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S. Mulay and S. Solomon

Administration of a dose of 45 mg streptozotocin/kg on day 2 of gestation produced a diabetic state in pregnant rats and was associated with fetal hyperinsulinaemia. Although there was no evidence of fetal macrosomia, the ratio of fetal liver and lung weight to body weight was greater in fetuses of diabetic rats, suggesting an increase in the size of these organs relative to the body weight.

Maternal and fetal plasma corticosterone levels of diabetic rats between 19 and 22 days of gestation was significantly lower than the corresponding control values. Maternal plasma progesterone levels of diabetic rats were lower than controls on days 19 and 20 of gestation, but higher than controls on day 21 of gestation. The absence of pregnancy-related changes in maternal and fetal plasma corticosterone levels and maternal progesterone levels in diabetic rats suggest that adrenocortical function as well as ovarian and/or placental function may be impaired, which may in turn be related to the observed delay in parturition of approximately 18 h as well as to the low survival rate of the pups.

There was a small increase in the cytoplasmic glucocorticoid receptor concentration in the lung but not in the liver of fetuses of diabetic mothers when compared with fetuses of controls, suggesting that the increased receptor concentration may be a compensatory mechanism to overcome the effect of decreased corticosterone levels and increased insulin levels in the fetuses of diabetic rats.

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P. Conliffe and S. Mulay


Experiments were carried out on Sprague–Dawley rats to determine whether changes in fetal corticosterone levels during maternal diabetes were caused by the accompanying fetal hyperinsulinaemia or fetal hyperglycaemia. Diabetes was induced by injecting streptozotocin (30–45 mg/kg, i.v.) on day 2 of gestation. Fetal adrenals were removed on day 20 of gestation and cultured. Streptozotocin caused moderate (blood glucose 14–22·5 mmol/l) to severe (blood glucose >25 mmol/l) diabetes. Both moderate and severe diabetes caused a decrease in fetal body weights. Relative to non-diabetic controls, maternal and fetal plasma concentrations of corticosterone were higher in the severely and lower in the moderately diabetic rats. Corticosterone production by fetal adrenal cells from control and moderately diabetic rats was comparable, but cells from the severely diabetic animals produced significantly greater amounts of corticosterone than did control cells. Neither glucose (28 mmol/l) nor insulin (1 nmol/l) exerted significant effects on [3H]thymidine uptake or corticosterone production by fetal adrenal cells from non-diabetic, moderately diabetic or severely diabetic rats. Human ACTH (0·02–20 nmol/l) caused a concentration-dependent increase in corticosterone output of comparable magnitude by cells from all three groups of animals. These data suggest that fetal growth abnormalities during diabetic pregnancy are not directly related to changes in glucocorticoid levels and that changes in glucocorticoid levels are not caused by any direct action of fetal hyperinsulinaemia or hyperglycaemia on adrenal cells.

Journal of Endocrinology (1989) 120, 393–399

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S. Mulay, D. R. Varma, and S. Solomon

The influence of dietary protein deficiency on maternal plasma corticosterone and progesterone levels as well as on maternal and fetal liver and lung cytoplasmic glucocorti-coid receptors has been studied in Sprague–Dawley rats during the last 3 days of gestation. Plasma corticosterone levels of control but not protein-deficient rats increased on days 20 and 21 of gestation; corticosterone levels of protein-deficient rats decreased on day 21 of gestation. Maternal adrenalectomy caused only a moderate decrease in corticosterone levels in both groups of pregnant rats. Fetal corticosterone levels of the two groups of rats were similar. Progesterone levels were consistently lower in protein-deficient than in control animals from day 20 of gestation until 2–12 h after parturition. There were no differences in the binding of [3H]dexamethasone to liver cytosol of non-pregnant control and protein-deficient rats. However, receptor levels were lower in pregnant controls than in pregnant protein-deficient rats. Maternal protein deficiency led to an increase in fetal liver glucocorticoid receptor levels but exerted no significant effect on receptor levels in fetal lung. It is suggested that lower levels of plasma corticosterone and progesterone and high levels of liver glucocorticoid receptors in protein-deficient rats might be related to some of the adverse consequences of maternal malnutrition on fetal development.

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S. Mulay, A. Philip, and S. Solomon

The influence of maternal diabetes on fetal development was studied in rats made diabetic by administration of streptozotocin on day 2 of gestation as well as in genetically diabetic BB Wistar rats. A dose of 65 mg streptozotocin/kg produced severe diabetes with plasma glucose levels of approximately 36 mmol/l, this was associated with fetal growth retardation but not fetal hyperinsulinaemia. In contrast, a smaller dose of streptozotocin (45 mg/kg) produced moderate diabetes with plasma glucose levels of approximately 20 mmol/l and was associated with fetal hyperinsulinaemia but only a marginal effect on fetal size. In both groups of diabetic animals, maternal body weight gain was decreased, maternal plasma insulin levels were low and fetal glucose levels were similar. In a small group of genetically diabetic BB rats on insulin therapy the fetuses were macrosomic and hyperinsulinaemic. The specific binding of 125I-labelled insulin to partially purified liver and lung membranes of fetuses of both groups of streptozotocin-induced diabetic rats was significantly lower than the binding to membranes from fetuses of control animals. The specific binding of 125I-labelled insulin to fetal liver and lung membranes from the diabetic BB Wistar rats also appeared to be reduced when compared to tissues from controls. Decreased insulin receptors in fetal lung and liver of diabetic rats suggest a role for insulin in the development of these organs during the fetal and neonatal period.

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S Omer, J Shan, DR Varma, and S Mulay

We tested the hypothesis that pregnancy might increase diabetes-associated nitric oxide (NO) production and renal hyperfiltration. Two weeks following i.v. streptozotocin (40 mg/kg), mean arterial pressure (MAP) was not modified by diabetes; glomerular filtration rate (GFR), renal plasma flow (RPF) and filtration fraction (FF) were higher in pregnant than in virgin controls and increased by diabetes to a greater extent in pregnant than in virgin rats. Urinary volume (UV), creatinine, albumin and sodium (UNaV) were significantly increased by diabetes. Diabetes led to an increase in renal, cardiac, aortic and uterine but not in placental NO synthase activities. Infusion of NG-nitro-l-arginine (l-NA) caused a dose-dependent reduction in GFR, RPF, plasma NO2-/NO3-, UV and UNaV; in general, diabetes increased these effects to a greater extent in pregnant than in virgin rats. l-NA increased MAP in all groups of rats but did not alter FF. Diabetes did not alter responses of thoracic aorta rings to vasoconstrictor effects of phenylephrine and the vasorelaxant effects of sodium nitroprusside but increased endothelium-dependent relaxant effects of acetylcholine. In general the effects of diabetes of 7 days duration were similar to those described above for diabetes of 14 days duration. These data suggest that diabetes-associated renal hyperfiltration and NO production are augmented by pregnancy.

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P Vaillancourt, S Omer, R Palfree, DR Varma, and S Mulay

The main objective of this study was to find out if the reported changes in the aldosterone-suppressant activity of atrial natriuretic peptide (ANP) during different hormonal states in rats are due to a modulation of ANP receptors. In zona glomerulosa cells, ribonuclease protection assay detected mRNAs for guanylate cyclase (GC)-coupled ANP GC-A and GC-B receptors, and for ANP C receptors, which are not coupled to GC. Western analysis using polyclonal anti-GC-A and anti-GC-B receptor antibodies revealed the presence of GC-A but not GC-B receptor proteins in zona glomerulosa cells. Pregnancy (days 7, 16 and 21), oestradiol-17 beta and progesterone decreased mRNAs for all the three ANP receptors in zona glomerulosa cells. Pregnancy decreased GC-A receptor proteins in zona glomerulosa cells, but these recovered to virgin values on day 2 postpartum. ANP receptor mRNAs in zona glomerulosa cells increased by postpartum day 2, but did not reach the values found in virgin rats. Zona fasciculata mainly contained GC-A receptor mRNA. It is concluded that ANP receptors in rat adrenal zona glomerulosa are modulated by pregnancy, oestrogen and progesterone; a decrease in ANP GC-A receptors during pregnancy might explain the accompanying decrease in the aldosterone-suppressant effects of ANP.

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P. R. Conliffe, H. P. J. Bennett, and S. Mulay


It was observed in the course of other studies that rat fetal lung extracts inhibited proliferation of fetal lung cells in culture. The purpose of the present study was to isolate and characterize this cytostatic factor. It was found that fetal lungs contained a 16 kDa cytostatic factor and its concentration was twofold greater in fetal lungs of diabetic rats compared with control rats. This fetal lung cytostatic protein (FLCP) was purified by reversed-phase, heparin-affinity and gel filtration high-performance liquid chromatography and SDS-PAGE. The purified protein was electroblotted onto polyvinylidene difluoride membrane and subjected to sequence analysis. The amino-terminal sequence of this fetal lung cytostatic protein was PEPAKSAPAPXKGIGKQXXKAX XKA... and showed significant homology with histone H2B; however, the amino acid composition of FLCP suggested that it may be structurally distinct from histone H2B. Ion-spray mass spectrometry suggested that FLCP was made up of at least two species of the protein with molecular weights of 13 776·1 and 14 007·3 and was different from the molecular weight of rat histone H2B predicted by its cDNA sequence. The concentration of FLCP, based on amino acid compositions, was 0·32 nmol/g and 0·83 nmol/g wet fetal lung from non-diabetic and diabetic rats respectively. These findings suggest that the fetal rat lung produces a regulatory factor bearing considerable homology with but possibly different from histone H2B and that fetal lung immaturity during diabetic pregnancy might be contributed to by an increase in this factor.

Journal of Endocrinology (1993) 139, 97–105

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S Mulay, P R Conliffe, and D R Varma


The main purpose of these studies was to determine whether diabetic pregnancy altered maternal and fetal atrial natriuretic peptide (ANP). Diabetes was induced in rats by intravenous injection of 40 mg streptozotocin/kg on day 2 of gestation. Immunoreactive ANP in plasma, amniotic fluid and hearts on day 20 of gestation was measured by radioimmunoassay; fetal cardiac natriuretic peptides (ANP, proANP and BNP) were separated by reverse-phase high pressure liquid chromatography. Diabetes caused an increase in fetal plasma insulin, placental weight, amniotic fluid volume, the ratio of the fetal heart to body weight, maternal and fetal plasma ANP, fetal cardiac ANP and fetal cardiac BNP. It is suggested that the maternal diabetes-induced increase in fetal ANP might be related to fetal myocardial hypertrophy and could contribute to hydramnios.

Journal of Endocrinology (1995) 146, 255–259

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P. R. Conliffe, G. L. Santos, D. R. Varma, and S. Mulay


Diabetic pregnancy is associated with a high incidence of fetal growth abnormalities which cannot be solely ascribed to fetal hyperglycaemia and hyperinsulinaemia. We therefore examined the possibility of other contributing factors using rats made diabetic with streptozotocin as the experimental model. Blood serum from virgin diabetic rats and, to a much greater extent, from pregnant diabetic rats inhibited [3H]thymidine incorporation by fetal lung cells in culture in a concentration- and time-dependent manner; cell number was also decreased. The cytotoxic activity of the serum was decreased by treatment of pregnant diabetic rats with insulin. Sera from non-diabetic rats and from rats at 6 h and 24 h after the injection of streptozotocin were not cytotoxic. The cytotoxic activity of diabetic rat serum was retained after dialysis and was not destroyed by heating it for 60 min at 60 °C. Diabetic rat serum antagonized the stimulatory effects of fetal bovine serum, insulin and insulin-like growth factors on thymidine incorporation by lung cells and inhibited corticosterone production by adrenal cells. Ultrafiltration of diabetic rat serum and high-performance gel permeation chromatography in phosphate buffer suggested that the molecular weight of the cytotoxic factor was approximately 40 kDa. However, gel permeation chromatography in 40% acetonitrile of the cytotoxic eluate from reversed-phase high-performance liquid chromatography using a C18 and C4 column revealed that the cytotoxic factor was a low molecular weight substance, which contained no amino acids. The apparent discrepancy in molecular weights using different separation procedures suggests that the cytotoxic factor is bound to serum proteins. The u.v. spectrum of this factor was different from those of ketone bodies but its exact chemical identity could not be established because of the scarcity of the material. It is suggested that the sera of pregnant diabetic rats and their fetuses contain a cytotoxic factor, which may contribute to fetal developmental abnormalities.

Journal of Endocrinology (1992) 134, 205–214