34 Chapter 2 preterm, especially those small for gestational age, had decreased bone mineral density and were shorter compared to term controls (40, 41). Interestingly, however, others found normal bonemass in 4 year old childrenwhowere born preterm (9). As stated by Stigson and colleagues, osteoblasts as well as adipocytes are derived from the same progenitor cells and the IGF system could be important in directing the differentiation to either adipocytes or osteoblasts (9). It may well be that states with low IGF I levels, such as critical illness, nutrient restriction and extreme prematurity, stimulate differentiation towards adipogenesis as a mechanism to ensure an easily accessible energy store, in this relatively catabolic state, as compared to anabolic states with high IGF I levels where sustainable growth through bone formation might be obtained. Nevertheless the role of IGF I in growth, body composition and development of the metabolic syndrome remains complex. For instance lower IGF I levels in infancy have been associated with higher IGF I levels in later life (22). This suggests that events in early life can program IGF I and possibly metabolic outcomes in later life. However low as well as high IGF I levels in adulthood have been associated with the metabolic syndrome and cardiovascular disease (42). Therefore it is difficult to give a clear-cut view of the role of IGF I alone in growth, body composition and the development of the metabolic syndrome. The role of IGF I in neurodevelopment In clinical studies, brain and cranial growth have been associated with subsequent neurodevelopment (5, 43). A polymorphism in the IGF I promotor gene, which is known to regulate serum IGF I levels, has been related with slower cranial growth from birth until 5 years of age (44). Moreover Hansen-Pupp and colleagues found IGF I levels to correlate with brain volumes while there was no association with cerebral spinal fluid volume. The authors hypothesize that this could imply that IGF I does not limit atrophy secondary to brain damage, but rather stimulates brain growth (45). In premature infants a higher rate of increase of IGF I until 35 weeks postmenstrual age has directly been related to a better neurodevelopmental outcome at 2 years of age (43). In line with that, Okuma and colleagues found that IGF I levels were associated with white matter organization (46). Interestingly, mean IGF I concentration was positively correlated to neurodevelopmental outcome during a period, from 30 to 35 weeks postmenstrual age, when a surge in IGF I levels occurred and infants started growing after a phase of postnatal growth restriction (14, 43). Thismay suggest that IGF I has to reach a certain level before it can enhance neurodevelopmental outcome. Even so, the premature disruption of the maternalplacental-fetal unit alters more neuroendocrine factors than merely IGF I, which also influences the final neurodevelopmental outcome.
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