48 research outputs found

    Deregulation of CREB Signaling Pathway Induced by Chronic Hyperglycemia Downregulates NeuroD Transcription

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    CREB mediates the transcriptional effects of glucose and incretin hormones in insulin-target cells and insulin-producing β-cells. Although the inhibition of CREB activity is known to decrease the β-cell mass, it is still unknown what factors inversely alter the CREB signaling pathway in β-cells. Here, we show that β-cell dysfunctions occurring in chronic hyperglycemia are not caused by simple inhibition of CREB activity but rather by the persistent activation of CREB due to decreases in protein phophatase PP2A. When freshly isolated rat pancreatic islets were chronically exposed to 25 mM (high) glucose, the PP2A activity was reduced with a concomitant increase in active pCREB. Brief challenges with 15 mM glucose or 30 µM forskolin after 2 hour fasting further increased the level of pCREB and consequently induced the persistent expression of ICER. The excessively produced ICER was sufficient to repress the transcription of NeuroD, insulin, and SUR1 genes. In contrast, when islets were grown in 5 mM (low) glucose, CREB was transiently activated in response to glucose or forskolin stimuli. Thus, ICER expression was transient and insufficient to repress those target genes. Importantly, overexpression of PP2A reversed the adverse effects of chronic hyperglycemia and successfully restored the transient activation of CREB and ICER. Conversely, depletion of PP2A with siRNA was sufficient to disrupt the negative feedback regulation of CREB and induce hyperglycemic phenotypes even under low glucose conditions. Our findings suggest that the failure of the negative feedback regulation of CREB is the primary cause for β-cell dysfunctions under conditions of pathogenic hyperglycemia, and PP2A can be a novel target for future therapies aiming to protect β-cells mass in the late transitional phase of non-insulin dependent type 2 diabetes (NIDDM)

    Flame/Wall interactions: laminar study of unburnt HC formation

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    International audienceThis work presents a numerical study dedicated to the formation of unburnt hydrocarbon. Two configurations: head-on quenching (HOQ) on a planar wall and in crevices, are considered. It is well known that they contribute for an important part to the sources of hydrocarbon (HC) emission in a combustion chamber. The aim of this work is to use laminar flame simulations (LFS) to understand how the unburnt HC are produced near walls in gasoline engine. A skeletal mechanism (29 species and 48 reactions) mimicking iso-octane combustion is used. In the HOQ configuration, the flame front propagates toward the cold wall where quenching occurs. The numerical procedure and the chemical scheme used in this study are first validated by comparisons with literature results for the 1D case. Several aspects of flame wall quenching such as oxidation of unburnt HC, wall heat flux, quench distances as well as HC families are investigated by varying parameters like wall temperature and equivalence ratio. In a second part, crevices are considered to study the impact of wall imperfections in combustion chambers. Configurations with different geometrical and thermodynamic properties are tested. It leads to a wide range of flame properties and HC production modes. When incomplete combustion occurs, total HC (fuel + HC) concentration can reach very high levels at the wall. When the crevice is not wide enough, the flame cannot propagate and the quantity of HC is smaller than in the case where the flame can propagate (but the fuel is not oxidizing). If the crevice is wide enough for the flame to propagate, HOQ occurs at the bottom of the crevice and HC accumulate in the corners. The computational results obtained in this work demonstrate the ability of LFS to reproduce incomplete combustion mechanisms that are responsible for a major part of HC production in gasoline engines
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