Key points Patients with renal failure undergoing maintenance haemodialysis are associated with insulin resistance and protein metabolism dysfunction. Novel research suggests that disruption to the transmembrane protein linkage between the cytoskeleton and the extracellular matrix in skeletal muscle may contribute to reduced amino acid metabolism and insulin resistance in haemodialysis. ILK, PINCH1 and pFAKTyr397 were significantly decreased in haemodialysis compared to controls, whereas Rac1 and Akt2 showed no different between groups. Rac1 deletion in the Rac1 knockout model did not alter the expression of integrin‐associated proteins. Phenylalanine kinetics were reduced in the haemodialysis group at 30 and 60 min post meal ingestion compared to controls; both groups showed similar levels of insulin sensitivity and β‐cell function. Key proteins in the integrin–cytoskeleton linkage are reduced in haemodialysis patients, suggesting for the first time that integrin‐associated proteins dysfunction may contribute to reduced phenylalanine flux without affecting insulin resistance in haemodialysis patients. Abstract Muscle atrophy, insulin resistance and reduced muscle phosphoinositide 3‐kinase‐Akt signalling are common characteristics of patients undergoing maintenance haemodialysis (MHD). Disruption to the transmembrane protein linkage between the cytoskeleton and the extracellular matrix in skeletal muscle may contribute to reduced amino acid metabolism and insulin resistance in MHD patients. Eight MHD patients (age: 56 ± 5 years: body mass index: 32 ± 2 kg m–2) and non‐diseased controls (age: 50 ± 2 years: body mass index: 31 ± 1 kg m–2) received primed continuous l‐[ring‐2H5]phenylalanine before consuming a mixed meal. Phenylalanine metabolism was determined using two‐compartment modelling. Muscle biopsies were collected prior to the meal and at 300 min postprandially. In a separate experiment, skeletal muscle tissue from muscle‐specific Rac1 knockout (Rac1 mKO) was harvested to investigate whether Rac1 depletion disrupted the cytoskeleton‐integrin linkage, allowing for cross‐model examination of proteins of interest. ILK, PINCH1 and pFAKTyr397 were significantly lower in MHD (P < 0.01). Rac1 and Akt showed no difference between groups for the human trial. Rac1 deletion in the Rac1 mKO model did not alter the expression of integrin‐associated proteins. Phenylalanine rates of appearance and disappearance, as well as metabolic clearance rates, were lower in the MHD group at 30 and 60 min post meal ingestion compared to controls (P < 0.05). Both groups showed similar levels of insulin sensitivity and β‐cell function. Key proteins in the integrin–cytoskeleton linkage are reduced in MHD patients, suggesting for the first time that integrin‐associated proteins dysfunction may contribute to reduced phenylalanine flux without affecting insulin resistance in haemodialysis patients.

Whole‐body euglycaemia is partly maintained by two cellular processes that encourage glucose uptake in skeletal muscle, the insulin‐ and contraction‐stimulated pathways, with research suggesting convergence between these two processes. The normal structural integrity of the skeletal muscle requires an intact actin cytoskeleton as well as integrin‐associated proteins, and thus those structures are likely fundamental for effective glucose uptake in skeletal muscle. In contrast, excessive extracellular matrix (ECM) remodelling and integrin expression in skeletal muscle may contribute to insulin resistance owing to an increased physical barrier causing reduced nutrient and hormonal flux. This review explores the role of the ECM and the actin cytoskeleton in insulin‐ and contraction‐mediated glucose uptake in skeletal muscle. This is a clinically important area of research given that defects in the structural integrity of the ECM and integrin‐associated proteins may contribute to loss of muscle function and decreased glucose uptake in type 2 diabetes.

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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.