There is growing interest in low-carbohydrate, high-fat (LCHF) diets (~50 g/day of carbohydrate) for their potential to improve insulin resistance and type 2 diabetes (T2D) (Bueno et al., 2013; Feinman et al., 2015; Hallberg et al., 2019). Within athletic populations, an increasing number of individuals are experimenting with LCHF diets because of body composition and/or to improve fat oxidation (Gregory et al., 2017; Michalczyk et al., 2018; Volek et al., 2016; Webster et al., 2016). However, LCHF diets are partly controversial because many commonly eaten LCHF foods have been implicated in heart disease, obesity, and T2D (Ludwig et al., 2018). A few days of consuming the LCHF diet can increase postprandial blood glucose concentrations in healthy individuals and reduce the capacity of skeletal muscle to oxidize a carbohydrate load, suggesting a typical state of poor glucose clearance rates synonymous with tissue insulin resistance (Bisschop et al., 2001; Himsworth, 1934, 1940; Numao et al., 2012). Although Himsworth (1934) showed that the LCHF diet causes reduced blood glucose clearance in healthy untrained men, the molecular mechanisms have yet to be established. Insulin receptor substrate 1 (IRS1) and glucose transporter 4 (GLUT4) are key proteins in the insulin signaling pathway of skeletal muscle. The binding of insulin to the insulin receptor results in IRS1 phosphorylation, which initiates a signaling cascade and GLUT4 translocation to the membrane and the rapid uptake of glucose (Copps & White, 2012). During a bout of exercise, however, GLUT4 translocation and its upregulation are regulated via the Ca2+-calmodulin kinase pathways, independent of insulin (Holloszy, 2011; Richter & Hargreaves, 2013). Impairments in the insulin signaling pathways are associated with insulin resistance and impaired glucose tolerance. The insulin signaling pathway has yet to be investigated after chronic carbohydrate restriction in healthy, well-trained individuals. The aim of this study was, therefore, to compare glucose tolerance, muscle GLUT4 and IRS1 content, and key enzyme activities representative of major energy pathways, in well-trained cyclists who had followed either a long-term LCHF or a mixed-macronutrient diet (Mixed). We hypothesized that the LCHF group would have lower glucose tolerance, lower GLUT4 and IRS1 content, and higher fat oxidation enzyme activities.
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