The sensitisation of insulin action in response to a meal (i.e. meal-induced insulin sensitisation, MIS) represents one of the major means of increased glucose disposal in peripheral tissues during the postprandial state. MIS occurs when the release of hepatic insulin-sensitising substance (HISS) stimulates skeletal muscle glucose uptake. Our previous study had demonstrated that the HISS pathway is impaired in age-associated insulin resistance, and in the rats which were part of that study, voluntary exercise improved the response to insulin by restoring HISS action. The present study tests the hypothesis that voluntary exercise would reverse insulin resistance in diet-induced models of insulin resistance, and that the benefits are attributed through the improvement in HISS action. In this study, two experimental diets, a high-fat diet (for 4 weeks) and 35 % sucrose solution (for 9 and 16 weeks), were used to induce insulin resistance in rats. These rats were assigned to the exercise/no-exercise intervention. The effect of 7 d voluntary running-wheel exercise was determined by measuring insulin- and HISS action in the exercised rats and comparing them with the non-exercised controls. Voluntary exercise reversed insulin resistance, caused by dietary manipulation, through restoration of the HISS action. The direct insulin action was not changed by either diet or exercise. The metabolic improvements and reduced adiposity correlated with the extent of reversal of HISS action induced by exercise. Exercise improves insulin sensitivity in diet-induced insulin resistance primarily by restoration of HISS-mediated glucose uptake.