Dapagliflozin stimulates glucagon secretion at high glucose: experiments and mathematical simulations of human A-cells.

Glucagon is one of the main regulators of blood glucose levels and dysfunctional stimulus secretion coupling in pancreatic A-cells is believed to be an important factor during development of diabetes. However, regulation of glucagon secretion is poorly understood. Recently it has been shown that Na(+)/glucose co-transporter (SGLT) inhibitors used for the treatment of diabetes increase glucagon levels in man. Here, we show experimentally that the SGLT2 inhibitor dapagliflozin increases glucagon secretion at high glucose levels both in human and mouse islets, but has little effect at low glucose concentrations. Because glucagon secretion is regulated by electrical activity we developed a mathematical model of A-cell electrical activity based on published data from human A-cells. With operating SGLT2, simulated glucose application leads to cell depolarization and inactivation of the voltage-gated ion channels carrying the action potential, and hence to reduce action potential height. According to our model, inhibition of SGLT2 reduces glucose-induced depolarization via electrical mechanisms. We suggest that blocking SGLTs partly relieves glucose suppression of glucagon secretion by allowing full-scale action potentials to develop. Based on our simulations we propose that SGLT2 is a glucose sensor and actively contributes to regulation of glucagon levels in humans which has clinical implications

Realistic modeling of strongly correlated electron systems: An introduction to the LDA+DMFT approach

The LDA+DMFT approach merges conventional band structure theory in the local density approximation (LDA) with a state-of-the-art many-body technique, the dynamical mean-field theory (DMFT). This new computational scheme has recently become a powerful tool for ab initio investigations of real materials with strong electronic correlations. In this paper an introduction to the basic ideas and the set-up of the LDA+DMFT approach is given. Results for the photoemission spectra of the transition metal oxide La_{1-x}Sr_xTiO_3, obtained by solving the DMFT-equations by quantum Monte-Carlo (QMC) simulations, are presented and are found to be in very good agreement with experiment. The numerically exact DMFT(QMC) solution is compared with results obtained by two approximative solutions, i.e., the iterative perturbation theory and the non-crossing approximation.Comment: 15 pages, 3 figures, SCES-Y2K Conference Proceeding

Oscillations, Intercellular Coupling, and Insulin Secretion in Pancreatic β Cells

Insulin is a potent metabolic regulator that is released by pancreatic beta-cells, which respond to body glucose concentrations. Here the authors explain the physiological basis of insulin release

On the origin of the Almahata-Sitta meteorite and 2008TC3 asteroid

Asteroid 2008TC3 was a Near Earth Asteroid that impacted the Earth on 2008 October 7. Meteorites were produced by the break-up of 2008TC3 in the high atmosphere and at present, about 600 meteorites - called Almahata Sitta - coming from 2008TC3 have been recovered. A mineralogical study of Almahata Sitta fragments shows that the asteroid 2008TC3 was made of meteorites of different types (ureilites, H, L, and E chondrites). Understanding the origin of this body and how it was put together remain a challenge. Here we perform a detailed spectroscopical and dynamical investigation to show that the most likely source region of 2008TC3 is in the inner Main Belt at low inclination (i<8 degrees). We show that asteroids with spectroscopic classes that can be associated with the different meteorite types of Almahata Sitta are present in the region of the Main Belt that includes the Nysa-Polana family and objects of the Background at low inclination. Searching for a possible scenario of formation for 2008TC3, we show that there is little chance that 2008TC3 was formed by low velocity collisions between asteroids of different mineralogies, in the current asteroid belt. It seems more likely that the heterogeneous composition of 2008TC3 was a inherited from a time when the asteroid belt was in a different dynamical state, most likely in the very early Solar System. Because ureilites are fragments of a large, thermally metamorphosed asteroid, this suggests that the phases of collisional erosion (the break-up of the ureilite parent-body) and collisional accretion (the formation of the parent body of 2008TC3) overlapped for some time in the primordial asteroid belt.Comment: 12 pages, 7 figures, accepted to MNRAS (2012 May 1

Inhibitory Effects of Leptin on Pancreatic α-Cell Function

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)OBJECTIVE-Leptin released from adipocytes plays a key role in the control of food intake, energy balance, and glucose homeostasis. In addition to its central action, leptin directly affects pancreatic beta-cells, inhibiting insulin secretion, and, thus, modulating glucose homeostasis. However, despite the importance of glucagon secretion in glucose homeostasis, the role of leptin in a-cell function has not been studied in detail. In the present study, we have investigated this functional interaction. RESEARCH DESIGN AND METHODS-The presence of leptin receptors (ObR) was demonstrated by RT-PCR analysis, Western blot, and immunocytochemistry. Electrical activity was analyzed by patch-clamp and Ca(2+) signals by confocal microscopy. Exocytosis and glucagon secretion were assessed using fluorescence methods and radioimmunoassay, respectively. RESULTS-The expression of several ObR isoforms (a-e) was detected in glucagon-secreting alpha TC1-9 cells. ObRb, the main isoform involved in leptin signaling, was identified at the protein level in alpha TC1-9 cells as well as in mouse and human alpha-cells. The application of leptin (6.25 nmol/l) hyperpolarized the alpha-cell membrane potential, suppressing the electrical activity induced by 0.5 mmol/l glucose. Additionally, leptin inhibited Ca(2+) signaling in alpha TC1-9 cells and in mouse and human alpha-cells within intact islets. A similar result occurred with 0.625 nmol/l leptin. These effects were accompanied by a decrease in glucagon secretion from mouse islets and were counteracted by the phosphatidylinositol 3-kinase inhibitor, wortmannin, suggesting the involvement of this pathway in leptin action. CONCLUSIONS-These results demonstrate that leptin inhibits alpha-cell function, and, thus, these cells are involved in the adipo-insular communication. Diabetes 58:1616-1624, 200958716161624Ministerio de Educacion y Ciencia [BFU2007-67607, PCI2005-A7-0131, BFU2008-01492, SAF2006-07382]Ministerio de Ciencia a InnovacionFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Ministerio de Educacion y Ciencia [BFU2007-67607, PCI2005-A7-0131, BFU2008-01492, SAF2006-07382]FAPESP [2008/53811-8

Active Reaction Sites for Oxygen Reduction in La0.9Sr0.1,MnO3/YSZ Electrodes

Active reaction sites for 02 reduction in La0.~Sr01MnO3 electrode have been characterized by addressing the origin of the cathodic polarization effects on this electrode material. Cathodic polarization (up to - 1.2 V vs. Pt reference electrode} had several effects on O2 reduction kinetics. First, the O2 reduction rate was favorably increased when the perovskite electrode was cathodically polarized. Second, in situ x-ray photoelectron spectroscopy results indicated that the Mn ions are electrochemically reduced and concomitantly the oxygen stoichiometry decreases. Reduction of Mn ions was further demonstrated in the cyclic voltammogram traced under nitrogen atmosphere. Third, hysteresis in cathodic currents was observed in the cyclic voltammograms of the perovskite/YSZ/Pt system, and the hysteresis phenomena were more prominent at higher O~ pressure. We interpreted these findings to mean that the internal and/or external surface oxide vacancies participate in the O2 reduction reaction. However, it has been explained from the Po2-dependent hysteresis phenomena that, even though those surface sites are active in the O2 reduction~ their activity is less than that of the three-phase boundary sites since additional diffusional processes are required for the former sites. Consequently, the three-phase boundary sites are the major reaction sites at lower O2 pressure, which leads to a small hysteresis. However, at higher 02 pressure, the surface sites also participate in the reaction, resulting in a larger hysteresis.Funding for this work was provided by the R&D Management Center for Energy and Resources (Korea). S. M. Oh gratefully acknowledges the financial support from the Alexander yon Humboldt Foundation

Oxygen non-stoichiometry, conductivity and gas sensor response of SnO2 pellets

SnO2 pellets lose a very small amount of oxygen at high temperatures to give, for instance, the stoichiometry SnO1.9989(1) at 1200°C in air. The oxygen deficiency, δ can be preserved at ambient temperature in quenched samples. The level of conductivity, which is n-type, depends on oxygen content, 2-δ and varies by several orders of magnitude; activation energies cover the range 1.1 eV for slow-cooled, fully oxidised samples to 0.52 eV for samples quenched from 1200°C. Quenched samples can be readily and reversibly reoxidised and reduced at temperatures as low as 700°C; at lower temperatures, down to ∼350°C, oxidation and reduction is mainly confined to sample surfaces on short timescales but, nevertheless, is sufficient for the conductivity to change by 1 to 2 orders of magnitude. Quenched, oxygen-deficient samples are also moisture-sensitive whereas fully oxidised samples are not. SnO2 shows similar sensitivity to both CO2 and N2, which is attributed to loss of O2 from the sample surface