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Recent studies in Europe, North America, and the developing world have shown that low birth weight and other indices of abnormal fetal growth in babies born at term are linked with a higher prevalence of glucose intolerance and NIDDM in adult life. Reduced fetal growth is also associated with a higher prevalence of the metabolic syndrome (in particular, hypertension and vascular disease) and with insulin resistance in adult life. Because birth size is determined largely bv nongenetic factors, these findings have led to the "fetal origins" hypothesis, which proposes that fetal adaptations to an adverse intrauterine environment that reduces fetal growth program lifelong physiological changes. These changes in turn predispose to diabetes and the metabolic syndrome. The mechanisms are unknown, but evidence from animal studies and preliminary human evidence suggests that adverse events in early life may influence the neuroendocrine development of the fetus. This results in long-term alterations in the setpoint of several major hormonal axes, including an increase in adrenal glucocorticoid secretion. These hormonal alterations may contribute to the predisposition to diabetes and the metabolic syndrome in people who were small at birth.
Abbreviations: HP.4A, hypothalamic-pituitary-adrenal axis.
Although NIDDM is by far the most common form of diabetes, its etiology is still poorly understood. Whereas there is general agreement that obesity is important for the development of the disease, it is also clear that obesity leads to diabetes only in susceptible individuals. Relatively little progress has been made in understanding the nature of this susceptibility Observations that the disease clusters in families, together with the results of twin studies that show higher con cor-dance rates for diabetes in identical compared with nonidentical twins, suggest a genetic basis. However, research over the past decade has suggested that developmental factors may also be important determinants of the susceptibility to subsequent diabetes. These studies suggest that diabetes may arise as a result of programming during critical periods. Programming is the term used for persisting changes in structure and function caused by environmental stimuli during critical periods of early development. Gestational diabetes provides an example of programming. The presence of diabetes or glucose intolerance during pregnancy exposes the fetus to an abnormal intrauterine environment. Although the immediate problem for the fetus is macrosomia, it is...