Perinatal and intergenerational influences on adult diabetes

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The aim of this project is to determine the effects of restriction of nutrient supply before and after birth on growth and the development of adult onset diabetes. Being born small and its associated neonatal catch-up growth independently predict adult diabetes. Placental restriction is a major cause of reduced nutrition and growth before birth and is implicated in this programming of disease. Our novel findings suggest that placental compromise increases appetite but also impairs milk quality and supply which limits overfeeding and catch-up growth initially, but on weaning, may independently lead to diabetes. We will determine if this is a direct result of poor nutrition and made worse by overfeeding in response to restored nutrition. We hypothesize that placental compromise permanently reduces an individual's metabolic capacity and that the extent of availability of nutrition after birth determines the consequences for insulin action and increased body fat. Manipulations of postnatal nutrition (by cross-fostering) and fat oxidation will be performed, which are pivotal to understanding the roles of catch-up growth and increased food intake in disease onset. We have found that cross-fostering small rat pups at birth onto mothers with normal lactation improves growth during lactation. The proposed studies will establish the cross-fostering effect on the development of diabetes and identify a developmental stage during which nutritional or other manipulations may have beneficial consequences for the health of the breastfeeding small infant. We propose to determine whether adult females, exposed to placental restriction as a fetus, produce offspring that develop diabetes, and establish whether this effect is caused by programming before conception and-or an altered fetal environment. Identification of critical periods after birth, rather than before, would offer a greater likelihood that practical public health interventions can be developed to improve adult health.