Many adult diseases, including type 2 diabetes, hypertension and cardiovascular disease, are related to low birth weight. The mechanistic basis of this relationship is not known. To investigate the role of fetal undernutrition, we used a rat model of maternal protein restriction in which dams were fed a diet containing 80 g protein/kg (v. 200 g/kg in the control group) throughout gestation and lactation. Offspring were born smaller than controls and in adulthood developed diabetes, hyperinsulinaemia and tissue insulin resistance. To determine possible mechanisms of fetal programming, circulating levels of several hormones were measured in maternal plasma at gestational days 14, 17 and 21 and fetal plasma at gestational day 21. Several differences were noted at day 14, when glucose concentrations in maternal and feto -placental blood were raised significantly (P¼0·04 and P¼ 0·0001 respectively); insulin levels in the low-protein (LP) dams were raised (P¼0·04), prolactin levels were raised (P¼ 0·047) and progesterone levels were reduced (P¼ 0·02). Circulating 17b-oestradiol in the LP dams was raised by 35 % over those of the controls from day 17 to day 21 (P¼0·008). A significant decrease in maternal leptin levels (P¼ 0·004) was observed at gestation on day 21. Neither oestradiol nor leptin levels were altered in the fetal circulation at day 21. Maternal and fetal corticosterone levels were comparable with control levels, suggesting that they do not initiate the programming effects in this model. Our present results suggest that maternal protein restriction imposes changes in maternal levels of glucose, insulin, prolactin, progesterone, oestradiol and leptin; these changes could influence the programming of eventual adult disease in the developing fetus.

No abstract

The activities of the two key enzymes involved in glutamine metabolism, glutaminase (EC 3.5.1.2) and glutamine synthetase (EC 6.3.1.2), have been measured in the various tissues of the gastrointestinal (GI) tract of the rat, from the mouth to the rectum. Glutaminase activity was particularly high in the mucosa of the small intestine, where its activity accounted for more than 80 % of the total activity of the GI tract. In contrast, the mouth and oesophagus had very low activities, accounting for less than 2 % of the total. Glutamine synthetase was mainly confined to the lower part of the stomach, which accounted for almost 90 % of the total activity of the GI tract. Activity in the small intestine was very low, accounting for less than 2 % of the total, and similarly low levels were found in the mouth and oesophagus. The data provide the most complete information on the distribution of these enzymes in the GI tract of the rat and suggest: (a) that the mucosa of the small intestine has the highest capacity for glutamine breakdown but the lowest capacity for its synthesis, and so requires an external source of this amino acid: (b) that there is little potential for glutamine synthesis or breakdown in the mouth and oesophagus; and (c) that the lower stomach has a substantial capacity to synthesize glutamine, in contrast to the rest of the GI tract. The results of the investigation are relevant to sites of glutamine metabolism in therapeutic studies involving glutamine administration discussed with reference to reports of the effects of glutamine administration on GI tract injury.

1. The activities of the two key enzymes involved in glutamine metabolism, glutaminase and glutamine synthetase, were measured in mucosal biopsies taken from different sites throughout the human gastrointestinal tract, from oesophagus to rectum. 2. The specific activity of glutamine synthetase was highest in the stomach (4.5 nmol glutamine formed per minute per mg of protein), but both small and large intestine and the oesophagus had little synthesizing capacity (less than 0.3 nmol of glutamine formed per minute per mg of protein). 3. Glutaminase specific activity was highest in the small intestine (53 nmol glutamate formed per minute per mg of protein by duodenal mucosa), intermediate in the large intestine and lowest in the oesophagus and stomach (less than 13 nmol of glutamate formed per minute per mg of protein). 4. The glutamine concentration in the mucosa was lower in the duodenum than in the colon (0.62 and 0.95 mmol/kg wet weight respectively), but both were much lower than the measured K(m) values of glutaminases obtained from these sites (3.8 and 4.0 nmol/kg wet weight respectively). 5. The concentration of glutamine in saliva, stomach juice, bile and duodenal juice suggests that very little glutamine passes into the gastrointestinal tract via these secretions. 6. The study provides the most complete information on the distribution of glutamine synthetase and glutaminase along the human gastrointestinal tract, and suggests that (i) both the small and large intestines have a high potential for glutamine metabolism, but little synthesizing capacity, thus both must derive their glutamine from other sources, and (ii) neither the stomach nor the oesophagus have a high glutaminase activity, although the stomach has substantial capacity to synthesize glutamine. The distribution of the enzymes along the gastrointestinal tract may help rationalize the use of glutamine for treating diseases that affect different parts of the gastrointestinal tract.