Intrauterine programming of fetal islet gene expression in rats effects of maternal protein restriction during gestation revealed by proteome analysis

Aims/hypothesis. Fetal undernutrition can result in intrauterine growth restriction and increased incidence of Type 2 diabetes mellitus. Intrauterine malnutrition in form of an isocaloric low-protein diet given to female rats throughout gestation decreases islet-cell proliferation, islet size and pancreatic insulin content, while increasing the apoptotic rate and sensitivity to nitrogen oxide and interleukin-1beta. Hence, the influence of a low-protein diet on the development of beta-cells and islets could also be of interest for the pathogenesis of Type 1 and Type 2 diabetes mellitus. We hypothesise that the effects of a low-protein diet in utero are caused by intrauterine programming of beta-cell gene expression. Methods. Pregnant Wistar rats were fed a low-protein diet (8% protein) or a control diet (20% protein) throughout gestation. At day 21.5 of gestation fetal pancreata were removed, digested and cultured for 7 days. Neoformed islets were collected and analysed by proteome analysis comprising 2-dimensional gel electrophoresis and mass spectrometry. Results. A total of 2810 different protein spots were identified, 70 of which were changed due to the low-protein diet. From 45 of the changed protein spots, identification was obtained by mass spectrometry (64% success rate). Proteins induced by the low-protein diet were grouped according to their biological functions, e.g. cell cycle and differentiation, protein synthesis and chaperoning. Conclusions/interpretation. Our study offers a possible explanation of the alterations induced by a low-protein diet in islets. It shows that in Wistar rats the intrauterine milieu could program islet gene expression in ways unfavourable for the future of the progeny. This could be important for our understanding of the development of Type 1 and Type 2 diabetes mellitus.