Adriëtte Oostvogels

5 133 Family history of diabetes and childhood outcomes in first-degree relatives found, similar to our study, no differences in T2DM risk in relatives with either a mother or father with diabetes, but having both a mother and father with T2DM increased the risk of diabetes. 4-6,22,30 Underlying mechanisms This study found that children with both maternal and paternal FHD have increased C-peptide levels compared to children with no, maternal or paternal FHD. This might be explained by shared genetic or lifestyle factors. Having these predisposing factors from both sides of the family, could possibly be more detrimental than only from a single side. The higher fat percentage in this group, found before adjusting, could indicate a possible tendency to developing T2DM in future life, as susceptibility of T2DM is a combination of genetic susceptibility and environmental influences related to a person’s health behaviour like decreased physical activity, increased caloric intake and nutrient composition. 33,34 This behaviour causes obesity which in turn causes metabolic inflammation resulting in insulin resistance as beta cells increase the production of insulin until they are no longer capable of maintaining normal glucose tolerance. 33,34 However, the differences found in body composition between the different FHD groups were explained by ethnicity, a proxy for both genetic and lifestyle factors. Ethnicity did not explain the results on C-peptide, even though children with both maternal and paternal FHD had more obesogenic lifestyles compared to the other children. Restricting our analyses to the Dutch children only made the differences in lifestyle factors less pronounced and still similar results were found. Therefore, at least in the Dutch sub- group, it seems more likely that lifestyle factors play a minor role in the development of the increased C-peptide levels found in the group with both maternal and paternal FHD compared to genetics. Heritability of both T1DM and T2DM is high, 35,36 and although children in our cohort are too young to already meet the clinical characteristics of diabetes mellitus themselves, children with both maternal and paternal FHD showed the signs of upcoming insulin resistance. This could have resulted from different sets of diabetogenic genes in children with both maternal and paternal FHD that could have been transmitted from maternal and paternal side, increasing their genetic risk score. 6 On the other hand, in case of recessive genes, transmission of the same set of genes from both parents will probably result in development of the disease. 6 Summarizing, although both parents and children with both maternal and paternal FHD had higher BMIs, indicating T2DM, 33 this could have been the result of our multi-ethnic population. Still, as the increased C-peptide levels, found in both our multi-ethnic study population as well as the Dutch only, are indicative for increased insulin production, 37 these increased C-peptide levels might be indicators of upcoming insulin resistance and the development of T2DM already early in life.