Adriëtte Oostvogels

5 123 Family history of diabetes and childhood outcomes Introduction Family history of diabetes (FHD) reflects a combination of genetic susceptibility and shared environmental and behavioural factors. 1 Environmental and behavioural factors are modifiable factors that can possibly decrease future disease risk of diabetes. Persons with FHD are often more aware of their future disease risk and more motivated to adhere to a healthy lifestyle. 2 Therefore, FHD could possibly be used as a public health tool to identify children at risk of developing diabetes in later life and preventing the development of the disease by lifestyle modification. 1 First-degree relatives of patients with diabetes are at an increased risk of developing the disease themselves, 3-7 and even if they are non-diabetic, their body composition and metabolic parameters are increased compared to people with no FHD. 4,8-15 Not only first-degree relatives are at increased risk, also second-degree relatives are at a twofold increased risk of developing diabetes or have adverse metabolic outcomes themselves. 14,16-21 Most studies investigating the influence of FHD in second-degree relatives are performed in young teens, and already found differences in body composition and glucose metabolism between children with and without FHD. 17-19 This raises the question whether these differences are already present in preschool aged children. Moreover, some previous studies had small study samples and/or only included overweight or obese children, 17,19-21 which hampers generalizability to the general population . Most of the studies described above did not distinguish between maternal or paternal line of FHD. Maternal FHD could have more influence on outcomes than paternal FHD, if mothers, as first-degree relatives of patients with diabetes, have a more adverse metabolism, to which the children are exposed in utero. 4,8-15 Children with maternal FHD could also inherit their mother’s mitochondrial DNA, containing possible pathogenic mutations deregulating glucose metabolism. 22-24 Two studies in children with overweight confirm the hypothesis that maternal FHD has a stronger influence than paternal FHD in second-degree relatives: children with maternal FHD had a greater decline in insulin sensitivity over time, a markedly increased glucose tolerance and significantly greater elevations in insulin levels. 19,20 This association warrants further investigation to elucidate whether this also holds in the general population. This study extends previous studies by studying the effects of FHD in second-degree relatives of maternal, paternal and both maternal and paternal second-degree FHD separately. Moreover, we study the effect of second-degree FHD on body composition and glucose metabolism at a younger age than in most previous studies and in a