Exercise and insulin sensitivity: interaction with intrahepatic triglyceride and hepatokines

Insulin resistance is central to the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM). Intrahepatic triglyceride (IHTG), the primary feature of NAFLD, strongly predicts insulin resistance in the liver and peripheral (skeletal muscle and adipose) tissues. Hepatokines (e.g. fibroblast growth factor 21 (FGF21), leukocyte cell-derived chemotaxin 2 (LECT2), follistatin, selenoprotein P, and fetuin-A) are liver-derived proteins with capacity to exert endocrine effects and may potentially modulate the link between IHTG and peripheral insulin sensitivity/glycaemic control. Exercise is integral to the management of NAFLD and T2DM, with evidence suggesting that high-intensity exercise may provide the greatest benefits. Chapter 4 of this thesis demonstrates that, in individuals without chronic metabolic disease, plasma concentrations of FGF21 and LECT2 are higher, and follistatin lower, in individuals with overweight or obesity compared with normal weight individuals. Furthermore, FGF21 and follistatin are transiently elevated for up to 6 h after acute aerobic exercise (60 min at 60% V̇O2 peak). The response of follistatin to acute moderate-intensity exercise is also present in individuals with impaired glucose regulation (Chapter 5), but the response of FGF21 is abolished. A single bout of low-volume high-intensity interval training has no effect on FGF21, follistatin or fetuin-A in individuals with dysglycaemia (Chapter 5). Chapter 6 demonstrates that six weeks of sprint interval training (SIT) is feasible for men with NAFLD and reduces IHTG despite no change in body weight. Peripheral insulin sensitivity tends to increase after SIT but hepatic insulin sensitivity and circulating hepatokines remain unchanged. Through meta-analyses, Chapter 7 confirms that exercise training reduces IHTG, even in the absence of weight loss. However, the magnitude of this effect is greater when weight loss occurs and benefits increase proportionally. Exercise training improves basal hepatic insulin sensitivity, but evidence in this area is currently limited (Chapter 7). Collectively, the studies in this thesis demonstrate that some hepatokines may be sensitive to acute and chronic changes in energy metabolism. However, further evidence is required before definitive statements can be made. Exercise training, including SIT, has the potential to reduce IHTG in men with NAFLD, even in the absence of weight loss. However, the greatest benefits on IHTG will likely be elicited when exercise training is performed in combination with dietary energy restriction to elicit sustained reduction in body weight.