Prolactin

During an oral glucose tolerance test (OGTT) glucose and insulin levels were measured in 26 patients with prolactin-producing pituitary tumours without growth hormone excess. Basal glucose and insulin levels did not differ from the values of an age-matched control group. After glucose load the hyperprolactinaemic patients showed a decrease in glucose tolerance and a hyperinsulinaemia. Bromocriptine (CB 154), which suppressed PRL, improved glucose tolerance and decreased insulin towards normal in a second OGTT. — Human PRL or CB 154 had no significant influence on insulin release due to glucose in the perfused rat pancreas. — These findings suggest a diabetogenic effect of PRL. CB 154 might be a useful drug in improving glucose utilization in hormone-active pituitary tumours

Effects of maternal iron restriction in the rat on blood pressure, glucose tolerance, and serum lipids in the 3-month-old offspring

Epidemiologic studies have demonstrated associations between low birth weight and increased rates of adult diseases such as hypertension and diabetes. Maternal iron restriction in the rat has been reported to both reduce birth weight and to elevate blood pressure at 40 days of age. The aim of the present study was to extend these findings to investigate the effects of maternal iron restriction on glucose tolerance and serum lipids, 2 important components of the metabolic syndrome, in adult offspring. Blood pressure, glucose tolerance, and serum lipids were measured in the 3-month-old offspring of iron-restricted dams. Rats were placed on control or iron-restricted diets 1 week before mating. At term, dams on the iron-restricted diet were anemic with decreased haemoglobin, red blood cell (RBC) count, hematocrit, and mean RBC volume compared with controls. Neonates from iron-restricted litters were more severely anemic than the dams. At birth, body weight was lower in the offspring of iron-restricted dams than in controls and was still decreased at 3 months of age. At this same age, systolic blood pressure was significantly elevated in the offspring of iron-restricted dams. Glucose tolerance was improved in the maternal iron-restricted group. Fasting serum insulin levels were not different between the control and maternal iron-restricted groups. Fasting serum triglyceride was decreased in the offspring of iron-restricted dams compared with controls. Fasting serum cholesterol and free fatty acid concentrations were similar in both groups. These results suggest that maternal iron restriction has long-term effects on physiology and metabolism in the offspring. Some of these findings are comparable to those reported for the maternal protein-restriction model. It is thus speculated that the long-term effects of maternal dietary restriction may result from common fetal metabolic responses to this restriction

The effects of trypsin on ATP-sensitive potassium channel properties and sulfonylurea receptors in the CRI-G1 insulin-secreting cell line

The effects of the proteolytic enzyme trypsin upon ATP-sensitive potassium (KATP) channel activity were examined in the CRI-G1 insulin-secreting cell line. Trypsin activated channels only when applied to the intracellular surface of the cell membrane. The activation could be prevented by the concomitant application of trypsin inhibitor or by heat inactivation of the enzyme. The trypsin-induced change in channel activity was accompanied by a reduction in the rate of channel rundown. However, trypsin did not affect the mean single channel conductance (55.2 pS), the ionic selectivity, or rectification of the KATP channel. Concentration response curves for various KATP channel inhibitors were constructed in the presence and absence of intracellular trypsin. The EC50 for tolbutamide was shifted from 30.0 +/- 4.5 microM, with 100 micrograms/ml heat-inactivated trypsin present to 9.7 +/- 1.0 mM with active trypsin in the intracellular solution. Treatment of the cells' external surface with 1 mg/ml trypsin did not alter the potency of tolbutamide. Intracellular trypsin also produced a significant fall in the potency of glibenclamide, meglitinide, and phentolamine but did not alter the effectiveness of thiopentone. Radioligand binding studies demonstrated a total loss of 3H-labeled glibenclamide binding when the intracellular surface of the cells was exposed to trypsin. In contrast, 3H-labeled glibenclamide binding was not affected when the enzyme was applied to the external surface. Trypsin treatment, therefore, alters a number of characteristics of KATP channel pharmacology, and we suggest that this is due to action at possibly more than one site but includes the functional cleavage of the sulfonylurea receptor from the KATP channel

Effects of maternal iron restriction on placental vascularization in the rat

To investigate the effects of maternal iron deficiency and anaemia on the placenta the composition and vascularization of the placental labyrinth was investigated in iron-restricted rats. Rats in the experimental groups were placed on iron-restricted diets either 1 or 2 weeks before mating and continued on these diets throughout gestation. Placentae were studied at day 21 of gestation. Tissue sections were stained with lectin to allow identification of fetal capillaries and analyzed using stereological techniques. Capillary surface area density and total capillary surface area were decreased in both iron-restricted groups compared with the control group. Capillary length density was decreased in both iron-restricted groups compared with the control group. Total capillary length was significantly reduced in the 1-week, but not in the 2-week, iron-restricted group compared with the control group. Endothelial cell volume was increased in both iron-restricted groups compared to the controls. There were no significant differences in the volume of fetal capillaries, the volume of the maternal blood spaces or the surface area of the maternal–fetal interface between the control and iron-restricted groups. Labyrinthine volume, labyrinthine tissue volume and the surface area of the maternal fetal interface were increased in the 2-week group when compared with the 1-week group. These changes in placental vascularization may contribute to the fetal growth retardation observed in iron-restricted litters

Long-term programming of blood pressure by maternal dietary iron restriction in the rat

We have reported that blood pressure was elevated in 3-month-old rats whose mothers were Fe-restricted during pregnancy. These animals also had improved glucose tolerance and decreased serum triacylglycerol. The aim of the present study was to determine whether these effects of maternal nutritional restriction, present in these animals at 3 months of age, can be observed in the same animals in later life. Pulmonary and serum angiotensin converting enzyme (ACE) concentrations were also measured to investigate whether the renin-angiotensin system was involved in the elevation of blood pressure observed in the offspring of Fe-restricted dams. Systolic blood pressure was higher in the offspring of Fe-restricted dams at 16 months of age. Heart and kidney weight were increased as a proportion of body weight in the offspring of Fe-restricted dams. The pulmonary ACE concentration was not significantly different between the groups. The serum ACE concentration was significantly elevated in the offspring of Fe-restricted dams at 3 but not 14 months of age. There was a strong correlation between serum ACE levels at 3 and 14 months of age. Glucose tolerance and serum insulin were not different between the maternal diet groups. Serum triacylglycerol tended to be lower in the offspring of Fe-restricted dams. There were no differences in serum non-esterified fatty acids or serum cholesterol between the maternal diet groups. This study provides further evidence that maternal nutrition has effects on the offspring that persist throughout life. At 16 months of age, the elevation of blood pressure in Fe-restricted offspring does not appear to be mediated via changes in ACE levels. Both cardiac hypertrophy and decreased serum triacylglycerol have also been observed in Fe-restricted fetuses, suggesting that these changes may be initiated in utero

Effects of maternal iron restriction in the rat on hypoxia-induced gene expression and fetal metabolite levels

The mechanism by which maternal Fe deficiency in the rat causes fetal growth retardation has not been clearly established. This study compared the effects on the fetuses from dams fed a control diet with two groups of dams fed Fe-restricted diets. One Fe-restricted group was fed the Fe-restricted diet for 1 week prior to mating and throughout gestation and the second Fe-restricted group was fed the Fe-restricted diet for 2 weeks prior to mating and throughout gestation. On day 21 of gestation Fe-restricted dams, and their fetuses, were anaemic. Fetal weight was reduced in both Fe-restricted groups compared with controls. Expression of hypoxia-inducible factor (HIF)-1 and vascular endothelial growth factor (VEGF) are induced by hypoxia. The levels of HIF-1 mRNA were highest in placenta, then in kidney, heart and liver but were not different between the groups. Levels of plasma VEGF were not different between the groups. Maternal plasma triacylglycerol was decreased in the 1-week Fe-restricted dams compared with controls. Maternal plasma cholesterol and free fatty acid levels were not different between the groups. In fetal plasma, levels of triacylglycerol and cholesterol were decreased in both Fe-restricted groups. In maternal plasma, levels of a number of amino acids were elevated in both Fe-restricted groups. In contrast, levels of a number of amino acids in fetal plasma were lower in both Fe-restricted groups. Fetal plasma lactate was increased in Fe-restricted fetuses but fetal plasma glucose and -hydroxybutyrate were not affected. These changes in fetal metabolism may contribute to fetal growth retardation in this model. This study does not support the hypothesis that the Fe-restricted fetus is hypoxic

Effect of maternal iron restriction during pregnancy on renal morphology in the adult rat offspring

In rats, maternal anaemia during pregnancy causes hypertension in the adult offspring, although the mechanism is unknown. The present study investigated the renal morphology of adult rats born to mothers who were Fe-deficient during pregnancy. Rats were fed either a control (153 mg Fe/kg diet, n 7) or low-Fe (3 mg/kg diet, n 6) diet from 1 week before mating and throughout gestation. At delivery, the Fe-restricted (IR) mothers were anaemic; the IR pups were also anaemic and growth-retarded at 2 d of age. At 3 and 16 months, systolic blood pressure in the IR offspring (163 (SEM 4) and 151 (SEM 4) mmHg respectively, n 13) was greater than in control animals (145 (SEM 3) and 119 (SEM 4) mmHg respectively, n 15, P<0·05). At post mortem at 18 months, there was no difference in kidney weight between treatment groups, although relative kidney weight as a fraction of body weight in the IR offspring was greater than in control animals (P<0·05). Glomerular number was lower in the IR offspring (11·4 (SEM 1·1) per 4 mm2, n 13) compared with control rats (14·8 (SEM 0·7), n 15, P<0·05). Maternal treatment had no effect on glomerular size, but overall, female rats had smaller and more numerous glomeruli per unit area than male rats. When all animals were considered, inverse relationships were observed between glomerular number and glomerular size (r-0·73, n 28, P<0·05), and glomerular number and systolic blood pressure at both 3 months (r-0·42, n 28, P<0·05) and 16 months of age (r-0·64, n 28, P<0·05). Therefore, in rats, maternal Fe restriction causes hypertension in the adult offspring that may be due, in part, to a deficit in nephron number

Testing the fetal origins hypothesis in twins: the Birmingham twin study

Aims/hypothesis: To test whether the link between birthsize and raised blood pressure or glucose tolerance is due to genetic or intrauterine factors, we studied whether differences in birthweight between pairs of monozygous and dizygous twins are associated with adult differences in blood pressure and glucose tolerance.Methods: A sample of 58 monozygous and 140 dizygous twins were identified from a register of births in Birmingham, United Kingdom, between 1950 and 1954. The twins had their blood pressure measured and underwent an oral glucose tolerance test.Results: There were no statistically significant associations between birthweight, length or ponderal index, and either blood pressure or glucose tolerance in the twins. Although there were substantial within-pair differences in birthweight between monozygous and dizygous twin pairs, these differences did not correlate with the adult outcomes. Monozygous correlations, however, for both blood pressure and glucose tolerance were statistically significantly higher than dizygous correlations and a quantitative genetic model suggested statistically significant heritability for these traits. In contrast correlations of birthsize were similar in monozygous and dizygous pairs suggesting only a small genetic component in determining fetal size.Conclusion/interpretation: Our results show that birthsize in twins does not predict adult blood pressure or glucose tolerance. We also suggest that shared genetic determinants for fetal growth and adult outcomes are not likely to be prevalent or powerful