Early malnutrition and programming of adult degenerative diseases: experimental, epidemiological and preventive studies

To understand the mechanisms responsible for the reduced ?-cell mass observed in early life in the offspring of mother fed on a protein restricted diet (PR, 8% instead of 20% during the entire pregnancy and until weaning). Maternal PR that also reduces the  cell mass, was associated with a normal glucocorticoid level but with alteration in the plasma amino acid levels. PR altered islet endocrine pancreas development by decreasing the cell multiplication and islet vascularisation, and increasing the "programmed cell death" or apoptosis. It also rendered the  cell more prone to be destroyed by toxic aggression like those playing a role in the pathogenesis of type 1 diabetes. This remained at adulthood even if a normal diet was given from weaning.

1. To investigate whether similar alterations in the programming of ?-cell development also occur in human foetuses born with IUGR and characterise the cellular mechanisms involved: differentiation, proliferation and apoptosis. 2. To examine the role of glucocorticoids on human pancreas development by studying the expression of the receptor. Two workpackages (WP6 and 7) aimed at favour the extrapolation of the results obtained in animal models to human. As mentioned in last year's report, a new strategy has been designed to verify if glucocorticoids and their receptor may be involved in human pancreas development as we have reported in rats (WP6). The studies over the past year were to gather a collection of human foetal pancreatic specimens from very early (9 weeks) until late stages of pregnancy. We showed an expression of the glucocorticoid receptor at very early stages of development, in several cell types, the expression following that of the transcription factor in the beta cell. This is consistent with a possible role for the glucocorticoid during human pancreas development

To understand the nutritional and mechanistic basis of the alterations of ?-cell development observed after maternal food restriction in rat (50% of ad libitum intake during the last week of pregnancy until the end of lactation and ad libitum feeding from weaning onwards). In the GFR model, the low beta cell mass appears to result from defective neogenesis of islets from precursor cells rather than to lower islet cell proliferation. We demonstrated a high glucocorticoid plasma level that alters the generation of pancreatic endocrine cells and favours the development of the exocrine component of the pancreas. This was revealed by changes in the expression of genes specifically involved in the pancreatic development. We suspected that the action of glucocorticoids was linked to binding of the glucocorticoid receptor to a region of the promoter of a gene which codes for the most important transcription factor governing the development of the  cells, i.e. Pdx-1. Contrary to what was found in case of Protein Restriction (WP2), the plasma and islet amino acids level were almost normal.

1. To investigate whether taurine supplementation also restores ?-cell mass dynamics to normal values, if it prevents the alterations of islet and brain vascularisation and the dysfunctions observed in the peripheral tissues of protein-restricted animals. 2. To understand the mechanisms by which taurine would restore the ? cell mass to normal. This last Workpackage consisted in finding new perspectives of prevention. We have highlighted the importance to have adequate taurine plasma levels to avoid abnormal development of the endocrine pancreas and its lasting consequences, since most of the alterations induced by the maternal PR diet were restored by the simple supplementation of the PR diet of the mother with taurine. We also showed that reduced neonatal pancreas vascularisation was restored by taurine and this year the same effect was observed on the adult brain blood vessels. This year we have performed DNA micro-arrays analysis, which has revealed that maternal PR diet modulated (up or down) 12 % of the 15.000 genes expressed in the foetal islets and that taurine supplementation restored 90 % of these altered genes.

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