaller size than those detected using other spacecraft in coincidence, a size spectrum is constructed which fits the -1.5 index power law down to 2.5 x 10 -5 erg cm -2 per event, at an occurrence rate of about once per month. (Auth.)

  13. Cosmic gamma-ray burst

    International Nuclear Information System (INIS)

    Yamagami, Takamasa

    1985-01-01

    Ballon experiments for searching gamma-ray burst were carried out by employing rotating-cross modulation collimators. From a very long observation of total 315 hours during 1975 to 1979, three gamma-ray intensity anomalies were observed which were speculated as a gamma-ray burst. As for the first gamma-ray intensity anomaly observed in 1975, the burst source could be located precisely but the source, heavenly body, could not be specified. Gamma-ray burst source estimation was made by analyzing distribution of burst source in the celestial sphere, burst size distribution, and burst peak. Using the above-mentioned data together with previously published ones, apparent inconsistency was found between the observed results and the adopted theory that the source was in the Galaxy, and this inconsistency was found due to the different time profiles of the burst observed with instruments of different efficiency. It was concluded by these analysis results that employment of logN - logP (relation between burst frequency and burst count) was better than that of logN - logS (burst size) in the examination of gamma-ray burst because the former was less uncertain than the latter. Analyzing the author's observed gamma-ray burst data and the related published data, it was clarified that the burst distribution was almost P -312 for the burst peak value larger than 10 -6 erg/cm 2 .sec. The author could indicate that the calculated celestial distribution of burst source was consistent with the observed results by the derivation using the logN - logP relationship and that the burst larger than 10 -6 erg/cm 2 .sec happens about one thousand times a year, about ten times of the previous value. (Takagi, S.)

  14. Central infusion of leptin improves insulin resistance and suppresses beta-cell function, but not beta-cell mass, primarily through the sympathetic nervous system in a type 2 diabetic rat model.

    Science.gov (United States)

    Park, Sunmin; Ahn, Il Sung; Kim, Da Sol

    2010-06-05

    We investigated whether hypothalamic leptin alters beta-cell function and mass directly via the sympathetic nervous system (SNS) or indirectly as the result of altered insulin resistant states. The 90% pancreatectomized male Sprague Dawley rats had sympathectomy into the pancreas by applying phenol into the descending aorta (SNSX) or its sham operation (Sham). Each group was divided into two sections, receiving either leptin at 300ng/kgbw/h or artificial cerebrospinal fluid (aCSF) via intracerebroventricular (ICV) infusion for 3h as a short-term study. After finishing the infusion study, ICV leptin (3mug/kg bw/day) or ICV aCSF (control) was infused in rats fed 30 energy % fat diets by osmotic pump for 4weeks. At the end of the long-term study, glucose-stimulated insulin secretion and islet morphometry were analyzed. Acute ICV leptin administration in Sham rats, but not in SNSX rats, suppressed the first- and second-phase insulin secretion at hyperglycemic clamp by about 48% compared to the control. Regardless of SNSX, the 4-week administration of ICV leptin improved glucose tolerance during oral glucose tolerance tests and insulin sensitivity at hyperglycemic clamp, compared to the control, while it suppressed second-phase insulin secretion in Sham rats but not in SNSX rats. However, the pancreatic beta-cell area and mass were not affected by leptin and SNSX, though ICV leptin decreased individual beta-cell size and concomitantly increased beta-cell apoptosis in Sham rats. Leptin directly decreases insulin secretion capacity mainly through the activation of SNS without modulating pancreatic beta-cell mass.

  15. Bone morphogenetic protein 4 inhibits insulin secretion from rodent beta cells through regulation of calbindin1 expression and reduced voltage-dependent calcium currents

    DEFF Research Database (Denmark)

    Christensen, Gitte L.; Jacobsen, Maria L. B.; Wendt, Anna

    2015-01-01

    AIMS/HYPOTHESIS: Type 2 diabetes is characterised by progressive loss of pancreatic beta cell mass and function. Therefore, it is of therapeutic interest to identify factors with the potential to improve beta cell proliferation and insulin secretion. Bone morphogenetic protein 4 (BMP4) expression...

  16. Beta-cell function, incretin effect, and incretin hormones in obese youth along the span of glucose tolerance from normal to prediabetes to Type 2 diabetes

    Science.gov (United States)

    Using the hyperglycemic and euglycemic clamp, we demonstrated impaired Beta-cell function in obese youth with increasing dysglycemia. Herein we describe oral glucose tolerance test (OGTT)-modeled Beta-cell function and incretin effect in obese adolescents spanning the range of glucose tolerance. Bet...

  17. The potential role of SOCS-3 in the interleukin-1beta-induced desensitization of insulin signaling in pancreatic beta-cells

    DEFF Research Database (Denmark)

    Emanuelli, Brice; Glondu, Murielle; Filloux, Chantal

    2004-01-01

    insulin signaling is required for the optimal beta-cell function, we assessed the effect of IL-1beta on the insulin pathway in a rat pancreatic beta-cell line. We show that IL-1beta decreases insulin-induced tyrosine phosphorylation of the insulin receptor (IR) and insulin receptor substrate (IRS...

  18. Study on cosmic gamma bursts in the ''KONUS'' experiment

    International Nuclear Information System (INIS)

    Mazets, E.P.; Golenetskij, S.V.; Il'inskij, V.N.; Panov, V.N.; Aptekar', R.L.; Gur'yan, Yu.A.; Sokolov, I.A.; Sokolova, Z.Ya.; Kharitonova, T.V.

    1979-01-01

    Made are the investigations of cosmic gamma bursts with the help of the ''Konus'' apparatus, positioned on the ''Venera 11'' and ''Venera 12'' automatic interplanetary stations. 37 gamma bursts have been recorded in the energy range from 50 to 150 keV during the observation period from September to December 1978. Time profiles of bursts on 4, 9 and 24.11.1978 are presented. For the most events the time of burst increase and decrease constitute parts and units of seconds. Differential energy spectra are measured for all recorded bursts. In many cases the spectrum shape is similar to the grade one with the 1.5-2.3 index. In a graphical form built up are the integral distributions of gamma bursts appearence frequency in dependence on their intensity and maximum capacity in the burst peak. Galaxy coordinates of the 17-teen bursts, for which a simple localization is possible, are put on the celestial sphere map. The type of the integral distributions and the source distribution about the celestial sphere show that the gamma burst sources are whithin the Galaxy

  19. High normal fasting glucose level in obese youth: a marker for insulin resistance and beta cell dysregulation.

    LENUS (Irish Health Repository)

    O'Malley, G

    2010-06-01

    A high but normal fasting plasma glucose level in adults is a risk factor for future development of type 2 diabetes mellitus and cardiovascular disease. We investigated whether normal fasting plasma glucose levels (<5.60 mmol\\/l) are associated with decreases in insulin sensitivity and beta cell function, as well as an adverse cardiovascular profile in obese youth.

  20. Pathway decision-making strategies for generating pancreatic beta-cells: systems biology or hit and miss?

    Science.gov (United States)

    Jensen, Jan

    2007-08-01

    Method selection strategies to achieve beta-cell differentiation from human embryonic stem cells are reviewed. Expectations are high for an embryonic stem cell derived cellular replacement method to cure diabetes, and recent observations indicate that mature beta-cells can be derived from human embryonic stem cells. In terms of the translational setting, however, we are not there yet; conversion of embryonic stem cells to fully mature beta-cells is not effective and does not provide an exclusive beta-cell population as the end-product. Studies emphasize that expecting development of a 'magic media bullet' that promotes endocrine fate is rather optimistic; consecutive administration of signaling inducers, carefully provided to mimic normal development, is more likely to succeed. To accomplish this task we need better understanding of the extracellular signaling pathways that drive progressive endodermal fate choices throughout development. Knowledge of cell-intrinsic control of fate assignments in pancreas is growing rapidly. Nevertheless, insufficient information regarding morphogen codes that operate in endoderm and pancreas is hindering development of better, directed differentiation schema of uncommitted embryonic stem cells toward endodermal, pancreatic, and subsequent endocrine specific fates. A systematic approach to defining morphogen codes in developing endoderm and pancreas appears timely and justified.

  1. Repetitive in vivo treatment with human recombinant interleukin-1 beta modifies beta-cell function in normal rats

    DEFF Research Database (Denmark)

    Wogensen, L D; Reimers, J; Nerup, J

    1992-01-01

    It is unknown whether interleukin-1 exerts a bimodal effect on Beta-cell function in vivo, and whether interleukin-1 has a diabetogenic action in normal animals. We therefore studied: (a) acute effects 2 h after an intraperitoneal bolus injection of 4 micrograms of recombinant human interleukin-1...

  2. Strain-dependent differences in sensitivity of rat beta-cells to interleukin 1 beta in vitro and in vivo

    DEFF Research Database (Denmark)

    Reimers, J I; Andersen, H U; Mauricio, D

    1996-01-01

    /kg) or vehicle for 5 days. All the strains investigated were susceptible to IL-1 beta-induced changes in body weight, food intake, temperature, and plasma glucagon and corticosterone. However, IL-1 beta induced hyperglycemia and impairment of beta-cell glucose responsiveness in WK/Mol and LS/Mol rats...

  3. The ectopic expression of Pax4 in the mouse pancreas converts progenitor cells into alpha and subsequently beta cells.

    Science.gov (United States)

    Collombat, Patrick; Xu, Xiaobo; Ravassard, Philippe; Sosa-Pineda, Beatriz; Dussaud, Sébastien; Billestrup, Nils; Madsen, Ole D; Serup, Palle; Heimberg, Harry; Mansouri, Ahmed

    2009-08-07

    We have previously reported that the loss of Arx and/or Pax4 gene activity leads to a shift in the fate of the different endocrine cell subtypes in the mouse pancreas, without affecting the total endocrine cell numbers. Here, we conditionally and ectopically express Pax4 using different cell-specific promoters and demonstrate that Pax4 forces endocrine precursor cells, as well as mature alpha cells, to adopt a beta cell destiny. This results in a glucagon deficiency that provokes a compensatory and continuous glucagon+ cell neogenesis requiring the re-expression of the proendocrine gene Ngn3. However, the newly formed alpha cells fail to correct the hypoglucagonemia since they subsequently acquire a beta cell phenotype upon Pax4 ectopic expression. Notably, this cycle of neogenesis and redifferentiation caused by ectopic expression of Pax4 in alpha cells is capable of restoring a functional beta cell mass and curing diabetes in animals that have been chemically depleted of beta cells.

  4. Characterization of membrane-shed micro-vesicles from cytokine-stimulated beta-cells using proteomics strategies

    DEFF Research Database (Denmark)

    Palmisano, Giuseppe; Jensen, Soren Skov; Le Bihan, Marie Catherine

    2012-01-01

    specific sites of protein phosphorylation and sialylated glycosylation in proteins associated with micro-vesicles from beta-cells. Using pathway analysis software we were able to map the most distinctive changes between micro-vesicles generated during growth and after cytokine stimulation to several cell...

  5. Pancreatic beta cell function increases in a linear dose-response manner following exercise training in adults with prediabetes

    DEFF Research Database (Denmark)

    Malin, Steven K; Solomon, Thomas; Blaszczak, Alecia

    2013-01-01

    While some studies suggest that a linear dose-response relationship exists between exercise and insulin sensitivity, the exercise dose required to enhance pancreatic beta-cell function is unknown. Thirty-five older, obese adults with prediabetes underwent a progressive 12-week supervised exercise...

  6. Inter-domain tagging implicates caveolin-1 in insulin receptor trafficking and Erk signaling bias in pancreatic beta-cells

    Directory of Open Access Journals (Sweden)

    Tobias Boothe

    2016-05-01

    Full Text Available Objective: The role and mechanisms of insulin receptor internalization remain incompletely understood. Previous trafficking studies of insulin receptors involved fluorescent protein tagging at their termini, manipulations that may be expected to result in dysfunctional receptors. Our objective was to determine the trafficking route and molecular mechanisms of functional tagged insulin receptors and endogenous insulin receptors in pancreatic beta-cells. Methods: We generated functional insulin receptors tagged with pH-resistant fluorescent proteins between domains. Confocal, TIRF and STED imaging revealed a trafficking pattern of inter-domain tagged insulin receptors and endogenous insulin receptors detected with antibodies. Results: Surprisingly, interdomain-tagged and endogenous insulin receptors in beta-cells bypassed classical Rab5a- or Rab7-mediated endocytic routes. Instead, we found that removal of insulin receptors from the plasma membrane involved tyrosine-phosphorylated caveolin-1, prior to trafficking within flotillin-1-positive structures to lysosomes. Multiple methods of inhibiting caveolin-1 significantly reduced Erk activation in vitro or in vivo, while leaving Akt signaling mostly intact. Conclusions: We conclude that phosphorylated caveolin-1 plays a role in insulin receptor internalization towards lysosomes through flotillin-1-positive structures and that caveolin-1 helps bias physiological beta-cell insulin signaling towards Erk activation. Author Video: Author Video Watch what authors say about their articles Keywords: Insulin receptor internalization, Insulin resistance, Pancreatic islet beta-cells, Autocrine insulin signaling

  7. Alkali pH directly activates ATP-sensitive K+ channels and inhibits insulin secretion in beta-cells.

    Science.gov (United States)

    Manning Fox, Jocelyn E; Karaman, Gunce; Wheeler, Michael B

    2006-11-17

    Glucose stimulation of pancreatic beta-cells is reported to lead to sustained alkalization, while extracellular application of weak bases is reported to inhibit electrical activity and decrease insulin secretion. We hypothesize that beta-cell K(ATP) channel activity is modulated by alkaline pH. Using the excised patch-clamp technique, we demonstrate a direct stimulatory action of alkali pH on recombinant SUR1/Kir6.2 channels due to increased open probability. Bath application of alkali pH similarly activates native islet beta-cell K(ATP) channels, leading to an inhibition of action potentials, and hyperpolarization of membrane potential. In situ pancreatic perfusion confirms that these cellular effects of alkali pH are observable at a functional level, resulting in decreases in both phase 1 and phase 2 glucose-stimulated insulin secretion. Our data are the first to report a stimulatory effect of a range of alkali pH on K(ATP) channel activity and link this to downstream effects on islet beta-cell function.

  8. Do immunotherapy and beta cell replacement play a synergistic role in the treatment of type 1 diabetes?

    Science.gov (United States)

    Li, Dong-Sheng; Warnock, Garth L; Tu, Han-Jun; Ao, Ziliang; He, Zehua; Lu, Hong; Dai, Long-Jun

    2009-10-07

    Type 1 diabetes (T1D) is the result of the autoimmune response against pancreatic insulin-producing ss-cells. Its ultimate consequence is beta-cell insufficiency-mediated dysregulation of blood glucose control. In terms of T1D treatment, immunotherapy addresses the cause of T1D, mainly through re-setting the balance between autoimmunity and regulatory mechanisms. Regulatory T cells play an important role in this immune intervention. An alternative T1D treatment is beta-cell replacement, which can reverse the consequence of the disease by replacing destroyed beta-cells in the diabetic pancreas. The applicable insulin-producing cells can be directly obtained from islet transplantation or generated from other cell sources such as autologous adult stem cells, embryonic stem cells, and induced pluripotent stem cells. In this review, we summarize the recent research progress and analyze the possible advantages and disadvantages of these two therapeutic options especially focusing on the potential synergistic effect on T1D treatment. Exploring the optimal combination of immunotherapy and beta-cell replacement will pave the way to the most effective cure for this devastating disease.

  9. Rising Intracellular Zinc by Membrane Depolarization and Glucose in Insulin-Secreting Clonal HIT-T15 Beta Cells

    Directory of Open Access Journals (Sweden)

    Kira G. Slepchenko

    2012-01-01

    Full Text Available Zinc (Zn2+ appears to be intimately involved in insulin metabolism since insulin secretion is correlated with zinc secretion in response to glucose stimulation, but little is known about the regulation of zinc homeostasis in pancreatic beta-cells. This study set out to identify the intracellular zinc transient by imaging free cytosolic zinc in HIT-T15 beta-cells with fluorescent zinc indicators. We observed that membrane depolarization by KCl (30–60 mM was able to induce a rapid increase in cytosolic concentration of zinc. Multiple zinc transients of similar magnitude were elicited during repeated stimulations. The amplitude of zinc responses was not affected by the removal of extracellular calcium or zinc. However, the half-time of the rising slope was significantly slower after removing extracellular zinc with zinc chelator CaEDTA, suggesting that extracellular zinc affect the initial rising phase of zinc response. Glucose (10 mM induced substantial and progressive increases in intracellular zinc concentration in a similar way as KCl, with variation in the onset and the duration of zinc mobilization. It is known that the depolarization of beta-cell membrane is coupled with the secretion of insulin. Rising intracellular zinc concentration may act as a critical signaling factor in insulin metabolism of pancreatic beta-cells.

  10. Rising intracellular zinc by membrane depolarization and glucose in insulin-secreting clonal HIT-T15 beta cells.

    Science.gov (United States)

    Slepchenko, Kira G; Li, Yang V

    2012-01-01

    Zinc (Zn(2+)) appears to be intimately involved in insulin metabolism since insulin secretion is correlated with zinc secretion in response to glucose stimulation, but little is known about the regulation of zinc homeostasis in pancreatic beta-cells. This study set out to identify the intracellular zinc transient by imaging free cytosolic zinc in HIT-T15 beta-cells with fluorescent zinc indicators. We observed that membrane depolarization by KCl (30-60 mM) was able to induce a rapid increase in cytosolic concentration of zinc. Multiple zinc transients of similar magnitude were elicited during repeated stimulations. The amplitude of zinc responses was not affected by the removal of extracellular calcium or zinc. However, the half-time of the rising slope was significantly slower after removing extracellular zinc with zinc chelator CaEDTA, suggesting that extracellular zinc affect the initial rising phase of zinc response. Glucose (10 mM) induced substantial and progressive increases in intracellular zinc concentration in a similar way as KCl, with variation in the onset and the duration of zinc mobilization. It is known that the depolarization of beta-cell membrane is coupled with the secretion of insulin. Rising intracellular zinc concentration may act as a critical signaling factor in insulin metabolism of pancreatic beta-cells.

  11. Bursting synchronization in clustered neuronal networks

    International Nuclear Information System (INIS)

    Yu Hai-Tao; Wang Jiang; Deng Bin; Wei Xi-Le

    2013-01-01

    Neuronal networks in the brain exhibit the modular (clustered) property, i.e., they are composed of certain subnetworks with differential internal and external connectivity. We investigate bursting synchronization in a clustered neuronal network. A transition to mutual-phase synchronization takes place on the bursting time scale of coupled neurons, while on the spiking time scale, they behave asynchronously. This synchronization transition can be induced by the variations of inter- and intracoupling strengths, as well as the probability of random links between different subnetworks. Considering that some pathological conditions are related with the synchronization of bursting neurons in the brain, we analyze the control of bursting synchronization by using a time-periodic external signal in the clustered neuronal network. Simulation results show a frequency locking tongue in the driving parameter plane, where bursting synchronization is maintained, even in the presence of external driving. Hence, effective synchronization suppression can be realized with the driving parameters outside the frequency locking region. (interdisciplinary physics and related areas of science and technology)

  12. Proinsulin maturation disorder is a contributor to the defect of subsequent conversion to insulin in {beta}-cells

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Jie, E-mail: jie.wang2@osumc.edu [Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, The Ohio State University, Columbus, OH (United States); Osei, Kwame [Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, The Ohio State University, Columbus, OH (United States)

    2011-07-22

    Highlights: {yields} Primary proinsulin maturation disorder is inherent in Ins2{sup +/Akita} islets/{beta}-cells. {yields} A consequence is the inefficient conversion of proinsulin to insulin. {yields} Post-translational defects occur as well in the involved PC1/3 and PC2 convertases. {yields} Proinsulin maturation chaos results in defects in the following conversion process. {yields} A link of the proinsulin maturation disorder and hyperproinsulinemia is suggested. -- Abstract: Disproportionate hyperproinsulinemia is an indicator of {beta}-cell dysfunction in diabetes and the basis underlying this abnormality remains obscure. Recently, we have found proinsulin is an aggregation-prone molecule inherent with a low relative folding rate and maintains a homeostatic balance of natively and plentiful non-natively folded states (i.e., proinsulin homeostasis, PIHO) in normal {beta}-cells as a result of the integration of maturation and disposal processes. PIHO is susceptible to environmental and genetic influences. Perturbation of PIHO produces a number of toxic consequences with known association to {beta}-cell failure in diabetes. To explore whether the perturbation of PIHO has a link to disproportionate hyperproinsulinemia, we investigated proinsulin conversion and the involved prohormone convertase 1/3 (PC1/3) and 2 (PC2) in mouse Ins2{sup +/Akita} islets/{beta}-cells that preserve a primary PIHO disorder due to a mutation (C96Y) in the insulin 2 (Ins2) gene. Our metabolic-labeling studies found an increased ratio of proinsulin to insulin in the cellular or released proteins of Ins2{sup +/Akita} islets. Histological, metabolic-labeling, and RT-PCR analyses revealed decreases of the PC1/3 and PC2 immunoreactivities in the {beta}-cells of Ins2{sup +/Akita} islets in spite of no declines of these two convertases at the transcriptional and translational levels. Immunoblot analyses in cloned Ins2{sup +/Akita} {beta}-cells further confirmed the increased ratio of proinsulin

  13. Nanolensed Fast Radio Bursts

    Science.gov (United States)

    Eichler, David

    2017-12-01

    It is suggested that fast radio bursts can probe gravitational lensing by clumpy dark matter objects that range in mass from 10-3 M ⊙-102 M ⊙. They may provide a more sensitive probe than observations of lensings of objects in the Magellanic Clouds, and could find or rule out clumpy dark matter with an extended mass spectrum.

  14. Effect of prolonged exposure to sublethal concentrations of DDT and DDE on protein expression in human pancreatic beta cells.

    Science.gov (United States)

    Pavlikova, Nela; Smetana, Pavel; Halada, Petr; Kovar, Jan

    2015-10-01

    Pollution of the environment represents one of less explored potential reasons for the worldwide epidemic of type 2 diabetes. One of the most prevalent organochlorine pollutants remains the pesticide DDT and its degradation product DDE. Despite some epidemiologic correlations between levels of DDT and DDE in human organism and the prevalence of diabetes, there is almost no information about the exact targets of these compounds inside pancreatic beta cells. To detect functional areas of pancreatic beta cells that could be affected by exposure to DDT and DDE, we analyzed changes in protein expression in the NES2Y human pancreatic beta cell line exposed to three sublethal concentrations (0.1 μM, 1 μM, 10 μM) of DDT and DDE for 1 month. Protein separation and identification was achieved using high-resolution 2D-electrophoresis, computer analysis and mass spectrometry. With these techniques, four proteins were found downregulated after exposure to 10 μM DDT: three cytoskeletal proteins (cytokeratin 8, cytokeratin 18 and actin) and one protein involved in glycolysis (alpha-enolase). Two proteins were downregulated after exposure to 10 μM DDE: cytokeratin 18 and heterogenous nuclear ribonucleoprotein H1 (HNRH1). These changes correlate with previously described effects of other stress conditions (e.g. exposure to palmitate, hyperglycemia, imidazoline derivative, and cytokines) on protein expression in pancreatic beta cells. We conclude that cytoskeletal proteins and their processing, glucose metabolism, and mRNA processing may represent targets affected by exposure to conditions hostile to pancreatic beta cells, including exposure to DDT and DDE. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. Stevioside improves pancreatic beta-cell function during glucotoxicity via regulation of acetyl-CoA carboxylase.

    Science.gov (United States)

    Chen, Jianguo; Jeppesen, Per Bendix; Nordentoft, Iver; Hermansen, Kjeld

    2007-06-01

    Chronic hyperglycemia is detrimental to pancreatic beta-cells, causing impaired insulin secretion and beta-cell turnover. The characteristic secretory defects are increased basal insulin secretion (BIS) and a selective loss of glucose-stimulated insulin secretion (GSIS). Several recent studies support the view that the acetyl-CoA carboxylase (ACC) plays a pivotal role for GSIS. We have shown that stevioside (SVS) enhances insulin secretion and ACC gene expression. Whether glucotoxicity influences ACC and whether this action can be counteracted by SVS are not known. To investigate this, we exposed isolated mouse islets as well as clonal INS-1E beta-cells for 48 h to 27 or 16.7 mM glucose, respectively. We found that 48-h exposure to high glucose impairs GSIS from mouse islets and INS-1E cells, an effect that is partly counteracted by SVS. The ACC dephosphorylation inhibitor okadaic acid (OKA, 10(-8) M), and 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR, 10(-4) M), an activator of 5'-AMP protein kinase that phosphorylates ACC, eliminated the beneficial effect of SVS. 5-Tetrade-cyloxy-2-furancarboxylic acid (TOFA), the specific ACC inhibitor, blocked the effect of SVS as well. During glucotoxity, ACC gene expression, ACC protein, and phosphorylated ACC protein were increased in INS-1E beta-cells. SVS pretreatment further increased ACC gene expression with strikingly elevated ACC activity and increased glucose uptake accompanied by enhanced GSIS. Our studies show that glucose is a potent stimulator of ACC and that SVS to some extent counteracts glucotoxicity via increased ACC activity. SVS possesses the potential to alleviate negative effects of glucotoxicity in beta-cells via a unique mechanism of action.

  16. PARP-1 and YY1 are important novel regulators of CXCL12 gene transcription in rat pancreatic beta cells.

    Directory of Open Access Journals (Sweden)

    Jelena Marković

    Full Text Available Despite significant progress, the molecular mechanisms responsible for pancreatic beta cell depletion and development of diabetes remain poorly defined. At present, there is no preventive measure against diabetes. The positive impact of CXCL12 expression on the pancreatic beta cell prosurvival phenotype initiated this study. Our aim was to provide novel insight into the regulation of rat CXCL12 gene (Cxcl12 transcription. The roles of poly(ADP-ribose polymerase-1 (PARP-1 and transcription factor Yin Yang 1 (YY1 in Cxcl12 transcription were studied by examining their in vitro and in vivo binding affinities for the Cxcl12 promoter in a pancreatic beta cell line by the electrophoretic mobility shift assay and chromatin immunoprecipitation. The regulatory activities of PARP-1 and YY1 were assessed in transfection experiments using a reporter vector with a Cxcl12 promoter sequence driving luciferase gene expression. Experimental evidence for PARP-1 and YY1 revealed their trans-acting potential, wherein PARP-1 displayed an inhibitory, and YY1 a strong activating effect on Cxcl12 transcription. Streptozotocin (STZ-induced general toxicity in pancreatic beta cells was followed by changes in Cxcl12 promoter regulation. PARP-1 binding to the Cxcl12 promoter during basal and in STZ-compromised conditions led us to conclude that PARP-1 regulates constitutive Cxcl12 expression. During the early stage of oxidative stress, YY1 exhibited less affinity toward the Cxcl12 promoter while PARP-1 displayed strong binding. These interactions were accompanied by Cxcl12 downregulation. In the later stages of oxidative stress and intensive pancreatic beta cell injury, YY1 was highly expressed and firmly bound to Cxcl12 promoter in contrast to PARP-1. These interactions resulted in higher Cxcl12 expression. The observed ability of PARP-1 to downregulate, and of YY1 to upregulate Cxcl12 promoter activity anticipates corresponding effects in the natural context where the

  17. Adult Human Pancreatic Islet Beta-Cells Display Limited Turnover and Long Lifespan as Determined by In-Vivo Thymidine Analog Incorporation and Radiocarbon Dating

    Energy Technology Data Exchange (ETDEWEB)

    Perl, S; Kushner, J A; Buchholz, B A; Meeker, A K; Stein, G M; Hsieh, M; Kirby, M; Pechhold, S; Liu, E H; Harlan, D M; Tisdale, J F

    2010-03-15

    Diabetes mellitus results from an absolute or relative deficiency of insulin producing pancreatic beta-cells. The adult human beta-cell's turnover rate remains unknown. We employed novel techniques to examine adult human islet beta-cell turnover and longevity in vivo. Subjects enrolled in NIH clinical trials received thymidine analogues [iododeoxyuridine (IdU) or bromodeoxyuridine (BrdU)] 8-days to 4-years prior to death. Archival autopsy samples from ten patients (aged 17-74 years) were employed to assess beta-cell turnover by scoring nuclear analog labeling within insulin staining cells. Human adult beta-cell longevity was determined by estimating the cells genomic DNA integration of atmospheric carbon-14 ({sup 14}C). DNA was purified from pancreatic islets isolated from cadaveric donors; whole islet prep DNA was obtained from a 15 year old donor, and purified beta-cell DNA was obtained from two donors (age 48 and 80 years). {sup 14}C levels were then determined using accelerator mass spectrometry (AMS). Cellular 'birth date' was determined by comparing the subject's DNA {sup 14}C content relative to a well-established {sup 14}C atmospheric prevalence curve. In the two subjects less than age 20 years, 1-2% of the beta-cell nuclei co-stained for BrdU/IdU. No beta-cell nuclei co-stained in the eight patients more than 30 years old. Consistent with the BrdU/IdU turnover data, beta-cell DNA {sup 14}C content indicated the cells 'birth date' occurred within the subject's first 30 years of life. Under typical circumstances, adult human beta-cells and their cellular precursors are established by young adulthood.

  18. Burst suppression in sleep in a routine outpatient EEG

    Directory of Open Access Journals (Sweden)

    Ammar Kheder

    2014-01-01

    Full Text Available Burst suppression (BS is an electroencephalogram (EEG pattern that is characterized by brief bursts of spikes, sharp waves, or slow waves of relatively high amplitude alternating with periods of relatively flat EEG or isoelectric periods. The pattern is usually associated with coma, severe encephalopathy of various etiologies, or general anesthesia. We describe an unusual case of anoxic brain injury in which a BS pattern was seen during behaviorally defined sleep during a routine outpatient EEG study.

  19. Burst suppression in sleep in a routine outpatient EEG ?

    OpenAIRE

    Kheder, Ammar; Bianchi, Matt T.; Westover, M. Brandon

    2014-01-01

    Burst suppression (BS) is an electroencephalogram (EEG) pattern that is characterized by brief bursts of spikes, sharp waves, or slow waves of relatively high amplitude alternating with periods of relatively flat EEG or isoelectric periods. The pattern is usually associated with coma, severe encephalopathy of various etiologies, or general anesthesia. We describe an unusual case of anoxic brain injury in which a BS pattern was seen during behaviorally defined sleep during a routine outpatient...

  20. Multi-Index Monitoring and Evaluation on Rock Burst in Yangcheng Mine

    Directory of Open Access Journals (Sweden)

    Yunliang Tan

    2015-01-01

    Full Text Available Based on the foreboding information monitoring of the energy released in the developing process of rock burst, prediction system for rock burst can be established. By using microseismic method, electromagnetic radiation method, and drilling bits method, rock burst in Yangcheng Mine was monitored, and a system of multi-index monitoring and evaluation on rock burst was established. Microseismic monitoring and electromagnetic radiation monitoring were early warning method, and drilling bits monitoring was burst region identification method. There were three identifying indexes: silence period in microseismic monitoring, rising period of the intensity, and rising period of pulse count in electromagnetic radiation monitoring. If there is identified burst risk in the workface, drilling bits method was used to ascertain the burst region, and then pressure releasing methods were carried out to eliminate the disaster.

  1. A repeating fast radio burst.

    Science.gov (United States)

    Spitler, L G; Scholz, P; Hessels, J W T; Bogdanov, S; Brazier, A; Camilo, F; Chatterjee, S; Cordes, J M; Crawford, F; Deneva, J; Ferdman, R D; Freire, P C C; Kaspi, V M; Lazarus, P; Lynch, R; Madsen, E C; McLaughlin, M A; Patel, C; Ransom, S M; Seymour, A; Stairs, I H; Stappers, B W; van Leeuwen, J; Zhu, W W

    2016-03-10

    Fast radio bursts are millisecond-duration astronomical radio pulses of unknown physical origin that appear to come from extragalactic distances. Previous follow-up observations have failed to find additional bursts at the same dispersion measure (that is, the integrated column density of free electrons between source and telescope) and sky position as the original detections. The apparent non-repeating nature of these bursts has led to the suggestion that they originate in cataclysmic events. Here we report observations of ten additional bursts from the direction of the fast radio burst FRB 121102. These bursts have dispersion measures and sky positions consistent with the original burst. This unambiguously identifies FRB 121102 as repeating and demonstrates that its source survives the energetic events that cause the bursts. Additionally, the bursts from FRB 121102 show a wide range of spectral shapes that appear to be predominantly intrinsic to the source and which vary on timescales of minutes or less. Although there may be multiple physical origins for the population of fast radio bursts, these repeat bursts with high dispersion measure and variable spectra specifically seen from the direction of FRB 121102 support an origin in a young, highly magnetized, extragalactic neutron star.

  2. Gamma-ray bursts

    CERN Document Server

    Wijers, Ralph A M J; Woosley, Stan

    2012-01-01

    Cosmic gamma ray bursts (GRBs) have fascinated scientists and the public alike since their discovery in the late 1960s. Their story is told here by some of the scientists who participated in their discovery and, after many decades of false starts, solved the problem of their origin. Fourteen chapters by active researchers in the field present a detailed history of the discovery, a comprehensive theoretical description of GRB central engine and emission models, a discussion of GRB host galaxies and a guide to how GRBs can be used as cosmological tools. Observations are grouped into three sets from the satellites CGRO, BeppoSAX and Swift, and followed by a discussion of multi-wavelength observations. This is the first edited volume on GRB astrophysics that presents a fully comprehensive review of the subject. Utilizing the latest research, Gamma-ray Bursts is an essential desktop companion for graduate students and researchers in astrophysics.

  3. Effect of prolonged exposure to sublethal concentrations of DDT and DDE on protein expression in human pancreatic beta cells

    Energy Technology Data Exchange (ETDEWEB)

    Pavlikova, Nela, E-mail: nela.pavlikova@lf3.cuni.cz [Department of Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Prague (Czech Republic); Smetana, Pavel [Department of Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Prague (Czech Republic); Halada, Petr [Laboratory of Molecular Structure Characterization, Institute of Microbiology, Academy of Sciences of the Czech Republic, Prague (Czech Republic); Kovar, Jan [Department of Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Prague (Czech Republic)

    2015-10-15

    Pollution of the environment represents one of less explored potential reasons for the worldwide epidemic of type 2 diabetes. One of the most prevalent organochlorine pollutants remains the pesticide DDT and its degradation product DDE. Despite some epidemiologic correlations between levels of DDT and DDE in human organism and the prevalence of diabetes, there is almost no information about the exact targets of these compounds inside pancreatic beta cells. To detect functional areas of pancreatic beta cells that could be affected by exposure to DDT and DDE, we analyzed changes in protein expression in the NES2Y human pancreatic beta cell line exposed to three sublethal concentrations (0.1 μM, 1 μM, 10 μM) of DDT and DDE for 1 month. Protein separation and identification was achieved using high-resolution 2D-electrophoresis, computer analysis and mass spectrometry. With these techniques, four proteins were found downregulated after exposure to 10 μM DDT: three cytoskeletal proteins (cytokeratin 8, cytokeratin 18 and actin) and one protein involved in glycolysis (alpha-enolase). Two proteins were downregulated after exposure to 10 μM DDE: cytokeratin 18 and heterogenous nuclear ribonucleoprotein H1 (HNRH1). These changes correlate with previously described effects of other stress conditions (e.g. exposure to palmitate, hyperglycemia, imidazoline derivative, and cytokines) on protein expression in pancreatic beta cells. We conclude that cytoskeletal proteins and their processing, glucose metabolism, and mRNA processing may represent targets affected by exposure to conditions hostile to pancreatic beta cells, including exposure to DDT and DDE. - Highlights: • Epidemiologic studies connect pollution with incidence of diabetes mellitus. • We explored the effect of DDT and DDE on protein expression in the NES2Y pancreatic beta cell line. • One month exposure to three sublethal concentrations of DDT and DDE was employed. • Expression of alpha-enolase, actin

  4. Effect of prolonged exposure to sublethal concentrations of DDT and DDE on protein expression in human pancreatic beta cells

    International Nuclear Information System (INIS)

    Pavlikova, Nela; Smetana, Pavel; Halada, Petr; Kovar, Jan

    2015-01-01

    Pollution of the environment represents one of less explored potential reasons for the worldwide epidemic of type 2 diabetes. One of the most prevalent organochlorine pollutants remains the pesticide DDT and its degradation product DDE. Despite some epidemiologic correlations between levels of DDT and DDE in human organism and the prevalence of diabetes, there is almost no information about the exact targets of these compounds inside pancreatic beta cells. To detect functional areas of pancreatic beta cells that could be affected by exposure to DDT and DDE, we analyzed changes in protein expression in the NES2Y human pancreatic beta cell line exposed to three sublethal concentrations (0.1 μM, 1 μM, 10 μM) of DDT and DDE for 1 month. Protein separation and identification was achieved using high-resolution 2D-electrophoresis, computer analysis and mass spectrometry. With these techniques, four proteins were found downregulated after exposure to 10 μM DDT: three cytoskeletal proteins (cytokeratin 8, cytokeratin 18 and actin) and one protein involved in glycolysis (alpha-enolase). Two proteins were downregulated after exposure to 10 μM DDE: cytokeratin 18 and heterogenous nuclear ribonucleoprotein H1 (HNRH1). These changes correlate with previously described effects of other stress conditions (e.g. exposure to palmitate, hyperglycemia, imidazoline derivative, and cytokines) on protein expression in pancreatic beta cells. We conclude that cytoskeletal proteins and their processing, glucose metabolism, and mRNA processing may represent targets affected by exposure to conditions hostile to pancreatic beta cells, including exposure to DDT and DDE. - Highlights: • Epidemiologic studies connect pollution with incidence of diabetes mellitus. • We explored the effect of DDT and DDE on protein expression in the NES2Y pancreatic beta cell line. • One month exposure to three sublethal concentrations of DDT and DDE was employed. • Expression of alpha-enolase, actin

  5. The Cytotoxic Role of Intermittent High Glucose on Apoptosis and Cell Viability in Pancreatic Beta Cells

    Directory of Open Access Journals (Sweden)

    Zhen Zhang

    2014-01-01

    Full Text Available Objectives. Glucose fluctuations are both strong predictor of diabetic complications and crucial factor for beta cell damages. Here we investigated the effect of intermittent high glucose (IHG on both cell apoptosis and proliferation activity in INS-1 cells and the potential mechanisms. Methods. Cells were treated with normal glucose (5.5 mmol/L, constant high glucose (CHG (25 mmol/L, and IHG (rotation per 24 h in 11.1 or 25 mmol/L for 7 days. Reactive oxygen species (ROS, xanthine oxidase (XOD level, apoptosis, cell viability, cell cycle, and expression of cyclinD1, p21, p27, and Skp2 were determined. Results. We found that IHG induced more significant apoptosis than CHG and normal glucose; intracellular ROS and XOD levels were more markedly increased in cells exposed to IHG. Cells treated with IHG showed significant decreased cell viability and increased cell proportion in G0/G1 phase. Cell cycle related proteins such as cyclinD1 and Skp2 were decreased significantly, but expressions of p27 and p21 were increased markedly. Conclusions. This study suggested that IHG plays a more toxic effect including both apoptosis-inducing and antiproliferative effects on INS-1 cells. Excessive activation of cellular stress and regulation of cyclins might be potential mechanism of impairment in INS-1 cells induced by IHG.

  6. Profile of blood glucose and ultrastucture of beta cells pancreatic islet in alloxan compound induced rats

    Directory of Open Access Journals (Sweden)

    I Nyoman Suarsana

    2010-06-01

    Full Text Available Diabetes is marked by elevated levels of blood glucose, and progressive changes of the structure of pancreatic islet histopathology. The objective of this research was to analyse the glucose level and histophatological feature in pancreatic islet in alloxan compound induced rats. A total of ten male Spraque Dawley rats of 2 months old were used in this study. The rats were divided into two groups: (1 negative control group (K-, and (2 positif induced alloxan group (diabetic group =DM. The rats were induced by a single dose intraperitonial injection of alloxan compound 120 mg/kg of body weight. The treatment was conducted for 28 days. Blood glucose levels of rats were analysed at 0, 4, 7, 14, 21, and 28 days following treatment. At the end of the experiment, rats were sacrificed by cervical dislocation. Pancreas was collected for analysis of histopathological study by Immunohistochemical technique, and ultrastructural study using transmission electron microscope (TEM. The result showed that Langerhans islet of diabetic rat (rat of DM group showed a marked reduction of size, number of Langerhans islet of diabetic rat decrease, and characterized by hyperglycemic condition. By using TEM, beta cells of DM group showed the rupture of mitochondrial membrane, the lost of cisternal structure of inner membrane of mitocondria, reduction of insulin secretory granules, linkage between cells acinar with free Langerhans islet, and the caryopicnotic of nucleus.

  7. GTP- and GDP-Dependent Rab27a Effectors in Pancreatic Beta-Cells.

    Science.gov (United States)

    Yamaoka, Mami; Ishizaki, Toshimasa; Kimura, Toshihide

    2015-01-01

    Small guanosine triphosphatases (GTPases) participate in a wide variety of cellular functions including proliferation, differentiation, adhesion, and intracellular transport. Conventionally, only the guanosine 5'-triphosphate (GTP)-bound small GTPase interacts with effector proteins, and the resulting downstream signals control specific cellular functions. Therefore, the GTP-bound form is regarded as active, and the focus has been on searching for proteins that bind the GTP form to look for their effectors. The Rab family small GTPase Rab27a is highly expressed in some secretory cells and is involved in the control of membrane traffic. The present study reviews recent progress in our understanding of the roles of Rab27a and its effectors in pancreatic beta-cells. In the basal state, GTP-bound Rab27a controls insulin secretion at pre-exocytic stages via its GTP-dependent effectors. We previously identified novel guanosine 5'-diphosphate (GDP)-bound Rab27-interacting proteins. Interestingly, GDP-bound Rab27a controls endocytosis of the secretory membrane via its interaction with these proteins. We also demonstrated that the insulin secretagogue glucose converts Rab27a from its GTP- to GDP-bound forms. Thus, GTP- and GDP-bound Rab27a regulate pre-exocytic and endocytic stages in membrane traffic, respectively. Since the physiological importance of GDP-bound GTPases has been largely overlooked, we consider that the investigation of GDP-dependent effectors for other GTPases is necessary for further understanding of cellular function.

  8. Longitudinal Changes in Insulin Resistance, Beta-Cell Function and Glucose Regulation Status in Prediabetes.

    Science.gov (United States)

    Kim, Chul-Hee; Kim, Hong-Kyu; Kim, Eun-Hee; Bae, Sung-Jin; Choe, Jaewon; Park, Joong-Yeol

    2018-01-01

    The changes in insulin resistance and insulin secretion and their association with changes in glucose regulation status in Asians with prediabetes remain uncertain. We included Korean adults (aged 20-79 years) with prediabetes who underwent routine medical check-ups at a mean interval of 5 years. Prediabetes was defined as fasting plasma glucose (FPG) 5.6-6.9mmol/l or HbA1c 5.7-6.4% (39-46mmol/mol). Insulin resistance (HOMA-IR) and beta-cell function (HOMA-%B) indices were assessed by homeostasis model assessment. Incident diabetes was defined as FPG ≥ 7.0mmol/l, HbA1c ≥ 6.5% (48mmol/mol), or initiation of antidiabetic medications. Among the 7,208 participants with prediabetes, 4,410 (61.2%) remained as prediabetes (control group), 2,123 (29.5%) reverted to normal glucose regulation (regressors), and 675 (9.4%) progressed to type 2 diabetes (progressors) after 5 years. Compared with the control group, the progressors had higher baseline HOMA-IR (2.48 ± 1.45 versus 2.06 ± 1.20, P prediabetes, longitudinal change in insulin resistance was the predominant factor in Koreans. Copyright © 2018 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.

  9. Oxidative Stress Type Influences the Properties of Antioxidants Containing Polyphenols in RINm5F Beta Cells

    Directory of Open Access Journals (Sweden)

    Nathalie Auberval

    2015-01-01

    Full Text Available The in vitro methods currently used to screen bioactive compounds focus on the use of a single model of oxidative stress. However, this simplistic view may lead to conflicting results. The aim of this study was to evaluate the antioxidant properties of two natural extracts (a mix of red wine polyphenols (RWPs and epigallocatechin gallate (EGCG with three models of oxidative stress induced with hydrogen peroxide (H2O2, a mixture of hypoxanthine and xanthine oxidase (HX/XO, or streptozotocin (STZ in RINm5F beta cells. We employed multiple approaches to validate their potential as therapeutic treatment options, including cell viability, reactive oxygen species production, and antioxidant enzymes expression. All three oxidative stresses induced a decrease in cell viability and an increase in apoptosis, whereas the level of ROS production was variable depending on the type of stress. The highest level of ROS was found for the HX/XO-induced stress, an increase that was reflected by higher expression antioxidant enzymes. Further, both antioxidant compounds presented beneficial effects during oxidative stress, but EGCG appeared to be a more efficient antioxidant. These data indicate that the efficiency of natural antioxidants is dependent on both the nature of the compound and the type of oxidative stress generated.

  10. Measuring phospholipase D activity in insulin-secreting pancreatic beta-cells and insulin-responsive muscle cells and adipocytes.

    Science.gov (United States)

    Cazzolli, Rosanna; Huang, Ping; Teng, Shuzhi; Hughes, William E

    2009-01-01

    Phospholipase D (PLD) is an enzyme producing phosphatidic acid and choline through hydrolysis of phosphatidylcholine. The enzyme has been identified as a member of a variety of signal transduction cascades and as a key regulator of numerous intracellular vesicle trafficking processes. A role for PLD in regulating glucose homeostasis is emerging as the enzyme has recently been identified in events regulating exocytosis of insulin from pancreatic beta-cells and also in insulin-stimulated glucose uptake through controlling GLUT4 vesicle exocytosis in muscle and adipose tissue. We present methodologies for assessing cellular PLD activity in secretagogue-stimulated insulin-secreting pancreatic beta-cells and also insulin-stimulated adipocyte and muscle cells, two of the principal insulin-responsive cell types controlling blood glucose levels.

  11. Impaired beta cell sensitivity to incretins in type 2 diabetes is insufficiently compensated by higher incretin response

    DEFF Research Database (Denmark)

    Tura, A.; Bagger, J. I.; Ferrannini, E.

    2017-01-01

    Background and aims The incretin effect is impaired in type 2 diabetes (T2D), but the underlying mechanisms are only partially understood. We investigated the relationships between the time course of the incretin effect and that of glucose-dependent insulinotropic polypeptide (GIP) and glucagon......-like peptide-1 (GLP-1) during oral glucose tolerance tests (OGTTs), thereby estimating incretin sensitivity of the beta cell, and its associated factors. Methods and results Eight patients with T2D and eight matched subjects with normal glucose tolerance (NGT) received 25, 75, and 125 g OGTTs and corresponding...... was correlated with that of both GIP and GLP-1 in each subject (median r = 0.67 in NGT and 0.45 in T2D). We calculated an individual beta cell sensitivity to incretins (SINCR) using a weighted average of GIP and GLP-1 (pooled incretin concentration, PIC), as the slope of the relationship between PINCR and PIC...

  12. Insulin resistance and beta-cell function in different ethnic groups in Kenya: the role of abdominal fat distribution

    DEFF Research Database (Denmark)

    Christensen, D.L.; Faurholt-Jepsen, D.; Faerch, K.

    2014-01-01

    Little is known about the pathophysiology of diabetes in Africans. Thus, we assessed whether insulin resistance and beta-cell function differed by ethnicity in Kenya and whether differences were modified by abdominal fat distribution. A cross-sectional study in 1,087 rural Luo (n = 361), Kamba (n...... to the Luo and Kamba, respectively. Adjustments of SAT (range 0.1–7.1 cm) and VAT (range 1.5–14.2 cm) largely explained these inter-group differences with the Maasai having the highest combined abdominal fat accumulation. The Maasai had the highest insulin resistance and secretion, but the lowest relative...... beta-cell function compared to the Luo and Kamba. These differences were primarily explained by abdominal fat distribution....

  13. Role of transcription factor KLF11 and its diabetes-associated gene variants in pancreatic beta cell function

    DEFF Research Database (Denmark)

    Neve, Bernadette; Fernandez-Zapico, Martin E; Ashkenazi-Katalan, Vered

    2005-01-01

    in beta cells. Genetic analysis of the KLF11 gene revealed two rare variants (Ala347Ser and Thr220Met) that segregate with diabetes in families with early-onset type 2 diabetes, and significantly impair its transcriptional activity. In addition, analysis of 1,696 type 2 diabetes mellitus and 1......,776 normoglycemic subjects show a frequent polymorphic Gln62Arg variant that significantly associates with type 2 diabetes mellitus in North European populations (OR = 1.29, P = 0.00033). Moreover, this variant alters the corepressor mSin3A-binding activity of KLF11, impairs the activation of the insulin promoter...... and shows lower levels of insulin expression in pancreatic beta cells. In addition, subjects carrying the Gln62Arg allele show decreased plasma insulin after an oral glucose challenge. Interestingly, all three nonsynonymous KLF11 variants show increased repression of the catalase 1 promoter, suggesting...

  14. Phenotypic and gene expression changes between low (glucose-responsive) and High (glucose non-responsive) MIN-6 beta cells

    DEFF Research Database (Denmark)

    O´Driscoll, L.; Gammell, p.; McKierman, E.

    2006-01-01

    The long-term potential to routinely use replacement beta cells/islets as cell therapy for type 1 diabetes relies on our ability to culture such cells/islets, in vitro, while maintaining their functional status. Previous beta cell studies, by ourselves and other researchers, have indicated...... that the glucose-stimulated insulin secretion (GSIS) phenotype is relatively unstable, in long-term culture. This study aimed to investigate phenotypic and gene expression changes associated with this loss of GSIS, using the MIN-6 cell line as model. Phenotypic differences between MIN-6(L, low passage) and MIN-6(H......, high passage) were determined by ELISA (assessing GSIS and cellular (pro)insulin content), proliferation assays, phase contrast light microscopy and analysis of alkaline phosphatase expression. Differential mRNA expression was investigated using microarray, bioinformatics and real-time PCR technologies...

  15. Different types of bursting calcium oscillations in non-excitable cells

    International Nuclear Information System (INIS)

    Perc, Matjaz; Marhl, Marko

    2003-01-01

    In the paper different types of bursting Ca 2+ oscillations are presented. We analyse bursting behaviour in four recent mathematical models for Ca 2+ oscillations in non-excitable cells. Separately, regular, quasi-periodic, and chaotic bursting Ca 2+ oscillations are classified into several subtypes. The classification is based on the dynamics of separated fast and slow subsystems, the so-called fast-slow burster analysis. For regular bursting Ca 2+ oscillations two types of bursting are specified: Point-Point and Point-Cycle bursting. In particular, the slow passage effect, important for the Hopf-Hopf and SubHopf-SubHopf bursting subtypes, is explained by local divergence calculated for the fast subsystem. Quasi-periodic bursting Ca 2+ oscillations can be found in only one of the four studied mathematical models and appear via a homoclinic bifurcation with a homoclinic torus structure. For chaotic bursting Ca 2+ oscillations, we found that bursting patterns resulting from the period doubling root to chaos considerably differ from those appearing via intermittency and have to be treated separately. The analysis and classification of different types of bursting Ca 2+ oscillations provides better insight into mechanisms of complex intra- and intercellular Ca 2+ signalling. This improves our understanding of several important biological phenomena in cellular signalling like complex frequency-amplitude signal encoding and synchronisation of intercellular signal transduction between coupled cells in tissue

  16. Metabolomic and proteomic analysis of a clonal insulin-producing beta-cell line (INS-1 832/13).

    Science.gov (United States)

    Fernandez, Céline; Fransson, Ulrika; Hallgard, Elna; Spégel, Peter; Holm, Cecilia; Krogh, Morten; Wårell, Kristofer; James, Peter; Mulder, Hindrik

    2008-01-01

    Metabolites generated from fuel metabolism in pancreatic beta-cells control exocytosis of insulin, a process which fails in type 2 diabetes. To identify and quantify these metabolites, global and unbiased analysis of cellular metabolism is required. To this end, polar metabolites, extracted from the clonal 832/13 beta-cell line cultured at 2.8 and 16.7 mM glucose for 48 h, were derivatized followed by identification and quantification, using gas chromatography (GC) and mass spectrometry (MS). After culture at 16.7 mM glucose for 48 h, 832/13 beta-cells exhibited a phenotype reminiscent of glucotoxicity with decreased content and secretion of insulin. The metabolomic analysis revealed alterations in the levels of 7 metabolites derived from glycolysis, the TCA cycle and pentose phosphate shunt, and 4 amino acids. Principal component analysis of the metabolite data showed two clusters, corresponding to the cells cultured at 2.8 and 16.7 mM glucose, respectively. Concurrent changes in protein expression were analyzed by 2-D gel electrophoresis followed by LC-MS/MS. The identities of 86 spots corresponding to 75 unique proteins that were significantly different in 832/13 beta-cells cultured at 16.7 mM glucose were established. Only 5 of these were found to be metabolic enzymes that could be involved in the metabolomic alterations observed. Anticipated changes in metabolite levels in cells exposed to increased glucose were observed, while changes in enzyme levels were much less profound. This suggests that substrate availability, allosteric regulation, and/or post-translational modifications are more important determinants of metabolite levels than enzyme expression at the protein level.

  17. Pancreas-Specific Sirt1-Deficiency in Mice Compromises Beta-Cell Function without Development of Hyperglycemia.

    Science.gov (United States)

    Pinho, Andreia V; Bensellam, Mohammed; Wauters, Elke; Rees, Maxine; Giry-Laterriere, Marc; Mawson, Amanda; Ly, Le Quan; Biankin, Andrew V; Wu, Jianmin; Laybutt, D Ross; Rooman, Ilse

    2015-01-01

    Sirtuin 1 (Sirt1) has been reported to be a critical positive regulator of glucose-stimulated insulin secretion in pancreatic beta-cells. The effects on islet cells and blood glucose levels when Sirt1 is deleted specifically in the pancreas are still unclear. This study examined islet glucose responsiveness, blood glucose levels, pancreatic islet histology and gene expression in Pdx1Cre; Sirt1ex4F/F mice that have loss of function and loss of expression of Sirt1 specifically in the pancreas. We found that in the Pdx1Cre; Sirt1ex4F/F mice, the relative insulin positive area and the islet size distribution were unchanged. However, beta-cells were functionally impaired, presenting with lower glucose-stimulated insulin secretion. This defect was not due to a reduced expression of insulin but was associated with a decreased expression of the glucose transporter Slc2a2/Glut2 and of the Glucagon like peptide-1 receptor (Glp1r) as well as a marked down regulation of endoplasmic reticulum (ER) chaperones that participate in the Unfolded Protein Response (UPR) pathway. Counter intuitively, the Sirt1-deficient mice did not develop hyperglycemia. Pancreatic polypeptide (PP) cells were the only other islet cells affected, with reduced numbers in the Sirt1-deficient pancreas. This study provides new mechanistic insights showing that beta-cell function in Sirt1-deficient pancreas is affected due to altered glucose sensing and deregulation of the UPR pathway. Interestingly, we uncovered a context in which impaired beta-cell function is not accompanied by increased glycemia. This points to a unique compensatory mechanism. Given the reduction in PP, investigation of its role in the control of blood glucose is warranted.

  18. Pancreas-Specific Sirt1-Deficiency in Mice Compromises Beta-Cell Function without Development of Hyperglycemia.

    Directory of Open Access Journals (Sweden)

    Andreia V Pinho

    Full Text Available Sirtuin 1 (Sirt1 has been reported to be a critical positive regulator of glucose-stimulated insulin secretion in pancreatic beta-cells. The effects on islet cells and blood glucose levels when Sirt1 is deleted specifically in the pancreas are still unclear.This study examined islet glucose responsiveness, blood glucose levels, pancreatic islet histology and gene expression in Pdx1Cre; Sirt1ex4F/F mice that have loss of function and loss of expression of Sirt1 specifically in the pancreas.We found that in the Pdx1Cre; Sirt1ex4F/F mice, the relative insulin positive area and the islet size distribution were unchanged. However, beta-cells were functionally impaired, presenting with lower glucose-stimulated insulin secretion. This defect was not due to a reduced expression of insulin but was associated with a decreased expression of the glucose transporter Slc2a2/Glut2 and of the Glucagon like peptide-1 receptor (Glp1r as well as a marked down regulation of endoplasmic reticulum (ER chaperones that participate in the Unfolded Protein Response (UPR pathway. Counter intuitively, the Sirt1-deficient mice did not develop hyperglycemia. Pancreatic polypeptide (PP cells were the only other islet cells affected, with reduced numbers in the Sirt1-deficient pancreas.This study provides new mechanistic insights showing that beta-cell function in Sirt1-deficient pancreas is affected due to altered glucose sensing and deregulation of the UPR pathway. Interestingly, we uncovered a context in which impaired beta-cell function is not accompanied by increased glycemia. This points to a unique compensatory mechanism. Given the reduction in PP, investigation of its role in the control of blood glucose is warranted.

  19. AMP-activated protein kinase (AMPK mediates nutrient regulation of thioredoxin-interacting protein (TXNIP in pancreatic beta-cells.

    Directory of Open Access Journals (Sweden)

    Maayan Shaked

    Full Text Available Thioredoxin-interacting protein (TXNIP regulates critical biological processes including inflammation, stress and apoptosis. TXNIP is upregulated by glucose and is a critical mediator of hyperglycemia-induced beta-cell apoptosis in diabetes. In contrast, the saturated long-chain fatty acid palmitate, although toxic to the beta-cell, inhibits TXNIP expression. The mechanisms involved in the opposing effects of glucose and fatty acids on TXNIP expression are unknown. We found that both palmitate and oleate inhibited TXNIP in a rat beta-cell line and islets. Palmitate inhibition of TXNIP was independent of fatty acid beta-oxidation or esterification. AMP-activated protein kinase (AMPK has an important role in cellular energy sensing and control of metabolic homeostasis; therefore we investigated its involvement in nutrient regulation of TXNIP. As expected, glucose inhibited whereas palmitate stimulated AMPK. Pharmacologic activators of AMPK mimicked fatty acids by inhibiting TXNIP. AMPK knockdown increased TXNIP expression in presence of high glucose with and without palmitate, indicating that nutrient (glucose and fatty acids effects on TXNIP are mediated in part via modulation of AMPK activity. TXNIP is transcriptionally regulated by carbohydrate response element-binding protein (ChREBP. Palmitate inhibited glucose-stimulated ChREBP nuclear entry and recruitment to the Txnip promoter, thereby inhibiting Txnip transcription. We conclude that AMPK is an important regulator of Txnip transcription via modulation of ChREBP activity. The divergent effects of glucose and fatty acids on TXNIP expression result in part from their opposing effects on AMPK activity. In light of the important role of TXNIP in beta-cell apoptosis, its inhibition by fatty acids can be regarded as an adaptive/protective response to glucolipotoxicity. The finding that AMPK mediates nutrient regulation of TXNIP may have important implications for the pathophysiology and treatment

  20. Role of transcription factor KLF11 and its diabetes-associated gene variants in pancreatic beta cell function

    Science.gov (United States)

    Neve, Bernadette; Fernandez-Zapico, Martin E.; Ashkenazi-Katalan, Vered; Dina, Christian; Hamid, Yasmin H.; Joly, Erik; Vaillant, Emmanuel; Benmezroua, Yamina; Durand, Emmanuelle; Bakaher, Nicolas; Delannoy, Valerie; Vaxillaire, Martine; Cook, Tiffany; Dallinga-Thie, Geesje M.; Jansen, Hans; Charles, Marie-Aline; Clément, Karine; Galan, Pilar; Hercberg, Serge; Helbecque, Nicole; Charpentier, Guillaume; Prentki, Marc; Hansen, Torben; Pedersen, Oluf; Urrutia, Raul; Melloul, Danielle; Froguel, Philippe

    2005-01-01

    KLF11 (TIEG2) is a pancreas-enriched transcription factor that has elicited significant attention because of its role as negative regulator of exocrine cell growth in vitro and in vivo. However, its functional role in the endocrine pancreas remains to be established. Here, we report, for the first time, to our knowledge, the characterization of KLF11 as a glucose-inducible regulator of the insulin gene. A combination of random oligonucleotide binding, EMSA, luciferase reporter, and chromatin immunoprecipitation assays shows that KLF11 binds to the insulin promoter and regulates its activity in beta cells. Genetic analysis of the KLF11 gene revealed two rare variants (Ala347Ser and Thr220Met) that segregate with diabetes in families with early-onset type 2 diabetes, and significantly impair its transcriptional activity. In addition, analysis of 1,696 type 2 diabetes mellitus and 1,776 normoglycemic subjects show a frequent polymorphic Gln62Arg variant that significantly associates with type 2 diabetes mellitus in North European populations (OR = 1.29, P = 0.00033). Moreover, this variant alters the corepressor mSin3A-binding activity of KLF11, impairs the activation of the insulin promoter and shows lower levels of insulin expression in pancreatic beta cells. In addition, subjects carrying the Gln62Arg allele show decreased plasma insulin after an oral glucose challenge. Interestingly, all three nonsynonymous KLF11 variants show increased repression of the catalase 1 promoter, suggesting a role in free radical clearance that may render beta cells more sensitive to oxidative stress. Thus, both functional and genetic analyses reveal that KLF11 plays a role in the regulation of pancreatic beta cell physiology, and its variants may contribute to the development of diabetes. PMID:15774581

  1. Activation of the Wnt/β-catenin pathway in pancreatic beta cells during the compensatory islet hyperplasia in prediabetic mice

    International Nuclear Information System (INIS)

    Maschio, D.A.; Oliveira, R.B.; Santos, M.R.; Carvalho, C.P.F.; Barbosa-Sampaio, H.C.L.; Collares-Buzato, C.B.

    2016-01-01

    The Wnt/β-catenin signaling pathway, also known as the canonical Wnt pathway, plays a role in cell proliferation and differentiation in several tissues/organs. It has been recently described in humans a relationship between type 2 diabetes (T2DM) and mutation in the gene encoding the transcription factor TCF7L2 associated to the Wnt/β-catenin pathway. In the present study, we demonstrated that hyperplastic pancreatic islets from prediabetic mice fed a high-fat diet (HFD) for 60 d displayed nuclear translocation of active β-catenin associated with significant increases in protein content and gene expression of β-catenin as well as of cyclins D1, D2 and c-Myc (target genes of the Wnt pathway) but not of Tcf7l2 (the transcription factor). Meanwhile, these alterations were not observed in pancreatic islets from 30 d HFD-fed mice, that do not display significant beta cell hyperplasia. These data suggest that the Wnt/β-catenin pathway is activated in pancreatic islets during prediabetes and may play a role in the induction of the compensatory beta cell hyperplasia observed at early phase of T2DM. - Highlights: • Exposure to high-fat diet for 60 days induced prediabetes and beta cell mass expansion. • Hyperplastic pancreatic islets displayed nuclear translocation of active β-catenin. • Hyperplastic islets showed increased expression of target genes of the Wnt/β-catenin pathway. • Wnt/β-catenin pathway is activated during compensatory beta cell hyperplasia in mice.

  2. Effects of low intensity laser acupoint irradiation on inhibiting islet beta-cell apoptosis in rats with type 2 diabetes

    Science.gov (United States)

    Xiong, Guoxin; Xiong, Leilei; Li, Xinzhong

    2016-09-01

    To investigate the effects of low intensity semiconductor laser acupoint irradiation on inhibiting islet beta-cell apoptosis in rats with type 2 diabetes, a method using a high-fat diet and low-dose intraperitoneal injections of streptozotocin established a type 2 diabetes mellitus rat model. Model rats were randomly divided into a laser acupoint irradiation group, rosiglitazone control group, and placebo group; each group had 10 rats. In addition, 10 normal male rats were selected for the normal control group. The Housanli, Neiting and Yishu acupoints of the rats in the laser acupoint irradiation group were irradiated with a 10 mW semiconductor laser; each point was irradiated for 15 min, once every 2 d over 28 d, for a total of 14 episodes of irradiation. The rosiglitazone group rats were given rosiglitazone (0.2 mg kg-1) intragastrically; the placebo group rats were given 0.9% brine (0.2 mg kg-1) intragastrically, once daily, for four consecutive weeks. The change of fasting blood glucose was determined before and after each treatment. The islet beta-cell apoptosis was determined. The islet beta-cell apoptosis rates of the laser acupoint irradiation group and the rosiglitazone group were significantly lower than the rate of the placebo group. Even though the rate was lower in the laser acupoint irradiation group than in the rosiglitazone group, there was no significant difference between them. It is shown that acupoint irradiation with a semiconductor laser can effectively inhibit islet beta-cell apoptosis in rats with type 2 diabetes.

  3. Drp1 guarding of the mitochondrial network is important for glucose-stimulated insulin secretion in pancreatic beta cells

    Energy Technology Data Exchange (ETDEWEB)

    Reinhardt, Florian; Schultz, Julia; Waterstradt, Rica; Baltrusch, Simone, E-mail: simone.baltrusch@med.uni-rostock.de

    2016-06-10

    Mitochondria form a tubular network in mammalian cells, and the mitochondrial life cycle is determined by fission, fusion and autophagy. Dynamin-related protein 1 (Drp1) has a pivotal role in these processes because it alone is able to constrict mitochondria. However, the regulation and function of Drp1 have been shown to vary between cell types. Mitochondrial morphology affects mitochondrial metabolism and function. In pancreatic beta cells mitochondrial metabolism is a key component of the glucose-induced cascade of insulin secretion. The goal of the present study was to investigate the action of Drp1 in pancreatic beta cells. For this purpose Drp1 was down-regulated by means of shDrp1 in insulin-secreting INS1 cells and mouse pancreatic islets. In INS1 cells reduced Drp1 expression resulted in diminished expression of proteins regulating mitochondrial fusion, namely mitofusin 1 and 2, and optic atrophy protein 1. Diminished mitochondrial dynamics can therefore be assumed. After down-regulation of Drp1 in INS1 cells and spread mouse islets the initially homogenous mitochondrial network characterised by a moderate level of interconnections shifted towards high heterogeneity with elongated, clustered and looped mitochondria. These morphological changes were found to correlate directly with functional alterations. Mitochondrial membrane potential and ATP generation were significantly reduced in INS1 cells after Drp1down-regulation. Finally, a significant loss of glucose-stimulated insulin secretion was demonstrated in INS1 cells and mouse pancreatic islets. In conclusion, Drp1 expression is important in pancreatic beta cells to maintain the regulation of insulin secretion. -- Highlights: •Down-regulation of Drp1 in INS1 cells reduces mitochondrial fusion protein expression. •Mitochondrial membrane potential in INS1 cells is diminished after Drp1 down-regulation. •Mitochondria become elongated after down-regulation of Drp1 in beta cells. •Down-regulation of

  4. PHYSICAL CONSTRAINTS ON FAST RADIO BURSTS

    Energy Technology Data Exchange (ETDEWEB)

    Luan, Jing; Goldreich, Peter, E-mail: jingluan@caltech.edu [California Institute of Technology, Pasadena, CA 91125 (United States)

    2014-04-20

    Fast radio bursts (FRBs) are isolated, ms radio pulses with dispersion measure (DM) of order 10{sup 3} pc cm{sup –3}. Galactic candidates for the DM of high latitude bursts detected at GHz frequencies are easily dismissed. DM from bursts emitted in stellar coronas are limited by free-free absorption and those from H II regions are bounded by the nondetection of associated free-free emission at radio wavelengths. Thus, if astronomical, FRBs are probably extragalactic. FRB 110220 has a scattering tail of ∼5.6 ± 0.1 ms. If the electron density fluctuations arise from a turbulent cascade, the scattering is unlikely to be due to propagation through the diffuse intergalactic plasma. A more plausible explanation is that this burst sits in the central region of its host galaxy. Pulse durations of order ms constrain the sizes of FRB sources implying high brightness temperatures that indicates coherent emission. Electric fields near FRBs at cosmological distances would be so strong that they could accelerate free electrons from rest to relativistic energies in a single wave period.

  5. PHYSICAL CONSTRAINTS ON FAST RADIO BURSTS

    International Nuclear Information System (INIS)

    Luan, Jing; Goldreich, Peter

    2014-01-01

    Fast radio bursts (FRBs) are isolated, ms radio pulses with dispersion measure (DM) of order 10 3 pc cm –3 . Galactic candidates for the DM of high latitude bursts detected at GHz frequencies are easily dismissed. DM from bursts emitted in stellar coronas are limited by free-free absorption and those from H II regions are bounded by the nondetection of associated free-free emission at radio wavelengths. Thus, if astronomical, FRBs are probably extragalactic. FRB 110220 has a scattering tail of ∼5.6 ± 0.1 ms. If the electron density fluctuations arise from a turbulent cascade, the scattering is unlikely to be due to propagation through the diffuse intergalactic plasma. A more plausible explanation is that this burst sits in the central region of its host galaxy. Pulse durations of order ms constrain the sizes of FRB sources implying high brightness temperatures that indicates coherent emission. Electric fields near FRBs at cosmological distances would be so strong that they could accelerate free electrons from rest to relativistic energies in a single wave period

  6. Beneficial Effect of Jojoba Seed Extracts on Hyperglycemia-Induced Oxidative Stress in RINm5f Beta Cells

    Directory of Open Access Journals (Sweden)

    Sahla Belhadj

    2018-03-01

    Full Text Available Hyperglycemia occurs during diabetes and insulin resistance. It causes oxidative stress by increasing reactive oxygen species (ROS levels, leading to cellular damage. Polyphenols play a central role in defense against oxidative stress. In our study, we investigated the antioxidant properties of simmondsin, a pure molecule present in jojoba seeds, and of the aqueous extract of jojoba seeds on fructose-induced oxidative stress in RINm5f beta cells. The exposure of RINm5f beta cells to fructose triggered the loss of cell viability (−48%, p < 0.001 and disruption of insulin secretion (p < 0.001 associated with of reactive oxygen species (ROS production and a modulation of pro-oxidant and antioxidant signaling pathway. Cell pre-treatments with extracts considerably increased cell viability (+86% p < 0.001 for simmondsin and +74% (p < 0.001 for aqueous extract and insulin secretion. The extracts also markedly decreased ROS (−69% (p < 0.001 for simmondsin and −59% (p < 0.001 for aqueous extract and caspase-3 activation and improved antioxidant defense, inhibiting p22phox and increasing nuclear factor (erythroid-derived 2-like 2 (Nrf2 levels (+70%, p < 0.001 for aqueous extract. Simmondsin had no impact on Nrf2 levels. The richness and diversity of molecules present in jojoba seed extract makes jojoba a powerful agent to prevent the destruction of RINm5f beta cells induced by hyperglycemia.

  7. EPConDB: a web resource for gene expression related to pancreatic development, beta-cell function and diabetes.

    Science.gov (United States)

    Mazzarelli, Joan M; Brestelli, John; Gorski, Regina K; Liu, Junmin; Manduchi, Elisabetta; Pinney, Deborah F; Schug, Jonathan; White, Peter; Kaestner, Klaus H; Stoeckert, Christian J

    2007-01-01

    EPConDB (http://www.cbil.upenn.edu/EPConDB) is a public web site that supports research in diabetes, pancreatic development and beta-cell function by providing information about genes expressed in cells of the pancreas. EPConDB displays expression profiles for individual genes and information about transcripts, promoter elements and transcription factor binding sites. Gene expression results are obtained from studies examining tissue expression, pancreatic development and growth, differentiation of insulin-producing cells, islet or beta-cell injury, and genetic models of impaired beta-cell function. The expression datasets are derived using different microarray platforms, including the BCBC PancChips and Affymetrix gene expression arrays. Other datasets include semi-quantitative RT-PCR and MPSS expression studies. For selected microarray studies, lists of differentially expressed genes, derived from PaGE analysis, are displayed on the site. EPConDB provides database queries and tools to examine the relationship between a gene, its transcriptional regulation, protein function and expression in pancreatic tissues.

  8. Nuclear import of glucokinase in pancreatic beta-cells is mediated by a nuclear localization signal and modulated by SUMOylation.

    Science.gov (United States)

    Johansson, Bente Berg; Fjeld, Karianne; Solheim, Marie Holm; Shirakawa, Jun; Zhang, Enming; Keindl, Magdalena; Hu, Jiang; Lindqvist, Andreas; Døskeland, Anne; Mellgren, Gunnar; Flatmark, Torgeir; Njølstad, Pål Rasmus; Kulkarni, Rohit N; Wierup, Nils; Aukrust, Ingvild; Bjørkhaug, Lise

    2017-10-15

    The localization of glucokinase in pancreatic beta-cell nuclei is a controversial issue. Although previous reports suggest such a localization, the mechanism for its import has so far not been identified. Using immunofluorescence, subcellular fractionation and mass spectrometry, we present evidence in support of glucokinase localization in beta-cell nuclei of human and mouse pancreatic sections, as well as in human and mouse isolated islets, and murine MIN6 cells. We have identified a conserved, seven-residue nuclear localization signal ( 30 LKKVMRR 36 ) in the human enzyme. Substituting the residues KK 31,32 and RR 35,36 with AA led to a loss of its nuclear localization in transfected cells. Furthermore, our data indicates that SUMOylation of glucokinase modulates its nuclear import, while high glucose concentrations do not significantly alter the enzyme nuclear/cytosolic ratio. Thus, for the first time, we provide data in support of a nuclear import of glucokinase mediated by a redundant mechanism, involving a nuclear localization signal, and which is modulated by its SUMOylation. These findings add new knowledge to the functional role of glucokinase in the pancreatic beta-cell. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Soudan 2 muons in coincidence with BATSE bursts

    International Nuclear Information System (INIS)

    DeMuth, D.M.; Marshak, M.L.; Wagner, G.L.

    1994-01-01

    We explore the possibilities of statistically significant temporal and spatial coincidences between underground muons at Soudan 2 and Gamma Ray Bursts at the GRO-BATSE detector. Our search uses data from the April 91 to March 92 BATSE burst catalog to seek correlations within a 100 second window of coincidence. Sixteen of 180 BATSE triggers have temporally and spatially coincident muons in the Soudan 2 detector. We estimate the chance probability of each coincidence assuming the null hypothesis on the basis of a study of the multiplicities of spatially coincident muons observed over a two day period centered on the time of burst

  10. Bright x-ray flares in gamma-ray burst afterglows.

    Science.gov (United States)

    Burrows, D N; Romano, P; Falcone, A; Kobayashi, S; Zhang, B; Moretti, A; O'brien, P T; Goad, M R; Campana, S; Page, K L; Angelini, L; Barthelmy, S; Beardmore, A P; Capalbi, M; Chincarini, G; Cummings, J; Cusumano, G; Fox, D; Giommi, P; Hill, J E; Kennea, J A; Krimm, H; Mangano, V; Marshall, F; Mészáros, P; Morris, D C; Nousek, J A; Osborne, J P; Pagani, C; Perri, M; Tagliaferri, G; Wells, A A; Woosley, S; Gehrels, N

    2005-09-16

    Gamma-ray burst (GRB) afterglows have provided important clues to the nature of these massive explosive events, providing direct information on the nearby environment and indirect information on the central engine that powers the burst. We report the discovery of two bright x-ray flares in GRB afterglows, including a giant flare comparable in total energy to the burst itself, each peaking minutes after the burst. These strong, rapid x-ray flares imply that the central engines of the bursts have long periods of activity, with strong internal shocks continuing for hundreds of seconds after the gamma-ray emission has ended.

  11. Gamma-Ray Bursts

    Science.gov (United States)

    Pellizza, L. J.

    Gamma-ray bursts are the brightest transient sources in the gamma-ray sky. Since their discovery in the late 1960s, the investigation of the astrophysical sys- tems in which these phenomena take place, and the physical mechanisms that drive them, has become a vast and prolific area of modern astrophysics. In this work I will briefly describe the most relevant observations of these sources, and the models that describe their nature, emphasizing on the in- vestigations about the progenitor astrophysical systems. FULL TEXT IN SPANISH

  12. Gamma Ray Bursts

    Science.gov (United States)

    Gehrels, Neil; Meszaros, Peter

    2012-01-01

    Gamma-ray bursts (GRBs) are bright flashes of gamma-rays coming from the cosmos. They occur roughly once per day ,last typically lOs of seconds and are the most luminous events in the universe. More than three decades after their discovery, and after pioneering advances from space and ground experiments, they still remain mysterious. The launch of the Swift and Fermi satellites in 2004 and 2008 brought in a trove of qualitatively new data. In this review we survey the interplay between these recent observations and the theoretical models of the prompt GRB emission and the subsequent afterglows.

  13. Identifying crucial parameter correlations maintaining bursting activity.

    Directory of Open Access Journals (Sweden)

    Anca Doloc-Mihu

    2014-06-01

    Full Text Available Recent experimental and computational studies suggest that linearly correlated sets of parameters (intrinsic and synaptic properties of neurons allow central pattern-generating networks to produce and maintain their rhythmic activity regardless of changing internal and external conditions. To determine the role of correlated conductances in the robust maintenance of functional bursting activity, we used our existing database of half-center oscillator (HCO model instances of the leech heartbeat CPG. From the database, we identified functional activity groups of burster (isolated neuron and half-center oscillator model instances and realistic subgroups of each that showed burst characteristics (principally period and spike frequency similar to the animal. To find linear correlations among the conductance parameters maintaining functional leech bursting activity, we applied Principal Component Analysis (PCA to each of these four groups. PCA identified a set of three maximal conductances (leak current, [Formula: see text]Leak; a persistent K current, [Formula: see text]K2; and of a persistent Na+ current, [Formula: see text]P that correlate linearly for the two groups of burster instances but not for the HCO groups. Visualizations of HCO instances in a reduced space suggested that there might be non-linear relationships between these parameters for these instances. Experimental studies have shown that period is a key attribute influenced by modulatory inputs and temperature variations in heart interneurons. Thus, we explored the sensitivity of period to changes in maximal conductances of [Formula: see text]Leak, [Formula: see text]K2, and [Formula: see text]P, and we found that for our realistic bursters the effect of these parameters on period could not be assessed because when varied individually bursting activity was not maintained.

  14. Gamma-ray burst spectra

    International Nuclear Information System (INIS)

    Teegarden, B.J.

    1982-01-01

    A review of recent results in gamma-ray burst spectroscopy is given. Particular attention is paid to the recent discovery of emission and absorption features in the burst spectra. These lines represent the strongest evidence to date that gamma-ray bursts originate on or near neutron stars. Line parameters give information on the temperature, magnetic field and possibly the gravitational potential of the neutron star. The behavior of the continuum spectrum is also discussed. A remarkably good fit to nearly all bursts is obtained with a thermal-bremsstrahlung-like continuum. Significant evolution is observed of both the continuum and line features within most events

  15. UWB dual burst transmit driver

    Science.gov (United States)

    Dallum, Gregory E [Livermore, CA; Pratt, Garth C [Discovery Bay, CA; Haugen, Peter C [Livermore, CA; Zumstein, James M [Livermore, CA; Vigars, Mark L [Livermore, CA; Romero, Carlos E [Livermore, CA

    2012-04-17

    A dual burst transmitter for ultra-wideband (UWB) communication systems generates a pair of precisely spaced RF bursts from a single trigger event. An input trigger pulse produces two oscillator trigger pulses, an initial pulse and a delayed pulse, in a dual trigger generator. The two oscillator trigger pulses drive a gated RF burst (power output) oscillator. A bias driver circuit gates the RF output oscillator on and off and sets the RF burst packet width. The bias driver also level shifts the drive signal to the level that is required for the RF output device.

  16. Design and optimization of beta-cell temperature sensor based on 63Ni–Si

    International Nuclear Information System (INIS)

    Ghasemi Nejad, Gholam Reza; Rahmani, Faezeh; Abaeiani, Gholam Reza

    2014-01-01

    A theoretical study of the use of a beta-cell as a temperature sensor using MCNP4C Monte Carlo code is presented in this paper. Nickel-63 and silicon were selected as the beta source and semiconductor material, respectively. The maximum open-circuit voltage (V OC ) is equal to 0.445 V with doping concentrations of N A =4×10 18 #/cm 3 and N D =8×10 19 #/cm 3 in the base and the emitter region, respectively, which, depending on the source activity, enables measurement in a wide range of temperature. The effects of the activity and its change over time on V OC were also studied. The results demonstrated that V OC exhibited smaller changes for higher activities. The temperature sensitivity of this sensor ranges from −2.42 mV/K to −3.41 mV/K for source activities from 100 mCi to 0.001 mCi, respectively, so the optimal activity can be determined according to the desired temperature range and sensitivity. - Highlights: • A silicon p–n junction using 63 Ni is used as a temperature sensor. • The rate of electron–hole generation in silicon was simulated using Monte Carlo MCNP4c code. • The effects of the structural properties of the semiconductor, such as doping concentration and the thickness of the emitter, on the sensitivity and temperature range were studied. • The source thickness and the effect of the activity and its change over time on V OC were investigated at various temperatures

  17. Relationship Between Beta Cell Dysfunction and Severity of Disease Among Critically Ill Children: A STROBE-Compliant Prospective Observational Study.

    Science.gov (United States)

    Liu, Ping-Ping; Lu, Xiu-Lan; Xiao, Zheng-Hui; Qiu, Jun; Zhu, Yi-Min

    2016-05-01

    Although beta cell dysfunction has been proved to predict prognosis among humans and animals, its prediction on severity of disease remains unclear among children. The present study was aimed to examine the relationship between beta cell dysfunction and severity of disease among critically ill children.This prospective study included 1146 critically ill children, who were admitted to Pediatric Intensive Care Unit (PICU) of Hunan Children's Hospital from November 2011 to August 2013. Information on characteristics, laboratory tests, and prognostic outcomes was collected. Homeostasis model assessment (HOMA)-β, evaluating beta cell function, was used to divide all participants into 4 groups: HOMA-β = 100% (group I, n = 339), 80% ≤ HOMA-β multiple organ dysfunction syndrome (MODS), mechanical ventilation (MV) and mortality. Logistic regression analysis was used to evaluate the risk of developing poor outcomes among patients in different HOMA-β groups, with group I as the reference group.Among 1146 children, incidence of HOMA-β decrement of HOMA-β (P < 0.01). C-reactive protein and procalcitonin levels, rather than white blood cell, were significantly different among 4 groups (P < 0.01). In addition, the worst SOFA score and the worst PRISMIII score increased with declined HOMA-β. For example, the worst SOFA score in group I, II, III, and IV was 1.55 ± 1.85, 1.71 ± 1.93, 1.92 ± 1.63, and 2.18 ± 1.77, respectively. Furthermore, patients with declined HOMA-β had higher risk of developing septic shock, MODS, MV, and mortality, even after adjusting age, gender, myocardial injury, and lung injury. For instance, compared with group I, the multivariate-adjusted odds ratio (95% confidence interval) for developing septic shock was 2.17 (0.59, 8.02), 2.94 (2.18, 6.46), and 2.76 (1.18, 6.46) among patients in group II, III, and IV, respectively.Beta cell dysfunction reflected the severity of disease among critically ill children

  18. **-Postprandial pancreatic ["1"1C]methionine uptake after pancreaticoduodenectomy mirrors basal beta cell function and insulin release

    International Nuclear Information System (INIS)

    Steiner, Emanuel; Kazianka, Lukas; Breuer, Robert; Miholic, Johannes; Hacker, Marcus; Wadsak, Wolfgang; Mitterhauser, Markus; Stimpfl, Thomas; Reiter, Birgit; Karanikas, Georgios

    2017-01-01

    [S-methyl-"1"1C]-L-methionine (["1"1C]MET) uptake in the pancreas might be a central indicator of beta cell function. Since gastric emptying was recently shown to influence glycemic control in subjects after pancreaticoduodenectomy (PD, the surgical treatment of neoplasms of the pancreas head), we looked for imaginable relationships between gastric emptying, pre- and postprandial insulin concentrations, and ["1"1C]MET uptake. Nineteen tumor-free survivors after PD (age mean ± SD: 61 ± 8.7 yrs.; 10 male, 9 female) and 10 healthy controls (age: 27 ± 8.7 yrs.; 7 male, 3 female) were given a mixed test meal. One gram of paracetamol was ingested with the meal to evaluate the speed of gastric emptying. Insulin, glucose, and paracetamol plasma concentrations were measured before and over 180 minutes after ingestion. Beta cell function was calculated from fasting glucose and insulin plasma concentrations. Simultaneously, 800 MBq of ["1"1C]MET were administered and the activity (maximum tissue standardized uptake values [SUVmax]) over the pancreas was measured at 15, 30, and 60 minutes after injection. Total integrated SUVmax (area under the curve [AUC]) and incremental SUVmax were calculated. The uptake of ["1"1C]MET in the pancreas was significantly higher (p < 0.0001) in controls compared to the PD group. Gastric emptying was significantly slower in controls compared to pancreatectomy subjects (p < 0.0001). Paracetamol AUC_3_0 correlated with the SUVmax increment between 15 and 30 minutes (R"2 = 0.27, p = 0.0263), suggesting a relationship between gastric emptying and the uptake of ["1"1C]MET. Total integrated SUVmax correlated with insulin AUC_6_0 (R"2 = 0.66,p < 0.0001) in patients after PD. Multivariate regression analysis revealed insulin AUC_6_0 and beta cell function, calculated from the fasting insulin to glucose ratio, as independent predictors of "1"1C-methionine uptake, i.e. total integrated SUVmax, in patients after PD (R"2 = 0.78, p < 0.0001). Postprandial

  19. **-Postprandial pancreatic [{sup 11}C]methionine uptake after pancreaticoduodenectomy mirrors basal beta cell function and insulin release

    Energy Technology Data Exchange (ETDEWEB)

    Steiner, Emanuel; Kazianka, Lukas; Breuer, Robert; Miholic, Johannes [Medical University of Vienna, Department of Surgery, Vienna (Austria); Hacker, Marcus; Wadsak, Wolfgang; Mitterhauser, Markus [Medical University of Vienna, Department of Biomedical Imaging and Image-Guided Therapy, Division of Nuclear Medicine, Vienna (Austria); Stimpfl, Thomas; Reiter, Birgit [Medical University of Vienna, Clinical Institute of Laboratory Medicine, Forensic Toxicology, Vienna (Austria); Karanikas, Georgios [Medical University of Vienna, Department of Biomedical Imaging and Image-Guided Therapy, Division of Nuclear Medicine, Divisional Head PET-PET/CT (Nuclear Medicine), Vienna (Austria)

    2017-03-15

    [S-methyl-{sup 11}C]-L-methionine ([{sup 11}C]MET) uptake in the pancreas might be a central indicator of beta cell function. Since gastric emptying was recently shown to influence glycemic control in subjects after pancreaticoduodenectomy (PD, the surgical treatment of neoplasms of the pancreas head), we looked for imaginable relationships between gastric emptying, pre- and postprandial insulin concentrations, and [{sup 11}C]MET uptake. Nineteen tumor-free survivors after PD (age mean ± SD: 61 ± 8.7 yrs.; 10 male, 9 female) and 10 healthy controls (age: 27 ± 8.7 yrs.; 7 male, 3 female) were given a mixed test meal. One gram of paracetamol was ingested with the meal to evaluate the speed of gastric emptying. Insulin, glucose, and paracetamol plasma concentrations were measured before and over 180 minutes after ingestion. Beta cell function was calculated from fasting glucose and insulin plasma concentrations. Simultaneously, 800 MBq of [{sup 11}C]MET were administered and the activity (maximum tissue standardized uptake values [SUVmax]) over the pancreas was measured at 15, 30, and 60 minutes after injection. Total integrated SUVmax (area under the curve [AUC]) and incremental SUVmax were calculated. The uptake of [{sup 11}C]MET in the pancreas was significantly higher (p < 0.0001) in controls compared to the PD group. Gastric emptying was significantly slower in controls compared to pancreatectomy subjects (p < 0.0001). Paracetamol AUC{sub 30} correlated with the SUVmax increment between 15 and 30 minutes (R{sup 2} = 0.27, p = 0.0263), suggesting a relationship between gastric emptying and the uptake of [{sup 11}C]MET. Total integrated SUVmax correlated with insulin AUC{sub 60} (R{sup 2} = 0.66,p < 0.0001) in patients after PD. Multivariate regression analysis revealed insulin AUC{sub 60} and beta cell function, calculated from the fasting insulin to glucose ratio, as independent predictors of {sup 11}C-methionine uptake, i.e. total integrated SUVmax, in

  20. Neutron stars as X-ray burst sources. II. Burst energy histograms and why they burst

    International Nuclear Information System (INIS)

    Baan, W.A.

    1979-01-01

    In this work we explore some of the implications of a model for X-ray burst sources where bursts are caused by Kruskal-Schwarzschild instabilities at the magnetopause of an accreting and rotating neutron star. A number of simplifying assumptions are made in order to test the model using observed burst-energy histograms for the rapid burster MXB 1730--335. The predicted histograms have a correct general shape, but it appears that other effects are important as well, and that mode competition, for instance, may suppress the histograms at high burst energies. An explanation is ventured for the enhancement in the histogram at the highest burst energies, which produces the bimodal shape in high accretion rate histograms. Quantitative criteria are given for deciding when accreting neutron stars are steady sources or burst sources, and these criteria are tested using the X-ray pulsars

  1. Bifurcation structure of a model of bursting pancreatic cells

    DEFF Research Database (Denmark)

    Mosekilde, Erik; Lading, B.; Yanchuk, S.

    2001-01-01

    One- and two-dimensional bifurcation studies of a prototypic model of bursting oscillations in pancreatic P-cells reveal a squid-formed area of chaotic dynamics in the parameter plane, with period-doubling bifurcations on one side of the arms and saddle-node bifurcations on the other. The transit......One- and two-dimensional bifurcation studies of a prototypic model of bursting oscillations in pancreatic P-cells reveal a squid-formed area of chaotic dynamics in the parameter plane, with period-doubling bifurcations on one side of the arms and saddle-node bifurcations on the other....... The transition from this structure to the so-called period-adding structure is found to involve a subcritical period-doubling bifurcation and the emergence of type-III intermittency. The period-adding transition itself is not smooth but consists of a saddle-node bifurcation in which (n + 1)-spike bursting...

  2. Bifurcation structure of a model of bursting pancreatic cells

    DEFF Research Database (Denmark)

    Mosekilde, Erik; Lading, B.; Yanchuk, S.

    2001-01-01

    . The transition from this structure to the so-called period-adding structure is found to involve a subcritical period-doubling bifurcation and the emergence of type-III intermittency. The period-adding transition itself is not smooth but consists of a saddle-node bifurcation in which (n + 1)-spike bursting...... behavior is born, slightly overlapping with a subcritical period-doubling bifurcation in which n-spike bursting behavior loses its stability.......One- and two-dimensional bifurcation studies of a prototypic model of bursting oscillations in pancreatic P-cells reveal a squid-formed area of chaotic dynamics in the parameter plane, with period-doubling bifurcations on one side of the arms and saddle-node bifurcations on the other...

  3. Minor long-term changes in weight have beneficial effects on insulin sensitivity and beta-cell function in obese subjects

    DEFF Research Database (Denmark)

    Rosenfalck, A M; Hendel, Helle Westergren; Rasmussen, M H

    2002-01-01

    To evaluate the long-term effect of changes in body composition induced by weight loss on insulin sensitivity (SI), non-insulin mediated glucose disposal, glucose effectiveness (SG)and beta-cell function.......To evaluate the long-term effect of changes in body composition induced by weight loss on insulin sensitivity (SI), non-insulin mediated glucose disposal, glucose effectiveness (SG)and beta-cell function....

  4. [Associations of insulin resistance and pancreatic beta-cell function with plasma glucose level in type 2 diabetes].

    Science.gov (United States)

    Nian, Xiaoping; Sun, Gaisheng; Dou, Chunmei; Hou, Hongbo; Fan, Xiuping; Yu, Hongmei; Ma, Ling; He, Bingxian

    2002-06-10

    To investigate the influence of insulin resistance and pancreatic beta-cell function on plasma glucose level in type 2 diabetes so as to provide theoretical basis for reasonable selection of hypoglycemic agents. The plasma non-specific insulin (NSINS), true insulin (TI) and glucose in eight-one type 2 diabetics, 38 males and 43 females, with a mean age of 53 years, were examined 0, 30, 60 and 120 minutes after they had 75 grams of instant noodles. The patients were divided into two groups according to their fasting plasma glucose (FPG): group A (FPG = 8.89 mmol/L). The insulin resistance was evaluated by HOMA-IR, the beta-cell function was evaluated by HOMA-beta formula and the formula deltaI(30)/deltaG(30) = (deltaI(30)-deltaI(0))/(deltaG(30)-deltaG(0)). The insulin area under curve (INSAUC) was evaluated by the formula INSAUC=FINS/2+INS(30)+INS(60)+INS(120)/2. The mean FPG was 6.23 mmol/L in group A and 12.6 mmol/L in group B. PG2H was 11.7 mmol/L in group A and 19.2 mmol/L in group B. The TI levels in group B at 0, 30, 60, 120 min during standard meal test were significantly higher than those in group A: 6.15 +/- 1.06 vs 4.77 +/- 1.06, 9.76 +/- 1.1 vs 5.88 +/- 1.1,14.68 +/- 1.11 vs 6.87 +/- 1.1 and 17.13 +/- 1.12 vs 8.0 +/- 1.1 microU/dl (all P< 0.01). The NSINS showed the same trend. The insulin resistance in group B was 1.5 times that in group A. With the insulin resistance adjusted, the beta cell function in group A was 5 to 6 times that in group B. The INSAUC in group A was 1.66 times larger than that in group B, especially the INSAUC for true insulin (2 times larger). The contribution of insulin resistance and beta cell function to PG2H was half by half in group A and 1:8 in group B. beta cell function calculated by insulin (Homa-beta) explained 41% of the plasma glucose changes in group A and 54% of the plasma glucose changes in group B. The contribution of insulin deficiency to plasma glocose was 3.3.times that of insulin resistance in group A and was 9

  5. Increased secretion of insulin and proliferation of islet {beta}-cells in rats with mesenteric lymph duct ligation

    Energy Technology Data Exchange (ETDEWEB)

    Nagino, Ko; Yokozawa, Junji; Sasaki, Yu; Matsuda, Akiko; Takeda, Hiroaki [Department of Gastroenterology, Faculty of Medicine, Yamagata University, Yamagata 990-9585 (Japan); Kawata, Sumio, E-mail: Sumio_Kawata@pref.hyogo.lg.jp [Department of Gastroenterology, Faculty of Medicine, Yamagata University, Yamagata 990-9585 (Japan); Hyogo Prefectural Nishinomiya Hospital, 13-9 Rokutanji-cho, Nishinomiya 662-0918 (Japan)

    2012-08-24

    Highlights: Black-Right-Pointing-Pointer Insulin secretion was increased during the OGTT or IVGTT in mesenteric lymph duct-ligated rats. Black-Right-Pointing-Pointer Proliferation of islet {beta}-cells was upregulated in lymph duct-ligated rats. Black-Right-Pointing-Pointer Mesenteric lymph duct flow has a role in glucose metabolism. -- Abstract: Background and aims: It has been suggested that intestinal lymph flow plays an important role in insulin secretion and glucose metabolism after meals. In this study, we investigated the influence of ligation of the mesenteric lymph duct on glucose metabolism and islet {beta}-cells in rats. Methods: Male Sprague-Dawley rats (10 weeks old) were divided into two groups: one underwent ligation of the mesenteric lymph duct above the cistern (ligation group), and the other underwent a sham operation (sham group). After 1 and 2 weeks, fasting plasma concentrations of glucose, insulin, triglyceride, glucose-dependent insulinotropic polypeptide (GIP), and the active form of glucagon-like peptide-1 (GLP-1) were measured. At 2 weeks after the operation, the oral glucose tolerance test (OGTT) and intravenous glucose tolerance test (IVGTT) were performed. After the rats had been sacrificed, the insulin content of the pancreas was measured and the proliferation of {beta}-cells was assessed immunohistochemically using antibodies against insulin and Ki-67. Results: During the OGTT, the ligation group showed a significant decrease in the plasma glucose concentration at 120 min (p < 0.05) and a significant increase in the plasma insulin concentration by more than 2-fold at 15 min (p < 0.01). On the other hand, the plasma GIP concentration was significantly decreased at 60 min (p < 0.01) in the ligated group, while the active form of GLP-1 showed a significantly higher level at 90 min (1.7-fold; p < 0.05) and 120 min (2.5-fold; p < 0.01). During the IVGTT, the plasma insulin concentration in the ligation group was significantly higher at 2

  6. Powerful Radio Burst Indicates New Astronomical Phenomenon

    Science.gov (United States)

    2007-09-01

    Astronomers studying archival data from an Australian radio telescope have discovered a powerful, short-lived burst of radio waves that they say indicates an entirely new type of astronomical phenomenon. Region of Strong Radio Burst Visible-light (negative greyscale) and radio (contours) image of Small Magellanic Cloud and area where burst originated. CREDIT: Lorimer et al., NRAO/AUI/NSF Click on image for high-resolution file ( 114 KB) "This burst appears to have originated from the distant Universe and may have been produced by an exotic event such as the collision of two neutron stars or the death throes of an evaporating black hole," said Duncan Lorimer, Assistant Professor of Physics at West Virginia University (WVU) and the National Radio Astronomy Observatory (NRAO). The research team led by Lorimer consists of Matthew Bailes of Swinburne University in Australia, Maura McLaughlin of WVU and NRAO, David Narkevic of WVU, and Fronefield Crawford of Franklin and Marshall College in Lancaster, Pennsylvania. The astronomers announced their findings in the September 27 issue of the online journal Science Express. The startling discovery came as WVU undergraduate student David Narkevic re-analyzed data from observations of the Small Magellanic Cloud made by the 210-foot Parkes radio telescope in Australia. The data came from a survey of the Magellanic Clouds that included 480 hours of observations. "This survey had sought to discover new pulsars, and the data already had been searched for the type of pulsating signals they produce," Lorimer said. "We re-examined the data, looking for bursts that, unlike the usual ones from pulsars, are not periodic," he added. The survey had covered the Magellanic Clouds, a pair of small galaxies in orbit around our own Milky Way Galaxy. Some 200,000 light-years from Earth, the Magellanic Clouds are prominent features in the Southern sky. Ironically, the new discovery is not part of these galaxies, but rather is much more distant

  7. Rock Burst Monitoring by Integrated Microseismic and Electromagnetic Radiation Methods

    Science.gov (United States)

    Li, Xuelong; Wang, Enyuan; Li, Zhonghui; Liu, Zhentang; Song, Dazhao; Qiu, Liming

    2016-11-01

    For this study, microseismic (MS) and electromagnetic radiation (EMR) monitoring systems were installed in a coal mine to monitor rock bursts. The MS system monitors coal or rock mass ruptures in the whole mine, whereas the EMR equipment monitors the coal or rock stress in a small area. By analysing the MS energy, number of MS events, and EMR intensity with respect to rock bursts, it has been shown that the energy and number of MS events present a "quiet period" 1-3 days before the rock burst. The data also show that the EMR intensity reaches a peak before the rock burst and this EMR intensity peak generally corresponds to the MS "quiet period". There is a positive correlation between stress and EMR intensity. Buckling failure of coal or rock depends on the rheological properties and occurs after the peak stress in the high-stress concentration areas in deep mines. The MS "quiet period" before the rock burst is caused by the heterogeneity of the coal and rock structures, the transfer of high stress into internal areas, locked patches, and self-organized criticality near the stress peak. This study increases our understanding of coal and rock instability in deep mines. Combining MS and EMR to monitor rock burst could improve prediction accuracy.

  8. Understanding the Generation of Network Bursts by Adaptive Oscillatory Neurons

    Directory of Open Access Journals (Sweden)

    Tanguy Fardet

    2018-02-01

    Full Text Available Experimental and numerical studies have revealed that isolated populations of oscillatory neurons can spontaneously synchronize and generate periodic bursts involving the whole network. Such a behavior has notably been observed for cultured neurons in rodent's cortex or hippocampus. We show here that a sufficient condition for this network bursting is the presence of an excitatory population of oscillatory neurons which displays spike-driven adaptation. We provide an analytic model to analyze network bursts generated by coupled adaptive exponential integrate-and-fire neurons. We show that, for strong synaptic coupling, intrinsically tonic spiking neurons evolve to reach a synchronized intermittent bursting state. The presence of inhibitory neurons or plastic synapses can then modulate this dynamics in many ways but is not necessary for its appearance. Thanks to a simple self-consistent equation, our model gives an intuitive and semi-quantitative tool to understand the bursting behavior. Furthermore, it suggests that after-hyperpolarization currents are sufficient to explain bursting termination. Through a thorough mapping between the theoretical parameters and ion-channel properties, we discuss the biological mechanisms that could be involved and the relevance of the explored parameter-space. Such an insight enables us to propose experimentally-testable predictions regarding how blocking fast, medium or slow after-hyperpolarization channels would affect the firing rate and burst duration, as well as the interburst interval.

  9. Observing a Burst with Sunglasses

    Science.gov (United States)

    2003-11-01

    polarisation properties of the afterglow of GRB 030329 as it developed after the explosion. Hypernovae, the source of GRBs, are indeed so far away that they can only be seen as unresolved points of light. To probe their spatial structure, astronomers have thus to rely on a trick: polarimetry (see ESO PR 23/03). Polarimetry works as follows: light is composed of electromagnetic waves which oscillate in certain directions (planes). Reflection or scattering of light favours certain orientations of the electric and magnetic fields over others. This is why polarising sunglasses can filter out the glint of sunlight reflecting off a pond. The radiation in a gamma-ray burst is generated in an ordered magnetic field, as so-called synchrotron radiation [3]. If the hypernova is spherically symmetric, all orientations of the electromagnetic waves will be present equally and will average out, so there will be no net polarisation. If, however, the gas is not ejected symmetrically, but into a jet, a slight net polarisation will be imprinted on the light. This net polarisation will change with time since the opening angle of the jet widens with time, and we see a different fraction of the emission cone. Studying the polarisation properties of the afterglow of a gamma-ray burst thus allows to gain knowledge about the underlying spatial structures and the strength and orientation of the magnetic field in the region where the radiation is generated. " And doing this over a long period of time, as the afterglow fades and evolves, provides us with a unique diagnostic tool for gamma-ray burst studies ", says Jochen Greiner . Although previous single measurements of the polarisation of GRB's optical afterglow exist, no detailed study has ever been done of the evolution of polarisation with time. This is indeed a very demanding task, only possible with an extremely stable instrument on the largest telescope... and a sufficient bright optical afterglow. As soon as GRB 030329 was detected, the team of

  10. Quantum key based burst confidentiality in optical burst switched networks.

    Science.gov (United States)

    Balamurugan, A M; Sivasubramanian, A

    2014-01-01

    The optical burst switching (OBS) is an emergent result to the technology concern that could achieve a feasible network in future. They are endowed with the ability to meet the bandwidth requirement of those applications that require intensive bandwidth. There are more domains opening up in the OBS that evidently shows their advantages and their capability to face the future network traffic. However, the concept of OBS is still far from perfection facing issues in case of security threat. The transfer of optical switching paradigm to optical burst switching faces serious downfall in the fields of burst aggregation, routing, authentication, dispute resolution, and quality of service (QoS). This paper deals with employing RC4 (stream cipher) to encrypt and decrypt bursts thereby ensuring the confidentiality of the burst. Although the use of AES algorithm has already been proposed for the same issue, by contrasting the two algorithms under the parameters of burst encryption and decryption time, end-to-end delay, it was found that RC4 provided better results. This paper looks to provide a better solution for the confidentiality of the burst in OBS networks.

  11. Quantum Key Based Burst Confidentiality in Optical Burst Switched Networks

    Directory of Open Access Journals (Sweden)

    A. M. Balamurugan

    2014-01-01

    Full Text Available The optical burst switching (OBS is an emergent result to the technology concern that could achieve a feasible network in future. They are endowed with the ability to meet the bandwidth requirement of those applications that require intensive bandwidth. There are more domains opening up in the OBS that evidently shows their advantages and their capability to face the future network traffic. However, the concept of OBS is still far from perfection facing issues in case of security threat. The transfer of optical switching paradigm to optical burst switching faces serious downfall in the fields of burst aggregation, routing, authentication, dispute resolution, and quality of service (QoS. This paper deals with employing RC4 (stream cipher to encrypt and decrypt bursts thereby ensuring the confidentiality of the burst. Although the use of AES algorithm has already been proposed for the same issue, by contrasting the two algorithms under the parameters of burst encryption and decryption time, end-to-end delay, it was found that RC4 provided better results. This paper looks to provide a better solution for the confidentiality of the burst in OBS networks.

  12. Bursting behaviours in cascaded stimulated Brillouin scattering

    International Nuclear Information System (INIS)

    Liu Zhan-Jun; He Xian-Tu; Zheng Chun-Yang; Wang Yu-Gang

    2012-01-01

    Stimulated Brillouin scattering is studied by numerically solving the Vlasov—Maxwell system. A cascade of stimulated Brillouin scattering can occur when a linearly polarized laser pulse propagates in a plasma. It is found that a stimulated Brillouin scattering cascade can reduce the scattering and increase the transmission of light, as well as introduce a bursting behaviour in the evolution of the laser-plasma interaction. The bursting time in the reflectivity is found to be less than half the ion acoustic period. The ion temperature can affect the stimulated Brillouin scattering cascade, which can repeat several times at low ion temperatures and can be completely eliminated at high ion temperatures. For stimulated Brillouin scattering saturation, higher-harmonic generation and wave—wave interaction of the excited ion acoustic waves can restrict the amplitude of the latter. In addition, stimulated Brillouin scattering cascade can restrict the amplitude of the scattered light. (physics of gases, plasmas, and electric discharges)

  13. Coherent combining pulse bursts in time domain

    Science.gov (United States)

    Galvanauskas, Almantas

    2018-01-09

    A beam combining and pulse stacking technique is provided that enhances laser pulse energy by coherent stacking pulse bursts (i.e. non-periodic pulsed signals) in time domain. This energy enhancement is achieved by using various configurations of Fabry-Perot, Gires-Tournois and other types of resonant cavities, so that a multiple-pulse burst incident at either a single input or multiple inputs of the system produces an output with a solitary pulse, which contains the summed energy of the incident multiple pulses from all beams. This disclosure provides a substantial improvement over conventional coherent-combining methods in that it achieves very high pulse energies using a relatively small number of combined laser systems, thus providing with orders of magnitude reduction in system size, complexity, and cost compared to current combining approaches.

  14. Enhanced Glucose Tolerance and Pancreatic Beta Cell Function by Low Dose Aspirin in Hyperglycemic Insulin-Resistant Type 2 Diabetic Goto-Kakizaki (GK Rats

    Directory of Open Access Journals (Sweden)

    Layla Amiri

    2015-07-01

    Full Text Available Background/Aim: Type 2 diabetes is the most common metabolic disorder, characterized by insulin resistance and pancreatic islet beta-cell failure. The most common complications associated with type 2 diabetes are hyperinsulinemia, hyperglycemia, hyperlipidemia, increased inflammatory and reduced insulin response. Aspirin (ASA and other non-steroidal anti-inflammatory drugs (NSAIDs have been associated with the prevention of diabetes, obesity and related cardiovascular disorders. Aspirin has been used in many clinical and experimental trials for the prevention of diabetes and associated complications. Methods: In this study, five month old Goto-Kakizaki (GK rats, which showed signs of mild hyperglycemia (fasting blood glucose 80-95 mg/dl vs 55-60 mg/dl Wistar control rats were used. Two subgroups of GK and Wistar control rats were injected intraperitoneally with 100 mg aspirin/kg body weight/ day for 5 weeks. Animals were sacrificed and blood and tissues were collected after performing glucose tolerance (2 h post 2g IP glucose ingestion tests in experimental and control groups. Results: Aspirin caused a moderate decrease in hyperglycemia. However, we observed a significant improvement in glucose tolerance after ASA treatment in GK rats compared to the nondiabetic Wistar rats. Also, the ASA treated GK rats exhibited a significant decrease in insulinemia. ASA treatment also caused a marked reduction in the pro-inflammatory prostaglandin, PGE2, which was significantly higher in GK rats. On the other hand, no significant organ toxicity was observed after ASA treatment at this dose and time period. However, the total cholesterol and lipoprotein levels were significantly increased in GK rats, which decreased after ASA treatment. Immunofluorescence staining for insulin/glucagon secreting pancreatic cells showed improved beta-cell structural and functional integrity in ASA-treated rats which was also confirmed by SDS-PAGE and Western blot analysis

  15. Reactive hypoglycemia in lean young women with PCOS and correlations with insulin sensitivity and with beta cell function.

    Science.gov (United States)

    Altuntas, Yuksel; Bilir, Muammer; Ucak, Sema; Gundogdu, Sadi

    2005-04-01

    Reactive hypoglycemia (RH), which is a postprandial hypoglycemic state, occurs within 2-5 h after food intake. It is classified as idiopathic, alimentary, or diabetic reactive hypoglycemia. We studied the incidence of reactive hypoglycemia and looked for any correlations between it and the presence of insulin sensitivity and/or beta cell function in young lean polycystic ovary syndrome (PCOS) patients. This study was designed as a cross-sectional study in 64 lean young women with PCOS (BMI lean young women with PCOS. DHEA-S and PRL levels were found to be lower in subjects with RH (P 0.05, respectively). Beta cell function indices such as the insulinogenic index (at 120 min), CIR (at 120 min) and HOMA beta cell index were found to be insignificantly higher in the RH group than the nonreactive hypoglycemia (NRH) group. The 4 h glucose level, but not the 3 h glucose level, was significantly correlated with insulin resistance indices, such as fasting insulin level, HOMA-IR, Quicky index, and FIRI in the RH group. Significantly decreased DHEA-S levels were an interesting finding. In conclusion, there is an urgent need to investigate RH in lean young women with PCOS. Our results indicate that more definite insulin resistance occurs in subjects with RH in the fourth hour of the OGTT than those with RH in the third hour. In addition, RH in the fourth hour together with a low DHEA-S level may be predictive of future diabetes in young women with PCOS even when they are not obese.

  16. Maternal obesity accelerates fetal pancreatic beta-cell but not alpha-cell development in sheep: prenatal consequences.

    Science.gov (United States)

    Ford, Stephen P; Zhang, Liren; Zhu, Meijun; Miller, Myrna M; Smith, Derek T; Hess, Bret W; Moss, Gary E; Nathanielsz, Peter W; Nijland, Mark J

    2009-09-01

    Maternal obesity affects offspring weight, body composition, and organ function, increasing diabetes and metabolic syndrome risk. We determined effects of maternal obesity and a high-energy diet on fetal pancreatic development. Sixty days prior to breeding, ewes were assigned to control [100% of National Research Council (NRC) recommendations] or obesogenic (OB; 150% NRC) diets. At 75 days gestation, OB ewes exhibited elevated insulin-to-glucose ratios at rest and during a glucose tolerance test, demonstrating insulin resistance compared with control ewes. In fetal studies, ewes ate their respective diets from 60 days before to 75 days after conception when animals were euthanized under general anesthesia. OB and control ewes increased in body weight by approximately 43% and approximately 6%, respectively, from diet initiation until necropsy. Although all organs were heavier in fetuses from OB ewes, only pancreatic weight increased as a percentage of fetal weight. Blood glucose, insulin, and cortisol were elevated in OB ewes and fetuses on day 75. Insulin-positive cells per unit pancreatic area were 50% greater in fetuses from OB ewes as a result of increased beta-cell mitoses rather than decreased programmed cell death. Lambs of OB ewes were born earlier but weighed the same as control lambs; however, their crown-to-rump length was reduced, and their fat mass was increased. We conclude that increased systemic insulin in fetuses from OB ewes results from increased glucose exposure and/or cortisol-induced accelerated fetal beta-cell maturation and may contribute to premature beta-cell function loss and predisposition to obesity and metabolic disease in offspring.

  17. Biotin uptake by mouse and human pancreatic beta cells/islets: a regulated, lipopolysaccharide-sensitive carrier-mediated process

    Science.gov (United States)

    Ghosal, Abhisek; Sekar, Thillai V.

    2014-01-01

    Biotin is essential for the normal function of pancreatic beta cells. These cells obtain biotin from their surroundings via transport across their cell membrane. Little is known about the uptake mechanism involved, how it is regulated, and how it is affected by internal and external factors. We addressed these issues using the mouse-derived pancreatic beta-TC-6 cells and freshly isolated mouse and human primary pancreatic beta cells as models. The results showed biotin uptake by pancreatic beta-TC-6 cells occurs via a Na+-dependent, carrier-mediated process, that is sensitive to desthiobiotin, as well as to pantothenic acid and lipoate; the process is also saturable as a function of concentration (apparent Km = 22.24 ± 5.5 μM). These cells express the sodium-dependent multivitamin transporter (SMVT), whose knockdown (with doxycycline-inducible shRNA) led to a sever inhibition in biotin uptake. Similarly, uptake of biotin by mouse and human primary pancreatic islets is Na+-dependent and carrier-mediated, and both cell types express SMVT. Biotin uptake by pancreatic beta-TC-6 cells is also adaptively regulated (via transcriptional mechanism) by extracellular substrate level. Chronic treatment of pancreatic beta-TC-6 cells with bacterial lipopolysaccharides (LPS) leads to inhibition in biotin uptake. This inhibition is mediated via a Toll-Like receptor 4-mediated process and involves a decrease in membrane expression of SMVT. These findings show, for the first time, that pancreatic beta cells/islets take up biotin via a specific and regulated carrier-mediated process, and that the process is sensitive to the effect of LPS. PMID:24904078

  18. In vivo and in vitro characterization of [18F]-FE-(+)-DTBZ as a tracer for beta-cell mass

    International Nuclear Information System (INIS)

    Eriksson, Olof; Jahan, Mahabuba; Johnstroem, Peter; Korsgren, Olle; Sundin, Anders; Halldin, Christer; Johansson, Lars

    2010-01-01

    Introduction: The positron emission tomography (PET) tracer 9-[ 18 F]fluoroethyl-(+)-dihydrotetrabenazine ([ 18 F]-FE-(+)-DTBZ) is a potential candidate for quantifying beta-cell mass in vivo. The purpose was to investigate in vitro and in vivo utility of this tracer for the assessment of beta-cell mass. Methods: Three pigs were intravenously administered [ 18 F]-FE-(+)-DTBZ and examined by PET/computed tomography. Binding parameters were estimated by kinetic modeling. In vitro k D and B max were determined by saturation binding studies of endocrine and exocrine human tissue homogenates. In vitro pancreatic uptake was determined by tissue autoradiography with pancreases from patients with types 1 (T1DM) and 2 diabetes mellitus (T2DM) and healthy controls. Results: [ 18 F]-FE-(+)-DTBZ had a k D of 3.5±1.0 nM, a B max of 382±108 fmol/mg protein and a specificity of 89±1.8% in islet homogenates. The total exocrine uptake was lower and 65% was nondisplaceable. No uptake difference was observed in pancreatic tissue slices from patients with T1DM, T2DM or healthy controls. The in vivo porcine pancreatic uptake reached a peak of standardized uptake value (SUV) of 2.8 with a low distribution volume ratio in all animals. Moderate to high tracer uptake was identified in the bile system and in bone. Conclusions: [ 18 F]-FE-(+)-DTBZ binds to vesicular monoamine transporter 2 (VMAT2) with high specificity in pure islet tissue in vitro. However, there is high nondisplaceable binding to exocrine tissue. In addition, in vivo tracer metabolism and dehalogenation result in severe underestimation of porcine pancreatic VMAT2 expression and BCM. The results do not support [ 18 F]-FE-(+)-DTBZ as a suitable tracer for in vivo beta-cell imaging.

  19. Solar microwave bursts - A review

    Science.gov (United States)

    Kundu, M. R.; Vlahos, L.

    1982-01-01

    Observational and theoretical results on the physics of microwave bursts that occur in the solar atmosphere are reviewed. Special attention is given to the advances made in burst physics over the last few years with the great improvement in spatial and time resolution, especially with instruments like the NRAO three-element interferometer, the Westerbork Synthesis Radio Telescope, and more recently the Very Large Array. Observations made on the preflare build-up of an active region at centimeter wavelengths are reviewed. Three distinct phases in the evolution of cm bursts, namely the impulsive phase, the post-burst phase, and the gradual rise and fall, are discussed. Attention is also given to the flux density spectra of centimeter bursts. Descriptions are given of observations of fine structures with temporal resolution of 10-100 ms in the intensity profiles of cm-wavelength bursts. High spatial resolution observations are analyzed, with special reference to the one- and two-dimensional maps of cm burst sources.

  20. Arsenic exposure and calpain-10 polymorphisms impair the function of pancreatic beta-cells in humans: a pilot study of risk factors for T2DM.

    Directory of Open Access Journals (Sweden)

    Andrea Díaz-Villaseñor

    Full Text Available The incidence of type 2 diabetes mellitus (T2DM is increasing worldwide and diverse environmental and genetic risk factors are well recognized. Single nucleotide polymorphisms (SNPs in the calpain-10 gene (CAPN-10, which encodes a protein involved in the secretion and action of insulin, and chronic exposure to inorganic arsenic (iAs through drinking water have been independently associated with an increase in the risk for T2DM. In the present work we evaluated if CAPN-10 SNPs and iAs exposure jointly contribute to the outcome of T2DM. Insulin secretion (beta-cell function and insulin sensitivity were evaluated indirectly through validated indexes (HOMA2 in subjects with and without T2DM who have been exposed to a gradient of iAs in their drinking water in northern Mexico. The results were analyzed taking into account the presence of the risk factor SNPs SNP-43 and -44 in CAPN-10. Subjects with T2DM had significantly lower beta-cell function and insulin sensitivity. An inverse association was found between beta-cell function and iAs exposure, the association being more pronounced in subjects with T2DM. Subjects without T2DM who were carriers of the at-risk genotype SNP-43 or -44, also had significantly lower beta-cell function. The association of SNP-43 with beta-cell function was dependent on iAs exposure, age, gender and BMI, whereas the association with SNP-44 was independent of all of these factors. Chronic exposure to iAs seems to be a risk factor for T2DM in humans through the reduction of beta-cell function, with an enhanced effect seen in the presence of the at-risk genotype of SNP-43 in CAPN-10. Carriers of CAPN-10 SNP-44 have also shown reduced beta-cell function.

  1. Islet-selectivity of G-protein coupled receptor ligands evaluated for PET imaging of pancreatic {beta}-cell mass

    Energy Technology Data Exchange (ETDEWEB)

    Cline, Gary W., E-mail: gary.cline@yale.edu [Yale University School of Medicine (United States); Zhao, Xiaojian [Yale University School of Medicine (United States); Jakowski, Amy B.; Soeller, Walter C.; Treadway, Judith L. [Pfizer Global Research and Development, Pfizer Inc., Groton CT (United States)

    2011-09-02

    Highlights: {yields} We screened G-protein coupled receptors for imaging pancreatic. {yields} Database mining and immunohistochemistry identified GPCRs enriched in {beta}-cells. {yields} In vitro and in vivo assays were used to determine exocrine vs endocrine specificity. {yields} GPCR candidates for imaging of {beta}-cell mass are Prokineticin-1R, mGluR5, and GLP-1R. -- Abstract: A critical unmet need exists for methods to quantitatively measure endogenous pancreatic {beta}-cell mass (BCM) for the clinical evaluation of therapies to prevent or reverse loss of BCM and diabetes progression. Our objective was to identify G-protein coupled receptors (GPCRs) that are expressed with a high degree of specificity to islet {beta}-cells for receptor-targeted imaging of BCM. GPCRs enriched in pancreatic islets relative to pancreas acinar and hepatic tissue were identified using a database screen. Islet-specific expression was confirmed by human pancreas immunohistochemistry (IHC). In vitro selectivity assessment was determined from the binding and uptake of radiolabeled ligands to the rat insulinoma INS-1 832/13 cell line and isolated rat islets relative to the exocrine pancreas cell-type, PANC-1. Tail-vein injections of radioligands into rats were used to determine favorable image criteria of in vivo biodistribution to the pancreas relative to other internal organs (i.e., liver, spleen, stomach, and lungs). Database and IHC screening identified four candidate receptors for further in vitro and in vivo evaluation for PET imaging of BCM: prokineticin-1 receptor (PK-1R), metabotropic glutamate receptor type-5 (mGluR5), neuropeptide Y-2 receptor (NPY-2R), and glucagon-like peptide 1 receptor (GLP-1R). In vitro specificity ratios gave the following receptor rank order: PK-1R > GLP-1R > NPY-2R > mGluR5. The biodistribution rank order of selectivity to the pancreas was found to be PK-1R > VMAT2 {approx} GLP-1R > mGluR5. Favorable islet selectivity and biodistribution

  2. Characterization of stimulus-secretion coupling in the human pancreatic EndoC-βH1 beta cell line.

    Directory of Open Access Journals (Sweden)

    Lotta E Andersson

    Full Text Available Studies on beta cell metabolism are often conducted in rodent beta cell lines due to the lack of stable human beta cell lines. Recently, a human cell line, EndoC-βH1, was generated. Here we investigate stimulus-secretion coupling in this cell line, and compare it with that in the rat beta cell line, INS-1 832/13, and human islets.Cells were exposed to glucose and pyruvate. Insulin secretion and content (radioimmunoassay, gene expression (Gene Chip array, metabolite levels (GC/MS, respiration (Seahorse XF24 Extracellular Flux Analyzer, glucose utilization (radiometric, lactate release (enzymatic colorimetric, ATP levels (enzymatic bioluminescence and plasma membrane potential and cytoplasmic Ca2+ responses (microfluorometry were measured. Metabolite levels, respiration and insulin secretion were examined in human islets.Glucose increased insulin release, glucose utilization, raised ATP production and respiratory rates in both lines, and pyruvate increased insulin secretion and respiration. EndoC-βH1 cells exhibited higher insulin secretion, while plasma membrane depolarization was attenuated, and neither glucose nor pyruvate induced oscillations in intracellular calcium concentration or plasma membrane potential. Metabolite profiling revealed that glycolytic and TCA-cycle intermediate levels increased in response to glucose in both cell lines, but responses were weaker in EndoC-βH1 cells, similar to those observed in human islets. Respiration in EndoC-βH1 cells was more similar to that in human islets than in INS-1 832/13 cells.Functions associated with early stimulus-secretion coupling, with the exception of plasma membrane potential and Ca2+ oscillations, were similar in the two cell lines; insulin secretion, respiration and metabolite responses were similar in EndoC-βH1 cells and human islets. While both cell lines are suitable in vitro models, with the caveat of replicating key findings in isolated islets, EndoC-βH1 cells have the

  3. Immune-mediated beta-cell destruction in vitro and in vivo-A pivotal role for galectin-3

    DEFF Research Database (Denmark)

    Karlsen, Allan E; Størling, Zenia M; Sparre, Thomas

    2006-01-01

    Pro-apoptotic cytokines are toxic to the pancreatic beta-cells and have been associated with the pathogenesis of Type 1 diabetes (T1D). Proteome analysis of IL-1beta exposed isolated rat islets identified galectin-3 (gal-3) as the most up-regulated protein. Here analysis of human and rat islets a....... In summary, combined proteome-transcriptome-genome and functional analyses identify gal-3 as a candidate gene/protein in T1D susceptibility that may prove valuable in future intervention/prevention strategies....

  4. Progenitor potential of nkx6.1-expressing cells throughout zebrafish life and during beta cell regeneration.

    Science.gov (United States)

    Ghaye, Aurélie P; Bergemann, David; Tarifeño-Saldivia, Estefania; Flasse, Lydie C; Von Berg, Virginie; Peers, Bernard; Voz, Marianne L; Manfroid, Isabelle

    2015-09-02

    In contrast to mammals, the zebrafish has the remarkable capacity to regenerate its pancreatic beta cells very efficiently. Understanding the mechanisms of regeneration in the zebrafish and the differences with mammals will be fundamental to discovering molecules able to stimulate the regeneration process in mammals. To identify the pancreatic cells able to give rise to new beta cells in the zebrafish, we generated new transgenic lines allowing the tracing of multipotent pancreatic progenitors and endocrine precursors. Using novel bacterial artificial chromosome transgenic nkx6.1 and ascl1b reporter lines, we established that nkx6.1-positive cells give rise to all the pancreatic cell types and ascl1b-positive cells give rise to all the endocrine cell types in the zebrafish embryo. These two genes are initially co-expressed in the pancreatic primordium and their domains segregate, not as a result of mutual repression, but through the opposite effects of Notch signaling, maintaining nkx6.1 expression while repressing ascl1b in progenitors. In the adult zebrafish, nkx6.1 expression persists exclusively in the ductal tree at the tip of which its expression coincides with Notch active signaling in centroacinar/terminal end duct cells. Tracing these cells reveals that they are able to differentiate into other ductal cells and into insulin-expressing cells in normal (non-diabetic) animals. This capacity of ductal cells to generate endocrine cells is supported by the detection of ascl1b in the nkx6.1:GFP ductal cell transcriptome. This transcriptome also reveals, besides actors of the Notch and Wnt pathways, several novel markers such as id2a. Finally, we show that beta cell ablation in the adult zebrafish triggers proliferation of ductal cells and their differentiation into insulin-expressing cells. We have shown that, in the zebrafish embryo, nkx6.1+ cells are bona fide multipotent pancreatic progenitors, while ascl1b+ cells represent committed endocrine precursors. In

  5. Phenomenological vessel burst investigations

    International Nuclear Information System (INIS)

    Hippelein, K.W.; Julisch, P.; Muz, J.; Schiedermaier, J.

    1985-07-01

    Fourteen burst experiments have been carried out using vessels with circumferential and longitudinal flaws, for investigation of the fracture behaviour, i.e. the time-related fracture opening. The vessels had dimensions (outer diameter x wall thickness = 800 x 47 mm) which correspond to the dimensions of the main coolant piping of a 1300 MW e PWR. The test specimens had been made of the base-safe material 20 MnMoNi 55 and of a special, 22 NiMoCr 37 base alloy. The experimental conditions with regard to pressure and temperature have been chosen so as to correspond to normal operating conditions of a PWR (p∝17.5 MPa, T∝300 0 C), i.e. the flaws have been so dimensioned that failure was to be expected at a pressure of p∝17.5 MPa. As a rule, water has been used as the pressure medium, or in some cases air, in order to influence the time-dependent pressure decrease. Fluid and structural dynamics calculations have also been made. In order to determine the impact of a fast propagating crack on the leak-to-fracture curve, which normally is defined by quasistationary experiments, suitable tests have been made with large-volume, cylindrical vessels (outer diameter x wall thickness x length = 3000 x 21 x 14000 mm) made of the material WSt E 43. The leak-before-fracture criterion has been confirmed. (orig./HP) [de

  6. Thermonuclear model for γ-ray bursts

    International Nuclear Information System (INIS)

    Woosley, S.E.

    1981-01-01

    The evolution of magnetized neutron stars with field strengths of approx. 10 12 gauss that are accreting mass onto kilometer-sized polar regions at a rate of approx. 13 M 0 yr -1 is examined. Based on the results of one-dimensional calculations, one finds that stable hydrogen burning, mediated by the hot CNO-cycle, will lead to a critical helium mass in the range 10 20 to 10 22 g km -2 . Owing to the extreme degeneracy of the electron gas providing pressure support, helium burning occurs as a violent thermonuclear runaway which may propagate either as a convective deflagration (Type I burst) or as a detonation wave (Type II burst). Complete combustion of helium into 56 Ni releases from 10 38 to 10 40 erg km -2 and pushes hot plasma with β > 1 above the surface of the neutron star. Rapid expansion of the plasma channels a substantial fraction of the explosion energy into magnetic field stress. Spectral properties are expected to be complex with emission from both thermal and non-thermal processes. The hard γ-outburst of several seconds softens as the event proceeds and is followed by a period, typically of several minutes duration, of softer x-ray emission as the subsurface ashes of the thermonuclear explosion cool. In this model, most γ-ray bursts currently being observed are located at a distance of several hundred parsecs and should recur on a timescale of months to centuries with convective deflagrations (Type I bursts) being the more common variety. An explanation for Jacobson-like transients is also offered

  7. Effect of long-term transfusion therapy on the glycometabolic status and pancreatic beta cell function in patients with beta Thalassemia major

    Directory of Open Access Journals (Sweden)

    Kamalakshi G Bhat

    2014-01-01

    Full Text Available Background: Diabetes mellitus is a major complication of iron overload in patients with beta thalassemia major. Design: This is a descriptive study conducted in a Tertiary Care Teaching Hospital to analyze beta cell function and insulin resistance, and their relation to iron overload status in beta thalassemia major. Fasting glucose, two-hour post load glucose, fasting insulin, alanine amino transaminase (ALT, and ferritin were used as outcome measures. The homeostatic model assessment (HOMA model was used to calculate the beta cell function and insulin resistance index. Results: Of the 30 cases, 20% had impaired fasting glucose, 3.3% had impaired glucose tolerance, and none had diabetes. Fasting glucose was not significant between the cases and controls (P = 0.113. Fasting insulin (P = 0.001, ferritin (P = 0.001, and ALT (P = 0.001 levels were significantly high in the cases. Insulin resistance index was significantly higher in the cases (P = 0.001 as also the beta cell function (P = 0.001. With increase in age and the number of units transfused there is a decline in beta cell function, fasting insulin, and insulin resistance after attaining the maximum level. This suggests that initial insulin resistance is followed by insulin depletion due to loss of beta cell function, leading to diabetes mellitus. Conclusion: Impaired glucose tolerance (IGT and insulin resistance precede the onset of insulin-dependent diabetes and adequate chelation therapy is essential for delaying the onset or for prevention of diabetes.

  8. High-fat, carbohydrate-free diet markedly aggravates obesity but prevents beta-cell loss and diabetes in the obese, diabetes-susceptible db/db strain.

    Science.gov (United States)

    Mirhashemi, Farshad; Kluth, Oliver; Scherneck, Stephan; Vogel, Heike; Kluge, Reinhart; Schurmann, Annette; Joost, Hans-Georg; Neschen, Susanne

    2008-01-01

    We have previously reported that a high-fat, carbohydrate-free diet prevents diabetes and beta-cell destruction in the New Zealand Obese (NZO) mouse strain. Here we investigated the effect of diets with and without carbohydrates on obesity and development of beta-cell failure in a second mouse model of type 2 diabetes, the db/db mouse. When kept on a carbohydrate-containing standard (SD; with (w/w) 5.1, 58.3, and 17.6% fat, carbohydrates and protein, respectively) or high-fat diet (HFD; 14.6, 46.7 and 17.1%), db/db mice developed severe diabetes (blood glucose >20 mmol/l, weight loss, polydipsia and polyurea) associated with a selective loss of pancreatic beta-cells, reduced GLUT2 expression in the remaining beta-cells, and reduced plasma insulin levels. In contrast, db/db mice kept on a high-fat, carbohydrate-free diet (CFD; with 30.2 and 26.4% (w/w) fat or protein) did not develop diabetes and exhibited near-normal, hyperplastic islets in spite of a morbid obesity (fat content >60%) associated with hyperinsulinaemia. These data indicate that in genetically different mouse models of obesity-associated diabetes, obesity and dietary fat are not sufficient, and dietary carbohydrates are required, for beta-cell destruction.

  9. 30 CFR 57.3461 - Rock bursts.

    Science.gov (United States)

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Rock bursts. 57.3461 Section 57.3461 Mineral...-Underground Only § 57.3461 Rock bursts. (a) Operators of mines which have experienced a rock burst shall— (1) Within twenty four hours report to the nearest MSHA office each rock burst which: (i) Causes persons to...

  10. Chimera states in bursting neurons

    OpenAIRE

    Bera, Bidesh K.; Ghosh, Dibakar; Lakshmanan, M.

    2015-01-01

    We study the existence of chimera states in pulse-coupled networks of bursting Hindmarsh-Rose neurons with nonlocal, global and local (nearest neighbor) couplings. Through a linear stability analysis, we discuss the behavior of stability function in the incoherent (i.e. disorder), coherent, chimera and multi-chimera states. Surprisingly, we find that chimera and multi-chimera states occur even using local nearest neighbor interaction in a network of identical bursting neurons alone. This is i...

  11. The enteroinsular axis and endocrine pancreatic function in chronic alcohol consumers: evidence for early beta-cell hypofunction.

    Science.gov (United States)

    Patto, R J; Russo, E K; Borges, D R; Neves, M M

    1993-09-01

    Chronic alcohol consumers may have, as judged by functional criteria, exocrine as well as endocrine pancreatic dysfunction, the latter represented by a decreased insulin response to an oral glucose load. To investigate whether this decreased insulin response was due to an ethanol-induced beta-cell dysfunction or to an ethanol-induced dysfunction of the enteroinsular axis, we determined glucose, insulin, and C-peptide plasma concentrations following an oral and an intravenous glucose load in 16 healthy volunteer nonalcohol consumers and in 10 chronic alcohol consumers. In each group, total integrated response for glucose did not significantly change whether glucose was given orally or intravenously, indicating isoglycemic glucose loads. The total integrated response values for insulin in the alcoholic group following both glucose loads as well as C-peptide plasma concentrations were significantly lower than in the control group. Moreover, in both groups the insulin TIR values following the oral glucose load were significantly greater than the values obtained following the intravenous glucose load, indicating an incretin effect. These results indicate that the decreased insulin response observed in alcoholics was not caused by a dysfunction of the enteroinsular axis because it also occurred following an intravenous glucose load, but by an ethanol-induced beta-cell dysfunction because C-peptide and insulin were proportionally decreased in this group.

  12. Relationship of Soluble RAGE with Insulin Resistance and Beta Cell Function during Development of Type 2 Diabetes Mellitus

    Directory of Open Access Journals (Sweden)

    Subrata Kumar Biswas

    2015-01-01

    Full Text Available This study examined whether circulating levels of soluble receptor for advanced glycation end products (sRAGE alter in prediabetes and correlate with insulin resistance (IR and beta cell function in prediabetes and newly diagnosed type 2 diabetes mellitus (T2DM. Subjects without previous history of diabetes were recruited and grouped as control, prediabetes, and newly diagnosed T2DM. The control subjects (n=40 and people with prediabetes (n=52 and diabetes (n=66 were similar in terms of age, sex, BMI, systolic and diastolic BP, and fasting insulin level. HOMA-IR was found significantly higher in people with diabetes than control subjects (p<0.001 and people with prediabetes (p=0.005; and HOMA-%B was found significantly deteriorated in people with diabetes (p<0.001 compared to control subjects and people with prediabetes. However, serum sRAGE levels did not show any significant alteration in people with prediabetes compared to control subjects. Moreover, univariate and multivariate analyses did not identify any significant correlation and statistical association of sRAGE with HOMA-IR and HOMA-%B in people with prediabetes and newly diagnosed T2DM. Our data suggest that serum sRAGE levels do not alter in people with prediabetes compared to control subjects and do not correlate or associate with IR and beta cell function during development of T2DM.

  13. Fetal pancreatic beta-cell function in pregnancies complicated by maternal diabetes mellitus: relationship to fetal acidemia and macrosomia.

    Science.gov (United States)

    Salvesen, D R; Brudenell, J M; Proudler, A J; Crook, D; Nicolaides, K H

    1993-05-01

    Our purpose was to investigate the relationship between fetal pancreatic beta-cell function and fetal acidemia and macrosomia in pregnancies complicated by maternal diabetes mellitus. A cross-sectional study at the Harris Birthright Research Centre for Fetal Medicine, London, was performed. In 32 pregnancies complicated by maternal diabetes mellitus cordocentesis was performed at 36 to 39 weeks' gestation for the measurement of umbilical venous blood pH, PO2, PCO2, lactate, and glucose concentration; plasma insulin immunoreactivity; and insulin/glucose ratio. A reference range for plasma insulin and insulin/glucose ratio was constructed by studying fetal blood samples from 80 women who did not have diabetes mellitus. Mean umbilical venous blood pH was significantly lower and plasma insulin immunoreactivity and insulin/glucose ratio were significantly higher than the appropriate normal mean for gestation. There were significant associations between (1) maternal and fetal blood glucose concentrations (r = 0.95, p < 0.0001), (2) fetal blood glucose and plasma insulin immunoreactivity (r = 0.57, p < 0.01), (3) fetal plasma insulin immunoreactivity and blood pH (r = -0.39, p < 0.05), and (4) fetal insulin/glucose ratio and degree of macrosomia (r = 0.76, p < 0.0001). Fetal pancreatic beta-cell hyperplasia is implicated in the pathogenesis of both fetal acidemia and macrosomia.

  14. Circulating microRNA levels predict residual beta cell function and glycaemic control in children with type 1 diabetes mellitus

    DEFF Research Database (Denmark)

    Samandari, Nasim; Mirza, Aashiq H; Nielsen, Lotte B

    2017-01-01

    AIMS/HYPOTHESIS: We aimed to identify circulating microRNA (miRNA) that predicts clinical progression in a cohort of 123 children with new-onset type 1 diabetes mellitus. METHODS: Plasma samples were prospectively obtained at 1, 3, 6, 12 and 60 months after diagnosis from a subset of 40 children......RNAs revealed significant enrichment for pathways related to gonadotropin-releasing hormone receptor and angiogenesis pathways. CONCLUSIONS/INTERPRETATION: The miRNA hsa-miR-197-3p at 3 months was the strongest predictor of residual beta cell function 1 year after diagnosis in children with type 1 diabetes...... from the Danish Remission Phase Cohort, and profiled for miRNAs. At the same time points, meal-stimulated C-peptide and HbA1c levels were measured and insulin-dose adjusted HbA1c (IDAA1c) calculated. miRNAs that at 3 months after diagnosis predicted residual beta cell function and glycaemic control...

  15. Fetal and neonatal nicotine exposure in Wistar rats causes progressive pancreatic mitochondrial damage and beta cell dysfunction.

    Directory of Open Access Journals (Sweden)

    Jennifer E Bruin

    Full Text Available Nicotine replacement therapy (NRT is currently recommended as a safe smoking cessation aid for pregnant women. However, fetal and neonatal nicotine exposure in rats causes mitochondrial-mediated beta cell apoptosis at weaning, and adult-onset dysglycemia, which we hypothesize is related to progressive mitochondrial dysfunction in the pancreas. Therefore in this study we examined the effect of fetal and neonatal exposure to nicotine on pancreatic mitochondrial structure and function during postnatal development. Female Wistar rats were given saline (vehicle control or nicotine bitartrate (1 mg/kg/d via subcutaneous injection for 2 weeks prior to mating until weaning. At 3-4, 15 and 26 weeks of age, oral glucose tolerance tests were performed, and pancreas tissue was collected for electron microscopy, enzyme activity assays and islet isolation. Following nicotine exposure mitochondrial structural abnormalities were observed beginning at 3 weeks and worsened with advancing age. Importantly the appearance of these structural defects in nicotine-exposed animals preceded the onset of glucose intolerance. Nicotine exposure also resulted in significantly reduced pancreatic respiratory chain enzyme activity, degranulation of beta cells, elevated islet oxidative stress and impaired glucose-stimulated insulin secretion compared to saline controls at 26 weeks of age. Taken together, these data suggest that maternal nicotine use during pregnancy results in postnatal mitochondrial dysfunction that may explain, in part, the dysglycemia observed in the offspring from this animal model. These results clearly indicate that further investigation into the safety of NRT use during pregnancy is warranted.

  16. Detection circuit for gamma-ray burst

    International Nuclear Information System (INIS)

    Murakami, Hiroyuki; Yamagami, Takamasa; Mori, Kunishiro; Uchiyama, Sadayuki.

    1982-01-01

    A new gamma-ray burst detection system is described. The system was developed as an environmental monitor of an accelerator, and can be used as the burst detection system. The system detects the arrival time of burst. The difference between the arrival times detected at different places will give information on the burst source. The frequency of detecting false burst was estimated, and the detection limit under the estimated frequency of false burst was also calculated. Decision whether the signal is false or true burst was made by the statistical treatment. (Kato, T.)

  17. Gamma-ray burst models.

    Science.gov (United States)

    King, Andrew

    2007-05-15

    I consider various possibilities for making gamma-ray bursts, particularly from close binaries. In addition to the much-studied neutron star+neutron star and black hole+neutron star cases usually considered good candidates for short-duration bursts, there are also other possibilities. In particular, neutron star+massive white dwarf has several desirable features. These systems are likely to produce long-duration gamma-ray bursts (GRBs), in some cases definitely without an accompanying supernova, as observed recently. This class of burst would have a strong correlation with star formation and occur close to the host galaxy. However, rare members of the class need not be near star-forming regions and could have any type of host galaxy. Thus, a long-duration burst far from any star-forming region would also be a signature of this class. Estimates based on the existence of a known progenitor suggest that this type of GRB may be quite common, in agreement with the fact that the absence of a supernova can only be established in nearby bursts.

  18. Solar Drift-Pair Bursts

    Science.gov (United States)

    Stanislavsky, A.; Volvach, Ya.; Konovalenko, A.; Koval, A.

    2017-08-01

    In this paper a new sight on the study of solar bursts historically called drift pairs (DPs) is presented. Having a simple morphology on dynamic spectra of radio records (two short components separated in time, and often they are very similar) and discovered at the dawn of radio astronomy, their features remain unexplained totally up to now. Generally, the DPs are observed during the solar storms of type III bursts, but not every storm of type III bursts is linked with DPs. Detected by ground-based instruments at decameter and meter wavelengths, the DP bursts are limited in frequency bandwidth. They can drift from high frequencies to low ones and vice versa. Their frequency drift rate may be both lower and higher than typical rates of type III bursts at the same frequency range. The development of low-frequency radio telescopes and data processing provide additional possibilities in the research. In this context the fresh analysis of DPs, made from recent observations in the summer campaign of 2015, are just considered. Their study was implemented by updated tools of the UTR-2 radio telescope at 9-33 MHz. During 10-12 July of 2015, DPs forming the longest patterns on dynamic spectra are about 7% of the total number of recorded DPs. Their marvelous resemblance in frequency drift rates with the solar S-bursts is discussed.

  19. X-ray bursts: Observation versus theory

    Science.gov (United States)

    Lewin, W. H. G.

    1981-01-01

    Results of various observations of common type I X-ray bursts are discussed with respect to the theory of thermonuclear flashes in the surface layers of accreting neutron stars. Topics covered include burst profiles; irregular burst intervals; rise and decay times and the role of hydrogen; the accuracy of source distances; accuracy in radii determination; radius increase early in the burst; the super Eddington limit; temperatures at burst maximum; and the role of the magnetic field.

  20. AUTOMATIC RECOGNITION OF CORONAL TYPE II RADIO BURSTS: THE AUTOMATED RADIO BURST IDENTIFICATION SYSTEM METHOD AND FIRST OBSERVATIONS

    International Nuclear Information System (INIS)

    Lobzin, Vasili V.; Cairns, Iver H.; Robinson, Peter A.; Steward, Graham; Patterson, Garth

    2010-01-01

    Major space weather events such as solar flares and coronal mass ejections are usually accompanied by solar radio bursts, which can potentially be used for real-time space weather forecasts. Type II radio bursts are produced near the local plasma frequency and its harmonic by fast electrons accelerated by a shock wave moving through the corona and solar wind with a typical speed of ∼1000 km s -1 . The coronal bursts have dynamic spectra with frequency gradually falling with time and durations of several minutes. This Letter presents a new method developed to detect type II coronal radio bursts automatically and describes its implementation in an extended Automated Radio Burst Identification System (ARBIS 2). Preliminary tests of the method with spectra obtained in 2002 show that the performance of the current implementation is quite high, ∼80%, while the probability of false positives is reasonably low, with one false positive per 100-200 hr for high solar activity and less than one false event per 10000 hr for low solar activity periods. The first automatically detected coronal type II radio burst is also presented.

  1. Recent results from the gamma-ray burst studies in the KONUS experiment

    International Nuclear Information System (INIS)

    Mazets, E.P.; Golenetskii, S.V.

    1981-01-01

    Observations of 85 gamma bursts by the KONUS instruments on the Venera 11 and Venera 12 spacecraft in the period September 1978 to May 1979 inclusive have provided proof of a galactic localization of the gamma-burst sources based on an analysis of the log N-log S plot and the revealed anisotropy in the angular distribution of sources over the celestial sphere. Evaluation of the energy released in the sources yields 10 40 -10 41 erg. There apparently exist several types of gamma bursts differing in time profile, duration and shape of their energy spectrum. In some cases, extensive evolution of the energy spectrum is observed during a burst. The discovery of a flaring X-ray pulsar in Dorado has provided the first observational evidence for a connection of gamma bursts with neutron stars. Repeated short bursts from this source have revealed for the first time the recurrent features of this phenomenon. Repeated bursts have been detected from one more source in the short burst class. The data obtained thus far impose a number of restrictions on the applicability of many theoretical suggestions concerning the nature of the gamma bursts. The most plausible model for the gamma-burst source appears to be a binary with a neutron star with strongly non-stationary accretion involving, possibly, non-stationary thermonuclear fusion of matter falling onto the surface of a degenerate star. (orig.)

  2. Defective glucose and lipid metabolism in human immunodeficiency virus-infected patients with lipodystrophy involve liver, muscle tissue and pancreatic beta-cells

    DEFF Research Database (Denmark)

    Haugaard, Steen B; Andersen, Ove; Dela, Flemming

    2005-01-01

    .01. Disposition index (i.e. first-phase insulin response to intravenous glucose multiplied by incremental glucose disposal) was reduced by 46% (P = 0.05) in LIPO compared with the combined groups of NONLIPO and NAIVE, indicating an impaired adaptation of beta-cell function to insulin resistance in LIPO...... of glucose metabolism, lipid metabolism and beta-cell function in lipodystrophic HIV-infected patients. METHODS: [3-3H]glucose was applied during euglycaemic hyperinsulinaemic clamps in association with indirect calorimetry in 43 normoglycaemic HIV-infected patients (18 lipodystrophic patients on HAART (LIPO......), 18 patients without lipodystrophy on HAART (NONLIPO) and seven patients who were naive to antiretroviral therapy (NAIVE) respectively). beta-cell function was evaluated by an intravenous glucose tolerance test. RESULTS: Compared with NONLIPO and NAIVE separately, LIPO displayed markedly reduced ratio...

  3. Cytokines interleukin-1beta and tumor necrosis factor-alpha regulate different transcriptional and alternative splicing networks in primary beta-cells

    DEFF Research Database (Denmark)

    Ortis, Fernanda; Naamane, Najib; Flamez, Daisy

    2010-01-01

    by the cytokines interleukin (IL)-1beta + interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha + IFN-gamma in primary rat beta-cells. RESEARCH DESIGN AND METHODS: Fluorescence-activated cell sorter-purified rat beta-cells were exposed to IL-1beta + IFN-gamma or TNF-alpha + IFN-gamma for 6 or 24 h......-cells, with temporal differences in the number of genes modulated by IL-1beta + IFNgamma or TNF-alpha + IFN-gamma. These cytokine combinations induced differential expression of inflammatory response genes, which is related to differential induction of IFN regulatory factor-7. Both treatments decreased the expression...... of genes involved in the maintenance of beta-cell phenotype and growth/regeneration. Cytokines induced hypoxia-inducible factor-alpha, which in this context has a proapoptotic role. Cytokines also modified the expression of >20 genes involved in RNA splicing, and exon array analysis showed cytokine...

  4. Lack of TXNIP protects against mitochondria-mediated apoptosis but not against fatty acid-induced ER stress-mediated beta-cell death.

    Science.gov (United States)

    Chen, Junqin; Fontes, Ghislaine; Saxena, Geetu; Poitout, Vincent; Shalev, Anath

    2010-02-01

    We have previously shown that lack of thioredoxin-interacting protein (TXNIP) protects against diabetes and glucotoxicity-induced beta-cell apoptosis. Because the role of TXNIP in lipotoxicity is unknown, the goal of the present study was to determine whether TXNIP expression is regulated by fatty acids and whether TXNIP deficiency also protects beta-cells against lipoapoptosis. RESARCH DESIGN AND METHODS: To determine the effects of fatty acids on beta-cell TXNIP expression, INS-1 cells and isolated islets were incubated with/without palmitate and rats underwent cyclic infusions of glucose and/or Intralipid prior to islet isolation and analysis by quantitative real-time RT-PCR and immunoblotting. Using primary wild-type and TXNIP-deficient islets, we then assessed the effects of palmitate on apoptosis (transferase-mediated dUTP nick-end labeling [TUNEL]), mitochondrial death pathway (cytochrome c release), and endoplasmic reticulum (ER) stress (binding protein [BiP], C/EBP homologous protein [CHOP]). Effects of TXNIP deficiency were also tested in the context of staurosporine (mitochondrial damage) or thapsigargin (ER stress). Glucose elicited a dramatic increase in islet TXNIP expression both in vitro and in vivo, whereas fatty acids had no such effect and, when combined with glucose, even abolished the glucose effect. We also found that TXNIP deficiency does not effectively protect against palmitate or thapsigargin-induced beta-cell apoptosis, but specifically prevents staurosporine- or glucose-induced toxicity. Our results demonstrate that unlike glucose, fatty acids do not induce beta-cell expression of proapoptotic TXNIP. They further reveal that TXNIP deficiency specifically inhibits the mitochondrial death pathway underlying beta-cell glucotoxicity, whereas it has very few protective effects against ER stress-mediated lipoapoptosis.

  5. Human beta-cell precursors mature into functional insulin-producing cells in an immunoisolation device: implications for diabetes cell therapies.

    Science.gov (United States)

    Lee, Seung-Hee; Hao, Ergeng; Savinov, Alexei Y; Geron, Ifat; Strongin, Alex Y; Itkin-Ansari, Pamela

    2009-04-15

    Islet transplantation is limited by the need for chronic immunosuppression and the paucity of donor tissue. As new sources of human beta-cells are developed (e.g., stem cell-derived tissue), transplanting them in a durable device could obviate the need for immunosuppression, while also protecting the patient from any risk of tumorigenicity. Here, we studied (1) the survival and function of encapsulated human beta-cells and their progenitors and (2) the engraftment of encapsulated murine beta-cells in allo- and autoimmune settings. Human islets and human fetal pancreatic islet-like cell clusters were encapsulated in polytetrafluorethylene devices (TheraCyte) and transplanted into immunodeficient mice. Graft survival and function was measured by immunohistochemistry, circulating human C-peptide levels, and blood glucose levels. Bioluminescent imaging was used to monitor encapsulated neonatal murine islets. Encapsulated human islet-like cell clusters survived, replicated, and acquired a level of glucose responsive insulin secretion sufficient to ameliorate hyperglycemia in diabetic mice. Bioluminescent imaging of encapsulated murine neonatal islets revealed a dynamic process of cell death followed by regrowth, resulting in robust long-term allograft survival. Further, in the non-obese diabetic (NOD) mouse model of type I diabetes, encapsulated primary beta-cells ameliorated diabetes without stimulating a detectable T-cell response. We demonstrate for the first time that human beta-cells function is compatible with encapsulation in a durable, immunoprotective device. Moreover, our study suggests that encapsulation of beta-cells before terminal differentiation will be a successful approach for new cell-based therapies for diabetes, such as those derived from stem cells.

  6. Development of biomarker specific of pancreatic beta cells (incretin radiolabelled) for image of beta functional mass in diabetic and obese: study in animal model

    International Nuclear Information System (INIS)

    Seo, Daniele

    2017-01-01

    Increased prevalence of obesity worldwide, has become a vast concern, stimulating investigations focusing prevention and therapy of this condition. The association of type 2 diabetes or insulin resistance aggravates the prognosis of obesity. Even patients successfully submitted to bariatric or metabolic surgery, may not be cured of diabetes, as improvement of circulating values of glucose and insulin not necessarily reflects recovery of pancreatic beta cell mass. There is no consensus about how to estimate beta cell mass in vivo. Available tools suffer from low sensitivity and specificity, often being as well cumbersome and expensive. Radiolabeled incretins, such as glucagon-like-peptide 1 (GLP-1) analogs, seem to be promising options for the measurement of beta cell mass in diabetes and insulinoma. The objective of this study was the development of two conjugates of GLP-1 analog, radiolabeled with 99m Technetium, as a noninvasive imaging method for the estimation of pancreatic beta cell mass, in the presence of obesity. Animal models were selected, including hyperlipidic diet-induced obesity, diet restricted obesity, and as controls, alloxan diabetes. Results indicated that both radiotracers achieved over 97% radiochemical yield. The most successful product was 99m Tc-HYNIC-βAla-Exendin-4. Low beta cell mass uptake occurred in diet-induced obesity. Diet-restricted obesity, with substantial shedding of excess body weight, was followed by remarkable decrease of fasting blood glucose, however beta cell mass uptake was only mildly improved. Future studies are recommended in obesity, type 2 diabetes, and dieting, including bariatric and metabolic operations. (author)

  7. Detection of intensity bursts using Hawkes processes: An application to high-frequency financial data

    Science.gov (United States)

    Rambaldi, Marcello; Filimonov, Vladimir; Lillo, Fabrizio

    2018-03-01

    Given a stationary point process, an intensity burst is defined as a short time period during which the number of counts is larger than the typical count rate. It might signal a local nonstationarity or the presence of an external perturbation to the system. In this paper we propose a procedure for the detection of intensity bursts within the Hawkes process framework. By using a model selection scheme we show that our procedure can be used to detect intensity bursts when both their occurrence time and their total number is unknown. Moreover, the initial time of the burst can be determined with a precision given by the typical interevent time. We apply our methodology to the midprice change in foreign exchange (FX) markets showing that these bursts are frequent and that only a relatively small fraction is associated with news arrival. We show lead-lag relations in intensity burst occurrence across different FX rates and we discuss their relation with price jumps.

  8. Heterogeneity in Short Gamma-Ray Bursts

    Science.gov (United States)

    Norris, Jay P.; Gehrels Neil; Scargle, Jeffrey D.

    2011-01-01

    We analyze the Swift/BAT sample of short gamma-ray bursts, using an objective Bayesian Block procedure to extract temporal descriptors of the bursts' initial pulse complexes (IPCs). The sample comprises 12 and 41 bursts with and without extended emission (EE) components, respectively. IPCs of non-EE bursts are dominated by single pulse structures, while EE bursts tend to have two or more pulse structures. The medians of characteristic timescales - durations, pulse structure widths, and peak intervals - for EE bursts are factors of approx 2-3 longer than for non-EE bursts. A trend previously reported by Hakkila and colleagues unifying long and short bursts - the anti-correlation of pulse intensity and width - continues in the two short burst groups, with non-EE bursts extending to more intense, narrower pulses. In addition we find that preceding and succeeding pulse intensities are anti-correlated with pulse interval. We also examine the short burst X-ray afterglows as observed by the Swift/XRT. The median flux of the initial XRT detections for EE bursts (approx 6 X 10(exp -10) erg / sq cm/ s) is approx > 20 x brighter than for non-EE bursts, and the median X-ray afterglow duration for EE bursts (approx 60,000 s) is approx 30 x longer than for non-EE bursts. The tendency for EE bursts toward longer prompt-emission timescales and higher initial X-ray afterglow fluxes implies larger energy injections powering the afterglows. The longer-lasting X-ray afterglows of EE bursts may suggest that a significant fraction explode into more dense environments than non-EE bursts, or that the sometimes-dominant EE component efficiently p()wers the afterglow. Combined, these results favor different progenitors for EE and non-EE short bursts.

  9. HETEROGENEITY IN SHORT GAMMA-RAY BURSTS

    International Nuclear Information System (INIS)

    Norris, Jay P.; Gehrels, Neil; Scargle, Jeffrey D.

    2011-01-01

    We analyze the Swift/BAT sample of short gamma-ray bursts, using an objective Bayesian Block procedure to extract temporal descriptors of the bursts' initial pulse complexes (IPCs). The sample is comprised of 12 and 41 bursts with and without extended emission (EE) components, respectively. IPCs of non-EE bursts are dominated by single pulse structures, while EE bursts tend to have two or more pulse structures. The medians of characteristic timescales-durations, pulse structure widths, and peak intervals-for EE bursts are factors of ∼2-3 longer than for non-EE bursts. A trend previously reported by Hakkila and colleagues unifying long and short bursts-the anti-correlation of pulse intensity and width-continues in the two short burst groups, with non-EE bursts extending to more intense, narrower pulses. In addition, we find that preceding and succeeding pulse intensities are anti-correlated with pulse interval. We also examine the short burst X-ray afterglows as observed by the Swift/X-Ray Telescope (XRT). The median flux of the initial XRT detections for EE bursts (∼6x10 -10 erg cm -2 s -1 ) is ∼>20x brighter than for non-EE bursts, and the median X-ray afterglow duration for EE bursts (∼60,000 s) is ∼30x longer than for non-EE bursts. The tendency for EE bursts toward longer prompt-emission timescales and higher initial X-ray afterglow fluxes implies larger energy injections powering the afterglows. The longer-lasting X-ray afterglows of EE bursts may suggest that a significant fraction explode into denser environments than non-EE bursts, or that the sometimes-dominant EE component efficiently powers the afterglow. Combined, these results favor different progenitors for EE and non-EE short bursts.

  10. Suppressor of cytokine signalling (SOCS)-3 protects beta cells against IL-1beta-mediated toxicity through inhibition of multiple nuclear factor-kappaB-regulated proapoptotic pathways

    DEFF Research Database (Denmark)

    Karlsen, Allan Ertman; Heding, P E; Frobøse, H

    2004-01-01

    The proinflammatory cytokine IL-1beta induces apoptosis in pancreatic beta cells via pathways dependent on nuclear factor-kappaB (NF-kappaB), mitogen-activated protein kinase, and protein kinase C. We recently showed suppressor of cytokine signalling (SOCS)-3 to be a natural negative feedback reg...... regulator of IL-1beta- and IFN-gamma-mediated signalling in rat islets and beta cell lines, preventing their deleterious effects. However, the mechanisms underlying SOCS-3 inhibition of IL-1beta signalling and prevention against apoptosis remain unknown....

  11. Selective destruction of mouse islet beta cells by human T lymphocytes in a newly-established humanized type 1 diabetic model

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Yong, E-mail: yongzhao@uic.edu [Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612 (United States); Guo, Chengshan; Hwang, David; Lin, Brian; Dingeldein, Michael; Mihailescu, Dan; Sam, Susan; Sidhwani, Seema [Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612 (United States); Zhang, Yongkang [Department of Pharmacology, University of Illinois at Chicago, Chicago, IL 60612 (United States); Jain, Sumit [Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612 (United States); Skidgel, Randal A. [Department of Pharmacology, University of Illinois at Chicago, Chicago, IL 60612 (United States); Prabhakar, Bellur S. [Department of Immunology and Microbiology, University of Illinois at Chicago, Chicago, IL 60612 (United States); Mazzone, Theodore [Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612 (United States); Holterman, Mark J. [Department of Surgery, University of Illinois at Chicago, Chicago, IL 60612 (United States)

    2010-09-03

    Research highlights: {yields} Establish a human immune-mediated type 1 diabetic model in NOD-scid IL2r{gamma}{sup null} mice. {yields} Using the irradiated diabetic NOD mouse spleen mononuclear cells as trigger. {yields} The islet {beta} cells were selectively destroyed by infiltrated human T cells. {yields} The model can facilitate translational research to find a cure for type 1 diabetes. -- Abstract: Type 1 diabetes (T1D) is caused by a T cell-mediated autoimmune response that leads to the loss of insulin-producing {beta} cells. The optimal preclinical testing of promising therapies would be aided by a humanized immune-mediated T1D model. We develop this model in NOD-scid IL2r{gamma}{sup null} mice. The selective destruction of pancreatic islet {beta} cells was mediated by human T lymphocytes after an initial trigger was supplied by the injection of irradiated spleen mononuclear cells (SMC) from diabetic nonobese diabetic (NOD) mice. This resulted in severe insulitis, a marked loss of total {beta}-cell mass, and other related phenotypes of T1D. The migration of human T cells to pancreatic islets was controlled by the {beta} cell-produced highly conserved chemokine stromal cell-derived factor 1 (SDF-1) and its receptor C-X-C chemokine receptor (CXCR) 4, as demonstrated by in vivo blocking experiments using antibody to CXCR4. The specificity of humanized T cell-mediated immune responses against islet {beta} cells was generated by the local inflammatory microenvironment in pancreatic islets including human CD4{sup +} T cell infiltration and clonal expansion, and the mouse islet {beta}-cell-derived CD1d-mediated human iNKT activation. The selective destruction of mouse islet {beta} cells by a human T cell-mediated immune response in this humanized T1D model can mimic those observed in T1D patients. This model can provide a valuable tool for translational research into T1D.

  12. Islet immunity and beta cell reserve of indigenous Black South Africans with ketoacidosis at initial diagnosis of diabetes.

    Science.gov (United States)

    Ekpebegh, Chukwuma; Longo-Mbenza, Benjamin; Blanco-Blanco, Ernesto

    2013-01-01

    Islet immunity and beta cell reserve status were utilized to classify persons with ketoacidosis as the initial manifestation of diabetes. The clinical features of the various diabetes classes were also characterized. Prospective cross sectional study. Nelson Mandela Academic Hospital, Mthatha, Eastern Cape Province, South Africa. Indigenous Black South Africans with ketoacidosis as the initial manifestation of diabetes. Islet immunity and beta cell reserve were respectively assessed using serum anti-glutamic acid decarboxylase 65 (GAD) antibody and serum C-peptide after 1 mg of intravenous glucagon. Serum anti-GAD 65 antibody > or = 5 units/L and or = 0.5 ng/mL and < 0.5 ng/mL, respectively. The proportions of patients with A+beta-, A+beta+, A-beta- and A-beta+ and their clinical characteristics were determined. Of the 38 males and 33 females who participated in the study, patients were categorized in various classes: A-beta+, 46.5% (n=33/ 71); A-beta-, 26.8% (n=19/71); A+beta-, 22.5% (n=16/71); and A+beta+, 4.2% (n=3/71). The ages of the various classes were: 41.8 +/- 13.8 years for A-beta+ (n=33); 36.5 +/- 14.6 years for A-beta- (n=19); and 20.6 +/- 7.1 years for the combination of A+beta- with A+beta+ (n=19) (P<.0001, P<.0001 for the combination of A+beta- and A+beta+ vs A-beta+, P=.001 for the combination of A+beta- and A+beta+ vs A-beta-and P=.2 for A-beta- vs A-beta+. The clinical features of type 2 diabetes were most prevalent in A-beta+ class while the A+beta- and A+beta+ groups had the clinical profile of type 1A diabetes. Most of the indigenous Black South African patients with ketoacidosis as the initial manifestation of diabetes had islet immunity, beta cell reserve status and clinical profiles of type 2 diabetes.

  13. Different Types of X-Ray Bursts from GRS 1915+105 and Their Origin

    Science.gov (United States)

    Yadav, J. S.; Rao, A. R.; Agrawal, P. C.; Paul, B.; Seetha, S.; Kasturirangan, K.

    1999-06-01

    We report X-ray observations of the Galactic X-ray transient source GRS 1915+105 with the pointed proportional counters of the Indian X-ray Astronomy Experiment (IXAE) onboard the Indian satellite IRS-P3, which show remarkable richness in temporal variability. The observations were carried out on 1997 June 12-29 and August 7-10, in the energy range of 2-18 keV and revealed the presence of very intense X-ray bursts. All the observed bursts have a slow exponential rise, a sharp linear decay, and broadly can be put in two classes: irregular and quasi-regular bursts in one class, and regular bursts in the other. The regular bursts are found to have two distinct timescales and to persist over extended durations. There is a strong correlation between the preceding quiescent time and the burst duration for the quasi-regular and irregular bursts. No such correlation is found for the regular bursts. The ratio of average flux during the burst time to the average flux during the quiescent phase is high and variable for the quasi-regular and irregular bursts, while it is low and constant for the regular bursts. We present a comprehensive picture of the various types of bursts observed in GRS 1915+105 in the light of the recent theories of advective accretion disks. We suggest that the peculiar bursts that we have seen are characteristic of the change of state of the source. The source can switch back and forth between the low-hard state and the high-soft state near critical accretion rates in a very short timescale, giving rise to the irregular and quasi-regular bursts. The fast timescale for the transition of the state is explained by invoking the appearance and disappearance of the advective disk in its viscous timescale. The periodicity of the regular bursts is explained by matching the viscous timescale with the cooling timescale of the postshock region. A test of the model is presented using the publicly available 13-60 keV RXTE/PCA data for irregular and regular bursts

  14. The dipeptidyl peptidase-4 inhibitor vildagliptin improves beta-cell function and insulin sensitivity in subjects with impaired fasting glucose

    DEFF Research Database (Denmark)

    Utzschneider, Kristina M; Tong, Jenny; Montgomery, Brenda

    2007-01-01

    OBJECTIVE: To evaluate the effect of treatment with the dipeptidyl peptidase (DPP)-4 inhibitor vildagliptin on insulin sensitivity and beta-cell function in subjects with impaired fasting glucose (IFG). RESEARCH DESIGN AND METHODS: A total of 22 subjects with IFG (11 female and 11 male, mean +/- SD...... age 59.6 +/- 11.5 years) were treated orally with 100 mg vildagliptin once daily in a single-blind study. Subjects received placebo for 2 weeks (run-in) followed by vildagliptin for 6 weeks (treatment) and then placebo for 2 weeks (washout). A frequently sampled intravenous glucose tolerance test....... RESULTS: Fasting plasma glucose did not change after 6 weeks of vildagliptin treatment. With treatment, mean +/- SEM AIR(g) increased from 224 +/- 44 to 286 +/- 52 pmol/l (P

  15. Non-invasive phenotyping and drug testing in single cardiomyocytes or beta-cells by calcium imaging and optogenetics.

    Directory of Open Access Journals (Sweden)

    Yu-Fen Chang

    Full Text Available Identification of drug induced electrical instability of the heart curtails development, and introduction, of potentially proarrhythmic drugs. This problem usually requires complimentary contact based approaches such as patch-clamp electrophysiology combined with field stimulation electrodes to observe and control the cell. This produces data with high signal to noise but requires direct physical contact generally preventing high-throughput, or prolonged, phenotyping of single cells or tissues. Combining genetically encoded optogenetic control and spectrally compatible calcium indicator tools into a single adenoviral vector allows the analogous capability for cell control with simultaneous cellular phenotyping without the need for contact. This combination can be applied to single rodent primary adult cardiomyocytes, and human stem cell derived cardiomyocytes, enabling contactless small molecule evaluation for inhibitors of sodium, potassium and calcium channels suggesting it may be useful for early toxicity work. In pancreatic beta-cells it reveals the effects of glucose and the KATP inhibitor gliclazide.

  16. The beta-cell response to glucagon and mixed meal stimulation in non-insulin dependent diabetes

    DEFF Research Database (Denmark)

    Gjessing, H J; Damsgaard, E M; Matzen, L E

    1988-01-01

    The aim of this study was to evaluate the correlations of the C-peptide and insulin responses after stimulation with glucagon intravenously as well as the 24-h urinary excretion of C-peptide to the C-peptide response to a standard mixed meal in 30 patients with non-insulin dependent diabetes...... plasma C-peptide (r = 0.55, p less than 0.01). The C-peptide and insulin responses after meal stimulation correlated modestly inversely with HbA1. In conclusion, measurement of C-peptide in fasting state, as well as measurements of C-peptide and insulin after glucagon stimulation, only modestly predict...... the C-peptide response to physiologic stimulation in NIDDM. Twenty-four-hour urinary C-peptide excretion does not predict this response. Patients with NIDDM seem to show a better metabolic control if they have a more pronounced beta-cell response to physiologic stimulation....

  17. Optical observations of Gamma-Ray Bursts

    International Nuclear Information System (INIS)

    Hjorth, J.; Pian, E.; Fynbo, J.P.U.

    2004-01-01

    We briefly review the status and recent progress in the field of optical observations of gamma-ray burst afterglows. We will focus on the fundamental observational evidence for the relationship between gamma-ray bursts and the final evolutionary phases of massive stars. In particular, we will address (i) gamma-ray burst host galaxies, (ii) optically dark gamma-ray burst afterglows, (iii) the gamma-ray burst-supernova connection, and (iv) the relation between X-ray flashes, gamma-ray bursts, and supernovae

  18. Elevated androgen levels induce hyperinsulinemia through increase in Ins1 transcription in pancreatic beta cells in female rats.

    Science.gov (United States)

    Mishra, Jay S; More, Amar S; Kumar, Sathish

    2018-01-22

    Hyperandrogenism is associated with hyperinsulinemia and insulin resistance in adult females. We tested whether androgens dysregulate pancreatic beta cell function to induce hyperinsulinemia through transcriptional regulation of insulin gene (Ins) in the islets. Adult female Wistar rats implanted with dihydrotestosterone (DHT; 7.5-mg, 90-d release) or placebo pellets were examined after 10 weeks. DHT exposure increased plasma DHT levels by 2-fold similar to that in polycystic ovary syndrome in women. DHT exposure induced hyperinsulinemia with increased HOMA-IR index in fasting state and glucose intolerance and exaggerated insulin responses following glucose tolerance test. DHT females had no change in islet number, size and beta cell proliferation/apoptosis but exhibited significant mitochondrial dysfunction (higher ADP/ATP ratio, decreased mtDNA copy number, increased reactive oxygen production and downregulation of mitochondrial biogenesis) and enhanced glucose-stimulated insulin secretion. Ins expression was increased in DHT islets. In vitro incubation of control islets with DHT dose-dependently stimulated Ins transcription. Analysis of Ins1 gene revealed a putative androgen responsive element in the promoter. Chromatin-immunoprecipitation assays showed that androgen receptors bind to this element in response to DHT stimulation. Furthermore, reporter assays showed that the promoter element is highly responsive to androgens. Insulin stimulated glucose uptake in skeletal muscle was decreased with associated decrease in IRβ expression in DHT females. Our studies identified a novel androgen-mediated mechanism for the control of Ins expression via transcriptional regulation providing a molecular mechanism linking elevated androgens and hyperinsulemia. Decreased IRβ expression in the skeletal muscles may contribute, in part, to glucose intolerance in this model. © The Author(s) 2018. Published by Oxford University Press on behalf of Society for the Study of

  19. Elevated systemic glutamic acid level in the non-obese diabetic mouse is Idd linked and induces beta cell apoptosis.

    Science.gov (United States)

    Banday, Viqar Showkat; Lejon, Kristina

    2017-02-01

    Although type 1 diabetes (T1D) is a T-cell-mediated disease in the effector stage, the mechanism behind the initial beta cell assault is less understood. Metabolomic differences, including elevated levels of glutamic acid, have been observed in patients with T1D before disease onset, as well as in pre-diabetic non-obese diabetic (NOD) mice. Increased levels of glutamic acid damage both neurons and beta cells, implying that this could contribute to the initial events of T1D pathogenesis. We investigated the underlying genetic factors and consequences of the increased levels of glutamic acid in NOD mice. Serum glutamic acid levels from a (NOD×B6)F 2 cohort (n = 182) were measured. By genome-wide and Idd region targeted microsatellite mapping, genetic association was detected for six regions including Idd2, Idd4 and Idd22. In silico analysis of potential enzymes and transporters located in and around the mapped regions that are involved in glutamic acid metabolism consisted of alanine aminotransferase, glutamic-oxaloacetic transaminase, aldehyde dehydrogenase 18 family, alutamyl-prolyl-tRNA synthetase, glutamic acid transporters GLAST and EAAC1. Increased EAAC1 protein expression was observed in lysates from livers of NOD mice compared with B6 mice. Functional consequence of the elevated glutamic acid level in NOD mice was tested by culturing NOD. Rag2 -/- Langerhans' islets with glutamic acid. Induction of apoptosis of the islets was detected upon glutamic acid challenge using TUNEL assay. Our results support the notion that a dysregulated metabolome could contribute to the initiation of T1D. We suggest that targeting of the increased glutamic acid in pre-diabetic patients could be used as a potential therapy. © 2016 John Wiley & Sons Ltd.

  20. Burst-Suppression Ratio on Electrocorticography Depends on Interelectrode Distance

    DEFF Research Database (Denmark)

    Moldovan, Mihai; Calin, Alexandru; Kumaraswamy, Vishakhadatta M.

    2016-01-01

    Introduction: With deepening of anesthesia-induced comatose states, the EEG becomes fragmented by increasing periods of suppression. When measured from conventional EEG recordings, the binary burst-suppression signal (BS) appears similar across the scalp. As such, the BS ratio (BSR), quantifying...

  1. Cosmic gamma-ray bursts

    International Nuclear Information System (INIS)

    Hurley, K.

    1989-01-01

    This paper reviews the essential aspects of the gamma-ray burst (GRB) phenomenon, with emphasis on the more recent results. GRBs are introduced by their time histories, which provide some evidence for a compact object origin. The energy spectra of bursts are presented and they are seen to demonstrate practically unambiguously that the origin of some GRBs involves neutron stars. Counterpart searches are reviewed briefly and the statistical properties of bursters treated. This paper presents a review of the three known repeating bursters (the Soft Gamma Repeaters). Extragalactic and galactic models are discussed and future prospects are assessed

  2. SHOCKS Fast-Fracture Periodic-Intermittency VS. Random-Sporadicity in Burst Acoustic-Emission (BAE): Dislocation-Line-Defects Special-Relativity Classical Acoustic-Phonon Maser(CAPM) EDDTA Orgins of ``Bak''-``SOC''

    Science.gov (United States)

    Neumann, Peter; Klimontovich, Yuri; Nabarro, Frank; Brailsford, Alan; Siegel, Edward

    2011-06-01

    Glassy fast-fracture instabilities and patterns, long-known semi-infinite crack-propagation sub-terminal-velocity Rayleigh-wave-speed versus ``2''-D linear-elasticity theory predictions, but rather asymptotic to maximum-speed < 0.6 v(Rayleigh), explicitly experimentally identifies a fast-fracture DYNAMIC-instability(FFDI) not included within fracture linear-elasticity theory. FFDI causes PERIODIC-BAE[E. S.:MSE 8.310(71); PSS:(a) 5, 601/ 607 (71); Xl..-Latt. Defects 5, 277(74);Scripta-Met.:6,785(72);8, 587/617(74); 3rd Tokyo A.-E. Symp. (76); Acta- Met.25,383(77); JMMM 7,312(78); ...] emitted/radiated from advancing-crack in addition to crack-velocity fluctuations causing such low sub-Rayleigh crack-velocities, hinting at dimensionality-dominance in 2-D VS. 3-D lattice-``models'' very-provacatively yet another special-case subset of Siegel[MRS Fall-Mtg.,Boston:Symp. On Fractals(89)-5-papers!!!; Symp. On Scaling(90)] SPD/FUZZYICS. Hirth-Lothe-Nabarro-Weertman-... provocative finite Burgers-vector dislocations/line-defects singularities terminal-velocity special-case of Einstein's special-relativity, almost word-for-word Jackson electromagnetics, replaces light-speed by sound-speed!!! Siegel[3rd Tokyo A.-E. Symp.(76); Intl.Quantum-Electronics Conf., Boston (80)

  3. Model Atmospheres for X-ray Bursting Neutron Stars

    OpenAIRE

    Medin, Zach; von Steinkirch, Marina; Calder, Alan C.; Fontes, Christopher J.; Fryer, Chris L.; Hungerford, Aimee L.

    2016-01-01

    The hydrogen and helium accreted by X-ray bursting neutron stars is periodically consumed in runaway thermonuclear reactions that cause the entire surface to glow brightly in X-rays for a few seconds. With models of the emission, the mass and radius of the neutron star can be inferred from the observations. By simultaneously probing neutron star masses and radii, X-ray bursts are one of the strongest diagnostics of the nature of matter at extremely high densities. Accurate determinations of t...

  4. Beta cell function following 1 year vildagliptin or placebo treatment and after 12 week washout in drug-naive patients with type 2 diabetes and mild hyperglycaemia: a randomised controlled trial

    NARCIS (Netherlands)

    Foley, J.E.; Bunck, M.C.M.; Moller-Goede, D.L.; Poelma, M.; Nijpels, G.; Eekhoff, E.M.; Schweizer, A.; Heine, R.J.; Diamant, M.

    2011-01-01

    Aims/hypothesis: Traditional blood glucose lowering agents do not prevent the progressive loss of beta cell function in patients with type 2 diabetes. The dipeptidylpeptidase (DPP)-4 inhibitor vildagliptin improves beta cell function both acutely and chronically (up to 2 years). Whether this effect

  5. Bridging the gap between protein carboxyl methylation and phospholipid methylation to understand glucose-stimulated insulin secretion from the pancreatic beta cell.

    Science.gov (United States)

    Kowluru, Anjaneyulu

    2008-01-15

    Recent findings have implicated post-translational modifications at C-terminal cysteines [e.g., methylation] of specific proteins [e.g., G-proteins] in glucose-stimulated insulin secretion [GSIS]. Furthermore, methylation at the C-terminal leucine of the catalytic subunit of protein phosphatase 2A [PP2Ac] has also been shown to be relevant for GSIS. In addition to these two classes of protein methyl transferases, a novel class of glucose-activated phospholipid methyl transferases have also been identified in the beta cell. These enzymes catalyze three successive methylations of phosphatidylethanolamine to yield phosphatidylcholine. The "newly formed" phosphatidylcholine is felt to induce alterations in the membrane fluidity, which might favor vesicular fusion with the plasma membrane for the exocytosis of insulin. The objectives of this commentary are to: (i) review the existing evidence on the regulation, by glucose and other insulin secretagogues, of post-translational carboxylmethylation [CML] of specific proteins in the beta cell; (ii) discuss the experimental evidence, which implicates regulation, by glucose and other insulin secretagogues, of phosphatidylethanolamine methylation in the islet beta cell; (iii) propose a model for potential cross-talk between the protein and lipid methylation pathways in the regulation of GSIS and (iv) highlight potential avenues for future research, including the development of specific pharmacological inhibitors to further decipher regulatory roles for these methylation reactions in islet beta cell function.

  6. Restoring Mitochondrial Function: A Small Molecule-mediated Approach to Enhance Glucose Stimulated Insulin Secretion in Cholesterol Accumulated Pancreatic beta cells

    Science.gov (United States)

    Asalla, Suman; Girada, Shravan Babu; Kuna, Ramya S.; Chowdhury, Debabrata; Kandagatla, Bhaskar; Oruganti, Srinivas; Bhadra, Utpal; Bhadra, Manika Pal; Kalivendi, Shasi Vardhan; Rao, Swetha Pavani; Row, Anupama; Ibrahim, A.; Ghosh, Partha Pratim; Mitra, Prasenjit

    2016-06-01

    Dyslipidemia, particularly the elevated serum cholesterol levels, aggravate the pathophysiology of type 2 diabetes. In the present study we explored the relationship between fasting blood sugar and serum lipid parameters in human volunteers which revealed a significant linear effect of serum cholesterol on fasting blood glucose. Short term feeding of cholesterol enriched diet to rodent model resulted in elevated serum cholesterol levels, cholesterol accumulation in pancreatic islets and hyperinsulinemia with modest increase in plasma glucose level. To explore the mechanism, we treated cultured BRIN-BD11 pancreatic beta cells with soluble cholesterol. Our data shows that cholesterol treatment of cultured pancreatic beta cells enhances total cellular cholesterol. While one hour cholesterol exposure enhances insulin exocytosis, overnight cholesterol accumulation in cultured pancreatic beta cells affects cellular respiration, and inhibits Glucose stimulated insulin secretion. We further report that (E)-4-Chloro-2-(1-(2-(2,4,6-trichlorophenyl) hydrazono) ethyl) phenol (small molecule M1) prevents the cholesterol mediated blunting of cellular respiration and potentiates Glucose stimulated insulin secretion which was abolished in pancreatic beta cells on cholesterol accumulation.

  7. Dipeptidyl peptidase-4 inhibitor, vildagliptin, inhibits pancreatic beta cell apoptosis in association with its effects suppressing endoplasmic reticulum stress in db/db mice.

    Science.gov (United States)

    Wu, Yan-ju; Guo, Xin; Li, Chun-jun; Li, Dai-qing; Zhang, Jie; Yang, Yiping; Kong, Yan; Guo, Hang; Liu, De-min; Chen, Li-ming

    2015-02-01

    Vildagliptin promotes beta cell survival by inhibiting cell apoptosis. It has been suggested that chronic ER (endoplasmic reticulum) stress triggers beta cell apoptosis. The objective of the study is to explore whether the pro-survival effect of vildagliptin is associated with attenuation of endoplasmic reticulum stress in islets of db/db mice. Vildagliptin was orally administered to db/db mice for 6 weeks, followed by evaluation of beta cell apoptosis by caspase3 activity and TUNEL staining method. Endoplasmic reticulum stress markers were determined with quantitative RT-PCR, immunohistochemistry and immunoblot analysis. After 6 weeks of treatment, vildagliptin treatment increased plasma active GLP-1 levels (22.63±1.19 vs. 11.69±0.44, Pvildagliptin treatment down-regulated several genes related to endoplasmic reticulum stress including TRIB3 (tribbles homolog 3) (15.9±0.4 vs. 33.3±1.7, ×10⁻³, PVildagliptin promoted beta cell survival in db/db mice in association with down-regulating markers of endoplasmic reticulum stress including TRIB3, ATF-4 as well as CHOP. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  8. Differences in beta-cell function and insulin secretion in Black vs. White obese adolescents: Do incretin hormones play a role?

    Science.gov (United States)

    Black youth are at higher risk for type 2 diabetes (T2D) than their White peers. Previously we demonstrated that for the same degree of insulin sensitivity, Black youth have an upregulated beta-cell function and insulin hypersecretion, in response to intravenous (IV) glucose, compared with Whites. T...

  9. Pancreatic beta cells from db/db mice show cell-specific [Ca2+]i and NADH responses to glucose but not to alpha-ketoisocaproic acid

    DEFF Research Database (Denmark)

    Gustavsson, Natalia; Larsson-Nyrén, Gerd; Lindström, Per

    2005-01-01

    OBJECTIVE: We recently showed that timing and magnitude of the glucose-induced cytoplasmic calcium [Ca2+]i response are reproducible and specific for the individual beta cell. We now wanted to identify which step(s) of stimulus-secretion coupling determine the cell specificity of the [Ca2+]i resp...

  10. Exposure to the viral by-product dsRNA or Coxsackievirus B5 triggers pancreatic beta cell apoptosis via a Bim / Mcl-1 imbalance.

    Directory of Open Access Journals (Sweden)

    Maikel L Colli

    2011-09-01

    Full Text Available The rise in type 1 diabetes (T1D incidence in recent decades is probably related to modifications in environmental factors. Viruses are among the putative environmental triggers of T1D. The mechanisms regulating beta cell responses to viruses, however, remain to be defined. We have presently clarified the signaling pathways leading to beta cell apoptosis following exposure to the viral mimetic double-stranded RNA (dsRNA and a diabetogenic enterovirus (Coxsackievirus B5. Internal dsRNA induces cell death via the intrinsic mitochondrial pathway. In this process, activation of the dsRNA-dependent protein kinase (PKR promotes eIF2α phosphorylation and protein synthesis inhibition, leading to downregulation of the antiapoptotic Bcl-2 protein myeloid cell leukemia sequence 1 (Mcl-1. Mcl-1 decrease results in the release of the BH3-only protein Bim, which activates the mitochondrial pathway of apoptosis. Indeed, Bim knockdown prevented both dsRNA- and Coxsackievirus B5-induced beta cell death, and counteracted the proapoptotic effects of Mcl-1 silencing. These observations indicate that the balance between Mcl-1 and Bim is a key factor regulating beta cell survival during diabetogenic viral infections.

  11. STAT5 activity in pancreatic beta-cells influences the severity of diabetes in animal models of type 1 and 2 diabetes

    DEFF Research Database (Denmark)

    Jackerott, Malene; Møldrup, Annette; Thams, Peter

    2006-01-01

    Pancreatic beta-cell growth and survival and insulin production are stimulated by growth hormone and prolactin through activation of the transcription factor signal transducer and activator of transcription (STAT)5. To assess the role of STAT5 activity in beta-cells in vivo, we generated transgen...... and type 2 diabetes....... reduced beta-cell proliferation at 6 months of age. The inhibitory effect of high-fat diet or leptin on insulin secretion was diminished in isolated islets from RIP-DNSTAT5 mice compared with wild-type islets. Upon multiple low-dose streptozotocin treatment, RIP-DNSTAT5 mice exhibited higher plasma...... of glucose tolerance, whereas RIP-CASTAT5 mice were more glucose tolerant and less hyperleptinemic than wild-type mice. Although the pancreatic insulin content and relative beta-cell area were increased in high-fat diet-fed RIP-DNSTAT5 mice compared with wild-type or RIP-CASTAT5 mice, RIP-DNSTAT5 mice showed...

  12. Peripheral insulin resistance rather than beta cell dysfunction accounts for geographical differences in impaired fasting blood glucose among sub-Saharan African individuals : findings from the RODAM study

    NARCIS (Netherlands)

    Meeks, Karlijn A C; Stronks, Karien; Adeyemo, Adebowale; Addo, Juliet; Bahendeka, Silver; Beune, Erik; Owusu-Dabo, Ellis; Danquah, Ina; Galbete, Cecilia; Henneman, Peter; Klipstein-Grobusch, Kerstin; Mockenhaupt, Frank P; Osei, Kwame; Schulze, Matthias B; Spranger, Joachim; Smeeth, Liam; Agyemang, Charles

    2017-01-01

    AIMS/HYPOTHESIS: The aim of this study was to assess the extent to which insulin resistance and beta cell dysfunction account for differences in impaired fasting blood glucose (IFBG) levels in sub-Saharan African individuals living in different locations in Europe and Africa. We also aimed to

  13. Peripheral insulin resistance rather than beta cell dysfunction accounts for geographical differences in impaired fasting blood glucose among sub-Saharan African individuals: findings from the RODAM study

    NARCIS (Netherlands)

    Meeks, Karlijn A. C.; Stronks, Karien; Adeyemo, Adebowale; Addo, Juliet; Bahendeka, Silver; Beune, Erik; Owusu-Dabo, Ellis; Danquah, Ina; Galbete, Cecilia; Henneman, Peter; Klipstein-Grobusch, Kerstin; Mockenhaupt, Frank P.; Osei, Kwame; Schulze, Matthias B.; Spranger, Joachim; Smeeth, Liam; Agyemang, Charles

    2017-01-01

    The aim of this study was to assess the extent to which insulin resistance and beta cell dysfunction account for differences in impaired fasting blood glucose (IFBG) levels in sub-Saharan African individuals living in different locations in Europe and Africa. We also aimed to identify determinants

  14. Cytosolic triglycerides and oxidative stress in central obesity : the missing link between excessive atherosclerosis, endothelial dysfunction, and beta-cell failure?

    NARCIS (Netherlands)

    Bakker, SJL; IJzerman, RG; Teerlink, T; Westerhoff, HV; Gans, ROB; Heine, RJ

    Central obesity is increasingly recognized as a risk factor for atherosclerosis and type 2 diabetes mellitus. Here we present a hypothesis that may explain the excess atherosclerosis, endothelial dysfunction and progressive beta-cell failure. Central obesity is associated with increased cytosolic

  15. MODEL ATMOSPHERES FOR X-RAY BURSTING NEUTRON STARS

    International Nuclear Information System (INIS)

    Medin, Zach; Fontes, Christopher J.; Fryer, Chris L.; Hungerford, Aimee L.; Steinkirch, Marina von; Calder, Alan C.

    2016-01-01

    The hydrogen and helium accreted by X-ray bursting neutron stars is periodically consumed in runaway thermonuclear reactions that cause the entire surface to glow brightly in X-rays for a few seconds. With models of the emission, the mass and radius of the neutron star can be inferred from the observations. By simultaneously probing neutron star masses and radii, X-ray bursts (XRBs) are one of the strongest diagnostics of the nature of matter at extremely high densities. Accurate determinations of these parameters are difficult, however, due to the highly non-ideal nature of the atmospheres where XRBs occur. Observations from X-ray telescopes such as RXTE and NuStar can potentially place strong constraints on nuclear matter once uncertainties in atmosphere models have been reduced. Here we discuss current progress on modeling atmospheres of X-ray bursting neutron stars and some of the challenges still to be overcome.

  16. MODEL ATMOSPHERES FOR X-RAY BURSTING NEUTRON STARS

    Energy Technology Data Exchange (ETDEWEB)

    Medin, Zach; Fontes, Christopher J.; Fryer, Chris L.; Hungerford, Aimee L. [Los Alamos National Laboratory, Los Alamos, NM 87545 (United States); Steinkirch, Marina von; Calder, Alan C. [Department of Physics and Astronomy, Stony Brook University, Stony Brook, NY 11794 (United States)

    2016-12-01

    The hydrogen and helium accreted by X-ray bursting neutron stars is periodically consumed in runaway thermonuclear reactions that cause the entire surface to glow brightly in X-rays for a few seconds. With models of the emission, the mass and radius of the neutron star can be inferred from the observations. By simultaneously probing neutron star masses and radii, X-ray bursts (XRBs) are one of the strongest diagnostics of the nature of matter at extremely high densities. Accurate determinations of these parameters are difficult, however, due to the highly non-ideal nature of the atmospheres where XRBs occur. Observations from X-ray telescopes such as RXTE and NuStar can potentially place strong constraints on nuclear matter once uncertainties in atmosphere models have been reduced. Here we discuss current progress on modeling atmospheres of X-ray bursting neutron stars and some of the challenges still to be overcome.

  17. BATSE/OSSE Rapid Burst Response

    National Research Council Canada - National Science Library

    Matz, S. M; Grove, J. E; Johnson, W. N; Kurfess, J. D; Share, G. H; Fishman, G. J; Meegan, Charles A

    1995-01-01

    ...) slew the OSSE detectors to burst locations determined on-board by BATSE. This enables OSSE to make sensitive searches for prompt and delayed post-burst line and continuum emission above 50 keV...

  18. US Army Nuclear Burst Detection System (NBDS)

    International Nuclear Information System (INIS)

    Glaser, R.F.

    1980-07-01

    The Nuclear Burst Detection System (NBDS) was developed to meet the Army requirements of an unattended, automatic nuclear burst reporting system. It provides pertinent data for battlefield commanders on a timely basis with high reliability

  19. Short duration gamma ray bursts

    Indian Academy of Sciences (India)

    Observations have revealed that long bursts, with recorded afterglow, tend to reside in the star forming regions of normal galaxies. Moreover, GRB 980425 ... observer is negligible due to the special relativistic time dilation. However, because of deceleration, eventually Γ−1 > θj and thereafter, sideways expansion becomes.

  20. Optothermally actuated capillary burst valve

    DEFF Research Database (Denmark)

    Eriksen, Johan; Bilenberg, Brian; Kristensen, Anders

    2017-01-01

    be burst by raising the temperature due to the temperature dependence of the fluid surface tension. We address individual valves by using a local heating platform based on a thin film of near infrared absorber dye embedded in the lid used to seal the microfluidic device [L. H. Thamdrup et al., Nano Lett...

  1. Dark gamma-ray bursts

    Science.gov (United States)

    Brdar, Vedran; Kopp, Joachim; Liu, Jia

    2017-03-01

    Many theories of dark matter (DM) predict that DM particles can be captured by stars via scattering on ordinary matter. They subsequently condense into a DM core close to the center of the star and eventually annihilate. In this work, we trace DM capture and annihilation rates throughout the life of a massive star and show that this evolution culminates in an intense annihilation burst coincident with the death of the star in a core collapse supernova. The reason is that, along with the stellar interior, also its DM core heats up and contracts, so that the DM density increases rapidly during the final stages of stellar evolution. We argue that, counterintuitively, the annihilation burst is more intense if DM annihilation is a p -wave process than for s -wave annihilation because in the former case, more DM particles survive until the supernova. If among the DM annihilation products are particles like dark photons that can escape the exploding star and decay to standard model particles later, the annihilation burst results in a flash of gamma rays accompanying the supernova. For a galactic supernova, this "dark gamma-ray burst" may be observable in the Čerenkov Telescope Array.

  2. Association of NEFA composition with insulin sensitivity and beta cell function in the Prospective Metabolism and Islet Cell Evaluation (PROMISE) cohort.

    Science.gov (United States)

    Johnston, Luke W; Harris, Stewart B; Retnakaran, Ravi; Giacca, Adria; Liu, Zhen; Bazinet, Richard P; Hanley, Anthony J

    2018-04-01

    Our aim was to determine the longitudinal associations of individual NEFA with the pathogenesis of diabetes, specifically with differences in insulin sensitivity and beta cell function over 6 years in a cohort of individuals who are at risk for diabetes. In the Prospective Metabolism and Islet Cell Evaluation (PROMISE) longitudinal cohort, 477 participants had serum NEFA measured at the baseline visit and completed an OGTT at three time points over 6 years. Outcome variables were calculated using the OGTT values. At each visit, insulin sensitivity was assessed using the HOMA2 of insulin sensitivity (HOMA2-%S) and the Matsuda index, while beta cell function was assessed using the insulinogenic index over HOMA-IR (IGI/IR) and the insulin secretion-sensitivity index-2 (ISSI-2). Generalised estimating equations were used, adjusting for time, waist, sex, ethnicity, baseline age, alanine aminotransferase (ALT) and physical activity. NEFA were analysed as both concentrations (nmol/ml) and proportions (mol%) of the total fraction. Participants' (73% female, 70% with European ancestry) insulin sensitivity and beta cell function declined by 14-21% over 6 years of follow-up. In unadjusted models, several NEFA (e.g. 18:1 n-7, 22:4 n-6) were associated with lower insulin sensitivity, however, nearly all of these associations were attenuated in fully adjusted models. In adjusted models, total NEFA, 16:0, 18:1 n-9 and 18:2 n-6 (as concentrations) were associated with 3.7-8.0% lower IGI/IR and ISSI-2, while only 20:5 n-3 (as mol%) was associated with 7.7% higher HOMA2-%S. Total NEFA concentration was a strong predictor of lower beta cell function over 6 years. Our results suggest that the association with beta cell function is due to the absolute size of the serum NEFA fraction, rather than the specific fatty acid composition.

  3. Activation of the transcription factor carbohydrate-responsive element-binding protein by glucose leads to increased pancreatic beta cell differentiation in rats.

    Science.gov (United States)

    Soggia, A; Flosseau, K; Ravassard, P; Szinnai, G; Scharfmann, R; Guillemain, G

    2012-10-01

    Pancreatic cell development is a tightly controlled process. Although information is available regarding the mesodermal signals that control pancreatic development, little is known about the role of environmental factors such as nutrients, including glucose, on pancreatic development. We previously showed that glucose and its metabolism through the hexosamine biosynthesis pathway (HBP) promote pancreatic endocrine cell differentiation. Here, we analysed the role of the transcription factor carbohydrate-responsive element-binding protein (ChREBP) in this process. This transcription factor is activated by glucose, and has been recently described as a target of the HBP. We used an in vitro bioassay in which pancreatic endocrine and exocrine cells develop from rat embryonic pancreas in a way that mimics in vivo pancreatic development. Using this model, gain-of-function and loss-of-function experiments were undertaken. ChREBP was produced in the endocrine lineage during pancreatic development, its abundance increasing with differentiation. When rat embryonic pancreases were cultured in the presence of glucose or xylitol, the production of ChREBP targets was induced. Concomitantly, beta cell differentiation was enhanced. On the other hand, when embryonic pancreases were cultured with inhibitors decreasing ChREBP activity or an adenovirus producing a dominant-negative ChREBP, beta cell differentiation was reduced, indicating that ChREBP activity was necessary for proper beta cell differentiation. Interestingly, adenovirus producing a dominant-negative ChREBP also reduced the positive effect of N-acetylglucosamine, a substrate of the HBP acting on beta cell differentiation. Our work supports the idea that glucose, through the transcription factor ChREBP, controls beta cell differentiation from pancreatic progenitors.

  4. Clinical characteristics and beta cell function in Chinese patients with newly diagnosed type 2 diabetes mellitus with different levels of serum triglyceride.

    Science.gov (United States)

    Zheng, Shuang; Zhou, Huan; Han, Tingting; Li, Yangxue; Zhang, Yao; Liu, Wei; Hu, Yaomin

    2015-04-29

    To explore clinical characteristics and beta cell function in Chinese patients with newly diagnosed drug naive type 2 diabetes mellitus (T2DM) with different levels of serum triglyceride (TG). Patients with newly diagnosed T2DM (n = 624) were enrolled and divided into different groups according to levels of serum TG. All patients underwent oral glucose tolerance tests and insulin releasing tests. Demographic data, lipid profiles, glucose levels, and insulin profiles were compared between different groups. Basic insulin secretion function index (homeostasis model assessment for beta cell function index, HOMA-β), modified beta cell function index (MBCI), glucose disposition indices (DI), and early insulin secretion function index (insulinogenic index, IGI) were used to evaluate the beta cell function. Patients of newly diagnosed T2DM with hypertriglyceridemia were younger, fatter and had worse lipid profiles, glucose profiles, and high insulin levels than those with normal TG. There is no difference in early phase insulin secretion among groups of newly diagnosed T2DM patients with different TG levels. The basal beta cell function (HOMA-β and MBCI) initially increased along rising TG levels and then decreased as the TG levels rose further. The insulin sensitivity was relatively high in patients with a low level of TG and low with a high level of TG. Hypertriglyceridemia influences clinical characteristics and β cell function of Chinese patients with newly diagnosed T2DM. A better management of dyslipidemia may, to some extent, reduce the effect of lipotoxicity, thereby improving glucose homeostasis in patients with newly diagnosed T2DM.

  5. Stellar Sources of Gamma-ray Bursts

    OpenAIRE

    Luchkov, B. I.

    2011-01-01

    Correlation analysis of Swift gamma-ray burst coordinates and nearby star locations (catalog Gliese) reveals 4 coincidences with good angular accuracy. The random probability is 4\\times 10^{-5}, so evidencing that coincident stars are indeed gamma-ray burst sources. Some additional search of stellar gamma-ray bursts is discussed.

  6. Detecting pipe bursts by monitoring water demand

    NARCIS (Netherlands)

    Bakker, M.; Vreeburg, J.H.G.; Van der Roer, M.; Sperber, V.

    2012-01-01

    An algorithm which compares measured and predicted water demands to detect pipe bursts was developed and tested on three data sets of water demand and reported pipe bursts of three years. The algorithm proved to be able to detect bursts where the water loss exceeds 30% of the average water demand in

  7. Fine structure in fast drift storm bursts

    International Nuclear Information System (INIS)

    McConnell, D.; Ellis, G.R.A.

    1981-01-01

    Recent observations with high time resolution of fast drift storm (FDS) solar bursts are described. A new variety of FDS bursts characterised by intensity maxima regularly placed in the frequency domain is reported. Possible interpretations of this are mentioned and the implications of the short duration of FDS bursts are discussed. (orig.)

  8. Fast Fourier transformation results from gamma-ray burst profiles

    Science.gov (United States)

    Kouveliotou, Chryssa; Norris, Jay P.; Fishman, Gerald J.; Meegan, Charles A.; Wilson, Robert B.; Paciesas, W. S.

    1992-01-01

    Several gamma-ray bursts in the BATSE data have sufficiently long durations and complex temporal structures with pulses that appear to be spaced quasi-periodically. In order to test and quantify these periods we have applied fast Fourier transformations (FFT) to all these events. We have also performed cross spectral analyses of the FFT of the two extreme (high-low) energy bands in each case to determine the lead/lag of the pulses in different energies.

  9. Levels of betatrophin decrease during pregnancy despite increased insulin resistance, beta-cell function and triglyceride levels.

    Science.gov (United States)

    Zielińska, A; Maciulewski, R; Siewko, K; Popławska-Kita, A; Lipińska, D; Kozłowska, G; Górska, M; Szelachowska, M

    2016-12-01

    Evidence in support of an association between betatrophin and insulin resistance (IR) is mounting, with studies demonstrating that betatrophin is elevated in patients with type 2 diabetes, obesity and gestational diabetes. The aim of this study was to evaluate the role of betatrophin in IR and physiological proliferation of beta cells during pregnancy in healthy women. Eighty healthy pregnant women were examined at each trimester [T1 (first), T2 (second), T3 (third)], with a subgroup (n=45) that was also examined at 3 months postpartum (3MPP). The controls comprised 30 non-pregnant healthy women (HW) of reproductive age. Also measured were levels of betatrophin (ELISA), glucose (enzymatic method with hexokinase), insulin (IRMA), C-peptide (EASIA) and HbA 1c (HPLC), while HOMA-IR and HOMA-β scores were calculated. Betatrophin concentration was highest at T1, and differed significantly from T2 and T3 (1.84 [Q 1 =1.16, Q 3 =2.67]ng/mL vs 1.46 [Q 1 =0.96, Q 3 =2.21]ng/mL; Pindex scores increased during gestation, peaking at T3 (2.3 [Q 1 =1.66, Q 3 =2.72] and 227.7 [Q 1 =185.49, Q 3 =326.31], respectively) and returning to levels similar to those of HW at 3MPP (1.53 [Q 1 =1.12, Q 3 =2.41] and 88.86 [Q 1 =62.73, Q 3 =130.45] vs 1.35 [Q 1 =1.02, Q 3 =1.62] and 92.5 [Q 1 =74.20, Q 3 =111.47], respectively). Concentrations of betatrophin decrease during pregnancy, suggesting that the hormone does not play a significant role in the expansion of beta-cell mass and IR during pregnancy. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  10. Solar Radio Bursts and Space Weather

    Science.gov (United States)

    Gopalswamy, Natchimuthuk,

    2012-01-01

    Radio bursts from the Sun are produced by electron accelerated to relativistic energies by physical processes on the Sun such as solar flares and coronal mass ejections (CMEs). The radio bursts are thus good indicators of solar eruptions. Three types of nonthermal radio bursts are generally associated with CMEs. Type III bursts due to accelerated electrons propagating along open magnetic field lines. The electrons are thought to be accelerated at the reconnection region beneath the erupting CME, although there is another view that the electrons may be accelerated at the CME-driven shock. Type II bursts are due to electrons accelerated at the shock front. Type II bursts are also excellent indicators of solar energetic particle (SEP) events because the same shock is supposed accelerate electrons and ions. There is a hierarchical relationship between the wavelength range of type /I bursts and the CME kinetic energy. Finally, Type IV bursts are due to electrons trapped in moving or stationary structures. The low frequency stationary type IV bursts are observed occasionally in association with very fast CMEs. These bursts originate from flare loops behind the erupting CME and hence indicate tall loops. This paper presents a summary of radio bursts and their relation to CMEs and how they can be useful for space weather predictions.

  11. Some polarization features of solar microwave bursts

    Energy Technology Data Exchange (ETDEWEB)

    Uralov, A M; Nefed' ev, V P [AN SSSR, Irkutsk. Sibirskij Inst. Zemnogo Magnetizma Ionosfery i Rasprostraneniya Radiovoln

    1977-01-01

    Consequences of the thermal microwave burst model proposed earlier have been considered. According to the model the centimeter burst is generated at the heat propagation to the upper atmosphere. The polarization features of the burst are explained: a change of the polarization sign in a frequency range, a rapid change of the polarization sign in the development of a burst at a fixed frequency, a lack of time coincidence of the moments of the burst maximum of the polarization and of the total flux. From the model the consequences are obtained, which are still not confirmed by experiment. An ordinary-type wave prevails in the burst radiation, in the course of which the polarization degree falls on the ascending branch of bursts development. At the change of the polarization sign at the fixed frequency prior to the sign change an ordinary-type wave should be present in excess and later an extreordinary type wave.

  12. Stimulus induced bursts in severe postanoxic encephalopathy.

    Science.gov (United States)

    Tjepkema-Cloostermans, Marleen C; Wijers, Elisabeth T; van Putten, Michel J A M

    2016-11-01

    To report on a distinct effect of auditory and sensory stimuli on the EEG in comatose patients with severe postanoxic encephalopathy. In two comatose patients admitted to the Intensive Care Unit (ICU) with severe postanoxic encephalopathy and burst-suppression EEG, we studied the effect of external stimuli (sound and touch) on the occurrence of bursts. In patient A bursts could be induced by either auditory or sensory stimuli. In patient B bursts could only be induced by touching different facial regions (forehead, nose and chin). When stimuli were presented with relatively long intervals, bursts persistently followed the stimuli, while stimuli with short intervals (encephalopathy can be induced by external stimuli, resulting in stimulus-dependent burst-suppression. Stimulus induced bursts should not be interpreted as prognostic favourable EEG reactivity. Copyright © 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

  13. Bursting in the Belousov-Zhabotinsky Reaction added with Phenol in a Batch Reactor

    International Nuclear Information System (INIS)

    Cadena, Ariel; Agreda, Jesus; Barragan, Daniel

    2013-01-01

    The classic Belousov-Zhabotinski reaction was modified by adding phenol as a second organic substrate that kinetically competes with the malonic acid in the reduction of Ce 4+ to Ce 3+ and in the removal of molecular bromine of the reaction mixture. The oscillating reaction of two substrates exhibited burst firing and an oscillatory period of long duration. Analysis of experimental data shows an increasing of the bursting phenomenon, with a greater spiking in the burst firing and with a longer quiescent state, as a function of the initial phenol concentration increase. It was hypothesized that the bursting phenomenon can be explained introducing a redox cycle between the reduced phenolic species (hydroxyphenols) and the oxidized ones (quinones). The hypothesis was experimentally and numerically tested and from the results it is possible to conclude that the bursting phenomenon exhibited by the oscillating reaction of two substrates is mainly driven by a p-di-hydroxy-benzene/p-benzoquinone redox cycle (author)

  14. Predicting rock bursts in mines

    Science.gov (United States)

    Spall, H.

    1979-01-01

    In terms of lives lost, rock bursts in underground mines can be as hazardous as earthquakes on the surface. So it is not surprising that fo the last 40 years the U.S Bureau of Mines has been using seismic methods for detecting areas in underground mines where there is a high differential stress which could lead to structural instability of the rock mass being excavated.

  15. Improved function and proliferation of adult human beta cells engrafted in diabetic immunodeficient NOD-scid IL2rγnull mice treated with alogliptin

    Directory of Open Access Journals (Sweden)

    Jurczyk A

    2013-12-01

    Full Text Available Agata Jurczyk,1 Philip diIorio,1 Dean Brostowin,1 Linda Leehy,1 Chaoxing Yang,1 Fumihiko Urano,2 David M Harlan,3 Leonard D Shultz,4 Dale L Greiner,1 Rita Bortell1 1Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 2Department of Medicine, Washington University School of Medicine, St Louis, MO, 3Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 4The Jackson Laboratory, Bar Harbor, ME, USA Purpose: Dipeptidyl-peptidase-4 (DPP-4 inhibitors are known to increase insulin secretion and beta cell proliferation in rodents. To investigate the effects on human beta cells in vivo, we utilize immunodeficient mice transplanted with human islets. The study goal was to determine the efficacy of alogliptin, a DPP-4 inhibitor, to enhance human beta cell function and proliferation in an in vivo context using diabetic immunodeficient mice engrafted with human pancreatic islets. Methods: Streptozotocin-induced diabetic NOD-scid IL2rγnull (NSG mice were transplanted with adult human islets in three separate trials. Transplanted mice were treated daily by gavage with alogliptin (30 mg/kg/day or vehicle control. Islet graft function was compared using glucose tolerance tests and non-fasting plasma levels of human insulin and C-peptide; beta cell proliferation was determined by bromodeoxyuridine (BrdU incorporation. Results: Glucose tolerance tests were significantly improved by alogliptin treatment for mice transplanted with islets from two of the three human islet donors. Islet-engrafted mice treated with alogliptin also had significantly higher plasma levels of human insulin and C-peptide compared to vehicle controls. The percentage of insulin+BrdU+ cells in human islet grafts from alogliptin-treated mice was approximately 10-fold more than from vehicle control mice, consistent with a significant increase in human beta cell proliferation. Conclusion: Human islet-engrafted immunodeficient mice

  16. EX4 stabilizes and activates Nrf2 via PKCδ, contributing to the prevention of oxidative stress-induced pancreatic beta cell damage

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Mi-Hwi; Kim, Eung-Hwi [College of Pharmacy, Gachon Institute of Pharmaceutical Science, Gachon University, Yeonsu-ku, Incheon (Korea, Republic of); Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Yeonsu-ku, Incheon (Korea, Republic of); Jung, Hye Seung [Department of Internal Medicine, Seoul National University College of Medicine, Seoul (Korea, Republic of); Yang, Dongki [Department of Physiology, Gachon University College of Medicine, Incheon (Korea, Republic of); Park, Eun-Young, E-mail: parkey@mokpo.ac.kr [College of Pharmacy, Natural Medicine Research Institute, Mokpo National University, Muan-gun, Jeonnam (Korea, Republic of); Jun, Hee-Sook, E-mail: hsjun@gachon.ac.kr [College of Pharmacy, Gachon Institute of Pharmaceutical Science, Gachon University, Yeonsu-ku, Incheon (Korea, Republic of); Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Yeonsu-ku, Incheon (Korea, Republic of); Gachon Medical Research Institute, Gil Hospital, Incheon (Korea, Republic of)

    2017-01-15

    Oxidative stress in pancreatic beta cells can inhibit insulin secretion and promote apoptotic cell death. Exendin-4 (EX4), a glucagon-like peptide-1 receptor agonist, can suppress beta cell apoptosis, improve beta cell function and protect against oxidative damage. In this study, we investigated the molecular mechanisms for antioxidative effects of EX4 in pancreatic beta cells. INS-1 cells, a rat insulinoma cell line, were pretreated with EX4 and exposed to palmitate or H{sub 2}O{sub 2}. Reactive oxygen species (ROS) production, and glutathione and insulin secretion were measured. The mRNA and protein expression levels of antioxidant genes were examined. The level of nuclear factor erythroid 2-related factor 2 (Nrf2), its binding to antioxidant response element (ARE), and its ubiquination in the presence of EX4 were determined. The Nrf2 signaling pathway was determined using rottlerin (protein kinase [PK]Cδ inhibitor), H89 (PKA inhibitor) and LY294002 (phosphatidylinositide 3-kinase [PI3K] inhibitor). EX4 treatment decreased ROS production, recovered cellular glutathione levels and insulin secretion in the presence of oxidative stress in INS-1 cells. The expression levels of glutamate-cysteine ligase catalytic subunit and heme oxygenase-1 were increased by EX4 treatment. EX4 promoted Nrf2 translocation, ARE binding activity and enhanced stabilization of Nrf2 by inhibition of ubiquitination. Knockdown of Nrf2 abolished the effect of EX4 on increased insulin secretion. Inhibition of PKCδ attenuated Nrf2 translocation and antioxidative gene expression by EX4 treatment. We suggest that EX4 activates and stabilizes Nrf2 through PKCδ activation, contributing to the increase of antioxidant gene expression and consequently improving beta cell function in the presence of oxidative stress. - Highlights: • EX4 protects against oxidative stress-induced pancreatic beta cell dysfunction. • EX4 increases antioxidant gene expression. • Antioxidative effect of EX4 is

  17. EX4 stabilizes and activates Nrf2 via PKCδ, contributing to the prevention of oxidative stress-induced pancreatic beta cell damage

    International Nuclear Information System (INIS)

    Kim, Mi-Hwi; Kim, Eung-Hwi; Jung, Hye Seung; Yang, Dongki; Park, Eun-Young; Jun, Hee-Sook

    2017-01-01

    Oxidative stress in pancreatic beta cells can inhibit insulin secretion and promote apoptotic cell death. Exendin-4 (EX4), a glucagon-like peptide-1 receptor agonist, can suppress beta cell apoptosis, improve beta cell function and protect against oxidative damage. In this study, we investigated the molecular mechanisms for antioxidative effects of EX4 in pancreatic beta cells. INS-1 cells, a rat insulinoma cell line, were pretreated with EX4 and exposed to palmitate or H 2 O 2 . Reactive oxygen species (ROS) production, and glutathione and insulin secretion were measured. The mRNA and protein expression levels of antioxidant genes were examined. The level of nuclear factor erythroid 2-related factor 2 (Nrf2), its binding to antioxidant response element (ARE), and its ubiquination in the presence of EX4 were determined. The Nrf2 signaling pathway was determined using rottlerin (protein kinase [PK]Cδ inhibitor), H89 (PKA inhibitor) and LY294002 (phosphatidylinositide 3-kinase [PI3K] inhibitor). EX4 treatment decreased ROS production, recovered cellular glutathione levels and insulin secretion in the presence of oxidative stress in INS-1 cells. The expression levels of glutamate-cysteine ligase catalytic subunit and heme oxygenase-1 were increased by EX4 treatment. EX4 promoted Nrf2 translocation, ARE binding activity and enhanced stabilization of Nrf2 by inhibition of ubiquitination. Knockdown of Nrf2 abolished the effect of EX4 on increased insulin secretion. Inhibition of PKCδ attenuated Nrf2 translocation and antioxidative gene expression by EX4 treatment. We suggest that EX4 activates and stabilizes Nrf2 through PKCδ activation, contributing to the increase of antioxidant gene expression and consequently improving beta cell function in the presence of oxidative stress. - Highlights: • EX4 protects against oxidative stress-induced pancreatic beta cell dysfunction. • EX4 increases antioxidant gene expression. • Antioxidative effect of EX4 is mediated by

  18. NICER Eyes on Bursting Stars

    Science.gov (United States)

    Kohler, Susanna

    2018-03-01

    What happens to a neutron stars accretion disk when its surface briefly explodes? A new instrument recently deployed at the International Space Station (ISS) is now watching bursts from neutron stars and reporting back.Deploying a New X-Ray MissionLaunch of NICER aboard a Falcon 9 rocket in June 2017. [NASA/Tony Gray]In early June of 2017, a SpaceX Dragon capsule on a Falcon 9 rocket launched on a resupply mission to the ISS. The pressurized interior of the Dragon contained the usual manifest of crew supplies, spacewalk equipment, and vehicle hardware. But the unpressurized trunk of the capsule held something a little different: the Neutron star Interior Composition Explorer (NICER).In the two weeks following launch, NICER was extracted from the SpaceX Dragon capsule and installed on the ISS. And by the end of the month, the instrument was already collecting its first data set: observations of a bright X-ray burst from Aql X-1, a neutron star accreting matter from a low-mass binary companion.Impact of BurstsNICERs goal is to provide a new view of neutron-star physics at X-ray energies of 0.212 keV a window that allows us to explore bursts of energy that neutron stars sometimes emit from their surfaces.Artists impression of an X-ray binary, in which a compact object accretes material from a companion star. [ESA/NASA/Felix Mirabel]In X-ray burster systems, hydrogen- and helium-rich material from a low-mass companion star piles up in an accretion disk around the neutron star. This material slowly funnels onto the neutron stars surface, forming a layer that gravitationally compresses and eventually becomes so dense and hot that runaway nuclear fusion ignites.Within seconds, the layer of material is burned up, producing a burst of emission from the neutron star that outshines even the inner regions of the hot accretion disk. Then more material funnels onto the neutron star and the process begins again.Though we have a good picture of the physics that causes these bursts

  19. Bubble bursting at an interface

    Science.gov (United States)

    Kulkarni, Varun; Sajjad, Kumayl; Anand, Sushant; Fezzaa, Kamel

    2017-11-01

    Bubble bursting is crucial to understanding the life span of bubbles at an interface and more importantly the nature of interaction between the bulk liquid and the outside environment from the point of view of chemical and biological material transport. The dynamics of the bubble as it rises from inside the liquid bulk to its disappearance on the interface after bursting is an intriguing process, many aspects of which are still being explored. In our study, we make detailed high speed imaging measurements to examine carefully the hole initiation and growth in bursting bubbles that unearth some interesting features of the process. Previous analyses available in literature are revisited based on our novel experimental visualizations. Using a combination of experiments and theory we investigate the role of various forces during the rupturing process. This work aims to further our current knowledge of bubble dynamics at an interface with an aim of predicting better the bubble evolution from its growth to its eventual integration with the liquid bulk.

  20. Characterization of Phospholipids in Insulin Secretory Granules and Mitochondria in Pancreatic Beta Cells and Their Changes with Glucose Stimulation*

    Science.gov (United States)

    MacDonald, Michael J.; Ade, Lacmbouh; Ntambi, James M.; Ansari, Israr-Ul H.; Stoker, Scott W.

    2015-01-01

    The lipid composition of insulin secretory granules (ISG) has never previously been thoroughly characterized. We characterized the phospholipid composition of ISG and mitochondria in pancreatic beta cells without and with glucose stimulation. The phospholipid/protein ratios of most phospholipids containing unsaturated fatty acids were higher in ISG than in whole cells and in mitochondria. The concentrations of negatively charged phospholipids, phosphatidylserine, and phosphatidylinositol in ISG were 5-fold higher than in the whole cell. In ISG phosphatidylserine, phosphatidylinositol, phosphatidylethanolamine, and sphingomyelin, fatty acids 12:0 and 14:0 were high, as were phosphatidylserine and phosphatidylinositol containing 18-carbon unsaturated FA. With glucose stimulation, the concentration of many ISG phosphatidylserines and phosphatidylinositols increased; unsaturated fatty acids in phosphatidylserine increased; and most phosphatidylethanolamines, phosphatidylcholines, sphingomyelins, and lysophosphatidylcholines were unchanged. Unsaturation and shorter fatty acid length in phospholipids facilitate curvature and fluidity of membranes, which favors fusion of membranes. Recent evidence suggests that negatively charged phospholipids, such as phosphatidylserine, act as coupling factors enhancing the interaction of positively charged regions in SNARE proteins in synaptic or secretory vesicle membrane lipid bilayers with positively charged regions in SNARE proteins in the plasma membrane lipid bilayer to facilitate docking of vesicles to the plasma membrane during exocytosis. The results indicate that ISG phospholipids are in a dynamic state and are consistent with the idea that changes in ISG phospholipids facilitate fusion of ISG with the plasma membrane-enhancing glucose-stimulated insulin exocytosis. PMID:25762724

  1. Characterization of phospholipids in insulin secretory granules and mitochondria in pancreatic beta cells and their changes with glucose stimulation.

    Science.gov (United States)

    MacDonald, Michael J; Ade, Lacmbouh; Ntambi, James M; Ansari, Israr-Ul H; Stoker, Scott W

    2015-04-24

    The lipid composition of insulin secretory granules (ISG) has never previously been thoroughly characterized. We characterized the phospholipid composition of ISG and mitochondria in pancreatic beta cells without and with glucose stimulation. The phospholipid/protein ratios of most phospholipids containing unsaturated fatty acids were higher in ISG than in whole cells and in mitochondria. The concentrations of negatively charged phospholipids, phosphatidylserine, and phosphatidylinositol in ISG were 5-fold higher than in the whole cell. In ISG phosphatidylserine, phosphatidylinositol, phosphatidylethanolamine, and sphingomyelin, fatty acids 12:0 and 14:0 were high, as were phosphatidylserine and phosphatidylinositol containing 18-carbon unsaturated FA. With glucose stimulation, the concentration of many ISG phosphatidylserines and phosphatidylinositols increased; unsaturated fatty acids in phosphatidylserine increased; and most phosphatidylethanolamines, phosphatidylcholines, sphingomyelins, and lysophosphatidylcholines were unchanged. Unsaturation and shorter fatty acid length in phospholipids facilitate curvature and fluidity of membranes, which favors fusion of membranes. Recent evidence suggests that negatively charged phospholipids, such as phosphatidylserine, act as coupling factors enhancing the interaction of positively charged regions in SNARE proteins in synaptic or secretory vesicle membrane lipid bilayers with positively charged regions in SNARE proteins in the plasma membrane lipid bilayer to facilitate docking of vesicles to the plasma membrane during exocytosis. The results indicate that ISG phospholipids are in a dynamic state and are consistent with the idea that changes in ISG phospholipids facilitate fusion of ISG with the plasma membrane-enhancing glucose-stimulated insulin exocytosis. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  2. DPP-4 inhibitor des-F-sitagliptin treatment increased insulin exocytosis from db/db mice {beta} cells

    Energy Technology Data Exchange (ETDEWEB)

    Nagamatsu, Shinya, E-mail: shinya@ks.kyorin-u.ac.jp [Department of Biochemistry, Kyorin University School of Medicine, Mitaka, Tokyo 181-8611 (Japan); Ohara-Imaizumi, Mica; Nakamichi, Yoko; Aoyagi, Kyota; Nishiwaki, Chiyono [Department of Biochemistry, Kyorin University School of Medicine, Mitaka, Tokyo 181-8611 (Japan)

    2011-09-09

    Highlights: {yields} Anti-diabetic new drug, DPP-4 inhibitor, can affect the insulin exocytosis. {yields} DPP-4 inhibitor treatment altered syntaxin 1 expression. {yields} Treatment of db/db mice with DPP-4 inhibitor increased insulin release. -- Abstract: Incretin promotes insulin secretion acutely. Recently, orally-administered DPP-4 inhibitors represent a new class of anti-hyperglycemic agents. Indeed, inhibitors of dipeptidyl peptidase-IV (DPP-4), sitagliptin, has just begun to be widely used as therapeutics for type 2 diabetes. However, the effects of sitagliptin-treatment on insulin exocytosis from single {beta}-cells are yet unknown. We therefore investigated how sitagliptin-treatment in db/db mice affects insulin exocytosis by treating db/db mice with des-F-sitagliptin for 2 weeks. Perfusion studies showed that 2 weeks-sitagliptin treatment potentiated insulin secretion. We then analyzed insulin granule motion and SNARE protein, syntaxin 1, by TIRF imaging system. TIRF imaging of insulin exocytosis showed the increased number of docked insulin granules and increased fusion events from them during first-phase release. In accord with insulin exocytosis data, des-F-sitagliptin-treatment increased the number of syntaxin 1 clusters on the plasma membrane. Thus, our data demonstrated that 2-weeks des-F-sitagliptin-treatment increased the fusion events of insulin granules, probably via increased number of docked insulin granules and that of syntaxin 1 clusters.

  3. Interactions between the metabolism of L-leucine and D-glucose in the pancreatic. beta. -cells

    Energy Technology Data Exchange (ETDEWEB)

    Gylfe, E; Sehlin, J [Umeaa Univ. (Sweden). Dept. of Histology

    1976-01-01

    ..beta..-cell-rich pancreatic islets microdissected from obese-hyperglycemic mice were used to study interactions between the metabolism of L-leucine and D-glucose. L-leucine reduced the islet content of aspartic acid whereas D-glucose, when added to L-leucine-incubated islets, increased the contents of aspartic acid and ..gamma..-aminobutyric acid (GABA). D-glucose also increased the incorporation of L-leucine carbon into aspartic acid, GABA and glutamic acid, suggesting stimulation of a malate shuttle mechanism. When expressed per mole of the individual amino acids, the incorporation of L-leucine carbon into GABA was 2.5 - 4 times higher than into glutamic acid indicating intracellular compartmentation of the latter amino acid. Both L-leucine and D-leucine stimulated /sup 14/CO/sub 2/ production from /sup 14/C-labelled D-glucose. L-leucine did not affect /sup 3/H/sub 2/O production from tritiated D-glucose. The present data do not indicate a role of other amino acids or D-glucose in L-leucine-stimulated insulin release.

  4. Results of using engineering and technological measures for rock burst prevention. [USSR

    Energy Technology Data Exchange (ETDEWEB)

    Kulikov, A P; Nechaev, A V; Khmara, O I

    1980-01-01

    The paper evaluates methods for rock burst forecasting and rock burst prevention used in the Donbass, Kuzbass, Karaganda and Pechora basins. Forecasting methods are based on measuring the initial velocity of gas flow from test boreholes and/or quantity ratio of drillings leaving a test borehole and monitoring seismoacoustic signals. Number of working faces at which each of the methods for rock burst forecasting is used is given. Methods for rock burst prevention are comparatively evaluated: explosive fracturing of rocks in seam roof or seam floor, fluid injection (water and surfactants), drilling destressing boreholes, cutting destressing slots using cutting machines or water jets, mining protective coal seams first for reducing rock burst hazard in protected coal seams, using narrow web coal cutter loaders, remote control of coal cutters at working faces with extremely high rock burst hazard, using mining schemes which reduce rock burst hazards (e.g. long pillar mining system). From 1976 to 1979 number of rock bursts in underground coal mines in the USSR decreased by 5 times in comparison to the period 1961 to 1965. (3 refs.) (In Russian)

  5. Fuzzy-Based Adaptive Hybrid Burst Assembly Technique for Optical Burst Switched Networks

    Directory of Open Access Journals (Sweden)

    Abubakar Muhammad Umaru

    2014-01-01

    Full Text Available The optical burst switching (OBS paradigm is perceived as an intermediate switching technology for future all-optical networks. Burst assembly that is the first process in OBS is the focus of this paper. In this paper, an intelligent hybrid burst assembly algorithm that is based on fuzzy logic is proposed. The new algorithm is evaluated against the traditional hybrid burst assembly algorithm and the fuzzy adaptive threshold (FAT burst assembly algorithm via simulation. Simulation results show that the proposed algorithm outperforms the hybrid and the FAT algorithms in terms of burst end-to-end delay, packet end-to-end delay, and packet loss ratio.

  6. Glucose, other secretagogues, and nerve growth factor stimulate mitogen-activated protein kinase in the insulin-secreting beta-cell line, INS-1

    DEFF Research Database (Denmark)

    Frödin, M; Sekine, N; Roche, E

    1995-01-01

    The signaling pathways whereby glucose and hormonal secretagogues regulate insulin-secretory function, gene transcription, and proliferation of pancreatic beta-cells are not well defined. We show that in the glucose-responsive beta-cell line INS-1, major secretagogue-stimulated signaling pathways...... converge to activate 44-kDa mitogen-activated protein (MAP) kinase. Thus, glucose-induced insulin secretion was found to be associated with a small stimulatory effect on 44-kDa MAP kinase, which was synergistically enhanced by increased levels of intracellular cAMP and by the hormonal secretagogues......-1. Phorbol ester, an activator of protein kinase C, stimulated 44-kDa MAP kinase by both Ca(2+)-dependent and -independent pathways. Nerve growth factor, independently of changes in cytosolic Ca2+, efficiently stimulated 44-kDa MAP kinase without causing insulin release, indicating that activation...

  7. Effect of atorvastatin on pancreatic Beta-cell function and insulin resistance in type 2 diabetes mellitus patients: a randomized pilot study.

    Science.gov (United States)

    Goyal, Aman; Singh, Surender; Tandon, Nikhil; Gupta, Nandita; Gupta, Yogendra Kumar

    2014-12-01

    Statins are commonly used for the management of dyslipidemia in type 2 diabetes mellitus patients. We hypothesized that atorvastatin could modulate the beta-cell function by altering the levels of proapoptotic and antiapoptotic lipoproteins and could also have an effect on insulin resistance. The aim of the present pilot study was to assess the effect of atorvastatin 10 mg on pancreatic beta-cell function and insulin resistance in patients with hyperlipidemia and type 2 diabetes by using the homeostasis model assessment-2 (HOMA2) index. Fifty-one type 2 diabetes patients receiving oral antidiabetes drugs, not taking statins, with baseline low-density lipoprotein cholesterol between 2.6 mmol/L and 4.1 mmol/L were included. Forty-three patients (21 in placebo group and 22 in atorvastatin group) completed the study and were taken up for final analysis. Fasting blood samples were obtained at baseline and at 12 weeks to determine levels of blood glucose, lipid profile, insulin, C-peptide and glycosylated hemoglobin (A1C). Atorvastatin nonsignificantly increased fasting serum insulin (+14.29%, p=0.18), accompanied by marginal nonsignificant increases in fasting plasma glucose and A1C. There was a decrease in HOMA2 percent beta-cell function (-2.9%, p=0.72) and increase in HOMA2 insulin resistance (+14%, p=0.16) in the atorvastatin group as compared with baseline, but the difference was not statistically significant. Atorvastatin in the dose used failed to produce significant change in pancreatic beta-cell function and insulin resistance in type 2 diabetes patients as assessed by the HOMA2 index. The possible explanations include absence of lipotoxicity at prevailing levels of dyslipidemia at baseline or inadequacy of statin dose used in the study. (Clinical Trials Registry-India: CTRI/2008/091/000099). Copyright © 2014 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.

  8. Defective glucose and lipid metabolism in human immunodeficiency virus-infected patients with lipodystrophy involve liver, muscle tissue and pancreatic beta-cells

    DEFF Research Database (Denmark)

    Haugaard, Steen B; Andersen, Ove; Dela, Flemming

    2005-01-01

    ), 18 patients without lipodystrophy on HAART (NONLIPO) and seven patients who were naive to antiretroviral therapy (NAIVE) respectively). beta-cell function was evaluated by an intravenous glucose tolerance test. RESULTS: Compared with NONLIPO and NAIVE separately, LIPO displayed markedly reduced ratio...... of limb to trunk fat (RLF; > 34%, P 40%, P disposal (>50%, P 50%, P ... acids (P disposal (r = 0.71) and incremental exogenous glucose storage (r = 0.40), all P

  9. Diabetic beta-cells can achieve self-protection against oxidative stress through an adaptive up-regulation of their antioxidant defenses.

    Directory of Open Access Journals (Sweden)

    Grégory Lacraz

    Full Text Available BACKGROUND: Oxidative stress (OS, through excessive and/or chronic reactive oxygen species (ROS, is a mediator of diabetes-related damages in various tissues including pancreatic beta-cells. Here, we have evaluated islet OS status and beta-cell response to ROS using the GK/Par rat as a model of type 2 diabetes. METHODOLOGY/PRINCIPAL FINDINGS: Localization of OS markers was performed on whole pancreases. Using islets isolated from 7-day-old or 2.5-month-old male GK/Par and Wistar control rats, 1 gene expression was analyzed by qRT-PCR; 2 insulin secretion rate was measured; 3 ROS accumulation and mitochondrial polarization were assessed by fluorescence methods; 4 antioxidant contents were quantified by HPLC. After diabetes onset, OS markers targeted mostly peri-islet vascular and inflammatory areas, and not islet cells. GK/Par islets revealed in fact protected against OS, because they maintained basal ROS accumulation similar or even lower than Wistar islets. Remarkably, GK/Par insulin secretion also exhibited strong resistance to the toxic effect of exogenous H(2O(2 or endogenous ROS exposure. Such adaptation was associated to both high glutathione content and overexpression (mRNA and/or protein levels of a large set of genes encoding antioxidant proteins as well as UCP2. Finally, we showed that such a phenotype was not innate but spontaneously acquired after diabetes onset, as the result of an adaptive response to the diabetic environment. CONCLUSIONS: The GK/Par model illustrates the effectiveness of adaptive response to OS by beta-cells to achieve self-tolerance. It remains to be determined to what extend such islet antioxidant defenses upregulation might contribute to GK/Par beta-cell secretory dysfunction.

  10. Improved pancreatic beta-cell function in type 2 diabetic patients after lifestyle-induced weight loss is related to glucose-dependent insulinotropic polypeptide

    DEFF Research Database (Denmark)

    Solomon, Thomas; Haus, Jacob M; Kelly, Karen R

    2010-01-01

    Restoration of insulin secretion is critical for the treatment of type 2 diabetes. Exercise and diet can alter glucose-induced insulin responses, but whether this is due to changes in beta-cell function per se is not clear. The mechanisms by which lifestyle intervention may modify insulin secretion...... in type 2 diabetes have also not been examined but may involve the incretin axis....

  11. Activation of PPAR{delta} up-regulates fatty acid oxidation and energy uncoupling genes of mitochondria and reduces palmitate-induced apoptosis in pancreatic {beta}-cells

    Energy Technology Data Exchange (ETDEWEB)

    Wan, Jun; Jiang, Li; Lue, Qingguo; Ke, Linqiu [Department of Endocrinology, West China Hospital of Sichuan University, 37 Guoxue Lane, Chengdu, Sichuan 610041 (China); Li, Xiaoyu [State Key Laboratory of Oral Diseases, Sichuan University, No. 14, 3rd Section, Renmin South Road, Chengdu, Sichuan 610041 (China); Tong, Nanwei, E-mail: buddyjun@hotmail.com [Department of Endocrinology, West China Hospital of Sichuan University, 37 Guoxue Lane, Chengdu, Sichuan 610041 (China)

    2010-01-15

    Recent evidence indicates that decreased oxidative capacity, lipotoxicity, and mitochondrial aberrations contribute to the development of insulin resistance and type 2 diabetes. The goal of this study was to investigate the effects of peroxisome proliferator-activated receptor {delta} (PPAR{delta}) activation on lipid oxidation, mitochondrial function, and insulin secretion in pancreatic {beta}-cells. After HIT-T15 cells (a {beta}-cell line) were exposed to high concentrations of palmitate and GW501516 (GW; a selective agonist of PPAR{delta}), we found that administration of GW increased the expression of PPAR{delta} mRNA. GW-induced activation of PPAR{delta} up-regulated carnitine palmitoyltransferase 1 (CPT1), long-chain acyl-CoA dehydrogenase (LCAD), pyruvate dehydrogenase kinase 4 (PDK4), and uncoupling protein 2 (UCP2); alleviated mitochondrial swelling; attenuated apoptosis; and reduced basal insulin secretion induced by increased palmitate in HIT cells. These results suggest that activation of PPAR{delta} plays an important role in protecting pancreatic {beta}-cells against aberrations caused by lipotoxicity in metabolic syndrome and diabetes.

  12. Vildagliptin, a dipeptidyl peptidase-IV inhibitor, improves model-assessed beta-cell function in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Mari, A; Sallas, W M; He, Y L

    2005-01-01

    in diabetic patients, suggesting that more sophisticated measures are necessary to ascertain the influence of vildagliptin on beta-cell function. METHODS: This study examined the effects of 28-d treatment with vildagliptin (100 mg, twice daily; n = 9) vs. placebo (n = 11) on beta-cell function in diabetic...... and other factors. RESULTS: Vildagliptin significantly increased the insulin secretory rate at 7 mmol/liter glucose (secretory tone), calculated from the dose response; the difference in least squares mean (deltaLSM) was 101 +/- 51 pmol.min(-1).m(-2) (P = 0.002). The slope of the beta-cell dose response......, the derivative component, and the potentiation factor were not affected. Vildagliptin also significantly decreased mean prandial glucose (deltaLSM, -1.2 +/- 0.4 mmol/liter; P = 0.01) and glucagon (deltaLSM, -10.7 +/- 4.8 ng/liter; P = 0.03) levels and increased plasma levels of intact GLP-1 (deltaLSM, +10...

  13. A novel dual-color reporter for identifying insulin-producing beta-cells and classifying heterogeneity of insulinoma cell lines.

    Directory of Open Access Journals (Sweden)

    Nan Sook Lee

    Full Text Available Many research studies use immortalized cell lines as surrogates for primary beta- cells. We describe the production and use of a novel "indirect" dual-fluorescent reporter system that leads to mutually exclusive expression of EGFP in insulin-producing (INS(+ beta-cells or mCherry in non-beta-cells. Our system uses the human insulin promoter to initiate a Cre-mediated shift in reporter color within a single transgene construct and is useful for FACS selection of cells from single cultures for further analysis. Application of our reporter to presumably clonal HIT-T15 insulinoma cells, as well as other presumably clonal lines, indicates that these cultures are in fact heterogeneous with respect to INS(+ phenotype. Our strategy could be easily applied to other cell- or tissue-specific promoters. We anticipate its utility for FACS purification of INS(+ and glucose-responsive beta-like-cells from primary human islet cell isolates or in vitro differentiated pluripotent stem cells.

  14. A Plant-Based Dietary Intervention Improves Beta-Cell Function and Insulin Resistance in Overweight Adults: A 16-Week Randomized Clinical Trial.

    Science.gov (United States)

    Kahleova, Hana; Tura, Andrea; Hill, Martin; Holubkov, Richard; Barnard, Neal D

    2018-02-09

    The aim of this study was to test the effect of a plant-based dietary intervention on beta-cell function in overweight adults with no history of diabetes. Participants ( n = 75) were randomized to follow a low-fat plant-based diet ( n = 38) or to make no diet changes ( n = 37) for 16 weeks. At baseline and 16 weeks, beta-cell function was quantified with a mathematical model. Using a standard meal test, insulin secretory rate was calculated by C-peptide deconvolution. The Homeostasis Model Assessment (HOMA-IR) index was used to assess insulin resistance while fasting. A marked increase in meal-stimulated insulin secretion was observed in the intervention group compared with controls (interaction between group and time, Gxt, p effect -1.0 (95% CI, -1.2 to -0.8); Gxt, p = 0.004). Changes in HOMA-IR correlated positively with changes in body mass index (BMI) and visceral fat volume ( r = 0.34; p = 0.009 and r = 0.42; p = 0.001, respectively). The latter remained significant after adjustment for changes in BMI ( r = 0.41; p = 0.002). Changes in glucose-induced insulin secretion correlated negatively with BMI changes ( r = -0.25; p = 0.04), but not with changes in visceral fat. Beta-cell function and insulin sensitivity were significantly improved through a low-fat plant-based diet in overweight adults.

  15. Positron emission tomography study on pancreatic somatostatin receptors in normal and diabetic rats with 68Ga-DOTA-octreotide: a potential PET tracer for beta cell mass measurement.

    Science.gov (United States)

    Sako, Takeo; Hasegawa, Koki; Nishimura, Mie; Kanayama, Yousuke; Wada, Yasuhiro; Hayashinaka, Emi; Cui, Yilong; Kataoka, Yosky; Senda, Michio; Watanabe, Yasuyoshi

    2013-12-06

    Diabetes mellitus (DM) is a metabolic disorder characterized by hyperglycemia, and the loss or dysfunction of pancreatic beta cells has been reported before the appearance of clinical symptoms and hyperglycemia. To evaluate beta cell mass (BCM) for improving the detection and treatment of DM at earlier stages, we focused on somatostatin receptors that are highly expressed in the pancreatic beta cells, and developed a positron emission tomography (PET) probe derived from octreotide, a metabolically stable somatostatin analog. Octreotide was conjugated with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), a chelating agent, and labeled with (68)Gallium ((68)Ga). After intravenous injection of (68)Ga-DOTA-octreotide, a 90-min emission scan of the abdomen was performed in normal and DM model rats. The PET studies showed that (68)Ga-DOTA-octreotide radioactivity was highly accumulated in the pancreas of normal rats and that the pancreatic accumulation was significantly reduced in the rats administered with an excess amount of unlabeled octreotide or after treatment with streptozotocin, which was used for the chemical induction of DM in rats. These results were in good agreement with the ex vivo biodistribution data. These results indicated that the pancreatic accumulation of (68)Ga-DOTA-octreotide represented specific binding to the somatostatin receptors and reflected BCM. Therefore, PET imaging with (68)Ga-DOTA-octreotide could be a potential tool for evaluating BCM. Copyright © 2013 Elsevier Inc. All rights reserved.

  16. Cdk5 inhibitory peptide (CIP inhibits Cdk5/p25 activity induced by high glucose in pancreatic beta cells and recovers insulin secretion from p25 damage.

    Directory of Open Access Journals (Sweden)

    Ya-Li Zheng

    Full Text Available Cdk5/p25 hyperactivity has been demonstrated to lead to neuron apoptosis and degenerations. Chronic exposure to high glucose (HG results in hyperactivity of Cdk5 and reduced insulin secretion. Here, we set out to determine whether abnormal upregulation of Cdk5/p25 activity may be induced in a pancreatic beta cell line, Min6 cells. We first confirmed that p25 were induced in overexpressed p35 cells treated with HG and increased time course dependence. Next, we showed that no p25 was detected under short time HG stimulation (4-12 hrs, however was detectable in the long exposure in HG cells (24 hrs and 48 hrs. Cdk5 activity in the above cells was much higher than low glucose treated cells and resulted in more than 50% inhibition of insulin secretion. We confirmed these results by overexpression of p25 in Min6 cells. As in cortical neurons, CIP, a small peptide, inhibited Cdk5/p25 activity and restored insulin secretion. The same results were detected in co-infection of dominant negative Cdk5 (DNCdk5 with p25. CIP also reduced beta cells apoptosis induced by Cdk5/p25. These studies indicate that Cdk5/p25 hyperactivation deregulates insulin secretion and induces cell death in pancreatic beta cells and suggests that CIP may serve as a therapeutic agent for type 2 diabetes.

  17. Relative clock verifies endogenous bursts of human dynamics

    Science.gov (United States)

    Zhou, Tao; Zhao, Zhi-Dan; Yang, Zimo; Zhou, Changsong

    2012-01-01

    Temporal bursts are widely observed in many human-activated systems, which may result from both endogenous mechanisms like the highest-priority-first protocol and exogenous factors like the seasonality of activities. To distinguish the effects from different mechanisms is thus of theoretical significance. This letter reports a new timing method by using a relative clock, namely the time length between two consecutive events of an agent is counted as the number of other agents' events appeared during this interval. We propose a model, in which agents act either in a constant rate or with a power-law inter-event time distribution, and the global activity either keeps unchanged or varies periodically vs. time. Our analysis shows that the bursts caused by the heterogeneity of global activity can be eliminated by setting the relative clock, yet the bursts from real individual behaviors still exist. We perform extensive experiments on four large-scale systems, the search engine by AOL, a social bookmarking system —Delicious, a short-message communication network, and a microblogging system —Twitter. Seasonality of global activity is observed, yet the bursts cannot be eliminated by using the relative clock.

  18. Simulations of the burst and coast swimming behavior of fish

    Science.gov (United States)

    Zhou, Quan; Moored, Keith; Smits, Alexander

    2013-11-01

    An investigation into the burst and coast swimming behavior of fish is simulated with a 2-D, inviscid Boundary Element Method. The fish is modeled as a thin pitching panel that is allowed to free swim. A simple drag model is used where drag is proportional to the velocity squared in order to calculate the cruising velocity. The burst-coast behavior is modeled by a coasting phase, where the panel is motionless, and a burst phase, where the panel pitches with a single sine wave motion. Varying the frequency of the fin-beat and the duration of the duty cycle (the ratio of the burst-phase to the entire period), it is found that it is possible to alter swimming motion to yield a decrease of 50% in the cost of transport with no sacrifice of time-averaged cruising velocity. The analyses of the wake structure demonstrate how vortices shed by the fish affect and shape swimming dynamics. Supported by the Office of Naval Research under Program Director Dr. Bob Brizzolara, MURI grant number N00014-08-1-0642.

  19. Transitions to Synchrony in Coupled Bursting Neurons

    Science.gov (United States)

    Dhamala, Mukeshwar; Jirsa, Viktor K.; Ding, Mingzhou

    2004-01-01

    Certain cells in the brain, for example, thalamic neurons during sleep, show spike-burst activity. We study such spike-burst neural activity and the transitions to a synchronized state using a model of coupled bursting neurons. In an electrically coupled network, we show that the increase of coupling strength increases incoherence first and then induces two different transitions to synchronized states, one associated with bursts and the other with spikes. These sequential transitions to synchronized states are determined by the zero crossings of the maximum transverse Lyapunov exponents. These results suggest that synchronization of spike-burst activity is a multi-time-scale phenomenon and burst synchrony is a precursor to spike synchrony.

  20. Transitions to synchrony in coupled bursting neurons

    International Nuclear Information System (INIS)

    Dhamala, Mukeshwar; Jirsa, Viktor K.; Ding Mingzhou

    2004-01-01

    Certain cells in the brain, for example, thalamic neurons during sleep, show spike-burst activity. We study such spike-burst neural activity and the transitions to a synchronized state using a model of coupled bursting neurons. In an electrically coupled network, we show that the increase of coupling strength increases incoherence first and then induces two different transitions to synchronized states, one associated with bursts and the other with spikes. These sequential transitions to synchronized states are determined by the zero crossings of the maximum transverse Lyapunov exponents. These results suggest that synchronization of spike-burst activity is a multi-time-scale phenomenon and burst synchrony is a precursor to spike synchrony

  1. Swift Burst Alert Telescope (BAT) Instrument Response

    International Nuclear Information System (INIS)

    Parsons, A.; Barthelmy, S.; Cummings, J.; Gehrels, N.; Hullinger, D.; Krimm, H.; Markwardt, C.; Tueller, J.; Fenimore, E.; Palmer, D.; Sato, G.; Takahashi, T.; Nakazawa, K.; Okada, Y.; Takahashi, H.; Suzuki, M.; Tashiro, M.

    2004-01-01

    The Burst Alert Telescope (BAT), a large coded aperture instrument with a wide field-of-view (FOV), provides the gamma-ray burst triggers and locations for the Swift Gamma-Ray Burst Explorer. In addition to providing this imaging information, BAT will perform a 15 keV - 150 keV all-sky hard x-ray survey based on the serendipitous pointings resulting from the study of gamma-ray bursts, and will also monitor the sky for transient hard x-ray sources. For BAT to provide spectral and photometric information for the gamma-ray bursts, the transient sources and the all-sky survey, the BAT instrument response must be determined to an increasingly greater accuracy. This paper describes the spectral models and the ground calibration experiments used to determine the BAT response to an accuracy suitable for gamma-ray burst studies

  2. Bursting star formation and the overabundance of Wolf-Rayet stars

    International Nuclear Information System (INIS)

    Bodigfee, G.; Deloore, C.

    1985-01-01

    The ratio of the number of WR-stars to their OB progenitors appears to be significantly higher in some extragalactic systems than in our Galaxy. This overabundance of Wolf-Rayet-stars can be explained as a consequence of a recent burst of star formation. It is suggested that this burst is the manifestation of a long period nonlinear oscillation in the star formation process, produced by positive feedback effects between young stars and the interstellar medium. Star burst galaxies with large numbers of WR-stars must generate gamma fluxes but due to the distance, all of them are beyond the reach of present-day detectors, except probably 30 Dor

  3. Fast Radio Burst/Gamma-Ray Burst Cosmography

    Science.gov (United States)

    Gao, He; Li, Zhuo; Zhang, Bing

    2014-06-01

    Recently, both theoretical arguments and observational evidence suggested that a small fraction of fast radio bursts (FRBs) could be associated with gamma-ray bursts (GRBs). If such FRB/GRB association systems are commonly detected in the future, the combination of dispersion measures (DM) derived from FRBs and redshifts derived from GRBs makes these systems a plausible tool to conduct cosmography. We quantify uncertainties in deriving the redshift-dependent DM_{IGM} as a function of z and test how well dark energy models can be constrained with Monte Carlo simulations. We show that with several tens of FRB/GRB systems potentially detected in a decade or so, one may reach reasonable constraints on wCDM models. When combined with Type Ia supernova (SN Ia) data, unprecedented constraints on the dark energy equation of state may be achieved, thanks to the prospects of detecting FRB/GRB systems at relatively high redshifts. The ratio between the mean value \\lt {DM_IGM} (z)\\gt and luminosity distance (D L(z)) is insensitive to dark energy models. This gives the prospect of applying SN Ia data to calibrate \\lt {DM_IGM} (z)\\gt using a relatively small sample of FRB/GRB systems, allowing a reliable constraint on the baryon inhomogeneity distribution as a function of redshift. The methodology developed in this paper can also be applied if the FRB redshifts can be measured by other means. Some caveats of putting this method into practice are also discussed.

  4. Fast radio burst/gamma-ray burst cosmography

    International Nuclear Information System (INIS)

    Gao, He; Zhang, Bing; Li, Zhuo

    2014-01-01

    Recently, both theoretical arguments and observational evidence suggested that a small fraction of fast radio bursts (FRBs) could be associated with gamma-ray bursts (GRBs). If such FRB/GRB association systems are commonly detected in the future, the combination of dispersion measures (DM) derived from FRBs and redshifts derived from GRBs makes these systems a plausible tool to conduct cosmography. We quantify uncertainties in deriving the redshift-dependent DM IGM as a function of z and test how well dark energy models can be constrained with Monte Carlo simulations. We show that with several tens of FRB/GRB systems potentially detected in a decade or so, one may reach reasonable constraints on wCDM models. When combined with Type Ia supernova (SN Ia) data, unprecedented constraints on the dark energy equation of state may be achieved, thanks to the prospects of detecting FRB/GRB systems at relatively high redshifts. The ratio between the mean value and luminosity distance (D L (z)) is insensitive to dark energy models. This gives the prospect of applying SN Ia data to calibrate using a relatively small sample of FRB/GRB systems, allowing a reliable constraint on the baryon inhomogeneity distribution as a function of redshift. The methodology developed in this paper can also be applied if the FRB redshifts can be measured by other means. Some caveats of putting this method into practice are also discussed.

  5. Fast radio burst/gamma-ray burst cosmography

    Energy Technology Data Exchange (ETDEWEB)

    Gao, He; Zhang, Bing [Department of Physics and Astronomy, University of Nevada Las Vegas, NV 89154 (United States); Li, Zhuo, E-mail: gaohe@physics.unlv.edu, E-mail: zhang@physics.unlv.edu, E-mail: zhuo.li@pku.edu.cn [Department of Astronomy, School of Physics, Peking University, Beijing 100871 (China)

    2014-06-20

    Recently, both theoretical arguments and observational evidence suggested that a small fraction of fast radio bursts (FRBs) could be associated with gamma-ray bursts (GRBs). If such FRB/GRB association systems are commonly detected in the future, the combination of dispersion measures (DM) derived from FRBs and redshifts derived from GRBs makes these systems a plausible tool to conduct cosmography. We quantify uncertainties in deriving the redshift-dependent DM{sub IGM} as a function of z and test how well dark energy models can be constrained with Monte Carlo simulations. We show that with several tens of FRB/GRB systems potentially detected in a decade or so, one may reach reasonable constraints on wCDM models. When combined with Type Ia supernova (SN Ia) data, unprecedented constraints on the dark energy equation of state may be achieved, thanks to the prospects of detecting FRB/GRB systems at relatively high redshifts. The ratio between the mean value and luminosity distance (D {sub L}(z)) is insensitive to dark energy models. This gives the prospect of applying SN Ia data to calibrate using a relatively small sample of FRB/GRB systems, allowing a reliable constraint on the baryon inhomogeneity distribution as a function of redshift. The methodology developed in this paper can also be applied if the FRB redshifts can be measured by other means. Some caveats of putting this method into practice are also discussed.

  6. Chaotic bursting in semiconductor lasers

    Science.gov (United States)

    Ruschel, Stefan; Yanchuk, Serhiy

    2017-11-01

    We investigate the dynamic mechanisms for low frequency fluctuations in semiconductor lasers subjected to delayed optical feedback, using the Lang-Kobayashi model. This system of delay differential equations displays pronounced envelope dynamics, ranging from erratic, so called low frequency fluctuations to regular pulse packages, if the time scales of fast oscillations and envelope dynamics are well separated. We investigate the parameter regions where low frequency fluctuations occur and compute their Lyapunov spectra. Using the geometric singular perturbation theory, we study this intermittent chaotic behavior and characterize these solutions as bursting slow-fast oscillations.

  7. Helium bubble bursting in tungsten

    International Nuclear Information System (INIS)

    Sefta, Faiza; Juslin, Niklas; Wirth, Brian D.

    2013-01-01

    Molecular dynamics simulations have been used to systematically study the pressure evolution and bursting behavior of sub-surface helium bubbles and the resulting tungsten surface morphology. This study specifically investigates how bubble shape and size, temperature, tungsten surface orientation, and ligament thickness above the bubble influence bubble stability and surface evolution. The tungsten surface is roughened by a combination of adatom “islands,” craters, and pinholes. The present study provides insight into the mechanisms and conditions leading to various tungsten topology changes, which we believe are the initial stages of surface evolution leading to the formation of nanoscale fuzz

  8. Neutrino burst identification in underground detectors

    International Nuclear Information System (INIS)

    Fulgione, W.; Mengotti-Silva, N.; Panaro, L.

    1996-01-01

    We discuss the problem of neutrino burst identification in underground ν-telescopes. First the usual statistical analysis based on the time structure of the events is reviewed, with special attention to the statistical significance of burst candidates. Next, we propose a second level analysis that can provide independent confirmation of burst detection. This exploits the spatial distribution of the single events of a burst candidate, and uses the formalism of the entropy of information. Examples of both techniques are shown, based on the LVD experiment at Gran Sasso. (orig.)

  9. Histone deacetylases 1 and 3 but not 2 mediate cytokine-induced beta cell apoptosis in INS-1 cells and dispersed primary islets from rats and are differentially regulated in the islets of type 1 diabetic children

    DEFF Research Database (Denmark)

    Lundh, M; Christensen, D P; Damgaard Nielsen, M

    2012-01-01

    onset, HDAC1 was upregulated in beta cells whereas HDAC2 and -3 were downregulated in comparison with five paediatric controls. CONCLUSIONS/INTERPRETATION: These data demonstrate non-redundant functions of islet class I HDACs and suggest that targeting HDAC1 and HDAC3 would provide optimal protection......AIMS/HYPOTHESIS: Histone deacetylases (HDACs) are promising pharmacological targets in cancer and autoimmune diseases. All 11 classical HDACs (HDAC1-11) are found in the pancreatic beta cell, and HDAC inhibitors (HDACi) protect beta cells from inflammatory insults. We investigated which HDACs...... of HDAC1, -2 and -3 rescued INS-1 cells from inflammatory damage. Small hairpin RNAs against HDAC1 and -3, but not HDAC2, reduced pro-inflammatory cytokine-induced beta cell apoptosis in INS-1 and primary rat islets. The protective properties of specific HDAC knock-down correlated with attenuated cytokine...

  10. Limitations of the HOMA-B score for assessment of beta-cell functionality in interventional trials-results from the PIOglim study.

    Science.gov (United States)

    Pfützner, Andreas; Derwahl, Michael; Jacob, Stephan; Hohberg, Cloth; Blümner, Ernst; Lehmann, Ute; Fuchs, Winfried; Forst, Thomas

    2010-08-01

    Drugs with unspecific stimulating effects on beta-cell secretion increase the homeostasis model assessment (HOMA)-B score, indicating improved beta-cell "function." We investigated whether the beta-cell protection provided by adding pioglitazone (PIO) to glimepiride (GLIM) in comparison to up-titrating the GLIM dose alone is reflected by appropriate changes in several measures of beta-cell function, including HOMA-B score. This double-blind, parallel prospective 6-month study was performed with 82 patients (47 men, 35 women; age, 61 +/- 9 years; duration of disease, 5.3 +/- 4.4 years; body mass index, 32.6 +/- 6.0 kg/m(2); hemoglobin A1c [HbA1c], 7.3 +/- 0.7%) with GLIM monotherapy (1-3 mg). They were randomized to receive a GLIM + PIO combination with up-titration (2 mg + 30 mg/4 mg + 30 mg/4 mg + 4 mg) or to remain on GLIM (up-titration 4/5/6 mg). Observation parameters determined at baseline and end point included HOMA-B, HOMA-IR, HbA1c, glucose, insulin, and intact proinsulin. There was a slight increase in the HOMA-B score in the GLIM group but not in the GLIM + PIO arm (baseline/end point: for GLIM, 71 +/- 48/88 +/- 64; for PIO + GLIM, 74 +/- 56/69 +/- 52). Improvements in the other observation parameters were predominantly detected in the PIO + GLIM group (HbA1c, 7.20 +/- 0.61%/6.36 +/- 0.90%; HOMA-IR, 7.0 +/- 4.5/4.1 +/- 2.1; intact proinsulin, 12.4 +/- 10.3/7.6 +/- 4.8 pmol/L [all P HOMA-IR, 7.4 +/- 4.5/7.5 +/- 4.3 [not significant]; intact proinsulin, 17.3 +/- 21.6/16.3 +/- 15.5 pmol/L [not significant]). The PIO + GLIM combination led to overall improvement of laboratory biomarkers for beta-cell function, except for HOMA-B. Glimepiride up-titration had no such effects but increased the HOMA-B score. HOMA-B seems to provide misleading results when used as a diagnostic tool in patients treated with sulfonylurea drugs. A corrective term for consideration of proinsulin in the HOMA-B equation may address this limitation.

  11. Microseismic Precursory Characteristics of Rock Burst Hazard in Mining Areas Near a Large Residual Coal Pillar: A Case Study from Xuzhuang Coal Mine, Xuzhou, China

    Science.gov (United States)

    Cao, An-ye; Dou, Lin-ming; Wang, Chang-bin; Yao, Xiao-xiao; Dong, Jing-yuan; Gu, Yu

    2016-11-01

    Identification of precursory characteristics is a key issue for rock burst prevention. The aim of this research is to provide a reference for assessing rock burst risk and determining potential rock burst risk areas in coal mining. In this work, the microseismic multidimensional information for the identification of rock bursts and spatial-temporal pre-warning was investigated in a specific coalface which suffered high rock burst risk in a mining area near a large residual coal pillar. Firstly, microseismicity evolution prior to a disastrous rock burst was qualitatively analysed, and the abnormal clustering of seismic sources, abnormal variations in daily total energy release, and event counts can be regarded as precursors to rock burst. Secondly, passive tomographic imaging has been used to locate high seismic activity zones and assess rock burst hazard when the coalface passes through residual pillar areas. The results show that high-velocity or velocity anomaly regions correlated well with strong seismic activities in future mining periods and that passive tomography has the potential to describe, both quantitatively and periodically, hazardous regions and assess rock burst risk. Finally, the bursting strain energy index was further used for short-term spatial-temporal pre-warning of rock bursts. The temporal sequence curve and spatial contour nephograms indicate that the status of the danger and the specific hazardous zones, and levels of rock burst risk can be quantitatively and rapidly analysed in short time and in space. The multidimensional precursory characteristic identification of rock bursts, including qualitative analysis, intermediate and short-time quantitative predictions, can guide the choice of measures implemented to control rock bursts in the field, and provides a new approach to monitor and forecast rock bursts in space and time.

  12. VizieR Online Data Catalog: WATCH Solar X-Ray Burst Catalogue (Crosby+ 1998)

    Science.gov (United States)

    Crosby, N.; Lund, N.; Vilmer, N.; Sunyaev, R.

    1998-01-01

    Catalogue containing solar X-ray bursts measured by the Danish Wide Angle Telescope for Cosmic Hard X-Rays (WATCH) experiment aboard the Russian satellite GRANAT in the deca-keV energy range. Table 1 lists the periods during which solar observations with WATCH are available (WATCH ON-TIME) and where the bursts listed in the catalogue have been observed. (2 data files).

  13. Analysis of historic bursts and burst detection in water supply areas of different size

    NARCIS (Netherlands)

    Bakker, M.; Trietsch, E.A.; Vreeburg, J.H.G.; Rietveld, L.C.

    2014-01-01

    Pipe bursts in water distribution networks lead to water losses and a risk of damaging the urban environment. We studied hydraulic data and customer contact records of 44 real bursts for a better understanding of the phenomena. We found that most bursts were reported to the water company shortly

  14. Fasting and meal-stimulated residual beta cell function is positively associated with serum concentrations of proinflammatory cytokines and negatively associated with anti-inflammatory and regulatory cytokines in patients with longer term type 1 diabetes

    DEFF Research Database (Denmark)

    Pham, Minh-Long; Kolb, H; Battelino, T

    2013-01-01

    Cytokines may promote or inhibit disease progression in type 1 diabetes. We investigated whether systemic proinflammatory, anti-inflammatory and regulatory cytokines associated differently with fasting and meal-stimulated beta cell function in patients with longer term type 1 diabetes.......Cytokines may promote or inhibit disease progression in type 1 diabetes. We investigated whether systemic proinflammatory, anti-inflammatory and regulatory cytokines associated differently with fasting and meal-stimulated beta cell function in patients with longer term type 1 diabetes....

  15. Eddington-limited X-Ray Bursts as Distance Indicators. I. Systematic Trends and Spherical Symmetry in Bursts from 4U 1728-34

    Science.gov (United States)

    Galloway, Duncan K.; Psaltis, Dimitrios; Chakrabarty, Deepto; Muno, Michael P.

    2003-06-01

    We investigate the limitations of thermonuclear X-ray bursts as a distance indicator for the weakly magnetized accreting neutron star 4U 1728-34. We measured the unabsorbed peak flux of 81 bursts in public data from the Rossi X-Ray Timing Explorer (RXTE). The distribution of peak fluxes was bimodal: 66 bursts exhibited photospheric radius expansion (presumably reaching the local Eddington limit) and were distributed about a mean bolometric flux of 9.2×10-8ergscm-2s-1, while the remaining (non-radius expansion) bursts reached 4.5×10-8ergscm-2s-1, on average. The peak fluxes of the radius expansion bursts were not constant, exhibiting a standard deviation of 9.4% and a total variation of 46%. These bursts showed significant correlations between their peak flux and the X-ray colors of the persistent emission immediately prior to the burst. We also found evidence for quasi-periodic variation of the peak fluxes of radius expansion bursts, with a timescale of ~=40 days. The persistent flux observed with RXTE/ASM over 5.8 yr exhibited quasi-periodic variability on a similar timescale. We suggest that these variations may have a common origin in reflection from a warped accretion disk. Once the systematic variation of the peak burst fluxes is subtracted, the residual scatter is only ~=3%, roughly consistent with the measurement uncertainties. The narrowness of this distribution strongly suggests that (1) the radiation from the neutron star atmosphere during radius expansion episodes is nearly spherically symmetric and (2) the radius expansion bursts reach a common peak flux that may be interpreted as a standard candle intensity. Adopting the minimum peak flux for the radius expansion bursts as the Eddington flux limit, we derive a distance for the source of 4.4-4.8 kpc (assuming RNS=10 km), with the uncertainty arising from the probable range of the neutron star mass MNS=1.4-2 Msolar.

  16. Recent results of zebra patterns in solar radio bursts

    International Nuclear Information System (INIS)

    Chernov, Gennady P.

    2010-01-01

    This review covers the most recent experimental results and theoretical research on zebra patterns (ZPs) in solar radio bursts. The basic attention is given to events with new peculiar elements of zebra patterns received over the last few years. All new properties are considered in light of both what was known earlier and new theoretical models. Large-scale ZPs consisting of small-scale fiber bursts could be explained by simultaneous inclusion of two mechanisms when whistler waves 'highlight' the levels of double plasma resonance (DPR). A unique fine structure was observed in the event on 2006 December 13: spikes in absorption formed dark ZP stripes against the absorptive type III-like bursts. The spikes in absorption can appear in accordance with well known mechanisms of absorptive bursts. The additional injection of fast particles filled the loss-cone (breaking the loss-cone distribution), and the generation of the continuum was quenched at these moments. The maximum absorptive effect occurs at the DPR levels. The parameters of millisecond spikes are determined by small dimensions of the particle beams and local scale heights in the radio source. Thus, the DPR model helps to understand several aspects of unusual elements of ZPs. However, the simultaneous existence of several tens of the DPR levels in the corona is impossible for any realistic profile of the plasma density and magnetic field. Three new theories of ZPs are examined. The formation of eigenmodes of transparency and opacity during the propagation of radio waves through regular coronal inhomogeneities is the most natural and promising mechanism. Two other models (nonlinear periodic space - charge waves and scattering of fast protons on ion-sound harmonics) could happen in large radio bursts. (invited reviews)

  17. Beta Cell Breakthroughs

    Science.gov (United States)

    ... Terms Research & News Recipes & Food Recipe Finder The Healthy Kitchen What Can I Eat? Main Dishes Salads & Sandwiches Breakfast Snacks Sides Dessert I'm Hungry! Body & Mind Well-Being Fitness Weight Loss Blood Glucose & Medications ...

  18. Method of separation of celestial gamma-ray bursts from solar flares

    International Nuclear Information System (INIS)

    Chuang, K.W.; White, R.S.; Klebesadel, R.W.; Laros, J.G.

    1991-01-01

    We recently discovered 217 ''new'' celestial gamma-ray burst candidates from the ''new'' burst search of the PVO real time data base. 1 The burst search covered the time period from September 1978 to July 1988. Sixty were confirmed by at lest on other spacecraft, e.g., ISEE-3, V-11, V-12, etc. None triggered the PVO high time resolution memory. In this paper we describe a new algorithm based ont eh relationship between time width T w and hardness ratio HR, to distinguish cosmic gamma-ray bursts from solar flares without knowing the directions of the events. The criteria for identification as a gamma-ray burst candidate are: If T ww ≤a then HR≥bT w , or T w >a then HR>c. Otherwise, the event is a solar flare candidate. Here, a, b, and c are parameter which differ for different gamma-ray burst detectors. For PVO, a=18.8 s, b=(1.38/18.8) s -1 , and c=1.38. This algorithm was tested with 83 triggered and 60 nontriggered confirmed gamma-ray burst and 30 confirmed solar flares from PVO

  19. Spatial variation in automated burst suppression detection in pharmacologically induced coma.

    Science.gov (United States)

    An, Jingzhi; Jonnalagadda, Durga; Moura, Valdery; Purdon, Patrick L; Brown, Emery N; Westover, M Brandon

    2015-01-01

    Burst suppression is actively studied as a control signal to guide anesthetic dosing in patients undergoing medically induced coma. The ability to automatically identify periods of EEG suppression and compactly summarize the depth of coma using the burst suppression probability (BSP) is crucial to effective and safe monitoring and control of medical coma. Current literature however does not explicitly account for the potential variation in burst suppression parameters across different scalp locations. In this study we analyzed standard 19-channel EEG recordings from 8 patients with refractory status epilepticus who underwent pharmacologically induced burst suppression as medical treatment for refractory seizures. We found that although burst suppression is generally considered a global phenomenon, BSP obtained using a previously validated algorithm varies systematically across different channels. A global representation of information from individual channels is proposed that takes into account the burst suppression characteristics recorded at multiple electrodes. BSP computed from this representative burst suppression pattern may be more resilient to noise and a better representation of the brain state of patients. Multichannel data integration may enhance the reliability of estimates of the depth of medical coma.

  20. Multifrequency Observations of Gamma-Ray Burst

    OpenAIRE

    Greiner, J.

    1995-01-01

    Neither a flaring nor a quiescent counterpart to a gamma-ray burst has yet been convincingly identified at any wavelength region. The present status of the search for counterparts of classical gamma-ray bursts is given. Particular emphasis is put on the search for flaring counterparts, i.e. emission during or shortly after the gamma-ray emission.

  1. Observations of short gamma-ray bursts.

    Science.gov (United States)

    Fox, Derek B; Roming, Peter W A

    2007-05-15

    We review recent observations of short-hard gamma-ray bursts and their afterglows. The launch and successful ongoing operations of the Swift satellite, along with several localizations from the High-Energy Transient Explorer mission, have provoked a revolution in short-burst studies: first, by quickly providing high-quality positions to observers; and second, via rapid and sustained observations from the Swift satellite itself. We make a complete accounting of Swift-era short-burst localizations and proposed host galaxies, and discuss the implications of these observations for the distances, energetics and environments of short bursts, and the nature of their progenitors. We then review the physical modelling of short-burst afterglows: while the simplest afterglow models are inadequate to explain the observations, there have been several notable successes. Finally, we address the case of an unusual burst that threatens to upset the simple picture in which long bursts are due to the deaths of massive stars, and short bursts to compact-object merger events.

  2. Neutrino bursts and gravitational waves experiments

    Energy Technology Data Exchange (ETDEWEB)

    Castagnoli, C; Galeotti, P; Saavedra, O [Consiglio Nazionale delle Ricerche, Turin (Italy). Lab. di Cosmo-Geofisica

    1978-05-01

    Several experiments have been performed in many countries to observe gravitational waves or neutrino bursts. Since their simultaneous emission may occur in stellar collapse, the authors evaluate the effect of neutrino bursts on gravitational wave antennas and suggest the usefulness of a time correlation among the different detectors.

  3. Spatiotemporal chaos from bursting dynamics

    International Nuclear Information System (INIS)

    Berenstein, Igal; De Decker, Yannick

    2015-01-01

    In this paper, we study the emergence of spatiotemporal chaos from mixed-mode oscillations, by using an extended Oregonator model. We show that bursting dynamics consisting of fast/slow mixed mode oscillations along a single attractor can lead to spatiotemporal chaotic dynamics, although the spatially homogeneous solution is itself non-chaotic. This behavior is observed far from the Hopf bifurcation and takes the form of a spatiotemporal intermittency where the system locally alternates between the fast and the slow phases of the mixed mode oscillations. We expect this form of spatiotemporal chaos to be generic for models in which one or several slow variables are coupled to activator-inhibitor type of oscillators

  4. The influence of maternal islet beta-cell autoantibodies in conjunction with gestational hyperglycemia on neonatal outcomes.

    Directory of Open Access Journals (Sweden)

    Zhe Li

    Full Text Available To determine the predictive value of the presence of maternal islet beta-cell autoantibodies with respect to neonatal outcomes.A total of 311 pregnant women with abnormal 75 g oral glucose tolerance test (OGTT results were enrolled in this study. Maternal glutamic acid decarboxylase autoantibodies (GADA, islet cell autoantibodies (ICA and insulin autoantibodies (IAA were tested in fasting blood both on the day following the routine OGTT and before delivery. The birth weight, Apgar score, blood glucose and outcomes of each neonate were later evaluated and recorded.1. In this study, 33.9% of the pregnant women with gestational hyperglycemia had detectable levels of one or more types of anti-islet cell antibodies in the third trimester. The proportion of women who produced GADA and/or ICA was significantly higher in the group of women with gestational hyperglycemia than in the control group (P<0.05. The groups similarly differed in the proportion of women who tested positive for any anti-islet cell antibody (P<0.05. 2. Of the patients in our study, those who produced GADA exhibited an increase in uterine and umbilical arterial pulsatility indexes (PIs during the third trimesters compared with the control group (P˂0.05. Additionally, an increased frequency of fetal growth restriction (FGR was observed in the infants of women who produced IAA during pregnancy compared with those without autoantibodies (P˂0.05. 3. The rate of newborn admission to the neonatal intensive care unit (NICU was significantly associated with the presence of maternal ICA during the third trimester (OR, 6.36; 95% CI, 1.22-33.26. 4. The incidence of neonatal asphyxia was associated with the presence of maternal GADA in both the second (OR, 10.44; 95% CI, 1.46-74.92 and the third (OR, 8.33; 95% CI, 1.45-47.82 trimesters.Approximately one-third of the women with gestational hyperglycemia produced anti-islet cell antibodies. The incidence of FGR was higher in women with

  5. Transition in complex calcium bursting induced by IP3 degradation

    International Nuclear Information System (INIS)

    Zhang Feng; Lu Qishao; Su Jianzhong

    2009-01-01

    Complex intracellular Ca 2+ oscillations are systematically investigated in a mathematical model based on the mechanism of Ca 2+ -induced Ca 2+ release (CICR), taking account of the Ca 2+ -stimulated degradation of inositol 1,4,5-trisphosphate (IP 3 ) by a 3-kinase. Periodic, quasi-periodic and chaotic bursting oscillations exist in a wide range of parameter values and occur alternatively as the parameters change slightly. The transition among them can be observed by the evidence in their interspike interval and the Lyapunov exponent. These results reveal the role of agonist-stimulated of IP 3 degradation as a possible source for complex patterns in Ca 2+ signaling.

  6. Synchronization of bursting neurons with a slowly varying d. c. current

    International Nuclear Information System (INIS)

    Upadhyay, Ranjit Kumar; Mondal, Argha

    2017-01-01

    Highlights: • To examine synchronization, noisy chemical and electrical coupling have been considered for a coupled bursting M-L neurons. • Bursting presents the precursor to spike synchronization and coupling strength increases the locking between neurons (anti phase and in phase). • The stability of synchronization is established via similarity function. • The necessary condition to occur CS state is observed using master stability function. • A network of four M-L neurons is considered to observe the synchronization. - Abstract: Bursting of neuronal firing is an interesting dynamical consequences depending on fast/slow dynamics. Certain cells in different brain regions produce spike-burst activity. We study such firing activity and its transitions to synchronization using identical as well as non-identical coupled bursting Morris-Lecar (M-L) neurons. Synchronization of different firing activity is a multi-time-scale phenomenon and burst synchronization presents the precursor to spike synchronization. Chemical synapses are one of the dynamical means of information processing between neurons. Electrical synapses play a major role for synchronous activity in a certain network of neurons. Synaptically coupled neural cells exhibit different types of synchronization such as in phase or anti-phase depending on the nature and strength of coupling functions and the synchronization regimes are analyzed by similarity functions. The sequential transitions to synchronization regime are examined by the maximum transverse Lyapunov exponents. Synchronization of voltage traces of two types of planar bursting mechanisms is explored for both kind of synapses under realistic conditions. The noisy influence effects on the transmission of signals and strongly acts to the firing activity (such as periodic firing and bursting) and integration of signals for a network. It has been examined using the mean interspike interval analysis. The transition to synchronization states of

  7. Fine structure near the starting frequency of solar type III radio bursts

    Energy Technology Data Exchange (ETDEWEB)

    Benz, A.O.; Zlobec, P.; Jaeggi, M.

    1982-06-01

    We have systematically analyzed the period in time and frequency adjacent to the beginning of type III bursts digitally recorded at Bleien during the second half of 1980. A surprisingly high percentage (10%, possibly more than 20%) of the type III bursts show fine structure in the form of narrow-banded spikes of 0.05 s and less duration, which form clusters of relatively large bandwidth. These spikes are not totally polarized (contrary to claims in the literature) and they are uniformly distributed over the disk. Individual spikes often show highly variable polarization, which may even change sense. The average degree of polarization of the clouds has a wider distribution than that of the associated type III bursts, but generally the same sign. Spikes are considerably different from type I bursts.

  8. Magnetar-like X-Ray Bursts Suppress Pulsar Radio Emission

    Energy Technology Data Exchange (ETDEWEB)

    Archibald, R. F.; Lyutikov, M.; Kaspi, V. M.; Tendulkar, S. P. [Department of Physics and McGill Space Institute, McGill University, 3600 University Street, Montreal, QC H3A 2T8 (Canada); Burgay, M.; Possenti, A. [INAF–Osservatorio Astronomico di Cagliari, Via della Scienza 5, I-09047 Selargius (Italy); Esposito, P.; Rea, N. [Anton Pannekoek Institute for Astronomy, University of Amsterdam, Postbus 94249, 1090 GE Amsterdam (Netherlands); Israel, G. [INAF–Osservatorio Astronomico di Roma, via Frascati 33, I-00040 Monteporzio Catone, Roma (Italy); Kerr, M. [Space Science Division, Naval Research Laboratory, Washington, DC 20375-5352 (United States); Sarkissian, J. [CSIRO Astronomy and Space Science, Parkes Observatory, P.O. Box 276, Parkes, NSW 2870 (Australia); Scholz, P., E-mail: archibald@astro.utoronto.ca [National Research Council of Canada, Herzberg Astronomy and Astrophysics, Dominion Radio Astrophysical Observatory, P.O. Box 248, Penticton, BC V2A 6J9 (Canada)

    2017-11-10

    Rotation-powered pulsars and magnetars are two different observational manifestations of neutron stars: rotation-powered pulsars are rapidly spinning objects that are mostly observed as pulsating radio sources, while magnetars, neutron stars with the highest known magnetic fields, often emit short-duration X-ray bursts. Here, we report simultaneous observations of the high-magnetic-field radio pulsar PSR J1119−6127 at X-ray, with XMM-Newton and NuSTAR , and at radio energies with the Parkes radio telescope, during a period of magnetar-like bursts. The rotationally powered radio emission shuts off coincident with the occurrence of multiple X-ray bursts and recovers on a timescale of ∼70 s. These observations of related radio and X-ray phenomena further solidify the connection between radio pulsars and magnetars and suggest that the pair plasma produced in bursts can disrupt the acceleration mechanism of radio-emitting particles.

  9. The Bursting Pulsar GRO J1744-28: the Slowest Transitional Pulsar?

    Science.gov (United States)

    Court, J. M. C.; Altamirano, D.; Sanna, A.

    2018-04-01

    GRO J1744-28 (the Bursting Pulsar) is a neutron star LMXB which shows highly structured X-ray variability near the end of its X-ray outbursts. In this letter we show that this variability is analogous to that seen in Transitional Millisecond Pulsars such as PSR J1023+0038: `missing link' systems consisting of a pulsar nearing the end of its recycling phase. As such, we show that the Bursting Pulsar may also be associated with this class of objects. We discuss the implications of this scenario; in particular, we discuss the fact that the Bursting Pulsar has a significantly higher spin period and magnetic field than any other known Transitional Pulsar. If the Bursting Pulsar is indeed transitional, then this source opens a new window of oppurtunity to test our understanding of these systems in an entirely unexplored physical regime.

  10. Insulin sensitivity and beta-cell function after carbohydrate oral loading in hip replacement surgery: a double-blind, randomised controlled clinical trial.

    Science.gov (United States)

    Ljunggren, Stefan; Hahn, Robert G; Nyström, Thomas

    2014-06-01

    Surgery initiates a series of physiological stress processes in the body, inducing transient insulin resistance. Preoperative carbohydrate treatment can reduce the latter phenomenon. We investigated the effects of carbohydrate loading on insulin sensitivity and beta-cell function after elective hip replacement. Twenty-three nondiabetic patients (mean age of 68 years) who underwent elective hip replacement surgery participated in this double-blind controlled study. The patients were randomised to a nutrition group, which ingested a carbohydrate-rich fluid (50 kcal/100 ml) (Preop(®)), or a control group (tap water flavoured with lemon) 800 ml + 400 ml before the surgery. The insulin response (beta-cell function) and the insulin sensitivity were measured with an intravenous glucose tolerance test (IVGTT) and a hyperinsulinaemic euglycaemic glucose clamp, respectively, one day before and two days after the surgery. Insulin sensitivity decreased by 51% (median; 25-75th percentiles 35-61) after ingesting Preop(®) and by 39% (21-51) after ingesting in the control group (n.s.). The postoperative IVGTT in the nutrition group was followed by a significantly larger area under the curve (AUC) for plasma insulin (+54% versus the preoperative IVGTT) compared to the control group (+7%). This difference was already apparent during the first phase (0-10 min) of insulin secretion (+20 and -21%, respectively; P water prior to the surgery demonstrated a significant but similar decrease in insulin sensitivity. The carbohydrates increased the beta-cell function as a compensatory response to the disposition index, resulting in a smaller reduction in surgery-induced insulin resistance compared to the tap water. The study was registered at http://www.clinicaltrials.gov (NCT01774084). Copyright © 2013 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

  11. Carriers of loss-of-function mutations in EXT display impaired pancreatic beta-cell reserve due to smaller pancreas volume.

    Directory of Open Access Journals (Sweden)

    Sophie J Bernelot Moens

    Full Text Available Exotosin (EXT proteins are involved in the chain elongation step of heparan sulfate (HS biosynthesis, which is intricately involved in organ development. Loss of function mutations (LOF in EXT1 and EXT2 result in hereditary exostoses (HME. Interestingly, HS plays a role in pancreas development and beta-cell function, and genetic variations in EXT2 are associated with an increased risk for type 2 diabetes mellitus. We hypothesized that loss of function of EXT1 or EXT2 in subjects with hereditary multiple exostoses (HME affects pancreatic insulin secretion capacity and development. We performed an oral glucose tolerance test (OGTT followed by hyperglycemic clamps to investigate first-phase glucose-stimulated insulin secretion (GSIS in HME patients and age and gender matched non-affected relatives. Pancreas volume was assessed with magnetic resonance imaging (MRI. OGTT did not reveal significant differences in glucose disposal, but there was a markedly lower GSIS in HME subjects during hyperglycemic clamp (iAUC HME: 0.72 [0.46-1.16] vs. controls 1.53 [0.69-3.36] nmol·l-1·min-1, p<0.05. Maximal insulin response following arginine challenge was also significantly attenuated (iAUC HME: 7.14 [4.22-10.5] vs. controls 10.2 [7.91-12.70] nmol·l-1·min-1 p<0.05, indicative of an impaired beta-cell reserve. MRI revealed a significantly smaller pancreatic volume in HME subjects (HME: 72.0±15.8 vs. controls 96.5±26.0 cm3 p = 0.04. In conclusion, loss of function of EXT proteins may affect beta-cell mass and insulin secretion capacity in humans, and render subjects at a higher risk of developing type 2 diabetes when exposed to environmental risk factors.

  12. In vivo and in vitro characterization of [{sup 18}F]-FE-(+)-DTBZ as a tracer for beta-cell mass

    Energy Technology Data Exchange (ETDEWEB)

    Eriksson, Olof [Division of Radiology, Department of Oncology, Radiology and Clinical Immunology, University Hospital, 751 87 Uppsala (Sweden)], E-mail: olof.eriksson@radiol.uu.se; Jahan, Mahabuba [Department of Clinical Neuroscience, Karolinska Institute, Section of Psychiatry, Karolinska Hospital, 171 76, Stockholm (Sweden); Johnstroem, Peter [Department of Clinical Neuroscience, Karolinska Institute, Section of Psychiatry, Karolinska Hospital, 171 76, Stockholm (Sweden); CNS and Pain Control, AstraZeneca R and D, 151 36, Soedertaelje (Sweden); Korsgren, Olle [Department of Oncology, Radiology and Clinical Immunology, Division of Clinical Immunology, University Hospital, 751 87 Uppsala (Sweden); Sundin, Anders [Division of Radiology, Department of Oncology, Radiology and Clinical Immunology, University Hospital, 751 87 Uppsala (Sweden); Department of Radiology, Karolinska University Hospital, 171 76, Stockholm (Sweden); Halldin, Christer [Department of Clinical Neuroscience, Karolinska Institute, Section of Psychiatry, Karolinska Hospital, 171 76, Stockholm (Sweden); Johansson, Lars [Division of Radiology, Department of Oncology, Radiology and Clinical Immunology, University Hospital, 751 87 Uppsala (Sweden); AstraZeneca R and D, 431 50, Moelndal (Sweden)

    2010-04-15

    Introduction: The positron emission tomography (PET) tracer 9-[{sup 18}F]fluoroethyl-(+)-dihydrotetrabenazine ([{sup 18}F]-FE-(+)-DTBZ) is a potential candidate for quantifying beta-cell mass in vivo. The purpose was to investigate in vitro and in vivo utility of this tracer for the assessment of beta-cell mass. Methods: Three pigs were intravenously administered [{sup 18}F]-FE-(+)-DTBZ and examined by PET/computed tomography. Binding parameters were estimated by kinetic modeling. In vitro k{sub D} and B{sub max} were determined by saturation binding studies of endocrine and exocrine human tissue homogenates. In vitro pancreatic uptake was determined by tissue autoradiography with pancreases from patients with types 1 (T1DM) and 2 diabetes mellitus (T2DM) and healthy controls. Results: [{sup 18}F]-FE-(+)-DTBZ had a k{sub D} of 3.5{+-}1.0 nM, a B{sub max} of 382{+-}108 fmol/mg protein and a specificity of 89{+-}1.8% in islet homogenates. The total exocrine uptake was lower and 65% was nondisplaceable. No uptake difference was observed in pancreatic tissue slices from patients with T1DM, T2DM or healthy controls. The in vivo porcine pancreatic uptake reached a peak of standardized uptake value (SUV) of 2.8 with a low distribution volume ratio in all animals. Moderate to high tracer uptake was identified in the bile system and in bone. Conclusions: [{sup 18}F]-FE-(+)-DTBZ binds to vesicular monoamine transporter 2 (VMAT2) with high specificity in pure islet tissue in vitro. However, there is high nondisplaceable binding to exocrine tissue. In addition, in vivo tracer metabolism and dehalogenation result in severe underestimation of porcine pancreatic VMAT2 expression and BCM. The results do not support [{sup 18}F]-FE-(+)-DTBZ as a suitable tracer for in vivo beta-cell imaging.

  13. A Plant-Based Dietary Intervention Improves Beta-Cell Function and Insulin Resistance in Overweight Adults: A 16-Week Randomized Clinical Trial

    Directory of Open Access Journals (Sweden)

    Hana Kahleova

    2018-02-01

    Full Text Available The aim of this study was to test the effect of a plant-based dietary intervention on beta-cell function in overweight adults with no history of diabetes. Participants (n = 75 were randomized to follow a low-fat plant-based diet (n = 38 or to make no diet changes (n = 37 for 16 weeks. At baseline and 16 weeks, beta-cell function was quantified with a mathematical model. Using a standard meal test, insulin secretory rate was calculated by C-peptide deconvolution. The Homeostasis Model Assessment (HOMA-IR index was used to assess insulin resistance while fasting. A marked increase in meal-stimulated insulin secretion was observed in the intervention group compared with controls (interaction between group and time, Gxt, p < 0.001. HOMA-IR index fell significantly (p < 0.001 in the intervention group (treatment effect −1.0 (95% CI, −1.2 to −0.8; Gxt, p = 0.004. Changes in HOMA-IR correlated positively with changes in body mass index (BMI and visceral fat volume (r = 0.34; p = 0.009 and r = 0.42; p = 0.001, respectively. The latter remained significant after adjustment for changes in BMI (r = 0.41; p = 0.002. Changes in glucose-induced insulin secretion correlated negatively with BMI changes (r = −0.25; p = 0.04, but not with changes in visceral fat. Beta-cell function and insulin sensitivity were significantly improved through a low-fat plant-based diet in overweight adults.

  14. Glucagon-like peptide-1 counteracts the detrimental effects of Advanced Glycation End-Products in the pancreatic beta cell line HIT-T 15

    International Nuclear Information System (INIS)

    Puddu, A.; Storace, D.; Durante, A.; Odetti, P.; Viviani, G.L.

    2010-01-01

    Research highlights: → GLP-1 prevents AGEs-induced cell death. → GLP-1 prevents AGEs-induced oxidative stress. → GLP-1 ameliorated AGEs-induced cell dysfunction. → GLP-1 attenuates AGEs-induced RAGE increment. → GLP-1 counteracts AGEs-induced pancreatic cell death and dysfunction. -- Abstract: Advanced Glycation End-Products (AGEs), a group of compounds resulting from the non-enzymatic reaction of reducing sugars with the free amino group of proteins, are implicated in diabetic complications. We previously demonstrated that exposure of the pancreatic islet cell line HIT-T 15 to high concentrations of AGEs significantly decreases cell proliferation and insulin secretion, and affects transcription factors regulating insulin gene transcription. The glucagon-like peptide-1 (GLP-1) is an incretin hormone that increases proinsulin biosynthesis, stimulates insulin secretion, and improves pancreatic beta-cell viability. The aim of this work was to investigate the effects of GLP-1 on the function and viability of HIT-T 15 cells cultured with AGEs. HIT-T 15 cells were cultured for 5 days in presence of AGEs alone, or supplemented with 10 nmol/l GLP-1. Cell viability, insulin secretion, redox balance, and expression of the AGEs receptor (RAGE) were then determined. The results showed that GLP-1 protected beta cell against AGEs-induced cell death preventing both apoptosis and necrosis. Moreover, addition of GLP-1 to the AGEs culture medium restored the redox balance, improved the responsiveness to glucose, and attenuated AGEs-induced RAGE expression. These findings provide evidence that GLP-1 protects beta cells from the dangerous effects of AGEs.

  15. cGMP may have trophic effects on beta cell function comparable to those of cAMP, implying a role for high-dose biotin in prevention/treatment of diabetes.

    Science.gov (United States)

    McCarty, Mark F

    2006-01-01

    Incretin hormones have trophic effects on beta cell function that can aid prevention and treatment of diabetes. cAMP is the primary mediator of these effects, and has been shown to potentiate glucose-stimulated insulin secretion, promote proper beta cells differentiation by increasing expression of the crucial transcription factor PDX-1, and prevent beta cell apoptosis. cGMP's role in beta cell function has received far less scrutiny, but there is emerging evidence that it may have a trophic impact on beta cell function analogous to that of cAMP. An increase in plasma glucose boosts beta cell production of cGMP, which acts as a feed-forward mediator to enhance glucose-stimulated insulin secretion. cGMP also has an anti-apoptotic effect in beta cells, and there is now indirect evidence that it promotes expression of PDX-1. Supraphysiological concentrations of biotin can directly activate guanylate cyclase, and there is limited evidence that high intakes of this vitamin can be therapeutically beneficial in diabetics and in rodent models of diabetes. Beneficial effects of cGMP on muscle insulin sensitivity and on control of hepatic glucose output may contribute to biotin's utility in diabetes. The fact that nitric oxide/cGMP exert a range of favorable effects on vascular health should further encourage exploration of biotin's preventive and therapeutic potential. If an appropriate high-dose biotin regimen could achieve a modest systemic increase in guanylate cyclase activity, without entailing unacceptable side effects or risks, such a regimen might have considerable potential for promoting vascular health and preventing or managing diabetes.

  16. Mixed-meal tolerance test versus glucagon stimulation test for the assessment of beta-cell function in therapeutic trials in type 1 diabetes

    DEFF Research Database (Denmark)

    Greenbaum, Carla J; Mandrup-Poulsen, Thomas; McGee, Paula Friedenberg

    2008-01-01

    OBJECTIVE: Beta-cell function in type 1 diabetes clinical trials is commonly measured by C-peptide response to a secretagogue in either a mixed-meal tolerance test (MMTT) or a glucagon stimulation test (GST). The Type 1 Diabetes TrialNet Research Group and the European C-peptide Trial (ECPT) Study...... Group conducted parallel randomized studies to compare the sensitivity, reproducibility, and tolerability of these procedures. RESEARCH DESIGN AND METHODS: In randomized sequences, 148 TrialNet subjects completed 549 tests with up to 2 MMTT and 2 GST tests on separate days, and 118 ECPT subjects...

  17. The EndoC-βH1 cell line is a valid model of human beta cells and applicable for screenings to identify novel drug target candidates.

    Science.gov (United States)

    Tsonkova, Violeta Georgieva; Sand, Fredrik Wolfhagen; Wolf, Xenia Asbæk; Grunnet, Lars Groth; Kirstine Ringgaard, Anna; Ingvorsen, Camilla; Winkel, Louise; Kalisz, Mark; Dalgaard, Kevin; Bruun, Christine; Fels, Johannes Josef; Helgstrand, Charlotte; Hastrup, Sven; Öberg, Fredrik Kryh; Vernet, Erik; Sandrini, Michael Paolo Bastner; Shaw, Allan Christian; Jessen, Carsten; Grønborg, Mads; Hald, Jacob; Willenbrock, Hanni; Madsen, Dennis; Wernersson, Rasmus; Hansson, Lena; Jensen, Jan Nygaard; Plesner, Annette; Alanentalo, Tomas; Petersen, Maja Borup Kjær; Grapin-Botton, Anne; Honoré, Christian; Ahnfelt-Rønne, Jonas; Hecksher-Sørensen, Jacob; Ravassard, Philippe; Madsen, Ole D; Rescan, Claude; Frogne, Thomas

    2018-02-01

    To characterize the EndoC-βH1 cell line as a model for human beta cells and evaluate its beta cell functionality, focusing on insulin secretion, proliferation, apoptosis and ER stress, with the objective to assess its potential as a screening platform for identification of novel anti-diabetic drug candidates. EndoC-βH1 was transplanted into mice for validation of in vivo functionality. Insulin secretion was evaluated in cells cultured as monolayer and as pseudoislets, as well as in diabetic mice. Cytokine induced apoptosis, glucolipotoxicity, and ER stress responses were assessed. Beta cell relevant mRNA and protein expression were investigated by qPCR and antibody staining. Hundreds of proteins or peptides were tested for their effect on insulin secretion and proliferation. Transplantation of EndoC-βH1 cells restored normoglycemia in streptozotocin induced diabetic mice. Both in vitro and in vivo, we observed a clear insulin response to glucose, and, in vitro, we found a significant increase in insulin secretion from EndoC-βH1 pseudoislets compared to monolayer cultures for both glucose and incretins. Apoptosis and ER stress were inducible in the cells and caspase 3/7 activity was elevated in response to cytokines, but not affected by the saturated fatty acid palmitate. By screening of various proteins and peptides, we found Bombesin (BB) receptor agonists and Pituitary Adenylate Cyclase-Activating Polypeptides (PACAP) to significantly induce insulin secretion and the proteins SerpinA6, STC1, and APOH to significantly stimulate proliferation. ER stress was readily induced by Tunicamycin and resulted in a reduction of insulin mRNA. Somatostatin (SST) was found to be expressed by 1% of the cells and manipulation of the SST receptors was found to significantly affect insulin secretion. Overall, the EndoC-βH1 cells strongly resemble human islet beta cells in terms of glucose and incretin stimulated insulin secretion capabilities. The cell line has an active

  18. PED/PEA-15 inhibits hydrogen peroxide-induced apoptosis in Ins-1E pancreatic beta-cells via PLD-1.

    Directory of Open Access Journals (Sweden)

    Francesca Fiory

    Full Text Available The small scaffold protein PED/PEA-15 is involved in several different physiologic and pathologic processes, such as cell proliferation and survival, diabetes and cancer. PED/PEA-15 exerts an anti-apoptotic function due to its ability to interfere with both extrinsic and intrinsic apoptotic pathways in different cell types. Recent evidence shows that mice overexpressing PED/PEA-15 present larger pancreatic islets and increased beta-cells mass. In the present work we investigated PED/PEA-15 role in hydrogen peroxide-induced apoptosis in Ins-1E beta-cells. In pancreatic islets isolated from Tg(PED/PEA-15 mice hydrogen peroxide-induced DNA fragmentation was lower compared to WT islets. TUNEL analysis showed that PED/PEA-15 overexpression increases the viability of Ins-1E beta-cells and enhances their resistance to apoptosis induced by hydrogen peroxide exposure. The activity of caspase-3 and the cleavage of PARP-1 were markedly reduced in Ins-1E cells overexpressing PED/PEA-15 (Ins-1E(PED/PEA-15. In parallel, we observed a decrease of the mRNA levels of pro-apoptotic genes Bcl-xS and Bad. In contrast, the expression of the anti-apoptotic gene Bcl-xL was enhanced. Accordingly, DNA fragmentation was higher in control cells compared to Ins-1E(PED/PEA-15 cells. Interestingly, the preincubation with propranolol, an inhibitor of the pathway of PLD-1, a known interactor of PED/PEA-15, responsible for its deleterious effects on glucose tolerance, abolishes the antiapoptotic effects of PED/PEA-15 overexpression in Ins-1E beta-cells. The same results have been obtained by inhibiting PED/PEA-15 interaction with PLD-1 in Ins-1E(PED/PEA-15. These results show that PED/PEA-15 overexpression is sufficient to block hydrogen peroxide-induced apoptosis in Ins-1E cells through a PLD-1 mediated mechanism.

  19. The EndoC-βH1 cell line is a valid model of human beta cells and applicable for screenings to identify novel drug target candidates

    Directory of Open Access Journals (Sweden)

    Violeta Georgieva Tsonkova

    2018-02-01

    Full Text Available Objective: To characterize the EndoC-βH1 cell line as a model for human beta cells and evaluate its beta cell functionality, focusing on insulin secretion, proliferation, apoptosis and ER stress, with the objective to assess its potential as a screening platform for identification of novel anti-diabetic drug candidates. Methods: EndoC-βH1 was transplanted into mice for validation of in vivo functionality. Insulin secretion was evaluated in cells cultured as monolayer and as pseudoislets, as well as in diabetic mice. Cytokine induced apoptosis, glucolipotoxicity, and ER stress responses were assessed. Beta cell relevant mRNA and protein expression were investigated by qPCR and antibody staining. Hundreds of proteins or peptides were tested for their effect on insulin secretion and proliferation. Results: Transplantation of EndoC-βH1 cells restored normoglycemia in streptozotocin induced diabetic mice. Both in vitro and in vivo, we observed a clear insulin response to glucose, and, in vitro, we found a significant increase in insulin secretion from EndoC-βH1 pseudoislets compared to monolayer cultures for both glucose and incretins.Apoptosis and ER stress were inducible in the cells and caspase 3/7 activity was elevated in response to cytokines, but not affected by the saturated fatty acid palmitate.By screening of various proteins and peptides, we found Bombesin (BB receptor agonists and Pituitary Adenylate Cyclase-Activating Polypeptides (PACAP to significantly induce insulin secretion and the proteins SerpinA6, STC1, and APOH to significantly stimulate proliferation.ER stress was readily induced by Tunicamycin and resulted in a reduction of insulin mRNA. Somatostatin (SST was found to be expressed by 1% of the cells and manipulation of the SST receptors was found to significantly affect insulin secretion. Conclusions: Overall, the EndoC-βH1 cells strongly resemble human islet beta cells in terms of glucose and incretin stimulated

  20. Swift: A gamma ray burst MIDEX

    International Nuclear Information System (INIS)

    Barthelmy, Scott

    2001-01-01

    Swift is a first of its kind multiwavelength transient observatory for gamma-ray burst astronomy. It has the optimum capabilities for the next breakthroughs in determining the origin of gamma-ray bursts and their afterglows as well as using bursts to probe the early Universe. Swift will also perform the first sensitive hard X-ray survey of the sky. The mission is being developed by an international collaboration and consists of three instruments, the Burst Alert Telescope (BAT), the X-ray Telescope (XRT), and the Ultraviolet and Optical Telescope (UVOT). The BAT, a wide-field gamma-ray detector, will detect ∼1 gamma-ray burst per day with a sensitivity 5 times that of BATSE. The sensitive narrow-field XRT and UVOT will be autonomously slewed to the burst location in 20 to 70 seconds to determine 0.3-5.0 arcsec positions and perform optical, UV, and X-ray spectrophotometry. On-board measurements of redshift will also be done for hundreds of bursts. Swift will incorporate superb, low-cost instruments using existing flight-spare hardware and designs. Strong education/public outreach and follow-up programs will help to engage the public and astronomical community. Swift has been selected by NASA for development and launch in late 2003

  1. Possible galactic origin of. gamma. -ray bursts

    Energy Technology Data Exchange (ETDEWEB)

    Manchanda, R K; Ramsden, D [Southampton Univ. (UK). Dept. of Physics

    1977-03-31

    It is stated that extragalactic models for the origin of non-solar ..gamma..-ray bursts include supernova bursts in remote galaxies, and the collapse of the cores of active stars, whilst galactic models are based on flare stars, thermonuclear explosions in neutron stars and the sudden accretion of cometary gas on to neutron stars. The acceptability of any of these models may be tested by the observed size spectrum of the ..gamma..-ray bursts. The extragalactic models predict a power law spectrum with number index -1.5, whilst for the galactic models the number index will be -1. Experimental data on ..gamma..-ray bursts is, however, still meagre, and so far only 44 confirmed events have been recorded by satellite-borne instruments. The number spectrum of the observed ..gamma..-ray bursts indicates that the observed distribution for events with an energy < 10/sup -4/ erg/cm/sup 2/ is flat; this makes the choice of any model completely arbitrary. An analysis of the observed ..gamma..-ray events is here presented that suggests very interesting possibilities for their origin. There appears to be a preferred mean energy for ..gamma..-ray bursts; some 90% of the recorded events show a mean energy between 5 x 10/sup -5/ and 5 x 10/sup -4/ erg/cm/sup 2/, contrary to the predicted characteristics of the number spectrum of various models. A remarkable similarity is found between the distribution of ..gamma..-ray bursts and that of supernova remnants, suggesting a genetic relationship between the two and the galactic origin of the ..gamma..-ray bursts, and the burst source could be identified with completely run down neutron stars, formed during supernova explosions.

  2. Bursting neurons and ultrasound avoidance in crickets

    Directory of Open Access Journals (Sweden)

    Gary eMarsat

    2012-07-01

    Full Text Available Decision making in invertebrates often relies on simple neural circuits composed of only a few identified neurons. The relative simplicity of these circuits makes it possible to identify the key computation and neural properties underlying decisions. In this review, we summarize recent research on the neural basis of ultrasound avoidance in crickets, a response that allows escape from echolocating bats. The key neural property shaping behavioral output is high-frequency bursting of an identified interneuron, AN2, which carries information about ultrasound stimuli from receptor neurons to the brain. AN2's spike train consists of clusters of spikes –bursts– that may be interspersed with isolated, non-burst spikes. AN2 firing is necessary and sufficient to trigger avoidance steering but only high-rate firing, such as occurs in bursts, evokes this response. AN2 bursts are therefore at the core of the computation involved in deciding whether or not to steer away from ultrasound. Bursts in AN2 are triggered by synaptic input from nearly synchronous bursts in ultrasound receptors. Thus the population response at the very first stage of sensory processing –the auditory receptor- already differentiates the features of the stimulus that will trigger a behavioral response from those that will not. Adaptation, both intrinsic to AN2 and within ultrasound receptors, scales the burst-generating features according to the stimulus statistics, thus filtering out background noise and ensuring that bursts occur selectively in response to salient peaks in ultrasound intensity. Furthermore AN2’s sensitivity to ultrasound varies adaptively with predation pressure, through both developmental and evolutionary mechanisms. We discuss how this key relationship between bursting and the triggering of avoidance behavior is also observed in other invertebrate systems such as the avoidance of looming visual stimuli in locusts or heat avoidance in beetles.

  3. Improved Pain Relief With Burst Spinal Cord Stimulation for Two Weeks in Patients Using Tonic Stimulation: Results From a Small Clinical Study.

    Science.gov (United States)

    Courtney, Peter; Espinet, Anthony; Mitchell, Bruce; Russo, Marc; Muir, Andrew; Verrills, Paul; Davis, Kristina

    2015-07-01

    Conventional spinal cord stimulation (SCS) delivers a tonic waveform with consistent stream of pulses; burst delivers groups of pulses separated by short pulse-free periods. The current study compared the short-term safety and efficacy of burst with tonic stimulation in subjects already receiving SCS. At 4 IRB-approved sites, 22 subjects previously implanted with an SCS device for intractable, chronic pain gave informed consent and received burst stimulation for 14 days. Subjects reported average daily Visual Analog Scale (VAS) for overall, trunk, and limb pain using tonic stimulation and after 7 and 14 days of burst stimulation. Thoughts about pain were assessed using the Pain Catastrophizing Scale. Areas of paresthesia were assessed during tonic and burst stimulation using body maps. Assessment of patient satisfaction and preferred stimulation occurred after 14 days of burst. Average daily overall VAS reduced 46% from a mean of 53.5 (±20.2) mm during tonic SCS to 28.5 (±18.1) mm during burst (p pain relief was the most common reason cited for preference. A majority of subjects reported improved pain relief using burst compared with tonic stimulation. Most subjects experienced less paresthesia during burst and preferred burst citing better pain relief. © 2015 The Authors. Neuromodulation: Technology at the Neural Interface published by Wiley Periodicals, Inc. on behalf of International Neuromodulation Society.

  4. Solar Type II Radio Bursts and IP Type II Events

    Science.gov (United States)

    Cane, H. V.; Erickson, W. C.

    2005-01-01

    We have examined radio data from the WAVES experiment on the Wind spacecraft in conjunction with ground-based data in order to investigate the relationship between the shocks responsible for metric type II radio bursts and the shocks in front of coronal mass ejections (CMEs). The bow shocks of fast, large CMEs are strong interplanetary (IP) shocks, and the associated radio emissions often consist of single broad bands starting below approx. 4 MHz; such emissions were previously called IP type II events. In contrast, metric type II bursts are usually narrowbanded and display two harmonically related bands. In addition to displaying complete dynamic spectra for a number of events, we also analyze the 135 WAVES 1 - 14 MHz slow-drift time periods in 2001-2003. We find that most of the periods contain multiple phenomena, which we divide into three groups: metric type II extensions, IP type II events, and blobs and bands. About half of the WAVES listings include probable extensions of metric type II radio bursts, but in more than half of these events, there were also other slow-drift features. In the 3 yr study period, there were 31 IP type II events; these were associated with the very fastest CMEs. The most common form of activity in the WAVES events, blobs and bands in the frequency range between 1 and 8 MHz, fall below an envelope consistent with the early signatures of an IP type II event. However, most of this activity lasts only a few tens of minutes, whereas IP type II events last for many hours. In this study we find many examples in the radio data of two shock-like phenomena with different characteristics that occur simultaneously in the metric and decametric/hectometric bands, and no clear example of a metric type II burst that extends continuously down in frequency to become an IP type II event. The simplest interpretation is that metric type II bursts, unlike IP type II events, are not caused by shocks driven in front of CMEs.

  5. Relativistic motion in gamma-ray bursts

    International Nuclear Information System (INIS)

    Krolik, J.H.; Pier, E.A.

    1991-01-01

    Three fundamental problems affect models of gamma-ray bursts, i.e., the energy source, the ability of high-energy photons to escape the radiation region, and the comparative weakness of X-ray emission. It is indicated that relativistic bulk motion of the gamma-ray-emitting plasma generically provides a solution to all three of these problems. Results show that, if the plasma that produces gamma-ray bursts has a bulk relativistic velocity with Lorentz factor gamma of about 10, several of the most troubling problems having to do with gamma-ray bursts are solved. 42 refs

  6. Frequency chirping during a fishbone burst

    International Nuclear Information System (INIS)

    Marchenko, V.S.; Reznik, S.N.

    2011-01-01

    It is shown that frequency chirping during fishbone activity can be attributed to the reactive torque exerted on the plasma during the instability burst, which slows down plasma rotation inside the q = 1 surface and reduces the mode frequency in the lab frame. Estimates show that the peak value of this torque can exceed the neutral beam torque in modern tokamaks. The simple line-broadened quasilinear burst model (Berk et al 1995 Nucl. Fusion 35 1661), properly adapted for the fishbone case, is capable of reproducing the key features of the bursting mode. (letter)

  7. Ballerina - pirouettes in search of gamma bursts

    DEFF Research Database (Denmark)

    Brandt, Søren Kristian; Lund, Niels; Pedersen, Henrik

    1999-01-01

    The cosmological origin of gamma ray bursts has now been established with reasonable certainty, Many more bursts will need to be studied to establish the typical distance scale, and to map out the large diversity in properties which have been indicated by the first handful of events. We are propo...... are proposing Ballerina, a small satellite to provide accurate positions and new data on the gamma-ray bursts. We anticipate a detection rate an order of magnitude larger than obtained from Beppo-SAX....

  8. Preliminary results of a gamma-ray burst study in the Konus experiment on the Venera-11 and Venera-12 space probes

    International Nuclear Information System (INIS)

    Mazets, Y.P.; Golentskii, S.V.; Ilinskii, V.N.; Panov, V.N.; Aptekar, R.L.

    Twenty-one gamma-ray bursts and 68 solar flares in the hard X-ray range were detected on Venera-11 and Venera-12 space probes during the initial 50-day observation period. Major characteristics of the equipment used and preliminary data on the temporal structure and energy spectra of the gamma-ray bursts are considered. The pattern of gamma-ray burst frequency distribution vs. intensity, N(S), is established

  9. Narrowband dm-spikes, intermediate drift bursts and pulsations in the solar flare of August 19, 1981

    International Nuclear Information System (INIS)

    Karlicky, M.

    1986-01-01

    In the initial phase (1251-1253 UT) of the flare of Aug. 19, 1981, an interesting group of narrowband dm-spikes, intermediate drift bursts and pulsations was observed. The paper tries to explain this group of bursts by a uniform model. It is shown that all these bursts are associated with acceleration and trapping of superthermal electrons in the flare loop. The parameters of the flare loop and the electric field in the acceleration process are estimated. An explanation is given of why the ''period'' of intermediate drift bursts and of pulsations is the same. Later the flare loop under study explodes and a shock wave (type II radio burst) is generated at a relatively high altitude of ∼ 100,000 km above the photosphere. This process is connected with the 10 cm radio flux decrease. (author)

  10. On Gamma-Ray Bursts

    CERN Document Server

    Ruffini, Remo; Bianco, Carlo Luciano; Caito, Letizia; Chardonnet, Pascal; Cherubini, Christian; Dainotti, Maria Giovanna; Fraschetti, Federico; Geralico, Andrea; Guida, Roberto; Patricelli, Barbara; Rotondo, Michael; Hernandez, Jorge Armando Rueda; Vereshchagin, Gregory; Xue, She-Sheng

    2008-01-01

    (Shortened) We show by example how the uncoding of Gamma-Ray Bursts (GRBs) offers unprecedented possibilities to foster new knowledge in fundamental physics and in astrophysics. After recalling some of the classic work on vacuum polarization in uniform electric fields by Klein, Sauter, Heisenberg, Euler and Schwinger, we summarize some of the efforts to observe these effects in heavy ions and high energy ion collisions. We then turn to the theory of vacuum polarization around a Kerr-Newman black hole, leading to the extraction of the blackholic energy, to the concept of dyadosphere and dyadotorus, and to the creation of an electron-positron-photon plasma. We then present a new theoretical approach encompassing the physics of neutron stars and heavy nuclei. It is shown that configurations of nuclear matter in bulk with global charge neutrality can exist on macroscopic scales and with electric fields close to the critical value near their surfaces. These configurations may represent an initial condition for the...

  11. Relativistic effects in gamma-ray bursts

    International Nuclear Information System (INIS)

    Eriksen, Erik; Groen, Oeyvind

    1999-01-01

    According to recent models of the sources of gamma-ray bursts the extremely energetic emission is caused by shells expanding with ultrarelativistic velocity. With the recent identification of optical sources at the positions of some gamma-ray bursts these ''fireball'' models have acquired an actuality that invites to use them as a motivating application when teaching special relativity. We demonstrate several relativistic effects associated with these models which are very pronounced due to the great velocity of the shell. For example a burst lasting for a month in the rest frame of an element of the shell lasts for a few seconds only, in the rest frame of our detector. It is shown how the observed properties of a burst are modified by aberration and the Doppler effect. The apparent luminosity as a function of time is calculated. Modifications due to the motion of the star away from the observer are calculated. (Author)

  12. Bursts from the very early universe

    International Nuclear Information System (INIS)

    Silk, J.; Stodolsky, L.

    2006-01-01

    Bursts of weakly interacting particles such as neutrinos or even more weakly interacting particles such as wimps and gravitons from the very early universe would offer a much deeper 'look back time' to early epochs than is possible with photons. We consider some of the issues related to the existence of such bursts and their detectability. Characterizing the burst rate by a probability P per Hubble four-volume we find, for events in the radiation-dominated era, that the natural unit of description is the present intensity of the CMB times P. The existence of such bursts would make the observation of phenomena associated with very early times in cosmology at least conceptually possible. One might even hope to probe the transplanckian epoch if complexes more weakly interacting than the graviton can exist. Other conceivable applications include the potential detectability of the formation of 'pocket universes' in a multiverse

  13. Bursts from the very early universe

    Energy Technology Data Exchange (ETDEWEB)

    Silk, J. [Department of Physics, University of Oxford, Oxford OX1 3RH (United Kingdom); Stodolsky, L. [Max-Planck-Institut fuer Physik, Foehringer Ring 6, 80805 Munich (Germany)]. E-mail: les@mppmu.mpg.de

    2006-07-27

    Bursts of weakly interacting particles such as neutrinos or even more weakly interacting particles such as wimps and gravitons from the very early universe would offer a much deeper 'look back time' to early epochs than is possible with photons. We consider some of the issues related to the existence of such bursts and their detectability. Characterizing the burst rate by a probability P per Hubble four-volume we find, for events in the radiation-dominated era, that the natural unit of description is the present intensity of the CMB times P. The existence of such bursts would make the observation of pheno associated with very early times in cosmology at least conceptually possible. One might even hope to probe the transplanckian epoch if complexes more weakly interacting than the graviton can exist. Other conceivable applications include the potential detectability of the formation of 'pocket universes' in a multiverse.

  14. Observations of gamma-ray bursts

    International Nuclear Information System (INIS)

    Strong, I.B.; Klebesadel, R.W.; Evans, W.D.

    1975-01-01

    Observational data on gamma-ray bursts are reviewed. Information is grouped into temporal properties, energy fluxes and spectral properties, and directions and distributions of the sources in space. (BJG)

  15. Damping of type III solar radio bursts

    International Nuclear Information System (INIS)

    Levin, B.N.

    1982-01-01

    The meter- and decameter-wavelength damping of type III bursts may be attributable to stabilization of the Langmuir-wave instability of the fast-electron streams through excitation of cyclotron-branch plasma waves

  16. Mixed-meal tolerance test versus glucagon stimulation test for the assessment of beta-cell function in therapeutic trials in type 1 diabetes.

    Science.gov (United States)

    Greenbaum, Carla J; Mandrup-Poulsen, Thomas; McGee, Paula Friedenberg; Battelino, Tadej; Haastert, Burkhard; Ludvigsson, Johnny; Pozzilli, Paolo; Lachin, John M; Kolb, Hubert

    2008-10-01

    Beta-cell function in type 1 diabetes clinical trials is commonly measured by C-peptide response to a secretagogue in either a mixed-meal tolerance test (MMTT) or a glucagon stimulation test (GST). The Type 1 Diabetes TrialNet Research Group and the European C-peptide Trial (ECPT) Study Group conducted parallel randomized studies to compare the sensitivity, reproducibility, and tolerability of these procedures. In randomized sequences, 148 TrialNet subjects completed 549 tests with up to 2 MMTT and 2 GST tests on separate days, and 118 ECPT subjects completed 348 tests (up to 3 each) with either two MMTTs or two GSTs. Among individuals with up to 4 years' duration of type 1 diabetes, >85% had measurable stimulated C-peptide values. The MMTT stimulus produced significantly higher concentrations of C-peptide than the GST. Whereas both tests were highly reproducible, the MMTT was significantly more so (R(2) = 0.96 for peak C-peptide response). Overall, the majority of subjects preferred the MMTT, and there were few adverse events. Some older subjects preferred the shorter duration of the GST. Nausea was reported in the majority of GST studies, particularly in the young age-group. The MMTT is preferred for the assessment of beta-cell function in therapeutic trials in type 1 diabetes.

  17. Is serum zinc associated with pancreatic beta cell function and insulin sensitivity in pre-diabetic and normal individuals? Findings from the Hunter Community Study.

    Directory of Open Access Journals (Sweden)

    Khanrin P Vashum

    Full Text Available AIM: To determine if there is a difference in serum zinc concentration between normoglycaemic, pre-diabetic and type-2 diabetic groups and if this is associated with pancreatic beta cell function and insulin sensitivity in the former 2 groups. METHOD: Cross sectional study of a random sample of older community-dwelling men and women in Newcastle, New South Wales, Australia. Beta cell function, insulin sensitivity and insulin resistance were calculated for normoglycaemic and prediabetes participants using the Homeostasis Model Assessment (HOMA-2 calculator. RESULT: A total of 452 participants were recruited for this study. Approximately 33% (N = 149 had diabetes, 33% (N = 151 had prediabetes and 34% (N = 152 were normoglycaemic. Homeostasis Model Assessment (HOMA parameters were found to be significantly different between normoglycaemic and prediabetes groups (p<0.001. In adjusted linear regression, higher serum zinc concentration was associated with increased insulin sensitivity (p = 0.01 in the prediabetic group. There was also a significant association between smoking and worse insulin sensitivity. CONCLUSION: Higher serum zinc concentration is associated with increased insulin sensitivity. Longitudinal studies are required to determine if low serum zinc concentration plays a role in progression from pre-diabetes to diabetes.

  18. Optimal Codes for the Burst Erasure Channel

    Science.gov (United States)

    Hamkins, Jon

    2010-01-01

    Deep space communications over noisy channels lead to certain packets that are not decodable. These packets leave gaps, or bursts of erasures, in the data stream. Burst erasure correcting codes overcome this problem. These are forward erasure correcting codes that allow one to recover the missing gaps of data. Much of the recent work on this topic concentrated on Low-Density Parity-Check (LDPC) codes. These are more complicated to encode and decode than Single Parity Check (SPC) codes or Reed-Solomon (RS) codes, and so far have not been able to achieve the theoretical limit for burst erasure protection. A block interleaved maximum distance separable (MDS) code (e.g., an SPC or RS code) offers near-optimal burst erasure protection, in the sense that no other scheme of equal total transmission length and code rate could improve the guaranteed correctible burst erasure length by more than one symbol. The optimality does not depend on the length of the code, i.e., a short MDS code block interleaved to a given length would perform as well as a longer MDS code interleaved to the same overall length. As a result, this approach offers lower decoding complexity with better burst erasure protection compared to other recent designs for the burst erasure channel (e.g., LDPC codes). A limitation of the design is its lack of robustness to channels that have impairments other than burst erasures (e.g., additive white Gaussian noise), making its application best suited for correcting data erasures in layers above the physical layer. The efficiency of a burst erasure code is the length of its burst erasure correction capability divided by the theoretical upper limit on this length. The inefficiency is one minus the efficiency. The illustration compares the inefficiency of interleaved RS codes to Quasi-Cyclic (QC) LDPC codes, Euclidean Geometry (EG) LDPC codes, extended Irregular Repeat Accumulate (eIRA) codes, array codes, and random LDPC codes previously proposed for burst erasure

  19. Nature of gamma-ray burst sources

    International Nuclear Information System (INIS)

    Ventura, J.

    1983-01-01

    Observational evidence suggests that gamma ray bursts have a local galactic origin involving neutron stars. In this light we make a critical review of physics of the thermonuclear runaway model placing emphasis on self-consistency. We further show that some of the proposed models can be observationally excluded in the light of existing data from the Einstein Observatory. The possibility of gamma bursts arising in low mass binaries is finally discussed in the light of evolutionary scenarios leading to low luminosity systems

  20. A Fast Radio Burst Host Galaxy

    OpenAIRE

    Keane, E. F.; Johnston, S.; Bhandari, S.; Barr, E.; Bhat, N. D. R.; Burgay, M.; Caleb, M.; Flynn, C.; Jameson, A.; Kramer, M.; Petroff, E.; Possenti, A.; van Straten, W.; Bailes, M.; Burke-Spolaor, S.

    2016-01-01

    In recent years, millisecond duration radio signals originating from distant galaxies appear to have been discovered in the so-called Fast Radio Bursts. These signals are dispersed according to a precise physical law and this dispersion is a key observable quantity which, in tandem with a redshift measurement, can be used for fundamental physical investigations. While every fast radio burst has a dispersion measurement, none before now have had a redshift measurement, due to the difficulty in...

  1. Peripheral insulin resistance rather than beta cell dysfunction accounts for geographical differences in impaired fasting blood glucose among sub-Saharan African individuals: findings from the RODAM study.

    Science.gov (United States)

    Meeks, Karlijn A C; Stronks, Karien; Adeyemo, Adebowale; Addo, Juliet; Bahendeka, Silver; Beune, Erik; Owusu-Dabo, Ellis; Danquah, Ina; Galbete, Cecilia; Henneman, Peter; Klipstein-Grobusch, Kerstin; Mockenhaupt, Frank P; Osei, Kwame; Schulze, Matthias B; Spranger, Joachim; Smeeth, Liam; Agyemang, Charles

    2017-05-01

    The aim of this study was to assess the extent to which insulin resistance and beta cell dysfunction account for differences in impaired fasting blood glucose (IFBG) levels in sub-Saharan African individuals living in different locations in Europe and Africa. We also aimed to identify determinants associated with insulin resistance and beta cell dysfunction among this population. Data from the cross-sectional multicentre Research on Obesity and Diabetes among African Migrants (RODAM) study were analysed. Participants included Ghanaian individuals without diabetes, aged 18-96 years old, who were residing in Amsterdam (n = 1337), Berlin (n = 502), London (n = 961), urban Ghana (n = 1309) and rural Ghana (n = 970). Glucose and insulin were measured in fasting venous blood samples. Anthropometrics were assessed during a physical examination. Questionnaires were used to assess demographics, physical activity, smoking status, alcohol consumption and energy intake. Insulin resistance and beta cell function were determined using homeostatic modelling (HOMA-IR and HOMA-B, respectively). Logistic regression analysis was used to study the contribution of HOMA-IR and inverse HOMA-B (beta cell dysfunction) to geographical differences in IFBG (fasting glucose 5.6-6.9 mmol/l). Multivariate linear regression analysis was used to identify determinants associated with HOMA-IR and inverse HOMA-B. IFBG was more common in individuals residing in urban Ghana (OR 1.41 [95% CI 1.08, 1.84]), Amsterdam (OR 3.44 [95% CI 2.69, 4.39]) and London (OR 1.58 [95% CI 1.20 2.08), but similar in individuals living in Berlin (OR 1.00 [95% CI 0.70, 1.45]), compared with those in rural Ghana (reference population). The attributable risk of IFBG per 1 SD increase in HOMA-IR was 69.3% and in inverse HOMA-B was 11.1%. After adjustment for HOMA-IR, the odds for IFBG reduced to 0.96 (95% CI 0.72, 1.27), 2.52 (95%CI 1.94, 3.26) and 1.02 (95% CI 0.78, 1.38) for individuals in Urban Ghana

  2. Formation of Radio Type II Bursts During a Multiple Coronal Mass Ejection Event

    Science.gov (United States)

    Al-Hamadani, Firas; Pohjolainen, Silja; Valtonen, Eino

    2017-12-01

    We study the solar event on 27 September 2001 that consisted of three consecutive coronal mass ejections (CMEs) originating from the same active region, which were associated with several periods of radio type II burst emission at decameter-hectometer (DH) wavelengths. Our analysis shows that the first radio burst originated from a low-density environment, formed in the wake of the first, slow CME. The frequency-drift of the burst suggests a low-speed burst driver, or that the shock was not propagating along the large density gradient. There is also evidence of band-splitting within this emission lane. The origin of the first shock remains unclear, as several alternative scenarios exist. The second shock showed separate periods of enhanced radio emission. This shock could have originated from a CME bow shock, caused by the fast and accelerating second or third CME. However, a shock at CME flanks is also possible, as the density depletion caused by the three CMEs would have affected the emission frequencies and hence the radio source heights could have been lower than usual. The last type II burst period showed enhanced emission in a wider bandwidth, which was most probably due to the CME-CME interaction. Only one shock that could reliably be associated with the investigated CMEs was observed to arrive near Earth.

  3. Automatic recognition of coronal type II radio bursts: The ARBIS 2 method and first observations

    Science.gov (United States)

    Lobzin, Vasili; Cairns, Iver; Robinson, Peter; Steward, Graham; Patterson, Garth

    Major space weather events such as solar flares and coronal mass ejections are usually accompa-nied by solar radio bursts, which can potentially be used for real-time space weather forecasts. Type II radio bursts are produced near the local plasma frequency and its harmonic by fast electrons accelerated by a shock wave moving through the corona and solar wind with a typi-cal speed of 1000 km s-1 . The coronal bursts have dynamic spectra with frequency gradually falling with time and durations of several minutes. We present a new method developed to de-tect type II coronal radio bursts automatically and describe its implementation in an extended Automated Radio Burst Identification System (ARBIS 2). Preliminary tests of the method with spectra obtained in 2002 show that the performance of the current implementation is quite high, ˜ 80%, while the probability of false positives is reasonably low, with one false positive per 100-200 hr for high solar activity and less than one false event per 10000 hr for low solar activity periods. The first automatically detected coronal type II radio bursts are also presented. ARBIS 2 is now operational with IPS Radio and Space Services, providing email alerts and event lists internationally.

  4. Balloon observation of gamma-ray burst

    International Nuclear Information System (INIS)

    Nishimura, Jun; Fujii, Masami; Yamagami, Takamasa; Oda, Minoru; Ogawara, Yoshiaki

    1978-01-01

    Cosmic gamma-ray burst is an interesting high energy astrophysical phenomenon, but the burst mechanism has not been well understood. Since 1975, long duration balloon flight has been conducted to search for gamma-ray bursts and to determine the source locations. A rotating cross-modulation collimator was employed to determine the locations of sources, and four NaI(Tl) scintillation counters were employed to detect hard X-ray with energy from 20 to 200 keV. The balloon light was performed at altitude of 8.3 mb from September 28, 1977, and the observation time of 79 hours was achieved. In this experiment, the monitor counter was not mounted. The count increase was observed at 16 h 22 m 31 s JST on October 1, 1977. The event disappeared after 1 sec. The total flux is estimated to be 1.6 x 10 -6 erg/cm 2 sec at the top of the atmosphere. When this event was observed, the solar-terrestrial environment was also quiet. Thus, this event was attributed to a small gamma-ray burst. Unfortunately, the duration of the burst was so short that the position of the burst source was not able to be determined. (Yoshimori, M.)

  5. Gamma Ray Bursts-Afterglows and Counterparts

    Science.gov (United States)

    Fishman, Gerald J

    1998-01-01

    Several breakthrough discoveries were made last year of x-ray, optical and radio afterglows and counterparts to gamma-ray bursts, and a redshift has been associated with at least one of these. These discoveries were made possible by the fast, accurate gamma-ray burst locations of the BeppoSAX satellite. It is now generally believed that the burst sources are at cosmological distances and that they represent the most powerful explosions in the Universe. These observations also open new possibilities for the study of early star formation, the physics of extreme conditions and perhaps even cosmology. This session will concentrate on recent x-ray, optical and radio afterglow observations of gamma-ray bursts, associated redshift measurements, and counterpart observations. Several review and theory talks will also be presented, along with a summary of the astrophysical implications of the observations. There will be additional poster contributions on observations of gamma-ray burst source locations at wavelengths other than gamma rays. Posters are also solicited that describe new observational capabilities for rapid follow-up observations of gamma-ray bursts.

  6. Green leaf volatiles and oxygenated metabolite emission bursts from mesquite branches following light-dark transitions.

    Science.gov (United States)

    Jardine, K; Barron-Gafford, G A; Norman, J P; Abrell, L; Monson, R K; Meyers, K T; Pavao-Zuckerman, M; Dontsova, K; Kleist, E; Werner, C; Huxman, T E

    2012-09-01

    Green leaf volatiles (GLVs) are a diverse group of fatty acid-derived compounds emitted by all plants and are involved in a wide variety of developmental and stress-related biological functions. Recently, GLV emission bursts from leaves were reported following light-dark transitions and hypothesized to be related to the stress response while acetaldehyde bursts were hypothesized to be due to the 'pyruvate overflow' mechanism. In this study, branch emissions of GLVs and a group of oxygenated metabolites (acetaldehyde, ethanol, acetic acid, and acetone) derived from the pyruvate dehydrogenase (PDH) bypass pathway were quantified from mesquite plants following light-dark transitions using a coupled GC-MS, PTR-MS, and photosynthesis system. Within the first minute after darkening following a light period, large emission bursts of both C(5) and C(6) GLVs dominated by (Z)-3-hexen-1-yl acetate together with the PDH bypass metabolites are reported for the first time. We found that branches exposed to CO(2)-free air lacked significant GLV and PDH bypass bursts while O(2)-free atmospheres eliminated the GLV burst but stimulated the PDH bypass burst. A positive relationship was observed between photosynthetic activity prior to darkening and the magnitude of the GLV and PDH bursts. Photosynthesis under (13)CO(2) resulted in bursts with extensive labeling of acetaldehyde, ethanol, and the acetate but not the C(6)-alcohol moiety of (Z)-3-hexen-1-yl acetate. Our observations are consistent with (1) the "pyruvate overflow" mechanism with a fast turnover time (3 h) responsible for the C(6) alcohol moiety of (Z)-3-hexen-1-yl acetate via the 13-lipoxygenase pathway. We conclude that our non-invasive method may provide a new valuable in vivo tool for studies of acetyl-CoA and fatty acid metabolism in plants at a variety of spatial scales.

  7. Pancreatic beta cells express two autoantigenic forms of glutamic acid decarboxylase, a 65-kDa hydrophilic form and a 64-kDa amphiphilic form which can be both membrane-bound and soluble

    DEFF Research Database (Denmark)

    Christgau, S; Schierbeck, H; Aanstoot, H J

    1991-01-01

    The 64-kDa pancreatic beta-cell autoantigen, which is a target of autoantibodies associated with early as well as progressive stages of beta-cell destruction, resulting in insulin-dependent diabetes (IDDM) in humans, has been identified as the gamma-aminobutyric acid-synthesizing enzyme glutamic...... acid decarboxylase. We have identified two autoantigenic forms of this protein in rat pancreatic beta-cells, a Mr 65,000 (GAD65) hydrophilic and soluble form of pI 6.9-7.1 and a Mr 64,000 (GAD64) component of pI 6.7. GAD64 is more abundant than GAD65 and has three distinct forms with regard to cellular...

  8. Control of bursting synchronization in networks of Hodgkin-Huxley-type neurons with chemical synapses.

    Science.gov (United States)

    Batista, C A S; Viana, R L; Ferrari, F A S; Lopes, S R; Batista, A M; Coninck, J C P

    2013-04-01

    Thermally sensitive neurons present bursting activity for certain temperature ranges, characterized by fast repetitive spiking of action potential followed by a short quiescent period. Synchronization of bursting activity is possible in networks of coupled neurons, and it is sometimes an undesirable feature. Control procedures can suppress totally or partially this collective behavior, with potential applications in deep-brain stimulation techniques. We investigate the control of bursting synchronization in small-world networks of Hodgkin-Huxley-type thermally sensitive neurons with chemical synapses through two different strategies. One is the application of an external time-periodic electrical signal and another consists of a time-delayed feedback signal. We consider the effectiveness of both strategies in terms of protocols of applications suitable to be applied by pacemakers.

  9. The SUrvey for Pulsars and Extragalactic Radio Bursts - I. Survey description and overview

    Science.gov (United States)

    Keane, E. F.; Barr, E. D.; Jameson, A.; Morello, V.; Caleb, M.; Bhandari, S.; Petroff, E.; Possenti, A.; Burgay, M.; Tiburzi, C.; Bailes, M.; Bhat, N. D. R.; Burke-Spolaor, S.; Eatough, R. P.; Flynn, C.; Jankowski, F.; Johnston, S.; Kramer, M.; Levin, L.; Ng, C.; van Straten, W.; Krishnan, V. Venkatraman

    2018-01-01

    We describe the Survey for Pulsars and Extragalactic Radio Bursts (SUPERB), an ongoing pulsar and fast transient survey using the Parkes radio telescope. SUPERB involves real-time acceleration searches for pulsars and single-pulse searches for pulsars and fast radio bursts. We report on the observational set-up, data analysis, multiwavelength/messenger connections, survey sensitivities to pulsars and fast radio bursts and the impact of radio frequency interference. We further report on the first 10 pulsars discovered in the project. Among these is PSR J1306-40, a millisecond pulsar in a binary system where it appears to be eclipsed for a large fraction of the orbit. PSR J1421-4407 is another binary millisecond pulsar; its orbital period is 30.7 d. This orbital period is in a range where only highly eccentric binaries are known, and expected by theory; despite this its orbit has an eccentricity of 10-5.

  10. Coronal mass ejections and solar radio bursts

    International Nuclear Information System (INIS)

    Kundu, M.R.

    1990-01-01

    The properties of coronal mass ejection (CME) events and their radio signatures are discussed. These signatures are mostly in the form of type II and type IV burst emissions. Although type II bursts are temporally associated with CMEs, it is shown that there is no spatial relationship between them. Type II's associated with CMEs have in most cases a different origin, and they are not piston-driven by CMEs. Moving type IV and type II bursts can be associated with slow CMEs with speeds as low as 200 km/s, contrary to the earlier belief that only CMEs with speeds >400 km/s are associated with radio bursts. A specific event has been discussed in which the CME and type IV burst has nearly the same speed and direction, but the type II burst location was behind the CME and its motion was transverse. The speed and motion of the type II burst strongly suggest that the type II shock was decoupled from the CME and was probably due to a flare behind the limb. Therefore only the type IV source could be directly associated with the slow CME. The electrons responsble for the type IV emission could be produced in the flare or in the type II and then become trapped in a plasmoid associated with the CME. The reconnected loop could then move outwards as in the usual palsmoid model. Alternatively, the type IV emission could be interpreted as due to electrons produced by acceleration in wave turbulence driven by currents in the shock front driven by the CME. The lower-hybrid model Lampe and Papadopoulos (1982), which operates at both fast and slow mode shocks, could be applied to this situation. (author). 31 refs., 12 figs

  11. Swift pointing and gravitational-wave bursts from gamma-ray burst events

    International Nuclear Information System (INIS)

    Sutton, Patrick J; Finn, Lee Samuel; Krishnan, Badri

    2003-01-01

    The currently accepted model for gamma-ray burst phenomena involves the violent formation of a rapidly rotating solar-mass black hole. Gravitational waves should be associated with the black-hole formation, and their detection would permit this model to be tested. Even upper limits on the gravitational-wave strength associated with gamma-ray bursts could constrain the gamma-ray burst model. This requires joint observations of gamma-ray burst events with gravitational and gamma-ray detectors. Here we examine how the quality of an upper limit on the gravitational-wave strength associated with gamma-ray bursts depends on the relative orientation of the gamma-ray-burst and gravitational-wave detectors, and apply our results to the particular case of the Swift Burst-Alert Telescope (BAT) and the LIGO gravitational-wave detectors. A result of this investigation is a science-based 'figure of merit' that can be used, together with other mission constraints, to optimize the pointing of the Swift telescope for the detection of gravitational waves associated with gamma-ray bursts

  12. Localization of Gamma-Ray Bursts Using the Fermi Gamma-Ray Burst Monitor

    NARCIS (Netherlands)

    Connaughton, V.; Briggs, M.S.; Goldstein, A.; Meegan, C.A.; Paciesas, W.S.; Preece, R.D.; Wilson-Hodge, C.A.; Gibby, M.H.; Greiner, J.; Gruber, D.; Jenke, P.; Kippen, R.M.; Pelassa, V.; Xiong, S.; Yu, H-F.; Bhat, P.N.; Burgess, J.M.; Byrne, D.; Fitzpatrick, G.; Foley, S.; Giles, M.M.; Guiriec, S.; van der Horst, A.J.; von Kienlin, A.; McBreen, S.; McGlynn, S.; Tierney, D.; Zhang, B..B.

    2015-01-01

    The Fermi Gamma-ray Burst Monitor (GBM) has detected over 1400 gamma-ray bursts (GRBs) since it began science operations in 2008 July. We use a subset of over 300 GRBs localized by instruments such as Swift, the Fermi Large Area Telescope, INTEGRAL, and MAXI, or through triangulations from the

  13. The GLP-1 analogue liraglutide improves first-phase insulin secretion and maximal beta-cell secretory capacity over 14 weeks of therapy in subjects with Type 2 diabetes

    DEFF Research Database (Denmark)

    Madsbad, Sten; Vilsbøll, Tina; Brock, Birgitte

    Aims: We investigated the clinical effect of liraglutide, a long- acting GLP-1 analogue, on insulin secretion in Type 2 diabetes. Methods: Thirty-nine subjects (28 completed) from a randomised trial received a hyperglycaemic clamp (20 mM) with intravenous arginine stimulation, and an insulin...... group. Conclusion: In subjects with Type 2 diabetes, 14 weeks’ once-daily liraglutide (1.25 and 1.9 mg/day) markedly improves beta-cell function, significantly increases first-phase insulin secretion and maximal beta-cell secretory capacity....

  14. Burst switching without guard interval in all-optical software-define star intra-data center network

    Science.gov (United States)

    Ji, Philip N.; Wang, Ting

    2014-02-01

    Optical switching has been introduced in intra-data center networks (DCNs) to increase capacity and to reduce power consumption. Recently we proposed a star MIMO OFDM-based all-optical DCN with burst switching and software-defined networking. Here, we introduce the control procedure for the star DCN in detail for the first time. The timing, signaling, and operation are described for each step to achieve efficient bandwidth resource utilization. Furthermore, the guidelines for the burst assembling period selection that allows burst switching without guard interval are discussed. The star all-optical DCN offers flexible and efficient control for next-generation data center application.

  15. Correlation Between Glycated Hemoglobin and Homa Indices in Type 2 Diabetes Mellitus: Prediction of Beta-Cell Function from Glycated Hemoglobin.

    Science.gov (United States)

    Al-Hakeim, Hussein Kadhem; Abdulzahra, Mohammed Saied

    2015-04-01

    The present study aimed to determine the most efficient insulin resistance function related to glycemic control expressed as glycated hemoglobin (HbA1c) in type 2 diabetes mellitus patients (T2DM). The other aim is to derive equations for the prediction of beta cell functions containing HbA1c as a parameter in addition to fasting glucose and insulin. T2DM Patients were grouped according to the following: (1) degree of control (good, fair, and poor control) and (2) insulin resistance as observed in obtained data and significant differences revealed by the homeostasis model assessment (HOMA) of related parameters (insulin resistance = HOMA2IR, beta-cell function = HOMA%B, and insulin sensitivity = HOMA%S) among groups. Correlations and forecasting regression analysis were calculated. HbA1c was found to be correlated with insulin resistance parameters in T2DM subgroups. This correlation was also significantly correlated with HOMA%B and the quantitative insulin sensitivity check index (QUICKI) in fair and poor control groups. Regression analysis was used to predict the forecasting equations for HOMA%B. The best applicable equations were derived for healthy control (HOMA2%B=-1.76*FBG+5.00*Insulin+4.69*HbA1c+189.84) and poor control groups (HOMA2%B=0.001* FBG+0.5*Insulin-8.67*HbA1c+101.96). These equations could be used to predict β-cell function (HOMA%B) after FBG, insulin and HbA1c values were obtained for healthy and poor control groups. In the good and fair control groups, the applicability of the HOMA model fails to yield appropriate results. Beta-cell function is correlated with QUICKI and HbA1c and could be predicted properly from HbA1c, insulin, and glucose in the healthy and poor control groups. New regression equations were established that involve HbA1c.

  16. QKD-Based Secured Burst Integrity Design for Optical Burst Switched Networks

    Science.gov (United States)

    Balamurugan, A. M.; Sivasubramanian, A.; Parvathavarthini, B.

    2016-03-01

    The field of optical transmission has undergone numerous advancements and is still being researched mainly due to the fact that optical data transmission can be done at enormous speeds. It is quite evident that people prefer optical communication when it comes to large amount of data involving its transmission. The concept of switching in networks has matured enormously with several researches, architecture to implement and methods starting with Optical circuit switching to Optical Burst Switching. Optical burst switching is regarded as viable solution for switching bursts over networks but has several security vulnerabilities. However, this work exploited the security issues associated with Optical Burst Switching with respect to integrity of burst. This proposed Quantum Key based Secure Hash Algorithm (QKBSHA-512) with enhanced compression function design provides better avalanche effect over the conventional integrity algorithms.

  17. Burst-suppression pattern in the electroencephalogram of newborns and infants. Its clinical expression

    Directory of Open Access Journals (Sweden)

    Cervantes Blanco Jorge Mauricio

    2014-07-01

    Full Text Available Burst-suppression pattern in the electroencephalogram (EEG is associated with severe brain damage and has a bad prognosis in 85% of the cases. Objectives. To identify the prevalence of the EEG burst-suppression pattern (BSP in fullterm newborns and infants, determine its etiol- ogy, clinical features and course. Methods. A retrospective study was conducted. Between January 2008 and December 2012, 4,891 EEGs were reviewed. The EEGs of newborns and infants (< 3 months of age with BSP were selected. Results. 11 cases identified with burst suppression pattern. The overall prevalence of which was 3.5%; 8.1% among the newborns and 1.2% among infants. Seizures were the main reason for doing an EEG in the newborn period in 7 patients and after day 28 in three. The clinical manifestations were abnormal level of consciousness (n=8, hypotonia (n=2, and spasticity (n=6. The main causes were hypoxic ischemic injury, stroke and kernicterus. There were two cases of early infantile epileptic encephalopathy. Two patients died before the third month of age; 8 survived an average of 13 months. All had epilepsy, neurologic retardation and disability. Two patients had persistent EEG burst-suppression pattern; 1 and 3 months after the neonatal period respectively; 7 had focal spikes and an asymmetric pattern. Conclusions. Electroencephalographic burst-suppression pat- tern predicts a severe neurologic injury in fullterm newborns and infants.

  18. Scientific Applications Performance Evaluation on Burst Buffer

    KAUST Repository

    Markomanolis, George S.

    2017-10-19

    Parallel I/O is an integral component of modern high performance computing, especially in storing and processing very large datasets, such as the case of seismic imaging, CFD, combustion and weather modeling. The storage hierarchy includes nowadays additional layers, the latest being the usage of SSD-based storage as a Burst Buffer for I/O acceleration. We present an in-depth analysis on how to use Burst Buffer for specific cases and how the internal MPI I/O aggregators operate according to the options that the user provides during his job submission. We analyze the performance of a range of I/O intensive scientific applications, at various scales on a large installation of Lustre parallel file system compared to an SSD-based Burst Buffer. Our results show a performance improvement over Lustre when using Burst Buffer. Moreover, we show results from a data hierarchy library which indicate that the standard I/O approaches are not enough to get the expected performance from this technology. The performance gain on the total execution time of the studied applications is between 1.16 and 3 times compared to Lustre. One of the test cases achieved an impressive I/O throughput of 900 GB/s on Burst Buffer.

  19. Sources of type III solar microwave bursts

    Directory of Open Access Journals (Sweden)

    Zhdanov D.A.

    2016-06-01

    Full Text Available Microwave fine structures allow us to study plasma evolution in an energy release region. The Siberian Solar Radio Telescope (SSRT is a unique instrument designed to examine fine structures at 5.7 GHz. A complex analysis of data from RATAN-600, 4–8 GHz spectropolarimeter, and SSRT, simultaneously with EUV data, made it possible to localize sources of III type microwave bursts in August 10, 2011 event within the entire frequency band of burst occurrence, as well as to determine the most probable region of primary energy release. To localize sources of III type bursts from RATAN-600 data, an original method for data processing has been worked out. At 5.7 GHz, the source of bursts was determined along two coordinates, whereas at 4.5, 4.7, 4.9, 5.1, 5.3, 5.5, and 6.0 GHz, their locations were identified along one coordinate. The size of the burst source at 5.1 GHz was found to be maximum as compared to those at other frequencies.

  20. Gluten-free diet increases beta-cell volume and improves glucose tolerance in an animal model of type 2 diabetes

    DEFF Research Database (Denmark)

    Haupt-Jørgensen, Martin; Buschard, Karsten; Hansen, Axel Kornerup

    2016-01-01

    Background Gluten-free (GF) diet alleviates type 1 diabetes in animal models and possibly in humans. We recently showed that fatty acid-induced insulin secretion is enhanced by enzymatically digested gluten (gliadin) stimulation in INS-1E insulinoma cells. We therefore hypothesized that GF diet...... would induce beta-cell rest and ameliorate type 2 diabetes. Methods C57BL/6JBomTac (B6) mice were fed a high-fat (HF), gluten-free high-fat (GF–HF), standard (STD) or gluten-free (GF) diet for 42 weeks. Results Short-term (6–24 weeks) GF–HF versus HF feeding impaired glucose tolerance and increased...... capacity controls pancreas volume. Thus, long-term GF diets may be beneficial for obese type 2 diabetes patients and trials should be performed....

  1. Liraglutide effects on beta-cell, insulin sensitivity and glucose effectiveness in patients with stable coronary artery disease and newly diagnosed type 2 diabetes

    DEFF Research Database (Denmark)

    Anholm, Christian; Kumarathurai, Preman; Pedersen, Lene R.

    2017-01-01

    characteristics were: HbA1c 47 mmol/mol (SD 6), BMI 31.6 kg/m2 (SD 4.8), fasting plasma-glucose 6.9 mmol/L (IQR 6.1; 7.4) and HOMA-IR 4.9 (IQR 3.0; 7.5). Liraglutide treatment improved AIRg by 3-fold, 497 mU × L−1 × min (IQR 342; 626, P ... weight loss of −2.7 kg (−6.7; −0.6) during liraglutide treatment, we found no improvement in HOMA-IR, Si or Sg. Weight loss during liraglutide therapy did not result in a carry-over effect. Conclusion: Liraglutide as add-on to metformin induces a clinically significant improvement in beta-cell function...

  2. Quantification of beta-cell function during IVGTT in Type II and non-diabetic subjects: assessment of insulin secretion by mathematical methods

    DEFF Research Database (Denmark)

    Kjems, L L; Vølund, A; Madsbad, Sten

    2001-01-01

    AIMS/HYPOTHESIS: We compared four methods to assess their accuracy in measuring insulin secretion during an intravenous glucose tolerance test in patients with Type II (non-insulin-dependent) diabetes mellitus and with varying beta-cell function and matched control subjects. METHODS: Eight control...... subjects and eight Type II diabetic patients underwent an intravenous glucose tolerance test with tolbutamide and an intravenous bolus injection of C-peptide to assess C-peptide kinetics. Insulin secretion rates were determined by the Eaton deconvolution (reference method), the Insulin SECretion method...... (ISEC) based on population kinetic parameters as well as one-compartment and two-compartment versions of the combined model of insulin and C-peptide kinetics. To allow a comparison of the accuracy of the four methods, fasting rates and amounts of insulin secreted during the first phase (0-10 min...

  3. Pancreatic beta-cell function is a stronger predictor of changes in glycemic control after an aerobic exercise intervention than insulin sensitivity

    DEFF Research Database (Denmark)

    Solomon, Thomas; Malin, Steven K; Karstoft, Kristian

    2013-01-01

    glucose-stimulated insulin secretion (GSIS), and disposition index (DI) were measured following 12-16-weeks of aerobic exercise training. Regression analyses were used to identify relationships between variables.ResultsFollowing training, 86% of subjects increased VO2max and lost weight. HbA1c, fasting......ContextUnderstanding inter-subject variability in glycemic control following exercise training will help individualize treatment.ObjectiveTo determine whether this variability is related to training-induced changes in insulin sensitivity or pancreatic beta-cell function.Design, Setting....... Training increased first- and second-phase DI in 83% and 74% of subjects. Training-induced changes in glycemic control were related to changes in GSIS (P...

  4. cPLA2alpha-evoked formation of arachidonic acid and lysophospholipids is required for exocytosis in mouse pancreatic beta-cells

    DEFF Research Database (Denmark)

    Juhl, Kirstine; Høy, Marianne; Olsen, Hervør L

    2003-01-01

    Using capacitance measurements, we investigated the effects of intracellularly applied recombinant human cytosolic phospholipase A2 (cPLA2alpha) and its lipolytic products arachidonic acid and lysophosphatidylcholine on Ca2+-dependent exocytosis in single mouse pancreatic beta-cells. cPLA2alpha...... from 70-80 to 280-300. cPLA2alpha-stimulated exocytosis was antagonized by the specific cPLA2 inhibitor AACOCF3. Ca2+-evoked exocytosis was reduced by 40% in cells treated with AACOCF3 or an antisense oligonucleotide against cPLA2alpha. The action of cPLA2alpha was mimicked by a combination...... of arachidonic acid and lysophosphatidylcholine (470% stimulation) in which each compound alone doubled the exocytotic response. Priming of insulin-containing secretory granules has been reported to involve Cl- uptake through ClC-3 Cl- channels. Accordingly, the stimulatory action of cPLA2alpha was inhibited...

  5. Fuzzy correlations of gamma-ray bursts

    International Nuclear Information System (INIS)

    Hartmann, D.H.; Linder, E.V.; Blumenthal, G.R.

    1991-01-01

    The origin of gamma-ray bursts is not known, both in the sense of the nature of the source emitting the radiation and literally, the position of the burst on the sky. Lacking unambiguously identified counterparts in any wavelength band studied to date, statistical approaches are required to determine the burster distance scale. Angular correlation analysis is one of the most powerful tools in this regard. However, poor detector resolution gives large localization errors, effectively beam smearing the positions. The resulting fuzzy angular correlation function is investigated and the generic isotropization that smearing induces on any intrinsic clustering is discussed. In particular, the extent to which gamma-ray burst observations by the BATSE detector aboard the Gamma-Ray Observatory might recover an intrinsic source correlation is investigated. 16 refs

  6. Gamma-ray burst polarimeter (GAP)

    International Nuclear Information System (INIS)

    Mihara, Tatehiro; Murakami, Toshio; Yonetoku, Daisuke; Gunji, Shuichi; Kubo, Shin

    2013-01-01

    The gamma-ray burst polarimeter (GAP: GAmma-ray burst Polarimeter), which had been almost handcrafted by scientists, has succeeded in working normally in interplanetary space, and in detecting the polarization of the gamma-ray from a mysterious astronomical object 'gamma-ray burst'. It is the first result of the detectors in the world exclusively aiming at detecting gamma-ray polarization. We mainly describe the hardware of our GAP equipment and show the method of preparing equipment to work in the cosmic space with a tight budget. The mechanical structure, the electronic circuits, the software on the equipment, the data analysis on the earth, and the scientific results gained by the observation just over one year, are presented after explaining the principle of gamma-ray polarization detection. Our design to protect equipment against mechanical shock and cosmic radiation may provide useful information for future preparation of compact satellite. (J.P.N.)

  7. Gamma-ray burst theory after Swift.

    Science.gov (United States)

    Piran, Tsvi; Fan, Yi-Zhong

    2007-05-15

    Afterglow observations in the pre-Swift era confirmed to a large extend the relativistic blast wave model for gamma-ray bursts (GRBs). Together with the observations of properties of host galaxies and the association with (type Ic) SNe, this has led to the generally accepted collapsar origin of long GRBs. However, most of the afterglow data was collected hours after the burst. The X-ray telescope and the UV/optical telescope onboard Swift are able to slew to the direction of a burst in real time and record the early broadband afterglow light curves. These observations, and in particular the X-ray observations, resulted in many surprises. While we have anticipated a smooth transition from the prompt emission to the afterglow, many observed that early light curves are drastically different. We review here how these observations are changing our understanding of GRBs.

  8. High sensitivity neutron bursts detecting system

    International Nuclear Information System (INIS)

    Shyam, A.; Kaushik, T.C.; Srinivasan, M.; Kulkarni, L.V.

    1993-01-01

    Technique and instrumentation to detect multiplicity of fast neutrons, emitted in sharp bursts, has been developed. A bank of 16 BF 3 detectors, in an appropriate thermalising assembly, efficiency ∼ 16%, is used to detect neutron bursts. The output from this setup, through appropriate electronics, is divided into two paths. The first is directly connected to a computer controlled scalar. The second is connected to another similar scalar through a delay time unit (DTU). The DTU design is such that once it is triggered by a count pulse than it does not allow any counts to be recorded for a fixed dead time set at ∼ 100 μs. The difference in counts recorded directly and through DTU gives the total number of neutrons produced in bursts. This setup is being used to study lattice cracking, anomalous effects in solid deuterium systems and various reactor physics experiments. (author). 3 refs., 1 fig

  9. Gamma-Ray Bursts: A Radio Perspective

    Directory of Open Access Journals (Sweden)

    Poonam Chandra

    2016-01-01

    Full Text Available Gamma-ray bursts (GRBs are extremely energetic events at cosmological distances. They provide unique laboratory to investigate fundamental physical processes under extreme conditions. Due to extreme luminosities, GRBs are detectable at very high redshifts and potential tracers of cosmic star formation rate at early epoch. While the launch of Swift and Fermi has increased our understanding of GRBs tremendously, many new questions have opened up. Radio observations of GRBs uniquely probe the energetics and environments of the explosion. However, currently only 30% of the bursts are detected in radio bands. Radio observations with upcoming sensitive telescopes will potentially increase the sample size significantly and allow one to follow the individual bursts for a much longer duration and be able to answer some of the important issues related to true calorimetry, reverse shock emission, and environments around the massive stars exploding as GRBs in the early Universe.

  10. Localised Microwave Bursts During ELMs on MAST

    Directory of Open Access Journals (Sweden)

    Freethy Simon

    2015-01-01

    Full Text Available Bursts of microwave emission are observed during ELM events on the Mega Ampère Spherical Tokamak. In agreement with observations on other machines, these bursts are up to 3 orders of magnitude more intense than the thermal background, but are electron cyclotron in nature. The peak in microwave emission is ~20μ before the peak in midplane Dα emission. Using the Synthetic Aperture Microwave Imaging radiometer, we are able to demonstrate that these bursts are often highly spatially localised and preferentially occur at the tokamak midplane. It is hypothesised that the localisation is a result of Doppler resonance broadening for electron Bernstein waves and the high perpendicular electron energies could be the result of pitch angle scattering in high collisionality regions of the plasma.

  11. Frequency Chirping during a Fishbone Burst

    Energy Technology Data Exchange (ETDEWEB)

    Marchenko, V.; Reznik, S., E-mail: march@kinr.kiev.ua [Institute for Nuclear Research, Kyiv (Ukraine)

    2012-09-15

    Full text: It is shown that gradual (more than a factor of two, in some cases - down to zero in the lab frame) reduction of the mode frequency (the so called frequency chirping) can be attributed to the reactive torque exerted on the plasma during the fishbone instability burst, which slows down the plasma rotation inside the q = 1 surface and reduces the mode frequency in the lab frame, while frequency in the plasma frame remains constant. This torque arises due to imbalance between the power transfered to the mode by energeric ions and the power of the mode dissipation by thermal species. Estimates show that the peak value of this torque exceeds the neutral beam torque in modern tokamaks and in ITER. The line-broadened quasilinear burst model, properly adapted for the fishbone case, is capable of reproducing the key features of the bursting mode. (author)

  12. Interaction function of coupled bursting neurons

    International Nuclear Information System (INIS)

    Shi Xia; Zhang Jiadong

    2016-01-01

    The interaction functions of electrically coupled Hindmarsh–Rose (HR) neurons for different firing patterns are investigated in this paper. By applying the phase reduction technique, the phase response curve (PRC) of the spiking neuron and burst phase response curve (BPRC) of the bursting neuron are derived. Then the interaction function of two coupled neurons can be calculated numerically according to the PRC (or BPRC) and the voltage time course of the neurons. Results show that the BPRC is more and more complicated with the increase of the spike number within a burst, and the curve of the interaction function oscillates more and more frequently with it. However, two certain things are unchanged: ϕ = 0, which corresponds to the in-phase synchronization state, is always the stable equilibrium, while the anti-phase synchronization state with ϕ = 0.5 is an unstable equilibrium. (paper)

  13. Unprotected daily sun exposure is differently associated with central adiposity and beta-cell dysfunction by gender: The Korean national health and nutrition examination survey (KNHANES) V

    Energy Technology Data Exchange (ETDEWEB)

    Ohn, Jung Hun [Division of Endocrinology and Metabolism, Department of Internal Medicine, Hallym University College of Medicine, Chuncheon (Korea, Republic of); Kwon, In Ho [Department of Dermatology, Hallym University Dongtan Sacred Heart Hospital, Hwaseong (Korea, Republic of); Park, Juri; Ryu, Ohk Hyun; Lee, Seong Jin; Kim, Doo-Man; Ihm, Sung-Hee; Choi, Moon-Gi; Yoo, Hyung Joon [Division of Endocrinology and Metabolism, Department of Internal Medicine, Hallym University College of Medicine, Chuncheon (Korea, Republic of); Hong, Eun-Gyoung, E-mail: hegletter@hallym.or.kr [Division of Endocrinology and Metabolism, Department of Internal Medicine, Hallym University College of Medicine, Chuncheon (Korea, Republic of)

    2014-08-15

    Background: Ultraviolet irradiation by sun exposure has been associated with both harms and benefits to metabolic health. Objective: The objective of this study was to determine whether unprotected daily sun exposure is associated with the prevalence of diabetes and explore the underlying mechanism. Methods: We analyzed the Korean National Health and Nutrition Survey V from 2010 to 2011. Participants 19–60 years of age were asked about the average amount of time they had been exposed to direct sunlight per day since the age of 19. We categorized participants into three groups with different levels of lifetime daily sun exposure and explored the association of sun exposure with the prevalence of diabetes. Results: The risk of diabetes was higher in subjects with more than 5 h of unprotected sun exposure per day, with an odds ratio of 2.39 (95% CI 1.75–3.25), compared to those with less than 2 h of sun exposure, and the association remained significant after adjusting for diabetes risk factors. Long-term sun exposure was associated with increased central obesity and the possibility of an increase in visceral adiposity, especially among women, and with decrease in beta cell function and peripheral adiposity or percent body fat in men. Conclusions: Our study provides a cutoff for upper limit of sun exposure and suggests unprotected daily sun exposure for more than 5 h should be avoided to prevent diabetes. Increased central adiposity and decreased beta cell function were observed in women and men, respectively, who had long-term unprotected daily sun exposure. - Highlights: • Sun exposure for more than 5 h per day is associated with diabetes risk. • Insulin resistance associated with visceral adiposity may play a role in women. • Insulin secretory defect may explain diabetes risk in men.

  14. Candidate gene association study in type 2 diabetes indicates a role for genes involved in beta-cell function as well as insulin action.

    Directory of Open Access Journals (Sweden)

    Inês Barroso

    2003-10-01

    Full Text Available Type 2 diabetes is an increasingly common, serious metabolic disorder with a substantial inherited component. It is characterised by defects in both insulin secretion and action. Progress in identification of specific genetic variants predisposing to the disease has been limited. To complement ongoing positional cloning efforts, we have undertaken a large-scale candidate gene association study. We examined 152 SNPs in 71 candidate genes for association with diabetes status and related phenotypes in 2,134 Caucasians in a case-control study and an independent quantitative trait (QT cohort in the United Kingdom. Polymorphisms in five of 15 genes (33% encoding molecules known to primarily influence pancreatic beta-cell function-ABCC8 (sulphonylurea receptor, KCNJ11 (KIR6.2, SLC2A2 (GLUT2, HNF4A (HNF4alpha, and INS (insulin-significantly altered disease risk, and in three genes, the risk allele, haplotype, or both had a biologically consistent effect on a relevant physiological trait in the QT study. We examined 35 genes predicted to have their major influence on insulin action, and three (9%-INSR, PIK3R1, and SOS1-showed significant associations with diabetes. These results confirm the genetic complexity of Type 2 diabetes and provide evidence that common variants in genes influencing pancreatic beta-cell function may make a significant contribution to the inherited component of this disease. This study additionally demonstrates that the systematic examination of panels of biological candidate genes in large, well-characterised populations can be an effective complement to positional cloning approaches. The absence of large single-gene effects and the detection of multiple small effects accentuate the need for the study of larger populations in order to reliably identify the size of effect we now expect for complex diseases.

  15. Outpatient versus inpatient mixed meal tolerance and arginine stimulation testing yields comparable measures of variability for assessment of beta cell function

    Directory of Open Access Journals (Sweden)

    Sudha S. Shankar

    2018-06-01

    Full Text Available Standard practice to minimize variability in beta cell function (BCF measurement is to test in inpatient (IP settings. IP testing strains trial subjects, investigators, and budgets. Outpatient (OP testing may be a solution although there are few reports on OP BCF testing variability. We compared variability metrics between OP and IP from a standardized mixed meal tolerance test (MMTT and arginine stimulation test (AST in two separate type 2 diabetes (T2DM cohorts (OP, n = 20; IP n = 22 in test-retest design. MMTT variables included: insulin sensitivity (Si; beta cell responsivity (Φtot; and disposition index (DItot = Si* Φtot following 470 kCal meal. AST variables included: acute insulin response to arginine (AIRarg and during hyperglycemia (AIRargMAX. Results: Baseline characteristics were well-matched. Between and within subject variance for each parameter across cohorts, and intraclass correlation coefficients (ICC-a measure of reproducibility across parameters were generally comparable for OP to IP. Table summarizes the ICC results for each key parameter and cohort.Test/ParameterOutpatient (95% CIInpatient (95% CIMMTT: Si0.49(0,0.690.28(0,0.60MMTT: Φtot0.65(0.16,0.890.81(0.44,0.93MMTT: DI0.67(0,0.830.36(0,0.69AST: AIR Arg0.96(0.88,0.980.84(0.59,0.94AST: AIR Arg Max0.97(0.90,0.990.95(0.86,0.97AST: ISR0.93(0.77,0.970.93(0.82,0.96In conclusion, the variability (reproducibility of BCF measures from standardized MMTT and AST is comparable between OP and IP settings. These observations have significant implications for complexity and cost of metabolic studies.

  16. Pancreatic beta-cell responses to GLP-1 after near-normalization of blood glucose in patients with type 2 diabetes.

    Science.gov (United States)

    Asmar, Meena; Højberg, Patricia V; Deacon, Carolyn F; Hare, Kristine; Holst, Jens J; Madsbad, Sten

    2010-02-25

    This study investigated the effects of strict glycaemic control on beta-cell function in nine obese subjects with type 2 diabetes (T2DM), using graded glucose infusions together with infusions of saline or GLP-1 before (HbA(1)c: 8.0+/-0.4%) and after four weeks of near-normalization of blood glucose (BG) using insulin (mean diurnal BG: 6.4+/-0.3 mmol/l; HbA(1)c: 6.6+/-0.3%). Nine matched healthy subjects acted as controls. In controls, area-under-curve (AUC) for amylin, C-peptide and proinsulin were higher with GLP-1 than saline (PAUC amylin/C-peptide ratio was similar on both days, while AUC proinsulin/C-peptide ratio was higher with GLP-1 (P=0.02). In the patients, amylin, C-peptide and proinsulin AUCs were unaltered by near-normoglycaemia per se. Proinsulin responses to GLP-1 were unchanged, but amylin and C-peptide AUCs increased (PAUC amylin/C-peptide ratios rose to control levels. Near-normoglycaemia tended to reduce AUC proinsulin/C-peptide ratio, which was significant (P=0.04) with GLP-1, but still higher than with saline (P=0.004). In conclusion, amylin, C-peptide and proinsulin responses to glucose were unaffected by four weeks of near-normoglycaemia, whereas GLP-1 increased amylin and C-peptide secretion and amylin/C-peptide ratio. Near-normoglycaemia reduced proinsulin/C-peptide ratio during stimulation with GLP-1, suggesting that strict glycaemic control might ameliorate some of the disturbances in beta-cell function characterizing T2DM. Copyright 2010 Elsevier B.V. All rights reserved.

  17. The species origin of the cellular microenvironment influences markers of beta cell fate and function in EndoC-βH1 cells.

    Science.gov (United States)

    Jeffery, N; Richardson, S; Beall, C; Harries, L W

    2017-12-15

    Interaction between islet cell subtypes and the extracellular matrix influences beta-cell function in mammals. The tissue architecture of rodent islets is very different to that of human islets; cell-to-cell communication and interaction with the extracellular matrix may vary between species. In this work, we have compared the responses of the human EndoC-βH1 cell line to non-human and human-derived growth matrices in terms of growth morphology, gene expression and glucose-stimulated insulin secretion (GSIS). EndoC-βH1 cells demonstrated a greater tendency to form cell clusters when cultured in a human microenvironment and exhibited reduced alpha cell markers at the mRNA level; mean expression difference - 0.23 and - 0.51; p = 0.009 and 0.002 for the Aristaless-related homeobox (ARX) and Glucagon (GCG) genes respectively. No differences were noted in the protein expression of mature beta cell markers such as Pdx1 and NeuroD1 were noted in EndoC-βH1 cells grown in a human microenvironment but cells were however more sensitive to glucose (4.3-fold increase in insulin secretion following glucose challenge compared with a 1.9-fold increase in cells grown in a non-human microenvironment; p = 0.0003). Our data suggests that the tissue origin of the cellular microenvironment has effects on the function of EndoC-βH1 cells in vitro, and the use of a more human-like culture microenvironment may bring benefits in terms of increased physiological relevance. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Unprotected daily sun exposure is differently associated with central adiposity and beta-cell dysfunction by gender: The Korean national health and nutrition examination survey (KNHANES) V

    International Nuclear Information System (INIS)

    Ohn, Jung Hun; Kwon, In Ho; Park, Juri; Ryu, Ohk Hyun; Lee, Seong Jin; Kim, Doo-Man; Ihm, Sung-Hee; Choi, Moon-Gi; Yoo, Hyung Joon; Hong, Eun-Gyoung

    2014-01-01

    Background: Ultraviolet irradiation by sun exposure has been associated with both harms and benefits to metabolic health. Objective: The objective of this study was to determine whether unprotected daily sun exposure is associated with the prevalence of diabetes and explore the underlying mechanism. Methods: We analyzed the Korean National Health and Nutrition Survey V from 2010 to 2011. Participants 19–60 years of age were asked about the average amount of time they had been exposed to direct sunlight per day since the age of 19. We categorized participants into three groups with different levels of lifetime daily sun exposure and explored the association of sun exposure with the prevalence of diabetes. Results: The risk of diabetes was higher in subjects with more than 5 h of unprotected sun exposure per day, with an odds ratio of 2.39 (95% CI 1.75–3.25), compared to those with less than 2 h of sun exposure, and the association remained significant after adjusting for diabetes risk factors. Long-term sun exposure was associated with increased central obesity and the possibility of an increase in visceral adiposity, especially among women, and with decrease in beta cell function and peripheral adiposity or percent body fat in men. Conclusions: Our study provides a cutoff for upper limit of sun exposure and suggests unprotected daily sun exposure for more than 5 h should be avoided to prevent diabetes. Increased central adiposity and decreased beta cell function were observed in women and men, respectively, who had long-term unprotected daily sun exposure. - Highlights: • Sun exposure for more than 5 h per day is associated with diabetes risk. • Insulin resistance associated with visceral adiposity may play a role in women. • Insulin secretory defect may explain diabetes risk in men

  19. Identification of beta cell dysfunction at the pre-symptomatic stage of diabetes mellitus by novel analytical system: liquid biopsy measurements in femtograms.

    Science.gov (United States)

    Krapfenbauer, Kurt

    2017-12-01

    Diabetes mellitus is produced and progresses as a consequence of complex and gradual processes, in which a variety of alterations of the endocrine pancreas, are involved and which mainly result in beta cell failure. Those molecular alterations can be found in the bloodstream, which suggests that we could quantify specific biomarkers in plasma or serum by very sensitive methods before the onset diabetes mellitus is diagnosed. However, classical methods of protein analysis such as electrophoresis, Western blot, ELISA, and liquid chromatography are generally time-consuming, lab-intensive, and not sensitive enough to detect such alteration in a pre-symptomatic state of the disease. A very sensitive and novel analytical detection conjugate system by using the combination of polyfluorophor technology with protein microchip method was developed. This innovative system facilitates the use of a very sensitive microchip assays that measure selected biomarkers in a small sample volume (10 μL) with a much higher sensitivity (92%) compare to common immune assay systems. Further advances of the application of this technology combine the power of miniaturization and faster quantification (around 10 min). The power of this technology offers great promise for point-of-care clinical testing and monitoring of specific biomarkers for diabetes in femtogram level in serum or plasma. In conclusion, the results indicate that the technical performance of this new technology is valid and that the assay is able to quantified PPY-specific antigens in plasma at femtogram levels which can be used for identification of beta cell dysfunction at the pre-symptomatic stage of diabetes mellitus.

  20. New decoding methods of interleaved burst error-correcting codes

    Science.gov (United States)

    Nakano, Y.; Kasahara, M.; Namekawa, T.

    1983-04-01

    A probabilistic method of single burst error correction, using the syndrome correlation of subcodes which constitute the interleaved code, is presented. This method makes it possible to realize a high capability of burst error correction with less decoding delay. By generalizing this method it is possible to obtain probabilistic method of multiple (m-fold) burst error correction. After estimating the burst error positions using syndrome correlation of subcodes which are interleaved m-fold burst error detecting codes, this second method corrects erasure errors in each subcode and m-fold burst errors. The performance of these two methods is analyzed via computer simulation, and their effectiveness is demonstrated.

  1. X-ray bursts observed with JEM-X

    DEFF Research Database (Denmark)

    Brandt, Søren Kristian; Chenevez, Jérôme; Lund, Niels

    2006-01-01

    We report on the search for X-ray bursts in the JEM-X X-ray monitor on INTEGRAL during the first two years of operations. More than 350 bursts from 25 different type-I X-ray burst sources were found.......We report on the search for X-ray bursts in the JEM-X X-ray monitor on INTEGRAL during the first two years of operations. More than 350 bursts from 25 different type-I X-ray burst sources were found....

  2. Broadband Spectral Investigations of Magnetar Bursts

    Science.gov (United States)

    Kırmızıbayrak, Demet; Şaşmaz Muş, Sinem; Kaneko, Yuki; Göğüş, Ersin

    2017-09-01

    We present our broadband (2-250 keV) time-averaged spectral analysis of 388 bursts from SGR J1550-5418, SGR 1900+14, and SGR 1806-20 detected with the Rossi X-ray Timing Explorer (RXTE) here and as a database in a companion web-catalog. We find that two blackbody functions (BB+BB), the sum of two modified blackbody functions (LB+LB), the sum of a blackbody function and a power-law function (BB+PO), and a power law with a high-energy exponential cutoff (COMPT) all provide acceptable fits at similar levels. We performed numerical simulations to constrain the best fitting model for each burst spectrum and found that 67.6% of burst spectra with well-constrained parameters are better described by the Comptonized model. We also found that 64.7% of these burst spectra are better described with the LB+LB model, which is employed in the spectral analysis of a soft gamma repeater (SGR) for the first time here, than with the BB+BB and BB+PO models. We found a significant positive lower bound trend on photon index, suggesting a decreasing upper bound on hardness, with respect to total flux and fluence. We compare this result with bursts observed from SGR and AXP (anomalous X-ray pulsar) sources and suggest that the relationship is a distinctive characteristic between the two. We confirm a significant anticorrelation between burst emission area and blackbody temperature, and find that it varies between the hot and cool blackbody temperatures differently than previously discussed. We expand on the interpretation of our results in the framework of a strongly magnetized neutron star.

  3. Broadband Spectral Investigations of Magnetar Bursts

    Energy Technology Data Exchange (ETDEWEB)

    Kırmızıbayrak, Demet; Şaşmaz Muş, Sinem; Kaneko, Yuki; Göğüş, Ersin, E-mail: demetk@sabanciuniv.edu [Faculty of Engineering and Natural Sciences, Sabancı University, Orhanlı Tuzla, Istanbul 34956 (Turkey)

    2017-09-01

    We present our broadband (2–250 keV) time-averaged spectral analysis of 388 bursts from SGR J1550−5418, SGR 1900+14, and SGR 1806−20 detected with the Rossi X-ray Timing Explorer ( RXTE ) here and as a database in a companion web-catalog. We find that two blackbody functions (BB+BB), the sum of two modified blackbody functions (LB+LB), the sum of a blackbody function and a power-law function (BB+PO), and a power law with a high-energy exponential cutoff (COMPT) all provide acceptable fits at similar levels. We performed numerical simulations to constrain the best fitting model for each burst spectrum and found that 67.6% of burst spectra with well-constrained parameters are better described by the Comptonized model. We also found that 64.7% of these burst spectra are better described with the LB+LB model, which is employed in the spectral analysis of a soft gamma repeater (SGR) for the first time here, than with the BB+BB and BB+PO models. We found a significant positive lower bound trend on photon index, suggesting a decreasing upper bound on hardness, with respect to total flux and fluence. We compare this result with bursts observed from SGR and AXP (anomalous X-ray pulsar) sources and suggest that the relationship is a distinctive characteristic between the two. We confirm a significant anticorrelation between burst emission area and blackbody temperature, and find that it varies between the hot and cool blackbody temperatures differently than previously discussed. We expand on the interpretation of our results in the framework of a strongly magnetized neutron star.

  4. The origin of behavioral bursts in decision-making circuitry.

    Directory of Open Access Journals (Sweden)

    Amanda Sorribes

    2011-06-01

    Full Text Available From ants to humans, the timing of many animal behaviors comes in bursts of activity separated by long periods of inactivity. Recently, mathematical modeling has shown that simple algorithms of priority-driven behavioral choice can result in bursty behavior. To experimentally test this link between decision-making circuitry and bursty dynamics, we have turned to Drosophila melanogaster. We have found that the statistics of intervals between activity periods in endogenous activity-rest switches of wild-type Drosophila are very well described by the Weibull distribution, a common distribution of bursty dynamics in complex systems. The bursty dynamics of wild-type Drosophila walking activity are shown to be determined by this inter-event distribution alone and not by memory effects, thus resembling human dynamics. Further, using mutant flies that disrupt dopaminergic signaling or the mushroom body, circuitry implicated in decision-making, we show that the degree of behavioral burstiness can be modified. These results are thus consistent with the proposed link between decision-making circuitry and bursty dynamics, and highlight the importance of using simple experimental systems to test general theoretical models of behavior. The findings further suggest that analysis of bursts could prove useful for the study and evaluation of decision-making circuitry.

  5. EDGE: explorer of diffuse emission and gamma-ray burst explosions

    NARCIS (Netherlands)

    den Herder, J.W.; Piro, L.; Ohashi, T.; Amati, L.; Atteia, J.; Barthelmy, S.D.; Barbera, M.; Barret, D.; Basso, S.; de Boer, M.; Borgani, S.; Boyarskiy, O.; Branchini, E.; Branduardi-Raymont, G.; Briggs, M.; Brunetti, G.; Budtz-Jorgensenf, C.; Burrows, D.N.; Campana, S.; Caroli, E.; Chincarini, G.; Christensen, F.; Cocchi, M.; Comastri, A.; Corsi, A.; Cotroneo, V.; Conconi, P.; Colasanti, L.; Cusamano, G.; Rosa, A.; Del Santo, M.; Ettori, S.; Ezoe, Y.; Ferrari, L.; Feroci, M.; Finger, M.; Fishman, G.; Fujimoto, R.; Galeazzi, M.; Galli, A.; Gatti, F.; Gehrels, N.; Gendre, B.; Ghirlanda, G.; Ghisellini, G.; Giommi, P.; Girardi, M.; Guzzo, L.; Haardt, F.; Hepburn, I.; Hermsen, W.; Hoevers, H.; Holland, A.; in 't Zand, J.J.M.; Ishisaki, Y.; Kawahara, H.; Kawai, N.; Kaastra, J.; Kippen, M.; de Korte, P.A.J.; Kouveliotou, C.; Kusenko, A.; Labanti, C.; Lieu, R.; Macculi, C.; Makishima, K.; Matt, G.; Mazotta, P.; McCammon, D.; Méndez, M.; Mineo, T.; Mitchell, S.; Mitsuda, K.; Molendi, S.; Moscardini, L.; Mushotzky, R.; Natalucci, L.; Nicastro, F.; O'Brien, P.; Osborne, J.; Paerels, F.; Page, M.; Paltani, S.; Pareschi, G.; Perinati, E.; Perola, C.; Ponman, T.; Rasmussen, A.; Roncarelli, M.; Rosati, P.; Ruchayskiy, O.; Quadrini, E.; Sakurai, I.; Salvaterra, R.; Sasaki, S.; Wijers, R.; et al., [Unknown

    2007-01-01

    How structures of various scales formed and evolved from the early Universe up to present time is a fundamental question of astrophysics. EDGE will trace the cosmic history of the baryons from the early generations of massive stars by Gamma-Ray Burst (GRB) explosions, through the period of galaxy

  6. Analytical model of a burst assembly algorithm for the VBR in the OBS networks

    International Nuclear Information System (INIS)

    Shargabi, M.A.A.; Mellah, H.; Abid, A.

    2008-01-01

    This paper presents a proposed analytical model for the number of bursts aggregated in a period of time in OBS networks. The model considers the case of VBR traffic with two different sending rates, which are SCR and PCR. The model is validated using extensive simulations. Where results from simulations are in total agreement with the results obtained by the proposed model. (author)

  7. INVESTIGATION OF PRIMORDIAL BLACK HOLE BURSTS USING INTERPLANETARY NETWORK GAMMA-RAY BURSTS

    Energy Technology Data Exchange (ETDEWEB)

    Ukwatta, T. N. [Director' s Postdoctoral Fellow, Space and Remote Sensing (ISR-2), Los Alamos National Laboratory, Los Alamos, NM 87545 (United States); Hurley, K. [University of California, Berkeley, Space Sciences Laboratory, 7 Gauss Way, Berkeley, CA 94720-7450 (United States); MacGibbon, J. H. [Department of Physics, University of North Florida, Jacksonville, FL 32224 (United States); Svinkin, D. S.; Aptekar, R. L.; Golenetskii, S. V.; Frederiks, D. D.; Pal' shin, V. D. [Ioffe Physical Technical Institute, St. Petersburg, 194021 (Russian Federation); Goldsten, J. [Applied Physics Laboratory, Johns Hopkins University, Laurel, MD 20723 (United States); Boynton, W. [Department of Planetary Sciences, University of Arizona, Tucson, AZ 85721 (United States); Kozyrev, A. S. [Space Research Institute, 84/32, Profsoyuznaya, Moscow 117997 (Russian Federation); Rau, A.; Kienlin, A. von; Zhang, X. [Max-Planck-Institut für extraterrestrische Physik, Giessenbachstrasse, Postfach 1312, Garching, D-85748 (Germany); Connaughton, V. [University of Alabama in Huntsville, NSSTC, 320 Sparkman Drive, Huntsville, AL 35805 (United States); Yamaoka, K. [Department of Physics and Mathematics, Aoyama Gakuin University, 5-10-1 Fuchinobe, Sagamihara, Kanagawa 229-8558 (Japan); Ohno, M. [Department of Physics, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8526 (Japan); Ohmori, N. [Department of Applied Physics, University of Miyazaki, 1-1 Gakuen kibanadai-nishi, Miyazaki-shi, Miyazaki 889-2192 (Japan); Feroci, M. [INAF/IAPS-Roma, via Fosso del Cavaliere 100, I-00133, Roma (Italy); Frontera, F., E-mail: tilan@lanl.gov [Department of Physics and Earth Science, University of Ferrara, via Saragat 1, I-44122 Ferrara (Italy); and others

    2016-07-20

    The detection of a gamma-ray burst (GRB) in the solar neighborhood would have very important implications for GRB phenomenology. The leading theories for cosmological GRBs would not be able to explain such events. The final bursts of evaporating primordial black holes (PBHs), however, would be a natural explanation for local GRBs. We present a novel technique that can constrain the distance to GRBs using detections from widely separated, non-imaging spacecraft. This method can determine the actual distance to the burst if it is local. We applied this method to constrain distances to a sample of 36 short-duration GRBs detected by the Interplanetary Network (IPN) that show observational properties that are expected from PBH evaporations. These bursts have minimum possible distances in the 10{sup 13}–10{sup 18} cm (7–10{sup 5} au) range, which are consistent with the expected PBH energetics and with a possible origin in the solar neighborhood, although none of the bursts can be unambiguously demonstrated to be local. Assuming that these bursts are real PBH events, we estimate lower limits on the PBH burst evaporation rate in the solar neighborhood.

  8. Bursting Smoke as an Infrared Countermeasure

    OpenAIRE

    Amarjit Singh; P. J. Kamale; S. A. Joshi; L. K. Bankar

    1998-01-01

    This paper describes the experimental setup for the evaluation of bursting smoke for anti-infrared role using SR-5000 spectroradiometer and a source of IR radiation (8-13 micrometer) using cadmium-mercury-telluride (CMI) detector cooled by liquid nitrogen. The particle size and shape of the powders used in the bursting smokes were determined microscopically using Carl Zeiss Jena Neophot- 21. Highest attenuation of 97 -lOO percent was produced for about 12 s using a mixture of bronze fl...

  9. Radon and rock bursts in deep mines

    International Nuclear Information System (INIS)

    Bulashevich, Yu.P.; Utkin, V.I.; Yurkov, A.K.; Nikolaev, V.V.

    1996-01-01

    Variation fields of radon concentration in time to ascertain stress-strain state of the North Ural bauxite mines have been studied. It is shown that dynamic changes in the stress-strain state of the rocks prior to the rock burst bring about variations in radon concentration in the observation wells. Depending on mutual positioning of the observation points and the rock burst epicenter, the above-mentioned variations differ in principle, reduction of radon concentration in the near zone and its increase in the far zone are observed [ru

  10. Spike Bursts from an Excitable Optical System

    Science.gov (United States)

    Rios Leite, Jose R.; Rosero, Edison J.; Barbosa, Wendson A. S.; Tredicce, Jorge R.

    Diode Lasers with double optical feedback are shown to present power drop spikes with statistical distribution controllable by the ratio of the two feedback times. The average time between spikes and the variance within long time series are studied. The system is shown to be excitable and present bursting of spikes created with specific feedback time ratios and strength. A rate equation model, extending the Lang-Kobayashi single feedback for semiconductor lasers proves to match the experimental observations. Potential applications to construct network to mimic neural systems having controlled bursting properties in each unit will be discussed. Brazilian Agency CNPQ.

  11. Glucose- and interleukin-1beta-induced beta-cell apoptosis requires Ca2+ influx and extracellular signal-regulated kinase (ERK) 1/2 activation and is prevented by a sulfonylurea receptor 1/inwardly rectifying K+ channel 6.2 (SUR/Kir6.2) selective potassium channel opener in human islets

    DEFF Research Database (Denmark)

    Maedler, Kathrin; Størling, Joachim; Sturis, Jeppe

    2004-01-01

    Increasing evidence indicates that a progressive decrease in the functional beta-cell mass is the hallmark of both type 1 and type 2 diabetes. The underlying causes, beta-cell apoptosis and impaired secretory function, seem to be partly mediated by macrophage production of interleukin (IL)-1beta ...

  12. Aliasing of the Schumann resonance background signal by sprite-associated Q-bursts

    Science.gov (United States)

    Guha, Anirban; Williams, Earle; Boldi, Robert; Sátori, Gabriella; Nagy, Tamás; Bór, József; Montanyà, Joan; Ortega, Pascal

    2017-12-01

    The Earth's naturally occurring Schumann resonances (SR) are composed of a quasi-continuous background component and a larger-amplitude, short-duration transient component, otherwise called 'Q-burst' (Ogawa et al., 1967). Sprites in the mesosphere are also known to accompany the energetic positive ground flashes that launch the Q-bursts (Boccippio et al., 1995). Spectra of the background Schumann Resonances (SR) require a natural stabilization period of ∼10-12 min for the three conspicuous modal parameters to be derived from Lorentzian fitting. Before the spectra are computed and the fitting process is initiated, the raw time series data need to be properly filtered for local cultural noise, narrow band interference as well as for large transients in the form of global Q-bursts. Mushtak and Williams (2009) describe an effective technique called Isolated Lorentzian (I-LOR), in which, the contributions from local cultural and various other noises are minimized to a great extent. An automated technique based on median filtering of time series data has been developed. These special lightning flashes are known to have greater contribution in the ELF range (below 1 kHz) compared to general negative CG strikes (Huang et al., 1999; Cummer et al., 2006). The global distributions of these Q-bursts have been studied by Huang et al. (1999) Rhode Island, USA by wave impedance methods from single station ELF measurements at Rhode Island, USA and from Japan Hobara et al. (2006). The present work aims to demonstrate the effect of Q-bursts on SR background spectra using GPS time-stamped observation of TLEs. It is observed that the Q-bursts selected for the present work do alias the background spectra over a 5-s period, though the amplitudes of these Q-bursts are far below the background threshold of 16 Core Standard Deviation (CSD) so that they do not strongly alias the background spectra of 10-12 min duration. The examination of one exceptional Q-burst shows that appreciable

  13. Na(+)/K(+) pump interacts with the h-current to control bursting activity in central pattern generator neurons of leeches.

    Science.gov (United States)

    Kueh, Daniel; Barnett, William H; Cymbalyuk, Gennady S; Calabrese, Ronald L

    2016-09-02

    The dynamics of different ionic currents shape the bursting activity of neurons and networks that control motor output. Despite being ubiquitous in all animal cells, the contribution of the Na(+)/K(+) pump current to such bursting activity has not been well studied. We used monensin, a Na(+)/H(+) antiporter, to examine the role of the pump on the bursting activity of oscillator heart interneurons in leeches. When we stimulated the pump with monensin, the period of these neurons decreased significantly, an effect that was prevented or reversed when the h-current was blocked by Cs(+). The decreased period could also occur if the pump was inhibited with strophanthidin or K(+)-free saline. Our monensin results were reproduced in model, which explains the pump's contributions to bursting activity based on Na(+) dynamics. Our results indicate that a dynamically oscillating pump current that interacts with the h-current can regulate the bursting activity of neurons and networks.

  14. Circulating Levels of MicroRNA from Children with Newly Diagnosed Type 1 Diabetes and Healthy Controls: Evidence That miR-25 Associates to Residual Beta-Cell Function and Glycaemic Control during Disease Progression

    DEFF Research Database (Denmark)

    Nielsen, Lotte B.; Wang, Cheng; Sorensen, Kaspar

    2012-01-01

    This study aims to identify key miRNAs in circulation, which predict ongoing beta-cell destruction and regeneration in children with newly diagnosed Type 1 Diabetes (T1D). We compared expression level of sera miRNAs from new onset T1D children and age-matched healthy controls and related the miRN...

  15. Studies of the Ala/Val98 polymorphism of the hepatocyte nuclear factor-1alpha gene and the relationship to beta-cell function during an OGTT in glucose-tolerant women with and without previous gestational diabetes mellitus

    DEFF Research Database (Denmark)

    Lauenborg, J; Damm, P; Ek, J

    2004-01-01

    In pregnancies complicated by gestational diabetes mellitus (GDM) an increased demand for insulin is not met due to beta-cell dysfunction. An Ala/Val polymorphism at codon 98 of the hepatocyte nuclear factor-1alpha (HNF-1alpha) gene has been associated with decreased serum insulin and C-peptide r...

  16. Bistability of bursting and silence regimes in a model of a leech heart interneuron

    Science.gov (United States)

    Malashchenko, Tatiana; Shilnikov, Andrey; Cymbalyuk, Gennady

    2011-10