Focal Adhesion Kinase contributes to insulin-induced actin reorganization into a mesh harboring Glucose transporter-4 in insulin resistant skeletal muscle cells

<p>Abstract</p> <p>Background</p> <p>Focal Adhesion Kinase (FAK) is recently reported to regulate insulin resistance by regulating glucose uptake in C2C12 skeletal muscle cells. However, the underlying mechanism for FAK-mediated glucose transporter-4 translocation (Glut-4), responsible for glucose uptake, remains unknown. Recently actin remodeling was reported to be essential for Glut-4 translocation. Therefore, we investigated whether FAK contributes to insulin-induced actin remodeling and harbor Glut-4 for glucose transport and whether downregulation of FAK affects the remodeling and causes insulin resistance.</p> <p>Results</p> <p>To address the issue we employed two approaches: gain of function by overexpressing FAK and loss of function by siRNA-mediated silencing of FAK. We observed that overexpression of FAK induces actin remodeling in skeletal muscle cells in presence of insulin. Concomitant to this Glut-4 molecules were also observed to be present in the vicinity of remodeled actin, as indicated by the colocalization studies. FAK-mediated actin remodeling resulted into subsequent glucose uptake via PI3K-dependent pathway. On the other hand FAK silencing reduced actin remodeling affecting Glut-4 translocation resulting into insulin resistance.</p> <p>Conclusion</p> <p>The data confirms that FAK regulates glucose uptake through actin reorganization in skeletal muscle. FAK overexpression supports actin remodeling and subsequent glucose uptake in a PI3K dependent manner. Inhibition of FAK prevents insulin-stimulated remodeling of actin filaments resulting into decreased Glut-4 translocation and glucose uptake generating insulin resistance. To our knowledge this is the first study relating FAK, actin remodeling, Glut-4 translocation and glucose uptake and their interrelationship in generating insulin resistance.</p

Subcellular trafficking of the substrate transporters GLUT4 and CD36 in cardiomyocytes

Cardiomyocytes use glucose as well as fatty acids for ATP production. These substrates are transported into the cell by glucose transporter 4 (GLUT4) and the fatty acid transporter CD36. Besides being located at the sarcolemma, GLUT4 and CD36 are stored in intracellular compartments. Raised plasma insulin concentrations and increased cardiac work will stimulate GLUT4 as well as CD36 to translocate to the sarcolemma. As so far studied, signaling pathways that regulate GLUT4 translocation similarly affect CD36 translocation. During the development of insulin resistance and type 2 diabetes, CD36 becomes permanently localized at the sarcolemma, whereas GLUT4 internalizes. This juxtaposed positioning of GLUT4 and CD36 is important for aberrant substrate uptake in the diabetic heart: chronically increased fatty acid uptake at the expense of glucose. To explain the differences in subcellular localization of GLUT4 and CD36 in type 2 diabetes, recent research has focused on the role of proteins involved in trafficking of cargo between subcellular compartments. Several of these proteins appear to be similarly involved in both GLUT4 and CD36 translocation. Others, however, have different roles in either GLUT4 or CD36 translocation. These trafficking components, which are differently involved in GLUT4 or CD36 translocation, may be considered novel targets for the development of therapies to restore the imbalanced substrate utilization that occurs in obesity, insulin resistance and diabetic cardiomyopathy

Factors associated with smoking cessation success in Lebanon

Objective: The objective is to assess factors associated with the success rate of smoking cessation among Lebanese smokers in a smoking cessation center. Methods: A cross-sectional data study, conducted between March 2014 and March 2016 in an outpatient smoking cessation center with 156 enrolled patients. The patient’s nicotine dependence and motivation to quit smoking were evaluated according to the Fagerstrom Test for Nicotine Dependence and Richmond tests respectively. Results: The number of packs smoked per year decreased the odds of smoking cessation success (p=0.004, ORa=0.982, CI 0.97-0.994), while the compliance with the offered treatment increased the odds of success by 7.68 times (p<0.001, ORa=7.68, CI 3.438-17.187). Highly dependent and highly motivated smokers had more success in the quitting process compared to those with a lower dependence and motivation respectively. Conclusion: Our findings showed that many factors can influence smoking cessation, an experience described as difficult, most significantly the number of packs per year and compliance with the smoking cessation treatment. Moreover, although these outcomes are not representative of the entire Lebanese population, we believe that health authorities could utilize these results when implementing upcoming smoking cessations programs. All attempts at cessation should have a goal of reducing the number of packs smoked per year to improve the chances of ceasing into the future