Gestational Diabetes 1979: Philosophical and Practical Aspects of a Major Public Health Problem

At a Ciba Symposium in March 1978, it was suggested that pregnancy may be viewed as a "tissue culture experience. " The analogy was based on the proposition that pregnancy is concerned primarily with new cells that are developing in an incubation medium of variable composition. This formulation assigns to the mother the role of an incubator and a supplier of incubation medium; it highlights that the success of the whole project depends on the extent to which optimum tissue culture conditions have been established. In many ways the formulation provides a philosophical basis for consideration of gestational diabetes. Within the "tissue culture" framework, the incubation medium originates from maternal fuels such as glucose, amino acids, and certain lipids (e.g., ketones and some fatty acids), which are made accessible by transplacental transfer" (Figure 1). Thus, maternal metabolism determines the mixture of nutrients to which the new cells are exposed as they proliferate and differentiate. Additional rate-limiting determinants may contribute, such as placental blood flow, placental transfer, biotransformations within the placenta or fetus," and even "genetic factors. " However, in view of the rather close parallelisms between the circulating levels of a number of metabolites in mother and fetus, what is happening in the mother may serve as a window upon what is available for the cultured tissue. Certain aspects deserve particular emphasis. First, the role of maternal insulin in determining the nutrient mix cannot be underestimated. Sluggish acute secretion in response to meals cause delayed disposition of the ingested nutrients ("underutilization"); inadequate basal release in the fasted state may result in increased generation of fuels from endogenous maternal stores ("overproduction"). In both instances, nutrients will persist in the maternal circulation in greater amounts and for longer periods of time; consequently, more will ultimately reach the fetus, since many nutrients cross the placenta in a concentrationdependent fashion (Figure 1). Thus, maternal insulin may be the ultimate arbiter of the quantitative characteristics of the incubation medium, and the excursions in the plasma concentrations of individual components may be greater during maternal insulinopenia than in any other situation. Second, maternal insulin may also influence the qualitative aspects. For example, the mother's insulin critically affects the generation of endogenous fuels such as ketones (which also seem to cross the placenta according to maternal blood levels)" (Figure 1). In the fetus, as in the adult, ketones can supplant other fuels for oxidative fulfillment. " Although such "sparing" actions by ketones may be physiologically desirable for fuel economy in mature cells, the possible biochemical implications during organogenesis and new cell formation in utero' remain to be clarified. Third, the effects of interrelationships between developing fetal tissues must be considered. For example, maternal insulin does not cross the placenta'' (Figure 1), whereas the formation and function of B-cells in the fetal pancreas may be influenced by the abundance of nutrient secretagogues in the fetal circulation. Thus, an increased delivery of nutrients from the mother will not only cause more insulin to be released by the fetus, but the "extra" fetal insulin will also enable more maternal nutrients to be retained by insulin-responsive tissues within the fetus. ~ (The positive feedback has prompted efforts to use neonatal insulin secretion as a retrospective indicator of the maternal fuels to which all the fetal cells were exposed in utero.) Finally, this relationship between nutrients in the fetus and the development of fetal B-cells underscores perhaps the most important aspect of the tissue culture formulation, i.e., the fact that all the cells that are newly forming in utero do not have equal capabilities for replication. ' Cells in tissues such as the gastrointestinal tract, liver, kidney, skin, or blood cells may be renewed throughout the lifetime of the host (Figure 2). Other cells, such as brain cells, adipocytes, muscle cells, and perhaps even the B-cells of the pancreas have more limited replicative potential; their renewal may be confined to finite intervals (of which intrauterine life may constitute a meaningful proportion) (Figure 2). The consequences of altered maternal metabolism may be different for the two types of cells. In the case of the freely renewing cells, neither deprivation nor plethora of key nutri-