Current understanding of increased insulin sensitivity after exercise - emerging candidates.

Exercise counteracts insulin resistance and improves glucose homeostasis in many ways. Apart from increasing muscle glucose uptake quickly, exercise also clearly increases muscle insulin sensitivity in the post-exercise period. This review will focus on the mechanisms responsible for this increased insulin sensitivity. It is believed that increased sarcolemmal content of the glucose transporter GLUT4 can explain the phenomenon to some extent. Surprisingly no improvement in the proximal insulin signalling pathway is observed at the level of the insulin receptor, IRS1, PI3K or Akt. Recently more distal signalling component in the insulin signalling pathway such as aPKC, Rac1, TBC1D4 and TBC1D1 have been described. These are all affected by both insulin and exercise which means that they are likely converging points in promoting GLUT4 translocation and therefore possible candidates for regulating insulin sensitivity after exercise. Whereas TBC1D1 does not appear to regulate insulin sensitivity after exercise, correlative evidence in contrast suggests TBC1D4 to be a relevant candidate. Little is known about aPKC and Rac1 in relation to insulin sensitivity after exercise. Besides mechanisms involved in signalling to GLUT4 translocation, factors influencing the trans-sarcolemmal glucose concentration gradient might also be important. With regard to the interstitial glucose concentration microvascular perfusion is particular relevant as correlative evidence supports a connection between insulin sensitivity and microvascular perfusion. Thus, there are new candidates at several levels which collectively might explain the phenomenon.

Potential role of TBC1D4 in enhanced post-exercise insulin action in human skeletal muscle.

AIMS/HYPOTHESIS: TBC1 domain family, member 4 (TBC1D4; also known as AS160) is a cellular signalling intermediate to glucose transport regulated by insulin-dependent and -independent mechanisms. Skeletal muscle insulin sensitivity is increased after acute exercise by an unknown mechanism that does not involve modulation at proximal insulin signalling intermediates. We hypothesised that signalling through TBC1D4 is involved in this effect of exercise as it is a common signalling element for insulin and exercise. METHODS: Insulin-regulated glucose metabolism was evaluated in 12 healthy moderately trained young men 4 h after one-legged exercise at basal and during a euglycaemic-hyperinsulinaemic clamp. Vastus lateralis biopsies were taken before and immediately after the clamp. RESULTS: Insulin stimulation increased glucose uptake in both legs, with greater effects (approximately 80%, p < 0.01) in the previously exercised leg. TBC1D4 phosphorylation, assessed using the phospho-AKT (protein kinase B)substrate antibody and phospho- and site-specific antibodies targeting six phosphorylation sites on TBC1D4, increased at similar degrees to insulin stimulation in the previously exercised and rested legs (p < 0.01). However, TBC1D4 phosphorylation on Ser-318, Ser-341, Ser-588 and Ser-751 was higher in the previously exercised leg, both in the absence and in the presence of insulin (p < 0.01; Ser-588, p = 0.09; observed power = 0.39). 14-3-3 binding capacity for TBC1D4 increased equally (p < 0.01) in both legs during insulin stimulation. CONCLUSION/INTERPRETATION: We provide evidence for site-specific phosphorylation of TBC1D4 in human skeletal muscle in response to physiological hyperinsulinaemia. The data support the idea that TBC1D4 is a nexus for insulin- and exercise-responsive signals that may mediate increased insulin action after exercise.