Normal Long-Term Health for Infants of Diabetic Mothers: Can We Achieve It?

Abstract

We are increasingly being made aware of the adverse risks associated with maternal pregestational (type1and type2diabetes) or gestationaldiabetesmellitus (GDM) to the long-term metabolic health of affected offspring (1–5). A key question relates to the extent to which the increased rates of obesity, metabolic syndrome, and type 2 diabetes in these individuals are acquired vs genetically predetermined because the former could be potentially preventable. The Developmental Origins of Health and Disease (DOHaD) hypothesis, supported by considerable research in animals and humans, suggests that acquired susceptibility is a very important component of the total risk for metabolic diseases and that much of this risk is programmed in utero and during early childhood years (6, 7). If this is the case, the objectives of managing diabetes in pregnancy should focus not only on reducing perinatal complications but also on reducing long-term adverse outcomes for offspring. The goal of the 1989 St Vincent Declaration was to approximate the pregnancy outcomes of women with diabetes to those of the background population (8). Unfortunately, despite definite improvements, this still is a long way from being realized for type 1 and type 2 diabetic pregnancies; serious adverse outcomes, including congenital malformations, perinatal mortality, prematurity, and large for gestational age neonates, still occur commonly (9, 10). Continued efforts to reduce these complications in women with pre-existing diabetes is therefore paramount, but this must be accompanied by increased vigilance of longer-term outcomes. For GDM, short-term outcomes with current treatment approaches are quite effective in reducing adverse pregnancy outcomes (11, 12), but quite possibly without the desired beneficial effects on the longterm health of offspring. For example, the standard approach used to treat GDM in the Australian Carbohydrate Intolerance Study (ACHOIS) markedly lowered macrosomia rates but had no effect on the body mass index of the children at 4–5 years of age (11, 13). Future advances in the management of GDM pregnancies, therefore, must move the focus to improving the long-term outcomes of these offspring. An obvious challenge to achieving this is the need for long-term follow-up studies—both difficult to conduct and quite costly. In this issue of the JCEM, new results are presented from one of the few cohort studies of the offspring of diabetic mothers into adulthood. Kelstrup et al (14) report insulin sensitivity and insulin secretion data from a Danish cohort of young adult offspring (mean age, 21–22 y) of mothers who had type 1 diabetes (O-type 1), diet-treated GDM (O-GDM), or risk factors for GDM but with normoglycemia (O-NoGDM), or were from the background population (O-BP). Previously in this cohort, the authors had reported increased occurrence of overweight, metabolic syndrome, glucose intolerance, and type 2 diabetes in the offspring of the diabetic mothers (4, 15). In this new work, the investigators now demonstrate that the glucose intolerance in these affected offspring is due to the combination of impaired insulin secretion and insulin sensitivity (14). They propose that it is the exposure to intrauterine hyperglycemia that causes the subsequent impairments of insulin secretion and insulin sensitivity in the young adults. Considering that the O-type 1 are unlikely to be genetically predisposed to type 2 diabetes, this is highly likely to be causative in this group. Also consistent with this view is the previous finding that the risk of impaired glucose tolerance and type 2 diabetes in the O-