Intrauterine exposure to diabetes conveys risks for type 2 diabetes and obesity: a study of discordant sibships.

Abstract

Intrauterine exposure to diabetes is associated with an excess of diabetes and obesity in the offspring, but the effects of intrauterine exposure are confounded by genetic factors. To determine the role of the intrauterine diabetic environment per se, the prevalence of diabetes and the mean BMI were compared in siblings born before and after their mother was recognized as having diabetes. Nuclear families in which at least one sibling was born before and one after the mother was diagnosed with type 2 diabetes were selected. Consequently, the siblings born before and after differed in their exposure to diabetes in utero. A total of 58 siblings from 19 families in which at least one sibling had diabetes were examined at similar ages (within 3 years). The risk of diabetes was significantly higher in siblings born after the mother developed diabetes than in those born before the mother's diagnosis of diabetes (odds ratio 3.7, P = 0.02). In 52 families, among 183 siblings without diabetes, the mean BMI was 2.6 kg/m 2 higher in offspring of diabetic than in offspring of nondiabetic pregnancies (P = 0.003). In contrast, there were no significant differences in risk of diabetes or BMI between offspring born before and after the father was diagnosed with diabetes. Intrauterine exposure to diabetes per se conveys a high risk for the development of diabetes and obesity in offspring in excess of risk attributable to genetic factors alone. Diabetes 49:2208-2211, 2000 T ype 2 diabetes has strong genetic and environmental risk factors. Previous studies have shown greater transmission of type 2 diabetes to offspring from mothers than from fathers (1-3), and a significantly higher prevalence of diabetes in offspring of women with diabetes during pregnancy than in offspring of nondiabetic and prediabetic women (2). Intrauterine exposure to diabetes is also associated with a higher prevalence of impaired glucose tolerance in adolescence (4) and with an excess of obesity, especially during the first 20 years of life (5-7). Nevertheless, the effects of intrauterine exposure to diabetes may be confounded by genetic factors. For example, women who develop diabetes at an earlier age might carry more diabetes-susceptibility genes than those who develop diabetes later. Hence, they might transmit greater genetic susceptibility to their offspring.The Pima Indians of Arizona have the world's highest incidence and prevalence of type 2 diabetes (8,9). Both genetic and environmental risk factors contribute to the high rate of diabetes in the Pimas. In Pima Indian children aged 5-19 years, the strongest single risk factor for type 2 diabetes was exposure to diabetes in utero (10). To determine the role of intrauterine diabetic environment, which is in addition to genetic transmission of susceptibility, a sibship study was designed to compare the prevalence of type 2 diabetes and the BMI in Pima Indian siblings born before and after their mother was diagnosed with type 2 diabetes. RESEARCH DESIGN AND METHODSData were taken from the longitudinal ...

Association of existing diabetes, gestational diabetes and glycosuria in pregnancy with macrosomia and offspring body mass index, waist and fat mass in later childhood: findings from a prospective pregnancy cohort

“…Studies of siblings among Pima Indians suggest that in that population the association of maternal gestational hyper- glycaemia with later offspring obesity is likely to be explained by specific intrauterine effects in addition to any genetic or behavioural mechanisms [10]. While some mothers in the ALSPAC study did have more than one live birth during the 2-year recruitment period, numbers of siblings within the study sample are too small to undertake within-sibling analyses.…”

“…In studies of Pima Indians, a marked excess in the risk of obesity has been found at all ages from birth to 20 years in offspring born to mothers who had diabetes during their pregnancy compared with the offspring of either mothers who developed diabetes later in their lives or those who never developed diabetes [7][8][9]. In a nuclear family study, also conducted in Pima Indians, obesity was greater among offspring born after the mother had been diagnosed with diabetes than in their sibs born before their mother's diagnosis [10]. These differences were not found in siblings born before and after the father was diagnosed with type 2 diabetes, suggesting that, in a population at high risk of obesity and diabetes, exposure to maternal diabetes in utero has long-term effects on the offspring that are in addition to genetic and shared familial factors.…”

Nutritional developmental epigenomics: immediate and long-lasting effects

“…In a vicious cycle prenatal development in a diabetic milieu favours development of diabetes later in life (11) . Alterations in maternal nutrition may induce long-term metabolic consequences in offspring.…”

Gestational weight gain in relation to offspring body mass index and obesity from infancy through adulthood

“…4 Furthermore, maternal overweight before pregnancy and maternal diabetes are associated with offspring obesity, possibly due to genetic effects, but perhaps also because of the intrauterine environment. [5][6][7][8] This transgenerational association implies that the maternal obesity may, by its effect on the offspring, induce a viscous cycle accelerating the obesity epidemic in successive generations. 7,9,10 Such acceleration has been observed in the stepwise development of the obesity epidemic in Denmark, where the second phase was much steeper than the first phase.…”