The long-term consequences of intra-uterine protein malnutrition for glucose metabolism

Our initial observations, in epidemiological studies, linking indices of po or early (fetal and infant) growth to the subsequent development of poor gl ucose tolerance and the insulin resistance syndrome in adult life, have bee n confirmed in studies in a wide variety of populations around the world. T hese findings led us 5 years ago to propose the 'thrifty phenotype' hypothe sis. Tests of this hypothesis in an animal model in which the pregnant and/ or lactating rat dams are fed on an isoenergetic diet containing just under half the normal protein content are consistent with the ideas put forward. They have also allowed us to refine the hypothesis in the light of the new data as follows: (1) the growth of the fetus (and possibly infant) is quan titatively and qualitatively altered by its nutritional environment (which may include maternal diet-dependent changes in maternal hormones); (2) thes e changes serve to select between the growth rates of different tissues acc ording to priorities which differ between males and females (nutritional th rift) and to alter organ function to constitute a thrifty offspring adapted to survival in poor nutritional circumstances (thrifty phenotype); (3) an individual so constituted suffers adverse consequences in adult life if he/ she experiences good or supranormal nutrition; (4) both poor insulin secret ion and insulin resistance can result from these adaptive processes; (5) th e adverse consequences include loss of glucose tolerance and hypertension. The precise outcome of growth retardation during early life may vary accord ing to the type and timing of the factors responsible for the retardation. It remains to be determined to what extent these potentially adverse effect s can be delayed or prevented by a suitable postnatal diet. Experiments in animal models are largely consistent with the concepts proposed from human epidemiological studies. They show that the metabolism of the liver, muscle and adipose tissue may be programmed by maternal nutrition during gestatio n and lactation. The combination of early growth restriction and subsequent adult obesity reproduced in the rat are the main features of the insulin r esistance syndrome.