Current Drug Targets, 2007, 8, 000-000 1 1389-4501/07 $50.00+.00 © 2007 Bentham Science Publishers Ltd. Fetal Determinants of Type 2 Diabetes Brigitte Reusens 1, * , Susan E. Ozanne 2 and Claude Remacle 1 1 Laboratoire de Biologie cellulaire, Institut des Sciences de la Vie, Université catholique de Louvain, 5 place Croix du Sud, 1348, Louvain-la-Neuve, Belgium and 2 Dept. of Clinical Biochemistry, University of Cambridge, Box 232, Level 4, Addenbrookes Hospital, Hills Road, Cambridge, CB2 2QR, UK Abstract: Type 2 diabetes, which has dramatically increased during the last decade normally results from a combination of pancreatic beta cell dysfunction and insulin resistance. One of the most recent factors identified for type 2 diabetes is a sub-optimal fetal and neonatal environment. Numerous human epidemiological studies worldwide have highlighted that a disturbed nutritional environment of the fetus, either poor or too abundant will compromise the health of the offspring by increasing the susceptibility to insulin resistance, to glucose intolerance and to diabetes in later life. In addition to adverse intrauterine events, the detrimental role of catch-up growth and of the mismatch between the prenatal and the postnatal metabolic environment in such pathology is now clear. To understand the mechanisms that are responsible for such pro- gramming and to be able to design prevention strategies, a number of animal models have been created. This manuscript reviews the data from several rodent models in which maternal or neonatal diet has been altered. These include models of maternal under-nutrition and over-nutrition as well as gestational diabetes. In general, abnormal beta cell mass and beta cell dysfunction are present at birth and insulin resistance, glucose intolerance and diabetes appear in adult offspring. Obesity, pregnancy and ageing exaggerate the phenotype and there is some evidence to suggest that the phenotype can be transmitted to a second generation independently of any further environmental modification. Possible underlying mecha- nisms are discussed and evidence for potential early intervention strategies are reported. Key Words: Programming, beta-cell development, insulin secretion, insulin resistance, glucose intolerance, rat. INTRODUCTION Type 2 diabetes and associated conditions such as car- diovas-cular disease and hypertension are major health care issues of the 21 st century. Over 250 million people world- wide currently have type 2 diabetes and it is a continually growing problem in both the developed and developing world. Understanding the major factors that influence sus- ceptibility to the development of type 2 diabetes is therefore an important research issue. The rapid rise in prevalence of type 2 diabetes suggests that the environment must be an important driving factor in this phenomenon. One of the most recent factors identified as increasing risk of type 2 diabetes has been a sub-optimal foetal environment. Type 2 diabetes is generally the result of a combination of pancreatic beta cell dysfunction and insulin resistance. The foetal envi- ronment has been demonstrated to impact on both of these processes. HUMAN STUDIES (a) Poor Foetal Growth It is now over fifteen years since the initial observations by Nick Hales, David Barker and colleagues that suggested that the foetal environment could play a role in determining future risk of type 2 diabetes. These studies on a group of men living in Hertfordshire in the U.K., who at the time of study were sixty-four years of age, demonstrated that those *Address correspondence to this author at the Laboratoire de Biologie cellu- laire, Institut des Sciences de la Vie, Université catholique de Louvain, 5 place Croix du Sud, 1348, Louvain-la-Neuve, Belgium; E-mail: julia.pyne@nottingham.ac.uk men who were smallest at birth were six times more likely to have type 2 diabetes compared to those individuals who were heavier at birth [1]. The relationship was shown to be continuous across the birth weight spectra. Since these initial studies in Hertfordshire there are now over forty other stud- ies that have reproduced these findings in many populations worldwide in multiple ethnic groups [2]. It is therefore widely accepted that the relationship exists, however the mechanistic basis of the relationship remains to be estab- lished. Consequent upon these findings, the Thrifty Phenotype Hypothesis was proposed to provide a conceptual and re- searchframework within which to explore these findings further [3]. Two essential elements of this hypothesis were that poor foetal nutrition, resulting from either poor maternal nutrition or poor delivery of nutrients to the foetus from other causes such as placental dysfunction, would result in structural and functional changes of key organs in a manner beneficial to survival in conditions of poor postnatal nutri- tion. This would include sparing growth of the brain at the expense of other tissues such as the endocrine pancreas, the muscle and the kidneys and programmed changes in metabo- lism enabling the organisms to efficiently store nutrients. It was also proposed that an adequate or excessive nutrition postnatally was a major factor that resulted in these other- wise beneficial adaptations leading to adult diseases such as type 2 diabetes, hypertension and ischaemic heart disease. Some of the strongest evidence to support this foetal pro- gramming hypothesis in humans has come from studies of twins [4; 5] that have shown that in monozygotic twin pairs