The major finding of the present study is that in overweight Hispanic children a combined maternal and paternal family history of T2DM is associated with higher leptin levels compared with a family history of diabetes in the maternal or paternal side alone. This association was independent of adiposity. No such association was observed for plasma adiponectin levels.
Several studies have shown that a family history of T2DM is associated with higher circulating leptin levels [11
]. Recent data from the Quebec family study suggest that genetic variation at the fat/fat mass and obesity associated (FTO) locus contributes to the aetiology of obesity, insulin resistance and increased plasma leptin levels [23
]. Several polymorphisms in the leptin gene affect the receptor binding activity of the protein [24
] and secretion by adipose tissue. For example, a polymorphism in the promoter region of the human leptin gene has been associated with T2DM or impaired glucose metabolism [25
]. This polymorphism increases leptin protein expression and secretion [26
]. Another polymorphism, located in an exonic region of the leptin gene, has been associated with glucose homeostasis in response to exercise [27
] and circulating leptin levels [28
]. However, the association between the polymorphism and leptin levels was not consistent in different studies [29
]. The association with a combined maternal and paternal family history of T2DM supports the hypothesis of a hereditary link between leptin and diabetes risk.
Other mechanisms explaining the association with a family history of diabetes could be related to epigenetic effects that are associated with both family history of T2DM and leptin [31
]. Fetal programming by maternal diabetes is unlikely to be the cause of the association, because all results were adjusted for gestational diabetes.
Hormonal changes during puberty result in gender-specific differences in levels of leptin levels; oestrogen is known to stimulate and testosterone to suppress leptin secretion [32
]. Jansson et al.
have shown that leptin levels were only higher in male subjects with a family history of diabetes, but not in female subjects, suggesting a pronounced gender difference in the association between family history of diabetes and leptin levels [11
]. In our study, however, no significant interaction was observed between gender and family history of T2DM, suggesting that gender differences in leptin levels did not affect the association between family history and leptin.
In the present study, a combined maternal and paternal history of T2DM was associated with leptin independent of the adjustment for adiposity. In analyses additionally adjusted for adiposity, the association was stronger in participants of Tanner stage 1 than in those in other Tanner stages. This observation suggests that with progress of puberty other adiposity-related changes outweigh the association between family history of T2DM and leptin. In contrast, studies in adults suggest that a family history of T2DM is associated with higher concentrations of circulating leptin [11
] independent of adiposity.
Several studies have also suggested an association between a family history of T2DM and adiponectin levels resulting in lower adiponectin levels in adult offspring of diabetic patients compared with control subjects [14
]. Several polymorphisms in the adiponectin gene have been associated with an increased risk of diabetes. In the present study, we did not observe any cumulative association between maternal and paternal family history of T2DM and adiponectin levels as observed for leptin. However, in the present study only subjects with a family history of diabetes were included, and no comparison between presence and absence of family history could be made.
The present study is limited by its cross-sectional design. Therefore, we could not address the association of leptin and adiponectin with the combined maternal and paternal family history of diabetes on longitudinal changes in adiponectin and leptin that may occur during puberty. We have recently shown in a longitudinal study of the same cohort that the association between a maternal family history of T2DM and insulin dynamics becomes more pronounced during growth [33
]. Longitudinal studies on the association between family history and leptin and adiponectin levels during growth will be necessary to demonstrate whether this is similar for leptin and adiponectin.
In conclusion, a combination of a maternal and paternal family history of T2DM is associated with higher leptin levels independent of adiposity and SI in overweight Latino children compared with a maternal or paternal family history alone. No such association was observed for adiponectin.