Exercise as an intervention to improve metabolic outcomes after 1 intrauterine growth restriction 2 3

37 Individuals born after intrauterine growth restriction (IUGR) are at an increased risk of 38 developing diabetes in their adult life. IUGR impairs β-cell function and reduces β-cell mass 39 thereby diminishing insulin secretion. IUGR also induces insulin resistance, with impaired 40 insulin signaling in muscle in adult humans who were small for gestational age (SGA) and in 41 rodent models of IUGR. There is epidemiological evidence in humans that exercise in adults 42 can reduce the risk of metabolic disease following IUGR. However, it is not clear whether 43 adult IUGR individuals benefit to the same extent from exercise as do normal birth weight 44 individuals, as our rat studies suggest less of a benefit in those born IUGR. Importantly, 45 however, there is some evidence from studies in rats that exercise in early life might be able 46 to reverse or reprogram the long-term metabolic effects of IUGR. Studies are needed to 47 address gaps in current knowledge, including determining the mechanisms involved in the 48 reprogramming effects of early exercise in rats, whether exercise early in life or in adulthood 49 has similar beneficial metabolic effects in larger animal models in which insulin resistance 50 develops after IUGR. Human studies are also needed to determine whether exercise training 51 improves insulin secretion and insulin sensitivity to the same extent in IUGR adults as in as 52 control populations. Such investigations will have implications for customising the 53 recommended level and timing of exercise to improve metabolic health after IUGR. 54 Gatford et al Exercise in those born after IUGR