PhD Lykke Sylow – University of Copenhagen

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Food, Fitness & Pharma > Scientists > PhD's from UNIK > PhD Lykke Sylow

PhD Lykke Sylow Hansen

Department of Nutrition Exercise and Sports

Affiliated with UNIK project no. 16

Title of thesis: Involvement of Rac1 and the actin cytoskeleton in insulin- and contraction-stimulated intracellular signaling and glucose uptake in mature skeletal muscle

Abstract: Type 2 diabetes (T2D) affects ~10 % of western adults and is associated with poor organ sensitivity to insulin that is secreted following a meal. Insulin resistance, particularly in the liver, fat, and skeletal muscle, is established as an early and key event in the pathogenesis of T2D and contributes to whole body hyperinsulinemia and hyperglycemia. Blood glucose is taken up into skeletal muscle when glucose transporter (GLUT) 4 translocates to the plasma membrane. In cultured muscle cells, GLUT4 translocation depends on activation of the GTPase, Rac1, which when activated stimulates reorganization of the actin cytoskeleton beneath the plasma membrane. This process is essential in cultured muscle cells for insulin-stimulated GLUT4 translocation.

Glucose uptake into skeletal muscle can also occur via insulin-independent mechanisms, such as during muscle contractions. Contraction-stimulated glucose uptake is not affected by insulin resistance, likely because the intracellular events that regulate GLUT4 translocation by insulin and muscle contraction are distinct. In addition, muscle contraction has insulin sensitizing effects, although the underlying mechanisms for this are not well understood. Because of these effects of muscle contraction, activation of glucose uptake by exercise is an important alternative way to maintain whole body glucose homeostasis in insulin resistant states.

Although the insulin- and contraction-stimulated signaling pathways that lead to glucose uptake have been studied extensively, the underlying mechanisms are not well understood. Before this thesis Rac1 was identified as a regulator of insulin-stimulated glucose uptake in cultured muscle cells, but the implications for Rac1 in mature skeletal muscle had not been investigated. Furthermore, the involvement of Rac1 in contraction-stimulated glucose uptake was completely unknown. It was also unknown whether Rac1 could be involved in the pathophysiology of insulin resistance and T2D.

The aim of the current PhD was therefore to investigate the involvement of Rac1 and the actin cytoskeleton in the regulation of insulin- and contraction-stimulated glucose uptake in mature skeletal muscle. Pharmacological inhibitors of Rac1 and the actin cytoskeleton, as well as inducible muscle-specific Rac1 knockout mice were used to test whether Rac1 is necessary for glucose transport in response to insulin and muscle contraction ex vivo as well as in vivo.

In the current PhD, Rac1 was found to be activated by both insulin and muscle contraction in mouse and human skeletal muscle. Most importantly, Rac1 was involved in the regulation of both insulin- and contraction-stimulated glucose uptake. At least for insulin, Rac1 seemed to act via the actin cytoskeleton, since both pharmacological inhibition of Rac1 and actin cytoskeleton depolymerization independently reduced glucose uptake by 30 %, effects that were not additive. We also found that Rac1 signaling was defective in skeletal muscle of insulin resistant obese and T2D human subjects as well as in ob/ob mice. These findings show that Rac1 is a regulator of insulin- and contraction-stimulated glucose uptake in skeletal muscle, and identify a novel mechanism by which skeletal muscle insulin resistance may develop. 

Publications

Lykke Sylow at Pubmed

Links

Lykke Sylow Hansen at LinkedIn