High‐intensity Interval Exercise Decreases IP6K1 Muscle Content & Improves Insulin Sensitivity (SI2*) in Pre‐diabetic Individuals

Insulin resistance in skeletal muscle contributes to whole body hyperglycaemia in pre‐diabetic and type 2 diabetic individuals. Insulin‐dependent glucose uptake in skeletal muscle requires the upregulation of the Akt‐AS160 signalling cascade (Bruss et al., 2005; Mackenzie & Elliott, 2014). Muscle contraction increases both insulin‐stimulated glucose uptake (Kramer et al., 2006) and Akt phosphorylation (Deshmukh et al., 2006) in the hours following exercise. Inositol hexakisphosphate kinase‐1 (IP6K1) produces IP7 (Chakraborty et al., 2010), which may inhibit insulin‐stimulated glucose transport in muscle by competing with PIP3 at the PH domain of Akt. Currently, there are no data on IP6K1 content in human skeletal muscle. Here we aimed to investigate the effects of two different types of exercise on insulin sensitivity and IP6K1 muscle content in pre‐diabetic individuals. This work also used an IP6K1 inhibitor (TNP) to investigate the potential role of IP6K1 in insulin signalling in the C2C12 skeletal muscle cell line.Nine pre‐diabetic [47 (3) yr; BMI, 32.0 (2.4); Body Fat, 39.0 (4.4)%; HbA1c 6.1 (0.2)%; fasting blood glucose 6.5 (0.4) mmol/l; HOMAIR 3.7 (0.7)] individuals were recruited to take part in a resting control, a continuous exercise (90% of lactate threshold) and a high‐intensity intermittent exercise trial (HIIE; 6 × 30 sec sprints). Muscle biopsies were taken pre‐ and post each 60‐minute trial. A labeled ([6,6‐2H2]glucose) intravenous glucose tolerance test (IVGTT) was performed immediately after the second muscle sample. The labelled IVGTT allows for the measurement of two‐compartment models of insulin sensitivity (SI2*) and hepatic glucose production (HGP). In an in vitro experiment, C2C12 cells were grown and differentiated under standard conditions before being treated with insulin (100 nM) +/− the IP6K1 inhibitor N2‐(m‐Trifluorobenzyl), N6‐(p‐nitrobenzyl)purine(TNP) (10μM) for 24 hours.Akt308 phosphorylation was significantly increased following HIIE (P = 0.003), with IP6K1 muscle protein content (P = 0.001) and mRNA expression (P = 0.02) reduced for the same exercise trial. Continuous exercise had no effect on either pAkt308 (P = 0.175) or IP6K1 protein content (P = 0.337). There was no effect on protein IP6K1 content following continuous exercise. HIIE also reduced HGP and improved SI2*. In addition, with HIIE, SI2* was significantly greater in the 4 hours after exercise than with continuous exercise. Chemical inhibition of IP6K1 with TNP in vitro increased p/t Akt308 and p/t AS160642 while decreasing IP6K1 in insulin treated myotubes.This work showed that high‐intensity interval exercise reduces muscle IP6K1 in prediabetic individuals, with the same exercise treatment increasing activity of the traditional insulin signaling cascade (Akt‐AS160). These data suggest that high‐intensity interval exercise is more effective than moderate‐intensity continuous exercise at improving glycaemic control acutely in individuals at risk of diabetes. Further, IP6K1 may be linked to reduced muscle responsiveness to insulin.Support or Funding InformationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.