Role of AMPK in Regulating Muscle Insulin Sensitivity

Publikation: Bog/antologi/afhandling/rapportPh.d.-afhandlingForskning

The ability of insulin to stimulate skeletal muscle glucose uptake is instrumental for controlling whole-body glucose homeostasis. Decreased peripheral sensitivity to insulin increases the risk of developing type 2 diabetes. Insulin sensitivity can be defined as the concentration of insulin that induces a half-maximal biological response (e.g., glucose uptake). Accordingly, the concentration of insulin that induces half-maximal glucose uptake is reduced with increased insulin sensitivity.
Skeletal muscle from both healthy and type 2 diabetic individuals display enhanced muscle insulin sensitivity in a prolonged period after a single bout of exercise. This phenomenon is associated with enhanced recruitment of GLUT4 to the cell surface membrane and is part of a mechanism ensuring replenishment of cellular energy-fuel stores after exercise. AMP-activated protein kinase (AMPK)
is activated in skeletal muscle in response to exercise and contraction. It is considered an important sensor of cellular energy-fuel status and fulfills the purpose of regulating energy-fuel homeostasis. Based on this, the aim of the present PhD was to investigate the involvement of AMPK in regulating insulin sensitivity following acute exercise in healthy and insulin resistant skeletal
muscle. This has been addressed in three studies that consist of various experimental procedures ranging from in vivo experiments in healthy obese and type 2 diabetic subjects to in situ and ex vivo experiments in AMPK-deficient mouse models.
Results obtained during this PhD support a role of AMPK in regulating muscle insulin sensitivity, which may occur through phosphorylation of the downstream target TBC1D4. We find that prior AICAR treatment (pharmacological AMPK activator) and in situ contraction enhance mouse muscle insulin sensitivity in an AMPK-dependent manner. This is associated with and positively correlated to an increased phosphorylation of TBC1D4 Thr642 and Ser704, of which Thr642 previously has been shown to be important for insulin-stimulated glucose uptake in skeletal muscle. Furthermore, we find intact regulation of AMPK activity and downstream signaling in skeletal muscle of type 2 diabetic patients in response to exercise. Interestingly, we observe that AMPK activity and phosphorylation of TBC1D4 Ser318, Ser341 and Ser704 are increased 3 hours into exercise recovery - a time point when post-exercise improvements in muscle insulin sensitivity prevail in healthy lean subjects.
In the present thesis, experimental results from the three studies as well as unpublished observations are placed in the context of existing literature in order to provide a general overview of the current understandings within this field of research.
ForlagDepartment of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen
Antal sider222
StatusUdgivet - 2016

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