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The contribution of altered post-transcriptional gene silencing to the development of insulin resistance and type 2 diabetes mellitus so far remains elusive. Here, we demonstrate that expression of microRNA (miR)-143 and 145 is upregulated in the liver of genetic and dietary mouse models of obesity. Induced transgenic overexpression of miR-143, but not miR-145, impairs insulin-stimulated AKT activation and glucose homeostasis. Conversely, mice deficient for the miR-143–145 cluster are protected from the development of obesity-associated insulin resistance. Quantitative-mass-spectrometry-based analysis of hepatic protein expression in miR-143-overexpressing mice revealed miR-143-dependent downregulation of oxysterol-binding-protein-related protein (ORP) 8. Reduced ORP8 expression in cultured liver cells impairs the ability of insulin to induce AKT activation, revealing an ORP8-dependent mechanism of AKT regulation. Our experiments provide direct evidence that dysregulated post-transcriptional gene silencing contributes to the development of obesity-induced insulin resistance, and characterize the miR-143–ORP8 pathway as a potential target for the treatment of obesity-associated diabetes.
In this paper, an approach to propulsion system modelling for hybrid-electric general aviation aircraft is presented. Because the focus is on general aviation aircraft, only combinations of electric motors and reciprocating combustion engines are explored. Gas turbine hybrids will not be considered. The level of the component's models is appropriate for the conceptual design stage. They are simple and adaptable, so that a wide range of designs with morphologically different propulsive system architectures can be quickly compared. Modelling strategies for both mass and efficiency of each part of the propulsion system (engine, motor, battery and propeller) will be presented.