Pre- and early postnatal nongenetic determinants of type 2 diabetes.
Epidemiological studies have revealed strong and internationally reproducible links between early growth restriction and subsequent risk of developing type 2 diabetes and the metabolic syndrome (glucose intolerance, hypertension and hypertriglyceridaemia). This effect can exist independently of genetic factors. There is also direct evidence that poor maternal nutrition and maternal smoking cause both a reduction in birthweight and subsequent loss of glucose tolerance. High rates of growth in childhood may add to these effects. The 'thrifty phenotype' hypothesis attempts to explain these associations in terms of an altered programming of growth and metabolism that aids survival both pre- and postnatally. Type 2 diabetes is envisaged as a consequence of a clash of this programming with adult obesity. Tests of this hypothesis in animal models have shown that both the metabolic syndrome and type 2 diabetes can result from early growth restriction in rats consequent upon rat dams being fed a reduced protein, isocaloric diet (in which the protein is replaced by an equal quantity of nonprotein energy). A variety of other models of early growth restriction in rats lead to a similar phenotype. Several structural and gene expression changes have been shown in many tissues, including pancreas, liver, kidney, muscle and adipose tissue. Changes in gene expression include those concerned with hormone receptors, signalling and glycolytic enzymes. Many important questions remain for future research.
Department of Clinical Biochemistry, University of Cambridge, Addenbrookes Hospital, Hills Road, Cambridge, CB2 2QR, UK.
Susan E
SE
Ozanne
C Nick
CN
Hales
D000818:Animals; D001724:Birth Weight; D031204:Caloric Restriction; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000209:etiology* / Q000378:metabolism*; D005260:Female; D005317:Fetal Growth Retardation; D018149:Glucose Intolerance / Q000378:metabolism; D006128:Growth; D006801:Humans; D039382:Maternal Nutritional Physiological Phenomena; D024821:Metabolic Syndrome / Q000453:epidemiology / Q000209:etiology / Q000378:metabolism*; D009765:Obesity; D012307:Risk Factors; D012907:Smoking