Activation of AMP kinase enhances sensitivity of muscle glucose transport to insulin

Abstract

Evidence has accumulated that activation of AMP kinase (AMPK) mediates the acute increase in glucose transport induced by exercise. As the exercise-induced, insulin-independent increase in glucose transport wears off, it is followed by an increase in muscle insulin sensitivity. The major purpose of this study was to determine whether hypoxia and 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR), which also activate AMPK and stimulate glucose transport, also induce an increase in insulin sensitivity. We found that the increase in glucose transport in response to 30 microU/ml insulin was about twofold greater in rat epitrochlearis muscles that had been made hypoxic or treated with AICAR 3.5 h previously than in untreated control muscles. This increase in insulin sensitivity was similar to that induced by a 2-h bout of swimming or 10 min of in vitro electrically stimulated contractions. Neither phosphatidylinositol 3-kinase activity nor protein kinase B (PKB) phosphorylation in response to 30 microU/ml insulin was enhanced by prior exercise or AICAR treatment that increased insulin sensitivity of glucose transport. Inhibition of protein synthesis by inclusion of cycloheximide in the incubation medium for 3.5 h after exercise did not prevent the increase in insulin sensitivity. Contractions, hypoxia, and treatment with AICAR all caused a two- to three-fold increase in AMPK activity over the resting level. These results provide evidence that the increase in insulin sensitivity of muscle glucose transport that follows exercise is mediated by activation of AMPK and involves a step beyond PKB in the pathway by which insulin stimulates glucose transport.

Direct demonstration of lipid sequestration as a mechanism by which rosiglitazone prevents fatty-acid-induced insulin resistance in the rat: comparison with metformin

“…Given the possibility that AMPK activation may play a role in increasing insulin action [19,20], this provides a possible common link in the protective effects of the two agents in preventing insulin resistance from developing in the liver. A possible mediator of enhanced AMPK activity induced by rosiglitazone is increased plasma adiponectin [10], a potential candidate mechanism for the insulin-sensitising action of TZDs which might act in addition to "lipid steal".…”

“…Its mechanism of action is unclear, but interestingly it was recently shown to enhance activity of AMP-activated protein kinase (AMPK) in isolated muscle and liver cells in vitro [16]. The AMPK pathway and its interactions were recently reviewed [17,18], but it is noteworthy that prior activation of AMPK has been associated with insulin sensitisation in muscle and/or liver [19,20]. However, we are not aware of any studies examining whether or not metformin's anti-hyperglycaemic actions are associated with altered in vivo fatty acid tissue distribution.…”

Role of AMP‐activated protein kinase in the metabolic syndrome and in heart disease

“…Since the insulin-mTOR pathway is thought to exert a feedback effect on insulin signalling via activation of S6 kinase I and consequent phosphorylation and down-regulation of insulin receptor substrate-1 (IRS1) [54][55][56], AMPK activation should increase subsequent insulin sensitivity by inhibiting mTOR. It is possible that this effect explains the ability of AMPK activators to mimic the effect of a single bout of muscle contraction to increase muscle insulin sensitivity [57].…”

Exercise training prevents skeletal muscle plasma membrane cholesterol accumulation, cortical actin filament loss, and insulin resistance in C57BL/6J mice fed a western-style high-fat diet

“…Importantly, this increase in insulin‐stimulated GLUT4 translocation after exercise is not dependent upon elevated muscle total GLUT4 content (Fisher et al. 2002). Notwithstanding, however, with multiple bouts of exercise muscle GLUT4 expression and content does increase and represents a key beneficial adaptation of chronic exercise along with increased capillary density, increased expression of other proteins regulating metabolism, and increased abundance of oxidative muscle fibers(Richter and Hargreaves 2013; Sylow et al.…”